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6519cfcf41a0e9834bc6add8c0c7296995c2f860 | wikidoc | CORONA Trial | CORONA Trial
# Objective
To study the effects of rosuvastatin 10 mg daily in patients with congestive heart failure.
# Methods
Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) was a double-blinded, randomized, placebo controlled trial wherein 5011 patients with congestive heart failure NYHA Class II, III or IV ischemic, systolic heart failure were enrolled and randomly assigned to treatment with either 10 mg rosuvastatin daily or placebo. The primary outcome was death from cardiovascular causes, non-fatal MI or non-fatal stroke.
# Results
Compared to placebo, rosuvastatin reduced serum LDL levels and raised HDL and triglyceride levels. However, there was no significant reduction in mortality rates from cardiovascular causes, coronary events and all-cause mortality. | CORONA Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Click here to download slides for CORONA Trial.
# Objective
To study the effects of rosuvastatin 10 mg daily in patients with congestive heart failure.
# Methods
Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) was a double-blinded, randomized, placebo controlled trial wherein 5011 patients with congestive heart failure NYHA Class II, III or IV ischemic, systolic heart failure were enrolled and randomly assigned to treatment with either 10 mg rosuvastatin daily or placebo. The primary outcome was death from cardiovascular causes, non-fatal MI or non-fatal stroke.
# Results
Compared to placebo, rosuvastatin reduced serum LDL levels and raised HDL and triglyceride levels. However, there was no significant reduction in mortality rates from cardiovascular causes, coronary events and all-cause mortality.[1][2][3][4] | https://www.wikidoc.org/index.php/CORONA_Trial | |
c9ad9f846a39e931a7e8112318b43dde65aa5232 | wikidoc | Cathepsin L2 | Cathepsin L2
Cathepsin L2, also known as cathepsin V and encoded by the CTSL2 gene, is a human gene.
The protein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that may play an important role in corneal physiology. This gene is expressed in colorectal and breast carcinomas but not in normal colon, mammary gland, or peritumoral tissues, suggesting a possible role for this gene in tumor processes.
# Clinical significance
Cathepsin L2 may play a role in the pathogenesis of keratoconus. | Cathepsin L2
Cathepsin L2, also known as cathepsin V and encoded by the CTSL2 gene, is a human gene.[1]
The protein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that may play an important role in corneal physiology. This gene is expressed in colorectal and breast carcinomas but not in normal colon, mammary gland, or peritumoral tissues, suggesting a possible role for this gene in tumor processes.
# Clinical significance
Cathepsin L2 may play a role in the pathogenesis of keratoconus.[2] | https://www.wikidoc.org/index.php/CTSV | |
7510c130054b0a6eccba63400ee90c628b71b7fb | wikidoc | Caplacizumab | Caplacizumab
# 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
Caplacizumab is a von Willebrand factor (vWF)-directed antibody fragment that is FDA approved for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy. Common adverse reactions include epistaxis, headache, and gingival bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Caplacizumab is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.
- For injection: 11 mg as a white lyophilized powder in a single-dose vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of caplacizumab in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Caplacizumab is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of the excipients. Hypersensitivity reactions have included urticaria.
# Warnings
- Caplacizumab increases the risk of bleeding. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of subjects. Overall, bleeding events occurred in approximately 58% of patients on caplacizumab versus 43% of patients on placebo.
- The risk of bleeding is increased in patients with underlying coagulopathies (e.g. hemophilia, other coagulation factor deficiencies). It is also increased with concomitant use of caplacizumab with drugs affecting hemostasis and coagulation.
- Interrupt use of caplacizumab if clinically significant bleeding occurs. If needed, von Willebrand factor concentrate may be administered to rapidly correct hemostasis. If caplacizumab is restarted, monitor closely for signs of bleeding.
- Withhold caplacizumab for 7 days prior to elective surgery, dental procedures or other invasive interventions. If emergency surgery is needed, the use of von Willebrand factor concentrate may be considered to correct hemostasis. After the risk of surgical bleeding has resolved, and caplacizumab is resumed, monitor closely for signs of bleeding.
# 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 safety of caplacizumab was evaluated in two placebo-controlled clinical studies (HERCULES, in which 71 patients received caplacizumab; and TITAN, in which 35 patients received caplacizumab). The data described below and in the Warnings and Precautions reflect exposure to caplacizumab during the blinded periods of both studies, which include 106 patients with aTTP who received at least one dose, age 18 to 79 years, of whom 69% were female and 73% were White. The median treatment duration with caplacizumab was 35 days (range 1–77 days).
- The most frequently reported adverse reactions (>15%) were epistaxis, headache and gingival bleeding. Seven patients (7%) in the caplacizumab group experienced an adverse reaction leading to study drug discontinuation. None of the adverse reactions leading to discontinuation were observed in more than 1% of patients.
- Among 106 patients treated with caplacizumab during the TITAN and HERCULES studies, serious bleeding adverse reactions reported in ≥2% patients included epistaxis (4%) and subarachnoid hemorrhage (2%).
- Adverse reactions that occurred in ≥2% of patients treated with caplacizumab and more frequently than in those treated with placebo across the pooled data from the two trials are summarized in Table 1. Urticaria was seen during plasma exchange.
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to caplacizumab-yhdp in the studies described below, with the incidence of antibodies in other studies, or to other products, may be misleading.
- The prevalence of pre-existing antibodies binding to caplacizumab-yhdp observed during clinical studies and during evaluation of commercially available human samples varied between 4% and 63%. In aTTP patients, pre-existing antibodies can be produced by the patient or can originate from donor plasma during plasma exchange. No clinically apparent impact of these pre-existing antibodies on clinical efficacy or safety was found. Treatment-emergent anti-drug antibodies (TE ADA) against caplacizumab-yhdp were detected in 3% of patients treated with caplacizumab in the HERCULES study. In the HERCULES study, TE ADA were further characterized as having neutralizing potential. There was no clinically apparent impact on clinical efficacy or safety.
## Postmarketing Experience
There is limited information regarding Caplacizumab Postmarketing Experience in the drug label.
# Drug Interactions
- Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Assess and monitor closely for bleeding with concomitant use.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no available data on caplacizumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. However, there are potential risks of hemorrhage in the mother and fetus associated with use of caplacizumab. In animal reproduction studies, there was no evidence of adverse developmental outcomes with intramuscular administration of caplacizumab-yhdp during organogenesis in guinea pigs at exposures approximately 30 times the AUC in humans at the recommended subcutaneous injection dose of 11 mg.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
- Caplacizumab may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.
- All patients receiving caplacizumab, including pregnant women, are at risk for bleeding. Pregnant women receiving caplacizumab should be carefully monitored for evidence of excessive bleeding.
Data
- Two separate reproduction studies were conducted in pregnant guinea pigs with administration of caplacizumab-yhdp during the organogenesis period.
- In an embryo-fetal development study, caplacizumab-yhdp was administered intramuscularly at doses up to 20 mg/kg/day from gestational day (GD) 6 to GD 41 in guinea pigs. No maternal toxicity or adverse developmental outcomes were observed.
- In a toxicokinetic study assessing the exposure of caplacizumab-yhdp in the dams and fetuses, caplacizumab-yhdp was administered once daily to female guinea pigs at doses up to 40 mg/kg/day (corresponding to a drug exposure of approximately 30 times the AUC in humans at the recommended dose of 11 mg) by intramuscular injection from GD 6 to GD 41 or GD 61. Exposure to caplacizumab-yhdp was observed in the dams and fetuses, with no effects on embryo-fetal development.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Caplacizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Caplacizumab during labor and delivery.
### Nursing Mothers
- There is no information regarding the presence of caplacizumab-yhdp in human milk, the effects on the breastfed child or the effects on milk production.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for caplacizumab and any potential adverse effects on the breastfed child from caplacizumab, or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of caplacizumab in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of caplacizumab did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Caplacizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Caplacizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Caplacizumab in patients with renal impairment.
### Hepatic Impairment
- No formal studies with caplacizumab have been conducted in patients with severe acute or chronic hepatic impairment and no data regarding the use of caplacizumab in these populations are available. Due to a potential increased risk of bleeding, use of caplacizumab in patients with severe hepatic impairment requires close monitoring for bleeding.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Caplacizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Caplacizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Caplacizumab should be administered upon initiation of plasma exchange therapy. The recommended dose of caplacizumab is as follows:
First day of treatment: 11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1.
Subsequent days of treatment during daily plasma exchange: 11 mg subcutaneous injection once daily following plasma exchange.
Treatment after plasma exchange period: 11 mg subcutaneous injection once daily continuing for 30 days following the last daily plasma exchange. If after initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remain present, treatment may be extended for a maximum of 28 days.
- First day of treatment: 11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1.
- Subsequent days of treatment during daily plasma exchange: 11 mg subcutaneous injection once daily following plasma exchange.
- Treatment after plasma exchange period: 11 mg subcutaneous injection once daily continuing for 30 days following the last daily plasma exchange. If after initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remain present, treatment may be extended for a maximum of 28 days.
- Discontinue caplacizumab if the patient experiences more than 2 recurrences of aTTP, while on caplacizumab.
Missed Dose
- If a dose of caplacizumab is missed during the plasma exchange period, it should be given as soon as possible. If a dose of caplacizumab is missed after the plasma exchange period, it can be administered within 12 hours of the scheduled time of administration. Beyond 12 hours, the missed dose should be skipped and the next daily dose administered according to the usual dosing schedule.
- Withhold caplacizumab treatment 7 days prior to elective surgery, dental procedures, or other invasive interventions.
- The first dose of caplacizumab should be administered by a healthcare provider as a bolus intravenous injection. Administer subsequent doses subcutaneously in the abdomen. Avoid injections around the navel. Do not administer consecutive injections in the same abdominal quadrant.
- Patients or caregivers may inject caplacizumab subcutaneously after proper training on the preparation and administration of caplacizumab, including aseptic technique.
Ensure the caplacizumab vial and diluent syringe are at room temperature.
Reconstitute caplacizumab before administration using the provided syringe containing 1 mL Sterile Water for Injection, USP, to yield an 11 mg/mL single-dose solution.
Using aseptic technique throughout the preparation of the solution, attach the vial adapter to the vial containing caplacizumab.
Remove the plastic cap from the syringe and attach it to the vial adapter by twisting it clockwise until it cannot twist any further.
Slowly push the syringe plunger down until the syringe is empty. Do not remove the syringe from the vial adapter.
Gently swirl the vial until the cake or powder is completely dissolved. Do not shake.
Visually inspect that the reconstituted solution is clear and colorless.
Withdraw all of the clear, colorless reconstituted solution from the vial into the syringe. Label the caplacizumab syringe.
Administer the full amount of reconstituted solution.
For the initial intravenous injection, if using an intravenous line, the glass syringe should be connected to a standard Luer lock (and not a needleless connector) and flushed with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
Use the caplacizumab solution immediately. If not, use caplacizumab within 4 hours after reconstitution when stored in the refrigerator at 2°C to 8°C (36°F to 46°F).
- Ensure the caplacizumab vial and diluent syringe are at room temperature.
- Reconstitute caplacizumab before administration using the provided syringe containing 1 mL Sterile Water for Injection, USP, to yield an 11 mg/mL single-dose solution.
- Using aseptic technique throughout the preparation of the solution, attach the vial adapter to the vial containing caplacizumab.
- Remove the plastic cap from the syringe and attach it to the vial adapter by twisting it clockwise until it cannot twist any further.
- Slowly push the syringe plunger down until the syringe is empty. Do not remove the syringe from the vial adapter.
- Gently swirl the vial until the cake or powder is completely dissolved. Do not shake.
- Visually inspect that the reconstituted solution is clear and colorless.
- Withdraw all of the clear, colorless reconstituted solution from the vial into the syringe. Label the caplacizumab syringe.
- Administer the full amount of reconstituted solution.
- For the initial intravenous injection, if using an intravenous line, the glass syringe should be connected to a standard Luer lock (and not a needleless connector) and flushed with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
- Use the caplacizumab solution immediately. If not, use caplacizumab within 4 hours after reconstitution when stored in the refrigerator at 2°C to 8°C (36°F to 46°F).
### Monitoring
There is limited information regarding Caplacizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Caplacizumab and IV administrations.
# Overdosage
- In case of overdose, based on the pharmacological action of caplacizumab, there is the potential for an increased risk of bleeding. Close monitoring for signs and symptoms of bleeding is recommended. If needed, the use of von Willebrand factor concentrate could be considered to correct hemostasis.
# Pharmacology
## Mechanism of Action
- Caplacizumab-yhdp targets the A1-domain of vWF, and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption.
## Structure
There is limited information regarding Caplacizumab Structure in the drug label.
## Pharmacodynamics
- Ristocetin cofactor (RICO) activity was used to assess vWF activity. Subcutaneous doses of caplacizumab-yhdp at greater than or equal to the approved recommended dosage to healthy subjects and patients with aTTP decreased RICO activity levels to below 20% approximately 4 hours post-dose. RICO activity returned to baseline values within 7 days of drug discontinuation.
- Caplacizumab-yhdp decreased vWF antigen and factor VIII:C levels. These reductions were transient and returned to baseline upon cessation of treatment.
## Pharmacokinetics
- Caplacizumab-yhdp pharmacokinetics depends on the expression of the target vWF and are not dose proportional. Higher levels of vWF antigen increase the fraction of drug-target complex retained in the circulation. Steady-state was reached following the first administration of caplacizumab in healthy subjects, with minimal accumulation. Following a single subcutaneous dose of 10 mg caplacizumab-yhdp to healthy subjects the mean (CV%) peak concentration (Cmax) was 528 (20%) ng/mL and AUC0–24 was 7951 (16%). Following subcutaneous dosing of 10 mg caplacizumab-yhdp daily for 14 days to healthy subjects, the mean (CV%) Cmax was 348 (30%) ng/mL and AUC0–τ was 6808 (26%) hr∙ng/mL.
Absorption
- The bioavailability of subcutaneous caplacizumab-yhdp is approximately 90%.
- The maximum concentration was observed 6 to 7 hours after subcutaneous dosing of 10 mg caplacizumab-yhdp once daily in healthy subjects.
Distribution
- Caplacizumab-yhdp central volume of distribution is 6.33 L in patients with aTTP.
Elimination
- The half-life of caplacizumab-yhdp is concentration and target-level dependent.
Metabolism
- The available data suggest target-bound caplacizumab-yhdp is metabolized within the liver. Because caplacizumab-yhdp is a monoclonal antibody fragment, it is expected to be catabolized by various proteolytic enzymes.
Excretion
- The available nonclinical data suggest unbound caplacizumab-yhdp is cleared renally.
Antidrug Antibodies
- No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed in patients with pre-existing or treatment-emergent anti-drug antibodies.
Specific Populations
- No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed based on age (18 to 79 years), sex (66% females), race (White and Black ), blood group (O and other groups ), or renal impairment (mild , moderate or severe ). The effect of hepatic impairment on the pharmacokinetics of caplacizumab-yhdp is unknown.
Drug Interaction Studies
- No dedicated drug-drug interaction studies with caplacizumab-yhdp have been conducted.
## Nonclinical Toxicology
- No studies have been performed to evaluate the potential of caplacizumab-yhdp for carcinogenicity or genotoxicity.
- Animal reproduction studies assessing the effects of caplacizumab-yhdp on male and female fertility have not been conducted.
# Clinical Studies
- The efficacy of caplacizumab for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy was established in a pivotal multicenter, randomized, double-blind, placebo-controlled trial (HERCULES) (NCT02553317).
- A total of 145 patients were enrolled in the HERCULES study; the median age was 45 (range: 18 to 79) years, 69% were female, 73% were White. Patients were randomized to either caplacizumab (n=72) or placebo (n=73). Patients in both groups received plasma exchange and immunosuppressive therapy. Patients were stratified according the severity of neurological involvement (Glasgow Coma Scale score ≤12 or 13 to 15). Patients with sepsis, infection with E. coli 0157, atypical hemolytic uremic syndrome, disseminated intravascular coagulation or congenital thrombotic thrombocytopenia purpura were not eligible for enrollment.
- Patients received a single 11 mg caplacizumab bolus intravenous injection or placebo prior to the first plasma exchange on study, followed by a daily subcutaneous injection of 11 mg caplacizumab or placebo after completion of plasma exchange, for the duration of the daily plasma exchange period and for 30 days thereafter. If after the initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remained present, treatment was extended for 7 day intervals for a maximum of 28 days.
- The median treatment duration with caplacizumab was 35 days.
- The clinical trial protocol specified the caplacizumab dose as 10 mg, to be delivered by withdrawing all of the reconstituted solution from the vial and administering the full amount. A dose recovery study showed that the mean dose that can be withdrawn from a vial is 11 mg. Therefore, based on the dose recovery study, the mean dose delivered in the trial was 11 mg.
- The efficacy of caplacizumab in patients with aTTP was established based on time to platelet count response (platelet count ≥150,000/µL followed by cessation of daily plasma exchange within 5 days). Time to platelet count response was shorter among patients treated with caplacizumab, compared to placebo.
- Treatment with caplacizumab resulted in a lower number of patients with TTP-related death, recurrence of TTP, or at least one treatment-emergent major thromboembolic event (a composite endpoint) during the treatment period (see TABLE 2).
- The proportion of patients with a recurrence of TTP in the overall study period (the drug treatment period plus the 28-day follow-up period after discontinuation of drug treatment) was lower in the caplacizumab group (9/72 patients ) compared to the placebo group (28/73 patients (p<0.001). In the 6 patients in the caplacizumab group who experienced a recurrence of TTP during the follow-up period (i.e., a relapse defined as recurrent thrombocytopenia after initial recovery of platelet count (platelet count ≥150,000/µL) that required reinitiation of daily plasma exchange, occurring after the 30-day post daily plasma exchange period), ADAMTS13 activity levels were <10% at the end of the study drug treatment, indicating that the underlying immunological disease was still active at the time caplacizumab was stopped.
# How Supplied
- Caplacizumab (caplacizumab-yhdp) for injection is a sterile, white, preservative-free, lyophilized powder in a single-dose vial. Each carton (NDC 58468-0225-1) contains:
-ne 11 mg caplacizumab single-dose vial (NDC 58468-0227-1)
-ne 1 mL Sterile Water for Injection, USP, prefilled glass syringe (diluent for caplacizumab) (NDC 58468-0229-1)
-ne sterile vial adapter
-ne sterile hypodermic needle (30 gauge)
two individually packaged alcohol swabs
- one 11 mg caplacizumab single-dose vial (NDC 58468-0227-1)
- one 1 mL Sterile Water for Injection, USP, prefilled glass syringe (diluent for caplacizumab) (NDC 58468-0229-1)
- one sterile vial adapter
- one sterile hypodermic needle (30 gauge)
- two individually packaged alcohol swabs
## Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Unopened vials may be stored in the original carton at room temperature up to 30°C (86°F) for a single period of up to 2 months. Do not return caplacizumab to the refrigerator after it has been stored at room temperature.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Caplacizumab Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-caplacizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Cablivi
# Look-Alike Drug Names
- There is limited information regarding caplacizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Caplacizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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
Caplacizumab is a von Willebrand factor (vWF)-directed antibody fragment that is FDA approved for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy. Common adverse reactions include epistaxis, headache, and gingival bleeding.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Caplacizumab is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.
- For injection: 11 mg as a white lyophilized powder in a single-dose vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of caplacizumab in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding caplacizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Caplacizumab is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of the excipients. Hypersensitivity reactions have included urticaria.
# Warnings
- Caplacizumab increases the risk of bleeding. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of subjects. Overall, bleeding events occurred in approximately 58% of patients on caplacizumab versus 43% of patients on placebo.
- The risk of bleeding is increased in patients with underlying coagulopathies (e.g. hemophilia, other coagulation factor deficiencies). It is also increased with concomitant use of caplacizumab with drugs affecting hemostasis and coagulation.
- Interrupt use of caplacizumab if clinically significant bleeding occurs. If needed, von Willebrand factor concentrate may be administered to rapidly correct hemostasis. If caplacizumab is restarted, monitor closely for signs of bleeding.
- Withhold caplacizumab for 7 days prior to elective surgery, dental procedures or other invasive interventions. If emergency surgery is needed, the use of von Willebrand factor concentrate may be considered to correct hemostasis. After the risk of surgical bleeding has resolved, and caplacizumab is resumed, monitor closely for signs of bleeding.
# 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 safety of caplacizumab was evaluated in two placebo-controlled clinical studies (HERCULES, in which 71 patients received caplacizumab; and TITAN, in which 35 patients received caplacizumab). The data described below and in the Warnings and Precautions reflect exposure to caplacizumab during the blinded periods of both studies, which include 106 patients with aTTP who received at least one dose, age 18 to 79 years, of whom 69% were female and 73% were White. The median treatment duration with caplacizumab was 35 days (range 1–77 days).
- The most frequently reported adverse reactions (>15%) were epistaxis, headache and gingival bleeding. Seven patients (7%) in the caplacizumab group experienced an adverse reaction leading to study drug discontinuation. None of the adverse reactions leading to discontinuation were observed in more than 1% of patients.
- Among 106 patients treated with caplacizumab during the TITAN and HERCULES studies, serious bleeding adverse reactions reported in ≥2% patients included epistaxis (4%) and subarachnoid hemorrhage (2%).
- Adverse reactions that occurred in ≥2% of patients treated with caplacizumab and more frequently than in those treated with placebo across the pooled data from the two trials are summarized in Table 1. Urticaria was seen during plasma exchange.
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to caplacizumab-yhdp in the studies described below, with the incidence of antibodies in other studies, or to other products, may be misleading.
- The prevalence of pre-existing antibodies binding to caplacizumab-yhdp observed during clinical studies and during evaluation of commercially available human samples varied between 4% and 63%. In aTTP patients, pre-existing antibodies can be produced by the patient or can originate from donor plasma during plasma exchange. No clinically apparent impact of these pre-existing antibodies on clinical efficacy or safety was found. Treatment-emergent anti-drug antibodies (TE ADA) against caplacizumab-yhdp were detected in 3% of patients treated with caplacizumab in the HERCULES study. In the HERCULES study, TE ADA were further characterized as having neutralizing potential. There was no clinically apparent impact on clinical efficacy or safety.
## Postmarketing Experience
There is limited information regarding Caplacizumab Postmarketing Experience in the drug label.
# Drug Interactions
- Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Assess and monitor closely for bleeding with concomitant use.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no available data on caplacizumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. However, there are potential risks of hemorrhage in the mother and fetus associated with use of caplacizumab. In animal reproduction studies, there was no evidence of adverse developmental outcomes with intramuscular administration of caplacizumab-yhdp during organogenesis in guinea pigs at exposures approximately 30 times the AUC in humans at the recommended subcutaneous injection dose of 11 mg.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background rate of major birth defects and miscarriage in the indicated population is unknown. In the U.S. general population, the estimated background rate of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
- Caplacizumab may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.
- All patients receiving caplacizumab, including pregnant women, are at risk for bleeding. Pregnant women receiving caplacizumab should be carefully monitored for evidence of excessive bleeding.
Data
- Two separate reproduction studies were conducted in pregnant guinea pigs with administration of caplacizumab-yhdp during the organogenesis period.
- In an embryo-fetal development study, caplacizumab-yhdp was administered intramuscularly at doses up to 20 mg/kg/day from gestational day (GD) 6 to GD 41 in guinea pigs. No maternal toxicity or adverse developmental outcomes were observed.
- In a toxicokinetic study assessing the exposure of caplacizumab-yhdp in the dams and fetuses, caplacizumab-yhdp was administered once daily to female guinea pigs at doses up to 40 mg/kg/day (corresponding to a drug exposure of approximately 30 times the AUC in humans at the recommended dose of 11 mg) by intramuscular injection from GD 6 to GD 41 or GD 61. Exposure to caplacizumab-yhdp was observed in the dams and fetuses, with no effects on embryo-fetal development.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Caplacizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Caplacizumab during labor and delivery.
### Nursing Mothers
- There is no information regarding the presence of caplacizumab-yhdp in human milk, the effects on the breastfed child or the effects on milk production.
- The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for caplacizumab and any potential adverse effects on the breastfed child from caplacizumab, or from the underlying maternal condition.
### Pediatric Use
- The safety and effectiveness of caplacizumab in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of caplacizumab did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Caplacizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Caplacizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Caplacizumab in patients with renal impairment.
### Hepatic Impairment
- No formal studies with caplacizumab have been conducted in patients with severe acute or chronic hepatic impairment and no data regarding the use of caplacizumab in these populations are available. Due to a potential increased risk of bleeding, use of caplacizumab in patients with severe hepatic impairment requires close monitoring for bleeding.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Caplacizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Caplacizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Caplacizumab should be administered upon initiation of plasma exchange therapy. The recommended dose of caplacizumab is as follows:
First day of treatment: 11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1.
Subsequent days of treatment during daily plasma exchange: 11 mg subcutaneous injection once daily following plasma exchange.
Treatment after plasma exchange period: 11 mg subcutaneous injection once daily continuing for 30 days following the last daily plasma exchange. If after initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remain present, treatment may be extended for a maximum of 28 days.
- First day of treatment: 11 mg bolus intravenous injection at least 15 minutes prior to plasma exchange followed by an 11 mg subcutaneous injection after completion of plasma exchange on day 1.
- Subsequent days of treatment during daily plasma exchange: 11 mg subcutaneous injection once daily following plasma exchange.
- Treatment after plasma exchange period: 11 mg subcutaneous injection once daily continuing for 30 days following the last daily plasma exchange. If after initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remain present, treatment may be extended for a maximum of 28 days.
- Discontinue caplacizumab if the patient experiences more than 2 recurrences of aTTP, while on caplacizumab.
Missed Dose
- If a dose of caplacizumab is missed during the plasma exchange period, it should be given as soon as possible. If a dose of caplacizumab is missed after the plasma exchange period, it can be administered within 12 hours of the scheduled time of administration. Beyond 12 hours, the missed dose should be skipped and the next daily dose administered according to the usual dosing schedule.
- Withhold caplacizumab treatment 7 days prior to elective surgery, dental procedures, or other invasive interventions.
- The first dose of caplacizumab should be administered by a healthcare provider as a bolus intravenous injection. Administer subsequent doses subcutaneously in the abdomen. Avoid injections around the navel. Do not administer consecutive injections in the same abdominal quadrant.
- Patients or caregivers may inject caplacizumab subcutaneously after proper training on the preparation and administration of caplacizumab, including aseptic technique.
Ensure the caplacizumab vial and diluent syringe are at room temperature.
Reconstitute caplacizumab before administration using the provided syringe containing 1 mL Sterile Water for Injection, USP, to yield an 11 mg/mL single-dose solution.
Using aseptic technique throughout the preparation of the solution, attach the vial adapter to the vial containing caplacizumab.
Remove the plastic cap from the syringe and attach it to the vial adapter by twisting it clockwise until it cannot twist any further.
Slowly push the syringe plunger down until the syringe is empty. Do not remove the syringe from the vial adapter.
Gently swirl the vial until the cake or powder is completely dissolved. Do not shake.
Visually inspect that the reconstituted solution is clear and colorless.
Withdraw all of the clear, colorless reconstituted solution from the vial into the syringe. Label the caplacizumab syringe.
Administer the full amount of reconstituted solution.
For the initial intravenous injection, if using an intravenous line, the glass syringe should be connected to a standard Luer lock (and not a needleless connector) and flushed with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
Use the caplacizumab solution immediately. If not, use caplacizumab within 4 hours after reconstitution when stored in the refrigerator at 2°C to 8°C (36°F to 46°F).
- Ensure the caplacizumab vial and diluent syringe are at room temperature.
- Reconstitute caplacizumab before administration using the provided syringe containing 1 mL Sterile Water for Injection, USP, to yield an 11 mg/mL single-dose solution.
- Using aseptic technique throughout the preparation of the solution, attach the vial adapter to the vial containing caplacizumab.
- Remove the plastic cap from the syringe and attach it to the vial adapter by twisting it clockwise until it cannot twist any further.
- Slowly push the syringe plunger down until the syringe is empty. Do not remove the syringe from the vial adapter.
- Gently swirl the vial until the cake or powder is completely dissolved. Do not shake.
- Visually inspect that the reconstituted solution is clear and colorless.
- Withdraw all of the clear, colorless reconstituted solution from the vial into the syringe. Label the caplacizumab syringe.
- Administer the full amount of reconstituted solution.
- For the initial intravenous injection, if using an intravenous line, the glass syringe should be connected to a standard Luer lock (and not a needleless connector) and flushed with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
- Use the caplacizumab solution immediately. If not, use caplacizumab within 4 hours after reconstitution when stored in the refrigerator at 2°C to 8°C (36°F to 46°F).
### Monitoring
There is limited information regarding Caplacizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Caplacizumab and IV administrations.
# Overdosage
- In case of overdose, based on the pharmacological action of caplacizumab, there is the potential for an increased risk of bleeding. Close monitoring for signs and symptoms of bleeding is recommended. If needed, the use of von Willebrand factor concentrate could be considered to correct hemostasis.
# Pharmacology
## Mechanism of Action
- Caplacizumab-yhdp targets the A1-domain of vWF, and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption.
## Structure
There is limited information regarding Caplacizumab Structure in the drug label.
## Pharmacodynamics
- Ristocetin cofactor (RICO) activity was used to assess vWF activity. Subcutaneous doses of caplacizumab-yhdp at greater than or equal to the approved recommended dosage to healthy subjects and patients with aTTP decreased RICO activity levels to below 20% approximately 4 hours post-dose. RICO activity returned to baseline values within 7 days of drug discontinuation.
- Caplacizumab-yhdp decreased vWF antigen and factor VIII:C levels. These reductions were transient and returned to baseline upon cessation of treatment.
## Pharmacokinetics
- Caplacizumab-yhdp pharmacokinetics depends on the expression of the target vWF and are not dose proportional. Higher levels of vWF antigen increase the fraction of drug-target complex retained in the circulation. Steady-state was reached following the first administration of caplacizumab in healthy subjects, with minimal accumulation. Following a single subcutaneous dose of 10 mg caplacizumab-yhdp to healthy subjects the mean (CV%) peak concentration (Cmax) was 528 (20%) ng/mL and AUC0–24 was 7951 (16%). Following subcutaneous dosing of 10 mg caplacizumab-yhdp daily for 14 days to healthy subjects, the mean (CV%) Cmax was 348 (30%) ng/mL and AUC0–τ was 6808 (26%) hr∙ng/mL.
Absorption
- The bioavailability of subcutaneous caplacizumab-yhdp is approximately 90%.
- The maximum concentration was observed 6 to 7 hours after subcutaneous dosing of 10 mg caplacizumab-yhdp once daily in healthy subjects.
Distribution
- Caplacizumab-yhdp central volume of distribution is 6.33 L in patients with aTTP.
Elimination
- The half-life of caplacizumab-yhdp is concentration and target-level dependent.
Metabolism
- The available data suggest target-bound caplacizumab-yhdp is metabolized within the liver. Because caplacizumab-yhdp is a monoclonal antibody fragment, it is expected to be catabolized by various proteolytic enzymes.
Excretion
- The available nonclinical data suggest unbound caplacizumab-yhdp is cleared renally.
Antidrug Antibodies
- No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed in patients with pre-existing or treatment-emergent anti-drug antibodies.
Specific Populations
- No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed based on age (18 to 79 years), sex (66% females), race (White [83%] and Black [17%]), blood group (O [41%] and other groups [59%]), or renal impairment (mild [CrCl: 60 to 90 mL/min], moderate [CrCl: 30 to 60 mL/min] or severe [CrCl: 15 to 30 mL/min]). The effect of hepatic impairment on the pharmacokinetics of caplacizumab-yhdp is unknown.
Drug Interaction Studies
- No dedicated drug-drug interaction studies with caplacizumab-yhdp have been conducted.
## Nonclinical Toxicology
- No studies have been performed to evaluate the potential of caplacizumab-yhdp for carcinogenicity or genotoxicity.
- Animal reproduction studies assessing the effects of caplacizumab-yhdp on male and female fertility have not been conducted.
# Clinical Studies
- The efficacy of caplacizumab for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy was established in a pivotal multicenter, randomized, double-blind, placebo-controlled trial (HERCULES) (NCT02553317).
- A total of 145 patients were enrolled in the HERCULES study; the median age was 45 (range: 18 to 79) years, 69% were female, 73% were White. Patients were randomized to either caplacizumab (n=72) or placebo (n=73). Patients in both groups received plasma exchange and immunosuppressive therapy. Patients were stratified according the severity of neurological involvement (Glasgow Coma Scale score ≤12 or 13 to 15). Patients with sepsis, infection with E. coli 0157, atypical hemolytic uremic syndrome, disseminated intravascular coagulation or congenital thrombotic thrombocytopenia purpura were not eligible for enrollment.
- Patients received a single 11 mg caplacizumab bolus intravenous injection or placebo prior to the first plasma exchange on study, followed by a daily subcutaneous injection of 11 mg caplacizumab or placebo after completion of plasma exchange, for the duration of the daily plasma exchange period and for 30 days thereafter. If after the initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remained present, treatment was extended for 7 day intervals for a maximum of 28 days.
- The median treatment duration with caplacizumab was 35 days.
- The clinical trial protocol specified the caplacizumab dose as 10 mg, to be delivered by withdrawing all of the reconstituted solution from the vial and administering the full amount. A dose recovery study showed that the mean dose that can be withdrawn from a vial is 11 mg. Therefore, based on the dose recovery study, the mean dose delivered in the trial was 11 mg.
- The efficacy of caplacizumab in patients with aTTP was established based on time to platelet count response (platelet count ≥150,000/µL followed by cessation of daily plasma exchange within 5 days). Time to platelet count response was shorter among patients treated with caplacizumab, compared to placebo.
- Treatment with caplacizumab resulted in a lower number of patients with TTP-related death, recurrence of TTP, or at least one treatment-emergent major thromboembolic event (a composite endpoint) during the treatment period (see TABLE 2).
- The proportion of patients with a recurrence of TTP in the overall study period (the drug treatment period plus the 28-day follow-up period after discontinuation of drug treatment) was lower in the caplacizumab group (9/72 patients [13%]) compared to the placebo group (28/73 patients [38%] (p<0.001). In the 6 patients in the caplacizumab group who experienced a recurrence of TTP during the follow-up period (i.e., a relapse defined as recurrent thrombocytopenia after initial recovery of platelet count (platelet count ≥150,000/µL) that required reinitiation of daily plasma exchange, occurring after the 30-day post daily plasma exchange period), ADAMTS13 activity levels were <10% at the end of the study drug treatment, indicating that the underlying immunological disease was still active at the time caplacizumab was stopped.
# How Supplied
- Caplacizumab (caplacizumab-yhdp) for injection is a sterile, white, preservative-free, lyophilized powder in a single-dose vial. Each carton (NDC 58468-0225-1) contains:
one 11 mg caplacizumab single-dose vial (NDC 58468-0227-1)
one 1 mL Sterile Water for Injection, USP, prefilled glass syringe (diluent for caplacizumab) (NDC 58468-0229-1)
one sterile vial adapter
one sterile hypodermic needle (30 gauge)
two individually packaged alcohol swabs
- one 11 mg caplacizumab single-dose vial (NDC 58468-0227-1)
- one 1 mL Sterile Water for Injection, USP, prefilled glass syringe (diluent for caplacizumab) (NDC 58468-0229-1)
- one sterile vial adapter
- one sterile hypodermic needle (30 gauge)
- two individually packaged alcohol swabs
## Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Unopened vials may be stored in the original carton at room temperature up to 30°C (86°F) for a single period of up to 2 months. Do not return caplacizumab to the refrigerator after it has been stored at room temperature.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Caplacizumab Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-caplacizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Cablivi
# Look-Alike Drug Names
- There is limited information regarding caplacizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cablivi | |
ab9efc1d2839094c2b71a41b08ee7095e807cf3f | wikidoc | Cabot's ring | Cabot's ring
Cabot's ring or Cabot-Schleip ring is a reddish, ringlike structure in the red blood cells in the peripheral blood.
Cabot's rings may be the form of partial loops, loops, or figure eights.
Cabot's ring may seen in:
- Hemolytic anemia
- Lead poisoning
- Pernicious anemia
- Thalassemia
- Megaloblastic anemia
- Severe anemia
# Etymology
It is named after Richard Clarke Cabot and Karl Friedrich Wilhelm Schleip. | Cabot's ring
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cabot's ring or Cabot-Schleip ring is a reddish, ringlike structure in the red blood cells in the peripheral blood.
Cabot's rings may be the form of partial loops, loops, or figure eights.
Cabot's ring may seen in:
- Hemolytic anemia
- Lead poisoning
- Pernicious anemia
- Thalassemia
- Megaloblastic anemia
- Severe anemia
# Etymology
It is named after Richard Clarke Cabot and Karl Friedrich Wilhelm Schleip.
Template:Skin and subcutaneous tissue symptoms and signs
Template:Nervous and musculoskeletal system symptoms and signs
Template:Urinary system symptoms and signs
Template:Cognition, perception, emotional state and behaviour symptoms and signs
Template:Speech and voice symptoms and signs
Template:General symptoms and signs
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cabot%27s_ring | |
68842dea804f5bbfc9875d335fa26ef4b9ba9ee0 | wikidoc | Cabozantinib | Cabozantinib
# 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
Cabozantinib is a multikinase inhibitor that is FDA approved for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).. Common adverse reactions include diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Cabozantinib is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)
- The recommended daily dose of Cabozantinib is 140 mg (one 80-mg and three 20-mg capsules). Do not administer Cabozantinib with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking Cabozantinib. Continue treatment until disease progression or unacceptable toxicity occurs.
- Swallow Cabozantinib capsules whole. Do not open Cabozantinib capsules.
- Do not take a missed dose within 12 hours of the next dose.
- Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during Cabozantinib treatment.
- For Adverse Reactions
- Withhold Cabozantinib for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions.
- Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows:
- If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule)
- If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules)
- If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue Cabozantinib
- Permanently discontinue Cabozantinib for any of the following:
- Development of visceral perforation or fistula formation
- Severe hemorrhage
- Serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction)
- Nephrotic syndrome
- Malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management
- Osteonecrosis of the jaw
- Reversible posterior leukoencephalopathy syndrome
- In Patients with Hepatic Impairment
- Cabozantinib is not recommended for use in patients with moderate and severe hepatic impairment .
- In Patients Taking CYP3A4 Inhibitors
- Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving Cabozantinib.
- For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily Cabozantinib dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.
- In Patients Taking Strong CYP3A4 Inducers
- Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available .
- Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity.
- For patients who require treatment with a strong CYP3A4 inducer, increase the daily Cabozantinib dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of Cabozantinib should not exceed 180 mg.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cabozantinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Cabozantinib in pediatric patients have not been studied.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
The safety and effectiveness of Cabozantinib in pediatric patients have not been studied.
### Non–Guideline-Supported Use
The safety and effectiveness of Cabozantinib in pediatric patients have not been studied.
# Contraindications
- None
# Warnings
- Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of Cabozantinib-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of Cabozantinib-treated patients. Two (1%) of these were fatal.
- Monitor patients for symptoms of perforations and fistulas. Discontinue Cabozantinib in patients who experience a perforation or a fistula.
- Serious and sometimes fatal hemorrhage occurred with Cabozantinib. The incidence of Grade ≥3 hemorrhagic events was higher in Cabozantinib-treated patients compared with placebo (3% vs. 1%).
- Do not administer Cabozantinib to patients with a recent history of hemorrhage or hemoptysis.
- Cabozantinib treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in Cabozantinib-treated and placebo-treated patients, respectively).
- Discontinue Cabozantinib in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.
- Wound complications have been reported with Cabozantinib. Stop treatment with Cabozantinib at least 28 days prior to scheduled surgery. Resume Cabozantinib therapy after surgery based on clinical judgment of adequate wound healing. Withhold Cabozantinib in patients with dehiscence or wound healing complications requiring medical intervention.
- Cabozantinib treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in Cabozantinib-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during Cabozantinib treatment. Withhold Cabozantinib for hypertension that is not adequately controlled with medical management; when controlled, resume Cabozantinib at a reduced dose. Discontinue Cabozantinib for severe hypertension that cannot be controlled with anti-hypertensive therapy.
- Osteonecrosis of the jaw (ONJ) occurred in 1% of Cabozantinib-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of Cabozantinib and periodically during Cabozantinib therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold Cabozantinib treatment for at least 28 days prior to scheduled surgery, if possible.
- Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with Cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold Cabozantinib in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume Cabozantinib at a reduced dose.
- Proteinuria was observed in 4 (2%) of patients receiving Cabozantinib, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during Cabozantinib treatment. Discontinue Cabozantinib in patients who develop nephrotic syndrome.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Cabozantinib in patients who develop RPLS.
- Avoid administration of Cabozantinib with agents that are strong CYP3A4 inducers or inhibitors.
- Cabozantinib is not recommended for use in patients with moderate or severe hepatic impairment .
- Cabozantinib can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed elsewhere in the label:
- Perforations and Fistula
- Hemorrhage
- Thromboembolic Events
- Wound Complications
- Hypertension
- Osteonecrosis of the Jaw
- Palmar-plantar erythrodysesthesia syndrome
- Proteinuria
- Reversible Posterior Leukoencephalopathy Syndrome
- 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 Cabozantinib was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg Cabozantinib (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, doubleblind, controlled trial.The data described below reflect a median exposure to Cabozantinib for 204 days. The population exposed to Cabozantinib was 70% male, 90% white, and had a median age of 55 years.
- Adverse reactions which occurred in ≥ 25% of Cabozantinib-treated patients occurring more frequently in the Cabozantinib arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of Cabozantinib-treated patients occurring more frequently in the Cabozantinib arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite.
- Fatal adverse reactions occurred in 6% of patients receiving Cabozantinib and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration.
- The dose was reduced in 79% of patients receiving Cabozantinib compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving Cabozantinib compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving Cabozantinib and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with Cabozantinib were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting.
- Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving Cabozantinib after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the Cabozantinib arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.
- Nearly all Cabozantinib-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in Cabozantinib-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Cabozantinib in the drug label.
# Drug Interactions
- Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking Cabozantinib.
- Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic co-administration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St.John’s Wort) with Cabozantinib
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on its mechanism of action, Cabozantinib can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose).
- In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose).
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabozantinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cabozantinib during labor and delivery.
### Nursing Mothers
- It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cabozantinib, 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 effectiveness of Cabozantinib in pediatric patients have not been studied.
### Geriatic Use
- Clinical studies of Cabozantinib did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients
### Gender
- Contraception
- Use effective contraception during treatment with Cabozantinib and up to 4 months after completion of therapy.
- Infertility
- There are no data on the effect of Cabozantinib on human fertility. Cabozantinib impaired male and female fertility in animal studies
### Race
There is no FDA guidance on the use of Cabozantinib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with Cabozantinib in patients with severe renal impairment.
### Hepatic Impairment
- Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). Cabozantinib is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cabozantinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cabozantinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cabozantinib in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Cabozantinib in the drug label.
# Overdosage
- One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented
# Pharmacology
## Mechanism of Action
- In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
## Structure
- Cabozantinib is the (S)-malate salt of cabozantinib. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5.C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:
- Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.
- Cabozantinib (cabozantinib) capsules are supplied as printed hard gelatin capsules containing cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib and the following inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid.
- The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cabozantinib in the drug label.
## Pharmacokinetics
- A population pharmacokinetic analysis of cabozantinib was performed using data collected from 289 patients with solid tumors including MTC following oral administration of 140 mg daily doses. The predicted effective half-life is approximately 55 hours, the oral volume of distribution (V/F) is approximately 349 L, and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr.
- Following oral administration of Cabozantinib, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose. Repeat daily dosing of Cabozantinib at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15. Cabozantinib is highly protein bound in human plasma (≥ 99.7%).
- A high-fat meal increased Cmax and AUC values by 41% and 57%, respectively relative to fasted conditions in healthy subjects administered a single 140 mg oral Cabozantinib dose.
- Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition of CYP3A4 reduced the formation of the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.
- Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy subjects, approximately 81% of the total administered radioactivity was recovered with 54% in feces and 27% in urine.
- Renal Impairment: No formal pharmacokinetic study of cabozantinib has been conducted in patients with renal impairment. The results of a population pharmacokinetic analysis suggested that mild to moderate renal impairment (creatinine clearance value ≥30 mL/min) does not have a clinically relevant effect on the clearance of cabozantinib.
- Hepatic Impairment: The pharmacokinetics of cabozantinib has not been studied in patients with hepatic impairment .
- Pediatric Population: The pharmacokinetics of cabozantinib has not been studied in the pediatric population .
- Effects of Age, Gender and Race: A population PK analysis did not identify clinically relevant differences in clearance of cabozantinib between females and males or between Whites (89%) and non-Whites (11%). Cabozantinib pharmacokinetics was not affected by age (20-86 years).
- CYP Enzyme Inhibition and Induction: Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive inhibitor of CYP3A4 (estimated Kiapp = 282 μM) in human liver microsomal (HLM) preparations. IC50 values >20 μM were observed for CYP1A2, CYP2D6, and CYP3A4 isozymes in both recombinant and HLM assay systems.
- Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (i.e., 75-100% of CYP1A1 positive control β-naphthoflavone induction), but not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-associated enzyme activities.
- Cabozantinib at steady-state plasma concentrations (≥100 mg/day daily for a minimum of 21 days) showed no effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) in patients with solid tumors.
- P-glycoprotein Inhibition: Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-gp transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp.
- The effect of orally administered Cabozantinib 140 mg on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with MTC. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating Cabozantinib. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No Cabozantinib-treated patients had a QTcF > 500 ms.
## Nonclinical Toxicology
- Studies examining the carcinogenic potential of cabozantinib have not been conducted.
- Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay.
- Based on nonclinical findings, male and female fertility may be impaired by treatment with Cabozantinib. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately equal to the human exposure by AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (approximately 50% of the human exposure by AUC at the recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and postimplantation losses.
- Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora luteain male and female dogs in a 6-month repeat dose study at exposures equal to 6% and 3%, respectively, the human exposure by AUC at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately equal to the human exposure by AUC at the recommended dose) exhibited ovarian necrosis.
# Clinical Studies
- The safety and efficacy of Cabozantinib was assessed in an international, multi-center, randomized, double-blind, controlled trial (Study 1) of 330 patients with metastatic medullary thyroid carcinoma (MTC). Patients were required to have evidence of actively progressive disease within 14 months prior to study entry confirmed by an Independent Radiology Review Committee (IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were randomized (2:1) to receive Cabozantinib 140 mg (n = 219) or placebo (n = 111) orally once daily, without food, until disease progression determined by the treating physician or until intolerable toxicity. Randomization was stratified by age (≤ 65 years vs. > 65 years) and prior use of a tyrosine kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The main efficacy outcome measures of progression-free survival (PFS), objective response (OR), and response duration were based on IRRC-confirmed events using modified RECIST criteria.
- Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years or older, 89% were white, 54% had a baseline ECOG performance status of 0, 92% had undergone a thyroidectomy, and 48% were reported to be RET mutation positive according to research-use assays. Twenty-five percent (25%) had two or more prior systemic therapies and 21% had been previously treated with a TKI.
- A statistically significant prolongation in PFS was demonstrated among Cabozantinib-treated patients compared to those receiving placebo , with median PFS times of 11.2 months and 4.0 months in the Cabozantinib and placebo arms, respectively.
- Partial responses were observed only among patients in the Cabozantinib arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with Cabozantinib. There was no statistically significant difference in overall survival between the treatment arms at the planned interim analysis.
# How Supplied
- Cabozantinib 20 mg capsules are supplied as hard gelatin capsules with grey cap and grey body, printed with "XL184 20mg" in black ink and containing cabozantinib (S)-malate salt equivalent to 20 mg cabozantinib.
- Cabozantinib 80 mg capsules are supplied as hard gelatin capsules with Swedish orange cap and Swedish orange body, printed with "XL184 80mg" in black ink and containing cabozantinib (S)- malate salt equivalent to 80 mg cabozantinib.
- Cabozantinib capsules are supplied as follows:
Cartons
- 140 mg daily-dose carton NDC#42388-011-14
Containing four 140 mg daily-dose blister cards
(each blister card contains seven 80-mg and twenty-one 20-mg capsules)
- 100 mg daily-dose carton NDC#42388-012-14
Containing four 100 mg daily-dose blister cards
(each blister card contains seven 80-mg and seven 20-mg capsules)
- 60 mg daily-dose carton NDC#42388-013-14
Containing four 60 mg daily-dose blister cards
(each blister card contains twenty-one 20-mg capsules)
- Bottle containing sixty 20-mg Cabozantinib capsules NDC#42388-014-25
## Storage
- Store Cabozantinib at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the following:
- Cabozantinib often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with Cabozantinib.
- Cabozantinib often causes palmar plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.
- Cabozantinib often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.
- Cabozantinib often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.
- To contact their healthcare provider before any planned surgeries, including dental procedures.
- Cabozantinib may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.
- Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of Cabozantinib.
- Breast-feeding mothers must discontinue nursing while receiving Cabozantinib therapy.
- Cabozantinib should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking Cabozantinib. Cabozantinib capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.
- Patients should not consume grapefruits or grapefruit juice while taking Cabozantinib treatment.
# Precautions with Alcohol
- Alcohol-Cabozantinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cometriq®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Cabozantinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Cabozantinib is a multikinase inhibitor that is FDA approved for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).. Common adverse reactions include diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Cabozantinib is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC)
- The recommended daily dose of Cabozantinib is 140 mg (one 80-mg and three 20-mg capsules). Do not administer Cabozantinib with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking Cabozantinib. Continue treatment until disease progression or unacceptable toxicity occurs.
- Swallow Cabozantinib capsules whole. Do not open Cabozantinib capsules.
- Do not take a missed dose within 12 hours of the next dose.
- Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during Cabozantinib treatment.
- For Adverse Reactions
- Withhold Cabozantinib for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions.
- Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows:
- If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule)
- If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules)
- If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue Cabozantinib
- Permanently discontinue Cabozantinib for any of the following:
- Development of visceral perforation or fistula formation
- Severe hemorrhage
- Serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction)
- Nephrotic syndrome
- Malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management
- Osteonecrosis of the jaw
- Reversible posterior leukoencephalopathy syndrome
- In Patients with Hepatic Impairment
- Cabozantinib is not recommended for use in patients with moderate and severe hepatic impairment .
- In Patients Taking CYP3A4 Inhibitors
- Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving Cabozantinib.
- For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily Cabozantinib dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor.
- In Patients Taking Strong CYP3A4 Inducers
- Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available .
- Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity.
- For patients who require treatment with a strong CYP3A4 inducer, increase the daily Cabozantinib dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of Cabozantinib should not exceed 180 mg.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cabozantinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Cabozantinib in pediatric patients have not been studied.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
The safety and effectiveness of Cabozantinib in pediatric patients have not been studied.
### Non–Guideline-Supported Use
The safety and effectiveness of Cabozantinib in pediatric patients have not been studied.
# Contraindications
- None
# Warnings
- Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of Cabozantinib-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of Cabozantinib-treated patients. Two (1%) of these were fatal.
- Monitor patients for symptoms of perforations and fistulas. Discontinue Cabozantinib in patients who experience a perforation or a fistula.
- Serious and sometimes fatal hemorrhage occurred with Cabozantinib. The incidence of Grade ≥3 hemorrhagic events was higher in Cabozantinib-treated patients compared with placebo (3% vs. 1%).
- Do not administer Cabozantinib to patients with a recent history of hemorrhage or hemoptysis.
- Cabozantinib treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in Cabozantinib-treated and placebo-treated patients, respectively).
- Discontinue Cabozantinib in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.
- Wound complications have been reported with Cabozantinib. Stop treatment with Cabozantinib at least 28 days prior to scheduled surgery. Resume Cabozantinib therapy after surgery based on clinical judgment of adequate wound healing. Withhold Cabozantinib in patients with dehiscence or wound healing complications requiring medical intervention.
- Cabozantinib treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in Cabozantinib-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during Cabozantinib treatment. Withhold Cabozantinib for hypertension that is not adequately controlled with medical management; when controlled, resume Cabozantinib at a reduced dose. Discontinue Cabozantinib for severe hypertension that cannot be controlled with anti-hypertensive therapy.
- Osteonecrosis of the jaw (ONJ) occurred in 1% of Cabozantinib-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of Cabozantinib and periodically during Cabozantinib therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold Cabozantinib treatment for at least 28 days prior to scheduled surgery, if possible.
- Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with Cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold Cabozantinib in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume Cabozantinib at a reduced dose.
- Proteinuria was observed in 4 (2%) of patients receiving Cabozantinib, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during Cabozantinib treatment. Discontinue Cabozantinib in patients who develop nephrotic syndrome.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Cabozantinib in patients who develop RPLS.
- Avoid administration of Cabozantinib with agents that are strong CYP3A4 inducers or inhibitors.
- Cabozantinib is not recommended for use in patients with moderate or severe hepatic impairment .
- Cabozantinib can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed elsewhere in the label:
- Perforations and Fistula
- Hemorrhage
- Thromboembolic Events
- Wound Complications
- Hypertension
- Osteonecrosis of the Jaw
- Palmar-plantar erythrodysesthesia syndrome
- Proteinuria
- Reversible Posterior Leukoencephalopathy Syndrome
- 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 Cabozantinib was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg Cabozantinib (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, doubleblind, controlled trial.The data described below reflect a median exposure to Cabozantinib for 204 days. The population exposed to Cabozantinib was 70% male, 90% white, and had a median age of 55 years.
- Adverse reactions which occurred in ≥ 25% of Cabozantinib-treated patients occurring more frequently in the Cabozantinib arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of Cabozantinib-treated patients occurring more frequently in the Cabozantinib arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite.
- Fatal adverse reactions occurred in 6% of patients receiving Cabozantinib and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration.
- The dose was reduced in 79% of patients receiving Cabozantinib compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving Cabozantinib compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving Cabozantinib and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with Cabozantinib were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting.
- Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving Cabozantinib after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the Cabozantinib arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.
- Nearly all Cabozantinib-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in Cabozantinib-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Cabozantinib in the drug label.
# Drug Interactions
- Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking Cabozantinib.
- Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic co-administration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St.John’s Wort) with Cabozantinib
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on its mechanism of action, Cabozantinib can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose).
- In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose).
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cabozantinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cabozantinib during labor and delivery.
### Nursing Mothers
- It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cabozantinib, 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 effectiveness of Cabozantinib in pediatric patients have not been studied.
### Geriatic Use
- Clinical studies of Cabozantinib did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients
### Gender
- Contraception
- Use effective contraception during treatment with Cabozantinib and up to 4 months after completion of therapy.
- Infertility
- There are no data on the effect of Cabozantinib on human fertility. Cabozantinib impaired male and female fertility in animal studies
### Race
There is no FDA guidance on the use of Cabozantinib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with Cabozantinib in patients with severe renal impairment.
### Hepatic Impairment
- Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). Cabozantinib is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cabozantinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cabozantinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cabozantinib in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Cabozantinib in the drug label.
# Overdosage
- One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented
# Pharmacology
## Mechanism of Action
- In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
## Structure
- Cabozantinib is the (S)-malate salt of cabozantinib. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5.C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:
- Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.
- Cabozantinib (cabozantinib) capsules are supplied as printed hard gelatin capsules containing cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib and the following inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid.
- The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cabozantinib in the drug label.
## Pharmacokinetics
- A population pharmacokinetic analysis of cabozantinib was performed using data collected from 289 patients with solid tumors including MTC following oral administration of 140 mg daily doses. The predicted effective half-life is approximately 55 hours, the oral volume of distribution (V/F) is approximately 349 L, and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr.
- Following oral administration of Cabozantinib, median time to peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose. Repeat daily dosing of Cabozantinib at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15. Cabozantinib is highly protein bound in human plasma (≥ 99.7%).
- A high-fat meal increased Cmax and AUC values by 41% and 57%, respectively relative to fasted conditions in healthy subjects administered a single 140 mg oral Cabozantinib dose.
- Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition of CYP3A4 reduced the formation of the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.
- Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy subjects, approximately 81% of the total administered radioactivity was recovered with 54% in feces and 27% in urine.
- Renal Impairment: No formal pharmacokinetic study of cabozantinib has been conducted in patients with renal impairment. The results of a population pharmacokinetic analysis suggested that mild to moderate renal impairment (creatinine clearance value ≥30 mL/min) does not have a clinically relevant effect on the clearance of cabozantinib.
- Hepatic Impairment: The pharmacokinetics of cabozantinib has not been studied in patients with hepatic impairment .
- Pediatric Population: The pharmacokinetics of cabozantinib has not been studied in the pediatric population .
- Effects of Age, Gender and Race: A population PK analysis did not identify clinically relevant differences in clearance of cabozantinib between females and males or between Whites (89%) and non-Whites (11%). Cabozantinib pharmacokinetics was not affected by age (20-86 years).
- CYP Enzyme Inhibition and Induction: Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive inhibitor of CYP3A4 (estimated Kiapp = 282 μM) in human liver microsomal (HLM) preparations. IC50 values >20 μM were observed for CYP1A2, CYP2D6, and CYP3A4 isozymes in both recombinant and HLM assay systems.
- Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (i.e., 75-100% of CYP1A1 positive control β-naphthoflavone induction), but not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-associated enzyme activities.
- Cabozantinib at steady-state plasma concentrations (≥100 mg/day daily for a minimum of 21 days) showed no effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) in patients with solid tumors.
- P-glycoprotein Inhibition: Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-gp transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp.
- The effect of orally administered Cabozantinib 140 mg on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with MTC. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating Cabozantinib. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No Cabozantinib-treated patients had a QTcF > 500 ms.
## Nonclinical Toxicology
- Studies examining the carcinogenic potential of cabozantinib have not been conducted.
- Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay.
- Based on nonclinical findings, male and female fertility may be impaired by treatment with Cabozantinib. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately equal to the human exposure by AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (approximately 50% of the human exposure by AUC at the recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and postimplantation losses.
- Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora luteain male and female dogs in a 6-month repeat dose study at exposures equal to 6% and 3%, respectively, the human exposure by AUC at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately equal to the human exposure by AUC at the recommended dose) exhibited ovarian necrosis.
# Clinical Studies
- The safety and efficacy of Cabozantinib was assessed in an international, multi-center, randomized, double-blind, controlled trial (Study 1) of 330 patients with metastatic medullary thyroid carcinoma (MTC). Patients were required to have evidence of actively progressive disease within 14 months prior to study entry confirmed by an Independent Radiology Review Committee (IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were randomized (2:1) to receive Cabozantinib 140 mg (n = 219) or placebo (n = 111) orally once daily, without food, until disease progression determined by the treating physician or until intolerable toxicity. Randomization was stratified by age (≤ 65 years vs. > 65 years) and prior use of a tyrosine kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The main efficacy outcome measures of progression-free survival (PFS), objective response (OR), and response duration were based on IRRC-confirmed events using modified RECIST criteria.
- Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years or older, 89% were white, 54% had a baseline ECOG performance status of 0, 92% had undergone a thyroidectomy, and 48% were reported to be RET mutation positive according to research-use assays. Twenty-five percent (25%) had two or more prior systemic therapies and 21% had been previously treated with a TKI.
- A statistically significant prolongation in PFS was demonstrated among Cabozantinib-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p <0.0001], with median PFS times of 11.2 months and 4.0 months in the Cabozantinib and placebo arms, respectively.
- Partial responses were observed only among patients in the Cabozantinib arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with Cabozantinib. There was no statistically significant difference in overall survival between the treatment arms at the planned interim analysis.
# How Supplied
- Cabozantinib 20 mg capsules are supplied as hard gelatin capsules with grey cap and grey body, printed with "XL184 20mg" in black ink and containing cabozantinib (S)-malate salt equivalent to 20 mg cabozantinib.
- Cabozantinib 80 mg capsules are supplied as hard gelatin capsules with Swedish orange cap and Swedish orange body, printed with "XL184 80mg" in black ink and containing cabozantinib (S)- malate salt equivalent to 80 mg cabozantinib.
- Cabozantinib capsules are supplied as follows:
Cartons
- 140 mg daily-dose carton NDC#42388-011-14
Containing four 140 mg daily-dose blister cards
(each blister card contains seven 80-mg and twenty-one 20-mg capsules)
- 100 mg daily-dose carton NDC#42388-012-14
Containing four 100 mg daily-dose blister cards
(each blister card contains seven 80-mg and seven 20-mg capsules)
- 60 mg daily-dose carton NDC#42388-013-14
Containing four 60 mg daily-dose blister cards
(each blister card contains twenty-one 20-mg capsules)
- Bottle containing sixty 20-mg Cabozantinib capsules NDC#42388-014-25
## Storage
- Store Cabozantinib at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the following:
- Cabozantinib often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with Cabozantinib.
- Cabozantinib often causes palmar plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.
- Cabozantinib often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.
- Cabozantinib often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.
- To contact their healthcare provider before any planned surgeries, including dental procedures.
- Cabozantinib may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.
- Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of Cabozantinib.
- Breast-feeding mothers must discontinue nursing while receiving Cabozantinib therapy.
- Cabozantinib should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking Cabozantinib. Cabozantinib capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.
- Patients should not consume grapefruits or grapefruit juice while taking Cabozantinib treatment.
# Precautions with Alcohol
- Alcohol-Cabozantinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cometriq®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cabozantinib | |
9b659e79d35cf710a46b90ba2ffe0c12e06a2e62 | wikidoc | Caffeic acid | Caffeic acid
Caffeic acid, C9H8O4 is a naturally occurring phenolic compound, (formerly called a carbolic acid), which is found in many fruits, vegetables, and herbs, including coffee, although varying in amounts depending on the plant.
Caffeic acid has been shown to act as a carcinogenic inhibitor. It is also known as an antioxidant in vitro and also in vivo.
Caffeic acid is a yellow crystalline acid that is soluble in hot water and alcohol. It is related to cinnamic acid, but it has two hydroxyl groups not found in cinnamic acid. Both are part of the carbocyclic carboxylic acid group.
Caffeic acid can be esterified with quinic acid to form chlorogenic acid. Both caffeic acid and chlorogenic acid are found in coffee beans. Caffeine is a different compound than caffeic acid. A derivative of caffeic acid is caffeic acid phenethyl ester (CAPE).
It is used as a matrix in MALDI mass spectroscopy analyses.
# Biological importance
Caffeic acid and its derivative caffeic acid phenethyl ester (CAPE) are produced in many plants including: pears, basil, thyme, verbena, tarragon, oregano, wood betony, burning bush, turmeric, dandelion, yarrow, horsetail, rosemary, hawthorn and coffee. The amount of caffeic acid is strongly dependent on the plant species.
Both caffeic acid and chlorogenic acid have been shown to be absorbed in humans. Caffeic acid absorption is hampered when it is esterified with quinic acid to form chlorogenic acid.
In laboratory experiments, colonies of a nut tree mould were grown on extracts of walnut and pistachio. Next, fungal colonies were exposed to three compounds thought to be antioxidants: gallic acid, which has aflatoxin-combating impacts in walnuts, and chlorogenic acid and caffeic acid.
Caffeic acid outperformed the other antioxidants, reducing aflatoxin production by more than 95 percent. The studies are the first to show that oxidative stress that would otherwise trigger or enhance Aspergillus flavus aflatoxin production can be stymied by caffeic acid. This opens the door to using natural anti-fungicide methods by supplementing trees with antioxidants.
# Pharmaceutical Uses
Oral administration of high doses of caffeic acid in rats has caused stomach papillomas, leading to the perception of caffeic acid as carcinogenic. In the same study, only high doses of combined antioxidants, including caffeic acid, showed a significant decrease in growth of colon tumors in those same rats. No significant effect was noted otherwise. .
Caffeic Acid is still listed under older Hazard Data sheets as a potential carcinogen because of two early experiments on rats and mice. More recent data show that bacteria in the rats' guts may alter the formation of metabolites of Caffeic Acid. and There have been no known ill-effects of Caffeic Acid in humans.
Caffeic Acid and its derivative, Caffeic Acid Phenethyl Ester (CAPE) have shown tumor-shrinking properties. When an anti-cancer drug was being sought, Caffeic Acid and CAPE were derived from Burning Bush (Euonymus alatus). "The subcutaneous and oral administrations of CA and CAPE significantly reduced liver metastasis. These results confirm the therapeutic potential of the compounds and suggest that the anti-metastatic and anti-tumor effects of CA and CAPE are mediated through the selective suppression of MMP-9 enzyme activity and transcriptional down-regulation by the dual inhibition of NF-B as well as MMP-9 catalytic activity."
A study using the caffeic acid phenethyl ester (CAPE) showed a positive effect on reducing carcinogenic incidence. Caffeic acid phenethyl ester (CAPE) is an active component of propolis from honeybee hives. It is known to have antimitogenic, anticarcinogenic, anti-inflammatory, and immunomodulatory properties.
Another study also showed that CAPE suppresses acute immune and inflammatory responses and holds promise for therapeutic uses to reduce inflammation.
This anti-inflammatory and anti-cancer property has also been shown to protect skin cells when exposed to ultraviolet (UV) radiation, in particular UVC radiation and UVB radiation. . This anti-cancer effect was also seen when mice skin was treated with bee propolis and exposed to TPA (a chemical) that induced skin papillomas. CAPE significantly reduced the number of papillomas.
Caffeic Acid and chlorogenic acid from coffee beans both reduced DNA methylation in vitro in two lines of human cancer cells. DNA methylation contributes to the growth of tumors and regulates the epigenetics of cells that are passed along with DNA to future generations . | Caffeic acid
Caffeic acid, C9H8O4 is a naturally occurring phenolic compound, (formerly called a carbolic acid), which is found in many fruits, vegetables, and herbs, including coffee, although varying in amounts depending on the plant.
Caffeic acid has been shown to act as a carcinogenic inhibitor. It is also known as an antioxidant in vitro and also in vivo.[1]
Caffeic acid is a yellow crystalline acid that is soluble in hot water and alcohol. It is related to cinnamic acid, but it has two hydroxyl groups not found in cinnamic acid. Both are part of the carbocyclic carboxylic acid group.[2]
Caffeic acid can be esterified with quinic acid to form chlorogenic acid. Both caffeic acid and chlorogenic acid are found in coffee beans. Caffeine is a different compound than caffeic acid. A derivative of caffeic acid is caffeic acid phenethyl ester (CAPE).
It is used as a matrix in MALDI mass spectroscopy analyses.[3]
# Biological importance
Caffeic acid and its derivative caffeic acid phenethyl ester (CAPE) are produced in many plants including: pears, basil, thyme, verbena, tarragon, oregano, wood betony, burning bush, turmeric, dandelion, yarrow, horsetail, rosemary, hawthorn and coffee. The amount of caffeic acid is strongly dependent on the plant species.[4]
Both caffeic acid and chlorogenic acid have been shown to be absorbed in humans. Caffeic acid absorption is hampered when it is esterified with quinic acid to form chlorogenic acid.[5]
In laboratory experiments, colonies of a nut tree mould were grown on extracts of walnut and pistachio. Next, fungal colonies were exposed to three compounds thought to be antioxidants: gallic acid, which has aflatoxin-combating impacts in walnuts, and chlorogenic acid and caffeic acid.
Caffeic acid outperformed the other antioxidants, reducing aflatoxin production by more than 95 percent. The studies are the first to show that oxidative stress that would otherwise trigger or enhance Aspergillus flavus aflatoxin production can be stymied by caffeic acid. This opens the door to using natural anti-fungicide methods by supplementing trees with antioxidants. [6]
# Pharmaceutical Uses
Oral administration of high doses of caffeic acid in rats has caused stomach papillomas, leading to the perception of caffeic acid as carcinogenic. In the same study, only high doses of combined antioxidants, including caffeic acid, showed a significant decrease in growth of colon tumors in those same rats. No significant effect was noted otherwise. [1][7].
Caffeic Acid is still listed under older Hazard Data sheets [8] as a potential carcinogen because of two early experiments on rats and mice. More recent data show that bacteria in the rats' guts may alter the formation of metabolites of Caffeic Acid. [9] and [10] There have been no known ill-effects of Caffeic Acid in humans.
Caffeic Acid and its derivative, Caffeic Acid Phenethyl Ester (CAPE) have shown tumor-shrinking properties. When an anti-cancer drug was being sought, Caffeic Acid and CAPE were derived from Burning Bush (Euonymus alatus). "The subcutaneous and oral administrations of CA and CAPE significantly reduced liver metastasis. These results confirm the therapeutic potential of the compounds and suggest that the anti-metastatic and anti-tumor effects of CA and CAPE are mediated through the selective suppression of MMP-9 enzyme activity and transcriptional down-regulation by the dual inhibition of NF-B as well as MMP-9 catalytic activity." [11]
A study using the caffeic acid phenethyl ester (CAPE) showed a positive effect on reducing carcinogenic incidence. Caffeic acid phenethyl ester (CAPE) is an active component of propolis from honeybee hives.[12] It is known to have antimitogenic, anticarcinogenic, anti-inflammatory, and immunomodulatory properties.
[13]
Another study also showed that CAPE suppresses acute immune and inflammatory responses and holds promise for therapeutic uses to reduce inflammation.
[14]
This anti-inflammatory and anti-cancer property has also been shown to protect skin cells when exposed to ultraviolet (UV) radiation, in particular UVC radiation [15] and UVB radiation. [16]. This anti-cancer effect was also seen when mice skin was treated with bee propolis and exposed to TPA (a chemical) that induced skin papillomas. CAPE significantly reduced the number of papillomas. [17] [18]
Caffeic Acid and chlorogenic acid from coffee beans both reduced DNA methylation in vitro in two lines of human cancer cells. DNA methylation contributes to the growth of tumors and regulates the epigenetics of cells that are passed along with DNA to future generations [19]. | https://www.wikidoc.org/index.php/Caffeic_acid | |
55d77ecb5e90900e9a5fd38a8e806deaf26dfd8a | wikidoc | Calabar bean | Calabar bean
The Calabar bean is the seed of a leguminous plant, Physostigma venenosum, a native of tropical Africa. It derives its scientific name from a curious beak-like appendage at the end of the stigma, in the centre of the flower; this appendage, though solid, was supposed to be hollow (hence the name from Template:Polytonic, a bladder, and stigma). The plant has a climbing habit like the scarlet runner, and attains a height of about 50 ft., with a stem an inch or two in thickness. The seed pods, which contain two or three seeds or beans, are 6 or 7 inches in length; and the beans are about the size of an ordinary horse bean but much thicker, with a deep chocolate-brown color.
# Historical and Medical Uses
They constitute the E-ser-e or ordeal beans of the people of Old Calabar, being administered to persons accused of witchcraft or other crimes. In cases where the poisonous material did its deadly work, it was held at once to indicate and rightly to punish guilt; but when it was rejected by the stomach of the accused, innocence was held to be satisfactorily established. A form of dueling with the seeds is also known among the natives, in which the two opponents divide a bean, each eating one half; that quantity has been known to kill both adversaries. Although thus highly poisonous, the bean has nothing in external aspect, taste or smell to distinguish it from any harmless leguminous seed, and very disastrous effects have resulted from its being incautiously left in the way of children. The beans were first introduced into England in the year 1840; but the plant was not accurately described till 1861, and its physiological effects were investigated in 1863 by Sir Thomas R. Fraser. The bean usually contains a little more than 1% of alkaloids. Of these two have been identified, one called calabarine with atropine-like effects, and the other, now a highly important drug, known as physostigmine, used in the treatment of glaucoma and delayed gastric emptying.
Physostigma venenosum is used as a medicine in homeopathy.
# Toxicology
The main antidote to Calabar bean poisoning is atropine, which may often succeed; and the other measures are those usually employed to stimulate the circulation and respiration. Unfortunately, the antagonism between physostigmine and atropine is not perfect, and Sir Thomas Fraser has shown that in such cases there comes a time when, if the action of the two drugs be summated, death results sooner than from either alone. Thus atropine will save life after three and a half times the fatal dose of physostigmine has been taken, but will hasten the end if four or more times the fatal dose has been ingested. | Calabar bean
The Calabar bean is the seed of a leguminous plant, Physostigma venenosum, a native of tropical Africa. It derives its scientific name from a curious beak-like appendage at the end of the stigma, in the centre of the flower; this appendage, though solid, was supposed to be hollow (hence the name from Template:Polytonic, a bladder, and stigma). The plant has a climbing habit like the scarlet runner, and attains a height of about 50 ft., with a stem an inch or two in thickness. The seed pods, which contain two or three seeds or beans, are 6 or 7 inches in length; and the beans are about the size of an ordinary horse bean but much thicker, with a deep chocolate-brown color.
# Historical and Medical Uses
They constitute the E-ser-e or ordeal beans of the people of Old Calabar, being administered to persons accused of witchcraft or other crimes. In cases where the poisonous material did its deadly work, it was held at once to indicate and rightly to punish guilt; but when it was rejected by the stomach of the accused, innocence was held to be satisfactorily established. A form of dueling with the seeds is also known among the natives, in which the two opponents divide a bean, each eating one half; that quantity has been known to kill both adversaries. Although thus highly poisonous, the bean has nothing in external aspect, taste or smell to distinguish it from any harmless leguminous seed, and very disastrous effects have resulted from its being incautiously left in the way of children. The beans were first introduced into England in the year 1840; but the plant was not accurately described till 1861, and its physiological effects were investigated in 1863 by Sir Thomas R. Fraser. The bean usually contains a little more than 1% of alkaloids. Of these two have been identified, one called calabarine with atropine-like effects, and the other, now a highly important drug, known as physostigmine, used in the treatment of glaucoma and delayed gastric emptying.
Physostigma venenosum is used as a medicine in homeopathy.
# Toxicology
Template:Wikisource1911Enc
The main antidote to Calabar bean poisoning is atropine, which may often succeed; and the other measures are those usually employed to stimulate the circulation and respiration. Unfortunately, the antagonism between physostigmine and atropine is not perfect, and Sir Thomas Fraser has shown that in such cases there comes a time when, if the action of the two drugs be summated, death results sooner than from either alone. Thus atropine will save life after three and a half times the fatal dose of physostigmine has been taken, but will hasten the end if four or more times the fatal dose has been ingested. | https://www.wikidoc.org/index.php/Calabar_bean | |
8779cfa79eab74e3ea8950d74117ffae0798a904 | wikidoc | Calcipotriol | Calcipotriol
# 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
Calcipotriol is a vitamin D3 analog that is FDA approved for the treatment of plaque psoriasis. Common adverse reactions include burning sensation, dermatitis, dry skin, peeling of skin, pruritus, rash and skin irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Plaque Psoriasis
Dosing information
- Apply a thin layer of Calcipotriene Cream to the affected skin twice daily and rub in gently and completely. The safety and efficacy of Calcipotriene Cream have been demonstrated in patients treated for eight weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Calcipotriol in adult patients.
### Non–Guideline-Supported Use
# Psoriasis vulgaris Of the body
Dosing information
- 50 mcg/g applied to the trunk and limbs once daily for up to 8 weeks.
# Vitiligo
Dosing information
- Applied twice daily
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of Calcipotriene Cream in pediatric patients have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Calcipotriol in pediatric patients.
### Non–Guideline-Supported Use
# Vitiligo
Dosing information
- 50 mcg/g was applied in the evening to depigmented skin.
# Contraindications
- Calcipotriene Cream is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. It should not be used by patients with demonstrated hypercalcemia or evidence of vitamin D toxicity. Calcipotriene Cream should not be used on the face.
# Warnings
- Use of Calcipotriene Cream may cause transient irritation of both lesions and surrounding uninvolved skin. If irritation develops, Calcipotriene Cream should be discontinued.
- For external use only. Keep out of the reach of children. Always wash hands thoroughly after use.
- Reversible elevation of serum calcium has occurred with use of topical calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.
# Adverse Reactions
## Clinical Trials Experience
- In controlled clinical trials, the most frequent adverse experiences reported for Calcipotriene (calcipotriene) Cream, 0.005% were cases of skin irritation, which occurred in approximately 10-15% of patients. Rash, pruritus, dermatitis and worsening of psoriasis were reported in 1 to 10% of patients.
## Postmarketing Experience
- FDA Package Insert for Calcipotriol contains no information regarding Postmarketing.
# Drug Interactions
- FDA Package Insert for Calcipotriol contains no information regarding Drug Interaction.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects: Pregnancy Category C
- Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the administered dose. Increased rabbit maternal and fetal toxicity was noted at 12 μg/kg/day (132 μg/m2/day). Rabbits administered 36 μg/kg/day (396 μg/m2/day) resulted in fetuses with a significant increase in the incidences of pubic bones, forelimb phalanges, and incomplete bone ossification. In a rat study, oral doses of 54 μg/kg/day (318 μg/m2/day) resulted in a significantly higher incidence of skeletal abnormalities consisting primarily of enlarged fontanelles and extra ribs. The enlarged fontanelles are most likely due to calcipotriene's effect upon calcium metabolism. The maternal and fetal calculated no-effect exposures in the rat (43.2 μg/m2/day) and rabbit (17.6 μg/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5 μg/m2/day) from dermal application. There are no adequate and well-controlled studies in pregnant women. Therefore, Calcipotriene Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Calcipotriol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Calcipotriol during labor and delivery.
### Nursing Mothers
- There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation, but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin. Because many drugs are excreted in human milk, caution should be exercised when Calcipotriene Cream is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of Calcipotriene Cream in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of systemic adverse effects when they are treated with topical medication.
### Geriatic Use
- Of the total number of patients in clinical studies of calcipotriene cream, approximately 15% were 65 or older, while approximately 3% were 75 and over. There were no significant differences in adverse events for subjects over 65 years compared to those under 65 years of age. However, the greater sensitivity of older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Calcipotriol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Calcipotriol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Calcipotriol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Calcipotriol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Calcipotriol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Calcipotriol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
- FDA Package Insert for Calcipotriol contains no information regarding Drug Monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been observed with excessive use of topical calcipotriene. If elevation in serum calcium should occur, discontinue treatment until normal calcium levels are restored.
# Pharmacology
## Mechanism of Action
- In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriene is a synthetic analog of vitamin D3.
## Structure
- Calcipotriene (calcipotriene) Cream, 0.005% contains calcipotriene monohydrate, a synthetic vitamin D3 derivative, for topical dermatological use.
- Chemically, calcipotriene monohydrate is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1α,3β,24-triol monohydrate, with the empirical formula C27H40O3H2O, a molecular weight of 430.6, and the following structural formula:
- Calcipotriene monohydrate is a white or off-white crystalline substance. Calcipotriene Cream contains calcipotriene monohydrate equivalent to 50 μg/g anhydrous calcipotriene in a cream base of cetearyl alcohol, ceteth-20, diazolidinyl urea, dichlorobenzyl alcohol, dibasic sodium phosphate, edetate disodium, dl-alpha tocopherol, glycerin, mineral oil, petrolatum, and water.
## Pharmacodynamics
- Clinical studies with radiolabelled calcipotriene ointment indicate that approximately 6% (± 3%, SD) of the applied dose of calcipotriene is absorbed systemically when the ointment is applied topically to psoriasis plaques, or 5% (± 2.6%, SD) when applied to normal skin, and much of the absorbed active is converted to inactive metabolites within 24 hours of application. Systemic absorption of the cream has not been studied.
## Pharmacokinetics
- Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The active form of the vitamin, 1,25-dihydroxy vitamin D3 (calcitriol), is known to be recycled via the liver and excreted in the bile. Calcipotriene metabolism following systemic uptake is rapid, and occurs via a similar pathway to the natural hormone.
## Nonclinical Toxicology
- When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 µg/kg/day (corresponding to 9, 30 and 90 µg/m2/day), no significant changes in tumor incidence were observed when compared to control. In a study in which albino hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of UVR to induce skin tumors. Patients that apply Calcipotriene Cream to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy in patients that use Calcipotriene Cream.
- Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, or in a micronucleus assay conducted in mice.
- Studies in rats at doses up to 54 μg/kg/day (324 μg/m2/day) of calcipotriene indicated no impairment of fertility or general reproductive performance.
# Clinical Studies
- Adequate and well-controlled trials of patients treated with Calcipotriene Cream have demonstrated improvement usually beginning after 2 weeks of therapy. This improvement continued with approximately 50% of patients showing at least marked improvement in the signs and symptoms of psoriasis after 8 weeks of therapy, but only approximately 4% showed complete clearing.
# How Supplied
- Calcipotriene (calcipotriene) Cream, 0.005% is available in:
- 60 gram aluminum tubes N 50222-260-06
- 120 gram aluminum tubes N 50222-260-12
## Storage
- Store at controlled room temperature 15° C - 25° C (59° F - 77° F). Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients using Calcipotriene Cream should receive the following information and instructions:
1. This medication is to be used only as directed by the physician. It is for external use only. Avoid contact with the face or eyes. As with any topical medication, patients should wash their hands after application.
2. This medication should not be used for any disorder other than that for which it was prescribed.
3. Patients should report to their physician any signs of adverse reactions.
4. Patients that apply Calcipotriene Cream to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.).
# Precautions with Alcohol
- Alcohol-Calcipotriol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dovonex
- Calcitrene
- Sorilux
# Look-Alike Drug Names
- There is limited information about the look alike drug names.
# Drug Shortage Status
# Price | Calcipotriol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Calcipotriol is a vitamin D3 analog that is FDA approved for the treatment of plaque psoriasis. Common adverse reactions include burning sensation, dermatitis, dry skin, peeling of skin, pruritus, rash and skin irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Plaque Psoriasis
Dosing information
- Apply a thin layer of Calcipotriene Cream to the affected skin twice daily and rub in gently and completely. The safety and efficacy of Calcipotriene Cream have been demonstrated in patients treated for eight weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Calcipotriol in adult patients.
### Non–Guideline-Supported Use
# Psoriasis vulgaris Of the body
Dosing information
- 50 mcg/g applied to the trunk and limbs once daily for up to 8 weeks.[1]
# Vitiligo
Dosing information
- Applied twice daily[2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness of Calcipotriene Cream in pediatric patients have not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Calcipotriol in pediatric patients.
### Non–Guideline-Supported Use
# Vitiligo
Dosing information
- 50 mcg/g was applied in the evening to depigmented skin.
# Contraindications
- Calcipotriene Cream is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. It should not be used by patients with demonstrated hypercalcemia or evidence of vitamin D toxicity. Calcipotriene Cream should not be used on the face.
# Warnings
- Use of Calcipotriene Cream may cause transient irritation of both lesions and surrounding uninvolved skin. If irritation develops, Calcipotriene Cream should be discontinued.
- For external use only. Keep out of the reach of children. Always wash hands thoroughly after use.
- Reversible elevation of serum calcium has occurred with use of topical calcipotriene. If elevation in serum calcium outside the normal range should occur, discontinue treatment until normal calcium levels are restored.
# Adverse Reactions
## Clinical Trials Experience
- In controlled clinical trials, the most frequent adverse experiences reported for Calcipotriene (calcipotriene) Cream, 0.005% were cases of skin irritation, which occurred in approximately 10-15% of patients. Rash, pruritus, dermatitis and worsening of psoriasis were reported in 1 to 10% of patients.
## Postmarketing Experience
- FDA Package Insert for Calcipotriol contains no information regarding Postmarketing.
# Drug Interactions
- FDA Package Insert for Calcipotriol contains no information regarding Drug Interaction.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects: Pregnancy Category C
- Studies of teratogenicity were done by the oral route where bioavailability is expected to be approximately 40-60% of the administered dose. Increased rabbit maternal and fetal toxicity was noted at 12 μg/kg/day (132 μg/m2/day). Rabbits administered 36 μg/kg/day (396 μg/m2/day) resulted in fetuses with a significant increase in the incidences of pubic bones, forelimb phalanges, and incomplete bone ossification. In a rat study, oral doses of 54 μg/kg/day (318 μg/m2/day) resulted in a significantly higher incidence of skeletal abnormalities consisting primarily of enlarged fontanelles and extra ribs. The enlarged fontanelles are most likely due to calcipotriene's effect upon calcium metabolism. The maternal and fetal calculated no-effect exposures in the rat (43.2 μg/m2/day) and rabbit (17.6 μg/m2/day) studies are approximately equal to the expected human systemic exposure level (18.5 μg/m2/day) from dermal application. There are no adequate and well-controlled studies in pregnant women. Therefore, Calcipotriene Cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Calcipotriol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Calcipotriol during labor and delivery.
### Nursing Mothers
- There is evidence that maternal 1,25-dihydroxy vitamin D3 (calcitriol) may enter the fetal circulation, but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin. Because many drugs are excreted in human milk, caution should be exercised when Calcipotriene Cream is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness of Calcipotriene Cream in pediatric patients have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of systemic adverse effects when they are treated with topical medication.
### Geriatic Use
- Of the total number of patients in clinical studies of calcipotriene cream, approximately 15% were 65 or older, while approximately 3% were 75 and over. There were no significant differences in adverse events for subjects over 65 years compared to those under 65 years of age. However, the greater sensitivity of older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Calcipotriol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Calcipotriol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Calcipotriol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Calcipotriol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Calcipotriol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Calcipotriol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
- FDA Package Insert for Calcipotriol contains no information regarding Drug Monitoring.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- Topically applied calcipotriene can be absorbed in sufficient amounts to produce systemic effects. Elevated serum calcium has been observed with excessive use of topical calcipotriene. If elevation in serum calcium should occur, discontinue treatment until normal calcium levels are restored.
# Pharmacology
## Mechanism of Action
- In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol) in the skin. Calcipotriene is a synthetic analog of vitamin D3.
## Structure
- Calcipotriene (calcipotriene) Cream, 0.005% contains calcipotriene monohydrate, a synthetic vitamin D3 derivative, for topical dermatological use.
- Chemically, calcipotriene monohydrate is (5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1α,3β,24-triol monohydrate, with the empirical formula C27H40O3•H2O, a molecular weight of 430.6, and the following structural formula:
- Calcipotriene monohydrate is a white or off-white crystalline substance. Calcipotriene Cream contains calcipotriene monohydrate equivalent to 50 μg/g anhydrous calcipotriene in a cream base of cetearyl alcohol, ceteth-20, diazolidinyl urea, dichlorobenzyl alcohol, dibasic sodium phosphate, edetate disodium, dl-alpha tocopherol, glycerin, mineral oil, petrolatum, and water.
## Pharmacodynamics
- Clinical studies with radiolabelled calcipotriene ointment indicate that approximately 6% (± 3%, SD) of the applied dose of calcipotriene is absorbed systemically when the ointment is applied topically to psoriasis plaques, or 5% (± 2.6%, SD) when applied to normal skin, and much of the absorbed active is converted to inactive metabolites within 24 hours of application. Systemic absorption of the cream has not been studied.
## Pharmacokinetics
- Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The active form of the vitamin, 1,25-dihydroxy vitamin D3 (calcitriol), is known to be recycled via the liver and excreted in the bile. Calcipotriene metabolism following systemic uptake is rapid, and occurs via a similar pathway to the natural hormone.
## Nonclinical Toxicology
- When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 µg/kg/day (corresponding to 9, 30 and 90 µg/m2/day), no significant changes in tumor incidence were observed when compared to control. In a study in which albino hairless mice were exposed to both UVR and topically applied calcipotriene, a reduction in the time required for UVR to induce the formation of skin tumors was observed (statistically significant in males only), suggesting that calcipotriene may enhance the effect of UVR to induce skin tumors. Patients that apply Calcipotriene Cream to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy in patients that use Calcipotriene Cream.
- Calcipotriene did not elicit any mutagenic effects in an Ames mutagenicity assay, a mouse lymphoma TK locus assay, a human lymphocyte chromosome aberration assay, or in a micronucleus assay conducted in mice.
- Studies in rats at doses up to 54 μg/kg/day (324 μg/m2/day) of calcipotriene indicated no impairment of fertility or general reproductive performance.
# Clinical Studies
- Adequate and well-controlled trials of patients treated with Calcipotriene Cream have demonstrated improvement usually beginning after 2 weeks of therapy. This improvement continued with approximately 50% of patients showing at least marked improvement in the signs and symptoms of psoriasis after 8 weeks of therapy, but only approximately 4% showed complete clearing.
# How Supplied
- Calcipotriene (calcipotriene) Cream, 0.005% is available in:
- 60 gram aluminum tubes N 50222-260-06
- 120 gram aluminum tubes N 50222-260-12
## Storage
- Store at controlled room temperature 15° C - 25° C (59° F - 77° F). Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients using Calcipotriene Cream should receive the following information and instructions:
1. This medication is to be used only as directed by the physician. It is for external use only. Avoid contact with the face or eyes. As with any topical medication, patients should wash their hands after application.
2. This medication should not be used for any disorder other than that for which it was prescribed.
3. Patients should report to their physician any signs of adverse reactions.
4. Patients that apply Calcipotriene Cream to exposed portions of the body should avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.).
# Precautions with Alcohol
- Alcohol-Calcipotriol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Dovonex
- Calcitrene
- Sorilux
# Look-Alike Drug Names
- There is limited information about the look alike drug names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Calcipotriene | |
a940d0d0b7b5c658e5e37a24431fd0b6310f7064 | wikidoc | Calciseptine | Calciseptine
Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-Type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.
# Sequence
Its amino acid sequence is: RICYI HKASL PRATK TCVEN TCYKM FIRTQ REYIS REGCG CPTAM WPYQT ECCKG DRCNK
# Isolation
Calciseptine is purified from the venom of black mamba Dendroaspis p. polyepsis via three isolation steps: (1) gel filtration, (2) ion exchange on TSK SP 5PW, and (3) reverse-phase chromatograghy on RP18. It represents 2.8% of the total venom components.
# Target
Calciseptine blocks L-type Ca2+ channels.
As a result, it blocks spontaneous contractions of rat portal vein, contractions of the rat thoracic aorta, uterus and cardiac preparations. | Calciseptine
Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-Type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.[1]
# Sequence
Its amino acid sequence is: RICYI HKASL PRATK TCVEN TCYKM FIRTQ REYIS REGCG CPTAM WPYQT ECCKG DRCNK
# Isolation
Calciseptine is purified from the venom of black mamba Dendroaspis p. polyepsis via three isolation steps: (1) gel filtration, (2) ion exchange on TSK SP 5PW, and (3) reverse-phase chromatograghy on RP18. It represents 2.8% of the total venom components. [2]
# Target
Calciseptine blocks L-type Ca2+ channels.[1]
As a result, it blocks spontaneous contractions of rat portal vein, contractions of the rat thoracic aorta, uterus and cardiac preparations. | https://www.wikidoc.org/index.php/Calciseptine | |
d4ae43eaf8c3a38c1fb22ab198cd51c2814d0f1e | wikidoc | Calreticulin | Calreticulin
Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the CALR gene.
Calreticulin is a multifunctional soluble protein that binds Ca2+ ions (a second messenger in signal transduction), rendering it inactive. The Ca2+ is bound with low affinity, but high capacity, and can be released on a signal (see inositol triphosphate). Calreticulin is located in storage compartments associated with the endoplasmic reticulum and is considered an ER resident protein.
The term "Mobilferrin" is considered to be the same as calreticulin by some sources.
# Function
Calreticulin binds to misfolded proteins and prevents them from being exported from the endoplasmic reticulum to the Golgi apparatus.
A similar quality-control molecular chaperone, calnexin, performs the same service for soluble proteins as does calreticulin, however it is a membrane-bound protein. Both proteins, calnexin and calreticulin, have the function of binding to oligosaccharides containing terminal glucose residues, thereby targeting them for degradation. Calreticulin and Calnexin's ability to bind carbohydrates associates them with the lectin protein family. In normal cellular function, trimming of glucose residues off the core oligosaccharide added during N-linked glycosylation is a part of protein processing. If "overseer" enzymes note that residues are misfolded, proteins within the rER will re-add glucose residues so that other calreticulin/calnexin can bind to these proteins and prevent them from proceeding to the Golgi. This leads these aberrantly folded proteins down a path whereby they are targeted for degradation.
Studies on transgenic mice reveal that calreticulin is a cardiac embryonic gene that is essential during development.
Calreticulin and calnexin are also integral proteins in the production of MHC class I Proteins. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state. After the β2-microglobulin binds to the peptide-loading complex (PLC), calreticulin (along with ERp57) takes over the job of chaperoning the MHC class I protein while the tapasin links the complex to the transporter associated with antigen processing (TAP) complex. This association prepares the MHC class I for binding an antigen for presentation on the cell surface.
## Transcription regulation
Calreticulin is also found in the nucleus, suggesting that it may have a role in transcription regulation. Calreticulin binds to the synthetic peptide KLGFFKR, which is almost identical to an amino acid sequence in the DNA-binding domain of the superfamily of nuclear receptors. The amino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. Calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element and can inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.
# Clinical significance
Calreticulin binds to antibodies in certain area of systemic lupus and Sjogren patients that contain anti-Ro/SSA antibodies. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin, but calreticulin is not a Ro/SS-A antigen. Earlier papers referred to calreticulin as an Ro/SS-A antigen, but this was later disproven. Increased autoantibody titer against human calreticulin is found in infants with complete congenital heart block of both the IgG and IgM classes.
In 2013, two groups detected calreticulin mutations in a majority of JAK2-negative/MPL-negative patients with essential thrombocythemia and primary myelofibrosis, which makes CALR mutations the second most common in myeloproliferative neoplasms. All mutations (insertions or deletions) affected the last exon, generating a reading frame shift of the resulting protein, that creates a novel terminal peptide and causes a loss of endoplasmic reticulum KDEL retention signal.
# Role in cancer
Calreticulin (CRT) is expressed in many cancer cells and plays a role to promote macrophages to engulf hazardous cancerous cells. The reason why most of the cells are not destroyed is the presence of another molecule with signal CD47, which blocks CRT. Hence antibodies that block CD47 might be useful as a cancer treatment. In mice models of myeloid leukemia and non-Hodgkin’s lymphoma, anti-CD47 were effective in clearing cancer cells while normal cells were unaffected.
# Interactions
Calreticulin has been shown to interact with Perforin and NK2 homeobox 1. | Calreticulin
Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein that in humans is encoded by the CALR gene.[1][2]
Calreticulin is a multifunctional soluble protein that binds Ca2+ ions (a second messenger in signal transduction), rendering it inactive. The Ca2+ is bound with low affinity, but high capacity, and can be released on a signal (see inositol triphosphate). Calreticulin is located in storage compartments associated with the endoplasmic reticulum and is considered an ER resident protein.[2]
The term "Mobilferrin"[3] is considered to be the same as calreticulin by some sources.[4]
# Function
Calreticulin binds to misfolded proteins and prevents them from being exported from the endoplasmic reticulum to the Golgi apparatus.
A similar quality-control molecular chaperone, calnexin, performs the same service for soluble proteins as does calreticulin, however it is a membrane-bound protein. Both proteins, calnexin and calreticulin, have the function of binding to oligosaccharides containing terminal glucose residues, thereby targeting them for degradation. Calreticulin and Calnexin's ability to bind carbohydrates associates them with the lectin protein family. In normal cellular function, trimming of glucose residues off the core oligosaccharide added during N-linked glycosylation is a part of protein processing. If "overseer" enzymes note that residues are misfolded, proteins within the rER will re-add glucose residues so that other calreticulin/calnexin can bind to these proteins and prevent them from proceeding to the Golgi. This leads these aberrantly folded proteins down a path whereby they are targeted for degradation.
Studies on transgenic mice reveal that calreticulin is a cardiac embryonic gene that is essential during development.[5]
Calreticulin and calnexin are also integral proteins in the production of MHC class I Proteins. As newly synthesized MHC class I α-chains enter the endoplasmic reticulum, calnexin binds on to them retaining them in a partly folded state.[6] After the β2-microglobulin binds to the peptide-loading complex (PLC), calreticulin (along with ERp57) takes over the job of chaperoning the MHC class I protein while the tapasin links the complex to the transporter associated with antigen processing (TAP) complex. This association prepares the MHC class I for binding an antigen for presentation on the cell surface.
## Transcription regulation
Calreticulin is also found in the nucleus, suggesting that it may have a role in transcription regulation. Calreticulin binds to the synthetic peptide KLGFFKR, which is almost identical to an amino acid sequence in the DNA-binding domain of the superfamily of nuclear receptors. The amino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. Calreticulin can inhibit the binding of androgen receptor to its hormone-responsive DNA element and can inhibit androgen receptor and retinoic acid receptor transcriptional activities in vivo, as well as retinoic acid-induced neuronal differentiation. Thus, calreticulin can act as an important modulator of the regulation of gene transcription by nuclear hormone receptors.
# Clinical significance
Calreticulin binds to antibodies in certain area of systemic lupus and Sjogren patients that contain anti-Ro/SSA antibodies. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin, but calreticulin is not a Ro/SS-A antigen. Earlier papers referred to calreticulin as an Ro/SS-A antigen, but this was later disproven. Increased autoantibody titer against human calreticulin is found in infants with complete congenital heart block of both the IgG and IgM classes.[7]
In 2013, two groups detected calreticulin mutations in a majority of JAK2-negative/MPL-negative patients with essential thrombocythemia and primary myelofibrosis, which makes CALR mutations the second most common in myeloproliferative neoplasms. All mutations (insertions or deletions) affected the last exon, generating a reading frame shift of the resulting protein, that creates a novel terminal peptide and causes a loss of endoplasmic reticulum KDEL retention signal.[8][9]
# Role in cancer
Calreticulin (CRT) is expressed in many cancer cells and plays a role to promote macrophages to engulf hazardous cancerous cells. The reason why most of the cells are not destroyed is the presence of another molecule with signal CD47, which blocks CRT. Hence antibodies that block CD47 might be useful as a cancer treatment. In mice models of myeloid leukemia and non-Hodgkin’s lymphoma, anti-CD47 were effective in clearing cancer cells while normal cells were unaffected.[10]
# Interactions
Calreticulin has been shown to interact with Perforin[11] and NK2 homeobox 1.[12] | https://www.wikidoc.org/index.php/Calreticulin | |
21ae0bcf13181c1c99c1a684d6b2f29056139957 | wikidoc | Calvin cycle | Calvin cycle
# Overview
The Calvin cycle (or Calvin-Benson-Bassham cycle or carbon fixation) is a series of biochemical reactions that takes place in the stroma of chloroplasts in photosynthetic organisms. It was discovered by Melvin Calvin, James Bassham and Andrew Benson at the University of California, Berkeley . It is one of the light-independent reactions or dark reactions.
# Overview
During photosynthesis, light energy is used to generate chemical free energy, stored in glucose. The light-independent Calvin cycle, also (misleadingly) known as the "dark reaction" or "dark stage", uses the energy from short-lived electronically-excited carriers to convert carbon dioxide and water into organic compounds that can be used by the organism (and by animals which feed on it). This set of reactions is also called carbon fixation. The key enzyme of the cycle is called RuBisCO. In the following equations, the chemical species (phosphates and carboxylic acids) exist in equilibria among their various ionized states as governed by the pH.
The enzymes in the Calvin cycle are functionally equivalent to many enzymes used in other metabolic pathways such as gluconeogenesis and the pentose phosphate pathway, but they are to be found in the chloroplast stroma instead of the cell cytoplasm, separating the reactions. They are activated in the light (which is why the name "dark reaction" is misleading), and also by products of the light-dependent reaction. These regulatory functions prevent the Calvin cycle from operating in reverse to respiration, which would create a continuous cycle of carbon dioxide being reduced to carbohydrates, and carbohydrates being respired to carbon dioxide. Energy (in the form of ATP) would be wasted in carrying out these reactions that have no net productivity.
The sum of reactions in the Calvin cycle is the following:
It should be noted that hexose (six carbon) sugars are not a product of the Calvin cycle. Although many texts list a product of photosynthesis as C6H12O6, this is mainly a convenience to counter the equation of respiration, where six-carbon sugars are oxidized in mitochondria. The carbohydrate products of the Calvin Cycle are three-carbon sugar phosphate molecules, or "triose phosphates," specifically, glyceraldehyde-3-phosphate.
# Steps of the Calvin cycle
- The enzyme RuBisCO catalyses the carboxylation of Ribulose-1,5-bisphosphate, a 5 carbon compound, by carbon dioxide (a total of 6 carbons) in a two-step reaction . Rubisco is a large, slow enzyme averaging 3 substrate per second compared to 1000/s for most other enzymes in the Calvin cycle. Two molecules of glycerate 3-phosphate, a 3-carbon compound, are created. (also: 3-phosphoglycerate, 3-phosphoglyceric acid, 3PGA)
- The enzyme phosphoglycerate kinase catalyses the phosphorylation of 3PGA by ATP (which was produced in the light-dependent stage). 1,3-bisphosphoglycerate (glycerate-1,3-bisphosphate) and ADP are the products. (However, note that two PGAs are produced for every CO2 that enters the cycle, so this step utilizes 2ATP per CO2 fixed.
- The enzyme G3P dehydrogenase catalyses the reduction of 1,3BPGA by NADPH (which is another product of the light-dependent stage). Glyceraldehyde 3-phosphate (also G3P, GP) is produced, and the NADPH itself was oxidized and becomes NADP+. Again, two NADPH are utilized per CO2 fixed. (Simplified versions of the Calvin cycle integrate the remaining steps, except for the last one, into one general step - the regeneration of RuBP - also, one G3P would exit here.)
- Triose phosphate isomerase converts some G3P reversibly into dihydroxyacetone phosphate (DHAP), also a 3-carbon molecule.
- Aldolase and fructose-1,6-bisphosphatase convert a G3P and a DHAP into fructose-6-phosphate (6C). A phosphate ion is lost into solution.
- Then fixation of another CO2 generates two more G3P.
- F6P has two carbons removed by transketolase, giving erythrose-4-phosphate. The two carbons on transketolase are added to a G3P, giving the ketose xylulose-5-phosphate (Xu5P).
- E4P and a DHAP (formed from one of the G3P from the second CO2 fixation) are converted into sedoheptulose-1,7-bisphosphate (7C) by aldolase enzyme.
- Sedoheptulose-1,7-bisphosphatase (one of only three enzymes of the Calvin cycle which are unique to plants) cleaves sedoheptulose-1,7-bisphosphate into sedoheptulose-7-phosphate, releasing an inorganic phosphate ion into solution.
- Fixation of a third CO2 generates two more G3P. The ketose S7P has two carbons removed by transketolase, giving ribose-5-phosphate (R5P), and the two carbons remaining on transketolase are transferred to one of the G3P, giving another Xu5P. This leaves one G3P as the product of fixation of 3 CO2, with generation of three pentoses which can be converted to Ru5P.
- R5P is converted into ribulose-5-phosphate (Ru5P, RuP) by phosphopentose isomerase. Xu5P is converted into RuP by phosphopentose epimerase.
- Finally, phosphoribulokinase (another plant unique enzyme of the pathway) phosphorylates RuP into RuBP, ribulose-1,5-bisphosphate, completing the Calvin cycle. This requires the input of one ATP.
Thus, of 6 G3P produced, three RuBP (5C) are made totalling 15 carbons, with only one available for subsequent conversion to hexose. This required 9 ATPs and 6 NADPH per 3 CO2.
RuBisCO also reacts competitively with O2 instead of CO2 in photorespiration. The rate of photorespiration is higher at high temperatures. "photorespiration" turns RuBP into 3PGA and 2-phosphoglycolate, a 2-carbon molecule which can be converted via glycolate and glyoxalate to glycine. Via the glycine cleavage system and tetrahydrofolate, two glycines are converted into serine +CO2. Serine can be converted back to 3-phosphoglycerate. Thus, only 3 of 4 carbons from two phosphoglycolates can be converted back to 3PGA. Obviously photorespiration has very negative consequences for the plant, because rather than fixing CO2, this process leads to loss of CO2. C4 carbon fixation evolved to circumvent photorespiration, but can only occur in certain plants living in very warm or tropical climates.
# Products of the Calvin cycle
The immediate product of the Calvin cycle is glyceraldehyde-3-phosphate (G3P) and water. Two G3P molecules (or one F6P molecule) that have exited the cycle are used to make larger carbohydrates. In simplified versions of the Calvin cycle they may be converted to F6P or F5P after exit, but this conversion is also part of the cycle.
Hexose isomerase converts about half of the F6P molecules in to glucose-6-phosphate. These are phosphorescent and the glucose can be used to form starch, which is stored in, for example, potatoes, or cellulose used to build up cell walls. Glucose, with fructose, forms sucrose, a non-reducing sugar which is a stable storage sugar, unlike glucose. | Calvin cycle
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Calvin cycle (or Calvin-Benson-Bassham cycle or carbon fixation) is a series of biochemical reactions that takes place in the stroma of chloroplasts in photosynthetic organisms. It was discovered by Melvin Calvin, James Bassham and Andrew Benson at the University of California, Berkeley .[1] It is one of the light-independent reactions or dark reactions.
# Overview
During photosynthesis, light energy is used to generate chemical free energy, stored in glucose. The light-independent Calvin cycle, also (misleadingly) known as the "dark reaction" or "dark stage", uses the energy from short-lived electronically-excited carriers to convert carbon dioxide and water into organic compounds that can be used by the organism (and by animals which feed on it). This set of reactions is also called carbon fixation. The key enzyme of the cycle is called RuBisCO. In the following equations, the chemical species (phosphates and carboxylic acids) exist in equilibria among their various ionized states as governed by the pH.
The enzymes in the Calvin cycle are functionally equivalent to many enzymes used in other metabolic pathways such as gluconeogenesis and the pentose phosphate pathway, but they are to be found in the chloroplast stroma instead of the cell cytoplasm, separating the reactions. They are activated in the light (which is why the name "dark reaction" is misleading), and also by products of the light-dependent reaction. These regulatory functions prevent the Calvin cycle from operating in reverse to respiration, which would create a continuous cycle of carbon dioxide being reduced to carbohydrates, and carbohydrates being respired to carbon dioxide. Energy (in the form of ATP) would be wasted in carrying out these reactions that have no net productivity.
The sum of reactions in the Calvin cycle is the following:
It should be noted that hexose (six carbon) sugars are not a product of the Calvin cycle. Although many texts list a product of photosynthesis as C6H12O6, this is mainly a convenience to counter the equation of respiration, where six-carbon sugars are oxidized in mitochondria. The carbohydrate products of the Calvin Cycle are three-carbon sugar phosphate molecules, or "triose phosphates," specifically, glyceraldehyde-3-phosphate.
# Steps of the Calvin cycle
- The enzyme RuBisCO catalyses the carboxylation of Ribulose-1,5-bisphosphate, a 5 carbon compound, by carbon dioxide (a total of 6 carbons) in a two-step reaction [2]. Rubisco is a large, slow enzyme averaging 3 substrate per second compared to 1000/s for most other enzymes in the Calvin cycle. Two molecules of glycerate 3-phosphate, a 3-carbon compound, are created. (also: 3-phosphoglycerate, 3-phosphoglyceric acid, 3PGA)
- The enzyme phosphoglycerate kinase catalyses the phosphorylation of 3PGA by ATP (which was produced in the light-dependent stage). 1,3-bisphosphoglycerate (glycerate-1,3-bisphosphate) and ADP are the products. (However, note that two PGAs are produced for every CO2 that enters the cycle, so this step utilizes 2ATP per CO2 fixed.
- The enzyme G3P dehydrogenase catalyses the reduction of 1,3BPGA by NADPH (which is another product of the light-dependent stage). Glyceraldehyde 3-phosphate (also G3P, GP) is produced, and the NADPH itself was oxidized and becomes NADP+. Again, two NADPH are utilized per CO2 fixed. (Simplified versions of the Calvin cycle integrate the remaining steps, except for the last one, into one general step - the regeneration of RuBP - also, one G3P would exit here.)
- Triose phosphate isomerase converts some G3P reversibly into dihydroxyacetone phosphate (DHAP), also a 3-carbon molecule.
- Aldolase and fructose-1,6-bisphosphatase convert a G3P and a DHAP into fructose-6-phosphate (6C). A phosphate ion is lost into solution.
- Then fixation of another CO2 generates two more G3P.
- F6P has two carbons removed by transketolase, giving erythrose-4-phosphate. The two carbons on transketolase are added to a G3P, giving the ketose xylulose-5-phosphate (Xu5P).
- E4P and a DHAP (formed from one of the G3P from the second CO2 fixation) are converted into sedoheptulose-1,7-bisphosphate (7C) by aldolase enzyme.
- Sedoheptulose-1,7-bisphosphatase (one of only three enzymes of the Calvin cycle which are unique to plants) cleaves sedoheptulose-1,7-bisphosphate into sedoheptulose-7-phosphate, releasing an inorganic phosphate ion into solution.
- Fixation of a third CO2 generates two more G3P. The ketose S7P has two carbons removed by transketolase, giving ribose-5-phosphate (R5P), and the two carbons remaining on transketolase are transferred to one of the G3P, giving another Xu5P. This leaves one G3P as the product of fixation of 3 CO2, with generation of three pentoses which can be converted to Ru5P.
- R5P is converted into ribulose-5-phosphate (Ru5P, RuP) by phosphopentose isomerase. Xu5P is converted into RuP by phosphopentose epimerase.
- Finally, phosphoribulokinase (another plant unique enzyme of the pathway) phosphorylates RuP into RuBP, ribulose-1,5-bisphosphate, completing the Calvin cycle. This requires the input of one ATP.
Thus, of 6 G3P produced, three RuBP (5C) are made totalling 15 carbons, with only one available for subsequent conversion to hexose. This required 9 ATPs and 6 NADPH per 3 CO2.
RuBisCO also reacts competitively with O2 instead of CO2 in photorespiration. The rate of photorespiration is higher at high temperatures. "photorespiration" turns RuBP into 3PGA and 2-phosphoglycolate, a 2-carbon molecule which can be converted via glycolate and glyoxalate to glycine. Via the glycine cleavage system and tetrahydrofolate, two glycines are converted into serine +CO2. Serine can be converted back to 3-phosphoglycerate. Thus, only 3 of 4 carbons from two phosphoglycolates can be converted back to 3PGA. Obviously photorespiration has very negative consequences for the plant, because rather than fixing CO2, this process leads to loss of CO2. C4 carbon fixation evolved to circumvent photorespiration, but can only occur in certain plants living in very warm or tropical climates.
# Products of the Calvin cycle
The immediate product of the Calvin cycle is glyceraldehyde-3-phosphate (G3P) and water. Two G3P molecules (or one F6P molecule) that have exited the cycle are used to make larger carbohydrates. In simplified versions of the Calvin cycle they may be converted to F6P or F5P after exit, but this conversion is also part of the cycle.
Hexose isomerase converts about half of the F6P molecules in to glucose-6-phosphate. These are phosphorescent and the glucose can be used to form starch, which is stored in, for example, potatoes, or cellulose used to build up cell walls. Glucose, with fructose, forms sucrose, a non-reducing sugar which is a stable storage sugar, unlike glucose. | https://www.wikidoc.org/index.php/Calvin-Benson_cycle | |
7b877fa634d3144de34cd4700362890a259b93c6 | wikidoc | Camp Sweeney | Camp Sweeney
Camp Sweeney is an American summer camp located in Gainesville, Texas. It is primarily for children with type 1 diabetes and sometimes their siblings. It has been in operation since 1950.
Though it offers normal summer camp activities such as swimming, hiking, archery, basketball, volleyball, waterpark, broadcasting and arts and crafts, its many facilities are designed with the diabetic child in mind. Built-in blood glucose testing stations are scattered throughout the camp, and counselors carry monitors and insulin with them at all times. During meals, each camper has their food tray prepared with the right number of carbohydrates for their chosen diet. The campers also go to medical lecture several times a week so that they can learn how to better care for their diabetes as well as keep up with the latest developments in diabetes research.
The camp serves children ages 5 to 18 and divides them into age appropriate cabins. The campers get to choose which activities they participate in during the day. Counselors, college students who are often recruited from The University of Notre Dame and other colleges around the nation, help younger children learn to administer their own insulin shots or change their own insulin pumps sites.
The purpose of Camp Sweeney is to help children with diabetes learn healthy habits that they can continue after they have left camp, and to build lasting relationships with other children dealing with the same problems that come with having diabetes. Extensive reaserch sudies conducted by the camp's parent, the Southwestern Diabetic Foundation, show that children and young adults attending Camp Sweeney lower their HBA1C (blood glucose average) by approx. 1 full point after attending the normal 20-day session. Beyond the purpose of better diabetes management, however, Camp Sweeney has the deeper and more extensive pourpose of building self-confidence and true friendships that last a lifetime. Camp Sweeney is a family, as many campers see it as much more than a simple summer camp program - It truly changes lives!
In addition to three summer sessions of 20 days each, Camp Sweeney also offers a one-week senior week, a five-day mini session, a family weekend in the spring, and a five-day Winter Session.
Camp Sweeney is the home of an FCC licensed non-commercial radio station, KPFC-FM. KPFC-FM transmits on the 91.9 FM frequency and its translator, K206CD, transmits on the 89.1 FM frequency.
# Camp Quotes
-"Where Friendship Begins and Never Ends."
"Man Camp Sweeney is the best place in the world you can't even put in to words
"It is the best camp ever and it is where I am with my ownkind,It is the place i truly consider home
"Camp Sweeney is the only place where dancing on tables and singing songs about chicken strips is considered ordinary, along with the only place where a day of the week is dedicated to the color purple. Its where you want to be yourself the most, because no matter how different you think you are, there will always be a place where you and your tie-dye shorts will fit in."
Wow, camp is everything in the world!! Carnivel Queen, Camper of the Week, and best of all, Code of Living. I've been blessed with these things! But I couldn't do it without the support of friends!
Sarah Henry- AKA, Tator Tot!! (2007)
From Broadcasting To Tumbling Camp Sweeney Has It All! But The Best Thing About Camp Sweeney Is The Support You Have From All Your Friends.
When you are at Camp Sweeney you are part of a family. It has a lott of coool stuff but I go 4 the friends Ive made.Camp Sweeney is truly my home.
"Camp has always been a place where I can just know everything (including my blood sugar) will be alright, it is my home and it will always have a special place in my heart, because if it wasn't for camp, I wouldn't be who I am today."
# Camp Song
"Im in love with you Camp Sweeney, for your deeds so true. Perseverance, faith, and courage, help our tests stay true. Forward, onward, never falter; watchword never fail. All our hopes and prayers forever, to our camp all hail! Happier times we've never known then our days spent here. Swims in lovely, blue Lake Dealy; classes we hold dear. Proteins, fats, and carbohydrates we can weigh with ease. Bravely we will face life's hurdles, HAIL to Camp Sweeney!"
The camp song is sung at many of the significant camp activities throughout each camping session, and is usually sung in a complete circle with each camper and staff member holding hands right over left. It is sung in reverence and in memory of past campers and staff that have passed though the program.
# Statistics
- Number of children that attend camp each year- over 1,000
- Number of campers served since 1950- over 20,000
- Record for most campers in 1 session-3rd session 2007,280 campers | Camp Sweeney
Camp Sweeney is an American summer camp located in Gainesville, Texas. It is primarily for children with type 1 diabetes and sometimes their siblings. It has been in operation since 1950.
Though it offers normal summer camp activities such as swimming, hiking, archery, basketball, volleyball, waterpark, broadcasting and arts and crafts, its many facilities are designed with the diabetic child in mind. Built-in blood glucose testing stations are scattered throughout the camp, and counselors carry monitors and insulin with them at all times. During meals, each camper has their food tray prepared with the right number of carbohydrates for their chosen diet. The campers also go to medical lecture several times a week so that they can learn how to better care for their diabetes as well as keep up with the latest developments in diabetes research.
The camp serves children ages 5 to 18 and divides them into age appropriate cabins. The campers get to choose which activities they participate in during the day. Counselors, college students who are often recruited from The University of Notre Dame and other colleges around the nation, help younger children learn to administer their own insulin shots or change their own insulin pumps sites.
The purpose of Camp Sweeney is to help children with diabetes learn healthy habits that they can continue after they have left camp, and to build lasting relationships with other children dealing with the same problems that come with having diabetes. Extensive reaserch sudies conducted by the camp's parent, the Southwestern Diabetic Foundation, show that children and young adults attending Camp Sweeney lower their HBA1C (blood glucose average) by approx. 1 full point after attending the normal 20-day session. Beyond the purpose of better diabetes management, however, Camp Sweeney has the deeper and more extensive pourpose of building self-confidence and true friendships that last a lifetime. Camp Sweeney is a family, as many campers see it as much more than a simple summer camp program - It truly changes lives!
In addition to three summer sessions of 20 days each, Camp Sweeney also offers a one-week senior week, a five-day mini session, a family weekend in the spring, and a five-day Winter Session.
Camp Sweeney is the home of an FCC licensed non-commercial radio station, KPFC-FM. KPFC-FM transmits on the 91.9 FM frequency and its translator, K206CD, transmits on the 89.1 FM frequency.
# Camp Quotes
-"Where Friendship Begins and Never Ends."
"Man Camp Sweeney is the best place in the world you can't even put in to words
"It is the best camp ever and it is where I am with my ownkind,It is the place i truly consider home
"Camp Sweeney is the only place where dancing on tables and singing songs about chicken strips is considered ordinary, along with the only place where a day of the week is dedicated to the color purple. Its where you want to be yourself the most, because no matter how different you think you are, there will always be a place where you and your tie-dye shorts will fit in."
Wow, camp is everything in the world!! Carnivel Queen, Camper of the Week, and best of all, Code of Living. I've been blessed with these things! But I couldn't do it without the support of friends!
Sarah Henry- AKA, Tator Tot!! (2007)
From Broadcasting To Tumbling Camp Sweeney Has It All! But The Best Thing About Camp Sweeney Is The Support You Have From All Your Friends.
When you are at Camp Sweeney you are part of a family. It has a lott of coool stuff but I go 4 the friends Ive made.Camp Sweeney is truly my home.
"Camp has always been a place where I can just know everything (including my blood sugar) will be alright, it is my home and it will always have a special place in my heart, because if it wasn't for camp, I wouldn't be who I am today."
# Camp Song
"Im in love with you Camp Sweeney, for your deeds so true. Perseverance, faith, and courage, help our tests stay true. Forward, onward, never falter; watchword never fail. All our hopes and prayers forever, to our camp all hail! Happier times we've never known then our days spent here. Swims in lovely, blue Lake Dealy; classes we hold dear. Proteins, fats, and carbohydrates we can weigh with ease. Bravely we will face life's hurdles, HAIL to Camp Sweeney!"
The camp song is sung at many of the significant camp activities throughout each camping session, and is usually sung in a complete circle with each camper and staff member holding hands right over left. It is sung in reverence and in memory of past campers and staff that have passed though the program.
# Statistics
- Number of children that attend camp each year- over 1,000
- Number of campers served since 1950- over 20,000
- Record for most campers in 1 session-3rd session 2007,280 campers
# External links
- Camp Sweeney
cs.campsweeney.org
Template:Geolinks-US-hoodscale
Template:TX Camp Facilities | https://www.wikidoc.org/index.php/Camp_Sweeney | |
5e27393ce9f5dfe359974d8fc754fe898d6563f9 | wikidoc | Camptothecin | Camptothecin
# Overview
Camptothecin is a plant secondary metabolite used as an anti-cancer drug that damages DNA, leading to the destruction of the cell.
It comes from Camptotheca acuminata, a deciduous tree found in southern China. Stem woods of Nothopodytes foetida (previously known as Mappia foetida) found in the western ghats of India are an even better source of camptothecin.(2) A close analogue, 9-methoxycamptothecin, is also present in the same source.
# Mechanism of action
Camptothecin affects the activity of the enzyme topoisomerase I, whose normal action is to cleave, unwind, and religate DNA.
When camptothecin binds to topoisomerase I, it will be able to cleave but not to religate DNA. Thereby, camptothecin causes single strand breaks in DNA.
# Related medications
Since Camptothecin manifested a severe life threatening adverse reaction in the form of cystitis (Inflammation of the urinary bladder and ureters) concerted efforts over years by many research institutions, academic as well as industrial, resulted in chemically related analogues with less toxicity and enhanced therapeutic potency.Topotecan (trade name Hycamtin) and irinotecan {trade name Camptosar, also known as CPT-11) are camptothecin derivatives marketed as anti-cancer drugs by GlaxoSmithKline and Pfizer, respectively.
Topotecan is indicated for small cell lung cancer after failure of first-line chemotherapy and metastatic carcinoma of the ovary following failure of initial or subsequent chemotherapy. Irinotecan is indicated for colorectal cancers and is usually taken with other drugs in chemotherapy. | Camptothecin
# Overview
Camptothecin is a plant secondary metabolite used as an anti-cancer drug that damages DNA, leading to the destruction of the cell.
It comes from Camptotheca acuminata, a deciduous tree found in southern China. Stem woods of Nothopodytes foetida (previously known as Mappia foetida) found in the western ghats of India are an even better source of camptothecin.(2)[citation needed] A close analogue, 9-methoxycamptothecin, is also present in the same source.
# Mechanism of action
Camptothecin affects the activity of the enzyme topoisomerase I, whose normal action is to cleave, unwind, and religate DNA. [1]
When camptothecin binds to topoisomerase I, it will be able to cleave but not to religate DNA. Thereby, camptothecin causes single strand breaks in DNA.
# Related medications
Since Camptothecin manifested a severe life threatening adverse reaction in the form of cystitis (Inflammation of the urinary bladder and ureters) concerted efforts over years by many research institutions, academic as well as industrial, resulted in chemically related analogues with less toxicity and enhanced therapeutic potency.Topotecan (trade name Hycamtin) and irinotecan {trade name Camptosar, also known as CPT-11) are camptothecin derivatives marketed as anti-cancer drugs by GlaxoSmithKline and Pfizer, respectively.
Topotecan is indicated for small cell lung cancer after failure of first-line chemotherapy and metastatic carcinoma of the ovary following failure of initial or subsequent chemotherapy. Irinotecan is indicated for colorectal cancers and is usually taken with other drugs in chemotherapy. | https://www.wikidoc.org/index.php/Camptothecin | |
7b462b1f15c91b337ed4f77d5c44e58f811cc739 | wikidoc | Canary grass | Canary grass
# Overview
Canary Grass is a plant, Phalaris canariensis, belonging to the family Poaceae. Originally a native of the Mediterranean region, it is now grown commercially in several parts of the world for birdseed, hence the name. This large, coarse grass has erect, hairless stems, usually from 2 to 6 feet (0.6- 1.8 metres) tall. The ligule is prominent and membranous, ¼ inch (0.6 cm) long and rounded at the apex. The gradually tapering leaf blades are 3½–10 inches (8.9–25.4 cm) long, ¼–¾ inch (0.6–1.9 cm) wide, flat, and often harsh on both surfaces. The compact panicles are erect or sometimes slightly spreading and range from 3–16 inches (7.6–40.6 cm) long with branches ½–1½ inches (1.2–3.8 cm) long. Single flowers occur in dense clusters in May to mid-June or August. Inflorescences are green or slightly purple at first, then become tan.
The seeds are shiny brown. The seed is used as bird food and is generally mixed with rapeseed and other seeds that cheapen it. It should be kept in a dry place and away from vermin. Industrially, a flour made from seed is employed in the manufacture of fine cotton goods and silk stuffs.
Reed canary grass (Phalaris arundinacea L.) is a perennial forage crop and a wild grass. Although heads of both crops are panicles, annual canary grass (Phalaris canariensis) heads resemble club wheat.
In the Canary Islands, Italy and North Africa, it is used as food.
In certain parts of Mexico, such as Valle de Bravo, it is prepared and sold by street food vendors as a much appreciated form of atole. | Canary grass
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Canary Grass is a plant, Phalaris canariensis, belonging to the family Poaceae. Originally a native of the Mediterranean region, it is now grown commercially in several parts of the world for birdseed, hence the name. This large, coarse grass has erect, hairless stems, usually from 2 to 6 feet (0.6- 1.8 metres) tall. The ligule is prominent and membranous, ¼ inch (0.6 cm) long and rounded at the apex. The gradually tapering leaf blades are 3½–10 inches (8.9–25.4 cm) long, ¼–¾ inch (0.6–1.9 cm) wide, flat, and often harsh on both surfaces. The compact panicles are erect or sometimes slightly spreading and range from 3–16 inches (7.6–40.6 cm) long with branches ½–1½ inches (1.2–3.8 cm) long. Single flowers occur in dense clusters in May to mid-June or August. Inflorescences are green or slightly purple at first, then become tan.
The seeds are shiny brown. The seed is used as bird food and is generally mixed with rapeseed and other seeds that cheapen it. It should be kept in a dry place and away from vermin. Industrially, a flour made from seed is employed in the manufacture of fine cotton goods and silk stuffs.
Reed canary grass (Phalaris arundinacea L.) is a perennial forage crop and a wild grass. Although heads of both crops are panicles, annual canary grass (Phalaris canariensis) heads resemble club wheat.
In the Canary Islands, Italy and North Africa, it is used as food.
In certain parts of Mexico, such as Valle de Bravo, it is prepared and sold by street food vendors as a much appreciated form of atole. | https://www.wikidoc.org/index.php/Canary_grass | |
8e5d2aa701e3fcda733e17e9e3a26ef882e80cd3 | wikidoc | Canine tooth | Canine tooth
# Overview
In mammalian oral anatomy, the canine teeth, also called cuspids, dogteeth, fangs, or (in the case of those of the upper jaw) eye teeth, are relatively long, pointed teeth. However, they can appear more flattened, causing them to resemble incisors and leading them to be called incisiform. They evolved and are used primarily for firmly holding food in order to tear it apart, and occasionally as weapons. They are often the largest teeth in a mammal's mouth. Most species that develop them normally have four per individual, two in the upper jaw and two in the lower, separated within each jaw by its incisors; humans and dogs are examples. In most animals, canines are the anterior-most teeth in the maxillary bone. It is a common fallacy to describe canine teeth as being the hallmark of a carnivorous diet - the teeth associated with carnivory are the carnassial teeth.
The four canines in humans are the two maxillary canines and the two mandibular canines.
# Details
There are four Canine Teeth: two in the upper (maxillary) and two in the lower (mandibular) arch. A canine is placed laterally to each lateral incisor. They are larger and stronger than the incisors, and their roots sink deeply into the bones, and cause well-marked prominences upon the surface.
The crown is large and conical, very convex on its labial surface, a little hollowed and uneven on its lingual surface, and tapering to a blunted point or cusp, which projects beyond the level of the other teeth. The root is single, but longer and thicker than that of the incisors, conical in form, compressed laterally, and marked by a slight groove on each side.
The upper canine teeth (popularly called eye teeth) are larger and longer than the lower, and usually present a distinct basal ridge. The name "eyeteeth" derives from a superstition that the roots of the canines are involved with the eyes in such a way that loss of the eyeteeth can cause blindness. The expression of giving one's eyeteeth for something refers to this superstition and to the importance of these teeth in the dentition.
The lower canine teeth (popularly called stomach teeth) are placed nearer the middle line than the upper, so that their summits correspond to the intervals between the upper canines and the lateral incisors.
# Additional images
- Mouth (oral cavity)
- Left maxilla. Outer surface.
- Base of skull. Inferior surface. | Canine tooth
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Infobox Anatomy
In mammalian oral anatomy, the canine teeth, also called cuspids, dogteeth, fangs, or (in the case of those of the upper jaw) eye teeth, are relatively long, pointed teeth. However, they can appear more flattened, causing them to resemble incisors and leading them to be called incisiform. They evolved and are used primarily for firmly holding food in order to tear it apart, and occasionally as weapons. They are often the largest teeth in a mammal's mouth. Most species that develop them normally have four per individual, two in the upper jaw and two in the lower, separated within each jaw by its incisors; humans and dogs are examples. In most animals, canines are the anterior-most teeth in the maxillary bone. It is a common fallacy to describe canine teeth as being the hallmark of a carnivorous diet - the teeth associated with carnivory are the carnassial teeth.
The four canines in humans are the two maxillary canines and the two mandibular canines.
# Details
There are four Canine Teeth: two in the upper (maxillary) and two in the lower (mandibular) arch. A canine is placed laterally to each lateral incisor. They are larger and stronger than the incisors, and their roots sink deeply into the bones, and cause well-marked prominences upon the surface.
The crown is large and conical, very convex on its labial surface, a little hollowed and uneven on its lingual surface, and tapering to a blunted point or cusp, which projects beyond the level of the other teeth. The root is single, but longer and thicker than that of the incisors, conical in form, compressed laterally, and marked by a slight groove on each side.
The upper canine teeth (popularly called eye teeth) are larger and longer than the lower, and usually present a distinct basal ridge. The name "eyeteeth" derives from a superstition that the roots of the canines are involved with the eyes in such a way that loss of the eyeteeth can cause blindness. The expression of giving one's eyeteeth for something refers to this superstition and to the importance of these teeth in the dentition.
The lower canine teeth (popularly called stomach teeth) are placed nearer the middle line than the upper, so that their summits correspond to the intervals between the upper canines and the lateral incisors.
# Additional images
- Mouth (oral cavity)
- Left maxilla. Outer surface.
- Base of skull. Inferior surface. | https://www.wikidoc.org/index.php/Canine | |
d916ab4887429221c172b2fb83e60e2cc607866f | wikidoc | Cannabinoids | Cannabinoids
# Overview
Cannabinoids are a group of terpenophenolic compounds present in Cannabis (Cannabis sativa L). The broader definition of cannabinoids refer to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors. The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and arylsulphonamides and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors.
The term cannabinoids also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. Currently, there are three general types of cannabinoids: herbal cannabinoids occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and synthetic cannabinoids are similar compounds produced in a laboratory.
# Cannabinoid receptors
Before the 1980's, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. There are currently two known types of cannabinoid receptors, termed CB1 and CB2.
- CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain stem that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
- CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.
# Natural cannabinoids
Natural cannabinoids, also called herbal cannabinoids and classical cannabinoids, are nearly insoluble in water but soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols they form more water-soluble phenolate salts under strongly alkaline conditions. All natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation; that is, catalyzed by heat, light, or alkaline conditions. Natural cannabinoids are only known to occur naturally in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odour of the cannabis plant.
There are today seventy known herbal cannabinoids. To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.
Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common ones are listed below:
- CBG Cannabigerol
- CBC Cannabichromene
- CBL Cannabicyclol
- CBV Cannabivarin
- THCV Tetrahydrocannabivarin
- CBDV Cannabidivarin
- CBCV Cannabichromevarin
- CBGV Cannabigerovarin
- CBGM Cannabigerol Monoethyl Ether
THC is the primary psychoactive component of the plant. Medically, it appears to ease moderate pain and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors. Its effects are perceived to be more cerebral.
CBD is not psychoactive, and appears to moderate the euphoric effects of THC. It may decrease the rate of THC clearance from the body, perhaps by interfering with the metabolism of THC in the liver. Medically, it appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor. It is perceived to have more effect on the body.
CBN is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive, and is perceived to be sedative or stupefying.
These compounds may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called delta-9-THC, while the minor form is called delta-8-THC. Under the alternate terpene numbering system, these same compounds are called delta-1-THC and delta-6-THC, respectively.
Most herbal cannabinoid compounds are 21 carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side chain attached to the aromatic ring. In THC, CBD, and CBN, this side chain is a pentyl (5 carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3 carbon) chain. Cannabinoids with the propyl side chain are named using the suffix "varin", and are designated, for example, THCV, CBDV, or CBNV. It appears that shorter chains increase the intensity and decrease the duration of the activity of the chemicals.
Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964. Due to molecular similarity and ease of synthetic conversion, it was originally believed that CBD was a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant. Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBG. Next, CBG is independently converted to either CBD or CBC by two separate synthase enzymes. CBC is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV.
Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant's cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains which are used as fiber (commonly called hemp), are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content, or for a specific chemical balance. Some strains of more than 20% THC have been created.
Quantitative analysis of a plant's cannabinoid profile is usually determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, although these are often only semi-quantitative or qualitative. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.
Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, although some is stored in fat. Delta-9-THC is metabolized to 11-hydroxy-delta-9-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body after several weeks.
Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Supercritical solvent extraction with carbon dioxide is an alternative technique. Although this process requires high pressures, there is minimal risk of fire or toxicity, solvent removal is simple and efficient, and extract quality can be well-controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. However, to produce high purity cannabinoids, chemical synthesis or semisynthesis is generally required.
# Endogenous cannabinoids
Endocannabinoids are naturally produced in the bodies of animals. After the first cannabinoid receptor was discovered in 1988, scientists began searching for natural compounds that activate these receptors.
In 1992, the first such compound was identified as arachidonoyl ethanolamide and named anandamide, a name derived from the Sanskrit word for bliss and amide. Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to both the central (CB1) and peripheral (CB2) cannabinoid receptors, and is found in nearly all tissues in a wide range of animals. It is about as potent as THC. Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamide, have similar pharmacology. All of these are members of a family of signalling lipids called N-acylethanolamides which also include the noncannabimimetic palmitoylethanolamide and oleoylethanolamide which have anti-inflammatory and orexigenic effects, respectively. Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors, and is more abundant and a full efficacy agonist, clearly more potent than anandamide, in mediating CB, receptor-dependent G-protein activity in native membranes. Many N-acylethanolamides have also been identified in plant seeds and in molluscs. In 2001 was reported a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. It binds to the CB1 cannabinoid receptor (Ki = 21.2 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB2 receptor.
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine, GABA or dopamine, endocannabinoids differ in numerous ways from them. Neurotransmitters are commonly small, water-soluble molecules that are contained within, and released from, tiny membrane-bound vesicles inside cells. Vesicles are often found in the tips, ‘terminals’, of long cellular branches called axons, and complex morphological and biochemical specializations mark the location from which vesicular release occurs. Endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.
Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids are described as ‘retrograde’ transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow. They are in effect released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid releasing cell depends on the nature of the conventional transmitter that is being controlled. When the release of the inhibitory transmitter, GABA, is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. Conversely, when release of the excitatory neurotransmitter, glutamate, is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.
Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.
Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.
Scientific American published an article in December of 2004, entitled "The Brain's Own Marijuana" discussing the endogenous cannabinoid system.
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence.
# Synthetic & Patented Cannabinoids
Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.
Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.
Medications containing natural, synthetic, or cannabinoids analogs:
- Dronabinol (Marinol), an analog of Δ9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic and analgesic.
- Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol which is Schedule III.
- Sativex, a cannabinoid extract oral spray containing both THC and CBD used for neuropathic pain and spasticity in Canada and Spain.
- Rimonabant (SR141716), a selective cannabinoid (CB1) receptor antagonist used as an anti-obesity drug under the proprietary name, Acomplia. It is also used for smoking cessation.
Other notable synthetic cannabinoids include:
- CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC
- HU-210, about 100 times as potent as THC.
- SR144528, a CB2 receptor antagonists
- WIN 55,212-2, a potent cannabinoid receptor agonist
- JWH-133, a potent selective CB2 receptor agonist.
- Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine.
# Miscellaneous
- delta-9-Tetrahydrocannabinol (Δ9-THC, THC) and delta-8-tetrahydrocannabinol (Δ8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The THCs produce the high associated with cannabis by binding to the CB1 cannabinoid receptors in the brain.
- Tetrahydrocannabivarin (THCV), prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC.
- Cannabidiol (CBD), non-psychoactive and not affecting psychoactivity of THC. CBD has anti-inflammatory effects. CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains.
- Cannabinol (CBN), a degradation product of THC, produces a depressant effect
- Cannabichromene (CBC), non-psychoactive and not affecting psychoactivity of THC, a precursor of CBD and THC
- Cannabigerol (CBG), non-psychoactive
- Cannabinoids are good substrates for cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus suplementing with CYP 2C9 inhibitors leads to extended intoxication.
# Table of natural cannabinoids | Cannabinoids
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cannabinoids are a group of terpenophenolic compounds present in Cannabis (Cannabis sativa L). The broader definition of cannabinoids refer to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors. The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and arylsulphonamides and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors.[1]
The term cannabinoids also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. Currently, there are three general types of cannabinoids: herbal cannabinoids occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and synthetic cannabinoids are similar compounds produced in a laboratory.
# Cannabinoid receptors
Before the 1980's, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors. The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate. These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles. There are currently two known types of cannabinoid receptors, termed CB1 and CB2.
- CB1 receptors are found primarily in the brain, specifically in the basal ganglia and in the limbic system, including the hippocampus. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain stem that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
- CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.
# Natural cannabinoids
Natural cannabinoids, also called herbal cannabinoids and classical cannabinoids, are nearly insoluble in water but soluble in lipids, alcohols, and other non-polar organic solvents. However, as phenols they form more water-soluble phenolate salts under strongly alkaline conditions. All natural cannabinoids are derived from their respective 2-carboxylic acids (2-COOH) by decarboxylation; that is, catalyzed by heat, light, or alkaline conditions. Natural cannabinoids are only known to occur naturally in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes. In addition to cannabinoids, the resin is rich in terpenes, which are largely responsible for the odour of the cannabis plant.
There are today seventy known herbal cannabinoids. To the right the main classes of natural cannabinoids are shown. All classes derive from cannabigerol-type compounds and differ mainly in the way this precursor is cyclized.
Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) are the most prevalent natural cannabinoids and have received the most study. Other common ones are listed below:
- CBG Cannabigerol
- CBC Cannabichromene
- CBL Cannabicyclol
- CBV Cannabivarin
- THCV Tetrahydrocannabivarin
- CBDV Cannabidivarin
- CBCV Cannabichromevarin
- CBGV Cannabigerovarin
- CBGM Cannabigerol Monoethyl Ether
THC is the primary psychoactive component of the plant. Medically, it appears to ease moderate pain and to be neuroprotective. THC has approximately equal affinity for the CB1 and CB2 receptors.[2] Its effects are perceived to be more cerebral.
CBD is not psychoactive, and appears to moderate the euphoric effects of THC. It may decrease the rate of THC clearance from the body, perhaps by interfering with the metabolism of THC in the liver. Medically, it appears to relieve convulsion, inflammation, anxiety, and nausea. CBD has a greater affinity for the CB2 receptor than for the CB1 receptor. It is perceived to have more effect on the body.
CBN is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive, and is perceived to be sedative or stupefying.
These compounds may be in different forms depending on the position of the double bond in the alicyclic carbon ring. There is potential for confusion because there are different numbering systems used to describe the position of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC is called delta-9-THC, while the minor form is called delta-8-THC. Under the alternate terpene numbering system, these same compounds are called delta-1-THC and delta-6-THC, respectively.
Most herbal cannabinoid compounds are 21 carbon compounds. However, some do not follow this rule, primarily because of variation in the length of the side chain attached to the aromatic ring. In THC, CBD, and CBN, this side chain is a pentyl (5 carbon) chain. In the most common homologue, the pentyl chain is replaced with a propyl (3 carbon) chain. Cannabinoids with the propyl side chain are named using the suffix "varin", and are designated, for example, THCV, CBDV, or CBNV. It appears that shorter chains increase the intensity and decrease the duration of the activity of the chemicals.
Cannabinoids were first discovered in the 1940s, when CBD and CBN were identified. The structure of THC was first determined in 1964. Due to molecular similarity and ease of synthetic conversion, it was originally believed that CBD was a natural precursor to THC. However, it is now known that CBD and THC are produced independently in the cannabis plant. Cannabinoid production starts when an enzyme causes geranyl pyrophosphate and olivetolic acid to combine and form CBG. Next, CBG is independently converted to either CBD or CBC by two separate synthase enzymes. CBC is then enzymatically cyclized to THC. For the propyl homologues (THCV, CBDV and CBNV), there is a similar pathway that is based on CBGV.
Cannabis plants can exhibit wide variation in the quantity and type of cannabinoids they produce. The mixture of cannabinoids produced by a plant is known as the plant's cannabinoid profile. Selective breeding has been used to control the genetics of plants and modify the cannabinoid profile. For example, strains which are used as fiber (commonly called hemp), are bred such that they are low in psychoactive chemicals like THC. Strains used in medicine are often bred for high CBD content, and strains used for recreational purposes are usually bred for high THC content, or for a specific chemical balance. Some strains of more than 20% THC have been created.
Quantitative analysis of a plant's cannabinoid profile is usually determined by gas chromatography (GC), or more reliably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, although these are often only semi-quantitative or qualitative. There have been systematic attempts to monitor the cannabinoid profile of cannabis over time, but their accuracy is impeded by the illegal status of the plant in many countries.
Cannabinoids can be administered by smoking, vaporizing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in the body, most cannabinoids are metabolized in the liver, although some is stored in fat. Delta-9-THC is metabolized to 11-hydroxy-delta-9-THC, which is then metabolized to 9-carboxy-THC. Some cannabis metabolites can be detected in the body after several weeks.
Cannabinoids can be separated from the plant by extraction with organic solvents. Hydrocarbons and alcohols are often used as solvents. However, these solvents are flammable and many are toxic. Supercritical solvent extraction with carbon dioxide is an alternative technique. Although this process requires high pressures, there is minimal risk of fire or toxicity, solvent removal is simple and efficient, and extract quality can be well-controlled. Once extracted, cannabinoid blends can be separated into individual components using wiped film vacuum distillation or other distillation techniques. However, to produce high purity cannabinoids, chemical synthesis or semisynthesis is generally required.
# Endogenous cannabinoids
Endocannabinoids are naturally produced in the bodies of animals. After the first cannabinoid receptor was discovered in 1988, scientists began searching for natural compounds that activate these receptors.
In 1992, the first such compound was identified as arachidonoyl ethanolamide and named anandamide, a name derived from the Sanskrit word for bliss and amide. Anandamide is derived from the essential fatty acid arachidonic acid. It has a pharmacology similar to THC, although its chemical structure is different. Anandamide binds to both the central (CB1) and peripheral (CB2) cannabinoid receptors, and is found in nearly all tissues in a wide range of animals. It is about as potent as THC. Two analogs of anandamide, 7,10,13,16-docosatetraenoylethanolamide and homo-γ-linolenoylethanolamide, have similar pharmacology. All of these are members of a family of signalling lipids called N-acylethanolamides which also include the noncannabimimetic palmitoylethanolamide and oleoylethanolamide which have anti-inflammatory and orexigenic effects, respectively. Another endocannabinoid, 2-arachidonoyl glycerol, binds to both the CB1 and CB2 receptors, and is more abundant and a full efficacy agonist, clearly more potent than anandamide, in mediating CB, receptor-dependent G-protein activity in native membranes.[3] Many N-acylethanolamides have also been identified in plant seeds[4] and in molluscs.[5] In 2001 was reported a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain.[6] It binds to the CB1 cannabinoid receptor (Ki = 21.2 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB2 receptor.
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine, GABA or dopamine, endocannabinoids differ in numerous ways from them. Neurotransmitters are commonly small, water-soluble molecules that are contained within, and released from, tiny membrane-bound vesicles inside cells. Vesicles are often found in the tips, ‘terminals’, of long cellular branches called axons, and complex morphological and biochemical specializations mark the location from which vesicular release occurs. Endocannabinoids are lipophilic molecules that are not very soluble in water. They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells. They are believed to be synthesized 'on-demand' rather than made and stored for later use. The mechanisms and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active research.
Conventional neurotransmitters are released from a ‘presynaptic’ cell and activate appropriate receptors on a ‘postsynaptic’ cell, where presynaptic and postsynaptic designate the sending and receiving sides of a synapse, respectively. Endocannabinoids are described as ‘retrograde’ transmitters because they most commonly travel ‘backwards’ against the usual synaptic transmitter flow. They are in effect released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid releasing cell depends on the nature of the conventional transmitter that is being controlled. When the release of the inhibitory transmitter, GABA, is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. Conversely, when release of the excitatory neurotransmitter, glutamate, is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell.
Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous medium surrounding the cells from which they are released, and therefore act locally on nearby target cells. Hence, although emanating diffusely from their source cells, they have much more restricted spheres of influence than do hormones, which can affect cells throughout the body.
Endocannabinoids constitute a versatile system for affecting neuronal network properties in the nervous system.
Scientific American published an article in December of 2004, entitled "The Brain's Own Marijuana" discussing the endogenous cannabinoid system. [7]
The current understanding recognizes the role that endocannabinoids play in almost every major life function in the human body. Cannabinoids act as a bioregulatory mechanism for most life processes, which reveals why medical cannabis has been cited as treatments for many diseases and ailments in anecdotal reports and scientific literature. Some of these ailments include: pain, arthritic conditions, migraine headaches, anxiety, epileptic seizures, insomnia, loss of appetite, GERD (chronic heartburn), nausea, glaucoma, AIDS wasting syndrome, depression, bipolar disorder (particularly depression-manic-normal), multiple sclerosis, menstrual cramps, Parkinson's, trigeminal neuralgia (tic douloureux), high blood pressure, irritable bowel syndrome, and bladder incontinence.
# Synthetic & Patented Cannabinoids
Historically, laboratory synthesis of cannabinoids were often based on the structure of herbal cannabinoids and a large number of analogs have been produced and tested, especially in a group led by Roger Adams as early as 1941 and later in a group led by Raphael Mechoulam. Newer compounds are no longer related to natural cannabinoids or are based on the structure of the endogenous cannabinoids.
Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modifications of cannabinoid molecules.
Medications containing natural, synthetic, or cannabinoids analogs:
- Dronabinol (Marinol), an analog of Δ9-tetrahydrocannabinol (THC), used as an appetite stimulant, anti-emetic and analgesic.
- Nabilone (Cesamet), a synthetic cannabinoid and an analog of Marinol. It is Schedule II unlike Marinol which is Schedule III.
- Sativex, a cannabinoid extract oral spray containing both THC and CBD used for neuropathic pain and spasticity in Canada and Spain.
- Rimonabant (SR141716), a selective cannabinoid (CB1) receptor antagonist used as an anti-obesity drug under the proprietary name, Acomplia. It is also used for smoking cessation.
Other notable synthetic cannabinoids include:
- CP-55940, produced in 1974, this synthetic cannabinoid receptor agonist is many times more potent than THC
- HU-210, about 100 times as potent as THC[8].
- SR144528, a CB2 receptor antagonists
- WIN 55,212-2, a potent cannabinoid receptor agonist
- JWH-133, a potent selective CB2 receptor agonist.
- Levonantradol (Nantrodolum), an anti-emetic and analgesic but not currently in use in medicine.
# Miscellaneous
- delta-9-Tetrahydrocannabinol (Δ9-THC, THC) and delta-8-tetrahydrocannabinol (Δ8-THC), mimic the action of anandamide, a neurotransmitter produced naturally in the body. The THCs produce the high associated with cannabis by binding to the CB1 cannabinoid receptors in the brain.
- Tetrahydrocannabivarin (THCV), prevalent in certain South African and Southeast Asian strains of Cannabis. It is an antagonist of THC at CB1 receptors and attenuates the psychoactive effects of THC.[9]
- Cannabidiol (CBD), non-psychoactive and not affecting psychoactivity of THC.[10] CBD has anti-inflammatory effects. CBD shares a precursor with THC and is the main cannabinoid in low-THC Cannabis strains.
- Cannabinol (CBN), a degradation product of THC, produces a depressant effect
- Cannabichromene (CBC), non-psychoactive and not affecting psychoactivity of THC,[10] a precursor of CBD and THC
- Cannabigerol (CBG), non-psychoactive
- Cannabinoids are good substrates for cytochrome P450 mixed-function oxidases, mainly CYP 2C9. Thus suplementing with CYP 2C9 inhibitors leads to extended intoxication.
# Table of natural cannabinoids
# External links
- [2] Homepage of the ICRS - the International Cannabinoid Research Society
- Cannabis Report (Ministry of Public Health of Belgium) - 2002 at trimbos.nl
- Senate Report on Cannabis (Canada) - 2002 at Parliament of Canada
- The Health and Psychological Effects of Cannabis Use (Australia - Monograph 44) - 2001 at Department of Health and Ageing (Australia)
- Marijuana and Medicine - Assessing the Science Base (Institute of Medicine) - 1999 at National Academies Press
- House of Lords Report - Cannabis (United Kingdom) - 1998 at Parliament of the United Kingdom
- Cannabis: A Health Perspective and Research Agenda - 1997 at World Health Organization
- Overview of the Endocannabinoid signalling System at endocannabinoid.net
- Chemical Ecology of Cannabis (J. Intl. Hemp Assn. - 1994) at hempfood.com
- What Every Doctor Should Know About Cannabinoids at California Cannabis Research Medical Group
- Therapeutic Potential in Spotlight at Cannabinoid Researchers' Meeting at California Cannabis Research Medical Group
- THC (tetrahydrocannabinol) accumulation in glands of Cannabis (Cannabaceae) at hempreport.com
- Inheritance of Chemical Phenotype in Cannabis Sativa (Genetics) at Genetics Society of America
- Medicinal marijuana laws, policies and news at cannabishq.com
- Compounds found in Cannabis sativa at Erowid
# Cited Sources
- ↑ Lambert DM, Fowler CJ (2005). "The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications". J. Med. Chem. 48 (16): 5059–87. doi:10.1021/jm058183t. PMID 16078824..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}
- ↑ Huffman JW (2000). "The search for selective ligands for the CB2 receptor". Curr. Pharm. Des. 6 (13): 1323–37. PMID 10903395.
- ↑ "British Journal of Pharmacology - Abstract of article: Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB1 receptor-dependent G-protein activation in rat cerebellar membranes". Retrieved 2007-06-24.
- ↑ "N-Acylethanolamines in Seeds. Quantification of Molecular Species and Their Degradation upon Imbibition -- Chapman et al. 120 (4): 1157 -- PLANT PHYSIOLOGY". Retrieved 2007-06-24.
- ↑ "ScienceDirect - Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism : Bioactive long chain N-acylethanolamines in five species of edible bivalve molluscs: Possible implications for mollusc physiology and sea food industry". Retrieved 2007-06-24.
- ↑ Hanus L, Abu-Lafi S, Fride E; et al. (2001). "2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor". Proc. Natl. Acad. Sci. U.S.A. 98 (7): 3662–5. doi:10.1073/pnas.061029898. PMID 11259648.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Nicoll RA, Alger BE (2004). "The brain's own marijuana". Sci. Am. 291 (6): 68–75. PMID 15597982.
- ↑ http://www.marijuana.org/mydna10-12-05.htm
- ↑ "British Journal of Pharmacology - Abstract of article: Evidence that the plant cannabinoid [Delta]9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist". Retrieved 2007-06-24.
- ↑ Jump up to: 10.0 10.1 "Behavioural Pharmacology - Abstract: Volume 16(5-6) September 2005 p 487-496 Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids". Retrieved 2007-06-24. | https://www.wikidoc.org/index.php/Cannabinoid | |
4c22c80453357c883ea6dd9177d3bf70b4dff378 | wikidoc | Capecitabine | Capecitabine
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# Black Box Warning
# Overview
Capecitabine is an antimetabolite that is FDA approved for the treatment of adjuvant colon cancer, metastatic colorectal cancer, metastatic breast cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine in the adjuvant treatment of Dukes’ C colon cancer.
- Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with capecitabine monotherapy. Use of capecitabine instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
- Capecitabine tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
- Capecitabine tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.
- Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
- The recommended dose of capecitabine is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period given as 3 week cycles (see Table 1).
- Adjuvant treatment in patients with Dukes’ C colon cancer is recommended for a total of 6 months i.e., capecitabine 1250 mg/m2 orally twice daily for 2 weeks followed by a 1 week rest period, given as 3 week cycles for a total of 8 cycles (24 weeks).
- In Combination With Docetaxel (Metastatic Breast Cancer)
- In combination with docetaxel, the recommended dose of capecitabine is 1250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, combined with docetaxel at 75 mg/m2 as a 1 hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the capecitabine tablets plus docetaxel combination. Table 1 displays the total daily dose of capecitabine by body surface area and the number of tablets to be taken at each dose.
- General
- Capecitabine dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of capecitabine should be modified as necessary to accommodate individual patient tolerance to treatment. Toxicity due to capecitabine tablet administration may be managed by symptomatic treatment, dose interruptions and adjustment of capecitabine dose. Once the dose has been reduced, it should not be increased at a later time. Doses of capecitabine omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
- The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with capecitabine tablets.
- Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
- Capecitabine dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.
- In Combination with Docetaxel (Metastatic Breast Cancer)
- Dose modifications of capecitabine tablets for toxicity should be made according to Table 2 above for capecitabine. At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.
- The dose reduction schedule for docetaxel when used in combination with capecitabine for the treatment of metastatic breast cancer is shown in Table 3.
- Renal Impairment
- No adjustment to the starting dose of capecitabine is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the capecitabine starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine monotherapy and capecitabine in combination use with docetaxel.
- Geriatrics
- Physicians should exercise caution in monitoring the effects of capecitabine tablets in the elderly. Insufficient data are available to provide a dosage recommendation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosing Information
- Oral capecitabine 1000 mg/m(2) twice daily days 1 to 14) repeated every 3 weeks.
- Dosing Information
- Oral capecitabine 2500 mg/m(2)/day given twice daily for 14 days.
### Non–Guideline-Supported Use
- Dosing Information
- Capecitabine 1000 mg/m(2) orally twice daily on days 1 to 14 of a 3-week cycle for a total of 8 cycles.
- Dosing Information
- Oral capecitabine 1000 mg/m(2) twice daily for 2 weeks (wk) of a 3-wk cycle.
- Dosing Information
- Capecitabine 1000 mg/m(2) orally twice daily for 14 days.
- Dosing Information
- Oral capecitabine 625 mg/m(2) twice daily.
- Dosing Information
- 1250 (mg/m(2) of oral capecitabine twice daily in 3-week cycles.
- Dosing Information
- Capecitabine 830 mg/m(2) orally twice daily for 3 weeks.
- Dosing Information
- Oral capecitabine 2500 mg/m(2)/day in 2 divided doses for 14 days on and 7 days off of a 21-day cycle.
- Dosing Information
- Capecitabine 1250 mg/m(2) twice daily for 14 days, followed by 1 week of rest every 3 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Capecitabine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Capecitabine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Capecitabine in pediatric patients.
# Contraindications
- Dihydropyrimidine Dehydrogenase (DPD) Deficiency
- Capecitabine is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
- Severe Renal Impairment
- Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min).
- Hypersensitivity
- Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.
# Warnings
### Precautions
- Diarrhea
- Capecitabine can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption and grade 4 diarrhea as an increase of ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of capecitabine should be decreased. Standard antidiarrheal treatments (e.g., loperamide) are recommended.
- Necrotizing enterocolitis (typhlitis) has been reported.
- Coagulopathy
- Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly.
- Cardiotoxicity
- The cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
- Dihydropyrimidine Dehydrogenase Deficiency
- Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.
- Renal Insufficiency
- Patients with moderate renal impairment at baseline require dose reduction. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2.
- Pregnancy
- Capecitabine may cause fetal harm when given to a pregnant woman. Capecitabine caused embryolethality and teratogenicity in mice and embryolethality in monkeys when administered during organogenesis. If this drug is used during pregnancy or if a patient becomes pregnant while receiving capecitabine, the patient should be apprised of the potential hazard to the fetus.
- Hand-and-Foot Syndrome
- Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient’s activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine should be decreased.
- Hyperbilirubinemia
- In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1 week rest period, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 15.2% (n = 133) of patients and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 3.9% (n = 34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n = 31) also had post-baseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n = 46) had post-baseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n = 20) and 71.7% (n = 33), had liver metastases at baseline. In addition, 57.5% (n = 96) and 35.3% (n = 59) of the 167 patients had elevations (grades 1 to 4) at both pre-baseline and post-baseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n = 13) and 3% (n = 5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.
- In the 596 patients treated with capecitabine as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with capecitabine. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.
- In 251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n = 17) and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 2% (n = 5).
- If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3 x ULN.
- Hematologic
- In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1 week rest period, 3.2%, 1.7% and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia and 9.6% had grade 3 or 4 anemia.
- Patients with baseline neutrophil counts of < 1.5 x 109/L and/or thrombocyte counts of < 100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine should be interrupted.
- Geriatric Patients
- Patients ≥ 80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, 62% of the 21 patients ≥ 80 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: diarrhea in six (28.6%), nausea in three (14.3%), hand-foot syndrome in three (14.3%) and vomiting in two (9.5%) patients. Among the ten patients 70 years of age and greater (no patients were > 80 years of age) treated with capecitabine in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.
- Among the 67 patients ≥ 60 years of age receiving capecitabine in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the < 60 years of age patient group.
- In 995 patients receiving capecitabine as adjuvant therapy for Dukes’ C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥ 65 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: hand-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in six (1.5%) and nausea in five (1.3%) patients. In patients ≥ 65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes’ C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for capecitabine compared to 5-FU/LV were 1.01 (95% C.I. 0.80 to 1.27) and 1.04 (95% C.I. 0.79 to 1.37), respectively.
- Hepatic Insufficiency
- Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known.
- Combination with Other Drugs
- Use of capecitabine in combination with irinotecan has not been adequately studied.
# Adverse Reactions
## Clinical Trials Experience
- Adjuvant Colon Cancer
- Table 4 shows the adverse reactions occurring in ≥ 5% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1 week rest period and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1 to 5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to capecitabine and 10 (1%) randomized to 5-FU/LV.
- Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥ 1% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment.
- Metastatic Colorectal Cancer
- Monotherapy
- Table 6 shows the adverse reactions occurring in ≥ 5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1 week rest period and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to capecitabine and 32 (5.4%) randomized to 5-FU/LV.
- Breast Cancer
- In Combination with Docetaxel
- The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1 hour intravenous infusion at a dose of 75 mg/m2 on the first day of each 3 week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1 hour intravenous infusion at a dose of 100 mg/m2 on the first day of each 3 week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.
- Monotherapy
- The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m2 administered twice daily for 2 weeks followed by a 1 week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.
- Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
- Capecitabine In Combination with Docetaxel (Metastatic Breast Cancer)
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Capecitabine in the drug label.
# Drug Interactions
- Anticoagulants
- Altered coagulation parameters and/or bleeding have been reported in patients taking Capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating Capecitabine therapy and, in a few cases, within 1 month after stopping Capecitabine. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.
- Phenytoin
- The level of phenytoin should be carefully monitored in patients taking Capecitabine and phenytoin dose may need to be reduced. Postmarketing reports indicate that some patients receiving Capecitabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.
- Leucovorin
- The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
- CYP2C9 substrates
- Other than warfarin, no formal drug-drug interaction studies between Capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when Capecitabine is coadministered with CYP2C9 substrates.
- Drug-Food Interaction
- Food was shown to reduce both the rate and extent of absorption of capecitabine. In all clinical trials, patients were instructed to administer Capecitabine within 30 minutes after a meal. It is recommended that Capecitabine be administered with food.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Capecitabine can cause fetal harm when administered to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose.
- There are no adequate and well controlled studies of Capecitabine in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Capecitabine, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with Capecitabine.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Capecitabine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Capecitabine during labor and delivery.
### Nursing Mothers
- Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from capecitabine, 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 effectiveness of Capecitabine in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to Capecitabine was similar.
- The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m2 to 850 mg/m2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.
- The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles.
- There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials.
- The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).
### Geriatic Use
Physicians should pay particular attention to monitoring the adverse effects of Capecitabine in the elderly.
### Gender
There is no FDA guidance on the use of Capecitabine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Capecitabine with respect to specific racial populations.
### Renal Impairment
- Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-FDUR, and FBAL than in those with normal renal function.
### Hepatic Impairment
- Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with Capecitabine. The effect of severe hepatic dysfunction on Capecitabine is not known.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Capecitabine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Capecitabine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Capecitabine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Capecitabine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression.
- Single doses of Capecitabine were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m2 basis).
### Management
- Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for Capecitabine overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low–molecular-weight metabolite of the parent compound.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Capecitabine in the drug label.
# Pharmacology
## Mechanism of Action
- Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.
## Structure
- Capecitabine (capecitabine) is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil.
- The chemical name for capecitabine is 5'-deoxy-5-fluoro-N--cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula:
- Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.
- Capecitabine is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in Capecitabine include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Capecitabine in the drug label.
## Pharmacokinetics
- Absorption
- Following oral administration of 1255 mg/m2 BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean Cmax and AUC0-∞ decreased by 60% and 35%, respectively. The Cmax and AUC0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours.
- The pharmacokinetics of Capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m2/day. Over this range, the pharmacokinetics of Capecitabine and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the Cmax and AUC of 5-FU was greater than 85%.
- Distribution
- Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding.
- Bioactivation and Metabolism
- Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of Capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.
- The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.
- In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.
- Excretion
- Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.
- Effect of Age, Gender, and Race on the Pharmacokinetics of Capecitabine
- A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered Capecitabine at 1250 mg/m2 twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL.
- Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).
- Effect of Hepatic Insufficiency
- Capecitabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m2 dose of Capecitabine. Both AUC0-∞ and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC0-∞ and Cmax of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when Capecitabine is administered. The effect of severe hepatic dysfunction on Capecitabine is not known.
- Effect of Renal Insufficiency
- Following oral administration of 1250 mg/m2 capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance 80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients.
- Effect of Capecitabine on the Pharmacokinetics of Warfarin
- In four patients with cancer, chronic administration of capecitabine (1250 mg/m2 bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91%.
- Effect of Antacids on the Pharmacokinetics of Capecitabine
- When Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after Capecitabine (1250 mg/m2, n=12 cancer patients), AUC and Cmax increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of Capecitabine.
- Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa
- A Phase 1 study evaluated the effect of Capecitabine on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of Capecitabine was conducted in 26 patients with solid tumors. Capecitabine was found to have no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Adequate studies investigating the carcinogenic potential of Capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.
- Impairment of Fertility
- In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m2/day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose
# Clinical Studies
- Adjuvant Colon Cancer
- A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes' C colon cancer (X-ACT) provided data concerning the use of Capecitabine for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving Capecitabine to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with Capecitabine 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m2 and 20 mg/m2 IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes' stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5×109/L, platelets ≥ 100×109/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.
- The baseline demographics for Capecitabine and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.
- All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m2 orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for Capecitabine included dose reductions, cycle delays and treatment interruptions (see Table 11).
- The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for Capecitabine compared to 5-FU/LV was 0.88 (95% C.I. 0.77 – 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, Capecitabine was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for Capecitabine compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 – 1.01). The 5-year overall survival rates were 71.4% for Capecitabine and 68.4% for 5-FU/LV (see Figure 2).
- Metastatic Colorectal Cancer
- General
- The recommended dose of Capecitabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m2/day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m2/day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m2/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to Capecitabine; however, toxicity was increased. Capecitabine, 1250 mg/m2 twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.
- Monotherapy
- Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of Capecitabine in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with Capecitabine at a dose of 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days).
- In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis.
- The baseline demographics for Capecitabine and 5-FU/LV patients are shown in Table 13.
- Capecitabine was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of Capecitabine and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that Capecitabine has a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by Capecitabine. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and Capecitabine, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs Capecitabine difference. These results do not exclude the possibility of true equivalence of Capecitabine to 5-FU/LV (see Table 14, Table 15, and Figure 3).
- Breast Cancer
- Capecitabine has been evaluated in clinical trials in combination with docetaxel (Taxotere®) and as monotherapy.
- In Combination With Docetaxel
- The dose of Capecitabine used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of Capecitabine (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 administered in 3-week cycles of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of Capecitabine administered in 3-week cycles. The approved dose of 100 mg/m2 of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.
- Capecitabine in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive Capecitabine 1250 mg/m2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.
- Capecitabine in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.
- Monotherapy
- The antitumor activity of Capecitabine as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. Capecitabine was administered at a dose of 1255 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen.
- Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.
- For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days.
# How Supplied
- 150 mg
- Color: Light peach
- Engraving: Capecitabine on one side and 150 on the other 150 mg tablets are packaged in bottles of 60 (NDC 0004-1100-20).
- 500 mg
- Color: Peach
- Engraving: Capecitabine on one side and 500 on the other 500 mg tablets are packaged in bottles of 120 (NDC 0004-1101-50).
- Storage and Handling
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY CLOSED.
- Care should be exercised in the handling of Capecitabine. Capecitabine tablets should not be cut or crushed. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of tablets. If powder from broken Capecitabine tablets contacts the skin, wash the skin immediately and thoroughly with soap and water. If Capecitabine contacts the mucous membranes, flush thoroughly with water.
- Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.1-4
## Storage
There is limited information regarding Capecitabine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients and patients' caregivers should be informed of the expected adverse effects of Capecitabine, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary. As described below, patients taking Capecitabine should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with Capecitabine treatment.
- Diarrhea
- Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking Capecitabine immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.
- Nausea
- Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking Capecitabine immediately. Initiation of symptomatic treatment is recommended.
- Vomiting
- Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking Capecitabine immediately. Initiation of symptomatic treatment is recommended.
- Hand-and-Foot Syndrome
- Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking Capecitabine immediately.
- Stomatitis
- Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking Capecitabine immediately. Initiation of symptomatic treatment is recommended.
- Fever and Neutropenia
- Patients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician.
- Patient Package Insert
- Read this leaflet before you start taking Capecitabine® and each time you refill your prescription in case the information has changed. This leaflet contains important information about Capecitabine. However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of Capecitabine. Your doctor should always be your first choice for discussing your medical condition and this medicine.
- What is Capecitabine?
- Capecitabine is a medicine you take by mouth (orally). Capecitabine is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor.
- Capecitabine is used to treat:
- cancer of the colon after surgery
- cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). You should know that in studies, other medicines showed improved survival when they were taken together with 5-FU and leucovorin. In studies, Capecitabine was no worse than 5-FU and leucovorin taken together but did not improve survival compared to these two medicines.
- breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (TAXOTERE ®)
- breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (TAXOL ®) and anthracycline-containing medicine such as Adriamycin™ and doxorubicin
- What is the most important information about Capecitabine?
- Capecitabine may increase the effect of other medicines used to thin your blood such as warfarin (COUMADIN®). It is very important that your doctor knows if you are taking a blood thinner such as warfarin because Capecitabine may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and Capecitabine, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.
- Who should not take Capecitabine?
- DO NOT TAKE Capecitabine IF YOU
are nursing a baby. Tell your doctor if you are nursing. Capecitabine may pass to the baby in your milk and harm the baby.
are allergic to 5-fluorouracil
are allergic to capecitabine or to any of the ingredients in Capecitabine
have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)
- are nursing a baby. Tell your doctor if you are nursing. Capecitabine may pass to the baby in your milk and harm the baby.
- are allergic to 5-fluorouracil
- are allergic to capecitabine or to any of the ingredients in Capecitabine
- have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)
- TELL YOUR DOCTOR IF YOU
- take a blood thinner such as warfarin (COUMADIN). This is very important because Capecitabine may increase the effect of the blood thinner. If you are taking blood thinners and Capecitabine, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.
- take phenytoin (DILANTIN®). Your doctor needs to test the levels of phenytoin in your blood more often or change your dose of phenytoin.
- are pregnant or think you may be pregnant. Capecitabine may harm your unborn child.
- have kidney problems. Your doctor may prescribe a different medicine or lower the Capecitabine dose.
- have liver problems. You may need to be checked for liver problems while you take Capecitabine.
- have heart problems because you could have more side effects related to your heart.
- take the vitamin folic acid. It may affect how Capecitabine works.
- How should I take Capecitabine?
- Take Capecitabine exactly as your doctor tells you to. Your doctor will prescribe a dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are light peach in color with 150 on one side. The 500 mg tablets are peach in color with 500 on one side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe Capecitabine Tablets with docetaxel (TAXOTERE) injection.
Capecitabine is taken in 2 daily doses, a morning dose and an evening dose
Take Capecitabine tablets within 30 minutes after the end of a meal (breakfast and dinner)
Swallow Capecitabine tablets whole with water
If you miss a dose of Capecitabine, do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.
Capecitabine is usually taken for 14 days followed by a 7-day rest period (no drug), for a 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.
If you take too much Capecitabine, contact your doctor or local poison control center or emergency room right away.
- Capecitabine is taken in 2 daily doses, a morning dose and an evening dose
- Take Capecitabine tablets within 30 minutes after the end of a meal (breakfast and dinner)
- Swallow Capecitabine tablets whole with water
- If you miss a dose of Capecitabine, do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.
- Capecitabine is usually taken for 14 days followed by a 7-day rest period (no drug), for a 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.
- If you take too much Capecitabine, contact your doctor or local poison control center or emergency room right away.
- What should I avoid while taking Capecitabine?
- Women should not become pregnant while taking Capecitabine. Capecitabine may harm your unborn child. Use effective birth control while taking Capecitabine. Tell your doctor if you become pregnant.
- Do not breast-feed. Capecitabine may pass through your milk and harm your baby.
- Men should use birth control while taking Capecitabine
- What are the most common side effects of Capecitabine?
- The most common side effects of Capecitabine are:
diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.
hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss
tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems
- diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.
- hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss
- tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems
- These side effects may differ when taking Capecitabine with docetaxel (TAXOTERE). Please consult your doctor for possible side effects that may be caused by taking Capecitabine with docetaxel (TAXOTERE).
- If you are concerned about these or any other side effects while taking Capecitabine, talk to your doctor.
- Stop taking Capecitabine immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust Capecitabine to a dose that is right for you or stop your Capecitabine treatment for a while. This should help to reduce the side effects and stop them from getting worse.
- Diarrhea: if you have an additional 4 bowel movements each day beyond what is normal or any diarrhea at night
Vomiting: if you vomit more than once in a 24-hour time period
Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual
Stomatitis: if you have pain, redness, swelling or sores in your mouth
Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity
Fever or Infection: if you have a temperature of 100.5°F or greater, or other signs of infection
- Diarrhea: if you have an additional 4 bowel movements each day beyond what is normal or any diarrhea at night
- Vomiting: if you vomit more than once in a 24-hour time period
- Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual
- Stomatitis: if you have pain, redness, swelling or sores in your mouth
- Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity
- Fever or Infection: if you have a temperature of 100.5°F or greater, or other signs of infection
- Your doctor may tell you to lower the dose or to stop Capecitabine treatment for a while. If caught early, most of these side effects usually improve after you stop taking Capecitabine. If they do not improve within 2 to 3 days, call your doctor again. After your side effects have improved, your doctor will tell you whether to start taking Capecitabine again and what dose to take. Adjusting the dose of Capecitabine to be right for each patient is an important part of treatment.
- How should I store and use Capecitabine?
- Never share Capecitabine with anyone
- Store Capecitabine at normal room temperature (about 65° to 85°F)
- Keep Capecitabine and all other medicines out of the reach of children
- If you take too much Capecitabine by mistake, contact your doctor or local poison control center or emergency room right away
- General advice about prescription medicines:
- Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Capecitabine for a condition for which it was not prescribed. Do not give Capecitabine to other people, even if they have the same symptoms you have. It may harm them.
- This leaflet summarizes the most important information about Capecitabine. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Capecitabine that is written for health professionals.
# Precautions with Alcohol
- Alcohol-Capecitabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- XELODA®
# Look-Alike Drug Names
- Capecitabine® — Xenical®
# Drug Shortage Status
# Price | Capecitabine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]; Sree Teja Yelamanchili, MBBS [3]
# 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
Capecitabine is an antimetabolite that is FDA approved for the treatment of adjuvant colon cancer, metastatic colorectal cancer, metastatic breast cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Capecitabine tablets are indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred. Capecitabine was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Physicians should consider results of combination chemotherapy trials, which have shown improvement in DFS and OS, when prescribing single-agent capecitabine in the adjuvant treatment of Dukes’ C colon cancer.
- Capecitabine tablets are indicated as first-line treatment of patients with metastatic colorectal carcinoma when treatment with fluoropyrimidine therapy alone is preferred. Combination chemotherapy has shown a survival benefit compared to 5-FU/LV alone. A survival benefit over 5-FU/LV has not been demonstrated with capecitabine monotherapy. Use of capecitabine instead of 5-FU/LV in combinations has not been adequately studied to assure safety or preservation of the survival advantage.
- Capecitabine tablets in combination with docetaxel are indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.
- Capecitabine tablets monotherapy is also indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated (e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents). Resistance is defined as progressive disease while on treatment, with or without an initial response or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.
- Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
- The recommended dose of capecitabine is 1250 mg/m2 administered orally twice daily (morning and evening; equivalent to 2500 mg/m2 total daily dose) for 2 weeks followed by a 1 week rest period given as 3 week cycles (see Table 1).
- Adjuvant treatment in patients with Dukes’ C colon cancer is recommended for a total of 6 months i.e., capecitabine 1250 mg/m2 orally twice daily for 2 weeks followed by a 1 week rest period, given as 3 week cycles for a total of 8 cycles (24 weeks).
- In Combination With Docetaxel (Metastatic Breast Cancer)
- In combination with docetaxel, the recommended dose of capecitabine is 1250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period, combined with docetaxel at 75 mg/m2 as a 1 hour intravenous infusion every 3 weeks. Pre-medication, according to the docetaxel labeling, should be started prior to docetaxel administration for patients receiving the capecitabine tablets plus docetaxel combination. Table 1 displays the total daily dose of capecitabine by body surface area and the number of tablets to be taken at each dose.
- General
- Capecitabine dosage may need to be individualized to optimize patient management. Patients should be carefully monitored for toxicity and doses of capecitabine should be modified as necessary to accommodate individual patient tolerance to treatment. Toxicity due to capecitabine tablet administration may be managed by symptomatic treatment, dose interruptions and adjustment of capecitabine dose. Once the dose has been reduced, it should not be increased at a later time. Doses of capecitabine omitted for toxicity are not replaced or restored; instead the patient should resume the planned treatment cycles.
- The dose of phenytoin and the dose of coumarin-derivative anticoagulants may need to be reduced when either drug is administered concomitantly with capecitabine tablets.
- Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
- Capecitabine dose modification scheme as described below (see Table 2) is recommended for the management of adverse reactions.
- In Combination with Docetaxel (Metastatic Breast Cancer)
- Dose modifications of capecitabine tablets for toxicity should be made according to Table 2 above for capecitabine. At the beginning of a treatment cycle, if a treatment delay is indicated for either capecitabine or docetaxel, then administration of both agents should be delayed until the requirements for restarting both drugs are met.
- The dose reduction schedule for docetaxel when used in combination with capecitabine for the treatment of metastatic breast cancer is shown in Table 3.
- Renal Impairment
- No adjustment to the starting dose of capecitabine is recommended in patients with mild renal impairment (creatinine clearance = 51 to 80 mL/min). In patients with moderate renal impairment (baseline creatinine clearance = 30 to 50 mL/min), a dose reduction to 75% of the capecitabine starting dose when used as monotherapy or in combination with docetaxel (from 1250 mg/m2 to 950 mg/m2 twice daily) is recommended. Subsequent dose adjustment is recommended as outlined in Table 2 and Table 3 (depending on the regimen) if a patient develops a grade 2 to 4 adverse event. The starting dose adjustment recommendations for patients with moderate renal impairment apply to both capecitabine monotherapy and capecitabine in combination use with docetaxel.
- Geriatrics
- Physicians should exercise caution in monitoring the effects of capecitabine tablets in the elderly. Insufficient data are available to provide a dosage recommendation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosing Information
- Oral capecitabine 1000 mg/m(2) twice daily days 1 to 14) repeated every 3 weeks.[1]
- Dosing Information
- Oral capecitabine 2500 mg/m(2)/day given twice daily for 14 days.[2]
### Non–Guideline-Supported Use
- Dosing Information
- Capecitabine 1000 mg/m(2) orally twice daily on days 1 to 14 of a 3-week cycle for a total of 8 cycles.[3]
- Dosing Information
- Oral capecitabine 1000 mg/m(2) twice daily for 2 weeks (wk) of a 3-wk cycle.[4]
- Dosing Information
- Capecitabine 1000 mg/m(2) orally twice daily for 14 days.[5]
- Dosing Information
- Oral capecitabine 625 mg/m(2) twice daily.[6]
- Dosing Information
- 1250 (mg/m(2) of oral capecitabine twice daily in 3-week cycles.
- Dosing Information
- Capecitabine 830 mg/m(2) orally twice daily for 3 weeks.[7]
- Dosing Information
- Oral capecitabine 2500 mg/m(2)/day in 2 divided doses for 14 days on and 7 days off of a 21-day cycle.[8]
- Dosing Information
- Capecitabine 1250 mg/m(2) twice daily for 14 days, followed by 1 week of rest every 3 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Capecitabine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Capecitabine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Capecitabine in pediatric patients.
# Contraindications
- Dihydropyrimidine Dehydrogenase (DPD) Deficiency
- Capecitabine is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
- Severe Renal Impairment
- Capecitabine is contraindicated in patients with severe renal impairment (creatinine clearance below 30 mL/min).
- Hypersensitivity
- Capecitabine is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components. Capecitabine is contraindicated in patients who have a known hypersensitivity to 5-fluorouracil.
# Warnings
### Precautions
- Diarrhea
- Capecitabine can induce diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, the median time to first occurrence of grade 2 to 4 diarrhea was 34 days (range from 1 to 369 days). The median duration of grade 3 to 4 diarrhea was 5 days. National Cancer Institute of Canada (NCIC) grade 2 diarrhea is defined as an increase of 4 to 6 stools/day or nocturnal stools, grade 3 diarrhea as an increase of 7 to 9 stools/day or incontinence and malabsorption and grade 4 diarrhea as an increase of ≥ 10 stools/day or grossly bloody diarrhea or the need for parenteral support. If grade 2, 3 or 4 diarrhea occurs, administration of capecitabine should be immediately interrupted until the diarrhea resolves or decreases in intensity to grade 1. Following a reoccurrence of grade 2 diarrhea or occurrence of any grade 3 or 4 diarrhea, subsequent doses of capecitabine should be decreased. Standard antidiarrheal treatments (e.g., loperamide) are recommended.
- Necrotizing enterocolitis (typhlitis) has been reported.
- Coagulopathy
- Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored closely with great frequency and the anticoagulant dose should be adjusted accordingly.
- Cardiotoxicity
- The cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
- Dihydropyrimidine Dehydrogenase Deficiency
- Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded.
- Renal Insufficiency
- Patients with moderate renal impairment at baseline require dose reduction. Patients with mild and moderate renal impairment at baseline should be carefully monitored for adverse reactions. Prompt interruption of therapy with subsequent dose adjustments is recommended if a patient develops a grade 2 to 4 adverse event as outlined in Table 2.
- Pregnancy
- Capecitabine may cause fetal harm when given to a pregnant woman. Capecitabine caused embryolethality and teratogenicity in mice and embryolethality in monkeys when administered during organogenesis. If this drug is used during pregnancy or if a patient becomes pregnant while receiving capecitabine, the patient should be apprised of the potential hazard to the fetus.
- Hand-and-Foot Syndrome
- Hand-and-foot syndrome (palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema) is a cutaneous toxicity. Median time to onset was 79 days (range from 11 to 360 days) with a severity range of grades 1 to 3 for patients receiving capecitabine monotherapy in the metastatic setting. Grade 1 is characterized by any of the following: numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of the hands and/or feet and/or discomfort which does not disrupt normal activities. Grade 2 hand-and-foot syndrome is defined as painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patient’s activities of daily living. Grade 3 hand-and-foot syndrome is defined as moist desquamation, ulceration, blistering or severe pain of the hands and/or feet and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living. If grade 2 or 3 hand-and-foot syndrome occurs, administration of capecitabine should be interrupted until the event resolves or decreases in intensity to grade 1. Following grade 3 hand-and-foot syndrome, subsequent doses of capecitabine should be decreased.
- Hyperbilirubinemia
- In 875 patients with either metastatic breast or colorectal cancer who received at least one dose of capecitabine 1250 mg/m2 twice daily as monotherapy for 2 weeks followed by a 1 week rest period, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 15.2% (n = 133) of patients and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 3.9% (n = 34) of patients. Of 566 patients who had hepatic metastases at baseline and 309 patients without hepatic metastases at baseline, grade 3 or 4 hyperbilirubinemia occurred in 22.8% and 12.3%, respectively. Of the 167 patients with grade 3 or 4 hyperbilirubinemia, 18.6% (n = 31) also had post-baseline elevations (grades 1 to 4, without elevations at baseline) in alkaline phosphatase and 27.5% (n = 46) had post-baseline elevations in transaminases at any time (not necessarily concurrent). The majority of these patients, 64.5% (n = 20) and 71.7% (n = 33), had liver metastases at baseline. In addition, 57.5% (n = 96) and 35.3% (n = 59) of the 167 patients had elevations (grades 1 to 4) at both pre-baseline and post-baseline in alkaline phosphatase or transaminases, respectively. Only 7.8% (n = 13) and 3% (n = 5) had grade 3 or 4 elevations in alkaline phosphatase or transaminases.
- In the 596 patients treated with capecitabine as first-line therapy for metastatic colorectal cancer, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the overall clinical trial safety database of capecitabine monotherapy. The median time to onset for grade 3 or 4 hyperbilirubinemia in the colorectal cancer population was 64 days and median total bilirubin increased from 8 μm/L at baseline to 13 μm/L during treatment with capecitabine. Of the 136 colorectal cancer patients with grade 3 or 4 hyperbilirubinemia, 49 patients had grade 3 or 4 hyperbilirubinemia as their last measured value, of which 46 had liver metastases at baseline.
- In 251 patients with metastatic breast cancer who received a combination of capecitabine and docetaxel, grade 3 (1.5 to 3 x ULN) hyperbilirubinemia occurred in 7% (n = 17) and grade 4 (> 3 x ULN) hyperbilirubinemia occurred in 2% (n = 5).
- If drug-related grade 3 to 4 elevations in bilirubin occur, administration of capecitabine should be immediately interrupted until the hyperbilirubinemia decreases to ≤ 3 x ULN.
- Hematologic
- In 875 patients with either metastatic breast or colorectal cancer who received a dose of 1250 mg/m2 administered twice daily as monotherapy for 2 weeks followed by a 1 week rest period, 3.2%, 1.7% and 2.4% of patients had grade 3 or 4 neutropenia, thrombocytopenia or decreases in hemoglobin, respectively. In 251 patients with metastatic breast cancer who received a dose of capecitabine in combination with docetaxel, 68% had grade 3 or 4 neutropenia, 2.8% had grade 3 or 4 thrombocytopenia and 9.6% had grade 3 or 4 anemia.
- Patients with baseline neutrophil counts of < 1.5 x 109/L and/or thrombocyte counts of < 100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments during a treatment cycle show grade 3 or 4 hematologic toxicity, treatment with capecitabine should be interrupted.
- Geriatric Patients
- Patients ≥ 80 years old may experience a greater incidence of grade 3 or 4 adverse reactions. In 875 patients with either metastatic breast or colorectal cancer who received capecitabine monotherapy, 62% of the 21 patients ≥ 80 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: diarrhea in six (28.6%), nausea in three (14.3%), hand-foot syndrome in three (14.3%) and vomiting in two (9.5%) patients. Among the ten patients 70 years of age and greater (no patients were > 80 years of age) treated with capecitabine in combination with docetaxel, 30% (3 out of 10) of patients experienced grade 3 or 4 diarrhea and stomatitis and 40% (4 out of 10) experienced grade 3 hand-and-foot syndrome.
- Among the 67 patients ≥ 60 years of age receiving capecitabine in combination with docetaxel, the incidence of grade 3 or 4 treatment-related adverse reactions, treatment-related serious adverse reactions, withdrawals due to adverse reactions, treatment discontinuations due to adverse reactions and treatment discontinuations within the first two treatment cycles was higher than in the < 60 years of age patient group.
- In 995 patients receiving capecitabine as adjuvant therapy for Dukes’ C colon cancer after resection of the primary tumor, 41% of the 398 patients ≥ 65 years of age treated with capecitabine experienced a treatment-related grade 3 or 4 adverse event: hand-foot syndrome in 75 (18.8%), diarrhea in 52 (13.1%), stomatitis in 12 (3%), neutropenia/granulocytopenia in 11 (2.8%), vomiting in six (1.5%) and nausea in five (1.3%) patients. In patients ≥ 65 years of age (all randomized population; capecitabine 188 patients, 5-FU/LV 208 patients) treated for Dukes’ C colon cancer after resection of the primary tumor, the hazard ratios for disease-free survival and overall survival for capecitabine compared to 5-FU/LV were 1.01 (95% C.I. 0.80 to 1.27) and 1.04 (95% C.I. 0.79 to 1.37), respectively.
- Hepatic Insufficiency
- Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored when capecitabine is administered. The effect of severe hepatic dysfunction on the disposition of capecitabine is not known.
- Combination with Other Drugs
- Use of capecitabine in combination with irinotecan has not been adequately studied.
# Adverse Reactions
## Clinical Trials Experience
- Adjuvant Colon Cancer
- Table 4 shows the adverse reactions occurring in ≥ 5% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1 week rest period and 974 patients were administered 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU on days 1 to 5 every 28 days). The median duration of treatment was 164 days for capecitabine-treated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to capecitabine and 10 (1%) randomized to 5-FU/LV.
- Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥ 1% of patients from one phase 3 trial in patients with Dukes’ C colon cancer who received at least one dose of study medication and had at least one safety assessment.
- Metastatic Colorectal Cancer
- Monotherapy
- Table 6 shows the adverse reactions occurring in ≥ 5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m2 twice a day of capecitabine administered for 2 weeks followed by a 1 week rest period and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to capecitabine and 32 (5.4%) randomized to 5-FU/LV.
- Breast Cancer
- In Combination with Docetaxel
- The following data are shown for the combination study with capecitabine and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the capecitabine and docetaxel combination arm the treatment was capecitabine administered orally 1250 mg/m2 twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1 hour intravenous infusion at a dose of 75 mg/m2 on the first day of each 3 week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1 hour intravenous infusion at a dose of 100 mg/m2 on the first day of each 3 week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.
- Monotherapy
- The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m2 administered twice daily for 2 weeks followed by a 1 week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.
- Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)
- Capecitabine In Combination with Docetaxel (Metastatic Breast Cancer)
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Capecitabine in the drug label.
# Drug Interactions
- Anticoagulants
- Altered coagulation parameters and/or bleeding have been reported in patients taking Capecitabine concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon. These events occurred within several days and up to several months after initiating Capecitabine therapy and, in a few cases, within 1 month after stopping Capecitabine. These events occurred in patients with and without liver metastases. In a drug interaction study with single-dose warfarin administration, there was a significant increase in the mean AUC of S-warfarin. The maximum observed INR value increased by 91%. This interaction is probably due to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.
- Phenytoin
- The level of phenytoin should be carefully monitored in patients taking Capecitabine and phenytoin dose may need to be reduced. Postmarketing reports indicate that some patients receiving Capecitabine and phenytoin had toxicity associated with elevated phenytoin levels. Formal drug-drug interaction studies with phenytoin have not been conducted, but the mechanism of interaction is presumed to be inhibition of the CYP2C9 isoenzyme by capecitabine and/or its metabolites.
- Leucovorin
- The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
- CYP2C9 substrates
- Other than warfarin, no formal drug-drug interaction studies between Capecitabine and other CYP2C9 substrates have been conducted. Care should be exercised when Capecitabine is coadministered with CYP2C9 substrates.
- Drug-Food Interaction
- Food was shown to reduce both the rate and extent of absorption of capecitabine. In all clinical trials, patients were instructed to administer Capecitabine within 30 minutes after a meal. It is recommended that Capecitabine be administered with food.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Capecitabine can cause fetal harm when administered to a pregnant woman. Capecitabine at doses of 198 mg/kg/day during organogenesis caused malformations and embryo death in mice. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.2 times the corresponding values in patients administered the recommended daily dose. Malformations in mice included cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail and dilation of cerebral ventricles. At doses of 90 mg/kg/day, capecitabine given to pregnant monkeys during organogenesis caused fetal death. This dose produced 5'-DFUR AUC values about 0.6 times the corresponding values in patients administered the recommended daily dose.
- There are no adequate and well controlled studies of Capecitabine in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving Capecitabine, the patient should be apprised of the potential hazard to the fetus. Women should be advised to avoid becoming pregnant while receiving treatment with Capecitabine.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Capecitabine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Capecitabine during labor and delivery.
### Nursing Mothers
- Lactating mice given a single oral dose of capecitabine excreted significant amounts of capecitabine metabolites into the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from capecitabine, 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 effectiveness of Capecitabine in pediatric patients have not been established. No clinical benefit was demonstrated in two single arm trials in pediatric patients with newly diagnosed brainstem gliomas and high grade gliomas. In both trials, pediatric patients received an investigational pediatric formulation of capecitabine concomitantly with and following completion of radiation therapy (total dose of 5580 cGy in 180 cGy fractions). The relative bioavailability of the investigational formulation to Capecitabine was similar.
- The first trial was conducted in 22 pediatric patients (median age 8 years, range 5-17 years) with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas and high grade gliomas. In the dose-finding portion of the trial, patients received capecitabine with concomitant radiation therapy at doses ranging from 500 mg/m2 to 850 mg/m2 every 12 hours for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles. The maximum tolerated dose (MTD) of capecitabine administered concomitantly with radiation therapy was 650 mg/m2 every 12 hours. The major dose limiting toxicities were palmar-plantar erythrodysesthesia and alanine aminotransferase (ALT) elevation.
- The second trial was conducted in 34 additional pediatric patients with newly diagnosed non-disseminated intrinsic diffuse brainstem gliomas (median age 7 years, range 3-16 years) and 10 pediatric patients who received the MTD of capecitabine in the dose-finding trial and met the eligibility criteria for this trial. All patients received 650 mg/m2 capecitabine every 12 hours with concomitant radiation therapy for up to 9 weeks. After a 2 week break, patients received 1250 mg/m2 capecitabine every 12 hours on Days 1-14 of a 21-day cycle for up to 3 cycles.
- There was no improvement in one-year progression-free survival rate and one-year overall survival rate in pediatric patients with newly diagnosed intrinsic brainstem gliomas who received capecitabine relative to a similar population of pediatric patients who participated in other clinical trials.
- The adverse reaction profile of capecitabine was consistent with the known adverse reaction profile in adults, with the exception of laboratory abnormalities which occurred more commonly in pediatric patients. The most frequently reported laboratory abnormalities (per-patient incidence ≥40%) were increased ALT (75%), lymphocytopenia (73%), leukopenia (73%), hypokalemia (68%), thrombocytopenia (57%), hypoalbuminemia (55%), neutropenia (50%), low hematocrit (50%), hypocalcemia (48%), hypophosphatemia (45%) and hyponatremia (45%).
### Geriatic Use
Physicians should pay particular attention to monitoring the adverse effects of Capecitabine in the elderly.
### Gender
There is no FDA guidance on the use of Capecitabine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Capecitabine with respect to specific racial populations.
### Renal Impairment
- Patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed higher exposure for capecitabine, 5-FDUR, and FBAL than in those with normal renal function.
### Hepatic Impairment
- Exercise caution when patients with mild to moderate hepatic dysfunction due to liver metastases are treated with Capecitabine. The effect of severe hepatic dysfunction on Capecitabine is not known.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Capecitabine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Capecitabine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Capecitabine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Capecitabine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The manifestations of acute overdose would include nausea, vomiting, diarrhea, gastrointestinal irritation and bleeding, and bone marrow depression.
- Single doses of Capecitabine were not lethal to mice, rats, and monkeys at doses up to 2000 mg/kg (2.4, 4.8, and 9.6 times the recommended human daily dose on a mg/m2 basis).
### Management
- Medical management of overdose should include customary supportive medical interventions aimed at correcting the presenting clinical manifestations. Although no clinical experience using dialysis as a treatment for Capecitabine overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5'-DFUR, a low–molecular-weight metabolite of the parent compound.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Capecitabine in the drug label.
# Pharmacology
## Mechanism of Action
- Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deoxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis.
## Structure
- Capecitabine (capecitabine) is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5'-deoxy-5-fluorouridine (5'-DFUR) which is converted to 5-fluorouracil.
- The chemical name for capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the following structural formula:
- Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg/mL at 20°C.
- Capecitabine is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in Capecitabine include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Capecitabine in the drug label.
## Pharmacokinetics
- Absorption
- Following oral administration of 1255 mg/m2 BID to cancer patients, capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of capecitabine with mean Cmax and AUC0-∞ decreased by 60% and 35%, respectively. The Cmax and AUC0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 hours.
- The pharmacokinetics of Capecitabine and its metabolites have been evaluated in about 200 cancer patients over a dosage range of 500 to 3500 mg/m2/day. Over this range, the pharmacokinetics of Capecitabine and its metabolite, 5'-DFCR were dose proportional and did not change over time. The increases in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The interpatient variability in the Cmax and AUC of 5-FU was greater than 85%.
- Distribution
- Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration-dependent. Capecitabine was primarily bound to human albumin (approximately 35%). Capecitabine has a low potential for pharmacokinetic interactions related to plasma protein binding.
- Bioactivation and Metabolism
- Capecitabine is extensively metabolized enzymatically to 5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme, thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug 5-FU. Many tissues throughout the body express thymidine phosphorylase. Some human carcinomas express this enzyme in higher concentrations than surrounding normal tissues. Following oral administration of Capecitabine 7 days before surgery in patients with colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been evaluated in breast cancer patients or compared to 5-FU infusion.
- The enzyme dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL) which is cleared in the urine.
- In vitro enzymatic studies with human liver microsomes indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and FBAL) did not inhibit the metabolism of test substrates by cytochrome P450 isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.
- Excretion
- Capecitabine and its metabolites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. The elimination half-life of both parent capecitabine and 5-FU was about 0.75 hour.
- Effect of Age, Gender, and Race on the Pharmacokinetics of Capecitabine
- A population analysis of pooled data from the two large controlled studies in patients with metastatic colorectal cancer (n=505) who were administered Capecitabine at 1250 mg/m2 twice a day indicated that gender (202 females and 303 males) and race (455 white/Caucasian patients, 22 black patients, and 28 patients of other race) have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC of FBAL.
- Following oral administration of 825 mg/m2 capecitabine twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and 24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian patients. The clinical significance of these differences is unknown. No significant differences occurred in the exposure to other metabolites (5'-DFCR, 5'-DFUR, and 5-FU).
- Effect of Hepatic Insufficiency
- Capecitabine has been evaluated in 13 patients with mild to moderate hepatic dysfunction due to liver metastases defined by a composite score including bilirubin, AST/ALT and alkaline phosphatase following a single 1255 mg/m2 dose of Capecitabine. Both AUC0-∞ and Cmax of capecitabine increased by 60% in patients with hepatic dysfunction compared to patients with normal hepatic function (n=14). The AUC0-∞ and Cmax of 5-FU were not affected. In patients with mild to moderate hepatic dysfunction due to liver metastases, caution should be exercised when Capecitabine is administered. The effect of severe hepatic dysfunction on Capecitabine is not known.
- Effect of Renal Insufficiency
- Following oral administration of 1250 mg/m2 capecitabine twice a day to cancer patients with varying degrees of renal impairment, patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine clearance <30 mL/min) renal impairment showed 85% and 258% higher systemic exposure to FBAL on day 1 compared to normal renal function patients (creatinine clearance >80 mL/min). Systemic exposure to 5'-DFUR was 42% and 71% greater in moderately and severely renal impaired patients, respectively, than in normal patients. Systemic exposure to capecitabine was about 25% greater in both moderately and severely renal impaired patients.
- Effect of Capecitabine on the Pharmacokinetics of Warfarin
- In four patients with cancer, chronic administration of capecitabine (1250 mg/m2 bid) with a single 20 mg dose of warfarin increased the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum observed mean INR value was increased by 91%.
- Effect of Antacids on the Pharmacokinetics of Capecitabine
- When Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing antacid, was administered immediately after Capecitabine (1250 mg/m2, n=12 cancer patients), AUC and Cmax increased by 16% and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for 5'-DFCR. No effect was observed on the other three major metabolites (5'-DFUR, 5-FU, FBAL) of Capecitabine.
- Effect of Capecitabine on the Pharmacokinetics of Docetaxel and Vice Versa
- A Phase 1 study evaluated the effect of Capecitabine on the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of Capecitabine was conducted in 26 patients with solid tumors. Capecitabine was found to have no effect on the pharmacokinetics of docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of capecitabine and the 5-FU precursor 5'-DFUR.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Adequate studies investigating the carcinogenic potential of Capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo.
- Impairment of Fertility
- In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2300 mg/m2/day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5'-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose
# Clinical Studies
- Adjuvant Colon Cancer
- A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes' C colon cancer (X-ACT) provided data concerning the use of Capecitabine for the adjuvant treatment of patients with colon cancer. The primary objective of the study was to compare disease-free survival (DFS) in patients receiving Capecitabine to those receiving IV 5-FU/LV alone. In this trial, 1987 patients were randomized either to treatment with Capecitabine 1250 mg/m2 orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m2 and 20 mg/m2 IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6 cycles (24 weeks). Patients in the study were required to be between 18 and 75 years of age with histologically-confirmed Dukes' stage C colon cancer with at least one positive lymph node and to have undergone (within 8 weeks prior to randomization) complete resection of the primary tumor without macroscopic or microscopic evidence of remaining tumor. Patients were also required to have no prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5×109/L, platelets ≥ 100×109/L, serum creatinine ≤ 1.5 ULN, total bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of randomization.
- The baseline demographics for Capecitabine and 5-FU/LV patients are shown in Table 10. The baseline characteristics were well-balanced between arms.
- All patients with normal renal function or mild renal impairment began treatment at the full starting dose of 1250 mg/m2 orally twice daily. The starting dose was reduced in patients with moderate renal impairment (calculated creatinine clearance 30 to 50 mL/min) at baseline. Subsequently, for all patients, doses were adjusted when needed according to toxicity. Dose management for Capecitabine included dose reductions, cycle delays and treatment interruptions (see Table 11).
- The median follow-up at the time of the analysis was 83 months (6.9 years). The hazard ratio for DFS for Capecitabine compared to 5-FU/LV was 0.88 (95% C.I. 0.77 – 1.01) (see Table 12 and Figure 1). Because the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, Capecitabine was non-inferior to 5-FU/LV. The choice of the non-inferiority margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV effect on DFS. The hazard ratio for Capecitabine compared to 5-FU/LV with respect to overall survival was 0.86 (95% C.I. 0.74 – 1.01). The 5-year overall survival rates were 71.4% for Capecitabine and 68.4% for 5-FU/LV (see Figure 2).
- Metastatic Colorectal Cancer
- General
- The recommended dose of Capecitabine was determined in an open-label, randomized clinical study, exploring the efficacy and safety of continuous therapy with capecitabine (1331 mg/m2/day in two divided doses, n=39), intermittent therapy with capecitabine (2510 mg/m2/day in two divided doses, n=34), and intermittent therapy with capecitabine in combination with oral leucovorin (LV) (capecitabine 1657 mg/m2/day in two divided doses, n=35; leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal carcinoma in the first-line metastatic setting. There was no apparent advantage in response rate to adding leucovorin to Capecitabine; however, toxicity was increased. Capecitabine, 1250 mg/m2 twice daily for 14 days followed by a 1-week rest, was selected for further clinical development based on the overall safety and efficacy profile of the three schedules studied.
- Monotherapy
- Data from two open-label, multicenter, randomized, controlled clinical trials involving 1207 patients support the use of Capecitabine in the first-line treatment of patients with metastatic colorectal carcinoma. The two clinical studies were identical in design and were conducted in 120 centers in different countries. Study 1 was conducted in the US, Canada, Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized to treatment with Capecitabine at a dose of 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles; 604 patients were randomized to treatment with 5-FU and leucovorin (20 mg/m2 leucovorin IV followed by 425 mg/m2 IV bolus 5-FU, on days 1 to 5, every 28 days).
- In both trials, overall survival, time to progression and response rate (complete plus partial responses) were assessed. Responses were defined by the World Health Organization criteria and submitted to a blinded independent review committee (IRC). Differences in assessments between the investigator and IRC were reconciled by the sponsor, blinded to treatment arm, according to a specified algorithm. Survival was assessed based on a non-inferiority analysis.
- The baseline demographics for Capecitabine and 5-FU/LV patients are shown in Table 13.
- Capecitabine was superior to 5-FU/LV for objective response rate in Study 1 and Study 2. The similarity of Capecitabine and 5-FU/LV in these studies was assessed by examining the potential difference between the two treatments. In order to assure that Capecitabine has a clinically meaningful survival effect, statistical analyses were performed to determine the percent of the survival effect of 5-FU/LV that was retained by Capecitabine. The estimate of the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized studies from the published literature comparing 5-FU to regimens of 5-FU/LV that were similar to the control arms used in these Studies 1 and 2. The method for comparing the treatments was to examine the worst case (95% confidence upper bound) for the difference between 5-FU/LV and Capecitabine, and to show that loss of more than 50% of the 5-FU/LV survival effect was ruled out. It was demonstrated that the percent of the survival effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1. The pooled result is consistent with a retention of at least 50% of the effect of 5-FU/LV. It should be noted that these values for preserved effect are based on the upper bound of the 5-FU/LV vs Capecitabine difference. These results do not exclude the possibility of true equivalence of Capecitabine to 5-FU/LV (see Table 14, Table 15, and Figure 3).
- Breast Cancer
- Capecitabine has been evaluated in clinical trials in combination with docetaxel (Taxotere®) and as monotherapy.
- In Combination With Docetaxel
- The dose of Capecitabine used in the phase 3 clinical trial in combination with docetaxel was based on the results of a phase 1 study, where a range of doses of docetaxel administered in 3-week cycles in combination with an intermittent regimen of Capecitabine (14 days of treatment, followed by a 7-day rest period) were evaluated. The combination dose regimen was selected based on the tolerability profile of the 75 mg/m2 administered in 3-week cycles of docetaxel in combination with 1250 mg/m2 twice daily for 14 days of Capecitabine administered in 3-week cycles. The approved dose of 100 mg/m2 of docetaxel administered in 3-week cycles was the control arm of the phase 3 study.
- Capecitabine in combination with docetaxel was assessed in an open-label, multicenter, randomized trial in 75 centers in Europe, North America, South America, Asia, and Australia. A total of 511 patients with metastatic breast cancer resistant to, or recurring during or after an anthracycline-containing therapy, or relapsing during or recurring within 2 years of completing an anthracycline-containing adjuvant therapy were enrolled. Two hundred and fifty-five (255) patients were randomized to receive Capecitabine 1250 mg/m2 twice daily for 14 days followed by 1 week without treatment and docetaxel 75 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. In the monotherapy arm, 256 patients received docetaxel 100 mg/m2 as a 1-hour intravenous infusion administered in 3-week cycles. Patient demographics are provided in Table 16.
- Capecitabine in combination with docetaxel resulted in statistically significant improvement in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 17, Figure 4, and Figure 5.
- Monotherapy
- The antitumor activity of Capecitabine as a monotherapy was evaluated in an open-label single-arm trial conducted in 24 centers in the US and Canada. A total of 162 patients with stage IV breast cancer were enrolled. The primary endpoint was tumor response rate in patients with measurable disease, with response defined as a ≥50% decrease in sum of the products of the perpendicular diameters of bidimensionally measurable disease for at least 1 month. Capecitabine was administered at a dose of 1255 mg/m2 twice daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles. The baseline demographics and clinical characteristics for all patients (n=162) and those with measurable disease (n=135) are shown in Table 18. Resistance was defined as progressive disease while on treatment, with or without an initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant chemotherapy regimen.
- Antitumor responses for patients with disease resistant to both paclitaxel and an anthracycline are shown in Table 19.
- For the subgroup of 43 patients who were doubly resistant, the median time to progression was 102 days and the median survival was 255 days. The objective response rate in this population was supported by a response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients with measurable disease, who were less resistant to chemotherapy (see Table 18). The median time to progression was 90 days and the median survival was 306 days.
# How Supplied
- 150 mg
- Color: Light peach
- Engraving: Capecitabine on one side and 150 on the other 150 mg tablets are packaged in bottles of 60 (NDC 0004-1100-20).
- 500 mg
- Color: Peach
- Engraving: Capecitabine on one side and 500 on the other 500 mg tablets are packaged in bottles of 120 (NDC 0004-1101-50).
- Storage and Handling
- Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY CLOSED.
- Care should be exercised in the handling of Capecitabine. Capecitabine tablets should not be cut or crushed. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of tablets. If powder from broken Capecitabine tablets contacts the skin, wash the skin immediately and thoroughly with soap and water. If Capecitabine contacts the mucous membranes, flush thoroughly with water.
- Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.1-4
## Storage
There is limited information regarding Capecitabine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients and patients' caregivers should be informed of the expected adverse effects of Capecitabine, particularly nausea, vomiting, diarrhea, and hand-and-foot syndrome, and should be made aware that patient-specific dose adaptations during therapy are expected and necessary. As described below, patients taking Capecitabine should be informed of the need to interrupt treatment immediately if moderate or severe toxicity occurs. Patients should be encouraged to recognize the common grade 2 toxicities associated with Capecitabine treatment.
- Diarrhea
- Patients experiencing grade 2 diarrhea (an increase of 4 to 6 stools/day or nocturnal stools) or greater should be instructed to stop taking Capecitabine immediately. Standard antidiarrheal treatments (eg, loperamide) are recommended.
- Nausea
- Patients experiencing grade 2 nausea (food intake significantly decreased but able to eat intermittently) or greater should be instructed to stop taking Capecitabine immediately. Initiation of symptomatic treatment is recommended.
- Vomiting
- Patients experiencing grade 2 vomiting (2 to 5 episodes in a 24-hour period) or greater should be instructed to stop taking Capecitabine immediately. Initiation of symptomatic treatment is recommended.
- Hand-and-Foot Syndrome
- Patients experiencing grade 2 hand-and-foot syndrome (painful erythema and swelling of the hands and/or feet and/or discomfort affecting the patients' activities of daily living) or greater should be instructed to stop taking Capecitabine immediately.
- Stomatitis
- Patients experiencing grade 2 stomatitis (painful erythema, edema or ulcers of the mouth or tongue, but able to eat) or greater should be instructed to stop taking Capecitabine immediately. Initiation of symptomatic treatment is recommended.
- Fever and Neutropenia
- Patients who develop a fever of 100.5°F or greater or other evidence of potential infection should be instructed to call their physician.
- Patient Package Insert
- Read this leaflet before you start taking Capecitabine® [zeh-LOE-duh] and each time you refill your prescription in case the information has changed. This leaflet contains important information about Capecitabine. However, this information does not take the place of talking with your doctor. This information cannot cover all possible risks and benefits of Capecitabine. Your doctor should always be your first choice for discussing your medical condition and this medicine.
- What is Capecitabine?
- Capecitabine is a medicine you take by mouth (orally). Capecitabine is changed in the body to 5-fluorouracil (5-FU). In some patients with colon, rectum or breast cancer, 5-FU stops cancer cells from growing and decreases the size of the tumor.
- Capecitabine is used to treat:
- cancer of the colon after surgery
- cancer of the colon or rectum (colorectal cancer) that has spread to other parts of the body (metastatic colorectal cancer). You should know that in studies, other medicines showed improved survival when they were taken together with 5-FU and leucovorin. In studies, Capecitabine was no worse than 5-FU and leucovorin taken together but did not improve survival compared to these two medicines.
- breast cancer that has spread to other parts of the body (metastatic breast cancer) together with another medicine called docetaxel (TAXOTERE ®)
- breast cancer that has spread to other parts of the body and has not improved after treatment with other medicines such as paclitaxel (TAXOL ®) and anthracycline-containing medicine such as Adriamycin™ and doxorubicin
- What is the most important information about Capecitabine?
- Capecitabine may increase the effect of other medicines used to thin your blood such as warfarin (COUMADIN®). It is very important that your doctor knows if you are taking a blood thinner such as warfarin because Capecitabine may increase the effect of this medicine and could lead to serious side effects. If you are taking blood thinners and Capecitabine, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.
- Who should not take Capecitabine?
- DO NOT TAKE Capecitabine IF YOU
are nursing a baby. Tell your doctor if you are nursing. Capecitabine may pass to the baby in your milk and harm the baby.
are allergic to 5-fluorouracil
are allergic to capecitabine or to any of the ingredients in Capecitabine
have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)
- are nursing a baby. Tell your doctor if you are nursing. Capecitabine may pass to the baby in your milk and harm the baby.
- are allergic to 5-fluorouracil
- are allergic to capecitabine or to any of the ingredients in Capecitabine
- have been told that you lack the enzyme DPD (dihydropyrimidine dehydrogenase)
- TELL YOUR DOCTOR IF YOU
- take a blood thinner such as warfarin (COUMADIN). This is very important because Capecitabine may increase the effect of the blood thinner. If you are taking blood thinners and Capecitabine, your doctor needs to check more often how fast your blood clots and change the dose of the blood thinner, if needed.
- take phenytoin (DILANTIN®). Your doctor needs to test the levels of phenytoin in your blood more often or change your dose of phenytoin.
- are pregnant or think you may be pregnant. Capecitabine may harm your unborn child.
- have kidney problems. Your doctor may prescribe a different medicine or lower the Capecitabine dose.
- have liver problems. You may need to be checked for liver problems while you take Capecitabine.
- have heart problems because you could have more side effects related to your heart.
- take the vitamin folic acid. It may affect how Capecitabine works.
- How should I take Capecitabine?
- Take Capecitabine exactly as your doctor tells you to. Your doctor will prescribe a dose and treatment plan that is right for you. Your doctor may want you to take both 150 mg and 500 mg tablets together for each dose. If so, you must be able to identify the tablets. Taking the wrong tablets could cause an overdose (too much medicine) or underdose (too little medicine). The 150 mg tablets are light peach in color with 150 on one side. The 500 mg tablets are peach in color with 500 on one side. Your doctor may change the amount of medicine you take during your treatment. Your doctor may prescribe Capecitabine Tablets with docetaxel (TAXOTERE) injection.
Capecitabine is taken in 2 daily doses, a morning dose and an evening dose
Take Capecitabine tablets within 30 minutes after the end of a meal (breakfast and dinner)
Swallow Capecitabine tablets whole with water
If you miss a dose of Capecitabine, do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.
Capecitabine is usually taken for 14 days followed by a 7-day rest period (no drug), for a 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.
If you take too much Capecitabine, contact your doctor or local poison control center or emergency room right away.
- Capecitabine is taken in 2 daily doses, a morning dose and an evening dose
- Take Capecitabine tablets within 30 minutes after the end of a meal (breakfast and dinner)
- Swallow Capecitabine tablets whole with water
- If you miss a dose of Capecitabine, do not take the missed dose at all and do not double the next dose. Instead, continue your regular dosing schedule and check with your doctor.
- Capecitabine is usually taken for 14 days followed by a 7-day rest period (no drug), for a 21-day cycle. Your doctor will tell you how many cycles of treatment you will need.
- If you take too much Capecitabine, contact your doctor or local poison control center or emergency room right away.
- What should I avoid while taking Capecitabine?
- Women should not become pregnant while taking Capecitabine. Capecitabine may harm your unborn child. Use effective birth control while taking Capecitabine. Tell your doctor if you become pregnant.
- Do not breast-feed. Capecitabine may pass through your milk and harm your baby.
- Men should use birth control while taking Capecitabine
- What are the most common side effects of Capecitabine?
- The most common side effects of Capecitabine are:
diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.
hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss
tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems
- diarrhea, nausea, vomiting, sores in the mouth and throat (stomatitis), stomach area pain (abdominal pain), upset stomach, constipation, loss of appetite, and too much water loss from the body (dehydration). These side effects are more common in patients age 80 and older.
- hand-and-foot syndrome (palms of the hands or soles of the feet tingle, become numb, painful, swollen or red), rash, dry, itchy or discolored skin, nail problems, and hair loss
- tiredness, weakness, dizziness, headache, fever, pain (including chest, back, joint, and muscle pain), trouble sleeping, and taste problems
- These side effects may differ when taking Capecitabine with docetaxel (TAXOTERE). Please consult your doctor for possible side effects that may be caused by taking Capecitabine with docetaxel (TAXOTERE).
- If you are concerned about these or any other side effects while taking Capecitabine, talk to your doctor.
- Stop taking Capecitabine immediately and contact your doctor right away if you have the side effects listed below, or other side effects that concern you. Your doctor can then adjust Capecitabine to a dose that is right for you or stop your Capecitabine treatment for a while. This should help to reduce the side effects and stop them from getting worse.
- Diarrhea: if you have an additional 4 bowel movements each day beyond what is normal or any diarrhea at night
Vomiting: if you vomit more than once in a 24-hour time period
Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual
Stomatitis: if you have pain, redness, swelling or sores in your mouth
Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity
Fever or Infection: if you have a temperature of 100.5°F or greater, or other signs of infection
- Diarrhea: if you have an additional 4 bowel movements each day beyond what is normal or any diarrhea at night
- Vomiting: if you vomit more than once in a 24-hour time period
- Nausea: if you lose your appetite, and the amount of food you eat each day is much less than usual
- Stomatitis: if you have pain, redness, swelling or sores in your mouth
- Hand-and-Foot Syndrome: if you have pain, swelling or redness of your hands or feet that prevents normal activity
- Fever or Infection: if you have a temperature of 100.5°F or greater, or other signs of infection
- Your doctor may tell you to lower the dose or to stop Capecitabine treatment for a while. If caught early, most of these side effects usually improve after you stop taking Capecitabine. If they do not improve within 2 to 3 days, call your doctor again. After your side effects have improved, your doctor will tell you whether to start taking Capecitabine again and what dose to take. Adjusting the dose of Capecitabine to be right for each patient is an important part of treatment.
- How should I store and use Capecitabine?
- Never share Capecitabine with anyone
- Store Capecitabine at normal room temperature (about 65° to 85°F)
- Keep Capecitabine and all other medicines out of the reach of children
- If you take too much Capecitabine by mistake, contact your doctor or local poison control center or emergency room right away
- General advice about prescription medicines:
- Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Capecitabine for a condition for which it was not prescribed. Do not give Capecitabine to other people, even if they have the same symptoms you have. It may harm them.
- This leaflet summarizes the most important information about Capecitabine. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Capecitabine that is written for health professionals.
# Precautions with Alcohol
- Alcohol-Capecitabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- XELODA®[9]
# Look-Alike Drug Names
- Capecitabine® — Xenical®[10]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Capecitabine | |
41af91bdd89a460c771b395681ad280cea153866 | wikidoc | Capromorelin | Capromorelin
Capromorelin is an investigational medication developed by the Pfizer drug company. It functions as a growth hormone secretagogue and ghrelin mimetic which causes the body to secrete human growth hormone in a way usually seen at puberty and in young adulthood. Initial studies have shown the drug to directly raise insulin growth factor 1 (IGF-1) levels.
The drug is being considered for its therapeutic value in aging adults because elderly people have much lower levels of growth hormone -- and less lean muscle mass, which can result in weakness and frailty.
Patients who got the drug gained an average of 3 pounds (1.4 kg) in lean muscle mass after six months, and also were better able to walk a straight line -- a test of balance, strength and coordination. Some of the improvements were evident a year later.
Capromorelin, however, has not been approved by the FDA, and is not expected to be so any time soon. This is because the FDA does not consider aging a disease, and so requires extraordinary evidence of benefit and non-toxicity to approve a drug for use as an anti-aging agent.
# Researchers
- Pfizer
- Merck
- University of Washington/VA Puget Sound Health Care System: Dr. George Merriam
- University of Poland: Dr. Agnieszka Baranowska-Bik | Capromorelin
Capromorelin is an investigational medication developed by the Pfizer drug company. It functions as a growth hormone secretagogue and ghrelin mimetic which causes the body to secrete human growth hormone in a way usually seen at puberty and in young adulthood. Initial studies have shown the drug to directly raise insulin growth factor 1 (IGF-1) levels.
The drug is being considered for its therapeutic value in aging adults because elderly people have much lower levels of growth hormone -- and less lean muscle mass, which can result in weakness and frailty.
Patients who got the drug gained an average of 3 pounds (1.4 kg) in lean muscle mass after six months, and also were better able to walk a straight line -- a test of balance, strength and coordination. Some of the improvements were evident a year later.
Capromorelin, however, has not been approved by the FDA, and is not expected to be so any time soon. This is because the FDA does not consider aging a disease, and so requires extraordinary evidence of benefit and non-toxicity to approve a drug for use as an anti-aging agent.
# Researchers
- Pfizer
- Merck
- University of Washington/VA Puget Sound Health Care System: Dr. George Merriam
- University of Poland: Dr. Agnieszka Baranowska-Bik
# External links
- Clinical Trials
- Capromorelin Information
Template:Pharma-stub | https://www.wikidoc.org/index.php/Capromorelin | |
a556f33396dddfedfcc0a26d1067c82c4a3fd990 | wikidoc | Pepper spray | Pepper spray
Pepper spray (also known as OC spray (from "Oleoresin Capsicum"), OC gas, capsicum spray, or oleoresin capsicum) is a lachrymatory agent (a chemical compound that irritates the eyes to cause tears, pain, and even temporary blindness) that is used in riot control, crowd control, and personal self-defense, including defense against dogs and bears. It is a less lethal agent that can be deadly in rare cases. The American Civil Liberties Union documented fourteen fatalities from the use of pepper spray as of 1995. The active ingredient in pepper spray is capsaicin, which is a chemical derived from the fruit of plants in the Capsicum genus, including chilis. Long-term effects of pepper spray have not been effectively researched.
Extraction of oleoresin capsicum from peppers involves finely ground capsicum, then the capsaicin is extracted in an organic solvent such as ethanol. The solvent is then evaporated, and the remaining resin is the oleoresin capsicum. An additive such as propylene glycol is used to suspend the OC in water, and pressurized to make it aerosol in pepper spray. The high performance liquid chromatography (HPLC) method is used to measure the amount of capsaicin within pepper sprays. Scoville Heat Units (SHU) are used to measure the hotness of pepper spray.
A synthetic analogue of capsaicin, pelargonic acid vanillylamide (desmethyldihydrocapsaicin), is used in another version of pepper spray known as PAVA spray which is used in England. Another synthetic counterpart of pepper spray, pelargonic acid morpholide, was developed and is widely used in Russia. Its effectiveness compared to natural pepper spray is unclear and it has caused some injuries.
Pepper spray typically comes in canisters, which are often small enough to be carried or concealed in a pocket or purse. Pepper spray can also be bought concealed in items such as rings. There are also pepper spray projectiles available, which can be fired from a paintball gun. Having been used for years against demonstrators , it is increasingly being used by police in routine interventions.
# Effects
Pepper spray is an inflammatory. It causes immediate closing of the eyes, difficulty breathing, runny nose, and coughing. The duration of its effects depend on the strength of the spray but the average full effect lasts around thirty to forty-five minutes, with diminished effects lasting for hours.
The Journal of Investigative Ophthalmology and Visual Science published a study that concluded that single exposure of the eye to OC is harmless, but repeated exposure can result in long-lasting changes in corneal sensitivity. They found no lasting decrease in visual acuity.
The European Parliament Scientific and Technological Options Assessment (STOA) published in 1998 “An Appraisal of Technologies of Political Control” with extensive information on pepper spray and tear gas. They write:
For those with asthma, taking other drugs, or subject to restraining techniques which restrict the breathing passages, there is a risk of death. The Los Angeles Times has reported at least 61 deaths associated with police use of pepper spray since 1990 in the USA, and the American Civil Liberties Union (ACLU) documented 27 deaths in custody of people sprayed with pepper spray in California alone, since 1993.
The US Army concluded in a 1993 Aberdeen Proving Ground study that pepper spray could cause "Mutagenic effects, carcinogenic effects, sensitization, cardiovascular and pulmonary toxicity, neurotoxicity, as well as possible human fatalities. There is a risk in using this product on a large and varied population". However, the pepper spray was widely approved in the US despite the reservations of the US military scientists after it passed FBI tests in 1991. As of 1999, it was in use by more than 2000 public safety agencies.
The head of the FBI's Less-Than lethal Weapons Program at the time of the 1991 study, Special Agent Thomas W. W. Ward, was fired by the FBI and was sentenced to 2 months in prison for receiving payments from a peppergas manufacturer while conducting and authoring the FBI study that eventually approved pepper spray for FBI use."Prosecutors said that from December 1989 through 1990, Ward received about $5,000 a month for a total of $57,500, from Luckey Police Products, a Fort Lauderdale, Florida-based company that was a major producer and supplier of pepper spray. The payments were paid through a Florida company owned by Ward's wife.
Like tasers, pepper spray has been associated with positional asphyxiation of individuals in police custody. There is much debate over the actual "cause" of death in these cases. There have been few controlled clinical studies of the human health effects of pepper spray marketed for police use, and those studies are contradictory. Some studies have found no harmful effects beyond the effects described above.
# Deactivation and first aid
Though there is no way of completely neutralizing pepper spray, its effect can be minimized or stopped. Capsaicin is not soluble in water, and even large volumes of water will not wash it off. Victims should be encouraged to blink vigorously in order to encourage tears, which will help flush the irritant from the eyes. The spray can be washed off the face using soap, shampoo, dish washing detergent, or other detergents. Any cooling like ice, cold water, cold surface, or a fan will provide some relief. Milk has been shown to provide some relief and is frequently recommended for treatment of natural capsaicin exposure (chile peppers, hot sauces, spices). To avoid rubbing the spray into the skin, thereby prolonging the burning sensation, and in order to not spread the compound to other parts of the body, victims should try to avoid touching affected areas. Application of oils, or oil containing creams can trap the capsaicin to the skin and result in more severe chemical burns and blistering.
North American street medics use a non-toxic eyedrop solution of 1:1 water and aluminum hydroxide (Maalox) which helps neutralize pepper spray and relieve symptoms.
Some "triple-action" pepper sprays also contain "tear gas" (CS gas), which can be neutralized with sodium metabisulfite (Campden tablets, used in homebrewing), though it, too, is not water soluble and could be washed off using the same procedure as for pepper spray, Some sprays also contain a UV "blanketing" dye (little can be done against this, but its effects are not nearly as dramatic).
# Legality
Pepper spray is banned for use in war by Article I.5 of the Chemical Weapons Convention which bans the use of all riot control agents in warfare whether lethal or non-lethal.
In Western Australia, it is legal for a person to carry pepper spray for lawful defense, if that person has, on reasonable grounds, a suspicion or belief that he or she will require the pepper spray to defend himself or herself. However, the person found carrying the pepper spray carries the burden of proving a "reasonable belief or suspicion" rather than the prosecution. In all other states and territories in Australia, pepper spray is considered illegal.
In Belgium it is classified as a prohibited weapon, and it is illegal for anyone other than police officers to carry a capsicum spray.
In Canada all products with a label containing the words pepper spray, mace, etc, or otherwise originally produced for use on humans are classified as a restricted weapon. Only Peace Officers, and individuals/corporations who have special government permits may legally carry or possess pepper spray. Any similar canister with the labels reading "dog spray" and/or "bear spray" may be legally carried by anyone. The legality of using spray intended for animal deterent on a person would be decided in court on a case-by-case basis.
In Denmark possession of pepper spray is illegal for private citizens, but a trial period is currently in effect, where police officers in most metropolitan areas carry pepper spray as part of their standard equipment. This trial period has been initiated following the shooting (and often killing) of a number of mentally ill citizens who have behaved violently or in a threatening manner, leaving the police force in want of a defensive, non-lethal weapon.
In the Dominican Republic, it is legal to own and purchase pepper spray at any age over the counter, CS spray is regulated and may be used only by military personnel on duty. Owning civilian grade pepper spray is endorsed by authorities as means of defense against stray dogs, also as a means of defense against human assailants as opposed to the use of a firearm.
In Finland it is classified as a device governed by the firearm act and possession of pepper spray requires a license. Licenses are issued for defensive purposes and to individuals working jobs where such a device is needed such as the private security sector.
Government organizations such as defense forces and police are exempt. Concentrations are also limited to 5% active ingredient in OC sprays and 2%/2% in combinations sprays such as CN/OC.
In Germany pepper sprays labelled for the purpose of defense against animals may be owned and carried by anyone (even minors). Such sprays are not legally considered as weapons §1 WaffG. Carrying it at (or on the way to and from) demonstrations may still be punished Sprays that are not labelled "animal-defense spray" or do not bear the test mark of the Materialprüfungsanstalt (MPA) (material testing institute) are classified as prohibited weapons. Justified use against humans as self-defense is allowed .
CS sprays bearing a test mark of the MPA may be owned and carried by anyone over the age of 14..
In Hong Kong. pepper spray is classified as "arms" under HK Laws. Chap 238 FIREARMS AND AMMUNITION ORDINANCE. Without a valid license from the Hong Kong Police Force, it is a crime and can result a fine of $100,000 and to imprisonment for 14 years.
In Israel, OC and CS spray cans may be purchased by any member of the public without restriction and carried in public. In the 1980s a firearms license was required for doing so, but since then these sprays have been deregulated.
In Italy OC it is considered a self-defense weapon and it is legal to own it when the active principle is less than 10%. Spray made with CS is illegal.
In Latvia pepper spray is classified as a self-defense weapon, and it is available to anyone over 16. Anyone over 18 can buy gas pistol loaded with pepper or tear gas cartridges for self defense.
In the Netherlands it is classified as a Class II weapon of the Weapons and Munition Act(or Wet Wapens en Munitie, in Dutch), putting it in the same class of regulation as fully automatic fire-arms, explosive devices and other war gasses such as organophosphate nerve gasses. It is a prohibited weapon except for police officers, who carry it as a less than lethal weapon, as an alternative for using their side-arm.
In New Zealand pepper spray is carried by police offers in place of a firearm.
In Norway real pepper spray is only used by the police. The publicly available defense spray often called pepper spray is actually based on isopropyl alcohol.
In Poland pepper spray is not classified as a weapon, so it is available to anyone over 18.
In Russia pepper spray is a fully legal self-defense weapon and can be bought without license by any person over the age of 18 (passport being required for purchase). Its effect on animals is advertised as additional feature, compared with tear gas sprays. Carrying it at demonstrations is prohibited by law.
In South Africa it is not a licensed product and is freely available as an over the counter security product. Generally carried and used by private security officers and armed reaction officers as well as police and members of the public. A pepper spray projectile is also available also without license. Anyone using pepper spray as anything but a defensive weapon can still be charged with a firearms offense.
In Sweden it is classified as an offensive weapon and possession of pepper spray requires a license. However, as of 2006, no such license has been issued.
In Spain approved pepper spray made with 5% CS is available to anyone over 18.
In South Korea Pepper spray containing OC is legal, however gas-gun types need a simple license to own. CS is only available for police and private security firms.
In the United Kingdom, "Any weapon of whatever description designed or adapted for the discharge of any noxious liquid, gas or other thing" is classed as a section 5 firearm (Firearms Act 1968). The same act covers other prohibited weapons such as automatic firearms and rocket launchers, all of which can only be possessed by permission of the Home Secretary. Although legal for police officers, recent debates have arisen whether such a weapon should be legal for civilians as means of defensive purposes only. At present a number of legal alternative dye sprays are sold in the UK which have the effect of temporarily blinding the attacker but do not constitute noxious substances and so do not contravene this act.
Laws on pepper spray in the United States of America differ between states.
- Massachusetts, Massachusetts residents may only purchase defense sprays from licensed Firearms Dealers in that state, and must hold a valid Firearms Identification Card (FIC).
- Wisconsin, Tear gas is not permissible. By regulation, OC products with a maximum OC concentration of 10% and weight range of oleoresin of capsicum and inert ingredients of 15-60 grams are authorized. This is 1/2 oz. and 2 oz. spray. Further, the product cannot be camouflaged, and must have a safety feature designed to prevent accidental discharge. The units may not have an effective range of over 20 feet and must have an effective range of six feet. In addition there are certain labeling and packaging requirements: must state cannot sell to anyone under 18 and the phone number of the manufacturer has to be on the label. The units must also be sold in sealed tamper-proof packages.
- Michigan, pepper spray is legal if it has less than 2% of the active ingredient, this decreases the length of the effects but not the SHU. Sprays containing a mixture of CN/CS are also banned, though tear gas containing only CS is legal. Agents meeting these criteria can be possessed by anyone over the age of 18.
- New York, pepper spray may be legally possessed by any person age 18 or over; however, it must be purchased in person (i.e. cannot be purchased by mail-order or internet sale) either at a pharmacy or from a licensed firearm retailer (NY Penal Law 265.20 14 (a)), and the seller must keep a record of purchases. The use of pepper spray to prevent a public official from performing his/her official duties is a class-E felony;
- In many (but not all) other states, pepper spray can be purchased at various stores and carried legally by anyone over 18. | Pepper spray
Template:Chemical warfare vert
Template:Pepper
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pepper spray (also known as OC spray (from "Oleoresin Capsicum"), OC gas, capsicum spray, or oleoresin capsicum) is a lachrymatory agent (a chemical compound that irritates the eyes to cause tears, pain, and even temporary blindness) that is used in riot control, crowd control, and personal self-defense, including defense against dogs and bears. It is a less lethal agent that can be deadly in rare cases. The American Civil Liberties Union documented fourteen fatalities from the use of pepper spray as of 1995.[1] The active ingredient in pepper spray is capsaicin, which is a chemical derived from the fruit of plants in the Capsicum genus, including chilis. Long-term effects of pepper spray have not been effectively researched.
Extraction of oleoresin capsicum from peppers involves finely ground capsicum, then the capsaicin is extracted in an organic solvent such as ethanol. The solvent is then evaporated, and the remaining resin is the oleoresin capsicum. An additive such as propylene glycol is used to suspend the OC in water, and pressurized to make it aerosol in pepper spray. The high performance liquid chromatography (HPLC) method is used to measure the amount of capsaicin within pepper sprays. Scoville Heat Units (SHU) are used to measure the hotness of pepper spray.
A synthetic analogue of capsaicin, pelargonic acid vanillylamide (desmethyldihydrocapsaicin), is used in another version of pepper spray known as PAVA spray which is used in England. Another synthetic counterpart of pepper spray, pelargonic acid morpholide, was developed and is widely used in Russia. Its effectiveness compared to natural pepper spray is unclear and it has caused some injuries.
Pepper spray typically comes in canisters, which are often small enough to be carried or concealed in a pocket or purse. Pepper spray can also be bought concealed in items such as rings. There are also pepper spray projectiles available, which can be fired from a paintball gun. Having been used for years against demonstrators [2], it is increasingly being used by police in routine interventions.[3]
# Effects
Pepper spray is an inflammatory. It causes immediate closing of the eyes, difficulty breathing, runny nose, and coughing. The duration of its effects depend on the strength of the spray but the average full effect lasts around thirty to forty-five minutes, with diminished effects lasting for hours.
The Journal of Investigative Ophthalmology and Visual Science published a study that concluded that single exposure of the eye to OC is harmless, but repeated exposure can result in long-lasting changes in corneal sensitivity. They found no lasting decrease in visual acuity.[4]
The European Parliament Scientific and Technological Options Assessment (STOA) published in 1998 “An Appraisal of Technologies of Political Control”[5] with extensive information on pepper spray and tear gas. They write:
For those with asthma, taking other drugs, or subject to restraining techniques which restrict the breathing passages, there is a risk of death. The Los Angeles Times has reported at least 61 deaths associated with police use of pepper spray since 1990 in the USA,[6] and the American Civil Liberties Union (ACLU) documented 27 deaths in custody of people sprayed with pepper spray in California alone, since 1993.[7][8]
The US Army concluded in a 1993 Aberdeen Proving Ground study that pepper spray could cause "Mutagenic effects, carcinogenic effects, sensitization, cardiovascular and pulmonary toxicity, neurotoxicity, as well as possible human fatalities. There is a risk in using this product on a large and varied population".[9] However, the pepper spray was widely approved in the US despite the reservations of the US military scientists after it passed FBI tests in 1991. As of 1999, it was in use by more than 2000 public safety agencies.[10]
The head of the FBI's Less-Than lethal Weapons Program at the time of the 1991 study, Special Agent Thomas W. W. Ward, was fired by the FBI and was sentenced to 2 months in prison for receiving payments from a peppergas manufacturer while conducting and authoring the FBI study that eventually approved pepper spray for FBI use."[8][11][12]Prosecutors said that from December 1989 through 1990, Ward received about $5,000 a month for a total of $57,500, from Luckey Police Products, a Fort Lauderdale, Florida-based company that was a major producer and supplier of pepper spray. The payments were paid through a Florida company owned by Ward's wife.[13]
Like tasers, pepper spray has been associated with positional asphyxiation of individuals in police custody. There is much debate over the actual "cause" of death in these cases. There have been few controlled clinical studies of the human health effects of pepper spray marketed for police use, and those studies are contradictory. Some studies have found no harmful effects beyond the effects described above. [14]
# Deactivation and first aid
Though there is no way of completely neutralizing pepper spray, its effect can be minimized or stopped. Capsaicin is not soluble in water, and even large volumes of water will not wash it off. Victims should be encouraged to blink vigorously in order to encourage tears, which will help flush the irritant from the eyes. The spray can be washed off the face using soap, shampoo, dish washing detergent, or other detergents. Any cooling like ice, cold water, cold surface, or a fan will provide some relief. Milk has been shown to provide some relief and is frequently recommended for treatment of natural capsaicin exposure (chile peppers, hot sauces, spices). To avoid rubbing the spray into the skin, thereby prolonging the burning sensation, and in order to not spread the compound to other parts of the body, victims should try to avoid touching affected areas. Application of oils, or oil containing creams can trap the capsaicin to the skin and result in more severe chemical burns and blistering.
North American street medics use a non-toxic eyedrop solution of 1:1 water and aluminum hydroxide (Maalox) which helps neutralize pepper spray and relieve symptoms.[citation needed]
Some "triple-action" pepper sprays also contain "tear gas" (CS gas), which can be neutralized with sodium metabisulfite (Campden tablets, used in homebrewing), though it, too, is not water soluble and could be washed off using the same procedure as for pepper spray, Some sprays also contain a UV "blanketing" dye (little can be done against this, but its effects are not nearly as dramatic).
# Legality
Pepper spray is banned for use in war by Article I.5 of the Chemical Weapons Convention which bans the use of all riot control agents in warfare whether lethal or non-lethal.
In Western Australia, it is legal for a person to carry pepper spray for lawful defense, if that person has, on reasonable grounds, a suspicion or belief that he or she will require the pepper spray to defend himself or herself. However, the person found carrying the pepper spray carries the burden of proving a "reasonable belief or suspicion" rather than the prosecution. In all other states and territories in Australia, pepper spray is considered illegal.[citation needed]
In Belgium it is classified as a prohibited weapon, and it is illegal for anyone other than police officers to carry a capsicum spray.[15]
In Canada all products with a label containing the words pepper spray, mace, etc, or otherwise originally produced for use on humans are classified as a restricted weapon[16]. Only Peace Officers, and individuals/corporations who have special government permits may legally carry or possess pepper spray. Any similar canister with the labels reading "dog spray" and/or "bear spray" may be legally carried by anyone. The legality of using spray intended for animal deterent on a person would be decided in court on a case-by-case basis.
In Denmark possession of pepper spray is illegal for private citizens, but a trial period is currently in effect, where police officers in most metropolitan areas carry pepper spray as part of their standard equipment. This trial period has been initiated following the shooting (and often killing) of a number of mentally ill citizens who have behaved violently or in a threatening manner, leaving the police force in want of a defensive, non-lethal weapon.[citation needed]
In the Dominican Republic, it is legal to own and purchase pepper spray at any age over the counter, CS spray is regulated and may be used only by military personnel on duty. Owning civilian grade pepper spray is endorsed by authorities as means of defense against stray dogs, also as a means of defense against human assailants as opposed to the use of a firearm.[citation needed]
In Finland it is classified as a device governed by the firearm act and possession of pepper spray requires a license. Licenses are issued for defensive purposes and to individuals working jobs where such a device is needed such as the private security sector.[17]
Government organizations such as defense forces and police are exempt. Concentrations are also limited to 5% active ingredient in OC sprays and 2%/2% in combinations sprays such as CN/OC.[citation needed]
In Germany pepper sprays labelled for the purpose of defense against animals may be owned and carried by anyone (even minors). Such sprays are not legally considered as weapons §1 WaffG. Carrying it at (or on the way to and from) demonstrations may still be punished [18] Sprays that are not labelled "animal-defense spray" or do not bear the test mark of the Materialprüfungsanstalt[2] (MPA) (material testing institute) are classified as prohibited weapons. Justified use against humans as self-defense is allowed [19].
CS sprays bearing a test mark of the MPA may be owned and carried by anyone over the age of 14.[20].
In Hong Kong. pepper spray is classified as "arms" under HK Laws. Chap 238 FIREARMS AND AMMUNITION ORDINANCE. Without a valid license from the Hong Kong Police Force, it is a crime and can result a fine of $100,000 and to imprisonment for 14 years.[21]
In Israel, OC and CS spray cans may be purchased by any member of the public without restriction and carried in public. In the 1980s a firearms license was required for doing so, but since then these sprays have been deregulated.[citation needed]
In Italy OC it is considered a self-defense weapon and it is legal to own it when the active principle is less than 10%. Spray made with CS is illegal.[citation needed]
In Latvia pepper spray is classified as a self-defense weapon, and it is available to anyone over 16. Anyone over 18 can buy gas pistol loaded with pepper or tear gas cartridges for self defense.[citation needed]
In the Netherlands it is classified as a Class II weapon of the Weapons and Munition Act(or Wet Wapens en Munitie, in Dutch), putting it in the same class of regulation as fully automatic fire-arms, explosive devices and other war gasses such as organophosphate nerve gasses. It is a prohibited weapon except for police officers, who carry it as a less than lethal weapon, as an alternative for using their side-arm.[citation needed]
In New Zealand pepper spray is carried by police offers in place of a firearm.[citation needed]
In Norway real pepper spray is only used by the police. The publicly available defense spray often called pepper spray is actually based on isopropyl alcohol.[citation needed]
In Poland pepper spray is not classified as a weapon, so it is available to anyone over 18.[citation needed]
In Russia pepper spray is a fully legal self-defense weapon and can be bought without license by any person over the age of 18 (passport being required for purchase). Its effect on animals is advertised as additional feature, compared with tear gas sprays. Carrying it at demonstrations is prohibited by law.[citation needed]
In South Africa it is not a licensed product and is freely available as an over the counter security product. Generally carried and used by private security officers and armed reaction officers as well as police and members of the public. A pepper spray projectile is also available also without license. Anyone using pepper spray as anything but a defensive weapon can still be charged with a firearms offense.[citation needed]
In Sweden it is classified as an offensive weapon and possession of pepper spray requires a license. However, as of 2006, no such license has been issued.[citation needed]
In Spain approved pepper spray made with 5% CS is available to anyone over 18.[citation needed]
In South Korea Pepper spray containing OC is legal, however gas-gun types need a simple license to own. CS is only available for police and private security firms.
In the United Kingdom, "Any weapon of whatever description designed or adapted for the discharge of any noxious liquid, gas or other thing" is classed as a section 5 firearm (Firearms Act 1968). The same act covers other prohibited weapons such as automatic firearms and rocket launchers, all of which can only be possessed by permission of the Home Secretary. Although legal for police officers, recent debates have arisen whether such a weapon should be legal for civilians as means of defensive purposes only. At present a number of legal alternative dye sprays are sold in the UK which have the effect of temporarily blinding the attacker but do not constitute noxious substances and so do not contravene this act.[22]
Laws on pepper spray in the United States of America differ between states.
- Massachusetts, Massachusetts residents may only purchase defense sprays from licensed Firearms Dealers in that state, and must hold a valid Firearms Identification Card (FIC). [23]
- Wisconsin, Tear gas is not permissible. By regulation, OC products with a maximum OC concentration of 10% and weight range of oleoresin of capsicum and inert ingredients of 15-60 grams are authorized. This is 1/2 oz. and 2 oz. spray. Further, the product cannot be camouflaged, and must have a safety feature designed to prevent accidental discharge. The units may not have an effective range of over 20 feet and must have an effective range of six feet. In addition there are certain labeling and packaging requirements: must state cannot sell to anyone under 18 and the phone number of the manufacturer has to be on the label. The units must also be sold in sealed tamper-proof packages.[24]
- Michigan, pepper spray is legal if it has less than 2% of the active ingredient, this decreases the length of the effects but not the SHU. Sprays containing a mixture of CN/CS are also banned, though tear gas containing only CS is legal.[25] Agents meeting these criteria can be possessed by anyone over the age of 18.
- New York, pepper spray may be legally possessed by any person age 18 or over; however, it must be purchased in person (i.e. cannot be purchased by mail-order or internet sale) either at a pharmacy or from a licensed firearm retailer (NY Penal Law 265.20 14 (a)), and the seller must keep a record of purchases. The use of pepper spray to prevent a public official from performing his/her official duties is a class-E felony;
- In many (but not all) other states, pepper spray can be purchased at various stores and carried legally by anyone over 18. | https://www.wikidoc.org/index.php/Capsicum_Oleoresin | |
5933f72e3556bc7d92f759dd61b1aef97777f75f | wikidoc | Fusion beats | Fusion beats
Synonyms and keywords: Capture beats; fusion complexes; fusion QRS complexes
# Overview
A fusion beat occurs when electrical impulses from different sources act upon the same region of the heart at the same time. If it acts upon the ventricular chambers, it is called a ventricular fusion beat, wheres colliding currents in the atrial chambers produce atrial fusion beats.
# Pathophysiology
Ventricular fusion beats can occur when the heart's natural rhythm and the impulse from a pacemaker coincide to activate the same part of a ventricle at the same time, causing visible variation in configuration and height of the QRS complex of an electrocardiogram reading of the heart's activity. This contrasts with the pseudofusion beat wherein the pacemaker impulse does not affect the complex of the natural beat of the heart. Pseudofusion beats are normal. Rare or isolated fusion beats caused by pacemakers are normal as well, but if they occur too frequently may reduce cardiac output and so can require adjustment of the pacemaker.
In some cases of VT with AV dissociation the SA node may transiently "capture" the ventricles, producing a capture beat, which has a normal QRS duration, or a fusion beat, in which the sinus and ventricular beats coincide to produce a hybrid complex.
# Electrocardiogram
In the example below, "late" (end-diastolic) PVCs are illustrated with varying degrees of fusion with normal conduction. For a fusion beat to occur the sinus P wave must successfully make its way to the ventricles to start the activation sequence, but before ventricular activation is completed by the late PCV. The resulting QRS complex resembles both the normal QRS, as well as the PVC and hence the term fusion QRS or fusion beat. The fusion beats are marked by an F in the illustration below: | Fusion beats
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Capture beats; fusion complexes; fusion QRS complexes
# Overview
A fusion beat occurs when electrical impulses from different sources act upon the same region of the heart at the same time.[1] If it acts upon the ventricular chambers, it is called a ventricular fusion beat, wheres colliding currents in the atrial chambers produce atrial fusion beats.
# Pathophysiology
Ventricular fusion beats can occur when the heart's natural rhythm and the impulse from a pacemaker coincide to activate the same part of a ventricle at the same time, causing visible variation in configuration and height of the QRS complex of an electrocardiogram reading of the heart's activity.[2] This contrasts with the pseudofusion beat wherein the pacemaker impulse does not affect the complex of the natural beat of the heart. Pseudofusion beats are normal. Rare or isolated fusion beats caused by pacemakers are normal as well, but if they occur too frequently may reduce cardiac output and so can require adjustment of the pacemaker.[3]
In some cases of VT with AV dissociation the SA node may transiently "capture" the ventricles, producing a capture beat, which has a normal QRS duration, or a fusion beat, in which the sinus and ventricular beats coincide to produce a hybrid complex. [4][5]
# Electrocardiogram
In the example below, "late" (end-diastolic) PVCs are illustrated with varying degrees of fusion with normal conduction. For a fusion beat to occur the sinus P wave must successfully make its way to the ventricles to start the activation sequence, but before ventricular activation is completed by the late PCV. The resulting QRS complex resembles both the normal QRS, as well as the PVC and hence the term fusion QRS or fusion beat. The fusion beats are marked by an F in the illustration below: | https://www.wikidoc.org/index.php/Capture_beat | |
2501db25d494e04486a4f14fe28500d85bad086d | wikidoc | Carat (mass) | Carat (mass)
The carat is a unit of mass used for measuring gems and pearls. Currently a carat is defined as exactly 200 mg (0.007,055 oz, 3.086 grains). This definition, known as the metric carat, was adopted in 1907 at the Fourth General Conference on Weights and Measures, and soon afterwards in many countries around the world. It is universally used today. The carat is divisible into one hundred points of two milligrams each.
For diamonds, a paragon is a flawless stone of at least 100 carats (20 g). The ANSI X.12 EDI standard abbreviation for the carat is CD.
The word came to English from French, derived from the Greek kerátion (κεράτιον), “fruit of the carob”, via Arabic qīrāṭ (قيراط) and Italian carato. The Latin word for carat is siliqua. In past centuries, different countries each had their own carat unit, all roughly equivalent to the mass of a carob seed. These units were often used for weighing gold.
Carob seeds were used as weights on precision scales because of their reputation for having a uniform weight. However, a 2006 study found carob seeds to have as much variation in their weights as do other seeds, though it seems that it is easier than with other seeds to recognize particularly large or small specimens and remove them. Thus, the carob seed was used as a weight not because it was naturally more uniform in weight, but because it could be more easily standardized.
# Historical definitions in the United Kingdom
## Board of Trade carat
In the United Kingdom, before 1888, the Board of Trade carat was exactly 3\,\tfrac{1647}{9691} grains; after 1887, the Board of Trade carat was exactly 3\,\tfrac{17}{101} grains. Despite it being a non-metric unit, a number of metric countries used this unit for its limited range of application.
The Board of Trade carat was divisible into four diamond grains, but measurements were typically made in multiples of \tfrac{1}{64} carat.
## Pound carat and ounce carat
There were also two varieties of refiners’ carats once used in the United Kingdom — the pound carat and the ounce carat. The pound troy was divisible into 24 pound carats of 240 grains troy each; the pound carat was divisible into four pound grains of 60 grains troy each; and the pound grain was divisible into four pound quarters of 15 grains troy each. Similarly, the ounce troy was divisible into 24 ounce carats of 20 grains troy each; the ounce carat was divisible into four ounce grains of 5 grains troy each; and the ounce grain was divisible into four ounce quarters of 1¼ grains troy each.
# The carat of the Romans and Greeks
The solidus (carat) was also a Roman weight unit. There is literary evidence that the weight of 72 coins of the type called solidus was exactly a Roman pound, and that the weight of a solidus was 24 siliquae. The weight of a Roman pound is generally believed to have been 327.45 g or possibly up to 5 g grams less. Therefore the metric equivalent of 1 solidus was approximately 189 mg. The Greeks had a similar unit of the same value.
# The carat in Byzantine Egypt
A carob based weight unit was also used in Egypt in the Byzantine and early Arab periods. In this region, glass weights were used for weighing coins. From these the weight of the Egypt carat has been reconstructed as 196 mg. This is consistent with the average weights of carob seeds in the region.
# The Syrian and Arabic carat in Mohammad's time
According to literary sources, the Arabic carat was only 2% less than the Syrian carat. Based on coins and glass weights their weight was reconstructed as approximately 212 mg. This is consistent with literary information that a solidus weighed slightly less than 22 carats.
# Notes
- ↑ The United States adopted the metric carat definition on July 1, 1913, the United Kingdom on 1 April 1914.
- ↑ The literal translation of κεράτιον is little horn, which describes the seed pod.
- ↑ Turnbull, Lindsay, et al. “Seed size variability: from carob to carats”
- ↑ “Did carob seeds allow shady diamond deals?”, New Scientist, page 20, 6 May 2006.
- ↑ The pre-1888 Board of Trade carat, of which there were exactly 151\,\tfrac{27}{64} per ounce troy, was approximately 205.4094 mg.
- ↑ The post-1887 Board of Trade carat, of which there were exactly 151½ per ounce troy, was approximately 205.3035 mg.
- ↑ Unlike the modern carat, the Board of Trade carat was not used for measuring pearls; those were measured with pearl grains.
- ↑ The refiners’ carats were the offspring of the carat as a measure of fineness for gold.
- ↑ Chaffers, William. 1883. Hall Marks on Gold and Silver Plate. 6th edition. London: Bickers & Son.
- ↑ Jump up to: 10.0 10.1 10.2 Grierson, Philip (1960). "The Monetary Reforms of'Abd Al-Malik". Journal of the Economic and Social History of the Orient. 3: p. 241–264. doi:10.1163/156852060X00098.CS1 maint: Extra text (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} | Carat (mass)
The carat is a unit of mass used for measuring gems and pearls. Currently a carat is defined as exactly 200 mg (0.007,055 oz, 3.086 grains). This definition, known as the metric carat, was adopted in 1907 at the Fourth General Conference on Weights and Measures, and soon afterwards in many countries around the world.[1] It is universally used today. The carat is divisible into one hundred points of two milligrams each.
For diamonds, a paragon is a flawless stone of at least 100 carats (20 g). The ANSI X.12 EDI standard abbreviation for the carat is CD.
The word came to English from French, derived from the Greek kerátion (κεράτιον), “fruit of the carob”,[2] via Arabic qīrāṭ (قيراط) and Italian carato. The Latin word for carat is siliqua. In past centuries, different countries each had their own carat unit, all roughly equivalent to the mass of a carob seed. These units were often used for weighing gold.
Carob seeds were used as weights on precision scales because of their reputation for having a uniform weight.[citation needed] However, a 2006 study[3] found carob seeds to have as much variation in their weights as do other seeds, though it seems that it is easier than with other seeds to recognize particularly large or small specimens and remove them.[4] Thus, the carob seed was used as a weight not because it was naturally more uniform in weight, but because it could be more easily standardized.
# Historical definitions in the United Kingdom
## Board of Trade carat
In the United Kingdom, before 1888, the Board of Trade carat was exactly <math>3\,\tfrac{1647}{9691}</math> grains;[5] after 1887, the Board of Trade carat was exactly <math>3\,\tfrac{17}{101}</math> grains.[6] Despite it being a non-metric unit, a number of metric countries used this unit for its limited range of application.
The Board of Trade carat was divisible into four diamond grains,[7] but measurements were typically made in multiples of <math>\tfrac{1}{64}</math> carat.
## Pound carat and ounce carat
There were also two varieties of refiners’ carats once used in the United Kingdom — the pound carat and the ounce carat.[8] The pound troy was divisible into 24 pound carats of 240 grains troy each; the pound carat was divisible into four pound grains of 60 grains troy each; and the pound grain was divisible into four pound quarters of 15 grains troy each. Similarly, the ounce troy was divisible into 24 ounce carats of 20 grains troy each; the ounce carat was divisible into four ounce grains of 5 grains troy each; and the ounce grain was divisible into four ounce quarters of 1¼ grains troy each.[9]
# The carat of the Romans and Greeks
The solidus (carat) was also a Roman weight unit. There is literary evidence that the weight of 72 coins of the type called solidus was exactly a Roman pound, and that the weight of a solidus was 24 siliquae. The weight of a Roman pound is generally believed to have been 327.45 g or possibly up to 5 g grams less. Therefore the metric equivalent of 1 solidus was approximately 189 mg. The Greeks had a similar unit of the same value.[10]
# The carat in Byzantine Egypt
A carob based weight unit was also used in Egypt in the Byzantine and early Arab periods. In this region, glass weights were used for weighing coins. From these the weight of the Egypt carat has been reconstructed as 196 mg. This is consistent with the average weights of carob seeds in the region.[10]
# The Syrian and Arabic carat in Mohammad's time
According to literary sources, the Arabic carat was only 2% less than the Syrian carat. Based on coins and glass weights their weight was reconstructed as approximately 212 mg. This is consistent with literary information that a solidus weighed slightly less than 22 carats.[10]
# Notes
- ↑ The United States adopted the metric carat definition on July 1, 1913, the United Kingdom on 1 April 1914.
- ↑ The literal translation of κεράτιον is little horn, which describes the seed pod.
- ↑ Turnbull, Lindsay, et al. “Seed size variability: from carob to carats”
- ↑ “Did carob seeds allow shady diamond deals?”, New Scientist, page 20, 6 May 2006.
- ↑ The pre-1888 Board of Trade carat, of which there were exactly <math>151\,\tfrac{27}{64}</math> per ounce troy, was approximately 205.4094 mg.
- ↑ The post-1887 Board of Trade carat, of which there were exactly 151½ per ounce troy, was approximately 205.3035 mg.
- ↑ Unlike the modern carat, the Board of Trade carat was not used for measuring pearls; those were measured with pearl grains.
- ↑ The refiners’ carats were the offspring of the carat as a measure of fineness for gold.
- ↑ Chaffers, William. 1883. Hall Marks on Gold and Silver Plate. 6th edition. London: Bickers & Son.
- ↑ Jump up to: 10.0 10.1 10.2 Grierson, Philip (1960). "The Monetary Reforms of'Abd Al-Malik". Journal of the Economic and Social History of the Orient. 3: p. 241–264. doi:10.1163/156852060X00098.CS1 maint: Extra text (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}
# External links
- A chart showing the size of various round diamond carat weights.
- A PDF chart showing the size of various fancy shaped diamond carat weights.
bs:Karat
bg:Карат (маса)
ca:Quirat
cs:Karát
da:Karat (masseenhed)
de:Karat
et:Karaat
eo:Karato
hr:Karat
io:Karato
it:Carato
he:קרט (יחידת משקל)
ka:კარატი
lt:Karatas
hu:Karát
mn:Карат (масс)
nl:Karaat
no:Karat (masse)
sq:Karati
sk:Karát
sl:Karat
fi:Karaatti
sv:Karat
th:กะรัต
uk:Карат | https://www.wikidoc.org/index.php/Carat_(mass) | |
961b9a2398aa95f11e2274f4043491488c72a945 | wikidoc | Carbocations | Carbocations
A carbocation (Template:PronEng) is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability (octet rule). Therefore carbocations are often reactive, seeking to fill the octet of valence electrons as well as regain a neutral charge. One could reasonably assume a carbocation to have sp3 hybridization with an empty sp3 orbital giving positive charge. However, the reactivity of a carbocation more closely resembles sp2 hybridization with a trigonal planar molecular geometry.
# Definitions
A carbocation was previously often called a carbonium ion but questions arose on the exact meaning . In present day chemistry a carbocation is any positively charged carbon atom. Two special types have been suggested: carbenium ions are trivalent and carbonium ions are pentavalent or hexavalent. University level textbooks only discuss carbocations as if they are carbenium ions , or discuss carbocations with a fleeting reference to the older phrase of carbonium ion or carbenium and carbonium ions . One textbook to this day clings on to the older name of carbonium ion for carbenium ion and reserves the phrase hypervalent carbenium ion for CH5+ .
# History
The history of carbocations dates back to 1891 when G. Merling reported that he added bromine to tropylidene (cycloheptatriene) and then heated the product to obtain a crystalline, water soluble material, C7H7Br. He did not suggest a structure for it; however Doering and Knox convincingly showed that it was tropylium (cycloheptatrienylium) bromide. This ion is predicted to be aromatic by the Hückel Rule.
In 1902 Norris and Kehrman independently discovered that colorless triphenylmethanol gave deep yellow solutions in concentrated sulfuric acid. Triphenylmethyl chloride similarly formed orange complexes with aluminium and tin chlorides. Adolf von Baeyer recognized in 1902 the salt like character of the compounds formed.
He dubbed the relationship between color and salt formation halochromy of which malachite green is a prime example.
Carbocations are reactive intermediates in many organic reactions. This idea, first proposed by Julius Stieglitz in 1899 (On the Constitution of the Salts of Imido-Ethers and other Carbimide Derivatives; Am. Chem. J. 21, 101; ISSN: 0096-4085) was further developed by Hans Meerwein in his 1922 study of the Wagner-Meerwein rearrangement. Carbocations were also found to be involved in the SN1 reaction and E1 reaction and in rearrangement reactions such as the Whitmore 1,2 shift. The chemical establishment was reluctant to accept the notion of a carbocation and for a long time the Journal of the American Chemical Society refused articles that mentioned them.
The first NMR spectrum of a stable carbocation in solution was published by Doering et al. . It was the heptamethylbenzenonium ion, made by treating hexamethylbenzene with methyl chloride and aluminium chloride. The stable 7-norbornadienyl cation was prepared by Story et al. by reacting norbornadienyl chloride with silver tetrafluoroborate in sulfur dioxide at −80°C . The NMR spectrum established that it was nonclassically bridged (the first stable non-classical ion observed).
In 1962 Olah directly observed the tert-butyl carbocation by Nuclear magnetic resonance as a stable species on dissolving tert-butyl fluoride in magic acid. The NMR of norbornyl cation was first reported by Schleyer et al. and it was shown to undergo proton scrambling over a barrier by Saunders et al. .
# Properties
In organic chemistry, a carbocation is often the target of nucleophilic attack by nucleophiles like OH- ions or halogen ions.
Carbocations are classified as primary, secondary, or tertiary depending on the number of carbon atoms bonded to the ionized carbon. Primary carbocations have one or zero carbons attached to the ionized carbon, secondary carbocations have two carbons attached to the ionized carbon, and tertiary carbocations have three carbons attached to the ionized carbon.
Stability of the carbocation increases with the number of alkyl groups bonded to the charge-bearing carbon. Tertiary carbocations are more stable (and form more readily) than secondary carbocations; primary carbocations are highly unstable because, while ionized higher-order carbons are stabilized by Hyperconjugation, unsubstituted (primary) carbons are not. Therefore, reactions such as the SN1 reaction and the E1 elimination reaction normally do not occur if a primary carbocation would be formed. An exception to this occurs when there is a carbon-carbon double bond next to the ionized carbon. Such cations as allyl cation CH2=CH-CH2+ and benzyl cation C6H5-CH2+ are more stable than most other carbocations. Molecules which can form allyl or benzyl carbocations are especially reactive.
Carbocations undergo rearrangement reactions from less stable structures to equally stable or more stable ones with rate constants in excess of 1.0E9/sec. This fact complicates synthetic pathways to many compounds. For example, when 3-pentanol is heated with aqueous HCl, the initially formed 3-pentyl carbocation rearranges to a statistical mixture of the 3-pentyl and 2-pentyl. These cations react with chloride ion to produce about 1/3 3-chloropentane and 2/3 2-chloropentane.
Some carbocations such as the norbornyl cation exhibit more or less symmetrical three centre bonding. Cations of this sort have been referred to as non-classical ions. The energy difference between "classical" carbocations and "non-classical" isomers is often very small, and there is generally little, if any activation energy involved in the transition between "classical" and "non-classical" structures. The "non-classical" form of the 2-butyl carbocation is essentially 2-butene with a proton directly above the centre of what would be the carbon-carbon double bond. "Non-classical" carbocations were once the subject of great controversy. One of George Olah's greatest contributions to chemistry was resolving this controversy . | Carbocations
A carbocation (Template:PronEng) is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability (octet rule). Therefore carbocations are often reactive, seeking to fill the octet of valence electrons as well as regain a neutral charge. One could reasonably assume a carbocation to have sp3 hybridization with an empty sp3 orbital giving positive charge. However, the reactivity of a carbocation more closely resembles sp2 hybridization with a trigonal planar molecular geometry.
# Definitions
A carbocation was previously often called a carbonium ion but questions arose on the exact meaning [1]. In present day chemistry a carbocation is any positively charged carbon atom. Two special types have been suggested: carbenium ions are trivalent and carbonium ions are pentavalent or hexavalent. University level textbooks only discuss carbocations as if they are carbenium ions [2], or discuss carbocations with a fleeting reference to the older phrase of carbonium ion [3] or carbenium and carbonium ions [4]. One textbook to this day clings on to the older name of carbonium ion for carbenium ion and reserves the phrase hypervalent carbenium ion for CH5+ [5].
# History
The history of carbocations dates back to 1891 when G. Merling [6] reported that he added bromine to tropylidene (cycloheptatriene) and then heated the product to obtain a crystalline, water soluble material, C7H7Br. He did not suggest a structure for it; however Doering and Knox [7] convincingly showed that it was tropylium (cycloheptatrienylium) bromide. This ion is predicted to be aromatic by the Hückel Rule.
In 1902 Norris and Kehrman independently discovered that colorless triphenylmethanol gave deep yellow solutions in concentrated sulfuric acid. Triphenylmethyl chloride similarly formed orange complexes with aluminium and tin chlorides. Adolf von Baeyer recognized in 1902 the salt like character of the compounds formed.
He dubbed the relationship between color and salt formation halochromy of which malachite green is a prime example.
Carbocations are reactive intermediates in many organic reactions. This idea, first proposed by Julius Stieglitz in 1899 (On the Constitution of the Salts of Imido-Ethers and other Carbimide Derivatives; Am. Chem. J. 21, 101; ISSN: 0096-4085) was further developed by Hans Meerwein in his 1922 study [8] of the Wagner-Meerwein rearrangement. Carbocations were also found to be involved in the SN1 reaction and E1 reaction and in rearrangement reactions such as the Whitmore 1,2 shift. The chemical establishment was reluctant to accept the notion of a carbocation and for a long time the Journal of the American Chemical Society refused articles that mentioned them.
The first NMR spectrum of a stable carbocation in solution was published by Doering et al. [9]. It was the heptamethylbenzenonium ion, made by treating hexamethylbenzene with methyl chloride and aluminium chloride. The stable 7-norbornadienyl cation was prepared by Story et al. [10] by reacting norbornadienyl chloride with silver tetrafluoroborate in sulfur dioxide at −80°C . The NMR spectrum established that it was nonclassically bridged (the first stable non-classical ion observed).
In 1962 Olah directly observed the tert-butyl carbocation by Nuclear magnetic resonance as a stable species on dissolving tert-butyl fluoride in magic acid. The NMR of norbornyl cation was first reported by Schleyer et al. [11] and it was shown to undergo proton scrambling over a barrier by Saunders et al. [12].
# Properties
In organic chemistry, a carbocation is often the target of nucleophilic attack by nucleophiles like OH- ions or halogen ions.
Carbocations are classified as primary, secondary, or tertiary depending on the number of carbon atoms bonded to the ionized carbon. Primary carbocations have one or zero carbons attached to the ionized carbon, secondary carbocations have two carbons attached to the ionized carbon, and tertiary carbocations have three carbons attached to the ionized carbon.
Stability of the carbocation increases with the number of alkyl groups bonded to the charge-bearing carbon. Tertiary carbocations are more stable (and form more readily) than secondary carbocations; primary carbocations are highly unstable because, while ionized higher-order carbons are stabilized by Hyperconjugation, unsubstituted (primary) carbons are not. Therefore, reactions such as the SN1 reaction and the E1 elimination reaction normally do not occur if a primary carbocation would be formed. An exception to this occurs when there is a carbon-carbon double bond next to the ionized carbon. Such cations as allyl cation CH2=CH-CH2+ and benzyl cation C6H5-CH2+ are more stable than most other carbocations. Molecules which can form allyl or benzyl carbocations are especially reactive.
Carbocations undergo rearrangement reactions from less stable structures to equally stable or more stable ones with rate constants in excess of 1.0E9/sec. This fact complicates synthetic pathways to many compounds. For example, when 3-pentanol is heated with aqueous HCl, the initially formed 3-pentyl carbocation rearranges to a statistical mixture of the 3-pentyl and 2-pentyl. These cations react with chloride ion to produce about 1/3 3-chloropentane and 2/3 2-chloropentane.
Some carbocations such as the norbornyl cation exhibit more or less symmetrical three centre bonding. Cations of this sort have been referred to as non-classical ions. The energy difference between "classical" carbocations and "non-classical" isomers is often very small, and there is generally little, if any activation energy involved in the transition between "classical" and "non-classical" structures. The "non-classical" form of the 2-butyl carbocation is essentially 2-butene with a proton directly above the centre of what would be the carbon-carbon double bond. "Non-classical" carbocations were once the subject of great controversy. One of George Olah's greatest contributions to chemistry was resolving this controversy [13]. | https://www.wikidoc.org/index.php/Carbocations | |
38be8842cc4c15f16a9f388a2cd39ddc89a088bf | wikidoc | Carbohydrate | Carbohydrate
Carbohydrates (from 'hydrates of carbon') or saccharides (Greek σάκχαρον meaning "sugar") are simple organic compounds that are aldehydes or ketones with many hydroxyl groups added, usually one on each carbon atom that is not part of the aldehyde or ketone functional group. Carbohydrates are the most abundant of the four major classes of biomolecules, which also include proteins, lipids and nucleic acids. They fill numerous roles in living things, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals). Additionally, carbohydrates and their derivatives play major roles in the working process of the immune system, fertilization, pathogenesis, blood clotting, and development.
The basic carbohydrate units are called monosaccharides, such as glucose, galactose, and fructose. The general stoichiometric formula of an unmodified monosaccharide is (C·H2O)n, where n is any number of three or greater; however, many molecules with formulae that differ slightly from this are still called carbohydrates and other compounds that possess formulae that agree with this general rule may not be in fact carbohydrates (eg formaldehyde). Despite the inexactness of the term, "carbohydrate" remains a useful descriptive name and with a little experience even a novice will soon become aware of what is, and is not, a carbohydrate. Monosaccharides can be linked together in almost limitless ways. Many carbohydrates contain one or more modified monosaccharide units that have had one or more groups replaced or removed. For example, deoxyribose, a component of DNA, is a modified version of ribose; chitin is composed of repeating units of N-acetylglucosamine, a nitrogen-containing form of glucose. The names of carbohydrates often end in the suffix -ose.
# Monosaccharides
Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates. The general chemical formula of an unmodified monosaccharide is (CH2O)n, where n is any number of three or greater.
## Classification of monosaccharides
The α and β anomers of glucose. Note the position of the anomeric carbon (red or green) relative to the CH2OH group bound to carbon 5: they are either on the opposite sides (α), or the same side (β).
Monosaccharides are classified according to three different characteristics: the placement of its carbonyl group, the number of carbon atoms it contains, and its chiral handedness. If the carbonyl group is an aldehyde, the monosaccharide is an aldose; if the carbonyl group is a ketone, the monosaccharide is a ketose. Monosaccharides with three carbon atoms are called trioses, those with four are called tetroses, five are called pentoses, six are hexoses, and so on. These two systems of classification are often combined. For example, glucose is an aldohexose (a six-carbon aldehyde), ribose is an aldopentose (a five-carbon aldehyde), and fructose is a ketohexose (a six-carbon ketone).
Each carbon atom bearing a hydroxyl group (-OH), with the exception of the first and last carbons, are asymmetric, making them stereocenters with two possible configurations each (R or S). Because of this asymmetry, a number of isomers may exist for any given monosaccharide formula. The aldohexose D-glucose, for example, has the formula (C·H2O)6, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of 24 = 16 possible stereoisomers. In the case of glyceraldehyde, an aldotriose, there is one pair of possible stereoisomers, which are enantiomers and epimers. 1,3-dihydroxyacetone, the ketose corresponding to the aldose glyceraldehye, is a symmetric molecule with no stereocenters). The assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar. Because D sugars are biologically far more common, the D is often omitted.
## Conformation
The aldehyde or ketone group of a straight-chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form.
During the conversion from straight-chain form to cyclic form, the carbon atom containing the carbonyl oxygen, called the anomeric carbon, becomes a chiral center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring. The resulting possible pair of stereoisomers are called anomers. In the α anomer, the -OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the CH2OH side branch. The alternative form, in which the CH2OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called the β anomer. Because the ring and straight-chain forms readily interconvert, both anomers exist in equilibrium.
## Use in living organisms
Monosaccharides are the major source of fuel for metabolism, being used both as an energy source (glucose being the most important in nature) and in biosynthesis. When monosaccharides are not needed by cells they are quickly converted into another form, such as polysaccharides.
# Disaccharides
Two joined monosaccharides are called disaccharides and represent the simplest polysaccharides. Examples include sucrose and lactose. They are composed of two monosaccharide units bound together by a covalent bond known as a glycosidic linkage formed via a dehydration reaction, resulting in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from the other. The formula of unmodified disaccharides is C12H22O11. Although there are numerous kinds of disaccharides, a handful of disaccharides are particularly notable.
Sucrose, pictured to the right, is the most abundant disaccharide and the main form in which carbohydrates are transported in plants. It is composed of one D-glucose molecule and one D-fructose molecule. The systematic name for sucrose, O-α-D-glucopyranosyl-(1→2)-D-fructofuranoside, indicates four things:
- Its monosaccharides: glucose and fructose
- Their ring types: glucose is a pyranose, and fructose is a furanose
- How they are linked together: the oxygen on carbon number 1 (C1) of α-D-glucose is linked to the C2 of D-fructose.
- The -oside suffix indicates that the anomeric carbon of both monosaccharides participates in the glycosidic bond.
Lactose, a disaccharide composed of one D-galactose molecule and one D-glucose molecule, occurs naturally in milk. The systematic name for lactose is O-β-D-galactopyranosyl-(1→4)-D-glucopyranose. Other notable disaccharides include maltose (two D-glucoses linked α-1,4) and cellobiose (two D-glucoses linked β-1,4).
# Oligosaccharides and polysaccharides
Oligosaccharides and polysaccharides are composed of longer chains of monosaccharide units bound together by glycosidic bonds. The distinction between the two is based upon the number of monosaccharide units present in the chain. Oligosaccharides typically contain between two and nine monosaccharide units, and polysaccharides contain greater than ten monosaccharide units. Definitions of how large a carbohydrate must be to fall into each category vary according to personal opinion. Examples of oligosaccharides include the disaccharides mentioned above, the trisaccharide raffinose and the tetrasaccharide stachyose.
Oligosaccharides are found as a common form of protein posttranslational modification. Such posttranslational modifications include the Lewis and ABO oligosaccharides responsible for blood group incompatibilities, the alpha-Gal epitope responsible for hyperacute rejection in xenotransplanation, and O-GlcNAc modifications.
Polysaccharides represent an important class of biological polymer. Their function in living organisms is usually either structure or storage related. Starch is used as a storage polysaccharide in plants, being found in the form of both amylose and the branched amylopectin. In animals, the structurally similar but more densely branched glycogen is used instead. Glycogen's properties allow it to be metabolized more quickly, which suits the active lives of locomotive animals.
Cellulose and chitin are examples of structural polysaccharides. Cellulose is used in the cell walls of plants and other organisms, and is claimed to be the most abundant organic molecule on earth. It has a variety of uses including in the paper and textile industry and as a feedstock for the production of rayon (in the viscose process), cellulose acetate, celluloid and nitrocellulose. Chitin has a similar structure to cellulose but has nitrogen containing side branches, increasing its strength. It is found in arthropod exoskeletons and in the cell walls of some fungi. It has a variety of uses, for example in surgical threads.
Other polysaccharides include callose or laminarin, xylan, mannan, fucoidan, and galactomannan.
# Nutrition
Carbohydrates require less water to digest than proteins or fats and are the most common source of energy. Proteins and fat are vital building components for body tissue and cells, and thus it could be considered advisable not to deplete such resources by necessitating their use in energy production.
Carbohydrates are not essential nutrients: the body can obtain all its energy from protein and fats . The brain cannot burn fat and needs glucose for energy, but the body can make this glucose from protein. Carbohydrates and proteins contain 4 kilocalories per gram while fats contain 9 kilocalories and alcohol contains 7 kilocalories per gram.
Foods that are high in carbohydrates include breads, pastas, beans, potatoes, bran, rice and cereals.
Based on evidence for risk of heart disease and obesity, the Institute of Medicine recommends that American and Canadian adults get between 40-65% of dietary energy from carbohydrates.
The Food and Agriculture Organization and World Health Organization jointly recommend that national dietary guidelines set a goal of 55-75% of total energy from carbohydrates, but only 10% should be from Free sugars (their definition of simple carbohydrates).
The distinction between "good carbs" and "bad carbs" is an important attribute of low-carbohydrate diets, which promote a reduction in the consumption of grains and starches in favor of protein. The result is a reduction in insulin levels used to metabolize sugars, and an increase in the use of fat for energy through ketosis, a process also known as Rabbit starvation.
## Classification
Dieticians and nutritionists commonly classify carbohydrates as simple (monosaccharides and disaccharides) or complex (oligosaccharides and polysaccharides). The term complex carbohydrate was first used in the Senate Select Committee publication Dietary Goals for the United States (1977), where it denoted "fruit, vegetables and whole-grains". Dietary guidelines generally recommend that complex carbohydrates and nutrient-rich simple carbohydrates such as fruit and dairy products should make up the bulk of carbohydrate consumption. The USDA's Dietary Guidelines for Americans 2005 dispenses with the simple/complex distinction, instead recommending fiber-rich foods and whole grains.
The glycemic index and glycemic load systems are popular alternative classification methods which rank carbohydrate-rich foods based on their effect on blood glucose levels. The insulin index is a similar, more recent classification method which ranks foods based on their effects on blood insulin levels. This system assumes that high glycemic index foods and low glycemic index foods can be mixed to make the intake of high glycemic foods more acceptable.
The World Health Organisation and Food and Agriculture Organization's joint expert report on Diet, Nutrition and the Prevention of Chronic Diseases (WHO Technical Report Series 916) advises carbohydrate consumption of 55-75% carbohydrate, but restricts "Free sugar" intake to 10%. Its definition is "The term "free sugars" refers to all monosaccharides and disaccharides added to foods by the manufacturer, cook or consumer, plus sugars naturally present in honey, syrups and fruit juices." (page 56 of the report; note to Table 6: Ranges of population nutrient intake goals). This is their effective split between simple and complex carbohydrates.
# Metabolism
## Catabolism
Catabolism is the metabolic reaction cells undergo in order to extract energy. There are two major metabolic pathways of monosaccharide catabolism:
- Glycolysis
- Citric acid cycle
Oligo/polysaccharides are cleaved first to smaller monosaccharides by enzymes called Glycoside hydrolases. The monosaccharide units can then enter into monosaccharide catabolism.
# Carbohydrate chemistry
Carbohydrates are reactants in many organic reactions. For example:
- Carbohydrate acetalisation
- Cyanohydrin reaction
- Lobry-de Bruyn-van Ekenstein transformation
- Amadori rearrangement
- Nef reaction
- Wohl degradation
- Koenigs-Knorr reaction
An artificial carbohydrate is sorbitol. | Carbohydrate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Carbohydrates (from 'hydrates of carbon') or saccharides (Greek σάκχαρον meaning "sugar") are simple organic compounds that are aldehydes or ketones with many hydroxyl groups added, usually one on each carbon atom that is not part of the aldehyde or ketone functional group. Carbohydrates are the most abundant of the four major classes of biomolecules, which also include proteins, lipids and nucleic acids. They fill numerous roles in living things, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals). Additionally, carbohydrates and their derivatives play major roles in the working process of the immune system, fertilization, pathogenesis, blood clotting, and development.
The basic carbohydrate units are called monosaccharides, such as glucose, galactose, and fructose. The general stoichiometric formula of an unmodified monosaccharide is (C·H2O)n, where n is any number of three or greater; however, many molecules with formulae that differ slightly from this are still called carbohydrates and other compounds that possess formulae that agree with this general rule may not be in fact carbohydrates (eg formaldehyde).[1] Despite the inexactness of the term, "carbohydrate" remains a useful descriptive name and with a little experience even a novice will soon become aware of what is, and is not, a carbohydrate. Monosaccharides can be linked together in almost limitless ways. Many carbohydrates contain one or more modified monosaccharide units that have had one or more groups replaced or removed. For example, deoxyribose, a component of DNA, is a modified version of ribose; chitin is composed of repeating units of N-acetylglucosamine, a nitrogen-containing form of glucose. The names of carbohydrates often end in the suffix -ose.
# Monosaccharides
Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates. The general chemical formula of an unmodified monosaccharide is (C•H2O)n, where n is any number of three or greater.
## Classification of monosaccharides
The α and β anomers of glucose. Note the position of the anomeric carbon (red or green) relative to the CH2OH group bound to carbon 5: they are either on the opposite sides (α), or the same side (β).
Monosaccharides are classified according to three different characteristics: the placement of its carbonyl group, the number of carbon atoms it contains, and its chiral handedness. If the carbonyl group is an aldehyde, the monosaccharide is an aldose; if the carbonyl group is a ketone, the monosaccharide is a ketose. Monosaccharides with three carbon atoms are called trioses, those with four are called tetroses, five are called pentoses, six are hexoses, and so on. These two systems of classification are often combined. For example, glucose is an aldohexose (a six-carbon aldehyde), ribose is an aldopentose (a five-carbon aldehyde), and fructose is a ketohexose (a six-carbon ketone).
Each carbon atom bearing a hydroxyl group (-OH), with the exception of the first and last carbons, are asymmetric, making them stereocenters with two possible configurations each (R or S). Because of this asymmetry, a number of isomers may exist for any given monosaccharide formula. The aldohexose D-glucose, for example, has the formula (C·H2O)6, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of 24 = 16 possible stereoisomers. In the case of glyceraldehyde, an aldotriose, there is one pair of possible stereoisomers, which are enantiomers and epimers. 1,3-dihydroxyacetone, the ketose corresponding to the aldose glyceraldehye, is a symmetric molecule with no stereocenters). The assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar. Because D sugars are biologically far more common, the D is often omitted.
## Conformation
The aldehyde or ketone group of a straight-chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form.
During the conversion from straight-chain form to cyclic form, the carbon atom containing the carbonyl oxygen, called the anomeric carbon, becomes a chiral center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring. The resulting possible pair of stereoisomers are called anomers. In the α anomer, the -OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the CH2OH side branch. The alternative form, in which the CH2OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called the β anomer. Because the ring and straight-chain forms readily interconvert, both anomers exist in equilibrium.
## Use in living organisms
Monosaccharides are the major source of fuel for metabolism, being used both as an energy source (glucose being the most important in nature) and in biosynthesis. When monosaccharides are not needed by cells they are quickly converted into another form, such as polysaccharides.
# Disaccharides
Two joined monosaccharides are called disaccharides and represent the simplest polysaccharides. Examples include sucrose and lactose. They are composed of two monosaccharide units bound together by a covalent bond known as a glycosidic linkage formed via a dehydration reaction, resulting in the loss of a hydrogen atom from one monosaccharide and a hydroxyl group from the other. The formula of unmodified disaccharides is C12H22O11. Although there are numerous kinds of disaccharides, a handful of disaccharides are particularly notable.
Sucrose, pictured to the right, is the most abundant disaccharide and the main form in which carbohydrates are transported in plants. It is composed of one D-glucose molecule and one D-fructose molecule. The systematic name for sucrose, O-α-D-glucopyranosyl-(1→2)-D-fructofuranoside, indicates four things:
- Its monosaccharides: glucose and fructose
- Their ring types: glucose is a pyranose, and fructose is a furanose
- How they are linked together: the oxygen on carbon number 1 (C1) of α-D-glucose is linked to the C2 of D-fructose.
- The -oside suffix indicates that the anomeric carbon of both monosaccharides participates in the glycosidic bond.
Lactose, a disaccharide composed of one D-galactose molecule and one D-glucose molecule, occurs naturally in milk. The systematic name for lactose is O-β-D-galactopyranosyl-(1→4)-D-glucopyranose. Other notable disaccharides include maltose (two D-glucoses linked α-1,4) and cellobiose (two D-glucoses linked β-1,4).
# Oligosaccharides and polysaccharides
Oligosaccharides and polysaccharides are composed of longer chains of monosaccharide units bound together by glycosidic bonds. The distinction between the two is based upon the number of monosaccharide units present in the chain. Oligosaccharides typically contain between two and nine monosaccharide units, and polysaccharides contain greater than ten monosaccharide units. Definitions of how large a carbohydrate must be to fall into each category vary according to personal opinion. Examples of oligosaccharides include the disaccharides mentioned above, the trisaccharide raffinose and the tetrasaccharide stachyose.
Oligosaccharides are found as a common form of protein posttranslational modification. Such posttranslational modifications include the Lewis and ABO oligosaccharides responsible for blood group incompatibilities, the alpha-Gal epitope responsible for hyperacute rejection in xenotransplanation, and O-GlcNAc modifications.
Polysaccharides represent an important class of biological polymer. Their function in living organisms is usually either structure or storage related. Starch is used as a storage polysaccharide in plants, being found in the form of both amylose and the branched amylopectin. In animals, the structurally similar but more densely branched glycogen is used instead. Glycogen's properties allow it to be metabolized more quickly, which suits the active lives of locomotive animals.
Cellulose and chitin are examples of structural polysaccharides. Cellulose is used in the cell walls of plants and other organisms, and is claimed to be the most abundant organic molecule on earth.[2] It has a variety of uses including in the paper and textile industry and as a feedstock for the production of rayon (in the viscose process), cellulose acetate, celluloid and nitrocellulose. Chitin has a similar structure to cellulose but has nitrogen containing side branches, increasing its strength. It is found in arthropod exoskeletons and in the cell walls of some fungi. It has a variety of uses, for example in surgical threads.
Other polysaccharides include callose or laminarin, xylan, mannan, fucoidan, and galactomannan.
# Nutrition
Carbohydrates require less water to digest than proteins or fats and are the most common source of energy. Proteins and fat are vital building components for body tissue and cells, and thus it could be considered advisable not to deplete such resources by necessitating their use in energy production.
Carbohydrates are not essential nutrients: the body can obtain all its energy from protein and fats [3] [4]. The brain cannot burn fat and needs glucose for energy, but the body can make this glucose from protein. Carbohydrates and proteins contain 4 kilocalories per gram while fats contain 9 kilocalories and alcohol contains 7 kilocalories per gram.[citation needed]
Foods that are high in carbohydrates include breads, pastas, beans, potatoes, bran, rice and cereals.
Based on evidence for risk of heart disease and obesity, the Institute of Medicine recommends that American and Canadian adults get between 40-65% of dietary energy from carbohydrates.[5]
The Food and Agriculture Organization and World Health Organization jointly recommend that national dietary guidelines set a goal of 55-75% of total energy from carbohydrates, but only 10% should be from Free sugars (their definition of simple carbohydrates).[6]
The distinction between "good carbs" and "bad carbs" is an important attribute of low-carbohydrate diets, which promote a reduction in the consumption of grains and starches in favor of protein. The result is a reduction in insulin levels used to metabolize sugars, and an increase in the use of fat for energy through ketosis, a process also known as Rabbit starvation.
## Classification
Dieticians and nutritionists commonly classify carbohydrates as simple (monosaccharides and disaccharides) or complex (oligosaccharides and polysaccharides). The term complex carbohydrate was first used in the Senate Select Committee publication Dietary Goals for the United States (1977), where it denoted "fruit, vegetables and whole-grains".[7] Dietary guidelines generally recommend that complex carbohydrates and nutrient-rich simple carbohydrates such as fruit and dairy products should make up the bulk of carbohydrate consumption. The USDA's Dietary Guidelines for Americans 2005 dispenses with the simple/complex distinction, instead recommending fiber-rich foods and whole grains.[8]
The glycemic index and glycemic load systems are popular alternative classification methods which rank carbohydrate-rich foods based on their effect on blood glucose levels. The insulin index is a similar, more recent classification method which ranks foods based on their effects on blood insulin levels. This system assumes that high glycemic index foods and low glycemic index foods can be mixed to make the intake of high glycemic foods more acceptable.[citation needed]
The World Health Organisation and Food and Agriculture Organization's joint expert report on Diet, Nutrition and the Prevention of Chronic Diseases (WHO Technical Report Series 916) advises carbohydrate consumption of 55-75% carbohydrate, but restricts "Free sugar" intake to 10%. Its definition is "The term "free sugars" refers to all monosaccharides and disaccharides added to foods by the manufacturer, cook or consumer, plus sugars naturally present in honey, syrups and fruit juices." (page 56 of the report; note to Table 6: Ranges of population nutrient intake goals). This is their effective split between simple and complex carbohydrates.
# Metabolism
## Catabolism
Catabolism is the metabolic reaction cells undergo in order to extract energy. There are two major metabolic pathways of monosaccharide catabolism:
- Glycolysis
- Citric acid cycle
Oligo/polysaccharides are cleaved first to smaller monosaccharides by enzymes called Glycoside hydrolases. The monosaccharide units can then enter into monosaccharide catabolism.
# Carbohydrate chemistry
Carbohydrates are reactants in many organic reactions. For example:
- Carbohydrate acetalisation
- Cyanohydrin reaction
- Lobry-de Bruyn-van Ekenstein transformation
- Amadori rearrangement
- Nef reaction
- Wohl degradation
- Koenigs-Knorr reaction
An artificial carbohydrate is sorbitol. | https://www.wikidoc.org/index.php/Carbohydrate | |
fb7a4a4d14023d34d54cb0526dfc51762b5d8120 | wikidoc | Carbon black | Carbon black
# Overview
Carbon black is a material, today usually produced by the incomplete combustion of petroleum products. Carbon black is a form of amorphous carbon that has an extremely high surface area to volume ratio, and as such it is one of the first nanomaterials to find common use. It is similar to soot but with a much higher surface area to volume ratio. Carbon black is often used as a pigment and reinforcement in rubber and plastic products.
The current International Agency for Research on Cancer (IARC) evaluation is that, "Carbon black is possibly carcinogenic to humans (Group 2B)". Short-term exposure to high concentrations of the carbon black dust may produce discomfort to the upper respiratory tract, through mechanical irritation.
# Common uses
The most common use of carbon black is as a pigment and reinforcing phase in automobile tires. Carbon black also helps conduct heat away from the tread and belt area of the tire, reducing thermal damage and increasing tire life. Carbon black particles are also employed in some radar absorbent materials and in printer toner.
Total production is about 8.1 million tonnes (2006). About 20% of world production goes into belts, hoses, and other rubber goods. The balance is used in inks and as a pigment for products other than tires.
Carbon black from vegetable origin is used as a food coloring, in Europe known as additive E153.
# Reinforcing carbon blacks
The highest volume use of carbon black is as a reinforcing filler in rubber products, especially tires. While a pure gum vulcanizate of SBR has a tensile strength of no more than 2.5 MPa, and almost nonexistent abrasion resistance, compounding it with 50% of its weight of carbon black improves its tensile strength and wear resistance as shown in the below table.
Practically all rubber products where tensile and abrasion wear properties are crucial use carbon black, so they are black in color. Where physical properties are important but colors other than black are desired, such as white tennis shoes, precipitated or fumed silica is a decent competitor to carbon black in reinforcing ability. Silica based fillers are also gaining market share in automotive tires because they provide better fuel efficiency due to a lower rolling loss compared to carbon black filled tires. Traditionally silica fillers had worse abrasion wear properties, but the technology has gradually improved to where they can match carbon black abrasion performance.
# Pigment
Carbon black (Colour Index International, PBL-7) is the name of a common black pigment, traditionally produced from charring organic materials such as wood or bone. It consists of pure elemental carbon, and it appears black because it reflects almost no light in the visible part of the spectrum. It is known by a variety of names, each of which reflects a traditional method for producing carbon black:
- Ivory black was traditionally produced by charring ivory or animal bones (see bone char).
- Vine black was traditionally produced by charring desiccated grape vines and stems.
- Lamp black was traditionally produced by collecting soot, also known as lampblack, from oil lamps.
Newer methods of producing carbon black have superseded these traditional sources, although some materials are still produced using traditional methods, for Artisanal purposes.
# Surface chemistry
All carbon blacks have chemisorbed oxygen complexes (i.e., carboxylic, quinonic, lactonic, phenolic groups and others) on their surfaces to varying degrees depending on the conditions of manufacture. These surface oxygen groups are collectively referred to as volatile content. It is also known to be a non-conductive material due to its volatile content.
The coatings and inks industries prefer grades of carbon black that are acid oxidized. Acid is sprayed in high temperature dryers during the manufacturing process to change the inherent surface chemistry of the black. The amount of chemically-bonded oxygen on the surface area of the black is increased to enhance performance characteristics. | Carbon black
# Overview
Carbon black is a material, today usually produced by the incomplete combustion of petroleum products. Carbon black is a form of amorphous carbon that has an extremely high surface area to volume ratio, and as such it is one of the first nanomaterials to find common use. It is similar to soot but with a much higher surface area to volume ratio. Carbon black is often used as a pigment and reinforcement in rubber and plastic products.
The current International Agency for Research on Cancer (IARC) evaluation is that, "Carbon black is possibly carcinogenic to humans (Group 2B)". Short-term exposure to high concentrations of the carbon black dust may produce discomfort to the upper respiratory tract, through mechanical irritation.
# Common uses
The most common use [70%] of carbon black is as a pigment and reinforcing phase in automobile tires. Carbon black also helps conduct heat away from the tread and belt area of the tire, reducing thermal damage and increasing tire life. Carbon black particles are also employed in some radar absorbent materials and in printer toner.
Total production is about 8.1 million tonnes (2006)[1]. About 20% of world production goes into belts, hoses, and other rubber goods. The balance is used in inks and as a pigment for products other than tires.
Carbon black from vegetable origin is used as a food coloring, in Europe known as additive E153.
# Reinforcing carbon blacks
The highest volume use of carbon black is as a reinforcing filler in rubber products, especially tires. While a pure gum vulcanizate of SBR has a tensile strength of no more than 2.5 MPa, and almost nonexistent abrasion resistance, compounding it with 50% of its weight of carbon black improves its tensile strength and wear resistance as shown in the below table.
Practically all rubber products where tensile and abrasion wear properties are crucial use carbon black, so they are black in color. Where physical properties are important but colors other than black are desired, such as white tennis shoes, precipitated or fumed silica is a decent competitor to carbon black in reinforcing ability. Silica based fillers are also gaining market share in automotive tires because they provide better fuel efficiency due to a lower rolling loss compared to carbon black filled tires. Traditionally silica fillers had worse abrasion wear properties, but the technology has gradually improved to where they can match carbon black abrasion performance.
# Pigment
Carbon black (Colour Index International, PBL-7) is the name of a common black pigment, traditionally produced from charring organic materials such as wood or bone. It consists of pure elemental carbon, and it appears black because it reflects almost no light in the visible part of the spectrum. It is known by a variety of names, each of which reflects a traditional method for producing carbon black:
- Ivory black was traditionally produced by charring ivory or animal bones (see bone char).
- Vine black was traditionally produced by charring desiccated grape vines and stems.
- Lamp black was traditionally produced by collecting soot, also known as lampblack, from oil lamps.
Newer methods of producing carbon black have superseded these traditional sources, although some materials are still produced using traditional methods, for Artisanal purposes.
# Surface chemistry
All carbon blacks have chemisorbed oxygen complexes (i.e., carboxylic, quinonic, lactonic, phenolic groups and others) on their surfaces to varying degrees depending on the conditions of manufacture. These surface oxygen groups are collectively referred to as volatile content. It is also known to be a non-conductive material due to its volatile content.
The coatings and inks industries prefer grades of carbon black that are acid oxidized. Acid is sprayed in high temperature dryers during the manufacturing process to change the inherent surface chemistry of the black. The amount of chemically-bonded oxygen on the surface area of the black is increased to enhance performance characteristics. | https://www.wikidoc.org/index.php/Carbon_black | |
76ba7ab7265a357cfdd069270e2b0180669f36fe | wikidoc | Carbon cycle | Carbon cycle
The carbon cycle is the biogeochemical cycle by which carbon is exchanged between the biosphere, geosphere, hydrosphere, and atmosphere of the Earth.
The cycle is usually thought of as four major reservoirs of carbon interconnected by pathways of exchange. The reservoirs are the atmosphere, the terrestrial biosphere (which usually includes freshwater systems and non-living organic material, such as soil carbon), the oceans (which includes dissolved inorganic carbon and living and non-living marine biota), and the sediments (which includes fossil fuels). The annual movements of carbon, the carbon exchanges between reservoirs, occur because of various chemical, physical, geological, and biological processes. The ocean contains the largest active pool of carbon near the surface of the Earth, but the deep ocean part of this pool does not rapidly exchange with the atmosphere.
The global carbon budget is the balance of the exchanges (incomes and losses) of carbon between the carbon reservoirs or between one specific loop (e.g., atmosphere - biosphere) of the carbon cycle. An examination of the carbon budget of a pool or reservoir can provide information about whether the pool or reservoir is functioning as a source or sink for carbon dioxide.
# In the atmosphere
Carbon exists in the Earth's atmosphere primarily as the gas carbon dioxide (CO2). Although it is a very tiny percent of the atmosphere (approximately 0.04% on a molar basis, though rising), it plays an important role in supporting life. Other gases containing carbon in the atmosphere are methane and chlorofluorocarbons (the latter is entirely anthropogenic). The overall atmospheric concentration of these greenhouse gases has been increasing in recent decades, theoretically contributing to global warming. Because of their size and composition, these houses are rarely collected in such traps, so most biogeochemical analyses have erroneously ignored them.
Carbon storage in the biosphere is influenced by a number of processes on different time-scales: while net primary productivity follows a diurnal and seasonal cycle, carbon can be stored up to several hundreds of years in trees and up to thousands of years in soils. Changes in those long term carbon pools (e.g. through de- or afforestation or through temperature-related changes in soil respiration) may thus affect global climate change.
# In the ocean
The oceans contain around 36,000 gigatonnes of carbon, mostly in the form of bicarbonate ion. Inorganic carbon, that is carbon compounds with no carbon-carbon or carbon-hydrogen bonds, is important in its reactions within water. This carbon exchange becomes important in controlling pH in the ocean and can also vary as a source or sink for carbon. Carbon is readily exchanged between the atmosphere and ocean. In regions of oceanic upwelling, carbon is released to the atmosphere. Conversely, regions of downwelling transfer carbon (CO2) from the atmosphere to the ocean. When CO2 enters the ocean, carbonic acid is formed:
This reaction has a forward and reverse rate, that is it achieves a chemical equilibrium. Another reaction important in controlling oceanic pH levels is the release of hydrogen ions and bicarbonate. This reaction controls large changes in pH:
In the oceans, bicarbonate can combine with calcium to form limestone (calcium carbonate, CaCO3, with silica), which precipitates to the ocean floor. Limestone is the largest reservoir of carbon in the carbon cycle. The calcium comes from the weathering of calcium-silicate rocks, which causes the silicon in the rocks to combine with oxygen to form sand or quartz (silicon dioxide), leaving calcium ions available to form
limestone. | Carbon cycle
The carbon cycle is the biogeochemical cycle by which carbon is exchanged between the biosphere, geosphere, hydrosphere, and atmosphere of the Earth.
The cycle is usually thought of as four major reservoirs of carbon interconnected by pathways of exchange. The reservoirs are the atmosphere, the terrestrial biosphere (which usually includes freshwater systems and non-living organic material, such as soil carbon), the oceans (which includes dissolved inorganic carbon and living and non-living marine biota), and the sediments (which includes fossil fuels). The annual movements of carbon, the carbon exchanges between reservoirs, occur because of various chemical, physical, geological, and biological processes. The ocean contains the largest active pool of carbon near the surface of the Earth, but the deep ocean part of this pool does not rapidly exchange with the atmosphere.
The global carbon budget is the balance of the exchanges (incomes and losses) of carbon between the carbon reservoirs or between one specific loop (e.g., atmosphere - biosphere) of the carbon cycle. An examination of the carbon budget of a pool or reservoir can provide information about whether the pool or reservoir is functioning as a source or sink for carbon dioxide.
# In the atmosphere
Carbon exists in the Earth's atmosphere primarily as the gas carbon dioxide (CO2). Although it is a very tiny percent of the atmosphere (approximately 0.04% on a molar basis, though rising), it plays an important role in supporting life. Other gases containing carbon in the atmosphere are methane and chlorofluorocarbons (the latter is entirely anthropogenic). The overall atmospheric concentration of these greenhouse gases has been increasing in recent decades, theoretically contributing to global warming. Because of their size and composition, these houses are rarely collected in such traps, so most biogeochemical analyses have erroneously ignored them.
Carbon storage in the biosphere is influenced by a number of processes on different time-scales: while net primary productivity follows a diurnal and seasonal cycle, carbon can be stored up to several hundreds of years in trees and up to thousands of years in soils. Changes in those long term carbon pools (e.g. through de- or afforestation or through temperature-related changes in soil respiration) may thus affect global climate change.
# In the ocean
The oceans contain around 36,000 gigatonnes of carbon, mostly in the form of bicarbonate ion. Inorganic carbon, that is carbon compounds with no carbon-carbon or carbon-hydrogen bonds, is important in its reactions within water. This carbon exchange becomes important in controlling pH in the ocean and can also vary as a source or sink for carbon. Carbon is readily exchanged between the atmosphere and ocean. In regions of oceanic upwelling, carbon is released to the atmosphere. Conversely, regions of downwelling transfer carbon (CO2) from the atmosphere to the ocean. When CO2 enters the ocean, carbonic acid is formed:
This reaction has a forward and reverse rate, that is it achieves a chemical equilibrium. Another reaction important in controlling oceanic pH levels is the release of hydrogen ions and bicarbonate. This reaction controls large changes in pH:
In the oceans, bicarbonate can combine with calcium to form limestone (calcium carbonate, CaCO3, with silica), which precipitates to the ocean floor. Limestone is the largest reservoir of carbon in the carbon cycle. The calcium comes from the weathering of calcium-silicate rocks, which causes the silicon in the rocks to combine with oxygen to form sand or quartz (silicon dioxide), leaving calcium ions available to form
limestone[1]. | https://www.wikidoc.org/index.php/Carbon_cycle | |
4924d48a16e30b7dda223e40efae4ca36aac3a91 | wikidoc | Carbon group | Carbon group
# Overview
The carbon group is group 14 (IUPAC style) in the periodic table. Once also known as the tetrels (from Latin tetra, four), stemming from the earlier naming convention of this group as Group IVB.
Each of the elements in this group has 4 electrons in its outer energy level. The last orbital of all these elements is the p2 orbital. In most cases, the elements share their electrons. The tendency to lose electrons increases as the size of the atom increases, as it does with increasing atomic number.
Carbon alone forms negative ions, in the form of carbide (C4-) ions.
Silicon and germanium, both metalloids, each can form +4 ions.
Tin and lead both are metals while ununquadium is a synthetic shortlived radioactive metal.
The group consists of carbon (C), silicon (Si), germanium (Ge), tin (Sn), lead (Pb), and ununquadium (Uuq).
ar:مجموعة كربون
ast:Elementos del grupu 14
ca:Grup del carboni
cs:Tetrely
de:Kohlenstoffgruppe
eo:Elemento de grupo 14
ko:14족 원소
it:Gruppo del carbonio
lmo:Grupp del carbòni
nl:Koolstofgroep
nn:Gruppe 14
nds:Cheemsch Elementen vun de 14. Grupp
sr:14. група хемијских елемената
sh:14. grupa hemijskih elemenata
fi:Hiiliryhmä
sv:Kolgruppen
th:หมู่คาร์บอน | Carbon group
# Overview
The carbon group is group 14 (IUPAC style) in the periodic table. Once also known as the tetrels (from Latin tetra, four), stemming from the earlier naming convention of this group as Group IVB.
Each of the elements in this group has 4 electrons in its outer energy level. The last orbital of all these elements is the p2 orbital. In most cases, the elements share their electrons. The tendency to lose electrons increases as the size of the atom increases, as it does with increasing atomic number.
Carbon alone forms negative ions, in the form of carbide (C4-) ions.
Silicon and germanium, both metalloids, each can form +4 ions.
Tin and lead both are metals while ununquadium is a synthetic shortlived radioactive metal.
The group consists of carbon (C), silicon (Si), germanium (Ge), tin (Sn), lead (Pb), and ununquadium (Uuq).
Template:PeriodicTablesFooter
ar:مجموعة كربون
ast:Elementos del grupu 14
ca:Grup del carboni
cs:Tetrely
de:Kohlenstoffgruppe
eo:Elemento de grupo 14
ko:14족 원소
it:Gruppo del carbonio
lmo:Grupp del carbòni
nl:Koolstofgroep
nn:Gruppe 14
nds:Cheemsch Elementen vun de 14. Grupp
sr:14. група хемијских елемената
sh:14. grupa hemijskih elemenata
fi:Hiiliryhmä
sv:Kolgruppen
th:หมู่คาร์บอน
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Carbon_family | |
3614803a9d22c09dcc1718101cd9c7174868ab31 | wikidoc | Carbon fiber | Carbon fiber
Carbon fiber (alternately called graphite or trade named hexilinium fiber) is a material consisting of extremely thin fibers about 0.0002-0.0004 inches (0.005-0.010 mm) in diameter and composed mostly of carbon atoms. The carbon atoms are bonded together in microscopic crystals that are more or less aligned parallel to the long axis of the fiber. The crystal alignment makes the fiber incredibly strong for its size. Several thousand carbon fibers are twisted together to form a yarn, which may be used by itself or woven into a fabric. Carbon fiber can be combined with a plastic resin and wound or molded to form composite materials such as carbon fiber reinforced plastic (also referenced as carbon fiber) to provide a high strength-to-weight ratio material. The density of carbon fiber is also considerably lower than the density of steel, making it ideal for applications requiring low weight. The properties of carbon fiber such as high tensile strength, low weight, and low thermal expansion make it very popular in aerospace, military, and motorsports, along with other competition sports.
# History of Carbon Fiber
In 1958, Dr. Roger Bacon created the first high-performance carbon fibers at the Union Carbide Parma Technical Center, located outside of Cleveland, Ohio.The first fibers were manufactured by heating strands of rayon until they carbonized. This process proved to be inefficient, as the resulting fibers contained only about 20% carbon and had low strength and stiffness properties. In the early 1960s, a process was developed using polyacrylonitrile as a raw material. This produced a carbon fiber that contained about 55% carbon and had much better properties. The polyacrylonitrile conversion process quickly became the primary method for producing carbon fibers.
On January 14, 1969 Carr Reinforcements wove the first ever carbon fiber fabric in the world.
During the 1970s, experimental work to find alternative raw materials led to the introduction of carbon fibers made from a petroleum pitch derived from oil processing. These fibers contained about 85% carbon and had excellent flexural strength.
# Structure and properties
Carbon fibers are the closest to asbestos in a number of properties.
Each carbon filament thread is a bundle of many thousand carbon filaments. A single such filament is a thin tube with a diameter of 5–8 micrometers and consists almost exclusively of carbon.
The atomic structure of carbon fiber is similar to that of graphite, consisting of sheets of carbon atoms (graphene sheets) arranged in a regular hexagonal pattern. The difference lies in the way these sheets interlock. Graphite is a crystalline material in which the sheets are stacked parallel to one another in regular fashion. The chemical bonds between the sheets are relatively weak Van der Waals forces, giving graphite its soft and brittle characteristics. Depending upon the precursor to make the fiber, carbon fiber may be turbostratic or graphitic, or have a hybrid structure with both graphitic and turbostratic parts present. In turbostratic carbon fiber the sheets of carbon atoms are haphazardly folded, or crumpled, together. Carbon fibers derived from Polyacrylonitrile (PAN) are turbostratic, whereas carbon fibers derived from mesophase pitch are graphitic after heat treatment at temperatures exceeding 2200 C. Turbostratic carbon fibers tend to have high tensile strength, wheresas heat-treated mesophase-pitch-derived carbon fibers have high Young's modulus and high thermal conductivity.
# Applications
Carbon fiber is most notably used to reinforce composite materials, particularly the class of materials known as Carbon fiber or graphite reinforced polymers. Another utilization of Carbon Fiber is its added aesthetic value to various consumer products.
Carbon Fiber as a tough and lightweight material is applied in the production of watch cases and dials. In watchmaking the material is often combined with polymer to improve its strength.
Non-polymer materials can also be used as the matrix for carbon fibers. Due to the formation of metal carbides (i.e., water-soluble AlC) and corrosion considerations, carbon has seen limited success in metal matrix composite applications. Reinforced carbon-carbon (RCC) consists of carbon fiber-reinforced graphite, and is used structurally in high-temperature applications. The fiber also finds use in filtration of high-temperature gases, as an electrode with high surface area and impeccable corrosion resistance, and as an anti-static component.
Carbon fiber is also used in compressed gas tanks, including compressed air tanks.
Carbon fiber has recently been used for various decorative reasons such as doors and chairs.
# Synthesis
Each carbon filament is made out of long, thin filaments of carbon sometimes transformed to graphite. A common method of making carbon filaments is the oxidation and thermal pyrolysis of polyacrylonitrile (PAN), a polymer based on acrylonitrile used in the creation of synthetic materials. Like all polymers, polyacrylonitrile molecules are long chains, which are aligned in the process of drawing continuous filaments. A common method of manufacture involves heating the PAN to approximately 300 °C in air, which breaks many of the hydrogen bonds and oxidizes the material. The oxidized PAN is then placed into a furnace having an inert atmosphere of a gas such as argon, and heated to approximately 2000 °C, which induces graphitization of the material, changing the molecular bond structure. When heated in the correct conditions, these chains bond side-to-side (ladder polymers), forming narrow graphene sheets which eventually merge to form a single, jelly roll-shaped or round filament. The result is usually 93-95% carbon. Lower-quality fiber can be manufactured using pitch or rayon as the precursor instead of PAN. The carbon can become further enhanced, as high modulus, or high strength carbon, by heat treatment processes. Carbon heated in the range of 1500-2000 °C (carbonization) exhibits the highest tensile strength (820,000 psi or 5,650 MPa or 5,650 N/mm²), while carbon fiber heated from 2500 to 3000 °C (graphitizing) exhibits a higher modulus of elasticity (77,000,000 psi or 531 GPa or 531 kN/mm²).
# Textile
There are several categories of carbon fibers: standard modulus (250 GPa), intermediate modulus (300 GPa), and high modulus (> 300 GPa). The tensile strength of different yarn types varies between 2000 and 7000 MPa. A typical density of carbon fiber is 1750 kg/m3.
Precursors for carbon fibers are PAN, rayon and pitch. Carbon fiber filament yarns are used in several processing techniques: the direct uses are for prepregging, filament winding, pultrusion, weaving, braiding etc. Carbon fiber yarn is rated by the linear density (weight per unit length = 1 g/1000 m = tex) or by number of filaments per yarn count, in thousands. For example, 200 tex for 3,000 filaments of carbon fiber is 3 times as strong as 1,000 carbon fibers but is also 3 times as heavy. This thread can then be used to weave a carbon fiber filament fabric or cloth. The appearance of this fabric generally depends on the linear density of the yarn and the weave chosen. Some commonly used types of weave are twill, satin and plain.
# Manufacturers
PAN aerospace/high end carbon fiber:
Toray Industries (largest worldwide manufacturer)
Toho Tenax
Mitsubishi
Hexcel
Cytec Industries
PAN commercial grade carbon fiber:
Zoltek
SGL
Fortafil
Pitch carbon fiber:
Sumitomo | Carbon fiber
Template:Cleanup
Carbon fiber (alternately called graphite or trade named hexilinium fiber) is a material consisting of extremely thin fibers about 0.0002-0.0004 inches (0.005-0.010 mm) in diameter and composed mostly of carbon atoms. The carbon atoms are bonded together in microscopic crystals that are more or less aligned parallel to the long axis of the fiber. The crystal alignment makes the fiber incredibly strong for its size. Several thousand carbon fibers are twisted together to form a yarn, which may be used by itself or woven into a fabric.[1] Carbon fiber can be combined with a plastic resin and wound or molded to form composite materials such as carbon fiber reinforced plastic (also referenced as carbon fiber) to provide a high strength-to-weight ratio material. The density of carbon fiber is also considerably lower than the density of steel, making it ideal for applications requiring low weight.[2] The properties of carbon fiber such as high tensile strength, low weight, and low thermal expansion make it very popular in aerospace, military, and motorsports, along with other competition sports.
# History of Carbon Fiber
In 1958, Dr. Roger Bacon created the first high-performance carbon fibers at the Union Carbide Parma Technical Center, located outside of Cleveland, Ohio.[3]The first fibers were manufactured by heating strands of rayon until they carbonized. This process proved to be inefficient, as the resulting fibers contained only about 20% carbon and had low strength and stiffness properties. In the early 1960s, a process was developed using polyacrylonitrile as a raw material. This produced a carbon fiber that contained about 55% carbon and had much better properties. The polyacrylonitrile conversion process quickly became the primary method for producing carbon fibers.[1]
On January 14, 1969 Carr Reinforcements wove the first ever carbon fiber fabric in the world.[4]
During the 1970s, experimental work to find alternative raw materials led to the introduction of carbon fibers made from a petroleum pitch derived from oil processing. These fibers contained about 85% carbon and had excellent flexural strength.[1]
# Structure and properties
Carbon fibers are the closest to asbestos in a number of properties.[5]
Each carbon filament thread is a bundle of many thousand carbon filaments. A single such filament is a thin tube with a diameter of 5–8 micrometers and consists almost exclusively of carbon.
The atomic structure of carbon fiber is similar to that of graphite, consisting of sheets of carbon atoms (graphene sheets) arranged in a regular hexagonal pattern. The difference lies in the way these sheets interlock. Graphite is a crystalline material in which the sheets are stacked parallel to one another in regular fashion. The chemical bonds between the sheets are relatively weak Van der Waals forces, giving graphite its soft and brittle characteristics. Depending upon the precursor to make the fiber, carbon fiber may be turbostratic or graphitic, or have a hybrid structure with both graphitic and turbostratic parts present. In turbostratic carbon fiber the sheets of carbon atoms are haphazardly folded, or crumpled, together. Carbon fibers derived from Polyacrylonitrile (PAN) are turbostratic, whereas carbon fibers derived from mesophase pitch are graphitic after heat treatment at temperatures exceeding 2200 C. Turbostratic carbon fibers tend to have high tensile strength, wheresas heat-treated mesophase-pitch-derived carbon fibers have high Young's modulus and high thermal conductivity.
# Applications
Template:For2
Carbon fiber is most notably used to reinforce composite materials, particularly the class of materials known as Carbon fiber or graphite reinforced polymers. Another utilization of Carbon Fiber is its added aesthetic value to various consumer products.
Carbon Fiber as a tough and lightweight material is applied in the production of watch cases and dials. In watchmaking the material is often combined with polymer to improve its strength.[6]
Non-polymer materials can also be used as the matrix for carbon fibers. Due to the formation of metal carbides (i.e., water-soluble AlC) and corrosion considerations, carbon has seen limited success in metal matrix composite applications. Reinforced carbon-carbon (RCC) consists of carbon fiber-reinforced graphite, and is used structurally in high-temperature applications. The fiber also finds use in filtration of high-temperature gases, as an electrode with high surface area and impeccable corrosion resistance, and as an anti-static component.
Carbon fiber is also used in compressed gas tanks, including compressed air tanks.
Carbon fiber has recently been used for various decorative reasons such as doors and chairs.
# Synthesis
Each carbon filament is made out of long, thin filaments of carbon sometimes transformed to graphite. A common method of making carbon filaments is the oxidation and thermal pyrolysis of polyacrylonitrile (PAN), a polymer based on acrylonitrile used in the creation of synthetic materials. Like all polymers, polyacrylonitrile molecules are long chains, which are aligned in the process of drawing continuous filaments. A common method of manufacture involves heating the PAN to approximately 300 °C in air, which breaks many of the hydrogen bonds and oxidizes the material. The oxidized PAN is then placed into a furnace having an inert atmosphere of a gas such as argon, and heated to approximately 2000 °C, which induces graphitization of the material, changing the molecular bond structure. When heated in the correct conditions, these chains bond side-to-side (ladder polymers), forming narrow graphene sheets which eventually merge to form a single, jelly roll-shaped or round filament. The result is usually 93-95% carbon. Lower-quality fiber can be manufactured using pitch or rayon as the precursor instead of PAN. The carbon can become further enhanced, as high modulus, or high strength carbon, by heat treatment processes. Carbon heated in the range of 1500-2000 °C (carbonization) exhibits the highest tensile strength (820,000 psi or 5,650 MPa or 5,650 N/mm²), while carbon fiber heated from 2500 to 3000 °C (graphitizing) exhibits a higher modulus of elasticity (77,000,000 psi or 531 GPa or 531 kN/mm²).
# Textile
There are several categories of carbon fibers: standard modulus (250 GPa), intermediate modulus (300 GPa), and high modulus (> 300 GPa).[7] The tensile strength of different yarn types varies between 2000 and 7000 MPa. A typical density of carbon fiber is 1750 kg/m3.
Precursors for carbon fibers are PAN, rayon and pitch. Carbon fiber filament yarns are used in several processing techniques: the direct uses are for prepregging, filament winding, pultrusion, weaving, braiding etc. Carbon fiber yarn is rated by the linear density (weight per unit length = 1 g/1000 m = tex) or by number of filaments per yarn count, in thousands. For example, 200 tex for 3,000 filaments of carbon fiber is 3 times as strong as 1,000 carbon fibers but is also 3 times as heavy. This thread can then be used to weave a carbon fiber filament fabric or cloth. The appearance of this fabric generally depends on the linear density of the yarn and the weave chosen. Some commonly used types of weave are twill, satin and plain.
# Manufacturers
PAN aerospace/high end carbon fiber:
Toray Industries (largest worldwide manufacturer)
Toho Tenax
Mitsubishi
Hexcel
Cytec Industries
PAN commercial grade carbon fiber:
Zoltek
SGL
Fortafil
Pitch carbon fiber:
Sumitomo | https://www.wikidoc.org/index.php/Carbon_fiber | |
d80fbf2f4e9e209f7e98291c9bb36ca46838f821 | wikidoc | Nutmeg liver | Nutmeg liver
Synonyms and keywords: Cardiac cirrhosis
# Overview
Nutmeg liver is the pathological appearance of the liver caused by chronic passive congestion of the liver secondary to right heart failure. The liver appears "speckled" like a grated nutmeg kernel, from the dilated, congested central veins (dark spots) and paler, unaffected surrounding liver tissue. When severe and longstanding, hepatic congestion can lead to cirrhosis, a state described as cardiac cirrhosis.
# Pathophysiology
Increased pressure in the sublobular branches of the hepatic veins causes an engorgement of venous blood, and is most frequently due to chronic cardiac lesions, especially those affecting the right heart, the blood being dammed back in the inferior vena cava and hepatic veins.
## Gross Pathology
Central regions of the hepatic lobes are red/brown and stand out against the non-congested tan colored liver. Centrilobular necrosis occurs. Macroscopically liver has a pale and spotty appearance in affected areas as stasis of the blood causes pericentral hepatocytes (liver cells surrounding the periportal venules of the liver) to become deoxygenated compared to the relatively better oxygenated periportal hepatocytes adjacent to the hepatic arterioles. This retardation of the blood also occurs in pulmonary lesions, such as chronic interstitial pneumonia, pleural effusions, and intrathoracic tumors.
## Pathological Findings
Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology
- Passive Congestion: Gross natural color typical nutmeg liver
- Chronic Passive Congestion: Gross looks like natural color classical nutmeg liver
- Chronic Passive Congestion: Gross natural color frontal section nutmeg liver really a shock liver
- Liver: Congestive heart failure, liver fibrosis; Central hepatic veins are pale spots, nutmeg liver
- Liver: Passive Congestion: Gross close-up excellent nutmeg appearance
- Passive Congestion: Gross split picture with liver on one side and a polished nutmeg on the other (very good demonstration)
- Passive Congestion: Gross close-up of cut surface natural color looks almost exactly like a nutmeg
# Symptoms
These depend largely upon the primary lesions giving rise to it. In addition to the cardiac or pulmonary symptoms, there will be a sense of fullness and tenderness in the right hypochondriac region. Gastro-intestinal catarrh is usually present, and hematemesis may occur. There is usually more or less jaundice. Owing to portal obstruction, ascites occurs, followed later by general dropsy. The stools are light or clay colored, and the urine is colored by bile. On palpation, the liver is found enlarged and tender, sometimes extending several inches below the costal margin of the ribs.
# Treatment
This is directed largely to removing the cause, or, where that is impossible, to modifying its effects. Thus hygienic and dietary measures must be carried out, even although it is due to valvular lesions. | Nutmeg liver
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor: Cafer Zorkun, M.D., Ph.D. [2]
Synonyms and keywords: Cardiac cirrhosis
# Overview
Nutmeg liver is the pathological appearance of the liver caused by chronic passive congestion of the liver secondary to right heart failure. The liver appears "speckled" like a grated nutmeg kernel, from the dilated, congested central veins (dark spots) and paler, unaffected surrounding liver tissue. When severe and longstanding, hepatic congestion can lead to cirrhosis, a state described as cardiac cirrhosis.[1]
# Pathophysiology
Increased pressure in the sublobular branches of the hepatic veins causes an engorgement of venous blood, and is most frequently due to chronic cardiac lesions, especially those affecting the right heart, the blood being dammed back in the inferior vena cava and hepatic veins.
## Gross Pathology
Central regions of the hepatic lobes are red/brown and stand out against the non-congested tan colored liver. Centrilobular necrosis occurs. Macroscopically liver has a pale and spotty appearance in affected areas as stasis of the blood causes pericentral hepatocytes (liver cells surrounding the periportal venules of the liver) to become deoxygenated compared to the relatively better oxygenated periportal hepatocytes adjacent to the hepatic arterioles. This retardation of the blood also occurs in pulmonary lesions, such as chronic interstitial pneumonia, pleural effusions, and intrathoracic tumors.
## Pathological Findings
Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology
- Passive Congestion: Gross natural color typical nutmeg liver
- Chronic Passive Congestion: Gross looks like natural color classical nutmeg liver
- Chronic Passive Congestion: Gross natural color frontal section nutmeg liver really a shock liver
- Liver: Congestive heart failure, liver fibrosis; Central hepatic veins are pale spots, nutmeg liver
- Liver: Passive Congestion: Gross close-up excellent nutmeg appearance
- Passive Congestion: Gross split picture with liver on one side and a polished nutmeg on the other (very good demonstration)
- Passive Congestion: Gross close-up of cut surface natural color looks almost exactly like a nutmeg
# Symptoms
These depend largely upon the primary lesions giving rise to it. In addition to the cardiac or pulmonary symptoms, there will be a sense of fullness and tenderness in the right hypochondriac region. Gastro-intestinal catarrh is usually present, and hematemesis may occur. There is usually more or less jaundice. Owing to portal obstruction, ascites occurs, followed later by general dropsy. The stools are light or clay colored, and the urine is colored by bile. On palpation, the liver is found enlarged and tender, sometimes extending several inches below the costal margin of the ribs.
# Treatment
This is directed largely to removing the cause, or, where that is impossible, to modifying its effects. Thus hygienic and dietary measures must be carried out, even although it is due to valvular lesions. | https://www.wikidoc.org/index.php/Cardiac_Cirrhosis | |
30fe50cbf52211c3e71324f98f33576ffbaf26b8 | wikidoc | Sinus rhythm | Sinus rhythm
Sinus rhythm is a term used in medicine to describe the normal beating of the heart, as measured by an electrocardiogram (ECG). It has certain generic features that serve as hallmarks for comparison with normal ECGs.
## ECG Structure
There are typically five distinct waves (identified by the letters P, Q, R, S, and T) in a single beat of the heart in sinus rhythm, and they occur in a specific order, over specific periods of time, with specific relative sizes. While there is a significant range within which variations in rhythm are considered normal, anything that deviates from sinus rhythm by more than a certain amount may be indicative of heart disease.
## Sinus Rhythm on ECG
Sinus rhythm is characterized by a usual rate of anywhere between 60-100 bpm. Every QRS complex is preceded by a P wave and every P wave must be followed by a QRS (the opposite occurs if there is second or third degree AV block). The P wave morphology and axis must be normal and the PR interval will usually be 120 ms or greater.
In normal sinus rhythm, electrical impulses from the SA node travel to the AV node with successful contraction of the two atria. The electrical impulses from the AV node successfully contract the ventricles. On the ECG, there are normal PQRST elements with no evidence of arrhythmia, tachycardia, or bradycardia.
# Depolarization of the SA Node
In Normal Sinus Rhythm the pacemaker impulse is formed in the SA node which is located near the junction of the superior vena cava and right atrium. The impulse now spreads leftward and inferiorly through the atria (at first only in the RA, then in both RA and LA and finally only in the LA). Small fascicles of tissue which resemble conduction tissue can be demonstrated in the atria, called intra-atrial pathways which connect both atria and help organize atrial depolarization. A reasonable concept is to consider the spread of electrical stimulation through the atria as ripples on a pond with the pebble falling into the pond at the SA node and then spreading throughout the atria. Atrial depolarization inscribes the P wave on the ECG.
# Depolarization of the AV Node
After depolarization of the atria, the impulse now arrives at the AV node. This is the only normal electrical connection between the atria and ventricles and serves as a safety valve to prevent too many atrial impulses from reaching the ventricles. The AV node is very complex and consists of several layers of cells having different action potentials and conduction characteristics. Since the atrial stimulus is delayed in the junctional area and there is no deplolarization of myocardium the ECG returns to the baseline as the PR segment.
# Depolarization of the His Bundle and Right and Left Bundle or His Purkinje System (HPS)
Once the stimulus leaves the AV node it arrives at the His Bundle. The His bundle shortly divides into the right bundle branch and left bundle branch. The Left Bundle divides into a smaller anterior and a larger posterior radiation which fans out in the endocardial layers and meets again in the periphery as fibers of the Purkinje System. Conduction down all three major fascicles (Left anterior, Left posterior, and Right Bundle) is very rapid and is not represented on the ECG. The stimulus is then delivered to the endocardial surfaces of the RV and LV very rapidly and the myocardium depolarizes to form the QRS.
# EKG Examples
- Normal sinus rhythm.
- Normal sinus rhythm. | Sinus rhythm
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Sinus rhythm is a term used in medicine to describe the normal beating of the heart, as measured by an electrocardiogram (ECG). It has certain generic features that serve as hallmarks for comparison with normal ECGs.
## ECG Structure
There are typically five distinct waves (identified by the letters P, Q, R, S, and T) in a single beat of the heart in sinus rhythm, and they occur in a specific order, over specific periods of time, with specific relative sizes. While there is a significant range within which variations in rhythm are considered normal, anything that deviates from sinus rhythm by more than a certain amount may be indicative of heart disease.
## Sinus Rhythm on ECG
Sinus rhythm is characterized by a usual rate of anywhere between 60-100 bpm. Every QRS complex is preceded by a P wave and every P wave must be followed by a QRS (the opposite occurs if there is second or third degree AV block). The P wave morphology and axis must be normal and the PR interval will usually be 120 ms or greater.
In normal sinus rhythm, electrical impulses from the SA node travel to the AV node with successful contraction of the two atria. The electrical impulses from the AV node successfully contract the ventricles. On the ECG, there are normal PQRST elements with no evidence of arrhythmia, tachycardia, or bradycardia.
# Depolarization of the SA Node
In Normal Sinus Rhythm the pacemaker impulse is formed in the SA node which is located near the junction of the superior vena cava and right atrium. The impulse now spreads leftward and inferiorly through the atria (at first only in the RA, then in both RA and LA and finally only in the LA). Small fascicles of tissue which resemble conduction tissue can be demonstrated in the atria, called intra-atrial pathways which connect both atria and help organize atrial depolarization. A reasonable concept is to consider the spread of electrical stimulation through the atria as ripples on a pond with the pebble falling into the pond at the SA node and then spreading throughout the atria. Atrial depolarization inscribes the P wave on the ECG.
# Depolarization of the AV Node
After depolarization of the atria, the impulse now arrives at the AV node. This is the only normal electrical connection between the atria and ventricles and serves as a safety valve to prevent too many atrial impulses from reaching the ventricles. The AV node is very complex and consists of several layers of cells having different action potentials and conduction characteristics. Since the atrial stimulus is delayed in the junctional area and there is no deplolarization of myocardium the ECG returns to the baseline as the PR segment.
# Depolarization of the His Bundle and Right and Left Bundle or His Purkinje System (HPS)
Once the stimulus leaves the AV node it arrives at the His Bundle. The His bundle shortly divides into the right bundle branch and left bundle branch. The Left Bundle divides into a smaller anterior and a larger posterior radiation which fans out in the endocardial layers and meets again in the periphery as fibers of the Purkinje System. Conduction down all three major fascicles (Left anterior, Left posterior, and Right Bundle) is very rapid and is not represented on the ECG. The stimulus is then delivered to the endocardial surfaces of the RV and LV very rapidly and the myocardium depolarizes to form the QRS.
# EKG Examples
- Normal sinus rhythm.
- Normal sinus rhythm.
# External links
- Normal Sinus Rhythm
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cardiac_rhythm | |
76ffa2d88aa7e303e25563bc4d137852f321c5c4 | wikidoc | Cardioplegia | Cardioplegia
# Overview
Cardioplegia is the intentional and temporary cessation of cardiac activity, primarily used in cardiac surgery.
The most common procedure for accomplishing asystole is infusing cold crystalloid cardioplegia into the coronary circulation. This process is considered the most successful because it protects the myocardium, or heart muscle, from damage . In most cases, the patient is first exposed to mild hypothermia (34 degrees celsius). Then an iced (4 degrees celsius) solution of dextrose, potassium chloride, and other ingredients is introduced into coronary circulation via specialized cannulae.
When solution is introduced into the aortic root (with an aortic cross-clamp on the distal aorta to limit systemic circulation), this is called Antegrade Cardioplegia. When introduced into the coronary sinus it is called Retrograde Cardioplegia. | Cardioplegia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cardioplegia is the intentional and temporary cessation of cardiac activity, primarily used in cardiac surgery.
The most common procedure for accomplishing asystole is infusing cold crystalloid cardioplegia into the coronary circulation. This process is considered the most successful because it protects the myocardium, or heart muscle, from damage [1]. In most cases, the patient is first exposed to mild hypothermia (34 degrees celsius). Then an iced (4 degrees celsius) solution of dextrose, potassium chloride, and other ingredients [2] is introduced into coronary circulation via specialized cannulae.
When solution is introduced into the aortic root (with an aortic cross-clamp on the distal aorta to limit systemic circulation), this is called Antegrade Cardioplegia. When introduced into the coronary sinus it is called Retrograde Cardioplegia. [3] | https://www.wikidoc.org/index.php/Cardioplegia | |
ea11cf3ae255e9c7c60487479a65afd0129340b3 | wikidoc | Care centers | Care centers
# Overview
The initial urgent care centers opened in the 1970s. Since then this sector of the healthcare industry has rapidly expanded to an approximately 17,000 centers. Many of these centers have been started by entrepreneurial physicians who have responded to the public need for convenient access to unscheduled medical care. Other centers have been opened by hospital systems, seeking to attract patients. Much of the growth of these centers has been fueled by the significant savings that urgent care centers provide over the care in a hospital emergency department.
Many managed care organizations (MCOs) now encourage their customers to utilize the urgent care option.
# Other ambulatory healthcare facilities
Urgent care centers are distinguished from other similar types of ambulatory healthcare centers.
## Emergency departments
Emergency departments are located within hospitals and are prepared to care for patients suffering true emergencies, such as myocardial infarctions ("heart attacks"), serious motor vehicle accidents, suicide attempts, and other such life-threatening conditions. Being located within a hospital, these centers are positioned to provide ready access to major surgeries and critical care units. Emergency departments are usually staffed by physicians with specialized training or board certification in emergency medicine. Most states in the USA require all hospitals to house an emergency department within the hospital building. A few states in the USA allow freestanding emergency departments to be built outside of a hospital building. Many authorities would consider this type of facility to be a high-acuity urgent care center, rather than a true emergency department.
## Primary care offices with extended hours
Many primary care offices are open for some hours in the evenings and weekends. However, unless these centers are open for walk-in patients at all times when open for patients, offer on-site x-ray facilities, and care for most simple fractures and lacerations--these primary care physician offices are not considered to be true urgent care centers.
## Walk-in primary care offices
Allowing walk-in patients is not a sufficient criterion to define a physician office as an urgent care. If the office does not offer the expanded services and significant after-hours care, then the physician office would not fit the definition of an urgent care center.
## Mid-level provider offices in retail stores
In 2000, medical treatment began to be offered at small offices in retail stores with onsite pharmacies. These centers are generally staffed with nurse practitioners or physician assistants. Prices are generally posted in public view and patients can do shopping while waiting. Some experts consider these medical treatment sites to be the wave of the future in light of consumer driven health plans such as Health Savings Accounts. These retail clinics are not true urgent care centers, because of the limited level of care that can be provided without a physician nor x-ray facilities on site. Concerns about conflict of interest and incentives to over-prescribe medications in a facility rented from a pharmacy have yet to be fully addressed by organized medicine or governmental agencies.
# Organized medicine and urgent care
The Urgent Care Association of America (UCAOA) holds an annual spring convention and, also, offers an annual fall conference. The American Academy of Urgent Care Medicine (AAUCM), also, holds an annual convention. Many leaders in organized urgent care medicine anticipate the full establishment of urgent care as a fully-recognized specialty.
Examples of resources for care centers:
- AIDS Care Center
- Amputees
- Breast Cancer Care Center
- Colon Cancer Care Center
- Heart Attack
- Lung Cancer Care Center
- Stroke Care Center
- Wilson's Disease Care Center
- Women's Health Care Center | Care centers
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The initial urgent care centers opened in the 1970s. Since then this sector of the healthcare industry has rapidly expanded to an approximately 17,000 centers. Many of these centers have been started by entrepreneurial physicians who have responded to the public need for convenient access to unscheduled medical care. Other centers have been opened by hospital systems, seeking to attract patients. Much of the growth of these centers has been fueled by the significant savings that urgent care centers provide over the care in a hospital emergency department.
Many managed care organizations (MCOs) now encourage their customers to utilize the urgent care option.
# Other ambulatory healthcare facilities
Urgent care centers are distinguished from other similar types of ambulatory healthcare centers.
## Emergency departments
Emergency departments are located within hospitals and are prepared to care for patients suffering true emergencies, such as myocardial infarctions ("heart attacks"), serious motor vehicle accidents, suicide attempts, and other such life-threatening conditions. Being located within a hospital, these centers are positioned to provide ready access to major surgeries and critical care units. Emergency departments are usually staffed by physicians with specialized training or board certification in emergency medicine. Most states in the USA require all hospitals to house an emergency department within the hospital building. A few states in the USA allow freestanding emergency departments to be built outside of a hospital building. Many authorities would consider this type of facility to be a high-acuity urgent care center, rather than a true emergency department.
## Primary care offices with extended hours
Many primary care offices are open for some hours in the evenings and weekends. However, unless these centers are open for walk-in patients at all times when open for patients, offer on-site x-ray facilities, and care for most simple fractures and lacerations--these primary care physician offices are not considered to be true urgent care centers.
## Walk-in primary care offices
Allowing walk-in patients is not a sufficient criterion to define a physician office as an urgent care. If the office does not offer the expanded services and significant after-hours care, then the physician office would not fit the definition of an urgent care center.
## Mid-level provider offices in retail stores
In 2000, medical treatment began to be offered at small offices in retail stores with onsite pharmacies. These centers are generally staffed with nurse practitioners or physician assistants. Prices are generally posted in public view and patients can do shopping while waiting. Some experts consider these medical treatment sites to be the wave of the future in light of consumer driven health plans such as Health Savings Accounts. These retail clinics are not true urgent care centers, because of the limited level of care that can be provided without a physician nor x-ray facilities on site. Concerns about conflict of interest and incentives to over-prescribe medications in a facility rented from a pharmacy have yet to be fully addressed by organized medicine or governmental agencies.
# Organized medicine and urgent care
The Urgent Care Association of America (UCAOA) holds an annual spring convention and, also, offers an annual fall conference. The American Academy of Urgent Care Medicine (AAUCM), also, holds an annual convention. Many leaders in organized urgent care medicine anticipate the full establishment of urgent care as a fully-recognized specialty.
Examples of resources for care centers:
- AIDS Care Center
- Amputees
- Breast Cancer Care Center
- Colon Cancer Care Center
- Heart Attack
- Lung Cancer Care Center
- Stroke Care Center
- Wilson's Disease Care Center
- Women's Health Care Center
# External links
- Homepage of Immediate Care Business magazine
- Homepage of the American Academy of Urgent Care Medicine
- Homepage of the Urgent Care Journal
- Homepage of the National Association For Ambulatory Care
- Homepage of the Urgent Care Association of America
- Homepage of the Journal of Urgent Care Medicine (JUCM)
Template:WS | https://www.wikidoc.org/index.php/Care_Centers | |
5a7f6185cd288b79620632dc557224890150faec | wikidoc | Carey Coombs | Carey Coombs
Carey Franklin Coombs (1879-1932) was an English cardiologist who practiced medicine at Bristol General Hospital.
Coombs is remembered for his work involving rheumatic and coronary heart disease.
# Murmur
- He performed important studies of rheumatic fever, and described a rumbling mid-diastolic cardiac murmur that occurs in the acute phase of rheumatic fever which disappears as the valvulitis improves.
- It is often associated with an S3 gallop rhythm, and can be distinguished from the diastolic murmur of mitral stenosis by the absence of an opening snap before the murmur.
- The murmur is caused by increased blood flow across a thickened mitral valve.
This cardiac murmur is now referred to as the Carey Coombs murmur. In 1910 he made one of the earliest diagnoses of coronary thrombosis, and before his death in 1932, he had documented 144 cases of this condition.
His best known written work is Rheumatic Heart Disease, which was published in 1924. He is also remembered for his work in the management and prevention of childhood heart disease.
# Related Chapters
- Rheumatic fever | Carey Coombs
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Carey Franklin Coombs (1879-1932) was an English cardiologist who practiced medicine at Bristol General Hospital.
Coombs is remembered for his work involving rheumatic and coronary heart disease.
# Murmur
- He performed important studies of rheumatic fever, and described a rumbling mid-diastolic cardiac murmur that occurs in the acute phase of rheumatic fever which disappears as the valvulitis improves.
- It is often associated with an S3 gallop rhythm, and can be distinguished from the diastolic murmur of mitral stenosis by the absence of an opening snap before the murmur.
- The murmur is caused by increased blood flow across a thickened mitral valve.
This cardiac murmur is now referred to as the Carey Coombs murmur. In 1910 he made one of the earliest diagnoses of coronary thrombosis, and before his death in 1932, he had documented 144 cases of this condition.
His best known written work is Rheumatic Heart Disease, which was published in 1924. He is also remembered for his work in the management and prevention of childhood heart disease.
# Related Chapters
- Rheumatic fever | https://www.wikidoc.org/index.php/Carey-Coombs_murmur | |
aeda8ddf61da4f3d160011703bbbc1df2c9ec0a7 | wikidoc | Carnauba wax | Carnauba wax
Carnauba is a wax derived from the leaves of the carnauba palm (Copernicia prunifera), a plant native to northeastern Brazil. It is known as "queen of waxes" and usually comes in the form of hard yellow-brown flakes. It is obtained from the leaves of the carnauba palm by collecting them, beating them to loosen the wax, then refining and bleaching the wax.
# Composition
Carnauba wax contains mainly esters of fatty acids (80-85%), fatty alcohols (10-16%), acids (3-6%) and hydrocarbons (1-3%). Specific for carnauba wax is the content of esterified fatty diols (about 20%), hydroxylated fatty acids (about 6%) and cinnamic acid (about 10%). Cinnamic acid, an antioxidant, may be hydroxylated or methoxylated.
# Uses
Carnauba wax can produce a glossy finish and as such is used in automobile waxes, shoe polishes, food products such as candy corn, instrument polishes, and floor and furniture polishes, especially when mixed with beeswax. It is used as a coating on dental floss. Use for paper coatings is the most common application in the United States. It is the main ingredient in surfboard wax, combined with coconut oil.
Carnauba wax is a prominent ingredient in cosmetics formulas: lipsticks, eyeliners, mascara, eye shadows, foundations, blushers, skin care preparations, sun care preparations, etc.
It is the finish of choice for most briar pipes. It produces a high gloss finish when buffed on to wood. This finish dulls with time rather than flaking off (as is the case with most other finishes used.)
In foods, it is used as a formulation aid, lubricant, release agent, anticaking agent, and surface finishing agent in baked foods and mixes, chewing gum, confections, frostings, fresh fruits and juices, gravies, sauces, processed fruits and juices, soft candy, tic tacs and Altoids.
It is also used in the pharmaceutical industry as a tablet coating agent.
In 1890, Charles Tainter patented the use of carnauba wax on phonograph cylinders as a replacement for a mixture of paraffin and beeswax.
When used as a mold release, carnauba, unlike silicone or PTFE, is suitable for use with liquid epoxy, epoxy molding compounds (EMC) and some other plastic types. Carnauba wax is compatible with epoxies and generally enhances its properties along with those of most other engineering plastics.
An aerosol mold release is formed by suspending carnauba wax in a solvent. This aerosol version is used extensively in molds for semiconductor devices. Semiconductor manufacturers also use chunks of carnauba wax to break in new epoxy molds or to release the plunger when it sticks.
# Technical characteristics
- INCI name is Copernicia Cerifera (carnauba) wax
- E Number is E903.
- melting point: 78-85 °C, among the highest of natural waxes.
- relative density is about 0.97
- It is among the hardest of natural waxes, being harder than concrete in its pure form.
- It is practically insoluble in water, soluble on heating in ethyl acetate and in xylene, practically insoluble in ethyl alcohol. | Carnauba wax
Carnauba is a wax derived from the leaves of the carnauba palm (Copernicia prunifera), a plant native to northeastern Brazil. It is known as "queen of waxes"[1] and usually comes in the form of hard yellow-brown flakes. It is obtained from the leaves of the carnauba palm by collecting them, beating them to loosen the wax, then refining and bleaching the wax.
# Composition
Carnauba wax contains mainly esters of fatty acids (80-85%), fatty alcohols (10-16%), acids (3-6%) and hydrocarbons (1-3%). Specific for carnauba wax is the content of esterified fatty diols (about 20%), hydroxylated fatty acids (about 6%) and cinnamic acid (about 10%). Cinnamic acid, an antioxidant, may be hydroxylated or methoxylated.
# Uses
Carnauba wax can produce a glossy finish and as such is used in automobile waxes, shoe polishes, food products such as candy corn, instrument polishes, and floor and furniture polishes, especially when mixed with beeswax. It is used as a coating on dental floss. Use for paper coatings is the most common application in the United States. It is the main ingredient in surfboard wax, combined with coconut oil.
Carnauba wax is a prominent ingredient in cosmetics formulas: lipsticks, eyeliners, mascara, eye shadows, foundations, blushers, skin care preparations, sun care preparations, etc.[citation needed]
It is the finish of choice for most briar pipes. It produces a high gloss finish when buffed on to wood. This finish dulls with time rather than flaking off (as is the case with most other finishes used.)
In foods, it is used as a formulation aid, lubricant, release agent, anticaking agent, and surface finishing agent in baked foods and mixes, chewing gum, confections, frostings, fresh fruits and juices, gravies, sauces, processed fruits and juices, soft candy, tic tacs and Altoids.
It is also used in the pharmaceutical industry as a tablet coating agent.
In 1890, Charles Tainter patented the use of carnauba wax on phonograph cylinders as a replacement for a mixture of paraffin and beeswax.
When used as a mold release, carnauba, unlike silicone or PTFE, is suitable for use with liquid epoxy, epoxy molding compounds (EMC) and some other plastic types. Carnauba wax is compatible with epoxies and generally enhances its properties along with those of most other engineering plastics.
An aerosol mold release is formed by suspending carnauba wax in a solvent. This aerosol version is used extensively in molds for semiconductor devices. Semiconductor manufacturers also use chunks of carnauba wax to break in new epoxy molds or to release the plunger when it sticks.
# Technical characteristics
- INCI name is Copernicia Cerifera (carnauba) wax
- E Number is E903.
- melting point: 78-85 °C, among the highest of natural waxes.
- relative density is about 0.97
- It is among the hardest of natural waxes, being harder than concrete in its pure form.
- It is practically insoluble in water, soluble on heating in ethyl acetate and in xylene, practically insoluble in ethyl alcohol. | https://www.wikidoc.org/index.php/Carnauba_wax | |
ad41d41b34653c39d95c45d68672c5592fbfa0a6 | wikidoc | Carotid body | Carotid body
The carotid body (or carotid glomus) is a small cluster of chemoreceptors and supporting cells located near the bifurcation of the carotid artery.
It measures changes in the composition of arterial blood flowing through it, including the partial pressures of oxygen and carbon dioxide and is also sensitive to changes in pH and temperature.
The carotid body is made up of two types of cell: type I (glomus) cells, and type II (sustentacular) cells. Glomus cells are derived from Neural Crest (Gonzalez et al, 1994). They release a variety of neurotransmitters, including acetylcholine, ATP, and dopamine that trigger EPSP's in synapsed neurons leading to the respiratory center.
Type II cells resemble glia and act as supporting cells.
While the central chemoreceptors in the brainstem are highly sensitive to CO2 the carotid body is a peripheral chemoreceptor that provides afferent input to the respiratory center that is highly O2 dependent.
The output of the carotid bodies is low at an oxygen partial pressure above about 100 mmHg (torr) (at normal physiological pH), but below this the activity of the type I glomus cells increases rapidly.
The peripheral chemoreceptor's input is usually secondary to CO2 central chemoreceptors in healthy patients, but becomes the primary driver of ventilation in individuals who suffer from chronic hypercapnia (such as emphysema). Non-responsive hypercapnia can induce a tolerance mechanism within the cerebrospinal fluid, effectively negating carbon dioxide as a ventilation stimulus. In major cases this can prevent the use of general anaesthesia, as the carotid body is unable to communicate with the central nervous system sufficiently to stimulate breathing during recovery.
The feedback from the carotid body is sent to the respiratory centers in the medulla oblongata via the afferent branches of the glossopharyngeal nerve (IX). These centers, in turn, regulate breathing and blood pressure.
# Disorders
A paraganglioma is a tumor that may involve the carotid body.
# How they work
The type 1 glomus cells in the carotid (and aortic bodies) are derived from neuroectoderm, and are electrically excitable. A decrease in oxygen partial pressure, an increase in carbon dioxide partial pressure, and a decrease in arterial pH can all cause depolarization of the cell membrane, and they effect this by blocking potassium currents. This reduction in the membrane potential opens voltage-gated calcium channels, which causes a rise in intracellular calcium concentration. This causes exocytosis of vesicles containing a variety of neurotransmitters, including acetylcholine, noradrenaline, dopamine, substance P, and met-enkephalin. These act on receptors on the afferent nerve fibres which lie in apposition to the glomus cell to cause an action potential. This relays the information from the glomus cell to the respiratory centres.
The mechanism for detecting reductions in PO2 is not well understood. There may be a heme-containing protein in the glomus cell which responds to the loss of complexed oxygen by reducing the probability of potassium channels being open. Another possibility is that low PO2 inhibits NADPH oxidase in mitochondria. This would increase the ratio of reduced glutathione to oxidised glutathione, which blocks potassium channels.
An increased PCO2 is detected because the CO2 diffuses into the cell, where it increase the concentration of carbonic acid and thus protons. These protons displace calcium from high-conductance calcium channels, reducing potassium current.
Arterial acidosis (either metabolic or from altered PCO2) inhibits acid-base transporters (e.g. Na+-H+) which raise intracellular pH, and activates transporters (e.g. Cl--HCO3-) which decrease it. Changes in proton concentration caused by acidosis (or the opposite from alkalosis) inside the cell stimulates the same pathways involved in PCO2 sensing. | Carotid body
Template:Infobox Anatomy
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The carotid body (or carotid glomus) is a small cluster of chemoreceptors and supporting cells located near the bifurcation of the carotid artery.
It measures changes in the composition of arterial blood flowing through it, including the partial pressures of oxygen and carbon dioxide and is also sensitive to changes in pH and temperature.
The carotid body is made up of two types of cell: type I (glomus) cells, and type II (sustentacular) cells. Glomus cells are derived from Neural Crest (Gonzalez et al, 1994). They release a variety of neurotransmitters, including acetylcholine, ATP, and dopamine that trigger EPSP's in synapsed neurons leading to the respiratory center.
Type II cells resemble glia and act as supporting cells.
While the central chemoreceptors in the brainstem are highly sensitive to CO2 the carotid body is a peripheral chemoreceptor that provides afferent input to the respiratory center that is highly O2 dependent.
The output of the carotid bodies is low at an oxygen partial pressure above about 100 mmHg (torr) (at normal physiological pH), but below this the activity of the type I glomus cells increases rapidly.
The peripheral chemoreceptor's input is usually secondary to CO2 central chemoreceptors in healthy patients, but becomes the primary driver of ventilation in individuals who suffer from chronic hypercapnia (such as emphysema). Non-responsive hypercapnia can induce a tolerance mechanism within the cerebrospinal fluid, effectively negating carbon dioxide as a ventilation stimulus. In major cases this can prevent the use of general anaesthesia, as the carotid body is unable to communicate with the central nervous system sufficiently to stimulate breathing during recovery.
The feedback from the carotid body is sent to the respiratory centers in the medulla oblongata via the afferent branches of the glossopharyngeal nerve (IX). These centers, in turn, regulate breathing and blood pressure.
# Disorders
A paraganglioma is a tumor that may involve the carotid body.
# How they work
The type 1 glomus cells in the carotid (and aortic bodies) are derived from neuroectoderm, and are electrically excitable. A decrease in oxygen partial pressure, an increase in carbon dioxide partial pressure, and a decrease in arterial pH can all cause depolarization of the cell membrane, and they effect this by blocking potassium currents. This reduction in the membrane potential opens voltage-gated calcium channels, which causes a rise in intracellular calcium concentration. This causes exocytosis of vesicles containing a variety of neurotransmitters, including acetylcholine, noradrenaline, dopamine, substance P, and met-enkephalin. These act on receptors on the afferent nerve fibres which lie in apposition to the glomus cell to cause an action potential. This relays the information from the glomus cell to the respiratory centres.
The mechanism for detecting reductions in PO2 is not well understood. There may be a heme-containing protein in the glomus cell which responds to the loss of complexed oxygen by reducing the probability of potassium channels being open. Another possibility is that low PO2 inhibits NADPH oxidase in mitochondria. This would increase the ratio of reduced glutathione to oxidised glutathione, which blocks potassium channels.
An increased PCO2 is detected because the CO2 diffuses into the cell, where it increase the concentration of carbonic acid and thus protons. These protons displace calcium from high-conductance calcium channels, reducing potassium current.
Arterial acidosis (either metabolic or from altered PCO2) inhibits acid-base transporters (e.g. Na+-H+) which raise intracellular pH, and activates transporters (e.g. Cl--HCO3-) which decrease it. Changes in proton concentration caused by acidosis (or the opposite from alkalosis) inside the cell stimulates the same pathways involved in PCO2 sensing. | https://www.wikidoc.org/index.php/Carotid_bodies | |
81ebd37cd09de3bcc5c68ef017f25f04e1246a6a | wikidoc | Case-control | Case-control
Case-control studies are one type of epidemiological study design. They are used to identify factors that may contribute to a medical condition by comparing a group of patients who have that condition with a group of patients who do not.
Case-control studies are a relatively inexpensive and frequently-used type of epidemiological study that can be carried out by small teams or individual researchers in single facilities in a way that more structured trials often cannot be. They have pointed the way to a number of important discoveries and advances, but their retrospective, non-randomized nature limits the conclusions that can be drawn from them.
The great triumph of the case-control study was the demonstration of the link between tobacco smoking and lung cancer, by Sir Richard Doll and others after him. Doll was able to show a statistically significant association between the two in a large case control study. Opponents, usually backed by the tobacco industry, argued (correctly) for many years that this type of study cannot prove causation, but the eventual results of cohort studies confirmed the causal link which the case-control studies suggested, and it is now accepted that tobacco smoking is the cause of about 87% of all lung cancer mortality in the US.
# Case-control studies
While the 'gold standard' of study design is the double blind randomized controlled trial, randomized controlled trials cannot be used to evaluate the effects of toxic substances. Studying infrequent events such as death from cancer using randomized clinical trials or other controlled prospective studies requires that large populations be tracked for lengthy periods to observe disease development. In the case of lung cancer this could involve 20 to 40 years, longer than the careers of most epidemiologists. In addition, these studies, which generally rely on government funding, are unlikely to be supported because of the low likelihood that the population will develop the disease. Case-control studies use patients who already have a disease or other condition and look back to see if there are characteristics of these patients that differ from those who don’t have the disease.
The case-control study provides a cheaper and quicker study of risk factors; if the evidence found is convincing enough, then resources can be allocated to more "credible" and comprehensive studies.
One major disadvantage of case-control studies is that they do not give any indication of the absolute risk of the factor in question. For instance, a case-control study may tell you that a certain behavior may be associated with a tenfold increased risk of death as compared with the control group. Although this sounds alarming, it would not tell you that the actual risk of death would change from one in ten million to one in one million, which is quite a bit less alarming. For that information, data from outside the case-control study must be consulted.
## Study methodology
## Comparison with cross-sectional studies
Cross-sectional studies (usually from "snapshot" surveys), sometimes called prevalence studies, can frequently be carried out on pre-existing data, such as that collected by the Census Bureau or the Centers for Disease Control. Such studies can cover study groups as large as the entire population of the United States; However, others could be small and geographically limited.
Cross-sectional studies can contain individual-level data (one record per individual, for example, in national health surveys). Others, however, might only convey group-level information; that is, no individual records are available to the researcher. Recent census data is not provided on individuals - in the UK individual census data is released only after a century. Instead data are aggregated at the group level. For example, by zip code, urban zone, or even by states/provinces or country.
For example, although cross-sectional studies confirm that people who consume large amounts of alcohol also show high rates of many other diseases, they can not determine with certainty which variable is the cause and which one is the effect. It only shows that these variables were "associated" at some point in time. The temporality or succession of events is not objectively certain.
Another problem may occur if the survey or cross-sectional study gathers information at the group level (or the administrator of the survey provides you only with group-level data and no individual-level data). In this case, you may not be able to access information needed to assess the contributions of other variables. For instance, high alcohol consumption is also associated with improper nutrition and hygiene, high rates of smoking and abuse of illegal drugs, and many other risk factors for disease. Ecological design containing only group-level information Cross-sectional studies cannot differentiate between these possible causes, but case-control studies can determine that gastrointestinal bleeding, say, is directly associated with high alcohol consumption, whereas memory deterioration is more associated with improper nutrition among alcoholics.
The advantage of case-control studies over cross-sectional studies that contain only group-level information, then, is the ability to determine the association between potential cause and effect on an individual basis. In the cross-sectional study individual variables are aggregated over the population as a whole, then an association is sought between the aggregated variables; These limitations, however, do not apply to case-control studies containing individual-level data; in this case, the "ecological fallacy" is not present. Cross-sectional design with individual-level data allows for computation of absolute risks (from prevalence) and relative risks or odds ratios.
In the case-control study, the association is determined for each individual case-control pair, then aggregated. This provides a more specific analysis of the possible associations, and potentially determines more accurately which possible causes are directly related to the effect being studied, and which are merely related by a common cause.
One benefit of cross-sectional studies is that they are considered to be "hypothesis generating", such that clues to exposure/disease relationships can often be seen in these studies, and then other studies, such as case-control, cohort studies or even sometimes randomized trials can be implemented to study this relationship.
# Problems with case-control studies
They are rated as low quality, grade 3, on a standard scale of medical evidence.
One problem is that of confounding. The nature of case-control studies is such that it is difficult, often impossible, to separate the chooser from the choice. For example, studies of road accident victims found that those wearing seat belts were 80% less likely to suffer serious injury or death in a collision, but data comparing rates for those collisions involving two front-seat occupants of a vehicle, one belted and one unbelted, show a measured efficacy only around half that. Several case-control studies have shown a link between bicycle helmet use and reductions in head injury, but long-term trends - including from countries which have substantially increased helmet use through compulsion - show no such benefit. Analysis of the studies shows substantial differences between the 'case' and 'control' populations, with much of the measured benefit being due to fundamental differences between those who choose to wear helmets voluntarily and those who do not.
More controversially, a significant number of case-control studies identified a link between combined hormone replacement therapy (HRT) and reductions in incidence of coronary heart disease (CHD) in women. Credible mechanisms were advanced as to why this link might be causal, and a consensus arose that HRT was protective against CHD (e.g. Estrogen replacement therapy and coronary heart disease; a quantitive assessment of the epidemiological evidence Stampfer M, Colditz G. Int Jour Epid 2004;33:445-53). The evidence was sufficiently compelling that a full clinical trial was initiated - and this indicated that the effect was both far smaller and in the opposite direction - combined HRT showed a small but significant increase in risk of CHD in the study population. Subsequent analysis has shown that the group of women opting for HRT were predominantly from higher socio-economic groups and therefore had, on average, better diet and exercise habits. The studies had falsely attributed the benefits of these confounding factors to the intervention itself (see The hormone replacement - coronary heart disease conundrum: is this the death of observational epidemiology? Lawlor DA, Smith GD & Ebrahim S, International Journal of Epidemiology, 2004;33:464-467). There have been similar controversies regarding links between vitamins and cancer; MMR and autism; antibiotics and asthma; cannabis and psychosis. All these have been identified through small-scale case-control studies but fail to show any effect in whole population time series or other investigations.
A comparison with the tobacco/cancer link is instructive. Here the case-control studies pointed the way, but further confirmation was available in the form of time series showing rates of lung cancer tracking levels of smoking in whole populations, and in the form of laboratory experiments on animals.
A further problem is that case-control studies depend on correct and honest reporting of the risk factor, which may be many years in the past or may be seen as socially (un)desirable. Case-control studies can be biased if the risk factor inquired about is incorrectly reported. Recent research has shown that a substantial majority of highly cited case-control studies are subsequently contradicted or found to be substantially over-ambitious when more rigorous investigations are conducted.
As a result the following guidelines have been proposed when assessing case-control evidence :
- Do not turn a blind eye to contradiction. Do not ignore contradictory evidence but try to understand the reasons behind the contradictions.
- Do not be seduced by mechanism. Even where a plausible mechanism exists, do not assume that we know everything about that mechanism and how it might interact with other factors.
- Suspend belief. Of the researchers defending observational studies, Pettiti says this: "belief caused them to be unstrenuous in considering confounding as an explanation for the studies". Do not be seduced by your desire to prove your case.
- Maintain scepticism. Question whether the factor under investigation can really be that important; consider what other differences might characterise the case and control groups. Do not extrapolate results beyond the limits of reasonable certainty (e.g. with grandiose forecasts of "lives saved").
Case-control studies are a valuable investigative tool, providing rapid results at low cost, but caution should be exercised unless results are confirmed by other, more robust evidence. | Case-control
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Case-control studies are one type of epidemiological study design. They are used to identify factors that may contribute to a medical condition by comparing a group of patients who have that condition with a group of patients who do not.
Case-control studies are a relatively inexpensive and frequently-used type of epidemiological study that can be carried out by small teams or individual researchers in single facilities in a way that more structured trials often cannot be. They have pointed the way to a number of important discoveries and advances, but their retrospective, non-randomized nature limits the conclusions that can be drawn from them.
The great triumph of the case-control study was the demonstration of the link between tobacco smoking and lung cancer, by Sir Richard Doll and others after him. Doll was able to show a statistically significant association between the two in a large case control study.[1] Opponents, usually backed by the tobacco industry, argued (correctly) for many years that this type of study cannot prove causation, but the eventual results of cohort studies confirmed the causal link which the case-control studies suggested, and it is now accepted that tobacco smoking is the cause of about 87% of all lung cancer mortality in the US.
# Case-control studies
While the 'gold standard' of study design is the double blind randomized controlled trial, randomized controlled trials cannot be used to evaluate the effects of toxic substances. Studying infrequent events such as death from cancer using randomized clinical trials or other controlled prospective studies requires that large populations be tracked for lengthy periods to observe disease development. In the case of lung cancer this could involve 20 to 40 years, longer than the careers of most epidemiologists. In addition, these studies, which generally rely on government funding, are unlikely to be supported because of the low likelihood that the population will develop the disease. Case-control studies use patients who already have a disease or other condition and look back to see if there are characteristics of these patients that differ from those who don’t have the disease.
The case-control study provides a cheaper and quicker study of risk factors; if the evidence found is convincing enough, then resources can be allocated to more "credible" and comprehensive studies.
One major disadvantage of case-control studies is that they do not give any indication of the absolute risk of the factor in question. For instance, a case-control study may tell you that a certain behavior may be associated with a tenfold increased risk of death as compared with the control group. Although this sounds alarming, it would not tell you that the actual risk of death would change from one in ten million to one in one million, which is quite a bit less alarming. For that information, data from outside the case-control study must be consulted.
## Study methodology
## Comparison with cross-sectional studies
Cross-sectional studies (usually from "snapshot" surveys), sometimes called prevalence studies, can frequently be carried out on pre-existing data, such as that collected by the Census Bureau or the Centers for Disease Control. Such studies can cover study groups as large as the entire population of the United States; However, others could be small and geographically limited.
Cross-sectional studies can contain individual-level data (one record per individual, for example, in national health surveys). Others, however, might only convey group-level information; that is, no individual records are available to the researcher. Recent census data is not provided on individuals - in the UK individual census data is released only after a century. Instead data are aggregated at the group level. For example, by zip code, urban zone, or even by states/provinces or country.
For example, although cross-sectional studies confirm that people who consume large amounts of alcohol also show high rates of many other diseases, they can not determine with certainty which variable is the cause and which one is the effect. It only shows that these variables were "associated" at some point in time. The temporality or succession of events is not objectively certain.
Another problem may occur if the survey or cross-sectional study gathers information at the group level (or the administrator of the survey provides you only with group-level data and no individual-level data). In this case, you may not be able to access information needed to assess the contributions of other variables. For instance, high alcohol consumption is also associated with improper nutrition and hygiene, high rates of smoking and abuse of illegal drugs, and many other risk factors for disease. Ecological design containing only group-level information Cross-sectional studies cannot differentiate between these possible causes, but case-control studies can determine that gastrointestinal bleeding, say, is directly associated with high alcohol consumption, whereas memory deterioration is more associated with improper nutrition among alcoholics.
The advantage of case-control studies over cross-sectional studies that contain only group-level information, then, is the ability to determine the association between potential cause and effect on an individual basis. In the cross-sectional study individual variables are aggregated over the population as a whole, then an association is sought between the aggregated variables; These limitations, however, do not apply to case-control studies containing individual-level data; in this case, the "ecological fallacy" is not present. Cross-sectional design with individual-level data allows for computation of absolute risks (from prevalence) and relative risks or odds ratios.
In the case-control study, the association is determined for each individual case-control pair, then aggregated. This provides a more specific analysis of the possible associations, and potentially determines more accurately which possible causes are directly related to the effect being studied, and which are merely related by a common cause.
One benefit of cross-sectional studies is that they are considered to be "hypothesis generating", such that clues to exposure/disease relationships can often be seen in these studies, and then other studies, such as case-control, cohort studies or even sometimes randomized trials can be implemented to study this relationship.
# Problems with case-control studies
They are rated as low quality, grade 3, on a standard scale of medical evidence.[2]
One problem is that of confounding. The nature of case-control studies is such that it is difficult, often impossible, to separate the chooser from the choice. For example, studies of road accident victims found that those wearing seat belts were 80% less likely to suffer serious injury or death in a collision, but data comparing rates for those collisions involving two front-seat occupants of a vehicle, one belted and one unbelted, show a measured efficacy only around half that. Several case-control studies have shown a link between bicycle helmet use and reductions in head injury, but long-term trends - including from countries which have substantially increased helmet use through compulsion - show no such benefit. Analysis of the studies shows substantial differences between the 'case' and 'control' populations, with much of the measured benefit being due to fundamental differences between those who choose to wear helmets voluntarily and those who do not.
More controversially, a significant number of case-control studies identified a link between combined hormone replacement therapy (HRT) and reductions in incidence of coronary heart disease (CHD) in women. Credible mechanisms were advanced as to why this link might be causal, and a consensus arose that HRT was protective against CHD (e.g. Estrogen replacement therapy and coronary heart disease; a quantitive assessment of the epidemiological evidence Stampfer M, Colditz G. Int Jour Epid 2004;33:445-53). The evidence was sufficiently compelling that a full clinical trial was initiated - and this indicated that the effect was both far smaller and in the opposite direction - combined HRT showed a small but significant increase in risk of CHD in the study population. Subsequent analysis has shown that the group of women opting for HRT were predominantly from higher socio-economic groups and therefore had, on average, better diet and exercise habits. The studies had falsely attributed the benefits of these confounding factors to the intervention itself (see The hormone replacement - coronary heart disease conundrum: is this the death of observational epidemiology? Lawlor DA, Smith GD & Ebrahim S, International Journal of Epidemiology, 2004;33:464-467). There have been similar controversies regarding links between vitamins and cancer; MMR and autism; antibiotics and asthma; cannabis and psychosis. All these have been identified through small-scale case-control studies but fail to show any effect in whole population time series or other investigations.
A comparison with the tobacco/cancer link is instructive. Here the case-control studies pointed the way, but further confirmation was available in the form of time series showing rates of lung cancer tracking levels of smoking in whole populations, and in the form of laboratory experiments on animals.
A further problem is that case-control studies depend on correct and honest reporting of the risk factor, which may be many years in the past or may be seen as socially (un)desirable. Case-control studies can be biased if the risk factor inquired about is incorrectly reported. Recent research has shown that a substantial majority of highly cited case-control studies are subsequently contradicted or found to be substantially over-ambitious when more rigorous investigations are conducted.
As a result the following guidelines have been proposed when assessing case-control evidence [3]:
- Do not turn a blind eye to contradiction. Do not ignore contradictory evidence but try to understand the reasons behind the contradictions.
- Do not be seduced by mechanism. Even where a plausible mechanism exists, do not assume that we know everything about that mechanism and how it might interact with other factors.
- Suspend belief. Of the researchers defending observational studies, Pettiti says this: "belief caused them to be unstrenuous in considering confounding as an explanation for the studies". Do not be seduced by your desire to prove your case.
- Maintain scepticism. Question whether the factor under investigation can really be that important; consider what other differences might characterise the case and control groups. Do not extrapolate results beyond the limits of reasonable certainty (e.g. with grandiose forecasts of "lives saved").
Case-control studies are a valuable investigative tool, providing rapid results at low cost, but caution should be exercised unless results are confirmed by other, more robust evidence. | https://www.wikidoc.org/index.php/Case-control | |
432d1fb1b0a920ea20d8cb73d7cde786ee467ec1 | wikidoc | Case Studies | Case Studies
To go to the main page, click here.
# Introduction to the Page
- The page name should be "(Disease name) case study one", with only the first letter of the title capitalized.
- Goal: To provide a case reports of the disease seen in the hospital.
- As with all microchapter pages linking to the main page, at the top of the edit box put {{CMG}}, your name template, and the microchapter navigation template you created at the beginning.
- Remember to create links within Wikidoc by placing ] around key words which you want to link to other pages. Make sure you makes your links as specific as possible. For example if a sentence contained the phrase anterior spinal artery syndrome, the link should be to anterior spinal artery syndrome not anterior or artery or syndrome. For more information on how to create links click here.
- Remember to follow the same format and capitalization of letters as outlined in the template below.
# Patient Presentation
- Here case should be described in detail as it is presented in the morning reports.
- It should include symptoms at presentation, and the history of present illness.
- It should include medications and supplements currently being taken by the patient.
- A review of systems may be included here.
# Patient History
- In this section, describe the patients past medical history, past hospitalizations, past surgeries.
- The history of illness in family members can also be included here.
# Physical Exam
- Include vital signs here.
- Include pertinent postives and pertinent negatives seen on physical examination.
# Diagnostic Approach
- In this section you may describe the diagnostic approach such as laboratory studies, imaging and other diagnostic studies.]Describe how the diagnostic approach works to rule out various diagnoses in the differential diagnosis list.
# Laboratory and Imaging Findings
- Include pertinent laboratory findings here.
- Include findings seen on imaging, and results of other diagnostic studies here.
# Diagnosis and Management
- Describe the diagnosis here, and how the diagnosis was made.
- Describe the treatment here, and if any prophylactic measures are used to prevent complications of the condition. | Case Studies
To go to the main page, click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2] Aditya Govindavarjhulla, M.B.B.S. [3]
# Introduction to the Page
- The page name should be "(Disease name) case study one", with only the first letter of the title capitalized.
- Goal: To provide a case reports of the disease seen in the hospital.
- As with all microchapter pages linking to the main page, at the top of the edit box put {{CMG}}, your name template, and the microchapter navigation template you created at the beginning.
- Remember to create links within Wikidoc by placing [[square brackets]] around key words which you want to link to other pages. Make sure you makes your links as specific as possible. For example if a sentence contained the phrase anterior spinal artery syndrome, the link should be to anterior spinal artery syndrome not anterior or artery or syndrome. For more information on how to create links click here.
- Remember to follow the same format and capitalization of letters as outlined in the template below.
# Patient Presentation
- Here case should be described in detail as it is presented in the morning reports.
- It should include symptoms at presentation, and the history of present illness.
- It should include medications and supplements currently being taken by the patient.
- A review of systems may be included here.
# Patient History
- In this section, describe the patients past medical history, past hospitalizations, past surgeries.
- The history of illness in family members can also be included here.
# Physical Exam
- Include vital signs here.
- Include pertinent postives and pertinent negatives seen on physical examination.
# Diagnostic Approach
- In this section you may describe the diagnostic approach such as laboratory studies, imaging and other diagnostic studies.]Describe how the diagnostic approach works to rule out various diagnoses in the differential diagnosis list.
# Laboratory and Imaging Findings
- Include pertinent laboratory findings here.
- Include findings seen on imaging, and results of other diagnostic studies here.
# Diagnosis and Management
- Describe the diagnosis here, and how the diagnosis was made.
- Describe the treatment here, and if any prophylactic measures are used to prevent complications of the condition. | https://www.wikidoc.org/index.php/Case_Studies | |
9fb8bee2705d4343629fc6d15b32f337bf980a8c | wikidoc | Cassie's law | Cassie's law
# Overview
Cassie's law describes the effective contact angle θc for a liquid on a composite surface . The law explains how simply roughing up a surface increases the apparent surface angle. The law is stated as:
where by θ1 is the contact angle for component 1 with areal fraction γ1 and θ2 is the contact angle for component 2 with areal fraction γ2 present in the composite material. This equation takes on special meaning when in a 2-component system one component is air with a contact angle of 180°. With cosine(180) = -1, the equation reduces to:
which implies that with a small γ1 and a large θ1 it is possible to create surfaces with a very large contact angle. Cassie's research pointed out that the water repelling quality of ducks is due to the very nature of the composite formed between air and feather and not by other causes such as the presence of exceptional proofing agents like oils. Water striders also exploit this phenomenon. Artificial superhydrophobic materials such as nanopin film exist in the laboratory that also make use of this law. | Cassie's law
# Overview
Cassie's law describes the effective contact angle θc for a liquid on a composite surface [1]. The law explains how simply roughing up a surface increases the apparent surface angle. The law is stated as:
where by θ1 is the contact angle for component 1 with areal fraction γ1 and θ2 is the contact angle for component 2 with areal fraction γ2 present in the composite material. This equation takes on special meaning when in a 2-component system one component is air with a contact angle of 180°. With cosine(180) = -1, the equation reduces to:
which implies that with a small γ1 and a large θ1 it is possible to create surfaces with a very large contact angle. Cassie's research pointed out that the water repelling quality of ducks is due to the very nature of the composite formed between air and feather and not by other causes such as the presence of exceptional proofing agents like oils. Water striders also exploit this phenomenon. Artificial superhydrophobic materials such as nanopin film exist in the laboratory that also make use of this law. | https://www.wikidoc.org/index.php/Cassie%27s_law | |
75365b1349bd37921d3e66967312de29369086dc | wikidoc | Catharanthus | Catharanthus
Catharanthus (Madagascar Periwinkle) is a genus of eight species of herbaceous perennial plants, seven endemic to the island of Madagascar, the eighth native to the Indian subcontinent in southern Asia.
- Catharanthus coriaceus Markgr. Madagascar.
- Catharanthus lanceus (Bojer ex A.DC.) Pichon. Madagascar.
- Catharanthus longifolius (Pichon) Pichon. Madagascar.
- Catharanthus ovalis Markgr. Madagascar.
- Catharanthus pusillus (Murray) G.Don. Indian subcontinent.
- Catharanthus roseus (L.) G.Don. Madagascar.
- Catharanthus scitulus (Pichon) Pichon. Madagascar.
- Catharanthus trichophyllus (Baker) Pichon. Madagascar.
# Uses and cultivation
The species are self-propagating from seed; the seeds require a period of total darkness to germinate. Cuttings from mature plants will also root readily.
One species, C. roseus, has been widely cultivated and introduced, becoming an invasive species in some areas.
# Pharmacological uses
C. roseus has gained interest from the pharmaceutical industry; the alkaloids vincristine and vinblastine from its sap have been shown to be an effective treatment for leukaemia. Although the sap is poisonous if ingested, some 70 useful alkaloids have been identified from it. In Madagascar, extracts have been used for hundreds of years in herbal medicine for the treatment of diabetes, as hemostatics and tranquilizers, to lower blood pressure, and as disinfectants. The extracts are not without their side effects, however, which include hair loss.
## Vinca alkaloids
Vinca alkaloids are anti-mitotic and anti-microtubule agents. They are nowadays produced synthetically and used as drugs in cancer therapy and as immunosuppressive drugs. These compounds are vinblastine, vincristine, vindesine and vinorelbine. Periwinkle extracts and derivatives, such as vinpocetine, are also used as nootropic drugs.
Catharanthus lanceus contains up to 6% yohimbine in its leaves. | Catharanthus
Catharanthus (Madagascar Periwinkle) is a genus of eight species of herbaceous perennial plants, seven endemic to the island of Madagascar, the eighth native to the Indian subcontinent in southern Asia.[1][2]
- Catharanthus coriaceus Markgr. Madagascar.
- Catharanthus lanceus (Bojer ex A.DC.) Pichon. Madagascar.
- Catharanthus longifolius (Pichon) Pichon. Madagascar.
- Catharanthus ovalis Markgr. Madagascar.
- Catharanthus pusillus (Murray) G.Don. Indian subcontinent.
- Catharanthus roseus (L.) G.Don. Madagascar.
- Catharanthus scitulus (Pichon) Pichon. Madagascar.
- Catharanthus trichophyllus (Baker) Pichon. Madagascar.
# Uses and cultivation
The species are self-propagating from seed; the seeds require a period of total darkness to germinate. Cuttings from mature plants will also root readily.
One species, C. roseus, has been widely cultivated and introduced, becoming an invasive species in some areas.
# Pharmacological uses
C. roseus has gained interest from the pharmaceutical industry; the alkaloids vincristine and vinblastine from its sap have been shown to be an effective treatment for leukaemia. Although the sap is poisonous if ingested, some 70 useful alkaloids have been identified from it. In Madagascar, extracts have been used for hundreds of years in herbal medicine for the treatment of diabetes, as hemostatics and tranquilizers, to lower blood pressure, and as disinfectants. The extracts are not without their side effects, however, which include hair loss.
## Vinca alkaloids
Vinca alkaloids are anti-mitotic and anti-microtubule agents. They are nowadays produced synthetically and used as drugs in cancer therapy and as immunosuppressive drugs. These compounds are vinblastine, vincristine, vindesine and vinorelbine. Periwinkle extracts and derivatives, such as vinpocetine, are also used as nootropic drugs.[3]
Catharanthus lanceus contains up to 6% yohimbine in its leaves.[4] | https://www.wikidoc.org/index.php/Catharanthus | |
35d7ad61fef6dd3eb69be95725b1c3b5afc6c450 | wikidoc | Cathelicidin | Cathelicidin
Cathelicidin-related antimicrobial peptides are a family of polypeptides primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes (PMNs). Cathelicidins serve a critical role in mammalian innate immune defense against invasive bacterial infection. The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous.
Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain.
Cathelicidin peptides have been isolated from many different species of mammals. Cathelicidins were originally found in neutrophils, but have since been found in many other cells including epithelial cells and macrophages after activation by bacteria, viruses, fungi, or the hormone 1,25-D, which is the hormonally active form of vitamin D. The protein encoded by the human cathelicidin gene, CAMP, is cleaved into the LL-37 peptide, which has several immunological functions.
# Characteristics
Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures. Most cathelicidins are linear peptides with 23-37 amino acid residues, and fold into amphipathic α-helices. Additionally cathelicidins may also be small-sized molecules (12-18 residues) with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides (39-80 amino acid residues) are also present. These larger cathelicidins display repetitive proline motifs forming extended polyproline-type structures.
The cathelicidin family shares primary sequence homology with the cystatin family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.
# Mechanism of antimicrobial activity
The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration (damaging and puncturing) of cell membranes of organisms toward which the peptide is active.
# Mammalian orthologs
Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, and horses.
Currently identified cathelicidins include the following:
- Human: hCAP-18 (cleaved into LL-37 and FALL-39)
- Rhesus monkey: RL-37
- Mice:CRAMP-1/2, (Cathelicidin-related Antimicrobial Peptide
- Rats: rCRAMP
- Rabbits: CAP-18
- Guinea pig: CAP-11
- Pigs: PR-39, Prophenin, PMAP-23,36,37
- Cattle: BMAP-27,28,34 (Bovine Myeloid Antimicrobial Peptides); Bac5, Bac7
- Frogs: cathelicidin-AL (found in Amolops loloensis)
- Sheep:
- Goats:
- Chickens: Four cathelicidins, fowlicidins 1,2,3 and cathelicidin Beta-1
- Horses:
- Pandas:
- Tasmanian Devil: Saha-CATH5
- Salmonids: CATH1 and CATH2
# Clinical significance
NOTE: This article seems to be split between two pages. More about cathelicidin's clinical significance can be found on the page for its encoding gene, LL-37.
Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea. Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.
Higher plasma levels of human cathelicidin antimicrobial protein (hCAP18), which are up-regulated by vitamin D, appear to significantly reduce the risk of death from infection in dialysis patients. Patients with a high level of this protein were 3.7 times more likely to survive kidney dialysis for a year without a fatal infection.
Vitamin D up-regulates genetic expression of cathelicidin, which exhibits broad-spectrum microbicidal activity against bacteria, fungi, and viruses. Cathelicidin rapidly destroys the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages. | Cathelicidin
Cathelicidin-related antimicrobial peptides are a family of polypeptides primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes (PMNs).[1] Cathelicidins serve a critical role in mammalian innate immune defense against invasive bacterial infection.[2] The cathelicidin family of peptides are classified as antimicrobial peptides (AMPs). The AMP family also includes the defensins. Whilst the defensins share common structural features, cathelicidin-related peptides are highly heterogeneous.[2]
Members of the cathelicidin family of antimicrobial polypeptides are characterized by a highly conserved region (cathelin domain) and a highly variable cathelicidin peptide domain.[2]
Cathelicidin peptides have been isolated from many different species of mammals. Cathelicidins were originally found in neutrophils, but have since been found in many other cells including epithelial cells and macrophages after activation by bacteria, viruses, fungi, or the hormone 1,25-D, which is the hormonally active form of vitamin D.[3] The protein encoded by the human cathelicidin gene, CAMP, is cleaved into the LL-37 peptide, which has several immunological functions.
# Characteristics
Cathelicidins range in size from 12 to 80 amino acid residues and have a wide range of structures.[4] Most cathelicidins are linear peptides with 23-37 amino acid residues, and fold into amphipathic α-helices. Additionally cathelicidins may also be small-sized molecules (12-18 residues) with beta-hairpin structures, stabilized by one or two disulphide bonds. Even larger cathelicidin peptides (39-80 amino acid residues) are also present. These larger cathelicidins display repetitive proline motifs forming extended polyproline-type structures.[2]
The cathelicidin family shares primary sequence homology with the cystatin[5] family of cysteine proteinase inhibitors, although amino acid residues thought to be important in such protease inhibition are usually lacking.
# Mechanism of antimicrobial activity
The general rule of the mechanism triggering cathelicidin action, like that of other antimicrobial peptides, involves the disintegration (damaging and puncturing) of cell membranes of organisms toward which the peptide is active.[6]
# Mammalian orthologs
Cathelicidin peptides have been found in humans, monkeys, mice, rats, rabbits, guinea pigs, pandas, pigs, cattle, frogs, sheep, goats, chickens, and horses.
Currently identified cathelicidins include the following:[2]
- Human: hCAP-18 (cleaved into LL-37 and FALL-39)
- Rhesus monkey: RL-37
- Mice:CRAMP-1/2, (Cathelicidin-related Antimicrobial Peptide[7]
- Rats: rCRAMP
- Rabbits: CAP-18
- Guinea pig: CAP-11
- Pigs: PR-39, Prophenin, PMAP-23,36,37
- Cattle: BMAP-27,28,34 (Bovine Myeloid Antimicrobial Peptides); Bac5, Bac7
- Frogs: cathelicidin-AL (found in Amolops loloensis)[8]
- Sheep:
- Goats:
- Chickens: Four cathelicidins, fowlicidins 1,2,3 and cathelicidin Beta-1 [9]
- Horses:
- Pandas:
- Tasmanian Devil: Saha-CATH5 [10]
- Salmonids: CATH1 and CATH2
# Clinical significance
NOTE: This article seems to be split between two pages. More about cathelicidin's clinical significance can be found on the page for its encoding gene, LL-37.
Patients with rosacea have elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin is cleaved into the antimicrobial peptide LL-37 by both kallikrein 5 and kallikrein 7 serine proteases. Excessive production of LL-37 is suspected to be a contributing cause in all subtypes of Rosacea.[11] Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.[12]
Higher plasma levels of human cathelicidin antimicrobial protein (hCAP18), which are up-regulated by vitamin D, appear to significantly reduce the risk of death from infection in dialysis patients. Patients with a high level of this protein were 3.7 times more likely to survive kidney dialysis for a year without a fatal infection.[13]
Vitamin D up-regulates genetic expression of cathelicidin, which exhibits broad-spectrum microbicidal activity against bacteria, fungi, and viruses.[14][15] Cathelicidin rapidly destroys the lipoprotein membranes of microbes enveloped in phagosomes after fusion with lysosomes in macrophages. | https://www.wikidoc.org/index.php/Cathelicidin | |
2ff5177f6cecf071ea9b98bcd61d844794caf645 | wikidoc | Caulophyllum | Caulophyllum
Caulophyllum is a small genus of perennial herbs in the family Berberidaceae. It is native to eastern Asia and eastern North America. These plants are distinctive spring wildflowers, which grow in moist, rich woodland, it is known for its large triple-compound leaf, and large blue, berry-like fruits. Unlike many spring wildflowers, it is not ephemeral and persists throughout much of the summer. Common names for plants in this genus include Blue Cohosh, Squaw Root, and Papoose Root. As hinted at by its common names, this plant is well known as an alternative medicine for inducing childbirth and menstrual flow; it is also considered a poisonous plant.
# Description
These large, smooth plants (0.3m-0.9m tall) have a single to few stems with each stem bearing normally one, but on large stems two, large triple-compound leafs which the casual observer might assume to be several smaller leaves arranged on three separate branches. Each leaflet ends in three to five distinct tips. Plants produce under ground stems called rhizomes that give rise to the leaves each spring and in the fall when the foliage dies back a scar is left on the rhizome and a new bud is formed that will grow into the foliage next spring. Plants are long lived and can live for more than 50 years, they are found in wooded locations with moisture retentive soils.
In April or May, each mature stem bears a spike of flowers. Each flower has six petal-like sepals which range from greenish-yellow to purple. The different rates of maturity between the stamens and the pistil insures cross pollination. There are six fleshy nectar glands at the base of each sepal which attract pollinators. Each fertilized flower matures into a large (1 cm) deep-blue berry-like fruit which houses two bitter seeds. The large seeds are covered with a characteristic blue coat and the fruits remain on the plants until fall. Seed germination can take a few years and the seedlings are hypogeal, the cotyledons remaining underground after germination and seedling emergence, the seedlings need a few years of growth before they are large enough to flower.
# Species
All species in this genus are very similar. Until recently, this genus was considered to be composed of only two species, however the Flora of North America recognizes Caulophyllum giganteum, as a distinct species rather than a subspecies of Caulophyllum thalictroides. Caulophyllum giganteum is slightly larger, has a more northerly (but overlapping) distribution, and blooms two weeks earlier than Caulophyllum thalictroides. Caulophyllum giganteum also has fewer flowers, that are consistently purplish.
- Caulophyllum thalictroides -Blue Cohosh (E. North America)
- Caulophyllum giganteum -Giant Blue Cohosh (E. North America)
- Caulophyllum robustum -Asian Blue Cohosh (Japan, E. Asia)
# Uses
These poisonous plants has been used for many things throughout history, the three similar species generally have similar properties and uses. This plant is occasionally used in woodland gardens as an ornamental. Children should not be allowed to eat the attractive blue fruits, as these plants contain chemicals that are known to cause cell damage. The powdered roots have been shown to cause dermatitis and irritation of the mucus membranes.
## Food
Historically, the roasted seeds have been used as a coffee substitute; this beverage does not contain caffeine.
## Medicine
WARNING: This plants should not be used by pregnant women. As this is a known poisonous plant, care should be taken by anyone using this plant.
Historically the root of Caulophyllum has been used as a medicine for: cancer, internal parasites, smooth muscle function, spasms, diuretic, menstruation, and childbirth. It is best known for the latter two uses. Various Native American tribes are also recorded as having used this plant for similar medicinal purposes. While no current widely marketed medicines are based on this plant, modern herbalists and practitioners of alternative medicine still utilize this plant as a natural therapy. Research on the medicinal potentials of this plant are ongoing. | Caulophyllum
Caulophyllum is a small genus of perennial herbs in the family Berberidaceae. It is native to eastern Asia and eastern North America. These plants are distinctive spring wildflowers, which grow in moist, rich woodland, it is known for its large triple-compound leaf, and large blue, berry-like fruits. Unlike many spring wildflowers, it is not ephemeral and persists throughout much of the summer. Common names for plants in this genus include Blue Cohosh, Squaw Root, and Papoose Root. As hinted at by its common names, this plant is well known as an alternative medicine for inducing childbirth and menstrual flow; it is also considered a poisonous plant.[1]
# Description
These large, smooth plants (0.3m-0.9m tall) have a single to few stems with each stem bearing normally one, but on large stems two, large triple-compound leafs which the casual observer might assume to be several smaller leaves arranged on three separate branches. Each leaflet ends in three to five distinct tips. Plants produce under ground stems called rhizomes that give rise to the leaves each spring and in the fall when the foliage dies back a scar is left on the rhizome and a new bud is formed that will grow into the foliage next spring. Plants are long lived and can live for more than 50 years, they are found in wooded locations with moisture retentive soils.
In April or May, each mature stem bears a spike of flowers. Each flower has six petal-like sepals which range from greenish-yellow to purple. The different rates of maturity between the stamens and the pistil insures cross pollination. There are six fleshy nectar glands at the base of each sepal which attract pollinators. Each fertilized flower matures into a large (1 cm) deep-blue berry-like fruit which houses two bitter seeds. The large seeds are covered with a characteristic blue coat and the fruits remain on the plants until fall. Seed germination can take a few years and the seedlings are hypogeal, the cotyledons remaining underground after germination and seedling emergence, the seedlings need a few years of growth before they are large enough to flower.
# Species
All species in this genus are very similar. Until recently, this genus was considered to be composed of only two species, however the Flora of North America recognizes Caulophyllum giganteum, as a distinct species rather than a subspecies of Caulophyllum thalictroides.[2] Caulophyllum giganteum is slightly larger, has a more northerly (but overlapping) distribution, and blooms two weeks earlier than Caulophyllum thalictroides. Caulophyllum giganteum also has fewer flowers, that are consistently purplish.
- Caulophyllum thalictroides -Blue Cohosh (E. North America)
- Caulophyllum giganteum -Giant Blue Cohosh (E. North America)
- Caulophyllum robustum -Asian Blue Cohosh (Japan, E. Asia)
# Uses
These poisonous plants has been used for many things throughout history, the three similar species generally have similar properties and uses.[3] This plant is occasionally used in woodland gardens as an ornamental. Children should not be allowed to eat the attractive blue fruits, as these plants contain chemicals that are known to cause cell damage.[4] The powdered roots have been shown to cause dermatitis and irritation of the mucus membranes.
## Food
Historically, the roasted seeds have been used as a coffee substitute; this beverage does not contain caffeine.[3] [5]
## Medicine
WARNING: This plants should not be used by pregnant women. As this is a known poisonous plant, care should be taken by anyone using this plant.
Historically the root of Caulophyllum has been used as a medicine for: cancer, internal parasites, smooth muscle function, spasms, diuretic, menstruation, and childbirth.[1] It is best known for the latter two uses. Various Native American tribes are also recorded as having used this plant for similar medicinal purposes.[6] While no current widely marketed medicines are based on this plant, modern herbalists and practitioners of alternative medicine still utilize this plant as a natural therapy. Research on the medicinal potentials of this plant are ongoing. | https://www.wikidoc.org/index.php/Caulophyllum | |
e71346db5def3f17a55923ae42d415ee50c314c4 | wikidoc | Cefaloridine | Cefaloridine
# Overview
Cephaloridine (or cefaloridine) is a first generation semisynthetic derivative of cephalosporin C. It is unique among cephalosporins in that it exists as a zwitterion.
# History
Since the discovery of cephalosporins P, N and C in 1948 there have been many studies describing the antibiotic action of cephalosporins and the possibility to synthesize derivatives. Hydrolysis of cephalosporin C, isolation of 7-aminocephalosporanic acid and the addition of side chains opened the possibility to produce various semi-synthetic cephalosporins. In 1962, cephalothin and cephaloridine were introduced.
Cephaloridine was temporarily popular because it was better tolerated intramuscularly and attained in higher and more sustained levels in blood than cephalothin. However, it binds to proteins to a much lesser extent than cephalothin. Because it is also poorly absorbed after oral administration the use of this drug for humans declined rapidly, especially since the second generation of cephalosporins was introduced in the 1970s. Today it is more commonly used in veterinary practice to treat mild to severe bacterial infections caused by penicillin resistant and penicillin sensitive Staphylococcus aureus, Escherichia coli, Streptococcus pyogenes, Streptococcus pneumoniae, Bacillus sutbtilis, Klebsiella, Clostridium diptheriae, Salmonella and Shigella. Interest in studying cephalosporins was brought about by some unusual properties of cephaloridine. This antibiotic stands in sharp contrast to various other cephalosporins and to the structurally related penicillins in undergoing little or no net secretion by the mammalian kidney. Cephaloridine is, however, highly cytotoxic to the proximal renal tubule, the segment of the nephron responsible for the secretion of organic anions, including para-am-minohippurate (PAH), as well as the various penicillin and cephalosporin antibiotics. The cytotoxicity of cephaloridine is completely prevented by probenecid and several other inhibitors of organic anion transport, including the nearly nontoxic cephalothin.
# Structure & reactivity
Cephaloridine is a cephalosporin compound with pyridinium-1-ylmethyl and 2-thienylacetamido side groups. The molecular nucleus, of which all cephalosporins are derivatives, is A3-7-aminocephalosporanic acid. Conformations around the β-lactam rings are quite similar to the molecular nucleus of penicillin, while those at the carboxyl group exocyclic to the dihydrothiazine and thiazolidine rings respectively are different.
# Synthesis
Cephaloridine can be synthesised from Cephalotin and pyridine by deacetylation. This can be done by heating an aquous mixture of cephalotin, thiocyanate, pyridine and phosphoric acid for several hours. After cooling, diluting with water, and adjusting the pH with mineral acid, cephaloridine thiocyanate salt precipitates. This can be purified and converted to cephaloridine by pH adjustment or by interaction with ion-exchange resin.
# Clinical use of cephaloridine
Before the 1970s, cephaloridine was used to treat patients with urinary tract infections. Besides the drugs has been used successfully in the treatment of various lower respiratory tract infections. Cephaloridine was very effective to cure pneumococcal pneumonia. It has a high clinical and bacteriological rate of success in staphylococcal and streptococcal infections.
# Kinetics
## Absorption
Cephaloridine is easy absorbed after intramuscular injection and poorly absorbed from the gastrointestinal tract.
## Distribution
The minor pathway of elimination is biliary excretion. When the blood serum concentration is 24 µg/ml, the corresponding biliary concentration is 10 µg/ml. In de spinal fluid the concentration of cephaloridine is 6-12% of the concentration in de blood and serum.
Cephaloridine is distributed well into the liver, stomach wall, lung and spleen and is also found in fresh wounds one hour after injection. The concentration in the wound will decrease as the wound age increases. However, the drug is poorly penetrated into the cerebrospinal fluid and is found in a much smaller amount in the cerebral cortex.
### Pregnancy
When cephaloridine is administered to pregnant women, the drug crosses the placenta. Cephaloridine concentrations can be measured in the serum of the newborn up to 22 hours after labor, and can reach a level of 54% of the concentration in the maternal serum. When given an intramuscular dose of 1 g, a peak occurs in the cord blood after 4 hours. In amniotic fluid, the concentration takes about 3 hours to reach its antibacterial effect.
## Metabolism and Excretion
Urine specimens showed that no other microbiologically active metabolites were present except cephaloridine and that cephaloridine is excreted unchanged.
Renal clearances were reported to be 146-280 ml/min, a plasma clearance of 167 ml/min/1,73m2 and a renal clearance of 125 ml/min/1,73m2. A serum half-life of 1,1-1,5 hour and a volume of distribution of 16 liters were reported.
## Pharmacokinetics
Pharmacokinetic analysis is not possible because appropriate data is not published. The physicochemical properties are almost the same as the other cephalosporins, therefore the pharmacokinetics are comparable.
# Adverse effects
## Toxicity
Cephaloridine can cause kidney damage in humans, since it is actively taken up from the blood by the proximal tubular cells via an organic anion transporter (OAT) in the basolateral membrane. Organic anions are secreted through the proximal tubular cells via unidirectional transcellular transport. The organic anions are taken up from the blood into the cells across the basolateral membrane and extruded across the brush border membrane into the tubular fluid. Cephaloridine is a substrate for OAT1 and thus can be transported into the proximal tubular cells, which form the renal cortex.
The drugs, however, cannot move readily across the luminal membrane since it is a zwitterion. The cationic group (pyridinium ring) of the compound probably inhibits the efflux through the membrane. This results in an accumulation of cephaloridine in the renal cortex of the kidney, causing damage and necrosis of the S2 segment of the tubule. However, there are no adverse effects on renal function if serum levels of cephaloridine are maintained between 20 and 80 μg/ml.
## Metabolism
Cephaloridine is excreted in the urine without undergoing metabolism.
It inhibits organic ion transport in the kidney. This process is preceded by the lipid peroxidation. Thereafter, probably a combination of events, such as formation of a reactive intermediate, a free radical and stimulation of lipid peroxidation, lead to peroxidative damage to cell membranes and mitochondria. It is not yet clear whether metabolic activation by cytochromes P-450, chemical rearrangements, reductive activation or all these actions are involved.
The hypotheses made about the mechanism of action causing the toxiciy of cephaloridine are:
- Reactive metabolites are formed by cytochromes P-450 or emerge from destabilization of the β –lactam ring. Metabolic activation of the drugs might take place via cytochromes P-450, producing reactive metabolites. This hypothesis is based on the behaviour of some inhibitors of CYTP450, which decrease the toxicity, and some inducers of the monooxygenases which increase toxicity. It could also be possible that a reactive intermediate is formed due to the unstable β -lactam ring. The pyridinium side-group of cephaloridine has unstable bonds to the core of the compound (in comparison with other cephalosporins). When this side-group leaves, the β –lactam ring is destabalized by intramolecular electron shifts. Thus, the leaving group creates a reactive product.
- Both lipid peroxidation and oxidative stress can cause membrane damage. Lipid peroxidation and oxidative stress take place as lipid peroxidation products, such as malondialdehyde, have been detected. Reduced glutathione (GSH) and NADPH are both depleted. Consequently, GSSG cannot be reduced to GSH. This leads to an increased toxicity since oxidative stress cannot be reduced. In addition, nephrotoxicity is augmented by deficiency of selenium or tocopherol. The pyridinium side-group interacts with the reduced NADP in a redox cycle. It has been suggested that superoxide anion radicals and hydroxyl radicals may be formed and that lipid peroxidation could be responsible for the toxicity of cephaloridine.
- Damage to the mitochondria and intracellular respiratory processes and reduced mitochondrial respiration can cause nephrotoxicity. The previously mentioned damages have been detected after exposure to cephalosporins. β-lactam antibiotics injure mitochondria by an attack on the metabolic substrate carriers of the inner membrane. Respiratory toxicity is caused by inactivation of mitochondrial anion substrate carriers.
## Symptoms of kidney damage caused by cephaloridine
Some symptoms caused by cephaloridine are: asymptomatic, enzymuria, proteinuria, tubular necrosis, increased urea level in blood, anemia, increased hydrogen ion level in blood, fatigue, increased blood pressure, increased blood electrolyte level, kidney dysfunction, kidney damage, impaired body water balance and impaired electrolyte balance.
## Complications caused by cephaloridine
Complications caused by the use of cephaloridine include seizures, coma, chronic kidney failure, acute kidney failure and death.
## Treatment of kidney damage caused by cephaloridine
The damage of the kidneys can be treated by removing the toxin from the body, monitoring and supporting kidney function (dialysis if necessary) and, in severe cases, kidney transplant. Supportive therapy in the acute phase can be done by fluid, electrolyte and hypertension management. Longer term management includes monitoring of renal function, close management of high blood pressure. Furthermore, dietary management may include protein and sodium management, adequate hydration and phosphate and potassium restriction. In case of chronic renal failure dietary management also includes erythropoietin agonists (since anaemia is associated with chronic renal failure), phosphate binders (in case of hyperphosphatemia), calcium supplements, Vitamin D supplements and sodium bicarbonate (to correct the acid-base disturbance). | Cefaloridine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cephaloridine (or cefaloridine) is a first generation semisynthetic derivative of cephalosporin C. It is unique among cephalosporins in that it exists as a zwitterion.
# History
Since the discovery of cephalosporins P, N and C in 1948 there have been many studies describing the antibiotic action of cephalosporins and the possibility to synthesize derivatives. Hydrolysis of cephalosporin C, isolation of 7-aminocephalosporanic acid and the addition of side chains opened the possibility to produce various semi-synthetic cephalosporins. In 1962, cephalothin and cephaloridine were introduced.[1]
Cephaloridine was temporarily popular because it was better tolerated intramuscularly and attained in higher and more sustained levels in blood than cephalothin. However, it binds to proteins to a much lesser extent than cephalothin. Because it is also poorly absorbed after oral administration the use of this drug for humans declined rapidly, especially since the second generation of cephalosporins was introduced in the 1970s.[1] Today it is more commonly used in veterinary practice to treat mild to severe bacterial infections caused by penicillin resistant and penicillin sensitive Staphylococcus aureus, Escherichia coli, Streptococcus pyogenes, Streptococcus pneumoniae, Bacillus sutbtilis, Klebsiella, Clostridium diptheriae, Salmonella and Shigella.[2] Interest in studying cephalosporins was brought about by some unusual properties of cephaloridine. This antibiotic stands in sharp contrast to various other cephalosporins and to the structurally related penicillins in undergoing little or no net secretion by the mammalian kidney. Cephaloridine is, however, highly cytotoxic to the proximal renal tubule, the segment of the nephron responsible for the secretion of organic anions, including para-am-minohippurate (PAH), as well as the various penicillin and cephalosporin antibiotics. The cytotoxicity of cephaloridine is completely prevented by probenecid and several other inhibitors of organic anion transport, including the nearly nontoxic cephalothin.[3]
# Structure & reactivity
Cephaloridine is a cephalosporin compound with pyridinium-1-ylmethyl and 2-thienylacetamido side groups. The molecular nucleus, of which all cephalosporins are derivatives, is A3-7-aminocephalosporanic acid. Conformations around the β-lactam rings are quite similar to the molecular nucleus of penicillin, while those at the carboxyl group exocyclic to the dihydrothiazine and thiazolidine rings respectively are different.[4]
# Synthesis
Cephaloridine can be synthesised from Cephalotin and pyridine by deacetylation. This can be done by heating an aquous mixture of cephalotin, thiocyanate, pyridine and phosphoric acid for several hours. After cooling, diluting with water, and adjusting the pH with mineral acid, cephaloridine thiocyanate salt precipitates. This can be purified and converted to cephaloridine by pH adjustment or by interaction with ion-exchange resin.[5]
# Clinical use of cephaloridine
Before the 1970s, cephaloridine was used to treat patients with urinary tract infections. Besides the drugs has been used successfully in the treatment of various lower respiratory tract infections. Cephaloridine was very effective to cure pneumococcal pneumonia. It has a high clinical and bacteriological rate of success in staphylococcal and streptococcal infections.[6]
# Kinetics
## Absorption
Cephaloridine is easy absorbed after intramuscular injection and poorly absorbed from the gastrointestinal tract.[7]
## Distribution
The minor pathway of elimination is biliary excretion. When the blood serum concentration is 24 µg/ml, the corresponding biliary concentration is 10 µg/ml. In de spinal fluid the concentration of cephaloridine is 6-12% of the concentration in de blood and serum.
Cephaloridine is distributed well into the liver, stomach wall, lung and spleen and is also found in fresh wounds one hour after injection. The concentration in the wound will decrease as the wound age increases. However, the drug is poorly penetrated into the cerebrospinal fluid and is found in a much smaller amount in the cerebral cortex.[7]
### Pregnancy
When cephaloridine is administered to pregnant women, the drug crosses the placenta. Cephaloridine concentrations can be measured in the serum of the newborn up to 22 hours after labor, and can reach a level of 54% of the concentration in the maternal serum. When given an intramuscular dose of 1 g, a peak occurs in the cord blood after 4 hours. In amniotic fluid, the concentration takes about 3 hours to reach its antibacterial effect.[6]
## Metabolism and Excretion
Urine specimens showed that no other microbiologically active metabolites were present except cephaloridine and that cephaloridine is excreted unchanged.
Renal clearances were reported to be 146-280 ml/min, a plasma clearance of 167 ml/min/1,73m2 and a renal clearance of 125 ml/min/1,73m2. A serum half-life of 1,1-1,5 hour and a volume of distribution of 16 liters were reported.[7]
## Pharmacokinetics
Pharmacokinetic analysis is not possible because appropriate data is not published. The physicochemical properties are almost the same as the other cephalosporins, therefore the pharmacokinetics are comparable.[7]
# Adverse effects
## Toxicity
Cephaloridine can cause kidney damage in humans, since it is actively taken up from the blood by the proximal tubular cells via an organic anion transporter (OAT) in the basolateral membrane. Organic anions are secreted through the proximal tubular cells via unidirectional transcellular transport. The organic anions are taken up from the blood into the cells across the basolateral membrane and extruded across the brush border membrane into the tubular fluid.[8] Cephaloridine is a substrate for OAT1 and thus can be transported into the proximal tubular cells, which form the renal cortex.[9]
The drugs, however, cannot move readily across the luminal membrane since it is a zwitterion. The cationic group (pyridinium ring) of the compound probably inhibits the efflux through the membrane.[9][10] This results in an accumulation of cephaloridine in the renal cortex of the kidney, causing damage and necrosis of the S2 segment of the tubule.[8][9] However, there are no adverse effects on renal function if serum levels of cephaloridine are maintained between 20 and 80 μg/ml.[11]
## Metabolism
Cephaloridine is excreted in the urine without undergoing metabolism.[12]
It inhibits organic ion transport in the kidney. This process is preceded by the lipid peroxidation. Thereafter, probably a combination of events, such as formation of a reactive intermediate, a free radical and stimulation of lipid peroxidation, lead to peroxidative damage to cell membranes and mitochondria. It is not yet clear whether metabolic activation by cytochromes P-450, chemical rearrangements, reductive activation or all these actions are involved.[9]
The hypotheses made about the mechanism of action causing the toxiciy of cephaloridine are:
- Reactive metabolites are formed by cytochromes P-450 or emerge from destabilization of the β –lactam ring. Metabolic activation of the drugs might take place via cytochromes P-450, producing reactive metabolites. This hypothesis is based on the behaviour of some inhibitors of CYTP450, which decrease the toxicity, and some inducers of the monooxygenases which increase toxicity. It could also be possible that a reactive intermediate is formed due to the unstable β -lactam ring.[9] The pyridinium side-group of cephaloridine has unstable bonds to the core of the compound (in comparison with other cephalosporins). When this side-group leaves, the β –lactam ring is destabalized by intramolecular electron shifts.[13] Thus, the leaving group creates a reactive product.
- Both lipid peroxidation and oxidative stress can cause membrane damage. Lipid peroxidation and oxidative stress take place as lipid peroxidation products, such as malondialdehyde, have been detected. Reduced glutathione (GSH) and NADPH are both depleted. Consequently, GSSG cannot be reduced to GSH. This leads to an increased toxicity since oxidative stress cannot be reduced. In addition, nephrotoxicity is augmented by deficiency of selenium or tocopherol. The pyridinium side-group interacts with the reduced NADP in a redox cycle. It has been suggested that superoxide anion radicals and hydroxyl radicals may be formed and that lipid peroxidation could be responsible for the toxicity of cephaloridine.[9][13]
- Damage to the mitochondria and intracellular respiratory processes and reduced mitochondrial respiration can cause nephrotoxicity. The previously mentioned damages have been detected after exposure to cephalosporins.[9] β-lactam antibiotics injure mitochondria by an attack on the metabolic substrate carriers of the inner membrane.[13] Respiratory toxicity is caused by inactivation of mitochondrial anion substrate carriers.[8]
## Symptoms of kidney damage caused by cephaloridine
Some symptoms caused by cephaloridine are: asymptomatic, enzymuria, proteinuria, tubular necrosis, increased urea level in blood, anemia, increased hydrogen ion level in blood, fatigue, increased blood pressure, increased blood electrolyte level, kidney dysfunction, kidney damage, impaired body water balance and impaired electrolyte balance.[14]
## Complications caused by cephaloridine
Complications caused by the use of cephaloridine include seizures, coma, chronic kidney failure, acute kidney failure and death.[14]
## Treatment of kidney damage caused by cephaloridine
The damage of the kidneys can be treated by removing the toxin from the body, monitoring and supporting kidney function (dialysis if necessary) and, in severe cases, kidney transplant. Supportive therapy in the acute phase can be done by fluid, electrolyte and hypertension management. Longer term management includes monitoring of renal function, close management of high blood pressure. Furthermore, dietary management may include protein and sodium management, adequate hydration and phosphate and potassium restriction. In case of chronic renal failure dietary management also includes erythropoietin agonists (since anaemia is associated with chronic renal failure), phosphate binders (in case of hyperphosphatemia), calcium supplements, Vitamin D supplements and sodium bicarbonate (to correct the acid-base disturbance).[14] | https://www.wikidoc.org/index.php/Cefaloridine | |
d62922c7333b722d0e69031c8b22e287cc7eb815 | wikidoc | Cefoperazone | Cefoperazone
# Overview
Cefoperazone is a third-generation cephalosporin antibiotic, marketed by Pfizer under the name Cefobid, and also marked by Pharco B International under the name Cefazone and also marketed by Sigmatec Pharmaceuticals under the name Cefoperazone. It is one of few cephalosporin antibiotics effective in treating Pseudomonas bacterial infections which are otherwise resistant to these antibiotics.
Cefina-SB is a combination of sulbactam and cefoperazone. Cefoperazone exerts its bactericidal effect by inhibiting the bacterial cell wall synthesis, and sulbactam acts as a beta-lactamase inhibitor, to increase the antibacterial activity of cefoperazone against beta-lactamase-producing organisms. In some countries, the combination is sold as Sulperazone. Gepach International markets this combination of cefoperazone with sulbactam under the brand name Bacperazone.In India and SriLanka (Cefoperazone-Sulbactam) is manufacterd by Pfizer under the brand name of Magnex/Magnex-Forte depending on the Cefoperazone-Sulbactam ratio.
# Spectrum of bacterial susceptibility
Cefoperazone has a broad spectrum of activity and has been used to target bacteria responsible for causing infections of the respiratory and urinary tract, skin, and the female genital tract. The following represents MIC susceptibility data for a few medically significant microorganisms.
- Haemophilus influenzae: 0.12 - 0.25 µg/ml
- Staphylococcus aureus: 0.125 - 32 µg/ml
- Streptococcus pneumoniae: ≤0.007 - 1 µg/ml
# Adverse effects
Cefoperazone contains an N-methylthiotetrazole (NMTT or 1-MTT) side chain. As the antibiotic is broken down in the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of the enzyme vitamin K epoxide reductase) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase. | Cefoperazone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cefoperazone is a third-generation cephalosporin antibiotic, marketed by Pfizer under the name Cefobid, and also marked by Pharco B International under the name Cefazone and also marketed by Sigmatec Pharmaceuticals under the name Cefoperazone. It is one of few cephalosporin antibiotics effective in treating Pseudomonas bacterial infections which are otherwise resistant to these antibiotics.
Cefina-SB is a combination of sulbactam and cefoperazone. Cefoperazone exerts its bactericidal effect by inhibiting the bacterial cell wall synthesis, and sulbactam acts as a beta-lactamase inhibitor, to increase the antibacterial activity of cefoperazone against beta-lactamase-producing organisms. In some countries, the combination is sold as Sulperazone. Gepach International markets this combination of cefoperazone with sulbactam under the brand name Bacperazone.In India and SriLanka (Cefoperazone-Sulbactam) is manufacterd by Pfizer under the brand name of Magnex/Magnex-Forte depending on the Cefoperazone-Sulbactam ratio.
# Spectrum of bacterial susceptibility
Cefoperazone has a broad spectrum of activity and has been used to target bacteria responsible for causing infections of the respiratory and urinary tract, skin, and the female genital tract. The following represents MIC susceptibility data for a few medically significant microorganisms.
- Haemophilus influenzae: 0.12 - 0.25 µg/ml
- Staphylococcus aureus: 0.125 - 32 µg/ml
- Streptococcus pneumoniae: ≤0.007 - 1 µg/ml[1][2]
# Adverse effects
Cefoperazone contains an N-methylthiotetrazole (NMTT or 1-MTT) side chain. As the antibiotic is broken down in the body, it releases free NMTT, which can cause hypoprothrombinemia (likely due to inhibition of the enzyme vitamin K epoxide reductase) and a reaction with ethanol similar to that produced by disulfiram (Antabuse), due to inhibition of aldehyde dehydrogenase.[3] | https://www.wikidoc.org/index.php/Cefobid | |
800c7ef5e121d95316ce10e9865b016f721c8ce2 | wikidoc | Cell biology | Cell biology
Cell biology (also called cellular biology or formerly cytology, from the Greek kytos, "container") is an academic discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level. Cell biology research extends to both the great diversity of single-celled organisms like bacteria and the many specialized cells in multicellular organisms like humans.
Knowing the composition of cells and how cells work is fundamental to all of the biological sciences. Appreciating the similarities and also differences between cell types is particularly important to the fields of cell and molecular biology. These fundamental similarities and differences provide a unifying theme, allowing the principles learned from studying one cell type to be extrapolated and generalized to other cell types.
Research in cell biology is closely related to genetics, biochemistry, molecular biology and developmental biology.
# Processes
## Movement of proteins
Each type of protein is usually sent to a particular part of the cell. An important part of cell biology is the investigation of molecular mechanisms by which proteins are moved to different places inside cells or secreted from cells.
Most proteins are synthesized by ribosomes in the cytoplasm. This process is also known as protein biosynthesis or simply protein translation. Some proteins, such as those to be incorporated in membranes (known as membrane proteins), are transported into the endoplasmic reticulum (ER) during synthesis. This process can be followed by transportation and processing in the Golgi apparatus. From the Golgi, membrane proteins can move to the plasma membrane, to other subcellular compartments, or they can be secreted from the cell. The ER and Golgi can be thought of as the "membrane protein synthesis compartment" and the "membrane protein processing compartment", respectively. There is a semi-constant flux of proteins through these compartments. ER and Golgi-resident proteins associate with other proteins but remain in their respective compartments. Other proteins "flow" through the ER and Golgi to the plasma membrane. Motor proteins transport membrane protein-containing vesicles along cytoskeletal tracks to distant parts of cells such as axon terminals.
Some proteins that are made in the cytoplasm contain structural features that target them for transport into mitochondria or the nucleus. Some mitochondrial proteins are made inside mitochondria and are coded for by mitochondrial DNA. In plants, chloroplasts also make some cell proteins.
Extracellular and cell surface proteins destined to be degraded can move back into intracellular compartments upon being incorporated into endocytosed vesicles. Some of these vesicles fuse with lysosomes where the proteins are broken down to their individual amino acids. The degradation of some membrane proteins begins while still at the cell surface when they are cleaved by secretases. Proteins that function in the cytoplasm are often degraded by proteasomes.
## Other cellular processes
- Cell division - a cell division process called mitosis.
- Cell signaling - Regulation of cell behavior by signals from outside.
- Active transport and Passive transport - Movement of molecules into and out of cells.
- Adhesion - Holding together cells and tissues.
- Transcription and mRNA splicing - gene expression.
- Cell movement: Chemotaxis, Contraction, cilia and flagella
- DNA repair and Cell death
- Metabolism: Glycolysis, respiration, Photosynthesis
- Autophagy - The process whereby cells "eat" their own internal components or microbial invaders
# Internal cellular structures
- Organelle - term used for major subcellular structures
- Chloroplast - key organelle for photosynthesis
- Cilia - motile microtubule-containing structures of eukaryotes
- Cytoplasm - contents of the main fluid-filled space inside cells
- Cytoskeleton - protein filaments inside cells
- Ribosome - RNA and protein complex required for protein synthesis in cells
- Endoplasmic reticulum - major site of membrane protein synthesis
- Flagella - motile structures of bacteria, archaea and eukaryotes
- Golgi apparatus - site of protein glycosylation in the endomembrane system
- Membrane lipid and protein barrier
- Lipid bilayer - fundamental organizational structure of cell membranes
- Vesicle - small membrane-bounded spheres inside cells
- Mitochondrion - major energy-producing organelle
- Nucleus - holds most of the DNA of eukaryotic cells
# Techniques used to study cells
Cells may be observed under the microscope. This includes the Optical Microscope, Transmission Electron Microscope, Scanning Electron Microscope, Fluorescence Microscope, and by Confocal Microscopy.
Immunostaining can also be imploded to observe cells. Such examples are:
- Gene knockdown and Transfection
- Cell culture and Radioactive tracers
- PCR and In situ hybridization
- DNA microarray screens of gene expression
- Computational genomics approaches are used to find patterns in genomic information
Purification of cells and their parts
Purification may be performed using the following methods:
- Flow cytometry
- Cell fractionation
Release of cellular organelles by disruption of cells.
Separation of different organelles by centrifugation.
- Release of cellular organelles by disruption of cells.
- Separation of different organelles by centrifugation.
- Proteins extracted from cell membranes by detergents and salts or other kinds of chemicals.
- Immunoprecipitation. | Cell biology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cell biology (also called cellular biology or formerly cytology, from the Greek kytos, "container") is an academic discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level. Cell biology research extends to both the great diversity of single-celled organisms like bacteria and the many specialized cells in multicellular organisms like humans.
Knowing the composition of cells and how cells work is fundamental to all of the biological sciences. Appreciating the similarities and also differences between cell types is particularly important to the fields of cell and molecular biology. These fundamental similarities and differences provide a unifying theme, allowing the principles learned from studying one cell type to be extrapolated and generalized to other cell types.
Research in cell biology is closely related to genetics, biochemistry, molecular biology and developmental biology.
# Processes
## Movement of proteins
Each type of protein is usually sent to a particular part of the cell. An important part of cell biology is the investigation of molecular mechanisms by which proteins are moved to different places inside cells or secreted from cells.
Most proteins are synthesized by ribosomes in the cytoplasm. This process is also known as protein biosynthesis or simply protein translation. Some proteins, such as those to be incorporated in membranes (known as membrane proteins), are transported into the endoplasmic reticulum (ER) during synthesis. This process can be followed by transportation and processing in the Golgi apparatus. From the Golgi, membrane proteins can move to the plasma membrane, to other subcellular compartments, or they can be secreted from the cell. The ER and Golgi can be thought of as the "membrane protein synthesis compartment" and the "membrane protein processing compartment", respectively. There is a semi-constant flux of proteins through these compartments. ER and Golgi-resident proteins associate with other proteins but remain in their respective compartments. Other proteins "flow" through the ER and Golgi to the plasma membrane. Motor proteins transport membrane protein-containing vesicles along cytoskeletal tracks to distant parts of cells such as axon terminals.
Some proteins that are made in the cytoplasm contain structural features that target them for transport into mitochondria or the nucleus. Some mitochondrial proteins are made inside mitochondria and are coded for by mitochondrial DNA. In plants, chloroplasts also make some cell proteins.
Extracellular and cell surface proteins destined to be degraded can move back into intracellular compartments upon being incorporated into endocytosed vesicles. Some of these vesicles fuse with lysosomes where the proteins are broken down to their individual amino acids. The degradation of some membrane proteins begins while still at the cell surface when they are cleaved by secretases. Proteins that function in the cytoplasm are often degraded by proteasomes.
## Other cellular processes
- Cell division - a cell division process called mitosis.
- Cell signaling - Regulation of cell behavior by signals from outside.
- Active transport and Passive transport - Movement of molecules into and out of cells.
- Adhesion - Holding together cells and tissues.
- Transcription and mRNA splicing - gene expression.
- Cell movement: Chemotaxis, Contraction, cilia and flagella
- DNA repair and Cell death
- Metabolism: Glycolysis, respiration, Photosynthesis
- Autophagy - The process whereby cells "eat" their own internal components or microbial invaders
# Internal cellular structures
- Organelle - term used for major subcellular structures
- Chloroplast - key organelle for photosynthesis
- Cilia - motile microtubule-containing structures of eukaryotes
- Cytoplasm - contents of the main fluid-filled space inside cells
- Cytoskeleton - protein filaments inside cells
- Ribosome - RNA and protein complex required for protein synthesis in cells
- Endoplasmic reticulum - major site of membrane protein synthesis
- Flagella - motile structures of bacteria, archaea and eukaryotes
- Golgi apparatus - site of protein glycosylation in the endomembrane system
- Membrane lipid and protein barrier
- Lipid bilayer - fundamental organizational structure of cell membranes
- Vesicle - small membrane-bounded spheres inside cells
- Mitochondrion - major energy-producing organelle
- Nucleus - holds most of the DNA of eukaryotic cells
# Techniques used to study cells
Cells may be observed under the microscope. This includes the Optical Microscope, Transmission Electron Microscope, Scanning Electron Microscope, Fluorescence Microscope, and by Confocal Microscopy.
Immunostaining can also be imploded to observe cells. Such examples are:
- Gene knockdown and Transfection
- Cell culture and Radioactive tracers
- PCR and In situ hybridization
- DNA microarray screens of gene expression
- Computational genomics approaches are used to find patterns in genomic information [1]
Purification of cells and their parts
Purification may be performed using the following methods:
- Flow cytometry
- Cell fractionation
Release of cellular organelles by disruption of cells.
Separation of different organelles by centrifugation.
- Release of cellular organelles by disruption of cells.
- Separation of different organelles by centrifugation.
- Proteins extracted from cell membranes by detergents and salts or other kinds of chemicals.
- Immunoprecipitation. | https://www.wikidoc.org/index.php/Cell_Biology | |
28438de3432a52e5c1a36eef0ebe13ef83045b4a | wikidoc | Cell culture | Cell culture
# Overview
Cell culture is the process by which either prokaryotic or eukaryotic cells are grown under controlled conditions. In practice the term "cell culture" has come to refer to the culturing of cells derived from multicellular eukaryotes, especially animal cells. The historical development and methods of cell culture are closely interrelated to those of tissue culture and organ culture.
Animal cell culture became a routine laboratory technique in the 1950s, but the concept of maintaining live cell lines separated from their original tissue source was discovered in the 19th century.
# History
The 19th-century English physiologist Sydney Ringer developed salt solutions containing the chlorides of sodium, potassium, calcium and magnesium suitable for maintaining the beating of an isolated animal heart outside of the body.
In 1885 Wilhelm Roux removed a portion of the medullary plate of an embryonic chicken and maintained it in a warm saline solution for several days, establishing the principle of tissue culture. Ross Granville Harrison, working at Johns Hopkins Medical School and then at Yale University, published results of his experiments from 1907-1910, establishing the methodology of tissue culture.
Cell culture techniques were advanced significantly in the 1940s and 1950s to support research in virology. Growing viruses in cell cultures allowed preparation of purified viruses for the manufacture of vaccines. The Salk polio vaccine was one of the first products mass-produced using cell culture techniques. This vaccine was made possible by the cell culture research of John Franklin Enders, Thomas Huckle Weller, and Frederick Chapman Robbins, who were awarded a Nobel Prizefor their discovery of a method of growing the virus in monkey kidney cell cultures.
# Concepts in mammalian cell culture
## Isolation of cells
Cells can be isolated from tissues for ex vivo culture in several ways. Cells can be easily purified from blood, however only the white cellsare capable of growth in culture. Mononuclear cells can be released from soft tissues by enzymatic digestion with enzymes such as collagenase, trypsin, or pronase, which break down the extracellular matrix. Alternatively, pieces of tissue can be placed in growth media, and the cells that grow out are available for culture. This method is known as explant culture.
Cells that are cultured directly from a subject are known as primary cells. With the exception of some derived from tumours, most primary cell cultures have limited lifespan. After a certain number of population doublings cells undergo the process of senescence and stop dividing, while generally retaining viability.
An established or immortalised cell line has acquired the ability to proliferate indefinitely either through random mutation or deliberate modification, such as artificial expression of the telomerase gene.
There are numerous well established cell lines representative of particular cell types.
## Maintaining cells in culture
Cells are grown and maintained at an appropriate temperature and gas mixture (typically, 37°C, 5% CO2) in a cell incubator. Culture conditions vary widely for each cell type, and variation of conditions for a particular cell type can result in different phenotypes being expressed.
Aside from temperature and gas mixture, the most commonly varied factor in culture systems is the growth medium. Recipes for growth media can vary in pH, glucose concentration, growth factors, and the presence of other nutrient components. The growth factors used to supplement media are often derived from animal blood, such as calf serum. These blood-derived ingredients pose the potential for contamination of derived pharmaceutical products with viruses or prions. Current practice is to minimize or eliminate the use of these ingredients where possible.
Some cells naturally live without attaching to a surface, such as cells that exist in the bloodstream. Others require a surface, such as most cells derived from solid tissues. Cells grown unattached to a surface are referred to as suspension cultures. Other adherent cultures cells can be grown on tissue culture plastic, which may be coated with extracellular matrix components (e.g. collagen or fibronectin) to increase its adhesion properties and provide other signals needed for growth.
## Manipulation of cultured cells
As cells generally continue to divide in culture, they generally grow to fill the available area or volume. This can generate several issues:
- Nutrient depletion in the growth media
- Accumulation of apoptotic/necrotic (dead) cells.
- Cell-to-cell contact can stimulate cell cycle arrest, causing cells to stop dividing known as contact inhibition.
- Cell-to-cell contact can stimulate promiscuous and unwanted cellular differentiation.
These issues can be dealt with using tissue culture methods that rely on sterile technique. These methods aim to avoid contamination with bacteria or yeast that will compete with mammalian cells for nutrients and/or cause cell infection and cell death. Manipulations are typically carried out in a biosafety hood or laminar flow cabinet to exclude contaminating micro-organisms. Antibiotics can also be added to the growth media.
Amongst the common manipulations carried out on culture cells are media changes, passaging cells, and transfecting cells.
### Media changes
The purpose of media changes is to replenish nutrients and avoid the build up of potentially harmful metabolic byproducts and dead cells. In the case of suspension cultures, cells can be separated from the media by centrifugation and resuspended in fresh media. In the case of adherent cultures, the media can be removed directly by aspiration and replaced.
### Passaging cells
Passaging or splitting cells involves transferring a small number of cells into a new vessel. Cells can be cultured for a longer time if they are split regularly, as it avoids the senescence associated with prolonged high cell density. Suspension cultures are easily passaged with a small amount of culture containing a few cells diluted in a larger volume of fresh media. For adherent cultures, cells first need to be detached; this was historically done with a mixture of trypsin-EDTA, however other enzyme mixes are now available for this purpose. A small number of detached cells can then be used to seed a new culture.
### Transfection and transduction
Another common method for manipulating cells involves the introduction of foreign DNA by transfection. This is often performed to cause cells to express a protein of interest. More recently, the transfection of RNAi constructs have been realised as a convenient mechanism for suppressing the expression of a particular gene/protein.
DNA can also be inserted into cells using viruses, in methods referred to as transduction, infection or transformation. Viruses, as parasitic agents, are well suited to introducing DNA into cells, as this is a part of their normal course of reproduction.
## Established human cell lines
Cell lines that originate with humans have been somewhat controversial in bioethics, as they may outlive their parent organism and later be used in the discovery of lucrative medical treatments. In the pioneering decision in this area, the Supreme Court of California held in 1990 that human patients have no property rights in cell lines derived from organs removed with their consent.
It is estimated that about 20% of human cell lines are not the kind of cells they were generally assumed to be. The reason for this is that some cell lines exhibit vigorous growth and thus can cross-contaminate cultures of other cell lines, in time overgrowing and displacing the original cells. The most common contaminant is the HeLa cell line. While this may not be of significance when general properties such as cell metabolism are researched, it is highly relevant e.g. in medical research focusing on a specific type of cell. Results of such research will be at least flawed, if not outright wrong in their conclusion, with possible consequences if therapeutic approaches are developed based on it.
## Generation of hybridomas
It is possible to fuse normal cells with an immortalised cell line. This method is used to produce monoclonal antibodies. In brief, lymphocytes isolated from the blood of an immunised animal are combined with hybridoma cell lines in a selective growth medium: only the fused cells survive.
# Applications of cell culture
Mass culture of animal cell lines is fundamental to the manufacture of viral vaccines and many products of biotechnology. Biological products produced by recombinant DNA (rDNA) technology in animal cell cultures include enzymes, hormones, immunobiologicals (monoclonal antibodies, interleukins, lymphokines), andanticancer agents. Although many simpler proteins can be produced using rDNA in bacterial cultures, more complex proteins that are glycosylated (carbohydrate-modified), currently must be made in animal cells. An important example of such a complex protein is the hormone erythropoietin. The cost of growing mammalian cell cultures is high, so research is underway to produce such complex proteins in insect cells or in higher plants.
## Tissue culture and engineering
Cell culture is a fundamental component of tissue culture and tissue engineering, as it establishes the basics of growing and maintaining cells ex vivo. I
## Vaccines
Vaccines for polio, measles, mumps, rubella, and chickenpox are currently made in cell cultures. Due to the H5N1 pandemic threat, research into using cell culture for flu vaccines is being funded by the United States government. Novel ideas in the field include recombinant DNA-based vaccines, such as one made using human adenovirus (a common cold virus) as a vector, or the use of adjuvants.
# Culture of non-mammalian cells
## Plant cell culture methods
Plant cell cultures are typically grown as cell suspension cultures in liquid medium or as callus cultures on solid medium. The culturing of undifferentiated plant cells and calli requires the proper balance of the plant growth hormones auxin and cytokinin.
## Bacterial/Yeast culture methods
For bacteria and yeast, small quantities of cells are usually grown on a solid support that contains nutrients embedded in it, usually a gel such as agar, while large-scale cultures are grown with the cells suspended in a nutrient broth.
## Viral culture methods
The culture of viruses requires the culture of cells of mammalian, plant, fungal or bacterial origin as hosts for the growth and replication of the virus. Wholewild type viruses, recombinant viruses or viral products may be generated in cell types other than their natural hosts under the right conditions. Depending on the species of the virus, infection and viral replication may result in host cell lysis and formation of a viral plaque.
# Common cell lines
- National Cancer Institute's 60 cancer cell lines
- MCF-7 (breast cancer)
- MDA-MB-438 (breast cancer)
- U87 (glioblastoma)
- A172 (glioma)
- HeLa (cervical cancer)
- HL60 (promyelocytic leukemia)
- A549 (lung cancer)
- HEK 293 cells (kidney - original HEK line is contaminated with HeLa)
- SHSY5Y Human neuroblastoma cells, cloned from a myeloma
- Jurkat cell line, derived from a patient with T cell leukemia
- BCP-1 cells (PEL)
- Lncap (Prostate Cancer)
- Vero (African green monkey Chlorocebus kidney epithelial cell line initiated 1962)
- COS-7 (African Green Monkey Kidney Cells)
- GH3 (pituitary tumor)
- 9L (glioblastoma)
- PC12 (pheochromocytoma)
- 3T3 cells
- MC3T3 (embryonic calvarial)
- C3H-10T1/2 (embryonic mesenchymal)
- NIH-3T3 (embryonic fibroblast)
- C6/36 Aedes albopictus (Asian tiger mosquito) larva
- Insect cell line Sf21
- Tobacco BY-2 cells (kept as cell suspension culture, they are model system of plant cell)
- zebrafish ZF4 and AB9 cells.
- Madin-Darby Canine Kidney (MDCK) epithelial cell line
- Chinese Hamster Ovary CHO cells
- Xenopus A6 kidney epithelial cells.
# List of cell lines | Cell culture
# Overview
Cell culture is the process by which either prokaryotic or eukaryotic cells are grown under controlled conditions. In practice the term "cell culture" has come to refer to the culturing of cells derived from multicellular eukaryotes, especially animal cells. The historical development and methods of cell culture are closely interrelated to those of tissue culture and organ culture.
Animal cell culture became a routine laboratory technique in the 1950s,[1] but the concept of maintaining live cell lines separated from their original tissue source was discovered in the 19th century.[2]
# History
The 19th-century English physiologist Sydney Ringer developed salt solutions containing the chlorides of sodium, potassium, calcium and magnesium suitable for maintaining the beating of an isolated animal heart outside of the body.[1]
In 1885 Wilhelm Roux removed a portion of the medullary plate of an embryonic chicken and maintained it in a warm saline solution for several days, establishing the principle of tissue culture.[3] Ross Granville Harrison, working at Johns Hopkins Medical School and then at Yale University, published results of his experiments from 1907-1910, establishing the methodology of tissue culture.[4]
Cell culture techniques were advanced significantly in the 1940s and 1950s to support research in virology. Growing viruses in cell cultures allowed preparation of purified viruses for the manufacture of vaccines. The Salk polio vaccine was one of the first products mass-produced using cell culture techniques. This vaccine was made possible by the cell culture research of John Franklin Enders, Thomas Huckle Weller, and Frederick Chapman Robbins, who were awarded a Nobel Prizefor their discovery of a method of growing the virus in monkey kidney cell cultures.
# Concepts in mammalian cell culture
## Isolation of cells
Cells can be isolated from tissues for ex vivo culture in several ways. Cells can be easily purified from blood, however only the white cellsare capable of growth in culture. Mononuclear cells can be released from soft tissues by enzymatic digestion with enzymes such as collagenase, trypsin, or pronase, which break down the extracellular matrix. Alternatively, pieces of tissue can be placed in growth media, and the cells that grow out are available for culture. This method is known as explant culture.
Cells that are cultured directly from a subject are known as primary cells. With the exception of some derived from tumours, most primary cell cultures have limited lifespan. After a certain number of population doublings cells undergo the process of senescence and stop dividing, while generally retaining viability.
An established or immortalised cell line has acquired the ability to proliferate indefinitely either through random mutation or deliberate modification, such as artificial expression of the telomerase gene.
There are numerous well established cell lines representative of particular cell types.
## Maintaining cells in culture
Cells are grown and maintained at an appropriate temperature and gas mixture (typically, 37°C, 5% CO2) in a cell incubator. Culture conditions vary widely for each cell type, and variation of conditions for a particular cell type can result in different phenotypes being expressed.
Aside from temperature and gas mixture, the most commonly varied factor in culture systems is the growth medium. Recipes for growth media can vary in pH, glucose concentration, growth factors, and the presence of other nutrient components. The growth factors used to supplement media are often derived from animal blood, such as calf serum. These blood-derived ingredients pose the potential for contamination of derived pharmaceutical products with viruses or prions. Current practice is to minimize or eliminate the use of these ingredients where possible.
Some cells naturally live without attaching to a surface, such as cells that exist in the bloodstream. Others require a surface, such as most cells derived from solid tissues. Cells grown unattached to a surface are referred to as suspension cultures. Other adherent cultures cells can be grown on tissue culture plastic, which may be coated with extracellular matrix components (e.g. collagen or fibronectin) to increase its adhesion properties and provide other signals needed for growth.
## Manipulation of cultured cells
As cells generally continue to divide in culture, they generally grow to fill the available area or volume. This can generate several issues:
- Nutrient depletion in the growth media
- Accumulation of apoptotic/necrotic (dead) cells.
- Cell-to-cell contact can stimulate cell cycle arrest, causing cells to stop dividing known as contact inhibition.
- Cell-to-cell contact can stimulate promiscuous and unwanted cellular differentiation.
These issues can be dealt with using tissue culture methods that rely on sterile technique. These methods aim to avoid contamination with bacteria or yeast that will compete with mammalian cells for nutrients and/or cause cell infection and cell death. Manipulations are typically carried out in a biosafety hood or laminar flow cabinet to exclude contaminating micro-organisms. Antibiotics can also be added to the growth media.
Amongst the common manipulations carried out on culture cells are media changes, passaging cells, and transfecting cells.
### Media changes
The purpose of media changes is to replenish nutrients and avoid the build up of potentially harmful metabolic byproducts and dead cells. In the case of suspension cultures, cells can be separated from the media by centrifugation and resuspended in fresh media. In the case of adherent cultures, the media can be removed directly by aspiration and replaced.
### Passaging cells
Passaging or splitting cells involves transferring a small number of cells into a new vessel. Cells can be cultured for a longer time if they are split regularly, as it avoids the senescence associated with prolonged high cell density. Suspension cultures are easily passaged with a small amount of culture containing a few cells diluted in a larger volume of fresh media. For adherent cultures, cells first need to be detached; this was historically done with a mixture of trypsin-EDTA, however other enzyme mixes are now available for this purpose. A small number of detached cells can then be used to seed a new culture.
### Transfection and transduction
Another common method for manipulating cells involves the introduction of foreign DNA by transfection. This is often performed to cause cells to express a protein of interest. More recently, the transfection of RNAi constructs have been realised as a convenient mechanism for suppressing the expression of a particular gene/protein.
DNA can also be inserted into cells using viruses, in methods referred to as transduction, infection or transformation. Viruses, as parasitic agents, are well suited to introducing DNA into cells, as this is a part of their normal course of reproduction.
## Established human cell lines
Cell lines that originate with humans have been somewhat controversial in bioethics, as they may outlive their parent organism and later be used in the discovery of lucrative medical treatments. In the pioneering decision in this area, the Supreme Court of California held in 1990 that human patients have no property rights in cell lines derived from organs removed with their consent. [5]
It is estimated that about 20% of human cell lines are not the kind of cells they were generally assumed to be.[6] The reason for this is that some cell lines exhibit vigorous growth and thus can cross-contaminate cultures of other cell lines, in time overgrowing and displacing the original cells. The most common contaminant is the HeLa cell line. While this may not be of significance when general properties such as cell metabolism are researched, it is highly relevant e.g. in medical research focusing on a specific type of cell. Results of such research will be at least flawed, if not outright wrong in their conclusion, with possible consequences if therapeutic approaches are developed based on it. [7]
## Generation of hybridomas
It is possible to fuse normal cells with an immortalised cell line. This method is used to produce monoclonal antibodies. In brief, lymphocytes isolated from the blood of an immunised animal are combined with hybridoma cell lines in a selective growth medium: only the fused cells survive.
# Applications of cell culture
Mass culture of animal cell lines is fundamental to the manufacture of viral vaccines and many products of biotechnology. Biological products produced by recombinant DNA (rDNA) technology in animal cell cultures include enzymes, hormones, immunobiologicals (monoclonal antibodies, interleukins, lymphokines), andanticancer agents. Although many simpler proteins can be produced using rDNA in bacterial cultures, more complex proteins that are glycosylated (carbohydrate-modified), currently must be made in animal cells. An important example of such a complex protein is the hormone erythropoietin. The cost of growing mammalian cell cultures is high, so research is underway to produce such complex proteins in insect cells or in higher plants.
## Tissue culture and engineering
Cell culture is a fundamental component of tissue culture and tissue engineering, as it establishes the basics of growing and maintaining cells ex vivo. I
## Vaccines
Vaccines for polio, measles, mumps, rubella, and chickenpox are currently made in cell cultures. Due to the H5N1 pandemic threat, research into using cell culture for flu vaccines is being funded by the United States government. Novel ideas in the field include recombinant DNA-based vaccines, such as one made using human adenovirus (a common cold virus) as a vector,[8][9] or the use of adjuvants.[10]
# Culture of non-mammalian cells
## Plant cell culture methods
Plant cell cultures are typically grown as cell suspension cultures in liquid medium or as callus cultures on solid medium. The culturing of undifferentiated plant cells and calli requires the proper balance of the plant growth hormones auxin and cytokinin.
## Bacterial/Yeast culture methods
For bacteria and yeast, small quantities of cells are usually grown on a solid support that contains nutrients embedded in it, usually a gel such as agar, while large-scale cultures are grown with the cells suspended in a nutrient broth.
## Viral culture methods
The culture of viruses requires the culture of cells of mammalian, plant, fungal or bacterial origin as hosts for the growth and replication of the virus. Wholewild type viruses, recombinant viruses or viral products may be generated in cell types other than their natural hosts under the right conditions. Depending on the species of the virus, infection and viral replication may result in host cell lysis and formation of a viral plaque.
# Common cell lines
- National Cancer Institute's 60 cancer cell lines
- MCF-7 (breast cancer)
- MDA-MB-438 (breast cancer)
- U87 (glioblastoma)
- A172 (glioma)
- HeLa (cervical cancer)
- HL60 (promyelocytic leukemia)
- A549 (lung cancer)
- HEK 293 cells (kidney - original HEK line is contaminated with HeLa)
- SHSY5Y Human neuroblastoma cells, cloned from a myeloma
- Jurkat cell line, derived from a patient with T cell leukemia
- BCP-1 cells (PEL)
- Lncap (Prostate Cancer)
- Vero (African green monkey Chlorocebus kidney epithelial cell line initiated 1962)
- COS-7 (African Green Monkey Kidney Cells)
- GH3 (pituitary tumor)
- 9L (glioblastoma)
- PC12 (pheochromocytoma)
- 3T3 cells
- MC3T3 (embryonic calvarial)
- C3H-10T1/2 (embryonic mesenchymal)
- NIH-3T3 (embryonic fibroblast)
- C6/36 Aedes albopictus (Asian tiger mosquito) larva
- Insect cell line Sf21
- Tobacco BY-2 cells (kept as cell suspension culture, they are model system of plant cell)
- zebrafish ZF4 and AB9 cells.
- Madin-Darby Canine Kidney (MDCK) epithelial cell line
- Chinese Hamster Ovary CHO cells
- Xenopus A6 kidney epithelial cells.
# List of cell lines | https://www.wikidoc.org/index.php/Cell_culture | |
6b94a92a3e849519b038b11743566563e62ee89d | wikidoc | Cell nucleus | Cell nucleus
In cell biology, the nucleus (pl. nuclei; from Latin error: {{lang}}: text has italic markup (help) or error: {{lang}}: text has italic markup (help), "little nut" or kernel) is a membrane-enclosed organelle found in most eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these chromosomes are the cell's nuclear genome. The function of the nucleus is to maintain the integrity of these genes and to control the activities of the cell by regulating gene expression.
The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and separates its contents from the cellular cytoplasm, and the nuclear lamina, a meshwork within the nucleus that adds mechanical support, much like the cytoskeleton supports the cell as a whole. Because the nuclear membrane is impermeable to most molecules, nuclear pores are required to allow movement of molecules across the envelope. These pores cross both of the membranes, providing a channel that allows free movement of small molecules and ions. The movement of larger molecules such as proteins is carefully controlled, and requires active transport regulated by carrier proteins. Nuclear transport is crucial to cell function, as movement through the pores is required for both gene expression and chromosomal maintenance.
Although the interior of the nucleus does not contain any membrane-bound subcompartments, its contents are not uniform, and a number of subnuclear bodies exist, made up of unique proteins, RNA molecules, and particular parts of the chromosomes. The best known of these is the nucleolus, which is mainly involved in the assembly of ribosomes. After being produced in the nucleolus, ribosomes are exported to the cytoplasm where they translate mRNA.
# History
The nucleus was the first organelle to be discovered, and was first described by Franz Bauer in 1802.
It was later described in more detail by Scottish botanist Robert Brown in 1831 in a talk at the Linnean Society of London. Brown was studying orchids microscopically when he observed an opaque area, which he called the areola or nucleus, in the cells of the flower's outer layer.
He did not suggest a potential function. In 1838 Matthias Schleiden proposed that the nucleus plays a role in generating cells, thus he introduced the name "Cytoblast" (cell builder). He believed that he had observed new cells assembling around "cytoblasts". Franz Meyen was a strong opponent of this view having already described cells multiplying by division and believing that many cells would have no nuclei. The idea that cells can be generated de novo, by the "cytoblast" or otherwise, contradicted work by Robert Remak (1852) and Rudolf Virchow (1855) who decisively propagated the new paradigm that cells are generated solely by cells ("Omnis cellula e cellula"). The function of the nucleus remained unclear.
Between 1876 and 1878 Oscar Hertwig published several studies on the fertilization of sea urchin eggs, showing that the nucleus of the sperm enters the oocyte and fuses with its nucleus. This was the first time it was suggested that an individual develops from a (single) nucleated cell. This was in contradiction to Ernst Haeckel's theory that the complete phylogeny of a species would be repeated during embryonic development, including generation of the first nucleated cell from a "Monerula", a structureless mass of primordial mucus ("Urschleim"). Therefore, the necessity of the sperm nucleus for fertilization was discussed for quite some time. However, Hertwig confirmed his observation in other animal groups, e.g. amphibians and molluscs. Eduard Strasburger produced the same results for plants (1884). This paved the way to assign the nucleus an important role in heredity. In 1873 August Weismann postulated the equivalence of the maternal and paternal germ cells for heredity. The function of the nucleus as carrier of genetic information became clear only later, after mitosis was discovered and the Mendelian rules were rediscovered at the beginning of the 20th century; the chromosome theory of heredity was developed.
# Structure
The nucleus is the largest cellular organelle in animals.
In mammalian cells, the average diameter typically varies from 11 to 22 micrometers (μm) and occupies about 10% of the total volume. The viscous liquid within it is called nucleoplasm, and is similar to the cytoplasm found outside the nucleus.
## Nuclear envelope and pores
The nuclear envelope consists of two cellular membranes, an inner and an outer membrane, arranged parallel to one another and separated by 10 to 50 nanometers (nm). The nuclear envelope completely encloses the nucleus and separates the cell's genetic material from the surrounding cytoplasm, serving as a barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm. The outer nuclear membrane is continuous with the membrane of the rough endoplasmic reticulum (RER), and is similarly studded with ribosomes. The space between the membranes is called the perinuclear space and is continuous with the RER lumen.
Nuclear pores, which provide aqueous channels through the envelope, are composed of multiple proteins, collectively referred to as nucleoporins. The pores are about 125 million daltons in molecular weight and consist of around 50 (in yeast) to 100 proteins (in vertebrates). The pores are 100 nm in total diameter; however, the gap through which molecules freely diffuse is only about 9 nm wide, due to the presence of regulatory systems within the center of the pore. This size allows the free passage of small water-soluble molecules while preventing larger molecules, such as nucleic acids and proteins, from inappropriately entering or exiting the nucleus. These large molecules must be actively transported into the nucleus instead. The nucleus of a typical mammalian cell will have about 3000 to 4000 pores throughout its envelope, each of which contains a donut-shaped, eightfold-symmetric ring-shaped structure at a position where the inner and outer membranes fuse. Attached to the ring is a structure called the nuclear basket that extends into the nucleoplasm, and a series of filamentous extensions that reach into the cytoplasm. Both structures serve to mediate binding to nuclear transport proteins.
Most proteins, ribosomal subunits, and some RNAs are transported through the pore complexes in a process mediated by a family of transport factors known as karyopherins. Those karyopherins that mediate movement into the nucleus are also called importins, while those that mediate movement out of the nucleus are called exportins. Most karyopherins interact directly with their cargo, although some use adaptor proteins. Steroid hormones such as cortisol and aldosterone, as well as other small lipid-soluble molecules involved in intercellular signaling can diffuse through the cell membrane and into the cytoplasm, where they bind nuclear receptor proteins that are trafficked into the nucleus. There they serve as transcription factors when bound to their ligand; in the absence of ligand many such receptors function as histone deacetylases that repress gene expression.
## Cytoskeleton
In animal cells, two networks of intermediate filaments provide the nucleus with mechanical support: the nuclear lamina forms an organized meshwork on the internal face of the envelope, while less organized support is provided on the cytosolic face of the envelope. Both systems provide structural support for the nuclear envelope and anchoring sites for chromosomes and nuclear pores.
The nuclear lamina is mostly composed of lamin proteins. Like all proteins, lamins are synthesized in the cytoplasm and later transported into the nucleus interior, where they are assembled before being incorporated into the existing network of nuclear lamina. Lamins are also found inside the nucleoplasm where they form another regular structure, known as the nucleoplasmic veil, that is visible using fluorescence microscopy. The actual function of the veil is not clear, although it is excluded from the nucleolus and is present during interphase. The lamin structures that make up the veil bind chromatin and disrupting their structure inhibits transcription of protein-coding genes.
Like the components of other intermediate filaments, the lamin monomer contains an alpha-helical domain used by two monomers to coil around each other, forming a dimer structure called a coiled coil. Two of these dimer structures then join side by side, in an antiparallel arrangement, to form a tetramer called a protofilament. Eight of these protofilaments form a lateral arrangement that is twisted to form a ropelike filament. These filaments can be assembled or disassembled in a dynamic manner, meaning that changes in the length of the filament depend on the competing rates of filament addition and removal.
Mutations in lamin genes leading to defects in filament assembly are known as laminopathies. The most notable laminopathy is the family of diseases known as progeria, which causes the appearance of premature aging in its sufferers. The exact mechanism by which the associated biochemical changes give rise to the aged phenotype is not well understood.
## Chromosomes
The cell nucleus contains the majority of the cell's genetic material, in the form of multiple linear DNA molecules organized into structures called chromosomes. During most of the cell cycle these are organized in a DNA-protein complex known as chromatin, and during cell division the chromatin can be seen to form the well defined chromosomes familiar from a karyotype. A small fraction of the cell's genes are located instead in the mitochondria.
There are two types of chromatin. Euchromatin is the less compact DNA form, and contains genes that are frequently expressed by the cell. The other type, heterochromatin, is the more compact form, and contains DNA that are infrequently transcribed. This structure is further categorized into facultative heterochromatin, consisting of genes that are organized as heterochromatin only in certain cell types or at certain stages of development, and constitutive heterochromatin that consists of chromosome structural components such as telomeres and centromeres. During interphase the chromatin organizes itself into discrete individual patches, called chromosome territories. Active genes, which are generally found in the euchromatic region of the chromosome, tend to be located towards the chromosome's territory boundary.
Antibodies to certain types of chromatin organization, particularly nucleosomes, have been associated with a number of autoimmune diseases, such as systemic lupus erythematosus. These are known as anti-nuclear antibodies (ANA) and have also been observed in concert with multiple sclerosis as part of general immune system dysfunction. As in the case of progeria, the role played by the antibodies in inducing the symptoms of autoimmune diseases is not obvious.
## Nucleolus
The nucleolus is a discrete densely-stained structure found in the nucleus. It is not surrounded by a membrane, and is sometimes called a suborganelle. It forms around tandem repeats of rDNA, DNA coding for ribosomal RNA (rRNA). These regions are called nucleolar organizer regions (NOR). The main roles of the nucleolus are to synthesize rRNA and assemble ribosomes. The structural cohesion of the nucleolus depends on its activity, as ribosomal assembly in the nucleolus results in the transient association of nucleolar components, facilitating further ribosomal assembly, and hence further association. This model is supported by observations that inactivation of rDNA results in intermingling of nucleolar structures.
The first step in ribosomal assembly is transcription of the rDNA, by a protein called RNA polymerase I, forming a large pre-rRNA precursor. This is cleaved into the subunits 5.8S, 18S, and 28S rRNA. The transcription, post-transcriptional processing, and assembly of rRNA occurs in the nucleolus, aided by small nucleolar RNA (snoRNA) molecules, some of which are derived from spliced introns from messenger RNAs encoding genes related to ribosomal function. The assembled ribosomal subunits are the largest structures passed through the nuclear pores.
When observed under the electron microscope, the nucleolus can be seen to consist of three distinguishable regions: the innermost fibrillar centers (FCs), surrounded by the dense fibrillar component (DFC), which in turn is bordered by the granular component (GC). Transcription of the rDNA occurs either in the FC or at the FC-DFC boundary, and therefore when rDNA transcription in the cell is increased more FCs are detected. Most of the cleavage and modification of rRNAs occurs in the DFC, while the latter steps involving protein assembly onto the ribosomal subunits occurs in the GC.
## Other subnuclear bodies
Besides the nucleolus, the nucleus contains a number of other non-membrane delineated bodies. These include Cajal bodies, Gemini of coiled bodies, polymorphic interphase karyosomal association (PIKA), promyelocytic leukaemia (PML) bodies, paraspeckles and splicing speckles. Although little is known about a number of these domains, they are significant in that they show that the nucleoplasm is not uniform mixture, but rather contains organized functional subdomains.
Other subnuclear structures appear as part of abnormal disease processes. For example, the presence of small intranuclear rods have been reported in some cases of nemaline myopathy. This condition typically results from mutations in actin, and the rods themselves consist of mutant actin as well as other cytoskeletal proteins.
### Cajal bodies and gems
A nucleus typically contains between 1 and 10 compact structures called Cajal bodies or coiled bodies (CB), whose diameter measures between 0.2 µm and 2.0 µm depending on the cell type and species. When seen under an electron microscope, they resemble balls of tangled thread and are dense foci of distribution for the protein coilin. CBs are involved in a number of different roles relating to RNA processing, specifically small nucleolar RNA (snoRNA) and small nuclear RNA (snRNA) maturation, and histone mRNA modification.
Similar to Cajal bodies are Gemini of coiled bodies, or gems, whose name is derived from the Gemini constellation in reference to their close "twin" relationship with CBs. Gems are similar in size and shape to CBs, and in fact are virtually indistinguishable under the microscope. Unlike CBs, gems do not contain small nuclear ribonucleoproteins (snRNPs), but do contain a protein called survivor of motor neurons (SMN) whose function relates to snRNP biogenesis. Gems are believed to assist CBs in snRNP biogenesis, though it has also been suggested from microscopy evidence that CBs and gems are different manifestations of the same structure.
### PIKA and PTF domains
PIKA domains, or polymorphic interphase karyosomal associations, were first described in microscopy studies in 1991. Their function was and remains unclear, though they were not thought to be associated with active DNA replication, transcription, or RNA processing. They have been found to often associate with discrete domains defined by dense localization of the transcription factor PTF, which promotes transcription of snRNA.
### PML bodies
Promyelocytic leukaemia bodies (PML bodies) are spherical bodies found scattered throughout the nucleoplasm, measuring around 0.2–1.0 µm. They are known by a number of other names, including nuclear domain 10 (ND10), Kremer bodies, and PML oncogenic domains. They are often seen in the nucleus in association with Cajal bodies and cleavage bodies. It has been suggested that they play a role in regulating transcription.
### Paraspeckles
Discovered by Fox et al. in 2002, paraspeckles are irregularly shaped compartments in the nucleus' interchromatin space. First documented in HeLa cells, where there are generally 10–30 per nucleus, paraspeckles are now known to also exist in all human primary cells, transformed cell lines and tissue sections. Their name is derived from their distribution in the nucleus; the "para" is short for parallel and the "speckles" refers to the splicing speckles to which they are always in close proximity.
Paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They are transcription dependent and in the absence of RNA Pol II transcription, the paraspeckle disappears and all of its associated protein components (PSP1, p54nrb, PSP2, CFI(m)68 and PSF) form a crescent shaped perinucleolar cap in the nucleolus. This phenomenon is demonstrated during the cell cycle. In the cell cycle, paraspeckles are present during interphase and during all of mitosis except for telophase. During telophase, when the two daughter nuclei are formed, there is no RNA Pol II transcription so the protein components instead form a perinucleolar cap.
### Splicing speckles
Sometimes referred to as interchromatin granule clusters, speckles are rich in splicing snRNPs and other splicing proteins necessary for pre-mRNA processing. Because of a cell's changing requirements, the composition and location of these bodies changes according to mRNA transcription and regulation via phosphorylation of specific proteins.
# Function
The main function of the cell nucleus is to control gene expression and mediate the replication of DNA during the cell cycle. The nucleus provides a site for genetic transcription that is segregated from the location of translation in the cytoplasm, allowing levels of gene regulation that are not available to prokaryotes.
## Cell compartmentalization
The nuclear envelope allows the nucleus to control its contents, and separate them from the rest of the cytoplasm where necessary. This is important for controlling processes on either side of the nuclear membrane. In some cases where a cytoplasmic process needs to be restricted, a key participant is removed to the nucleus, where it interacts with transcription factors to downregulate the production of certain enzymes in the pathway. This regulatory mechanism occurs in the case of glycolysis, a cellular pathway for breaking down glucose to produce energy. Hexokinase is an enzyme responsible for the first the step of glycolysis, forming glucose-6-phosphate from glucose. At high concentrations of fructose-6-phosphate, a molecule made later from glucose-6-phosphate, a regulator protein removes hexokinase to the nucleus, where it forms a transcriptional repressor complex with nuclear proteins to reduce the expression of genes involved in glycolysis.
In order to control which genes are being transcribed, the cell separates some transcription factor proteins responsible for regulating gene expression from physical access to the DNA until they are activated by other signaling pathways. This prevents even low levels of inappropriate gene expression. For example in the case of NF-κB-controlled genes, which are involved in most inflammatory responses, transcription is induced in response to a signal pathway such as that initiated by the signaling molecule TNF-α, binds to a cell membrane receptor, resulting in the recruitment of signalling proteins, and eventually activating the transcription factor NF-κB. A nuclear localisation signal on the NF-κB protein allows it to be transported through the nuclear pore and into the nucleus, where it stimulates the transcription of the target genes.
The compartmentalization allows the cell to prevent translation of unspliced mRNA. Eukaryotic mRNA contains introns that must be removed before being translated to produce functional proteins. The splicing is done inside the nucleus before the mRNA can be accessed by ribosomes for translation. Without the nucleus ribosomes would translate newly transcribed (unprocessed) mRNA resulting in misformed and nonfunctional proteins.
## Gene expression
Gene expression first involves transcription, in which DNA is used as a template to produce RNA. In the case of genes encoding proteins, that RNA produced from this process is messenger RNA (mRNA), which then needs to be translated by ribosomes to form a protein. As ribosomes are located outside the nucleus, mRNA produced needs to be exported.
Since the nucleus is the site of transcription, it also contains a variety of proteins which either directly mediate transcription or are involved in regulating the process. These proteins include helicases that unwind the double-stranded DNA molecule to facilitate access to it, RNA polymerases that synthesize the growing RNA molecule, topoisomerases that change the amount of supercoiling in DNA, helping it wind and unwind, as well as a large variety of transcription factors that regulate expression.
## Processing of pre-mRNA
Newly synthesized mRNA molecules are known as primary transcripts or pre-mRNA. They must undergo post-transcriptional modification in the nucleus before being exported to the cytoplasm; mRNA that appears in the nucleus without these modifications is degraded rather than used for protein translation. The three main modifications are 5' capping, 3' polyadenylation, and RNA splicing. While in the nucleus, pre-mRNA is associated with a variety of proteins in complexes known as heterogeneous ribonucleoprotein particles (hnRNPs). Addition of the 5' cap occurs co-transcriptionally and is the first step in post-transcriptional modification. The 3' poly-adenine tail is only added after transcription is complete.
RNA splicing, carried out by a complex called the spliceosome, is the process by which introns, or regions of DNA that do not code for protein, are removed from the pre-mRNA and the remaining exons connected to re-form a single continuous molecule. This process normally occurs after 5' capping and 3' polyadenylation but can begin before synthesis is complete in transcripts with many exons. Many pre-mRNAs, including those encoding antibodies, can be spliced in multiple ways to produce different mature mRNAs that encode different protein sequences. This process is known as alternative splicing, and allows production of a large variety of proteins from a limited amount of DNA.
# Dynamics and regulation
## Nuclear transport
The entry and exit of large molecules from the nucleus is tightly controlled by the nuclear pore complexes. Although small molecules can enter the nucleus without regulation, macromolecules such as RNA and proteins require association karyopherins called importins to enter the nucleus and exportins to exit. "Cargo" proteins that must be translocated from the cytoplasm to the nucleus contain short amino acid sequences known as nuclear localization signals which are bound by importins, while those transported from the nucleus to the cytoplasm carry nuclear export signals bound by exportins. The ability of importins and exportins to transport their cargo is regulated by GTPases, enzymes that hydrolyze the molecule guanosine triphosphate to release energy. The key GTPase in nuclear transport is Ran, which can bind either GTP or GDP (guanosine diphosphate) depending on whether it is located in the nucleus or the cytoplasm. Whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in order to bind to their cargo.
Nuclear import depends on the importin binding its cargo in the cytoplasm and carrying it through the nuclear pore into the nucleus. Inside the nucleus, RanGTP acts to separate the cargo from the importin, allowing the importin to exit the nucleus and be reused. Nuclear export is similar, as the exportin binds the cargo inside the nucleus in a process facilitated by RanGTP, exits through the nuclear pore, and separates from its cargo in the cytoplasm.
Specialized export proteins exist for translocation of mature mRNA and tRNA to the cytoplasm after post-transcriptional modification is complete. This quality-control mechanism is important due to the these molecules' central role in protein translation; mis-expression of a protein due to incomplete excision of exons or mis-incorporation of amino acids could have negative consequences for the cell; thus incompletely modified RNA that reaches the cytoplasm is degraded rather than used in translation.
## Assembly and disassembly
During its lifetime a nucleus may be broken down, either in the process of cell division or as a consequence of apoptosis, a regulated form of cell death. During these events, the structural components of the nucleus—the envelope and lamina—are systematically degraded.
During the cell cycle the cell divides to form two cells. In order for this process to be possible, each of the new daughter cells must have a full set of genes, a process requiring replication of the chromosomes as well as segregation of the separate sets. This occurs by the replicated chromosomes, the sister chromatids, attaching to microtubules, which in turn are attached to different centrosomes. The sister chromatids can then be pulled to separate locations in the cell. However, in many cells the centrosome is located in the cytoplasm, outside the nucleus, the microtubules would be unable to attach to the chromatids in the presence of the nuclear envelope. Therefore the early stages in the cell cycle, beginning in prophase and until around prometaphase, the nuclear membrane is dismantled. Likewise, during the same period, the nuclear lamina is also disassembled, a process regulated by phosphorylation of the lamins. Towards the end of the cell cycle, the nuclear membrane is reformed, and around the same time, the nuclear lamina are reassembled by dephosphorylating the lamins.
Apoptosis is a controlled process in which the cell's structural components are destroyed, resulting in death of the cell. Changes associated with apoptosis directly affect the nucleus and its contents, for example in the condensation of chromatin and the disintegration of the nuclear envelope and lamina. The destruction of the lamin networks is controlled by specialized apoptotic proteases called caspases, which cleave the lamin proteins and thus degrade the nucleus' structural integrity. Lamin cleavage is sometimes used as a laboratory indicator of caspase activity in assays for early apoptotic activity. Cells that express mutant caspase-resistant lamins are deficient in nuclear changes related to apoptosis, suggesting that lamins play a role in initiating the events that lead to apoptotic degradation of the nucleus. Inhibition of lamin assembly itself is an inducer of apoptosis.
The nuclear envelope acts as a barrier that prevents both DNA and RNA viruses from entering the nucleus. Some viruses require access to proteins inside the nucleus in order to replicate and/or assemble. DNA viruses, such as herpesvirus replicate and assemble in the cell nucleus, and exit by budding through the inner nuclear membrane. This process is accompanied by disassembly of the lamina on the nuclear face of the inner membrane.
# Anucleated and polynucleated cells
Although most cells have a single nucleus, some cell types have no nucleus, and others have many nuclei. This can be a normal process, as in the maturation of mammalian red blood cells, or an anomalous result of faulty cell division.
Anucleated cells contain no nucleus and are therefore incapable of dividing to produce daughter cells. The best-known anucleated cell is the mammalian red blood cell, or erythrocyte, which also lacks other organelles such as mitochondria and serves primarily as a transport vessel to ferry oxygen from the lungs to the body's tissues. Erythrocytes mature via erythropoiesis in the bone marrow, where they lose their nuclei, organelles, and ribosomes. The nucleus is expelled during the process of differentiation from an erythroblast to a reticulocyte, the immediate precursor of the mature erythrocyte. The presence of mutagens may induce the release of some immature "micronucleated" erythrocytes into the bloodstream. Anucleated cells can also arise from flawed cell division in which one daughter lacks a nucleus and the other is binucleate.
Polynucleated cells contain multiple nuclei. Most Acantharean species of protozoa and some fungi in mycorrhizae have naturally polynucleated cells. In humans, skeletal muscle cells, called myocytes, become polynucleated during development; the resulting arrangement of nuclei near the periphery of the cells allows maximal intracellular space for myofibrils. Multinucleated cells can also be abnormal in humans; for example, cells arising from the fusion of monocytes and macrophages, known as giant multinucleated cells, sometimes accompany inflammation and are also implicated in tumor formation.
# Evolution
As the major defining characteristic of the eukaryotic cell, the nucleus' evolutionary origin has been the subject of much speculation. Four major theories have been proposed to explain the existence of the nucleus, although none have yet earned widespread support.
The theory known as the "syntrophic model" proposes that a symbiotic relationship between the archaea and bacteria created the nucleus-containing eukaryotic cell. It is hypothesized that the symbiosis originated when ancient archaea, similar to modern methanogenic archaea, invaded and lived within bacteria similar to modern myxobacteria, eventually forming the early nucleus. This theory is analogous to the accepted theory for the origin of eukaryotic mitochondria and chloroplasts, which are thought to have developed from a similar endosymbiotic relationship between proto-eukaryotes and aerobic bacteria. The archaeal origin of the nucleus is supported by observations that archaea and eukarya have similar genes for certain proteins, including histones. Observations that myxobacteria are motile, can form multicellular complexes, and possess kinases and G proteins similar to eukarya, support a bacterial origin for the eukaryotic cell.
A second model proposes that proto-eukaryotic cells evolved from bacteria without an endosymbiotic stage. This model is based on the existence of modern planctomycetes bacteria that possess a nuclear structure with primitive pores and other compartmentalized membrane structures. A similar proposal states that a eukaryote-like cell, the chronocyte, evolved first and phagocytosed archaea and bacteria to generate the nucleus and the eukaryotic cell.
The most controversial model, known as viral eukaryogenesis, posits that the membrane-bound nucleus, along with other eukaryotic features, originated from the infection of a prokaryote by a virus. The suggestion is based on similarities between eukaryotes and viruses such as linear DNA strands, mRNA capping, and tight binding to proteins (analogizing histones to viral envelopes). One version of the proposal suggests that the nucleus evolved in concert with phagocytosis to form an early cellular "predator". Another variant proposes that eukaryotes originated from early archaea infected by poxviruses, on the basis of observed similarity between the DNA polymerases in modern poxviruses and eukaryotes. It has been suggested that the unresolved question of the evolution of sex could be related to the viral eukaryogenesis hypothesis.
Finally, a very recent proposal suggests that traditional variants of the endosymbiont theory are insufficiently powerful to explain the origin of the eukaryotic nucleus. This model, termed the exomembrane hypothesis, suggests that the nucleus instead originated from a single ancestral cell that evolved a second exterior cell membrane; the interior membrane enclosing the original cell then became the nuclear membrane and evolved increasingly elaborate pore structures for passage of internally synthesized cellular components such as ribosomal subunits. | Cell nucleus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In cell biology, the nucleus (pl. nuclei; from Latin [nucleus] error: {{lang}}: text has italic markup (help) or [nuculeus] error: {{lang}}: text has italic markup (help), "little nut" or kernel) is a membrane-enclosed organelle found in most eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these chromosomes are the cell's nuclear genome. The function of the nucleus is to maintain the integrity of these genes and to control the activities of the cell by regulating gene expression.
The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and separates its contents from the cellular cytoplasm, and the nuclear lamina, a meshwork within the nucleus that adds mechanical support, much like the cytoskeleton supports the cell as a whole. Because the nuclear membrane is impermeable to most molecules, nuclear pores are required to allow movement of molecules across the envelope. These pores cross both of the membranes, providing a channel that allows free movement of small molecules and ions. The movement of larger molecules such as proteins is carefully controlled, and requires active transport regulated by carrier proteins. Nuclear transport is crucial to cell function, as movement through the pores is required for both gene expression and chromosomal maintenance.
Although the interior of the nucleus does not contain any membrane-bound subcompartments, its contents are not uniform, and a number of subnuclear bodies exist, made up of unique proteins, RNA molecules, and particular parts of the chromosomes. The best known of these is the nucleolus, which is mainly involved in the assembly of ribosomes. After being produced in the nucleolus, ribosomes are exported to the cytoplasm where they translate mRNA.
# History
The nucleus was the first organelle to be discovered, and was first described by Franz Bauer in 1802.[1]
It was later described in more detail by Scottish botanist Robert Brown in 1831 in a talk at the Linnean Society of London. Brown was studying orchids microscopically when he observed an opaque area, which he called the areola or nucleus, in the cells of the flower's outer layer.[2]
He did not suggest a potential function. In 1838 Matthias Schleiden proposed that the nucleus plays a role in generating cells, thus he introduced the name "Cytoblast" (cell builder). He believed that he had observed new cells assembling around "cytoblasts". Franz Meyen was a strong opponent of this view having already described cells multiplying by division and believing that many cells would have no nuclei. The idea that cells can be generated de novo, by the "cytoblast" or otherwise, contradicted work by Robert Remak (1852) and Rudolf Virchow (1855) who decisively propagated the new paradigm that cells are generated solely by cells ("Omnis cellula e cellula"). The function of the nucleus remained unclear.[3]
Between 1876 and 1878 Oscar Hertwig published several studies on the fertilization of sea urchin eggs, showing that the nucleus of the sperm enters the oocyte and fuses with its nucleus. This was the first time it was suggested that an individual develops from a (single) nucleated cell. This was in contradiction to Ernst Haeckel's theory that the complete phylogeny of a species would be repeated during embryonic development, including generation of the first nucleated cell from a "Monerula", a structureless mass of primordial mucus ("Urschleim"). Therefore, the necessity of the sperm nucleus for fertilization was discussed for quite some time. However, Hertwig confirmed his observation in other animal groups, e.g. amphibians and molluscs. Eduard Strasburger produced the same results for plants (1884). This paved the way to assign the nucleus an important role in heredity. In 1873 August Weismann postulated the equivalence of the maternal and paternal germ cells for heredity. The function of the nucleus as carrier of genetic information became clear only later, after mitosis was discovered and the Mendelian rules were rediscovered at the beginning of the 20th century; the chromosome theory of heredity was developed.[3]
# Structure
The nucleus is the largest cellular organelle in animals.[4]
In mammalian cells, the average diameter typically varies from 11 to 22 micrometers (μm) and occupies about 10% of the total volume.[5] The viscous liquid within it is called nucleoplasm, and is similar to the cytoplasm found outside the nucleus.
## Nuclear envelope and pores
The nuclear envelope consists of two cellular membranes, an inner and an outer membrane, arranged parallel to one another and separated by 10 to 50 nanometers (nm). The nuclear envelope completely encloses the nucleus and separates the cell's genetic material from the surrounding cytoplasm, serving as a barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm.[6] The outer nuclear membrane is continuous with the membrane of the rough endoplasmic reticulum (RER), and is similarly studded with ribosomes. The space between the membranes is called the perinuclear space and is continuous with the RER lumen.
Nuclear pores, which provide aqueous channels through the envelope, are composed of multiple proteins, collectively referred to as nucleoporins. The pores are about 125 million daltons in molecular weight and consist of around 50 (in yeast) to 100 proteins (in vertebrates).[4] The pores are 100 nm in total diameter; however, the gap through which molecules freely diffuse is only about 9 nm wide, due to the presence of regulatory systems within the center of the pore. This size allows the free passage of small water-soluble molecules while preventing larger molecules, such as nucleic acids and proteins, from inappropriately entering or exiting the nucleus. These large molecules must be actively transported into the nucleus instead. The nucleus of a typical mammalian cell will have about 3000 to 4000 pores throughout its envelope,[7] each of which contains a donut-shaped, eightfold-symmetric ring-shaped structure at a position where the inner and outer membranes fuse.[8] Attached to the ring is a structure called the nuclear basket that extends into the nucleoplasm, and a series of filamentous extensions that reach into the cytoplasm. Both structures serve to mediate binding to nuclear transport proteins.[4]
Most proteins, ribosomal subunits, and some RNAs are transported through the pore complexes in a process mediated by a family of transport factors known as karyopherins. Those karyopherins that mediate movement into the nucleus are also called importins, while those that mediate movement out of the nucleus are called exportins. Most karyopherins interact directly with their cargo, although some use adaptor proteins.[9] Steroid hormones such as cortisol and aldosterone, as well as other small lipid-soluble molecules involved in intercellular signaling can diffuse through the cell membrane and into the cytoplasm, where they bind nuclear receptor proteins that are trafficked into the nucleus. There they serve as transcription factors when bound to their ligand; in the absence of ligand many such receptors function as histone deacetylases that repress gene expression.[4]
## Cytoskeleton
In animal cells, two networks of intermediate filaments provide the nucleus with mechanical support: the nuclear lamina forms an organized meshwork on the internal face of the envelope, while less organized support is provided on the cytosolic face of the envelope. Both systems provide structural support for the nuclear envelope and anchoring sites for chromosomes and nuclear pores.[5]
The nuclear lamina is mostly composed of lamin proteins. Like all proteins, lamins are synthesized in the cytoplasm and later transported into the nucleus interior, where they are assembled before being incorporated into the existing network of nuclear lamina.[10][11] Lamins are also found inside the nucleoplasm where they form another regular structure, known as the nucleoplasmic veil,[12] that is visible using fluorescence microscopy. The actual function of the veil is not clear, although it is excluded from the nucleolus and is present during interphase.[13] The lamin structures that make up the veil bind chromatin and disrupting their structure inhibits transcription of protein-coding genes.[14]
Like the components of other intermediate filaments, the lamin monomer contains an alpha-helical domain used by two monomers to coil around each other, forming a dimer structure called a coiled coil. Two of these dimer structures then join side by side, in an antiparallel arrangement, to form a tetramer called a protofilament. Eight of these protofilaments form a lateral arrangement that is twisted to form a ropelike filament. These filaments can be assembled or disassembled in a dynamic manner, meaning that changes in the length of the filament depend on the competing rates of filament addition and removal.[5]
Mutations in lamin genes leading to defects in filament assembly are known as laminopathies. The most notable laminopathy is the family of diseases known as progeria, which causes the appearance of premature aging in its sufferers. The exact mechanism by which the associated biochemical changes give rise to the aged phenotype is not well understood.[15]
## Chromosomes
The cell nucleus contains the majority of the cell's genetic material, in the form of multiple linear DNA molecules organized into structures called chromosomes. During most of the cell cycle these are organized in a DNA-protein complex known as chromatin, and during cell division the chromatin can be seen to form the well defined chromosomes familiar from a karyotype. A small fraction of the cell's genes are located instead in the mitochondria.
There are two types of chromatin. Euchromatin is the less compact DNA form, and contains genes that are frequently expressed by the cell.[16] The other type, heterochromatin, is the more compact form, and contains DNA that are infrequently transcribed. This structure is further categorized into facultative heterochromatin, consisting of genes that are organized as heterochromatin only in certain cell types or at certain stages of development, and constitutive heterochromatin that consists of chromosome structural components such as telomeres and centromeres.[17] During interphase the chromatin organizes itself into discrete individual patches,[18] called chromosome territories.[19] Active genes, which are generally found in the euchromatic region of the chromosome, tend to be located towards the chromosome's territory boundary.[20]
Antibodies to certain types of chromatin organization, particularly nucleosomes, have been associated with a number of autoimmune diseases, such as systemic lupus erythematosus.[21] These are known as anti-nuclear antibodies (ANA) and have also been observed in concert with multiple sclerosis as part of general immune system dysfunction.[22] As in the case of progeria, the role played by the antibodies in inducing the symptoms of autoimmune diseases is not obvious.
## Nucleolus
The nucleolus is a discrete densely-stained structure found in the nucleus. It is not surrounded by a membrane, and is sometimes called a suborganelle. It forms around tandem repeats of rDNA, DNA coding for ribosomal RNA (rRNA). These regions are called nucleolar organizer regions (NOR). The main roles of the nucleolus are to synthesize rRNA and assemble ribosomes. The structural cohesion of the nucleolus depends on its activity, as ribosomal assembly in the nucleolus results in the transient association of nucleolar components, facilitating further ribosomal assembly, and hence further association. This model is supported by observations that inactivation of rDNA results in intermingling of nucleolar structures.[23]
The first step in ribosomal assembly is transcription of the rDNA, by a protein called RNA polymerase I, forming a large pre-rRNA precursor. This is cleaved into the subunits 5.8S, 18S, and 28S rRNA.[24] The transcription, post-transcriptional processing, and assembly of rRNA occurs in the nucleolus, aided by small nucleolar RNA (snoRNA) molecules, some of which are derived from spliced introns from messenger RNAs encoding genes related to ribosomal function. The assembled ribosomal subunits are the largest structures passed through the nuclear pores.[4]
When observed under the electron microscope, the nucleolus can be seen to consist of three distinguishable regions: the innermost fibrillar centers (FCs), surrounded by the dense fibrillar component (DFC), which in turn is bordered by the granular component (GC). Transcription of the rDNA occurs either in the FC or at the FC-DFC boundary, and therefore when rDNA transcription in the cell is increased more FCs are detected. Most of the cleavage and modification of rRNAs occurs in the DFC, while the latter steps involving protein assembly onto the ribosomal subunits occurs in the GC.[24]
## Other subnuclear bodies
Besides the nucleolus, the nucleus contains a number of other non-membrane delineated bodies. These include Cajal bodies, Gemini of coiled bodies, polymorphic interphase karyosomal association (PIKA), promyelocytic leukaemia (PML) bodies, paraspeckles and splicing speckles. Although little is known about a number of these domains, they are significant in that they show that the nucleoplasm is not uniform mixture, but rather contains organized functional subdomains.[27]
Other subnuclear structures appear as part of abnormal disease processes. For example, the presence of small intranuclear rods have been reported in some cases of nemaline myopathy. This condition typically results from mutations in actin, and the rods themselves consist of mutant actin as well as other cytoskeletal proteins.[29]
### Cajal bodies and gems
A nucleus typically contains between 1 and 10 compact structures called Cajal bodies or coiled bodies (CB), whose diameter measures between 0.2 µm and 2.0 µm depending on the cell type and species.[25] When seen under an electron microscope, they resemble balls of tangled thread[26] and are dense foci of distribution for the protein coilin.[30] CBs are involved in a number of different roles relating to RNA processing, specifically small nucleolar RNA (snoRNA) and small nuclear RNA (snRNA) maturation, and histone mRNA modification.[25]
Similar to Cajal bodies are Gemini of coiled bodies, or gems, whose name is derived from the Gemini constellation in reference to their close "twin" relationship with CBs. Gems are similar in size and shape to CBs, and in fact are virtually indistinguishable under the microscope.[30] Unlike CBs, gems do not contain small nuclear ribonucleoproteins (snRNPs), but do contain a protein called survivor of motor neurons (SMN) whose function relates to snRNP biogenesis. Gems are believed to assist CBs in snRNP biogenesis,[31] though it has also been suggested from microscopy evidence that CBs and gems are different manifestations of the same structure.[30]
### PIKA and PTF domains
PIKA domains, or polymorphic interphase karyosomal associations, were first described in microscopy studies in 1991. Their function was and remains unclear, though they were not thought to be associated with active DNA replication, transcription, or RNA processing.[32] They have been found to often associate with discrete domains defined by dense localization of the transcription factor PTF, which promotes transcription of snRNA.[33]
### PML bodies
Promyelocytic leukaemia bodies (PML bodies) are spherical bodies found scattered throughout the nucleoplasm, measuring around 0.2–1.0 µm. They are known by a number of other names, including nuclear domain 10 (ND10), Kremer bodies, and PML oncogenic domains. They are often seen in the nucleus in association with Cajal bodies and cleavage bodies. It has been suggested that they play a role in regulating transcription.[27]
### Paraspeckles
Discovered by Fox et al. in 2002, paraspeckles are irregularly shaped compartments in the nucleus' interchromatin space.[34] First documented in HeLa cells, where there are generally 10–30 per nucleus,[35] paraspeckles are now known to also exist in all human primary cells, transformed cell lines and tissue sections.[36] Their name is derived from their distribution in the nucleus; the "para" is short for parallel and the "speckles" refers to the splicing speckles to which they are always in close proximity.[35]
Paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They are transcription dependent[34] and in the absence of RNA Pol II transcription, the paraspeckle disappears and all of its associated protein components (PSP1, p54nrb, PSP2, CFI(m)68 and PSF) form a crescent shaped perinucleolar cap in the nucleolus. This phenomenon is demonstrated during the cell cycle. In the cell cycle, paraspeckles are present during interphase and during all of mitosis except for telophase. During telophase, when the two daughter nuclei are formed, there is no RNA Pol II transcription so the protein components instead form a perinucleolar cap.[36]
### Splicing speckles
Sometimes referred to as interchromatin granule clusters, speckles are rich in splicing snRNPs and other splicing proteins necessary for pre-mRNA processing. Because of a cell's changing requirements, the composition and location of these bodies changes according to mRNA transcription and regulation via phosphorylation of specific proteins.[37]
# Function
The main function of the cell nucleus is to control gene expression and mediate the replication of DNA during the cell cycle. The nucleus provides a site for genetic transcription that is segregated from the location of translation in the cytoplasm, allowing levels of gene regulation that are not available to prokaryotes.
## Cell compartmentalization
The nuclear envelope allows the nucleus to control its contents, and separate them from the rest of the cytoplasm where necessary. This is important for controlling processes on either side of the nuclear membrane. In some cases where a cytoplasmic process needs to be restricted, a key participant is removed to the nucleus, where it interacts with transcription factors to downregulate the production of certain enzymes in the pathway. This regulatory mechanism occurs in the case of glycolysis, a cellular pathway for breaking down glucose to produce energy. Hexokinase is an enzyme responsible for the first the step of glycolysis, forming glucose-6-phosphate from glucose. At high concentrations of fructose-6-phosphate, a molecule made later from glucose-6-phosphate, a regulator protein removes hexokinase to the nucleus,[38] where it forms a transcriptional repressor complex with nuclear proteins to reduce the expression of genes involved in glycolysis.[39]
In order to control which genes are being transcribed, the cell separates some transcription factor proteins responsible for regulating gene expression from physical access to the DNA until they are activated by other signaling pathways. This prevents even low levels of inappropriate gene expression. For example in the case of NF-κB-controlled genes, which are involved in most inflammatory responses, transcription is induced in response to a signal pathway such as that initiated by the signaling molecule TNF-α, binds to a cell membrane receptor, resulting in the recruitment of signalling proteins, and eventually activating the transcription factor NF-κB. A nuclear localisation signal on the NF-κB protein allows it to be transported through the nuclear pore and into the nucleus, where it stimulates the transcription of the target genes.[5]
The compartmentalization allows the cell to prevent translation of unspliced mRNA.[40] Eukaryotic mRNA contains introns that must be removed before being translated to produce functional proteins. The splicing is done inside the nucleus before the mRNA can be accessed by ribosomes for translation. Without the nucleus ribosomes would translate newly transcribed (unprocessed) mRNA resulting in misformed and nonfunctional proteins.
## Gene expression
Gene expression first involves transcription, in which DNA is used as a template to produce RNA. In the case of genes encoding proteins, that RNA produced from this process is messenger RNA (mRNA), which then needs to be translated by ribosomes to form a protein. As ribosomes are located outside the nucleus, mRNA produced needs to be exported.[41]
Since the nucleus is the site of transcription, it also contains a variety of proteins which either directly mediate transcription or are involved in regulating the process. These proteins include helicases that unwind the double-stranded DNA molecule to facilitate access to it, RNA polymerases that synthesize the growing RNA molecule, topoisomerases that change the amount of supercoiling in DNA, helping it wind and unwind, as well as a large variety of transcription factors that regulate expression.[42]
## Processing of pre-mRNA
Newly synthesized mRNA molecules are known as primary transcripts or pre-mRNA. They must undergo post-transcriptional modification in the nucleus before being exported to the cytoplasm; mRNA that appears in the nucleus without these modifications is degraded rather than used for protein translation. The three main modifications are 5' capping, 3' polyadenylation, and RNA splicing. While in the nucleus, pre-mRNA is associated with a variety of proteins in complexes known as heterogeneous ribonucleoprotein particles (hnRNPs). Addition of the 5' cap occurs co-transcriptionally and is the first step in post-transcriptional modification. The 3' poly-adenine tail is only added after transcription is complete.
RNA splicing, carried out by a complex called the spliceosome, is the process by which introns, or regions of DNA that do not code for protein, are removed from the pre-mRNA and the remaining exons connected to re-form a single continuous molecule. This process normally occurs after 5' capping and 3' polyadenylation but can begin before synthesis is complete in transcripts with many exons.[4] Many pre-mRNAs, including those encoding antibodies, can be spliced in multiple ways to produce different mature mRNAs that encode different protein sequences. This process is known as alternative splicing, and allows production of a large variety of proteins from a limited amount of DNA.
# Dynamics and regulation
## Nuclear transport
The entry and exit of large molecules from the nucleus is tightly controlled by the nuclear pore complexes. Although small molecules can enter the nucleus without regulation,[43] macromolecules such as RNA and proteins require association karyopherins called importins to enter the nucleus and exportins to exit. "Cargo" proteins that must be translocated from the cytoplasm to the nucleus contain short amino acid sequences known as nuclear localization signals which are bound by importins, while those transported from the nucleus to the cytoplasm carry nuclear export signals bound by exportins. The ability of importins and exportins to transport their cargo is regulated by GTPases, enzymes that hydrolyze the molecule guanosine triphosphate to release energy. The key GTPase in nuclear transport is Ran, which can bind either GTP or GDP (guanosine diphosphate) depending on whether it is located in the nucleus or the cytoplasm. Whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in order to bind to their cargo.[9]
Nuclear import depends on the importin binding its cargo in the cytoplasm and carrying it through the nuclear pore into the nucleus. Inside the nucleus, RanGTP acts to separate the cargo from the importin, allowing the importin to exit the nucleus and be reused. Nuclear export is similar, as the exportin binds the cargo inside the nucleus in a process facilitated by RanGTP, exits through the nuclear pore, and separates from its cargo in the cytoplasm.
Specialized export proteins exist for translocation of mature mRNA and tRNA to the cytoplasm after post-transcriptional modification is complete. This quality-control mechanism is important due to the these molecules' central role in protein translation; mis-expression of a protein due to incomplete excision of exons or mis-incorporation of amino acids could have negative consequences for the cell; thus incompletely modified RNA that reaches the cytoplasm is degraded rather than used in translation.[4]
## Assembly and disassembly
During its lifetime a nucleus may be broken down, either in the process of cell division or as a consequence of apoptosis, a regulated form of cell death. During these events, the structural components of the nucleus—the envelope and lamina—are systematically degraded.
During the cell cycle the cell divides to form two cells. In order for this process to be possible, each of the new daughter cells must have a full set of genes, a process requiring replication of the chromosomes as well as segregation of the separate sets. This occurs by the replicated chromosomes, the sister chromatids, attaching to microtubules, which in turn are attached to different centrosomes. The sister chromatids can then be pulled to separate locations in the cell. However, in many cells the centrosome is located in the cytoplasm, outside the nucleus, the microtubules would be unable to attach to the chromatids in the presence of the nuclear envelope.[44] Therefore the early stages in the cell cycle, beginning in prophase and until around prometaphase, the nuclear membrane is dismantled.[12] Likewise, during the same period, the nuclear lamina is also disassembled, a process regulated by phosphorylation of the lamins.[45] Towards the end of the cell cycle, the nuclear membrane is reformed, and around the same time, the nuclear lamina are reassembled by dephosphorylating the lamins.[45]
Apoptosis is a controlled process in which the cell's structural components are destroyed, resulting in death of the cell. Changes associated with apoptosis directly affect the nucleus and its contents, for example in the condensation of chromatin and the disintegration of the nuclear envelope and lamina. The destruction of the lamin networks is controlled by specialized apoptotic proteases called caspases, which cleave the lamin proteins and thus degrade the nucleus' structural integrity. Lamin cleavage is sometimes used as a laboratory indicator of caspase activity in assays for early apoptotic activity.[12] Cells that express mutant caspase-resistant lamins are deficient in nuclear changes related to apoptosis, suggesting that lamins play a role in initiating the events that lead to apoptotic degradation of the nucleus.[12] Inhibition of lamin assembly itself is an inducer of apoptosis.[46]
The nuclear envelope acts as a barrier that prevents both DNA and RNA viruses from entering the nucleus. Some viruses require access to proteins inside the nucleus in order to replicate and/or assemble. DNA viruses, such as herpesvirus replicate and assemble in the cell nucleus, and exit by budding through the inner nuclear membrane. This process is accompanied by disassembly of the lamina on the nuclear face of the inner membrane.[12]
# Anucleated and polynucleated cells
Although most cells have a single nucleus, some cell types have no nucleus, and others have many nuclei. This can be a normal process, as in the maturation of mammalian red blood cells, or an anomalous result of faulty cell division.
Anucleated cells contain no nucleus and are therefore incapable of dividing to produce daughter cells. The best-known anucleated cell is the mammalian red blood cell, or erythrocyte, which also lacks other organelles such as mitochondria and serves primarily as a transport vessel to ferry oxygen from the lungs to the body's tissues. Erythrocytes mature via erythropoiesis in the bone marrow, where they lose their nuclei, organelles, and ribosomes. The nucleus is expelled during the process of differentiation from an erythroblast to a reticulocyte, the immediate precursor of the mature erythrocyte.[47] The presence of mutagens may induce the release of some immature "micronucleated" erythrocytes into the bloodstream.[48][49] Anucleated cells can also arise from flawed cell division in which one daughter lacks a nucleus and the other is binucleate.
Polynucleated cells contain multiple nuclei. Most Acantharean species of protozoa[50] and some fungi in mycorrhizae[51] have naturally polynucleated cells. In humans, skeletal muscle cells, called myocytes, become polynucleated during development; the resulting arrangement of nuclei near the periphery of the cells allows maximal intracellular space for myofibrils.[4] Multinucleated cells can also be abnormal in humans; for example, cells arising from the fusion of monocytes and macrophages, known as giant multinucleated cells, sometimes accompany inflammation[52] and are also implicated in tumor formation.[53]
# Evolution
As the major defining characteristic of the eukaryotic cell, the nucleus' evolutionary origin has been the subject of much speculation. Four major theories have been proposed to explain the existence of the nucleus, although none have yet earned widespread support.[54]
The theory known as the "syntrophic model" proposes that a symbiotic relationship between the archaea and bacteria created the nucleus-containing eukaryotic cell. It is hypothesized that the symbiosis originated when ancient archaea, similar to modern methanogenic archaea, invaded and lived within bacteria similar to modern myxobacteria, eventually forming the early nucleus. This theory is analogous to the accepted theory for the origin of eukaryotic mitochondria and chloroplasts, which are thought to have developed from a similar endosymbiotic relationship between proto-eukaryotes and aerobic bacteria.[55] The archaeal origin of the nucleus is supported by observations that archaea and eukarya have similar genes for certain proteins, including histones. Observations that myxobacteria are motile, can form multicellular complexes, and possess kinases and G proteins similar to eukarya, support a bacterial origin for the eukaryotic cell.[56]
A second model proposes that proto-eukaryotic cells evolved from bacteria without an endosymbiotic stage. This model is based on the existence of modern planctomycetes bacteria that possess a nuclear structure with primitive pores and other compartmentalized membrane structures.[57] A similar proposal states that a eukaryote-like cell, the chronocyte, evolved first and phagocytosed archaea and bacteria to generate the nucleus and the eukaryotic cell.[58]
The most controversial model, known as viral eukaryogenesis, posits that the membrane-bound nucleus, along with other eukaryotic features, originated from the infection of a prokaryote by a virus. The suggestion is based on similarities between eukaryotes and viruses such as linear DNA strands, mRNA capping, and tight binding to proteins (analogizing histones to viral envelopes). One version of the proposal suggests that the nucleus evolved in concert with phagocytosis to form an early cellular "predator".[59] Another variant proposes that eukaryotes originated from early archaea infected by poxviruses, on the basis of observed similarity between the DNA polymerases in modern poxviruses and eukaryotes.[60][61] It has been suggested that the unresolved question of the evolution of sex could be related to the viral eukaryogenesis hypothesis.[62]
Finally, a very recent proposal suggests that traditional variants of the endosymbiont theory are insufficiently powerful to explain the origin of the eukaryotic nucleus. This model, termed the exomembrane hypothesis, suggests that the nucleus instead originated from a single ancestral cell that evolved a second exterior cell membrane; the interior membrane enclosing the original cell then became the nuclear membrane and evolved increasingly elaborate pore structures for passage of internally synthesized cellular components such as ribosomal subunits.[63] | https://www.wikidoc.org/index.php/Cell_nucleus | |
6ba2ce761dc13e7644ffd73be5994c5676db1b41 | wikidoc | Cell therapy | Cell therapy
Cell therapy describes the process of introducing new cells into a tissue in order to treat a disease. Cell therapies often focus on the treatment of hereditary diseases, with or without the addition of gene therapy.
There are many potential forms of cell therapy:
- The transplantation of stem cells that are autologous (from the patient) or allogeneic (from another donor).
- The transplantation of mature, functional cells.
- The application of modified human cells that are used to produce a needed substance.
- The xenotransplantation of non-human cells that are used to produce a needed substance. For example, treating diabetic patients by introducing insulin-producing pig cells directly into their muscle.
Increasingly, mesenchymal stem cells are being proposed as agents for cell-based therapies, due to their plasticity, established isolation procedures, and capacity for ex vivo expansion. | Cell therapy
Cell therapy describes the process of introducing new cells into a tissue in order to treat a disease. Cell therapies often focus on the treatment of hereditary diseases, with or without the addition of gene therapy.
There are many potential forms of cell therapy:
- The transplantation of stem cells that are autologous (from the patient) or allogeneic (from another donor).
- The transplantation of mature, functional cells.
- The application of modified human cells that are used to produce a needed substance.
- The xenotransplantation of non-human cells that are used to produce a needed substance. For example, treating diabetic patients by introducing insulin-producing pig cells directly into their muscle.
Increasingly, mesenchymal stem cells are being proposed as agents for cell-based therapies, due to their plasticity, established isolation procedures, and capacity for ex vivo expansion.
# External links
- Cell Therapy News
ar:علاج خلوي
Template:WS | https://www.wikidoc.org/index.php/Cell_therapy | |
4b56da4c72596a40b736d42bba592d3e7968c598 | wikidoc | Cementoblast | Cementoblast
# Overview
A cementoblast is a biological cell that forms from the follicular cells around the root of a tooth, and whose biological function is cementogenesis, which is the creation of cementum (the hard tissue that covers the root of the tooth).
Cementoblasts lay down the organic matrix of cementum which later gets mineralised by minerals from oral fluids. Thus the cementoblasts lay down collagen and secrete osteocalcin and sialoprotein. They possess all the organelles associated with protein synthesis such as RER and Golgi apparatus.
The mechanism of differentiation of the cementoblasts is controversial but circumstantial evidence suggests that an epithelium or epithelial componenet may cause dental follicle cells to differentiate into cementoblasts, characterised by an increase in length.
The initially formed cementum in coronal two-thirds of the root is acellular, but when the cementoblasts get trapped in lacunae in their own matrix like bone cells, the cementum is called cellular or secondary cementum and is present only in the apical third of the root.
Once in this situation, the cementoblasts lose their secretory activity and become cementocytes. | Cementoblast
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A cementoblast is a biological cell that forms from the follicular cells around the root of a tooth, and whose biological function is cementogenesis, which is the creation of cementum (the hard tissue that covers the root of the tooth).
Cementoblasts lay down the organic matrix of cementum which later gets mineralised by minerals from oral fluids. Thus the cementoblasts lay down collagen and secrete osteocalcin and sialoprotein. They possess all the organelles associated with protein synthesis such as RER and Golgi apparatus.
The mechanism of differentiation of the cementoblasts is controversial but circumstantial evidence suggests that an epithelium or epithelial componenet may cause dental follicle cells to differentiate into cementoblasts, characterised by an increase in length.
The initially formed cementum in coronal two-thirds of the root is acellular, but when the cementoblasts get trapped in lacunae in their own matrix like bone cells, the cementum is called cellular or secondary cementum and is present only in the apical third of the root.
Once in this situation, the cementoblasts lose their secretory activity and become cementocytes.
Template:Embryology of head and neck
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cementoblast | |
a1326d1433ce644db90ffd9297b88fbf37bd3680 | wikidoc | Horror vacui | Horror vacui
# Overview
In visual art, horror vacui (/ˈhɔːrər ˈvɑːkjuːaɪ/; from Latin "fear of empty space"), also kenophobia, from Greek "fear of the empty"), is the filling of the entire surface of a space or an Work of art|artwork with Complexity|detail.
# Origins
The term is associated with the Italian art critic and scholar Mario Praz, who used it to describe the suffocating atmosphere and clutter of interior design in the Victorian age. Older, and more artistically esteemed examples can be seen on Migration period art objects like the carpet pages of Insular art|Insular illuminated manuscripts such as the Book of Kells. This feeling of meticulously filling empty spaces also permeates Arabesque (Islamic art)|Arabesque Islamic art from ancient times to the present. Another example comes from ancient Greece during the Geometric Art|Geometric Age (1100 - 900 BCE), when horror vacui was considered a stylistic element of all art. The mature work of the French Renaissance engraver Jean Duvet consistently exhibits horror vacui.
# Examples
Some examples of horror vacui in art come from, or are influenced by, the mentally ill|mentally unstable and inmates of psychiatric hospitals, such as Richard Dadd in the 19th century, and many modern examples fall under the category of Outsider Art. Horror vacui may have also had an impact, consciously or unconsciously, on graphic design by artists like David Carson (graphic designer)|David Carson or Vaughan Oliver, and in the underground comix movement in the work of S. Clay Wilson, Robert Crumb, Robert Williams (artist)|Robert Williams, and on later comic artists such as Mark Beyer (comics)|Mark Beyer. The paintings of Williams, Faris Badwan, Emerson Barrett, Joe Coleman (painter)|Joe Coleman and Todd Schorr are further examples of horror vacui in the modern Lowbrow (art movement)|Lowbrow art movement.
The entheogen-inspired visionary art of certain indigenous peoples, such as the Huichol people|Huichol yarn paintings and the ayahuasca-inspired art of Pablo Amaringo, often exhibits this style, as does the psychedelic art movement of the 1960s counterculture. Sometimes the patterned art in clothing of indigenous peoples of Middle and South America exhibits horror vacui. For example the geometric Mola (art form)|molas of Kuna (people)|Kuna people and the traditional clothing on Shipibo-Conibo people.
The artwork in the Where's Wally? series of children's books is a commonly known example of horror vacui, as are many of the small books written or illustrated by the macabre imagination of Edward Gorey.
The Tingatinga (painting)|Tingatinga painting style of Dar es Salaam in Tanzania is a contemporary example of horror vacui. Other African artists such as Malangatana of Mozambique (Malangatana Ngwenya) also fill the canvas in this way.
The arrangement of Ancient Egyptian hieroglyphs suggests an abhorrence of empty space. Signs are repeated or phonetic complements added to prevent gaps.
# Current usage and meaning
There is an inverse relationship between horror vacui and value perception, and commercial designers favour minimalism in shop window displays and advertising to appeal to affluent and well-educated consumers, on the premise that understatement and restraint appeals more to affluent and well-educated audiences. | Horror vacui
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In visual art, horror vacui (/ˈhɔːrər ˈvɑːkjuːaɪ/; from Latin "fear of empty space"), also kenophobia, from Greek "fear of the empty"),[1] is the filling of the entire surface of a space or an Work of art|artwork with Complexity|detail.
# Origins
The term is associated with the Italian art critic and scholar Mario Praz, who used it to describe the suffocating atmosphere and clutter of interior design in the Victorian age.[2] Older, and more artistically esteemed examples can be seen on Migration period art objects like the carpet pages of Insular art|Insular illuminated manuscripts such as the Book of Kells. This feeling of meticulously filling empty spaces also permeates Arabesque (Islamic art)|Arabesque Islamic art from ancient times to the present. Another example comes from ancient Greece during the Geometric Art|Geometric Age (1100 - 900 BCE), when horror vacui was considered a stylistic element of all art. The mature work of the French Renaissance engraver Jean Duvet consistently exhibits horror vacui.
# Examples
Some examples of horror vacui in art come from, or are influenced by, the mentally ill|mentally unstable and inmates of psychiatric hospitals, such as Richard Dadd in the 19th century, and many modern examples fall under the category of Outsider Art.[citation needed] Horror vacui may have also had an impact, consciously or unconsciously, on graphic design by artists like David Carson (graphic designer)|David Carson or Vaughan Oliver, and in the underground comix movement in the work of S. Clay Wilson, Robert Crumb, Robert Williams (artist)|Robert Williams, and on later comic artists such as Mark Beyer (comics)|Mark Beyer. The paintings of Williams, Faris Badwan, Emerson Barrett, Joe Coleman (painter)|Joe Coleman and Todd Schorr are further examples of horror vacui in the modern Lowbrow (art movement)|Lowbrow art movement.[citation needed]
The entheogen-inspired visionary art of certain indigenous peoples, such as the Huichol people|Huichol yarn paintings and the ayahuasca-inspired art of Pablo Amaringo, often exhibits this style, as does the psychedelic art movement of the 1960s counterculture. Sometimes the patterned art in clothing of indigenous peoples of Middle and South America exhibits horror vacui. For example the geometric Mola (art form)|molas of Kuna (people)|Kuna people and the traditional clothing on Shipibo-Conibo people.
The artwork in the Where's Wally? series of children's books is a commonly known example of horror vacui, as are many of the small books written or illustrated by the macabre imagination of Edward Gorey.
The Tingatinga (painting)|Tingatinga painting style of Dar es Salaam in Tanzania is a contemporary example of horror vacui. Other African artists such as Malangatana of Mozambique (Malangatana Ngwenya) also fill the canvas in this way.
The arrangement of Ancient Egyptian hieroglyphs suggests an abhorrence of empty space. Signs are repeated or phonetic complements added to prevent gaps.
# Current usage and meaning
There is an inverse relationship between horror vacui and value perception, and commercial designers favour minimalism in shop window displays and advertising to appeal to affluent and well-educated consumers, on the premise that understatement and restraint appeals more to affluent and well-educated audiences.[2] | https://www.wikidoc.org/index.php/Cenophobia | |
9a31d977583d985b6ce851463ebda49890bc381b | wikidoc | Fosphenytoin | Fosphenytoin
# 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
Fosphenytoin is a anticonvulsant , central nervous system agent and hydantoin that is FDA approved for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, ataxia, dizziness, headache, paresthesia, somnolence and nystagmus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Fosphenytoin sodium is indicated for the control of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin sodium can also be substituted, short-term, for oral phenytoin. Fosphenytoin sodium should be used only when oral phenytoin administration is not possible. Fosphenytoin sodium must not be given orally.
### Dosing Information
- The dose, concentration, and infusion rate of Fosphenytoin sodium should always be expressed as phenytoin sodium equivalents (PE). There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin sodium should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE).
- Do not confuse the concentration of Fosphenytoin sodium with the total amount of drug in the vial.
- Caution must be used when administering Fosphenytoin sodium due to the risk of dosing errors (see WARNINGS). Medication errors associated with Fosphenytoin sodium have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. Both vials contain a concentration of 50 mg PE/mL. Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE. These errors have resulted in two- or ten-fold overdoses of Fosphenytoin sodium since each of the vials actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of Fosphenytoin sodium should always be expressed in milligrams of phenytoin equivalents (mg PE). Additionally, when ordering and storing Fosphenytoin sodium, consider displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500 mg PE/ 10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of Fosphenytoin sodium is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some Fosphenytoin sodium medication errors from occurring.
- Prior to IV infusion, dilute Fosphenytoin sodium in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL. The maximum concentration of Fosphenytoin sodium in any solution should be 25 mg PE/mL. When Fosphenytoin sodium is given as an intravenous infusion, Fosphenytoin sodium needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- The loading dose of Fosphenytoin sodium is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.
- Because of the risk of hypotension, Fosphenytoin sodium should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of Fosphenytoin sodium infusions.
- Because the full antiepileptic effect of phenytoin, whether given as Fosphenytoin sodium or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus.
- The loading dose should be followed by maintenance doses of either Fosphenytoin sodium or phenytoin.
- If administration of Fosphenytoin sodium does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
- Even though loading doses of Fosphenytoin sodium have been given by the IM route for other indications when IV access is impossible, IM Fosphenytoin sodium should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
- Because of the risks of cardiac and local toxicity associated with intravenous Fosphenytoin sodium, oral phenytoin should be used whenever possible.
- The loading dose of Fosphenytoin sodium is 10 – 20 mg PE/kg given IV or IM. The rate of administration for IV Fosphenytoin sodium should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of Fosphenytoin sodium infusion).
- The initial daily maintenance dose of Fosphenytoin sodium is 4 – 6 mg PE/kg/day in divided doses.
- When treatment with oral phenytoin is not possible, Fosphenytoin sodium can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as Fosphenytoin sodium, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV Fosphenytoin sodium is substituted for oral phenytoin sodium therapy. The rate of administration for IV Fosphenytoin sodium should be no greater than 150 mg PE/min. In controlled trials, IM Fosphenytoin sodium was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing.
- Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see CLINICAL PHARMACOLOGY: SPECIAL POPULATIONS). Unbound phenytoin concentrations may be more useful in these patient populations. After IV Fosphenytoin sodium administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).
- Age does not have a significant impact on the pharmacokinetics of fosphenytoin following Fosphenytoin sodium administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fosphenytoin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fosphenytoin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Fosphenytoin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fosphenytoin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fosphenytoin in pediatric patients.
# Contraindications
- Fosphenytoin sodium is contraindicated in patients who have demonstrated hypersensitivity to Fosphenytoin sodium or its ingredients, or to phenytoin or other hydantoins. Because of the effect of parenteral phenytoin on ventricular automaticity, Fosphenytoin sodium is contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome.
- Coadministration of Fosphenytoin sodium is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.
# Warnings
- DOSES OF Fosphenytoin sodium ARE ALWAYS EXPRESSED IN TERMS OF MILLIGRAMS OF PHENYTOIN SODIUM EQUIVALENTS (mg PE) 1 MG PE IS EQUIVALENT TO 1 MG PHENYTOIN SODIUM.
- DO NOT, THEREFORE, MAKE ANY ADJUSTMENT IN THE RECOMMENDED DOSES WHEN SUBSTITUTING Fosphenytoin sodium FOR PHENYTOIN SODIUM OR VICE VERSA. FOR EXAMPLE, IF A PATIENT IS RECEIVING 1000 MG PE OF Fosphenytoin sodium, THAT IS EQUIVALENT TO 1000 MG OF PHENYTOIN SODIUM.
- The following warnings are based on experience with Fosphenytoin sodium or phenytoin.
- Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial.
- Medication errors associated with Fosphenytoin sodium have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/ mL. Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE. These errors have resulted in two- or ten-fold overdoses of Fosphenytoin sodium since each vial actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of Fosphenytoin sodium should always be expressed in milligrams of phenytoin equivalents (mg PE) (see DOSAGE AND ADMINISTRATION). Additionally, when ordering and storing Fosphenytoin sodium, consider displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500 mg PE/ 10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of Fosphenytoin sodium is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some Fosphenytoin sodium medication errors from occurring.
- Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, do not administer Fosphenytoin sodium at a rate greater than 150 mg PE/min.
- The dose of IV Fosphenytoin sodium (15 to 20 mg PE/kg) that is used to treat status epilepticus is administered at a maximum rate of 150 mg PE/min. The typical Fosphenytoin sodium infusion administered to a 50 kg patient would take between 5 and 7 minutes. Note that the delivery of an identical molar dose of phenytoin using parenteral Dilantin or generic phenytoin sodium injection cannot be accomplished in less than 15 to 20 minutes because of the untoward cardiovascular effects that accompany the direct intravenous administration of phenytoin at rates greater than 50 mg/min.
- If rapid phenytoin loading is a primary goal, IV administration of Fosphenytoin sodium is preferred because the time to achieve therapeutic plasma phenytoin concentrations is greater following IM than that following IV administration (see DOSAGE AND ADMINISTRATION).
- As non-emergency therapy, intravenous Fosphenytoin sodium should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV Fosphenytoin sodium, oral phenytoin should be used whenever possible.
- Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Fosphenytoin sodium. Reduction in rate of administration or discontinuation of dosing may be needed.
- Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.
- Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.
- Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Fosphenytoin sodium should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan Hypersensitivity below).
- Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding Fosphenytoin sodium as an alternative for carbamazepine patients positive for HLA-B*1502.
- The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin and Fosphenytoin sodium. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Fosphenytoin sodium should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
- Fosphenytoin sodium and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Fosphenytoin sodium.
- Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Fosphenytoin sodium should be immediately discontinued and not readministered.
- Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports that have suggested a relationship between phenytoin and the development of lymphadenopathy (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.
- Acute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use may decrease plasma concentrations.
### Usage in Pregnancy
- An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, LABORATORY TESTS). However, postpartum restoration of the original dosage will probably be indicated.
- If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
- Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two-to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
- A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
- Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal anomalies), death, growth retardation, and functional impairment (chromodacryorrhea, hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg PE/kg or higher (approximately 30% of the maximum human loading dose or higher on a mg/m2 basis), which produced peak maternal plasma phenytoin concentrations of approximately 20 µg/mL or greater. Maternal toxicity was often associated with these doses and plasma concentrations, however, there is no evidence to suggest that the developmental effects were secondary to the maternal effects. The single occurrence of a rare brain malformation at a non-maternotoxic dose of 17 mg PE/kg (approximately 10% of the maximum human loading dose on a mg/m2 basis) was also considered drug-induced. The developmental effects of fosphenytoin in rats were similar to those which have been reported following administration of phenytoin to pregnant rats. No effects on embryo-fetal development were observed when rabbits were given up to 33 mg PE/kg of fosphenytoin (approximately 50% of the maximum human loading dose on a mg/m2 basis) during pregnancy. Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.
### PRECAUTIONS
- Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers administered IV Fosphenytoin sodium at a dose of 1200 mg PE at the maximum rate of administration (150 mg PE/min). The severe sensory disturbance lasted from 3 to 50 minutes in 6 of these subjects and for 14 hours in the seventh subject. In some cases, milder sensory disturbances persisted for as long as 24 hours. The location of the discomfort varied among subjects with the groin mentioned most frequently as an area of discomfort. In a separate cohort of 16 normal volunteers (taken from 2 other studies) who were administered IV Fosphenytoin sodium at a dose of 1200 mg PE at the maximum rate of administration (150 mg PE/min), none experienced severe disturbances, but most experienced mild to moderate itching or tingling. Patients administered Fosphenytoin sodium at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree. The occurrence and intensity of the discomfort can be lessened by slowing or temporarily stopping the infusion. The effect of continuing infusion unaltered in the presence of these sensations is unknown. No permanent sequelae have been reported thus far. The pharmacologic basis for these positive sensory phenomena is unknown, but other phosphate ester drugs, which deliver smaller phosphate loads, have been associated with burning, itching, and/or tingling predominantly in the groin area.
- Edema, discoloration, and pain distal to the site of injection (described as "purple glove syndrome") have also been reported following peripheral intravenous Fosphenytoin sodium injection. This may or may not be associated with extravasation. The syndrome may not develop for several days after injection.
- The phosphate load provided by Fosphenytoin sodium (0.0037 mmol phosphate/mg PE Fosphenytoin sodium) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment.
- IV Loading in Renal and/or Hepatic Disease or in Those with Hypoalbuminemia
- After IV administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see CLINICAL PHARMACOLOGY: SPECIAL POPULATIONS, and DOSAGE AND ADMINISTRATION: DOSING IN SPECIAL POPULATIONS).
- Fosphenytoin sodium is not indicated for the treatment of absence seizures.
- A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined.
- Phenytoin has been infrequently associated with the exacerbation of porphyria. Caution should be exercised when Fosphenytoin sodium is used in patients with this disease.
- Hyperglycemia, resulting from phenytoin's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose concentrations in diabetic patients.
- Plasma concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium," "psychosis," or "encephalopathy," or rarely, irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, determination of plasma phenytoin concentrations is recommended (see PRECAUTIONS: LABORATORY TESTS). Fosphenytoin sodium dose reduction is indicated if phenytoin concentrations are excessive; if symptoms persist, administration of Fosphenytoin sodium should be discontinued.
- The liver is the primary site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.
- Phenytoin and other hydantoins are not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.
- Phenytoin has the potential to lower serum folate levels.
# Adverse Reactions
## Clinical Trials Experience
- The more important adverse clinical events caused by the IV use of Fosphenytoin sodium or phenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when either drug is administered rapidly by the IV route. The rate of administration is very important; for Fosphenytoin sodium, it should not exceed 150 mg PE/min. The adverse clinical events most commonly observed with the use of Fosphenytoin sodium in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With two exceptions, these events are commonly associated with the administration of IV phenytoin. Paresthesia and pruritus, however, were seen much more often following Fosphenytoin sodium administration and occurred more often with IV Fosphenytoin sodium administration than with IM Fosphenytoin sodium administration. These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ≥15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently as a site of involvement. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of Fosphenytoin sodium infusion. Some patients experienced symptoms for hours. These events did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen (see PRECAUTIONS, SENSORY DISTURBANCES). Approximately 2% of the 859 individuals who received Fosphenytoin sodium in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%).
- The incidence of adverse events tended to increase as both dose and infusion rate increased. In particular, at doses of ≥15mg PE/kg and rates ≥150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often than at lower doses or rates.
- All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the tables and listings below with the frequencies representing the proportion of individuals exposed to Fosphenytoin sodium or comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.
- Table 2 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with IV Fosphenytoin sodium at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and Fosphenytoin sodium administration would have resulted in equivalent systemic exposure to phenytoin.
- Table 3 lists treatment-emergent adverse events that occurred in at least 2% of Fosphenytoin sodium-treated patients in a double-blind, randomized, controlled clinical trial of adult epilepsy patients receiving either IM Fosphenytoin sodium substituted for oral Dilantin or continuing oral Dilantin. Both treatments were administered for 5 days.
- Fosphenytoin sodium has been administered to 859 individuals during all clinical trials. All adverse events seen at least twice are listed in the following, except those already included in previous tables and listings. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 individuals; infrequent adverse events are those occurring in 1/100 to 1/1000 individuals.
- Frequent: fever, injection-site reaction, infection, chills, face edema, injection-site pain; Infrequent: sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis.
- Frequent:
- Hypertension
- Infrequent:
- Cardiac arrest, migraine, syncope, cerebral hemorrhage, palpitation, sinus bradycardia, atrial flutter, bundle branch block, cardiomegaly, cerebral infarct, postural hypotension, pulmonary embolus, QT interval prolongation, thrombophlebitis, ventricular extrasystoles, congestive heart failure.
- Frequent:
- Constipation
- Infrequent:
- Dyspepsia, diarrhea, anorexia, gastrointestinal hemorrhage, increased salivation, liver function tests abnormal, tenesmus, tongue edema, dysphagia, flatulence, gastritis, ileus.
- Infrequent:
- Diabetes insipidus.
- Infrequent:
- Thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia.
- Frequent:
- Hypokalemia;
- Infrequent:
- Hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis.
- Frequent:
- Myasthenia; Infrequent: myopathy, leg cramps, arthralgia, myalgia.
- Frequent:
- Reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness, hypesthesia; Infrequent: confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, brain edema, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis.
- Frequent:
- Pneumonia
- Infrequent:
- Pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration pneumonia, asthma, dyspnea, atelectasis, cough increased, sputum increased, epistaxis, hypoxia, pneumothorax, hemoptysis, bronchitis.
- Frequent:
- Rash
- Infrequent:
- Maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule.
- Frequent:
- Taste perversion
- Infrequent:
- Deafness, visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss.
- Infrequent:
- Urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of fosphenytoin. 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.
- There have been post-marketing reports of anaphylactoid reaction and anaphylaxis.
### Other Phenytoin-Associated Adverse Events
- Dyskinesia.
# Drug Interactions
- Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL, (unbound phenytoin concentrations of 1 to 2 mcg/mL). Following Fosphenytoin sodium administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of IV infusion and 4 hours after IM injection. Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx®/TDxFLx™ (fluorescence polarization) and Emit® 2000 (enzyme multiplied), may significantly overestimate plasma phenytoin concentrations because of cross-reactivity with fosphenytoin. The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by Fosphenytoin sodium dose, route and rate of administration, and time of sampling relative to dosing), and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin. However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved.
- No drugs are known to interfere with the conversion of fosphenytoin to phenytoin. Conversion could be affected by alterations in the level of phosphatase activity, but given the abundance and wide distribution of phosphatases in the body it is unlikely that drugs would affect this activity enough to affect conversion of fosphenytoin to phenytoin. Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin. Although, it is unknown whether this could result in clinically significant effects, caution is advised when administering Fosphenytoin sodium with other drugs that significantly bind to serum albumin. The pharmacokinetics and protein binding of fosphenytoin, phenytoin, and diazepam were not altered when diazepam and Fosphenytoin sodium were concurrently administered in single submaximal doses. The most significant drug interactions following administration of Fosphenytoin sodium are expected to occur with drugs that interact with phenytoin. Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes.
- The most commonly occurring drug interactions are listed below:
- Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted.
- Drugs that may increase plasma phenytoin concentrations include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
- Drugs that may decrease plasma phenytoin concentrations include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John's Wort, theophylline, and vigabatrin.
- Drugs that may either increase or decrease plasma phenytoin concentrations include: phenobarbital, valproic acid, and sodium valproate. Similarly, the effects of phenytoin on phenobarbital, valproic acid and sodium plasma valproate concentrations are unpredictable.
- The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.
- Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS).
- Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D.
- Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.
- Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), antiepileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin and verapamil.
- Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
- Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
- The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
- Monitoring of plasma phenytoin concentrations may be helpful when possible drug interactions are suspected.
- Phenytoin may decrease serum concentrations of T4. It may also produce artifactually low results in dexamethasone or metyrapone tests. Phenytoin may also cause increased serum concentrations of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following Fosphenytoin sodium administration.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
### Usage in Pregnancy
- An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, LABORATORY TESTS). However, postpartum restoration of the original dosage will probably be indicated.
- If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
- Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two-to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
- A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
- Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal anomalies), death, growth retardation, and functional impairment (chromodacryorrhea, hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg PE/kg or higher (approximately 30% of the maximum human loading dose or higher on a mg/m2 basis), which produced peak maternal plasma phenytoin concentrations of approximately 20 µg/mL or greater. Maternal toxicity was often associated with these doses and plasma concentrations, however, there is no evidence to suggest that the developmental effects were secondary to the maternal effects. The single occurrence of a rare brain malformation at a non-maternotoxic dose of 17 mg PE/kg (approximately 10% of the maximum human loading dose on a mg/m2 basis) was also considered drug-induced. The developmental effects of fosphenytoin in rats were similar to those which have been reported following administration of phenytoin to pregnant rats. No effects on embryo-fetal development were observed when rabbits were given up to 33 mg PE/kg of fosphenytoin (approximately 50% of the maximum human loading dose on a mg/m2 basis) during pregnancy. Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fosphenytoin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fosphenytoin during labor and delivery.
### Nursing Mothers
- It is not known whether fosphenytoin is excreted in human milk.
- Following administration of Dilantin, phenytoin appears to be excreted in low concentrations in human milk. Therefore, breast-feeding is not recommended for women receiving Fosphenytoin sodium.
### Pediatric Use
There is no FDA guidance on the use of Fosphenytoin with respect to pediatric patients.
### Geriatic Use
- No systematic studies in geriatric patients have been conducted. Phenytoin clearance tends to decrease with increasing ag
### Gender
There is no FDA guidance on the use of Fosphenytoin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fosphenytoin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fosphenytoin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fosphenytoin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fosphenytoin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fosphenytoin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
- Intravenous
### Monitoring
- The rate of intravenous Fosphenytoin sodium administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Fosphenytoin sodium. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed.
- As non-emergency therapy, intravenous CEREBYX should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV CEREBYX, oral phenytoin should be used whenever possible.
- Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous CEREBYX. Reduction in rate of administration or discontinuation of dosing may be needed.
- Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.
- Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL, (unbound phenytoin concentrations of 1 to 2 mcg/mL). Following CEREBYX administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of IV infusion and 4 hours after IM injection. Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx®/TDxFLx™ (fluorescence polarization) and Emit® 2000 (enzyme multiplied), may significantly overestimate plasma phenytoin concentrations because of cross-reactivity with fosphenytoin. The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by CEREBYX dose, route and rate of administration, and time of sampling relative to dosing), and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin. However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved.
- Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
- Monitoring of plasma phenytoin concentrations may be helpful when possible drug interactions are suspected.
- The loading dose of CEREBYX is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.
- Because of the risk of hypotension, CEREBYX should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of CEREBYX infusions.
- Because the full antiepileptic effect of phenytoin, whether given as CEREBYX or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus.
- The loading dose should be followed by maintenance doses of either CEREBYX or phenytoin.
If administration of CEREBYX does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
- Even though loading doses of CEREBYX have been given by the IM route for other indications when IV access is impossible, IM CEREBYX should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
- Because of the risks of cardiac and local toxicity associated with intravenous CEREBYX, oral phenytoin should be used whenever possible.
- The loading dose of CEREBYX is 10 – 20 mg PE/kg given IV or IM. The rate of administration for IV CEREBYX should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of CEREBYX infusion).
# IV Compatibility
There is limited information regarding IV Compatibility of Fosphenytoin in the drug label.
# Overdosage
- Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin.
- The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.
- Because Fosphenytoin sodium is a prodrug of phenytoin, the following information may be helpful. Initial symptoms of acute phenytoin toxicity are nystagmus, ataxia, and dysarthria. Other signs include tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting, coma, and hypotension. Depression of respiratory and circulatory systems leads to death. There are marked variations among individuals with respect to plasma phenytoin concentrations where toxicity occurs. Lateral gaze nystagmus usually appears at 20 µg/mL, ataxia at 30 µg/mL, and dysarthria and lethargy appear when the plasma concentration is over 40 µg/mL. However, phenytoin concentrations as high as 50 µg/mL have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in plasma phenytoin concentrations over 100 µg/mL, with complete recovery.
- Treatment is nonspecific since there is no known antidote to Fosphenytoin sodium or phenytoin overdosage. The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
- Formate and phosphate are metabolites of fosphenytoin and therefore may contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with severe anion-gap metabolic acidosis. Large amounts of phosphate, delivered rapidly, could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. Ionized free calcium levels can be measured and, if low, used to guide treatment.
# Pharmacology
There is limited information regarding Fosphenytoin Pharmacology in the drug label.
## Mechanism of Action
- Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. After IV administration to mice, fosphenytoin blocked the tonic phase of maximal electroshock seizures at doses equivalent to those effective for phenytoin. In addition to its ability to suppress maximal electroshock seizures in mice and rats, phenytoin exhibits anticonvulsant activity against kindled seizures in rats, audiogenic seizures in mice, and seizures produced by electrical stimulation of the brainstem in rats. The cellular mechanisms of phenytoin thought to be responsible for its anticonvulsant actions include modulation of voltage-dependent sodium channels of neurons, inhibition of calcium flux across neuronal membranes, modulation of voltage-dependent calcium channels of neurons, and enhancement of the sodium-potassium ATPase activity of neurons and glial cells. The modulation of sodium channels may be a primary anticonvulsant mechanism because this property is shared with several other anticonvulsants in addition to phenytoin.
## Structure
- Fosphenytoin sodium® (fosphenytoin sodium injection) is a prodrug intended for parenteral administration; its active metabolite is phenytoin. 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg phenytoin sodium equivalents (PE). The amount and concentration of fosphenytoin is always expressed in terms of mg PE.
- Fosphenytoin sodium is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL. Fosphenytoin sodium is supplied in vials as a ready-mixed solution in Water for Injection, USP, and Tromethamine, USP (TRIS), buffer adjusted to pH 8.6 to 9.0 with either Hydrochloric Acid, NF, or Sodium Hydroxide, NF. Fosphenytoin sodium is a clear, colorless to pale yellow, sterile solution.
## Pharmacodynamics
- Following parenteral administration of Fosphenytoin sodium, fosphenytoin is converted to the anticonvulsant phenytoin. For every mmol of fosphenytoin administered, one mmol of phenytoin is produced. The pharmacological and toxicological effects of fosphenytoin include those of phenytoin. However, the hydrolysis of fosphenytoin to phenytoin yields two metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which is in turn metabolized via a folate dependent mechanism. Although phosphate and formaldehyde (formate) have potentially important biological effects, these effects typically occur at concentrations considerably in excess of those obtained when Fosphenytoin sodium is administered under conditions of use recommended in this labeling.
## Pharmacokinetics
### Fosphenytoin
### Absorption/Bioavailability
- When Fosphenytoin sodium is administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion. Fosphenytoin has a half-life of approximately 15 minutes. Intramuscular: Fosphenytoin is completely bioavailable following IM administration of Fosphenytoin sodium. Peak concentrations occur at approximately 30 minutes postdose. Plasma fosphenytoin concentrations following IM administration are lower but more sustained than those following IV administration due to the time required for absorption of fosphenytoin from the injection site.
- Fosphenytoin is extensively bound (95% to 99%) to human plasma proteins, primarily albumin. Binding to plasma proteins is saturable with the result that the percent bound decreases as total fosphenytoin concentrations increase. Fosphenytoin displaces phenytoin from protein binding sites. The volume of distribution of fosphenytoin increases with Fosphenytoin sodium dose and rate, and ranges from 4.3 to 10.8 liters.
- The conversion half-life of fosphenytoin to phenytoin is approximately 15 minutes. The mechanism of fosphenytoin conversion has not been determined, but phosphatases probably play a major role. Fosphenytoin is not excreted in urine. Each mmol of fosphenytoin is metabolized to 1 mmol of phenytoin, phosphate, and formate.
### Phenytoin (after Fosphenytoin sodium administration)
- In general, IM administration of Fosphenytoin sodium generates systemic phenytoin concentrations that are similar enough to oral phenytoin sodium to allow essentially interchangeable use. The pharmacokinetics of fosphenytoin following IV administration of Fosphenytoin sodium, however, are complex, and when used in an emergency setting (eg, status epilepticus), differences in rate of availability of phenytoin could be critical. Studies have therefore empirically determined an infusion rate for Fosphenytoin sodium that gives a rate and extent of phenytoin systemic availability similar to that of a 50 mg/min phenytoin sodium infusion. A dose of 15 to 20 mg PE/kg of Fosphenytoin sodium infused at 100 to 150 mg PE/min yields plasma free phenytoin concentrations over time that approximate those achieved when an equivalent dose of phenytoin sodium (eg, parenteral DILANTIN®) is administered at 50 mg/min.
- FIGURE 1. Mean plasma unbound phenytoin concentrations following IV administration of 1200 mg PE Fosphenytoin sodium infused at 100 mg PE/min (triangles) or 150 mg PE/min (squares) and 1200 mg Dilantin infused at 50 mg/min (diamonds) to healthy subjects (N = 12). Inset shows time course for the entire 96-hour sampling period.
- Following administration of single IV Fosphenytoin sodium doses of 400 to 1200 mg PE, mean maximum total phenytoin concentrations increase in proportion to dose, but do not change appreciably with changes in infusion rate. In contrast, mean maximum unbound phenytoin concentrations increase with both dose and rate.
- Fosphenytoin is completely converted to phenytoin following IV administration, with a half-life of approximately 15 minutes. Fosphenytoin is also completely converted to phenytoin following IM administration and plasma total phenytoin concentrations peak in approximately 3 hours.
- Phenytoin is highly bound to plasma proteins, primarily albumin, although to a lesser extent than fosphenytoin. In the absence of fosphenytoin, approximately 12% of total plasma phenytoin is unbound over the clinically relevant concentration range. However, fosphenytoin displaces phenytoin from plasma protein binding sites. This increases the fraction of phenytoin unbound (up to 30% unbound) during the period required for conversion of fosphenytoin to phenytoin (approximately 0.5 to 1 hour postinfusion).
- Phenytoin derived from administration of Fosphenytoin sodium is extensively metabolized in the liver and excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1%–5% of the Fosphenytoin sodium dose) is recovered in urine. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19. Phenytoin hepatic metabolism is saturable, and following administration of single IV Fosphenytoin sodium doses of 400 to 1200 mg PE, total and unbound phenytoin AUC values increase disproportionately with dose. Mean total phenytoin half-life values (12.0 to 28.9 hr) following Fosphenytoin sodium administration at these doses are similar to those after equal doses of parenteral Dilantin and tend to be greater at higher plasma phenytoin concentrations.
### Special Populations
- Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. After IV administration of Fosphenytoin sodium to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).
- The effect of age was evaluated in patients 5 to 98 years of age. Patient age had no significant impact on fosphenytoin pharmacokinetics. Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20–30 years of age). Phenytoin dosing requirements are highly variable and must be individualized.
- Gender and race have no significant impact on fosphenytoin or phenytoin pharmacokinetics.
- The safety and efficacy of Fosphenytoin sodium in pediatric patients have not been established.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Fosphenytoin in the drug label.
# Clinical Studies
- Infusion tolerance was evaluated in clinical studies. One double-blind study assessed infusion-site tolerance of equivalent loading doses (15–20 mg PE/kg) of Fosphenytoin sodium infused at 150 mg PE/min or phenytoin infused at 50 mg/min. The study demonstrated better local tolerance (pain and burning at the infusion site), fewer disruptions of the infusion, and a shorter infusion period for Fosphenytoin sodium-treated patients (Table 1).
- Fosphenytoin sodium-treated patients, however, experienced more systemic sensory disturbances (see PRECAUTIONS, SENSORY DISTURBANCES). Infusion disruptions in Fosphenytoin sodium-treated patients were primarily due to systemic burning, pruritus, and/or paresthesia while those in phenytoin-treated patients were primarily due to pain and burning at the infusion site (see TABLE 1). In a double-blind study investigating temporary substitution of Fosphenytoin sodium for oral phenytoin, IM Fosphenytoin sodium was as well-tolerated as IM placebo. IM Fosphenytoin sodium resulted in a slight increase in transient, mild to moderate local itching (23% of patients vs 11% of IM placebo-treated patients at any time during the study). This study also demonstrated that equimolar doses of IM Fosphenytoin sodium may be substituted for oral phenytoin sodium with no dosage adjustments needed when initiating IM or returning to oral therapy. In contrast, switching between IM and oral phenytoin requires dosage adjustments because of slow and erratic phenytoin absorption from muscle.
# How Supplied
CEREBYX Injection is supplied as follows:
10 mL per vial — Each 10 mL vial contains 500 mg phenytoin sodium equivalents (PE):
NDC 0069-6001-10. Package of 1.
NDC 0069-6001-21. Packages of 10.
2 mL per vial — Each 2 mL vial contains 100 mg of phenytoin sodium equivalents (PE):
NDC 0069-6001-02. Package of 1.
NDC 0069-6001-25. Packages of 25.
Both sizes of vials contain Tromethamine, USP (TRIS), Hydrochloric Acid, NF, or Sodium Hydroxide, NF, and Water for Injection, USP.
CEREBYX should always be prescribed in phenytoin sodium equivalents (PE) (see DOSAGE AND ADMINISTRATION).
1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin's weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa.
## Storage
- Store under refrigeration at 2°C to 8°C (36°F to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.
# Images
## Drug Images
## Package and Label Display Panel
10 mL Vial
NDC 0069-6001-10
Cerebyx®
(Fosphenytoin Sodium Injection)
500 mg PE/10 mL
(50 mg PE/mL)
(PE = phenytoin sodium equivalents)
For Intramuscular or Intravenous Use
10 Vials (10 mL each)
NDC 0069-6001-21
Contains 10 of NDC 0069-6001-10
Cerebyx®
(Fosphenytoin Sodium Injection)
500 mg PE/10 mL
(50 mg PE/mL)
(PE = phenytoin sodium equivalents)
For Intramuscular or Intravenous Use
Pfizer Injectables
Rx only
2 mL Vial
NDC 0069-6001-02
Cerebyx®
(Fosphenytoin Sodium Injection)
100 mg PE/2 mL
(50 mg PE/mL)
(PE = phenytoin sodium equivalents)
25 Vials (2 mL each)
NDC 0069-6001-25
Contains 25 of NDC 0069-6001-02
Cerebyx®
(Fosphenytoin Sodium Injection)
100 mg PE/2 mL
(50 mg PE/mL)
(PE = phenytoin sodium equivalents)
For Intramuscular or Intravenous Use
Pfizer Injectables
Rx only
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Fosphenytoin in the drug label.
# Precautions with Alcohol
- Acute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use may decrease plasma concentrations.
- Drugs that may increase plasma phenytoin concentrations include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
- Drugs that may decrease plasma phenytoin concentrations include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John's Wort, theophylline, and vigabatrin.
# Brand Names
- Cerebyx®
# Look-Alike Drug Names
- Cerebyx® - CeleBREX®
- Cerebyx® - CeleXA®
# Drug Shortage Status
# Price | Fosphenytoin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
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# Black Box Warning
# Overview
Fosphenytoin is a anticonvulsant , central nervous system agent and hydantoin that is FDA approved for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. There is a Black Box Warning for this drug as shown here. Common adverse reactions include pruritus, ataxia, dizziness, headache, paresthesia, somnolence and nystagmus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Fosphenytoin sodium is indicated for the control of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin sodium can also be substituted, short-term, for oral phenytoin. Fosphenytoin sodium should be used only when oral phenytoin administration is not possible. Fosphenytoin sodium must not be given orally.
### Dosing Information
- The dose, concentration, and infusion rate of Fosphenytoin sodium should always be expressed as phenytoin sodium equivalents (PE). There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin sodium should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE).
- Do not confuse the concentration of Fosphenytoin sodium with the total amount of drug in the vial.
- Caution must be used when administering Fosphenytoin sodium due to the risk of dosing errors (see WARNINGS). Medication errors associated with Fosphenytoin sodium have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. Both vials contain a concentration of 50 mg PE/mL. Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE. These errors have resulted in two- or ten-fold overdoses of Fosphenytoin sodium since each of the vials actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of Fosphenytoin sodium should always be expressed in milligrams of phenytoin equivalents (mg PE). Additionally, when ordering and storing Fosphenytoin sodium, consider displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500 mg PE/ 10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of Fosphenytoin sodium is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some Fosphenytoin sodium medication errors from occurring.
- Prior to IV infusion, dilute Fosphenytoin sodium in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL. The maximum concentration of Fosphenytoin sodium in any solution should be 25 mg PE/mL. When Fosphenytoin sodium is given as an intravenous infusion, Fosphenytoin sodium needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- The loading dose of Fosphenytoin sodium is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.
- Because of the risk of hypotension, Fosphenytoin sodium should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of Fosphenytoin sodium infusions.
- Because the full antiepileptic effect of phenytoin, whether given as Fosphenytoin sodium or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus.
- The loading dose should be followed by maintenance doses of either Fosphenytoin sodium or phenytoin.
- If administration of Fosphenytoin sodium does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
- Even though loading doses of Fosphenytoin sodium have been given by the IM route for other indications when IV access is impossible, IM Fosphenytoin sodium should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
- Because of the risks of cardiac and local toxicity associated with intravenous Fosphenytoin sodium, oral phenytoin should be used whenever possible.
- The loading dose of Fosphenytoin sodium is 10 – 20 mg PE/kg given IV or IM. The rate of administration for IV Fosphenytoin sodium should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of Fosphenytoin sodium infusion).
- The initial daily maintenance dose of Fosphenytoin sodium is 4 – 6 mg PE/kg/day in divided doses.
- When treatment with oral phenytoin is not possible, Fosphenytoin sodium can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as Fosphenytoin sodium, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV Fosphenytoin sodium is substituted for oral phenytoin sodium therapy. The rate of administration for IV Fosphenytoin sodium should be no greater than 150 mg PE/min. In controlled trials, IM Fosphenytoin sodium was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing.
- Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see CLINICAL PHARMACOLOGY: SPECIAL POPULATIONS). Unbound phenytoin concentrations may be more useful in these patient populations. After IV Fosphenytoin sodium administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).
- Age does not have a significant impact on the pharmacokinetics of fosphenytoin following Fosphenytoin sodium administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fosphenytoin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fosphenytoin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Fosphenytoin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Fosphenytoin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Fosphenytoin in pediatric patients.
# Contraindications
- Fosphenytoin sodium is contraindicated in patients who have demonstrated hypersensitivity to Fosphenytoin sodium or its ingredients, or to phenytoin or other hydantoins. Because of the effect of parenteral phenytoin on ventricular automaticity, Fosphenytoin sodium is contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome.
- Coadministration of Fosphenytoin sodium is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.
# Warnings
- DOSES OF Fosphenytoin sodium ARE ALWAYS EXPRESSED IN TERMS OF MILLIGRAMS OF PHENYTOIN SODIUM EQUIVALENTS (mg PE) 1 MG PE IS EQUIVALENT TO 1 MG PHENYTOIN SODIUM.
- DO NOT, THEREFORE, MAKE ANY ADJUSTMENT IN THE RECOMMENDED DOSES WHEN SUBSTITUTING Fosphenytoin sodium FOR PHENYTOIN SODIUM OR VICE VERSA. FOR EXAMPLE, IF A PATIENT IS RECEIVING 1000 MG PE OF Fosphenytoin sodium, THAT IS EQUIVALENT TO 1000 MG OF PHENYTOIN SODIUM.
- The following warnings are based on experience with Fosphenytoin sodium or phenytoin.
- Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial.
- Medication errors associated with Fosphenytoin sodium have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/ mL. Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE. These errors have resulted in two- or ten-fold overdoses of Fosphenytoin sodium since each vial actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of Fosphenytoin sodium should always be expressed in milligrams of phenytoin equivalents (mg PE) (see DOSAGE AND ADMINISTRATION). Additionally, when ordering and storing Fosphenytoin sodium, consider displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500 mg PE/ 10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of Fosphenytoin sodium is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some Fosphenytoin sodium medication errors from occurring.
- Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, do not administer Fosphenytoin sodium at a rate greater than 150 mg PE/min.
- The dose of IV Fosphenytoin sodium (15 to 20 mg PE/kg) that is used to treat status epilepticus is administered at a maximum rate of 150 mg PE/min. The typical Fosphenytoin sodium infusion administered to a 50 kg patient would take between 5 and 7 minutes. Note that the delivery of an identical molar dose of phenytoin using parenteral Dilantin or generic phenytoin sodium injection cannot be accomplished in less than 15 to 20 minutes because of the untoward cardiovascular effects that accompany the direct intravenous administration of phenytoin at rates greater than 50 mg/min.
- If rapid phenytoin loading is a primary goal, IV administration of Fosphenytoin sodium is preferred because the time to achieve therapeutic plasma phenytoin concentrations is greater following IM than that following IV administration (see DOSAGE AND ADMINISTRATION).
- As non-emergency therapy, intravenous Fosphenytoin sodium should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV Fosphenytoin sodium, oral phenytoin should be used whenever possible.
- Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Fosphenytoin sodium. Reduction in rate of administration or discontinuation of dosing may be needed.
- Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.
- Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.
- Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Fosphenytoin sodium should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan Hypersensitivity below).
- Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding Fosphenytoin sodium as an alternative for carbamazepine patients positive for HLA-B*1502.
- The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity
- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin and Fosphenytoin sodium. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Fosphenytoin sodium should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
- Fosphenytoin sodium and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to Fosphenytoin sodium.
- Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, Fosphenytoin sodium should be immediately discontinued and not readministered.
- Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. There have been a number of reports that have suggested a relationship between phenytoin and the development of lymphadenopathy (local or generalized), including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling DRESS. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.
- Acute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use may decrease plasma concentrations.
### Usage in Pregnancy
- An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, LABORATORY TESTS). However, postpartum restoration of the original dosage will probably be indicated.
- If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
- Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two-to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
- A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
- Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal anomalies), death, growth retardation, and functional impairment (chromodacryorrhea, hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg PE/kg or higher (approximately 30% of the maximum human loading dose or higher on a mg/m2 basis), which produced peak maternal plasma phenytoin concentrations of approximately 20 µg/mL or greater. Maternal toxicity was often associated with these doses and plasma concentrations, however, there is no evidence to suggest that the developmental effects were secondary to the maternal effects. The single occurrence of a rare brain malformation at a non-maternotoxic dose of 17 mg PE/kg (approximately 10% of the maximum human loading dose on a mg/m2 basis) was also considered drug-induced. The developmental effects of fosphenytoin in rats were similar to those which have been reported following administration of phenytoin to pregnant rats. No effects on embryo-fetal development were observed when rabbits were given up to 33 mg PE/kg of fosphenytoin (approximately 50% of the maximum human loading dose on a mg/m2 basis) during pregnancy. Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.
### PRECAUTIONS
- Severe burning, itching, and/or paresthesia were reported by 7 of 16 normal volunteers administered IV Fosphenytoin sodium at a dose of 1200 mg PE at the maximum rate of administration (150 mg PE/min). The severe sensory disturbance lasted from 3 to 50 minutes in 6 of these subjects and for 14 hours in the seventh subject. In some cases, milder sensory disturbances persisted for as long as 24 hours. The location of the discomfort varied among subjects with the groin mentioned most frequently as an area of discomfort. In a separate cohort of 16 normal volunteers (taken from 2 other studies) who were administered IV Fosphenytoin sodium at a dose of 1200 mg PE at the maximum rate of administration (150 mg PE/min), none experienced severe disturbances, but most experienced mild to moderate itching or tingling. Patients administered Fosphenytoin sodium at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree. The occurrence and intensity of the discomfort can be lessened by slowing or temporarily stopping the infusion. The effect of continuing infusion unaltered in the presence of these sensations is unknown. No permanent sequelae have been reported thus far. The pharmacologic basis for these positive sensory phenomena is unknown, but other phosphate ester drugs, which deliver smaller phosphate loads, have been associated with burning, itching, and/or tingling predominantly in the groin area.
- Edema, discoloration, and pain distal to the site of injection (described as "purple glove syndrome") have also been reported following peripheral intravenous Fosphenytoin sodium injection. This may or may not be associated with extravasation. The syndrome may not develop for several days after injection.
- The phosphate load provided by Fosphenytoin sodium (0.0037 mmol phosphate/mg PE Fosphenytoin sodium) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment.
- IV Loading in Renal and/or Hepatic Disease or in Those with Hypoalbuminemia
- After IV administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see CLINICAL PHARMACOLOGY: SPECIAL POPULATIONS, and DOSAGE AND ADMINISTRATION: DOSING IN SPECIAL POPULATIONS).
- Fosphenytoin sodium is not indicated for the treatment of absence seizures.
- A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined.
- Phenytoin has been infrequently associated with the exacerbation of porphyria. Caution should be exercised when Fosphenytoin sodium is used in patients with this disease.
- Hyperglycemia, resulting from phenytoin's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose concentrations in diabetic patients.
- Plasma concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium," "psychosis," or "encephalopathy," or rarely, irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, determination of plasma phenytoin concentrations is recommended (see PRECAUTIONS: LABORATORY TESTS). Fosphenytoin sodium dose reduction is indicated if phenytoin concentrations are excessive; if symptoms persist, administration of Fosphenytoin sodium should be discontinued.
- The liver is the primary site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.
- Phenytoin and other hydantoins are not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.
- Phenytoin has the potential to lower serum folate levels.
# Adverse Reactions
## Clinical Trials Experience
- The more important adverse clinical events caused by the IV use of Fosphenytoin sodium or phenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when either drug is administered rapidly by the IV route. The rate of administration is very important; for Fosphenytoin sodium, it should not exceed 150 mg PE/min. The adverse clinical events most commonly observed with the use of Fosphenytoin sodium in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With two exceptions, these events are commonly associated with the administration of IV phenytoin. Paresthesia and pruritus, however, were seen much more often following Fosphenytoin sodium administration and occurred more often with IV Fosphenytoin sodium administration than with IM Fosphenytoin sodium administration. These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ≥15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently as a site of involvement. The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of Fosphenytoin sodium infusion. Some patients experienced symptoms for hours. These events did not increase in severity with repeated administration. Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen (see PRECAUTIONS, SENSORY DISTURBANCES). Approximately 2% of the 859 individuals who received Fosphenytoin sodium in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%).
- The incidence of adverse events tended to increase as both dose and infusion rate increased. In particular, at doses of ≥15mg PE/kg and rates ≥150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often than at lower doses or rates.
- All adverse events were recorded during the trials by the clinical investigators using terminology of their own choosing. Similar types of events were grouped into standardized categories using modified COSTART dictionary terminology. These categories are used in the tables and listings below with the frequencies representing the proportion of individuals exposed to Fosphenytoin sodium or comparative therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.
- Table 2 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with IV Fosphenytoin sodium at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and Fosphenytoin sodium administration would have resulted in equivalent systemic exposure to phenytoin.
- Table 3 lists treatment-emergent adverse events that occurred in at least 2% of Fosphenytoin sodium-treated patients in a double-blind, randomized, controlled clinical trial of adult epilepsy patients receiving either IM Fosphenytoin sodium substituted for oral Dilantin or continuing oral Dilantin. Both treatments were administered for 5 days.
- Fosphenytoin sodium has been administered to 859 individuals during all clinical trials. All adverse events seen at least twice are listed in the following, except those already included in previous tables and listings. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 individuals; infrequent adverse events are those occurring in 1/100 to 1/1000 individuals.
- Frequent: fever, injection-site reaction, infection, chills, face edema, injection-site pain; Infrequent: sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis.
- Frequent:
- Hypertension
- Infrequent:
- Cardiac arrest, migraine, syncope, cerebral hemorrhage, palpitation, sinus bradycardia, atrial flutter, bundle branch block, cardiomegaly, cerebral infarct, postural hypotension, pulmonary embolus, QT interval prolongation, thrombophlebitis, ventricular extrasystoles, congestive heart failure.
- Frequent:
- Constipation
- Infrequent:
- Dyspepsia, diarrhea, anorexia, gastrointestinal hemorrhage, increased salivation, liver function tests abnormal, tenesmus, tongue edema, dysphagia, flatulence, gastritis, ileus.
- Infrequent:
- Diabetes insipidus.
- Infrequent:
- Thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia.
- Frequent:
- Hypokalemia;
- Infrequent:
- Hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis.
- Frequent:
- Myasthenia; Infrequent: myopathy, leg cramps, arthralgia, myalgia.
- Frequent:
- Reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness, hypesthesia; Infrequent: confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, brain edema, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis.
- Frequent:
- Pneumonia
- Infrequent:
- Pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration pneumonia, asthma, dyspnea, atelectasis, cough increased, sputum increased, epistaxis, hypoxia, pneumothorax, hemoptysis, bronchitis.
- Frequent:
- Rash
- Infrequent:
- Maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule.
- Frequent:
- Taste perversion
- Infrequent:
- Deafness, visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss.
- Infrequent:
- Urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of fosphenytoin. 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.
- There have been post-marketing reports of anaphylactoid reaction and anaphylaxis.
### Other Phenytoin-Associated Adverse Events
- Dyskinesia.
# Drug Interactions
- Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL, (unbound phenytoin concentrations of 1 to 2 mcg/mL). Following Fosphenytoin sodium administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of IV infusion and 4 hours after IM injection. Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx®/TDxFLx™ (fluorescence polarization) and Emit® 2000 (enzyme multiplied), may significantly overestimate plasma phenytoin concentrations because of cross-reactivity with fosphenytoin. The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by Fosphenytoin sodium dose, route and rate of administration, and time of sampling relative to dosing), and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin. However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved.
- No drugs are known to interfere with the conversion of fosphenytoin to phenytoin. Conversion could be affected by alterations in the level of phosphatase activity, but given the abundance and wide distribution of phosphatases in the body it is unlikely that drugs would affect this activity enough to affect conversion of fosphenytoin to phenytoin. Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin. Although, it is unknown whether this could result in clinically significant effects, caution is advised when administering Fosphenytoin sodium with other drugs that significantly bind to serum albumin. The pharmacokinetics and protein binding of fosphenytoin, phenytoin, and diazepam were not altered when diazepam and Fosphenytoin sodium were concurrently administered in single submaximal doses. The most significant drug interactions following administration of Fosphenytoin sodium are expected to occur with drugs that interact with phenytoin. Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes.
- The most commonly occurring drug interactions are listed below:
- Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted.
- Drugs that may increase plasma phenytoin concentrations include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
- Drugs that may decrease plasma phenytoin concentrations include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John's Wort, theophylline, and vigabatrin.
- Drugs that may either increase or decrease plasma phenytoin concentrations include: phenobarbital, valproic acid, and sodium valproate. Similarly, the effects of phenytoin on phenobarbital, valproic acid and sodium plasma valproate concentrations are unpredictable.
- The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.
- Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS).
- Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline, and vitamin D.
- Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.
- Phenytoin decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), antiepileptic agents (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin and verapamil.
- Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
- Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
- The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
- Monitoring of plasma phenytoin concentrations may be helpful when possible drug interactions are suspected.
- Phenytoin may decrease serum concentrations of T4. It may also produce artifactually low results in dexamethasone or metyrapone tests. Phenytoin may also cause increased serum concentrations of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following Fosphenytoin sodium administration.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
### Usage in Pregnancy
- An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS, LABORATORY TESTS). However, postpartum restoration of the original dosage will probably be indicated.
- If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
- Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two-to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
- A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
- Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal anomalies), death, growth retardation, and functional impairment (chromodacryorrhea, hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg PE/kg or higher (approximately 30% of the maximum human loading dose or higher on a mg/m2 basis), which produced peak maternal plasma phenytoin concentrations of approximately 20 µg/mL or greater. Maternal toxicity was often associated with these doses and plasma concentrations, however, there is no evidence to suggest that the developmental effects were secondary to the maternal effects. The single occurrence of a rare brain malformation at a non-maternotoxic dose of 17 mg PE/kg (approximately 10% of the maximum human loading dose on a mg/m2 basis) was also considered drug-induced. The developmental effects of fosphenytoin in rats were similar to those which have been reported following administration of phenytoin to pregnant rats. No effects on embryo-fetal development were observed when rabbits were given up to 33 mg PE/kg of fosphenytoin (approximately 50% of the maximum human loading dose on a mg/m2 basis) during pregnancy. Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Fosphenytoin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Fosphenytoin during labor and delivery.
### Nursing Mothers
- It is not known whether fosphenytoin is excreted in human milk.
- Following administration of Dilantin, phenytoin appears to be excreted in low concentrations in human milk. Therefore, breast-feeding is not recommended for women receiving Fosphenytoin sodium.
### Pediatric Use
There is no FDA guidance on the use of Fosphenytoin with respect to pediatric patients.
### Geriatic Use
- No systematic studies in geriatric patients have been conducted. Phenytoin clearance tends to decrease with increasing ag
### Gender
There is no FDA guidance on the use of Fosphenytoin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Fosphenytoin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Fosphenytoin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Fosphenytoin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Fosphenytoin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Fosphenytoin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intramuscular
- Intravenous
### Monitoring
- The rate of intravenous Fosphenytoin sodium administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous Fosphenytoin sodium. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed.
- As non-emergency therapy, intravenous CEREBYX should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV CEREBYX, oral phenytoin should be used whenever possible.
- Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous CEREBYX. Reduction in rate of administration or discontinuation of dosing may be needed.
- Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.
- Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL, (unbound phenytoin concentrations of 1 to 2 mcg/mL). Following CEREBYX administration, it is recommended that phenytoin concentrations not be monitored until conversion to phenytoin is essentially complete. This occurs within approximately 2 hours after the end of IV infusion and 4 hours after IM injection. Prior to complete conversion, commonly used immunoanalytical techniques, such as TDx®/TDxFLx™ (fluorescence polarization) and Emit® 2000 (enzyme multiplied), may significantly overestimate plasma phenytoin concentrations because of cross-reactivity with fosphenytoin. The error is dependent on plasma phenytoin and fosphenytoin concentration (influenced by CEREBYX dose, route and rate of administration, and time of sampling relative to dosing), and analytical method. Chromatographic assay methods accurately quantitate phenytoin concentrations in biological fluids in the presence of fosphenytoin. Prior to complete conversion, blood samples for phenytoin monitoring should be collected in tubes containing EDTA as an anticoagulant to minimize ex vivo conversion of fosphenytoin to phenytoin. However, even with specific assay methods, phenytoin concentrations measured before conversion of fosphenytoin is complete will not reflect phenytoin concentrations ultimately achieved.
- Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other nondepolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
- Monitoring of plasma phenytoin concentrations may be helpful when possible drug interactions are suspected.
- The loading dose of CEREBYX is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min.
- Because of the risk of hypotension, CEREBYX should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of CEREBYX infusions.
- Because the full antiepileptic effect of phenytoin, whether given as CEREBYX or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus.
- The loading dose should be followed by maintenance doses of either CEREBYX or phenytoin.
If administration of CEREBYX does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
- Even though loading doses of CEREBYX have been given by the IM route for other indications when IV access is impossible, IM CEREBYX should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
- Because of the risks of cardiac and local toxicity associated with intravenous CEREBYX, oral phenytoin should be used whenever possible.
- The loading dose of CEREBYX is 10 – 20 mg PE/kg given IV or IM. The rate of administration for IV CEREBYX should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of CEREBYX infusion).
# IV Compatibility
There is limited information regarding IV Compatibility of Fosphenytoin in the drug label.
# Overdosage
- Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin.
- The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.
- Because Fosphenytoin sodium is a prodrug of phenytoin, the following information may be helpful. Initial symptoms of acute phenytoin toxicity are nystagmus, ataxia, and dysarthria. Other signs include tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting, coma, and hypotension. Depression of respiratory and circulatory systems leads to death. There are marked variations among individuals with respect to plasma phenytoin concentrations where toxicity occurs. Lateral gaze nystagmus usually appears at 20 µg/mL, ataxia at 30 µg/mL, and dysarthria and lethargy appear when the plasma concentration is over 40 µg/mL. However, phenytoin concentrations as high as 50 µg/mL have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in plasma phenytoin concentrations over 100 µg/mL, with complete recovery.
- Treatment is nonspecific since there is no known antidote to Fosphenytoin sodium or phenytoin overdosage. The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children. In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
- Formate and phosphate are metabolites of fosphenytoin and therefore may contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with severe anion-gap metabolic acidosis. Large amounts of phosphate, delivered rapidly, could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. Ionized free calcium levels can be measured and, if low, used to guide treatment.
# Pharmacology
There is limited information regarding Fosphenytoin Pharmacology in the drug label.
## Mechanism of Action
- Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. After IV administration to mice, fosphenytoin blocked the tonic phase of maximal electroshock seizures at doses equivalent to those effective for phenytoin. In addition to its ability to suppress maximal electroshock seizures in mice and rats, phenytoin exhibits anticonvulsant activity against kindled seizures in rats, audiogenic seizures in mice, and seizures produced by electrical stimulation of the brainstem in rats. The cellular mechanisms of phenytoin thought to be responsible for its anticonvulsant actions include modulation of voltage-dependent sodium channels of neurons, inhibition of calcium flux across neuronal membranes, modulation of voltage-dependent calcium channels of neurons, and enhancement of the sodium-potassium ATPase activity of neurons and glial cells. The modulation of sodium channels may be a primary anticonvulsant mechanism because this property is shared with several other anticonvulsants in addition to phenytoin.
## Structure
- Fosphenytoin sodium® (fosphenytoin sodium injection) is a prodrug intended for parenteral administration; its active metabolite is phenytoin. 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg phenytoin sodium equivalents (PE). The amount and concentration of fosphenytoin is always expressed in terms of mg PE.
- Fosphenytoin sodium is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL. Fosphenytoin sodium is supplied in vials as a ready-mixed solution in Water for Injection, USP, and Tromethamine, USP (TRIS), buffer adjusted to pH 8.6 to 9.0 with either Hydrochloric Acid, NF, or Sodium Hydroxide, NF. Fosphenytoin sodium is a clear, colorless to pale yellow, sterile solution.
## Pharmacodynamics
- Following parenteral administration of Fosphenytoin sodium, fosphenytoin is converted to the anticonvulsant phenytoin. For every mmol of fosphenytoin administered, one mmol of phenytoin is produced. The pharmacological and toxicological effects of fosphenytoin include those of phenytoin. However, the hydrolysis of fosphenytoin to phenytoin yields two metabolites, phosphate and formaldehyde. Formaldehyde is subsequently converted to formate, which is in turn metabolized via a folate dependent mechanism. Although phosphate and formaldehyde (formate) have potentially important biological effects, these effects typically occur at concentrations considerably in excess of those obtained when Fosphenytoin sodium is administered under conditions of use recommended in this labeling.
## Pharmacokinetics
### Fosphenytoin
### Absorption/Bioavailability
- When Fosphenytoin sodium is administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion. Fosphenytoin has a half-life of approximately 15 minutes. Intramuscular: Fosphenytoin is completely bioavailable following IM administration of Fosphenytoin sodium. Peak concentrations occur at approximately 30 minutes postdose. Plasma fosphenytoin concentrations following IM administration are lower but more sustained than those following IV administration due to the time required for absorption of fosphenytoin from the injection site.
- Fosphenytoin is extensively bound (95% to 99%) to human plasma proteins, primarily albumin. Binding to plasma proteins is saturable with the result that the percent bound decreases as total fosphenytoin concentrations increase. Fosphenytoin displaces phenytoin from protein binding sites. The volume of distribution of fosphenytoin increases with Fosphenytoin sodium dose and rate, and ranges from 4.3 to 10.8 liters.
- The conversion half-life of fosphenytoin to phenytoin is approximately 15 minutes. The mechanism of fosphenytoin conversion has not been determined, but phosphatases probably play a major role. Fosphenytoin is not excreted in urine. Each mmol of fosphenytoin is metabolized to 1 mmol of phenytoin, phosphate, and formate.
### Phenytoin (after Fosphenytoin sodium administration)
- In general, IM administration of Fosphenytoin sodium generates systemic phenytoin concentrations that are similar enough to oral phenytoin sodium to allow essentially interchangeable use. The pharmacokinetics of fosphenytoin following IV administration of Fosphenytoin sodium, however, are complex, and when used in an emergency setting (eg, status epilepticus), differences in rate of availability of phenytoin could be critical. Studies have therefore empirically determined an infusion rate for Fosphenytoin sodium that gives a rate and extent of phenytoin systemic availability similar to that of a 50 mg/min phenytoin sodium infusion. A dose of 15 to 20 mg PE/kg of Fosphenytoin sodium infused at 100 to 150 mg PE/min yields plasma free phenytoin concentrations over time that approximate those achieved when an equivalent dose of phenytoin sodium (eg, parenteral DILANTIN®) is administered at 50 mg/min.
- FIGURE 1. Mean plasma unbound phenytoin concentrations following IV administration of 1200 mg PE Fosphenytoin sodium infused at 100 mg PE/min (triangles) or 150 mg PE/min (squares) and 1200 mg Dilantin infused at 50 mg/min (diamonds) to healthy subjects (N = 12). Inset shows time course for the entire 96-hour sampling period.
- Following administration of single IV Fosphenytoin sodium doses of 400 to 1200 mg PE, mean maximum total phenytoin concentrations increase in proportion to dose, but do not change appreciably with changes in infusion rate. In contrast, mean maximum unbound phenytoin concentrations increase with both dose and rate.
- Fosphenytoin is completely converted to phenytoin following IV administration, with a half-life of approximately 15 minutes. Fosphenytoin is also completely converted to phenytoin following IM administration and plasma total phenytoin concentrations peak in approximately 3 hours.
- Phenytoin is highly bound to plasma proteins, primarily albumin, although to a lesser extent than fosphenytoin. In the absence of fosphenytoin, approximately 12% of total plasma phenytoin is unbound over the clinically relevant concentration range. However, fosphenytoin displaces phenytoin from plasma protein binding sites. This increases the fraction of phenytoin unbound (up to 30% unbound) during the period required for conversion of fosphenytoin to phenytoin (approximately 0.5 to 1 hour postinfusion).
- Phenytoin derived from administration of Fosphenytoin sodium is extensively metabolized in the liver and excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1%–5% of the Fosphenytoin sodium dose) is recovered in urine. Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19. Phenytoin hepatic metabolism is saturable, and following administration of single IV Fosphenytoin sodium doses of 400 to 1200 mg PE, total and unbound phenytoin AUC values increase disproportionately with dose. Mean total phenytoin half-life values (12.0 to 28.9 hr) following Fosphenytoin sodium administration at these doses are similar to those after equal doses of parenteral Dilantin and tend to be greater at higher plasma phenytoin concentrations.
### Special Populations
- Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations. After IV administration of Fosphenytoin sodium to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).
- The effect of age was evaluated in patients 5 to 98 years of age. Patient age had no significant impact on fosphenytoin pharmacokinetics. Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20–30 years of age). Phenytoin dosing requirements are highly variable and must be individualized.
- Gender and race have no significant impact on fosphenytoin or phenytoin pharmacokinetics.
- The safety and efficacy of Fosphenytoin sodium in pediatric patients have not been established.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Fosphenytoin in the drug label.
# Clinical Studies
- Infusion tolerance was evaluated in clinical studies. One double-blind study assessed infusion-site tolerance of equivalent loading doses (15–20 mg PE/kg) of Fosphenytoin sodium infused at 150 mg PE/min or phenytoin infused at 50 mg/min. The study demonstrated better local tolerance (pain and burning at the infusion site), fewer disruptions of the infusion, and a shorter infusion period for Fosphenytoin sodium-treated patients (Table 1).
- Fosphenytoin sodium-treated patients, however, experienced more systemic sensory disturbances (see PRECAUTIONS, SENSORY DISTURBANCES). Infusion disruptions in Fosphenytoin sodium-treated patients were primarily due to systemic burning, pruritus, and/or paresthesia while those in phenytoin-treated patients were primarily due to pain and burning at the infusion site (see TABLE 1). In a double-blind study investigating temporary substitution of Fosphenytoin sodium for oral phenytoin, IM Fosphenytoin sodium was as well-tolerated as IM placebo. IM Fosphenytoin sodium resulted in a slight increase in transient, mild to moderate local itching (23% of patients vs 11% of IM placebo-treated patients at any time during the study). This study also demonstrated that equimolar doses of IM Fosphenytoin sodium may be substituted for oral phenytoin sodium with no dosage adjustments needed when initiating IM or returning to oral therapy. In contrast, switching between IM and oral phenytoin requires dosage adjustments because of slow and erratic phenytoin absorption from muscle.
# How Supplied
CEREBYX Injection is supplied as follows:
10 mL per vial — Each 10 mL vial contains 500 mg phenytoin sodium equivalents (PE):
NDC 0069-6001-10. Package of 1.
NDC 0069-6001-21. Packages of 10.
2 mL per vial — Each 2 mL vial contains 100 mg of phenytoin sodium equivalents (PE):
NDC 0069-6001-02. Package of 1.
NDC 0069-6001-25. Packages of 25.
Both sizes of vials contain Tromethamine, USP (TRIS), Hydrochloric Acid, NF, or Sodium Hydroxide, NF, and Water for Injection, USP.
CEREBYX should always be prescribed in phenytoin sodium equivalents (PE) (see DOSAGE AND ADMINISTRATION).
1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (PE). Fosphenytoin's weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa.
## Storage
- Store under refrigeration at 2°C to 8°C (36°F to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.
# Images
## Drug Images
## Package and Label Display Panel
10 mL Vial
NDC 0069-6001-10
Cerebyx®
(Fosphenytoin Sodium Injection)
500 mg PE/10 mL
(50 mg PE/mL)
(PE = phenytoin sodium equivalents)
For Intramuscular or Intravenous Use
10 Vials (10 mL each)
NDC 0069-6001-21
Contains 10 of NDC 0069-6001-10
Cerebyx®
(Fosphenytoin Sodium Injection)
500 mg PE/10 mL
(50 mg PE/mL)
(PE = phenytoin sodium equivalents)
For Intramuscular or Intravenous Use
Pfizer Injectables
Rx only
2 mL Vial
NDC 0069-6001-02
Cerebyx®
(Fosphenytoin Sodium Injection)
100 mg PE/2 mL
(50 mg PE/mL)
(PE = phenytoin sodium equivalents)
25 Vials (2 mL each)
NDC 0069-6001-25
Contains 25 of NDC 0069-6001-02
Cerebyx®
(Fosphenytoin Sodium Injection)
100 mg PE/2 mL
(50 mg PE/mL)
(PE = phenytoin sodium equivalents)
For Intramuscular or Intravenous Use
Pfizer Injectables
Rx only
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Fosphenytoin in the drug label.
# Precautions with Alcohol
- Acute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use may decrease plasma concentrations.
- Drugs that may increase plasma phenytoin concentrations include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
- Drugs that may decrease plasma phenytoin concentrations include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John's Wort, theophylline, and vigabatrin.
# Brand Names
- Cerebyx®
# Look-Alike Drug Names
- Cerebyx® - CeleBREX®
- Cerebyx® - CeleXA®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cerebyx | |
e2adee13928c6b725c98ef179ff7fa1a69afaeb4 | wikidoc | Daunorubicin | Daunorubicin
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# Black Box Warning
# Overview
Daunorubicin is an antineoplastic agent that is FDA approved for the treatment of remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include reversible alopecia,acute nausea and vomiting,diarrhea and abdominal pain,if extravasation occurs during administration, severe local tissue necrosis, severe cellulitis, thrombophlebitis, and painful induration can result..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Daunorubicin hydrochloride injection in combination with other approved anticancer drugs is indicated for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults
- Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit.
- In order to eradicate the leukemic cells and induce a complete remission, a profound suppression of the bone marrow is usually required. Evaluation of both the peripheral blood and bone marrow is mandatory in the formulation of appropriate treatment plans.
- It is recommended that the dosage of daunorubicin hydrochloride be reduced in instances of hepatic or renal impairment. For example, using serum bilirubin and serum creatinine as indicators of liver and kidney function, the following dose modifications are recommended:
- In Combination
- For patients under age 60, daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses.
- For patients 60 years of age and above, daunorubicin hydrochloride 30 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses. This daunorubicin hydrochloride dose-reduction is based on a single study and may not be appropriate if optimal supportive care is available.
- The attainment of a normal-appearing bone marrow may require up to three courses of induction therapy. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction treatment is required.
- For remission induction in acute lymphocytic leukemia of children and adults.
- In Combination
- Daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2/day PO on days 1 through 22, then tapered between days 22 to 29; L-asparaginase 500 IU/kg/day X 10 days IV on days 22 through 32.
- The sterile 4 mL vial contents provide 20 mg of daunorubicin with 5 mg of daunorubicin per mL. The desired dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% sodium chloride injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 5% dextrose injection, USP or 0.9% sodium chloride injection, USP. Daunorubicin hydrochloride should not be administered mixed with other drugs or heparin.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of daunorubicin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of daunorubicin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- In Combination
- Daunorubicin hydrochloride 25 mg/m2 IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 PO daily. Generally, a complete remission will be obtained within four such courses of therapy; however, if after four courses the patient is in partial remission, an additional one or, if necessary, two courses may be given in an effort to obtain a complete remission.
- In children less than 2 years of age or below 0.5 m2 body surface area, it has been recommended that the daunorubicin hydrochloride dosage calculation should be based on weight (1 mg/kg) instead of body surface area.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of daunorubicin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of daunorubicin in pediatric patients.
# Contraindications
- Daunorubicin hydrochloride is contraindicated in patients who have shown a hypersensitivity to it.
# Warnings
- Daunorubicin hydrochloride is a potent bone marrow suppressant. Suppression will occur in all patients given a therapeutic dose of this drug. Therapy with daunorubicin hydrochloride should not be started in patients with preexisting drug-induced bone marrow suppression unless the benefit from such treatment warrants the risk. Persistent, severe myelosuppression may result in superinfection or hemorrhage.
- Special attention must be given to the potential cardiac toxicity of daunorubicin hydrochloride, particularly in infants and children. Preexisting heart disease and previous therapy with doxorubicin are co-factors of increased risk of daunorubicin-induced cardiac toxicity and the benefit-to-risk ratio of daunorubicin hydrochloride therapy in such patients should be weighed before starting daunorubicin hydrochloride. In adults, at total cumulative doses less than 550 mg/m2, acute congestive heart failure is seldom encountered. However, rare instances of pericarditis-myocarditis, not dose-related, have been reported.
- In adults, at cumulative doses exceeding 550 mg/m2, there is an increased incidence of drug-induced congestive heart failure. Based on prior clinical experience with doxorubicin, this limit appears lower, namely 400 mg/m2, in patients who received radiation therapy that encompassed the heart.
- In infants and children, there appears to be a greater susceptibility to anthracycline-induced cardiotoxicity compared to that in adults, which is more clearly dose-related. Anthracycline therapy (including daunorubicin) in pediatric patients has been reported to produce impaired left ventricular systolic performance, reduced contractility, congestive heart failure or death. These conditions may occur months to years following cessation of chemotherapy. This appears to be dose-dependent and aggravated by thoracic irradiation. Long-term periodic evaluation of cardiac function in such patients should, thus, be performed. *In both children and adults, the total dose of daunorubicin hydrochloride administered should also take into account any previous or concomitant therapy with other potentially cardiotoxic agents or related compounds such as doxorubicin.
- There is no absolutely reliable method of predicting the patients in whom acute congestive heart failure will develop as a result of the cardiac toxic effect of daunorubicin hydrochloride. However, certain changes in the electrocardiogram and a decrease in the systolic ejection fraction from pretreatment baseline may help to recognize those patients at greatest risk to develop congestive heart failure. On the basis of the electrocardiogram, a decrease equal to or greater than 30% in limb lead QRS voltage has been associated with a significant risk of drug-induced cardiomyopathy. Therefore, an electrocardiogram and/or determination of systolic ejection fraction should be performed before each course of daunorubicin hydrochloride. In the event that one or the other of these predictive parameters should occur, the benefit of continued therapy must be weighed against the risk of producing cardiac damage.
- Early clinical diagnosis of drug-induced congestive heart failure appears to be essential for successful treatment.
- There have been reports of secondary leukemias in patients exposed to topoisomerase II inhibitors when used in combination with other antineoplastic agents or radiation therapy.
- Extravasation of daunorubicin hydrochloride at the site of intravenous administration can cause severe local tissue necrosis
### Precautions
- Therapy with daunorubicin hydrochloride requires close patient observation and frequent complete blood-count determinations. Cardiac, renal, and hepatic function should be evaluated prior to each course of treatment.
- Appropriate measures must be taken to control any systemic infection before beginning therapy with daunorubicin hydrochloride.
- Daunorubicin hydrochloride may transiently impart a red coloration to the urine after administration, and patients should be advised to expect this.
# Adverse Reactions
## Clinical Trials Experience
Dose-limiting toxicity includes myelosuppression and cardiotoxicity . Other reactions include:
- Reversible alopecia occurs in most patients. Rash, contact dermatitis and urticaria have occurred rarely.
- Acute nausea and vomiting occur but are usually mild. Antiemetic therapy may be of some help. Mucositis may occur 3 to 7 days after administration. Diarrhea and abdominal pain have occasionally been reported.
- If extravasation occurs during administration, severe local tissue necrosis, severe cellulitis, thrombophlebitis, or painful induration can result.
- Rarely, anaphylactoid reaction, fever, and chills can occur. Hyperuricemia may occur, especially in patients with leukemia, and serum uric acid levels should be monitored.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of daunorubicin in the drug label.
# Drug Interactions
- Use of daunorubicin in a patient who has previously received doxorubicin increases the risk of cardiotoxicity. Daunorubicin hydrochloride should not be used in patients who have previously received the recommended maximum cumulative doses of doxorubicin or daunorubicin hydrochloride. Cyclophosphamide used concurrently with daunorubicin hydrochloride may also result in increased cardiotoxicity.
- Dosage reduction of daunorubicin hydrochloride may be required when used concurrently with other myelosuppressive agents.
- Hepatotoxic medications, such as high-dose methotrexate, may impair liver function and increase the risk of toxicity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Daunorubicin hydrochloride may cause fetal harm when administered to a pregnant woman. An increased incidence of fetal abnormalities (parieto-occipital cranioschisis, umbilical hernias, or rachischisis) and abortions was reported in rabbits at doses of 0.05 mg/kg/day or approximately 1/100th of the highest recommended human dose on a body surface area basis. Rats showed an increased incidence of esophageal, cardiovascular and urogenital abnormalities as well as rib fusions at doses of 4 mg/kg/day or approximately 1/2 the human dose on a body surface area basis.
- Decreases in fetal birth weight and post-delivery growth rate were observed in mice. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of daunorubicin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of daunorubicin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from daunorubicin, mothers should be advised to discontinue nursing during daunorubicin therapy.
### Pediatric Use
- Although appropriate studies with daunorubicin hydrochloride have not been performed in the pediatric population, cardiotoxicity may be more frequent and occur at lower cumulative doses in children.
### Geriatic Use
- Although appropriate studies with daunorubicin hydrochloride have not been performed in the geriatric population, cardiotoxicity may be more frequent in the elderly. Caution should also be used in patients who have inadequate bone marrow reserves due to old age. *In addition, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving daunorubicin hydrochloride.
### Gender
There is no FDA guidance on the use of daunorubicin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of daunorubicin with respect to specific racial populations.
### Renal Impairment
- Doses of daunorubicin hydrochloride should be reduced in patients with renal impairment. Patients with serum creatinine concentrations of greater than 3 mg/dL should receive 50% of the usual daily dose.
### Hepatic Impairment
- Doses of daunorubicin hydrochloride should be reduced in patients with hepatic impairment. Patients with serum bilirubin concentrations of 1.2 to 3 mg/dL should receive 75% of the usual daily dose and patients with serum bilirubin concentrations greater than 3 mg/dL should receive 50% of the usual daily dose.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of daunorubicin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of daunorubicin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Daunorubicin hydrochloride may induce hyperuricemia secondary to rapid lysis of leukemic cells. As a precaution, allopurinol administration is usually begun prior to initiating antileukemic therapy. Blood uric acid levels should be monitored and appropriate therapy initiated in the event that hyperuricemia develops.
# IV Compatibility
There is limited information regarding IV Compatibility of daunorubicin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of daunorubicin in the drug label.
# Pharmacology
## Mechanism of Action
- Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action. Daunorubicin forms complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Single strand and double strand DNA breaks result.
- Daunorubicin hydrochloride may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA.
- Daunorubicin hydrochloride possesses an antitumor effect against a wide spectrum of animal tumors, either grafted or spontaneous.
## Structure
- Daunorubicin Hydrochloride Injection consists of the hydrochloride salt of an anthracycline cytotoxic antibiotic produced by a strain of Streptomyces coeruleorubidus. It is provided as a deep red sterile liquid in vials for intravenous administration only. Each mL contains daunorubicin hydrochloride, USP equivalent to 5 mg of daunorubicin, 9 mg sodium chloride, hydrochloric acid (to adjust pH), and water for injection, q.s. It has the following structural formula which may be described with the chemical name of (1S,3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside hydrochloride.
C27H29NO10HCl M.W. 563.99
- It is a hygroscopic crystalline powder. The pH of a 5 mg/mL aqueous solution is 3 to 4.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of daunorubicin in the drug label.
## Pharmacokinetics
- Following intravenous injection of daunorubicin hydrochloride, plasma levels of daunorubicin decline rapidly, indicating rapid tissue uptake and concentration. Thereafter, plasma levels decline slowly with a half-life of 45 minutes in the initial phase and 18.5 hours in the terminal phase. By 1 hour after drug administration, the predominant plasma species is daunorubicinol, an active metabolite, which disappears with a half-life of 26.7 hours.
- Daunorubicin hydrochloride is rapidly and widely distributed in tissues, with highest levels in the spleen, kidneys, liver, lungs, and heart. The drug binds to many cellular components, particularly nucleic acids. There is no evidence that daunorubicin crosses the blood-brain barrier, but the drug apparently crosses the placenta.
- Daunorubicin hydrochloride is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of daunorubicin. Further metabolism via reduction cleavage of the glycosidic bond, 4-O demethylation, and conjugation with both sulfate and glucuronide have been demonstrated. Simple glycosidic cleavage of daunorubicin or daunorubicinol is not a significant metabolic pathway in man. *Twenty-five percent of an administered dose of daunorubicin hydrochloride is eliminated in an active form by urinary excretion and an estimated 40% by biliary excretion.
## Nonclinical Toxicology
- Daunorubicin hydrochloride, when injected subcutaneously into mice, causes a fibrosarcomas to develop at the injection site. When administered to mice thrice weekly intraperitoneally, no carcinogenic effect was noted after 18 months of observation. In male rats administered daunorubicin thrice weekly for 6 months, at 1/70th the recommended human dose on a body surface area basis, peritoneal sarcomas were found at 18 months. A single IV dose of daunorubicin administered to rats at 1.6 fold the recommended human dose on a body surface area basis caused mammary adenocarcinomas to appear at 1 year. Daunorubicin was mutagenic in vitro (Ames assay, V79 hamster cell assay), and clastogenic in vitro (CCRFCEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow) tests.
- In male dogs at a daily dose of 0.25 mg/kg administered intravenously, testicular atrophy was noted at autopsy. Histologic examination revealed total aplasia of the spermatocyte series in the seminiferous tubules with complete aspermatogenesis.
# Clinical Studies
- In the treatment of adult acute nonlymphocytic leukemia, daunorubicin hydrochloride, used as a single agent, has produced complete remission rates of 40 to 50%, and in combination with cytarabine, has produced complete remission rates of 53 to 65%.
- The addition of daunorubicin hydrochloride to the two-drug induction regimen of vincristine-prednisone in the treatment of childhood acute lymphocytic leukemia does not increase the rate of complete remission. In children receiving identical CNS prophylaxis and maintenance therapy (without consolidation), there is prolongation of complete remission duration (statistically significant, p < 0.02) in those children induced with the three drug (daunorubicin-vincristine-prednisone) regimen as compared to two drugs. There is no evidence of any impact of daunorubicin hydrochloride on the duration of complete remission when a consolidation (intensification) phase is employed as part of a total treatment program.
- In adult acute lymphocytic leukemia, in contrast to childhood acute lymphocytic leukemia, daunorubicin hydrochloride during induction significantly increases the rate of complete remission, but not remission duration, compared to that obtained with vincristine, prednisone, and L-asparaginase alone. The use of daunorubicin hydrochloride in combination with vincristine, prednisone, and L-asparaginase has produced complete remission rates of 83% in contrast to a 47% remission in patients not receiving daunorubicin hydrochloride.
# How Supplied
- Daunorubicin Hydrochloride Injection, 5 mg (base)/mL, is available as follows:
- The 20 mg base/4 mL vials are packaged in tens.
## Storage
- Store unopened vials in refrigerator, 2° to 8°C (36° to 46°F). Store prepared solution for infusion at room temperature, 20° to 25°C (68° to 77°F) for up to 24 hours. Contains no preservative. Discard unused portion. Protect from light. Retain in carton until time of use.
- If daunorubicin hydrochloride contacts the skin or mucosae, the area should be washed thoroughly with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of daunorubicin in the drug label.
# Precautions with Alcohol
- Alcohol-daunorubicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cerubidine®
# Look-Alike Drug Names
- DAUNOrubicin - DAUNOrubicin citrate liposomal
- DAUNOrubicin - DOXOrubicin
- daunorubicin - idarubicin
# Drug Shortage Status
# Price | Daunorubicin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Daunorubicin is an antineoplastic agent that is FDA approved for the treatment of remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include reversible alopecia,acute nausea and vomiting,diarrhea and abdominal pain,if extravasation occurs during administration, severe local tissue necrosis, severe cellulitis, thrombophlebitis, and painful induration can result..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Daunorubicin hydrochloride injection in combination with other approved anticancer drugs is indicated for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults
- Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit.
- In order to eradicate the leukemic cells and induce a complete remission, a profound suppression of the bone marrow is usually required. Evaluation of both the peripheral blood and bone marrow is mandatory in the formulation of appropriate treatment plans.
- It is recommended that the dosage of daunorubicin hydrochloride be reduced in instances of hepatic or renal impairment. For example, using serum bilirubin and serum creatinine as indicators of liver and kidney function, the following dose modifications are recommended:
- In Combination
- For patients under age 60, daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses.
- For patients 60 years of age and above, daunorubicin hydrochloride 30 mg/m2/day IV on days 1, 2, and 3 of the first course and on days 1, 2 of subsequent courses AND cytosine arabinoside 100 mg/m2/day IV infusion daily for 7 days for the first course and for 5 days for subsequent courses. This daunorubicin hydrochloride dose-reduction is based on a single study and may not be appropriate if optimal supportive care is available.
- The attainment of a normal-appearing bone marrow may require up to three courses of induction therapy. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction treatment is required.
- For remission induction in acute lymphocytic leukemia of children and adults.
- In Combination
- Daunorubicin hydrochloride 45 mg/m2/day IV on days 1, 2, and 3 AND vincristine 2 mg IV on days 1, 8, and 15; prednisone 40 mg/m2/day PO on days 1 through 22, then tapered between days 22 to 29; L-asparaginase 500 IU/kg/day X 10 days IV on days 22 through 32.
- The sterile 4 mL vial contents provide 20 mg of daunorubicin with 5 mg of daunorubicin per mL. The desired dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% sodium chloride injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 5% dextrose injection, USP or 0.9% sodium chloride injection, USP. Daunorubicin hydrochloride should not be administered mixed with other drugs or heparin.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of daunorubicin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of daunorubicin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- In Combination
- Daunorubicin hydrochloride 25 mg/m2 IV on day 1 every week, vincristine 1.5 mg/m2 IV on day 1 every week, prednisone 40 mg/m2 PO daily. Generally, a complete remission will be obtained within four such courses of therapy; however, if after four courses the patient is in partial remission, an additional one or, if necessary, two courses may be given in an effort to obtain a complete remission.
- In children less than 2 years of age or below 0.5 m2 body surface area, it has been recommended that the daunorubicin hydrochloride dosage calculation should be based on weight (1 mg/kg) instead of body surface area.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of daunorubicin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of daunorubicin in pediatric patients.
# Contraindications
- Daunorubicin hydrochloride is contraindicated in patients who have shown a hypersensitivity to it.
# Warnings
- Daunorubicin hydrochloride is a potent bone marrow suppressant. Suppression will occur in all patients given a therapeutic dose of this drug. Therapy with daunorubicin hydrochloride should not be started in patients with preexisting drug-induced bone marrow suppression unless the benefit from such treatment warrants the risk. Persistent, severe myelosuppression may result in superinfection or hemorrhage.
- Special attention must be given to the potential cardiac toxicity of daunorubicin hydrochloride, particularly in infants and children. Preexisting heart disease and previous therapy with doxorubicin are co-factors of increased risk of daunorubicin-induced cardiac toxicity and the benefit-to-risk ratio of daunorubicin hydrochloride therapy in such patients should be weighed before starting daunorubicin hydrochloride. In adults, at total cumulative doses less than 550 mg/m2, acute congestive heart failure is seldom encountered. However, rare instances of pericarditis-myocarditis, not dose-related, have been reported.
- In adults, at cumulative doses exceeding 550 mg/m2, there is an increased incidence of drug-induced congestive heart failure. Based on prior clinical experience with doxorubicin, this limit appears lower, namely 400 mg/m2, in patients who received radiation therapy that encompassed the heart.
- In infants and children, there appears to be a greater susceptibility to anthracycline-induced cardiotoxicity compared to that in adults, which is more clearly dose-related. Anthracycline therapy (including daunorubicin) in pediatric patients has been reported to produce impaired left ventricular systolic performance, reduced contractility, congestive heart failure or death. These conditions may occur months to years following cessation of chemotherapy. This appears to be dose-dependent and aggravated by thoracic irradiation. Long-term periodic evaluation of cardiac function in such patients should, thus, be performed. *In both children and adults, the total dose of daunorubicin hydrochloride administered should also take into account any previous or concomitant therapy with other potentially cardiotoxic agents or related compounds such as doxorubicin.
- There is no absolutely reliable method of predicting the patients in whom acute congestive heart failure will develop as a result of the cardiac toxic effect of daunorubicin hydrochloride. However, certain changes in the electrocardiogram and a decrease in the systolic ejection fraction from pretreatment baseline may help to recognize those patients at greatest risk to develop congestive heart failure. On the basis of the electrocardiogram, a decrease equal to or greater than 30% in limb lead QRS voltage has been associated with a significant risk of drug-induced cardiomyopathy. Therefore, an electrocardiogram and/or determination of systolic ejection fraction should be performed before each course of daunorubicin hydrochloride. In the event that one or the other of these predictive parameters should occur, the benefit of continued therapy must be weighed against the risk of producing cardiac damage.
- Early clinical diagnosis of drug-induced congestive heart failure appears to be essential for successful treatment.
- There have been reports of secondary leukemias in patients exposed to topoisomerase II inhibitors when used in combination with other antineoplastic agents or radiation therapy.
- Extravasation of daunorubicin hydrochloride at the site of intravenous administration can cause severe local tissue necrosis
### Precautions
- Therapy with daunorubicin hydrochloride requires close patient observation and frequent complete blood-count determinations. Cardiac, renal, and hepatic function should be evaluated prior to each course of treatment.
- Appropriate measures must be taken to control any systemic infection before beginning therapy with daunorubicin hydrochloride.
- Daunorubicin hydrochloride may transiently impart a red coloration to the urine after administration, and patients should be advised to expect this.
# Adverse Reactions
## Clinical Trials Experience
Dose-limiting toxicity includes myelosuppression and cardiotoxicity . Other reactions include:
- Reversible alopecia occurs in most patients. Rash, contact dermatitis and urticaria have occurred rarely.
- Acute nausea and vomiting occur but are usually mild. Antiemetic therapy may be of some help. Mucositis may occur 3 to 7 days after administration. Diarrhea and abdominal pain have occasionally been reported.
- If extravasation occurs during administration, severe local tissue necrosis, severe cellulitis, thrombophlebitis, or painful induration can result.
- Rarely, anaphylactoid reaction, fever, and chills can occur. Hyperuricemia may occur, especially in patients with leukemia, and serum uric acid levels should be monitored.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of daunorubicin in the drug label.
# Drug Interactions
- Use of daunorubicin in a patient who has previously received doxorubicin increases the risk of cardiotoxicity. Daunorubicin hydrochloride should not be used in patients who have previously received the recommended maximum cumulative doses of doxorubicin or daunorubicin hydrochloride. Cyclophosphamide used concurrently with daunorubicin hydrochloride may also result in increased cardiotoxicity.
- Dosage reduction of daunorubicin hydrochloride may be required when used concurrently with other myelosuppressive agents.
- Hepatotoxic medications, such as high-dose methotrexate, may impair liver function and increase the risk of toxicity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Daunorubicin hydrochloride may cause fetal harm when administered to a pregnant woman. An increased incidence of fetal abnormalities (parieto-occipital cranioschisis, umbilical hernias, or rachischisis) and abortions was reported in rabbits at doses of 0.05 mg/kg/day or approximately 1/100th of the highest recommended human dose on a body surface area basis. Rats showed an increased incidence of esophageal, cardiovascular and urogenital abnormalities as well as rib fusions at doses of 4 mg/kg/day or approximately 1/2 the human dose on a body surface area basis.
- Decreases in fetal birth weight and post-delivery growth rate were observed in mice. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of daunorubicin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of daunorubicin during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from daunorubicin, mothers should be advised to discontinue nursing during daunorubicin therapy.
### Pediatric Use
- Although appropriate studies with daunorubicin hydrochloride have not been performed in the pediatric population, cardiotoxicity may be more frequent and occur at lower cumulative doses in children.
### Geriatic Use
- Although appropriate studies with daunorubicin hydrochloride have not been performed in the geriatric population, cardiotoxicity may be more frequent in the elderly. Caution should also be used in patients who have inadequate bone marrow reserves due to old age. *In addition, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving daunorubicin hydrochloride.
### Gender
There is no FDA guidance on the use of daunorubicin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of daunorubicin with respect to specific racial populations.
### Renal Impairment
- Doses of daunorubicin hydrochloride should be reduced in patients with renal impairment. Patients with serum creatinine concentrations of greater than 3 mg/dL should receive 50% of the usual daily dose.
### Hepatic Impairment
- Doses of daunorubicin hydrochloride should be reduced in patients with hepatic impairment. Patients with serum bilirubin concentrations of 1.2 to 3 mg/dL should receive 75% of the usual daily dose and patients with serum bilirubin concentrations greater than 3 mg/dL should receive 50% of the usual daily dose.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of daunorubicin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of daunorubicin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Daunorubicin hydrochloride may induce hyperuricemia secondary to rapid lysis of leukemic cells. As a precaution, allopurinol administration is usually begun prior to initiating antileukemic therapy. Blood uric acid levels should be monitored and appropriate therapy initiated in the event that hyperuricemia develops.
# IV Compatibility
There is limited information regarding IV Compatibility of daunorubicin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of daunorubicin in the drug label.
# Pharmacology
## Mechanism of Action
- Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action. Daunorubicin forms complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Single strand and double strand DNA breaks result.
- Daunorubicin hydrochloride may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA.
- Daunorubicin hydrochloride possesses an antitumor effect against a wide spectrum of animal tumors, either grafted or spontaneous.
## Structure
- Daunorubicin Hydrochloride Injection consists of the hydrochloride salt of an anthracycline cytotoxic antibiotic produced by a strain of Streptomyces coeruleorubidus. It is provided as a deep red sterile liquid in vials for intravenous administration only. Each mL contains daunorubicin hydrochloride, USP equivalent to 5 mg of daunorubicin, 9 mg sodium chloride, hydrochloric acid (to adjust pH), and water for injection, q.s. It has the following structural formula which may be described with the chemical name of (1S,3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1-naphthacenyl 3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranoside hydrochloride.
C27H29NO10•HCl M.W. 563.99
- It is a hygroscopic crystalline powder. The pH of a 5 mg/mL aqueous solution is 3 to 4.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of daunorubicin in the drug label.
## Pharmacokinetics
- Following intravenous injection of daunorubicin hydrochloride, plasma levels of daunorubicin decline rapidly, indicating rapid tissue uptake and concentration. Thereafter, plasma levels decline slowly with a half-life of 45 minutes in the initial phase and 18.5 hours in the terminal phase. By 1 hour after drug administration, the predominant plasma species is daunorubicinol, an active metabolite, which disappears with a half-life of 26.7 hours.
- Daunorubicin hydrochloride is rapidly and widely distributed in tissues, with highest levels in the spleen, kidneys, liver, lungs, and heart. The drug binds to many cellular components, particularly nucleic acids. There is no evidence that daunorubicin crosses the blood-brain barrier, but the drug apparently crosses the placenta.
- Daunorubicin hydrochloride is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of daunorubicin. Further metabolism via reduction cleavage of the glycosidic bond, 4-O demethylation, and conjugation with both sulfate and glucuronide have been demonstrated. Simple glycosidic cleavage of daunorubicin or daunorubicinol is not a significant metabolic pathway in man. *Twenty-five percent of an administered dose of daunorubicin hydrochloride is eliminated in an active form by urinary excretion and an estimated 40% by biliary excretion.
## Nonclinical Toxicology
- Daunorubicin hydrochloride, when injected subcutaneously into mice, causes a fibrosarcomas to develop at the injection site. When administered to mice thrice weekly intraperitoneally, no carcinogenic effect was noted after 18 months of observation. In male rats administered daunorubicin thrice weekly for 6 months, at 1/70th the recommended human dose on a body surface area basis, peritoneal sarcomas were found at 18 months. A single IV dose of daunorubicin administered to rats at 1.6 fold the recommended human dose on a body surface area basis caused mammary adenocarcinomas to appear at 1 year. Daunorubicin was mutagenic in vitro (Ames assay, V79 hamster cell assay), and clastogenic in vitro (CCRFCEM human lymphoblasts) and in vivo (SCE assay in mouse bone marrow) tests.
- In male dogs at a daily dose of 0.25 mg/kg administered intravenously, testicular atrophy was noted at autopsy. Histologic examination revealed total aplasia of the spermatocyte series in the seminiferous tubules with complete aspermatogenesis.
# Clinical Studies
- In the treatment of adult acute nonlymphocytic leukemia, daunorubicin hydrochloride, used as a single agent, has produced complete remission rates of 40 to 50%, and in combination with cytarabine, has produced complete remission rates of 53 to 65%.
- The addition of daunorubicin hydrochloride to the two-drug induction regimen of vincristine-prednisone in the treatment of childhood acute lymphocytic leukemia does not increase the rate of complete remission. In children receiving identical CNS prophylaxis and maintenance therapy (without consolidation), there is prolongation of complete remission duration (statistically significant, p < 0.02) in those children induced with the three drug (daunorubicin-vincristine-prednisone) regimen as compared to two drugs. There is no evidence of any impact of daunorubicin hydrochloride on the duration of complete remission when a consolidation (intensification) phase is employed as part of a total treatment program.
- In adult acute lymphocytic leukemia, in contrast to childhood acute lymphocytic leukemia, daunorubicin hydrochloride during induction significantly increases the rate of complete remission, but not remission duration, compared to that obtained with vincristine, prednisone, and L-asparaginase alone. The use of daunorubicin hydrochloride in combination with vincristine, prednisone, and L-asparaginase has produced complete remission rates of 83% in contrast to a 47% remission in patients not receiving daunorubicin hydrochloride.
# How Supplied
- Daunorubicin Hydrochloride Injection, 5 mg (base)/mL, is available as follows:
- The 20 mg base/4 mL vials are packaged in tens.
## Storage
- Store unopened vials in refrigerator, 2° to 8°C (36° to 46°F). Store prepared solution for infusion at room temperature, 20° to 25°C (68° to 77°F) for up to 24 hours. Contains no preservative. Discard unused portion. Protect from light. Retain in carton until time of use.
- If daunorubicin hydrochloride contacts the skin or mucosae, the area should be washed thoroughly with soap and water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of daunorubicin in the drug label.
# Precautions with Alcohol
- Alcohol-daunorubicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cerubidine®
# Look-Alike Drug Names
- DAUNOrubicin - DAUNOrubicin citrate liposomal
- DAUNOrubicin - DOXOrubicin
- daunorubicin - idarubicin
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cerubidine | |
9827b9b83a34fc11444697483fc2ef37804396a8 | wikidoc | Cervical rib | Cervical rib
# Overview
A cervical rib is a supernumerary (extra) rib which arises from the seventh cervical vertebra. It is a congenital abnormality located above the normal first rib.
# Epidemiology and Demographics
A cervical rib is present in only about 1 in 200 (0.5%) of people; in even rarer cases, an individual may have not one but two cervical ribs.
# Natural History, Complications, and Prognosis
The presence of a cervical rib can cause a form of thoracic outlet syndrome due to compression of the brachial plexus or subclavian artery. Compression of the brachial plexus may be identified by weakness of the muscles around the muscles in the hand, near the base of the thumb. Compression of the subclavian artery is often diagnosed by finding a positive Adson's sign on examination, where the radial pulse in the arm is lost during abduction and external rotation of the shoulder.
- Cervical rib chest X-ray | Cervical rib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A cervical rib is a supernumerary (extra) rib which arises from the seventh cervical vertebra. It is a congenital abnormality located above the normal first rib.
# Epidemiology and Demographics
A cervical rib is present in only about 1 in 200 (0.5%) of people; in even rarer cases, an individual may have not one but two cervical ribs.
# Natural History, Complications, and Prognosis
The presence of a cervical rib can cause a form of thoracic outlet syndrome due to compression of the brachial plexus or subclavian artery. Compression of the brachial plexus may be identified by weakness of the muscles around the muscles in the hand, near the base of the thumb. Compression of the subclavian artery is often diagnosed by finding a positive Adson's sign on examination, where the radial pulse in the arm is lost during abduction and external rotation of the shoulder.
- Cervical rib chest X-ray | https://www.wikidoc.org/index.php/Cervical_rib | |
4df201affeb916ebe363b4e65a0db034d6738a24 | wikidoc | Chaetophobia | Chaetophobia
# Overview
Chaetophobia is fear of hair, a type of specific phobia. Sufferers fear may be associated with human hair and/or animal hair. They fear people or animals with an excess amount of hair. They may also fear the hair on their own body. Some only fear detached or loose hair and do not mind attached hair. The term chaetophobia comes from the Greek χαίτη - khaitē, meaning "loose, flowing hair" and φόβος - phobos, meaning "fear".)
# Causes
As with most phobias this fear could be the result of a negative experience with hair and/or a hairy person. The anxiety starts when the person remembers an experience whenever they are near a person with an excess amount of hair. Hair loss can be a trigger to this phobia, such as men going bald.
## Fear
Some sufferers fear the hair on their own bodies because they think it is dirty or unattractive. They may fear things such as dandruff or Headlouse|head lice. This phobia is thought to be a spin-off of germaphobia, the fear of germs. They become obsessed with removing every hair on their body. This fear is often hygiene-related and sufferers feel uncomfortable in environments such as salons where hair is detached and on the ground. Some fear loose hair in their food or on furniture even if it is their own.
# Treatment
Intensive therapy and/or medication may have an effect on the anxiety side of the phobia. As with most phobias support groups and self relaxation techniques are some times effective in helping with the fear. | Chaetophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chaetophobia is fear of hair, a type of specific phobia.[citation needed][1] Sufferers fear may be associated with human hair and/or animal hair. They fear people or animals with an excess amount of hair. They may also fear the hair on their own body. Some only fear detached or loose hair and do not mind attached hair. The term chaetophobia comes from the Greek χαίτη - khaitē, meaning "loose, flowing hair"[2] and φόβος - phobos, meaning "fear".[3])
# Causes
As with most phobias this fear could be the result of a negative experience with hair and/or a hairy person. The anxiety starts when the person remembers an experience whenever they are near a person with an excess amount of hair. Hair loss can be a trigger to this phobia, such as men going bald.
## Fear
Some sufferers fear the hair on their own bodies because they think it is dirty or unattractive. They may fear things such as dandruff or Headlouse|head lice. This phobia is thought to be a spin-off of germaphobia, the fear of germs. They become obsessed with removing every hair on their body. This fear is often hygiene-related and sufferers feel uncomfortable in environments such as salons where hair is detached and on the ground. Some fear loose hair in their food or on furniture even if it is their own.
# Treatment
Intensive therapy and/or medication may have an effect on the anxiety side of the phobia. As with most phobias support groups and self relaxation techniques are some times effective in helping with the fear. | https://www.wikidoc.org/index.php/Chaetophobia | |
9d39d9b5d8b890db3937cb76d955e74c939600f9 | wikidoc | Chaos theory | Chaos theory
In mathematics and physics, chaos theory describes the behavior of certain nonlinear dynamical systems that may exhibit dynamics that are highly sensitive to initial conditions (popularly referred to as the butterfly effect). As a result of this sensitivity, which manifests itself as an exponential growth of perturbations in the initial conditions, the behavior of chaotic systems appears to be random. This happens even though these systems are deterministic, meaning that their future dynamics are fully defined by their initial conditions, with no random elements involved. This behavior is known as deterministic chaos, or simply chaos.
# Overview
Chaotic behavior has been observed in the laboratory in a variety of systems including electrical circuits, lasers, oscillating chemical reactions, fluid dynamics, and mechanical and magneto-mechanical devices. Observations of chaotic behaviour in nature include the dynamics of satellites in the solar system, the time evolution of the magnetic field of celestial bodies, population growth in ecology, the dynamics of the action potentials in neurons, and molecular vibrations. Everyday examples of chaotic systems include weather and climate. There is some controversy over the existence of chaotic dynamics in the plate tectonics and in economics.
Systems that exhibit mathematical chaos are deterministic and thus orderly in some sense; this technical use of the word chaos is at odds with common parlance, which suggests complete disorder. A related field of physics called quantum chaos theory studies systems that follow the laws of quantum mechanics. Recently, another field, called relativistic chaos, has emerged to describe systems that follow the laws of general relativity.
As well as being orderly in the sense of being deterministic, chaotic systems usually have well defined statistics. For example, the Lorenz system pictured is chaotic, but has a clearly defined structure. Bounded chaos is a useful term for describing models of disorder.
# History
The first discoverer of chaos can plausibly be argued to be Jacques Hadamard, who in 1898 published an influential study of the chaotic motion of a free particle gliding frictionlessly on a surface of constant negative curvature. In the system studied, Hadamard's billiards, Hadamard was able to show that all trajectories are unstable, in that all particle trajectories diverge exponentially from one another, with a positive Lyapunov exponent.
In the early 1900s Henri Poincaré, while studying the three-body problem, found that there can be orbits which are nonperiodic, and yet not forever increasing nor approaching a fixed point. Much of the early theory was developed almost entirely by mathematicians, under the name of ergodic theory. Later studies, also on the topic of nonlinear differential equations, were carried out by G.D. Birkhoff, A.N. Kolmogorov, M.L. Cartwright, J.E. Littlewood, and Stephen Smale. Except for Smale, these studies were all directly inspired by physics: the three-body problem in the case of Birkhoff, turbulence and astronomical problems in the case of Kolmogorov, and radio engineering in the case of Cartwright and Littlewood. Although chaotic planetary motion had not been observed, experimentalists had encountered turbulence in fluid motion and nonperiodic oscillation in radio circuits without the benefit of a theory to explain what they were seeing.
Despite initial insights in the first half of the century, chaos theory became formalized as such only after mid-century, when it first became evident for some scientists that linear theory, the prevailing system theory at that time, simply could not explain the observed behaviour of certain experiments like that of the logistic map. What had been beforehand excluded as measure imprecision and simple "noise" was considered by chaos theories as a full component of the studied systems.
The main catalyst for the development of chaos theory was the electronic computer. Much of the mathematics of chaos theory involves the repeated iteration of simple mathematical formulas, which would be impractical to do by hand. Electronic computers made these repeated calculations practical, while figures and images made it possible to visualize these systems. One of the earliest electronic digital computers, ENIAC, was used to run simple weather forecasting models.
An early pioneer of the theory was Edward Lorenz whose interest in chaos came about accidentally through his work on weather prediction in 1961. Lorenz was using a simple digital computer, a Royal McBee LGP-30, to run his weather simulation. He wanted to see a sequence of data again and to save time he started the simulation in the middle of its course. He was able to do this by entering a printout of the data corresponding to conditions in the middle of his simulation which he had calculated last time.
To his surprise the weather that the machine began to predict was completely different from the weather calculated before. Lorenz tracked this down to the computer printout. The computer worked with 6-digit precision, but the printout rounded variables off to a 3-digit number, so a value like 0.506127 was printed as 0.506. This difference is tiny and the consensus at the time would have been that it should have had practically no effect. However Lorenz had discovered that small changes in initial conditions produced large changes in the long-term outcome. Lorenz's discovery, which gave its name to Lorenz attractors, proved that meteorology could not reasonably predict weather beyond a weekly period (at most).
The year before, Benoit Mandelbrot found recurring patterns at every scale in data on cotton prices. Beforehand, he had studied information theory and concluded noise was patterned like a Cantor set: on any scale the proportion of noise-containing periods to error-free periods was a constant-- thus errors were inevitable and must be planned for by incorporating redundancy. Mandelbrot described both the Noah effect (in which sudden discontinuous changes can occur, e.g., in a stock's prices after bad news, thus challenging normal distribution theory in statistics, aka Bell Curve) and the Joseph effect (in which persistence of a value can occur for a while, yet suddenly change afterwards). In 1967, he published How Long Is the Coast of Britain? Statistical Self-Similarity and Fractional Dimension, showing that a coastline's length varies with the scale of the measuring instrument, resembles itself at all scales, and is infinite in length for an infinitesimally small measuring device. Arguing that a ball of twine appears to be 1-dimensional (far), 3-dimensional (fairly near), or 1-dimensional (close), he argued that the dimensions of an object are relative to the observer and may be fractional. An object whose irregularity is constant over different scales ("self-similarity") is a fractal (for example, the Koch curve or "snowflake", which is infinitely long yet encloses a finite space with dimensions = 1.2618; or the Menger sponge and the Sierpinski gasket). In 1975 Mandelbrot published The Fractal Geometry of Nature, which became a classic of chaos theory. Biological systems such as the branching of the circulatory and bronchial systems proved to fit a fractal model.
Yoshisuke Ueda independently identified a chaotic phenomenon as such by using an analog computer on November 27, 1961. The chaos exhibited by an analog computer is a real phenomenon, in contrast with those that digital computers calculate, which has a different kind of limit on precision. Ueda's supervising professor, Hayashi, did not believe in chaos, and thus he prohibited Ueda from publishing his findings until 1970.
In December 1977 the New York Academy of Sciences organized the first symposium on Chaos, attended by David Ruelle, Robert May, James Yorke (coiner of the term "chaos" as used in mathematics), Robert Shaw (a physicist, part of the Eudaemons group with J. Doyne Farmer and Norman Packard who tried to find a mathematical method to beat roulette, and then created with them the Dynamical Systems Collective in Santa Cruz), and the meteorologist Edward Lorenz.
The following year, Mitchell Feigenbaum published the noted article "Quantitative Universality for a Class of Nonlinear Transformations", where he described logistic maps. Feigenbaum had applied fractal geometry to the study of natural forms such as coastlines. Feigenbaum notably discovered the universality in chaos, permitting an application of chaos theory to many different phenomena.
In 1979, Albert J. Libchaber during a symposium organized in Aspen by Pierre Hohenberg his experimental observation of the bifurcation cascade that leads to chaos and turbulence in convective Rayleigh-Benard systems. He was awarded the Wolf Prize in Physics in 1986 along with Mitchell J. Feigenbaum "for his brilliant experimental demonstration of the transition to turbulence and chaos in dynamical systems".
The New York Academy of Sciences then co-organized, in 1986, with the National Institute of Mental Health and the Office of Naval Research the first important conference on Chaos in biology and medicine. Bernardo Huberman thereby presented a mathematical model of the eye tracking disorder among schizophrenics . Chaos theory thereafter renewed physiology in the 1980s, for example in the study of pathological cardiac cycles.
In 1987, Per Bak, Chao Tang and Kurt Wiesenfeld published a paper in Physical Review Letters describing for the first time self-organized criticality (SOC), considered to be one of the mechanisms by which complexity arises in nature.
Alongside largely lab-based approaches such as the Bak-Tang-Wiesenfeld sandpile, many other investigations have centred around large-scale natural or social systems that are known (or suspected) to display scale-invariant behaviour. Although these approaches were not always welcomed (at least initially) by specialists in the subjects examined, SOC has nevertheless become established as a strong candidate for explaining a number of natural phenomena, including: earthquakes (which, long before SOC was discovered, were known as a source of scale-invariant behaviour such as the Gutenberg-Richter law describing the statistical distribution of earthquake sizes, and the Omori law describing the frequency of aftershocks); solar flares; fluctuations in economic systems such as financial markets (references to SOC are common in econophysics); landscape formation; forest fires; landslides; epidemics; and biological evolution (where SOC has been invoked, for example, as the dynamical mechanism behind the theory of "punctuated equilibria" put forward by Niles Eldredge and Stephen Jay Gould). Worryingly, given the implications of a scale-free distribution of event sizes, some researchers have suggested that another phenomenon that should be considered an example of SOC is the occurrence of wars. These "applied" investigations of SOC have included both attempts at modelling (either developing new models or adapting existing ones to the specifics of a given natural system), and extensive data analysis to determine the existence and/or characteristics of natural scaling laws.
The same year, James Gleick published Chaos: Making a New Science, which became a best-seller and introduced general principles of chaos theory as well as its history to the broad public. At first the domains of work of a few, isolated individuals, chaos theory progressively emerged as a transdisciplinary and institutional discipline, mainly under the name of nonlinear systems analysis. Alluding to Thomas Kuhn's concept of a paradigm shift exposed in The Structure of Scientific Revolutions (1962), many "chaologists" (as some self-nominated themselves) claimed that this new theory was an example of such as shift, a thesis upheld by J. Gleick.
The availability of cheaper, more powerful computers broadens the applicability of chaos theory. Currently, chaos theory continues to be a very active area of research, involving many different disciplines (mathematics, topology, physics, population biology, biology, meteorology, astrophysics, information theory, etc.).
# Chaotic dynamics
For a dynamical system to be classified as chaotic, it must have the following properties:
- it must be sensitive to initial conditions,
- it must be topologically mixing, and
- its periodic orbits must be dense.
Sensitivity to initial conditions means that each point in such a system is arbitrarily closely approximated by other points with significantly different future trajectories. Thus, an arbitrarily small perturbation of the current trajectory may lead to significantly different future behaviour.
Sensitivity to initial conditions is popularly known as the "butterfly effect", so called because of the title of a paper given by Edward Lorenz in 1972 to the American Association for the Advancement of Science in Washington, D.C. entitled Predictability: Does the Flap of a Butterfly’s Wings in Brazil set off a Tornado in Texas? The flapping wing represents a small change in the initial condition of the system, which causes a chain of events leading to large-scale phenomena. Had the butterfly not flapped its wings, the trajectory of the system might have been vastly different.
Sensitivity to initial conditions is often confused with chaos in popular accounts. It can also be a subtle property, since it depends on a choice of metric, or the notion of distance in the phase space of the system. For example, consider the simple dynamical system produced by repeatedly doubling an initial value (defined by the mapping on the real line from x to 2x). This system has sensitive dependence on initial conditions everywhere,
since any pair of nearby points will eventually become widely separated. However, it has extremely simple behaviour, as all points except 0 tend to infinity. If instead we use the bounded metric on the line obtained by adding the point at infinity and viewing the result as a circle, the system no longer is sensitive to initial conditions. For this reason, in defining chaos, attention is normally restricted to systems with bounded metrics, or closed, bounded invariant subsets of unbounded systems.
Even for bounded systems, sensitivity to initial conditions is not identical with chaos. For example, consider the two-dimensional torus described by a pair of angles (x,y), each ranging between zero and 2π. Define a mapping that takes any point (x,y) to (2x, y + a), where a is any number
such that a/2π is irrational. Because of the doubling in the first coordinate, the mapping exhibits sensitive dependence on initial conditions. However, because of the irrational rotation in the second coordinate, there are no periodic orbits, and hence the mapping is not chaotic according to the definition above.
Topologically mixing means that the system will evolve over time so that any given region or open set of its phase space will eventually overlap with any other given region. Here, "mixing" is really meant to correspond to the standard intuition: the mixing of colored dyes or fluids is an example of a chaotic system.
## Attractors
Some dynamical systems are chaotic everywhere (see e.g. Anosov diffeomorphisms) but in many cases chaotic behaviour is found only in a subset of phase space. The cases of most interest arise when the chaotic behaviour takes place on an attractor, since then a large set of initial conditions will lead to orbits that converge to this chaotic region.
An easy way to visualize a chaotic attractor is to start with a point in the basin of attraction of the attractor, and then simply plot its subsequent orbit. Because of the topological transitivity condition, this is likely to produce a picture of the entire final attractor.
For instance, in a system describing a pendulum, the phase space might be two-dimensional, consisting of information about position and velocity. One might plot the position of a pendulum against its velocity. A pendulum at rest will be plotted as a point, and one in periodic motion will be plotted as a simple closed curve. When such a plot forms a closed curve, the curve is called an orbit. Our pendulum has an infinite number of such orbits, forming a pencil of nested ellipses about the origin.
## Strange attractors
While most of the motion types mentioned above give rise to very simple attractors, such as points and circle-like curves called limit cycles, chaotic motion gives rise to what are known as strange attractors, attractors that can have great detail and complexity.
For instance, a simple three-dimensional model of the Lorenz weather system gives rise to the famous Lorenz attractor. The Lorenz attractor is perhaps one of the best-known chaotic system diagrams, probably because not only was it one of the first, but it is one of the most complex and as such gives rise to a very interesting pattern which looks like the wings of a butterfly. Another such attractor is the Rössler map, which experiences period-two doubling route to chaos, like the logistic map.
Strange attractors occur in both continuous dynamical systems (such as the Lorenz system) and in some discrete systems (such as the Hénon map). Other discrete dynamical systems have a repelling structure called a Julia set which forms at the boundary between basins of attraction of fixed points - Julia sets can be thought of as strange repellers. Both strange attractors and Julia sets typically have a fractal structure.
The Poincaré-Bendixson theorem shows that a strange attractor can only arise in a continuous dynamical system if it has three or more dimensions. However, no such restriction applies to discrete systems, which can exhibit strange attractors in two or even one dimensional systems.
The initial conditions of three or more bodies interacting through gravitational attraction (see the n-body problem) can be arranged to produce chaotic motion.
## Minimum complexity of a chaotic system
Simple systems can also produce chaos without relying on differential equations. An example is the logistic map, which is a difference equation (recurrence relation) that describes population growth over time.
Even the evolution of simple discrete systems, such as cellular automata, can heavily depend on initial conditions. Stephen Wolfram has investigated a cellular automaton with this property, termed by him rule 30.
A minimal model for conservative (reversible) chaotic behavior is provided by Arnold's cat map.
## Mathematical theory
Sarkovskii's theorem is the basis of the Li and Yorke (1975) proof that any one-dimensional system which exhibits a regular cycle of period three will also display regular cycles of every other length as well as completely chaotic orbits.
Mathematicians have devised many additional ways to make quantitative statements about chaotic systems. These include: fractal dimension of the attractor, Lyapunov exponents, recurrence plots, Poincaré maps, bifurcation diagrams, and transfer operator.
# Distinguishing random from chaotic data
It can be difficult to tell from data whether a physical or other observed process is random or chaotic, because in practice no time series consists of pure 'signal.' There will always be some form of corrupting noise, even if it is present as round-off or truncation error. Thus any real time series, even if mostly deterministic, will contain some randomness.
All methods for distinguishing deterministic and stochastic processes rely on the fact that a deterministic system always evolves in the same way from a given starting point. Thus, given a time series to test for determinism, one can:
- pick a test state;
- search the time series for a similar or 'nearby' state; and
- compare their respective time evolutions.
Define the error as the difference between the time evolution of the 'test' state and the time evolution of the nearby state. A deterministic system will have an error that either remains small (stable, regular solution) or increases exponentially with time (chaos). A stochastic system will have a randomly distributed error.
Essentially all measures of determinism taken from time series rely upon finding the closest states to a given 'test' state (i.e., correlation dimension, Lyapunov exponents, etc.). To define the state of a system one typically relies on phase space embedding methods.
Typically one chooses an embedding dimension, and investigates the propagation of the error between two nearby states. If the error looks random, one increases the dimension. If you can increase the dimension to obtain a deterministic looking error, then you are done. Though it may sound simple it is not really. One complication is that as the dimension increases the search for a nearby state requires a lot more computation time and a lot of data (the amount of data required increases exponentially with embedding dimension) to find a suitably close candidate. If the embedding dimension (number of measures per state) is chosen too small (less than the 'true' value) deterministic data can appear to be random but in theory there is no problem choosing the dimension too large – the method will work.
Practically, anything approaching about 10 dimensions is considered so large that a stochastic description is probably more suitable and convenient anyway.
# Applications
Chaos theory is applied in many scientific disciplines: mathematics, biology, computer science, economics, engineering, finance, philosophy, physics, politics, population dynamics, psychology, and robotics.
Chaos theory is also currently being applied to medical studies of epilepsy, specifically to the prediction of seemingly random seizures by observing initial conditions.
# Chaos theory in the media
## Movies
- The 1993 movie Jurassic Park
- The 1998 movie π
- The 2004 movie The Butterfly Effect
- The 2006 movie The Science of Sleep
- The 2006 movie Chaos
## Books
- Michael Crichton's Jurassic Park and The Lost World
- Ray Bradbury's A Sound of Thunder
## Theatre
- Tom Stoppard's "Arcadia" (a fictional account of early and contemporary studies; also thermodynamics and determinism) | Chaos theory
Template:Otheruses2
In mathematics and physics, chaos theory describes the behavior of certain nonlinear dynamical systems that may exhibit dynamics that are highly sensitive to initial conditions (popularly referred to as the butterfly effect). As a result of this sensitivity, which manifests itself as an exponential growth of perturbations in the initial conditions, the behavior of chaotic systems appears to be random. This happens even though these systems are deterministic, meaning that their future dynamics are fully defined by their initial conditions, with no random elements involved. This behavior is known as deterministic chaos, or simply chaos.
# Overview
Chaotic behavior has been observed in the laboratory in a variety of systems including electrical circuits, lasers, oscillating chemical reactions, fluid dynamics, and mechanical and magneto-mechanical devices. Observations of chaotic behaviour in nature include the dynamics of satellites in the solar system, the time evolution of the magnetic field of celestial bodies, population growth in ecology, the dynamics of the action potentials in neurons, and molecular vibrations. Everyday examples of chaotic systems include weather and climate.[1] There is some controversy over the existence of chaotic dynamics in the plate tectonics and in economics.[2] [3] [4]
Systems that exhibit mathematical chaos are deterministic and thus orderly in some sense; this technical use of the word chaos is at odds with common parlance, which suggests complete disorder. A related field of physics called quantum chaos theory studies systems that follow the laws of quantum mechanics. Recently, another field, called relativistic chaos,[5] has emerged to describe systems that follow the laws of general relativity.
As well as being orderly in the sense of being deterministic, chaotic systems usually have well defined statistics. For example, the Lorenz system pictured is chaotic, but has a clearly defined structure. Bounded chaos is a useful term for describing models of disorder.
# History
The first discoverer of chaos can plausibly be argued to be Jacques Hadamard, who in 1898 published an influential study of the chaotic motion of a free particle gliding frictionlessly on a surface of constant negative curvature. In the system studied, Hadamard's billiards, Hadamard was able to show that all trajectories are unstable, in that all particle trajectories diverge exponentially from one another, with a positive Lyapunov exponent.
In the early 1900s Henri Poincaré, while studying the three-body problem, found that there can be orbits which are nonperiodic, and yet not forever increasing nor approaching a fixed point. Much of the early theory was developed almost entirely by mathematicians, under the name of ergodic theory. Later studies, also on the topic of nonlinear differential equations, were carried out by G.D. Birkhoff, A.N. Kolmogorov, M.L. Cartwright, J.E. Littlewood, and Stephen Smale. Except for Smale, these studies were all directly inspired by physics: the three-body problem in the case of Birkhoff, turbulence and astronomical problems in the case of Kolmogorov, and radio engineering in the case of Cartwright and Littlewood. Although chaotic planetary motion had not been observed, experimentalists had encountered turbulence in fluid motion and nonperiodic oscillation in radio circuits without the benefit of a theory to explain what they were seeing.
Despite initial insights in the first half of the century, chaos theory became formalized as such only after mid-century, when it first became evident for some scientists that linear theory, the prevailing system theory at that time, simply could not explain the observed behaviour of certain experiments like that of the logistic map. What had been beforehand excluded as measure imprecision and simple "noise" was considered by chaos theories as a full component of the studied systems.
The main catalyst for the development of chaos theory was the electronic computer. Much of the mathematics of chaos theory involves the repeated iteration of simple mathematical formulas, which would be impractical to do by hand. Electronic computers made these repeated calculations practical, while figures and images made it possible to visualize these systems. One of the earliest electronic digital computers, ENIAC, was used to run simple weather forecasting models.
An early pioneer of the theory was Edward Lorenz whose interest in chaos came about accidentally through his work on weather prediction in 1961. Lorenz was using a simple digital computer, a Royal McBee LGP-30, to run his weather simulation. He wanted to see a sequence of data again and to save time he started the simulation in the middle of its course. He was able to do this by entering a printout of the data corresponding to conditions in the middle of his simulation which he had calculated last time.
To his surprise the weather that the machine began to predict was completely different from the weather calculated before. Lorenz tracked this down to the computer printout. The computer worked with 6-digit precision, but the printout rounded variables off to a 3-digit number, so a value like 0.506127 was printed as 0.506. This difference is tiny and the consensus at the time would have been that it should have had practically no effect. However Lorenz had discovered that small changes in initial conditions produced large changes in the long-term outcome. Lorenz's discovery, which gave its name to Lorenz attractors, proved that meteorology could not reasonably predict weather beyond a weekly period (at most).
The year before, Benoit Mandelbrot found recurring patterns at every scale in data on cotton prices. Beforehand, he had studied information theory and concluded noise was patterned like a Cantor set: on any scale the proportion of noise-containing periods to error-free periods was a constant-- thus errors were inevitable and must be planned for by incorporating redundancy. Mandelbrot described both the Noah effect (in which sudden discontinuous changes can occur, e.g., in a stock's prices after bad news, thus challenging normal distribution theory in statistics, aka Bell Curve) and the Joseph effect (in which persistence of a value can occur for a while, yet suddenly change afterwards). In 1967, he published How Long Is the Coast of Britain? Statistical Self-Similarity and Fractional Dimension, showing that a coastline's length varies with the scale of the measuring instrument, resembles itself at all scales, and is infinite in length for an infinitesimally small measuring device. Arguing that a ball of twine appears to be 1-dimensional (far), 3-dimensional (fairly near), or 1-dimensional (close), he argued that the dimensions of an object are relative to the observer and may be fractional. An object whose irregularity is constant over different scales ("self-similarity") is a fractal (for example, the Koch curve or "snowflake", which is infinitely long yet encloses a finite space with dimensions = 1.2618; or the Menger sponge and the Sierpinski gasket). In 1975 Mandelbrot published The Fractal Geometry of Nature, which became a classic of chaos theory. Biological systems such as the branching of the circulatory and bronchial systems proved to fit a fractal model.
Yoshisuke Ueda independently identified a chaotic phenomenon as such by using an analog computer on November 27, 1961. The chaos exhibited by an analog computer is a real phenomenon, in contrast with those that digital computers calculate, which has a different kind of limit on precision. Ueda's supervising professor, Hayashi, did not believe in chaos, and thus he prohibited Ueda from publishing his findings until 1970.
In December 1977 the New York Academy of Sciences organized the first symposium on Chaos, attended by David Ruelle, Robert May, James Yorke (coiner of the term "chaos" as used in mathematics), Robert Shaw (a physicist, part of the Eudaemons group with J. Doyne Farmer and Norman Packard who tried to find a mathematical method to beat roulette, and then created with them the Dynamical Systems Collective in Santa Cruz), and the meteorologist Edward Lorenz.
The following year, Mitchell Feigenbaum published the noted article "Quantitative Universality for a Class of Nonlinear Transformations", where he described logistic maps. Feigenbaum had applied fractal geometry to the study of natural forms such as coastlines. Feigenbaum notably discovered the universality in chaos, permitting an application of chaos theory to many different phenomena.
In 1979, Albert J. Libchaber during a symposium organized in Aspen by Pierre Hohenberg his experimental observation of the bifurcation cascade that leads to chaos and turbulence in convective Rayleigh-Benard systems. He was awarded the Wolf Prize in Physics in 1986 along with Mitchell J. Feigenbaum "for his brilliant experimental demonstration of the transition to turbulence and chaos in dynamical systems".[6]
The New York Academy of Sciences then co-organized, in 1986, with the National Institute of Mental Health and the Office of Naval Research the first important conference on Chaos in biology and medicine. Bernardo Huberman thereby presented a mathematical model of the eye tracking disorder among schizophrenics [7]. Chaos theory thereafter renewed physiology in the 1980s, for example in the study of pathological cardiac cycles.
In 1987, Per Bak, Chao Tang and Kurt Wiesenfeld published a paper in Physical Review Letters describing for the first time self-organized criticality (SOC), considered to be one of the mechanisms by which complexity arises in nature.
Alongside largely lab-based approaches such as the Bak-Tang-Wiesenfeld sandpile, many other investigations have centred around large-scale natural or social systems that are known (or suspected) to display scale-invariant behaviour. Although these approaches were not always welcomed (at least initially) by specialists in the subjects examined, SOC has nevertheless become established as a strong candidate for explaining a number of natural phenomena, including: earthquakes (which, long before SOC was discovered, were known as a source of scale-invariant behaviour such as the Gutenberg-Richter law describing the statistical distribution of earthquake sizes, and the Omori law describing the frequency of aftershocks); solar flares; fluctuations in economic systems such as financial markets (references to SOC are common in econophysics); landscape formation; forest fires; landslides; epidemics; and biological evolution (where SOC has been invoked, for example, as the dynamical mechanism behind the theory of "punctuated equilibria" put forward by Niles Eldredge and Stephen Jay Gould). Worryingly, given the implications of a scale-free distribution of event sizes, some researchers have suggested that another phenomenon that should be considered an example of SOC is the occurrence of wars. These "applied" investigations of SOC have included both attempts at modelling (either developing new models or adapting existing ones to the specifics of a given natural system), and extensive data analysis to determine the existence and/or characteristics of natural scaling laws.
The same year, James Gleick published Chaos: Making a New Science, which became a best-seller and introduced general principles of chaos theory as well as its history to the broad public. At first the domains of work of a few, isolated individuals, chaos theory progressively emerged as a transdisciplinary and institutional discipline, mainly under the name of nonlinear systems analysis. Alluding to Thomas Kuhn's concept of a paradigm shift exposed in The Structure of Scientific Revolutions (1962), many "chaologists" (as some self-nominated themselves) claimed that this new theory was an example of such as shift, a thesis upheld by J. Gleick.
The availability of cheaper, more powerful computers broadens the applicability of chaos theory. Currently, chaos theory continues to be a very active area of research, involving many different disciplines (mathematics, topology, physics, population biology, biology, meteorology, astrophysics, information theory, etc.).
# Chaotic dynamics
For a dynamical system to be classified as chaotic, it must have the following properties:[8]
- it must be sensitive to initial conditions,
- it must be topologically mixing, and
- its periodic orbits must be dense.
Sensitivity to initial conditions means that each point in such a system is arbitrarily closely approximated by other points with significantly different future trajectories. Thus, an arbitrarily small perturbation of the current trajectory may lead to significantly different future behaviour.
Sensitivity to initial conditions is popularly known as the "butterfly effect", so called because of the title of a paper given by Edward Lorenz in 1972 to the American Association for the Advancement of Science in Washington, D.C. entitled Predictability: Does the Flap of a Butterfly’s Wings in Brazil set off a Tornado in Texas? The flapping wing represents a small change in the initial condition of the system, which causes a chain of events leading to large-scale phenomena. Had the butterfly not flapped its wings, the trajectory of the system might have been vastly different.
Sensitivity to initial conditions is often confused with chaos in popular accounts. It can also be a subtle property, since it depends on a choice of metric, or the notion of distance in the phase space of the system. For example, consider the simple dynamical system produced by repeatedly doubling an initial value (defined by the mapping on the real line from x to 2x). This system has sensitive dependence on initial conditions everywhere,
since any pair of nearby points will eventually become widely separated. However, it has extremely simple behaviour, as all points except 0 tend to infinity. If instead we use the bounded metric on the line obtained by adding the point at infinity and viewing the result as a circle, the system no longer is sensitive to initial conditions. For this reason, in defining chaos, attention is normally restricted to systems with bounded metrics, or closed, bounded invariant subsets of unbounded systems.
Even for bounded systems, sensitivity to initial conditions is not identical with chaos. For example, consider the two-dimensional torus described by a pair of angles (x,y), each ranging between zero and 2π. Define a mapping that takes any point (x,y) to (2x, y + a), where a is any number
such that a/2π is irrational. Because of the doubling in the first coordinate, the mapping exhibits sensitive dependence on initial conditions. However, because of the irrational rotation in the second coordinate, there are no periodic orbits, and hence the mapping is not chaotic according to the definition above.
Topologically mixing means that the system will evolve over time so that any given region or open set of its phase space will eventually overlap with any other given region. Here, "mixing" is really meant to correspond to the standard intuition: the mixing of colored dyes or fluids is an example of a chaotic system.
## Attractors
Some dynamical systems are chaotic everywhere (see e.g. Anosov diffeomorphisms) but in many cases chaotic behaviour is found only in a subset of phase space. The cases of most interest arise when the chaotic behaviour takes place on an attractor, since then a large set of initial conditions will lead to orbits that converge to this chaotic region.
An easy way to visualize a chaotic attractor is to start with a point in the basin of attraction of the attractor, and then simply plot its subsequent orbit. Because of the topological transitivity condition, this is likely to produce a picture of the entire final attractor.
For instance, in a system describing a pendulum, the phase space might be two-dimensional, consisting of information about position and velocity. One might plot the position of a pendulum against its velocity. A pendulum at rest will be plotted as a point, and one in periodic motion will be plotted as a simple closed curve. When such a plot forms a closed curve, the curve is called an orbit. Our pendulum has an infinite number of such orbits, forming a pencil of nested ellipses about the origin.
## Strange attractors
While most of the motion types mentioned above give rise to very simple attractors, such as points and circle-like curves called limit cycles, chaotic motion gives rise to what are known as strange attractors, attractors that can have great detail and complexity.
For instance, a simple three-dimensional model of the Lorenz weather system gives rise to the famous Lorenz attractor. The Lorenz attractor is perhaps one of the best-known chaotic system diagrams, probably because not only was it one of the first, but it is one of the most complex and as such gives rise to a very interesting pattern which looks like the wings of a butterfly. Another such attractor is the Rössler map, which experiences period-two doubling route to chaos, like the logistic map.
Strange attractors occur in both continuous dynamical systems (such as the Lorenz system) and in some discrete systems (such as the Hénon map). Other discrete dynamical systems have a repelling structure called a Julia set which forms at the boundary between basins of attraction of fixed points - Julia sets can be thought of as strange repellers. Both strange attractors and Julia sets typically have a fractal structure.
The Poincaré-Bendixson theorem shows that a strange attractor can only arise in a continuous dynamical system if it has three or more dimensions. However, no such restriction applies to discrete systems, which can exhibit strange attractors in two or even one dimensional systems.
The initial conditions of three or more bodies interacting through gravitational attraction (see the n-body problem) can be arranged to produce chaotic motion.
## Minimum complexity of a chaotic system
Simple systems can also produce chaos without relying on differential equations. An example is the logistic map, which is a difference equation (recurrence relation) that describes population growth over time.
Even the evolution of simple discrete systems, such as cellular automata, can heavily depend on initial conditions. Stephen Wolfram has investigated a cellular automaton with this property, termed by him rule 30.
A minimal model for conservative (reversible) chaotic behavior is provided by Arnold's cat map.
## Mathematical theory
Sarkovskii's theorem is the basis of the Li and Yorke (1975) proof that any one-dimensional system which exhibits a regular cycle of period three will also display regular cycles of every other length as well as completely chaotic orbits.
Mathematicians have devised many additional ways to make quantitative statements about chaotic systems. These include: fractal dimension of the attractor, Lyapunov exponents, recurrence plots, Poincaré maps, bifurcation diagrams, and transfer operator.
# Distinguishing random from chaotic data
It can be difficult to tell from data whether a physical or other observed process is random or chaotic, because in practice no time series consists of pure 'signal.' There will always be some form of corrupting noise, even if it is present as round-off or truncation error. Thus any real time series, even if mostly deterministic, will contain some randomness.[9]
All methods for distinguishing deterministic and stochastic processes rely on the fact that a deterministic system always evolves in the same way from a given starting point.[10][9] Thus, given a time series to test for determinism, one can:
- pick a test state;
- search the time series for a similar or 'nearby' state; and
- compare their respective time evolutions.
Define the error as the difference between the time evolution of the 'test' state and the time evolution of the nearby state. A deterministic system will have an error that either remains small (stable, regular solution) or increases exponentially with time (chaos). A stochastic system will have a randomly distributed error.[11]
Essentially all measures of determinism taken from time series rely upon finding the closest states to a given 'test' state (i.e., correlation dimension, Lyapunov exponents, etc.). To define the state of a system one typically relies on phase space embedding methods.[12]
Typically one chooses an embedding dimension, and investigates the propagation of the error between two nearby states. If the error looks random, one increases the dimension. If you can increase the dimension to obtain a deterministic looking error, then you are done. Though it may sound simple it is not really. One complication is that as the dimension increases the search for a nearby state requires a lot more computation time and a lot of data (the amount of data required increases exponentially with embedding dimension) to find a suitably close candidate. If the embedding dimension (number of measures per state) is chosen too small (less than the 'true' value) deterministic data can appear to be random but in theory there is no problem choosing the dimension too large – the method will work.
Practically, anything approaching about 10 dimensions is considered so large that a stochastic description is probably more suitable and convenient anyway.[citation needed]
# Applications
Chaos theory is applied in many scientific disciplines: mathematics, biology, computer science, economics, engineering, finance, philosophy, physics, politics, population dynamics, psychology, and robotics.[13]
Chaos theory is also currently being applied to medical studies of epilepsy, specifically to the prediction of seemingly random seizures by observing initial conditions.[14]
# Chaos theory in the media
## Movies
- The 1993 movie Jurassic Park
- The 1998 movie π
- The 2004 movie The Butterfly Effect
- The 2006 movie The Science of Sleep
- The 2006 movie Chaos
## Books
- Michael Crichton's Jurassic Park and The Lost World
- Ray Bradbury's A Sound of Thunder
## Theatre
- Tom Stoppard's "Arcadia" (a fictional account of early and contemporary studies; also thermodynamics and determinism) | https://www.wikidoc.org/index.php/Chaos_theory | |
0252f425f5845dcfcca45e5ab9529af30466ec86 | wikidoc | Chapped lips | Chapped lips
# Overview
Chapped lips is a condition whereby the lips become dry and possibly cracked. It may be caused by the evaporation of moisture.
# Treatments
Chapstick can often provide temporary relief, though it should not be used extensively.
Avoid licking your lips. Saliva evaporates quickly, leaving lips drier than before you licked them. | Chapped lips
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chapped lips is a condition whereby the lips become dry and possibly cracked. It may be caused by the evaporation of moisture.
# Treatments
Chapstick can often provide temporary relief, though it should not be used extensively.
Avoid licking your lips. Saliva evaporates quickly, leaving lips drier than before you licked them. | https://www.wikidoc.org/index.php/Chapped_lips | |
88a4582ef70cccac4ed3322d940c55a06612fb50 | wikidoc | Chemiosmosis | Chemiosmosis
# Overview
Chemiosmosis is the diffusion of ions across a selectively-permeable membrane. More specifically, it relates to the generation of ATP by the movement of hydrogen ions across a membrane during cellular respiration.
Hydrogen ions (protons) will diffuse from an area of high proton concentration to an area of lower proton concentration. Peter Mitchell proposed that an electrochemical concentration gradient of protons across a membrane could be harnessed to make ATP. He likened this process to osmosis, the diffusion of water across a membrane, which is why it is called chemiosmosis.
ATP synthase is the enzyme that makes ATP by chemiosmosis. It allows protons to pass through the membrane using the kinetic energy to phosphorylate ADP making ATP. The generation of ATP by chemiosmosis occurs in chloroplasts and mitochondria as well as in some bacteria.
# The Chemiosmotic Theory
Peter D. Mitchell proposed the chemiosmotic hypothesis in 1961.
The theory suggests essentially that most ATP synthesis in respiring cells comes from the electrochemical gradient across the inner membranes of mitochondria by using the energy of NADH and FADH2 formed from the breaking down of energy rich molecules such as glucose.
Molecules such as glucose are metabolized to produce acetyl CoA as an energy-rich intermediate. The oxidation of acetyl CoA in the mitochondrial matrix is coupled to the reduction of a carrier molecule such as NAD and FAD.
The carriers pass electrons to the electron transport chain (ETC) in the inner mitochondrial membrane, which in turn pass them to other proteins in the ETC. The energy available in the electrons is used to pump protons from the matrix across the inner mitochondrial membrane, storing energy in the form of a transmembrane electrochemical gradient. The protons move back across the inner membrane through the enzyme ATP synthase. The flow of protons back into the matrix of the mitochondrion via ATP synthase provides enough energy for ADP to combine with inorganic phosphate to form ATP. The electrons and protons at the last pump in the ETC are taken up by oxygen to form water.
This was a radical proposal at the time, and was not well accepted. The prevailing view was that the energy of electron transfer was stored as a stable high potential intermediate, a chemically more conservative concept.
The problem with the older paradigm is that no high energy intermediate was ever found, and the evidence for proton pumping by the complexes of the electron transfer chain grew too great to be ignored. Eventually the weight of evidence began to favor the chemiosmotic hypothesis, and in 1978, Peter Mitchell was awarded the Nobel Prize in Chemistry.
Chemiosmotic coupling is important for ATP production in chloroplasts
and many bacteria.
# The proton-motive force
In all cells, chemiosmosis involves the proton-motive force (PMF) in some step. This can be described as the storing of energy as a combination of a proton and voltage gradient across a membrane. The chemical potential energy refers to the difference in concentration of the protons and the electrical potential energy as a consequence of the charge separation (when the protons move without a counter-ion).
In most cases the proton motive force is generated by an electron transport chain which acts as both an electron and proton pump, pumping electrons in opposite directions, creating a separation of charge. In mitochondria free energy released from the electron transport chain is used to move protons from the mitochondrial matrix to the intermembrane space of the mitochondrion. Moving the protons to the outer parts of the mitochondrion creates a higher concentration of positively charged particles, resulting in a slightly positive, and slightly negative side (then electrical potential gradient is about -200 mV (inside negative). This charge difference results in an electrochemical gradient. This gradient is composed of both the pH gradient and the electrical gradient. The pH gradient is a result of the H+ ion concentration difference. Together the electrochemical gradient of protons is both a concentration and charge difference and is often called the proton motive force (PMF). In mitochondria the PMF is almost entirely made up of the electrical component but in chloroplasts the PMF is made up mostly of the pH gradient. In either case the PMF needs to be about 50 kJ/mol for the ATP synthase to be able to make ATP.
# In mitochondria
The complete breakdown of glucose in the presence of oxygen is called cellular respiration. The last steps of this process occur in the mitochondria. High energy molecules NADH and FADH2 are generated by the Krebs cycle and glycolysis. These molecules dump electrons onto an electron transport chain to create a proton gradient across the inner mitochondrial membrane. ATP synthase is then used to generate ATP by chemiosmosis. This process is called oxidative phosphorylation because oxygen is the final electron acceptor in the mitochondrial electron transport chain.
Chemiosmotic phosphorylation is the third, and final, biological pathway responsible for the production of ATP from an inorganic phosphate and an ADP molecule via oxidative phosphorylation.
Occurring in the mitochondria of cells, the chemical energy of NADH, produced in the Krebs Cycle is used to build up a gradient of hydrogen ions (protons), with a higher concentration present in the mitochondrial cristae and a lower concentration in the mitochondrial matrix. This is the only step of oxidative phosphorylation for which oxygen is required: oxygen is used as an electron acceptor, combining with free electrons and hydrogen ions to form water.
# In plants
The Light reactions of photosynthesis generate energy by chemiosmosis. Chlorophyll loses an electron when energized by light. This electron travels down a photosynthetic electron transport chain ending on the high energy molecule NADPH. The electrochemical gradient generated across the thylakoid membrane drives the production of ATP by ATP Synthase. This process is known as photophosphorylation.
# In prokaryotes
Bacteria and archaea also can use chemiosmosis to generate ATP. Cyanobacteria, green sulfur bacteria, and purple bacteria create energy by a process called photophosphorylation. These bacteria use the energy of light to create a proton gradient using a photosynthetic electron transport chain. Non-photosynthetic bacteria such as E. coli also contain ATP synthase.
In fact, mitochondria and chloroplasts are believed to have been formed when early eukaryotic cells ingested bacteria that could create energy using chemiosmosis. This is called the endosymbiotic theory. | Chemiosmosis
# Overview
Chemiosmosis is the diffusion of ions across a selectively-permeable membrane. More specifically, it relates to the generation of ATP by the movement of hydrogen ions across a membrane during cellular respiration.
Hydrogen ions (protons) will diffuse from an area of high proton concentration to an area of lower proton concentration. Peter Mitchell proposed that an electrochemical concentration gradient of protons across a membrane could be harnessed to make ATP. He likened this process to osmosis, the diffusion of water across a membrane, which is why it is called chemiosmosis.
ATP synthase is the enzyme that makes ATP by chemiosmosis. It allows protons to pass through the membrane using the kinetic energy to phosphorylate ADP making ATP. The generation of ATP by chemiosmosis occurs in chloroplasts and mitochondria as well as in some bacteria.
# The Chemiosmotic Theory
Peter D. Mitchell proposed the chemiosmotic hypothesis in 1961.[1]
The theory suggests essentially that most ATP synthesis in respiring cells comes from the electrochemical gradient across the inner membranes of mitochondria by using the energy of NADH and FADH2 formed from the breaking down of energy rich molecules such as glucose.
Molecules such as glucose are metabolized to produce acetyl CoA as an energy-rich intermediate. The oxidation of acetyl CoA in the mitochondrial matrix is coupled to the reduction of a carrier molecule such as NAD and FAD.[2]
The carriers pass electrons to the electron transport chain (ETC) in the inner mitochondrial membrane, which in turn pass them to other proteins in the ETC. The energy available in the electrons is used to pump protons from the matrix across the inner mitochondrial membrane, storing energy in the form of a transmembrane electrochemical gradient. The protons move back across the inner membrane through the enzyme ATP synthase. The flow of protons back into the matrix of the mitochondrion via ATP synthase provides enough energy for ADP to combine with inorganic phosphate to form ATP. The electrons and protons at the last pump in the ETC are taken up by oxygen to form water.
This was a radical proposal at the time, and was not well accepted. The prevailing view was that the energy of electron transfer was stored as a stable high potential intermediate, a chemically more conservative concept.
The problem with the older paradigm is that no high energy intermediate was ever found, and the evidence for proton pumping by the complexes of the electron transfer chain grew too great to be ignored. Eventually the weight of evidence began to favor the chemiosmotic hypothesis, and in 1978, Peter Mitchell was awarded the Nobel Prize in Chemistry.[3]
Chemiosmotic coupling is important for ATP production in chloroplasts[4]
and many bacteria.[5]
# The proton-motive force
In all cells, chemiosmosis involves the proton-motive force (PMF) in some step. This can be described as the storing of energy as a combination of a proton and voltage gradient across a membrane. The chemical potential energy refers to the difference in concentration of the protons and the electrical potential energy as a consequence of the charge separation (when the protons move without a counter-ion).
In most cases the proton motive force is generated by an electron transport chain which acts as both an electron and proton pump, pumping electrons in opposite directions, creating a separation of charge. In mitochondria free energy released from the electron transport chain is used to move protons from the mitochondrial matrix to the intermembrane space of the mitochondrion. Moving the protons to the outer parts of the mitochondrion creates a higher concentration of positively charged particles, resulting in a slightly positive, and slightly negative side (then electrical potential gradient is about -200 mV (inside negative). This charge difference results in an electrochemical gradient. This gradient is composed of both the pH gradient and the electrical gradient. The pH gradient is a result of the H+ ion concentration difference. Together the electrochemical gradient of protons is both a concentration and charge difference and is often called the proton motive force (PMF). In mitochondria the PMF is almost entirely made up of the electrical component but in chloroplasts the PMF is made up mostly of the pH gradient. In either case the PMF needs to be about 50 kJ/mol for the ATP synthase to be able to make ATP.
# In mitochondria
The complete breakdown of glucose in the presence of oxygen is called cellular respiration. The last steps of this process occur in the mitochondria. High energy molecules NADH and FADH2 are generated by the Krebs cycle and glycolysis. These molecules dump electrons onto an electron transport chain to create a proton gradient across the inner mitochondrial membrane. ATP synthase is then used to generate ATP by chemiosmosis. This process is called oxidative phosphorylation because oxygen is the final electron acceptor in the mitochondrial electron transport chain.
Chemiosmotic phosphorylation is the third, and final, biological pathway responsible for the production of ATP from an inorganic phosphate and an ADP molecule via oxidative phosphorylation.
Occurring in the mitochondria of cells, the chemical energy of NADH, produced in the Krebs Cycle is used to build up a gradient of hydrogen ions (protons), with a higher concentration present in the mitochondrial cristae and a lower concentration in the mitochondrial matrix. This is the only step of oxidative phosphorylation for which oxygen is required: oxygen is used as an electron acceptor, combining with free electrons and hydrogen ions to form water.
# In plants
The Light reactions of photosynthesis generate energy by chemiosmosis. Chlorophyll loses an electron when energized by light. This electron travels down a photosynthetic electron transport chain ending on the high energy molecule NADPH. The electrochemical gradient generated across the thylakoid membrane drives the production of ATP by ATP Synthase. This process is known as photophosphorylation.
# In prokaryotes
Bacteria and archaea also can use chemiosmosis to generate ATP. Cyanobacteria, green sulfur bacteria, and purple bacteria create energy by a process called photophosphorylation. These bacteria use the energy of light to create a proton gradient using a photosynthetic electron transport chain. Non-photosynthetic bacteria such as E. coli also contain ATP synthase.
In fact, mitochondria and chloroplasts are believed to have been formed when early eukaryotic cells ingested bacteria that could create energy using chemiosmosis. This is called the endosymbiotic theory. | https://www.wikidoc.org/index.php/Chemiosmosis | |
360b504cc578cb9ed6ffa4cf8e72331aa95297db | wikidoc | Chemometrics | Chemometrics
Chemometrics is the application of mathematical or statistical methods to chemical data.
The International Chemometrics Society (ICS) offers the following definition:
Chemometric research spans a wide area of different methods which can be applied in chemistry. There are techniques for collecting good data (optimization of experimental parameters, design of experiments, calibration, signal processing) and for getting information from these data (statistics, pattern recognition, modeling, structure-property-relationship estimations).
Chemometrics tries to build a bridge between the methods and their application in chemistry.
# Applications
In spectroscopy, the applications of chemometrics is most often in calibration. Calibration is achieved by using the spectra as multivariate descriptors to predict concentrations of constituents of interest using statistical approaches such as Multiple Linear Regression, Principal components analysis and Partial Least Squares. Other popular chemometry techniques include approaches for ab initio prediction of number of components, noise reduction and multivariate curve resolution. | Chemometrics
Chemometrics is the application of mathematical or statistical methods to chemical data.
The International Chemometrics Society (ICS) offers the following definition:
Template:Cquote2
Chemometric research spans a wide area of different methods which can be applied in chemistry. There are techniques for collecting good data (optimization of experimental parameters, design of experiments, calibration, signal processing) and for getting information from these data (statistics, pattern recognition, modeling, structure-property-relationship estimations).
Chemometrics tries to build a bridge between the methods and their application in chemistry.
# Applications
In spectroscopy, the applications of chemometrics is most often in calibration. Calibration is achieved by using the spectra as multivariate descriptors to predict concentrations of constituents of interest using statistical approaches such as Multiple Linear Regression, Principal components analysis and Partial Least Squares. Other popular chemometry techniques include approaches for ab initio prediction of number of components, noise reduction and multivariate curve resolution. | https://www.wikidoc.org/index.php/Chemometrics | |
f2a42f25d528270782726ed2e906c52f191495c4 | wikidoc | Mohs surgery | Mohs surgery
# Overview
Mohs surgery, also known as chemosurgery, created by a general surgeon, Dr. Fredrick E. Mohs, is microscopically controlled surgery that is highly effective for common types of skin cancer, with a cure rate cited by most studies between 97% and 99.8% for primary basal cell carcinoma, the most common type of skin cancer. Mohs procedure is also used for squamous cell carcinoma, but with a lower cure rate. Two isolated studies reported cure rate for primary basal cell cancer as low as 95% and 96% (see discussion on "Why is the Cure Rate so Varied?). Recurrent basal cell cancer has a lower cure rate with Mohs surgery, more in the range of 94%. It has been used in the removal of melanoma-in-situ (cure rate 77% to 98% depending on surgeon), and certain types of melanoma (cure rate 52%). Another study of melanoma-in-situ revealed Mohs cure rate of 95% for frozen section Mohs, and 98 to 99% for fixed tissue Mohs method. Other indications for Mohs surgery include dermatofibrosarcoma protuberans, keratoacanthoma, spindle cell tumors, sebaceous carcinomas, microcystic adnexal carcinoma, merkel cell carcinoma, Pagets's disease of the breast, atypical fibroxanthoma, leimyosarcoma, and angiosarcoma. Because the Mohs procedure is micrographically controlled, it provides precise removal of the cancerous tissue, while healthy tissue is spared. Mohs surgery is relatively expensive when compared to other surgical modalities. However, in anatomically important areas (eyelid, nose, lips), tissue sparing and low recurrence rate makes it a procedure of choice by many physicians.
# History
Originally, Dr. Mohs used an escharotic agent made of zinc chloride and bloodroot (the root of the plant Sanguinaria canadensis, which contains the alkaloid sanguinarine). The original ingredients were 40.0 gm Stibnite, 10.0 gm Sanguinaria canadensis, and 34.5 ml of saturated zinc chloride solution. This paste is very similar to "Hoxsey's paste" (see Hoxsey Therapy). Harry Hoxsey, a lay cancer specialist was developing a herbal tonic and paste designed to treat internal and external cancers. Hoxsey recommended applying paste to the affected area and within days to weeks, the area would necrose (cell death), separate from surrounding tissue and fall out. Dr. Mohs applied a very similar paste after experimenting with a number of compounds to the wound of his skin cancer patients. They were to leave the paste on the wound overnight, and the following day, the skin cancer and surrounding skin would be anesthetic, and ready to be removed. The specimen was then excised, and the tissue examined under the microscope. If cancer remained, more paste was applied, and the patient would return the following day. Later, local anesthetic and frozen section histopathology applied to fresh tissue allowed the procedure to be performed the same day, with less tissue destruction, and similar cure rate. The term "chemosurgery" remains today, and is used synonymously with Mohs micrographic surgery.
# Mohs procedure
The Mohs procedure is essentially a pathology sectioning method that allows for the complete examination of the surgical margin. It is different from the standard bread loafing technique of sectioning, where random samples of the surgical margin is examined.
Mohs surgery is performed in four steps:
- Surgical removal of tissue (Surgical Oncology)
- Mapping the piece of tissue, freezing and cutting the tissue between 5 and 10 micrometers using a cryostat, and staining with hematoxylin and eosin (H&E) or other stains (including T. Blue)
- Interpretation of microscope slides (Pathology)
- Reconstruction of the surgical defect (Reconstructive Surgery)
The procedure is usually performed in a physician's office under local anesthetic. A small scalpel is utilized to cut around the visible tumor. A very small surgical margin is utilized, usually with 1 to 1.5 mm of "free margin" or uninvolved skin. The amount of free margin removed is much less than the usual 4 to 6 mm required for the standard excision of skin cancers. After each surgical removal of tissue, the specimen is processed, cut on the cryostat and placed on slides, stained with H&E and then read by the Mohs surgeon/pathologist who examines the sections for cancerous cells. If cancer is found, its location is marked on the map (drawing of the tissue) and the surgeon removes the indicated cancerous tissue from the patient. This procedure is repeated until no further cancer is found.
The method is well described in current references. The mapping combined with the unique "smashing the pie pan" method of processing is the essential of Mohs surgery. If one imagines an aluminum pie pan as the blood covered surgical margin, and the top of the pie is the crust covered surface of the skin - the goal is to flatten the aluminum pie pan into one flat sheet, mark it, stain it, and examine it under the microscope. Another author uses the example of peeling the skin off an orange. Imagine an orange cut in half as the Mohs layer. The peel is the surgical margin. One remove this peel and flatten it out on a glass slide to examine the roots of the invasive cancer. The mapping is simply how one stains and labels the sections for a microscopic examination. The sections can be processed in one piece (using relaxing incisions at multiple points, or hemisectioned like a "Pac-Man" figure), cut in halves, cut in quarters, or cut in multiple pieces. Single piece processing is acceptable for small cancers, and multiple piece sectioning facilitates processing and prevent artifacts. Single piece sectioning prevents errors introduced by soft, hard-to-handle tissue; or from accidental dropping or mislabeling of specimen. Multiple sectioning prevents compression artifacts, separation of tissue, and other logistical problems with handling large thin sheets of frozen skin.
Some physicians believe that frozen section histology is the same as Mohs micrographic surgery, and it is not. Mohs surgery is performed using fresh tissue and frozen section histology. However, standard frozen section histology usually utilizes a random tissue sampling technique called "bread loafing". Bread loafing is a statistical sampling method which exams less than 5% of the total surgical margin (imagine pulling 5 slices of bread out of a whole loaf of sliced bread and examining only those 5 slices to visualize the whole loaf). In Mohs processing, the entire surgical margin is examined (imagine one who examined the entire outside crust of the same loaf of bread). In statistical terms, the more slices of bread one examines, the lower the "false negative" rate will become. False negatives occur when a pathologist reads cancer excision as "free of residual carcinoma", even though cancer might be present in the wound and missed because of the random sampling. In reality, most pathology labs examine only 3 to 8 sections of the "loaf" in their margin determination. While a diligent pathologist can cut and process a standard excision to get the same margin control as Mohs surgery, it is seldom done since tissue processing is very difficult in practice. The alternative to Mohs surgery is when a pathologist requests the processing to be done by "cutting through the block". Again, this method approaches that of Mohs surgery, but still is not as good. Cutting through the block will result in the random discarding of many slices, but does greatly decrease the incidence of "false negative" reports. Dr. Mohs perfected a simple and efficient way to "flatten" and examine the entire surgical margin.
## Staining Convention
Each surgeon has their own convention. A typical convention is as follows
# Differences between histology of transverse sections and vertical sections
Often, for legal purpose, a second opinion will be asked of a pathologist to review pathology slides from Mohs cases. Traditional histology of skin tissue uses vertical sectioning - with the subcutanous tissue at the bottom and the epidermis at the top. Mohs surgery uses tangential or horizontal sectioning, which can confuse the pathologists trained in the traditional method.
First, one has to determine the method of chromacoding or color coding. The orientation of the Mohs map must be able to distinguish between medial, lateral, superior, and inferior.
Next, one has to determine if the surgeon followed the convention of mounting only 2 sections per case; as preferred by some author; or did he/she performed serial sectioning through the block as preferred by some author. If serial sectioning is performed, the distance between sections should be confirmed. Some surgeons utilizes 100 micrometres between each sections, and some utilizes 200 micrometres between the first two sections, and 100 micrometres between subsequent sections (10 crank of tissue set at 6 to 10 micrometre is roughly equal to 100 micrometres if one allow for physical compression due to the blade).
Next, one determine if the entire epidermal border is present. Ideally 100% of the epithelial border should be present. Convention requires at least 95% of the epidermis to be present. However, some surgeon will make an exception for some missing epithelium at the apices of an elliptical excision around the specimen. Ideally, oval sections should be performed. However, for practical purpose on some lesions, a surgeon might cut the Mohs section to approximate the final closure defect. The apexes are often 1 cm or more from the tumor, so clear margins at the apices can be ignored. Not ideal by convention, but appropriate on a case by case basis.
Next, one determine if the surgical margin is clear. With serial sectioning, one has to recreate the surgical specimen in a 3 dimensional way. The first section that touches the blade begin the 3 dimensional reconstruction. By using the 3-D reconstruction of the specimen, one can say that all the epithelial margin is present as one progresses from deep to superficial. If only 2 sections are present, ideally, both the sections should be clear. If the deeper sections is positive, one has to ascertain the distance between the section. Convention often call for a clear margin of at least 200 micrometres. For ambiguous structures that resembles both adnexal structure and carcinoma, following the serial sections will allow for one to identify the structure as benign or malignant. With the 2 slides method, this might be impossible to perform, as no 3-D reconstruction is possible with only 2 sections.
Carcinoma appearance under Mohs micrographic sectioning can be deceptively difficult. Tangential cut of squamous cell can mimic squamous cell carcinoma (but without the atypia). Sections through the buds of hair follicles resembles isolated islands of basal cell cancers, often even with retraction artifact. Serial section analysis is best for Mohs surgery. But one will often find cases where only 2 slides are mounted.
It is best to leave the professional evaluation of Mohs section to an expert. The expert should not only be a pathologist who is familiar with one style of Mohs processing (i.e. 2 section mounting), one should also be familiar with all the sectioning protocols (whole tissue, pacman one piece, double pacman one piece, or multiple sections). Each methods has its limitation, but as long as good quality slides are cut - the end result is the same.
# The Mohs Surgery Team
The team consists of the Mohs surgeon, histotechnician, pathologist and the reconstructive surgeon. The Mohs surgeon identifies the cancer and its margin, often with the aid of dermatoscopy. He removes the cancer under local anesthetic and prepares it for histology processing. This is accomplished by cutting the specimen (if required), staining the specimen for orientation, and sending it to the lab.
The histotechnician prepares the tissue for Mohs processing by flattening the surgical margin on a flat surface first. Then the flat surgical surface is mounted on a cryostat to be sectioned and prepared for glass slides to be read by the pathologist.
The pathologist examine the slide for residual tumors, and marks the location of the tumor on the pathology report and sends it back to the Mohs surgeon. He informs the Mohs surgeon when the surgery has completely removed the cancer.
The reconstructive surgeon does the plastic repair of the surgical defect in a cosmetic manner. Some Mohs surgeons utilize a plastic or reconstructive surgeon to repair the defect. Most Mohs surgeons perform their own surgical repair, except on exceptional cases.
There are some Mohs surgeons who fulfill all 4 roles - Mohs surgeon, histotechnician, pathologist and reconstructive surgeon. Most Mohs surgeons also perform the duty of pathologist and reconstructive surgeon. Regardless of who performs what procedures, any weakness in the link between these 4 individuals can result in a poor cure rate, or bad cosmetic outcome.
# Why is the cure rate so varied?
These are topics for discussion, but errors introduced in the technique can introduce false negative errors. There are numerous reasons why the cure rate is not 100%. Some of Dr. Mohs data revealed a cure rate as low as 96%, but these were often very large tumor, and previously been treated by other modalities. Some authors claim that their 5 year cure rate for primary basal cell cancer exceeded 99% while other noted more conservative cure rate of 97%. The quoted cure rate for Mohs surgery on previously treated basal cell cancer is about 94%.
1. Modern frozen section method. Frozen section histology does not give the added margin of safety by the cytotoxic Mohs paste, originally used by Dr. Mohs. This paste might have destroyed any residual cancer cells not detected by the pathologist.
2. Missing epidermal margins. Ideally, the Mohs section should include 100% of the epidermal margin, but greater than 95% is often accepted. Unfortunately, vigorous scrubbing, poorly controlled initial curettage, poor tissue health, technician's error, and surgeon's error can introduce areas missing epithelial margin. Some surgeon consider 70% epithelial margin acceptable, while other suggests 100% margin. In the ideal situation, 100% of the epithelial margin should be available to be reviewed on serial sectioning of the Mohs specimen.
3. Misreading of the pathology slide. It is difficult to differentiate between a small island of basal cell carcinoma and a hair follicle structure. Many Mohs surgeon limits their tissue processing to include only 2 sections of tissue. This severely hampers their ability to determine if a structure is a hair follicle or a carcinoma. Two histologic sections can not fully distinguish these two nearly identical structures, and can lead to either "false negative" or "false positive" errors by either calling a section clear of tumor, or calling a section positive for tumor, respectively. Serial sectioning of the tumor is preferred by other surgeons. Surgeons who performs serial sectioning through the block of tissue (usually 100 micrometres apart) are assured the contiguous nature of his tumor, the distance of the tumor from the surgical margin, and is familiarized with the nature of the tumor. Serial sectioning also makes it easier to work with three dimensional tumor with difficult to compress margins.
4. Compression artifact, freezing artifact, cautery artifact, tissue folds, crush artifact from forceps, relaxing incision artifact, cartilage dropping out, fat compression, poor staining, dropping of tumor, etc. These can be introduced as the tumor is "flattened". Stain can run from the surgical edge, and stain the surgical margin - giving a false impression that the entire surgical margin is clear, when it is not. While some surgeon unfamiliar with the "whole piece" or "PacMan" methods of processing might suggest that multiple piece sectioning is better than one. The more tissue sections are cut, the more artifacts in staining and tissue malformation will be introduced. It is imperative for the surgeon to be fully familiar with tissue handling and processing; and not simply relying on a trained technologist to perform his sectioning.
5. Hard to see tumor in heavy inflammatory infiltrate. This can occur with squamous cell carcinoma, especially when complicated with local infection, or intrinsic lymphoproliferative disorders (chronic lymphocytic leukemia). Because of abnormal peripheral blood profile, response to inflammatory skin conditions with patients with myelomonocytic leukemia can have appearance of atypical cells at sites of inflammation, confusing the Mohs surgeon.
6. Perineural spread, and benign changes simulating perineural spread. Tumor spreading along a nerve can be difficult to visualize, and sometime benign plasma cells can surround the nerve, simulating cancer.
7. Difficult to cut and process anatomical area. Examples would be the ear, and other three dimensional structures like eyelids. The ability to make a scallop shaped incision is increasingly difficult when the surgical surface is no longer a flat plane, but is a three dimensional rigid structure.
8. Recurrent skin cancer with multiple islands of recurrence. This can occur with either previous excision, or after electrodessication and curettage. As these residual skin cancer are often bound in scar tissue, and present in multiple location in the scar of the previous surgical defect - they are no longer contiguous in nature. Some surgeons advocate the removal of the complete scar in the treatment of "recurrent" skin cancers. Others advocate removing only the island of local recurrence, and leaving the previous surgical scar behind. The decision is often made depending on the location of the tumor, and the goal of the patient and physician.
9. Unreported or underreported recurrence. Many patients simply will not return to the original surgeon to report a recurrence. Consulting surgeon on the repeat surgery will often not inform the first surgeon of the recurrence. The time it takes for a recurrent tumor to be visible to the patient might be 5 or more years. Quoted "cure" rates must be looked upon with the understanding that a 5 year cure rate might not necessary be correct. As basal cell carcinoma is a very slowly progressing tumor, a 5 year no recurrence rate might not be adequate. Longer follow up might be needed to detect a slow growing tumor left in the surgical scar.
10. Poor training of the surgeon/pathologist/histotechnologist. While Mohs surgery is essentially a technical method of tissue handling and processing, the skill and training of the surgeon can greatly affect the outcome. The house of card is built with a foundation of good tissue handling, good surgical skill and hemostasis, and the bricks are the tissue processing and staining technique. A surgeon without a good histotechnologist is a house built with straw, and a histotechnologist without a good surgeon can not produce quality slides. While originally, surgeons learned the procedure by spending a few hours to several months with Dr. Mohs; today, surgeons complete residency and fellowship spending hundreds of hours observing and doing Mohs surgery. It is highly encouraged that a physician interested in learning Mohs surgery should spend extended time observing, cutting, processing, and staining Mohs specimens. The histology block should be correctly mounted and cut the first time, as there is no second chances in Mohs histology. It is not a procedure that can be taught or learn in one weekend. Many residency and Mohs fellowship continue to teach the processing of only 2 Mohs sections per tumor.
Irrespective of the problems associated with Mohs surgery, a true cure rate approaching 100% can occur with primary basal cell carcinoma (previously untreated) if proper respect of the physician's limitation, the procedure's limitation, and his laboratory staff's limitation. Conservative approach such as serial sectioning, good staining technique, and conservative Mohs margin (example: tumor at least 200 micrometre from the surgical margin) can assure the lowest recurrence rate.
# Comparison to other modalities of treatment
It often occurs in medicine as in real life, "When you go to Midas, you get a muffler". Mohs surgery is not the answer for all skin cancers. Studies comparing the effectiveness of Mohs surgery to other modalities often fail to specify surgical margin, method of processing (bread loafing with 3 or 4 sections, bread loafing with 0.1 mm spacing, margin controlled, frozen section vs. standard histology); leaving little argument one way or another. Once a pathologist understands the simplistic nature of Mohs surgery, and its margin control ability - little need is called for clinical trial comparing Mohs surgery to surgical excision.
In reality, Mohs micrographic surgery is nothing more than frozen section histology using a unique peripheral margin control tissue processing technique. There is nothing magical about its cure rate or why years of training is required. When compared to many other described peripheral margin control tissue processing technique - the end result is the same - allowing for the complete examination of 100% of the surgical margin. The method is unique only in that it is a simple way to handle soft, hard to cut tissue. Once learned, any pathologists currently doing frozen section histology would realize how simple the technique is. It is better than doing serial bread loafing at 0.1 mm interval for improved false negative error rate simply in requiring less time, less tissue handling, and fewer glass slides mounted. Once mounted as tangential or horizontal sections, the pathologist simply has to relearn how to visualize skin structure on a tangential to horizontal view. In absent of a Mohs trained pathologist, peripheral sectioning followed by horizontal sectioning of the remaining center is equivalent to the Mohs method.
The clinical quotes for cure rate of Mohs surgery is from 97% to 99.8% after 5 years for newly diagnosed basal cell cancer, decreasing to 94% or less for recurrent basal cell cancer. Radiation oncologists quote cure rate from 90 to 95% for BCC's less than 1 or 2 cm, and 85 to 90% for BCC's larger than 1 or 2 cm. Surgical excision cure rate varies from 99% for wide margin (4 to 6 mm) and small tumor, to as low as 70% for narrow margins applied to large tumors. Here the weakness of the procedure is the histopathological processing, and not the surgeon himself. The fault of the surgeon is lack of understanding pathology laboratory methods, and failing to follow the standard of care for adequate surgical margin. Usually the cure rate using standard bread loafing is very low for narrow surgical margin and a large tumor, and very high for large margins on small tumors. It is the pathology lab that makes the difference, especially when frozen section is utilized in the operating theater. A randomized study assigning patients with recurrent facial basal cell cancer to either Mohs surgery or standard excision revealed no statistical difference in the treatment of primary basal cell carcinoma. It found a higher cure rate with Mohs surgery in the treatment of recurrent basal cell carcinoma (5 year recurrence rate of 2.4% for Mohs vs 12.1% for standard).
Cosmetic appearance for Mohs surgery is very good, if combined with good reconstructive surgical skills. Some Mohs surgeon utilize a plastic or reconstructive surgeon for the closure, and some Mohs surgeon perform the reconstruction by himself. There are dermatologists who are great reconstructive surgeons, and plastic surgeons who are poor reconstructive surgeons. In certain area, the tip of the nose, and the nasal ala, Mohs surgery can result in significant deformity, and might require multiple staged reconstruction to rebuild the nose cosmetically. Radiation offers a very good non-traumatic option in these difficult to reconstruct areas.
In choosing a Mohs surgeon or reconstructive surgeon, it is mandatory that a patient request to see pictorial representation of his/her previous work. Then one can proceed to make a decision whether the Mohs surgeon should also be the reconstructive surgeon.
# Controversy About Mohs Surgery
Few individuals argue about the cure rate for Mohs, especially pathologists familiar with the procedure. However, in recent years, a few surgeons attempted to throw the baby out with the bath water by claiming that Mohs surgery is no better than standard excision based on one study. The author in this study did not conclude the adequacy of the study as it is limited in size and short duration of the study (30 months). Extensive studies performed by Dr. Mohs involving thousands of patients with both fixed tissue and fresh tissue cases have been reported in the literature. Other surgeons repeated the studies with also thousands of cases, with nearly the same results.
Clinical 5 year cure rates with Mohs surgery: 1. 4085 cases of primary and recurrent cancer of face, scalp, and neck. Cure rate of 96.6%. 2. 1065 cases of squamous cell carcinoma of face, scalp, and neck - cure rate 94.8% 3. 2075 cases of basal cell cancer of the nose both primary and recurrent, cure rate 99.1%. 4. Cure rate for basal cell cancer of the ear, less than 1 cm, 124 cases, cure rate 100%. 5. Cure rate of basal cell cancer of the ear, 1 to 2 cm, 170 cases, 100%. One needs to keep in mind that the cases performed by Dr. Mohs were for large and extensive tumors, often treated numerous times before by other surgeons. Regardless, his cure rate for small primary tumors either were 100% or near 100% when separated out from larger or recurrent tumors.
Experienced Mohs surgeons have reported cure rates for melanoma-in-situ from 95% to 98% (depending on if it is small MIS, or lentigo maligna variant), much higher than previously reported by Dr. Mikhail of 77%.
These are only a small number of cases reported by Dr. Mohs, and numerous other articles by other authors have shown tremendous cure rates for primary basal cell carcinoma. However, with studies by Smeet, et al. showing a Mohs cure rate of about 95%, and another study in Sweden showing Mohs cure rate of about 94%; we really have to question if methodology practiced by Mohs surgeons around the world is of the same standard. We also will have to question if the standard 2 sections performed by some Mohs surgeons is adequate to control for false negative Mohs reports.
# Where Mohs surgery is allowed
An example where clinical guidelines are issued by insurance companies; these guidelines are not indication that Mohs is the best method for the cancers described. These guidelines are subjective (why is younger than 40 years old a criterion?), and might not have any clear objective basis. Clinical guidelines currently adapted by Medicare insurance of the United States:
Medicare will cover reimbursement for Mohs micrographic surgery for accepted diagnoses and indications as listed below.
1. Basal Cell, Squamous Cell, or Basalosquamous Cell Carcinomas in anatomic locations where they are prone to recur:
- Central facial areas, periauricular, nose, and temple areas of the face (the so-called "mask area" of the face)
- Lips, cutaneous and vermilion
- Eyelids and periorbital areas
- Auricular helix and canal
- Chin and mandible
2. Other Skin lesions:
-Angiosarcoma of the skin
-Keratoacanthoma, recurrent
-Dermatofibrosarcoma protuberans
-Malignant fibrous histiocytoma
-Sebaceous gland carcinoma
-Microcystic adnexal carcinoma
-Extramammary Paget's disease
-Bowenoid papulosis
-Merkel cell carcinoma
-Bowen's disease (squamous cell carcinoma in situ)
-Adenoid type of squamous cell carcinoma
-Rapid growth in a squamous cell carcinoma
-Longstanding duration of a squamous cell carcinoma
-Verrucous carcinoma
-Atypical Fibroxanthoma
-Leiomyosarcoma or other spindle cell neoplasms of the skin
-Adenocystic carcinoma of the skin
-Erythroplasia of Queryrat
-Oral and central facial, paranasal sinus neoplasm
-Apocrine carcinoma of the skin
-Malignant melanoma (facial, auricular, genital and digital) when anatomical or technical -difficulties do not allow conventional excision with appropriate margins.
-Basal Cell carcinomas, squamous cell carcinomas, or basalosquamous carcinomas that have one or more of the following features:
- o Recurrent
- o Aggressive pathology in the following areas: Hands and feet, Genitalia, and Nail unit/periungual
- o Large size (2.0 cm or greater)
- o Positive margins on recent excision
- o Poorly defined borders
- o In the very young (<40 years age)
- o Radiation-induced
- o In patients with proven difficulty with skin cancers or who are immunocompromised
- o Basal cell nevus syndrome
- o In an old scar (e.g., a Marjolin's ulcer)
- o Associated with xeroderma pigmentosum
- o Perineural invasion on biopsy
- o Deeply infiltrating lesion or difficulty estimating depth of lesion
3. Laryngeal Carcinoma
# Future applications of Mohs surgery
Mohs surgery can be applied to any relatively non-aggressive locally invasive tumors with contiguous growth pattern (i.e. no skipped growth, or metastasis). Today, most Mohs procedures are performed by dermatologists. However, pathologists, plastic surgeons, and otolaryngologists have been trained and are ulitizing Mohs surgery in their practice as well. Hopefully, as more physicians are trained in the method, Mohs surgery can be applied to other organs systems beside the skin. The limitation of this application to other tumors (i.e. prostate cancer, cervical cancer, laryngeal cancer) is that the tumor must be in the earliest stages and no metastasis has occur. The second problem with Mohs surgery is the prolonged procedural time, which might require prolonged general anesthesia.
Currently, the American College of Mohs Surgery has limited training to physicians who have done a dermatology residency. The American Society for Mohs Surgery continues to encourage the training of physicians of all specialties to learn and apply the method invented by Dr. Frederick Mohs. The argument against physicians of other specialties than dermatology gaining Mohs training is that they are not adequately trained in dermatopathology. The argument for training other physicians beside dermatologists is that most Mohs surgeon do not make the initial diagnosis of the skin cancer - thus misdiagnosis can be avoided. The pathology of Mohs sections are then limited to a few easily identifiable cancers; and the pathology of normal skin is simple enough to gain in a short preceptorship; even if you are not a dermatologist or a pathologist.
Dr. Mohs, a general surgeon, encouraged physicians of all surgical specialties to learn and apply his technique to the treatment of skin cancer; it is understood that he never intended to limit his method to be utilized by dermatologists alone. In countries where dermatology is not well developed, the Mohs procedure can easily be learned by any surgeon or pathologist after a short preceptorship - the same way Dr. Mohs taught many current Mohs surgeons.
This is a direct quote of Dr. Frederick Mohs in his book's preface:
"The book should be useful to physicians who may be called on to treat or advise regarding treatment of skin cancers and other conditions that are described. This includes dermatologists, surgeons, plastic surgeons, otolaryngologists, gynecologists, urologists, proctologists, pathologists, internists, and general practitioners."
From: Frederic E. Mohs, B.Sc., M.D. Clinical Professor of Surgery, University of Wisconsin. CHEMOSURGERY, Microscopically Controlled Surgery For Skin Cancer, Charles C. Thomas, Publisher, 1956. p. vii.
# Associations
The American College of Mohs Surgery is the organization that sets standards of care for fellowship trained Mohs surgeons who perform Mohs surgery as a primary function of their practice.
The American Society of Mohs Surgery is an organization of dermatologists who perform dermatology and Mohs surgery in their practice. ASMS Mohs surgeons are certified by a written and practical exam, and are required to submit to yearly peer review of their cases.
The American Board of Medical Subspecialities is in the process of reviewing Mohs micrographic surgery as a separate subspecialty. Mohs surgery has not been recognized as a separate subspeciality and there is no certifying board for Mohs Surgery at this time.
The American Academy of Dermatology is the largest organization of board certified dermatologists, many of whom perform dermatologic and Mohs micrographic surgery. With a membership of over 15,000, it represents virtually all practicing dermatologists in the United States and Canada and has specific member information regarding those performing Mohs micrographic surgery.
The American Osteopathic College of Dermatology is the only organization that recognized Mohs surgery as a separate subspecialty. The organization offers board certification exam through the auspice of the American Osteopathic Association. The recipient of the board certification receives a certificate of added qualification (CAQ) to the primary board certification of dermatology. Currently American Osteopathic College of Dermatology is the only organization offer this credential to mohs surgeons.
The American Society for Dermatologic Surgery founded in 1970 is the largest organization of board certified dermasurgeons with over 5000 members who perform dermatologic surgeries including Mohs micrographic surgery.
The Association of Academic Dermatologic Surgeons has board certified dermasurgeon professors who have faculty appointments at major teaching hospitals and universities and are engaged in training medical students and residents in the practice of dermatologic surgery and Mohs micrographic surgery.
# Mohs Surgery Case Studies
Photos courtesy of Dr. B. Cowan
CASE STUDY 1: Left Nasal Rim Skin Cancer
Click to view complete slide-show and the surgeon's comments for the Left Nasal Rim Skin Cancer case study
CASE STUDY 2: Right Lower Lip Skin Cancer
Click to view complete slide-show and the surgeon's comments for the Right Lower Lip Skin Cancer case study
CASE STUDY 3: Left Temple Basal Cell Cancer
Click to view complete slide-show and the surgeon's comments for the Left Temple Basal Cell Cancer case study | Mohs surgery
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2]
# Overview
Mohs surgery, also known as chemosurgery, created by a general surgeon, Dr. Fredrick E. Mohs, is microscopically controlled surgery that is highly effective for common types of skin cancer, with a cure rate cited by most studies between 97% and 99.8%[1] for primary basal cell carcinoma, the most common type of skin cancer. Mohs procedure is also used for squamous cell carcinoma, but with a lower cure rate. Two isolated studies reported cure rate for primary basal cell cancer as low as 95% and 96% (see discussion on "Why is the Cure Rate so Varied?).[2][3][4] Recurrent basal cell cancer has a lower cure rate with Mohs surgery, more in the range of 94%.[5] It has been used in the removal of melanoma-in-situ (cure rate 77% to 98% depending on surgeon), and certain types of melanoma (cure rate 52%).[6][7] Another study of melanoma-in-situ revealed Mohs cure rate of 95% for frozen section Mohs, and 98 to 99% for fixed tissue Mohs method.[8][9] Other indications for Mohs surgery include dermatofibrosarcoma protuberans, keratoacanthoma, spindle cell tumors, sebaceous carcinomas, microcystic adnexal carcinoma, merkel cell carcinoma, Pagets's disease of the breast, atypical fibroxanthoma, leimyosarcoma, and angiosarcoma.[10] Because the Mohs procedure is micrographically controlled, it provides precise removal of the cancerous tissue, while healthy tissue is spared. Mohs surgery is relatively expensive when compared to other surgical modalities.[11] However, in anatomically important areas (eyelid, nose, lips), tissue sparing and low recurrence rate makes it a procedure of choice by many physicians.
# History
Originally, Dr. Mohs used an escharotic agent made of zinc chloride and bloodroot (the root of the plant Sanguinaria canadensis, which contains the alkaloid sanguinarine). The original ingredients were 40.0 gm Stibnite, 10.0 gm Sanguinaria canadensis, and 34.5 ml of saturated zinc chloride solution.[12] This paste is very similar to "Hoxsey's paste" (see Hoxsey Therapy). Harry Hoxsey, a lay cancer specialist was developing a herbal tonic and paste designed to treat internal and external cancers. Hoxsey recommended applying paste to the affected area and within days to weeks, the area would necrose (cell death), separate from surrounding tissue and fall out. Dr. Mohs applied a very similar paste after experimenting with a number of compounds to the wound of his skin cancer patients. They were to leave the paste on the wound overnight, and the following day, the skin cancer and surrounding skin would be anesthetic, and ready to be removed. The specimen was then excised, and the tissue examined under the microscope. If cancer remained, more paste was applied, and the patient would return the following day. Later, local anesthetic and frozen section histopathology applied to fresh tissue allowed the procedure to be performed the same day, with less tissue destruction, and similar cure rate.[13] The term "chemosurgery" remains today, and is used synonymously with Mohs micrographic surgery.
# Mohs procedure
The Mohs procedure is essentially a pathology sectioning method that allows for the complete examination of the surgical margin. It is different from the standard bread loafing technique of sectioning,[14] where random samples of the surgical margin is examined.[15][16]
Mohs surgery is performed in four steps:
- Surgical removal of tissue (Surgical Oncology)
- Mapping the piece of tissue, freezing and cutting the tissue between 5 and 10 micrometers using a cryostat, and staining with hematoxylin and eosin (H&E) or other stains (including T. Blue)
- Interpretation of microscope slides (Pathology)
- Reconstruction of the surgical defect (Reconstructive Surgery)
The procedure is usually performed in a physician's office under local anesthetic. A small scalpel is utilized to cut around the visible tumor. A very small surgical margin is utilized, usually with 1 to 1.5 mm of "free margin" or uninvolved skin. The amount of free margin removed is much less than the usual 4 to 6 mm required for the standard excision of skin cancers.[17] After each surgical removal of tissue, the specimen is processed, cut on the cryostat and placed on slides, stained with H&E and then read by the Mohs surgeon/pathologist who examines the sections for cancerous cells. If cancer is found, its location is marked on the map (drawing of the tissue) and the surgeon removes the indicated cancerous tissue from the patient. This procedure is repeated until no further cancer is found.
The method is well described in current references.[18][19][20] The mapping combined with the unique "smashing the pie pan" method of processing is the essential of Mohs surgery. If one imagines an aluminum pie pan as the blood covered surgical margin, and the top of the pie is the crust covered surface of the skin - the goal is to flatten the aluminum pie pan into one flat sheet, mark it, stain it, and examine it under the microscope. Another author uses the example of peeling the skin off an orange.[21] Imagine an orange cut in half as the Mohs layer. The peel is the surgical margin. One remove this peel and flatten it out on a glass slide to examine the roots of the invasive cancer. The mapping is simply how one stains and labels the sections for a microscopic examination. The sections can be processed in one piece[22] (using relaxing incisions at multiple points, or hemisectioned like a "Pac-Man" figure),[23] cut in halves, cut in quarters, or cut in multiple pieces. Single piece processing is acceptable for small cancers, and multiple piece sectioning facilitates processing and prevent artifacts. Single piece sectioning prevents errors introduced by soft, hard-to-handle tissue; or from accidental dropping or mislabeling of specimen. Multiple sectioning prevents compression artifacts, separation of tissue, and other logistical problems with handling large thin sheets of frozen skin.
Some physicians believe that frozen section histology is the same as Mohs micrographic surgery, and it is not.[24] Mohs surgery is performed using fresh tissue and frozen section histology. However, standard frozen section histology usually utilizes a random tissue sampling technique called "bread loafing". Bread loafing is a statistical sampling method which exams less than 5% of the total surgical margin (imagine pulling 5 slices of bread out of a whole loaf of sliced bread and examining only those 5 slices to visualize the whole loaf). In Mohs processing, the entire surgical margin is examined (imagine one who examined the entire outside crust of the same loaf of bread). In statistical terms, the more slices of bread one examines, the lower the "false negative" rate will become.[25] False negatives occur when a pathologist reads cancer excision as "free of residual carcinoma", even though cancer might be present in the wound and missed because of the random sampling.[26] In reality, most pathology labs examine only 3 to 8 sections of the "loaf" in their margin determination. While a diligent pathologist can cut and process a standard excision to get the same margin control as Mohs surgery, it is seldom done since tissue processing is very difficult in practice. The alternative to Mohs surgery is when a pathologist requests the processing to be done by "cutting through the block". Again, this method approaches that of Mohs surgery, but still is not as good. Cutting through the block will result in the random discarding of many slices, but does greatly decrease the incidence of "false negative" reports. Dr. Mohs perfected a simple and efficient way to "flatten" and examine the entire surgical margin.
## Staining Convention
Each surgeon has their own convention. A typical convention is as follows[27]
# Differences between histology of transverse sections and vertical sections
Often, for legal purpose, a second opinion will be asked of a pathologist to review pathology slides from Mohs cases. Traditional histology of skin tissue uses vertical sectioning - with the subcutanous tissue at the bottom and the epidermis at the top. Mohs surgery uses tangential or horizontal sectioning, which can confuse the pathologists trained in the traditional method.
First, one has to determine the method of chromacoding or color coding. The orientation of the Mohs map must be able to distinguish between medial, lateral, superior, and inferior.
Next, one has to determine if the surgeon followed the convention of mounting only 2 sections per case; as preferred by some author;[28] or did he/she performed serial sectioning through the block as preferred by some author.[29] If serial sectioning is performed, the distance between sections should be confirmed. Some surgeons utilizes 100 micrometres between each sections, and some utilizes 200 micrometres between the first two sections, and 100 micrometres between subsequent sections (10 crank of tissue set at 6 to 10 micrometre is roughly equal to 100 micrometres if one allow for physical compression due to the blade).
Next, one determine if the entire epidermal border is present. Ideally 100% of the epithelial border should be present. Convention requires at least 95% of the epidermis to be present.[30] However, some surgeon will make an exception for some missing epithelium at the apices of an elliptical excision around the specimen. Ideally, oval sections should be performed. However, for practical purpose on some lesions, a surgeon might cut the Mohs section to approximate the final closure defect. The apexes are often 1 cm or more from the tumor, so clear margins at the apices can be ignored. Not ideal by convention, but appropriate on a case by case basis.
Next, one determine if the surgical margin is clear. With serial sectioning, one has to recreate the surgical specimen in a 3 dimensional way. The first section that touches the blade begin the 3 dimensional reconstruction. By using the 3-D reconstruction of the specimen, one can say that all the epithelial margin is present as one progresses from deep to superficial. If only 2 sections are present, ideally, both the sections should be clear. If the deeper sections is positive, one has to ascertain the distance between the section. Convention often call for a clear margin of at least 200 micrometres. For ambiguous structures that resembles both adnexal structure and carcinoma, following the serial sections will allow for one to identify the structure as benign or malignant. With the 2 slides method, this might be impossible to perform, as no 3-D reconstruction is possible with only 2 sections.
Carcinoma appearance under Mohs micrographic sectioning can be deceptively difficult. Tangential cut of squamous cell can mimic squamous cell carcinoma (but without the atypia). Sections through the buds of hair follicles resembles isolated islands of basal cell cancers, often even with retraction artifact. Serial section analysis is best for Mohs surgery. But one will often find cases where only 2 slides are mounted.[31]
It is best to leave the professional evaluation of Mohs section to an expert. The expert should not only be a pathologist who is familiar with one style of Mohs processing (i.e. 2 section mounting), one should also be familiar with all the sectioning protocols (whole tissue, pacman one piece,[32] double pacman one piece,[33] or multiple sections). Each methods has its limitation, but as long as good quality slides are cut - the end result is the same.
# The Mohs Surgery Team
The team consists of the Mohs surgeon, histotechnician, pathologist and the reconstructive surgeon. The Mohs surgeon identifies the cancer and its margin, often with the aid of dermatoscopy. He removes the cancer under local anesthetic and prepares it for histology processing. This is accomplished by cutting the specimen (if required), staining the specimen for orientation, and sending it to the lab.
The histotechnician prepares the tissue for Mohs processing by flattening the surgical margin on a flat surface first. Then the flat surgical surface is mounted on a cryostat to be sectioned and prepared for glass slides to be read by the pathologist.
The pathologist examine the slide for residual tumors, and marks the location of the tumor on the pathology report and sends it back to the Mohs surgeon. He informs the Mohs surgeon when the surgery has completely removed the cancer.
The reconstructive surgeon does the plastic repair of the surgical defect in a cosmetic manner. Some Mohs surgeons utilize a plastic or reconstructive surgeon to repair the defect. Most Mohs surgeons perform their own surgical repair, except on exceptional cases.
There are some Mohs surgeons who fulfill all 4 roles - Mohs surgeon, histotechnician, pathologist and reconstructive surgeon. Most Mohs surgeons also perform the duty of pathologist and reconstructive surgeon. Regardless of who performs what procedures, any weakness in the link between these 4 individuals can result in a poor cure rate, or bad cosmetic outcome.
# Why is the cure rate so varied?
These are topics for discussion, but errors introduced in the technique can introduce false negative errors. There are numerous reasons why the cure rate is not 100%. Some of Dr. Mohs data revealed a cure rate as low as 96%, but these were often very large tumor, and previously been treated by other modalities. Some authors claim that their 5 year cure rate for primary basal cell cancer exceeded 99% while other noted more conservative cure rate of 97%. The quoted cure rate for Mohs surgery on previously treated basal cell cancer is about 94%.[34]
1. Modern frozen section method. Frozen section histology does not give the added margin of safety by the cytotoxic Mohs paste,[35] originally used by Dr. Mohs. This paste might have destroyed any residual cancer cells not detected by the pathologist.
2. Missing epidermal margins. Ideally, the Mohs section should include 100% of the epidermal margin, but greater than 95% is often accepted.[36] Unfortunately, vigorous scrubbing, poorly controlled initial curettage, poor tissue health, technician's error, and surgeon's error can introduce areas missing epithelial margin. Some surgeon consider 70% epithelial margin acceptable, while other suggests 100% margin. In the ideal situation, 100% of the epithelial margin should be available to be reviewed on serial sectioning of the Mohs specimen.
3. Misreading of the pathology slide. It is difficult to differentiate between a small island of basal cell carcinoma and a hair follicle structure. Many Mohs surgeon limits their tissue processing to include only 2 sections of tissue.[37] This severely hampers their ability to determine if a structure is a hair follicle or a carcinoma. Two histologic sections can not fully distinguish these two nearly identical structures,[38] and can lead to either "false negative" or "false positive" errors by either calling a section clear of tumor, or calling a section positive for tumor, respectively. Serial sectioning of the tumor is preferred by other surgeons.[39] Surgeons who performs serial sectioning through the block of tissue (usually 100 micrometres apart) are assured the contiguous nature of his tumor, the distance of the tumor from the surgical margin, and is familiarized with the nature of the tumor. Serial sectioning also makes it easier to work with three dimensional tumor with difficult to compress margins.
4. Compression artifact, freezing artifact, cautery artifact, tissue folds, crush artifact from forceps, relaxing incision artifact, cartilage dropping out, fat compression, poor staining, dropping of tumor, etc.[40] These can be introduced as the tumor is "flattened". Stain can run from the surgical edge, and stain the surgical margin - giving a false impression that the entire surgical margin is clear, when it is not. While some surgeon unfamiliar with the "whole piece" or "PacMan"[41] methods of processing might suggest that multiple piece sectioning is better than one. The more tissue sections are cut, the more artifacts in staining and tissue malformation will be introduced. It is imperative for the surgeon to be fully familiar with tissue handling and processing; and not simply relying on a trained technologist to perform his sectioning.
5. Hard to see tumor in heavy inflammatory infiltrate.[42] This can occur with squamous cell carcinoma, especially when complicated with local infection, or intrinsic lymphoproliferative disorders (chronic lymphocytic leukemia). Because of abnormal peripheral blood profile, response to inflammatory skin conditions with patients with myelomonocytic leukemia can have appearance of atypical cells at sites of inflammation, confusing the Mohs surgeon.[43]
6. Perineural spread, and benign changes simulating perineural spread. Tumor spreading along a nerve can be difficult to visualize, and sometime benign plasma cells can surround the nerve, simulating cancer.[44]
7. Difficult to cut and process anatomical area.[45] Examples would be the ear, and other three dimensional structures like eyelids. The ability to make a scallop shaped incision is increasingly difficult when the surgical surface is no longer a flat plane, but is a three dimensional rigid structure.
8. Recurrent skin cancer with multiple islands of recurrence. This can occur with either previous excision, or after electrodessication and curettage. As these residual skin cancer are often bound in scar tissue, and present in multiple location in the scar of the previous surgical defect - they are no longer contiguous in nature. Some surgeons advocate the removal of the complete scar in the treatment of "recurrent" skin cancers. Others advocate removing only the island of local recurrence, and leaving the previous surgical scar behind. The decision is often made depending on the location of the tumor, and the goal of the patient and physician.
9. Unreported or underreported recurrence. Many patients simply will not return to the original surgeon to report a recurrence. Consulting surgeon on the repeat surgery will often not inform the first surgeon of the recurrence. The time it takes for a recurrent tumor to be visible to the patient might be 5 or more years. Quoted "cure" rates must be looked upon with the understanding that a 5 year cure rate might not necessary be correct. As basal cell carcinoma is a very slowly progressing tumor, a 5 year no recurrence rate might not be adequate. Longer follow up might be needed to detect a slow growing tumor left in the surgical scar.
10. Poor training of the surgeon/pathologist/histotechnologist. While Mohs surgery is essentially a technical method of tissue handling and processing, the skill and training of the surgeon can greatly affect the outcome. The house of card is built with a foundation of good tissue handling, good surgical skill and hemostasis, and the bricks are the tissue processing and staining technique. A surgeon without a good histotechnologist is a house built with straw, and a histotechnologist without a good surgeon can not produce quality slides. While originally, surgeons learned the procedure by spending a few hours to several months with Dr. Mohs;[46] today, surgeons complete residency and fellowship spending hundreds of hours observing and doing Mohs surgery. It is highly encouraged that a physician interested in learning Mohs surgery should spend extended time observing, cutting, processing, and staining Mohs specimens. The histology block should be correctly mounted and cut the first time, as there is no second chances in Mohs histology. It is not a procedure that can be taught or learn in one weekend. Many residency and Mohs fellowship continue to teach the processing of only 2 Mohs sections per tumor.[47]
Irrespective of the problems associated with Mohs surgery, a true cure rate approaching 100% can occur with primary basal cell carcinoma (previously untreated) if proper respect of the physician's limitation, the procedure's limitation, and his laboratory staff's limitation. Conservative approach such as serial sectioning, good staining technique, and conservative Mohs margin (example: tumor at least 200 micrometre from the surgical margin) can assure the lowest recurrence rate.
# Comparison to other modalities of treatment
It often occurs in medicine as in real life, "When you go to Midas, you get a muffler". Mohs surgery is not the answer for all skin cancers. Studies comparing the effectiveness of Mohs surgery to other modalities often fail to specify surgical margin, method of processing (bread loafing with 3 or 4 sections, bread loafing with 0.1 mm spacing, margin controlled, frozen section vs. standard histology); leaving little argument one way or another. Once a pathologist understands the simplistic nature of Mohs surgery, and its margin control ability - little need is called for clinical trial comparing Mohs surgery to surgical excision.
In reality, Mohs micrographic surgery is nothing more than frozen section histology using a unique peripheral margin control tissue processing technique. There is nothing magical about its cure rate or why years of training is required. When compared to many other described peripheral margin control tissue processing technique - the end result is the same - allowing for the complete examination of 100% of the surgical margin. The method is unique only in that it is a simple way to handle soft, hard to cut tissue. Once learned, any pathologists currently doing frozen section histology would realize how simple the technique is. It is better than doing serial bread loafing at 0.1 mm interval for improved false negative error rate simply in requiring less time, less tissue handling, and fewer glass slides mounted. Once mounted as tangential or horizontal sections, the pathologist simply has to relearn how to visualize skin structure on a tangential to horizontal view. In absent of a Mohs trained pathologist, peripheral sectioning followed by horizontal sectioning of the remaining center is equivalent to the Mohs method.[48][49]
The clinical quotes for cure rate of Mohs surgery is from 97% to 99.8% after 5 years for newly diagnosed basal cell cancer, decreasing to 94% or less for recurrent basal cell cancer. Radiation oncologists quote cure rate from 90 to 95% for BCC's less than 1 or 2 cm, and 85 to 90% for BCC's larger than 1 or 2 cm. Surgical excision cure rate varies from 99% for wide margin (4 to 6 mm) and small tumor, to as low as 70% for narrow margins applied to large tumors. Here the weakness of the procedure is the histopathological processing, and not the surgeon himself. The fault of the surgeon is lack of understanding pathology laboratory methods, and failing to follow the standard of care for adequate surgical margin. Usually the cure rate using standard bread loafing is very low for narrow surgical margin and a large tumor, and very high for large margins on small tumors.[50][51][52] It is the pathology lab that makes the difference, especially when frozen section is utilized in the operating theater. A randomized study assigning patients with recurrent facial basal cell cancer to either Mohs surgery or standard excision revealed no statistical difference in the treatment of primary basal cell carcinoma. It found a higher cure rate with Mohs surgery in the treatment of recurrent basal cell carcinoma (5 year recurrence rate of 2.4% for Mohs vs 12.1% for standard).[53]
Cosmetic appearance for Mohs surgery is very good, if combined with good reconstructive surgical skills. Some Mohs surgeon utilize a plastic or reconstructive surgeon for the closure, and some Mohs surgeon perform the reconstruction by himself. There are dermatologists who are great reconstructive surgeons, and plastic surgeons who are poor reconstructive surgeons. In certain area, the tip of the nose, and the nasal ala, Mohs surgery can result in significant deformity, and might require multiple staged reconstruction to rebuild the nose cosmetically. Radiation offers a very good non-traumatic option in these difficult to reconstruct areas.
In choosing a Mohs surgeon or reconstructive surgeon, it is mandatory that a patient request to see pictorial representation of his/her previous work. Then one can proceed to make a decision whether the Mohs surgeon should also be the reconstructive surgeon.
# Controversy About Mohs Surgery
Few individuals argue about the cure rate for Mohs, especially pathologists familiar with the procedure.[54] However, in recent years, a few surgeons attempted to throw the baby out with the bath water by claiming that Mohs surgery is no better than standard excision based on one study.[55][56] The author in this study did not conclude the adequacy of the study as it is limited in size and short duration of the study (30 months). Extensive studies performed by Dr. Mohs involving thousands of patients with both fixed tissue and fresh tissue cases have been reported in the literature.[57] Other surgeons repeated the studies with also thousands of cases, with nearly the same results.[58]
Clinical 5 year cure rates with Mohs surgery: 1. 4085 cases of primary and recurrent cancer of face, scalp, and neck. Cure rate of 96.6%.[59] 2. 1065 cases of squamous cell carcinoma of face, scalp, and neck - cure rate 94.8%[60] 3. 2075 cases of basal cell cancer of the nose both primary and recurrent, cure rate 99.1%.[61] 4. Cure rate for basal cell cancer of the ear, less than 1 cm, 124 cases, cure rate 100%.[62] 5. Cure rate of basal cell cancer of the ear, 1 to 2 cm, 170 cases, 100%. One needs to keep in mind that the cases performed by Dr. Mohs were for large and extensive tumors, often treated numerous times before by other surgeons. Regardless, his cure rate for small primary tumors either were 100% or near 100% when separated out from larger or recurrent tumors.
Experienced Mohs surgeons have reported cure rates for melanoma-in-situ from 95% to 98% (depending on if it is small MIS, or lentigo maligna variant), much higher than previously reported by Dr. Mikhail of 77%.[63]
These are only a small number of cases reported by Dr. Mohs, and numerous other articles by other authors have shown tremendous cure rates for primary basal cell carcinoma. However, with studies by Smeet, et al. showing a Mohs cure rate of about 95%, and another study in Sweden showing Mohs cure rate of about 94%;[64] we really have to question if methodology practiced by Mohs surgeons around the world is of the same standard. We also will have to question if the standard 2 sections performed by some Mohs surgeons is adequate to control for false negative Mohs reports.
# Where Mohs surgery is allowed
An example where clinical guidelines are issued by insurance companies; these guidelines are not indication that Mohs is the best method for the cancers described. These guidelines are subjective (why is younger than 40 years old a criterion?), and might not have any clear objective basis. Clinical guidelines currently adapted by Medicare insurance of the United States:[65]
Medicare will cover reimbursement for Mohs micrographic surgery for accepted diagnoses and indications as listed below.
1. Basal Cell, Squamous Cell, or Basalosquamous Cell Carcinomas in anatomic locations where they are prone to recur:
- Central facial areas, periauricular, nose, and temple areas of the face (the so-called "mask area" of the face)
- Lips, cutaneous and vermilion
- Eyelids and periorbital areas
- Auricular helix and canal
- Chin and mandible
2. Other Skin lesions:
-Angiosarcoma of the skin
-Keratoacanthoma, recurrent
-Dermatofibrosarcoma protuberans
-Malignant fibrous histiocytoma
-Sebaceous gland carcinoma
-Microcystic adnexal carcinoma
-Extramammary Paget's disease
-Bowenoid papulosis
-Merkel cell carcinoma
-Bowen's disease (squamous cell carcinoma in situ)
-Adenoid type of squamous cell carcinoma
-Rapid growth in a squamous cell carcinoma
-Longstanding duration of a squamous cell carcinoma
-Verrucous carcinoma
-Atypical Fibroxanthoma
-Leiomyosarcoma or other spindle cell neoplasms of the skin
-Adenocystic carcinoma of the skin
-Erythroplasia of Queryrat
-Oral and central facial, paranasal sinus neoplasm
-Apocrine carcinoma of the skin
-Malignant melanoma (facial, auricular, genital and digital) when anatomical or technical -difficulties do not allow conventional excision with appropriate margins.
-Basal Cell carcinomas, squamous cell carcinomas, or basalosquamous carcinomas that have one or more of the following features:
- o Recurrent
- o Aggressive pathology in the following areas: Hands and feet, Genitalia, and Nail unit/periungual
- o Large size (2.0 cm or greater)
- o Positive margins on recent excision
- o Poorly defined borders
- o In the very young (<40 years age)
- o Radiation-induced
- o In patients with proven difficulty with skin cancers or who are immunocompromised
- o Basal cell nevus syndrome
- o In an old scar (e.g., a Marjolin's ulcer)
- o Associated with xeroderma pigmentosum
- o Perineural invasion on biopsy
- o Deeply infiltrating lesion or difficulty estimating depth of lesion
3. Laryngeal Carcinoma
# Future applications of Mohs surgery
Mohs surgery can be applied to any relatively non-aggressive locally invasive tumors with contiguous growth pattern (i.e. no skipped growth, or metastasis). Today, most Mohs procedures are performed by dermatologists. However, pathologists, plastic surgeons, and otolaryngologists[66] have been trained and are ulitizing Mohs surgery in their practice as well. Hopefully, as more physicians are trained in the method, Mohs surgery can be applied to other organs systems beside the skin. The limitation of this application to other tumors (i.e. prostate cancer, cervical cancer, laryngeal cancer) is that the tumor must be in the earliest stages and no metastasis has occur. The second problem with Mohs surgery is the prolonged procedural time, which might require prolonged general anesthesia.
Currently, the American College of Mohs Surgery has limited training to physicians who have done a dermatology residency.[67] The American Society for Mohs Surgery continues to encourage the training of physicians of all specialties to learn and apply the method invented by Dr. Frederick Mohs. The argument against physicians of other specialties than dermatology gaining Mohs training is that they are not adequately trained in dermatopathology. The argument for training other physicians beside dermatologists is that most Mohs surgeon do not make the initial diagnosis of the skin cancer - thus misdiagnosis can be avoided. The pathology of Mohs sections are then limited to a few easily identifiable cancers; and the pathology of normal skin is simple enough to gain in a short preceptorship; even if you are not a dermatologist or a pathologist.
Dr. Mohs, a general surgeon, encouraged physicians of all surgical specialties to learn and apply his technique to the treatment of skin cancer; it is understood that he never intended to limit his method to be utilized by dermatologists alone. In countries where dermatology is not well developed, the Mohs procedure can easily be learned by any surgeon or pathologist after a short preceptorship - the same way Dr. Mohs taught many current Mohs surgeons.
This is a direct quote of Dr. Frederick Mohs in his book's preface:
"The book should be useful to physicians who may be called on to treat or advise regarding treatment of skin cancers and other conditions that are described. This includes dermatologists, surgeons, plastic surgeons, otolaryngologists, gynecologists, urologists, proctologists, pathologists, internists, and general practitioners."
From: Frederic E. Mohs, B.Sc., M.D. Clinical Professor of Surgery, University of Wisconsin. CHEMOSURGERY, Microscopically Controlled Surgery For Skin Cancer, Charles C. Thomas, Publisher, 1956. p. vii.
# Associations
The American College of Mohs Surgery is the organization that sets standards of care for fellowship trained Mohs surgeons who perform Mohs surgery as a primary function of their practice.
The American Society of Mohs Surgery is an organization of dermatologists who perform dermatology and Mohs surgery in their practice. ASMS Mohs surgeons are certified by a written and practical exam, and are required to submit to yearly peer review of their cases.
The American Board of Medical Subspecialities is in the process of reviewing Mohs micrographic surgery as a separate subspecialty. Mohs surgery has not been recognized as a separate subspeciality and there is no certifying board for Mohs Surgery at this time.
The American Academy of Dermatology is the largest organization of board certified dermatologists, many of whom perform dermatologic and Mohs micrographic surgery. With a membership of over 15,000, it represents virtually all practicing dermatologists in the United States and Canada and has specific member information regarding those performing Mohs micrographic surgery.
The American Osteopathic College of Dermatology is the only organization that recognized Mohs surgery as a separate subspecialty. The organization offers board certification exam through the auspice of the American Osteopathic Association. The recipient of the board certification receives a certificate of added qualification (CAQ) to the primary board certification of dermatology. Currently American Osteopathic College of Dermatology is the only organization offer this credential to mohs surgeons.[68]
The American Society for Dermatologic Surgery founded in 1970 is the largest organization of board certified dermasurgeons with over 5000 members who perform dermatologic surgeries including Mohs micrographic surgery.
The Association of Academic Dermatologic Surgeons has board certified dermasurgeon professors who have faculty appointments at major teaching hospitals and universities and are engaged in training medical students and residents in the practice of dermatologic surgery and Mohs micrographic surgery.
# Mohs Surgery Case Studies
Photos courtesy of Dr. B. Cowan
CASE STUDY 1: Left Nasal Rim Skin Cancer
Click to view complete slide-show and the surgeon's comments for the Left Nasal Rim Skin Cancer case study
CASE STUDY 2: Right Lower Lip Skin Cancer
Click to view complete slide-show and the surgeon's comments for the Right Lower Lip Skin Cancer case study
CASE STUDY 3: Left Temple Basal Cell Cancer
Click to view complete slide-show and the surgeon's comments for the Left Temple Basal Cell Cancer case study | https://www.wikidoc.org/index.php/Chemosurgery | |
e59c6d9bc87b3fba62f8c262b8f3348c21586448 | wikidoc | Chevron plot | Chevron plot
A chevron plot is a way of representing protein folding kinetic data in the presence of varying concentrations of denaturant that disrupts the protein's native tertiary structure. The plot is known as "chevron" plot because of the canonical v, or chevron shape observed when the logarithm of the observed relaxation rate is plotted as a function of the denaturant concentration. In a two-state system, folding and unfolding rates dominate the observed relaxation rates below and above the denaturation midpoint (Cm). This gives rise to the terminology of folding and unfolding arms for the limbs of the chevron. Apriori information on the Cm of a protein can be obtained from equilibrium experiments. In fitting to a two-state model, the logarithm of the folding and unfolding rates are assumed to depend linearly on the denaturant concentration, thus resulting in the slopes mf and mu, called the folding and unfolding m-values, respectively (also called the kinetic m-values). The sum of the two rates is the observed relaxation rate. An agreement between equilibrium m-value and the absolute sum of the kinetic m-values is typically seen as a signature for two-state behavior. Most of the reported denaturation experiments have been carried out at 298 K with either urea or guanidinium chloride (GuHCl) as denaturants.
# Experimental methodology
To generate the folding limb of the chevron, the protein in a highly concentrated denaturant solution is diluted rapidly (in less than a millisecond) in an appropriate buffer to a particular denaturant concentration by means of a stopped flow apparatus. The relaxation to the new equilibrium is monitored by spectroscopic probes such as fluorescence or less frequently by circular dichroism (CD). The volume of the dilution is adjusted to obtain the relaxation rate at a specific denaturant concentration. The final protein concentration in the mixture is usually 1-20 uM, depending on the constraints imposed by the amplitude of relaxation and the signal-to-noise ratio. The unfolding limb is generated in a similar fashion by mixing denaturant-free protein with a concentrated denaturant solution in buffer. When the logarithm of these relaxation rates are plotted as a function of the final denaturant concentration, a chevron plot results.
The mixing of the solutions determines the dead-time of the instrument, which is about a millisecond. Therefore, a stopped-flow apparatus can be employed only for proteins which have a relaxation time of the order of a few milliseconds. In cases where the relaxation time is smaller than the dead-time of the instrument, the experimental temperature is lowered (thus increasing the viscosity of water/buffer) to increase the relaxation time to a few milliseconds. On the other hand, for fast-folding proteins (i.e., those which have a relaxation rate of the order of 1-100 microseconds), temperature-jump (T-jump; dead time~few nanoseconds) or continuous flow mixing (dead time~few microseconds), can be carried out at different denaturant concentrations to obtain a chevron plot.
# Chevron roll-overs
Though the limbs of the chevron are assumed to be linear with denaturant concentration, it is not always the case. Non-linearities are usually observed in the either both the limbs or one of them and are termed chevron roll-overs. The reason for such an observation is not clear. Many interpretations including on-pathway intermediates, dead-time limitations, transition state movements (Hammond effect), aggregation artifacts, downhill folding, and salt-induced Debye-Huckel effects have been proposed to explain this behavior. In many cases the folding limb roll-overs are ignored as they occur at low denaturant concentrations, and the data is fit to a two-state model with a linear dependence of the rates. The folding rates reported for such proteins in the absence of denaturants are therefore an over-estimation. | Chevron plot
A chevron plot is a way of representing protein folding kinetic data in the presence of varying concentrations of denaturant that disrupts the protein's native tertiary structure. The plot is known as "chevron" plot because of the canonical v, or chevron shape observed when the logarithm of the observed relaxation rate is plotted as a function of the denaturant concentration. In a two-state system, folding and unfolding rates dominate the observed relaxation rates below and above the denaturation midpoint (Cm). This gives rise to the terminology of folding and unfolding arms for the limbs of the chevron. Apriori information on the Cm of a protein can be obtained from equilibrium experiments. In fitting to a two-state model, the logarithm of the folding and unfolding rates are assumed to depend linearly on the denaturant concentration, thus resulting in the slopes mf and mu, called the folding and unfolding m-values, respectively (also called the kinetic m-values). The sum of the two rates is the observed relaxation rate. An agreement between equilibrium m-value and the absolute sum of the kinetic m-values is typically seen as a signature for two-state behavior. Most of the reported denaturation experiments have been carried out at 298 K with either urea or guanidinium chloride (GuHCl) as denaturants.
# Experimental methodology
To generate the folding limb of the chevron, the protein in a highly concentrated denaturant solution is diluted rapidly (in less than a millisecond) in an appropriate buffer to a particular denaturant concentration by means of a stopped flow apparatus. The relaxation to the new equilibrium is monitored by spectroscopic probes such as fluorescence or less frequently by circular dichroism (CD). The volume of the dilution is adjusted to obtain the relaxation rate at a specific denaturant concentration. The final protein concentration in the mixture is usually 1-20 uM, depending on the constraints imposed by the amplitude of relaxation and the signal-to-noise ratio. The unfolding limb is generated in a similar fashion by mixing denaturant-free protein with a concentrated denaturant solution in buffer. When the logarithm of these relaxation rates are plotted as a function of the final denaturant concentration, a chevron plot results.
The mixing of the solutions determines the dead-time of the instrument, which is about a millisecond. Therefore, a stopped-flow apparatus can be employed only for proteins which have a relaxation time of the order of a few milliseconds. In cases where the relaxation time is smaller than the dead-time of the instrument, the experimental temperature is lowered (thus increasing the viscosity of water/buffer) to increase the relaxation time to a few milliseconds. On the other hand, for fast-folding proteins (i.e., those which have a relaxation rate of the order of 1-100 microseconds), temperature-jump (T-jump; dead time~few nanoseconds) or continuous flow mixing (dead time~few microseconds),[1] can be carried out at different denaturant concentrations to obtain a chevron plot.
# Chevron roll-overs
Though the limbs of the chevron are assumed to be linear with denaturant concentration, it is not always the case. Non-linearities are usually observed in the either both the limbs or one of them and are termed chevron roll-overs. The reason for such an observation is not clear. Many interpretations including on-pathway intermediates,[2] dead-time limitations, transition state movements (Hammond effect),[3] aggregation artifacts,[4] downhill folding,[5] and salt-induced Debye-Huckel effects[6] have been proposed to explain this behavior. In many cases the folding limb roll-overs are ignored as they occur at low denaturant concentrations, and the data is fit to a two-state model with a linear dependence of the rates. The folding rates reported for such proteins in the absence of denaturants are therefore an over-estimation. | https://www.wikidoc.org/index.php/Chevron_plot | |
309caafe5ba2858813ef1896540d4e3bfb33181e | wikidoc | Chili pepper | Chili pepper
The chili pepper, or more simply just "chili", is the fruit of the plants from the Genus Capsicum and the nightshade family, Solanaceae.
The name, which is spelled differently in many regions (chili, chile or chilli), comes from Nahuatl via the Spanish word chile. The term chili in most of the world refers exclusively to the smaller, hot types of capsicum. The mild larger types are called bell pepper in the USA, simply pepper in Britain and Ireland, capsicum in India and Australasia and paprika in many European countries.
Chili peppers and their various cultivars originate in the Americas; they are now grown around the world because they are widely used as spices or vegetables in cuisine, and as medicine.
# History
Chili peppers have been a part of the human diet in the Americas since at least 7500 BC and perhaps earlier. There is archaeological evidence at sites located in southwestern Ecuador that chili peppers were already well domesticated more than 6000 years ago , and is one of the first cultivated crops in the Americas.
Chili peppers are thought to have been domesticated at least five times by prehistoric peoples in different parts of South and North America, from Peru in the south to Mexico in the north and parts of Colorado and New Mexico (Ancient Pueblo Peoples).
In the publication Svensk Botanisk Tidskrift (1995), Professor Hakon Hjelmqvist published an article on pre-Columbian chili peppers in Europe. In an archaeological dig in the block of St. Botulf in Lund, archaeologists claimed to have found a Capsicum frutescens in a layer dating to the 13th century. Hjelmqvist also claims that Capsicum was described by the Greek Therophrasteus (370-286 BC). He also mentions other antique sources. The Roman poet Martialis (around the 1st century) described "Pipervee crudum" (raw pepper) to be long and containing seeds. The description of the plants does not fit pepper (Piper nigrum), which does not grow well in European climates.
Christopher Columbus was one of the first Europeans to encounter them (in the Caribbean), and called them "peppers" because of their similarity in taste (though not in appearance) with the Old World peppers of the Piper genus. Columbus was keen to propose that he had in fact opened a new direct nautical route to Asia, contrary to reality and the expert consensus of the time, and it has been speculated that he was therefore inclined to denote these new substances as "pepper" in order to associate them with the known Asian spice.
Chilis were cultivated around the globe after Columbus' time. Diego Álvarez Chanca, a physician on Columbus' second voyage to the West Indies in 1493, brought the first chili peppers to Spain, and first wrote about their medicinal effects in 1494.
From Mexico, at the time the Spanish colony that controlled commerce with Asia, chili peppers spread rapidly into the Philippines and then to India, China, Korea and Japan with the aid of European sailors. The new spice was quickly incorporated into the local cuisines.
An alternate sequence for chili peppers' spread has the Portuguese picking up the pepper from Spain, and thence to India, as described by Lizzie Collingham in her book Curry. The evidence provided is that the chili pepper figures heavily in the cuisine of the Goan region of India, which was the site of a Portuguese colony (e.g. Vindaloo, an Indian interpretation of a Portuguese dish). Collingham also describes the journey of chili peppers from India, through Central Asia and Turkey, to Hungary, where it became the national spice in the form of paprika.
Currently India is the largest producer of Chillies with around one million tons per year, where the Guntur-Market (largest in Asia) alone processes one million bags(100lb each) .
# Species and cultivars
The most common species of chili peppers are:
- Capsicum annuum, which includes many common varieties such as bell peppers, paprika, cayenne, jalapeños, and the chiltepin
- Capsicum frutescens, which includes the tabasco peppers
- Capsicum chinense, which includes the hottest peppers such as the naga, habanero and Scotch bonnet
- Capsicum pubescens, which includes the South American rocoto peppers
- Capsicum baccatum, which includes the South American aji peppers
Though there are only a few commonly used species, there are many cultivars and methods of preparing chili peppers that have different common names for culinary use. Bell peppers, for example, are the same cultivar of C. annuum; immature peppers being green and mature peppers being red. In the same species are the jalapeño, the poblano (when dried is referred to as ancho), New Mexico (which is also known as chile colorado), Anaheim, Serrano, and other cultivars.
Jamaicans, Scotch bonnets, and habaneros are common varieties of C. chinense.
The species C. frutescens appears as chiles de árbol, aji, pequin, tabasco, cherry peppers, malagueta and others.
Peppers are commonly broken down into three groupings: bell peppers, sweet peppers, and hot peppers. Most popular pepper varieties are seen as falling into one of these categories or as a cross between them.
# Intensity
The substances that gives chili peppers their intensity when ingested or applied topically are capsaicin (8-methyl-N-vanillyl-6-nonenamide) and several related chemicals, collectively called capsaicinoids. Capsaicin is the primary ingredient in pepper spray.
When consumed, capsaicinoids bind with pain receptors in the mouth and throat that are normally responsible for sensing heat. Once activated by the capsaicinoids, these receptors send a message to the brain that the person has consumed something hot. The brain responds to the burning sensation by raising the heart rate, increasing perspiration and releasing the body's natural painkilling chemical, endorphin.
The "heat" of chili peppers is measured in Scoville units (SHU). Bell peppers rank at 0 (SHU), New Mexico green chilis at about 1,500 SHU, jalapeños at 3,000–6,000 SHU, and habaneros at 300,000 SHU. The record for the hottest chili pepper was assigned by the Guinness Book of Records to the Naga Jolokia, measuring over 1,000,000 SHU. Pure capsaicin, which is a hydrophobic, colorless, odorless, crystalline to waxy solid at room temperature, measures 16,000,000 SHU.
# Culinary use
The chili has a long association with Mexican cuisine as later adapted into Tex-Mex cuisine. Although unknown in Asia until Europeans introduced it there, chili has also become a part of the Korean, Indian, Indonesian, Szechuan, Thai and other cooking traditions. Its popularity has seen it adopted into many cuisines of the World.
### Chili fruit
The fruit is eaten raw or cooked for its fiery hot flavour which is concentrated along the top of the pod. The stem end of the pod has glands which produce the capsaicin, which then flows down through the pod. The white pith, that surrounds the seeds, contains the highest concentrations of capsaicin. Removing the seeds and inner membranes is thus effective at reducing the heat of a pod.
Chili is often sold worldwide as a spice in dried and powdered form. In the United States, it is often made from the Mexican chile ancho variety, but with small amounts of cayenne added for heat. In the Southwest United States, dried ground chili peppers, cumin, garlic and oregano is often known as chili powder. Chipotles are dry, smoked red (ripe) jalapeños.
Chili peppers are also often used around the world to make a wide variety of sauces, known as hot sauce, chili sauce, or pepper sauce. There are countless recipes.
Indian cooking has multiple uses for chilies, from snacks like bajji where the chilies are dipped in batter and fried to the infamously hot vindaloo. Chilies are also dried and roasted and salted for later use as a side dish for rice varieties like vadam (a kind of pappad). In Turkish or Ottoman cuisine, chilies are widely used where it is known as Kırmızı Biber (Red Pepper) or Acı Biber (Hot Pepper). Sambal is dipping sauce made from chili peppers with many other ingredients such as garlic, onion, shallots, salt, vinegar and sugar, which is very popular in Indonesia, Malaysia and Singapore. Chili powder is an important spice in Persian cuisine and is used moderately in a variety of dishes.
### Chili leaves
The leaves of the chili pepper plant, which are mildly bitter, are cooked as greens in Filipino cuisine, where they are called dahon ng sili (literally "chili leaves"). They are often used in the chicken soup dish known as tinola. In Korean cuisine, the leaves are also used to produce kimchi (풋고추잎 깍두기).
# Decoration
There are entire breeds of chili pepper which are not intended for consumption at all, but are grown only for their decorative qualities, generally referred to as "ornamental peppers". Some of them are too hot for most common cooking techniques, or simply don't taste good. Some are grown for both decoration and food. Either way, they tend to have peppers of unusual shapes or colors. Examples of these include Thai Ornamental, Black Pearl, Marble, Numex Twilight, and the Medusa pepper. Numex Twilight is a green plant which produces fruit starting purple, then ripening to yellow, orange, and red. Black Pearl has black leaves and round red fruit. In India, the chili, along with lime is used to ward off evil spirits and is often seen in vehicles and in homes to that effect. It is also used to check the evil eye and remove its effects in Hinduism as people will also be asked to spit into a handful of chilies kept in that plate, which are then thrown into fire. If the chilies make a noise - as they should - then there is no case of "drishti" (evil eye); if on the other hand they don't make any sound, then the spell of the evil eye is removed in the fire.
# Popularity
Chili peppers are popular in food. They are rich in vitamin C and are believed to have many beneficial effects on health. Psychologist Paul Rozin suggests that eating chilis is an example of a "constrained risk" like riding a roller coaster, in which extreme sensations like pain and fear can be enjoyed because individuals know that these sensations are not actually harmful.
Birds do not have the same sensitivity to capsaicin as mammals, as capsaicin acts on a specific nerve receptor in mammals, and avian nervous systems are rather different. Chili peppers are in fact a favorite food of many birds living in the chili peppers' natural range. The flesh of the peppers provides the birds with a nutritious meal rich in vitamin C. In return, the seeds of the peppers are distributed by the birds, as they drop the seeds while eating the pods or the seeds pass through the digestive tract unharmed. This relationship is theorized to have promoted the evolution of the protective capsaicin.
# Spelling and usage
The three primary spellings are chili, chile and chilli, all of which are recognized by dictionaries.
- Chili is widely used, but this spelling is discouraged by some, since it is more commonly used to refer to a popular Southwestern-American dish (also known as chili con carne (literally chili with meat), the official state dish of Texas), as well as to the mixture of cumin and other spices (chili powder) used to flavor it. Chili powder and chile powder, on the other hand, can both refer to dried, ground chili peppers.
- Chile is the American spelling (uncommon elsewhere) which refers specifically to this plant and its fruit. This orthography is common in much of the Spanish-speaking world, although in much of South America the plant and its fruit are better known as ají and locoto or rocoto. In the American southwest (particularly northern New Mexico), chile also denotes a thick, spicy, un-vinegared sauce, which is available in red and green varieties and which is often served over most New Mexican cuisine.
- Chilli was the original Romanization of the Aztec word for the fruit and is the preferred spelling according to the Oxford English Dictionary, although it also lists chile and chili as variants.
The name of this plant bears no relation to Chile, the country, which is named after the Quechua chin ("cold"), tchili ("snow"), or chilli ("where the land ends"). Chile is one of the Spanish-speaking countries where chilis are known as ají, a word of Taíno origin.
There is some disagreement about whether it is proper to use the word "pepper" when discussing chili peppers because "pepper" originally referred to the genus Piper, not Capsicum. Despite this dispute, a sense of pepper referring to Capsicum is supported by English dictionaries, including the Oxford English Dictionary (sense 2b of pepper) and Merriam-Webster. Furthermore, the word "pepper" is commonly used in the botanical and culinary fields in the names of different types of chili peppers.
# Nutritional value
Red chilis contain some amounts of vitamin C and provitamin A. Yellow and especially green chilis (which are essentially unripe fruit) contain a considerably lower amount of both substances. In addition, peppers are a good source of most B vitamins, and vitamin B6 in particular. They are very high in potassium and high in magnesium and iron. Their high vitamin C content can also substantially increase the uptake of non-heme iron from other ingredients in a meal, such as beans and grains.
# Possible health benefits
All chili peppers contain phytochemicals known collectively as capsaicinoids.
- Capsaicins have been shown, in laboratory settings, to shrink cancerous tumors in rats with minimal side-effects.
- Recent research in mice shows that chilli (capsaicin in particular) may offer some hope of weight loss for people suffering from obesity.
- Canadian researchers used capsaicin from chillies to kill nerve cells in the pancreases of mice with Type 1 diabetes, thus allowing the insulin producing cells to start producing insulin again.
- Research in humans found that "after adding chili to the diet, the LDL, or bad cholesterol, actually resisted oxidation for a longer period of time, (delaying) the development of a major risk for cardiovascular disease".
- Australian researchers at the University of Tasmania found that the amount of insulin required to lower blood sugar after a meal is reduced if the meal contains chili pepper.
- Chilli peppers are being probed as a treatment for alleviating chronic pain.
- Spices, including chilli, are theorized to control the microbial contamination levels of food in countries with minimal or no refrigeration.
- Hot peppers can provide symptomatic relief from rhinitis and possibly bronchitis by thinning and clearing mucus from stuffed noses or congested lungs.
# Precautions
- Chronic ingestion of chilli products may induce gastroesophageal reflux (GER).
- Chilli may increase the number of daily bowel movements and lower pain thresholds for people with irritable bowel syndrome.
- A high consumption of chilli is associated with stomach cancer.
- Chillis should never be swallowed whole; there are cases where unchewed chillis have caused bowel obstruction and perforation.
- Consumption of red chillies after anal fissure surgery should be forbidden to avoid postoperative symptoms.
- Chillis may sometimes be adulterated with Sudan I, II, III IIV, para-Red, and other illegal dyes.
- Aflatoxins and N-nitroso compounds, which are carcinogenic, are frequently found in chilli powder. | Chili pepper
The chili pepper, or more simply just "chili", is the fruit of the plants from the Genus Capsicum and the nightshade family, Solanaceae.
The name, which is spelled differently in many regions (chili, chile or chilli), comes from Nahuatl via the Spanish word chile. The term chili in most of the world refers exclusively to the smaller, hot types of capsicum. The mild larger types are called bell pepper in the USA, simply pepper in Britain and Ireland, capsicum in India and Australasia and paprika in many European countries.
Chili peppers and their various cultivars originate in the Americas; they are now grown around the world because they are widely used as spices or vegetables in cuisine, and as medicine.
# History
Chili peppers have been a part of the human diet in the Americas since at least 7500 BC and perhaps earlier. There is archaeological evidence at sites located in southwestern Ecuador that chili peppers were already well domesticated more than 6000 years ago [1][2], and is one of the first cultivated crops in the Americas.
Chili peppers are thought to have been domesticated at least five times by prehistoric peoples in different parts of South and North America, from Peru in the south to Mexico in the north and parts of Colorado and New Mexico (Ancient Pueblo Peoples).[3]
In the publication Svensk Botanisk Tidskrift (1995), Professor Hakon Hjelmqvist published an article on pre-Columbian chili peppers in Europe. In an archaeological dig in the block of St. Botulf in Lund, archaeologists claimed to have found a Capsicum frutescens in a layer dating to the 13th century. Hjelmqvist also claims that Capsicum was described by the Greek Therophrasteus (370-286 BC). He also mentions other antique sources. The Roman poet Martialis (around the 1st century) described "Pipervee crudum" (raw pepper) to be long and containing seeds. The description of the plants does not fit pepper (Piper nigrum), which does not grow well in European climates. [4]
Christopher Columbus was one of the first Europeans to encounter them (in the Caribbean), and called them "peppers" because of their similarity in taste (though not in appearance) with the Old World peppers of the Piper genus. Columbus was keen to propose that he had in fact opened a new direct nautical route to Asia, contrary to reality and the expert consensus of the time, and it has been speculated that he was therefore inclined to denote these new substances as "pepper" in order to associate them with the known Asian spice.[citation needed]
Chilis were cultivated around the globe after Columbus' time.[5] [6] Diego Álvarez Chanca, a physician on Columbus' second voyage to the West Indies in 1493, brought the first chili peppers to Spain, and first wrote about their medicinal effects in 1494.
From Mexico, at the time the Spanish colony that controlled commerce with Asia, chili peppers spread rapidly into the Philippines and then to India, China, Korea and Japan with the aid of European sailors. The new spice was quickly incorporated into the local cuisines.
An alternate sequence for chili peppers' spread has the Portuguese picking up the pepper from Spain, and thence to India, as described by Lizzie Collingham in her book Curry.[7] The evidence provided is that the chili pepper figures heavily in the cuisine of the Goan region of India, which was the site of a Portuguese colony (e.g. Vindaloo, an Indian interpretation of a Portuguese dish). Collingham also describes the journey of chili peppers from India, through Central Asia and Turkey, to Hungary, where it became the national spice in the form of paprika.
Currently India is the largest producer of Chillies with around one million tons per year, where the Guntur-Market (largest in Asia) alone processes one million bags(100lb each) [8].
# Species and cultivars
Template:Seealso
The most common species of chili peppers are:
- Capsicum annuum, which includes many common varieties such as bell peppers, paprika, cayenne, jalapeños, and the chiltepin
- Capsicum frutescens, which includes the tabasco peppers
- Capsicum chinense, which includes the hottest peppers such as the naga, habanero and Scotch bonnet
- Capsicum pubescens, which includes the South American rocoto peppers
- Capsicum baccatum, which includes the South American aji peppers
Though there are only a few commonly used species, there are many cultivars and methods of preparing chili peppers that have different common names for culinary use. Bell peppers, for example, are the same cultivar of C. annuum; immature peppers being green and mature peppers being red. In the same species are the jalapeño, the poblano (when dried is referred to as ancho), New Mexico (which is also known as chile colorado), Anaheim, Serrano, and other cultivars.
Jamaicans, Scotch bonnets, and habaneros are common varieties of C. chinense.
The species C. frutescens appears as chiles de árbol, aji, pequin, tabasco, cherry peppers, malagueta and others.
Peppers are commonly broken down into three groupings: bell peppers, sweet peppers, and hot peppers. Most popular pepper varieties are seen as falling into one of these categories or as a cross between them.
# Intensity
The substances that gives chili peppers their intensity when ingested or applied topically are capsaicin (8-methyl-N-vanillyl-6-nonenamide) and several related chemicals, collectively called capsaicinoids. Capsaicin is the primary ingredient in pepper spray.
When consumed, capsaicinoids bind with pain receptors in the mouth and throat that are normally responsible for sensing heat. Once activated by the capsaicinoids, these receptors send a message to the brain that the person has consumed something hot. The brain responds to the burning sensation by raising the heart rate, increasing perspiration and releasing the body's natural painkilling chemical, endorphin.
The "heat" of chili peppers is measured in Scoville units (SHU). Bell peppers rank at 0 (SHU), New Mexico green chilis at about 1,500 SHU, jalapeños at 3,000–6,000 SHU, and habaneros at 300,000 SHU. The record for the hottest chili pepper was assigned by the Guinness Book of Records to the Naga Jolokia, measuring over 1,000,000 SHU. Pure capsaicin, which is a hydrophobic, colorless, odorless, crystalline to waxy solid at room temperature, measures 16,000,000 SHU.
# Culinary use
The chili has a long association with Mexican cuisine as later adapted into Tex-Mex cuisine. Although unknown in Asia until Europeans introduced it there, chili has also become a part of the Korean, Indian, Indonesian, Szechuan, Thai and other cooking traditions. Its popularity has seen it adopted into many cuisines of the World.
### Chili fruit
The fruit is eaten raw or cooked for its fiery hot flavour which is concentrated along the top of the pod. The stem end of the pod has glands which produce the capsaicin, which then flows down through the pod. The white pith, that surrounds the seeds, contains the highest concentrations of capsaicin. Removing the seeds and inner membranes is thus effective at reducing the heat of a pod.
Chili is often sold worldwide as a spice in dried and powdered form. In the United States, it is often made from the Mexican chile ancho variety, but with small amounts of cayenne added for heat. In the Southwest United States, dried ground chili peppers, cumin, garlic and oregano is often known as chili powder. Chipotles are dry, smoked red (ripe) jalapeños.
Chili peppers are also often used around the world to make a wide variety of sauces, known as hot sauce, chili sauce, or pepper sauce. There are countless recipes.
Indian cooking has multiple uses for chilies, from snacks like bajji where the chilies are dipped in batter and fried to the infamously hot vindaloo. Chilies are also dried and roasted and salted for later use as a side dish for rice varieties like vadam (a kind of pappad). In Turkish or Ottoman cuisine, chilies are widely used where it is known as Kırmızı Biber (Red Pepper) or Acı Biber (Hot Pepper). Sambal is dipping sauce made from chili peppers with many other ingredients such as garlic, onion, shallots, salt, vinegar and sugar, which is very popular in Indonesia, Malaysia and Singapore. Chili powder is an important spice in Persian cuisine and is used moderately in a variety of dishes.
### Chili leaves
The leaves of the chili pepper plant, which are mildly bitter, are cooked as greens in Filipino cuisine, where they are called dahon ng sili (literally "chili leaves"). They are often used in the chicken soup dish known as tinola.[1] In Korean cuisine, the leaves are also used to produce kimchi (풋고추잎 깍두기).[9]
# Decoration
There are entire breeds of chili pepper which are not intended for consumption at all, but are grown only for their decorative qualities, generally referred to as "ornamental peppers". Some of them are too hot for most common cooking techniques, or simply don't taste good. Some are grown for both decoration and food. Either way, they tend to have peppers of unusual shapes or colors. Examples of these include Thai Ornamental, Black Pearl, Marble, Numex Twilight, and the Medusa pepper. Numex Twilight is a green plant which produces fruit starting purple, then ripening to yellow, orange, and red. Black Pearl has black leaves and round red fruit. In India, the chili, along with lime is used to ward off evil spirits and is often seen in vehicles and in homes to that effect. It is also used to check the evil eye and remove its effects in Hinduism as people will also be asked to spit into a handful of chilies kept in that plate, which are then thrown into fire. If the chilies make a noise - as they should - then there is no case of "drishti" (evil eye); if on the other hand they don't make any sound, then the spell of the evil eye is removed in the fire.
# Popularity
Chili peppers are popular in food. They are rich in vitamin C and are believed to have many beneficial effects on health. Psychologist Paul Rozin suggests that eating chilis is an example of a "constrained risk" like riding a roller coaster, in which extreme sensations like pain and fear can be enjoyed because individuals know that these sensations are not actually harmful.[10]
Birds do not have the same sensitivity to capsaicin as mammals, as capsaicin acts on a specific nerve receptor in mammals, and avian nervous systems are rather different. Chili peppers are in fact a favorite food of many birds living in the chili peppers' natural range. The flesh of the peppers provides the birds with a nutritious meal rich in vitamin C. In return, the seeds of the peppers are distributed by the birds, as they drop the seeds while eating the pods or the seeds pass through the digestive tract unharmed. This relationship is theorized to have promoted the evolution of the protective capsaicin.
# Spelling and usage
The three primary spellings are chili, chile and chilli, all of which are recognized by dictionaries.
- Chili is widely used, but this spelling is discouraged by some, since it is more commonly used to refer to a popular Southwestern-American dish (also known as chili con carne (literally chili with meat), the official state dish of Texas[11]), as well as to the mixture of cumin and other spices (chili powder) used to flavor it. Chili powder and chile powder, on the other hand, can both refer to dried, ground chili peppers.
- Chile is the American spelling (uncommon elsewhere) which refers specifically to this plant and its fruit. This orthography is common in much of the Spanish-speaking world, although in much of South America the plant and its fruit are better known as ají and locoto or rocoto. In the American southwest (particularly northern New Mexico), chile also denotes a thick, spicy, un-vinegared sauce, which is available in red and green varieties and which is often served over most New Mexican cuisine.
- Chilli was the original Romanization of the Aztec word for the fruit[12] and is the preferred spelling according to the Oxford English Dictionary, although it also lists chile and chili as variants.
The name of this plant bears no relation to Chile, the country, which is named after the Quechua chin ("cold"), tchili ("snow"), or chilli ("where the land ends"). Chile is one of the Spanish-speaking countries where chilis are known as ají, a word of Taíno origin.
There is some disagreement about whether it is proper to use the word "pepper" when discussing chili peppers because "pepper" originally referred to the genus Piper, not Capsicum. Despite this dispute, a sense of pepper referring to Capsicum is supported by English dictionaries, including the Oxford English Dictionary (sense 2b of pepper) and Merriam-Webster.[13] Furthermore, the word "pepper" is commonly used in the botanical and culinary fields in the names of different types of chili peppers.
# Nutritional value
Red chilis contain some amounts of vitamin C and provitamin A. Yellow and especially green chilis (which are essentially unripe fruit) contain a considerably lower amount of both substances. In addition, peppers are a good source of most B vitamins, and vitamin B6 in particular. They are very high in potassium and high in magnesium and iron. Their high vitamin C content can also substantially increase the uptake of non-heme iron from other ingredients in a meal, such as beans and grains.
# Possible health benefits
All chili peppers contain phytochemicals known collectively as capsaicinoids.
- Capsaicins have been shown, in laboratory settings, to shrink cancerous tumors in rats with minimal side-effects.[14]
- Recent research in mice shows that chilli (capsaicin in particular) may offer some hope of weight loss for people suffering from obesity.[15][16]
- Canadian researchers used capsaicin from chillies to kill nerve cells in the pancreases of mice with Type 1 diabetes, thus allowing the insulin producing cells to start producing insulin again.[17][18]
- Research in humans found that "after adding chili to the diet, the LDL, or bad cholesterol, actually resisted oxidation for a longer period of time, (delaying) the development of a major risk for cardiovascular disease".[19][20]
- Australian researchers at the University of Tasmania found that the amount of insulin required to lower blood sugar after a meal is reduced if the meal contains chili pepper.[21]
- Chilli peppers are being probed as a treatment for alleviating chronic pain.[22][23]
- Spices, including chilli, are theorized to control the microbial contamination levels of food in countries with minimal or no refrigeration.[24]
- Hot peppers can provide symptomatic relief from rhinitis and possibly bronchitis by thinning and clearing mucus from stuffed noses or congested lungs.[citation needed]
# Precautions
- Chronic ingestion of chilli products may induce gastroesophageal reflux (GER).[25]
- Chilli may increase the number of daily bowel movements and lower pain thresholds for people with irritable bowel syndrome.[26]
- A high consumption of chilli is associated with stomach cancer.[27]
- Chillis should never be swallowed whole; there are cases where unchewed chillis have caused bowel obstruction and perforation.[28]
- Consumption of red chillies after anal fissure surgery should be forbidden to avoid postoperative symptoms.[29]
- Chillis may sometimes be adulterated with Sudan I, II, III IIV, para-Red, and other illegal dyes.[30]
- Aflatoxins and N-nitroso compounds, which are carcinogenic, are frequently found in chilli powder.[31][32][33][34][35] | https://www.wikidoc.org/index.php/Chili_pepper | |
8ad9b1e43afb7732b1f87e331213e02b03f30312 | wikidoc | Stereocenter | Stereocenter
# Overview
A stereocenter, or stereogenic centre, is any atom in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer . In organic chemistry this usually refers to a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic chemistry.
A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers, the total number of hypothetically possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers.
The term stereocenter was introduced in 1984 by Mislow and Siegel .
The broad term stereocenter is often confused with that of the narrower set of chirality center. It is important to remember that a compound like 2-butene has two stereocenters forming two possible stereoisomers (cis and trans 2-butene) (and not 4!) and is not considered a meso compound
# Exceptions
Having two chiral centers may give a meso compound which is achiral. Certain configurations may not exist due to steric reasons. Cyclic compounds with chiral centers may not exhibit chirality due to the presence of a two-fold rotation axis. Planar chirality may also provide for chirality without having an actual chiral center present.
# Chiral carbon
A chiral carbon is a carbon atom which is asymmetric. Having a chiral carbon is usually a prerequisite for a molecule to have chirality, though the presence of a chiral carbon does not necessarily make a molecule chiral. A chiral carbon is often denoted by C*.
For the carbon to be chiral, it follows that:
- the carbon atom is sp3-hybridized
- there are four different groups attached to the carbon atom.
Almost any other configuration for the carbon would produce a center of symmetry. For example, an sp or sp2 hybridized molecule would be planar, with a mirror plane. Two identical groups would give a mirror plane bisecting the molecule.
The exceptions, probably due to the form of chirality exhibited (Axial chirality), are hardly ever mentioned in normal-level discussions on strereochemistry and form two groups:
- Allenes which are of the form RR'C=C=CRR'
- Spiranes which have asymmetric rings, which can be identical.
# Other chiral centers
Chirality is not limited to carbon atoms, though carbon atoms are often centers of chirality due to its ubiquity in organic chemistry.
Nitrogen and phosphorus atoms are also tetrahedral. Racemization by Walden inversion may be restricted (such as ammonium or phosphonium cations), or slow. This allows the presence of chirality.
Metal atoms with tetrahedral or octahedral geometries may also be chiral due to having different ligands. For the octahedral case, several chiralities are possible. Having three ligands of two types, the ligands may be lined up along the meridian, giving the mer-isomer, or forming a face — the fac isomer. Having three bidentate ligands of only one type gives a propeller-type structure, with two different enantiomers denoted Λ and Δ. | Stereocenter
# Overview
A stereocenter, or stereogenic centre, is any atom in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer [1]. In organic chemistry this usually refers to a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic chemistry.
A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers, the total number of hypothetically possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers.
The term stereocenter was introduced in 1984 by Mislow and Siegel [2].
The broad term stereocenter is often confused with that of the narrower set of chirality center. It is important to remember that a compound like 2-butene has two stereocenters forming two possible stereoisomers (cis and trans 2-butene) (and not 4!) and is not considered a meso compound [3]
# Exceptions
Having two chiral centers may give a meso compound which is achiral. Certain configurations may not exist due to steric reasons. Cyclic compounds with chiral centers may not exhibit chirality due to the presence of a two-fold rotation axis. Planar chirality may also provide for chirality without having an actual chiral center present.
# Chiral carbon
A chiral carbon is a carbon atom which is asymmetric. Having a chiral carbon is usually a prerequisite for a molecule to have chirality, though the presence of a chiral carbon does not necessarily make a molecule chiral. A chiral carbon is often denoted by C*.
For the carbon to be chiral, it follows that:
- the carbon atom is sp3-hybridized
- there are four different groups attached to the carbon atom.
Almost any other configuration for the carbon would produce a center of symmetry. For example, an sp or sp2 hybridized molecule would be planar, with a mirror plane. Two identical groups would give a mirror plane bisecting the molecule.
The exceptions, probably due to the form of chirality exhibited (Axial chirality), are hardly ever mentioned in normal-level discussions on strereochemistry and form two groups:
- Allenes which are of the form RR'C=C=CRR'
- Spiranes which have asymmetric rings, which can be identical.
# Other chiral centers
Chirality is not limited to carbon atoms, though carbon atoms are often centers of chirality due to its ubiquity in organic chemistry.
Nitrogen and phosphorus atoms are also tetrahedral. Racemization by Walden inversion may be restricted (such as ammonium or phosphonium cations), or slow. This allows the presence of chirality.
Metal atoms with tetrahedral or octahedral geometries may also be chiral due to having different ligands. For the octahedral case, several chiralities are possible. Having three ligands of two types, the ligands may be lined up along the meridian, giving the mer-isomer, or forming a face — the fac isomer. Having three bidentate ligands of only one type gives a propeller-type structure, with two different enantiomers denoted Λ and Δ. | https://www.wikidoc.org/index.php/Chiral_carbon | |
98b4fab7c98e575fb10c323d7099957fb557573e | wikidoc | Chiropractic | Chiropractic
Chiropractic (from Greek chiro- χειρο- "hand-" + praktikós πρακτικός "concerned with action") is a complementary and alternative medicine health care profession that focuses on diagnosis, treatment and prevention of mechanical disorders of the musculoskeletal system and the effects of these disorders on the functions of the nervous system and general health. It emphasizes manual therapy including spinal adjustment and other joint and soft-tissue manipulation. Today, according to the mainstream of the profession, it is based on the premise that spinal joint dysfunction can interfere with the nervous system and result in many different conditions of diminished health. The concept of what was called vertebral subluxation is now adhered to by a small minority and generally relegated to history. The term was defined quite differently by the chiropractic vs the medical professions, and thus incited much misunderstanding. Thus, this alternative form of therapy examines the relationship between structure and function and its impact on neurological mechanisms in both health and disease.
# Education
(See also Chiropractic - Education)
Doctors of Chiropractic usually obtain one of the following equivalent first professional degrees in chiropractic medicine: D.C., D.C.M., B.Chiro or M.Chiro. These programs are taken in specialized, accredited Chiropractic Colleges, some of which are in Universities, and in the US, are post-college, 10 semester (5 academic year) courses, including clinical practice (approx. PGY 1 - taken before receipt of the degree).
# Treatment
(See also Chiropractic - Treatment Methods)
In treating patients, chiropractors may develop a comprehensive treatment plan based on the patient's individual needs. Such a plan may include spinal adjustments, soft tissue therapy, prescription of exercises, and health and lifestyle counseling.
# Historical overview
(See also Chiropractic - History)
Chiropractic was founded in 1895 by D. D. Palmer in the USA, and is practiced in more than 100 countries. Since its inception, chiropractic has been controversial, both within the profession and in the medical and scientific community, particularly regarding the metaphysical approach espoused by its founders and advocated by the small, but vocal minority which historically were known as "straight" chiropractors. This same criticism may have been the catalyst that allowed some within the profession to emphasize primarily a neuromusculoskeletal approach in their educational curriculum, leading them away from the original metaphysical explanations of their predecessors towards more scientific ones.
# Popularity, and utilization
(See also Chiropractic - Economics)
The utilization of chiropractic has increased in popularity. The profession has remained unified with a continuous commitment to clinical care. Chiropractic's greatest contribution to health care may be its patient-physician relationship and hands-on treatment. Patients are usually satisfied with the treatment they received.
# Research, Evidence Based Practice
(See also Chiropractic - Research)
The principles of evidence-based medicine has grown in prominence and have been used to review research studies and generate practice guidelines. The efficacy of chiropractic treatment has not been rigorously proven. Chiropractic care is generally safe when employed skillfully and appropriately. The cost-effectiveness of maintenance chiropractic care is unknown. Vaccination remains controversial within the chiropractic community.
# Scope of practice
(See also Chiropractic - Scope)
Chiropractors are primary-contact health care practitioners who emphasize the conservative management of the neuromusculoskeletal system without the use of medicines or surgery. Although chiropractors have many attributes of primary care providers, chiropractic has more of the attributes of a medical specialty like dentistry. The practice of chiropractic medicine involves a range of diagnostic methods including skeletal imaging, observational and tactile assessments, orthopedic and neurological evaluation, laboratory tests, and specialized tests. A chiropractor may also refer a patient to an appropriate specialist, or co-manage with another health care provider. Common patient management involves:
- spinal manipulation and other manual therapies to the joints and soft tissues
- rehabilitative exercises
- health promotion
- electrical modalities
- conservative and complementary procedures
- lifestyle counseling.
- Nutritional medicine
In Some States, Chiropractic includes:
- Naturopathy, and Homeopathy
Since the profession never desired inclusion of legend drugs or surgery, the laws in the various States were not written to allow medical prescriptions for legend drugs; a 2003 survey of North American chiropractors found that a slight majority favored allowing them to write prescriptions for over-the-counter drugs. A notable exception is the state of Oregon which is considered to have an "expansive" scope of practice of chiropractic, which allows chiropractors to prescribe over-the-counter substances and perform minor surgery. In some locations chiropractors (DCs) and veterinarians (DVMs) with additional training and certification can practice veterinary chiropractic which includes the diagnosis, treatment and rehabilitation of injured animals. However, the official position of the American Chiropractic Association is that applying manipulative techniques to animals does not constitute chiropractic and that veterinary chiropractic is a misnomer.
# Global Distribution
Chiropractic medicine is established in the U.S., Canada, Australia, Switzerland, Great Britain, France, and Scandinavia, and is present to a lesser extent in more than 90 other countries. Similar to other primary contact health providers, chiropractors can specialize in different areas of chiropractic medicine. The most common post-graduate diplomate programs include neurology, sports sciences, clinical sciences, rehabilitation sciences, orthopedics and radiology which generally require 2–3 additional years of additional post graduate study and passing competency examinations. Chiropractors may further specialize in fields such as Chiropractic Orthopedics (DABCO), Chiropractic Radiology (DABCR), and Chiropractic Sports Physician (DABCSP) by completing additional study and passing the specified boards that are separate and distinctly different than medical boards.
# Chiropractic - Positions
The Chiropractic profession, working through its International and national associations has formulated certain positions statements on various controversial and non-controversial topics. Please see Chiropractic - Positions
# Safety
(See also Chiropractic - Safety)
There have been allegations that certain Chiropractic techniques were associated with vertebral artery or carotid dissections / or strokes post-manipulation. Several in depth major meta-surveys have now vindicated Chiropractic from that idea. All evidence now demonstrates clearly that the extremely rare event is statistically the same risk as a patient experiences from seeing a medical general practitioner, suggesting that such patients are seeing primary care providers because of symptoms which present in pre-stroke syndrome and not being damaged in some way by the ministrations of either kind of physician.
# Effectiveness
The effectiveness of chiropractic treatment depends on the medical condition and the type of chiropractic treatment. Opinions differ as to the efficacy of chiropractic treatment; many other medical procedures also lack rigorous proof of effectiveness. Chiropractic care, like all medical treatment, benefits from the placebo response. The efficacy of maintenance care in chiropractic is unknown.
Research has focused on spinal manipulation therapy (SMT) in general, rather than specifically on chiropractic SMT. There is little consensus as to who should administer the SMT, raising concerns by chiropractors that orthodox medical physicians could "steal" SMT procedures from chiropractors; the focus on SMT has also raised concerns that the resulting practice guidelines could limit the scope of chiropractic practice to treating backs and necks. Many controlled clinical studies of SMT are available, but their results disagree, and they are typically of low quality. It is hard to construct a trustworthy placebo for clinical trials of SMT, as experts often disagree whether a proposed placebo actually has no effect. Although a 2008 critical review found that with the possible exception of back pain, chiropractic SMT has not been shown to be effective for any medical condition, and suggested that many guidelines recommend chiropractic care for low back pain because no therapy has been shown to make a real difference, a 2008 supportive review found serious flaws in the critical approach, and found that SMT and mobilization are at least as effective for chronic low back pain as other efficacious and commonly used treatments.
Available evidence covers the following conditions:
- Low back pain. There is continuing conflict of opinion on the efficacy of SMT for nonspecific (i.e., unknown cause) low back pain; methods for formulating treatment guidelines differ significantly between countries, casting some doubt on the guidelines' reliability. A 2007 U.S. guideline weakly recommended SMT as one alternative therapy for spinal low back pain in nonpregnant adults when ordinary treatments fail, whereas the Swedish guideline for low back pain was updated in 2002 to no longer suggest considering SMT for acute low back pain for patients needing additional help, possibly because the guideline's recommendations were based on a high evidence level. A 2008 review found strong evidence that SMT is similar in effect to medical care with exercise, and moderate evidence that SMT is similar to physical therapy and other forms of conventional care. A 2007 literature synthesis found good evidence supporting SMT for low back pain and exercise for chronic low back pain; it also found fair evidence supporting customizable exercise programs for subacute low back pain, and supporting assurance and advice to stay active for subacute and chronic low back pain. Of four systematic reviews published between 2000 and May 2005, only one recommended SMT, and a 2004 Cochrane review () stated that SMT or mobilization is no more or less effective than other standard interventions for back pain.
- Whiplash and other neck pain. There is no overall consensus on manual therapies for neck pain. A 2008 review found evidence that educational videos, mobilization, and exercises appear more beneficial for whiplash than alternatives; that SMT, mobilization, supervised exercise, low-level laser therapy and perhaps acupuncture are more effective for non-whiplash neck pain than alternatives but none of these treatments is clearly superior; and that there is no evidence that any intervention improves prognosis. A 2007 review found that SMT and mobilization are effective for neck pain. Of three systematic reviews of SMT published between 2000 and May 2005, one reached a positive conclusion, and a 2004 Cochrane review () found that SMT and mobilization are beneficial only when combined with exercise, the benefits being pain relief, functional improvement, and global perceived effect for subacute/chronic mechanical neck disorder. A 2005 review found limited evidence supporting SMT for whiplash.
- Headache. A 2006 review found no rigorous evidence supporting SMT or other manual therapies for tension headache. A 2005 review found that the evidence was weak for effectiveness of chiropractic manipulation for tension headache, and that it was probably more effective for tension headache than for migraine. A 2004 review found that SMT may be effective for migraine and tension headache, and SMT and neck exercises may be effective for cervicogenic headache. Two other systematic reviews published between 2000 and May 2005 did not find conclusive evidence in favor of SMT.
- Other. There is a small amount of research into the efficacy of chiropractic treatment for upper limbs, and a lack of higher-quality publications supporting chiropractic management of leg conditions. A 2007 literature synthesis found fair evidence supporting assurance and advice to stay active for sciatica and radicular pain in the leg. There is very weak evidence for chiropractic care for adult scoliosis (curved or rotated spine) and no scientific data for idiopathic adolescent scoliosis. A 2007 systematic review found that few studies of chiropractic care for nonmusculoskeletal conditions are available, and they are typically not of high quality; it also found that the entire clinical encounter of chiropractic care (as opposed to just SMT) provides benefit to patients with asthma, cervicogenic dizziness, and baby colic, and that the evidence from reviews is negative, or too weak to draw conclusions, for a wide variety of other nonmusculoskeletal conditions, including ADHD/learning disabilities, dizzinesss, and vision conditions. Other reviews have found no evidence of benefit for baby colic, bedwetting, fibromyalgia, or menstrual cramps. | Chiropractic
Editor-in-Chief: Dr. Stephen J. Press [1]
Template:Alternative medical systems
Chiropractic (from Greek chiro- χειρο- "hand-" + praktikós πρακτικός "concerned with action") is a complementary and alternative medicine health care profession that focuses on diagnosis, treatment and prevention of mechanical disorders of the musculoskeletal system and the effects of these disorders on the functions of the nervous system and general health. It emphasizes manual therapy including spinal adjustment and other joint and soft-tissue manipulation.[1] Today, according to the mainstream of the profession, it is based on the premise that spinal joint dysfunction can interfere with the nervous system and result in many different conditions of diminished health. The concept of what was called vertebral subluxation is now adhered to by a small minority and generally relegated to history. The term was defined quite differently by the chiropractic vs the medical professions, and thus incited much misunderstanding. Thus, this alternative form of therapy examines the relationship between structure and function and its impact on neurological mechanisms in both health and disease.
# Education
(See also Chiropractic - Education)
Doctors of Chiropractic usually obtain one of the following equivalent first professional degrees in chiropractic medicine: D.C., D.C.M., B.Chiro or M.Chiro.[2][3][4] These programs are taken in specialized, accredited Chiropractic Colleges, some of which are in Universities, and in the US, are post-college, 10 semester (5 academic year) courses, including clinical practice (approx. PGY 1 - taken before receipt of the degree).
# Treatment
(See also Chiropractic - Treatment Methods)
In treating patients, chiropractors may develop a comprehensive treatment plan based on the patient's individual needs. Such a plan may include spinal adjustments, soft tissue therapy, prescription of exercises, and health and lifestyle counseling.[5]
# Historical overview
(See also Chiropractic - History)
Chiropractic was founded in 1895 by D. D. Palmer in the USA, and is practiced in more than 100 countries.[6] Since its inception, chiropractic has been controversial, both within the profession and in the medical and scientific community, particularly regarding the metaphysical approach espoused by its founders and advocated by the small, but vocal minority which historically were known as "straight" chiropractors. [7][8] This same criticism may have been the catalyst that allowed some within the profession to emphasize primarily a neuromusculoskeletal approach in their educational curriculum, leading them away from the original metaphysical explanations of their predecessors towards more scientific ones. [9][10]
# Popularity, and utilization
(See also Chiropractic - Economics)
The utilization of chiropractic has increased in popularity. [11] The profession has remained unified with a continuous commitment to clinical care. Chiropractic's greatest contribution to health care may be its patient-physician relationship and hands-on treatment. Patients are usually satisfied with the treatment they received. [12]
# Research, Evidence Based Practice
(See also Chiropractic - Research)
The principles of evidence-based medicine has grown in prominence and have been used to review research studies and generate practice guidelines.[13] The efficacy of chiropractic treatment has not been rigorously proven.[14] Chiropractic care is generally safe when employed skillfully and appropriately.[15] The cost-effectiveness of maintenance chiropractic care is unknown.[16] Vaccination remains controversial within the chiropractic community. [17]
# Scope of practice
(See also Chiropractic - Scope)
Chiropractors are primary-contact health care practitioners who emphasize the conservative management of the neuromusculoskeletal system without the use of medicines or surgery. [15] Although chiropractors have many attributes of primary care providers, chiropractic has more of the attributes of a medical specialty like dentistry.[18] The practice of chiropractic medicine involves a range of diagnostic methods including skeletal imaging, observational and tactile assessments, orthopedic and neurological evaluation, laboratory tests,[15] and specialized tests.[1] A chiropractor may also refer a patient to an appropriate specialist, or co-manage with another health care provider.[18] Common patient management involves:
- spinal manipulation and other manual therapies to the joints and soft tissues
- rehabilitative exercises
- health promotion
- electrical modalities
- conservative and complementary procedures
- lifestyle counseling.[19]
- Nutritional medicine
In Some States, Chiropractic includes:
- Naturopathy, and Homeopathy
Since the profession never desired inclusion of legend drugs or surgery, the laws in the various States were not written to allow medical prescriptions for legend drugs; a 2003 survey of North American chiropractors found that a slight majority favored allowing them to write prescriptions for over-the-counter drugs.[20] A notable exception is the state of Oregon which is considered to have an "expansive" scope of practice of chiropractic, which allows chiropractors to prescribe over-the-counter substances and perform minor surgery.[21] In some locations chiropractors (DCs) and veterinarians (DVMs) with additional training and certification can practice veterinary chiropractic which includes the diagnosis, treatment and rehabilitation of injured animals.[22][23] However, the official position of the American Chiropractic Association is that applying manipulative techniques to animals does not constitute chiropractic and that veterinary chiropractic is a misnomer.[24]
# Global Distribution
Chiropractic medicine is established in the U.S., Canada, Australia, Switzerland, Great Britain, France, and Scandinavia, and is present to a lesser extent in more than 90 other countries.[25] Similar to other primary contact health providers, chiropractors can specialize in different areas of chiropractic medicine. The most common post-graduate diplomate programs include neurology, sports sciences, clinical sciences, rehabilitation sciences, orthopedics and radiology which generally require 2–3 additional years of additional post graduate study and passing competency examinations.[26] Chiropractors may further specialize in fields such as Chiropractic Orthopedics (DABCO), Chiropractic Radiology (DABCR), and Chiropractic Sports Physician (DABCSP) by completing additional study and passing the specified boards that are separate and distinctly different than medical boards.[27]
# Chiropractic - Positions
The Chiropractic profession, working through its International and national associations has formulated certain positions statements on various controversial and non-controversial topics. Please see Chiropractic - Positions
# Safety
(See also Chiropractic - Safety)
There have been allegations that certain Chiropractic techniques were associated with vertebral artery or carotid dissections / or strokes post-manipulation. Several in depth major meta-surveys have now vindicated Chiropractic from that idea. All evidence now demonstrates clearly that the extremely rare event is statistically the same risk as a patient experiences from seeing a medical general practitioner, suggesting that such patients are seeing primary care providers because of symptoms which present in pre-stroke syndrome and not being damaged in some way by the ministrations of either kind of physician.
# Effectiveness
The effectiveness of chiropractic treatment depends on the medical condition and the type of chiropractic treatment. Opinions differ as to the efficacy of chiropractic treatment; many other medical procedures also lack rigorous proof of effectiveness.[14] Chiropractic care, like all medical treatment, benefits from the placebo response.[28] The efficacy of maintenance care in chiropractic is unknown.[16]
Research has focused on spinal manipulation therapy (SMT) in general,[29] rather than specifically on chiropractic SMT.[13] There is little consensus as to who should administer the SMT, raising concerns by chiropractors that orthodox medical physicians could "steal" SMT procedures from chiropractors; the focus on SMT has also raised concerns that the resulting practice guidelines could limit the scope of chiropractic practice to treating backs and necks.[13] Many controlled clinical studies of SMT are available, but their results disagree,[30] and they are typically of low quality.[31] It is hard to construct a trustworthy placebo for clinical trials of SMT, as experts often disagree whether a proposed placebo actually has no effect.[32] Although a 2008 critical review found that with the possible exception of back pain, chiropractic SMT has not been shown to be effective for any medical condition, and suggested that many guidelines recommend chiropractic care for low back pain because no therapy has been shown to make a real difference,[33] a 2008 supportive review found serious flaws in the critical approach, and found that SMT and mobilization are at least as effective for chronic low back pain as other efficacious and commonly used treatments.[34]
Available evidence covers the following conditions:
- Low back pain. There is continuing conflict of opinion on the efficacy of SMT for nonspecific (i.e., unknown cause) low back pain; methods for formulating treatment guidelines differ significantly between countries, casting some doubt on the guidelines' reliability.[35] A 2007 U.S. guideline weakly recommended SMT as one alternative therapy for spinal low back pain in nonpregnant adults when ordinary treatments fail,[36] whereas the Swedish guideline for low back pain was updated in 2002 to no longer suggest considering SMT for acute low back pain for patients needing additional help, possibly because the guideline's recommendations were based on a high evidence level.[35] A 2008 review found strong evidence that SMT is similar in effect to medical care with exercise, and moderate evidence that SMT is similar to physical therapy and other forms of conventional care.[34] A 2007 literature synthesis found good evidence supporting SMT for low back pain and exercise for chronic low back pain; it also found fair evidence supporting customizable exercise programs for subacute low back pain, and supporting assurance and advice to stay active for subacute and chronic low back pain.[37] Of four systematic reviews published between 2000 and May 2005, only one recommended SMT, and a 2004 Cochrane review ([38]) stated that SMT or mobilization is no more or less effective than other standard interventions for back pain.[30]
- Whiplash and other neck pain. There is no overall consensus on manual therapies for neck pain.[39] A 2008 review found evidence that educational videos, mobilization, and exercises appear more beneficial for whiplash than alternatives; that SMT, mobilization, supervised exercise, low-level laser therapy and perhaps acupuncture are more effective for non-whiplash neck pain than alternatives but none of these treatments is clearly superior; and that there is no evidence that any intervention improves prognosis.[40] A 2007 review found that SMT and mobilization are effective for neck pain.[39] Of three systematic reviews of SMT published between 2000 and May 2005, one reached a positive conclusion, and a 2004 Cochrane review ([41]) found that SMT and mobilization are beneficial only when combined with exercise, the benefits being pain relief, functional improvement, and global perceived effect for subacute/chronic mechanical neck disorder.[30] A 2005 review found limited evidence supporting SMT for whiplash.[42]
- Headache. A 2006 review found no rigorous evidence supporting SMT or other manual therapies for tension headache.[43] A 2005 review found that the evidence was weak for effectiveness of chiropractic manipulation for tension headache, and that it was probably more effective for tension headache than for migraine.[44] A 2004 review found that SMT may be effective for migraine and tension headache, and SMT and neck exercises may be effective for cervicogenic headache.[45] Two other systematic reviews published between 2000 and May 2005 did not find conclusive evidence in favor of SMT.[30]
- Other. There is a small amount of research into the efficacy of chiropractic treatment for upper limbs,[46] and a lack of higher-quality publications supporting chiropractic management of leg conditions.[47] A 2007 literature synthesis found fair evidence supporting assurance and advice to stay active for sciatica and radicular pain in the leg.[37] There is very weak evidence for chiropractic care for adult scoliosis (curved or rotated spine)[48] and no scientific data for idiopathic adolescent scoliosis.[49] A 2007 systematic review found that few studies of chiropractic care for nonmusculoskeletal conditions are available, and they are typically not of high quality; it also found that the entire clinical encounter of chiropractic care (as opposed to just SMT) provides benefit to patients with asthma, cervicogenic dizziness, and baby colic, and that the evidence from reviews is negative, or too weak to draw conclusions, for a wide variety of other nonmusculoskeletal conditions, including ADHD/learning disabilities, dizzinesss, and vision conditions.[50] Other reviews have found no evidence of benefit for baby colic,[51] bedwetting,[52] fibromyalgia,[53] or menstrual cramps.[54] | https://www.wikidoc.org/index.php/Chiropractic | |
ff43de3bddbd279a70da1105e7eb998fdadabbd5 | wikidoc | Chlorambucil | Chlorambucil
- Chlorambucil is a carcinogen in humans.
- Chlorambucil is probably mutagenic and teratogenic in humans.
- Chlorambucil produces human infertility.
# Dosing Information
- The usual oral dosage is 0.1 to 0.2 mg/kg body weight daily for 3 to 6 weeks as required. This usually amounts to 4 to 10 mg per day for the average patient.
- The entire daily dose may be given at one time.
- These dosages are for initiation of therapy or for short courses of treatment.
- The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as there is an abrupt fall in the white blood cell count.
- Patients with Hodgkin’s disease usually require 0.2 mg/kg daily, whereas patients with other lymphomas or chronic lymphocytic leukemia usually require only 0.1 mg/kg daily.
- When lymphocytic infiltration of the bone marrow is present, or when the bone marrow is hypoplastic, the daily dose should not exceed 0.1 mg/kg (about 6 mg for the average patient).
- Alternate schedules for the treatment of chronic lymphocytic leukemia employing intermittent, biweekly, or once-monthly pulse doses of chlorambucil have been reported.
- Intermittent schedules of chlorambucil begin with an initial single dose of 0.4 mg/kg.
- Doses are generally increased by 0.1 mg/kg until control of lymphocytosis or toxicity is observed.
- Subsequent doses are modified to produce mild hematologic toxicity.
- It is felt that the response rate of chronic lymphocytic leukemia to the biweekly or once-monthly schedule of chlorambucil administration is similar or better to that previously reported with daily administration and that hematologic toxicity was less than or equal to that encountered in studies using daily chlorambucil.
- Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage, and chlorambucil should be used with particular caution within 4 weeks of a full course of radiation therapy or chemotherapy.
- However, small doses of palliative radiation over isolated foci remote from the bone marrow will not usually depress the neutrophil and platelet count. *In these cases chlorambucil may be given in the customary dosage.
- It is presently felt that short courses of treatment are safer than continuous maintenance therapy, although both methods have been effective.
- It must be recognized that continuous therapy may give the appearance of “maintenance” in patients who are actually in remission and have no immediate need for further drug.
- If maintenance dosage is used, it should not exceed 0.1 mg/kg daily and may well be as low as 0.03 mg/kg daily.
- A typical maintenance dose is 2 mg to 4 mg daily, or less, depending on the status of the blood counts.
- It may, therefore, be desirable to withdraw the drug after maximal control has been achieved, since intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment.
- Procedures for proper handling and disposal of anticancer drugs should be used.
- Several guidelines on this subject have been published.
- There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
- Patients with hepatic impairment should be closely monitored for toxicity. As chlorambucil is primarily metabolized in the liver, dose reduction may be considered in patients with hepatic impairment when treated with chlorambucil. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation.
- Convulsions, infertility, leukemia, and secondary malignancies have been observed when chlorambucil was employed in the therapy of malignant and non-malignant diseases.
- There are many reports of acute leukemia arising in patients with both malignant and non-malignant diseases following chlorambucil treatment. In many instances, these patients also received other chemotherapeutic agents or some form of radiation therapy. The quantitation of the risk of chlorambucil-induction of leukemia or carcinoma in humans is not possible. Evaluation of published reports of leukemia developing in patients who have received chlorambucil (and other alkylating agents) suggests that the risk of leukemogenesis increases with both chronicity of treatment and large cumulative doses. However, it has proved impossible to define a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from chlorambucil therapy must be weighed on an individual basis against the possible risk of the induction of a secondary malignancy.
- Chlorambucil has been shown to cause chromatid or chromosome damage in humans. Both reversible and permanent sterility have been observed in both sexes receiving chlorambucil.
- A high incidence of sterility has been documented when chlorambucil is administered to prepubertal and pubertal males. Prolonged or permanent azoospermia has also been observed in adult males. While most reports of gonadal dysfunction secondary to chlorambucil have related to males, the induction of amenorrhea in females with alkylating agents is well documented and chlorambucil is capable of producing amenorrhea. Autopsy studies of the ovaries from women with malignant lymphoma treated with combination chemotherapy including chlorambucil have shown varying degrees of fibrosis, vasculitis, and depletion of primordial follicles.
- Rare instances of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome have been reported. Chlorambucil should be discontinued promptly in patients who develop skin reactions.
# PRECAUTIONS
- Many patients develop a slowly progressive lymphopenia during treatment. The lymphocyte count usually rapidly returns to normal levels upon completion of drug therapy. Most patients have some neutropenia after the third week of treatment and this may continue for up to 10 days after the last dose. Subsequently, the neutrophil count usually rapidly returns to normal. Severe neutropenia appears to be related to dosage and usually occurs only in patients who have received a total dosage of 6.5 mg/kg or more in one course of therapy with continuous dosing. About one quarter of all patients receiving the continuous-dose schedule, and one third of those receiving this dosage in 8 weeks or less may be expected to develop severe neutropenia.
- While it is not necessary to discontinue chlorambucil at the first evidence of a fall in neutrophil count, it must be remembered that the fall may continue for 10 days after the last dose, and that as the total dose approaches 6.5 mg/kg, there is a risk of causing irreversible bone marrow damage. The dose of chlorambucil should be decreased if leukocyte or platelet counts fall below normal values and should be discontinued for more severe depression.
- Chlorambucil should not be given at full dosages before 4 weeks after a full course of radiation therapy or chemotherapy because of the vulnerability of the bone marrow to damage under these conditions. If the pretherapy leukocyte or platelet counts are depressed from bone marrow disease process prior to institution of therapy, the treatment should be instituted at a reduced dosage.
- Persistently low neutrophil and platelet counts or peripheral lymphocytosis suggest bone marrow infiltration. If confirmed by bone marrow examination, the daily dosage of chlorambucil should not exceed 0.1 mg/kg. Chlorambucil appears to be relatively free from gastrointestinal side effects or other evidence of toxicity apart from the bone marrow depressant action. In humans, single oral doses of 20 mg or more may produce nausea and vomiting.
- Children with nephrotic syndrome and patients receiving high pulse doses of chlorambucil may have an increased risk of seizures. As with any potentially epileptogenic drug, caution should be exercised when administering chlorambucil to patients with a history of seizure disorder or head trauma, or who are receiving other potentially epileptogenic drugs.
- Administration of live vaccines to immunocompromised patients should be avoided.
- Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently.
- The most common side effect is bone marrow suppression, anemia, leukopenia, neutropenia, thrombocytopenia, or pancytopenia.
- Although bone marrow suppression frequently occurs, it is usually reversible if the chlorambucil is withdrawn early enough.
- However, irreversible bone marrow failure has been reported.
- Tremors, muscular twitching, myoclonia, confusion, agitation, ataxia, flaccid paresis, and hallucinations have been reported as rare adverse experiences to chlorambucil which resolve upon discontinuation of drug. Rare, focal and/or generalized seizures have been reported to occur in both children and adults at both therapeutic daily doses and pulse-dosing regimens, and in acute overdose.
- Allergic reactions such as urticaria and angioneurotic edema have been reported following initial or subsequent dosing. Skin hypersensitivity (including rare reports of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome) has been reported
- Other reported adverse reactions include: pulmonary fibrosis, hepatotoxicity and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chlorambucil in women who are pregnant.
- Patients must be followed carefully to avoid life-endangering damage to the bone marrow during treatment. Weekly examination of the blood should be made to determine hemoglobin levels, total and differential leukocyte counts, and quantitative platelet counts. Also, during the first 3 to 6 weeks of therapy, it is recommended that white blood cell counts be made 3 or 4 days after each of the weekly complete blood counts. Galton et al have suggested that in following patients it is helpful to plot the blood counts on a chart at the same time that body weight, temperature, spleen size, etc., are recorded. It is considered dangerous to allow a patient to go more than 2 weeks without hematological and clinical examination during treatment.
- Oral LD50 single doses in mice are 123 mg/kg. In rats, a single intraperitoneal dose of 12.5 mg/kg of chlorambucil produces typical nitrogen-mustard effects; these include atrophy of the intestinal mucous membrane and lymphoid tissues, severe lymphopenia becoming maximal in 4 days, anemia, and thrombocytopenia. After this dose, the animals begin to recover within 3 days and appear normal in about a week, although the bone marrow may not become completely normal for about 3 weeks. An intraperitoneal dose of 18.5 mg/kg kills about 50% of the rats with development of convulsions. As much as 50 mg/kg has been given orally to rats as a single dose, with recovery. Such a dose causes bradycardia, excessive salivation, hematuria, convulsions, and respiratory dysfunction.
- After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour and the terminal elimination half-life (t½) of the parent drug is estimated at 1.5 hours.
- Chlorambucil is rapidly and completely (>70%) absorbed from the gastrointestinal tract. Consistent with the rapid, predictable absorption of chlorambucil, the inter-individual variability in the plasma pharmacokinetics of chlorambucil has been shown to be relatively small following oral dosages of between 15 and 70 mg (2-fold intra-patient variability, and a 2 to 4 fold interpatient variability in AUC). The absorption of chlorambucil is reduced when taken after food. In a study of ten patients, food intake increased the median Tmax by 2-fold and reduced the dose-adjusted Cmax and AUC values by 55% and 20%, respectively.
- The apparent volume of distribution averaged 0.31 L/kg following a single 0.2 mg/kg oral dose of chlorambucil in 11 cancer patients with chronic lymphocytic leukemia.
- Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined.
- Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite undergo oxidative degradation to monohydroxy and dihydroxy derivatives.
- After a single dose of radiolabeled chlorambucil (14C), approximately 20% to 60% of the radioactivity appears in the urine after 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard.
Bottle of 50 (NDC 76388-635-50).
NDC 76388-635-50
Chlorambucil®
(chlorambucil) Tablets
2 mg
50 Tablets
Each tablet contains 2 mg chlorambucil.
Rx only | Chlorambucil
- Chlorambucil is a carcinogen in humans.
- Chlorambucil is probably mutagenic and teratogenic in humans.
- Chlorambucil produces human infertility.
### Dosing Information
- The usual oral dosage is 0.1 to 0.2 mg/kg body weight daily for 3 to 6 weeks as required. This usually amounts to 4 to 10 mg per day for the average patient.
- The entire daily dose may be given at one time.
- These dosages are for initiation of therapy or for short courses of treatment.
- The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as there is an abrupt fall in the white blood cell count.
- Patients with Hodgkin’s disease usually require 0.2 mg/kg daily, whereas patients with other lymphomas or chronic lymphocytic leukemia usually require only 0.1 mg/kg daily.
- When lymphocytic infiltration of the bone marrow is present, or when the bone marrow is hypoplastic, the daily dose should not exceed 0.1 mg/kg (about 6 mg for the average patient).
- Alternate schedules for the treatment of chronic lymphocytic leukemia employing intermittent, biweekly, or once-monthly pulse doses of chlorambucil have been reported.
- Intermittent schedules of chlorambucil begin with an initial single dose of 0.4 mg/kg.
- Doses are generally increased by 0.1 mg/kg until control of lymphocytosis or toxicity is observed.
- Subsequent doses are modified to produce mild hematologic toxicity.
- It is felt that the response rate of chronic lymphocytic leukemia to the biweekly or once-monthly schedule of chlorambucil administration is similar or better to that previously reported with daily administration and that hematologic toxicity was less than or equal to that encountered in studies using daily chlorambucil.
- Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage, and chlorambucil should be used with particular caution within 4 weeks of a full course of radiation therapy or chemotherapy.
- However, small doses of palliative radiation over isolated foci remote from the bone marrow will not usually depress the neutrophil and platelet count. *In these cases chlorambucil may be given in the customary dosage.
- It is presently felt that short courses of treatment are safer than continuous maintenance therapy, although both methods have been effective.
- It must be recognized that continuous therapy may give the appearance of “maintenance” in patients who are actually in remission and have no immediate need for further drug.
- If maintenance dosage is used, it should not exceed 0.1 mg/kg daily and may well be as low as 0.03 mg/kg daily.
- A typical maintenance dose is 2 mg to 4 mg daily, or less, depending on the status of the blood counts.
- It may, therefore, be desirable to withdraw the drug after maximal control has been achieved, since intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment.
- Procedures for proper handling and disposal of anticancer drugs should be used.
- Several guidelines on this subject have been published.
- There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
- Patients with hepatic impairment should be closely monitored for toxicity. As chlorambucil is primarily metabolized in the liver, dose reduction may be considered in patients with hepatic impairment when treated with chlorambucil. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation.
- Convulsions, infertility, leukemia, and secondary malignancies have been observed when chlorambucil was employed in the therapy of malignant and non-malignant diseases.
- There are many reports of acute leukemia arising in patients with both malignant and non-malignant diseases following chlorambucil treatment. In many instances, these patients also received other chemotherapeutic agents or some form of radiation therapy. The quantitation of the risk of chlorambucil-induction of leukemia or carcinoma in humans is not possible. Evaluation of published reports of leukemia developing in patients who have received chlorambucil (and other alkylating agents) suggests that the risk of leukemogenesis increases with both chronicity of treatment and large cumulative doses. However, it has proved impossible to define a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from chlorambucil therapy must be weighed on an individual basis against the possible risk of the induction of a secondary malignancy.
- Chlorambucil has been shown to cause chromatid or chromosome damage in humans. Both reversible and permanent sterility have been observed in both sexes receiving chlorambucil.
- A high incidence of sterility has been documented when chlorambucil is administered to prepubertal and pubertal males. Prolonged or permanent azoospermia has also been observed in adult males. While most reports of gonadal dysfunction secondary to chlorambucil have related to males, the induction of amenorrhea in females with alkylating agents is well documented and chlorambucil is capable of producing amenorrhea. Autopsy studies of the ovaries from women with malignant lymphoma treated with combination chemotherapy including chlorambucil have shown varying degrees of fibrosis, vasculitis, and depletion of primordial follicles.
- Rare instances of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome have been reported. Chlorambucil should be discontinued promptly in patients who develop skin reactions.
### PRECAUTIONS
- Many patients develop a slowly progressive lymphopenia during treatment. The lymphocyte count usually rapidly returns to normal levels upon completion of drug therapy. Most patients have some neutropenia after the third week of treatment and this may continue for up to 10 days after the last dose. Subsequently, the neutrophil count usually rapidly returns to normal. Severe neutropenia appears to be related to dosage and usually occurs only in patients who have received a total dosage of 6.5 mg/kg or more in one course of therapy with continuous dosing. About one quarter of all patients receiving the continuous-dose schedule, and one third of those receiving this dosage in 8 weeks or less may be expected to develop severe neutropenia.
- While it is not necessary to discontinue chlorambucil at the first evidence of a fall in neutrophil count, it must be remembered that the fall may continue for 10 days after the last dose, and that as the total dose approaches 6.5 mg/kg, there is a risk of causing irreversible bone marrow damage. The dose of chlorambucil should be decreased if leukocyte or platelet counts fall below normal values and should be discontinued for more severe depression.
- Chlorambucil should not be given at full dosages before 4 weeks after a full course of radiation therapy or chemotherapy because of the vulnerability of the bone marrow to damage under these conditions. If the pretherapy leukocyte or platelet counts are depressed from bone marrow disease process prior to institution of therapy, the treatment should be instituted at a reduced dosage.
- Persistently low neutrophil and platelet counts or peripheral lymphocytosis suggest bone marrow infiltration. If confirmed by bone marrow examination, the daily dosage of chlorambucil should not exceed 0.1 mg/kg. Chlorambucil appears to be relatively free from gastrointestinal side effects or other evidence of toxicity apart from the bone marrow depressant action. In humans, single oral doses of 20 mg or more may produce nausea and vomiting.
- Children with nephrotic syndrome and patients receiving high pulse doses of chlorambucil may have an increased risk of seizures. As with any potentially epileptogenic drug, caution should be exercised when administering chlorambucil to patients with a history of seizure disorder or head trauma, or who are receiving other potentially epileptogenic drugs.
- Administration of live vaccines to immunocompromised patients should be avoided.
- Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently.
- The most common side effect is bone marrow suppression, anemia, leukopenia, neutropenia, thrombocytopenia, or pancytopenia.
- Although bone marrow suppression frequently occurs, it is usually reversible if the chlorambucil is withdrawn early enough.
- However, irreversible bone marrow failure has been reported.
- Tremors, muscular twitching, myoclonia, confusion, agitation, ataxia, flaccid paresis, and hallucinations have been reported as rare adverse experiences to chlorambucil which resolve upon discontinuation of drug. Rare, focal and/or generalized seizures have been reported to occur in both children and adults at both therapeutic daily doses and pulse-dosing regimens, and in acute overdose.
- Allergic reactions such as urticaria and angioneurotic edema have been reported following initial or subsequent dosing. Skin hypersensitivity (including rare reports of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome) has been reported
- Other reported adverse reactions include: pulmonary fibrosis, hepatotoxicity and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chlorambucil in women who are pregnant.
- Patients must be followed carefully to avoid life-endangering damage to the bone marrow during treatment. Weekly examination of the blood should be made to determine hemoglobin levels, total and differential leukocyte counts, and quantitative platelet counts. Also, during the first 3 to 6 weeks of therapy, it is recommended that white blood cell counts be made 3 or 4 days after each of the weekly complete blood counts. Galton et al have suggested that in following patients it is helpful to plot the blood counts on a chart at the same time that body weight, temperature, spleen size, etc., are recorded. It is considered dangerous to allow a patient to go more than 2 weeks without hematological and clinical examination during treatment.
- Oral LD50 single doses in mice are 123 mg/kg. In rats, a single intraperitoneal dose of 12.5 mg/kg of chlorambucil produces typical nitrogen-mustard effects; these include atrophy of the intestinal mucous membrane and lymphoid tissues, severe lymphopenia becoming maximal in 4 days, anemia, and thrombocytopenia. After this dose, the animals begin to recover within 3 days and appear normal in about a week, although the bone marrow may not become completely normal for about 3 weeks. An intraperitoneal dose of 18.5 mg/kg kills about 50% of the rats with development of convulsions. As much as 50 mg/kg has been given orally to rats as a single dose, with recovery. Such a dose causes bradycardia, excessive salivation, hematuria, convulsions, and respiratory dysfunction.
- After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour and the terminal elimination half-life (t½) of the parent drug is estimated at 1.5 hours.
- Chlorambucil is rapidly and completely (>70%) absorbed from the gastrointestinal tract. Consistent with the rapid, predictable absorption of chlorambucil, the inter-individual variability in the plasma pharmacokinetics of chlorambucil has been shown to be relatively small following oral dosages of between 15 and 70 mg (2-fold intra-patient variability, and a 2 to 4 fold interpatient variability in AUC). The absorption of chlorambucil is reduced when taken after food. In a study of ten patients, food intake increased the median Tmax by 2-fold and reduced the dose-adjusted Cmax and AUC values by 55% and 20%, respectively.
- The apparent volume of distribution averaged 0.31 L/kg following a single 0.2 mg/kg oral dose of chlorambucil in 11 cancer patients with chronic lymphocytic leukemia.
- Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined.
- Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite undergo oxidative degradation to monohydroxy and dihydroxy derivatives.
- After a single dose of radiolabeled chlorambucil (14C), approximately 20% to 60% of the radioactivity appears in the urine after 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard.
Bottle of 50 (NDC 76388-635-50).
NDC 76388-635-50
Chlorambucil®
(chlorambucil) Tablets
2 mg
50 Tablets
Each tablet contains 2 mg chlorambucil.
Rx only | https://www.wikidoc.org/index.php/Chlorambucil | |
c6d9800b47a0fb595791468cf05c51ab186ba4d7 | wikidoc | Chloramine-T | Chloramine-T
N-chloro tosylamide sodium salt, sold as chloramine-T, is a N-chlorinated and N-deprotonated sulfonamide used as a biocide and a mild disinfectant. It is a white powder that gives unstable solutions with water.
# Chemistry
As a N-chloro compound, it contains active (electrophilic) chlorine and can be compared to the O-chlorinated sodium hypochlorite. Chloramine-T is nearly neutral (pH typically 8.5). In water, it breaks down to the disinfectant hypochlorite. It can be used as a source of electrophilic chlorine in organic synthesis.
The sulfur adjacent to the nitrogen can stabilize a nitrogen anion (R2N–), so that the N-chloro sulfonyamide moiety can be deprotonated at nitrogen even with only sodium hydroxide.
# Use as a biocide
Chloramine-T is used for disinfection and as an algicide, bactericide, germicide, for parasite control, and for drinking water disinfection. The molecular structure of toluenesulfonylamide is similar to para-aminobenzoic acid, an intermediate in bacterial metabolism, which is disrupted by this sulfonamide (in the same way as by a sulfa drug). Therefore, chloramine-T is capable of inhibiting with bacterial growth with two mechanisms, with the phenylsulfonamide moiety and the electrophilic chlorine. | Chloramine-T
Template:Chembox new
N-chloro tosylamide sodium salt, sold as chloramine-T, is a N-chlorinated and N-deprotonated sulfonamide used as a biocide and a mild disinfectant. It is a white powder that gives unstable solutions with water.
# Chemistry
As a N-chloro compound, it contains active (electrophilic) chlorine and can be compared to the O-chlorinated sodium hypochlorite. Chloramine-T is nearly neutral (pH typically 8.5). In water, it breaks down to the disinfectant hypochlorite. It can be used as a source of electrophilic chlorine in organic synthesis.
The sulfur adjacent to the nitrogen can stabilize a nitrogen anion (R2N–), so that the N-chloro sulfonyamide moiety can be deprotonated at nitrogen even with only sodium hydroxide.
# Use as a biocide
Chloramine-T is used for disinfection and as an algicide, bactericide, germicide, for parasite control, and for drinking water disinfection. The molecular structure of toluenesulfonylamide is similar to para-aminobenzoic acid, an intermediate in bacterial metabolism, which is disrupted by this sulfonamide (in the same way as by a sulfa drug). Therefore, chloramine-T is capable of inhibiting with bacterial growth with two mechanisms, with the phenylsulfonamide moiety and the electrophilic chlorine.
# External links
- Chemicalland21.com: [1]
- MSDS [2], ICSS [3]
nl:Chloramine-T
Template:WS | https://www.wikidoc.org/index.php/Chloramine-T | |
97ac30fb6a72a2f8476e31dc0df3a1ec18ebe125 | wikidoc | Chlorination | Chlorination
Chlorination is the process of adding the element chlorine to water as a method of water purification to make it fit for human consumption as drinking water. Water which has been treated with chlorine is effective in preventing the spread of disease.
The chlorination of public drinking supplies was originally met with resistance, as people were concerned about the health effects of the practice. The use of chlorine has greatly reduced the prevalence of waterborne disease as it is effective against almost all bacteria and viruses, as well as amoeba.
Chlorination is also used to sterilize the water in swimming pools and as a disinfection stage in sewage treatment. It can also apply to the addition of chlorine to other elements, such as gold in the formation of gold chloride.
# History
The technique of purification of drinking water by use of compressed liquefied chlorine gas was developed in 1910 by U.S. Army Major (later Brig. Gen.) Carl Rogers Darnall (1867-1941), Professor of Chemistry at the Army Medical School. Shortly thereafter, Major (later Col.) William J. L. Lyster (1869-1947) of the Army Medical Department used a solution of calcium hypochlorite in a linen bag to treat water. For many decades, Lyster's method remained the standard for U.S. ground forces in the field and in camps, implemented in the form of the familiar Lyster Bag (also spelled Lister Bag). Darnall's work became the basis for present day systems of municipal water purification.
# Chemistry in Water
When chlorine is added to water, it reacts to form a pH dependent equilibrium mixture of chlorine, hypochlorous acid and hydrochloric acid:
Depending on the pH, hypochlorous acid partly dissociates to hydrogen and hypochlorite ions:
In acidic solution, the major species are Cl2 and HOCl while in alkaline solution effectively only ClO- is present. Very small concentrations of ClO2-, ClO3-, ClO4- are also found.
# Drawbacks
Disinfection by chlorination can be problematic, in some circumstances. Chlorine can react with naturally occurring organic compounds found in the water supply to produce dangerous compounds, known as disinfection byproducts (DBPs). The most common DBPs are trihalomethanes (THMs) and haloacetic acids. Due to the carcinogenic potential of these compounds, federal regulations in the United States of America require regular monitoring of the concentration of these compounds in the distribution systems of municipal water systems. However, the World Health Organization has stated that the "Risks to health from DBPs are extremely small in comparison with inadequate disinfection."
There are also other concerns regarding chlorine including its volatile nature which causes it to disappear too quickly from the water system, and aesthetic concerns such as taste and odour.
# Alternatives
Several alternatives to traditional chlorination exist, and have been put into practice to varying extents. Ozonation is used by some municipalities in the United States. Due to current regulations, systems employing ozonation in the United States still must maintain chlorine residuals comparable to systems without ozonation.
Disinfection with chloramine is also becoming increasingly common. Unlike chlorine, chloramine has a longer half life in the distribution system and still maintains effective protection against pathogens. The reason chloramines persist in the distribution is due to the relatively lower redox potential in comparison to free chlorine. Chloramine is formed by the addition of ammonia into drinking water to form mono-, di-, and trichloramines.
Water treated by filtration may not need further disinfection; a very high proportion of pathogens are removed by microorganisms in the filter bed.
The advantage of chlorine in comparison to ozone is that the residual persists in the water for an extended period of time. This feature allows the chlorine to travel through the water supply system, effectively controlling pathogenic backflow contamination. In a large system this may not be adequate, and so chlorine levels may be boosted at points in the distribution system, or chloramine may be used, which remains in the water for longer before reacting or dissipating.
Another method which is gaining popularity is UV disinfection. It leaves no residue in the water. However, this method alone will not remove bacterially produced toxins, pesticides, heavy metals, etc from water. Some bacterial cell walls themselves are toxic to humans, whether dead or alive. Often, multiple steps are taken in commercially sold water. | Chlorination
Chlorination is the process of adding the element chlorine to water as a method of water purification to make it fit for human consumption as drinking water. Water which has been treated with chlorine is effective in preventing the spread of disease.
The chlorination of public drinking supplies was originally met with resistance, as people were concerned about the health effects of the practice. The use of chlorine has greatly reduced the prevalence of waterborne disease as it is effective against almost all bacteria and viruses, as well as amoeba.
Chlorination is also used to sterilize the water in swimming pools and as a disinfection stage in sewage treatment. It can also apply to the addition of chlorine to other elements, such as gold in the formation of gold chloride.
# History
The technique of purification of drinking water by use of compressed liquefied chlorine gas was developed in 1910 by U.S. Army Major (later Brig. Gen.) Carl Rogers Darnall (1867-1941), Professor of Chemistry at the Army Medical School. Shortly thereafter, Major (later Col.) William J. L. Lyster (1869-1947) of the Army Medical Department used a solution of calcium hypochlorite in a linen bag to treat water. For many decades, Lyster's method remained the standard for U.S. ground forces in the field and in camps, implemented in the form of the familiar Lyster Bag (also spelled Lister Bag). Darnall's work became the basis for present day systems of municipal water purification.
# Chemistry in Water
When chlorine is added to water, it reacts to form a pH dependent equilibrium mixture of chlorine, hypochlorous acid and hydrochloric acid:
Depending on the pH, hypochlorous acid partly dissociates to hydrogen and hypochlorite ions:
In acidic solution, the major species are Cl2 and HOCl while in alkaline solution effectively only ClO- is present. Very small concentrations of ClO2-, ClO3-, ClO4- are also found[1].
# Drawbacks
Disinfection by chlorination can be problematic, in some circumstances. Chlorine can react with naturally occurring organic compounds found in the water supply to produce dangerous compounds, known as disinfection byproducts (DBPs). The most common DBPs are trihalomethanes (THMs) and haloacetic acids. Due to the carcinogenic potential of these compounds, federal regulations in the United States of America require regular monitoring of the concentration of these compounds in the distribution systems of municipal water systems. However, the World Health Organization has stated that the "Risks to health from DBPs are extremely small in comparison with inadequate disinfection."
There are also other concerns regarding chlorine including its volatile nature which causes it to disappear too quickly from the water system, and aesthetic concerns such as taste and odour.
# Alternatives
Several alternatives to traditional chlorination exist, and have been put into practice to varying extents. Ozonation is used by some municipalities in the United States. Due to current regulations, systems employing ozonation in the United States still must maintain chlorine residuals comparable to systems without ozonation.
Disinfection with chloramine is also becoming increasingly common. Unlike chlorine, chloramine has a longer half life in the distribution system and still maintains effective protection against pathogens. The reason chloramines persist in the distribution is due to the relatively lower redox potential in comparison to free chlorine. Chloramine is formed by the addition of ammonia into drinking water to form mono-, di-, and trichloramines.
Water treated by filtration may not need further disinfection; a very high proportion of pathogens are removed by microorganisms in the filter bed.
The advantage of chlorine in comparison to ozone is that the residual persists in the water for an extended period of time. This feature allows the chlorine to travel through the water supply system, effectively controlling pathogenic backflow contamination. In a large system this may not be adequate, and so chlorine levels may be boosted at points in the distribution system, or chloramine may be used, which remains in the water for longer before reacting or dissipating.
Another method which is gaining popularity is UV disinfection. It leaves no residue in the water. However, this method alone will not remove bacterially produced toxins, pesticides, heavy metals, etc from water. Some bacterial cell walls themselves are toxic to humans, whether dead or alive. Often, multiple steps are taken in commercially sold water. | https://www.wikidoc.org/index.php/Chlorination | |
349eb97eb79b4d223b0419de4cc8d2c78eae77ed | wikidoc | Chlormethine | Chlormethine
# Overview
Chlormethine (INN, BAN), mechlorethamine (widely used in the US, not the USAN, however) also known as mustine and HN2 and in former USSR known as Embichin is a nitrogen mustard sold under the brand name Mustargen. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. As the chemical is a blister agent, its use is strongly restricted within the Chemical Weapons Convention where it is classified as a Schedule 1 substance.
Mechlorethamine belongs to the group of nitrogen mustard alkylating agents.
# Uses
It has been derivatized into the estrogen analogue estramustine, used to treat prostate cancer. It can also be used in chemical warfare where it has the code-name HN2. This chemical is a form of nitrogen mustard gas and a powerful vesicant. Historically, some uses of mechlorethamine have included lymphoid malignancies such as Hodgkin’s disease, lymphosarcoma, chronic myelocytic leukemia, polycythemia vera, and bronchogenic carcinoma Mechlorethamine is often administered intravenously, but when compounded into a topical formulation it can also be used to treat skin diseases. There have been studies demonstrating that topical administration of mechlorethamine has efficacy in mycosis fungoides-type cutaneous T cell lymphoma
Another important use of chlormethine is in the synthesis of meperidine (aka pethidine, demerol).
# Side effects
Mechlorethamine is a highly toxic medication, especially for women who are pregnant, breastfeeding, or of childbearing age.
The adverse effects of mechlorethamine depend on the formulation. Adverse effect include:
“Hypersensitivity reactions, including anaphylaxis…. Nausea, vomiting and depression of formed elements in the circulating blood are dose-limiting side effects and usually occur with the use of full doses of MUSTARGEN. Jaundice, alopecia, vertigo, tinnitus and diminished hearing may occur infrequently. Rarely, hemolytic anemia associated with such diseases as the lymphomas and chronic lymphocytic leukemia may be precipitated by treatment with alkylating agents including MUSTARGEN. Also, various chromosomal abnormalities have been reported in association with nitrogen mustard therapy.”
# History
Successful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-Kettering. The drug is a nitrogen-based analogue of mustard gas (which is sulfur-based) and was derived from chemical warfare research. Secret clinical trials of the agent for Hodgkin's disease and several other lymphomas and leukemias in humans began in December 1942. Because of wartime secrecy restrictions, it was not until 1946 that the results of these trials were published openly. | Chlormethine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chlormethine (INN, BAN), mechlorethamine (widely used in the US, not the USAN, however) also known as mustine and HN2 and in former USSR known as Embichin is a nitrogen mustard sold under the brand name Mustargen. It is the prototype of alkylating agents, a group of anticancer chemotherapeutic drugs. It works by binding to DNA, crosslinking two strands and preventing cell duplication. It binds to the N7 nitrogen on the DNA base guanine. As the chemical is a blister agent, its use is strongly restricted within the Chemical Weapons Convention where it is classified as a Schedule 1 substance.
Mechlorethamine belongs to the group of nitrogen mustard alkylating agents.[1][2]
# Uses
It has been derivatized into the estrogen analogue estramustine, used to treat prostate cancer. It can also be used in chemical warfare where it has the code-name HN2. This chemical is a form of nitrogen mustard gas and a powerful vesicant. Historically, some uses of mechlorethamine have included lymphoid malignancies such as Hodgkin’s disease, lymphosarcoma, chronic myelocytic leukemia, polycythemia vera, and bronchogenic carcinoma [3] Mechlorethamine is often administered intravenously,[4] but when compounded into a topical formulation it can also be used to treat skin diseases. There have been studies demonstrating that topical administration of mechlorethamine has efficacy in mycosis fungoides-type cutaneous T cell lymphoma [5][6][7]
Another important use of chlormethine is in the synthesis of meperidine (aka pethidine, demerol).
# Side effects
Mechlorethamine is a highly toxic medication, especially for women who are pregnant, breastfeeding, or of childbearing age.[8][9]
The adverse effects of mechlorethamine depend on the formulation.[10] Adverse effect include:
“Hypersensitivity reactions, including anaphylaxis…. Nausea, vomiting and depression of formed elements in the circulating blood are dose-limiting side effects and usually occur with the use of full doses of MUSTARGEN. Jaundice, alopecia, vertigo, tinnitus and diminished hearing may occur infrequently. Rarely, hemolytic anemia associated with such diseases as the lymphomas and chronic lymphocytic leukemia may be precipitated by treatment with alkylating agents including MUSTARGEN. Also, various chromosomal abnormalities have been reported in association with nitrogen mustard therapy.”
# History
Successful clinical use of chlormethine (mechlorethamine) resulted in development of the field of anticancer chemotherapy, led by Cornelius P. Rhoads at Memorial Sloan-Kettering. The drug is a nitrogen-based analogue of mustard gas (which is sulfur-based) and was derived from chemical warfare research. Secret clinical trials of the agent for Hodgkin's disease and several other lymphomas and leukemias in humans began in December 1942. Because of wartime secrecy restrictions, it was not until 1946 that the results of these trials were published openly.[11] | https://www.wikidoc.org/index.php/Chlormethine | |
7fc1e27512d39c68030803f299aa22d865f0e6c6 | wikidoc | Chloroethane | Chloroethane
# Overview
Chloroethane or monochloroethane, commonly known by its old name ethyl chloride, is a chemical compound once widely used in producing tetra-ethyl lead, a gasoline additive. It is a colorless, flammable gas or refrigerated liquid with a faintly sweet odor.
# Production
Ethyl chloride is produced by reacting ethylene and hydrogen chloride over an aluminium chloride catalyst at temperatures ranging from 130-250°C. Under these conditions, ethyl chloride is produced according to the chemical equation.
At various times in the past, ethyl chloride has also been produced from ethanol and hydrochloric acid, or from ethane and chlorine, but these routes are no longer economical. Some ethyl chloride is generated as a byproduct of polyvinyl chloride production. Should demand for ethyl chloride continue to fall to the point where making it for its own sake is not economical, this may become the leading source of the chemical.
# Uses
Beginning in 1922 and continuing through most of the 20th century, the major use of ethyl chloride was to produce tetraethyl lead (TEL), an anti-knock additive for gasoline. However, due to growing awareness of air pollution, TEL has been or is being phased out in most of the industrialized world, and the demand for ethyl chloride has fallen sharply.
Like other chlorinated hydrocarbons, ethyl chloride has been used as a refrigerant, an aerosol spray propellant, an anesthetic, and a blowing agent for foam packaging. For a time it was used as a promoter chemical in the aluminum chloride catalyzed process to produce ethylbenzene, the precursor for styrene monomer. At present though, it is not widely used in any of these roles.
The only remaining industrially important use of ethyl chloride is in treating cellulose to make ethylcellulose, a thickening agent and binder in paints, cosmetics, and similar products.
Ethyl chloride is a prescription drug in the US, supplied as a liquid in a spray bottle propelled by its own vapor pressure. It acts as a mild topical anesthetic by its chilling effect when sprayed on skin, such as when removing splinters in a clinical setting. The heat absorbed by the boiling liquid on tissues produces a deep and rapid chill, but since the boiling point is well above freezing, it presents no danger of frostbite. The vapor is flammable and narcotic, which requires care.
Ethyl chloride is a narcotic inhalant drug, sometimes referred to as "Duster". Similar to poppers, ethyl chloride is used as an inhalant (huffed) during sexual activity for an intense several-minute-long high that results in a prolonged orgasm. In Brazil, it is a traditional (though illegal) drug taken during Carnaval parades, known as "lança-perfume".
# Safety
Ethyl chloride is the least toxic of the chloroethanes. Like other chlorinated hydrocarbons, it is a central nervous system depressant, albeit a less potent one than many similar compounds. People breathing its vapors at less than 1% concentration in air usually experience no symptoms. At higher concentrations, victims usually exhibit symptoms similar to those of alcohol intoxication. Breathing its vapors at 15% or higher is often fatal.
Studies on the effects of chronic ethyl chloride exposure in animals have given inconsistent results, and there exists no data for its long-term effects on humans. Some studies have reported that prolonged exposure can produce liver or kidney damage, or uterine cancer in mice, but this data has been difficult to reproduce.
Recent information suggests carcinogenic potential; it has been designated as IARC category A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans. As a result, the State of California has incorporated it into Proposition 65 as a known carcinogen. Nonetheless, it is still used in medicine as a local anesthetic. | Chloroethane
Template:Chembox new
# Overview
Chloroethane or monochloroethane, commonly known by its old name ethyl chloride, is a chemical compound once widely used in producing tetra-ethyl lead, a gasoline additive. It is a colorless, flammable gas or refrigerated liquid with a faintly sweet odor.
# Production
Ethyl chloride is produced by reacting ethylene and hydrogen chloride over an aluminium chloride catalyst at temperatures ranging from 130-250°C. Under these conditions, ethyl chloride is produced according to the chemical equation.
At various times in the past, ethyl chloride has also been produced from ethanol and hydrochloric acid, or from ethane and chlorine, but these routes are no longer economical. Some ethyl chloride is generated as a byproduct of polyvinyl chloride production. Should demand for ethyl chloride continue to fall to the point where making it for its own sake is not economical, this may become the leading source of the chemical.
# Uses
Beginning in 1922 and continuing through most of the 20th century, the major use of ethyl chloride was to produce tetraethyl lead (TEL), an anti-knock additive for gasoline. However, due to growing awareness of air pollution, TEL has been or is being phased out in most of the industrialized world, and the demand for ethyl chloride has fallen sharply.
Like other chlorinated hydrocarbons, ethyl chloride has been used as a refrigerant, an aerosol spray propellant, an anesthetic, and a blowing agent for foam packaging. For a time it was used as a promoter chemical in the aluminum chloride catalyzed process to produce ethylbenzene, the precursor for styrene monomer. At present though, it is not widely used in any of these roles.
The only remaining industrially important use of ethyl chloride is in treating cellulose to make ethylcellulose, a thickening agent and binder in paints, cosmetics, and similar products.
Ethyl chloride is a prescription drug in the US, supplied as a liquid in a spray bottle propelled by its own vapor pressure. It acts as a mild topical anesthetic by its chilling effect when sprayed on skin, such as when removing splinters in a clinical setting. The heat absorbed by the boiling liquid on tissues produces a deep and rapid chill, but since the boiling point is well above freezing, it presents no danger of frostbite. The vapor is flammable and narcotic, which requires care.
Ethyl chloride is a narcotic inhalant drug, sometimes referred to as "Duster". Similar to poppers, ethyl chloride is used as an inhalant (huffed) during sexual activity for an intense several-minute-long high that results in a prolonged orgasm. In Brazil, it is a traditional (though illegal) drug taken during Carnaval parades, known as "lança-perfume".
# Safety
Ethyl chloride is the least toxic of the chloroethanes. Like other chlorinated hydrocarbons, it is a central nervous system depressant, albeit a less potent one than many similar compounds. People breathing its vapors at less than 1% concentration in air usually experience no symptoms. At higher concentrations, victims usually exhibit symptoms similar to those of alcohol intoxication. Breathing its vapors at 15% or higher is often fatal.
Studies on the effects of chronic ethyl chloride exposure in animals have given inconsistent results, and there exists no data for its long-term effects on humans. Some studies have reported that prolonged exposure can produce liver or kidney damage, or uterine cancer in mice, but this data has been difficult to reproduce.
Recent information suggests carcinogenic potential; it has been designated as IARC category A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans. As a result, the State of California has incorporated it into Proposition 65 as a known carcinogen. Nonetheless, it is still used in medicine as a local anesthetic. | https://www.wikidoc.org/index.php/Chloroethane | |
5bddc4a97a21d9307abc66358cac43cc0353a449 | wikidoc | Choline c-11 | Choline c-11
# 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
Choline c-11 is a diagnostic agent that is FDA approved for the treatment of positron emission tomography (PET) imaging of patients with suspected prostate cancer recurrence and non-informative bone scintigraphy, computerized tomography (CT) or magnetic resonance imaging (MRI). Common adverse reactions include mild injection site reactions.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Choline C 11 Injection is indicated for positron emission tomography (PET) imaging of patients with suspected prostate cancer recurrence and non-informative bone scintigraphy, computerized tomography (CT) or magnetic resonance imaging (MRI).
- In these patients, 11 C-choline PET imaging may help identify potential sites of prostate cancer recurrence for subsequent histologic confirmation. Suspected prostate recurrence is based upon elevated blood prostate specific antigen (PSA) levels following initial therapy. In clinical studies, images were produced with PET/CT coregistration.
- Limitation of Use: 11 C-choline PET imaging is not a replacement for histologic verification of recurrent prostate cancer.
- Choline C 11 Injection contains 148 – 1,225 MBq (4 – 33.1 mCi) per milliliter of 11C-choline at end of synthesis (EOS) calibration time in aqueous 0.9% sodium chloride solution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Choline c-11 in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Choline c-11 in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Choline c-11 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 Choline c-11 in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Choline c-11 in pediatric patients.
# Contraindications
There is limited information regarding Choline c-11 Contraindications in the drug label.
# Warnings
- Imaging errors have been reported with 11C-choline PET and PET/CT imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent cancer. 11C-choline uptake is not specific for prostate cancer and may occur with other types of cancer (such as lung carcinoma and brain tumors). Clinical correlation, including histopathological evaluation of the suspected recurrence site, is essential to proper use of the PET imaging information.
- Blood PSA levels < 2 ng/mL have been associated with poor performance of 11C-choline PET imaging (higher numbers of false positive and false negative results).
- Tissue inflammation as well as prostatic hyperplasia have been associated with false positive 11C-choline PET images.
- Concomitant colchicine or androgen-deprivation therapeutic drugs (such as luteinizing hormone-releasing analogs and anti-androgen drugs) may interfere with 11C-choline PET imaging. One published report of 18F-methylcholine PET imaging indicated that discontinuation of colchicine for two weeks resolved the colchicine effect. The impact of discontinuation of androgen-deprivation therapy upon 11C-choline PET imaging has not been established.
- As with any injectable drug product, allergic reactions and anaphylaxis may occur. Emergency resuscitation equipment and personnel should be immediately available.
- Choline C 11 Injection contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Safe handling should be ensured to minimize radiation exposure to the patient and health care workers.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Choline c-11 Clinical Trials Experience in the drug label.
## Postmarketing Experience
- Exclusive of an uncommon, mild injection site reaction, no adverse reactions to 11C-choline have been reported.
# Drug Interactions
- Colchicine and androgen-deprivation therapeutic drugs have been reported to interfere with choline-based PET imaging.
- The impact of androgen-deprivation therapeutic drugs upon 11C-choline PET imaging may depend upon the hormonal responsiveness of a patient’s recurrent prostate cancer. Clinical studies have not established this relationship but published reports suggest 11C-choline PET imaging may be productive in patients with “hormone resistant” recurrent prostate cancer even if the patients are receiving anti-androgen therapy. Imaging may prove unproductive or misleading due to failed or insufficient 11C-choline uptake in patients with hormone-responsive cancer if the patients are receiving androgen-deprivation therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well controlled studies with Choline C 11 Injection in pregnant women and the fetal radiation dose from a 11C-choline PET imaging study is unknown. It is not known whether Choline C 11 Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Animal reproduction studies have not been conducted with 11C-choline.
- All radiopharmaceuticals, including Choline C 11 Injection, have a potential to cause fetal harm. The likelihood of fetal harm depends on the stage of fetal development and the magnitude of the radiopharmaceutical dose. Assess pregnancy status before administering Choline C 11 Injection to a female of child bearing potential. Choline C 11 Injection should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Choline c-11 in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Choline c-11 during labor and delivery.
### Nursing Mothers
- Choline C 11 Injection is not indicated for use in women. It is not known whether Choline C 11 Injection is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for radiation exposure to nursing infants from Choline C 11 Injection, nursing mothers should use alternative infant nutrition sources (e.g., stored breast milk or infant formula) and pump and discard breast milk for 8 hours (>10 half lives of radioactive decay for 11C isotope) after administration of the drug or avoid use of the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of Choline C 11 Injection have not been established in pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Choline c-11 in geriatric settings.
### Gender
There is no FDA guidance on the use of Choline c-11 with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Choline c-11 with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Choline c-11 in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Choline c-11 in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Choline c-11 in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Choline c-11 in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intra venous
### Monitoring
There is limited information regarding Choline c-11 Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Choline c-11 and IV administrations.
# Overdosage
There is limited information regarding Choline c-11 overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Choline c-11 Pharmacology in the drug label.
## Mechanism of Action
- Choline C 11 Injection is a radiolabeled analog of choline, a precursor molecule essential for the biosynthesis of cell membrane phospholipids. Choline is involved in synthesis of the structural components of cell membranes, as well as modulation of trans-membrane signaling. Increased phospholipid synthesis (i.e., increased uptake of choline) has been associated with cell proliferation and the transformation process that occurs in tumor cells.
## Structure
## Pharmacodynamics
- In a study of men with prostatic hyperplasia or primary prostate cancer, PET imaging showed 11C-choline radioactivity accumulated rapidly within the prostate; uptake appeared to peak by five minutes following injection of the drug and activity was retained over the subsequent 30 minute scanning period. Little uptake was observed in the bladder and rectum.
## Pharmacokinetics
- Distribution: 11C-choline distributes mainly to the pancreas, kidneys, liver, spleen and colon. Based upon the relatively low urinary excretion of radioactivity, renal distribution is predominantly to the organ itself, rather than via formation of urine.
- Following intravenous administration, 11C-choline undergoes metabolism resulting in the detection of 11C-betaine as the major metabolite in blood. In a study of patients with prostate cancer or brain disorders, the fractional activities of 11C-choline and 11C-betaine in human arterial plasma appeared to reach a plateau within 25 minutes, with 11C-betaine representing 82± 9% of the total 11C detected at that time point. A small amount of unmetabolized 11C-choline was detected within the blood at the final sampling time point (40 minutes).
- Urinary excretion of 11C-choline was < 2% of the injected radioactivity at 1.5 hours after injection of the drug. The rate of 11C-choline excretion in urine was 0.014 mL/min.
## Nonclinical Toxicology
- Long term studies have not been performed to evaluate the carcinogenic potential of Choline C 11 Injection. The mutagenic potential of Choline C 11 Injection has not been adequately evaluated; however, any radiopharmaceutical, including Choline C 11 Injection, has the potential to be mutagenic. The effect of Choline C 11 Injection on fertility has not been evaluated.
# Clinical Studies
- A systematic review of published reports identified four studies that contained data sufficient to compare 11C-choline PET imaging to histopathology (truth standard) among patients with suspected prostate cancer recurrence and non-informative conventional imaging (for most patients, CT or MRI). In general, the suspected recurrence criteria consisted of at least two sequential PSA levels of > 0.2 ng/mL for men who had undergone prostatectomy and PSA levels of ≥ 2 ng/mL above the post-therapy nadir for men who had undergone radiotherapy. The studies were predominantly single clinical site experiences and image acquisition generally surveyed radioactivity distribution from the base of the pelvis to the base of the skull.
- Prospective studies: Two studies examined the ability of 11C-choline PET/CT to detect prostate cancer in pelvic and/or retroperitoneal lymph nodes among patients who had previously undergone radical prostatectomy. Both studies used a truth standard of lymph node histopathology. 11C-choline images were interpreted by readers masked to clinical information; surgical resection of lymph nodes was performed by surgeons aware of the 11C-choline PET/CT results.
- In Study One3, 25 patients who underwent 11C-choline PET/CT and conventional imaging (CT or MRI) were scheduled to undergo pelvic or pelvic plus retroperitoneal lymphadenectomy following the imaging identification of suspected lymph node metastases. The median PSA was 2.0 ng/mL (range 0.2 to 23.1 ng/mL). The study excluded subjects with metastatic disease detected by bone scintigraphy or isolated prostatic fossa recurrence. Among the 25 patients, 21 had positive 11C-choline PET/CT scans; histopathology verified cancer in 19 of these patients. Lymph node histopathology detected no cancer among the four patients who had surgery based only on positive conventional imaging; 11C-choline PET/CT was negative in all four patients. The study report included information for patients who had non-informative conventional imaging (CT or MRI, bone scintigraphy and transrectal ultrasound), as shown in Table 5.
- In Study Two4, 15 patients were scheduled to undergo pelvic or pelvis plus retroperitoneal lymphadenectomy solely based upon positive 11C-choline PET/CT imaging in the setting of negative conventional imaging (ultrasound and/or CTand/or MRI and/or bone scintigraphy). The median PSA was 2.0 ng/mL (range 1.0 to 8.0 ng/mL); all patients had previously undergone radical prostatectomy. Eight of the 15 patients had cancer verified by lymph node histology; histology detected no cancer in seven patients.
- Retrospective Studies: Two studies were retrospective reviews of patients who underwent 11C-choline PET/CT and had histopathology obtained from biopsy of the prostatic fossa or other suspected recurrence sites.
- In Study Three5, 11C-choline PET/CT imaging was performed among 36 patients with suspected prostate cancer recurrence and 13 subjects without suspected recurrence (controls). Prostatic fossa biopsies were performed among the patients with suspected recurrence. All the patients and control subjects had previously undergone radical prostatectomy; patient with suspected recurrence had no evidence of cancer using conventional clinical evaluations, including trans-rectal ultrasound and bone scintigraphy. PET/CT scans were interpreted by readers masked to clinical information. Median PSA was 2.0 ng/mL (range 0.3 – 12.1 ng/mL) for patients with suspected recurrence and 0.1 ng/mL (range 0.0 – 0.2 ng/mL) in control subjects. Prostatic fossa biopsy showed cancer in 33 of the 36 patients with suspected recurrence. PET/CT scans were positive in 25 of the 36 patients; two patients had false positive scans (one scan in a control subject and one scan in a suspected recurrence subject who had no cancer detected on prostatic fossa biopsy). Among the 13 control subjects, 12 had negative PET/CT scans.
- In Study Four6,7, 34 patients with negative conventional imaging underwent 11C-choline PET/CT and subsequently had biopsies of suspected recurrence sites. The median PSA level of the 34 patients was 3.9 ng/mL (range 0.2 – 65.0 ng/mL); 22 of the patients had previously undergone radical prostatectomy and 12 had received other therapy (radiotherapy, anti-androgen therapy or cryotherapy). 11C-choline PET/CT images were positive in 30 patients and negative in four patients. Cancer was verified by histopathology in 29 patients; 25 had positive PET/CT images and four had negative PET/CT images. Five patients with positive PET/CT images did not have cancer confirmed with histopathology.
- As shown in Table 5, within each study at least half the patients with non-informative conventional imaging had positive 11C-choline PET/CT images and histologically verified recurrent prostate cancer.
# How Supplied
- Choline C 11 Injection is packaged in a single dose glass vial containing between 148 MBq to 1,225 MBq (4 mCi to 33.1 mCi) per milliliter of 11C-choline at EOS calibration time in aqueous 0.9% sodium chloride solution.
## Storage
- Store Choline C 11 Injection at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F). Use the solution within 120 minutes of EOS calibration.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to drink plenty of water or other fluids (as tolerated) in the four hours before their PET/CT study.
- Instruct patients to void after completion of each image acquisition session and as often as possible for one hour after the PET/CT scan ends.
# Precautions with Alcohol
Alcohol-Choline c-11 interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CHOLINE C 11®
# Look-Alike Drug Names
There is limited information regarding Choline c-11 Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Choline c-11
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Choline c-11 is a diagnostic agent that is FDA approved for the treatment of positron emission tomography (PET) imaging of patients with suspected prostate cancer recurrence and non-informative bone scintigraphy, computerized tomography (CT) or magnetic resonance imaging (MRI). Common adverse reactions include mild injection site reactions.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Choline C 11 Injection is indicated for positron emission tomography (PET) imaging of patients with suspected prostate cancer recurrence and non-informative bone scintigraphy, computerized tomography (CT) or magnetic resonance imaging (MRI).
- In these patients, 11 C-choline PET imaging may help identify potential sites of prostate cancer recurrence for subsequent histologic confirmation. Suspected prostate recurrence is based upon elevated blood prostate specific antigen (PSA) levels following initial therapy. In clinical studies, images were produced with PET/CT coregistration.
- Limitation of Use: 11 C-choline PET imaging is not a replacement for histologic verification of recurrent prostate cancer.
- Choline C 11 Injection contains 148 – 1,225 MBq (4 – 33.1 mCi) per milliliter of 11C-choline at end of synthesis (EOS) calibration time in aqueous 0.9% sodium chloride solution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Choline c-11 in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Choline c-11 in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Choline c-11 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 Choline c-11 in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Choline c-11 in pediatric patients.
# Contraindications
There is limited information regarding Choline c-11 Contraindications in the drug label.
# Warnings
- Imaging errors have been reported with 11C-choline PET and PET/CT imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent cancer. 11C-choline uptake is not specific for prostate cancer and may occur with other types of cancer (such as lung carcinoma and brain tumors). Clinical correlation, including histopathological evaluation of the suspected recurrence site, is essential to proper use of the PET imaging information.
- Blood PSA levels < 2 ng/mL have been associated with poor performance of 11C-choline PET imaging (higher numbers of false positive and false negative results).
- Tissue inflammation as well as prostatic hyperplasia have been associated with false positive 11C-choline PET images.
- Concomitant colchicine or androgen-deprivation therapeutic drugs (such as luteinizing hormone-releasing analogs and anti-androgen drugs) may interfere with 11C-choline PET imaging. One published report of 18F-methylcholine PET imaging indicated that discontinuation of colchicine for two weeks resolved the colchicine effect. The impact of discontinuation of androgen-deprivation therapy upon 11C-choline PET imaging has not been established.
- As with any injectable drug product, allergic reactions and anaphylaxis may occur. Emergency resuscitation equipment and personnel should be immediately available.
- Choline C 11 Injection contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Safe handling should be ensured to minimize radiation exposure to the patient and health care workers.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Choline c-11 Clinical Trials Experience in the drug label.
## Postmarketing Experience
- Exclusive of an uncommon, mild injection site reaction, no adverse reactions to 11C-choline have been reported.
# Drug Interactions
- Colchicine and androgen-deprivation therapeutic drugs have been reported to interfere with choline-based PET imaging.
- The impact of androgen-deprivation therapeutic drugs upon 11C-choline PET imaging may depend upon the hormonal responsiveness of a patient’s recurrent prostate cancer. Clinical studies have not established this relationship but published reports suggest 11C-choline PET imaging may be productive in patients with “hormone resistant” recurrent prostate cancer even if the patients are receiving anti-androgen therapy. Imaging may prove unproductive or misleading due to failed or insufficient 11C-choline uptake in patients with hormone-responsive cancer if the patients are receiving androgen-deprivation therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well controlled studies with Choline C 11 Injection in pregnant women and the fetal radiation dose from a 11C-choline PET imaging study is unknown. It is not known whether Choline C 11 Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Animal reproduction studies have not been conducted with 11C-choline.
- All radiopharmaceuticals, including Choline C 11 Injection, have a potential to cause fetal harm. The likelihood of fetal harm depends on the stage of fetal development and the magnitude of the radiopharmaceutical dose. Assess pregnancy status before administering Choline C 11 Injection to a female of child bearing potential. Choline C 11 Injection should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Choline c-11 in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Choline c-11 during labor and delivery.
### Nursing Mothers
- Choline C 11 Injection is not indicated for use in women. It is not known whether Choline C 11 Injection is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for radiation exposure to nursing infants from Choline C 11 Injection, nursing mothers should use alternative infant nutrition sources (e.g., stored breast milk or infant formula) and pump and discard breast milk for 8 hours (>10 half lives of radioactive decay for 11C isotope) after administration of the drug or avoid use of the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of Choline C 11 Injection have not been established in pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Choline c-11 in geriatric settings.
### Gender
There is no FDA guidance on the use of Choline c-11 with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Choline c-11 with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Choline c-11 in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Choline c-11 in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Choline c-11 in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Choline c-11 in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intra venous
### Monitoring
There is limited information regarding Choline c-11 Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Choline c-11 and IV administrations.
# Overdosage
There is limited information regarding Choline c-11 overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Choline c-11 Pharmacology in the drug label.
## Mechanism of Action
- Choline C 11 Injection is a radiolabeled analog of choline, a precursor molecule essential for the biosynthesis of cell membrane phospholipids. Choline is involved in synthesis of the structural components of cell membranes, as well as modulation of trans-membrane signaling. Increased phospholipid synthesis (i.e., increased uptake of choline) has been associated with cell proliferation and the transformation process that occurs in tumor cells.
## Structure
## Pharmacodynamics
- In a study of men with prostatic hyperplasia or primary prostate cancer, PET imaging showed 11C-choline radioactivity accumulated rapidly within the prostate; uptake appeared to peak by five minutes following injection of the drug and activity was retained over the subsequent 30 minute scanning period. Little uptake was observed in the bladder and rectum.
## Pharmacokinetics
- Distribution: 11C-choline distributes mainly to the pancreas, kidneys, liver, spleen and colon. Based upon the relatively low urinary excretion of radioactivity, renal distribution is predominantly to the organ itself, rather than via formation of urine.
- Following intravenous administration, 11C-choline undergoes metabolism resulting in the detection of 11C-betaine as the major metabolite in blood. In a study of patients with prostate cancer or brain disorders, the fractional activities of 11C-choline and 11C-betaine in human arterial plasma appeared to reach a plateau within 25 minutes, with 11C-betaine representing 82± 9% of the total 11C detected at that time point. A small amount of unmetabolized 11C-choline was detected within the blood at the final sampling time point (40 minutes).
- Urinary excretion of 11C-choline was < 2% of the injected radioactivity at 1.5 hours after injection of the drug. The rate of 11C-choline excretion in urine was 0.014 mL/min.
## Nonclinical Toxicology
- Long term studies have not been performed to evaluate the carcinogenic potential of Choline C 11 Injection. The mutagenic potential of Choline C 11 Injection has not been adequately evaluated; however, any radiopharmaceutical, including Choline C 11 Injection, has the potential to be mutagenic. The effect of Choline C 11 Injection on fertility has not been evaluated.
# Clinical Studies
- A systematic review of published reports identified four studies that contained data sufficient to compare 11C-choline PET imaging to histopathology (truth standard) among patients with suspected prostate cancer recurrence and non-informative conventional imaging (for most patients, CT or MRI). In general, the suspected recurrence criteria consisted of at least two sequential PSA levels of > 0.2 ng/mL for men who had undergone prostatectomy and PSA levels of ≥ 2 ng/mL above the post-therapy nadir for men who had undergone radiotherapy. The studies were predominantly single clinical site experiences and image acquisition generally surveyed radioactivity distribution from the base of the pelvis to the base of the skull.
- Prospective studies: Two studies examined the ability of 11C-choline PET/CT to detect prostate cancer in pelvic and/or retroperitoneal lymph nodes among patients who had previously undergone radical prostatectomy. Both studies used a truth standard of lymph node histopathology. 11C-choline images were interpreted by readers masked to clinical information; surgical resection of lymph nodes was performed by surgeons aware of the 11C-choline PET/CT results.
- In Study One3, 25 patients who underwent 11C-choline PET/CT and conventional imaging (CT or MRI) were scheduled to undergo pelvic or pelvic plus retroperitoneal lymphadenectomy following the imaging identification of suspected lymph node metastases. The median PSA was 2.0 ng/mL (range 0.2 to 23.1 ng/mL). The study excluded subjects with metastatic disease detected by bone scintigraphy or isolated prostatic fossa recurrence. Among the 25 patients, 21 had positive 11C-choline PET/CT scans; histopathology verified cancer in 19 of these patients. Lymph node histopathology detected no cancer among the four patients who had surgery based only on positive conventional imaging; 11C-choline PET/CT was negative in all four patients. The study report included information for patients who had non-informative conventional imaging (CT or MRI, bone scintigraphy and transrectal ultrasound), as shown in Table 5.
- In Study Two4, 15 patients were scheduled to undergo pelvic or pelvis plus retroperitoneal lymphadenectomy solely based upon positive 11C-choline PET/CT imaging in the setting of negative conventional imaging (ultrasound and/or CTand/or MRI and/or bone scintigraphy). The median PSA was 2.0 ng/mL (range 1.0 to 8.0 ng/mL); all patients had previously undergone radical prostatectomy. Eight of the 15 patients had cancer verified by lymph node histology; histology detected no cancer in seven patients.
- Retrospective Studies: Two studies were retrospective reviews of patients who underwent 11C-choline PET/CT and had histopathology obtained from biopsy of the prostatic fossa or other suspected recurrence sites.
- In Study Three5, 11C-choline PET/CT imaging was performed among 36 patients with suspected prostate cancer recurrence and 13 subjects without suspected recurrence (controls). Prostatic fossa biopsies were performed among the patients with suspected recurrence. All the patients and control subjects had previously undergone radical prostatectomy; patient with suspected recurrence had no evidence of cancer using conventional clinical evaluations, including trans-rectal ultrasound and bone scintigraphy. PET/CT scans were interpreted by readers masked to clinical information. Median PSA was 2.0 ng/mL (range 0.3 – 12.1 ng/mL) for patients with suspected recurrence and 0.1 ng/mL (range 0.0 – 0.2 ng/mL) in control subjects. Prostatic fossa biopsy showed cancer in 33 of the 36 patients with suspected recurrence. PET/CT scans were positive in 25 of the 36 patients; two patients had false positive scans (one scan in a control subject and one scan in a suspected recurrence subject who had no cancer detected on prostatic fossa biopsy). Among the 13 control subjects, 12 had negative PET/CT scans.
- In Study Four6,7, 34 patients with negative conventional imaging underwent 11C-choline PET/CT and subsequently had biopsies of suspected recurrence sites. The median PSA level of the 34 patients was 3.9 ng/mL (range 0.2 – 65.0 ng/mL); 22 of the patients had previously undergone radical prostatectomy and 12 had received other therapy (radiotherapy, anti-androgen therapy or cryotherapy). 11C-choline PET/CT images were positive in 30 patients and negative in four patients. Cancer was verified by histopathology in 29 patients; 25 had positive PET/CT images and four had negative PET/CT images. Five patients with positive PET/CT images did not have cancer confirmed with histopathology.
- As shown in Table 5, within each study at least half the patients with non-informative conventional imaging had positive 11C-choline PET/CT images and histologically verified recurrent prostate cancer.
# How Supplied
- Choline C 11 Injection is packaged in a single dose glass vial containing between 148 MBq to 1,225 MBq (4 mCi to 33.1 mCi) per milliliter of 11C-choline at EOS calibration time in aqueous 0.9% sodium chloride solution.
## Storage
- Store Choline C 11 Injection at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F). Use the solution within 120 minutes of EOS calibration.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to drink plenty of water or other fluids (as tolerated) in the four hours before their PET/CT study.
- Instruct patients to void after completion of each image acquisition session and as often as possible for one hour after the PET/CT scan ends.
# Precautions with Alcohol
Alcohol-Choline c-11 interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CHOLINE C 11®[1]
# Look-Alike Drug Names
There is limited information regarding Choline c-11 Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Choline_c-11 | |
ae3a705801792717e47a37fc15efad776ca8820b | wikidoc | Chromic acid | Chromic acid
Chromic acid generally refers to a collection of compounds generated by the acidification of solutions containing chromate and dichromate anions or the dissolving of chromium trioxide in sulfuric acid. Often the species are assigned the formulas H2CrO4 and H2Cr2O7. The anhydride of these "chromic acids" is chromium trioxide, also called chromium(VI) oxide; industrially, this compound is sometimes sold as "chromic acid."
Regardless of its exact formula, chromic acid features chromium in an oxidation state of +6 (or VI), often referred to as hexavalent chromium. Chromium can exist in a number of oxidation states, hexavalent state is the highest. In its reactions chromic acid is reduced in redox reactions to the purple 3+ ion, or other Cr(III) species, which usually have a green colour.
# Uses
Chromic acid is an intermediate in chromium plating, and is also used in ceramic glazes, and colored glass. Because a solution of chromic acid in sulfuric acid (also known as a sulfochromic mixture) is a powerful oxidizing agent, it can be used to clean laboratory glassware. This application has declined due to environmental concerns. Furthermore the acid leaves residues that can interfere with certain applications, such as NMR spectroscopy.
Chromic acid has also been widely used in the band instrument repair industry, due to its ability to "brighten" raw brass. A chromic acid dip leaves behind a bright yellow patina on the brass. Due to growing health and environmental concerns, many have discontinued use of this chemical in their repair shops.
# Reactions
Chromic acid is capable of oxidizing many kinds of organic compounds and many variations on this reagent have been developed:
- Chromic acid in aqueous sulfuric acid and acetone is known as the Jones reagent, which will oxidize primary and secondary alcohols to carboxylic acids and ketones respectively, while rarely affecting unsaturated bonds.
- Pyridinium chlorochromate is generated from chromium trioxide and pyridinium hydrochloride. This reagent converts primary alcohols to the corresponding aldehydes (R-CHO).
- Collins reagent is an adduct of chromium trioxide and pyridine used for diverse oxidations.
- Chromyl chloride, CrO2Cl2 is a well-defined molecular compound that is generated from chromic acid.
### Illustrative transformations
- Oxidation of methylbenzenes to benzoic acids.
- Oxidative scission of indene to homophthalic acid.
- Oxidation of secondary alcohol to ketone (cyclooctanone) and nortricyclanone.
### Use in qualitative organic analysis
In organic chemistry, dilute solutions of hexavalent chromium can be used to oxidize primary or secondary alcohols to the corresponding aldehydes and ketones. Tertiary alcohol groups are unaffected. Because of the oxidation is signaled by a color change from orange to a blue-green, chromic acid is used as a qualitative analytical test for the presence of primary or secondary alcohols.
### Alternative reagents
In oxidations of alcohols or aldehydes into carboxylic acids, chromic acid is one of several reagents, including several that are catalytic. For example nickel(II) salts catalyze oxidations by bleach. Each oxidant offers advantages and disadvantages.
# Safety
Chromium(VI) compounds are toxic and carcinogenic. For this reason, chromic acid oxidation is not used on an industrial scale.
# Notes
- ↑ Freeman, F. "Chromic Acid" Encyclopedia of Reagents for Organic Synthesis (2001) John Wiley & Sons, doi:10.1002/047084289X.rc164
- ↑ Template:OrgSynth
- ↑ Template:OrgSynth
- ↑ Template:OrgSynth
- ↑ Template:OrgSynth
- ↑ J. M. Grill, J. W. Ogle, S. A. Miller (2006). "An Efficient and Practical System for the Catalytic Oxidation of Alcohols, Aldehydes, and α,β-Unsaturated Carboxylic Acids". J. Org. Chem. 71 (25): 9291–9296. doi:10.1021/jo0612574.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} | Chromic acid
Chromic acid generally refers to a collection of compounds generated by the acidification of solutions containing chromate and dichromate anions or the dissolving of chromium trioxide in sulfuric acid. Often the species are assigned the formulas H2CrO4 and H2Cr2O7. The anhydride of these "chromic acids" is chromium trioxide, also called chromium(VI) oxide; industrially, this compound is sometimes sold as "chromic acid."
Regardless of its exact formula, chromic acid features chromium in an oxidation state of +6 (or VI), often referred to as hexavalent chromium. Chromium can exist in a number of oxidation states, hexavalent state is the highest. In its reactions chromic acid is reduced in redox reactions to the purple [Cr(H2O)6]3+ ion, or other Cr(III) species, which usually have a green colour.
# Uses
Chromic acid is an intermediate in chromium plating, and is also used in ceramic glazes, and colored glass. Because a solution of chromic acid in sulfuric acid (also known as a sulfochromic mixture) is a powerful oxidizing agent, it can be used to clean laboratory glassware. This application has declined due to environmental concerns. Furthermore the acid leaves residues that can interfere with certain applications, such as NMR spectroscopy.
Chromic acid has also been widely used in the band instrument repair industry, due to its ability to "brighten" raw brass. A chromic acid dip leaves behind a bright yellow patina on the brass. Due to growing health and environmental concerns, many have discontinued use of this chemical in their repair shops.
# Reactions
Chromic acid is capable of oxidizing many kinds of organic compounds and many variations on this reagent have been developed:
- Chromic acid in aqueous sulfuric acid and acetone is known as the Jones reagent, which will oxidize primary and secondary alcohols to carboxylic acids and ketones respectively, while rarely affecting unsaturated bonds.[1]
- Pyridinium chlorochromate is generated from chromium trioxide and pyridinium hydrochloride. This reagent converts primary alcohols to the corresponding aldehydes (R-CHO).[1]
- Collins reagent is an adduct of chromium trioxide and pyridine used for diverse oxidations.
- Chromyl chloride, CrO2Cl2 is a well-defined molecular compound that is generated from chromic acid.
### Illustrative transformations
- Oxidation of methylbenzenes to benzoic acids.[2]
- Oxidative scission of indene to homophthalic acid.[3]
- Oxidation of secondary alcohol to ketone (cyclooctanone)[4] and nortricyclanone.[5]
### Use in qualitative organic analysis
In organic chemistry, dilute solutions of hexavalent chromium can be used to oxidize primary or secondary alcohols to the corresponding aldehydes and ketones. Tertiary alcohol groups are unaffected. Because of the oxidation is signaled by a color change from orange to a blue-green, chromic acid is used as a qualitative analytical test for the presence of primary or secondary alcohols.[1]
### Alternative reagents
In oxidations of alcohols or aldehydes into carboxylic acids, chromic acid is one of several reagents, including several that are catalytic. For example nickel(II) salts catalyze oxidations by bleach.[6] Each oxidant offers advantages and disadvantages.
# Safety
Chromium(VI) compounds are toxic and carcinogenic. For this reason, chromic acid oxidation is not used on an industrial scale.
# Notes
- ↑ Freeman, F. "Chromic Acid" Encyclopedia of Reagents for Organic Synthesis (2001) John Wiley & Sons, doi:10.1002/047084289X.rc164
- ↑ Template:OrgSynth
- ↑ Template:OrgSynth
- ↑ Template:OrgSynth
- ↑ Template:OrgSynth
- ↑ J. M. Grill, J. W. Ogle, S. A. Miller (2006). "An Efficient and Practical System for the Catalytic Oxidation of Alcohols, Aldehydes, and α,β-Unsaturated Carboxylic Acids". J. Org. Chem. 71 (25): 9291–9296. doi:10.1021/jo0612574.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} | https://www.wikidoc.org/index.php/Chromic_acid | |
65ad451351677dbccc13be59f1af013a4208fad4 | wikidoc | Chromophobia | Chromophobia
# Overview
Chromophobia (also known as chromatophobia or chrematophobia) is a persistent, irrational fear of, or aversion to, colors and is usually a conditioned response. While actual clinical phobias to color are rare, colors can elicit hormonal responses and psychological reactions.
Chromophobia may also refer to an aversion of use of color in products or design. Within cellular biology, "Chromophobe cell|chromophobic" cells are a classification of cells that do not attract hematoxylin, and is related to chromatolysis.
Names exist that mean fear of specific colors such as erythrophobia for the fear of red and leukophobia for the fear of white. A fear of the color red may be associated with a fear of blood.
In his book Chromophobia published in 2000, David Batchelor (artist and writer)|David Batchelor says that in Western culture, color has often been treated as corrupting, foreign or superficial. Michael Taussig states that the cultural aversion to color can be traced back a thousand years, with Batchelor stating that it can be traced back to Aristotle's privileging of line over color.
In a study, hatchling Loggerhead sea turtles were found to have an aversion to lights in the yellow wave spectrum which is thought to be a characteristic that helps orient themselves toward the ocean. The Mediterranean sand smelt, Atherina hepsetus, has shown an aversion to red objects placed next to a tank while it will investigate objects of other colors. In other experiments, geese]] have been conditioned to have adverse reactions to foods of a particular color, although the reaction was not observed in reaction to colored water.
The title character in Alfred Hitchcock]]'s Marnie (film)|Marnie has an aversion to the color red caused by a trauma during her childhood which Hitchcock presents through expressionistic techniques, such as a Wash (visual arts)|wash of red coloring a close up of Marnie. | Chromophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chromophobia (also known as chromatophobia[1] or chrematophobia[2]) is a persistent, irrational fear of, or aversion to, colors and is usually a conditioned response.[2] While actual clinical phobias to color are rare, colors can elicit hormonal responses and psychological reactions.[3]
Chromophobia may also refer to an aversion of use of color in products or design.[4] Within cellular biology, "Chromophobe cell|chromophobic" cells are a classification of cells that do not attract hematoxylin,[5] and is related to chromatolysis.[6]
Names exist that mean fear of specific colors such as erythrophobia for the fear of red and leukophobia for the fear of white.[2] A fear of the color red may be associated with a fear of blood.[2]
In his book Chromophobia published in 2000, David Batchelor (artist and writer)|David Batchelor says that in Western culture, color has often been treated as corrupting, foreign or superficial.[7] Michael Taussig states that the cultural aversion to color can be traced back a thousand years,[8] with Batchelor stating that it can be traced back to Aristotle's privileging of line over color.[9]
In a study, hatchling Loggerhead sea turtles were found to have an aversion to lights in the yellow wave spectrum which is thought to be a characteristic that helps orient themselves toward the ocean.[10][11] The Mediterranean sand smelt, Atherina hepsetus, has shown an aversion to red objects placed next to a tank while it will investigate objects of other colors.[12] In other experiments, geese]] have been conditioned to have adverse reactions to foods of a particular color, although the reaction was not observed in reaction to colored water.[13]
The title character in Alfred Hitchcock]]'s Marnie (film)|Marnie has an aversion to the color red caused by a trauma during her childhood[14] which Hitchcock presents through expressionistic techniques, such as a Wash (visual arts)|wash of red coloring a close up of Marnie.[15] | https://www.wikidoc.org/index.php/Chromophobia | |
7339c030e4ddb540c15870d2e2ca8a6bc66c6ed1 | wikidoc | Chromosome 1 | Chromosome 1
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which are the basic units of information for DNA. It represents about 8% of the total DNA in human cells.
It was the last completed chromosome, sequenced two decades after the beginning of the Human Genome Project.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 1. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## Gene list
The following is a partial list of genes on human chromosome 1. For complete list, see the link in the infobox on the right.
- DENN1B hypothesized to be related to asthma
### p-arm
Partial list of the genes located on p-arm (short arm) of human chromosome 1:
- AADACL3: Arylacetamide deacetylase-like 3
- AADACL4: Arylacetamide deacetylase-like 4
- ACADM: acyl-Coenzyme A dehydrogenase, C-4 to C-12 straight chain
- ACTL8: Actin-like 8
- ADGRL2 (1p31.1): adhesion G protein-coupled receptor L2
- ADPRHL2: Poly(ADP-ribose) glycohydrolase ARH3
- AMPD2: encoding enzyme AMP deaminase 2
- ARID1A (1p36)
- ATXN7L2: Ataxin 7-like 2
- AZIN2: encoding enzyme Antizyme inhibitor 2 (AzI2) also known as arginine decarboxylase (ADC)
- BCAS2: Breast carcinoma amplified sequence 2
- BCL10 (1p22)
- BCL2L15 (1p13)
- C1orf103: encoding protein Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1)
- C1orf109: chromosome 1 open reading frame 109
- C1orf123: chromosome 1 open reading frame 123
- CACHD1 encoding protein Cache domain containing 1
- CAMTA1 (1p36)
- CASP9 (1p36)
- CASZ1 (1p36): Castor zinc finger 1
- CSDE1: Cold shock domain containing E1
- CHD5 (1p36)
- CLIC4 (1p36)
- CLSPN (1p34)
- CMPK: UMP-CMP kinase
- COL16A1 (1p35)
- COL11A1: collagen, type XI, alpha 1
- CPT2: carnitine palmitoyltransferase II
- CRYZ: Crystallin zeta
- CYP4B1 (1p33)
- CYR61 (1p22)
- DBT: dihydrolipoamide branched chain transacylase E2
- DCLRE1B: DNA cross-link repair 1B
- DEPDC1 encoding protein DEP domain containing 1
- DIRAS3 (1p31): DIRAS family, GTP-binding RAS-like 3
- DPH5: Diphthine synthase
- DVL1 (1p36)
- ENO1 (1p36)
- EPHA2 (1p36)
- EPS15 (1p32)
- ESPN: espin (autosomal recessive deafness 36)
- EVI5: ecotropic viral integration site 5
- EXTL1: exostosin like glycosyltransferase 1
- EXTL2: exostosin like glycosyltransferase 2
- FAM46B: family with sequence similarity 46, member B
- FAM46C: family with sequence similarity 46, member C
- FAM76A: family with sequence similarity 76, member A
- FBXO2: F-box protein 2
- FNBP1L encoding protein Formin-binding protein 1-like
- FPGT: Fucose-1-phosphate guanylyltransferase
- FUBP1 (1p31)
- GALE: UDP-galactose-4-epimerase
- GADD45A (1p31)
- GBP1 (1p22)
- GBP2: guanylate binding protein 2
- GBP5 encoding protein Guanylate binding protein 5
- GJB3: gap junction protein, beta 3, 31kDa (connexin 31)
- GLMN (1p22)
- GNL2: G protein nucleolar 2
- GSTM1 (1p13)
- HDAC1 (1p35)
- HES2: Hes family bHLH transcription factor 2
- HES3: Hes family bHLH transcription factor 3
- HMGCL: 3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase (hydroxymethylglutaricaciduria)
- HAO2 encoding protein Hydroxyacid oxidase 2
- HMGCS2: 3-hydroxy-3-methylglutaryl-CoA synthase 2
- HP1BP3: Heterochromatin protein 1, binding protein 3
- IFI6: Interferon alpha-inducible protein 6
- IL22RA1 (1p36)
- INTS11: Integrator complex subunit 11
- JAK1 (1p31)
- JUN (1p32)
- KCNQ4: potassium voltage-gated channel, KQT-like subfamily, member 4
- KIF1B: kinesin family member 1B
- L1TD1: LINE-1 type transposase domain containing 1
- LCK (1p35)
- LRRC39: Leucine-rich repeat-containing protein 39
- LRRC40: Leucine-rich repeat-containing protein 40
- LRRC41: Leucine-rich repeat-containing protein 41
- LRRC8D: Leucine-rich repeat-containing protein 8D
- MAN1A2: Mannosyl-oligosaccharide 1,2-alpha-mannosidase IB
- MEAF6: MYST/ESA1 associated factor 6
- MECR: Trans-2-enoyl-CoA reductase, mitochondrial
- MFAP2: Microfibrillar-associated protein 2
- MIB2 (1p36)
- MIER1 (1p31)
- MFN2: mitofusin 2
- MFSD2: Major facilitator superfamily domain containing 2A
- MIR6079: microRNA 6079
- MMEL1: Membrane metallo-endopeptidase-like 1
- MTFR1L: mitochondrial fission regulator 1 like
- MTHFR (1p36): 5,10-methylenetetrahydrofolate reductase (NADPH)
- MUL1: Mitochondrial E3 ubiquitin protein ligase 1
- MUTYH (1p34): mutY homolog (E. coli)
- NBPF3: Neuroblastoma breakpoint family member 3
- NGF: Nerve Growth Factor
- NOL9: Nucleolar protein 9
- NRAS (1p13)
- NOTCH2 (1p12)
- OLFML3: Olfactomedin-like 3
- OMA1: Metalloendopeptidase OMA1, mitochondrial
- OVGP1: Oviductal glycoprotein 1
- PARK7 (1p36): Parkinson disease (autosomal recessive, early onset) 7
- PINK1: PTEN induced putative kinase 1
- PLOD1: procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1
- PRMT6: Protein arginine methyltransferase 6
- PSRC1: Proline/serine-rich coiled-coil protein 1
- RAD54L: RAD54-like
- RAP1A (1p13)
- RBM15 (1p13)
- RCC2: Regulator of chromosome condensation 2
- REG4 (1p12)
- RHBDL2: Rhomboid like 2
- RHOC (1p13)
- RLF: rearranged L-myc fusion
- RNF11 (1p32)
- RNF220: RING finger protein 220
- RPA2 (1p35)
- RSPO1 (1p34)
- S100A1 (1q21)
- SDC3: Syndecan-3
- SDHB (1p36)
- SFPQ (1p34)
- SGIP1: SH3 domain GRB2-like protein 3-interaction protein 1
- SH3BGRL3: SH3 domain-binding glutamic acid-rich-like protein 3
- SLC16A1 (1p13)
- SPSB1: SPRY domain-containing SOCS box protein 1
- STIL (1p33)
- SYCP1: Synaptonemal complex protein 1
- SZT2: Seizure threshold 2 homolog
- TACSTD2: tumor-associated calcium signal transducer 2
- TAL1 (1p33)
- TCEB3: Transcription elongation factor B polypeptide 3
- TGFBR3 (1p22)
- THRAP3 (1p34)
- TIE1 (1p34)
- TMCO4: encoding protein transmembrane and coiled-coil domains 4
- TMEM48: encoding protein nucleoporin NDC1
- TMEM50A: Transmembrane protein 50A
- TMEM59: Transmembrane protein 59
- TMEM69: Transmembrane protein 69
- TMEM201 encoding protein Transmembrane protein 201
- TMEM222: Transmembrane protein 222
- TOE1: Target of EGR1 protein 1
- TRAPPC3: Trafficking protein particle complex subunit 3
- TRIT1: tRNA isopentenyltransferase, mitochondrial
- TSHB: thyroid stimulating hormone, beta
- TTC39A: Tetratricopeptide repeat 39A
- UBR4: E3 ubiquitin-protein ligase component n-recognin 4
- UROD: uroporphyrinogen decarboxylase (the gene for porphyria cutanea tarda)
- USP1 (1p31)
- USP48: Ubiquitin carboxyl-terminal hydrolase 48
- VAV3 (1p13)
- VPS13D: Vacuolar protein sorting-associated protein 13D
- VTCN1 (1p13)
- WARS2: Tryptophanyl-tRNA synthetase, mitochondrial
- WDR77 (1p13)
- YBX1 (1p34)
- ZCCHC17: zinc finger CCHC-type containing 17
- ZMYM1 encoding protein Zinc finger MYM-type containing 1
- ZNF436: Zinc finger protein 436
- ZYG11B encoding protein Zyg-11 family member B, cell cycle regulator
- ZZZ3: ZZ-type zinc finger-containing protein 3
### q-arm
Partial list of the genes located on q-arm (long arm) of human chromosome 1:
- ABL2 (1q25)
- ADIPOR1 (1q32)
- AHCTF1: encoding protein ELYS
- AKT3 (1q43-44)
- ANGPTL1: Angiopoietin-related protein 1
- ARHGEF2 (1q22)
- ARID4B: encoding protein AT-rich interactive domain-containing protein 4B
- ARV1 encoding protein ARV1 homolog (S. cerevisiae)
- ARNT (1q21)
- ASPM (1q31): a brain size determinant
- ATF3 (1q32)
- ATP2B4 (1q32)
- BCL9 (1q21)
- C1orf21: chromosome 1 open reading frame 21
- C1orf35 encoding protein Chromosome 1 open reading frame 35
- C1orf49: chromosome 1 open reading frame 49
- C1orf74: chromosome 1 open reading frame 74
- C1orf106: chromosome 1 open reading frame 106
- CD5L: CD5 molecule like
- CENPL: Centromere protein L
- CENPF (1q41)
- CHTOP: Chromatin target of prmt1
- CNIH4: cornichon homolog 4
- CNST: Consortin
- CREG1: Cellular repressor of E1A stimulated genes 1
- CRP: C-reactive protein
- CRTC2 (1q21)
- CSRP1: Cysteine and glycine rich protein 1
- DDX59: DEAD-box helicase 59
- DPT: Dermatopontin
- DISC2, long non-coding RNA
- DUSP10 (1q41)
- DNAH14 encoding protein Dynein, axonemal, heavy chain 14
- ECM1 (1q21)
- EDEM3: ER degradation enhancing alpha-mannosidase like protein 3
- EGLN1 (1q42)
- ENAH (1q42)
- ESRRG (1q41)
- FAM20B: FAM20B, glycosaminoglycan xylosylkinase
- FAM63A: Family with sequence similarity 63, member A
- FAM78B: family with sequence similarity 78, member B
- FAM129A: family with sequence similarity 129, member A
- FBXO28: F-box protein 28
- FCMR: Fc fragment of IgM receptor
- FCGR2B (1q23)
- FH (1q43)
- FMO3: flavin containing monooxygenase 3
- FRA1J encoding protein Fragile site, 5-azacytidine type, common, fra(1)(q12)
- GAS5 (1q25)
- GBA: glucosidase, beta; acid (includes glucosylceramidase) (gene for Gaucher disease)
- GBAP1: glucosylceramidase beta pseudogene 1
- GLC1A: gene for glaucoma
- GON4L: gon-4 like
- GPA33 (1q24)
- GPR37L1 G protein-coupled receptor 37 like 1
- HEATR1: HEAT repeat-containing protein 1
- HFE2: hemochromatosis type 2 (juvenile)
- HIST2H2AB: Histone 2A type 2-B
- HIST2H2BF: Histone H2B type 2-F
- HIST2H3PS2: Histone cluster 2, H3, pseudogene 2
- HIST3H2A: Histone H2A type 3
- HIST3H2BB: Histone H2B type 3-B
- HPC1: gene for prostate cancer
- IGSF8 (1q23)
- INTS3: Integrator complex subunit 3
- IRF6: gene for connective tissue formation
- KCNH1 (1q32)
- KIF14 (1q32)
- LEFTY1: Left-right determination factor 1
- LHX9 encoding protein LIM homeobox 9
- LMNA: lamin A/C
- LOC645166 encoding protein Lymphocyte-specific protein 1 pseudogene
- LYPLAL1: Lysophospholipase-like 1
- MAPKAPK2 (1q32)
- MIR194-1: microRNA 194-1
- MIR5008: microRNA 5008
- MPC2: Mitochondrial pyruvate carrier 2
- MOSC1: MOCO sulphurase C-terminal domain containing 1
- MOSC2: MOSC domain-containing protein 2, mitochondrial
- MPZ: myelin protein zero (Charcot–Marie–Tooth neuropathy 1B)
- MSTO1: misato 1
- MTR: 5-methyltetrahydrofolate-homocysteine methyltransferase
- NAV1: Neuron navigator 1
- NBPF16: Neuroblastoma breakpoint family, member 16
- NOC2L: Nucleolar complex protein 2 homolog
- NUCKS1: Nuclear ubiquitous casein and cyclin-dependent kinases substrate
- NVL: Nuclear valosin-containing protein-like
- OLFML2B: Olfactomedin-like 2B
- OPTC: Opticin
- OTUD7B: OTU domain-containing protein 7B
- PACERR encoding protein PTGS2 antisense NFKB1 complex-mediated expression regulator RNA
- PBX1 (1q23)
- PEA15 (1q23)
- PGDB5: PiggyBac transposable element derived 5
- PIAS3 (1q21)
- PI4KB: Phosphatidylinositol 4-kinase beta
- PIP5K1A (1q21): Phosphatidylinositol-4-phosphate 5-kinase type-1 alpha
- PLA2G4A (1q31)
- PPOX: protoporphyrinogen oxidase
- PRCC (1q23)
- PRR9 encoding protein Proline rich 9
- PSEN2 (1q42): presenilin 2 (Alzheimer disease 4)
- PTGS2 (1q31)
- PTPN14 (1q32-41)
- PTPN7 (1q32)
- RABIF: RAB interacting factor
- RASSF5 (1q32)
- RGS2 (1q31)
- RN5S1@: RNA, 5S ribosomal 1q42 cluster
- RPS27 (1q21)
- SCAMP3: Secretory carrier-associated membrane protein 3
- SDHC (1q23)
- SELE (1q24)
- SHC1 (1q21)
- SLC39A1 (1q21)
- SLC50A1: Solute carrier family 50 member 1
- SMCP: Sperm mitochondrial-associated cysteine-rich protein
- SMG7: nonsense mediated mRNA decay factor
- SMYD3 (1q44)
- SPG23
- SPRR1A: Cornifin-A
- SPRR1B: Cornifin-B
- SPRR2A: Small proline rich protein 2A
- SPRTN: Spartan
- TARBP1: TAR (HIV-1) RNA-binding protein 1
- TBCE: Tubulin-specific chaperone E
- THBS3: Thrombospondin 3
- TMCO1: Transmembrane and coiled-coil domain-containing protein 1
- TMEM9: Transmembrane protein 9
- TMEM63A: Transmembrane protein 63A
- TNFSF18 (1q25)
- TNN (1q25)
- TNNT2: cardiac troponin T2
- TOR1AIP1: Torsin-1A-interacting protein 1
- TP53BP2 (1q41)
- TRP (1q31)
- UAP1: UDP-N-acetylhexosamine pyrophosphorylase
- USH2A: Usher syndrome 2A (autosomal recessive, mild)
- USF1 (1q23)
- VPS45: Vacuolar protein sorting-associated protein 45
- VPS72: Vacuolar protein sorting-associated protein 72
- YY1AP1: YY1-associated protein 1
- ZBED6: Zinc finger, BED-type containing 6
- ZC3H11A: Zing finger CCCH domain-containing protein 11A
- ZNF687: zing finger protein 687
- ZNF648 encoding protein Zinc finger protein 648
- ZNF695: Zinc finger protein 695
# Diseases and disorders
There are 890 known diseases related to this chromosome. Some of these diseases are hearing loss, Alzheimer's disease, glaucoma and breast cancer. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident.
Complete monosomy (only having one copy of the entire chromosome) is invariably lethal before birth. Complete trisomy (having three copies of the entire chromosome) is lethal within days after conception. Some partial deletions and partial duplications produce birth defects.
The following diseases are some of those related to genes on chromosome 1 (which contains the most known genetic diseases of any human chromosome):
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome
- Alzheimer's disease
- Breast cancer
- Brooke Greenberg Disease (Syndrome X)
- Carnitine palmitoyltransferase II deficiency
- Charcot–Marie–Tooth disease, types 1 and 2
- collagenopathy, types II and XI
- congenital hypothyroidism
- Ehlers-Danlos syndrome
- Factor V Leiden thrombophilia
- Familial adenomatous polyposis
- galactosemia
- Gaucher disease
- Gaucher-like disease
- Gelatinous drop-like corneal dystrophy
- Glaucoma
- Hearing loss, autosomal recessive deafness 36
- Hemochromatosis
- Hepatoerythropoietic porphyria
- Homocystinuria
- Hutchinson Gilford progeria syndrome
- 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
- Hypertrophic cardiomyopathy, autosomal dominant mutations of TNNT2; hypertrophy usually mild; restrictive phenotype may be present; may carry high risk of sudden cardiac death
- maple syrup urine disease
- medium-chain acyl-coenzyme A dehydrogenase deficiency
- Microcephaly
- Muckle-Wells Syndrome
- Nonsyndromic deafness
- Oligodendroglioma
- Parkinson disease
- Pheochromocytoma
- porphyria
- porphyria cutanea tarda
- popliteal pterygium syndrome
- prostate cancer
- Stickler syndrome
- TAR syndrome
- trimethylaminuria
- Usher syndrome
- Usher syndrome type II
- Van der Woude syndrome
- Variegate porphyria
# Cytogenetic band | Chromosome 1
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which are the basic units of information for DNA.[5] It represents about 8% of the total DNA in human cells.[6]
It was the last completed chromosome, sequenced two decades after the beginning of the Human Genome Project.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 1. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[7]
## Gene list
The following is a partial list of genes on human chromosome 1. For complete list, see the link in the infobox on the right.
- DENN1B hypothesized to be related to asthma
### p-arm
Partial list of the genes located on p-arm (short arm) of human chromosome 1:
- AADACL3: Arylacetamide deacetylase-like 3
- AADACL4: Arylacetamide deacetylase-like 4
- ACADM: acyl-Coenzyme A dehydrogenase, C-4 to C-12 straight chain
- ACTL8: Actin-like 8
- ADGRL2 (1p31.1): adhesion G protein-coupled receptor L2
- ADPRHL2: Poly(ADP-ribose) glycohydrolase ARH3
- AMPD2: encoding enzyme AMP deaminase 2
- ARID1A (1p36)
- ATXN7L2: Ataxin 7-like 2
- AZIN2: encoding enzyme Antizyme inhibitor 2 (AzI2) also known as arginine decarboxylase (ADC)
- BCAS2: Breast carcinoma amplified sequence 2
- BCL10 (1p22)
- BCL2L15 (1p13)
- C1orf103: encoding protein Ligand-dependent nuclear receptor-interacting factor 1 (LRIF1)
- C1orf109: chromosome 1 open reading frame 109
- C1orf123: chromosome 1 open reading frame 123
- CACHD1 encoding protein Cache domain containing 1
- CAMTA1 (1p36)
- CASP9 (1p36)
- CASZ1 (1p36): Castor zinc finger 1
- CSDE1: Cold shock domain containing E1
- CHD5 (1p36)
- CLIC4 (1p36)
- CLSPN (1p34)
- CMPK: UMP-CMP kinase
- COL16A1 (1p35)
- COL11A1: collagen, type XI, alpha 1
- CPT2: carnitine palmitoyltransferase II
- CRYZ: Crystallin zeta
- CYP4B1 (1p33)
- CYR61 (1p22)
- DBT: dihydrolipoamide branched chain transacylase E2
- DCLRE1B: DNA cross-link repair 1B
- DEPDC1 encoding protein DEP domain containing 1
- DIRAS3 (1p31): DIRAS family, GTP-binding RAS-like 3
- DPH5: Diphthine synthase
- DVL1 (1p36)
- ENO1 (1p36)
- EPHA2 (1p36)
- EPS15 (1p32)
- ESPN: espin (autosomal recessive deafness 36)
- EVI5: ecotropic viral integration site 5
- EXTL1: exostosin like glycosyltransferase 1
- EXTL2: exostosin like glycosyltransferase 2
- FAM46B: family with sequence similarity 46, member B
- FAM46C: family with sequence similarity 46, member C
- FAM76A: family with sequence similarity 76, member A
- FBXO2: F-box protein 2
- FNBP1L encoding protein Formin-binding protein 1-like
- FPGT: Fucose-1-phosphate guanylyltransferase
- FUBP1 (1p31)
- GALE: UDP-galactose-4-epimerase
- GADD45A (1p31)
- GBP1 (1p22)
- GBP2: guanylate binding protein 2
- GBP5 encoding protein Guanylate binding protein 5
- GJB3: gap junction protein, beta 3, 31kDa (connexin 31)
- GLMN (1p22)
- GNL2: G protein nucleolar 2
- GSTM1 (1p13)
- HDAC1 (1p35)
- HES2: Hes family bHLH transcription factor 2
- HES3: Hes family bHLH transcription factor 3
- HMGCL: 3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase (hydroxymethylglutaricaciduria)
- HAO2 encoding protein Hydroxyacid oxidase 2
- HMGCS2: 3-hydroxy-3-methylglutaryl-CoA synthase 2
- HP1BP3: Heterochromatin protein 1, binding protein 3
- IFI6: Interferon alpha-inducible protein 6
- IL22RA1 (1p36)
- INTS11: Integrator complex subunit 11
- JAK1 (1p31)
- JUN (1p32)
- KCNQ4: potassium voltage-gated channel, KQT-like subfamily, member 4
- KIF1B: kinesin family member 1B
- L1TD1: LINE-1 type transposase domain containing 1
- LCK (1p35)
- LRRC39: Leucine-rich repeat-containing protein 39
- LRRC40: Leucine-rich repeat-containing protein 40
- LRRC41: Leucine-rich repeat-containing protein 41
- LRRC8D: Leucine-rich repeat-containing protein 8D
- MAN1A2: Mannosyl-oligosaccharide 1,2-alpha-mannosidase IB
- MEAF6: MYST/ESA1 associated factor 6
- MECR: Trans-2-enoyl-CoA reductase, mitochondrial
- MFAP2: Microfibrillar-associated protein 2
- MIB2 (1p36)
- MIER1 (1p31)
- MFN2: mitofusin 2
- MFSD2: Major facilitator superfamily domain containing 2A
- MIR6079: microRNA 6079
- MMEL1: Membrane metallo-endopeptidase-like 1
- MTFR1L: mitochondrial fission regulator 1 like
- MTHFR (1p36): 5,10-methylenetetrahydrofolate reductase (NADPH)
- MUL1: Mitochondrial E3 ubiquitin protein ligase 1
- MUTYH (1p34): mutY homolog (E. coli)
- NBPF3: Neuroblastoma breakpoint family member 3
- NGF: Nerve Growth Factor
- NOL9: Nucleolar protein 9
- NRAS (1p13)
- NOTCH2 (1p12)
- OLFML3: Olfactomedin-like 3
- OMA1: Metalloendopeptidase OMA1, mitochondrial
- OVGP1: Oviductal glycoprotein 1
- PARK7 (1p36): Parkinson disease (autosomal recessive, early onset) 7
- PINK1: PTEN induced putative kinase 1
- PLOD1: procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1
- PRMT6: Protein arginine methyltransferase 6
- PSRC1: Proline/serine-rich coiled-coil protein 1
- RAD54L: RAD54-like
- RAP1A (1p13)
- RBM15 (1p13)
- RCC2: Regulator of chromosome condensation 2
- REG4 (1p12)
- RHBDL2: Rhomboid like 2
- RHOC (1p13)
- RLF: rearranged L-myc fusion
- RNF11 (1p32)
- RNF220: RING finger protein 220
- RPA2 (1p35)
- RSPO1 (1p34)
- S100A1 (1q21)
- SDC3: Syndecan-3
- SDHB (1p36)
- SFPQ (1p34)
- SGIP1: SH3 domain GRB2-like protein 3-interaction protein 1
- SH3BGRL3: SH3 domain-binding glutamic acid-rich-like protein 3
- SLC16A1 (1p13)
- SPSB1: SPRY domain-containing SOCS box protein 1
- STIL (1p33)
- SYCP1: Synaptonemal complex protein 1
- SZT2: Seizure threshold 2 homolog
- TACSTD2: tumor-associated calcium signal transducer 2
- TAL1 (1p33)
- TCEB3: Transcription elongation factor B polypeptide 3
- TGFBR3 (1p22)
- THRAP3 (1p34)
- TIE1 (1p34)
- TMCO4: encoding protein transmembrane and coiled-coil domains 4
- TMEM48: encoding protein nucleoporin NDC1
- TMEM50A: Transmembrane protein 50A
- TMEM59: Transmembrane protein 59
- TMEM69: Transmembrane protein 69
- TMEM201 encoding protein Transmembrane protein 201
- TMEM222: Transmembrane protein 222
- TOE1: Target of EGR1 protein 1
- TRAPPC3: Trafficking protein particle complex subunit 3
- TRIT1: tRNA isopentenyltransferase, mitochondrial
- TSHB: thyroid stimulating hormone, beta
- TTC39A: Tetratricopeptide repeat 39A
- UBR4: E3 ubiquitin-protein ligase component n-recognin 4
- UROD: uroporphyrinogen decarboxylase (the gene for porphyria cutanea tarda)
- USP1 (1p31)
- USP48: Ubiquitin carboxyl-terminal hydrolase 48
- VAV3 (1p13)
- VPS13D: Vacuolar protein sorting-associated protein 13D
- VTCN1 (1p13)
- WARS2: Tryptophanyl-tRNA synthetase, mitochondrial
- WDR77 (1p13)
- YBX1 (1p34)
- ZCCHC17: zinc finger CCHC-type containing 17
- ZMYM1 encoding protein Zinc finger MYM-type containing 1
- ZNF436: Zinc finger protein 436
- ZYG11B encoding protein Zyg-11 family member B, cell cycle regulator
- ZZZ3: ZZ-type zinc finger-containing protein 3
### q-arm
Partial list of the genes located on q-arm (long arm) of human chromosome 1:
- ABL2 (1q25)
- ADIPOR1 (1q32)
- AHCTF1: encoding protein ELYS
- AKT3 (1q43-44)
- ANGPTL1: Angiopoietin-related protein 1
- ARHGEF2 (1q22)
- ARID4B: encoding protein AT-rich interactive domain-containing protein 4B
- ARV1 encoding protein ARV1 homolog (S. cerevisiae)
- ARNT (1q21)
- ASPM (1q31): a brain size determinant
- ATF3 (1q32)
- ATP2B4 (1q32)
- BCL9 (1q21)
- C1orf21: chromosome 1 open reading frame 21
- C1orf35 encoding protein Chromosome 1 open reading frame 35
- C1orf49: chromosome 1 open reading frame 49
- C1orf74: chromosome 1 open reading frame 74
- C1orf106: chromosome 1 open reading frame 106
- CD5L: CD5 molecule like
- CENPL: Centromere protein L
- CENPF (1q41)
- CHTOP: Chromatin target of prmt1
- CNIH4: cornichon homolog 4
- CNST: Consortin
- CREG1: Cellular repressor of E1A stimulated genes 1
- CRP: C-reactive protein
- CRTC2 (1q21)
- CSRP1: Cysteine and glycine rich protein 1
- DDX59: DEAD-box helicase 59
- DPT: Dermatopontin
- DISC2, long non-coding RNA
- DUSP10 (1q41)
- DNAH14 encoding protein Dynein, axonemal, heavy chain 14
- ECM1 (1q21)
- EDEM3: ER degradation enhancing alpha-mannosidase like protein 3
- EGLN1 (1q42)
- ENAH (1q42)
- ESRRG (1q41)
- FAM20B: FAM20B, glycosaminoglycan xylosylkinase
- FAM63A: Family with sequence similarity 63, member A
- FAM78B: family with sequence similarity 78, member B
- FAM129A: family with sequence similarity 129, member A
- FBXO28: F-box protein 28
- FCMR: Fc fragment of IgM receptor
- FCGR2B (1q23)
- FH (1q43)
- FMO3: flavin containing monooxygenase 3
- FRA1J encoding protein Fragile site, 5-azacytidine type, common, fra(1)(q12)
- GAS5 (1q25)
- GBA: glucosidase, beta; acid (includes glucosylceramidase) (gene for Gaucher disease)
- GBAP1: glucosylceramidase beta pseudogene 1
- GLC1A: gene for glaucoma
- GON4L: gon-4 like
- GPA33 (1q24)
- GPR37L1 G protein-coupled receptor 37 like 1
- HEATR1: HEAT repeat-containing protein 1
- HFE2: hemochromatosis type 2 (juvenile)
- HIST2H2AB: Histone 2A type 2-B
- HIST2H2BF: Histone H2B type 2-F
- HIST2H3PS2: Histone cluster 2, H3, pseudogene 2
- HIST3H2A: Histone H2A type 3
- HIST3H2BB: Histone H2B type 3-B
- HPC1: gene for prostate cancer
- IGSF8 (1q23)
- INTS3: Integrator complex subunit 3
- IRF6: gene for connective tissue formation
- KCNH1 (1q32)
- KIF14 (1q32)
- LEFTY1: Left-right determination factor 1
- LHX9 encoding protein LIM homeobox 9
- LMNA: lamin A/C
- LOC645166 encoding protein Lymphocyte-specific protein 1 pseudogene
- LYPLAL1: Lysophospholipase-like 1
- MAPKAPK2 (1q32)
- MIR194-1: microRNA 194-1
- MIR5008: microRNA 5008
- MPC2: Mitochondrial pyruvate carrier 2
- MOSC1: MOCO sulphurase C-terminal domain containing 1
- MOSC2: MOSC domain-containing protein 2, mitochondrial
- MPZ: myelin protein zero (Charcot–Marie–Tooth neuropathy 1B)
- MSTO1: misato 1
- MTR: 5-methyltetrahydrofolate-homocysteine methyltransferase
- NAV1: Neuron navigator 1
- NBPF16: Neuroblastoma breakpoint family, member 16
- NOC2L: Nucleolar complex protein 2 homolog
- NUCKS1: Nuclear ubiquitous casein and cyclin-dependent kinases substrate
- NVL: Nuclear valosin-containing protein-like
- OLFML2B: Olfactomedin-like 2B
- OPTC: Opticin
- OTUD7B: OTU domain-containing protein 7B
- PACERR encoding protein PTGS2 antisense NFKB1 complex-mediated expression regulator RNA
- PBX1 (1q23)
- PEA15 (1q23)
- PGDB5: PiggyBac transposable element derived 5
- PIAS3 (1q21)
- PI4KB: Phosphatidylinositol 4-kinase beta
- PIP5K1A (1q21): Phosphatidylinositol-4-phosphate 5-kinase type-1 alpha
- PLA2G4A (1q31)
- PPOX: protoporphyrinogen oxidase
- PRCC (1q23)
- PRR9 encoding protein Proline rich 9
- PSEN2 (1q42): presenilin 2 (Alzheimer disease 4)
- PTGS2 (1q31)
- PTPN14 (1q32-41)
- PTPN7 (1q32)
- RABIF: RAB interacting factor
- RASSF5 (1q32)
- RGS2 (1q31)
- RN5S1@: RNA, 5S ribosomal 1q42 cluster
- RPS27 (1q21)
- SCAMP3: Secretory carrier-associated membrane protein 3
- SDHC (1q23)
- SELE (1q24)
- SHC1 (1q21)
- SLC39A1 (1q21)
- SLC50A1: Solute carrier family 50 member 1
- SMCP: Sperm mitochondrial-associated cysteine-rich protein
- SMG7: nonsense mediated mRNA decay factor
- SMYD3 (1q44)
- SPG23
- SPRR1A: Cornifin-A
- SPRR1B: Cornifin-B
- SPRR2A: Small proline rich protein 2A
- SPRTN: Spartan
- TARBP1: TAR (HIV-1) RNA-binding protein 1
- TBCE: Tubulin-specific chaperone E
- THBS3: Thrombospondin 3
- TMCO1: Transmembrane and coiled-coil domain-containing protein 1
- TMEM9: Transmembrane protein 9
- TMEM63A: Transmembrane protein 63A
- TNFSF18 (1q25)
- TNN (1q25)
- TNNT2: cardiac troponin T2
- TOR1AIP1: Torsin-1A-interacting protein 1
- TP53BP2 (1q41)
- TRP (1q31)
- UAP1: UDP-N-acetylhexosamine pyrophosphorylase
- USH2A: Usher syndrome 2A (autosomal recessive, mild)
- USF1 (1q23)
- VPS45: Vacuolar protein sorting-associated protein 45
- VPS72: Vacuolar protein sorting-associated protein 72
- YY1AP1: YY1-associated protein 1
- ZBED6: Zinc finger, BED-type containing 6
- ZC3H11A: Zing finger CCCH domain-containing protein 11A
- ZNF687: zing finger protein 687
- ZNF648 encoding protein Zinc finger protein 648
- ZNF695: Zinc finger protein 695
# Diseases and disorders
There are 890 known diseases related to this chromosome.[citation needed] Some of these diseases are hearing loss, Alzheimer's disease, glaucoma and breast cancer. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident.
Complete monosomy (only having one copy of the entire chromosome) is invariably lethal before birth.[14] Complete trisomy (having three copies of the entire chromosome) is lethal within days after conception.[14] Some partial deletions and partial duplications produce birth defects.
The following diseases are some of those related to genes on chromosome 1 (which contains the most known genetic diseases of any human chromosome):
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome
- Alzheimer's disease
- Breast cancer
- Brooke Greenberg Disease (Syndrome X)
- Carnitine palmitoyltransferase II deficiency
- Charcot–Marie–Tooth disease, types 1 and 2
- collagenopathy, types II and XI
- congenital hypothyroidism
- Ehlers-Danlos syndrome
- Factor V Leiden thrombophilia
- Familial adenomatous polyposis
- galactosemia
- Gaucher disease
- Gaucher-like disease
- Gelatinous drop-like corneal dystrophy
- Glaucoma
- Hearing loss, autosomal recessive deafness 36
- Hemochromatosis
- Hepatoerythropoietic porphyria
- Homocystinuria
- Hutchinson Gilford progeria syndrome
- 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
- Hypertrophic cardiomyopathy, autosomal dominant mutations of TNNT2; hypertrophy usually mild; restrictive phenotype may be present; may carry high risk of sudden cardiac death
- maple syrup urine disease
- medium-chain acyl-coenzyme A dehydrogenase deficiency
- Microcephaly
- Muckle-Wells Syndrome
- Nonsyndromic deafness
- Oligodendroglioma
- Parkinson disease
- Pheochromocytoma
- porphyria
- porphyria cutanea tarda
- popliteal pterygium syndrome
- prostate cancer
- Stickler syndrome
- TAR syndrome
- trimethylaminuria
- Usher syndrome
- Usher syndrome type II
- Van der Woude syndrome
- Variegate porphyria
# Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_1 | |
e92a8063a8276636e7cdd8966a109e33b6821dce | wikidoc | Chromosome 2 | Chromosome 2
Chromosome 2 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs (the building material of DNA) and representing almost 8% of the total DNA in human cells.
Chromosome 2 contains the HOXD homeobox gene cluster.
# Evolution
All members of Hominidae except humans, Neanderthals, and Denisovans have 24 pairs of chromosomes. Humans have only 23 pairs of chromosomes. Human chromosome 2 is a result of an end-to-end fusion of two ancestral chromosomes.
The evidence for this includes:
- The correspondence of chromosome 2 to two ape chromosomes. The closest human relative, the chimpanzee, has near-identical DNA sequences to human chromosome 2, but they are found in two separate chromosomes. The same is true of the more distant gorilla and orangutan.
- The presence of a vestigial centromere. Normally a chromosome has just one centromere, but in chromosome 2 there are remnants of a second centromere in the q21.3–q22.1 region.
- The presence of vestigial telomeres. These are normally found only at the ends of a chromosome, but in chromosome 2 there are additional telomere sequences in the q13 band, far from either end of the chromosome.
According to researcher Jacob W. Ijdo, "We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2."
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 2. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome vary (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## List of genes
The following is a partial list of genes on human chromosome 2. For complete list, see the link in the infobox on the right.
### p-arm
Partial list of the genes located on p-arm (short arm) of human chromosome 2:
- ACTR2: encoding protein Actin-related protein 2
- ADI1: encoding enzyme 1,2-dihydroxy-3-keto-5-methylthiopentene dioxygenase
- AFF3: encoding protein AF4/FMR2 family member 3
- AFTPH: encoding protein Aftiphilin
- ALMS1
- ABCG5 and ABCG8: ATP-binding cassette, subfamily A, members 5 and 8
- C2orf18: encoding protein Transmembrane protein C2orf18
- C2orf28: encoding protein Apoptosis-related protein 3
- CAPG: capping acting protein
- CCDC142: Coiled-Coil Domain Containing 142
- CTLA4: cytotoxic T-Lymphocyte Antigen 4
- DHX57: DExH-box helicase 57
- DPYSL5: Dihydropyrimidinase like 5
- ERLEC1: Endoplasmic reticulum lectin 1
- EVA1A: encoding protein Eva-1 homolog A (C. elegans)
- FAM49A: Family with sequence similarity 49 member A
- FAM98A: Family with sequence similarity 98 member A
- FAM136A: Family with sequence similarity 136 member A
- FBXO11: F-box protein 11
- GEN1 encoding protein GEN1, Holliday junction 5' flap endonuclease
- GFPT1: glutamine—fructose-6-phosphate transaminase 1
- GKN1: gastrokine 1
- GPATCH11: G-patch domain containing protein 11
- GTF2A1L: General transcription factor IIA subunit 1 like
- HADHA: hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha subunit
- HADHB: hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), beta subunit
- HSPC159: Galectin-related protein
- LEPQTL1: Leptin, serum levels of
- MEMO1: Mediator of cell motility 1
- MPHOSPH10: M-phase phosphoprotein 10
- MSH2: mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)
- MSH6: mutS homolog 6 (E. coli)
- MTHFD2: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
- MTIF2: mitochondrial translational initiation factor 2
- NRBP1: Nuclear receptor-binding protein 1
- ODC1: Ornithine decarboxylase
- OTOF: otoferlin
- PARK3 encoding protein Parkinson disease 3 (autosomal dominant, Lewy body)
- PCYOX1: prenylcysteine oxidase 1
- PELI1: Ubiquitin ligase
- PLGLB2: Plasminogen-related protein B
- POLR1A: DNA-directed RNA polymerase I subunit RPA1
- PREPL: Prolyl endopeptidase-like
- PXDN: Peroxidasin homolog
- QPCT: Glutaminyl-peptide cyclotransferase
- RETSAT: All-trans-retinol 13,14-reductase
- SH3YL1: SH3 and SYLF domain-containing 1
- TGOLN2: Trans-Golgi network integral membrane protein 2
- THADA: encoding protein Thyroid adenoma associated
- TIA1: TIA1 cytotoxic granule-associated RNA binding protein
- TMEM150: Transmembrane protein 150A
- TP53I3: Putative quinone oxidoreducatse
- TPO: thyroid peroxidase
- TTC7A: familial multiple intestinal atresia
- WBP1: WW domain-binding protein 1
- WDR35 (IFT121: TULP4): intraflagellar transport 121
### q-arm
Partial list of the genes located on q-arm (long arm) of human chromosome 2:
- ABCA12: ATP-binding cassette, sub-family A (ABC1), member 12
- ACTR1B: encoding protein Beta-centractin
- AGXT: alanine-glyoxylate aminotransferase (oxalosis I; hyperoxaluria I; glycolicaciduria; serine-pyruvate aminotransferase)
- ALS2: amyotrophic lateral sclerosis 2 (juvenile)
- ALS2CR8: encoding protein Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 8 protein also known as calcium-response factor (CaRF)
- ARMC9: encoding protein LisH domain-containing protein ARMC9
- B3GNT7: encoding protein UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 7
- BMPR2: bone morphogenetic protein receptor, type II (serine/threonine kinase)
- CCDC88A: Coiled-coil domain-containing protein 88A
- CCDC93: Coiled-coil domain-containing protein 93
- CCDC138: Coiled-coil domain-containing protein 138
- CDCA7: Cell division cycle associated protein 1
- CHPF: Chondroitin sulfate synthase 2
- COL3A1: collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant)
- COL4A3: collagen, type IV, alpha 3 (Goodpasture antigen)
- COL4A4: collagen, type IV, alpha 4
- COL5A2: collagen, type V, alpha 2
- DIS3L2: DIS3 mitotic control homolog-like 2
- ECEL1: Endothelin converting enzyme like 1
- EPC2: Enhancer of polycomb homolog 2
- EPB41L5: encoding protein Erythrocyte membrane protein band 4.1 like 5
- ERICH2: encoding protein Glutamate rich protein 2
- FASTKD1: FAST kinase domain-containing protein 1
- IMP4: U3 small nucleolar ribonucleoprotein
- INPP1: Inositol polyphosphate 1-phosphatase
- INPP4A: inositol polyphosphate-4-phosphatase type A
- ITM2C: Integral membrane protein 2C
- KANSL3: KAT8 regulatory NSL complex subunit 3
- KIAA1211L: Uncharacterized Protein KIAA1211- Like
- LANCL1: LanC like 1
- MALL: MAL-like protein
- MGAT5: mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase
- NABP1: Nucleic acid binding protein 1
- NEURL3: encoding protein Neuralized E3 ubiquitin protein ligase 3
- NCL: Nucleolin
- NR4A2: nuclear receptor subfamily 4, group A, member 2
- OLA1: Obg-like ATPase 1
- PARD3B encoding protein Partitioning defective 3 homolog B
- PAX3: paired box gene 3 (Waardenburg syndrome 1)
- PAX8: paired box gene 8
- POLR1B: DNA-directed RNA polymerase I subunit RPA2
- PRR21: Proline-rich protein 21
- PRSS56: Putative serine protease 56
- RIF1: replication timing regulatory factor 1
- RNU4ATAC: RNA, U4atac small nuclear (U12-dependent splicing)
- RPL37A: encoding protein 60S ribosomal protein L37a
- SATB2: Homeobox 2
- SDPR: Serum deprivation-response protein
- SGOL2: Shugoshin-like 2
- SH3BP4: SH3 domain-binding protein 4
- SLC9A4: solute carrier family 9 member A4
- SLC40A1: solute carrier family 40 (iron-regulated transporter), member 1
- SMPD4: Sphingomyelin phosphodiesterase 4
- SP140: encoding protein SP140 nuclear body protein
- SPATS2L: spermatogenesis associated, serine-rich 2-like protein
- SSB: Sjogren syndrome antigen B
- SSFA2: Sperm-specific antigen 2
- TBR1: T-box, brain, 1
- THAP4: THAP domain-containing protein 4
- TMBIM1: Transmembrane BAX inhibitor motif-containing protein 1
- TNRC15: PERQ amino acid-rich with GYF domain-containing protein 2
- TSGA10 encoding protein Testis specific 10
- TTN: titin
- UBXD2: UBX domain-containing protein 4
- UXS1: UDP-glucuronic acid decarboxylase 1
- XIRP2: Xin actin-binding repeat-containing protein 2
- ZNF142: zinc finger protein 142
# Related disorders and traits
The following diseases and traits are related to genes located on chromosome 2:
- 2p15-16.1 microdeletion syndrome
- Autism
- Alport syndrome
- Alström syndrome
- Amyotrophic lateral sclerosis
- Congenital hypothyroidism
- Crigler-Najjar types I/II
- Dementia with Lewy bodies
- Ehlers–Danlos syndrome
- Ehlers–Danlos syndrome, classical type
- Ehlers–Danlos syndrome, vascular type
- Fibrodysplasia ossificans progressiva
- Gilbert's syndrome
- Harlequin type ichthyosis
- Hemochromatosis
- Hemochromatosis type 4
- Hereditary nonpolyposis colorectal cancer
- Infantile-onset ascending hereditary spastic paralysis
- Juvenile primary lateral sclerosis
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
- Maturity onset diabetes of the young type 6
- Mitochondrial trifunctional protein deficiency
- Nonsyndromic deafness
- Primary hyperoxaluria
- Primary pulmonary hypertension
- Sitosterolemia (knockout of either ABCG5 or ABCG8)
- Sensenbrenner syndrome
- Synesthesia
- Waardenburg syndrome
# Cytogenetic band | Chromosome 2
Chromosome 2 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs[5] (the building material of DNA) and representing almost 8% of the total DNA in human cells.
Chromosome 2 contains the HOXD homeobox gene cluster.[6]
# Evolution
All members of Hominidae except humans, Neanderthals, and Denisovans have 24 pairs of chromosomes.[7] Humans have only 23 pairs of chromosomes. Human chromosome 2 is a result of an end-to-end fusion of two ancestral chromosomes.[8][9]
The evidence for this includes:
- The correspondence of chromosome 2 to two ape chromosomes. The closest human relative, the chimpanzee, has near-identical DNA sequences to human chromosome 2, but they are found in two separate chromosomes. The same is true of the more distant gorilla and orangutan.[10][11]
- The presence of a vestigial centromere. Normally a chromosome has just one centromere, but in chromosome 2 there are remnants of a second centromere in the q21.3–q22.1 region.[12]
- The presence of vestigial telomeres. These are normally found only at the ends of a chromosome, but in chromosome 2 there are additional telomere sequences in the q13 band, far from either end of the chromosome.[13]
According to researcher Jacob W. Ijdo, "We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomere-telomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2."[13]
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 2. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome vary (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[14]
## List of genes
The following is a partial list of genes on human chromosome 2. For complete list, see the link in the infobox on the right.
### p-arm
Partial list of the genes located on p-arm (short arm) of human chromosome 2:
- ACTR2: encoding protein Actin-related protein 2
- ADI1: encoding enzyme 1,2-dihydroxy-3-keto-5-methylthiopentene dioxygenase
- AFF3: encoding protein AF4/FMR2 family member 3
- AFTPH: encoding protein Aftiphilin
- ALMS1
- ABCG5 and ABCG8: ATP-binding cassette, subfamily A, members 5 and 8
- C2orf18: encoding protein Transmembrane protein C2orf18
- C2orf28: encoding protein Apoptosis-related protein 3
- CAPG: capping acting protein
- CCDC142: Coiled-Coil Domain Containing 142
- CTLA4: cytotoxic T-Lymphocyte Antigen 4
- DHX57: DExH-box helicase 57
- DPYSL5: Dihydropyrimidinase like 5
- ERLEC1: Endoplasmic reticulum lectin 1
- EVA1A: encoding protein Eva-1 homolog A (C. elegans)
- FAM49A: Family with sequence similarity 49 member A
- FAM98A: Family with sequence similarity 98 member A
- FAM136A: Family with sequence similarity 136 member A
- FBXO11: F-box protein 11
- GEN1 encoding protein GEN1, Holliday junction 5' flap endonuclease
- GFPT1: glutamine—fructose-6-phosphate transaminase 1
- GKN1: gastrokine 1
- GPATCH11: G-patch domain containing protein 11
- GTF2A1L: General transcription factor IIA subunit 1 like
- HADHA: hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha subunit
- HADHB: hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), beta subunit
- HSPC159: Galectin-related protein
- LEPQTL1: Leptin, serum levels of
- MEMO1: Mediator of cell motility 1
- MPHOSPH10: M-phase phosphoprotein 10
- MSH2: mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)
- MSH6: mutS homolog 6 (E. coli)
- MTHFD2: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
- MTIF2: mitochondrial translational initiation factor 2
- NRBP1: Nuclear receptor-binding protein 1
- ODC1: Ornithine decarboxylase
- OTOF: otoferlin
- PARK3 encoding protein Parkinson disease 3 (autosomal dominant, Lewy body)
- PCYOX1: prenylcysteine oxidase 1
- PELI1: Ubiquitin ligase
- PLGLB2: Plasminogen-related protein B
- POLR1A: DNA-directed RNA polymerase I subunit RPA1
- PREPL: Prolyl endopeptidase-like
- PXDN: Peroxidasin homolog
- QPCT: Glutaminyl-peptide cyclotransferase
- RETSAT: All-trans-retinol 13,14-reductase
- SH3YL1: SH3 and SYLF domain-containing 1
- TGOLN2: Trans-Golgi network integral membrane protein 2
- THADA: encoding protein Thyroid adenoma associated
- TIA1: TIA1 cytotoxic granule-associated RNA binding protein
- TMEM150: Transmembrane protein 150A
- TP53I3: Putative quinone oxidoreducatse
- TPO: thyroid peroxidase
- TTC7A: familial multiple intestinal atresia
- WBP1: WW domain-binding protein 1
- WDR35 (IFT121: TULP4): intraflagellar transport 121
### q-arm
Partial list of the genes located on q-arm (long arm) of human chromosome 2:
- ABCA12: ATP-binding cassette, sub-family A (ABC1), member 12
- ACTR1B: encoding protein Beta-centractin
- AGXT: alanine-glyoxylate aminotransferase (oxalosis I; hyperoxaluria I; glycolicaciduria; serine-pyruvate aminotransferase)
- ALS2: amyotrophic lateral sclerosis 2 (juvenile)
- ALS2CR8: encoding protein Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 8 protein also known as calcium-response factor (CaRF)
- ARMC9: encoding protein LisH domain-containing protein ARMC9
- B3GNT7: encoding protein UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 7
- BMPR2: bone morphogenetic protein receptor, type II (serine/threonine kinase)
- CCDC88A: Coiled-coil domain-containing protein 88A
- CCDC93: Coiled-coil domain-containing protein 93
- CCDC138: Coiled-coil domain-containing protein 138
- CDCA7: Cell division cycle associated protein 1
- CHPF: Chondroitin sulfate synthase 2
- COL3A1: collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant)
- COL4A3: collagen, type IV, alpha 3 (Goodpasture antigen)
- COL4A4: collagen, type IV, alpha 4
- COL5A2: collagen, type V, alpha 2
- DIS3L2: DIS3 mitotic control homolog-like 2
- ECEL1: Endothelin converting enzyme like 1
- EPC2: Enhancer of polycomb homolog 2
- EPB41L5: encoding protein Erythrocyte membrane protein band 4.1 like 5
- ERICH2: encoding protein Glutamate rich protein 2
- FASTKD1: FAST kinase domain-containing protein 1
- IMP4: U3 small nucleolar ribonucleoprotein
- INPP1: Inositol polyphosphate 1-phosphatase
- INPP4A: inositol polyphosphate-4-phosphatase type A
- ITM2C: Integral membrane protein 2C
- KANSL3: KAT8 regulatory NSL complex subunit 3
- KIAA1211L: Uncharacterized Protein KIAA1211- Like
- LANCL1: LanC like 1
- MALL: MAL-like protein
- MGAT5: mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase
- NABP1: Nucleic acid binding protein 1
- NEURL3: encoding protein Neuralized E3 ubiquitin protein ligase 3
- NCL: Nucleolin
- NR4A2: nuclear receptor subfamily 4, group A, member 2
- OLA1: Obg-like ATPase 1
- PARD3B encoding protein Partitioning defective 3 homolog B
- PAX3: paired box gene 3 (Waardenburg syndrome 1)
- PAX8: paired box gene 8
- POLR1B: DNA-directed RNA polymerase I subunit RPA2
- PRR21: Proline-rich protein 21
- PRSS56: Putative serine protease 56
- RIF1: replication timing regulatory factor 1
- RNU4ATAC: RNA, U4atac small nuclear (U12-dependent splicing)
- RPL37A: encoding protein 60S ribosomal protein L37a
- SATB2: Homeobox 2
- SDPR: Serum deprivation-response protein
- SGOL2: Shugoshin-like 2
- SH3BP4: SH3 domain-binding protein 4
- SLC9A4: solute carrier family 9 member A4
- SLC40A1: solute carrier family 40 (iron-regulated transporter), member 1
- SMPD4: Sphingomyelin phosphodiesterase 4
- SP140: encoding protein SP140 nuclear body protein
- SPATS2L: spermatogenesis associated, serine-rich 2-like protein
- SSB: Sjogren syndrome antigen B
- SSFA2: Sperm-specific antigen 2
- TBR1: T-box, brain, 1
- THAP4: THAP domain-containing protein 4
- TMBIM1: Transmembrane BAX inhibitor motif-containing protein 1
- TNRC15: PERQ amino acid-rich with GYF domain-containing protein 2
- TSGA10 encoding protein Testis specific 10
- TTN: titin
- UBXD2: UBX domain-containing protein 4
- UXS1: UDP-glucuronic acid decarboxylase 1
- XIRP2: Xin actin-binding repeat-containing protein 2
- ZNF142: zinc finger protein 142
# Related disorders and traits
The following diseases and traits are related to genes located on chromosome 2:
- 2p15-16.1 microdeletion syndrome
- Autism[21]
- Alport syndrome
- Alström syndrome
- Amyotrophic lateral sclerosis
- Congenital hypothyroidism
- Crigler-Najjar types I/II
- Dementia with Lewy bodies
- Ehlers–Danlos syndrome
- Ehlers–Danlos syndrome, classical type
- Ehlers–Danlos syndrome, vascular type
- Fibrodysplasia ossificans progressiva
- Gilbert's syndrome
- Harlequin type ichthyosis
- Hemochromatosis
- Hemochromatosis type 4
- Hereditary nonpolyposis colorectal cancer
- Infantile-onset ascending hereditary spastic paralysis
- Juvenile primary lateral sclerosis
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
- Maturity onset diabetes of the young type 6
- Mitochondrial trifunctional protein deficiency
- Nonsyndromic deafness
- Primary hyperoxaluria
- Primary pulmonary hypertension
- Sitosterolemia (knockout of either ABCG5 or ABCG8)
- Sensenbrenner syndrome
- Synesthesia
- Waardenburg syndrome
# Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_2 | |
5553e10a5284f4572fe4c16e20c11399aaa8fc75 | wikidoc | Chromosome 3 | Chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in cells.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 3. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## List of genes
The following is a partial list of genes on human chromosome 3. For complete list, see the link in the infobox on the right.
### p-arm
Partial list of the genes located on p-arm (short arm) of human chromosome 3:
- ALAS1: aminolevulinate, delta-, synthase 1
- APEH: encoding enzyme Acylamino-acid-releasing enzyme
- ARPP-21: Cyclic AMP-regulated phosphoprotein, 21 kDa
- AZI2: encoding protein 5-azacytidine-induced protein 2
- BRK1: SCAR/WAVE actin nucleating complex subunit
- BRPF1: bromodomain and PHD finger containing 1
- BTD: biotinidase
- C3orf14-Chromosome 3 open reading frame 14: predicted DNA binding protein.
- C3orf23: encoding protein Uncharacterized protein C3orf23
- C3orf60/NDUFAF3: encoding enzyme NADH dehydrogenase 1 alpha subcomplex assembly factor 3
- C3orf62: chromosome 3 open reading frame 62
- CACNA2D3: calcium channel, voltage-dependent, alpha 2/delta subunit 3
- CCR5: chemokine (C-C motif) receptor 5
- CGGBP1: CGG triplet repeat binding protein 1
- CMTM7: CKLF like MARVEL transmembrane domain containing 7
- CNTN4: Contactin 4
- COL7A1: Collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive)
- CRBN: Cereblon protein
- DCLK3: Doublecortin like kinase 3
- EAF1: ELL associated factor 1
- ENTPD3: ectonucleoside triphosphate diphosphohydrolase 3
- FAM107A: Family with sequence similarity 107 member A
- FAM19A1: Family with sequence similarity 19 member A1, C-C motif chemokine like
- FBXL2: F-box and leucine rich repeat protein 2
- FOXP1: Forkhead Box Protein P1
- FRA3A encoding protein Fragile site, aphidicolin type, common, fra(3)(p24.2)
- FRMD4B encoding protein FERM domain containing 4B
- GMPPB: GDP-mannose pyrophosphorylase B
- HEMK1: encoding protein HemK methyltransferase family member 1
- HIGD1A: HIG1 domain family member 1A
- LARS2: leucyl-tRNA synthetase, mitochondrial
- LIMD1: LIM domain-containing protein 1
- LINC00312: Long intergenic non-protein-coding RNA 312
- MITF: microphthalmia-associated transcription factor
- MLH1: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)
- MYRIP: Myosin VIIA and Rab interacting protein
- NBEAL2: Neurobeachin-like 2
- NKTR: NK-tumor recognition protein
- NPRL2: Nitrogen permease regulator 2-like protein
- OXTR: oxytocin receptor
- PHF7 encoding protein PHD finger protein 7
- PTHR1: parathyroid hormone receptor 1
- QRICH1: encoding protein QRICH1, also known as Glutamine-rich protein 1,
- RBM6: RNA-binding protein 6
- RPP14: Ribonuclease P protein subunit p14
- SCN5A: sodium channel, voltage-gated, type V, alpha (long QT syndrome 3)
- SETD5: SET domain containing 5
- SFMBT1: Scm-like with four mbt domains 1
- SLC25A20: solute carrier family 25 (carnitine/acylcarnitine translocase), member 20
- STT3B: catalytic subunit of the oligosaccharyltransferase complex
- SYNPR: synaptoporin
- TDGF1: Teratocarcinoma-derived growth factor 1
- TMEM158: Transmembrane protein 158
- TMIE: transmembrane inner ear
- TRAK1: trafficking kinesin-binding protein 1
- TRANK1: encoding protein Tetratricopeptide repeat and ankyrin repeat containing 1
- TUSC2: tumor suppressor candidate 2
- UCN2: Urocortin-2
- ULK4: UNC-51 like kinase 4
- VGLL3: vestigial-like family member 3
- VHL: von Hippel-Lindau tumor suppressor
- ZMYND10: zinc finger MYND-type containing 10
- ZNF502: encoding protein Zinc finger protein 502
- ZNF621: encoding protein Zinc finger protein 621
### q-arm
Partial list of the genes located on q-arm (long arm) of human chromosome 3:
- ADIPOQ: adiponectin
- AMOTL2: encoding protein Angiomotin-like protein 2
- ARHGAP31: Rho GRPase activating protein 31
- C3orf1: chromosome 3 open reading frame 1
- C3orf70 chromosome 3 open reading frame 70
- CAMPD1: Camptodactyly
- CCDC80: Coiled-coil domain containing protein 80
- CD200R1: Cell surface glycoprotein CD200 receptor 1
- CLDND1: Claudin domain containing 1
- CPN2: Carboxypeptidase N subunit 2
- CPOX: coproporphyrinogen oxidase (coproporphyria, harderoporphyria)
- DPPA2: Developmental pluripotency associated 2
- DZIP3 encoding protein DAZ interacting zinc finger protein 3
- EAF2: ELL associated factor 2
- EFCC1: EF-hand and coiled-coil domain containing 1
- ETM1: Essential tremor 1
- ETV5: ETS variant 5
- FAM43A: family with sequence similarity 43 member A
- FAM162A: family with sequence similarity 162 member A
- GYG1: Glycogenin-1
- HACD2 encoding protein 3-hydroxyacyl-CoA dehydratase 2
- HGD: homogentisate 1,2-dioxygenase (homogentisate oxidase)
- IFT122: intraflagellar transport gene 122
- KIAA1257: KIAA1257
- LMLN: encoding protein Leishmanolysin-like (metallopeptidase M8 family)
- LRRC15: leucine rich repeat containing 15
- LSG1: large subunit GTPase 1 homolog
- MB21D2: encoding protein Mab-21 domain containing 2
- MCCC1: methylcrotonoyl-Coenzyme A carboxylase 1 (alpha)
- MYLK: Telokin
- NFKBIZ: NF-kappa-B inhibitor zeta
- PARP14 encoding protein Poly(ADP-ribose) polymerase family member 14
- PCCB: propionyl Coenzyme A carboxylase, beta polypeptide
- PDCD10: programmed cell death 10
- PIK3CA: phosphoinositide-3-kinase, catalytic, alpha polypeptide
- PROSER1: Proline and serine rich protein 1
- RAB7: RAB7, member RAS oncogene family
- RETNLB: resistin-like beta
- RHO: rhodopsin visual pigment
- RIOX2: Ribosomal oxygenase 2
- SELT: Selenoprotein T
- SENP7: Sentrin-specific protease 7
- SERP1: Stress-associated endoplasmic reticulum protein 1
- SOX2: transcription factor
- SOX2OT: SOX2 overlapping transcript
- SPG14 encoding protein Spastic paraplegia 14 (autosomal recessive)
- SRPRB: Signal recognition particle receptor subunit beta
- TM4SF1: Transmembrane 4 L6 family member 1
- TRAT1: T-cell receptor-associated transmembrane adapter 1
- USH3A: Usher syndrome 3A
- ZBED2: encoding protein Zinc finger BED-type containing 2
- ZNF9: zinc finger protein 9 (a cellular retroviral nucleic acid binding protein)
# Diseases and disorders
The following diseases and disorders are some of those related to genes on chromosome 3:
- 3-methylcrotonyl-CoA carboxylase deficiency
- 3q29 microdeletion syndrome
- Acute Myeloid Leukemia (AML)
- Alkaptonuria
- Arrhythmogenic right ventricular dysplasia
- Atransferrinemia
- Autism
- Autosomal Dominant Optic Atrophy
- ADOA Plus Syndrome
- Biotinidase deficiency
- Blepharophimosis, epicanthus inversus and ptosis type 1
- Breast/colon/lung/pancreatic cancer
- Brugada syndrome
- Castillo fever
- Carnitine-acylcarnitine translocase deficiency
- Cataracts
- Cerebral cavernous malformation
- Charcot-Marie-Tooth disease, type 2
- Charcot-Marie-Tooth disease
- Chromosome 3q duplication syndrome
- Coproporphyria
- Dandy-Walker syndrome
- Deafness
- Diabetes
- Dystrophic epidermolysis bullosa
- Endplate acetylcholinesterase deficiency
- Essential tremors
- Ectrodactyly, Case 4
- Glaucoma, primary open angle
- Glycogen storage disease
- Hailey-Hailey disease
- Harderoporphyrinuria
- Heart block, progressive/nonprogressive
- Hereditary coproporphyria
- Hereditary nonpolyposis colorectal cancer
- HIV infection, susceptibility/resistance to
- Hypobetalipoproteinemia, familial
- Hypothermia
- Leukoencephalopathy with vanishing white matter
- Long QT syndrome
- Lymphomas
- Malignant hyperthermia susceptibility
- Metaphyseal chondrodysplasia, Murk Jansen type
- Microcoria
- Moebius syndrome
- Moyamoya disease
- Mucopolysaccharidosis
- Muir-Torre family cancer syndrome
- Myotonic dystrophy
- Neuropathy, hereditary motor and sensory, Okinawa type
- Night blindness
- Nonsyndromic deafness
- Ovarian cancer
- Porphyria
- Propionic acidemia
- Protein S deficiency
- Pseudo-Zellweger syndrome
- Retinitis pigmentosa
- Romano-Ward syndrome
- Seckel Syndrome
- Sensenbrenner syndrome
- Septo-optic dysplasia
- Short stature
- Spinocerebellar ataxia
- Sucrose intolerance
- T-cell leukemia translocation altered gene
- Usher syndrome
- von Hippel-Lindau syndrome
- Waardenburg syndrome
- Xeroderma pigmentosum, complementation group c
# Cytogenetic band | Chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in cells.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 3. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[5]
## List of genes
The following is a partial list of genes on human chromosome 3. For complete list, see the link in the infobox on the right.
### p-arm
Partial list of the genes located on p-arm (short arm) of human chromosome 3:
- ALAS1: aminolevulinate, delta-, synthase 1
- APEH: encoding enzyme Acylamino-acid-releasing enzyme
- ARPP-21: Cyclic AMP-regulated phosphoprotein, 21 kDa
- AZI2: encoding protein 5-azacytidine-induced protein 2
- BRK1: SCAR/WAVE actin nucleating complex subunit
- BRPF1: bromodomain and PHD finger containing 1
- BTD: biotinidase
- C3orf14-Chromosome 3 open reading frame 14: predicted DNA binding protein.
- C3orf23: encoding protein Uncharacterized protein C3orf23
- C3orf60/NDUFAF3: encoding enzyme NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3
- C3orf62: chromosome 3 open reading frame 62
- CACNA2D3: calcium channel, voltage-dependent, alpha 2/delta subunit 3
- CCR5: chemokine (C-C motif) receptor 5
- CGGBP1: CGG triplet repeat binding protein 1
- CMTM7: CKLF like MARVEL transmembrane domain containing 7
- CNTN4: Contactin 4
- COL7A1: Collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive)
- CRBN: Cereblon protein[12]
- DCLK3: Doublecortin like kinase 3
- EAF1: ELL associated factor 1
- ENTPD3: ectonucleoside triphosphate diphosphohydrolase 3
- FAM107A: Family with sequence similarity 107 member A
- FAM19A1: Family with sequence similarity 19 member A1, C-C motif chemokine like
- FBXL2: F-box and leucine rich repeat protein 2
- FOXP1: Forkhead Box Protein P1
- FRA3A encoding protein Fragile site, aphidicolin type, common, fra(3)(p24.2)
- FRMD4B encoding protein FERM domain containing 4B
- GMPPB: GDP-mannose pyrophosphorylase B
- HEMK1: encoding protein HemK methyltransferase family member 1
- HIGD1A: HIG1 domain family member 1A
- LARS2: leucyl-tRNA synthetase, mitochondrial
- LIMD1: LIM domain-containing protein 1
- LINC00312: Long intergenic non-protein-coding RNA 312
- MITF: microphthalmia-associated transcription factor
- MLH1: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)
- MYRIP: Myosin VIIA and Rab interacting protein
- NBEAL2: Neurobeachin-like 2
- NKTR: NK-tumor recognition protein
- NPRL2: Nitrogen permease regulator 2-like protein
- OXTR: oxytocin receptor
- PHF7 encoding protein PHD finger protein 7
- PTHR1: parathyroid hormone receptor 1
- QRICH1: encoding protein QRICH1, also known as Glutamine-rich protein 1,
- RBM6: RNA-binding protein 6
- RPP14: Ribonuclease P protein subunit p14
- SCN5A: sodium channel, voltage-gated, type V, alpha (long QT syndrome 3)
- SETD5: SET domain containing 5
- SFMBT1: Scm-like with four mbt domains 1
- SLC25A20: solute carrier family 25 (carnitine/acylcarnitine translocase), member 20
- STT3B: catalytic subunit of the oligosaccharyltransferase complex
- SYNPR: synaptoporin
- TDGF1: Teratocarcinoma-derived growth factor 1
- TMEM158: Transmembrane protein 158
- TMIE: transmembrane inner ear
- TRAK1: trafficking kinesin-binding protein 1
- TRANK1: encoding protein Tetratricopeptide repeat and ankyrin repeat containing 1
- TUSC2: tumor suppressor candidate 2
- UCN2: Urocortin-2
- ULK4: UNC-51 like kinase 4
- VGLL3: vestigial-like family member 3
- VHL: von Hippel-Lindau tumor suppressor
- ZMYND10: zinc finger MYND-type containing 10
- ZNF502: encoding protein Zinc finger protein 502
- ZNF621: encoding protein Zinc finger protein 621
### q-arm
Partial list of the genes located on q-arm (long arm) of human chromosome 3:
- ADIPOQ: adiponectin
- AMOTL2: encoding protein Angiomotin-like protein 2
- ARHGAP31: Rho GRPase activating protein 31
- C3orf1: chromosome 3 open reading frame 1
- C3orf70 chromosome 3 open reading frame 70
- CAMPD1: Camptodactyly
- CCDC80: Coiled-coil domain containing protein 80
- CD200R1: Cell surface glycoprotein CD200 receptor 1
- CLDND1: Claudin domain containing 1
- CPN2: Carboxypeptidase N subunit 2
- CPOX: coproporphyrinogen oxidase (coproporphyria, harderoporphyria)
- DPPA2: Developmental pluripotency associated 2
- DZIP3 encoding protein DAZ interacting zinc finger protein 3
- EAF2: ELL associated factor 2
- EFCC1: EF-hand and coiled-coil domain containing 1
- ETM1: Essential tremor 1
- ETV5: ETS variant 5
- FAM43A: family with sequence similarity 43 member A
- FAM162A: family with sequence similarity 162 member A
- GYG1: Glycogenin-1
- HACD2 encoding protein 3-hydroxyacyl-CoA dehydratase 2
- HGD: homogentisate 1,2-dioxygenase (homogentisate oxidase)
- IFT122: intraflagellar transport gene 122
- KIAA1257: KIAA1257
- LMLN: encoding protein Leishmanolysin-like (metallopeptidase M8 family)
- LRRC15: leucine rich repeat containing 15
- LSG1: large subunit GTPase 1 homolog
- MB21D2: encoding protein Mab-21 domain containing 2
- MCCC1: methylcrotonoyl-Coenzyme A carboxylase 1 (alpha)
- MYLK: Telokin
- NFKBIZ: NF-kappa-B inhibitor zeta
- PARP14 encoding protein Poly(ADP-ribose) polymerase family member 14
- PCCB: propionyl Coenzyme A carboxylase, beta polypeptide
- PDCD10: programmed cell death 10
- PIK3CA: phosphoinositide-3-kinase, catalytic, alpha polypeptide
- PROSER1: Proline and serine rich protein 1
- RAB7: RAB7, member RAS oncogene family
- RETNLB: resistin-like beta
- RHO: rhodopsin visual pigment
- RIOX2: Ribosomal oxygenase 2
- SELT: Selenoprotein T
- SENP7: Sentrin-specific protease 7
- SERP1: Stress-associated endoplasmic reticulum protein 1
- SOX2: transcription factor
- SOX2OT: SOX2 overlapping transcript
- SPG14 encoding protein Spastic paraplegia 14 (autosomal recessive)
- SRPRB: Signal recognition particle receptor subunit beta
- TM4SF1: Transmembrane 4 L6 family member 1
- TRAT1: T-cell receptor-associated transmembrane adapter 1
- USH3A: Usher syndrome 3A
- ZBED2: encoding protein Zinc finger BED-type containing 2
- ZNF9: zinc finger protein 9 (a cellular retroviral nucleic acid binding protein)
# Diseases and disorders
The following diseases and disorders are some of those related to genes on chromosome 3:
- 3-methylcrotonyl-CoA carboxylase deficiency
- 3q29 microdeletion syndrome
- Acute Myeloid Leukemia (AML)
- Alkaptonuria
- Arrhythmogenic right ventricular dysplasia
- Atransferrinemia
- Autism
- Autosomal Dominant Optic Atrophy
- ADOA Plus Syndrome
- Biotinidase deficiency
- Blepharophimosis, epicanthus inversus and ptosis type 1
- Breast/colon/lung/pancreatic cancer
- Brugada syndrome
- Castillo fever
- Carnitine-acylcarnitine translocase deficiency
- Cataracts
- Cerebral cavernous malformation
- Charcot-Marie-Tooth disease, type 2
- Charcot-Marie-Tooth disease
- Chromosome 3q duplication syndrome
- Coproporphyria
- Dandy-Walker syndrome
- Deafness
- Diabetes
- Dystrophic epidermolysis bullosa
- Endplate acetylcholinesterase deficiency
- Essential tremors
- Ectrodactyly, Case 4
- Glaucoma, primary open angle
- Glycogen storage disease
- Hailey-Hailey disease
- Harderoporphyrinuria
- Heart block, progressive/nonprogressive
- Hereditary coproporphyria
- Hereditary nonpolyposis colorectal cancer
- HIV infection, susceptibility/resistance to
- Hypobetalipoproteinemia, familial
- Hypothermia
- Leukoencephalopathy with vanishing white matter
- Long QT syndrome
- Lymphomas
- Malignant hyperthermia susceptibility
- Metaphyseal chondrodysplasia, Murk Jansen type
- Microcoria
- Moebius syndrome
- Moyamoya disease
- Mucopolysaccharidosis
- Muir-Torre family cancer syndrome
- Myotonic dystrophy
- Neuropathy, hereditary motor and sensory, Okinawa type
- Night blindness
- Nonsyndromic deafness
- Ovarian cancer
- Porphyria
- Propionic acidemia
- Protein S deficiency
- Pseudo-Zellweger syndrome
- Retinitis pigmentosa
- Romano-Ward syndrome
- Seckel Syndrome
- Sensenbrenner syndrome
- Septo-optic dysplasia
- Short stature
- Spinocerebellar ataxia
- Sucrose intolerance
- T-cell leukemia translocation altered gene
- Usher syndrome
- von Hippel-Lindau syndrome
- Waardenburg syndrome
- Xeroderma pigmentosum, complementation group c
# Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_3 | |
d2e1fc91009bbc89fd0e2e1d9a58cc85af6531eb | wikidoc | Chromosome 4 | Chromosome 4
Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the total DNA in cells.
# Genomics
The chromosome is ~191 megabases in length. In a 2012 paper, seven hundred and fifty seven protein-encoding genes were identified on this chromosome. Two-hundred and eleven (27.9%) of these coding sequences did not have any experimental evidence at the protein level, in 2012. Two-hundred and seventy-one appear to be membrane proteins. Fifty-four have been classified as cancer-associated proteins.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 4. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## Gene list
The following is a partial list of genes on human chromosome 4. For complete list, see the link in the infobox on the right.
- AASDH: aminoadipate-semialdehyde dehydrogenase
- ACVR1: activin-like kinase 2 (ALK-2)
- ACOX3: encoding enzyme Peroxisomal acyl-coenzyme A oxidase 3
- AGPAT9: encoding enzyme Glycerol-3-phosphate acyltransferase 3 a.k.a. 1-acylglycerol-3-phosphate O-acyltransferase 9
- ANK2: ankyrin 2, neuronal
- APBB2: encoding protein Amyloid beta A4 precursor protein-binding family B member 2
- ART3: encoding enzyme Ecto-ADP-ribosyltransferase 3
- ASAHL: encoding enzyme N-acylethanolamine-hydrolyzing acid amidase
- C4orf18: encoding protein Protein ENED
- C4orf21: zinc-finger GRF-type containing 1
- CCDC109B: Coiled-coil domain containing 109B
- Complement Factor I: Complement Factor I
- CRMP1: Collapsin response mediator protein 1, a member of CRMP family
- CSN2: Beta-casein
- CXCL1: chemokine (C-X-C motif) ligand 1, scyb1
- CXCL2: chemokine (C-X-C motif) ligand 2, scyb2
- CXCL3: chemokine (C-X-C motif) ligand 3, scyb3
- CXCL4: chemokine (C-X-C motif) ligand 4, Platelet factor-4, PF-4, scyb4
- CXCL5: chemokine (C-X-C motif) ligand 5, scyb5
- CXCL6: chemokine (C-X-C motif) ligand 6, scyb6
- CXCL7: chemokine (C-X-C motif) ligand 7, PPBP, scyb7
- CXCL8: chemokine (C-X-C motif) ligand 8, interleukin 8 (IL-8), scyb8
- CXCL9: chemokine (C-X-C motif) ligand 9, scyb9
- CXCL10: chemokine (C-X-C motif) ligand 10, scyb10
- CXCL11: chemokine (C-X-C motif) ligand 11, scyb11
- CXCL13: chemokine (C-X-C motif) ligand 13, scyb13
- CYTL1: Cytokine-like 1
- DCUN1D4: Defective in cullin neddylation 1 domain containing 4
- DHX15: DEAH-box helicase 15
- DKK2: Dickkopf-related protein 2
- DUX4: Thought to be inactive but 2010 research shows a key role in FSHD
- ELMOD2: Elmo domain-containing 2
- EMCN: Endomucin
- EVC: Ellis van Creveld syndrome
- EVC2: Ellis van Creveld syndrome 2 (limbin)
- Factor XI: Mutations cause Haemophilia C
- FAM47E-STBD1: FAM47E-STBD1 readthrough
- FAM114A1: Family with sequence similarity 114, member A1
- FAM149A: Family with sequence similarity 149, member A
- FAM193A: Family with sequence similarity 193, member A
- FAM221B: Family with sequence similarity 221, member B
- FGF2: Fibroblast growth factor 2 (basic fibroblast growth factor)
- FGFR3: fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism, bladder cancer)
- FGFRL1: fibroblast growth factor receptor-like 1
- FRG1: FSHD region gene 1
- GUF1: GUF1 homolog, GTPase
- HCL2 (also called RHA or RHC): related to red hair
- HTT (Huntingtin): huntingtin protein (Huntington's disease)
- IGJ: linker protein for immunoglobulin alpha and mu polypeptides
- INTS12: Integrator complex subunit 12
- KDR: Kinase insert domain receptor (Vascular endothelial growth factor receptor 2)
- KIAA1530: UV stimulated scaffold protein A
- LCORL: Ligand dependent nuclear receptor corepressor like
- LDB2: LIM domain-binding protein 2
- LGI2: Leucine-rich repeat LGI family member 2
- LOC100505912 encoding protein Uncharacterized LOC100505912
- LSM6: U6 snRNA-associated Sm-like protein
- LYAR: Cell growth-regulating nucleolar protein
- MAB21L2: Mab-21-like 2
- Marcksl1: encoding protein MARCKS-like 1
- MAML3: Mastermind-like 3
- MFSD7: encoding protein Major facilitator superfamily domain containing 7
- MIR1269A: microRNA 1269a
- MLF1IP: Centromere protein U
- MMAA: methylmalonic aciduria (cobalamin deficiency) cblA type
- MTHFD2L: NAD-dependent methylenetetrahydrofolate dehydrogenase 2-like protein
- MYL5: Myosin light chain 5
- NOA1: encoding protein Nitric oxide associated 1
- NUDT6: nudix hydrolase 6
- NUDT9: nudix hydrolase 9
- OTUD4: OTU domain-containing protein 4
- PABPC4L: encoding protein Poly(A) binding protein, cytoplasmic 4-like
- PARM1: Prostate androgen-regulated mucin-like protein 1
- PHOX2B: codes for a homeodomain transcription factor
- PI4K2B: Phosphatidylinositol 4-kinase type 2-beta
- PKD2: polycystic kidney disease 2 (autosomal dominant)
- PLK4: Serine/threonine-protein kinase PLK4
- PSAPL1: encoding protein Prosaposin-like 1 (gene/pseudogene)
- QDPR: quinoid dihydropteridine reductase
- RBM47: RNA binding motif protein 47
- SDAD1: protein SDA1 homolog
- SEC24B: Sec24 homolog B
- SEC24D: Sec24 homolog D
- SEPT11: Septin-11
- SLC9B2: solute carrier family 9 member B2
- SLC10A4: solute carrier family 10 member 4
- SMIM20: encoding protein Small integral membrane protein 20
- SNCA: synuclein, alpha (non A4 component of amyloid precursor)
- SPATA5: Spermatogenesis-associated protein 5
- STATH: gene with protein product
- TACC3: Transforming acidic coiled-coil-containing protein 3
- TENM3: Teneurin transmembrane protein 3
- THAP6: THAP domain-containing protein 6
- TMPRSS11D: Transmembrane protease, serine 11D
- TNIP2: TNFAIP3-interaction protein 2
- UCHL1: ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)
- UGT8: UDP glycosyltransferase 8
- UNC5C: netrin receptor UNC5C
- USP38: encoding protein Ubiquitin specific peptidase 38
- USP53: ubiquitin specific peptidase 53
- UTP3: small subunit processome component
- WFS1: Wolfram syndrome 1 (wolframin)
- ZNF621: encoding protein Zinc finger protein 621
# Diseases and disorders
The following are some of the diseases related to genes located on chromosome 4:
- Achondroplasia
- Autosomal dominant polycystic kidney disease (PKD-2)
- Bladder cancer
- Crouzonodermoskeletal syndrome
- Chronic lymphocytic leukemia
- Congenital central hypoventilation syndrome
- Ellis-van Creveld syndrome
- Facioscapulohumeral muscular dystrophy
- Fibrodysplasia ossificans progressiva (FOP)
- Haemophilia C
- Huntington's disease
- Hemolytic uremic syndrome
- Hereditary benign intraepithelial dyskeratosis
- Hirschprung's disease
- Hypochondroplasia
- Methylmalonic acidemia
- Mucopolysaccharidosis type I
- Muenke syndrome
- Nonsyndromic deafness
- Nonsyndromic deafness, autosomal dominant
- Parkinson's disease
- Polycystic kidney disease
- Romano-Ward syndrome
- SADDAN
- Tetrahydrobiopterin deficiency
- Thanatophoric dysplasia
Type 1
Type 2
- Type 1
- Type 2
- Wolfram syndrome
- Wolf–Hirschhorn syndrome
# Cytogenetic band | Chromosome 4
Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the total DNA in cells.
# Genomics
The chromosome is ~191 megabases in length. In a 2012 paper, seven hundred and fifty seven protein-encoding genes were identified on this chromosome.[5] Two-hundred and eleven (27.9%) of these coding sequences did not have any experimental evidence at the protein level, in 2012. Two-hundred and seventy-one appear to be membrane proteins. Fifty-four have been classified as cancer-associated proteins.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 4. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[6]
## Gene list
The following is a partial list of genes on human chromosome 4. For complete list, see the link in the infobox on the right.
- AASDH: aminoadipate-semialdehyde dehydrogenase
- ACVR1: activin-like kinase 2 (ALK-2)
- ACOX3: encoding enzyme Peroxisomal acyl-coenzyme A oxidase 3
- AGPAT9: encoding enzyme Glycerol-3-phosphate acyltransferase 3 a.k.a. 1-acylglycerol-3-phosphate O-acyltransferase 9
- ANK2: ankyrin 2, neuronal
- APBB2: encoding protein Amyloid beta A4 precursor protein-binding family B member 2
- ART3: encoding enzyme Ecto-ADP-ribosyltransferase 3
- ASAHL: encoding enzyme N-acylethanolamine-hydrolyzing acid amidase
- C4orf18: encoding protein Protein ENED
- C4orf21: zinc-finger GRF-type containing 1
- CCDC109B: Coiled-coil domain containing 109B
- Complement Factor I: Complement Factor I
- CRMP1: Collapsin response mediator protein 1, a member of CRMP family
- CSN2: Beta-casein
- CXCL1: chemokine (C-X-C motif) ligand 1, scyb1
- CXCL2: chemokine (C-X-C motif) ligand 2, scyb2
- CXCL3: chemokine (C-X-C motif) ligand 3, scyb3
- CXCL4: chemokine (C-X-C motif) ligand 4, Platelet factor-4, PF-4, scyb4
- CXCL5: chemokine (C-X-C motif) ligand 5, scyb5
- CXCL6: chemokine (C-X-C motif) ligand 6, scyb6
- CXCL7: chemokine (C-X-C motif) ligand 7, PPBP, scyb7
- CXCL8: chemokine (C-X-C motif) ligand 8, interleukin 8 (IL-8), scyb8
- CXCL9: chemokine (C-X-C motif) ligand 9, scyb9
- CXCL10: chemokine (C-X-C motif) ligand 10, scyb10
- CXCL11: chemokine (C-X-C motif) ligand 11, scyb11
- CXCL13: chemokine (C-X-C motif) ligand 13, scyb13
- CYTL1: Cytokine-like 1
- DCUN1D4: Defective in cullin neddylation 1 domain containing 4
- DHX15: DEAH-box helicase 15
- DKK2: Dickkopf-related protein 2
- DUX4: Thought to be inactive but 2010 research shows a key role in FSHD[13]
- ELMOD2: Elmo domain-containing 2
- EMCN: Endomucin
- EVC: Ellis van Creveld syndrome
- EVC2: Ellis van Creveld syndrome 2 (limbin)
- Factor XI: Mutations cause Haemophilia C
- FAM47E-STBD1: FAM47E-STBD1 readthrough
- FAM114A1: Family with sequence similarity 114, member A1
- FAM149A: Family with sequence similarity 149, member A
- FAM193A: Family with sequence similarity 193, member A
- FAM221B: Family with sequence similarity 221, member B
- FGF2: Fibroblast growth factor 2 (basic fibroblast growth factor)
- FGFR3: fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism, bladder cancer)
- FGFRL1: fibroblast growth factor receptor-like 1
- FRG1: FSHD region gene 1
- GUF1: GUF1 homolog, GTPase
- HCL2 (also called RHA or RHC): related to red hair
- HTT (Huntingtin): huntingtin protein (Huntington's disease)
- IGJ: linker protein for immunoglobulin alpha and mu polypeptides
- INTS12: Integrator complex subunit 12
- KDR: Kinase insert domain receptor (Vascular endothelial growth factor receptor 2)
- KIAA1530: UV stimulated scaffold protein A
- LCORL: Ligand dependent nuclear receptor corepressor like
- LDB2: LIM domain-binding protein 2
- LGI2: Leucine-rich repeat LGI family member 2
- LOC100505912 encoding protein Uncharacterized LOC100505912
- LSM6: U6 snRNA-associated Sm-like protein
- LYAR: Cell growth-regulating nucleolar protein
- MAB21L2: Mab-21-like 2
- Marcksl1: encoding protein MARCKS-like 1
- MAML3: Mastermind-like 3
- MFSD7: encoding protein Major facilitator superfamily domain containing 7
- MIR1269A: microRNA 1269a
- MLF1IP: Centromere protein U
- MMAA: methylmalonic aciduria (cobalamin deficiency) cblA type
- MTHFD2L: NAD-dependent methylenetetrahydrofolate dehydrogenase 2-like protein
- MYL5: Myosin light chain 5
- NOA1: encoding protein Nitric oxide associated 1
- NUDT6: nudix hydrolase 6
- NUDT9: nudix hydrolase 9
- OTUD4: OTU domain-containing protein 4
- PABPC4L: encoding protein Poly(A) binding protein, cytoplasmic 4-like
- PARM1: Prostate androgen-regulated mucin-like protein 1
- PHOX2B: codes for a homeodomain transcription factor
- PI4K2B: Phosphatidylinositol 4-kinase type 2-beta
- PKD2: polycystic kidney disease 2 (autosomal dominant)
- PLK4: Serine/threonine-protein kinase PLK4
- PSAPL1: encoding protein Prosaposin-like 1 (gene/pseudogene)
- QDPR: quinoid dihydropteridine reductase
- RBM47: RNA binding motif protein 47
- SDAD1: protein SDA1 homolog
- SEC24B: Sec24 homolog B
- SEC24D: Sec24 homolog D
- SEPT11: Septin-11
- SLC9B2: solute carrier family 9 member B2
- SLC10A4: solute carrier family 10 member 4
- SMIM20: encoding protein Small integral membrane protein 20
- SNCA: synuclein, alpha (non A4 component of amyloid precursor)
- SPATA5: Spermatogenesis-associated protein 5
- STATH: gene with protein product
- TACC3: Transforming acidic coiled-coil-containing protein 3
- TENM3: Teneurin transmembrane protein 3
- THAP6: THAP domain-containing protein 6
- TMPRSS11D: Transmembrane protease, serine 11D
- TNIP2: TNFAIP3-interaction protein 2
- UCHL1: ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)
- UGT8: UDP glycosyltransferase 8
- UNC5C: netrin receptor UNC5C
- USP38: encoding protein Ubiquitin specific peptidase 38
- USP53: ubiquitin specific peptidase 53
- UTP3: small subunit processome component
- WFS1: Wolfram syndrome 1 (wolframin)
- ZNF621: encoding protein Zinc finger protein 621
# Diseases and disorders
The following are some of the diseases related to genes located on chromosome 4:
- Achondroplasia
- Autosomal dominant polycystic kidney disease (PKD-2)
- Bladder cancer
- Crouzonodermoskeletal syndrome
- Chronic lymphocytic leukemia
- Congenital central hypoventilation syndrome
- Ellis-van Creveld syndrome
- Facioscapulohumeral muscular dystrophy
- Fibrodysplasia ossificans progressiva (FOP)
- Haemophilia C
- Huntington's disease
- Hemolytic uremic syndrome
- Hereditary benign intraepithelial dyskeratosis
- Hirschprung's disease
- Hypochondroplasia
- Methylmalonic acidemia
- Mucopolysaccharidosis type I
- Muenke syndrome
- Nonsyndromic deafness
- Nonsyndromic deafness, autosomal dominant
- Parkinson's disease
- Polycystic kidney disease
- Romano-Ward syndrome
- SADDAN
- Tetrahydrobiopterin deficiency
- Thanatophoric dysplasia
Type 1
Type 2
- Type 1
- Type 2
- Wolfram syndrome
- Wolf–Hirschhorn syndrome
# Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_4 | |
2703f31b7862768bea6d34c3faaedb5fad14c155 | wikidoc | Chromosome 5 | Chromosome 5
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Chromosome 5 is the 5th largest human chromosome, yet has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of non-coding and syntenic conservation with non-mammalian vertebrates, suggesting they are functionally constrained.
Because chromosome 5 is responsible for many forms of growth and development (cell divisions) changes may cause cancers. One example would be acute myeloid leukemia (AML).
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 5. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## Gene list
The following is a partial list of genes on human chromosome 5. For complete list, see the link in the infobox on the right.
- ABLIM3: encoding protein Actin-binding LIM protein 3
- ADAMTS2: ADAM metallopeptidase with thrombospondin type 1 motif, 2
- AGXT2: Alanine-glyoxylate aminotransferase 2
- ANKRD31: encoding protein Ankyrin repeat domain 31
- APBB3: encoding protein Amyloid beta A4 precursor protein-binding family B member 3
- APC: adenomatosis polyposis coli
- ARL15: encoding protein ADP-ribosylation factor-like 15
- BRIX1: Ribosome biogenesis protein BRX1 homolog (also BXDC2)
- C1QTNF3: Complement C1q tumor necrosis factor-related protein 3
- C5orf3: encoding protein FAM114A2
- C5orf13: Neuronal regeneration related protein
- C5orf21/FAM172A: encoding protein UPF0528 protein FAM172A
- C5orf42: Chromosome 5 open reading frame 42
- CAST: Calpastatin
- CPLX2: Complexin-2
- CREBRF: encoding protein CREB3 regulatory factor
- CXXC5: CXXC-type zing finger protein 5
- DPYSL3: Dihydropyrimidinase-like protein 3
- EGR1: early growth response protein 1
- ERAP1: endoplasmic reticulum aminopeptidase 1 (previously called ARTS-1)
- ERAP2: endoplasmic reticulum aminopeptidase 2
- ESM1: Endothelial cell-specific molecule 1
- DTDST: diastrophic dysplasia sulfate transporter
- EIF4E1B: encoding protein Eukaryotic translation initiation factor 4E family member 1B
- ERCC8: excision repair cross-complementing rodent repair deficiency, complementation group 8
- FAM71B: encoding protein Family with sequence similarity 71 member B
- FAM105B: encoding protein Family with sequence similarity 105, member B
- FASTKD3: FAST kinase domain-containing protein 3
- FBXL7: F-box/LRR-repeat protein 7
- FCHSD1: FCH and double SH3 domain protein 1
- FGF1: fibroblast growth factor 1 (acidic fibroblast growth factor)
- FGFR4: fibroblast growth factor receptor 4
- GM2A: GM2 ganglioside activator
- GNPDA1: Glucosamine-6-phosphate isomerase 1
- GPBP1: Vasculin
- HEXB: hexosaminidase B (beta polypeptide)
- HMGXB3: encoding protein HMG-box containing 3
- IK: Protein Red
- IRX1: Iroquois-class homeodomain protein (human)
- LARP1: La-related protein 1
- LMAN2: Lectin mannose binding 2
- LNCR3 encoding protein Lung cancer susceptibility 3
- LPCAT1: Lysophosphatidylcholine acyltransferase 1
- LYSMD3: LysM and putative peptidoglycan-binding domain-containing protein 3
- MAN2A1: Alpha-mannosidase 2
- MASS1: monogenic, audiogenic seizure susceptibility 1 homolog (mouse)
- MCC: Colorectal mutant cancer protein
- MCCC2: methylcrotonoyl-Coenzyme A carboxylase 2 (beta)
- MEF2C: Myocyte-specific enhancer factor 2C
- MEF2C-AS1: encoding protein MEF2C antisense RNA 1
- MGAT1: Mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase
- MIR146A: microRNA 146a
- MTRR: 5-methyltetrahydrofolate-homocysteine methyltransferase reductase
- MZB1: Marginal zone B and B1 cell-specific protein
- NIPBL: Nipped-B homolog (Drosophila)
- NSA2 encoding protein TGF beta-inducible nuclear protein 1
- NSD1: Transcription coregulator protein
- NSUN2: NOP2/Sun domain family, member 2
- NUDCD2: NudC domain-containing protein 2
- P4HA2: Prolyl 4-hydroxylase subunit alpha-2
- PCBD2: Pterin-4-alpha-carbinolamine dehydratase 2
- PELO: Pelota homolog
- PHAX: Phosphorylated adapter for RNA export
- Pikachurin: Responsible for the functioning of the ribbon synapses; allows the eye to track moving objects
- PFDN1: Prefoldin subunit 1
- POLR3G: encoding protein Polymerase (RNA) III (DNA directed) polypeptide G (32kD)
- PPIP5K2: Diphosphoinositol pentakisphosphate kinase 2
- PRCC1: Proline-rich coiled coil 1
- PURA: Purine-rich element-binding protein A
- PWWP2A: encoding protein PWWP domain containing 2A
- RANBP3L: encoding protein RAN binding protein 3-like
- RMND5B: Required for meiotic nuclear division 5 homolog B
- SFXN1: Sideroflexin-1
- SKIV2L2: Ski2 like RNA helicase 2
- SLC22A5: solute carrier family 22 (organic cation transporter), member 5
- SLC26A2: solute carrier family 26 (sulfate transporter), member 2
- SH3TC2: domain and tetratricopeptide repeats 2
- SLCO4C1: Solute carrier organic anion transporter family member 4c1
- SLU7: pre-mRNA-splicing factor SLU7
- SMN1: survival motor neuron 1, telomeric
- SMN2: survival motor neuron 2, centromeric
- SNCAIP: synuclein, alpha interacting protein (synphilin)
- SPEF2: Sperm flagellar protein 2
- SPINK5: serine protease inhibitor Kazal-type 5 (LEKTI)
- SPINK6: serine protease inhibitor Kazal-type 6
- SPINK9: serine protease inhibitor Kazal-type 9 (LEKTI-2)
- SPZ1: Spermatogenic leucine zipper protein 1
- STC2: Stanniocalcin-2
- TBCA: Tubulin-specific chaperone A
- TCOF1: Treacher Collins-Franceschetti syndrome 1
- TGFBI: keratoepithelin
- THG1L: Probable tRNA(His) guanylyltransferase
- TICAM2: TIR domain-containing adapter molecule 2
- TNFAIP8: Tumor necrosis factor, alpha-induced protein 8
- TTC37: Tetratricopeptide repeat domain 37
- UPF0488: encodes G protein-coupled receptor protein signaling pathway
- YIPF5: Yip1 domain family member 5
- YTHDC2: encoding protein YTH domain containing 2
- ZBED3: Zinc finger BED domain-containing protein 3
- ZNF608: encoding protein Zinc finger protein 608
# Diseases and disorders
The following are some of the diseases related to genes located on chromosome 5:
- Achondrogenesis type 1B
- Atelosteogenesis, type II
- Bosch Boonstra Schaaf Optic Atrophy Syndrome (NR2F1, BBSOAS)
- Charcot–Marie–Tooth disease, type 4
- Cockayne syndrome
- Cornelia de Lange syndrome
- Corneal dystrophy of Bowman layer
- Cri du chat
- Diastrophic dysplasia
- Ehlers-Danlos syndrome
- Familial adenomatous polyposis
- Granular corneal dystrophy type I
- Granular corneal dystrophy type II
- GM2-gangliosidosis, AB variant
- Homocystinuria
- 3-Methylcrotonyl-CoA carboxylase deficiency
- Myelodysplastic Syndrome
- Netherton syndrome
- Nicotine dependency
- Parkinson's disease
- Primary carnitine deficiency
- Recessive multiple epiphyseal dysplasia
- Sandhoff disease
- Spinal muscular atrophy
- Sotos Syndrome
- Survival motor neuron spinal muscular atrophy
- Treacher Collins syndrome
- Tricho-hepato-enteric syndrome
- Usher syndrome
# Chromosomal conditions
The following conditions are caused by changes in the structure or number of copies of chromosome 5:
- Cri-du-chat syndrome is caused by a deletion of the end of the short (p) arm of chromosome 5. This chromosomal change is written as 5p-. The signs and symptoms of cri-du-chat syndrome are probably related to the loss of multiple genes in this region. Researchers have not identified all of these genes or determined how their loss leads to the features of the disorder. They have discovered, however, that a larger deletion tends to result in more severe mental retardation and developmental delays in people with cri-du-chat syndrome.
- Familial Adenomatous Polyposis is caused by a deletion of the APC tumor suppressor gene on the long (q) arm of chromosome 5. This chromosomal change results in thousands of colonic polyps which gives the patient a 100% risk of colon cancer if total colectomy is not done.
- Chromosome 5q deletion syndrome is caused by the deletion of the q arm (long arm) of chromosome 5. This deletion has been linked to several blood related disorders including Myelodysplastic syndrome and Erythroblastopenia. This is a different condition than Cri-du-chat which was mentioned above.
- Other changes in the number or structure of chromosome 5 can have a variety of effects, including delayed growth and development, distinctive facial features, birth defects, and other medical problems. Changes to chromosome 5 include an extra segment of the short (p) or long (q) arm of the chromosome in each cell (partial trisomy 5p or 5q), a missing segment of the long arm of the chromosome in each cell (partial monosomy 5q), and a circular structure called ring chromosome 5. A ring chromosome occurs when both ends of a broken chromosome are reunited.
# Cytogenetic band | Chromosome 5
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. Chromosome 5 is the 5th largest human chromosome, yet has one of the lowest gene densities. This is partially explained by numerous gene-poor regions that display a remarkable degree of non-coding and syntenic conservation with non-mammalian vertebrates, suggesting they are functionally constrained.[5]
Because chromosome 5 is responsible for many forms of growth and development (cell divisions) changes may cause cancers. One example would be acute myeloid leukemia (AML).[6]
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 5. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[7]
## Gene list
The following is a partial list of genes on human chromosome 5. For complete list, see the link in the infobox on the right.
- ABLIM3: encoding protein Actin-binding LIM protein 3
- ADAMTS2: ADAM metallopeptidase with thrombospondin type 1 motif, 2
- AGXT2: Alanine-glyoxylate aminotransferase 2
- ANKRD31: encoding protein Ankyrin repeat domain 31
- APBB3: encoding protein Amyloid beta A4 precursor protein-binding family B member 3
- APC: adenomatosis polyposis coli
- ARL15: encoding protein ADP-ribosylation factor-like 15
- BRIX1: Ribosome biogenesis protein BRX1 homolog (also BXDC2)
- C1QTNF3: Complement C1q tumor necrosis factor-related protein 3
- C5orf3: encoding protein FAM114A2
- C5orf13: Neuronal regeneration related protein
- C5orf21/FAM172A: encoding protein UPF0528 protein FAM172A
- C5orf42: Chromosome 5 open reading frame 42
- CAST: Calpastatin
- CPLX2: Complexin-2
- CREBRF: encoding protein CREB3 regulatory factor
- CXXC5: CXXC-type zing finger protein 5
- DPYSL3: Dihydropyrimidinase-like protein 3
- EGR1: early growth response protein 1
- ERAP1: endoplasmic reticulum aminopeptidase 1 (previously called ARTS-1)
- ERAP2: endoplasmic reticulum aminopeptidase 2
- ESM1: Endothelial cell-specific molecule 1
- DTDST: diastrophic dysplasia sulfate transporter
- EIF4E1B: encoding protein Eukaryotic translation initiation factor 4E family member 1B
- ERCC8: excision repair cross-complementing rodent repair deficiency, complementation group 8
- FAM71B: encoding protein Family with sequence similarity 71 member B
- FAM105B: encoding protein Family with sequence similarity 105, member B
- FASTKD3: FAST kinase domain-containing protein 3
- FBXL7: F-box/LRR-repeat protein 7
- FCHSD1: FCH and double SH3 domain protein 1
- FGF1: fibroblast growth factor 1 (acidic fibroblast growth factor)
- FGFR4: fibroblast growth factor receptor 4
- GM2A: GM2 ganglioside activator
- GNPDA1: Glucosamine-6-phosphate isomerase 1
- GPBP1: Vasculin
- HEXB: hexosaminidase B (beta polypeptide)
- HMGXB3: encoding protein HMG-box containing 3
- IK: Protein Red
- IRX1: Iroquois-class homeodomain protein (human)
- LARP1: La-related protein 1
- LMAN2: Lectin mannose binding 2
- LNCR3 encoding protein Lung cancer susceptibility 3
- LPCAT1: Lysophosphatidylcholine acyltransferase 1
- LYSMD3: LysM and putative peptidoglycan-binding domain-containing protein 3
- MAN2A1: Alpha-mannosidase 2
- MASS1: monogenic, audiogenic seizure susceptibility 1 homolog (mouse)
- MCC: Colorectal mutant cancer protein
- MCCC2: methylcrotonoyl-Coenzyme A carboxylase 2 (beta)
- MEF2C: Myocyte-specific enhancer factor 2C
- MEF2C-AS1: encoding protein MEF2C antisense RNA 1
- MGAT1: Mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferase
- MIR146A: microRNA 146a
- MTRR: 5-methyltetrahydrofolate-homocysteine methyltransferase reductase
- MZB1: Marginal zone B and B1 cell-specific protein
- NIPBL: Nipped-B homolog (Drosophila)
- NSA2 encoding protein TGF beta-inducible nuclear protein 1
- NSD1: Transcription coregulator protein
- NSUN2: NOP2/Sun domain family, member 2
- NUDCD2: NudC domain-containing protein 2
- P4HA2: Prolyl 4-hydroxylase subunit alpha-2
- PCBD2: Pterin-4-alpha-carbinolamine dehydratase 2
- PELO: Pelota homolog
- PHAX: Phosphorylated adapter for RNA export
- Pikachurin: Responsible for the functioning of the ribbon synapses; allows the eye to track moving objects
- PFDN1: Prefoldin subunit 1
- POLR3G: encoding protein Polymerase (RNA) III (DNA directed) polypeptide G (32kD)
- PPIP5K2: Diphosphoinositol pentakisphosphate kinase 2
- PRCC1: Proline-rich coiled coil 1
- PURA: Purine-rich element-binding protein A
- PWWP2A: encoding protein PWWP domain containing 2A
- RANBP3L: encoding protein RAN binding protein 3-like
- RMND5B: Required for meiotic nuclear division 5 homolog B
- SFXN1: Sideroflexin-1
- SKIV2L2: Ski2 like RNA helicase 2
- SLC22A5: solute carrier family 22 (organic cation transporter), member 5
- SLC26A2: solute carrier family 26 (sulfate transporter), member 2
- SH3TC2: domain and tetratricopeptide repeats 2
- SLCO4C1: Solute carrier organic anion transporter family member 4c1
- SLU7: pre-mRNA-splicing factor SLU7
- SMN1: survival motor neuron 1, telomeric
- SMN2: survival motor neuron 2, centromeric
- SNCAIP: synuclein, alpha interacting protein (synphilin)
- SPEF2: Sperm flagellar protein 2
- SPINK5: serine protease inhibitor Kazal-type 5 (LEKTI)
- SPINK6: serine protease inhibitor Kazal-type 6
- SPINK9: serine protease inhibitor Kazal-type 9 (LEKTI-2)
- SPZ1: Spermatogenic leucine zipper protein 1
- STC2: Stanniocalcin-2
- TBCA: Tubulin-specific chaperone A
- TCOF1: Treacher Collins-Franceschetti syndrome 1
- TGFBI: keratoepithelin
- THG1L: Probable tRNA(His) guanylyltransferase
- TICAM2: TIR domain-containing adapter molecule 2
- TNFAIP8: Tumor necrosis factor, alpha-induced protein 8
- TTC37: Tetratricopeptide repeat domain 37
- UPF0488: encodes G protein-coupled receptor protein signaling pathway
- YIPF5: Yip1 domain family member 5
- YTHDC2: encoding protein YTH domain containing 2
- ZBED3: Zinc finger BED domain-containing protein 3
- ZNF608: encoding protein Zinc finger protein 608
# Diseases and disorders
The following are some of the diseases related to genes located on chromosome 5:
- Achondrogenesis type 1B
- Atelosteogenesis, type II
- Bosch Boonstra Schaaf Optic Atrophy Syndrome (NR2F1, BBSOAS)
- Charcot–Marie–Tooth disease, type 4
- Cockayne syndrome
- Cornelia de Lange syndrome
- Corneal dystrophy of Bowman layer
- Cri du chat
- Diastrophic dysplasia
- Ehlers-Danlos syndrome
- Familial adenomatous polyposis
- Granular corneal dystrophy type I
- Granular corneal dystrophy type II
- GM2-gangliosidosis, AB variant
- Homocystinuria
- 3-Methylcrotonyl-CoA carboxylase deficiency
- Myelodysplastic Syndrome
- Netherton syndrome
- Nicotine dependency
- Parkinson's disease
- Primary carnitine deficiency
- Recessive multiple epiphyseal dysplasia
- Sandhoff disease
- Spinal muscular atrophy
- Sotos Syndrome
- Survival motor neuron spinal muscular atrophy
- Treacher Collins syndrome
- Tricho-hepato-enteric syndrome
- Usher syndrome
# Chromosomal conditions
The following conditions are caused by changes in the structure or number of copies of chromosome 5:
- Cri-du-chat syndrome is caused by a deletion of the end of the short (p) arm of chromosome 5. This chromosomal change is written as 5p-. The signs and symptoms of cri-du-chat syndrome are probably related to the loss of multiple genes in this region. Researchers have not identified all of these genes or determined how their loss leads to the features of the disorder. They have discovered, however, that a larger deletion tends to result in more severe mental retardation and developmental delays in people with cri-du-chat syndrome.[14][15][16]
- Familial Adenomatous Polyposis is caused by a deletion of the APC tumor suppressor gene on the long (q) arm of chromosome 5. This chromosomal change results in thousands of colonic polyps which gives the patient a 100% risk of colon cancer if total colectomy is not done.
- Chromosome 5q deletion syndrome is caused by the deletion of the q arm (long arm) of chromosome 5. This deletion has been linked to several blood related disorders including Myelodysplastic syndrome and Erythroblastopenia. This is a different condition than Cri-du-chat which was mentioned above.
- Other changes in the number or structure of chromosome 5 can have a variety of effects, including delayed growth and development, distinctive facial features, birth defects, and other medical problems. Changes to chromosome 5 include an extra segment of the short (p) or long (q) arm of the chromosome in each cell (partial trisomy 5p or 5q), a missing segment of the long arm of the chromosome in each cell (partial monosomy 5q), and a circular structure called ring chromosome 5. A ring chromosome occurs when both ends of a broken chromosome are reunited.
# Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_5 | |
c355935d6cb7a9fdd66e7e9372468c4ecac07b1c | wikidoc | Chromosome 6 | Chromosome 6
Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total DNA in cells. It contains the Major Histocompatibility Complex, which contains over 100 genes related to the immune response, and plays a vital role in organ transplantation.
# Genes
The human leukocyte antigen lies on chromosome 6, with the exception of the gene for β2-microglobulin (which is located on chromosome 15), and encodes cell-surface antigen-presenting proteins among other functions.
## Number of genes
In 2003, the entirety of chromosome 6 was manually annotated for proteins, resulting in the identification of 1,557 genes, and 633 pseudogenes.
The following are some of the newer gene count estimates. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## Gene list
The following is a partial list of genes on human chromosome 6. For complete list, see the link in the infobox on the right.
### p-arm
The following are some of the genes located on p-arm (short arm) of human chromosome 6:
- ADTRP: encoding protein Androgen-dependent TFPI-regulating protein
- APOM: encoding protein Apolipoprotein M (6p21.33)
- C6orf10: encoding protein Uncharacterized protein C6orf10 (6p21.32)
- C6orf62: chromosome 6 open reading frame 62 (6p22.3)
- C6orf89: chromosome 6 open reading frame 89 (6p21.2)
- CDKAL1: CDK5 regulatory subunit associated protein 1 like 1 (6p22.3)
- COL11A2: collagen, type XI, alpha 2(6p21.3)
- CYP21A2: cytochrome P450, family 21, subfamily A, polypeptide 2 (6p21.33)
- DHX16: DEAH-box helicase 16 (6p21.33)
- DOM3Z: Decapping exoribonuclease (6p21.33)
- DSP: Desmoplakin gene linked to cardiomyopathy (6p24.3)
- ELOVL5: ELOVL fatty acid elongase 5 (6p12.1)
- FBXO9: F-box protein 9 (6p12.1)
- G6B: Protein G6b (6p21.33)
- GCNT2: N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (6p24.3)
- GMDS: GDP-mannose 4,6-dehydratase (6p25.3)
- HCG4P11: HLA complex group 4 pseudogene 11
- HFE: hemochromatosis (6p22.2)
- HIST1H2AH: histone cluster 1 H2A family member h (6p22.1)
- HLA-A, HLA-B, HLA-C: major histocompatibility complex (MHC), class I, A, B, and C loci. (6p21.3)
- HLA-DQA1 and HLA-DQB1 form HLA-DQ heterodimer MHC class II, DQ: Celiac1, IDDM (6p21.3)
- HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5 forms HLA-DR, heterodimer MHC class II, DR (6p21.3)
- HLA-DPA1 and HLA-DPB1 forms HLA-DR, MHC class II, DP (6p21.3)
- HLA-Cw*06:02: gene variation related to psoriasis (6p21.3)
- LY6G6E encoding protein Lymphocyte antigen 6 complex, locus G6E (pseudogene) (6p21.33)
- LST1: leukocyte specific transcript 1 (6p21.33)
- MIR4640: microRNA 4640 (6p21.33)
- MLIP: muscular LMNA interaction protein (6p12.1)
- MRPS18B: mitochondrial ribosomal protein S18B (6p21.33)
- MUT: methylmalonyl Coenzyme A mutase (6p12.3)
- NHLRC1: NHL repeat containing E3 ubiquitin protein ligase 1 (6p22.3)
- NOL7: nucleolar protein 7 (6p23)
- NQO2: N-ribosyldihydronicotinamide:quinone reductase 2 (6p25.2)
- NRSN1: neurensin 1 (6p22.3)
- NUDT3: nudix hydrolase 3 (6p21.31)
- PFDN6: prefoldin subunit 6 (6p21.32)
- PHACTR1: phosphatase and actin regulator 1 (6p24.1)
- PKHD1: polycystic kidney and hepatic disease 1 (autosomal recessive) (6p21.2-p12)
- PRICKLE4: prickle planar cell polarity protein 4 (6p21.1)
- PRSS16: protease, serine 16 (6p22.1)
- PSMB8-AS1: PSMB8 antisense RNA 1 (head to head) (6p21.32)
- RIPOR2: RHO family interacting cell polarization regulator 2 (6p22.3)
- RPL10A: encoding protein 60S ribosomal protein L10a (6p21.31)
- SKIV2L: Ski2 like RNA helicase (6p21.33)
- SSR1: signal sequence receptor subunit 1 (6p24.3)
- TCF19: transcription factor 19 (6p21.33)
- TCP11: t-complex 11 (6p21.31)
- TJAP1: tight junction associated protein 1 (6p21.1)
- TP53COR1 encoding protein Tumor protein p53 pathway corepressor 1 (non-protein coding)
- TMEM151B: encoding protein Transmembrane protein 151B
- TNXB: tenascin XB (6p21.3)
- TRAM2: translocation associated membrane protein 2 (6p12.2)
- UBR2: ubiquitin protein ligase E3 component n-recognin 2 (6p21.2)
- UNC5CL: encoding protein Unc-5 homolog C (C. elegans)-like
- VEGF: vascular endothelial growth factor A (angiogenic growth factor) (6p21.1)
- VPS52: GARP complex subunit
- ZNF76: zinc finger protein 76 (6p21.31)
- ZNF193: zinc finger protein 193 (6p22.1)
- ZNRD1: zinc ribbon domain containing 1 (6p22.1)
### q-arm
The following are some of the genes located on q-arm (long arm) of human chromosome 6:
- AIM1: encoding protein Absent in melanoma 1 protein (6q21)
- AIG1: encoding protein Androgen-induced protein 1 (6q24.2)
- AKIRIN2: akirin 2 (6q15)
- ARG1: arginase 1 (6q23.2)
- BCKDHB: branched-chain keto acid dehydrogenase E1, beta polypeptide (maple syrup urine disease) (6q14.1)
- BMIQ3: body mass index QTL 3
- C6orf35 encoding protein UPF0463 transmembrane protein C6orf35
- C6orf58: chromosome 6 open reading frame 58 (6q22.33)
- C6orf165: encoding protein DUF3508 (6q15)
- CMD1F: cardiomyopathy, dilated 1F
- CMD1K: cardiomyopathy, dilated 1K
- CNR1: cannabinoid 1 receptor (6q14-q15)
- DFNB38: deafness, autosomal recessive 38
- DYX4: dyslexia susceptibility 4
- ECT2L: encoding protein Epithelial cell transforming sequence 2 oncogene-like
- ESR1: Estrogen receptor 1 (6q25)
- EYA4: eyes absent homolog 4 (Drosophila)(6q23.2)
- FBXL4: F-box and leucine rich repeat protein 4 (6q16.1-q16.2)
- FEB5: febrile convulsions 5
- HACE1: HECT domain and Ankyrin repeat containing, E3 ubiquitin protein ligase 1 (6q21)
- HEBP2: heme binding protein 2 (6q24.1)
- IDDM8: insulin dependent diabetes mellitus 8
- IDDM15: insulin dependent diabetes mellitus 15
- IFNGR: interferon-γ receptor gene (6q23-q24)
- IGF2R: insulin-like growth factor 2 receptor (6q25.3)
- IMPG1: interphotoreceptor matrix proteoglylcan 1 (6q14.1)
- LIN28B: lin-28 homolog B (6q16.3-q21)
- MAN1A1: mannosidase alpha class 1A member 1 (6q22.31)
- MB21D1: encoding protein Mab-21 domain containing 1
- MCDR1: macular dystrophy, retinal, 1
- MDN1: midasin AAA ATPase 1 (6q15)
- MOXD1: monooxygenase DBH like 1 (6q23.2)
- MTO1: mitochondrial tRNA translation optimization 1 (6q13)
- MRT18: mental retardation, non-syndromic, autosomal recessive
- MRT28: mental retardation, non-syndromic, autosomal recessive
- MTRF1L: mitochondrial translational release factor 1 like (6q25.2)
- MYO6: myosin VI (6q14.1)
- OA3: ocular albinism 3
- OPRM1: μ-opioid receptors (6q24-q25)
- OTSC7: otosclerosis 7
- PLG: plasminogen (6q26)
- PBCRA1
- PARK2: Parkinson disease (autosomal recessive, juvenile) 2, parkin (6q26)
- PCMT1: protein-L-isoaspartate (D-aspartate) O-methyltransferase (6q25.1)
- PERP: p53 apoptosis effector related to PMP-22 (6q23.3)
- PKIB: cAMP-dependent protein kinase inhibitor beta (6p22.31)
- RCD1: retinal cone dystrophy 1
- RP63: retinitis pigmentosa 63
- SASH1: SAM and SH3 domain containing 1 (6q24.3-q25.1)
- SCZD5: schizophrenia disorder 5
- SEN6: senescence (cellular)-related 6
- SENP6: SUMO1/sentrin specific peptidase 6 (6q14.1)
- SERAC1: serine active site containing 1 (6q25.3)
- SERINC1: serine incorporator 1 (6q22.31)
- SF3B5: splicing factor 3b subunit 5 (6q24.2)
- SMAP1: small ArfGAP 1 (6q13)
- SOBP: sine oculis binding protein homolog (6q21)
- SPG25: spastic paraplegia 25
- ST8:suppression of tumorigenicity 8
- SYNJ2: synaptojanin 2 (6q25.3)
- T: T brachyury transcription factor (more commonly known as the T gene) linked to Hepatocellular carcinoma and Chordoma (6q27)
- TAAR1: trace amine associated receptor 1 (6q23.1)
- TAAR2: trace amine associated receptor 2 (6q24)
- TMEM200A: encoding protein Transmembrane protein 200A
- TSPYL1: TSPY like 1 (6q22.1)
- UNC93A: encoding protein Unc-93 homolog A (C. elegans)
- VNN1: vanin 1 (6q23.2)
- VNN2: vanin 2 (6q23.2)
- VTA1: Vesicle trafficking 1 (6q24.1-2)
- ZC2HC1: encoding protein Zinc finger C2HC-type containing 1B
- ZDHHC14: encoding protein Zinc finger, DHHC-type containing 14
# Diseases and disorders
The following diseases are some of those related to genes on chromosome 6:
- ankylosing spondylitis, HLA-B
- collagenopathy, types II and XI
- Coeliac disease HLA-DQA1 & DQB1
- Ehlers-Danlos syndrome, classical, hypermobility, and Tenascin-X types
- Hashimoto's thyroiditis
- hemochromatosis
- Hemochromatosis type 1
- 21-hydroxylase deficiency
- maple syrup urine disease
- methylmalonic acidemia
- Autosomal nonsyndromic deafness
- otospondylomegaepiphyseal dysplasia
- Parkinson disease
- polycystic kidney disease
- porphyria
- porphyria cutanea tarda
- Rheumatoid arthritis, HLA-DR
- Stickler syndrome, COL11A2
- Systemic lupus erythematosus
- Diabetes mellitus type 1, HLA-DR, DQA1 & DQB1
- X-linked sideroblastic anemia
- Epilepsy
- Guillain Barre Syndrome
- Chordoma
- Hepatocellular carcinoma
# Cytogenetic band | Chromosome 6
Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total DNA in cells. It contains the Major Histocompatibility Complex, which contains over 100 genes related to the immune response, and plays a vital role in organ transplantation.
# Genes
The human leukocyte antigen lies on chromosome 6, with the exception of the gene for β2-microglobulin (which is located on chromosome 15), and encodes cell-surface antigen-presenting proteins among other functions.
## Number of genes
In 2003, the entirety of chromosome 6 was manually annotated for proteins, resulting in the identification of 1,557 genes, and 633 pseudogenes.[5]
The following are some of the newer gene count estimates. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[6]
## Gene list
The following is a partial list of genes on human chromosome 6. For complete list, see the link in the infobox on the right.
### p-arm
The following are some of the genes located on p-arm (short arm) of human chromosome 6:
- ADTRP: encoding protein Androgen-dependent TFPI-regulating protein
- APOM: encoding protein Apolipoprotein M (6p21.33)
- C6orf10: encoding protein Uncharacterized protein C6orf10 (6p21.32)
- C6orf62: chromosome 6 open reading frame 62 (6p22.3)
- C6orf89: chromosome 6 open reading frame 89 (6p21.2)
- CDKAL1: CDK5 regulatory subunit associated protein 1 like 1 (6p22.3)
- COL11A2: collagen, type XI, alpha 2(6p21.3)
- CYP21A2: cytochrome P450, family 21, subfamily A, polypeptide 2 (6p21.33)
- DHX16: DEAH-box helicase 16 (6p21.33)
- DOM3Z: Decapping exoribonuclease (6p21.33)
- DSP: Desmoplakin gene linked to cardiomyopathy (6p24.3)
- ELOVL5: ELOVL fatty acid elongase 5 (6p12.1)
- FBXO9: F-box protein 9 (6p12.1)
- G6B: Protein G6b (6p21.33)
- GCNT2: N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (6p24.3)
- GMDS: GDP-mannose 4,6-dehydratase (6p25.3)
- HCG4P11: HLA complex group 4 pseudogene 11
- HFE: hemochromatosis (6p22.2)
- HIST1H2AH: histone cluster 1 H2A family member h (6p22.1)
- HLA-A, HLA-B, HLA-C: major histocompatibility complex (MHC), class I, A, B, and C loci. (6p21.3)
- HLA-DQA1 and HLA-DQB1 form HLA-DQ heterodimer MHC class II, DQ: Celiac1, IDDM (6p21.3)
- HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5 forms HLA-DR, heterodimer MHC class II, DR (6p21.3)
- HLA-DPA1 and HLA-DPB1 forms HLA-DR, MHC class II, DP (6p21.3)
- HLA-Cw*06:02: gene variation related to psoriasis (6p21.3)
- LY6G6E encoding protein Lymphocyte antigen 6 complex, locus G6E (pseudogene) (6p21.33)
- LST1: leukocyte specific transcript 1 (6p21.33)
- MIR4640: microRNA 4640 (6p21.33)
- MLIP: muscular LMNA interaction protein (6p12.1)
- MRPS18B: mitochondrial ribosomal protein S18B (6p21.33)
- MUT: methylmalonyl Coenzyme A mutase (6p12.3)
- NHLRC1: NHL repeat containing E3 ubiquitin protein ligase 1 (6p22.3)
- NOL7: nucleolar protein 7 (6p23)
- NQO2: N-ribosyldihydronicotinamide:quinone reductase 2 (6p25.2)
- NRSN1: neurensin 1 (6p22.3)
- NUDT3: nudix hydrolase 3 (6p21.31)
- PFDN6: prefoldin subunit 6 (6p21.32)
- PHACTR1: phosphatase and actin regulator 1 (6p24.1)
- PKHD1: polycystic kidney and hepatic disease 1 (autosomal recessive) (6p21.2-p12)
- PRICKLE4: prickle planar cell polarity protein 4 (6p21.1)
- PRSS16: protease, serine 16 (6p22.1)
- PSMB8-AS1: PSMB8 antisense RNA 1 (head to head) (6p21.32)
- RIPOR2: RHO family interacting cell polarization regulator 2 (6p22.3)
- RPL10A: encoding protein 60S ribosomal protein L10a (6p21.31)
- SKIV2L: Ski2 like RNA helicase (6p21.33)
- SSR1: signal sequence receptor subunit 1 (6p24.3)
- TCF19: transcription factor 19 (6p21.33)
- TCP11: t-complex 11 (6p21.31)
- TJAP1: tight junction associated protein 1 (6p21.1)
- TP53COR1 encoding protein Tumor protein p53 pathway corepressor 1 (non-protein coding)
- TMEM151B: encoding protein Transmembrane protein 151B
- TNXB: tenascin XB (6p21.3)
- TRAM2: translocation associated membrane protein 2 (6p12.2)
- UBR2: ubiquitin protein ligase E3 component n-recognin 2 (6p21.2)
- UNC5CL: encoding protein Unc-5 homolog C (C. elegans)-like
- VEGF: vascular endothelial growth factor A (angiogenic growth factor) (6p21.1)
- VPS52: GARP complex subunit
- ZNF76: zinc finger protein 76 (6p21.31)
- ZNF193: zinc finger protein 193 (6p22.1)
- ZNRD1: zinc ribbon domain containing 1 (6p22.1)
### q-arm
The following are some of the genes located on q-arm (long arm) of human chromosome 6:
- AIM1: encoding protein Absent in melanoma 1 protein (6q21)
- AIG1: encoding protein Androgen-induced protein 1 (6q24.2)
- AKIRIN2: akirin 2 (6q15)
- ARG1: arginase 1 (6q23.2)
- BCKDHB: branched-chain keto acid dehydrogenase E1, beta polypeptide (maple syrup urine disease) (6q14.1)
- BMIQ3: body mass index QTL 3
- C6orf35 encoding protein UPF0463 transmembrane protein C6orf35
- C6orf58: chromosome 6 open reading frame 58 (6q22.33)
- C6orf165: encoding protein DUF3508 (6q15)
- CMD1F: cardiomyopathy, dilated 1F
- CMD1K: cardiomyopathy, dilated 1K
- CNR1: cannabinoid 1 receptor (6q14-q15)[13]
- DFNB38: deafness, autosomal recessive 38
- DYX4: dyslexia susceptibility 4
- ECT2L: encoding protein Epithelial cell transforming sequence 2 oncogene-like
- ESR1: Estrogen receptor 1 (6q25)
- EYA4: eyes absent homolog 4 (Drosophila)(6q23.2)
- FBXL4: F-box and leucine rich repeat protein 4 (6q16.1-q16.2)
- FEB5: febrile convulsions 5
- HACE1: HECT domain and Ankyrin repeat containing, E3 ubiquitin protein ligase 1 (6q21)
- HEBP2: heme binding protein 2 (6q24.1)
- IDDM8: insulin dependent diabetes mellitus 8
- IDDM15: insulin dependent diabetes mellitus 15
- IFNGR: interferon-γ receptor gene (6q23-q24)
- IGF2R: insulin-like growth factor 2 receptor (6q25.3)
- IMPG1: interphotoreceptor matrix proteoglylcan 1 (6q14.1)
- LIN28B: lin-28 homolog B (6q16.3-q21)
- MAN1A1: mannosidase alpha class 1A member 1 (6q22.31)
- MB21D1: encoding protein Mab-21 domain containing 1
- MCDR1: macular dystrophy, retinal, 1
- MDN1: midasin AAA ATPase 1 (6q15)
- MOXD1: monooxygenase DBH like 1 (6q23.2)
- MTO1: mitochondrial tRNA translation optimization 1 (6q13)
- MRT18: mental retardation, non-syndromic, autosomal recessive
- MRT28: mental retardation, non-syndromic, autosomal recessive
- MTRF1L: mitochondrial translational release factor 1 like (6q25.2)
- MYO6: myosin VI (6q14.1)
- OA3: ocular albinism 3
- OPRM1: μ-opioid receptors (6q24-q25)
- OTSC7: otosclerosis 7
- PLG: plasminogen (6q26)
- PBCRA1
- PARK2: Parkinson disease (autosomal recessive, juvenile) 2, parkin (6q26)
- PCMT1: protein-L-isoaspartate (D-aspartate) O-methyltransferase (6q25.1)
- PERP: p53 apoptosis effector related to PMP-22 (6q23.3)
- PKIB: cAMP-dependent protein kinase inhibitor beta (6p22.31)
- RCD1: retinal cone dystrophy 1
- RP63: retinitis pigmentosa 63
- SASH1: SAM and SH3 domain containing 1 (6q24.3-q25.1)
- SCZD5: schizophrenia disorder 5
- SEN6: senescence (cellular)-related 6
- SENP6: SUMO1/sentrin specific peptidase 6 (6q14.1)
- SERAC1: serine active site containing 1 (6q25.3)
- SERINC1: serine incorporator 1 (6q22.31)
- SF3B5: splicing factor 3b subunit 5 (6q24.2)
- SMAP1: small ArfGAP 1 (6q13)
- SOBP: sine oculis binding protein homolog (6q21)
- SPG25: spastic paraplegia 25
- ST8:suppression of tumorigenicity 8
- SYNJ2: synaptojanin 2 (6q25.3)
- T: T brachyury transcription factor (more commonly known as the T gene) linked to Hepatocellular carcinoma and Chordoma (6q27)[14]
- TAAR1: trace amine associated receptor 1 (6q23.1)
- TAAR2: trace amine associated receptor 2 (6q24)
- TMEM200A: encoding protein Transmembrane protein 200A
- TSPYL1: TSPY like 1 (6q22.1)
- UNC93A: encoding protein Unc-93 homolog A (C. elegans)
- VNN1: vanin 1 (6q23.2)
- VNN2: vanin 2 (6q23.2)
- VTA1: Vesicle trafficking 1 (6q24.1-2)
- ZC2HC1: encoding protein Zinc finger C2HC-type containing 1B
- ZDHHC14: encoding protein Zinc finger, DHHC-type containing 14
# Diseases and disorders
The following diseases are some of those related to genes on chromosome 6:
- ankylosing spondylitis, HLA-B
- collagenopathy, types II and XI
- Coeliac disease HLA-DQA1 & DQB1
- Ehlers-Danlos syndrome, classical, hypermobility, and Tenascin-X types
- Hashimoto's thyroiditis
- hemochromatosis
- Hemochromatosis type 1
- 21-hydroxylase deficiency
- maple syrup urine disease
- methylmalonic acidemia
- Autosomal nonsyndromic deafness
- otospondylomegaepiphyseal dysplasia
- Parkinson disease
- polycystic kidney disease
- porphyria
- porphyria cutanea tarda
- Rheumatoid arthritis, HLA-DR
- Stickler syndrome, COL11A2
- Systemic lupus erythematosus
- Diabetes mellitus type 1, HLA-DR, DQA1 & DQB1
- X-linked sideroblastic anemia
- Epilepsy
- Guillain Barre Syndrome
- Chordoma
- Hepatocellular carcinoma
# Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_6 | |
40317a3c75d6ac5d5f4d31f55975a341de8238c8 | wikidoc | Chromosome 7 | Chromosome 7
Chromosome 7 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DNA in cells.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 7. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## Gene list
The following is a partial list of genes on human chromosome 7. For complete list, see the link in the infobox on the right.
- ACTR3B: actin-related protein 3B
- AEBP1: AE binding protein 1
- AGK: encoding enzyme mitochondrial acylglycerol kinase
- AASS: encoding enzyme Alpha-aminoadipic semialdehyde synthase, mitochondrial
- ARHGEF35: encoding protein Rho guanine nucleotide exchange factor (GEF) 35
- BCAP29: B-cell receptor-associated protein 29
- BRAT1: BRCA1-associated ATM activator 1
- C7orf20: encoding protein UPF0363 protein C7orf20
- C7orf25: protein UPF0415
- C7orf31: chromosome 7 open reading frame 31
- C7orf43: encoding protein
- CALU: Calumenin
- CDCA7L: Cell division cycle-associated 7-like protein
- CNOT4: CCR4-NOT transcription complex, subunit 4
- CPED1: cadherin like and PC-esterase domain containing 1
- CPVL: carboxypeptidase, vitellogenic like
- CROT: Peroxisomal carnitine O-octanoyltransferase
- DDX56: DEAD-box helicase 56
- DMTF1: Cyclin D binding myb like transcription factor 1
- ECOP: EGFR-coamplified and overexpressed protein
- EZH2: encoding enzyme histone-lysine N-methyltransferase for histone h3 lysine 27
- FAM71F2: family with sequence similarity 71 member F2
- FAM185A: family with sequence similarity 185 member A
- FAM200A: family with sequence similarity 200 member A
- FBXO24: F-box only protein 24
- GBAS: Glioblastoma amplified sequence; Protein NipSnap homolog 2
- GLCCI1: Glucocorticoid-induced transcript 1 protein
- ICA1: islet cell autoantigen 1
- ING3: inhibitor of growth protein 3
- INTS1: encoding protein Integrator complex subunit 1
- IQCE: IQ domain-containing protein E
- KDM7A: encoding protein Lysine demethylase 7A
- LRRC17: leucine-rich repeat containing protein 17
- LSM5: U6 small nuclear RNA and mRNA degradation associated
- LUC7L2: putative RNA-binding protein Luc7-like 2
- MDFIC: MyoD family inhibitor domain containing
- METTL2B: methyltransferase-like protein 2B
- MINDY4: MINDY lysine 48 deubiquitinase 4
- MIR96: microRNA 96
- MOSPD3: motile sperm domain containing 3
- MTERF: mitochondrial transcription termination factor 1
- NOM1: nucleolar protein with MIF4G domain 1
- NUDCD3: NudC domain-containing protein 3
- NUPL2: nucleoporin-like 2
- NXPH1: neurexophilin-1
- PDAP1: PDGFA associated protein 1
- PHTF2: putative homeodomain transcription factor 2
- PLOD3: procollagen-lysine,2-oxoglutarate 5-dioxygenase 3
- POM121: POM121 transmembrane nucleoporin
- POP7: ribonuclease P protein subunit p20
- PPP1R17: protein phosphatase 1 regulatory subunit 17
- PSPH: phosphoserine phosphatase
- PURB: purine-rich element binding protein B
- PVRIG: encoding protein Poliovirus receptor related immunoglobulin domain containing
- RADIL: ras-associating and dilute domain-containing protein
- RCP9: DNA-directed RNA polymerase III subunit RCP9
- REPIN1: replication initiator 1
- RNF216-IT1: encoding protein RNF216 intronic transcript 1
- SCIN: scinderin
- SCRN1: secernin 1
- SOSTDC1: sclerostin domain containing 1
- SPDYE1: speedy/RINGO cell cycle regulator family member E1
- SSC4D: scavenger receptor cysteine rich family member with 4 domains
- STEAP1: six transmembrane epithelial antigen of the prostate 1
- STEAP2: six transmembrane epithelial antigen of the prostate 2
- STEAP4: six transmembrane epithelial antigen of the prostate 4
- STYXL1: serine/threonine/tyrosine-interacting-like protein 1
- SUMF2: sulatase-modifying factor 2
- SYPL1: synaptophysin-like protein 1
- TARP: TCR gamma alternate reading frame protein
- TBRG4: transforming growth factor beta regulator 4
- TECPR1 encoding protein Tectonin beta-propeller repeat containing 1
- TMED4: transmembrane emp24 domain-containing protein 4
- TMEM130: transmembrane protein 130
- TMEM196 encoding protein Transmembrane protein 196
- TRBC1 encoding protein T cell receptor beta constant 1
- TRBC2 encoding protein T cell receptor beta constant 2
- TRIL: TRL4 interactor with leucine rich repeats
- URG4: up-regulated gene 4
- WBSCR17: polypeptide N-acetylgalactosaminyltransferase 17
- WDR91 encoding protein WD repeat domain 91
- ZC3HAV1: zinc finger CCCH-type containing
- ZC3HC1: zinc finger C3HC-type containing 1
- ZKSCAN1: zinc finger protein with KRAB and SCAN domains 1
- ZKSCAN5: zinc finger protein with KRAB and SCAN domains 5
- ZMIZ2: zinc finger MIZ domain-containing protein 2
- ZNF277P: zinc finger protein 277
- ZNF394: zinc finger protein 394
- ZNF398: zinc finger protein 398
- ZNF727: encoding protein Zinc finger protein 727
- ZNF786: encoding protein Zinc finger protein 786
- ZRF1: DnaJ heat shock protein family (Hsp40) member C2
- ZSCAN21: zinc finger and SCAN domain-containing protein 21
# Diseases and disorders
The following diseases are some of those related to genes on chromosome 7:
- argininosuccinic aciduria
- cerebral cavernous malformation
- Charcot–Marie–Tooth disease
- Cholestasis, progressive familial intrahepatic 3
- Citrullinemia, type II, adult-onset,
- congenital bilateral absence of vas deferens
- cystic fibrosis
- Developmental verbal dyspraxia
- distal spinal muscular atrophy, type V
- Ehlers–Danlos syndrome
- hemochromatosis, type 3
- Hereditary nonpolyposis colorectal cancer HNPCC4
- Lissencephaly syndrome, norman-roberts type
- Marfan syndrome
- maple syrup urine disease
- maturity onset diabetes of the young type 3
- mucopolysaccharidosis type VII or Sly syndrome
- Muscular dystrophy, limb-girdle, type 1D
- myelodysplastic syndrome
- Myotonia congenita
- nonsyndromic deafness
- osteogenesis imperfecta
- p47-phox-deficient chronic granulomatous disease
- Pendred syndrome
- Romano–Ward syndrome
- Shwachman–Diamond syndrome
- Schizophrenia
- Silver-Russell syndrome
- Specific language impairment
- Tritanopia or tritanomaly color blindness
- Williams syndrome
# Chromosomal disorders
The following conditions are caused by changes in the structure or number of copies of chromosome 7:
- Williams syndrome is caused by the deletion of genetic material from a portion of the long (q) arm of chromosome 7. The deleted region, which is located at position 11.23 (written as 7q11.23), is designated as the Williams syndrome critical region. This region includes more than 20 genes, and researchers believe that the characteristic features of Williams syndrome are probably related to the loss of multiple genes in this region.
While a few of the specific genes related to Williams syndrome have been identified, the relationship between most of the genes in the deleted region and the signs and symptoms of Williams syndrome is unknown.
- Other changes in the number or structure of chromosome 7 can cause delayed growth and development, mental disorder, characteristic facial features, skeletal abnormalities, delayed speech, and other medical problems. These changes include an extra copy of part of chromosome 7 in each cell (partial trisomy 7) or a missing segment of the chromosome in each cell (partial monosomy 7). In some cases, several DNA building blocks (nucleotides) are deleted or duplicated in part of chromosome 7. A circular structure called ring chromosome 7 is also possible. A ring chromosome occurs when both ends of a broken chromosome are reunited.
# Cytogenetic band
# In popular culture
## Novels
In the novel Performance Anomalies, researchers at Stanford University identify mutations in the long (q) arm of chromosome 7 as underlying the accelerated nervous system of the spy protagonist Cono, who receives the moniker Cono 7Q | Chromosome 7
Chromosome 7 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 7 spans about 159 million[5] base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DNA in cells.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 7. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[6]
## Gene list
The following is a partial list of genes on human chromosome 7. For complete list, see the link in the infobox on the right.
- ACTR3B: actin-related protein 3B
- AEBP1: AE binding protein 1
- AGK: encoding enzyme mitochondrial acylglycerol kinase
- AASS: encoding enzyme Alpha-aminoadipic semialdehyde synthase, mitochondrial
- ARHGEF35: encoding protein Rho guanine nucleotide exchange factor (GEF) 35
- BCAP29: B-cell receptor-associated protein 29
- BRAT1: BRCA1-associated ATM activator 1
- C7orf20: encoding protein UPF0363 protein C7orf20
- C7orf25: protein UPF0415
- C7orf31: chromosome 7 open reading frame 31
- C7orf43: encoding protein
- CALU: Calumenin
- CDCA7L: Cell division cycle-associated 7-like protein
- CNOT4: CCR4-NOT transcription complex, subunit 4
- CPED1: cadherin like and PC-esterase domain containing 1
- CPVL: carboxypeptidase, vitellogenic like
- CROT: Peroxisomal carnitine O-octanoyltransferase
- DDX56: DEAD-box helicase 56
- DMTF1: Cyclin D binding myb like transcription factor 1
- ECOP: EGFR-coamplified and overexpressed protein
- EZH2: encoding enzyme histone-lysine N-methyltransferase for histone h3 lysine 27
- FAM71F2: family with sequence similarity 71 member F2
- FAM185A: family with sequence similarity 185 member A
- FAM200A: family with sequence similarity 200 member A
- FBXO24: F-box only protein 24
- GBAS: Glioblastoma amplified sequence; Protein NipSnap homolog 2
- GLCCI1: Glucocorticoid-induced transcript 1 protein
- ICA1: islet cell autoantigen 1
- ING3: inhibitor of growth protein 3
- INTS1: encoding protein Integrator complex subunit 1
- IQCE: IQ domain-containing protein E
- KDM7A: encoding protein Lysine demethylase 7A
- LRRC17: leucine-rich repeat containing protein 17
- LSM5: U6 small nuclear RNA and mRNA degradation associated
- LUC7L2: putative RNA-binding protein Luc7-like 2
- MDFIC: MyoD family inhibitor domain containing
- METTL2B: methyltransferase-like protein 2B
- MINDY4: MINDY lysine 48 deubiquitinase 4
- MIR96: microRNA 96
- MOSPD3: motile sperm domain containing 3
- MTERF: mitochondrial transcription termination factor 1
- NOM1: nucleolar protein with MIF4G domain 1
- NUDCD3: NudC domain-containing protein 3
- NUPL2: nucleoporin-like 2
- NXPH1: neurexophilin-1
- PDAP1: PDGFA associated protein 1
- PHTF2: putative homeodomain transcription factor 2
- PLOD3: procollagen-lysine,2-oxoglutarate 5-dioxygenase 3
- POM121: POM121 transmembrane nucleoporin
- POP7: ribonuclease P protein subunit p20
- PPP1R17: protein phosphatase 1 regulatory subunit 17
- PSPH: phosphoserine phosphatase
- PURB: purine-rich element binding protein B
- PVRIG: encoding protein Poliovirus receptor related immunoglobulin domain containing
- RADIL: ras-associating and dilute domain-containing protein
- RCP9: DNA-directed RNA polymerase III subunit RCP9
- REPIN1: replication initiator 1
- RNF216-IT1: encoding protein RNF216 intronic transcript 1
- SCIN: scinderin
- SCRN1: secernin 1
- SOSTDC1: sclerostin domain containing 1
- SPDYE1: speedy/RINGO cell cycle regulator family member E1
- SSC4D: scavenger receptor cysteine rich family member with 4 domains
- STEAP1: six transmembrane epithelial antigen of the prostate 1
- STEAP2: six transmembrane epithelial antigen of the prostate 2
- STEAP4: six transmembrane epithelial antigen of the prostate 4
- STYXL1: serine/threonine/tyrosine-interacting-like protein 1
- SUMF2: sulatase-modifying factor 2
- SYPL1: synaptophysin-like protein 1
- TARP: TCR gamma alternate reading frame protein
- TBRG4: transforming growth factor beta regulator 4
- TECPR1 encoding protein Tectonin beta-propeller repeat containing 1
- TMED4: transmembrane emp24 domain-containing protein 4
- TMEM130: transmembrane protein 130
- TMEM196 encoding protein Transmembrane protein 196
- TRBC1 encoding protein T cell receptor beta constant 1
- TRBC2 encoding protein T cell receptor beta constant 2
- TRIL: TRL4 interactor with leucine rich repeats
- URG4: up-regulated gene 4
- WBSCR17: polypeptide N-acetylgalactosaminyltransferase 17
- WDR91 encoding protein WD repeat domain 91
- ZC3HAV1: zinc finger CCCH-type containing
- ZC3HC1: zinc finger C3HC-type containing 1
- ZKSCAN1: zinc finger protein with KRAB and SCAN domains 1
- ZKSCAN5: zinc finger protein with KRAB and SCAN domains 5
- ZMIZ2: zinc finger MIZ domain-containing protein 2
- ZNF277P: zinc finger protein 277
- ZNF394: zinc finger protein 394
- ZNF398: zinc finger protein 398
- ZNF727: encoding protein Zinc finger protein 727
- ZNF786: encoding protein Zinc finger protein 786
- ZRF1: DnaJ heat shock protein family (Hsp40) member C2
- ZSCAN21: zinc finger and SCAN domain-containing protein 21
# Diseases and disorders
The following diseases are some of those related to genes on chromosome 7:
- argininosuccinic aciduria[13][14][15]
- cerebral cavernous malformation[13][15]
- Charcot–Marie–Tooth disease[13]
- Cholestasis, progressive familial intrahepatic 3[13]
- Citrullinemia, type II, adult-onset,[13]
- congenital bilateral absence of vas deferens[13]
- cystic fibrosis[16][13][15]
- Developmental verbal dyspraxia[17]
- distal spinal muscular atrophy, type V[citation needed]
- Ehlers–Danlos syndrome
- hemochromatosis, type 3[13]
- Hereditary nonpolyposis colorectal cancer HNPCC4[13]
- Lissencephaly syndrome, norman-roberts type[13]
- Marfan syndrome[13]
- maple syrup urine disease[citation needed]
- maturity onset diabetes of the young type 3[citation needed]
- mucopolysaccharidosis type VII or Sly syndrome[13]
- Muscular dystrophy, limb-girdle, type 1D[13]
- myelodysplastic syndrome[18]
- Myotonia congenita[13][19]
- nonsyndromic deafness[13]
- osteogenesis imperfecta[citation needed]
- p47-phox-deficient chronic granulomatous disease[citation needed]
- Pendred syndrome[13][20]
- Romano–Ward syndrome[citation needed]
- Shwachman–Diamond syndrome[13][15]
- Schizophrenia[citation needed]
- Silver-Russell syndrome[21]
- Specific language impairment[13][17]
- Tritanopia or tritanomaly color blindness[13]
- Williams syndrome[16][13][22]
# Chromosomal disorders
The following conditions are caused by changes in the structure or number of copies of chromosome 7:
- Williams syndrome is caused by the deletion of genetic material from a portion of the long (q) arm of chromosome 7. The deleted region, which is located at position 11.23 (written as 7q11.23), is designated as the Williams syndrome critical region. This region includes more than 20 genes, and researchers believe that the characteristic features of Williams syndrome are probably related to the loss of multiple genes in this region.
While a few of the specific genes related to Williams syndrome have been identified, the relationship between most of the genes in the deleted region and the signs and symptoms of Williams syndrome is unknown.
- Other changes in the number or structure of chromosome 7 can cause delayed growth and development, mental disorder, characteristic facial features, skeletal abnormalities, delayed speech, and other medical problems. These changes include an extra copy of part of chromosome 7 in each cell (partial trisomy 7) or a missing segment of the chromosome in each cell (partial monosomy 7). In some cases, several DNA building blocks (nucleotides) are deleted or duplicated in part of chromosome 7. A circular structure called ring chromosome 7 is also possible. A ring chromosome occurs when both ends of a broken chromosome are reunited.[23]
# Cytogenetic band
# In popular culture
## Novels
In the novel Performance Anomalies, researchers at Stanford University identify mutations in the long (q) arm of chromosome 7 as underlying the accelerated nervous system of the spy protagonist Cono,[32] who receives the moniker Cono 7Q | https://www.wikidoc.org/index.php/Chromosome_7 | |
2cd5541b6830498a758ac4308a921abdf618f22f | wikidoc | Chromosome 8 | Chromosome 8
Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 145 million base pairs (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA in cells.
About 8% of its genes are involved in brain development and function, and about 16% are involved in cancer. A unique feature of 8p is a region of about 15 megabases that appears to have a high mutation rate. This region shows a significant divergence between human and chimpanzee, suggesting that its high mutation rates have contributed to the evolution of the human brain.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 8. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## Gene list
The following is a partial list of genes on human chromosome 8. For complete list, see the link in the infobox on the right.
- ADHFE1 encoding protein Alcohol dehydrogenase, iron containing 1
- AEG1 : Astrocyte Elevated Gene (linked to hepatocellular carcinoma and neuroblastoma)
- ANK1: ankyrin 1, erythrocytic
- Arc/Arg3.1
- ASAH1: N-acylsphingosine amidohydrolase (acid ceramidase) 1
- ASPH: encoding enzyme Aspartyl/asparaginyl beta-hydroxylase
- AZIN1: encoding protein Antizyme inhibitor 1
- BRF2: transcription factor IIIB 50 kDa subunit
- C8orf32/WDYHV1: encoding enzyme Protein N-terminal glutamine amidohydrolase
- C8orf33: chromosome 8, open reading frame 33
- C8orf4: encoding protein Uncharacterized protein C8orf4
- C8orf46: encoding protein chromosome 8 open reading frame 46 (C8orf46)
- C8orf48 encoding protein C8orf48
- C8orf58: chromosome 8 open reading frame 58
- CCAT1: colon cancer associated transcript 1
- CCDC25: coiled-coil domain containing protein 25
- CHD7: chromodomain helicase DNA binding protein 7
- CHMP4C: Charged multivesicular body protein 4c
- CHRAC1 encoding protein Chromatin accessibility complex 1
- CHRNA2: cholinergic receptor, nicotinic, alpha 2 (neuronal)
- CLN8: ceroid-lipofuscinosis, neuronal 8
- CNGB3: cyclic nucleotide gated channel beta 3
- COH1: vacuolar protein sorting 13B
- CRISPLD1 encoding protein Cysteine rich secretory protein LCCL domain containing 1
- CSGALNACT1: Chondroitin sulfate N-acetylgalactosaminyltransferase 1
- CTHRC1 encoding protein Collagen triple helix repeat containing 1
- CYP11B1: cytochrome P450, family 11, subfamily B, polypeptide 1
- CYP11B2: cytochrome P450, family 11, subfamily B, polypeptide 2
- DCSTAMP: dendrocyte expressed seven transmembrane protein
- DPYS: dihydropyrimidinase
- EBAG9: Estrogen receptor binding site associated antigen 9
- EPPK1: epiplakin
- ERICH5 encoding protein Glutamate rich 5
- ESCO2: establishment of sister chromatid cohesion N-acetyltransferase 2
- EXT1: exostosin glycosyltransferase 1
- EXTL3: exostosin-like glycosyltransferase 3
- EYA1: EYA transcriptional coactivator and phosphatase 1
- FABP9: fatty acid binding protein 9, testis
- FAM167A: family with sequence similarity 167, member A
- FAM203B: family with sequence similarity 203, member B
- FAM83A: family with sequence similarity 83, member A
- FAM83H: family with sequence similarity 83, member H
- FBXO16 encoding protein F-box protein 16
- FDFT1 encoding protein Farnesyl-diphosphate farnesyltransferase 1
- FGFR1: fibroblast growth factor receptor 1 (fms-related tyrosine kinase 2, Pfeiffer syndrome)
- FGL1: Fibrinogen-like protein 1
- GDAP1: ganglioside-induced differentiation-associated protein 1
- GDF6: growth differentiation factor 6
- GPIHBP1: GPI-anchored high density lipoprotein binding protein 1
- GRINA: encoding protein Glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (glutamate binding)
- GSDMC encoding protein Gasdermin C
- GULOP pseudogene: responsible for human inability to produce Vitamin C
- HGSNAT: heparan-alpha-glucosaminide N-acetyltransferase
- HMBOX1: encoding protein Homeobox containing 1, also known as homeobox telomere-binding protein 1 (HOT1)
- HRSP12 encoding enzyme Ribonuclease UK114
- INTS8: integrator complex subunit 8
- INTS9: integrator complex subunit 9
- KCNQ3: potassium channel, voltage gated KQT-like subfamily Q, member 3.
- KIAA0196: KIAA0196
- KIF13B encoding protein Kinesin family member 13B
- LACTB2: lactamase, beta 2
- LAPTM4B: lysosomal-associated transmembrane protein 4B
- LOC642658: encoding protein Basic helix-loop-helix transcription factor scleraxis
- LPL: lipoprotein lipase
- LSM1: U6 snRNA-associated Sm-like protein LSm1
- MAK16: MAK16 homolog
- MCPH1: microcephaly, primary autosomal recessive 1
- MIR6850 encoding protein MicroRNA 6850
- MRPL13 encoding protein Mitochondrial ribosomal protein L13
- MYBL1 encoding protein MYB proto-oncogene like 1
- NBN: nibrin
- NDRG1: N-myc downstream regulated gene 1
- NEF3: neurofilament 3 (150kDa medium)
- NEFL: neurofilament, light polypeptide 68kDa
- ODF1: outer dense fiber protein 1
- OTUD6B: OTU domain containing 6B
- PDP1: pyruvate dehydrogenase phosphatase catalytic subunit 1
- PKIA: cAMP-dependent protein kinase inhibitor alpha
- PLEC: plectin
- PNMA2: paraneoplastic antigen Ma2
- PREX2: phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 2
- PROSC: proline synthetase co-transcribe bacterial homolog protein
- GLI4: encoding protein Gli family zinc finger 4
- PURG encoding protein Purine-rich element binding protein G
- PVT1: Pvt1 oncogene
- RECQL4: RecQ protein-like 4
- RNF5P1: ring finger protein 5 pseudogene 1
- RRS1: ribosome biogenesis regulator homolog
- RUNX1T1: runt-related transcription factor 1; translocated to, 1 (cyclin D-related)
- SFTPC: surfactant protein C
- SLC20A2: Sodium-dependent phosphate transporter 2
- SLURP1: secreted LY6/PLAUR domain containing 1
- SNAI2: snail homolog 2 (Drosophila)
- SPAG11B: sperm-associated antigen 11B
- STAU2: staufen double-stranded RNA binding protein 2
- SYBU: Syntabulin
- TG: thyroglobulin
- THAP1: THAP domain containing, apoptosis associated protein 1
- TMEM67: encoding protein Meckelin
- TNFRSF11B: tumor necrosis factor receptor superfamily, member 11b
- TONSL: encoding protein Tonsoku-like, DNA repair protein
- TPA: tissue plasminogen activator
- TRMT12: tRNA methyltransferase 12 homolog
- TRPS1: trichorhinophalangeal syndrome I
- TTI2 encoding protein TELO2 interacting protein 2
- VCPIP1: valosin containing protein/p47 complex interacting protein 1
- VMAT1: vesicular monoamine transporter protein
- VPS13B: vacuolar protein sorting 13 homolog B (yeast)
- VPS37A: vacuolar protein sorting 37 homolog A
- WRN: Werner syndrome
- YTHDF3: YTH N6-methyladenosine RNA binding protein 3
- ZFP41: encoding protein ZFP41 zinc finger protein
- ZHX2: zinc fingers and homeoboxes protein 2
- ZMAT4: zinc finger matrin-type 4
- ZNF16: zinc finger protein 16
- ZNF395: encoding protein Zinc finger protein 395
- ZNF517 encoding protein Zinc finger protein 517
- ZNF696 encoding protein Zinc finger protein 696
- ZNF703: zinc finger protein 703
- ZNF706: zinc finger protein 706
- ZNF707: encoding protein Zinc finger protein 707
# Diseases and disorders
The following diseases and disorders are some of those related to genes on chromosome 8:
- 8p23.1 duplication syndrome
- Burkitt's lymphoma
- Charcot-Marie-Tooth disease
- COACH Syndrome
- Cleft lip and palate
- Cohen syndrome
- Congenital hypothyroidism
- Fahr's syndrome
- Hereditary Multiple Exostoses
- Lipoprotein lipase deficiency, familial
- Myelodysplastic syndrome
- Pfeiffer syndrome
- Primary microcephaly
- Rothmund-Thomson syndrome
- Schizophrenia, associated with 8p21-22 locus
- Waardenburg syndrome
- Werner syndrome
- Pingelapese blindness
- Langer-Giedion syndrome
- Roberts Syndrome
# Cytogenetic band | Chromosome 8
Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 145 million base pairs (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA in cells.[5]
About 8% of its genes are involved in brain development and function, and about 16% are involved in cancer. A unique feature of 8p is a region of about 15 megabases that appears to have a high mutation rate. This region shows a significant divergence between human and chimpanzee, suggesting that its high mutation rates have contributed to the evolution of the human brain.[5]
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 8. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[6]
## Gene list
The following is a partial list of genes on human chromosome 8. For complete list, see the link in the infobox on the right.
- ADHFE1 encoding protein Alcohol dehydrogenase, iron containing 1
- AEG1 : Astrocyte Elevated Gene (linked to hepatocellular carcinoma and neuroblastoma)
- ANK1: ankyrin 1, erythrocytic
- Arc/Arg3.1
- ASAH1: N-acylsphingosine amidohydrolase (acid ceramidase) 1
- ASPH: encoding enzyme Aspartyl/asparaginyl beta-hydroxylase
- AZIN1: encoding protein Antizyme inhibitor 1
- BRF2: transcription factor IIIB 50 kDa subunit
- C8orf32/WDYHV1: encoding enzyme Protein N-terminal glutamine amidohydrolase
- C8orf33: chromosome 8, open reading frame 33
- C8orf4: encoding protein Uncharacterized protein C8orf4
- C8orf46: encoding protein chromosome 8 open reading frame 46 (C8orf46)
- C8orf48 encoding protein C8orf48
- C8orf58: chromosome 8 open reading frame 58
- CCAT1: colon cancer associated transcript 1
- CCDC25: coiled-coil domain containing protein 25
- CHD7: chromodomain helicase DNA binding protein 7
- CHMP4C: Charged multivesicular body protein 4c
- CHRAC1 encoding protein Chromatin accessibility complex 1
- CHRNA2: cholinergic receptor, nicotinic, alpha 2 (neuronal)
- CLN8: ceroid-lipofuscinosis, neuronal 8
- CNGB3: cyclic nucleotide gated channel beta 3
- COH1: vacuolar protein sorting 13B
- CRISPLD1 encoding protein Cysteine rich secretory protein LCCL domain containing 1
- CSGALNACT1: Chondroitin sulfate N-acetylgalactosaminyltransferase 1
- CTHRC1 encoding protein Collagen triple helix repeat containing 1
- CYP11B1: cytochrome P450, family 11, subfamily B, polypeptide 1
- CYP11B2: cytochrome P450, family 11, subfamily B, polypeptide 2
- DCSTAMP: dendrocyte expressed seven transmembrane protein
- DPYS: dihydropyrimidinase
- EBAG9: Estrogen receptor binding site associated antigen 9
- EPPK1: epiplakin
- ERICH5 encoding protein Glutamate rich 5
- ESCO2: establishment of sister chromatid cohesion N-acetyltransferase 2
- EXT1: exostosin glycosyltransferase 1
- EXTL3: exostosin-like glycosyltransferase 3
- EYA1: EYA transcriptional coactivator and phosphatase 1
- FABP9: fatty acid binding protein 9, testis
- FAM167A: family with sequence similarity 167, member A
- FAM203B: family with sequence similarity 203, member B
- FAM83A: family with sequence similarity 83, member A
- FAM83H: family with sequence similarity 83, member H
- FBXO16 encoding protein F-box protein 16
- FDFT1 encoding protein Farnesyl-diphosphate farnesyltransferase 1
- FGFR1: fibroblast growth factor receptor 1 (fms-related tyrosine kinase 2, Pfeiffer syndrome)
- FGL1: Fibrinogen-like protein 1
- GDAP1: ganglioside-induced differentiation-associated protein 1
- GDF6: growth differentiation factor 6
- GPIHBP1: GPI-anchored high density lipoprotein binding protein 1
- GRINA: encoding protein Glutamate receptor, ionotropic, N-methyl D-aspartate-associated protein 1 (glutamate binding)
- GSDMC encoding protein Gasdermin C
- GULOP pseudogene: responsible for human inability to produce Vitamin C
- HGSNAT: heparan-alpha-glucosaminide N-acetyltransferase
- HMBOX1: encoding protein Homeobox containing 1, also known as homeobox telomere-binding protein 1 (HOT1)
- HRSP12 encoding enzyme Ribonuclease UK114
- INTS8: integrator complex subunit 8
- INTS9: integrator complex subunit 9
- KCNQ3: potassium channel, voltage gated KQT-like subfamily Q, member 3.
- KIAA0196: KIAA0196
- KIF13B encoding protein Kinesin family member 13B
- LACTB2: lactamase, beta 2
- LAPTM4B: lysosomal-associated transmembrane protein 4B
- LOC642658: encoding protein Basic helix-loop-helix transcription factor scleraxis
- LPL: lipoprotein lipase
- LSM1: U6 snRNA-associated Sm-like protein LSm1
- MAK16: MAK16 homolog
- MCPH1: microcephaly, primary autosomal recessive 1
- MIR6850 encoding protein MicroRNA 6850
- MRPL13 encoding protein Mitochondrial ribosomal protein L13
- MYBL1 encoding protein MYB proto-oncogene like 1
- NBN: nibrin
- NDRG1: N-myc downstream regulated gene 1
- NEF3: neurofilament 3 (150kDa medium)
- NEFL: neurofilament, light polypeptide 68kDa
- ODF1: outer dense fiber protein 1
- OTUD6B: OTU domain containing 6B
- PDP1: pyruvate dehydrogenase phosphatase catalytic subunit 1
- PKIA: cAMP-dependent protein kinase inhibitor alpha
- PLEC: plectin
- PNMA2: paraneoplastic antigen Ma2
- PREX2: phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 2
- PROSC: proline synthetase co-transcribe bacterial homolog protein
- GLI4: encoding protein Gli family zinc finger 4
- PURG encoding protein Purine-rich element binding protein G
- PVT1: Pvt1 oncogene
- RECQL4: RecQ protein-like 4
- RNF5P1: ring finger protein 5 pseudogene 1
- RRS1: ribosome biogenesis regulator homolog
- RUNX1T1: runt-related transcription factor 1; translocated to, 1 (cyclin D-related)
- SFTPC: surfactant protein C
- SLC20A2: Sodium-dependent phosphate transporter 2
- SLURP1: secreted LY6/PLAUR domain containing 1
- SNAI2: snail homolog 2 (Drosophila)
- SPAG11B: sperm-associated antigen 11B
- STAU2: staufen double-stranded RNA binding protein 2
- SYBU: Syntabulin
- TG: thyroglobulin
- THAP1: THAP domain containing, apoptosis associated protein 1
- TMEM67: encoding protein Meckelin
- TNFRSF11B: tumor necrosis factor receptor superfamily, member 11b
- TONSL: encoding protein Tonsoku-like, DNA repair protein
- TPA: tissue plasminogen activator
- TRMT12: tRNA methyltransferase 12 homolog
- TRPS1: trichorhinophalangeal syndrome I
- TTI2 encoding protein TELO2 interacting protein 2
- VCPIP1: valosin containing protein/p47 complex interacting protein 1
- VMAT1: vesicular monoamine transporter protein
- VPS13B: vacuolar protein sorting 13 homolog B (yeast)
- VPS37A: vacuolar protein sorting 37 homolog A
- WRN: Werner syndrome
- YTHDF3: YTH N6-methyladenosine RNA binding protein 3
- ZFP41: encoding protein ZFP41 zinc finger protein
- ZHX2: zinc fingers and homeoboxes protein 2
- ZMAT4: zinc finger matrin-type 4
- ZNF16: zinc finger protein 16
- ZNF395: encoding protein Zinc finger protein 395
- ZNF517 encoding protein Zinc finger protein 517
- ZNF696 encoding protein Zinc finger protein 696
- ZNF703: zinc finger protein 703
- ZNF706: zinc finger protein 706
- ZNF707: encoding protein Zinc finger protein 707
# Diseases and disorders
The following diseases and disorders are some of those related to genes on chromosome 8:
- 8p23.1 duplication syndrome
- Burkitt's lymphoma
- Charcot-Marie-Tooth disease
- COACH Syndrome
- Cleft lip and palate
- Cohen syndrome
- Congenital hypothyroidism
- Fahr's syndrome
- Hereditary Multiple Exostoses
- Lipoprotein lipase deficiency, familial
- Myelodysplastic syndrome
- Pfeiffer syndrome
- Primary microcephaly
- Rothmund-Thomson syndrome
- Schizophrenia, associated with 8p21-22 locus[13][14][15]
- Waardenburg syndrome
- Werner syndrome
- Pingelapese blindness
- Langer-Giedion syndrome
- Roberts Syndrome
# Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_8 | |
1c19c732e6b9aa25f73cf465ec1af1f75208a5be | wikidoc | Chromosome 9 | Chromosome 9
Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of DNA) and represents between 4 and 4.5 percent of the total DNA in cells.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 9. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## Gene list
The following is a partial list of genes on human chromosome 9. For complete list, see the link in the infobox on the right.
- ABO: ABO histo-blood group glycosyltransferases
- ACTL7A: encoding protein Actin-like protein 7A
- ADAMTS13: ADAM metallopeptidase with thrombospondin type 1 motif, 13
- AIF1L: allograft inflammatory factor 1-like
- ALAD: aminolevulinate, delta-, dehydratase
- ALS4: amyotrophic lateral sclerosis 4
- ANGPTL2: angiopoietin-related protein 2
- ASS: argininosuccinate synthetase
- BNC2: zinc finger protein basonuclin-2
- C9orf64: chromosome 9 open reading frame 64
- C9orf78: encoding protein Uncharacterized protein C9orf78
- C9orf84: chromosome 9 open reading frame 84
- C9orf135: encoding protein Chromosome 9 open reading frame 135
- C9orf152: chromosome 9 open reading frame 152
- CAAP1: caspase activity and apoptosis inhibitor 1
- CARD19: caspase recruitment domain family member 19
- CBWD1: COBW domain-containing protein 1
- CCDC180: Coiled coil domain-containing protein 180
- CCL21: chemokine (C-C motif) ligand 21, SCYA21
- CCL27: chemokine (C-C motif) ligand 27, SCYA27
- CFAP157: Cilia and flagella associated protein 157
- CHMP5: Charged multivesicular body protein 5
- CNTLN: centlein
- COL5A1: collagen, type V, alpha 1
- DDX31: DEAD box polypeptide 31
- DENND1A: DENN domain-containing protein 1A
- ENG: endoglin (Osler-Rendu-Weber syndrome 1)
- ENTPD2: encoding enzyme ectonucleoside triphosphate diphosphohydrolase 2
- EQTN: equatorin
- FAM73B: family with sequence similarity 73 member B
- FAM120A: Family with sequence similarity 120 member A
- FAM122a: encoding protein Family with sequence similarity 122A
- FBP1 Fructose-1,6-bisphosphatase 1
- FIBCD1: encoding protein Fibrinogen C domain containing 1
- FOCAD: focadhesin
- FXN: frataxin
- GALT: galactose-1-phosphate uridylyltransferase
- GAS1: growth arrest-specific protein 1
- GCNT1: glucosaminyl (N-acetyl) transferase 1
- GLE1L: Nucleoporin GLE1
- GPR107: G protein-coupled receptor 107
- GRHPR: glyoxylate redasductase/hydroxypyruvate reductase
- HAUS6: HAUS augmin-like complex subunit 6
- IFN1@: Interferon, type 1, cluster
- IKBKAP: inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein
- INSL6: insulin like 6
- ISCA1: iron-sulfur cluster assembly 1 homolog, mitochondrial
- KIAA1958: protein KIAA1958
- KYAT1: Kynurenine aminotransferase 1
- LINGO2: leucine rich repeat and Ig domain containing 2
- MGC50722: Protein MGC50722, Uncharacterized Protein LOC399693
- MIR181A2HG encoding protein MIR181A2 host gene
- MIR7-1: microRNA 7-1
- MSMP: encoding protein Microseminoprotein, prostate associated
- MTAP: S-methyl-5'-thioadenosine phosphorylase
- NAA35: encoding protein N(alpha)-acetyltransferase 35, NatC auxiliary subunit
- NANS: N-acetylneuraminate synthase
- NINJ1: ninjurin-1
- NOL6: nucleolar protein 6
- NUDT2: nudix hydrolase 2
- OLFM1: olfactomedin 1
- PHF2: PHD finger protein 2
- PHPT1: phosphohistidine phosphatase 1
- PIP5K1B: phosphatidylinositol-4-phosphate 5-kinase type-1 beta
- PLAA: phospholipase A-2-activating protein
- PMPCA: mitochondrial processing alpha subunit
- PRUNE2: protein prune homolog 2
- RABGAP1: RAB GTPase activating protein 1
- REXO4: RNA exonuclease 4
- RNF183: encoding protein Ring finger protein 183
- SARDH: sarcosine dehydrogenase, mitochondrial
- SIT1: signaling threshold regulating transmembrane adapter 1
- SLC25A25-AS1: encoding protein SLC25A25 antisense RNA 1
- SPAG8 sperm-associated antigen 8
- SPIN1: spindlin-1
- ST6GALNAC4 encoding enzyme ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 4, also known as sialyltransferase 3C (SIAT3-C) or sialyltransferase 7D (SIAT7-D)
- ST6GALNAC6: ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 6
- STOML2: stomatin-like protein 2
- STRBP: spermatid perinuclear RNA-binding protein
- TEX10: testis expressed 10
- TGFBR1: transforming growth factor beta, receptor type I
- TMC1: transmembrane channel-like 1
- TMEM215: encoding protein Transmembrane protein 215
- TMEM268: Transmembrane protein 268
- TOR2A encoding protein Torsin-2A
- TSC1: tuberous sclerosis complex]] 1
- TTC39B: tetratricopeptide repeat protein 39B
- UBAC1: ubiquitin-associated domain containing protein 1
- UBAP1: ubiquitin-associated protein 1
- UBAP2: ubiquitin-associated protein 2
- ZBTB43: zinc finger and BTB domain containing 43
- ZCCHC6: zinc finger, CCHC domain containing 6
- ZDHHC21: zinc finger DHHC-type containing 21
- ZNF79: zinc finger protein 79
- ZNF510: zinc finger protein 510
# Diseases and disorders
The following diseases are some of those related to genes on chromosome 9:
- acytosiosis
- ALA-D deficiency porphyria
- citrullinemia
- chronic myelogenous leukemia (t9;22 - the Philadelphia chromosome)
- Diaphyseal Medullary Stenosis with Malignant Fibrous Histiosytoma (DMS-MFH, Hardcastle Syndrome)
- Ehlers-Danlos syndrome
- familial dysautonomia
- Friedreich ataxia
- galactosemia
- Gorlin syndrome or nevoid basal cell carcinoma syndrome
- hereditary hemorrhagic telangiectasia
- lethal congenital contracture syndrome
- nail-patella syndrome (NPS)
- nonsyndromic deafness
- OCD
- polycythemia vera
- porphyria
- primary hyperoxaluria
- Tangier's disease
- tetrasomy 9p
- thrombotic thrombocytopenic purpura
- trisomy 9
- tuberous sclerosis
- VLDLR-associated cerebellar hypoplasia
# Cytogenetic band | Chromosome 9
Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of DNA) and represents between 4 and 4.5 percent of the total DNA in cells.
# Genes
## Number of genes
The following are some of the gene count estimates of human chromosome 9. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[5]
## Gene list
The following is a partial list of genes on human chromosome 9. For complete list, see the link in the infobox on the right.
- ABO: ABO histo-blood group glycosyltransferases
- ACTL7A: encoding protein Actin-like protein 7A
- ADAMTS13: ADAM metallopeptidase with thrombospondin type 1 motif, 13
- AIF1L: allograft inflammatory factor 1-like
- ALAD: aminolevulinate, delta-, dehydratase
- ALS4: amyotrophic lateral sclerosis 4
- ANGPTL2: angiopoietin-related protein 2
- ASS: argininosuccinate synthetase
- BNC2: zinc finger protein basonuclin-2
- C9orf64: chromosome 9 open reading frame 64
- C9orf78: encoding protein Uncharacterized protein C9orf78
- C9orf84: chromosome 9 open reading frame 84
- C9orf135: encoding protein Chromosome 9 open reading frame 135
- C9orf152: chromosome 9 open reading frame 152
- CAAP1: caspase activity and apoptosis inhibitor 1
- CARD19: caspase recruitment domain family member 19
- CBWD1: COBW domain-containing protein 1
- CCDC180: Coiled coil domain-containing protein 180
- CCL21: chemokine (C-C motif) ligand 21, SCYA21
- CCL27: chemokine (C-C motif) ligand 27, SCYA27
- CFAP157: Cilia and flagella associated protein 157
- CHMP5: Charged multivesicular body protein 5
- CNTLN: centlein
- COL5A1: collagen, type V, alpha 1
- DDX31: DEAD box polypeptide 31
- DENND1A: DENN domain-containing protein 1A
- ENG: endoglin (Osler-Rendu-Weber syndrome 1)
- ENTPD2: encoding enzyme ectonucleoside triphosphate diphosphohydrolase 2
- EQTN: equatorin
- FAM73B: family with sequence similarity 73 member B
- FAM120A: Family with sequence similarity 120 member A
- FAM122a: encoding protein Family with sequence similarity 122A
- FBP1 Fructose-1,6-bisphosphatase 1
- FIBCD1: encoding protein Fibrinogen C domain containing 1
- FOCAD: focadhesin
- FXN: frataxin
- GALT: galactose-1-phosphate uridylyltransferase
- GAS1: growth arrest-specific protein 1
- GCNT1: glucosaminyl (N-acetyl) transferase 1
- GLE1L: Nucleoporin GLE1
- GPR107: G protein-coupled receptor 107
- GRHPR: glyoxylate redasductase/hydroxypyruvate reductase
- HAUS6: HAUS augmin-like complex subunit 6
- IFN1@: Interferon, type 1, cluster
- IKBKAP: inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein
- INSL6: insulin like 6
- ISCA1: iron-sulfur cluster assembly 1 homolog, mitochondrial
- KIAA1958: protein KIAA1958
- KYAT1: Kynurenine aminotransferase 1
- LINGO2: leucine rich repeat and Ig domain containing 2
- MGC50722: Protein MGC50722, Uncharacterized Protein LOC399693
- MIR181A2HG encoding protein MIR181A2 host gene
- MIR7-1: microRNA 7-1
- MSMP: encoding protein Microseminoprotein, prostate associated
- MTAP: S-methyl-5'-thioadenosine phosphorylase
- NAA35: encoding protein N(alpha)-acetyltransferase 35, NatC auxiliary subunit
- NANS: N-acetylneuraminate synthase
- NINJ1: ninjurin-1
- NOL6: nucleolar protein 6
- NUDT2: nudix hydrolase 2
- OLFM1: olfactomedin 1
- PHF2: PHD finger protein 2
- PHPT1: phosphohistidine phosphatase 1
- PIP5K1B: phosphatidylinositol-4-phosphate 5-kinase type-1 beta
- PLAA: phospholipase A-2-activating protein
- PMPCA: mitochondrial processing alpha subunit
- PRUNE2: protein prune homolog 2
- RABGAP1: RAB GTPase activating protein 1
- REXO4: RNA exonuclease 4
- RNF183: encoding protein Ring finger protein 183
- SARDH: sarcosine dehydrogenase, mitochondrial
- SIT1: signaling threshold regulating transmembrane adapter 1
- SLC25A25-AS1: encoding protein SLC25A25 antisense RNA 1
- SPAG8 sperm-associated antigen 8
- SPIN1: spindlin-1
- ST6GALNAC4 encoding enzyme ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 4, also known as sialyltransferase 3C (SIAT3-C) or sialyltransferase 7D (SIAT7-D)
- ST6GALNAC6: ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 6
- STOML2: stomatin-like protein 2
- STRBP: spermatid perinuclear RNA-binding protein
- TEX10: testis expressed 10
- TGFBR1: transforming growth factor beta, receptor type I
- TMC1: transmembrane channel-like 1
- TMEM215: encoding protein Transmembrane protein 215
- TMEM268: Transmembrane protein 268
- TOR2A encoding protein Torsin-2A
- TSC1: tuberous sclerosis complex]] 1
- TTC39B: tetratricopeptide repeat protein 39B
- UBAC1: ubiquitin-associated domain containing protein 1
- UBAP1: ubiquitin-associated protein 1
- UBAP2: ubiquitin-associated protein 2
- ZBTB43: zinc finger and BTB domain containing 43
- ZCCHC6: zinc finger, CCHC domain containing 6
- ZDHHC21: zinc finger DHHC-type containing 21
- ZNF79: zinc finger protein 79
- ZNF510: zinc finger protein 510
# Diseases and disorders
The following diseases are some of those related to genes on chromosome 9:
- acytosiosis
- ALA-D deficiency porphyria
- citrullinemia
- chronic myelogenous leukemia (t9;22 - the Philadelphia chromosome)
- Diaphyseal Medullary Stenosis with Malignant Fibrous Histiosytoma (DMS-MFH, Hardcastle Syndrome)
- Ehlers-Danlos syndrome
- familial dysautonomia
- Friedreich ataxia
- galactosemia
- Gorlin syndrome or nevoid basal cell carcinoma syndrome
- hereditary hemorrhagic telangiectasia
- lethal congenital contracture syndrome
- nail-patella syndrome (NPS)
- nonsyndromic deafness
- OCD
- polycythemia vera
- porphyria
- primary hyperoxaluria
- Tangier's disease
- tetrasomy 9p
- thrombotic thrombocytopenic purpura
- trisomy 9
- tuberous sclerosis
- VLDLR-associated cerebellar hypoplasia
# Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_9 | |
6a3ab278861c97c2dc80aa9e4e6f3ebd68354775 | wikidoc | X chromosome | X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system. The X chromosome was named for its unique properties by early researchers, which resulted in the naming of its counterpart Y chromosome, for the next letter in the alphabet, following its subsequent discovery.
# Discovery
It was first noted that the X chromosome was special in 1890 by Hermann Henking in Leipzig. Henking was studying the testicles of Pyrrhocoris and noticed that one chromosome did not take part in meiosis. Chromosomes are so named because of their ability to take up staining (chroma in Greek means color). Although the X chromosome could be stained just as well as the others, Henking was unsure whether it was a different class of object and consequently named it X element, which later became X chromosome after it was established that it was indeed a chromosome.
The idea that the X chromosome was named after its similarity to the letter "X" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well defined shape during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during mitosis, has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape.
It was first suggested that the X chromosome was involved in sex determination by Clarence Erwin McClung in 1901. After comparing his work on locusts with Henking's and others, McClung noted that only half the sperm received an X chromosome. He called this chromosome an accessory chromosome, and insisted (correctly) that it was a proper chromosome, and theorized (incorrectly) that it was the male-determining chromosome.
# Inheritance pattern
Luke Hutchison noticed that a number of possible ancestors on the X chromosome inheritance line at a given ancestral generation follows the Fibonacci sequence. A male individual has an X chromosome, which he received from his mother, and a Y chromosome, which he received from his father. The male counts as the "origin" of his own X chromosome (F_1=1), and at his parents' generation, his X chromosome came from a single parent (F_2=1). The male's mother received one X chromosome from her mother (the son's maternal grandmother), and one from her father (the son's maternal grandfather), so two grandparents contributed to the male descendant's X chromosome (F_3=2). The maternal grandfather received his X chromosome from his mother, and the maternal grandmother received X chromosomes from both of her parents, so three great-grandparents contributed to the male descendant's X chromosome (F_4=3). Five great-great-grandparents contributed to the male descendant's X chromosome (F_5=5), etc. (Note that this assumes that all ancestors of a given descendant are independent, but if any genealogy is traced far enough back in time, ancestors begin to appear on multiple lines of the genealogy, until eventually, a population founder appears on all lines of the genealogy.)
# Humans
## Function
The X chromosome in humans spans more than 153 million base pairs (the building material of DNA). It represents about 800 protein-coding genes compared to the Y chromosome containing about 70 genes, out of 20,000–25,000 total genes in the human genome.
Each person usually has one pair of sex chromosomes in each cell. Females have two X chromosomes, whereas males have one X and one Y chromosome. Both males and females retain one of their mother's X chromosomes, and females retain their second X chromosome from their father. Since the father retains his X chromosome from his mother, a human female has one X chromosome from her paternal grandmother (father's side), and one X chromosome from her mother. This inheritance pattern follows the Fibonacci numbers at a given ancestral depth.
Genetic disorders that are due to mutations in genes on the X chromosome are described as X linked.
The X chromosome carries hundreds of genes but few, if any, of these have anything to do directly with sex determination. Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in nearly all somatic cells (cells other than egg and sperm cells). This phenomenon is called X-inactivation or Lyonization, and creates a Barr body. If X-inactivation in the somatic cell meant a complete de-functionalizing of one of the X-chromosomes, it would ensure that females, like males, had only one functional copy of the X chromosome in each somatic cell. This was previously assumed to be the case. However, recent research suggests that the Barr body may be more biologically active than was previously supposed.
## Genes
## Number of genes
The following are some of the gene count estimates of human X chromosome. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
## Gene list
The following is a partial list of genes on human chromosome X. For complete list, see the link in the infobox on the right.
- APOO: encoding protein Apolipoprotein O
- ARMCX6: encoding protein Armadillo repeat containing X-linked 6
- BEX1: encoding protein Brain-expressed X-linked protein 1
- BEX2: encoding protein Brain-expressed X-linked protein 2
- BEX4: encoding protein Brain expressed, X-linked 4
- CCDC120: encoding protein Coiled coil domain containing protein 120
- CCDC22: encoding protein Coiled-coil domain containing 22
- CD99L2: CD99 antigen-like protein 2
- CHRDL1: encoding protein Chordin-like 1
- CMTX2 encoding protein Charcot-Marie-Tooth neuropathy, X-linked 2 (recessive)
- CMTX3 encoding protein Charcot-Marie-Tooth neuropathy, X-linked 3 (dominant)
- CT45A5: encoding protein Cancer/testis antigen family 45, member A5
- CXorf36: encoding protein hypothetical protein LOC79742
- CXorf40A: Chromosome X open reading frame 40
- CXorf49: chromosome X open reading frame 49. encoding protein
- CXorf66: encoding protein Chromosome X Open Reading Frame 66
- CXorf67: encoding protein Uncharacterized protein CXorf67
- DACH2: encoding protein Dachshund homolog 2
- EFHC2: encoding protein EF-hand domain (C-terminal) containing 2
- ERCC6L encoding protein ERCC excision repair 6 like, spindle assembly checkpoint helicase
- F8A1: Factor VIII intron 22 protein
- FAM120C: encoding protein Family with sequence similarity 120C
- FAM122B: Family with sequence similarity 122 member B
- FAM122C: encoding protein Family with sequence similarity 122C
- FAM127A: CAAX box protein 1
- FAM50A: Family with sequence similarity 50 member A
- FATE1: Fetal and adult testis-expressed transcript protein
- FMR1-AS1: encoding a long non-coding RNA FMR1 antisense RNA 1
- FRMPD3: encoding protein FERM and PDZ domain containing 3
- FUNDC1: encoding protein FUN14 domain containing 1
- FUNDC2: FUN14 domain-containing protein 2
- GATA1: encoding GATA1 transcription factor
- GNL3L encoding protein G protein nucleolar 3 like
- GPRASP2: G-protein coupled receptor-associated sorting protein 2
- GRIPAP1: encoding protein GRIP1-associated protein 1
- HDHD1A: encoding enzyme Haloacid dehalogenase-like hydrolase domain-containing protein 1A
- LAS1L encoding protein LAS1-like protein
- MAGEA2: encoding protein Melanoma-associated antigen 2
- MAGEA5 encoding protein Melanoma antigen family A, 5
- MAGEA8: encoding protein Melanoma antigen family A, 8
- MAGED4B: encoding protein Melanoma-associated antigen D4
- MAGT1: encoding protein Magnesium transporter protein 1
- MBNL3: encoding protein Muscleblind-like protein 3
- MIR222: encoding microRNA MicroRNA 222
- MIR361: encoding microRNA MicroRNA 361
- MIR660: encoding protein MicroRNA 660
- MORF4L2: encoding protein Mortality factor 4-like protein 2
- MOSPD1: encoding protein Motile sperm domain containing 1
- MOSPD2: encoding protein Motile sperm domain containing 2
- NKRF: encoding protein NF-kappa-B-repressing factor
- NRK: encoding enzyme Nik-related protein kinase
- OTUD5: encoding protein OTU deubiquitinase 5
- PASD1: encoding protein PAS domain-containing protein 1
- PBDC1: encoding a protein of unestablished function
- PCYT1B: encoding enzyme Choline-phosphate cytidylyltransferase B
- PIN4: encoding enzyme Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4
- PLAC1: encoding protein Placenta-specific protein 1
- PLP2: encoding protein Proteolipid protein 2
- RPA4: encoding protein Replication protein A 30 kDa subunit
- RPS6KA6: encoding protein Ribosomal protein S6 kinase, 90kDa, polypeptide 6
- RRAGB: encoding protein Ras-related GTP-binding protein B
- SFRS17A: encoding protein Splicing factor, arginine/serine-rich 17A
- SLITRK2: encoding protein SLIT and NTRK-like protein 2
- SMARCA1: encoding protein Probable global transcription activator SNF2L1
- SMS: encoding enzyme Spermine synthase
- SSR4: encoding protein Translocon-associated protein subunit delta
- TAF7l: encoding protein TATA-box binding protein associated factor 7-like
- TCEAL1: encoding protein Transcription elongation factor A protein-like 1
- TCEAL4: encoding protein Transcription elongation factor A protein-like 4
- THOC2: encoding protein THO complex subunit 2
- TMEM29: encoding protein Protein FAM156A
- TMEM47: encoding protein Transmembrane protein 47
- TMLHE: encoding enzyme Trimethyllysine dioxygenase, mitochondrial
- TNMD encoding protein Tenomodulin (also referred to as tendin, myodulin, Tnmd and TeM)
- TRAPPC2P1 encoding protein Trafficking protein particle complex subunit 2
- TREX2: encoding enzyme Three prime repair exonuclease 2
- TRO: encoding protein Trophinin
- TSPYL2: encoding protein Testis-specific Y-encoded-like protein 2
- USP51: encoding enzyme Ubiquitin carboxyl-terminal hydrolase 51
- YIPF6: encoding protein Protein YIPF6
- ZC3H12B: encoding protein ZC3H12B
- ZFP92: encoding protein ZFP92 zinc finger protein
- ZMYM3: encoding protein Zinc finger MYM-type protein 3
- ZNF157: encoding protein Zinc finger protein 157
- ZNF182 encoding protein Zinc finger protein 182
- ZNF275: encoding protein Zinc finger protein 275
- ZNF674: encoding protein Zinc finger protein 674
## Structure
It is theorized by Ross et al. 2005 and Ohno 1967 that the X chromosome is at least partially derived from the autosomal (non-sex-related) genome of other mammals, evidenced from interspecies genomic sequence alignments.
The X chromosome is notably larger and has a more active euchromatin region than its Y chromosome counterpart. Further comparison of the X and Y reveal regions of homology between the two. However, the corresponding region in the Y appears far shorter and lacks regions that are conserved in the X throughout primate species, implying a genetic degeneration for Y in that region. Because males have only one X chromosome, they are more likely to have an X chromosome-related disease.
It is estimated that about 10% of the genes encoded by the X chromosome are associated with a family of "CT" genes, so named because they encode for markers found in both tumor cells (in cancer patients) as well as in the human testis (in healthy patients).
## Role in diseases
### Numerical abnormalities
Klinefelter syndrome:
- Klinefelter syndrome is caused by the presence of one or more extra copies of the X chromosome in a male's cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testicles from functioning normally and reducing the levels of testosterone.
- Males with Klinefelter syndrome typically have one extra copy of the X chromosome in each cell, for a total of two X chromosomes and one Y chromosome (47,XXY). It is less common for affected males to have two or three extra X chromosomes (48,XXXY or 49,XXXXY) or extra copies of both the X and Y chromosomes (48,XXYY) in each cell. The extra genetic material may lead to tall stature, learning and reading disabilities, and other medical problems. Each extra X chromosome lowers the child's IQ by about 15 points, which means that the average IQ in Klinefelter syndrome is in general in the normal range, although below average. When additional X and/or Y chromosomes are present in 48,XXXY, 48,XXYY, or 49,XXXXY, developmental delays and cognitive difficulties can be more severe and mild intellectual disability may be present.
- Klinefelter syndrome can also result from an extra X chromosome in only some of the body's cells. These cases are called mosaic 46,XY/47,XXY.
Triple X syndrome (also called 47,XXX or trisomy X):
- This syndrome results from an extra copy of the X chromosome in each of a female's cells. Females with trisomy X have three X chromosomes, for a total of 47 chromosomes per cell. The average IQ of females with this syndrome is 90, while the average IQ of unaffected siblings is 100. Their stature on average is taller than normal females. They are fertile and their children do not inherit the condition.
- Females with more than one extra copy of the X chromosome (48, XXXX syndrome or 49, XXXXX syndrome) have been identified, but these conditions are rare.
Turner syndrome:
- This results when each of a female's cells has one normal X chromosome and the other sex chromosome is missing or altered. The missing genetic material affects development and causes the features of the condition, including short stature and infertility.
- About half of individuals with Turner syndrome have monosomy X (45,X), which means each cell in a woman's body has only one copy of the X chromosome instead of the usual two copies. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely missing. Some women with Turner syndrome have a chromosomal change in only some of their cells. These cases are called Turner syndrome mosaics (45,X/46,XX).
### X-linked recessive disorders
Sex linkage was first discovered in insects, e.g., T. H. Morgan's 1910 discovery of the pattern of inheritance of the white eyes mutation in Drosophila melanogaster. Such discoveries helped to explain x-linked disorders in humans, e.g., haemophilia A and B, adrenoleukodystrophy, and red-green color blindness.
### Other disorders
XX male syndrome is a rare disorder, where the SRY region of the Y chromosome has recombined to be located on one of the X chromosomes. As a result, the XX combination after fertilization has the same effect as a XY combination, resulting in a male. However, the other genes of the X chromosome cause feminization as well.
X-linked endothelial corneal dystrophy is an extremely rare disease of cornea associated with Xq25 region. Lisch epithelial corneal dystrophy is associated with Xp22.3.
Megalocornea 1 is associated with Xq21.3-q22
Adrenoleukodystrophy, a rare and fatal disorder that is carried by the mother on the x-cell. It affects only boys between the ages of 5 and 10 and destroys the protective cell surrounding the nerves, myelin, in the brain. The female carrier hardly shows any symptoms because females have a copy of the x-cell. This disorder causes a once healthy boy to lose all abilities to walk, talk, see, hear, and even swallow. Within 2 years after diagnosis, most boys with Adrenoleukodystrophy die.
### Role in mental abilities and intelligence
The X-chromosome has played a crucial role in the development of sexually selected characteristics for over 300 million years. During that time it has accumulated a disproportionate number of genes concerned with mental functions. For reasons that are not yet understood, there is an excess proportion of genes on the X-chromosome that are associated with the development of intelligence, with no obvious links to other significant biological functions. . In other words, a significant proportion of genes associated with intelligence is passed on to the male offspring from the maternal side and to the female offspring from either/both maternal and paternal side.There has also been interest in the possibility that haploinsufficiency for one or more X-linked genes has a specific impact on development of the Amygdala and its connections with cortical centres involved in social–cognition processing or the ‘social brain'.
## Cytogenetic band | X chromosome
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system. The X chromosome was named for its unique properties by early researchers, which resulted in the naming of its counterpart Y chromosome, for the next letter in the alphabet, following its subsequent discovery.[5]
# Discovery
It was first noted that the X chromosome was special in 1890 by Hermann Henking in Leipzig. Henking was studying the testicles of Pyrrhocoris and noticed that one chromosome did not take part in meiosis. Chromosomes are so named because of their ability to take up staining (chroma in Greek means color). Although the X chromosome could be stained just as well as the others, Henking was unsure whether it was a different class of object and consequently named it X element,[6] which later became X chromosome after it was established that it was indeed a chromosome.[7]
The idea that the X chromosome was named after its similarity to the letter "X" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well defined shape during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during mitosis, has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape.[8]
It was first suggested that the X chromosome was involved in sex determination by Clarence Erwin McClung in 1901. After comparing his work on locusts with Henking's and others, McClung noted that only half the sperm received an X chromosome. He called this chromosome an accessory chromosome, and insisted (correctly) that it was a proper chromosome, and theorized (incorrectly) that it was the male-determining chromosome.[6]
# Inheritance pattern
Luke Hutchison noticed that a number of possible ancestors on the X chromosome inheritance line at a given ancestral generation follows the Fibonacci sequence.[9] A male individual has an X chromosome, which he received from his mother, and a Y chromosome, which he received from his father. The male counts as the "origin" of his own X chromosome (<math>F_1=1</math>), and at his parents' generation, his X chromosome came from a single parent (<math>F_2=1</math>). The male's mother received one X chromosome from her mother (the son's maternal grandmother), and one from her father (the son's maternal grandfather), so two grandparents contributed to the male descendant's X chromosome (<math>F_3=2</math>). The maternal grandfather received his X chromosome from his mother, and the maternal grandmother received X chromosomes from both of her parents, so three great-grandparents contributed to the male descendant's X chromosome (<math>F_4=3</math>). Five great-great-grandparents contributed to the male descendant's X chromosome (<math>F_5=5</math>), etc. (Note that this assumes that all ancestors of a given descendant are independent, but if any genealogy is traced far enough back in time, ancestors begin to appear on multiple lines of the genealogy, until eventually, a population founder appears on all lines of the genealogy.)
# Humans
## Function
The X chromosome in humans spans more than 153 million base pairs (the building material of DNA). It represents about 800 protein-coding genes compared to the Y chromosome containing about 70 genes, out of 20,000–25,000 total genes in the human genome.
Each person usually has one pair of sex chromosomes in each cell. Females have two X chromosomes, whereas males have one X and one Y chromosome. Both males and females retain one of their mother's X chromosomes, and females retain their second X chromosome from their father. Since the father retains his X chromosome from his mother, a human female has one X chromosome from her paternal grandmother (father's side), and one X chromosome from her mother. This inheritance pattern follows the Fibonacci numbers at a given ancestral depth.
Genetic disorders that are due to mutations in genes on the X chromosome are described as X linked.
The X chromosome carries hundreds of genes but few, if any, of these have anything to do directly with sex determination. Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in nearly all somatic cells (cells other than egg and sperm cells). This phenomenon is called X-inactivation or Lyonization, and creates a Barr body. If X-inactivation in the somatic cell meant a complete de-functionalizing of one of the X-chromosomes, it would ensure that females, like males, had only one functional copy of the X chromosome in each somatic cell. This was previously assumed to be the case. However, recent research suggests that the Barr body may be more biologically active than was previously supposed.[10]
## Genes
## Number of genes
The following are some of the gene count estimates of human X chromosome. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[11]
## Gene list
The following is a partial list of genes on human chromosome X. For complete list, see the link in the infobox on the right.
- APOO: encoding protein Apolipoprotein O
- ARMCX6: encoding protein Armadillo repeat containing X-linked 6
- BEX1: encoding protein Brain-expressed X-linked protein 1
- BEX2: encoding protein Brain-expressed X-linked protein 2
- BEX4: encoding protein Brain expressed, X-linked 4
- CCDC120: encoding protein Coiled coil domain containing protein 120
- CCDC22: encoding protein Coiled-coil domain containing 22
- CD99L2: CD99 antigen-like protein 2
- CHRDL1: encoding protein Chordin-like 1
- CMTX2 encoding protein Charcot-Marie-Tooth neuropathy, X-linked 2 (recessive)
- CMTX3 encoding protein Charcot-Marie-Tooth neuropathy, X-linked 3 (dominant)
- CT45A5: encoding protein Cancer/testis antigen family 45, member A5
- CXorf36: encoding protein hypothetical protein LOC79742
- CXorf40A: Chromosome X open reading frame 40
- CXorf49: chromosome X open reading frame 49. encoding protein
- CXorf66: encoding protein Chromosome X Open Reading Frame 66
- CXorf67: encoding protein Uncharacterized protein CXorf67
- DACH2: encoding protein Dachshund homolog 2
- EFHC2: encoding protein EF-hand domain (C-terminal) containing 2
- ERCC6L encoding protein ERCC excision repair 6 like, spindle assembly checkpoint helicase
- F8A1: Factor VIII intron 22 protein
- FAM120C: encoding protein Family with sequence similarity 120C
- FAM122B: Family with sequence similarity 122 member B
- FAM122C: encoding protein Family with sequence similarity 122C
- FAM127A: CAAX box protein 1
- FAM50A: Family with sequence similarity 50 member A
- FATE1: Fetal and adult testis-expressed transcript protein
- FMR1-AS1: encoding a long non-coding RNA FMR1 antisense RNA 1
- FRMPD3: encoding protein FERM and PDZ domain containing 3
- FUNDC1: encoding protein FUN14 domain containing 1
- FUNDC2: FUN14 domain-containing protein 2
- GATA1: encoding GATA1 transcription factor
- GNL3L encoding protein G protein nucleolar 3 like
- GPRASP2: G-protein coupled receptor-associated sorting protein 2
- GRIPAP1: encoding protein GRIP1-associated protein 1
- HDHD1A: encoding enzyme Haloacid dehalogenase-like hydrolase domain-containing protein 1A
- LAS1L encoding protein LAS1-like protein
- MAGEA2: encoding protein Melanoma-associated antigen 2
- MAGEA5 encoding protein Melanoma antigen family A, 5
- MAGEA8: encoding protein Melanoma antigen family A, 8
- MAGED4B: encoding protein Melanoma-associated antigen D4
- MAGT1: encoding protein Magnesium transporter protein 1
- MBNL3: encoding protein Muscleblind-like protein 3
- MIR222: encoding microRNA MicroRNA 222
- MIR361: encoding microRNA MicroRNA 361
- MIR660: encoding protein MicroRNA 660
- MORF4L2: encoding protein Mortality factor 4-like protein 2
- MOSPD1: encoding protein Motile sperm domain containing 1
- MOSPD2: encoding protein Motile sperm domain containing 2
- NKRF: encoding protein NF-kappa-B-repressing factor
- NRK: encoding enzyme Nik-related protein kinase
- OTUD5: encoding protein OTU deubiquitinase 5
- PASD1: encoding protein PAS domain-containing protein 1
- PBDC1: encoding a protein of unestablished function
- PCYT1B: encoding enzyme Choline-phosphate cytidylyltransferase B
- PIN4: encoding enzyme Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4
- PLAC1: encoding protein Placenta-specific protein 1
- PLP2: encoding protein Proteolipid protein 2
- RPA4: encoding protein Replication protein A 30 kDa subunit
- RPS6KA6: encoding protein Ribosomal protein S6 kinase, 90kDa, polypeptide 6
- RRAGB: encoding protein Ras-related GTP-binding protein B
- SFRS17A: encoding protein Splicing factor, arginine/serine-rich 17A
- SLITRK2: encoding protein SLIT and NTRK-like protein 2
- SMARCA1: encoding protein Probable global transcription activator SNF2L1
- SMS: encoding enzyme Spermine synthase
- SSR4: encoding protein Translocon-associated protein subunit delta
- TAF7l: encoding protein TATA-box binding protein associated factor 7-like
- TCEAL1: encoding protein Transcription elongation factor A protein-like 1
- TCEAL4: encoding protein Transcription elongation factor A protein-like 4
- THOC2: encoding protein THO complex subunit 2
- TMEM29: encoding protein Protein FAM156A
- TMEM47: encoding protein Transmembrane protein 47
- TMLHE: encoding enzyme Trimethyllysine dioxygenase, mitochondrial
- TNMD encoding protein Tenomodulin (also referred to as tendin, myodulin, Tnmd and TeM)
- TRAPPC2P1 encoding protein Trafficking protein particle complex subunit 2
- TREX2: encoding enzyme Three prime repair exonuclease 2
- TRO: encoding protein Trophinin
- TSPYL2: encoding protein Testis-specific Y-encoded-like protein 2
- USP51: encoding enzyme Ubiquitin carboxyl-terminal hydrolase 51
- YIPF6: encoding protein Protein YIPF6
- ZC3H12B: encoding protein ZC3H12B
- ZFP92: encoding protein ZFP92 zinc finger protein
- ZMYM3: encoding protein Zinc finger MYM-type protein 3
- ZNF157: encoding protein Zinc finger protein 157
- ZNF182 encoding protein Zinc finger protein 182
- ZNF275: encoding protein Zinc finger protein 275
- ZNF674: encoding protein Zinc finger protein 674
## Structure
It is theorized by Ross et al. 2005 and Ohno 1967 that the X chromosome is at least partially derived from the autosomal (non-sex-related) genome of other mammals, evidenced from interspecies genomic sequence alignments.
The X chromosome is notably larger and has a more active euchromatin region than its Y chromosome counterpart. Further comparison of the X and Y reveal regions of homology between the two. However, the corresponding region in the Y appears far shorter and lacks regions that are conserved in the X throughout primate species, implying a genetic degeneration for Y in that region. Because males have only one X chromosome, they are more likely to have an X chromosome-related disease.
It is estimated that about 10% of the genes encoded by the X chromosome are associated with a family of "CT" genes, so named because they encode for markers found in both tumor cells (in cancer patients) as well as in the human testis (in healthy patients).[18]
## Role in diseases
### Numerical abnormalities
Klinefelter syndrome:
- Klinefelter syndrome is caused by the presence of one or more extra copies of the X chromosome in a male's cells. Extra genetic material from the X chromosome interferes with male sexual development, preventing the testicles from functioning normally and reducing the levels of testosterone.
- Males with Klinefelter syndrome typically have one extra copy of the X chromosome in each cell, for a total of two X chromosomes and one Y chromosome (47,XXY). It is less common for affected males to have two or three extra X chromosomes (48,XXXY or 49,XXXXY) or extra copies of both the X and Y chromosomes (48,XXYY) in each cell. The extra genetic material may lead to tall stature, learning and reading disabilities, and other medical problems. Each extra X chromosome lowers the child's IQ by about 15 points,[19][20] which means that the average IQ in Klinefelter syndrome is in general in the normal range, although below average. When additional X and/or Y chromosomes are present in 48,XXXY, 48,XXYY, or 49,XXXXY, developmental delays and cognitive difficulties can be more severe and mild intellectual disability may be present.
- Klinefelter syndrome can also result from an extra X chromosome in only some of the body's cells. These cases are called mosaic 46,XY/47,XXY.
Triple X syndrome (also called 47,XXX or trisomy X):
- This syndrome results from an extra copy of the X chromosome in each of a female's cells. Females with trisomy X have three X chromosomes, for a total of 47 chromosomes per cell. The average IQ of females with this syndrome is 90, while the average IQ of unaffected siblings is 100.[21] Their stature on average is taller than normal females. They are fertile and their children do not inherit the condition.[22]
- Females with more than one extra copy of the X chromosome (48, XXXX syndrome or 49, XXXXX syndrome) have been identified, but these conditions are rare.
Turner syndrome:
- This results when each of a female's cells has one normal X chromosome and the other sex chromosome is missing or altered. The missing genetic material affects development and causes the features of the condition, including short stature and infertility.
- About half of individuals with Turner syndrome have monosomy X (45,X), which means each cell in a woman's body has only one copy of the X chromosome instead of the usual two copies. Turner syndrome can also occur if one of the sex chromosomes is partially missing or rearranged rather than completely missing. Some women with Turner syndrome have a chromosomal change in only some of their cells. These cases are called Turner syndrome mosaics (45,X/46,XX).
### X-linked recessive disorders
Sex linkage was first discovered in insects, e.g., T. H. Morgan's 1910 discovery of the pattern of inheritance of the white eyes mutation in Drosophila melanogaster.[23] Such discoveries helped to explain x-linked disorders in humans, e.g., haemophilia A and B, adrenoleukodystrophy, and red-green color blindness.
### Other disorders
XX male syndrome is a rare disorder, where the SRY region of the Y chromosome has recombined to be located on one of the X chromosomes. As a result, the XX combination after fertilization has the same effect as a XY combination, resulting in a male. However, the other genes of the X chromosome cause feminization as well.
X-linked endothelial corneal dystrophy is an extremely rare disease of cornea associated with Xq25 region. Lisch epithelial corneal dystrophy is associated with Xp22.3.
Megalocornea 1 is associated with Xq21.3-q22[medical citation needed]
Adrenoleukodystrophy, a rare and fatal disorder that is carried by the mother on the x-cell. It affects only boys between the ages of 5 and 10 and destroys the protective cell surrounding the nerves, myelin, in the brain. The female carrier hardly shows any symptoms because females have a copy of the x-cell. This disorder causes a once healthy boy to lose all abilities to walk, talk, see, hear, and even swallow. Within 2 years after diagnosis, most boys with Adrenoleukodystrophy die.
### Role in mental abilities and intelligence
The X-chromosome has played a crucial role in the development of sexually selected characteristics for over 300 million years. During that time it has accumulated a disproportionate number of genes concerned with mental functions. For reasons that are not yet understood, there is an excess proportion of genes on the X-chromosome that are associated with the development of intelligence, with no obvious links to other significant biological functions.[24][25] . In other words, a significant proportion of genes associated with intelligence is passed on to the male offspring from the maternal side and to the female offspring from either/both maternal and paternal side.There has also been interest in the possibility that haploinsufficiency for one or more X-linked genes has a specific impact on development of the Amygdala and its connections with cortical centres involved in social–cognition processing or the ‘social brain'.[24][26][clarification needed]
## Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_X_(human) | |
2abe6701055c53a2e896e099329860c809c6b23d | wikidoc | Y chromosome | Y chromosome
The Y chromosome is one of two sex chromosomes (allosomes) in mammals, including humans, and many other animals. The other is the X chromosome. Y is the sex-determining chromosome in many species, since it is the presence or absence of Y that determines the male or female sex of offspring produced in sexual reproduction. In mammals, the Y chromosome contains the gene SRY, which triggers testis development. The DNA in the human Y chromosome is composed of about 59 million base pairs. The Y chromosome is passed only from father to son. With a 30% difference between humans and chimpanzees, the Y chromosome is one of the fastest-evolving parts of the human genome. To date, over 200 Y-linked genes have been identified. All Y-linked genes are expressed and (apart from duplicated genes) hemizygous (present on only one chromosome) except in the cases of aneuploidy such as XYY syndrome or XXYY syndrome.
# Overview
## Discovery
The Y chromosome was identified as a sex-determining chromosome by Nettie Stevens at Bryn Mawr College in 1905 during a study of the mealworm Tenebrio molitor. Edmund Beecher Wilson independently discovered the same mechanisms the same year. Stevens proposed that chromosomes always existed in pairs and that the Y chromosome was the pair of the X chromosome discovered in 1890 by Hermann Henking. He realized that the previous idea of Clarence Erwin McClung, that the X chromosome determines sex, was wrong and that sex determination is, in fact, due to the presence or absence of the Y chromosome. Stevens named the chromosome "Y" simply to follow on from Henking's "X" alphabetically.
The idea that the Y chromosome was named after its similarity in appearance to the letter "Y" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well-defined shape during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during mitosis, has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape.
## Variations
Most therian mammals have only one pair of sex chromosomes in each cell. Males have one Y chromosome and one X chromosome, while females have two X chromosomes. In mammals, the Y chromosome contains a gene, SRY, which triggers embryonic development as a male. The Y chromosomes of humans and other mammals also contain other genes needed for normal sperm production.
There are exceptions, however. For example, the platypus relies on an XY sex-determination system based on five pairs of chromosomes. Platypus sex chromosomes have strong sequence similarity with the avian Z chromosome, (indicating close homology), and the SRY gene so central to sex-determination in most other mammals is apparently not involved in platypus sex-determination. Among humans, some men have two Xs and a Y ("XXY", see Klinefelter syndrome), or one X and two Ys (see XYY syndrome), and some women have three Xs or a single X instead of a double X ("X0", see Turner syndrome). There are other exceptions in which SRY is damaged (leading to an XY female), or copied to the X (leading to an XX male).
# Origins and evolution
## Before Y chromosome
Many ectothermic vertebrates have no sex chromosomes. If they have different sexes, sex is determined environmentally rather than genetically. For some of them, especially reptiles, sex depends on the incubation temperature; others are hermaphroditic (meaning they contain both male and female gametes in the same individual).
## Origin
The X and Y chromosomes are thought to have evolved from a pair of identical chromosomes, termed autosomes, when an ancestral animal developed an allelic variation, a so-called "sex locus" – simply possessing this allele caused the organism to be male. The chromosome with this allele became the Y chromosome, while the other member of the pair became the X chromosome. Over time, genes that were beneficial for males and harmful to (or had no effect on) females either developed on the Y chromosome or were acquired through the process of translocation.
Until recently, the X and Y chromosomes were thought to have diverged around 300 million years ago. However, research published in 2010, and particularly research published in 2008 documenting the sequencing of the platypus genome, has suggested that the XY sex-determination system would not have been present more than 166 million years ago, at the split of the monotremes from other mammals. This re-estimation of the age of the therian XY system is based on the finding that sequences that are on the X chromosomes of marsupials and eutherian mammals are present on the autosomes of platypus and birds. The older estimate was based on erroneous reports that the platypus X chromosomes contained these sequences.
## Recombination inhibition
Recombination between the X and Y chromosomes proved harmful—it resulted in males without necessary genes formerly found on the Y chromosome, and females with unnecessary or even harmful genes previously only found on the Y chromosome. As a result, genes beneficial to males accumulated near the sex-determining genes, and recombination in this region was suppressed in order to preserve this male specific region. Over time, the Y chromosome changed in such a way as to inhibit the areas around the sex determining genes from recombining at all with the X chromosome. As a result of this process, 95% of the human Y chromosome is unable to recombine. Only the tips of the Y and X chromosomes recombine. The tips of the Y chromosome that could recombine with the X chromosome are referred to as the pseudoautosomal region. The rest of the Y chromosome is passed on to the next generation intact, allowing for its use in tracking human evolution.
## Degeneration
By one estimate, the human Y chromosome has lost 1,393 of its 1,438 original genes over the course of its existence, and linear extrapolation of this 1,393-gene loss over 300 million years gives a rate of genetic loss of 4.6 genes per million years. Continued loss of genes at the rate of 4.6 genes per million years would result in a Y chromosome with no functional genes – that is the Y chromosome would lose complete function – within the next 10 million years, or half that time with the current age estimate of 160 million years. Comparative genomic analysis reveals that many mammalian species are experiencing a similar loss of function in their heterozygous sex chromosome. Degeneration may simply be the fate of all non-recombining sex chromosomes, due to three common evolutionary forces: high mutation rate, inefficient selection, and genetic drift.
However, comparisons of the human and chimpanzee Y chromosomes (first published in 2005) show that the human Y chromosome has not lost any genes since the divergence of humans and chimpanzees between 6–7 million years ago, and a scientific report in 2012 stated that only one gene had been lost since humans diverged from the rhesus macaque 25 million years ago. These facts provide direct evidence that the linear extrapolation model is flawed and suggest that the current human Y chromosome is either no longer shrinking or is shrinking at a much slower rate than the 4.6 genes per million years estimated by the linear extrapolation model.
### High mutation rate
The human Y chromosome is particularly exposed to high mutation rates due to the environment in which it is housed. The Y chromosome is passed exclusively through sperm, which undergo multiple cell divisions during gametogenesis. Each cellular division provides further opportunity to accumulate base pair mutations. Additionally, sperm are stored in the highly oxidative environment of the testis, which encourages further mutation. These two conditions combined put the Y chromosome at a greater risk of mutation than the rest of the genome. The increased mutation risk for the Y chromosome is reported by Graves as a factor 4.8. However, her original reference obtains this number for the relative mutation rates in male and female germ lines for the lineage leading to humans.
### Inefficient selection
Without the ability to recombine during meiosis, the Y chromosome is unable to expose individual alleles to natural selection. Deleterious alleles are allowed to "hitchhike" with beneficial neighbors, thus propagating maladapted alleles in to the next generation. Conversely, advantageous alleles may be selected against if they are surrounded by harmful alleles (background selection). Due to this inability to sort through its gene content, the Y chromosome is particularly prone to the accumulation of "junk" DNA. Massive accumulations of retrotransposable elements are scattered throughout the Y. The random insertion of DNA segments often disrupts encoded gene sequences and renders them nonfunctional. However, the Y chromosome has no way of weeding out these "jumping genes". Without the ability to isolate alleles, selection cannot effectively act upon them.
A clear, quantitative indication of this inefficiency is the entropy rate of the Y chromosome. Whereas all other chromosomes in the human genome have entropy rates of 1.5–1.9 bits per nucleotide (compared to the theoretical maximum of exactly 2 for no redundancy), the Y chromosome's entropy rate is only 0.84. This means the Y chromosome has a much lower information content relative to its overall length; it is more redundant.
### Genetic drift
Even if a well adapted Y chromosome manages to maintain genetic activity by avoiding mutation accumulation, there is no guarantee it will be passed down to the next generation. The population size of the Y chromosome is inherently limited to 1/4 that of autosomes: diploid organisms contain two copies of autosomal chromosomes while only half the population contains 1 Y chromosome. Thus, genetic drift is an exceptionally strong force acting upon the Y chromosome. Through sheer random assortment, an adult male may never pass on his Y chromosome if he only has female offspring. Thus, although a male may have a well adapted Y chromosome free of excessive mutation, it may never make it in to the next gene pool. The repeat random loss of well-adapted Y chromosomes, coupled with the tendency of the Y chromosome to evolve to have more deleterious mutations rather than less for reasons described above, contributes to the species-wide degeneration of Y chromosomes through Muller's ratchet.
## Gene conversion
As it has been already mentioned, the Y chromosome is unable to recombine during meiosis like the other human chromosomes; however, in 2003, researchers from MIT discovered a process which may slow down the process of degradation.
They found that human Y chromosome is able to "recombine" with itself, using palindrome base pair sequences. Such a "recombination" is called gene conversion.
In the case of the Y chromosomes, the palindromes are not noncoding DNA; these strings of bases contain functioning genes important for male fertility. Most of the sequence pairs are greater than 99.97% identical. The extensive use of gene conversion may play a role in the ability of the Y chromosome to edit out genetic mistakes and maintain the integrity of the relatively few genes it carries. In other words, since the Y chromosome is single, it has duplicates of its genes on itself instead of having a second, homologous, chromosome. When errors occur, it can use other parts of itself as a template to correct them.
Findings were confirmed by comparing similar regions of the Y chromosome in humans to the Y chromosomes of chimpanzees, bonobos and gorillas. The comparison demonstrated that the same phenomenon of gene conversion appeared to be at work more than 5 million years ago, when humans and the non-human primates diverged from each other.
## Future evolution
In the terminal stages of the degeneration of the Y chromosome, other chromosomes increasingly take over genes and functions formerly associated with it. Finally, the Y chromosome disappears entirely, and a new sex-determining system arises. Several species of rodent in the sister families Muridae and Cricetidae have reached these stages, in the following ways:
- The Transcaucasian mole vole, Ellobius lutescens, the Zaisan mole vole, Ellobius tancrei, and the Japanese spinous country rats Tokudaia osimensis and Tokudaia tokunoshimensis, have lost the Y chromosome and SRY entirely. Tokudaia spp. have relocated some other genes ancestrally present on the Y chromosome to the X chromosome. Both sexes of Tokudaia spp. and Ellobius lutescens have an XO genotype (Turner syndrome), whereas all Ellobius tancrei possess an XX genotype. The new sex-determining system(s) for these rodents remains unclear.
- The wood lemming Myopus schisticolor, the Arctic lemming, Dicrostonyx torquatus, and multiple species in the grass mouse genus Akodon have evolved fertile females who possess the genotype generally coding for males, XY, in addition to the ancestral XX female, through a variety of modifications to the X and Y chromosomes.
- In the creeping vole, Microtus oregoni, the females, with just one X chromosome each, produce X gametes only, and the males, XY, produce Y gametes, or gametes devoid of any sex chromosome, through nondisjunction.
Outside of the rodents, the black muntjac, Muntiacus crinifrons, evolved new X and Y chromosomes through fusions of the ancestral sex chromosomes and autosomes.
## 1:1 sex ratio
Fisher's principle outlines why almost all species using sexual reproduction have a sex ratio of 1:1. W. D. Hamilton gave the following basic explanation in his 1967 paper on "Extraordinary sex ratios", given the condition that males and females cost equal amounts to produce:
- Suppose male births are less common than female.
- A newborn male then has better mating prospects than a newborn female, and therefore can expect to have more offspring.
- Therefore, parents genetically disposed to produce males tend to have more than average numbers of grandchildren born to them.
- Therefore, the genes for male-producing tendencies spread, and male births become more common.
- As the 1:1 sex ratio is approached, the advantage associated with producing males dies away.
- The same reasoning holds if females are substituted for males throughout. Therefore, 1:1 is the equilibrium ratio.
# Non-mammal Y chromosome
Many groups of organisms in addition to mammals have Y chromosomes, but these Y chromosomes do not share common ancestry with mammalian Y chromosomes. Such groups include Drosophila, some other insects, some fish, some reptiles, and some plants. In Drosophila melanogaster, the Y chromosome does not trigger male development. Instead, sex is determined by the number of X chromosomes. The D. melanogaster Y chromosome does contain genes necessary for male fertility. So XXY D. melanogaster are female, and D. melanogaster with a single X (X0), are male but sterile. There are some species of Drosophila in which X0 males are both viable and fertile.
## ZW chromosomes
Other organisms have mirror image sex chromosomes: where the homogeneous sex is the male, said to have two Z chromosomes, and the female is the heterogeneous sex, and said to have a Z chromosome and a W chromosome. For example, female birds, snakes, and butterflies have ZW sex chromosomes, and males have ZZ sex chromosomes.
## Non-inverted Y chromosome
There are some species, such as the Japanese rice fish, the XY system is still developing and cross over between the X and Y is still possible. Because the male specific region is very small and contains no essential genes, it is even possible to artificially induce XX males and YY females to no ill effect.
# Human Y chromosome
In humans, the Y chromosome spans about 58 million base pairs (the building blocks of DNA) and represents approximately 1% of the total DNA in a male cell. The human Y chromosome contains over 200 genes, at least 72 of which code for proteins. Traits that are inherited via the Y chromosome are called Y-linked, or holandric traits.
Some cells, especially in older men and smokers, lack a Y chromosome. It has been found that men with a higher percentage of hematopoietic stem cells in blood lacking the Y chromosome (and perhaps a higher percentage of other cells lacking it) have a higher risk of certain cancers and have a shorter life expectancy. Men with "loss of Y" (which was defined as no Y in at least 18% of their hematopoietic cells) have been found to die 5.5 years earlier on average than others. This has been interpreted as a sign that the Y chromosome plays a role going beyond sex determination and reproduction (although the loss of Y may be an effect rather than a cause). And yet women, who have no Y chromosome, have lower rates of cancer. Male smokers have between 1.5 and 2 times the risk of non-respiratory cancers as female smokers.
## Non-combining region of Y (NRY)
The human Y chromosome is normally unable to recombine with the X chromosome, except for small pieces of pseudoautosomal regions at the telomeres (which comprise about 5% of the chromosome's length). These regions are relics of ancient homology between the X and Y chromosomes. The bulk of the Y chromosome, which does not recombine, is called the "NRY", or non-recombining region of the Y chromosome. The single-nucleotide polymorphisms (SNPs) in this region are used to trace direct paternal ancestral lines.
## Genes
### Number of genes
The following are some of the gene count estimates of human Y chromosome. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.
### Gene list
In general, the human Y chromosome is extremely gene poor—it is one of the largest gene deserts in the human genome. Disregarding pseudoautosomal genes, genes encoded on the human Y chromosome include:
- NRY, with corresponding gene on X chromosome
AMELY/AMELX (amelogenin)
RPS4Y1/RPS4Y2/RPS4X (Ribosomal protein S4)
DDX3Y (helicase)
X-transposed region (XTR), once dubbed "PAR3" but later refuted
PCDH11Y (PCDH11X)
TGIF2LY (TGIF2LX)
- AMELY/AMELX (amelogenin)
- RPS4Y1/RPS4Y2/RPS4X (Ribosomal protein S4)
- DDX3Y (helicase)
- X-transposed region (XTR), once dubbed "PAR3" but later refuted
PCDH11Y (PCDH11X)
TGIF2LY (TGIF2LX)
- PCDH11Y (PCDH11X)
- TGIF2LY (TGIF2LX)
- NRY, other
AZF1 (azoospermia factor 1)
BPY2 (basic protein on the Y chromosome)
DAZ1 (deleted in azoospermia)
DAZ2
DFNY1 encoding protein Deafness, Y-linked 1
PRKY (protein kinase, Y-linked)
RBMY1A1
SRY (sex-determining region)
TSPY (testis-specific protein)
USP9Y
UTY (ubiquitously transcribed TPR gene on Y chromosome)
ZFY (zinc finger protein)
- AZF1 (azoospermia factor 1)
- BPY2 (basic protein on the Y chromosome)
- DAZ1 (deleted in azoospermia)
- DAZ2
- DFNY1 encoding protein Deafness, Y-linked 1
- PRKY (protein kinase, Y-linked)
- RBMY1A1
- SRY (sex-determining region)
- TSPY (testis-specific protein)
- USP9Y
- UTY (ubiquitously transcribed TPR gene on Y chromosome)
- ZFY (zinc finger protein)
## Y-chromosome-linked diseases
Diseases linked to the Y chromosome typically involve an aneuploidy, an atypical number of chromosomes.
### Y chromosome microdeletion
Y chromosome microdeletion (YCM) is a family of genetic disorders caused by missing genes in the Y chromosome. Many affected men exhibit no symptoms and lead normal lives. However, YCM is also known to be present in a significant number of men with reduced fertility or reduced sperm count.
### Defective Y chromosome
This results in the person presenting a female phenotype (i.e., is born with female-like genitalia) even though that person possesses an XY karyotype. The lack of the second X results in infertility. In other words, viewed from the opposite direction, the person goes through defeminization but fails to complete masculinization.
The cause can be seen as an incomplete Y chromosome: the usual karyotype in these cases is 45X, plus a fragment of Y. This usually results in defective testicular development, such that the infant may or may not have fully formed male genitalia internally or externally. The full range of ambiguity of structure may occur, especially if mosaicism is present. When the Y fragment is minimal and nonfunctional, the child is usually a girl with the features of Turner syndrome or mixed gonadal dysgenesis.
### XXY
Klinefelter syndrome (47, XXY) is not an aneuploidy of the Y chromosome, but a condition of having an extra X chromosome, which usually results in defective postnatal testicular function. The mechanism is not fully understood; it does not seem to be due to direct interference by the extra X with expression of Y genes.
### XYY
47, XYY syndrome (simply known as XYY syndrome) is caused by the presence of a single extra copy of the Y chromosome in each of a male's cells. 47, XYY males have one X chromosome and two Y chromosomes, for a total of 47 chromosomes per cell. Researchers have found that an extra copy of the Y chromosome is associated with increased stature and an increased incidence of learning problems in some boys and men, but the effects are variable, often minimal, and the vast majority do not know their karyotype.
In 1965 and 1966 Patricia Jacobs and colleagues published a chromosome survey of 315 male patients at
Scotland's only special security hospital for the developmentally disabled,
finding a higher than expected number of patients to have an extra Y chromosome. The authors of this study wondered "whether an extra Y chromosome predisposes its carriers to unusually aggressive behaviour", and this conjecture "framed the next fifteen years of research on the human Y chromosome".
Through studies over the next decade, this conjecture was shown to be incorrect: the elevated crime rate of XYY males is due to lower median intelligence and not increased aggression, and increased height was the only characteristic that could be reliably associated with XYY males. The "criminal karyotype" concept is therefore inaccurate.
### Rare
The following Y-chromosome-linked diseases are rare, but notable because of their elucidating of the nature of the Y chromosome.
Greater degrees of Y chromosome polysomy (having more than one extra copy of the Y chromosome in every cell, e.g., XYYY) are rare. The extra genetic material in these cases can lead to skeletal abnormalities, decreased IQ, and delayed development, but the severity features of these conditions are variable.
XX male syndrome occurs when there has been a recombination in the formation of the male gametes, causing the SRY portion of the Y chromosome to move to the X chromosome. When such an X chromosome contributes to the child, the development will lead to a male, because of the SRY gene.
## Genetic genealogy
In human genetic genealogy (the application of genetics to traditional genealogy), use of the information contained in the Y chromosome is of particular interest because, unlike other chromosomes, the Y chromosome is passed exclusively from father to son, on the patrilineal line. Mitochondrial DNA, maternally inherited to both sons and daughters, is used in an analogous way to trace the matrilineal line.
## Brain function
Research is currently investigating whether male-pattern neural development is a direct consequence of Y-chromosome-related gene expression or an indirect result of Y-chromosome-related androgenic hormone production.
## Microchimerism
The presence of male chromosomes in fetal cells in the blood circulation of women was discovered in 1974.
In 1996, it was found that male fetal progenitor cells could persist postpartum in the maternal blood stream for as long as 27 years.
A 2004 study at the Fred Hutchinson Cancer Research Center, Seattle, investigated the origin of male chromosomes found in the peripheral blood of women who had not had male progeny. A total of 120 subjects (women who had never had sons) were investigated, and it was found that 21% of them had male DNA. The subjects were categorised into four groups based on their case histories:
- Group A (8%) had had only female progeny.
- Patients in Group B (22%) had a history of one or more miscarriages.
- Patients Group C (57%) had their pregnancies medically terminated.
- Group D (10%) had never been pregnant before.
The study noted that 10% of the women had never been pregnant before, raising the question of where the Y chromosomes in their blood could have come from. The study suggests that possible reasons for occurrence of male chromosome microchimerism could be one of the following:
- miscarriages,
- pregnancies,
- vanished male twin,
- possibly from sexual intercourse.
A 2012 study at the same institute has detected cells with the Y chromosome in multiple areas of the brains of deceased women.
## Cytogenetic band | Y chromosome
The Y chromosome is one of two sex chromosomes (allosomes) in mammals, including humans, and many other animals. The other is the X chromosome. Y is the sex-determining chromosome in many species, since it is the presence or absence of Y that determines the male or female sex of offspring produced in sexual reproduction. In mammals, the Y chromosome contains the gene SRY, which triggers testis development. The DNA in the human Y chromosome is composed of about 59 million base pairs.[5] The Y chromosome is passed only from father to son. With a 30% difference between humans and chimpanzees, the Y chromosome is one of the fastest-evolving parts of the human genome.[6] To date, over 200 Y-linked genes have been identified.[7] All Y-linked genes are expressed and (apart from duplicated genes) hemizygous (present on only one chromosome) except in the cases of aneuploidy such as XYY syndrome or XXYY syndrome.
# Overview
## Discovery
The Y chromosome was identified as a sex-determining chromosome by Nettie Stevens at Bryn Mawr College in 1905 during a study of the mealworm Tenebrio molitor. Edmund Beecher Wilson independently discovered the same mechanisms the same year. Stevens proposed that chromosomes always existed in pairs and that the Y chromosome was the pair of the X chromosome discovered in 1890 by Hermann Henking. He realized that the previous idea of Clarence Erwin McClung, that the X chromosome determines sex, was wrong and that sex determination is, in fact, due to the presence or absence of the Y chromosome. Stevens named the chromosome "Y" simply to follow on from Henking's "X" alphabetically.[8][9]
The idea that the Y chromosome was named after its similarity in appearance to the letter "Y" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well-defined shape during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during mitosis, has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape.[10]
## Variations
Most therian mammals have only one pair of sex chromosomes in each cell. Males have one Y chromosome and one X chromosome, while females have two X chromosomes. In mammals, the Y chromosome contains a gene, SRY, which triggers embryonic development as a male. The Y chromosomes of humans and other mammals also contain other genes needed for normal sperm production.
There are exceptions, however. For example, the platypus relies on an XY sex-determination system based on five pairs of chromosomes.[11] Platypus sex chromosomes have strong sequence similarity with the avian Z chromosome, (indicating close homology),[12] and the SRY gene so central to sex-determination in most other mammals is apparently not involved in platypus sex-determination.[13] Among humans, some men have two Xs and a Y ("XXY", see Klinefelter syndrome), or one X and two Ys (see XYY syndrome), and some women have three Xs or a single X instead of a double X ("X0", see Turner syndrome). There are other exceptions in which SRY is damaged (leading to an XY female), or copied to the X (leading to an XX male).
# Origins and evolution
## Before Y chromosome
Many ectothermic vertebrates have no sex chromosomes. If they have different sexes, sex is determined environmentally rather than genetically. For some of them, especially reptiles, sex depends on the incubation temperature; others are hermaphroditic (meaning they contain both male and female gametes in the same individual).
## Origin
The X and Y chromosomes are thought to have evolved from a pair of identical chromosomes,[14][15] termed autosomes, when an ancestral animal developed an allelic variation, a so-called "sex locus" – simply possessing this allele caused the organism to be male.[16] The chromosome with this allele became the Y chromosome, while the other member of the pair became the X chromosome. Over time, genes that were beneficial for males and harmful to (or had no effect on) females either developed on the Y chromosome or were acquired through the process of translocation.[17]
Until recently, the X and Y chromosomes were thought to have diverged around 300 million years ago.[18] However, research published in 2010,[19] and particularly research published in 2008 documenting the sequencing of the platypus genome,[12] has suggested that the XY sex-determination system would not have been present more than 166 million years ago, at the split of the monotremes from other mammals.[13] This re-estimation of the age of the therian XY system is based on the finding that sequences that are on the X chromosomes of marsupials and eutherian mammals are present on the autosomes of platypus and birds.[13] The older estimate was based on erroneous reports that the platypus X chromosomes contained these sequences.[11][20]
## Recombination inhibition
Recombination between the X and Y chromosomes proved harmful—it resulted in males without necessary genes formerly found on the Y chromosome, and females with unnecessary or even harmful genes previously only found on the Y chromosome. As a result, genes beneficial to males accumulated near the sex-determining genes, and recombination in this region was suppressed in order to preserve this male specific region.[16] Over time, the Y chromosome changed in such a way as to inhibit the areas around the sex determining genes from recombining at all with the X chromosome. As a result of this process, 95% of the human Y chromosome is unable to recombine. Only the tips of the Y and X chromosomes recombine. The tips of the Y chromosome that could recombine with the X chromosome are referred to as the pseudoautosomal region. The rest of the Y chromosome is passed on to the next generation intact, allowing for its use in tracking human evolution.[citation needed]
## Degeneration
By one estimate, the human Y chromosome has lost 1,393 of its 1,438 original genes over the course of its existence, and linear extrapolation of this 1,393-gene loss over 300 million years gives a rate of genetic loss of 4.6 genes per million years.[21] Continued loss of genes at the rate of 4.6 genes per million years would result in a Y chromosome with no functional genes – that is the Y chromosome would lose complete function – within the next 10 million years, or half that time with the current age estimate of 160 million years.[16][22] Comparative genomic analysis reveals that many mammalian species are experiencing a similar loss of function in their heterozygous sex chromosome. Degeneration may simply be the fate of all non-recombining sex chromosomes, due to three common evolutionary forces: high mutation rate, inefficient selection, and genetic drift.[16]
However, comparisons of the human and chimpanzee Y chromosomes (first published in 2005) show that the human Y chromosome has not lost any genes since the divergence of humans and chimpanzees between 6–7 million years ago,[23] and a scientific report in 2012 stated that only one gene had been lost since humans diverged from the rhesus macaque 25 million years ago.[24] These facts provide direct evidence that the linear extrapolation model is flawed and suggest that the current human Y chromosome is either no longer shrinking or is shrinking at a much slower rate than the 4.6 genes per million years estimated by the linear extrapolation model.
### High mutation rate
The human Y chromosome is particularly exposed to high mutation rates due to the environment in which it is housed. The Y chromosome is passed exclusively through sperm, which undergo multiple cell divisions during gametogenesis. Each cellular division provides further opportunity to accumulate base pair mutations. Additionally, sperm are stored in the highly oxidative environment of the testis, which encourages further mutation. These two conditions combined put the Y chromosome at a greater risk of mutation than the rest of the genome.[16] The increased mutation risk for the Y chromosome is reported by Graves as a factor 4.8.[16] However, her original reference obtains this number for the relative mutation rates in male and female germ lines for the lineage leading to humans.[25]
### Inefficient selection
Without the ability to recombine during meiosis, the Y chromosome is unable to expose individual alleles to natural selection. Deleterious alleles are allowed to "hitchhike" with beneficial neighbors, thus propagating maladapted alleles in to the next generation. Conversely, advantageous alleles may be selected against if they are surrounded by harmful alleles (background selection). Due to this inability to sort through its gene content, the Y chromosome is particularly prone to the accumulation of "junk" DNA. Massive accumulations of retrotransposable elements are scattered throughout the Y.[16] The random insertion of DNA segments often disrupts encoded gene sequences and renders them nonfunctional. However, the Y chromosome has no way of weeding out these "jumping genes". Without the ability to isolate alleles, selection cannot effectively act upon them.[citation needed]
A clear, quantitative indication of this inefficiency is the entropy rate of the Y chromosome. Whereas all other chromosomes in the human genome have entropy rates of 1.5–1.9 bits per nucleotide (compared to the theoretical maximum of exactly 2 for no redundancy), the Y chromosome's entropy rate is only 0.84.[26] This means the Y chromosome has a much lower information content relative to its overall length; it is more redundant.
### Genetic drift
Even if a well adapted Y chromosome manages to maintain genetic activity by avoiding mutation accumulation, there is no guarantee it will be passed down to the next generation. The population size of the Y chromosome is inherently limited to 1/4 that of autosomes: diploid organisms contain two copies of autosomal chromosomes while only half the population contains 1 Y chromosome. Thus, genetic drift is an exceptionally strong force acting upon the Y chromosome. Through sheer random assortment, an adult male may never pass on his Y chromosome if he only has female offspring. Thus, although a male may have a well adapted Y chromosome free of excessive mutation, it may never make it in to the next gene pool.[16] The repeat random loss of well-adapted Y chromosomes, coupled with the tendency of the Y chromosome to evolve to have more deleterious mutations rather than less for reasons described above, contributes to the species-wide degeneration of Y chromosomes through Muller's ratchet.[27]
## Gene conversion
As it has been already mentioned, the Y chromosome is unable to recombine during meiosis like the other human chromosomes; however, in 2003, researchers from MIT discovered a process which may slow down the process of degradation.
They found that human Y chromosome is able to "recombine" with itself, using palindrome base pair sequences.[28] Such a "recombination" is called gene conversion.
In the case of the Y chromosomes, the palindromes are not noncoding DNA; these strings of bases contain functioning genes important for male fertility. Most of the sequence pairs are greater than 99.97% identical. The extensive use of gene conversion may play a role in the ability of the Y chromosome to edit out genetic mistakes and maintain the integrity of the relatively few genes it carries. In other words, since the Y chromosome is single, it has duplicates of its genes on itself instead of having a second, homologous, chromosome. When errors occur, it can use other parts of itself as a template to correct them.[citation needed]
Findings were confirmed by comparing similar regions of the Y chromosome in humans to the Y chromosomes of chimpanzees, bonobos and gorillas. The comparison demonstrated that the same phenomenon of gene conversion appeared to be at work more than 5 million years ago, when humans and the non-human primates diverged from each other.[citation needed]
## Future evolution
In the terminal stages of the degeneration of the Y chromosome, other chromosomes increasingly take over genes and functions formerly associated with it. Finally, the Y chromosome disappears entirely, and a new sex-determining system arises.[16][neutrality is disputed][improper synthesis?] Several species of rodent in the sister families Muridae and Cricetidae have reached these stages,[29][30] in the following ways:
- The Transcaucasian mole vole, Ellobius lutescens, the Zaisan mole vole, Ellobius tancrei, and the Japanese spinous country rats Tokudaia osimensis and Tokudaia tokunoshimensis, have lost the Y chromosome and SRY entirely.[16][31][32] Tokudaia spp. have relocated some other genes ancestrally present on the Y chromosome to the X chromosome.[32] Both sexes of Tokudaia spp. and Ellobius lutescens have an XO genotype (Turner syndrome),[32] whereas all Ellobius tancrei possess an XX genotype.[16] The new sex-determining system(s) for these rodents remains unclear.
- The wood lemming Myopus schisticolor, the Arctic lemming, Dicrostonyx torquatus, and multiple species in the grass mouse genus Akodon have evolved fertile females who possess the genotype generally coding for males, XY, in addition to the ancestral XX female, through a variety of modifications to the X and Y chromosomes.[29][33][34]
- In the creeping vole, Microtus oregoni, the females, with just one X chromosome each, produce X gametes only, and the males, XY, produce Y gametes, or gametes devoid of any sex chromosome, through nondisjunction.[35]
Outside of the rodents, the black muntjac, Muntiacus crinifrons, evolved new X and Y chromosomes through fusions of the ancestral sex chromosomes and autosomes.[36]
## 1:1 sex ratio
Fisher's principle outlines why almost all species using sexual reproduction have a sex ratio of 1:1. W. D. Hamilton gave the following basic explanation in his 1967 paper on "Extraordinary sex ratios",[37] given the condition that males and females cost equal amounts to produce:
- Suppose male births are less common than female.
- A newborn male then has better mating prospects than a newborn female, and therefore can expect to have more offspring.
- Therefore, parents genetically disposed to produce males tend to have more than average numbers of grandchildren born to them.
- Therefore, the genes for male-producing tendencies spread, and male births become more common.
- As the 1:1 sex ratio is approached, the advantage associated with producing males dies away.
- The same reasoning holds if females are substituted for males throughout. Therefore, 1:1 is the equilibrium ratio.
# Non-mammal Y chromosome
Many groups of organisms in addition to mammals have Y chromosomes, but these Y chromosomes do not share common ancestry with mammalian Y chromosomes. Such groups include Drosophila, some other insects, some fish, some reptiles, and some plants. In Drosophila melanogaster, the Y chromosome does not trigger male development. Instead, sex is determined by the number of X chromosomes. The D. melanogaster Y chromosome does contain genes necessary for male fertility. So XXY D. melanogaster are female, and D. melanogaster with a single X (X0), are male but sterile. There are some species of Drosophila in which X0 males are both viable and fertile.[citation needed]
## ZW chromosomes
Other organisms have mirror image sex chromosomes: where the homogeneous sex is the male, said to have two Z chromosomes, and the female is the heterogeneous sex, and said to have a Z chromosome and a W chromosome. For example, female birds, snakes, and butterflies have ZW sex chromosomes, and males have ZZ sex chromosomes.[citation needed]
## Non-inverted Y chromosome
There are some species, such as the Japanese rice fish, the XY system is still developing and cross over between the X and Y is still possible. Because the male specific region is very small and contains no essential genes, it is even possible to artificially induce XX males and YY females to no ill effect.[38]
# Human Y chromosome
In humans, the Y chromosome spans about 58 million base pairs (the building blocks of DNA) and represents approximately 1% of the total DNA in a male cell.[39] The human Y chromosome contains over 200 genes, at least 72 of which code for proteins.[5] Traits that are inherited via the Y chromosome are called Y-linked, or holandric traits.
Some cells, especially in older men and smokers, lack a Y chromosome. It has been found that men with a higher percentage of hematopoietic stem cells in blood lacking the Y chromosome (and perhaps a higher percentage of other cells lacking it) have a higher risk of certain cancers and have a shorter life expectancy. Men with "loss of Y" (which was defined as no Y in at least 18% of their hematopoietic cells) have been found to die 5.5 years earlier on average than others. This has been interpreted as a sign that the Y chromosome plays a role going beyond sex determination and reproduction[40] (although the loss of Y may be an effect rather than a cause). And yet women, who have no Y chromosome, have lower rates of cancer. Male smokers have between 1.5 and 2 times the risk of non-respiratory cancers as female smokers.[41][42]
## Non-combining region of Y (NRY)
The human Y chromosome is normally unable to recombine with the X chromosome, except for small pieces of pseudoautosomal regions at the telomeres (which comprise about 5% of the chromosome's length). These regions are relics of ancient homology between the X and Y chromosomes. The bulk of the Y chromosome, which does not recombine, is called the "NRY", or non-recombining region of the Y chromosome.[43] The single-nucleotide polymorphisms (SNPs) in this region are used to trace direct paternal ancestral lines.
## Genes
### Number of genes
The following are some of the gene count estimates of human Y chromosome. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies (for technical details, see gene prediction). Among various projects, the collaborative consensus coding sequence project (CCDS) takes an extremely conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes.[44]
### Gene list
In general, the human Y chromosome is extremely gene poor—it is one of the largest gene deserts in the human genome. Disregarding pseudoautosomal genes, genes encoded on the human Y chromosome include:
- NRY, with corresponding gene on X chromosome
AMELY/AMELX (amelogenin)
RPS4Y1/RPS4Y2/RPS4X (Ribosomal protein S4)
DDX3Y (helicase)
X-transposed region (XTR),[51] once dubbed "PAR3"[52][53] but later refuted[54]
PCDH11Y (PCDH11X)
TGIF2LY (TGIF2LX)
- AMELY/AMELX (amelogenin)
- RPS4Y1/RPS4Y2/RPS4X (Ribosomal protein S4)
- DDX3Y (helicase)
- X-transposed region (XTR),[51] once dubbed "PAR3"[52][53] but later refuted[54]
PCDH11Y (PCDH11X)
TGIF2LY (TGIF2LX)
- PCDH11Y (PCDH11X)
- TGIF2LY (TGIF2LX)
- NRY, other
AZF1 (azoospermia factor 1)
BPY2 (basic protein on the Y chromosome)
DAZ1 (deleted in azoospermia)
DAZ2
DFNY1 encoding protein Deafness, Y-linked 1
PRKY (protein kinase, Y-linked)
RBMY1A1
SRY (sex-determining region)
TSPY (testis-specific protein)
USP9Y
UTY (ubiquitously transcribed TPR gene on Y chromosome)
ZFY (zinc finger protein)
- AZF1 (azoospermia factor 1)
- BPY2 (basic protein on the Y chromosome)
- DAZ1 (deleted in azoospermia)
- DAZ2
- DFNY1 encoding protein Deafness, Y-linked 1
- PRKY (protein kinase, Y-linked)
- RBMY1A1
- SRY (sex-determining region)
- TSPY (testis-specific protein)
- USP9Y
- UTY (ubiquitously transcribed TPR gene on Y chromosome)
- ZFY (zinc finger protein)
## Y-chromosome-linked diseases
Diseases linked to the Y chromosome typically involve an aneuploidy, an atypical number of chromosomes.
### Y chromosome microdeletion
Y chromosome microdeletion (YCM) is a family of genetic disorders caused by missing genes in the Y chromosome. Many affected men exhibit no symptoms and lead normal lives. However, YCM is also known to be present in a significant number of men with reduced fertility or reduced sperm count.[citation needed]
### Defective Y chromosome
This results in the person presenting a female phenotype (i.e., is born with female-like genitalia) even though that person possesses an XY karyotype. The lack of the second X results in infertility. In other words, viewed from the opposite direction, the person goes through defeminization but fails to complete masculinization.[citation needed]
The cause can be seen as an incomplete Y chromosome: the usual karyotype in these cases is 45X, plus a fragment of Y. This usually results in defective testicular development, such that the infant may or may not have fully formed male genitalia internally or externally. The full range of ambiguity of structure may occur, especially if mosaicism is present. When the Y fragment is minimal and nonfunctional, the child is usually a girl with the features of Turner syndrome or mixed gonadal dysgenesis.[citation needed]
### XXY
Klinefelter syndrome (47, XXY) is not an aneuploidy of the Y chromosome, but a condition of having an extra X chromosome, which usually results in defective postnatal testicular function. The mechanism is not fully understood; it does not seem to be due to direct interference by the extra X with expression of Y genes.[citation needed]
### XYY
47, XYY syndrome (simply known as XYY syndrome) is caused by the presence of a single extra copy of the Y chromosome in each of a male's cells. 47, XYY males have one X chromosome and two Y chromosomes, for a total of 47 chromosomes per cell. Researchers have found that an extra copy of the Y chromosome is associated with increased stature and an increased incidence of learning problems in some boys and men, but the effects are variable, often minimal, and the vast majority do not know their karyotype.[55]
In 1965 and 1966 Patricia Jacobs and colleagues published a chromosome survey of 315 male patients at
Scotland's only special security hospital for the developmentally disabled,
finding a higher than expected number of patients to have an extra Y chromosome.[56] The authors of this study wondered "whether an extra Y chromosome predisposes its carriers to unusually aggressive behaviour", and this conjecture "framed the next fifteen years of research on the human Y chromosome".[57]
Through studies over the next decade, this conjecture was shown to be incorrect: the elevated crime rate of XYY males is due to lower median intelligence and not increased aggression,[58] and increased height was the only characteristic that could be reliably associated with XYY males.[59] The "criminal karyotype" concept is therefore inaccurate.[55]
### Rare
The following Y-chromosome-linked diseases are rare, but notable because of their elucidating of the nature of the Y chromosome.
Greater degrees of Y chromosome polysomy (having more than one extra copy of the Y chromosome in every cell, e.g., XYYY) are rare. The extra genetic material in these cases can lead to skeletal abnormalities, decreased IQ, and delayed development, but the severity features of these conditions are variable.[citation needed]
XX male syndrome occurs when there has been a recombination in the formation of the male gametes, causing the SRY portion of the Y chromosome to move to the X chromosome. When such an X chromosome contributes to the child, the development will lead to a male, because of the SRY gene.[citation needed]
## Genetic genealogy
In human genetic genealogy (the application of genetics to traditional genealogy), use of the information contained in the Y chromosome is of particular interest because, unlike other chromosomes, the Y chromosome is passed exclusively from father to son, on the patrilineal line. Mitochondrial DNA, maternally inherited to both sons and daughters, is used in an analogous way to trace the matrilineal line.[citation needed]
## Brain function
Research is currently investigating whether male-pattern neural development is a direct consequence of Y-chromosome-related gene expression or an indirect result of Y-chromosome-related androgenic hormone production.[60]
## Microchimerism
The presence of male chromosomes in fetal cells in the blood circulation of women was discovered in 1974.[61]
In 1996, it was found that male fetal progenitor cells could persist postpartum in the maternal blood stream for as long as 27 years.[62]
A 2004 study at the Fred Hutchinson Cancer Research Center, Seattle, investigated the origin of male chromosomes found in the peripheral blood of women who had not had male progeny. A total of 120 subjects (women who had never had sons) were investigated, and it was found that 21% of them had male DNA. The subjects were categorised into four groups based on their case histories:[63]
- Group A (8%) had had only female progeny.
- Patients in Group B (22%) had a history of one or more miscarriages.
- Patients Group C (57%) had their pregnancies medically terminated.
- Group D (10%) had never been pregnant before.
The study noted that 10% of the women had never been pregnant before, raising the question of where the Y chromosomes in their blood could have come from. The study suggests that possible reasons for occurrence of male chromosome microchimerism could be one of the following:[63]
- miscarriages,
- pregnancies,
- vanished male twin,
- possibly from sexual intercourse.
A 2012 study at the same institute has detected cells with the Y chromosome in multiple areas of the brains of deceased women.[64]
## Cytogenetic band | https://www.wikidoc.org/index.php/Chromosome_Y_(human) | |
9c361bab4667eca957005eeb2d34333e4273c469 | wikidoc | Chronophilia | Chronophilia
Chronophilia refers to a group of patterns of sexual arousal associated with age discrepancy between the sexual partners. The term was coined by John Money, from the Greek roots chronos, "time" and philia, "love". The term has not been widely adopted by sexologists, who instead use terms that that refer to the specific age range in question.
# Sexual Preferences Based on Age
- Pedophilia refers to a sexual preference for prepubescent children (by definition including nepiophilia). It differs from all these conditions in that it is a clinically-recognized disorder in the Diagnostic and Statistical Manual of Mental Disorders.
- Hebephilia refers to a sexual preference for pubescent children. The term was introduced by Glueck (1955).
- Ephebophilia refers to a sexual preference for individuals in mid- to late adolescence, usually 15-19 years old.
- Teleiophilia (from Greek teleios, "full grown") is a term coined by sexologist Ray Blanchard to refer to the sexual interest in adults. It is used by professional sexologists when comparing (for example) pedophiles with teleiophiles, and Diederik Janssen, MD uses the term "Peripubescent Teleiophilia" in reference to "crush" phenomenon.. For gender-specific attractions to people in this age range, see gynephilia and androphilia.
- Gerontophilia refers to the sexual preference for the elderly. | Chronophilia
Chronophilia refers to a group of patterns of sexual arousal associated with age discrepancy between the sexual partners.[1] The term was coined by John Money, from the Greek roots chronos, "time" and philia, "love". The term has not been widely adopted by sexologists, who instead use terms that that refer to the specific age range in question.
# Sexual Preferences Based on Age
- Pedophilia refers to a sexual preference for prepubescent children (by definition including nepiophilia). It differs from all these conditions in that it is a clinically-recognized disorder in the Diagnostic and Statistical Manual of Mental Disorders.[2]
- Hebephilia refers to a sexual preference for pubescent children. The term was introduced by Glueck (1955).[3]
- Ephebophilia refers to a sexual preference for individuals in mid- to late adolescence,[4] usually 15-19 years old.[5]
- Teleiophilia (from Greek teleios, "full grown") is a term coined by sexologist Ray Blanchard to refer to the sexual interest in adults.[6] It is used by professional sexologists when comparing (for example) pedophiles with teleiophiles, and Diederik Janssen, MD uses the term "Peripubescent Teleiophilia" in reference to "crush" phenomenon.[7]. For gender-specific attractions to people in this age range, see gynephilia and androphilia.
- Gerontophilia refers to the sexual preference for the elderly.[8] | https://www.wikidoc.org/index.php/Chronophilia | |
d560a84fb990d601b9d116201eac25dcd57f5ec7 | wikidoc | Chronophobia | Chronophobia
# Overview
Chronophobia is described by Pamela Lee as the fear of time. There are three categories of phobia including agoraphobia, social phobia, and specific phobias which includes spiders, snakes, dogs, water, and heights. Rosemary Stolz states that chronophobia falls under the category of specific phobia because time is a specific object that one can fear. Chronophobia is especially common in prison inmates and the elderly, but it can manifest in any person who has an extreme amount of stress and anxiety in their life.
# Etymology
Chronophobia is a Greek word coming from “chronos” meaning time, and “phobos” meaning fear. It is based on chronoperception, the process where time is perceived by the central nervous system.
# Causes and contributing factors
In the book Chronophobia: On Time in the Art of the 1960s by Pamela Lee, Chronophobia is described as “an experience of unease and anxiety about time, a feeling that events are moving too fast and are thus hard to make sense of.” In Peter PaulAnnas Lichtenstein's review he reveals it can be caused by a traumatic experience in one's childhood, genetics, incarceration, or old age. Most traumatic experiences can lead to personal withdrawals from one's surroundings such as dissociation, depersonalization, or derealisation. A person may be genetically affected after the traumatic experience due to Adrenal insufficiency. Those with these insufficiencies are more susceptible to anxiety and fear. When people are incarcerated, they experience a heightened sense of anxiety. The stress of prison makes inmates especially at risk. Inmates start to contemplate time extensively because they are incarcerated for a certain amount of time. It is not uncommon for prison inmates to count-down the days until their release. The elderly also exhibit more of a risk because they feel that death is closer than it had ever been before in their life. The threat of death can cause an overwhelming sensation of chronophobia.
# Basic symptoms
The three main symptoms of chronophobia, and most phobias, are panic, anxiety, and claustrophobia. In some more serious cases, individuals can experience shaking, shortness of breath, excessive sweating, and irregular heartbeats. In the most serious cases individuals can exhibit symptoms of sickening states of mind, inability to articulate words, tunnel vision, and overwhelmingly haunting thoughts.
# Treatments
Mozhi Mani suggests that while no treatment has effectively cured chronophobia, certain methods may ease the individual's mind.
One of these treatments is hypnotherapy. It is a method that has been considered simple and effective by the American Medical Association since 1958. It involves using hypnosis to open the subconscious mind and change the behavioral patterns of the individual with the phobia.
Arne Ohman and Susan Mineka suggest another treatment that involves Neuro-Linguistic Programming. This method involves the use of psychotherapy to discover how people can create their own reality. A specialist can train a person to “remodel their thoughts and mental associations in order to fix preconceived notions.” Energy (esotericism) can provide treatment for those affected. Such techniques as acupuncture, yoga, t'ai chi ch'uan, pranayama, and energy medicine may prove useful. These practices can cure nausea and may provide some sense of security to those dealing with panic and fear.
There are some medications that can be taken to calm the nerves of those suffering from chronophobia. These prescriptions may cause side effects and do not erase fear but merely suppress symptoms.
A person may also wish to see a psychiatrist. Lloyd Williams assures that psychiatrists may be helpful because they serve as a medium for the patient to express their psychological problems, but without their own desire to overcome fear, the patient may not yield the intended results.
# The affected
Two main groups are affected by chronophobia. These groups involve prison inmates and the elderly.
Often referred to as Prison Neurosis, chronophobia can affect the incarcerated. Because of the length of time prison inmates spend in their cells, and because of the confined space that they share with others, they can develop psychological symptoms of chronophobia. Some symptoms include delusions, dissatisfaction with life, claustrophobia, depression, and feelings of panic and madness.
The elderly show these symptoms of chronophobia as well. When they feel that their lives are near to the end, they start to fear time because it threatens their existence. This fear is similar to chronoperception because it includes the idea that the speed of brain function depends on the metabolic rate in the hypothalamus. As people get older, their metabolism slows. The elderly may believe that as a result of their slowing metabolism, their brains do not function as well, which makes them more chronophobic.
# In literature
In her work Chronophobia: On Time in the Art of the 1960s, Pamela Lee studies art and technology in the 1960s. Within this period, such artists as Bridget Riley, Carolee Schneemann, Jean Tinguely, Andy Warhol, and On Kawara pique her interest. She “identifies an experience of time common to both , and she calls this experience 'chronophobia'.” After studying Michael Fried's essay Art and Objecthood, she discovers that as time goes by, art starts to reflect the quickness of time. Within her work, Lee references Alvin Toffler's book Future Shock. She *claims that “the concept of time they espouse is chronophobic as defined in her book, and their popularity means that their concept of time was widely shared.” In her work she fears “perpetual presentness, time is constant without conclusion.” Many chronophobes feel this way, they fear the fact that time is never ending.
Chronophobic characters are seen in Jerzy Kosinski's Being There. The character Chance Gardiner has no sense of time because he was raised watching television and now defines time in terms of technology. He is described as being in a state of “perpetual nowness.” He has no sense of the past or future, but lives only in the moment. Kosinski explains that the only way for Chance to overcome his chronophobia is if “peace filled his chest.” Kosinski believes that chronophobia “negates the possibility of full human development.”
Thomas Pynchon offers another view of chronophobia in his novel The Crying of Lot 49. The character Oedipa is similar to Chance Gardiner because she lacks dimension, but she is able to distinguish that events have occurred in the past, present or future. Her cure for chronophobia is to create a world where events are scrambled together randomly. Time becomes irrelevant to her.
Perhaps the most recognized literary work dealing with chronophobia lies in the story of Rip Van Winkle by Washington Irving. This tall-tale introduces a man that has slept for 20 years and wakes to a completely new society. His wife and friends have died, his dog is missing and his gun is rusty. The fact that his entire world has changed sends him into a feeling of fear and panic. At first he is confused and lost, but his chronophobia is cured when he realizes that although it seems that everything around him has changed, his core beliefs still exist. In this instance, chronophobia is overcome because Rip Van Winkle is able to make new friends, and regain parts of the life he lost while he was asleep.
# Prevention
Chronophobia can never really be prevented because it is normally caused by a traumatic experience that is not within one's power to stop. Some ways to relieve the stress that chronophobia can cause are to prevent anxiety or situations that could cause anxiety, to avoid getting stressed out about time, to be on time, and to participate in an activity that requires meditation, such as yoga or other forms of mild martial arts. | Chronophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chronophobia is described by Pamela Lee as the fear of time.[1] There are three categories of phobia including agoraphobia, social phobia, and specific phobias which includes spiders, snakes, dogs, water, and heights.[1] Rosemary Stolz states that chronophobia falls under the category of specific phobia because time is a specific object that one can fear. Chronophobia is especially common in prison inmates and the elderly, but it can manifest in any person who has an extreme amount of stress and anxiety in their life.[2]
# Etymology
Chronophobia is a Greek word coming from “chronos” meaning time, and “phobos” meaning fear.[1] It is based on chronoperception, the process where time is perceived by the central nervous system.[3]
# Causes and contributing factors
In the book Chronophobia: On Time in the Art of the 1960s by Pamela Lee, Chronophobia is described as “an experience of unease and anxiety about time, a feeling that events are moving too fast and are thus hard to make sense of.”[4] In Peter PaulAnnas Lichtenstein's review he reveals it can be caused by a traumatic experience in one's childhood, genetics, incarceration, or old age. Most traumatic experiences can lead to personal withdrawals from one's surroundings such as dissociation, depersonalization, or derealisation.[3] A person may be genetically affected after the traumatic experience due to Adrenal insufficiency. Those with these insufficiencies are more susceptible to anxiety and fear. When people are incarcerated, they experience a heightened sense of anxiety.[5] The stress of prison makes inmates especially at risk. Inmates start to contemplate time extensively because they are incarcerated for a certain amount of time. It is not uncommon for prison inmates to count-down the days until their release. The elderly also exhibit more of a risk because they feel that death is closer than it had ever been before in their life. The threat of death can cause an overwhelming sensation of chronophobia.[2]
# Basic symptoms
The three main symptoms of chronophobia, and most phobias, are panic, anxiety, and claustrophobia.[5] In some more serious cases, individuals can experience shaking, shortness of breath, excessive sweating, and irregular heartbeats. In the most serious cases individuals can exhibit symptoms of sickening states of mind, inability to articulate words, tunnel vision, and overwhelmingly haunting thoughts.[5]
# Treatments
Mozhi Mani suggests that while no treatment has effectively cured chronophobia, certain methods may ease the individual's mind.
One of these treatments is hypnotherapy.[6] It is a method that has been considered simple and effective by the American Medical Association since 1958. It involves using hypnosis to open the subconscious mind and change the behavioral patterns of the individual with the phobia.[5]
Arne Ohman and Susan Mineka suggest another treatment that involves Neuro-Linguistic Programming.[7] This method involves the use of psychotherapy to discover how people can create their own reality. A specialist can train a person to “remodel their thoughts and mental associations in order to fix [their] preconceived notions.” [5]Energy (esotericism) can provide treatment for those affected. Such techniques as acupuncture, yoga, t'ai chi ch'uan, pranayama, and energy medicine may prove useful. These practices can cure nausea and may provide some sense of security to those dealing with panic and fear.[5]
There are some medications that can be taken to calm the nerves of those suffering from chronophobia. These prescriptions may cause side effects and do not erase fear but merely suppress symptoms.[5]
A person may also wish to see a psychiatrist. Lloyd Williams assures that psychiatrists may be helpful because they serve as a medium for the patient to express their psychological problems, but without their own desire to overcome fear, the patient may not yield the intended results.[8]
# The affected
Two main groups are affected by chronophobia. These groups involve prison inmates and the elderly.
Often referred to as Prison Neurosis, chronophobia can affect the incarcerated. Because of the length of time prison inmates spend in their cells, and because of the confined space that they share with others, they can develop psychological symptoms of chronophobia.[2] Some symptoms include delusions, dissatisfaction with life, claustrophobia, depression, and feelings of panic and madness.[2]
The elderly show these symptoms of chronophobia as well. When they feel that their lives are near to the end, they start to fear time because it threatens their existence. This fear is similar to chronoperception because it includes the idea that the speed of brain function depends on the metabolic rate in the hypothalamus. As people get older, their metabolism slows. The elderly may believe that as a result of their slowing metabolism, their brains do not function as well, which makes them more chronophobic.[2]
# In literature
In her work Chronophobia: On Time in the Art of the 1960s, Pamela Lee studies art and technology in the 1960s. Within this period, such artists as Bridget Riley, Carolee Schneemann, Jean Tinguely, Andy Warhol, and On Kawara pique her interest. She “identifies an experience of time common to both [art and technology], and she calls this experience 'chronophobia'.” After studying Michael Fried's essay Art and Objecthood, she discovers that as time goes by, art starts to reflect the quickness of time. Within her work, Lee references Alvin Toffler's book Future Shock. She *claims that “the concept of time they espouse is chronophobic as defined in her book, and their popularity means that their concept of time was widely shared.” In her work she fears “perpetual presentness, [that is] time is constant without conclusion.” Many chronophobes feel this way, they fear the fact that time is never ending.[1]
Chronophobic characters are seen in Jerzy Kosinski's Being There. The character Chance Gardiner has no sense of time because he was raised watching television and now defines time in terms of technology. He is described as being in a state of “perpetual nowness.” He has no sense of the past or future, but lives only in the moment. Kosinski explains that the only way for Chance to overcome his chronophobia is if “peace filled his chest.” Kosinski believes that chronophobia “negates the possibility of full human development.”[9]
Thomas Pynchon offers another view of chronophobia in his novel The Crying of Lot 49. The character Oedipa is similar to Chance Gardiner because she lacks dimension, but she is able to distinguish that events have occurred in the past, present or future. Her cure for chronophobia is to create a world where events are scrambled together randomly. Time becomes irrelevant to her.[10]
Perhaps the most recognized literary work dealing with chronophobia lies in the story of Rip Van Winkle by Washington Irving. This tall-tale introduces a man that has slept for 20 years and wakes to a completely new society. His wife and friends have died, his dog is missing and his gun is rusty. The fact that his entire world has changed sends him into a feeling of fear and panic. At first he is confused and lost, but his chronophobia is cured when he realizes that although it seems that everything around him has changed, his core beliefs still exist. In this instance, chronophobia is overcome because Rip Van Winkle is able to make new friends, and regain parts of the life he lost while he was asleep.[11]
# Prevention
Chronophobia can never really be prevented because it is normally caused by a traumatic experience that is not within one's power to stop.[8] Some ways to relieve the stress that chronophobia can cause are to prevent anxiety or situations that could cause anxiety, to avoid getting stressed out about time, to be on time, and to participate in an activity that requires meditation, such as yoga or other forms of mild martial arts.[5] | https://www.wikidoc.org/index.php/Chronophobia | |
647829eb1e6051bd44733db1df51606244af5631 | wikidoc | Chronotropic | Chronotropic
# Overview
Chronotropic effects (from chrono-, meaning time) are those that change the heart rate.
Chronotropic drugs may change the heart rate by affecting the nerves controlling the heart, or by changing the rhythm produced by the sinoatrial node. Positive chronotropes increase heart rate; however, negative chronotropes decrease heart rate.
A dromotrope affects Atrioventricular node (AV node) conduction. A positive dromotrope increases AV nodal conduction, and a negative dromotrope decreases AV nodal conduction. A lusitrope is an agent that affects diastolic relaxation.
Many positive inotropes affect preload and afterload.
# Negative Chronotropes
Chronotropic variables in systolic myocardial performance can be split left and right. Left sided systolic chronotropy can be appreciated as Aortic Valve open to close time. Right sided variables are represented by Pulmonary valve open to close time. Inverted as diastolic chronotropy, the variables are aortic valve close to open and pulmonic close to open time. Pharmaceutical manipulation of chronotropic properties was perhaps first appreciated by the introduction of digitalis.
- Beta-blockers
- Acetylcholine
- Digoxin
- Diltiazem
- Verapamil
- Ivabradine
- Metoprolol
# Positive Chronotropes
- Atropine
- Quinidine
- Dopamine
- Dobutamine
- Epinephrine
- Isuprel
de:Chronotropie
uk:Хронотропний ефект | Chronotropic
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chronotropic effects (from chrono-, meaning time) are those that change the heart rate.
Chronotropic drugs may change the heart rate by affecting the nerves controlling the heart, or by changing the rhythm produced by the sinoatrial node. Positive chronotropes increase heart rate; however, negative chronotropes decrease heart rate.
A dromotrope affects Atrioventricular node (AV node) conduction. A positive dromotrope increases AV nodal conduction, and a negative dromotrope decreases AV nodal conduction. A lusitrope is an agent that affects diastolic relaxation.
Many positive inotropes affect preload and afterload.
# Negative Chronotropes
Chronotropic variables in systolic myocardial performance can be split left and right. Left sided systolic chronotropy can be appreciated as Aortic Valve open to close time. Right sided variables are represented by Pulmonary valve open to close time. Inverted as diastolic chronotropy, the variables are aortic valve close to open and pulmonic close to open time. Pharmaceutical manipulation of chronotropic properties was perhaps first appreciated by the introduction of digitalis.
- Beta-blockers
- Acetylcholine
- Digoxin
- Diltiazem
- Verapamil
- Ivabradine
- Metoprolol
# Positive Chronotropes
- Atropine
- Quinidine
- Dopamine
- Dobutamine
- Epinephrine
- Isuprel
de:Chronotropie
uk:Хронотропний ефект
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Chronotrope | |
b4f2bb35439037abe2c8baf2c7c7e2a18768454e | wikidoc | Chymotrypsin | Chymotrypsin
Chymotrypsin (EC 3.4.21.1, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme component of pancreatic juice acting in the duodenum, where it performs proteolysis, the breakdown of proteins and polypeptides. Chymotrypsin preferentially cleaves peptide amide bonds where the side chain of the amino acid N-terminal to the scissile amide bond (the P1 position) is a large hydrophobic amino acid (tyrosine, tryptophan, and phenylalanine). These amino acids contain an aromatic ring in their side chain that fits into a hydrophobic pocket (the S1 position) of the enzyme. It is activated in the presence of trypsin. The hydrophobic and shape complementarity between the peptide substrate P1 side chain and the enzyme S1 binding cavity accounts for the substrate specificity of this enzyme. Chymotrypsin also hydrolyzes other amide bonds in peptides at slower rates, particularly those containing leucine and methionine at the P1 position.
Structurally, it is the archetypal structure for its superfamily, the PA clan of proteases.
# Activation
Chymotrypsin is synthesized in the pancreas by protein biosynthesis as a precursor called chymotrypsinogen that is enzymatically inactive. Trypsin activates chymotrypsinogen by cleaving peptidic bonds in positions Arg15 - Ile16 and produces π-chymotrypsin. In turn, aminic group (-NH3+) of the Ile16 residue interacts with the side chain of Glu194, producing the "oxyanion hole" and the hydrophobic "S1 pocket". Moreover, chymotrypsin induces its own activation by cleaving in positions 14-15, 146-147, and 148-149, producing α-chymotrypsin (which is more active and stable than π-chymotrypsin). The resulting molecule is a three-polypeptide molecule interconnected via disulfide bonds.
# Mechanism of action and kinetics
In vivo, chymotrypsin is a proteolytic enzyme (serine protease) acting in the digestive systems of many organisms. It facilitates the cleavage of peptide bonds by a hydrolysis reaction, which despite being thermodynamically favorable, occurs extremely slowly in the absence of a catalyst. The main substrates of chymotrypsin are peptide bonds in which the amino acid N-terminal to the bond is a tryptophan, tyrosine, phenylalanine, or leucine. Like many proteases, chymotrypsin also hydrolyses amide bonds in vitro, a virtue that enabled the use of substrate analogs such as N-acetyl-L-phenylalanine p-nitrophenyl amide for enzyme assays.
Chymotrypsin cleaves peptide bonds by attacking the unreactive carbonyl group with a powerful nucleophile, the serine 195 residue located in the active site of the enzyme, which briefly becomes covalently bonded to the substrate, forming an enzyme-substrate intermediate. Along with histidine 57 and aspartic acid 102, this serine residue constitutes the catalytic triad of the active site.
These findings rely on inhibition assays and the study of the kinetics of cleavage of the aforementioned substrate, exploiting the fact that the enzyme-substrate intermediate p-nitrophenolate has a yellow colour, enabling measurement of its concentration by measuring light absorbance at 410 nm.
The reaction of chymotrypsin with its substrate was found to take place in two stages, an initial “burst” phase at the beginning of the reaction and a steady-state phase following Michaelis-Menten kinetics. The mode of action of chymotrypsin explains this as hydrolysis takes place in two steps. First, acylation of the substrate to form an acyl-enzyme intermediate, and then deacylation to return the enzyme to its original state. This occurs via the concerted action of the three-amino-acid residues in the catalytic triad. Aspartate hydrogen bonds to the N-δ hydrogen of histidine, increasing the pKa of its ε nitrogen, thus making it able to deprotonate serine. This deprotonation allows the serine side chain to act as a nucleophile and bind to the electron-deficient carbonyl carbon of the protein main chain. Ionization of the carbonyl oxygen is stabilized by formation of two hydrogen bonds to adjacent main chain N-hydrogens. This occurs in the oxyanion hole. This forms a tetrahedral adduct and breakage of the peptide bond. An acyl-enzyme intermediate, bound to the serine, is formed, and the newly formed amino terminus of the cleaved protein can dissociate. In the second reaction step, a water molecule is activated by the basic histidine, and acts as a nucleophile. The oxygen of water attacks the carbonyl carbon of the serine-bound acyl group, resulting in formation of a second tetrahedral adduct, regeneration of the serine -OH group, and release of a proton, as well as the protein fragment with the newly formed carboxyl terminus
# Isozymes | Chymotrypsin
Chymotrypsin (EC 3.4.21.1, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme component of pancreatic juice acting in the duodenum, where it performs proteolysis, the breakdown of proteins and polypeptides.[2] Chymotrypsin preferentially cleaves peptide amide bonds where the side chain of the amino acid N-terminal to the scissile amide bond (the P1 position) is a large hydrophobic amino acid (tyrosine, tryptophan, and phenylalanine). These amino acids contain an aromatic ring in their side chain that fits into a hydrophobic pocket (the S1 position) of the enzyme. It is activated in the presence of trypsin. The hydrophobic and shape complementarity between the peptide substrate P1 side chain and the enzyme S1 binding cavity accounts for the substrate specificity of this enzyme.[3][4] Chymotrypsin also hydrolyzes other amide bonds in peptides at slower rates, particularly those containing leucine and methionine at the P1 position.
Structurally, it is the archetypal structure for its superfamily, the PA clan of proteases.
# Activation
Chymotrypsin is synthesized in the pancreas by protein biosynthesis as a precursor called chymotrypsinogen that is enzymatically inactive. Trypsin activates chymotrypsinogen by cleaving peptidic bonds in positions Arg15 - Ile16 and produces π-chymotrypsin. In turn, aminic group (-NH3+) of the Ile16 residue interacts with the side chain of Glu194, producing the "oxyanion hole" and the hydrophobic "S1 pocket". Moreover, chymotrypsin induces its own activation by cleaving in positions 14-15, 146-147, and 148-149, producing α-chymotrypsin (which is more active and stable than π-chymotrypsin).[citation needed] The resulting molecule is a three-polypeptide molecule interconnected via disulfide bonds.
# Mechanism of action and kinetics
In vivo, chymotrypsin is a proteolytic enzyme (serine protease) acting in the digestive systems of many organisms. It facilitates the cleavage of peptide bonds by a hydrolysis reaction, which despite being thermodynamically favorable, occurs extremely slowly in the absence of a catalyst. The main substrates of chymotrypsin are peptide bonds in which the amino acid N-terminal to the bond is a tryptophan, tyrosine, phenylalanine, or leucine. Like many proteases, chymotrypsin also hydrolyses amide bonds in vitro, a virtue that enabled the use of substrate analogs such as N-acetyl-L-phenylalanine p-nitrophenyl amide for enzyme assays.
Chymotrypsin cleaves peptide bonds by attacking the unreactive carbonyl group with a powerful nucleophile, the serine 195 residue located in the active site of the enzyme, which briefly becomes covalently bonded to the substrate, forming an enzyme-substrate intermediate. Along with histidine 57 and aspartic acid 102, this serine residue constitutes the catalytic triad of the active site.
These findings rely on inhibition assays and the study of the kinetics of cleavage of the aforementioned substrate, exploiting the fact that the enzyme-substrate intermediate p-nitrophenolate has a yellow colour, enabling measurement of its concentration by measuring light absorbance at 410 nm.
The reaction of chymotrypsin with its substrate was found to take place in two stages, an initial “burst” phase at the beginning of the reaction and a steady-state phase following Michaelis-Menten kinetics. The mode of action of chymotrypsin explains this as hydrolysis takes place in two steps. First, acylation of the substrate to form an acyl-enzyme intermediate, and then deacylation to return the enzyme to its original state. This occurs via the concerted action of the three-amino-acid residues in the catalytic triad.[5] Aspartate hydrogen bonds to the N-δ hydrogen of histidine, increasing the pKa of its ε nitrogen, thus making it able to deprotonate serine. This deprotonation allows the serine side chain to act as a nucleophile and bind to the electron-deficient carbonyl carbon of the protein main chain. Ionization of the carbonyl oxygen is stabilized by formation of two hydrogen bonds to adjacent main chain N-hydrogens. This occurs in the oxyanion hole. This forms a tetrahedral adduct and breakage of the peptide bond. An acyl-enzyme intermediate, bound to the serine, is formed, and the newly formed amino terminus of the cleaved protein can dissociate. In the second reaction step, a water molecule is activated by the basic histidine, and acts as a nucleophile. The oxygen of water attacks the carbonyl carbon of the serine-bound acyl group, resulting in formation of a second tetrahedral adduct, regeneration of the serine -OH group, and release of a proton, as well as the protein fragment with the newly formed carboxyl terminus [5]
# Isozymes | https://www.wikidoc.org/index.php/Chymotrypsin | |
99b02c8aff3ebf310782527b1c1f5a4502f47e3c | wikidoc | Ciliary body | Ciliary body
The ciliary body is the circumferential tissue inside the eye composed of the ciliary muscle and ciliary processes. It is part of the uveal tract—the layer of tissue which provides most of the nutrients in the eye. There are three sets of ciliary muscles in the eye, the longitudinal, radial, and circular muscles. They are near the front of the eye, above and below the lens. They are attached to the lens by connective tissue called the zonule of Zinn, and are responsible for shaping the lens to focus light on the retina.
When the ciliary muscle relaxes, it flattens the lens, generally improving the focus for farther objects. When it contracts, the lens becomes more convex, generally improving the focus for closer objects.
# Functions
The ciliary body has three functions: accommodation, aqueous humor production and the production and maintenance of the lens zonules. One of the most essential roles of the ciliary body is the production of the aqueous humor, which is responsible for providing most of the nutrients for the lens and the cornea and involved in waste management of these areas.
# Clinical significance
It is the main target of drugs against glaucoma, as the ciliary body is responsible for aqueous humor production; lowering aqueous humor production will cause a subsequent drop in the intraocular pressure. | Ciliary body
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The ciliary body is the circumferential tissue inside the eye composed of the ciliary muscle and ciliary processes.[1] It is part of the uveal tract—the layer of tissue which provides most of the nutrients in the eye. There are three sets of ciliary muscles in the eye, the longitudinal, radial, and circular muscles. They are near the front of the eye, above and below the lens. They are attached to the lens by connective tissue called the zonule of Zinn, and are responsible for shaping the lens to focus light on the retina.
When the ciliary muscle relaxes, it flattens the lens, generally improving the focus for farther objects. When it contracts, the lens becomes more convex, generally improving the focus for closer objects.
# Functions
The ciliary body has three functions: accommodation, aqueous humor production and the production and maintenance of the lens zonules. One of the most essential roles of the ciliary body is the production of the aqueous humor, which is responsible for providing most of the nutrients for the lens and the cornea and involved in waste management of these areas.
# Clinical significance
It is the main target of drugs against glaucoma, as the ciliary body is responsible for aqueous humor production; lowering aqueous humor production will cause a subsequent drop in the intraocular pressure. | https://www.wikidoc.org/index.php/Ciliary_body | |
9d0dffe025d2d246083bfde778700e121a0bd54f | wikidoc | Cladosporium | Cladosporium
Cladosporium is a genus of fungi including some of the most common indoor and outdoor molds. Species produce olive-green to brown or black colonies, and have dark-pigmented conidia that are formed in simple or branching chains.
The many species of Cladosporium are commonly found on living and dead plant material. Some species are plant pathogens, others parasitize other fungi. Cladosporium spores are wind-dispersed and they are often extremely abundant in outdoor air. Indoors Cladosporium species may grow on surfaces when moisture is present.
Cladosporium fulvum, cause of tomato leaf mould, has been an important genetic model, in that the genetics of host resistance are understood.
# Health Effects
Cladosporium species are rarely pathogenic to humans, but have been reported to cause infections of the skin and toenails, as well as sinusitis and pulmonary infections. If left untreated, these infections could turn into respiratory infections like pneumonia.
The airborne spores of Cladosporium species are significant allergens, and in large amounts they can severely affect asthmatics and people with respiratory diseases. Cladosporium species produce no major mycotoxins of concern, but do produce volatile organic compounds (VOCs) associated with odours. | Cladosporium
Cladosporium is a genus of fungi including some of the most common indoor and outdoor molds. Species produce olive-green to brown or black colonies, and have dark-pigmented conidia that are formed in simple or branching chains.
The many species of Cladosporium are commonly found on living and dead plant material. Some species are plant pathogens, others parasitize other fungi. Cladosporium spores are wind-dispersed and they are often extremely abundant in outdoor air. Indoors Cladosporium species may grow on surfaces when moisture is present.
Cladosporium fulvum, cause of tomato leaf mould, has been an important genetic model, in that the genetics of host resistance are understood.[1]
# Health Effects
Cladosporium species are rarely pathogenic to humans, but have been reported to cause infections of the skin and toenails, as well as sinusitis and pulmonary infections. If left untreated, these infections could turn into respiratory infections like pneumonia.
The airborne spores of Cladosporium species are significant allergens, and in large amounts they can severely affect asthmatics and people with respiratory diseases. Cladosporium species produce no major mycotoxins of concern, but do produce volatile organic compounds (VOCs) associated with odours. | https://www.wikidoc.org/index.php/Cladosporium | |
c857cc6b6a27052e5c9251f90c1458e3f2899a31 | wikidoc | Clark's rule | Clark's rule
Clark's Rule is a medical term referring to a procedure used to calculate the amount of medicine to give to a child aged 2-17. The procedure is to take the child's weight in pounds, divide by 150 lb, and multiply the fractional result by the adult dose to find the equivalent child dosage.
For example: If an adult dose of medication calls for 30 mg and the child weighs 30 lb. Divide the weight by 150 (30/150) to get 1/5. Multiply 1/5 times 30 mg to get 6 mg.
Clark's Rule is not used clinically, but it is a popular dosage calculation formula for pediatric nursing instructors. | Clark's rule
Clark's Rule is a medical term referring to a procedure used to calculate the amount of medicine to give to a child aged 2-17. The procedure is to take the child's weight in pounds, divide by 150 lb, and multiply the fractional result by the adult dose to find the equivalent child dosage.
For example: If an adult dose of medication calls for 30 mg and the child weighs 30 lb. Divide the weight by 150 (30/150) to get 1/5. Multiply 1/5 times 30 mg to get 6 mg.
Clark's Rule is not used clinically, but it is a popular dosage calculation formula for pediatric nursing instructors.
# External links
- Clark's Rule
Template:WS | https://www.wikidoc.org/index.php/Clark%27s_rule | |
829df712b8f799b5657b88f49725a9784b30a3ec | wikidoc | MHC class II | MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells (APCs).
The peptides presented by class II molecules are derived from extracellular proteins (not cytosolic as in class I); hence, the MHC class II-dependent pathway of antigen presentation is called the endocytic or exogenous pathway.
Loading of class II molecules must still occur inside the cell; extracellular proteins are endocytosed, digested in lysosomes, and bound by the class II MHC molecule prior to the molecule's migration to the plasma membrane.
# Structure
Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homologous peptides, an α and β chain, both of which are encoded in the MHC.
Because the peptide-binding groove of MHC class II molecules is open at both ends while the corresponding groove on class I molecules is closed at each end, the peptides presented by MHC class II molecules are longer, generally between 15 and 24 amino acid residues long.
# Reaction to bacteria
Because class II MHC is loaded with extracellular proteins, it is mainly concerned with presentation of extracellular pathogens (for example, bacteria that might be infecting a wound or the blood). Class II molecules interact exclusively with CD4+ ("helper") T cells (THs). The helper T cells then help to trigger an appropriate immune response which may include localized inflammation and swelling due to recruitment of phagocytes or may lead to a full-force antibody immune response due to activation of B cells.
# Synthesis
During synthesis, MHC class II is the result of dimerization of α and β chains, with the assistance of an invariant chain.
# Genes | MHC class II
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells (APCs).
The peptides presented by class II molecules are derived from extracellular proteins (not cytosolic as in class I); hence, the MHC class II-dependent pathway of antigen presentation is called the endocytic or exogenous pathway.
Loading of class II molecules must still occur inside the cell; extracellular proteins are endocytosed, digested in lysosomes, and bound by the class II MHC molecule prior to the molecule's migration to the plasma membrane.
# Structure
Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homologous peptides, an α and β chain, both of which are encoded in the MHC.
Because the peptide-binding groove of MHC class II molecules is open at both ends while the corresponding groove on class I molecules is closed at each end, the peptides presented by MHC class II molecules are longer, generally between 15 and 24 amino acid residues long.
# Reaction to bacteria
Because class II MHC is loaded with extracellular proteins, it is mainly concerned with presentation of extracellular pathogens (for example, bacteria that might be infecting a wound or the blood). Class II molecules interact exclusively with CD4+ ("helper") T cells (THs). The helper T cells then help to trigger an appropriate immune response which may include localized inflammation and swelling due to recruitment of phagocytes or may lead to a full-force antibody immune response due to activation of B cells.
# Synthesis
During synthesis, MHC class II is the result of dimerization of α and β chains, with the assistance of an invariant chain.[1]
# Genes
# External links
- Histocompatibility+Antigens+Class+II at the US National Library of Medicine Medical Subject Headings (MeSH)
- MHC+Class+II+Genes at the US National Library of Medicine Medical Subject Headings (MeSH)
Template:WikiDoc Sources
- ↑ School of Crystallography The Invariant chain | https://www.wikidoc.org/index.php/Class_II_MHC | |
02a85b05ae20515fdfddb6fe5ce0d2cd59b3c250 | wikidoc | Ectrodactyly | Ectrodactyly
Ectrodactyly, commonly known as lobster claw syndrome , sometimes known as Karsch-Neugebauer syndrome, is a rare congenital deformity of the hand where the middle digit is missing, and the hand is cleft where the metacarpal of the finger should be. This split gives the hands the appearance of lobster claws.
Ectrodactyly may also be known as "lobster claw hand", "split hand deformity", "split hand/foot malformation (SHFM)", "cleft hand", "ectrodactilia of the hand" or "Karsch-Neugebauer syndrome", after J. Karsch and H. Neugebauer .
# Genetics
There are different forms of the disorder and each of them are connected with a different genetic mutation. Type I, the most frequent form has been found to be a mutation on chromosome 7 in a region that contains two homeobox genes, DLX5 and DLX6. Both are near SHFM1 ("split hand/foot malformation type 1").
Ectrodactyly is an inherited dysmelia, and often occurs in both the hands and the feet. Its inheritance pattern is autosomal dominant. It affects about 1 in 90,000 babies, with males and females equally likely to be affected.
Ectrodactylia may not be isolated and may exist in certain syndromes. EEC ie Ectrodactyly-ectodermal dysplasia-cleft syndrome happens due to a mutation in p63 a homologue of the famous p53.
# Treatment
It is treated surgically to improve function and appearance. Prosthetics may also be used, and genetic counselling given to parents with the condition.
# Famous people with ectrodactyly
- Vadoma
- Bree Walker - News anchor for 20 years KCBS news in Los Angeles; actress on HBO drama Carnivàle. She also appears in the fourth season premiere of FX's Nip/Tuck playing a real estate agent counseling parents expecting a child with ectrodactyly. Also appeared, along with her 2 children who also suffer from Ectrodactyly, on an episode of "My Unique Family" on The Learning Channel.
- Grady "Lobster Boy" Stiles | Ectrodactyly
Ectrodactyly, commonly known as lobster claw syndrome [1], sometimes known as Karsch-Neugebauer syndrome, is a rare congenital deformity of the hand where the middle digit is missing, and the hand is cleft where the metacarpal of the finger should be. This split gives the hands the appearance of lobster claws.
Ectrodactyly may also be known as "lobster claw hand", "split hand deformity", "split hand/foot malformation (SHFM)", "cleft hand", "ectrodactilia of the hand" or "Karsch-Neugebauer syndrome", after J. Karsch[2] and H. Neugebauer .[3]
# Genetics
There are different forms of the disorder and each of them are connected with a different genetic mutation. Type I, the most frequent form has been found to be a mutation on chromosome 7 in a region that contains two homeobox genes, DLX5 and DLX6.[4] Both are near SHFM1 ("split hand/foot malformation type 1").
Ectrodactyly is an inherited dysmelia, and often occurs in both the hands and the feet. Its inheritance pattern is autosomal dominant. It affects about 1 in 90,000 babies, with males and females equally likely to be affected.
Ectrodactylia may not be isolated and may exist in certain syndromes. EEC ie Ectrodactyly-ectodermal dysplasia-cleft syndrome happens due to a mutation in p63 a homologue of the famous p53.
# Treatment
It is treated surgically to improve function and appearance. Prosthetics may also be used, and genetic counselling given to parents with the condition.
# Famous people with ectrodactyly
- Vadoma
- Bree Walker[5] - News anchor for 20 years KCBS news in Los Angeles; actress on HBO drama Carnivàle. She also appears in the fourth season premiere of FX's Nip/Tuck playing a real estate agent counseling parents expecting a child with ectrodactyly. Also appeared, along with her 2 children who also suffer from Ectrodactyly, on an episode of "My Unique Family" on The Learning Channel.
- Grady "Lobster Boy" Stiles | https://www.wikidoc.org/index.php/Clawhand | |
7fda386c4f708cbf0b52a4e4648b265b0874dd5f | wikidoc | Medical sign | Medical sign
A sign is an indication of some fact or quality; and a medical sign is an objective indication of some medical fact or quality that is detected by a physician during a physical examination of a patient.
There is a strong implication that the signs have no meaning for a patient, and may not even be noticed by them; yet they are full of meaning for the physician, and are often significant in assisting a physician to identify the disease(s) responsible for the patient's symptoms.
Examples include elevated blood pressure, a clubbing of the fingers (which may be a sign of lung disease, or many other things), and arcus senilis.
The term sign is not to be confused with the term indication, which denotes a valid reason for using some treatment.
# Signs and semiotics
The art of interpreting clinical signs was originally called semiotics in English. This term, then spelt semeiotics (derived from the Greek adjective σημειοτικός: semeiotikos, "to do with signs"), was first used in English in 1670 by Henry Stubbes (1631-1676), to denote the branch of medical science relating to the interpretation of signs:
# Eponymous signs
A number of medical signs are named after the doctors who first described them.
# Signs versus symptoms
Signs are different from symptoms: the "subjective" experiences, such as the fatigue, that patients might report to their examining physician.
For convenience, signs are commonly distinguished from symptoms as follows: a symptom is something abnormal, that is relevant to disease, experienced by a patient, whilst a sign is something abnormal, that is relevant to disease, discovered by the physician during his examination of the patient:
According to King, it is an essential feature of a sign that there is both a sign and a thing signified. And, because "the essence of a sign is to convey information", it can only be a sign if it has meaning. Therefore, "a sign ceases to be a sign when you cannot read it".
A slightly different definition views signs as any indication of a disease that can be objectively observed (i.e. by someone who isn't the patient), whereas a symptom is merely any manifestation of a disease that is apparent to the patient (i.e. reasons why diseases are bad). From this definition, it can be said that an asymptomatic patient is uninhibited by disease. With this set of definitions, there is some overlap--certain things may qualify as both a sign and a symptom (e.g. a bloody nose).
# Types of signs
Medical signs may be classified by the type of inference that may be made from their presence, for example:
- Prognostic signs (from progignṓskein, προγιγνώσκειν, "to know beforehand"): signs that indicate the outcome of the current bodily state of the patient (i.e., rather than indicating the name of the disease). Prognostic signs always point to the future. Perhaps the most famous prognostic sign is the facies Hippocratica.
- Anamnestic signs (from anamnēstikós, ἀναμνηστικός, "able to recall to mind"): signs that (taking into account the current state of a patient's body), indicate the past existence of a certain disease or condition. Anamnestic signs always point to the past. (Whenever we see a man walking with a particular gait, with one arm paralysed in a particular way, we say “This man has had a stroke”; and, if we see a woman in her late 50s with one arm distorted in a particular way, we say “She had polio as a child”.)
- Diagnostic signs (from diagnōstikós, διαγνωστικός, "able to distinguish"): signs that lead to the recognition and identification of a disease (i.e., they indicate the name of the disease).
- Pathognomonic signs (from pathognomonikós, παθογνωμονικός, "skilled in diagnosis", derived from páthos, πάθος, "suffering, disease", and gnṓmon, γνώμον, "judge, indicator"): the particular signs whose presence means, beyond any doubt, that a particular disease is present. They represent a marked intensification of a diagnostic sign. (An example would be the palmar xanthomata seen on the hands of people suffering from hyperlipoproteinaemia.) Singular pathognonomic signs are relatively uncommon.
# Technological development creating signs detectable only by physicians
Prior to the nineteenth century there was little difference between physician and patient. Most medical practice was conducted as a joint co-operative interaction between the physician and the patient as equals. Whilst each noticed much the same things, the physician had a more informed interpretation of those things: “the physicians knew what the findings meant and the layman did not”.
## Advances in the 19th century
However, the patient was gradually removed from the medical interaction due to significant technological advances such as:
- the 1808 introduction of the percussion technique:
The techniques, which had been first described by the Viennese physician Leopold Auenbrugger (1722-1809) in 1761, became far more widely known following the publication of Corvisart’s translation of Auenbrugger's work in 1808.
- the 1819 introduction of the technique of auscultation following the 1819 publication of René Théophile Hyacinthe Laënnec's (1781-1826) findings on the use of his modified stethoscope. (He had invented a very crude form of stethoscope in 1816; but it was his subsequent modification of that later stethoscope that was the subject of his 1819 publication. Laënnec's 1819 publication was Forbes translated into English in four editions between 1821 and 1834 by Sir John Forbes.)
- The 1846 introduction by surgeon John Hutchinson (1811-1861) of the spirometer, an apparatus for assessing the mechanical properties of the lungs per medium of measurements of forced exhalation and forced inhalation. (The recorded lung volumes and air flow rates are used to distinguish between restrictive disease (in which the lung volumes are decreased: e.g., cystic fibrosis) and obstructive diseases (in which the lung volume is normal but the air flow rate is impeded; e.g., emphysema).)
- The 1851 invention, by Hermann von Helmholtz (1821-1894), of the opthalmoscope, which allowed physicians to examine the inside of the human eye.
- the 1895 clinical use of X-rays which began almost immediately after they had been discovered that year by the German Wilhelm Conrad Röntgen (1845-1923).
- the 1896 introduction of the sphygmomanometer, designed by Italian Scipione Riva-Rocci (1863-1937), to measure blood pressure.
## Alteration of the relationship between physician and patient
The introduction of the techniques of percussion and auscultation into medical practice immediately altered the relationship between physician and patient in a very significant way, specifically because these techniques relied almost entirely upon the physician listening. (King observes that the introduction of the stethoscope did not immediately revolutionize medicine; because, although the physicians could certainly hear some thing via these techniques, they had no idea whatsoever of what those particular sounds, in those particular rhythms, in those particular combinations actually meant. In other words, although they certainly were being bombarded with noises, they were noises that signified nothing at all.)
Not only did this greatly reduce the patient's capacity to observe and contribute to the process of diagnosis, it also meant that the patient was often instructed to stop talking, and remain silent.
As these sorts of evolutionary changes continued to take place in medical practice, it was increasingly necessary to uniquely identify data that was accessible only to the physician, and to be able to differentiate those observations from others that were also available to the patient, and it just seemed natural to use "signs" for the class of physician-specific data, and "symptoms" for the class of observations available to the patient.
King proposes a more advanced notion; namely, that a sign is something that has meaning, regardless of whether it is observed by the physician or reported by the patient:
# Signs as tests
In some senses, the process of diagnosis is always a matter of assessing the likelihood that a given condition is present in the patient. In a patient who presents with haemoptysis (coughing up blood), the haemoptysis is very much more likely to be caused by respiratory disease than by the patient having broken their toe. Each question in the history taking allows the medical practitioner to narrow down their view of the cause of the symptom, testing and building up their hypotheses as they go along.
Examination, which is essentially looking for clinical signs, allows the medical practitioner to see if there is evidence in the patient's body to support their hypotheses about the disease that might be present.
A patient who has given a good story to support a diagnosis of tuberculosis might be found, on examination, to show signs that lead the practitioner away from that diagnosis and more towards sarcoidosis, for example. Examination for signs tests the practitioner's hypotheses, and each time a sign is found that supports a given diagnosis, that diagnosis becomes more likely.
Special tests (blood tests, radiology, scans, a biopsy, etc.) also allow a hypothesis to be tested. These special tests are also said to show signs in a clinical sense. Again, a test can be considered pathognonomic for a given disease, but in that case the test is generally said to be "diagnostic" of that disease rather than pathognonomic. An example would be a history of a fall from a height, followed by a lot of pain in the leg. The signs (a swollen, tender, distorted lower leg) are only very strongly suggestive of a fracture; it might not actually be broken, and even if it is, the particular kind of fracture and its degree of dislocation need to be known, so the practitioner orders an x-ray. The x-ray film shows a fractured tibia, so the film is said to be diagnostic of the fracture.
# Examples of signs | Medical sign
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
A sign is an indication of some fact or quality; and a medical sign is an objective[1] indication of some medical fact or quality that is detected by a physician during a physical examination of a patient.[2]
There is a strong implication that the signs have no meaning for a patient, and may not even be noticed by them; yet they are full of meaning for the physician, and are often significant in assisting a physician to identify the disease(s) responsible for the patient's symptoms.
Examples include elevated blood pressure, a clubbing of the fingers (which may be a sign of lung disease, or many other things), and arcus senilis.
The term sign is not to be confused with the term indication, which denotes a valid reason for using some treatment.
# Signs and semiotics
The art of interpreting clinical signs was originally called semiotics in English. This term, then spelt semeiotics (derived from the Greek adjective σημειοτικός: semeiotikos, "to do with signs"), was first used in English in 1670 by Henry Stubbes (1631-1676), to denote the branch of medical science relating to the interpretation of signs:
# Eponymous signs
A number of medical signs are named after the doctors who first described them.[4]
# Signs versus symptoms
Signs are different from symptoms: the "subjective" experiences, such as the fatigue, that patients might report to their examining physician.
For convenience, signs are commonly distinguished from symptoms as follows: a symptom is something abnormal, that is relevant to disease, experienced by a patient, whilst a sign is something abnormal, that is relevant to disease, discovered by the physician during his examination of the patient:
According to King, it is an essential feature of a sign that there is both a sign and a thing signified. And, because "the essence of a sign is to convey information", it can only be a sign if it has meaning. Therefore, "a sign ceases to be a sign when you cannot read it".[6]
A slightly different definition views signs as any indication of a disease that can be objectively observed (i.e. by someone who isn't the patient), whereas a symptom is merely any manifestation of a disease that is apparent to the patient (i.e. reasons why diseases are bad). From this definition, it can be said that an asymptomatic patient is uninhibited by disease. With this set of definitions, there is some overlap--certain things may qualify as both a sign and a symptom (e.g. a bloody nose).
# Types of signs
Medical signs may be classified by the type of inference that may be made from their presence,[7] for example:
- Prognostic signs (from progignṓskein, προγιγνώσκειν, "to know beforehand"): signs that indicate the outcome of the current bodily state of the patient (i.e., rather than indicating the name of the disease). Prognostic signs always point to the future. Perhaps the most famous prognostic sign is the facies Hippocratica.
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- Anamnestic signs (from anamnēstikós, ἀναμνηστικός, "able to recall to mind"): signs that (taking into account the current state of a patient's body), indicate the past existence of a certain disease or condition. Anamnestic signs always point to the past. (Whenever we see a man walking with a particular gait, with one arm paralysed in a particular way, we say “This man has had a stroke”; and, if we see a woman in her late 50s with one arm distorted in a particular way, we say “She had polio as a child”.)
- Diagnostic signs (from diagnōstikós, διαγνωστικός, "able to distinguish"): signs that lead to the recognition and identification of a disease (i.e., they indicate the name of the disease).
- Pathognomonic signs (from pathognomonikós, παθογνωμονικός, "skilled in diagnosis", derived from páthos, πάθος, "suffering, disease", and gnṓmon, γνώμον, "judge, indicator"): the particular signs whose presence means, beyond any doubt, that a particular disease is present. They represent a marked intensification of a diagnostic sign. (An example would be the palmar xanthomata seen on the hands of people suffering from hyperlipoproteinaemia.) Singular pathognonomic signs are relatively uncommon.
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# Technological development creating signs detectable only by physicians
Prior to the nineteenth century there was little difference between physician and patient. Most medical practice was conducted as a joint co-operative interaction between the physician and the patient as equals.[8][9] Whilst each noticed much the same things, the physician had a more informed interpretation of those things: “the physicians knew what the findings meant and the layman did not”.[10]
## Advances in the 19th century
However, the patient was gradually removed from the medical interaction[8][9][11] due to significant technological advances such as:
- the 1808 introduction of the percussion technique:
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The techniques, which had been first described by the Viennese physician Leopold Auenbrugger (1722-1809) in 1761, became far more widely known following the publication of Corvisart’s translation of Auenbrugger's work in 1808.
- the 1819 introduction of the technique of auscultation following the 1819 publication of René Théophile Hyacinthe Laënnec's (1781-1826) findings on the use of his modified stethoscope. (He had invented a very crude form of stethoscope in 1816; but it was his subsequent modification of that later stethoscope that was the subject of his 1819 publication. Laënnec's 1819 publication was Forbes translated into English in four editions between 1821 and 1834 by Sir John Forbes.)
- The 1846 introduction by surgeon John Hutchinson (1811-1861) of the spirometer, an apparatus for assessing the mechanical properties of the lungs per medium of measurements of forced exhalation and forced inhalation. (The recorded lung volumes and air flow rates are used to distinguish between restrictive disease (in which the lung volumes are decreased: e.g., cystic fibrosis) and obstructive diseases (in which the lung volume is normal but the air flow rate is impeded; e.g., emphysema).)
- The 1851 invention, by Hermann von Helmholtz (1821-1894), of the opthalmoscope, which allowed physicians to examine the inside of the human eye.
- the 1895 clinical use of X-rays which began almost immediately after they had been discovered that year by the German Wilhelm Conrad Röntgen (1845-1923).
- the 1896 introduction of the sphygmomanometer, designed by Italian Scipione Riva-Rocci (1863-1937), to measure blood pressure.
## Alteration of the relationship between physician and patient
The introduction of the techniques of percussion and auscultation into medical practice immediately altered the relationship between physician and patient in a very significant way, specifically because these techniques relied almost entirely upon the physician listening. (King observes that the introduction of the stethoscope did not immediately revolutionize medicine; because, although the physicians could certainly hear some thing via these techniques, they had no idea whatsoever of what those particular sounds, in those particular rhythms, in those particular combinations actually meant. In other words, although they certainly were being bombarded with noises, they were noises that signified nothing at all.)[12]
Not only did this greatly reduce the patient's capacity to observe and contribute to the process of diagnosis, it also meant that the patient was often instructed to stop talking, and remain silent.
As these sorts of evolutionary changes continued to take place in medical practice, it was increasingly necessary to uniquely identify data that was accessible only to the physician, and to be able to differentiate those observations from others that were also available to the patient, and it just seemed natural to use "signs" for the class of physician-specific data, and "symptoms" for the class of observations available to the patient.
King proposes a more advanced notion; namely, that a sign is something that has meaning, regardless of whether it is observed by the physician or reported by the patient:
# Signs as tests
In some senses, the process of diagnosis is always a matter of assessing the likelihood that a given condition is present in the patient. In a patient who presents with haemoptysis (coughing up blood), the haemoptysis is very much more likely to be caused by respiratory disease than by the patient having broken their toe. Each question in the history taking allows the medical practitioner to narrow down their view of the cause of the symptom, testing and building up their hypotheses as they go along.
Examination, which is essentially looking for clinical signs, allows the medical practitioner to see if there is evidence in the patient's body to support their hypotheses about the disease that might be present.
A patient who has given a good story to support a diagnosis of tuberculosis might be found, on examination, to show signs that lead the practitioner away from that diagnosis and more towards sarcoidosis, for example. Examination for signs tests the practitioner's hypotheses, and each time a sign is found that supports a given diagnosis, that diagnosis becomes more likely.
Special tests (blood tests, radiology, scans, a biopsy, etc.) also allow a hypothesis to be tested. These special tests are also said to show signs in a clinical sense. Again, a test can be considered pathognonomic for a given disease, but in that case the test is generally said to be "diagnostic" of that disease rather than pathognonomic. An example would be a history of a fall from a height, followed by a lot of pain in the leg. The signs (a swollen, tender, distorted lower leg) are only very strongly suggestive of a fracture; it might not actually be broken, and even if it is, the particular kind of fracture and its degree of dislocation need to be known, so the practitioner orders an x-ray. The x-ray film shows a fractured tibia, so the film is said to be diagnostic of the fracture.
# Examples of signs | https://www.wikidoc.org/index.php/Clinical_signs | |
ed00e91c9180834b29ada60d3f5f8da15d9f73ff | wikidoc | Co-amilozide | Co-amilozide
Co-amilozide (BAN) is a non-proprietary name used to denote a combination of amiloride and hydrochlorothiazide. Co-amilozide is used in the treatment of hypertension and congestive heart failure with the tendency of the thiazide to cause low potassium levels (hypokalaemia) offset by the potassium-sparing effects of amiloride.
# Formulation
Two strengths of co-amilozide is currently available in the UK:
- 2.5 mg amiloride and 25 mg hydrochlorothiazide, BAN of Co-amilozide 2.5/25 (brand name Moduretic 25)
- 5 mg amiloride and 50 mg hydrochlorothiazide, BAN of Co-amilozide 5/50 (brand name Moduretic) | Co-amilozide
Co-amilozide (BAN) is a non-proprietary name used to denote a combination of amiloride and hydrochlorothiazide. Co-amilozide is used in the treatment of hypertension and congestive heart failure with the tendency of the thiazide to cause low potassium levels (hypokalaemia) offset by the potassium-sparing effects of amiloride.
# Formulation
Two strengths of co-amilozide is currently available in the UK:
- 2.5 mg amiloride and 25 mg hydrochlorothiazide, BAN of Co-amilozide 2.5/25 (brand name Moduretic 25)
- 5 mg amiloride and 50 mg hydrochlorothiazide, BAN of Co-amilozide 5/50 (brand name Moduretic) | https://www.wikidoc.org/index.php/Co-amilozide | |
3877a5c07031d7989f84d9820c07f68760c61f40 | wikidoc | Co-evolution | Co-evolution
In biology, co-evolution is the mutual evolutionary influence between two species. Each party in a co-evolutionary relationship exerts selective pressures on the other, thereby affecting each others' evolution. Co-evolution includes the evolution of a host species and its parasites, and examples of mutualism evolving through time. Evolution in response to abiotic factors, such as climate change, is not coevolution (since climate is not alive and does not undergo biological evolution). Evolution in a one-on-one interaction, such as that between predator and prey, host-symbiont or host-parasitic pair, is coevolution. But many cases are less clearcut: a species may evolve in response to a number of other species, each of which is also evolving in response to a set of species. This situation has been referred to as "diffuse coevolution". And, certainly, for many organisms, the biotic (living) environment is the most prominent selective pressure, resulting in evolutionary change.
Examples of co-evolution include pollination of Angraecoid orchids by African moths. These species co-evolve because the moths are dependent on the flowers for nectar and the flowers are dependent on the moths to spread their pollen so they can reproduce. The evolutionary process has led to deep flowers and moths with long probosci.
Co-evolution also occurs between predator and prey species as in the case of the Rough-skinned Newt (Taricha granulosa) and the common garter snake (Thamnophis sirtalis). In this case, the newts produce a potent nerve toxin that concentrates in their skin. Garter snakes have evolved resistance to this toxin through a set of genetic mutations, and prey upon the newts. The relationship between these animals has resulted in an evolutionary arms race that has driven toxin levels in the newt to extreme levels. Coevolution processes were modeling by Leigh Van Valen as the theory of the Red Queen. Emphasizing the importance of the sexual conflict, Thierry Lodé privilegied the role of antagonist interactions (notably sexual) in evolution leading to an antagonist coevolution.
Co-evolution does not imply mutual dependence. The host of a parasite, or prey of a predator, does not depend on its enemy for survival.
The existence of mitochondria within eukaryote cells is an example of co-evolution as the mitochondria has a different DNA sequence than that of the nucleus in the host cell. This concept is described further by the Endosymbiotic theory.
Co-evolutionary algorithms are also a class of algorithms used for generating artificial life as well as for optimization, game learning and machine learning. Pioneering results in the use of co-evolutionary methods were by Daniel Hillis (who co-evolved sorting networks) and Karl Sims (who co-evolved virtual creatures).
In his book The Self-organizing Universe, Erich Jantsch attributed the entire evolution of the cosmos to co-evolution.
In astronomy, an emerging theory states that black holes and galaxies develop in an interdependent way analogous to biological co-evolution.
# Specific examples
## Hummingbirds and ornithophilous flowers
Hummingbirds and ornithophilous flowers have evolved to form a mutualistic relationship. It is prevalent in the bird’s biology as well as in the flower’s. Hummingbird flowers have nectar chemistry associated with the bird’s diet. Their color and morphology also coincide with the bird’s vision and morphology. The blooming times of these ornithophilous flowers have also been found to coincide with hummingbirds' breeding seasons.
Flowers have converged to take advantage of similar birds (Brown et.al, 1979). Flowers compete for pollinators and adaptations reduce deleterious effects of this competition (Brown et al 1979). Bird-pollinated flowers usually show higher nectar volumes and sugar production (Stiles 1981). This reflects high energy requirements of the birds (Stiles 1981). Energetic criteria are the most important determinants of flower choice by birds (Stiles 1981). Following their respective breeding seasons, several species of hummingbirds co-occur in North America, and several hummingbird flowers bloom simultaneously in these habitats. These flowers seem to have converged to a common morphology and color (Stiles 1981). Different lengths and curvatures of the corolla tubes can affect the efficiency of extraction in hummingbird species in relation to differences in bill morphology (Stiles 1981). Tubular flowers force a bird to orient its bill in a particular way when probing the flower, especially when the bill and corolla are both curved; this also allows the plant to place pollen on a certain part of the bird’s body (Stiles 1981). This opens the door for a variety of morphological co-adaptations.
An important requisite for attraction is conspicuousness to birds, which reflects the properties of avian vision and habitat features (Stiles 1981). Birds have their greatest spectral sensitivity and finest hue discrimination at the long wavelength end of the visual spectrum (Stiles 1981). This is why red is so conspicuous to birds. Hummingbirds may also be able to see ultraviolet “colors” (Stiles 1981). The prevalence of ultraviolet patterns and nectar guides in nectar-poor entomophilous flowers allows the bird to avoid these flowers on sight (Stiles 1981). Two subfamilies in the family Trochilidae are Phaethorninae and Trochlinae. Each of these groups has evolved in conjunction with a particular set of flowers. Most Phaethorninae species are associated with large monocotyledonous herbs, and members of the subfamily Trochilinae are associated with dicotyledonous plant species (Stiles 1981).
# Bibliography
- Michael Pollan The Botany of Desire: A Plant's-eye View of the World. Bloomsbury. ISBN 0-7475-6300-4. Account of the co-evolution of plants and humans
- Dawkins, R. Unweaving the Rainbow and other books.
- Geffeney, Shana L., et al. “Evolutionary diversification of TTX-resistant sodium channels in a predator-prey interaction”. Nature 434 (2005): 759–763.
- Brown, James., Brown, Astrid.1979. Convergence, Competition, and Mimicry in a Temperate Community of Hummingbird Pollinated Flowers. Ecology 60:1022-1035
- Stiles, Gary. 1981. Geographical Aspects of Bird Flower Coevolution, with Particular Reference to Central America. Annals of the Missouri Botanical Garden 68:323-351.
- Thierry Lodé "La guerre des sexes chez les animaux, une histoire naturelle de la sexualité. 2006, Eds Odile Jacob,Paris ISBN 2-7381-1901-8 | Co-evolution
In biology, co-evolution is the mutual evolutionary influence between two species.[citation needed] Each party in a co-evolutionary relationship exerts selective pressures on the other, thereby affecting each others' evolution. Co-evolution includes the evolution of a host species and its parasites, and examples of mutualism evolving through time. Evolution in response to abiotic factors, such as climate change, is not coevolution (since climate is not alive and does not undergo biological evolution). Evolution in a one-on-one interaction, such as that between predator and prey, host-symbiont or host-parasitic pair, is coevolution. But many cases are less clearcut: a species may evolve in response to a number of other species, each of which is also evolving in response to a set of species. This situation has been referred to as "diffuse coevolution". And, certainly, for many organisms, the biotic (living) environment is the most prominent selective pressure, resulting in evolutionary change.
Examples of co-evolution include pollination of Angraecoid orchids by African moths. These species co-evolve because the moths are dependent on the flowers for nectar and the flowers are dependent on the moths to spread their pollen so they can reproduce. The evolutionary process has led to deep flowers and moths with long probosci.
Co-evolution also occurs between predator and prey species as in the case of the Rough-skinned Newt (Taricha granulosa) and the common garter snake (Thamnophis sirtalis). In this case, the newts produce a potent nerve toxin that concentrates in their skin. Garter snakes have evolved resistance to this toxin through a set of genetic mutations, and prey upon the newts. The relationship between these animals has resulted in an evolutionary arms race that has driven toxin levels in the newt to extreme levels. Coevolution processes were modeling by Leigh Van Valen as the theory of the Red Queen. Emphasizing the importance of the sexual conflict, Thierry Lodé[1] privilegied the role of antagonist interactions (notably sexual) in evolution leading to an antagonist coevolution.
Co-evolution does not imply mutual dependence. The host of a parasite, or prey of a predator, does not depend on its enemy for survival.
The existence of mitochondria within eukaryote cells is an example of co-evolution as the mitochondria has a different DNA sequence than that of the nucleus in the host cell. This concept is described further by the Endosymbiotic theory.
Co-evolutionary algorithms are also a class of algorithms used for generating artificial life as well as for optimization, game learning and machine learning. Pioneering results in the use of co-evolutionary methods were by Daniel Hillis (who co-evolved sorting networks) and Karl Sims (who co-evolved virtual creatures).
In his book The Self-organizing Universe, Erich Jantsch attributed the entire evolution of the cosmos to co-evolution.
In astronomy, an emerging theory states that black holes and galaxies develop in an interdependent way analogous to biological co-evolution.[1]
# Specific examples
## Hummingbirds and ornithophilous flowers
Hummingbirds and ornithophilous flowers have evolved to form a mutualistic relationship. It is prevalent in the bird’s biology as well as in the flower’s. Hummingbird flowers have nectar chemistry associated with the bird’s diet. Their color and morphology also coincide with the bird’s vision and morphology. The blooming times of these ornithophilous flowers have also been found to coincide with hummingbirds' breeding seasons.
Flowers have converged to take advantage of similar birds (Brown et.al, 1979). Flowers compete for pollinators and adaptations reduce deleterious effects of this competition (Brown et al 1979). Bird-pollinated flowers usually show higher nectar volumes and sugar production (Stiles 1981). This reflects high energy requirements of the birds (Stiles 1981). Energetic criteria are the most important determinants of flower choice by birds (Stiles 1981). Following their respective breeding seasons, several species of hummingbirds co-occur in North America, and several hummingbird flowers bloom simultaneously in these habitats. These flowers seem to have converged to a common morphology and color (Stiles 1981). Different lengths and curvatures of the corolla tubes can affect the efficiency of extraction in hummingbird species in relation to differences in bill morphology (Stiles 1981). Tubular flowers force a bird to orient its bill in a particular way when probing the flower, especially when the bill and corolla are both curved; this also allows the plant to place pollen on a certain part of the bird’s body (Stiles 1981). This opens the door for a variety of morphological co-adaptations.
An important requisite for attraction is conspicuousness to birds, which reflects the properties of avian vision and habitat features (Stiles 1981). Birds have their greatest spectral sensitivity and finest hue discrimination at the long wavelength end of the visual spectrum (Stiles 1981). This is why red is so conspicuous to birds. Hummingbirds may also be able to see ultraviolet “colors” (Stiles 1981). The prevalence of ultraviolet patterns and nectar guides in nectar-poor entomophilous flowers allows the bird to avoid these flowers on sight (Stiles 1981). Two subfamilies in the family Trochilidae are Phaethorninae and Trochlinae. Each of these groups has evolved in conjunction with a particular set of flowers. Most Phaethorninae species are associated with large monocotyledonous herbs, and members of the subfamily Trochilinae are associated with dicotyledonous plant species (Stiles 1981).
# Bibliography
- Michael Pollan The Botany of Desire: A Plant's-eye View of the World. Bloomsbury. ISBN 0-7475-6300-4. Account of the co-evolution of plants and humans
- Dawkins, R. Unweaving the Rainbow and other books.
- Geffeney, Shana L., et al. “Evolutionary diversification of TTX-resistant sodium channels in a predator-prey interaction”. Nature 434 (2005): 759–763.
- Brown, James., Brown, Astrid.1979. Convergence, Competition, and Mimicry in a Temperate Community of Hummingbird Pollinated Flowers. Ecology 60:1022-1035
- Stiles, Gary. 1981. Geographical Aspects of Bird Flower Coevolution, with Particular Reference to Central America. Annals of the Missouri Botanical Garden 68:323-351.
- Thierry Lodé "La guerre des sexes chez les animaux, une histoire naturelle de la sexualité. 2006, Eds Odile Jacob,Paris ISBN 2-7381-1901-8 | https://www.wikidoc.org/index.php/Co-evolution | |
55bba0c6f3c6429d4b626c411f25c37db8096930 | wikidoc | Coenzyme Q10 | Coenzyme Q10
# Overview
Coenzyme Q10 (also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQ10, CoQ, Q10, or Q) is a benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the isoprenyl chemical subunits.
This vitamin-like substance is, by nature, present in most human cells except red blood cells and eye lens cells (no mitochondria) and are responsible for the production of the body’s own energy. In each human cell, food energy is converted into energy in the mitochondria with the aid of CoQ10. Ninety-five percent of all the human body’s energy requirements (ATP) is converted with the aid of CoQ10. Therefore, those organs with the highest energy requirements – such as the heart and the liver – have the highest CoQ10 concentrations.
# History
CoQ10 was first discovered by Crane et al. in 1957 within beef heart mitochondria. This vitamin-like nutrient has since been implicated in three major biological processes, imparting its alternate name of “ubiquinone”. Floating within the inner membrane of mitochrodria, CoQ10 plays an important role in oxidative phosphorylation where it is responsible for the two electron oxidation of NADH. Second, CoQ10 serves as a free radical scavenger that is the only lipid-soluble antioxidant that can be enzymatically regenerated to a reduced, active form. In this capacity it plays an important role in decreasing the amount of superoxide radical (O2-). This radical is produced by physiological stress, such as that caused by disease, and reacts rapidly with endothelial nitric oxide (NO) which is important for endothelial health and NO-mediated vasodilation. Lastly, CoQ10 has more recently been identified as a potent gene regulator, significantly impacting the expression of genes encoding proteins involved in cell signaling, intermediate metabolism, transport, transcriptional control, disease mutation, phosphorylation, embryonal development, and binding.
# Occurrence in nature
CoQ10 occurs in mackerel and herring fresh heart tissue in concentrations of 105-148 μg/g. In fresh mackerel "red and white tissue," CoQ10 concentrations of 67 and 15 μg/g, respectively, have been reported. In fresh herring tissue, an amount of 15–24 μg/g of CoQ10 has been reported.
CoQ10 Content of various foods:
# Chemical properties
The oxidized structure of CoQ is given here. The various kinds of CoQ can be distinguished by the number of isoprenoid side-chains they have. The most common CoQ in human mitochondria is CoQ10. The image to the right has three isoprenoid units and would be called Q3.
If CoQ is reduced by one equivalent, the following structure results, a ubisemiquinone, and is denoted QH. Note the free-radical on one of the ring oxygens (either oxygen may become a free-radical, in this case the top oxygen is shown as such).
If CoQ is reduced by two equivalents, the compound becomes a ubiquinol, denoted QH2:
# Biochemical role
CoQ is found in the membranes of endoplasmic reticulum, peroxisomes, lysosomes, vesicles, and the inner membrane of the mitochondrion, where it is an important part of the electron transport chain; there it passes reducing equivalents to acceptors such as Coenzyme Q: cytochrome c - oxidoreductase:
CoQ is also essential in the formation of the apoptosome, along with other adapter proteins. The loss of trophic factors activates pro-apoptotic enzymes, causing the breakdown of mitochondria.
# Biosynthesis
The benzoquinone portion of CoQ10 is synthesized from tyrosine, whereas the isoprene sidechain is synthesized from acetyl-CoA through the mevalonate pathway. The mevalonate pathway is used for the first steps of cholesterol biosynthesis.
# Supplementation
Because of its ability to transfer electrons and therefore act as an antioxidant, CoQ10 is also used as a dietary supplement. When you are younger the body can synthesize Q10 from the lower-numbered ubiquinones such as Q6 or Q8. The sick and elderly may not be able to make enough, thus Q10 becomes a vitamin later in life and in illness.
## Mitochondrial disorders
Supplementation of CoQ10 is a treatment for some of the very rare and serious mitochondrial disorders and other metabolic disorders, where patients are not capable of producing enough CoQ10 because of their disorder. CoQ10 is then prescribed by a physician.
# Cardiac and Vascular Disease
In 1970 Folkers et al. demonstrated that between 70-75% of patients with heart disease have low levels of CoQ10. The increasing severity of heart disease was correlated with progressively declining blood and myocardial tissue levels of CoQ10 in 1972. Though it is thought that normal CoQ10 serum levels can be maintained by doses of 30-60mg/day (per 1kg), clinical benefit may not actually be obtained until serum CoQ10 levels reach 2-4 times their normal level. In patients with cardiomyopathy and low levels of myocardial CoQ10, the addition of 100mg/day of oral CoQ10 over a 2-8 month period has been shown to increase myocardial CoQ10 levels between 20 and 85%. Though these studies have correlated a CoQ10 deficit with cardiovascular disease and demonstrate that CoQ10 serum and myocardial levels can be elevated with CoQ10 supplementation, the true efficacy of CoQ10 supplementation in cardiovascular disease remains unclear.
## Hypertension
A 2007 meta-analysis of all published trials of the use of CoQ10 in the treating hypertension acts as the most comprehensive and current assessment of the efficacy and consistency of its therapeutic effect as well the incidence of side effects. The analysis included 12 clinical trials, including three randomized controlled trials, one crossover study, and eight open label studies. Combined, the trials enrolled 326 patients, 120 as part of randomized trials and 214 as part of open label studies. Within the randomized controlled trials, the treatment groups experienced a significant average drop in systolic and diastolic blood pressure compared to control groups (16.6 mm Hg and 8.2 mm Hg decrease, respectively; P<0.001). During the treatment phase of the lone 18 patient cross-over study systolic and diastolic pressures were on average also significantly decreased (11 mm Hg and 8 mm Hg decrease, respectively; P<0.001). Likewise, the weighted mean systolic and diastolic blood pressures of patients enrolled in open label observational studies were significantly lower after patients began taking CoQ10 (13.5 mm Hg and 10.3 mm Hg decrease, respectively, P<0.001). Overall, CoQ10 treatment resulted in systolic blood pressure decreases between 11 and 17 mm Hg and diastolic blood pressure decreases between 8 and 10 mm Hg. Among all the studies CoQ10 treatment produced minimal side effects, the most common being gastrointestinal effects.
The most likely physiological explanation for the the hypotensive effect of CoQ10 observed in this meta-analysis is oxidative stress relief. CoQ10 indirectly increases the amount of free NO by neutralizing destructive free radicals. Indeed, this explanation supports the finding that CoQ10 does not have a hypotensive or vasodilating effect in patients who are healthy and do not have NO activity suppressed by oxidative stress.
## Coronary Artery Disease
CoQ10 treatment has also proven beneficial in the treatment of coronary artery disease (CAD). A placebo-controlled study of 19 patients with CAD was conducted to evaluate the effect of 100 mg CoQ10 tid for one month on vascular function as evaluated by extracellular superoxide dismutase (ecSOD) activity and brachial artery vasomotility measured by flow-dependent endothelial-mediated dilation (FMD). A secondary endpoint was to determine the effect of CoQ10 on the cardiopulmonary test. A four-fold increase in serum CoQ10 levels was reported within the treatment group and was significantly correlated with endothelium-dependent (ED) relaxation. ecSOD activation, peak VO2, and O2 pulse increases were also significantly greater in the treatment group compared to the placebo group. The effect of CoQ10 treatment was greatest on patients with the lowest levels of ecSOD and hence most vulnerable to oxidative stress.
ecSOD is an enzyme highly expressed in the heart that has been examined for its role in several diseases, including vascular-related diseases such as CAD. These results build upon and confirm a 2000 study demonstrating that ecSOD activity is substantially reduced in patients with CAD and that endothelium-bound ecSOD activity level strongly correlates with endothelial-mediated dilation (FMD), a biomarker of vascular function. It it also known that NO can induce ecSOD expression. Therefore, likely physiological explanation for the benefit of CoQ10 for vascular health in CAD stems in part from the ability of CoQ10 to relieve oxidative stress on NO, resulting increased ecSOD activity. The effect of CoQ10 on peak VO2 and O2 pulse is most likely attributable to its bioenergetic properties.
## Congestive Heart Failure
Slides about the role of mitochondria in heart failure: File:Mitochondrial Dysfunction and CHF for wikidoc.pdf
CoQ10 levels are decreased in the setting of heart failure (HF), and progressive heart failure leads to lower and lower levels of CoQ10. There have been modest sized double blind randomized controlled trials that have demonstrated CoQ10 is associated with improved symptoms, functional capacity and quality of life in patients with heart failure. The drug is generally well tolerated, with few side effects.
Congestive heart failure (CHF) is the third most common cause of cardiovascular disease, the leading cause of morbidity and mortality in the U.S. and around the world. A 2006 double-blind, placebo-controlled cross-over design study of 23 patients divided into three groups treated with a differing orders and combinations of exercise, 100 mg tid CoQ10, and placebo demonstrated that both peak VO2 and endothelium-dependent dilation of the brachial artery (EDDBA) improved significantly after CoQ10 and after exercise treatment. As in other studies, CoQ10 supplementation resulted in a four-fold increase in plasma CoQ10 levels. This study showed additionally that exercise further increased plasma CoQ10 levels. While CoQ10 demonstrated a main effect on peak V02 (+ 9%), EDDBA (+38%), and the systolic wall thickening score index (SWTI) (-12%), exercise was also demonstrated to have comparable effects. While the combination of CoQ10 supplementation and exercise resulted in the greatest benefit in these categories, the only significant synergistic effect observed between the two treatments was for peak SWTI.
A 2013 meta-analysis serves as the most recent and comprehensive review of the effects of CoQ10 supplementation on HF, specifically its impact on the ejection fraction (EF) and New York Heart Association (NYHA) functional classification in patients with CHF. The study found 120 potentially relevant studies during a literature review and selected 13 for the analysis, of which 7 were crossover and 6 were parallel-arm studies, with 12 double-blinded studies and 1 single-blind study. The enrollment of the analyzed studies was 395. A confounder in the analysis was the wide range in study duration (4 to 28 weeks) and variable CoQ10 daily dosing (60 to 300mg). Supplementation with CoQ10 resulted in a pooled mean net change of 3.67% (95% CI: 1.60%, 5.74%) in the EF and a 0.30 decrease (95% CI: -0.66, 0.06) in the NYHA functional class. Significant improvement in EF was seen in crossover trials, trials twelve weeks long or longer, studies published before 1994, studies with a daily CoQ10 dose >=100 mg, and in patients with less severe CHF. The study cautiously suggests that CoQ10 supplementation may improve EF in patients with CHF.
In a modest sized, multicenter, double blind,randomized controlled trial, 420 patients with New York Heart Association (NYHA) Class III or IV heart failure who were receiving standard therapy, were randomized to either CoQ10 or placebo. The patients were followed for two years. . The primary endpoint (MACE=unplanned hospitalization due to worsening of heart failure, cardiovascular death, urgent cardiac transplantation and mechanical circulatory support) was reduced from 29 events (14%) in patients randomized to CoQ10 compared to 55 (25%) in patients randomized to placebo (hazard ratio=2; p=0.003 by time to event analysis). Randomization to CoQ10 was associated with a halving of all cause mortality: there were 18 (9%) deaths among patients in the CoQ10 group versus 36 (17%) deaths among patients in the placebo group (hazard ratio=2.1; p=0.01). Cardiovascular mortality was also reduced (p-0.02) as was the risk of rehospitalisations for heart failure (p=0.05). There tended to be fewer adverse events among patients randomized to CoQ10 compared to the placebo (p=0.073). It is unclear if there were greater benefits among patients treated with statins, drugs that lower CoQ10.
## Treatment of Statin Intolerance
CoQ10 shares a common biosynthetic pathway with cholesterol. The synthesis of an intermediary precursor of CoQ10, mevalonate, is inhibited by some beta blockers, blood pressure-lowering medication, and statins, a class of cholesterol-lowering drugs. Statins can reduce serum levels of CoQ10 by up to 40%. Some research suggests the logical option of supplementation with CoQ10 as a routine adjunct to any treatment that may reduce endogenous production of CoQ10, based on a balance of likely benefit against very small risk.
## Cardiac arrest
Another recent study shows a survival benefit after cardiac arrest if CoQ10 is administered in addition to commencing active cooling (to 32–34 degrees Celsius).
## Migraine headaches
Supplementation of CoQ10 has been found to have a beneficial effect on the condition of some sufferers of migraine headaches. So far, three studies have been done, of which two were small, did not have a placebo group, were not randomized, and were open-label, and one was a double-blind, randomized, placebo-controlled trial, which found statistically significant results despite its small sample size of 42 patients. Dosages were 150 to 300 mg/day.
# Cancer
It is also being investigated as a treatment for cancer, and as relief from cancer treatment side-effects.
# Brain health and neurodegenerative diseases
Recent studies have shown that the antioxidant properties of CoQ10 benefit the body and the brain in animal models. Some of these studies indicate that CoQ10 protects the brain from neurodegenerative disease such as Parkinson's, although it does not relieve the symptoms. Dosage was 300 mg per day.
# Lifespan
Studies have shown that low dosages of CoQ10 reduce oxidation and DNA double-strand breaks, and a combination of a diet rich in polyunsaturated fatty acids and CoQ10supplementation leads to a longer lifespan in rats
# See Also
- Idebenone - synthetic analog with reduced oxidant generating properties | Coenzyme Q10
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Coenzyme Q10 (also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQ10, CoQ, Q10, or Q) is a benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the isoprenyl chemical subunits.
This vitamin-like substance is, by nature, present in most human cells except red blood cells and eye lens cells (no mitochondria) and are responsible for the production of the body’s own energy. In each human cell, food energy is converted into energy in the mitochondria with the aid of CoQ10. Ninety-five percent of all the human body’s energy requirements (ATP) is converted with the aid of CoQ10.[1][2] Therefore, those organs with the highest energy requirements – such as the heart and the liver – have the highest CoQ10 concentrations.[3][4][5]
# History
CoQ10 was first discovered by Crane et al. in 1957 within beef heart mitochondria.[6] This vitamin-like nutrient has since been implicated in three major biological processes, imparting its alternate name of “ubiquinone”. Floating within the inner membrane of mitochrodria, CoQ10 plays an important role in oxidative phosphorylation where it is responsible for the two electron oxidation of NADH.[7][8] Second, CoQ10 serves as a free radical scavenger that is the only lipid-soluble antioxidant that can be enzymatically regenerated to a reduced, active form.[9][10][11] In this capacity it plays an important role in decreasing the amount of superoxide radical (O2-). This radical is produced by physiological stress, such as that caused by disease, and reacts rapidly with endothelial nitric oxide (NO) which is important for endothelial health and NO-mediated vasodilation. Lastly, CoQ10 has more recently been identified as a potent gene regulator, significantly impacting the expression of genes encoding proteins involved in cell signaling, intermediate metabolism, transport, transcriptional control, disease mutation, phosphorylation, embryonal development, and binding.[12]
# Occurrence in nature
CoQ10 occurs in mackerel and herring fresh heart tissue in concentrations of 105-148 μg/g. In fresh mackerel "red and white tissue," CoQ10 concentrations of 67 and 15 μg/g, respectively, have been reported. In fresh herring tissue, an amount of 15–24 μg/g of CoQ10 has been reported.[13]
CoQ10 Content of various foods:[14]
# Chemical properties
The oxidized structure of CoQ is given here. The various kinds of CoQ can be distinguished by the number of isoprenoid side-chains they have. The most common CoQ in human mitochondria is CoQ10. The image to the right has three isoprenoid units and would be called Q3.
If CoQ is reduced by one equivalent, the following structure results, a ubisemiquinone, and is denoted QH. Note the free-radical on one of the ring oxygens (either oxygen may become a free-radical, in this case the top oxygen is shown as such).
If CoQ is reduced by two equivalents, the compound becomes a ubiquinol, denoted QH2:
# Biochemical role
CoQ is found in the membranes of endoplasmic reticulum, peroxisomes, lysosomes, vesicles, and the inner membrane of the mitochondrion, where it is an important part of the electron transport chain; there it passes reducing equivalents to acceptors such as Coenzyme Q: cytochrome c - oxidoreductase:
CoQ is also essential in the formation of the apoptosome, along with other adapter proteins. The loss of trophic factors activates pro-apoptotic enzymes, causing the breakdown of mitochondria.
# Biosynthesis
The benzoquinone portion of CoQ10 is synthesized from tyrosine, whereas the isoprene sidechain is synthesized from acetyl-CoA through the mevalonate pathway. The mevalonate pathway is used for the first steps of cholesterol biosynthesis.
# Supplementation
Because of its ability to transfer electrons and therefore act as an antioxidant, CoQ10 is also used as a dietary supplement. When you are younger the body can synthesize Q10 from the lower-numbered ubiquinones such as Q6 or Q8. The sick and elderly may not be able to make enough, thus Q10 becomes a vitamin later in life and in illness.
## Mitochondrial disorders
Supplementation of CoQ10 is a treatment for some of the very rare and serious mitochondrial disorders and other metabolic disorders, where patients are not capable of producing enough CoQ10 because of their disorder. CoQ10 is then prescribed by a physician.[15]
# Cardiac and Vascular Disease
In 1970 Folkers et al. demonstrated that between 70-75% of patients with heart disease have low levels of CoQ10.[16] The increasing severity of heart disease was correlated with progressively declining blood and myocardial tissue levels of CoQ10 in 1972.[17] Though it is thought that normal CoQ10 serum levels can be maintained by doses of 30-60mg/day (per 1kg), clinical benefit may not actually be obtained until serum CoQ10 levels reach 2-4 times their normal level. In patients with cardiomyopathy and low levels of myocardial CoQ10, the addition of 100mg/day of oral CoQ10 over a 2-8 month period has been shown to increase myocardial CoQ10 levels between 20 and 85%.[18] Though these studies have correlated a CoQ10 deficit with cardiovascular disease and demonstrate that CoQ10 serum and myocardial levels can be elevated with CoQ10 supplementation, the true efficacy of CoQ10 supplementation in cardiovascular disease remains unclear.
## Hypertension
A 2007 meta-analysis of all published trials of the use of CoQ10 in the treating hypertension acts as the most comprehensive and current assessment of the efficacy and consistency of its therapeutic effect as well the incidence of side effects.[19] The analysis included 12 clinical trials, including three randomized controlled trials, one crossover study, and eight open label studies. Combined, the trials enrolled 326 patients, 120 as part of randomized trials and 214 as part of open label studies. Within the randomized controlled trials, the treatment groups experienced a significant average drop in systolic and diastolic blood pressure compared to control groups (16.6 mm Hg and 8.2 mm Hg decrease, respectively; P<0.001). During the treatment phase of the lone 18 patient cross-over study systolic and diastolic pressures were on average also significantly decreased (11 mm Hg and 8 mm Hg decrease, respectively; P<0.001). Likewise, the weighted mean systolic and diastolic blood pressures of patients enrolled in open label observational studies were significantly lower after patients began taking CoQ10 (13.5 mm Hg and 10.3 mm Hg decrease, respectively, P<0.001). Overall, CoQ10 treatment resulted in systolic blood pressure decreases between 11 and 17 mm Hg and diastolic blood pressure decreases between 8 and 10 mm Hg. Among all the studies CoQ10 treatment produced minimal side effects, the most common being gastrointestinal effects.
The most likely physiological explanation for the the hypotensive effect of CoQ10 observed in this meta-analysis is oxidative stress relief. CoQ10 indirectly increases the amount of free NO by neutralizing destructive free radicals. Indeed, this explanation supports the finding that CoQ10 does not have a hypotensive or vasodilating effect in patients who are healthy and do not have NO activity suppressed by oxidative stress.
## Coronary Artery Disease
CoQ10 treatment has also proven beneficial in the treatment of coronary artery disease (CAD). A placebo-controlled study of 19 patients with CAD was conducted to evaluate the effect of 100 mg CoQ10 tid for one month on vascular function as evaluated by extracellular superoxide dismutase (ecSOD) activity and brachial artery vasomotility measured by flow-dependent endothelial-mediated dilation (FMD). A secondary endpoint was to determine the effect of CoQ10 on the cardiopulmonary test.[20] A four-fold increase in serum CoQ10 levels was reported within the treatment group and was significantly correlated with endothelium-dependent (ED) relaxation. ecSOD activation, peak VO2, and O2 pulse increases were also significantly greater in the treatment group compared to the placebo group. The effect of CoQ10 treatment was greatest on patients with the lowest levels of ecSOD and hence most vulnerable to oxidative stress.
ecSOD is an enzyme highly expressed in the heart that has been examined for its role in several diseases, including vascular-related diseases such as CAD. These results build upon and confirm a 2000 study demonstrating that ecSOD activity is substantially reduced in patients with CAD and that endothelium-bound ecSOD activity level strongly correlates with endothelial-mediated dilation (FMD), a biomarker of vascular function.[21] It it also known that NO can induce ecSOD expression. Therefore, likely physiological explanation for the benefit of CoQ10 for vascular health in CAD stems in part from the ability of CoQ10 to relieve oxidative stress on NO, resulting increased ecSOD activity. The effect of CoQ10 on peak VO2 and O2 pulse is most likely attributable to its bioenergetic properties.
## Congestive Heart Failure
Slides about the role of mitochondria in heart failure: File:Mitochondrial Dysfunction and CHF for wikidoc.pdf
CoQ10 levels are decreased in the setting of heart failure (HF), and progressive heart failure leads to lower and lower levels of CoQ10. There have been modest sized double blind randomized controlled trials that have demonstrated CoQ10 is associated with improved symptoms, functional capacity and quality of life in patients with heart failure. The drug is generally well tolerated, with few side effects.
Congestive heart failure (CHF) is the third most common cause of cardiovascular disease, the leading cause of morbidity and mortality in the U.S. and around the world.[22] A 2006 double-blind, placebo-controlled cross-over design study of 23 patients divided into three groups treated with a differing orders and combinations of exercise, 100 mg tid CoQ10, and placebo demonstrated that both peak VO2 and endothelium-dependent dilation of the brachial artery (EDDBA) improved significantly after CoQ10 and after exercise treatment.[23] As in other studies, CoQ10 supplementation resulted in a four-fold increase in plasma CoQ10 levels. This study showed additionally that exercise further increased plasma CoQ10 levels. While CoQ10 demonstrated a main effect on peak V02 (+ 9%), EDDBA (+38%), and the systolic wall thickening score index (SWTI) (-12%), exercise was also demonstrated to have comparable effects. While the combination of CoQ10 supplementation and exercise resulted in the greatest benefit in these categories, the only significant synergistic effect observed between the two treatments was for peak SWTI.
A 2013 meta-analysis serves as the most recent and comprehensive review of the effects of CoQ10 supplementation on HF, specifically its impact on the ejection fraction (EF) and New York Heart Association (NYHA) functional classification in patients with CHF.[24] The study found 120 potentially relevant studies during a literature review and selected 13 for the analysis, of which 7 were crossover and 6 were parallel-arm studies, with 12 double-blinded studies and 1 single-blind study. The enrollment of the analyzed studies was 395. A confounder in the analysis was the wide range in study duration (4 to 28 weeks) and variable CoQ10 daily dosing (60 to 300mg). Supplementation with CoQ10 resulted in a pooled mean net change of 3.67% (95% CI: 1.60%, 5.74%) in the EF and a 0.30 decrease (95% CI: -0.66, 0.06) in the NYHA functional class. Significant improvement in EF was seen in crossover trials, trials twelve weeks long or longer, studies published before 1994, studies with a daily CoQ10 dose >=100 mg, and in patients with less severe CHF. The study cautiously suggests that CoQ10 supplementation may improve EF in patients with CHF.
In a modest sized, multicenter, double blind,randomized controlled trial, 420 patients with New York Heart Association (NYHA) Class III or IV heart failure who were receiving standard therapy, were randomized to either CoQ10 or placebo. The patients were followed for two years. [25]. The primary endpoint (MACE=unplanned hospitalization due to worsening of heart failure, cardiovascular death, urgent cardiac transplantation and mechanical circulatory support) was reduced from 29 events (14%) in patients randomized to CoQ10 compared to 55 (25%) in patients randomized to placebo (hazard ratio=2; p=0.003 by time to event analysis). Randomization to CoQ10 was associated with a halving of all cause mortality: there were 18 (9%) deaths among patients in the CoQ10 group versus 36 (17%) deaths among patients in the placebo group (hazard ratio=2.1; p=0.01). Cardiovascular mortality was also reduced (p-0.02) as was the risk of rehospitalisations for heart failure (p=0.05). There tended to be fewer adverse events among patients randomized to CoQ10 compared to the placebo (p=0.073). It is unclear if there were greater benefits among patients treated with statins, drugs that lower CoQ10.
## Treatment of Statin Intolerance
CoQ10 shares a common biosynthetic pathway with cholesterol. The synthesis of an intermediary precursor of CoQ10, mevalonate, is inhibited by some beta blockers, blood pressure-lowering medication,[26] and statins, a class of cholesterol-lowering drugs.[27] Statins can reduce serum levels of CoQ10 by up to 40%.[28] Some research suggests the logical option of supplementation with CoQ10 as a routine adjunct to any treatment that may reduce endogenous production of CoQ10, based on a balance of likely benefit against very small risk.[29][30]
## Cardiac arrest
Another recent study shows a survival benefit after cardiac arrest if CoQ10 is administered in addition to commencing active cooling (to 32–34 degrees Celsius).[31]
## Migraine headaches
Supplementation of CoQ10 has been found to have a beneficial effect on the condition of some sufferers of migraine headaches. So far, three studies have been done, of which two were small, did not have a placebo group, were not randomized, and were open-label,[32] and one was a double-blind, randomized, placebo-controlled trial, which found statistically significant results despite its small sample size of 42 patients.[33] Dosages were 150 to 300 mg/day.
# Cancer
It is also being investigated as a treatment for cancer, and as relief from cancer treatment side-effects.[34]
# Brain health and neurodegenerative diseases
Recent studies have shown that the antioxidant properties of CoQ10 benefit the body and the brain in animal models.[35] Some of these studies indicate that CoQ10 protects the brain from neurodegenerative disease such as Parkinson's,[36] although it does not relieve the symptoms.[37] Dosage was 300 mg per day.
# Lifespan
Studies have shown that low dosages of CoQ10 reduce oxidation and DNA double-strand breaks, and a combination of a diet rich in polyunsaturated fatty acids and CoQ10supplementation leads to a longer lifespan in rats[38]
# See Also
- Idebenone - synthetic analog with reduced oxidant generating properties
# External links
- A User-Friendly Summary of CoQ10
- An Introduction to Coenzyme Q10 at University of Washington
- Possible Health Benefits of Coenzyme Q10 at Oregon State University
- Study Suggests Coenzyme Q10 Slows Functional Decline in Parkinson's Disease at National Institute of Neurological Disorders and Stroke | https://www.wikidoc.org/index.php/CoQ10 | |
fdf1e7f01ed3bb327b3240e766fabd4b4d35a6ea | wikidoc | Spinal nerve | Spinal nerve
The term spinal nerve generally refers to the mixed spinal nerve, which is formed from the dorsal and ventral roots that come out of the spinal cord. The spinal nerve is the bit that passes out of the vertebrae through the intervertebral foramen. All spinal nerves are part of the peripheral nervous system (PNS).
# Numbering
There are a total of 31 bilaterally-paired spinal nerves :
- 8 cervical nerves (C1-C8)
- 12 thoracic nerves (T1-T12)
- 5 lumbar nerves (L1-L5)
- 5 sacral nerves (S1-S5)
- 1 coccygeal nerve (Co)
The first to seventh cervical nerves (C1 to C7) exit from the vertebral canal above the respective cervical vertebra (that is to say, C1 exits above the first cervical vertebra; C2 exits above the second, and so forth). The C8 spinal nerve exits below the seventh cervical vertebra, and all the other spinal nerves leave below their corresponding vertebra.
# Formation of the spinal nerves
Inside the spinal cord, there is grey matter, surrounded by white matter. From out of the grey matter, two dorsal roots (one on the left side, and one on the right side) and two ventral roots emerge. (Dorsal means back, ventral means front.) As the body is symmetrical, the same thing happens on both the left and right side of the body. This happens in each vertebra of the spine.
- The dorsal roots contain afferent sensory axons, and the ventral roots contain efferent motor axons. The dorsal roots of each side continue outwards, along the way forming a dorsal root ganglion (also called a spinal ganglion).
- The ventral roots similarly continue out from the spinal column, and meet and mix with their corresponding dorsal nerve root at a point after the ganglion.
At this point, the combination of the dorsal roots and ventral roots is called a mixed spinal nerve.
# Fate of the spinal nerve
After the dorsal and ventral roots fuse to form a spinal nerve, the nerve bifurcates into dorsal and ventral primary rami. Each primary ramus has two branches.
## Dorsal
- The dorsal primary ramus supplies the muscles and sensory nerves of the back.
The two main branches are a lateral and medial branch.
## Ventral
- The ventral primary ramus supplies the rest of the body wall.
The two main branches are an anterior and lateral cutaneous branch. In addition, the anterior cutaneous bifurcates, forming a medial and lateral branch, while the lateral cutaneous branch splits into an anterior and posterior branch. These secondary and tertiary branches themselves typically have muscular and sensory branches that innervate the body wall.
The ventral primary rami also give rise to the roots of the various nervous plexuses (e.g. the brachial plexus), which become the sensory and motor nerves of the limbs.
Before forming the plexuses, the ventral rami have two branches leading to a sympathetic ganglion. These ganglia connect to the one above and below them, forming the sympathetic chain.
# Importance of the spinal nerves
The muscles that one particular spinal root supplies are that nerve's myotome, and the dermatomes are the areas of sensory innervation on the skin for each spinal nerve.
This is of great importance in the diagnosis of neurological disorders, as lesions of one or more nerve roots result in typical patterns of neurologic defects (muscle weakness, loss of sensation) that allow localisation of the causating lesion.
# Additional images
- Cervical vertebra
- A portion of the spinal cord, showing its right lateral surface. The dura is opened and arranged to show the nerve roots.
- Distribution of cutaneous nerves. Ventral aspect.
- Distribution of cutaneous nerves. Dorsal aspect.
- The mechanism of the reflex arc | Spinal nerve
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Infobox Nerve
The term spinal nerve generally refers to the mixed spinal nerve, which is formed from the dorsal and ventral roots that come out of the spinal cord. The spinal nerve is the bit that passes out of the vertebrae through the intervertebral foramen. All spinal nerves are part of the peripheral nervous system (PNS).
# Numbering
There are a total of 31 bilaterally-paired spinal nerves :
- 8 cervical nerves (C1-C8)
- 12 thoracic nerves (T1-T12)
- 5 lumbar nerves (L1-L5)
- 5 sacral nerves (S1-S5)
- 1 coccygeal nerve (Co)
The first to seventh cervical nerves (C1 to C7) exit from the vertebral canal above the respective cervical vertebra (that is to say, C1 exits above the first cervical vertebra; C2 exits above the second, and so forth). The C8 spinal nerve exits below the seventh cervical vertebra, and all the other spinal nerves leave below their corresponding vertebra.
# Formation of the spinal nerves
Inside the spinal cord, there is grey matter, surrounded by white matter. From out of the grey matter, two dorsal roots (one on the left side, and one on the right side) and two ventral roots emerge. (Dorsal means back, ventral means front.) As the body is symmetrical, the same thing happens on both the left and right side of the body. This happens in each vertebra of the spine.
- The dorsal roots contain afferent sensory axons, and the ventral roots contain efferent motor axons. The dorsal roots of each side continue outwards, along the way forming a dorsal root ganglion (also called a spinal ganglion).
- The ventral roots similarly continue out from the spinal column, and meet and mix with their corresponding dorsal nerve root at a point after the ganglion.
At this point, the combination of the dorsal roots and ventral roots is called a mixed spinal nerve.
# Fate of the spinal nerve
After the dorsal and ventral roots fuse to form a spinal nerve, the nerve bifurcates into dorsal and ventral primary rami. Each primary ramus has two branches.
## Dorsal
- The dorsal primary ramus supplies the muscles and sensory nerves of the back.
The two main branches are a lateral and medial branch.
## Ventral
- The ventral primary ramus supplies the rest of the body wall.
The two main branches are an anterior and lateral cutaneous branch. In addition, the anterior cutaneous bifurcates, forming a medial and lateral branch, while the lateral cutaneous branch splits into an anterior and posterior branch. These secondary and tertiary branches themselves typically have muscular and sensory branches that innervate the body wall.
The ventral primary rami also give rise to the roots of the various nervous plexuses (e.g. the brachial plexus), which become the sensory and motor nerves of the limbs.
Before forming the plexuses, the ventral rami have two branches leading to a sympathetic ganglion. These ganglia connect to the one above and below them, forming the sympathetic chain.
# Importance of the spinal nerves
The muscles that one particular spinal root supplies are that nerve's myotome, and the dermatomes are the areas of sensory innervation on the skin for each spinal nerve.
This is of great importance in the diagnosis of neurological disorders, as lesions of one or more nerve roots result in typical patterns of neurologic defects (muscle weakness, loss of sensation) that allow localisation of the causating lesion.
# Additional images
- Cervical vertebra
- A portion of the spinal cord, showing its right lateral surface. The dura is opened and arranged to show the nerve roots.
- Distribution of cutaneous nerves. Ventral aspect.
- Distribution of cutaneous nerves. Dorsal aspect.
- The mechanism of the reflex arc
# External links
- Template:EMedicineDictionary
Template:Spinal nerves
Template:Spinal cord
Template:Vertebral column and spinal cord
de:Spinalnerv
hr:Moždinski živci
it:Nervo spinale
no:Spinalnerve
fi:Selkäydinhermo
sv:Ryggmärgsnerv
te:కశేరు నాడులు
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Coccygeal_nerves | |
78159dd519ef07eac9a57c904d360fe1ccb01308 | wikidoc | Cocoa butter | Cocoa butter
Cocoa butter, also called theobroma oil, is the pale-yellow, pure edible vegetable fat of the cacao bean. It is the substance used to make solid chocolate bars. It is mixed with varying amounts of cocoa powder to produce solid pieces of chocolate. Cocoa butter is extracted from the cacao beans and can be used to make chocolate, cocoa powder, pharmaceuticals, ointments, and toiletries. Cocoa butter has a mild chocolate flavor and aroma.
# Creation
During processing of the cacao bean, cocoa solids and cocoa butter are separated out at an early stage. The two are recombined in the manufacture of regular (brown) chocolate bars. The confection known as white chocolate contains cocoa butter but not cocoa powder.
# Uses
Because of the melting temperature of cocoa butter, it is often used in pharmaceuticals as a base for suppositories. It is able to be stored at room temperature, but readily melts at body temperature, releasing the medication.
Cocoa butter is one of the most stable fats known, containing natural antioxidants that prevent rancidity and give it a storage life of two to five years, making it a good choice for non-food products. The smooth texture, sweet fragrance and emollient property of cocoa butter make it a popular ingredient in cosmetics and skin care products, such as soaps and lotions.
# Chemical properties
The most common form of Cocoa butter has a melting point of around 34 to 38 degres Celsius (93 to 100 degrees Fahrenheit), rendering chocolate a solid at room temperature that readily melts once inside the mouth. Cocoa butter displays polymorphism, having α, γ, β', and β crystals, with melting points of 17, 23, 26, and 35–37 °C respectively. The production of chocolate typically uses only the β crystal for its high melting point. A uniform crystal structure will result in smooth texture, sheen, and snap. Overheating cocoa butter converts the structure to a less stable form that melts below room temperature. Given time, it will naturally return to the most stable β crystal form. | Cocoa butter
Cocoa butter, also called theobroma oil, is the pale-yellow, pure edible vegetable fat of the cacao bean. It is the substance used to make solid chocolate bars. It is mixed with varying amounts of cocoa powder to produce solid pieces of chocolate. Cocoa butter is extracted from the cacao beans and can be used to make chocolate, cocoa powder, pharmaceuticals, ointments, and toiletries.[1] Cocoa butter has a mild chocolate flavor and aroma.
# Creation
During processing of the cacao bean, cocoa solids and cocoa butter are separated out at an early stage. The two are recombined in the manufacture of regular (brown) chocolate bars. The confection known as white chocolate contains cocoa butter but not cocoa powder.
# Uses
Because of the melting temperature of cocoa butter, it is often used in pharmaceuticals as a base for suppositories. It is able to be stored at room temperature, but readily melts at body temperature, releasing the medication.
Cocoa butter is one of the most stable fats known, containing natural antioxidants that prevent rancidity and give it a storage life of two to five years, making it a good choice for non-food products. The smooth texture, sweet fragrance and emollient property of cocoa butter make it a popular ingredient in cosmetics and skin care products, such as soaps and lotions.
# Chemical properties
The most common form of Cocoa butter has a melting point of around 34 to 38 degres Celsius (93 to 100 degrees Fahrenheit), rendering chocolate a solid at room temperature that readily melts once inside the mouth. Cocoa butter displays polymorphism, having α, γ, β', and β crystals, with melting points of 17, 23, 26, and 35–37 °C respectively. The production of chocolate typically uses only the β crystal for its high melting point. A uniform crystal structure will result in smooth texture, sheen, and snap. Overheating cocoa butter converts the structure to a less stable form that melts below room temperature. Given time, it will naturally return to the most stable β crystal form. | https://www.wikidoc.org/index.php/Cocoa_butter | |
aa55d65d646ebd2a1ce39962508205ecf5fa08cf | wikidoc | Coconut milk | Coconut milk
Coconut milk is a sweet, milky white cooking base derived from the meat of a mature coconut. The color and rich taste of the milk can be attributed to the high oil content and sugars. In Malaysia, Brunei and Indonesia coconut milk is called santan and in the Philippines it is called gata. It should not be confused with coconut water (coconut juice), which is the naturally-occurring liquid found inside a coconut.
# Preparation
Two grades of coconut milk exist: thick and thin. Thick coconut milk is prepared by directly squeezing grated coconut meat through cheesecloth. The squeezed coconut meat is then soaked in warm water and squeezed a second or third time for thin coconut milk. Thick milk is used mainly to make desserts and rich, dry sauces. Thin milk is used for soups and general cooking. This distinction is usually not made in western nations since fresh coconut milk is usually not produced, and most consumers buy coconut milk in cans. Manufacturers of canned coconut milk typically combine the thin and thick squeezes, with the addition of water as a filler.
Depending on the brand and age of the milk itself, a thicker, more paste-like consistency floats to the top of the can, and is sometimes separated and used in recipes that require coconut cream rather than coconut milk. Shaking the can prior to opening will even it out to a cream-like thickness.
Once opened, cans of coconut milk must be refrigerated, and are usually only good for a few days. Coconut milk should never be left at room temperature, as the milk can sour and spoil easily.
You can make your own coconut milk by processing grated coconut with hot water or milk, which extracts the oil and aromatic compounds. It should not be confused with the coconut water discussed above, and has a fat content of approximately 17%. When refrigerated and left to set, coconut cream will rise to the top and separate out the milk.
# Cooking
Coconut milk is a common ingredient in many tropical cuisines, most notably that of Southeast Asia (especially Filipino, Indonesian, Burmese, Cambodia, Malaysian, and Singaporean, Sri Lankan and Thai), West African, Caribbean, and Polynesian cuisines. Coconut milk can usually be found in the Asian food sections of supermarkets either frozen or canned. Frozen coconut milk tends to stay fresh longer, which is important in dishes where the coconut flavor is not competing with curries and other spicy dishes.
Coconut milk is the base of most Thai curries. To make the curry sauce, the coconut milk is first cooked over fairly high heat to break down the milk and cream and allow the oil to separate. The curry paste is then added, as well as any other seasonings, meats, vegetables and garnishes.
# Medicinal properties
The monolaurins in the coconut oil have been found to be very powerful antibacterial, antiviral, and antifungal agents. Some people believe that coconut milk can be used as a laxative.
# Dishes
## Chinese
- Various sweet dim sum dishes
- Various sweet soups (tong sui)
## Thai
- Red curry
- Green curry
- Massaman curry
- Tom kha gai
- Satay
- Sweet sticky rice
- Tapioca pudding
- Ice Cream
- Coconut pudding
- Thai Shaved Ice or Nam Kang Sai, known as snow cone in the US. Another name is 'Wan-Yen'. In Thailand, this kind of cold dessert is very popular as well. The differences from other countries' shaved ice is that in the Thai version the toppings (mixings) are in the bottom and the shaved ice is on top. There are between 20-30 varieties of mixings that can be mixed in. Among them are young coconut that have been soaked in coconut milk, black sticky rice, chestnuts,sweetened taro, red beans, cheng-sim-ee (special flour that is very chewy and slippery) and many more.
## Malaysian
- Laksa
- Nasi lemak
- Rendang
## Indonesian
- Rendang
- Opor ayam
- Nasi liwet
- Nasi Uduk
## Sri Lankan
- Spicy chicken curry
- Spicy beef curry
- Spicy and non-spicy fish curry
- Dhal curry
- Potato curry
- Tomato sambol
- Green bean curry
- Coconut milk (Pol kiri) - a dish in itself, usually used for gravy with Pittu
- Milk gravy (Kiri hodi) - Coconut milk with a dash of saffron and onion, usually used for gravy with String-hoppers
## West Indian
- Rice and peas
- Callaloo
## Hawaiian
- Haupia (a gelatin-like pudding flavored with coconut milk)
- Kulolo
- Lu'au (taro leaves simmered in coconut milk)
## Indian (Kerala)
- Gothampu Payasam (Wheat Payasam)
## Filipino
- Adobo sa Gata (Meat sauteed in soy sauce, garlic, and pepper, thickened with coconut milk)
- Ginata (Various entrees or desserts simmered in coconut milk)
Ginataang Bilo Bilo (Rice dumpling dessert)
Ginataang Tilapia (White fish in creamy coconut)
- Ginataang Bilo Bilo (Rice dumpling dessert)
- Ginataang Tilapia (White fish in creamy coconut)
- Gulaman at Sago (Tapioca with coconut milk)
- Laing (Spicy taro dish seasoned with shrimp, pork, and ginger)
- Pancit Butong (Coconut noodles)
- Halo-halo (Shaved ice in coconut milk with sweet beans, ice cream, fruits, condensed milk, and other sundries)
## Burmese
- Halawa (a snack made of sticky rice, butter, coconut milk, similar to Indian halwa)
- Kyauk-kyaw (coconut jelly)
- Mont let saung (tapioca balls, glutinous rice, grated coconut and toasted sesame with jaggery syrup in coconut milk)
- Ohn-no hkauk-hswe (curried chicken and wheat noodles in a coconut milk broth)
- Shwegyi mont (unsweet cake of semolina, coconut milk, and poppy seeds)
# Drinks
Drinks using coconut milk as an ingredient include
- Piña Colada and its nonalcoholic variant Virgin Piña Colada (Coconut cream may also be used) | Coconut milk
Coconut milk is a sweet, milky white cooking base derived from the meat of a mature coconut. The color and rich taste of the milk can be attributed to the high oil content and sugars. In Malaysia, Brunei and Indonesia coconut milk is called santan and in the Philippines it is called gata. It should not be confused with coconut water (coconut juice), which is the naturally-occurring liquid found inside a coconut.
# Preparation
Two grades of coconut milk exist: thick and thin. Thick coconut milk is prepared by directly squeezing grated coconut meat through cheesecloth. The squeezed coconut meat is then soaked in warm water and squeezed a second or third time for thin coconut milk. Thick milk is used mainly to make desserts and rich, dry sauces. Thin milk is used for soups and general cooking. This distinction is usually not made in western nations since fresh coconut milk is usually not produced, and most consumers buy coconut milk in cans. Manufacturers of canned coconut milk typically combine the thin and thick squeezes, with the addition of water as a filler.
Depending on the brand and age of the milk itself, a thicker, more paste-like consistency floats to the top of the can, and is sometimes separated and used in recipes that require coconut cream rather than coconut milk. Shaking the can prior to opening will even it out to a cream-like thickness.
Once opened, cans of coconut milk must be refrigerated, and are usually only good for a few days. Coconut milk should never be left at room temperature, as the milk can sour and spoil easily.
You can make your own coconut milk by processing grated coconut with hot water or milk, which extracts the oil and aromatic compounds. It should not be confused with the coconut water discussed above, and has a fat content of approximately 17%. When refrigerated and left to set, coconut cream will rise to the top and separate out the milk.
# Cooking
Coconut milk is a common ingredient in many tropical cuisines, most notably that of Southeast Asia (especially Filipino, Indonesian, Burmese, Cambodia, Malaysian, and Singaporean, Sri Lankan and Thai), West African, Caribbean, and Polynesian cuisines. Coconut milk can usually be found in the Asian food sections of supermarkets either frozen or canned. Frozen coconut milk tends to stay fresh longer, which is important in dishes where the coconut flavor is not competing with curries and other spicy dishes.
Coconut milk is the base of most Thai curries. To make the curry sauce, the coconut milk is first cooked over fairly high heat to break down the milk and cream and allow the oil to separate. The curry paste is then added, as well as any other seasonings, meats, vegetables and garnishes.
# Medicinal properties
The monolaurins in the coconut oil have been found to be very powerful antibacterial, antiviral, and antifungal agents. Some people believe that coconut milk can be used as a laxative.[1]
# Dishes
## Chinese
- Various sweet dim sum dishes
- Various sweet soups (tong sui)
## Thai
- Red curry
- Green curry
- Massaman curry
- Tom kha gai
- Satay
- Sweet sticky rice
- Tapioca pudding
- Ice Cream
- Coconut pudding
- Thai Shaved Ice or Nam Kang Sai, known as snow cone in the US. Another name is 'Wan-Yen'. In Thailand, this kind of cold dessert is very popular as well. The differences from other countries' shaved ice is that in the Thai version the toppings (mixings) are in the bottom and the shaved ice is on top. There are between 20-30 varieties of mixings that can be mixed in. Among them are young coconut that have been soaked in coconut milk, black sticky rice, chestnuts,sweetened taro, red beans, cheng-sim-ee (special flour that is very chewy and slippery) and many more.
## Malaysian
- Laksa
- Nasi lemak
- Rendang
## Indonesian
- Rendang
- Opor ayam
- Nasi liwet
- Nasi Uduk
## Sri Lankan
- Spicy chicken curry
- Spicy beef curry
- Spicy and non-spicy fish curry
- Dhal curry
- Potato curry
- Tomato sambol
- Green bean curry
- Coconut milk (Pol kiri) - a dish in itself, usually used for gravy with Pittu
- Milk gravy (Kiri hodi) - Coconut milk with a dash of saffron and onion, usually used for gravy with String-hoppers
## West Indian
- Rice and peas
- Callaloo
## Hawaiian
- Haupia (a gelatin-like pudding flavored with coconut milk)
- Kulolo
- Lu'au (taro leaves simmered in coconut milk)
## Indian (Kerala)
- Gothampu Payasam (Wheat Payasam)
## Filipino
- Adobo sa Gata (Meat sauteed in soy sauce, garlic, and pepper, thickened with coconut milk)
- Ginata (Various entrees or desserts simmered in coconut milk)
Ginataang Bilo Bilo (Rice dumpling dessert)
Ginataang Tilapia (White fish in creamy coconut)
- Ginataang Bilo Bilo (Rice dumpling dessert)
- Ginataang Tilapia (White fish in creamy coconut)
- Gulaman at Sago (Tapioca with coconut milk)
- Laing (Spicy taro dish seasoned with shrimp, pork, and ginger)
- Pancit Butong (Coconut noodles)
- Halo-halo (Shaved ice in coconut milk with sweet beans, ice cream, fruits, condensed milk, and other sundries)
## Burmese
- Halawa (a snack made of sticky rice, butter, coconut milk, similar to Indian halwa)
- Kyauk-kyaw (coconut jelly)
- Mont let saung (tapioca balls, glutinous rice, grated coconut and toasted sesame with jaggery syrup in coconut milk)
- Ohn-no hkauk-hswe (curried chicken and wheat noodles in a coconut milk broth)
- Shwegyi mont (unsweet cake of semolina, coconut milk, and poppy seeds)
# Drinks
Drinks using coconut milk as an ingredient include
- Piña Colada and its nonalcoholic variant Virgin Piña Colada (Coconut cream may also be used) | https://www.wikidoc.org/index.php/Coconut_milk | |
9881c255d1fb1e5de76b6ba97dc1922257890492 | wikidoc | Genetic code | Genetic code
The genetic code is the set of rules by which information encoded in genetic material (DNA or RNA sequences) is translated into proteins (amino acid sequences) by living cells. Specifically, the code defines a mapping between tri-nucleotide sequences called codons and amino acids; every triplet of nucleotides in a nucleic acid sequence specifies a single amino acid. Because the vast majority of genes are encoded with exactly the same code (see #RNA codon table), this particular code is often referred to as the canonical or standard genetic code, or simply the genetic code, though in fact there are many variant codes; thus, the canonical genetic code is not universal. For example, in humans, protein synthesis in mitochondria relies on a genetic code that varies from the canonical code.
# Cracking the genetic code
After the structure of DNA was deciphered by James Watson, Francis Crick, Maurice Wilkins and Rosalind Franklin, serious efforts to understand the nature of the encoding of proteins began. George Gamov postulated that a three-letter code must be employed to encode the 20 different amino acids used by living cells to encode proteins (because 3 is the smallest n such that 4n is at least 20). The fact that codons did consist of three DNA bases was first demonstrated in the Crick, Brenner et al. experiment. The first elucidation of a codon was done by Marshall Nirenberg and Heinrich J. Matthaei in 1961 at the National Institutes of Health. They used a cell-free system to translate a poly-uracil RNA sequence (or UUUUU... in biochemical terms) and discovered that the polypeptide they had synthesized consisted of only the amino acid phenylalanine. They thereby deduced from this poly-phenylalanine that the codon UUU specified the amino-acid phenylalanine. Extending this work, Nirenberg and his coworkers were able to determine the nucleotide makeup of each codon. In order to determine the order of the sequence, trinucleotides were bound to ribosomes and radioactively labeled aminoacyl-tRNA was used to determine which amino acid corresponded to the codon. Nirenberg's group was able to determine the sequences of 54 out of 64 codons. Subsequent work by Har Gobind Khorana identified the rest of the code, and shortly thereafter Robert W. Holley determined the structure of transfer RNA, the adapter molecule that facilitates translation. In 1968, Khorana, Holley and Nirenberg shared the Nobel Prize in Physiology or Medicine for their work.
# Transfer of information via the genetic code
The genome of an organism is inscribed in DNA, or in some viruses RNA. The portion of the genome that codes for a protein or an RNA is referred to as a gene. Those genes that code for proteins are composed of tri-nucleotide units called codons, each coding for a single amino acid. Each nucleotide sub-unit consists of a phosphate, deoxyribose sugar and one of the 4 nitrogenous nucleotide bases. The purine bases adenine (A) and guanine (G) are larger and consist of two aromatic rings. The pyrimidine bases cytosine (C) and thymine (T) are smaller and consist of only one aromatic ring. In the double-helix configuration, two strands of DNA are joined to each other by hydrogen bonds in an arrangement known as base pairing. These bonds almost always form between an adenine base on one strand and a thymine on the other strand and between a cytosine base on one strand and a guanine base on the other. This means that the number of A and T residues will be the same in a given double helix as will the number of G and C residues. In RNA, thymine (T) is replaced by uracil (U), and the deoxyribose is substituted by ribose.
Each protein-coding gene is transcribed into a template molecule of the related polymer RNA, known as messenger RNA or mRNA. This in turn is translated on the ribosome into an amino acid chain or polypeptide. The process of translation requires transfer RNAs specific for individual amino acids with the amino acids covalently attached to them, guanosine triphosphate as an energy source, and a number of translation factors. tRNAs have anticodons complementary to the codons in mRNA and can be "charged" covalently with amino acids at their 3' terminal CCA ends. Individual tRNAs are charged with specific amino acids by enzymes known as aminoacyl tRNA synthetases which have high specificity for both their cognate amino acids and tRNAs. The high specificity of these enzymes is a major reason why the fidelity of protein translation is maintained.
There are 4³ = 64 different codon combinations possible with a triplet codon of three nucleotides. In reality, all 64 codons of the standard genetic code are assigned for either amino acids or stop signals during translation. If, for example, an RNA sequence, UUUAAACCC is considered and the reading-frame starts with the first U (by convention, 5' to 3'), there are three codons, namely, UUU, AAA and CCC, each of which specifies one amino acid. This RNA sequence will be translated into an amino acid sequence, three amino acids long.
The standard genetic code is shown in the following tables. Table 1 shows what amino acid each of the 64 codons specifies. Table 2 shows what codons specify each of the 20 standard amino acids involved in translation. These are called forward and reverse codon tables, respectively. For example, the codon AAU represents the amino acid asparagine, and UGU and UGC represent cysteine (standard three-letter designations, Asn and Cys respectively).
# RNA codon table
# Salient features
## Reading frame of a sequence
Note that a codon is defined by the initial nucleotide from which translation starts. For example, the string GGGAAACCC, if read from the first position, contains the codons GGG, AAA and CCC; and if read from the second position, it contains the codons GGA and AAC; if read starting from the third position, GAA and ACC. Partial codons have been ignored in this example. Every sequence can thus be read in three reading frames, each of which will produce a different amino acid sequence (in the given example, Gly-Lys-Pro, Gly-Asp, or Glu-Thr, respectively). With double-stranded DNA there are six possible reading frames, three in the forward orientation on one strand and three reverse (on the opposite strand).
The actual frame a protein sequence is translated in is defined by a start codon, usually the first AUG codon in the mRNA sequence. Mutations that disrupt the reading frame by insertions or deletions of a non-multiple of 3 nucleotide bases are known as frameshift mutations. These mutations may impair the function of the resulting protein, if it is formed, and are thus rare in in vivo protein-coding sequences. Often such misformed proteins are targeted for proteolytic degradation. In addition, a frame shift mutation is very likely to cause a stop codon to be read which truncates the creation of the protein (example ). One reason for the rareness of frame-shifted mutations being inherited is that if the protein being translated is essential for growth under the selective pressures the organism faces, absence of a functional protein may cause lethality before the organism is viable.
## Start/stop codons
Translation starts with a chain initiation codon (start codon). Unlike stop codons, the codon alone is not sufficient to begin the process. Nearby sequences and initiation factors are also required to start translation. The most common start codon is AUG, which codes for methionine, so most amino acid chains start with methionine.
The three stop codons have been given names: UAG is amber, UGA is opal (sometimes also called umber), and UAA is ochre. "Amber" was named by discoverers Richard Epstein and Charles Steinberg after their friend Harris Bernstein, whose last name means "amber" in German. The other two stop codons were named 'ochre" and "opal" in order to keep the "color names" theme. Stop codons are also called termination codons and they signal release of the nascent polypeptide from the ribosome due to binding of release factors in the absence of cognate tRNAs with anticodons complementary to these stop signals.
## Degeneracy of the genetic code
The genetic code has redundancy but no ambiguity. For example, although codons GAA and GAG both specify glutamic acid (redundancy), neither of them specifies any other amino acid (no ambiguity). Degenerate codons may differ in their third positions; e.g., both GAA and GAG code for the amino acid glutamic acid. A codon is said to be fourfold degenerate if any nucleotide at its third position specifies the same amino acid; it is said to be twofold degenerate if only two of four possible nucleotides at its third position specify the same amino acid. In twofold degenerate codons, the equivalent third position nucleotides are always either two purines (A/G) or two pyrimidines (C/T). Only two amino acids are specified by a single codon; one of these is the amino-acid methionine, specified by the codon AUG, which also specifies the start of translation; the other is tryptophan, specified by the codon UGG.
The degeneracy of the genetic code is what accounts for the existence of silent mutations.
Degeneracy results because a triplet code designates 20 amino acids and a stop codon. Because there are four bases, triplet codons are required to produce at least 21 different codes. For example, if there were two bases per codon, then only 16 amino acids could be coded for (4²=16). Because at least 21 codes are required, then 4³ gives 64 possible codons, meaning that some degeneracy must exist.
These properties of the genetic code make it more fault-tolerant for point mutations. For example, in theory, fourfold degenerate codons can tolerate any point mutation at the third position, although codon usage bias restricts this in practice in many organisms; twofold degenerate codons can tolerate one out of the three possible point mutations at the third position. Since transition mutations (purine to purine or pyrimidine to pyrimidine mutations) are more likely than transversion (purine to pyrimidine or vice-versa) mutations, the equivalence of purines or that of pyrimidines at twofold degenerate sites adds a further fault-tolerance.
A practical consequence of redundancy is that some errors in the genetic code only cause a silent mutation or an error that would not affect the protein because the hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. Even so, it is a single point mutation that causes a modified hemoglobin molecule in sickle-cell disease. The hydrophilic glutamate (Glu) is substituted by the hydrophobic valine (Val), which reduces the solubility of ß-globin. In this case, this mutation causes hemoglobin to form linear polymers linked by the hydrophobic interaction between the valine groups causing sickle-cell deformation of erythrocytes. Sickle-cell disease is generally not caused by a de novo mutation. Rather it is selected for in malarial regions (in a way similar to thalassemia), as heterozygous people have some resistance to the malarial Plasmodium parasite (heterozygote advantage).
These variable codes for amino acids are allowed because of modified bases in the first base of the anticodon of the tRNA, and the base-pair formed is called a wobble base pair. The modified bases include inosine and the Non-Watson-Crick U-G basepair.
# Variations to the standard genetic code
While slight variations on the standard code had been predicted earlier, none were discovered until 1979, when researchers studying human mitochondrial genes discovered they used an alternative code. Many slight variants have been discovered since, including various alternative mitochondrial codes, as well as small variants such as Mycoplasma translating the codon UGA as tryptophan. In bacteria and archaea, GUG and UUG are common start codons. However, in rare cases, certain specific proteins may use alternative initiation (start) codons not normally used by that species.
In certain proteins, non-standard amino acids are substituted for standard stop codons, depending upon associated signal sequences in the messenger RNA: UGA can code for selenocysteine and UAG can code for pyrrolysine as discussed in the relevant articles. Selenocysteine is now viewed as the 21st amino acid, and pyrrolysine is viewed as the 22nd. A detailed description of variations in the genetic code can be found at the NCBI web site.
However, all known codes have strong similarities to each other, and the coding mechanism is the same for all organisms: three-base codons, tRNA, and ribosomes, reading the code in the same direction, translating the code three letters at a time into sequences of amino acids.
# Theories on the origin of the genetic code
Despite the variations that exist, the genetic codes used by all known forms of life on Earth are very similar. Since there are many possible genetic codes that are thought to have similar utility to the one used by Earth life, the theory of evolution suggests that the genetic code was established very early in the history of life and meta-analysis of transfer RNA suggest it was established soon after the formation of earth.
One can ask the question: is the genetic code completely random, just one set of codon-amino acid correspondences that happened to establish itself and be "frozen in" early in evolution, although functionally any of the many other possible transcription tables would have done just as well? Already a cursory look at the table shows patterns that suggest that this is not the case.
There are three themes running through the many theories that seek to explain the evolution of the genetic code (and hence the origin of these patterns). One is illustrated by recent aptamer experiments which show that some amino acids have a selective chemical affinity for the base triplets that code for them. This suggests that the current, complex translation mechanism involving tRNA and associated enzymes may be a later development, and that originally, protein sequences were directly templated on base sequences. Another is that the standard genetic code that we see today grew from a simpler, earlier code through a process of "biosynthetic expansion". Here the idea is that primordial life 'discovered' new amino acids (e.g. as by-products of metabolism) and later back-incorporated some of these into the machinery of genetic coding. Although much circumstantial evidence has been found to suggest that fewer different amino acids were used in the past than today, precise and detailed hypotheses about exactly which amino acids entered the code in exactly what order has proved far more controversial. A third theory is that natural selection has led to codon assignments of the genetic code that minimize the effects of mutations.. | Genetic code
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
The genetic code is the set of rules by which information encoded in genetic material (DNA or RNA sequences) is translated into proteins (amino acid sequences) by living cells. Specifically, the code defines a mapping between tri-nucleotide sequences called codons and amino acids; every triplet of nucleotides in a nucleic acid sequence specifies a single amino acid. Because the vast majority of genes are encoded with exactly the same code (see #RNA codon table), this particular code is often referred to as the canonical or standard genetic code, or simply the genetic code, though in fact there are many variant codes; thus, the canonical genetic code is not universal. For example, in humans, protein synthesis in mitochondria relies on a genetic code that varies from the canonical code.
# Cracking the genetic code
After the structure of DNA was deciphered by James Watson, Francis Crick, Maurice Wilkins and Rosalind Franklin, serious efforts to understand the nature of the encoding of proteins began. George Gamov postulated that a three-letter code must be employed to encode the 20 different amino acids used by living cells to encode proteins (because 3 is the smallest n such that 4n is at least 20). The fact that codons did consist of three DNA bases was first demonstrated in the Crick, Brenner et al. experiment. The first elucidation of a codon was done by Marshall Nirenberg and Heinrich J. Matthaei in 1961 at the National Institutes of Health. They used a cell-free system to translate a poly-uracil RNA sequence (or UUUUU... in biochemical terms) and discovered that the polypeptide they had synthesized consisted of only the amino acid phenylalanine. They thereby deduced from this poly-phenylalanine that the codon UUU specified the amino-acid phenylalanine. Extending this work, Nirenberg and his coworkers were able to determine the nucleotide makeup of each codon. In order to determine the order of the sequence, trinucleotides were bound to ribosomes and radioactively labeled aminoacyl-tRNA was used to determine which amino acid corresponded to the codon. Nirenberg's group was able to determine the sequences of 54 out of 64 codons. Subsequent work by Har Gobind Khorana identified the rest of the code, and shortly thereafter Robert W. Holley determined the structure of transfer RNA, the adapter molecule that facilitates translation. In 1968, Khorana, Holley and Nirenberg shared the Nobel Prize in Physiology or Medicine for their work.
# Transfer of information via the genetic code
The genome of an organism is inscribed in DNA, or in some viruses RNA. The portion of the genome that codes for a protein or an RNA is referred to as a gene. Those genes that code for proteins are composed of tri-nucleotide units called codons, each coding for a single amino acid. Each nucleotide sub-unit consists of a phosphate, deoxyribose sugar and one of the 4 nitrogenous nucleotide bases. The purine bases adenine (A) and guanine (G) are larger and consist of two aromatic rings. The pyrimidine bases cytosine (C) and thymine (T) are smaller and consist of only one aromatic ring. In the double-helix configuration, two strands of DNA are joined to each other by hydrogen bonds in an arrangement known as base pairing. These bonds almost always form between an adenine base on one strand and a thymine on the other strand and between a cytosine base on one strand and a guanine base on the other. This means that the number of A and T residues will be the same in a given double helix as will the number of G and C residues. In RNA, thymine (T) is replaced by uracil (U), and the deoxyribose is substituted by ribose.
Each protein-coding gene is transcribed into a template molecule of the related polymer RNA, known as messenger RNA or mRNA. This in turn is translated on the ribosome into an amino acid chain or polypeptide. The process of translation requires transfer RNAs specific for individual amino acids with the amino acids covalently attached to them, guanosine triphosphate as an energy source, and a number of translation factors. tRNAs have anticodons complementary to the codons in mRNA and can be "charged" covalently with amino acids at their 3' terminal CCA ends. Individual tRNAs are charged with specific amino acids by enzymes known as aminoacyl tRNA synthetases which have high specificity for both their cognate amino acids and tRNAs. The high specificity of these enzymes is a major reason why the fidelity of protein translation is maintained.
There are 4³ = 64 different codon combinations possible with a triplet codon of three nucleotides. In reality, all 64 codons of the standard genetic code are assigned for either amino acids or stop signals during translation. If, for example, an RNA sequence, UUUAAACCC is considered and the reading-frame starts with the first U (by convention, 5' to 3'), there are three codons, namely, UUU, AAA and CCC, each of which specifies one amino acid. This RNA sequence will be translated into an amino acid sequence, three amino acids long.
The standard genetic code is shown in the following tables. Table 1 shows what amino acid each of the 64 codons specifies. Table 2 shows what codons specify each of the 20 standard amino acids involved in translation. These are called forward and reverse codon tables, respectively. For example, the codon AAU represents the amino acid asparagine, and UGU and UGC represent cysteine (standard three-letter designations, Asn and Cys respectively).
# RNA codon table
# Salient features
## Reading frame of a sequence
Note that a codon is defined by the initial nucleotide from which translation starts. For example, the string GGGAAACCC, if read from the first position, contains the codons GGG, AAA and CCC; and if read from the second position, it contains the codons GGA and AAC; if read starting from the third position, GAA and ACC. Partial codons have been ignored in this example. Every sequence can thus be read in three reading frames, each of which will produce a different amino acid sequence (in the given example, Gly-Lys-Pro, Gly-Asp, or Glu-Thr, respectively). With double-stranded DNA there are six possible reading frames, three in the forward orientation on one strand and three reverse (on the opposite strand).
The actual frame a protein sequence is translated in is defined by a start codon, usually the first AUG codon in the mRNA sequence. Mutations that disrupt the reading frame by insertions or deletions of a non-multiple of 3 nucleotide bases are known as frameshift mutations. These mutations may impair the function of the resulting protein, if it is formed, and are thus rare in in vivo protein-coding sequences. Often such misformed proteins are targeted for proteolytic degradation. In addition, a frame shift mutation is very likely to cause a stop codon to be read which truncates the creation of the protein (example [3]). One reason for the rareness of frame-shifted mutations being inherited is that if the protein being translated is essential for growth under the selective pressures the organism faces, absence of a functional protein may cause lethality before the organism is viable.
## Start/stop codons
Translation starts with a chain initiation codon (start codon). Unlike stop codons, the codon alone is not sufficient to begin the process. Nearby sequences and initiation factors are also required to start translation. The most common start codon is AUG, which codes for methionine, so most amino acid chains start with methionine.
The three stop codons have been given names: UAG is amber, UGA is opal (sometimes also called umber), and UAA is ochre. "Amber" was named by discoverers Richard Epstein and Charles Steinberg after their friend Harris Bernstein, whose last name means "amber" in German. The other two stop codons were named 'ochre" and "opal" in order to keep the "color names" theme. Stop codons are also called termination codons and they signal release of the nascent polypeptide from the ribosome due to binding of release factors in the absence of cognate tRNAs with anticodons complementary to these stop signals.[2]
## Degeneracy of the genetic code
The genetic code has redundancy but no ambiguity. For example, although codons GAA and GAG both specify glutamic acid (redundancy), neither of them specifies any other amino acid (no ambiguity). Degenerate codons may differ in their third positions; e.g., both GAA and GAG code for the amino acid glutamic acid. A codon is said to be fourfold degenerate if any nucleotide at its third position specifies the same amino acid; it is said to be twofold degenerate if only two of four possible nucleotides at its third position specify the same amino acid. In twofold degenerate codons, the equivalent third position nucleotides are always either two purines (A/G) or two pyrimidines (C/T). Only two amino acids are specified by a single codon; one of these is the amino-acid methionine, specified by the codon AUG, which also specifies the start of translation; the other is tryptophan, specified by the codon UGG.
The degeneracy of the genetic code is what accounts for the existence of silent mutations.
Degeneracy results because a triplet code designates 20 amino acids and a stop codon. Because there are four bases, triplet codons are required to produce at least 21 different codes. For example, if there were two bases per codon, then only 16 amino acids could be coded for (4²=16). Because at least 21 codes are required, then 4³ gives 64 possible codons, meaning that some degeneracy must exist.
These properties of the genetic code make it more fault-tolerant for point mutations. For example, in theory, fourfold degenerate codons can tolerate any point mutation at the third position, although codon usage bias restricts this in practice in many organisms; twofold degenerate codons can tolerate one out of the three possible point mutations at the third position. Since transition mutations (purine to purine or pyrimidine to pyrimidine mutations) are more likely than transversion (purine to pyrimidine or vice-versa) mutations, the equivalence of purines or that of pyrimidines at twofold degenerate sites adds a further fault-tolerance.
A practical consequence of redundancy is that some errors in the genetic code only cause a silent mutation or an error that would not affect the protein because the hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. Even so, it is a single point mutation that causes a modified hemoglobin molecule in sickle-cell disease. The hydrophilic glutamate (Glu) is substituted by the hydrophobic valine (Val), which reduces the solubility of ß-globin. In this case, this mutation causes hemoglobin to form linear polymers linked by the hydrophobic interaction between the valine groups causing sickle-cell deformation of erythrocytes. Sickle-cell disease is generally not caused by a de novo mutation. Rather it is selected for in malarial regions (in a way similar to thalassemia), as heterozygous people have some resistance to the malarial Plasmodium parasite (heterozygote advantage).
These variable codes for amino acids are allowed because of modified bases in the first base of the anticodon of the tRNA, and the base-pair formed is called a wobble base pair. The modified bases include inosine and the Non-Watson-Crick U-G basepair.
# Variations to the standard genetic code
While slight variations on the standard code had been predicted earlier,[3] none were discovered until 1979, when researchers studying human mitochondrial genes discovered they used an alternative code. Many slight variants have been discovered since,[4] including various alternative mitochondrial codes,[5] as well as small variants such as Mycoplasma translating the codon UGA as tryptophan. In bacteria and archaea, GUG and UUG are common start codons. However, in rare cases, certain specific proteins may use alternative initiation (start) codons not normally used by that species.[6]
In certain proteins, non-standard amino acids are substituted for standard stop codons, depending upon associated signal sequences in the messenger RNA: UGA can code for selenocysteine and UAG can code for pyrrolysine as discussed in the relevant articles. Selenocysteine is now viewed as the 21st amino acid, and pyrrolysine is viewed as the 22nd. A detailed description of variations in the genetic code can be found at the NCBI web site.
However, all known codes have strong similarities to each other, and the coding mechanism is the same for all organisms: three-base codons, tRNA, and ribosomes, reading the code in the same direction, translating the code three letters at a time into sequences of amino acids.
# Theories on the origin of the genetic code
Despite the variations that exist, the genetic codes used by all known forms of life on Earth are very similar. Since there are many possible genetic codes that are thought to have similar utility to the one used by Earth life, the theory of evolution suggests that the genetic code was established very early in the history of life and meta-analysis of transfer RNA suggest it was established soon after the formation of earth.
One can ask the question: is the genetic code completely random, just one set of codon-amino acid correspondences that happened to establish itself and be "frozen in" early in evolution, although functionally any of the many other possible transcription tables would have done just as well? Already a cursory look at the table shows patterns that suggest that this is not the case.
There are three themes running through the many theories that seek to explain the evolution of the genetic code (and hence the origin of these patterns).[7] One is illustrated by recent aptamer experiments which show that some amino acids have a selective chemical affinity for the base triplets that code for them.[8] This suggests that the current, complex translation mechanism involving tRNA and associated enzymes may be a later development, and that originally, protein sequences were directly templated on base sequences. Another is that the standard genetic code that we see today grew from a simpler, earlier code through a process of "biosynthetic expansion". Here the idea is that primordial life 'discovered' new amino acids (e.g. as by-products of metabolism) and later back-incorporated some of these into the machinery of genetic coding. Although much circumstantial evidence has been found to suggest that fewer different amino acids were used in the past than today,[9] precise and detailed hypotheses about exactly which amino acids entered the code in exactly what order has proved far more controversial.[10][11] A third theory is that natural selection has led to codon assignments of the genetic code that minimize the effects of mutations.[12]. | https://www.wikidoc.org/index.php/Codon | |
841a50f66c39b3780bcd797a3b094df25c0197f6 | wikidoc | Coffee enema | Coffee enema
# Overview
Coffee enemas are the enema-related procedure of inserting coffee into the anus to cleanse the rectum and small intestines. This procedure, although well documented, is considered by most medical authorities to be unproven, rash and possibly dangerous. A Murphy drip is an example of an apparatus that may be used to administer this medical procedure.
# History
While the idea of anal cleansing dates back to the Egyptians, the notion of caffeine as an enema-related substance is relatively new. It was conceived as early as 1917, and was even in the Merck Manual until 1972.
In 1920, German scientists investigated caffeine's effect on the bile duct and small intestines. Dr. Max Gerson proposed coffee enemas had a positive effect of the gastro-intestinal tract; Gerson said that coffee enemas had positive effects on patients with tuberculosis, and later even cancer. He claimed that unlike saline enemas, the caffeine traveled through the smooth muscle of the small intestine, and into the liver. This, he said, cleared even more the gastro-intestinal tract and removed more toxins and bile than a normal enema. He told his patients often that the "coffee enemas are not given for the function of the intestines but for the stimulation of the liver."
## Claims of efficacy
Caffeine, theophylline and theobromine stimulate the relaxation of smooth muscles in the anus and small intestine, which cause dilatation of blood vessels and bile ducts. This, combined with the close proximity of the anal walls and veins which make the caffeine enter the blood more quickly and in greater quantity, arguably have a better cleaning effect than a regular saline enema. Coffee can cause diarrhea which believers say aids in the detoxification process.
# Dangers
Coffee enemas are believed to have caused three deaths in the United States, described in the following references. Coffee enemas may cause electrolyte imbalances that, if severe enough, can cause death. Other adverse reactions that have been reported include enteric septicemia in a patient with widespread cancer, hepatic dysfunction and ascites, which the authors believed made this patient more likely to suffer from infections. If the coffee is inserted too quickly or too hot, it could cause internal burning or tearing. Because of the close proximity between veins and anal walls, caffeine finds itself in the veins in much greater quantities, and may lead to caffeine overdose, though since the coffee enema is expelled the likelihood of overdose may be less than when coffee is ingested and must remain in the body until metabolized. Excessive enemas may cause dehydration, and this is only amplified by the diuretic effect of caffeine in the coffee. Also, like all uses of coffee, it risks raising blood pressure, though not to a great extent in most individuals. | Coffee enema
# Overview
Coffee enemas are the enema-related procedure of inserting coffee into the anus to cleanse the rectum and small intestines. This procedure, although well documented, is considered by most medical authorities to be unproven, rash and possibly dangerous.[1][2] A Murphy drip is an example of an apparatus that may be used to administer this medical procedure.
# History
While the idea of anal cleansing dates back to the Egyptians, the notion of caffeine as an enema-related substance is relatively new. It was conceived as early as 1917, and was even in the Merck Manual until 1972.[3]
In 1920, German scientists investigated caffeine's effect on the bile duct and small intestines. Dr. Max Gerson proposed coffee enemas had a positive effect of the gastro-intestinal tract; Gerson said that coffee enemas had positive effects on patients with tuberculosis, and later even cancer. He claimed that unlike saline enemas, the caffeine traveled through the smooth muscle of the small intestine, and into the liver. This, he said, cleared even more the gastro-intestinal tract and removed more toxins and bile than a normal enema. He told his patients often that the "coffee enemas are not given for the function of the intestines but for the stimulation of the liver."[3]
## Claims of efficacy
Caffeine, theophylline and theobromine stimulate the relaxation of smooth muscles in the anus and small intestine, which cause dilatation of blood vessels and bile ducts.[citation needed] This, combined with the close proximity of the anal walls and veins which make the caffeine enter the blood more quickly and in greater quantity, arguably have a better cleaning effect than a regular saline enema.[citation needed] Coffee can cause diarrhea[4][5] which believers say aids in the detoxification process.
[6]
# Dangers
Coffee enemas are believed to have caused three deaths in the United States, described in the following references. Coffee enemas may cause electrolyte imbalances that, if severe enough, can cause death.[7] Other adverse reactions that have been reported include enteric septicemia in a patient with widespread cancer, hepatic dysfunction and ascites, which the authors believed made this patient more likely to suffer from infections.[8] If the coffee is inserted too quickly or too hot, it could cause internal burning[9] or tearing. Because of the close proximity between veins and anal walls, caffeine finds itself in the veins in much greater quantities, and may lead to caffeine overdose, though since the coffee enema is expelled the likelihood of overdose may be less than when coffee is ingested and must remain in the body until metabolized. Excessive enemas may cause dehydration, and this is only amplified by the diuretic effect of caffeine in the coffee.[10] Also, like all uses of coffee, it risks raising blood pressure, though not to a great extent in most individuals.[11] | https://www.wikidoc.org/index.php/Coffee_enema | |
7109cde7c892597a4d8732f8139a2cfd03f95e07 | wikidoc | Cohort study | Cohort study
# Overview
A cohort study or panel study is a form of longitudinal study used in medicine and social science. It is one type of study design and should be compared with a cross-sectional study.
A cohort is a group of people who share a common characteristic or experience within a defined period (e.g., are born, leave school, lose their job, are exposed to a drug or a vaccine, etc.). Thus a group of people who were born on a day or in a particular period, say 1948, form a birth cohort. The comparison group may be the general population from which the cohort is drawn, or it may be another cohort of persons thought to have had little or no exposure to the substance under investigation, but otherwise similar. Alternatively, subgroups within the cohort may be compared with each other.
# Application
In medicine, a cohort study is often undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease; failure to refute a hypothesis strengthens confidence in it. Crucially, the cohort is identified before the appearance of the disease under investigation. The study groups, so defined, are observed over a period of time to determine the frequency of new incidence of the studied disease among them. The cohort cannot therefore be defined as a group of people who already have the disease. Distinguishing causality from mere correlation cannot usually be done with results of a cohort study alone.
The advantage of cohort study data is the longitudinal observation of the individual through time, and the collection of data at regular intervals, so recall error is reduced. However, cohort studies are expensive to conduct, are sensitive to attrition and take a long time to generate useful data.
Some cohort studies track groups of children from their birth, and record a wide range of information (exposures) about them. The value of a cohort study depends on the researchers' capacity to stay in touch with all members of the cohort. Some of these studies have continued for decades.
# Examples
An example of an epidemiologic question that can be answered by the use of a cohort study is: does exposure to X (say, smoking) correlate with outcome Y (say, lung cancer)? Such a study would recruit a group of smokers and a group of non-smokers (the unexposed group) and follow them for a set period of time and note differences in the incidence of lung cancer between the groups at the end of this time. The groups are matched in terms of many other variables such as economic status and other health status so that the variable being assesed, the independent variable (in this case, smoking) can be isolated as the cause of the dependent variable (in this case, lung cancer).
In this example, a statistically significant increase in the incidence of lung cancer in the smoking group as compared to the non-smoking group is evidence in favor of the hypothesis. However, rare outcomes, such as lung cancer, are generally not studied with the use of a cohort study, but are rather studied with the use of a case-control study.
Shorter term studies are commonly used in medical research as a form of clinical trial, or means to test a particular hypothesis of clinical importance. Such studies typically follow two groups of patients for a period of time and compare an endpoint or outcome measure between the two groups.
Randomized controlled trials, or RCTs are a superior methodology in the hierarchy of evidence, because they limit the potential for bias by randomly assigning one patient pool to an intervention and another patient pool to non-intervention (or placebo). This minimises the chance that the incidence of confounding variables will differ between the two groups.
Nevertheless, it is sometimes not practical or ethical to perform RCTs to answer a clinical question. To take our example, if we already had reasonable evidence that smoking causes lung cancer then persuading a pool of non-smokers to take up smoking in order to test this hypothesis would generally be considered quite unethical.
An example of a cohort study that has been going on for more than 50 years is the Framingham Heart Study.
The largest cohort study in women is the Nurses' Health Study. Started in 1976, it is tracking over 120,000 nurses and has been analyzed for many different conditions and outcomes.
# Variations
## Retrospective cohort
A "prospective cohort" defines the groups before the study is done, while a "retrospective cohort" does the grouping after the data is collected. Whereas prospective cohorts should be summarized with the relative risk, retrospective cohorts should be summarized with the odds ratio. An example of a retrospective cohort is Long-Term Mortality after Gastric Bypass Surgery.
## Nested case-control study
An example of a nested case-control study is Inflammatory markers and the risk of coronary heart disease in men and women which was a case control analyses extracted from the Framingham Heart Study cohort.
## Household panel survey
Household panel surveys are an important sub-type of cohort study. These draw representative samples of households and survey them, following all individuals through time on a usually annual basis. Examples include the US Panel Study on Income Dynamics (since 1968), the German Socio-Economic Panel (since 1984), the British Household Panel Survey (since 1991), the Household, Income and Labour Dynamics in Australia Survey (since 2001) and the European Community Household Panel (1994-2001).
## Statistical analysis
Because the non-randomized allocation of subjects in a cohort study, several statistical approached have been developed to reduce confounding from selection bias.
A comparison of study in which three approaches (multiple regression, propensity score and grouped treatment variable) were compared in their ability to predict treatment outcomes in a cohort of patients who refused randomization in a chemotherapy trial. The comparison study examined how well three statistical approaches were able to use the nonrandomized patients to replicate the results of the patients who consented to randomization. This comparison found that the propensity score did not add to traditional multiple regression while the grouped treatment variable was least successful.
### Multiple regression
Multiple regression with the Cox proportional hazards ratio can be used to adjust for confounding variable. Multiple regression can only correct for confounding by independent variables that have been measured
### Grouped treatment variable
Creating a grouped treatment variable attempts to correct for unmeasured confounding influences. In the grouped treatment approach, the "treatment individually assigned is considered to be confounded by indication, which means that patients may be selected to receive one of the treatments because of known or unknown prognostic factors." For example, in an observational study that included several hospitals, creating a variable for the proportion of patients exposed to the treatment may account for biases in each hospital in deciding which patients get the treatment.
### Inverse probability weighting
The inverse probability weighting attempts to correct for unmeasured confounding influences.
Examples of cohort studies using this adjustment are:
- the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study of Human Immunodeficiency Virus.
- Ar post‐hoc analysis of a cohort in the ARISE trial
### Principal components analysis
Principal components analysis was developed by Pearson in 1901. The principal components analysis can only correct for confounding by independent variables that have been measured.
### Prior event rate ratio
The prior event rate ratio has been used to replicate with observational data from electronic health records the results of the Scandinavian Simvastatin Survival Study and the HOPE and EUROPA trials. Like the grouped treatment variable, the prior event ration attempts to correct for unmeasured confounding influences. However, unlike the grouped treatment variable which controls for the proportion of subjects selected for treatment, the prior event rate ratio uses the "ratio of event rates between the Exposed and Unexposed cohorts prior to study start time to adjust the study hazard ratio".
Limitations of the prior event ratio is that it cannot study outcomes that have not occurred prior to onset of treatment. So for example, the prior event ratio cannot control for confounding in studies of primary prevention.
### Propensity score matching
The propensity score was introduced by Rosenbaum in 1983. The propensity score is the "conditional probability of receiving one of the treatments under comparison ... given the observed covariates." The propensity score can only correct for confounding by independent variables that have been measured.
Cohort studies with propensity matching may or may not resemble the results of randomized controlled trials. THis may depend on how closely the cohort study emulated the protocol of a randomized controlled trial as done in the RCT-DUPLICATE.
### Sensitivity analysis
Sensitivity analysis can estimate how strong must a unmeasured confounder be to reduce the effect of a factor under study. An example of this analysis was a nonrandomized comparison of when to initial treatment for asymptomatic Human Immunodeficiency Virus in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study.
## Determining causality
### Bradford Hill criteria
If statistically significant associations are found, the Bradford Hill criteria can help determine whether the associations represent true causality. The Bradford Hill criteria were proposed in 1965:
- Strength or magnitude of association?
- Consistency of association across studies?
- Specificity of association?
- Temporality of association?
- Plausibility based on biological knowledge?
- Biological gradient: or dose-response relationship?
- Coherence? Does the proposed association explain other observations?
- Experimental evidence?
- Analogy?
# Biases
## Immortal time bias
"Immortal time is a span of cohort follow-up during which, because of exposure definition, the outcome under study could not occur."
# Assessing the quality
Many scales and checklists have been proposed for assessing the quality of cohort studies. The most common items assessed with these tools are:
- Selecting study participants (92% of tools)
- Measurement of study variables (exposure, outcome and/or confounding variables) (86% of tools)
- Sources of bias (including recall bias, interviewer bias and biased loss to follow-up but excluding confounding) (86% of tools)
- Control of confounding (78% of tools)
- Statistical methods (78% of tools)
- Conflict of interest (3% of tools)
Of these tools, only one was designed for use in comparing cohort studies in any clinical setting for the purpose of conducting a systematic review of cohort studies; however, this tool has been described as "extremely complex and require considerable input to calculate raw scores and to convert to final scores, depending on the primary study design and methods".
The Newcastle-Ottawa Scale (NOS) may help assess the quality of nonrandomized studies.
# Standards for reporting
Standards are available for the reporting of observational studies with accompanying explanation and elaboration.
# Alternative study designs
## Case-control study
Rare outcomes, or those that slowly develop over long periods, are generally not studied with the use of a cohort study, but are rather studied with the use of a case-control study. Retrospective studies may exaggeration associations.
## Randomized controlled trial
Randomized controlled trials (RCTs) are a superior methodology in the hierarchy of evidence, because they limit the potential for bias by randomly assigning one patient pool to an intervention and another patient pool to non-intervention (or placebo). This minimizes the chance that the incidence of confounding variables will differ between the two groups.
Empiric comparisons of observational studies and RCTs conflict and both find and do not find evidence of exaggerated results from cohort studies.
Nevertheless, it is sometimes not practical or ethical to perform RCTs to answer a clinical question. To take our example, if we already had reasonable evidence that smoking causes lung cancer then persuading a pool of non-smokers to take up smoking in order to test this hypothesis would generally be considered quite unethical. | Cohort study
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A cohort study or panel study is a form of longitudinal study used in medicine and social science. It is one type of study design and should be compared with a cross-sectional study.
A cohort is a group of people who share a common characteristic or experience within a defined period (e.g., are born, leave school, lose their job, are exposed to a drug or a vaccine, etc.). Thus a group of people who were born on a day or in a particular period, say 1948, form a birth cohort. The comparison group may be the general population from which the cohort is drawn, or it may be another cohort of persons thought to have had little or no exposure to the substance under investigation, but otherwise similar. Alternatively, subgroups within the cohort may be compared with each other.
# Application
In medicine, a cohort study is often undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease; failure to refute a hypothesis strengthens confidence in it. Crucially, the cohort is identified before the appearance of the disease under investigation. The study groups, so defined, are observed over a period of time to determine the frequency of new incidence of the studied disease among them. The cohort cannot therefore be defined as a group of people who already have the disease. Distinguishing causality from mere correlation cannot usually be done with results of a cohort study alone.
The advantage of cohort study data is the longitudinal observation of the individual through time, and the collection of data at regular intervals, so recall error is reduced. However, cohort studies are expensive to conduct, are sensitive to attrition and take a long time to generate useful data.
Some cohort studies track groups of children from their birth, and record a wide range of information (exposures) about them. The value of a cohort study depends on the researchers' capacity to stay in touch with all members of the cohort. Some of these studies have continued for decades.
# Examples
An example of an epidemiologic question that can be answered by the use of a cohort study is: does exposure to X (say, smoking) correlate with outcome Y (say, lung cancer)? Such a study would recruit a group of smokers and a group of non-smokers (the unexposed group) and follow them for a set period of time and note differences in the incidence of lung cancer between the groups at the end of this time. The groups are matched in terms of many other variables such as economic status and other health status so that the variable being assesed, the independent variable (in this case, smoking) can be isolated as the cause of the dependent variable (in this case, lung cancer).
In this example, a statistically significant increase in the incidence of lung cancer in the smoking group as compared to the non-smoking group is evidence in favor of the hypothesis. However, rare outcomes, such as lung cancer, are generally not studied with the use of a cohort study, but are rather studied with the use of a case-control study.
Shorter term studies are commonly used in medical research as a form of clinical trial, or means to test a particular hypothesis of clinical importance. Such studies typically follow two groups of patients for a period of time and compare an endpoint or outcome measure between the two groups.
Randomized controlled trials, or RCTs are a superior methodology in the hierarchy of evidence, because they limit the potential for bias by randomly assigning one patient pool to an intervention and another patient pool to non-intervention (or placebo). This minimises the chance that the incidence of confounding variables will differ between the two groups.
Nevertheless, it is sometimes not practical or ethical to perform RCTs to answer a clinical question. To take our example, if we already had reasonable evidence that smoking causes lung cancer then persuading a pool of non-smokers to take up smoking in order to test this hypothesis would generally be considered quite unethical.
An example of a cohort study that has been going on for more than 50 years is the Framingham Heart Study.
The largest cohort study in women is the Nurses' Health Study. Started in 1976, it is tracking over 120,000 nurses and has been analyzed for many different conditions and outcomes.
# Variations
## Retrospective cohort
A "prospective cohort" defines the groups before the study is done, while a "retrospective cohort" does the grouping after the data is collected. Whereas prospective cohorts should be summarized with the relative risk, retrospective cohorts should be summarized with the odds ratio. An example of a retrospective cohort is Long-Term Mortality after Gastric Bypass Surgery.[1]
## Nested case-control study
An example of a nested case-control study is Inflammatory markers and the risk of coronary heart disease in men and women which was a case control analyses extracted from the Framingham Heart Study cohort.[2]
## Household panel survey
Household panel surveys are an important sub-type of cohort study. These draw representative samples of households and survey them, following all individuals through time on a usually annual basis. Examples include the US Panel Study on Income Dynamics (since 1968), the German Socio-Economic Panel (since 1984), the British Household Panel Survey (since 1991), the Household, Income and Labour Dynamics in Australia Survey (since 2001) and the European Community Household Panel (1994-2001).
## Statistical analysis
Because the non-randomized allocation of subjects in a cohort study, several statistical approached have been developed to reduce confounding from selection bias.
A comparison of study in which three approaches (multiple regression, propensity score and grouped treatment variable) were compared in their ability to predict treatment outcomes in a cohort of patients who refused randomization in a chemotherapy trial.[3] The comparison study examined how well three statistical approaches were able to use the nonrandomized patients to replicate the results of the patients who consented to randomization. This comparison found that the propensity score did not add to traditional multiple regression while the grouped treatment variable was least successful.[3]
### Multiple regression
Multiple regression with the Cox proportional hazards ratio can be used to adjust for confounding variable. Multiple regression can only correct for confounding by independent variables that have been measured
### Grouped treatment variable
Creating a grouped treatment variable attempts to correct for unmeasured confounding influences.[4] In the grouped treatment approach, the "treatment individually assigned is considered to be confounded by indication, which means that patients may be selected to receive one of the treatments because of known or unknown prognostic factors."[3] For example, in an observational study that included several hospitals, creating a variable for the proportion of patients exposed to the treatment may account for biases in each hospital in deciding which patients get the treatment.[3]
### Inverse probability weighting
The inverse probability weighting attempts to correct for unmeasured confounding influences.[5]
Examples of cohort studies using this adjustment are:
- the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study of Human Immunodeficiency Virus.[6]
- Ar post‐hoc analysis of a cohort in the ARISE trial[7]
### Principal components analysis
Principal components analysis was developed by Pearson in 1901.[8] The principal components analysis can only correct for confounding by independent variables that have been measured.
### Prior event rate ratio
The prior event rate ratio has been used to replicate with observational data from electronic health records the results of the Scandinavian Simvastatin Survival Study[9] and the HOPE and EUROPA trials. [10][11] Like the grouped treatment variable, the prior event ration attempts to correct for unmeasured confounding influences. However, unlike the grouped treatment variable which controls for the proportion of subjects selected for treatment, the prior event rate ratio uses the "ratio of event rates between the Exposed and Unexposed cohorts prior to study start time to adjust the study hazard ratio".[10]
Limitations of the prior event ratio is that it cannot study outcomes that have not occurred prior to onset of treatment. So for example, the prior event ratio cannot control for confounding in studies of primary prevention.
### Propensity score matching
The propensity score was introduced by Rosenbaum in 1983.[12][13] The propensity score is the "conditional probability of receiving one of the treatments under comparison ... given the observed covariates."[3] The propensity score can only correct for confounding by independent variables that have been measured.
Cohort studies with propensity matching may[14] or may not[15] resemble the results of randomized controlled trials. THis may depend on how closely the cohort study emulated the protocol of a randomized controlled trial as done in the RCT-DUPLICATE[14].
### Sensitivity analysis
Sensitivity analysis can estimate how strong must a unmeasured confounder be to reduce the effect of a factor under study.[16] An example of this analysis was a nonrandomized comparison of when to initial treatment for asymptomatic Human Immunodeficiency Virus in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) study.[6]
## Determining causality
### Bradford Hill criteria
If statistically significant associations are found, the Bradford Hill criteria can help determine whether the associations represent true causality. The Bradford Hill criteria were proposed in 1965:[17]
- Strength or magnitude of association?
- Consistency of association across studies?
- Specificity of association?
- Temporality of association?
- Plausibility based on biological knowledge?
- Biological gradient: or dose-response relationship?
- Coherence? Does the proposed association explain other observations?
- Experimental evidence?
- Analogy?
# Biases
## Immortal time bias
"Immortal time is a span of cohort follow-up during which, because of exposure definition, the outcome under study could not occur."[18]
# Assessing the quality
Many scales and checklists have been proposed for assessing the quality of cohort studies.[19] The most common items assessed with these tools are:
- Selecting study participants (92% of tools)
- Measurement of study variables (exposure, outcome and/or confounding variables) (86% of tools)
- Sources of bias (including recall bias, interviewer bias and biased loss to follow-up but excluding confounding) (86% of tools)
- Control of confounding (78% of tools)
- Statistical methods (78% of tools)
- Conflict of interest (3% of tools)
Of these tools, only one was designed for use in comparing cohort studies in any clinical setting for the purpose of conducting a systematic review of cohort studies[20]; however, this tool has been described as "extremely complex and require considerable input to calculate raw scores and to convert to final scores, depending on the primary study design and methods".[19]
The Newcastle-Ottawa Scale (NOS) may help assess the quality of nonrandomized studies.[21][22]
# Standards for reporting
Standards are available for the reporting of observational studies[23][24][25][26] with accompanying explanation and elaboration[27].
# Alternative study designs
## Case-control study
Rare outcomes, or those that slowly develop over long periods, are generally not studied with the use of a cohort study, but are rather studied with the use of a case-control study. Retrospective studies may exaggeration associations.[28]
## Randomized controlled trial
Randomized controlled trials (RCTs) are a superior methodology in the hierarchy of evidence, because they limit the potential for bias by randomly assigning one patient pool to an intervention and another patient pool to non-intervention (or placebo). This minimizes the chance that the incidence of confounding variables will differ between the two groups.[29][30]
Empiric comparisons of observational studies and RCTs conflict and both find[31][32][33][34][35] and do not find[36][37] evidence of exaggerated results from cohort studies.
Nevertheless, it is sometimes not practical or ethical to perform RCTs to answer a clinical question. To take our example, if we already had reasonable evidence that smoking causes lung cancer then persuading a pool of non-smokers to take up smoking in order to test this hypothesis would generally be considered quite unethical. | https://www.wikidoc.org/index.php/Cohort | |
03d03a85912282aa11962497dca5c6cb7fb5b9e9 | wikidoc | Cold-blooded | Cold-blooded
Cold-blooded organisms (called "poikilotherms" - "of varying temperature") maintain their body temperatures in ways different from mammals and birds. The term is now outdated in scientific contexts. Cold-blooded creatures were, initially, presumed to be incapable of maintaining their body temperatures at all. They were presumed to be "slaves" to their environments. Whatever the environmental temperature was, so too was their body temperature. Cold-blooded animals are now called ectotherms, a term which signifies that their heat (therm) comes from outside (ecto) of them; the term cold-blooded is misleading.
Advances in the study of how creatures maintain their internal temperatures (termed: Thermophysiology) have shown that many of the earlier notions of what the terms "warm-blooded" and "cold-blooded" mean, were far from accurate (see below: Definitions). Today scientists realize that body temperature types are not a simple matter of black and white. Most creatures fit more in line with a graded spectrum from one extreme (cold-blooded) to another (warm-blooded).
# Definitions
Cold-bloodedness generally refers to three separate areas of thermoregulation.
- Ectothermy - This refers to creatures that control body temperature through external means , such as the sun, or flowing air/water. For more on this, see below.
- Poikilothermy - This refers to creatures whose internal temperatures vary, often matching the ambient temperature of the immediate environment (Greek: "poikilos" ποικίλος = "varied," "thermia" θερμία = "heat"). (In medicine, loss of normal thermoregulation in humans is referred to as poikilothermia.)
- Bradymetabolism - This term refers to creatures with a high active metabolism and a considerably slower resting metabolism (Greek: "brady" βραδύ = "slow," "metabolia" μεταβολία = "to change"). Bradymetabolic animals can often undergo dramatic changes in metabolic speed, according to food availability and temperature. Many bradymetabolic creatures in deserts and in areas that experience extreme winters are capable of "shutting down" their metabolisms to approach near-death states, until favourable conditions return (see hibernation and estivation).
Few creatures actually fit all three of the above criteria. Most animals use a combination of these three aspects of thermophysiology, along with their counterparts (endothermy, homeothermy & tachymetabolism) to create a broad spectrum of body temperature types. Most of the time, creatures that use any one of the previously defined aspects are usually pigeon-holed into the term cold-blooded.
Physiologists also coined the term heterothermy for creatures that exhibit a unique case of poikilothermy.
# Types of temperature control
Examples of temperature control include:
- Snakes and lizards sunning themselves on rocks.
- Fish changing depths in the water column to find a suitable temperature.
- Desert animals burrowing beneath the sand during the day.
- Insects that warm their flight muscles by vibrating them in place.
- Dilating or constricting peripheral blood vessels to adapt more or less quickly to the ambient temperature.
Many homeothermic, or warm-blooded, animals also make use of these techniques at times. For example, all animals are at risk of hypothermia on cold days, and most homeothermic animals can shiver to get warmer.
Poikilotherms often have more complex metabolisms than homeotherms (homopathics). For an important chemical reaction, poikilotherms may have four to ten enzyme systems that operate at different temperatures. As a result, poikilotherms often have larger, more complex genomes than homeotherms in the same ecological niche. Frogs are a notable example of this effect.
Because their metabolism is so variable, poikilothermic animals do not easily support complex, high-energy organ systems such as brains or wings. Some of the most complex adaptations known involve poikilotherms with such organ systems. One example is the swimming muscles of Tuna, which are warmed by a heat exchanger.
In general, poikilothermic animals do not use their metabolisms to heat or cool themselves. For the same body weight poikilotherms need ⅓ to 1/10 of the energy of homeotherms. They therefore eat only ⅓ to 1/10 of the food needed by homeothermic animals.
Some larger poikilotherms, by virtue of their substantial volume to surface area ratio, are able to maintain relatively high body temperatures and high metabolic rates. This phenomenon, known as gigantothermy (inertial homeothermy), has been observed in sea turtles and great white sharks, and was most likely present in many dinosaurs and ancient sea reptiles (such as ichthyosaurs and plesiosaurs). For example, some species of sea turtles are homeothermic some of the time. They float on the surface of the ocean to absorb heat and then, after submerging again, stay homeothermic for periods of time because of their sheer size. During long periods of time underwater their body temperature may decrease, depending on the temperature of the surrounding water. Their body temperature may also decrease when they float on the surface of the ocean at night, depending on the surrounding temperature.
However, large dinosaurs were probably not poikilotherms, but homeotherms (homeothermic all the time) due to the overwhelming mass of their bodies.
# Ecological niches
It is comparatively easy for a poikilotherm to accumulate enough energy to reproduce. Poikilotherms in the same ecological niche often have much shorter lifetimes than homeotherms: weeks rather than years.
This energy difference also means that a given niche of a given ecology can support three to ten times the number of poikilothermic animals as homeothermic animals. However, in a given niche, homeotherms often drive poikilothermic competitors to extinction because homeotherms can gather food for a greater fraction of each day.
Poikilotherms succeed in some niches, such as islands, or distinct bioregions (such as the small bioregions of the Amazon basin). These often do not have enough food to support a viable breeding population of homeothermic animals. In these niches, poikilotherms such as large lizards, crabs and frogs supplant homeotherms such as birds and mammals. | Cold-blooded
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cold-blooded organisms (called "poikilotherms" - "of varying temperature"[1]) maintain their body temperatures in ways different from mammals and birds. The term is now outdated in scientific contexts. Cold-blooded creatures were, initially, presumed to be incapable of maintaining their body temperatures at all. They were presumed to be "slaves" to their environments. Whatever the environmental temperature was, so too was their body temperature. Cold-blooded animals are now called ectotherms, a term which signifies that their heat (therm) comes from outside (ecto) of them; the term cold-blooded is misleading.
Advances in the study of how creatures maintain their internal temperatures (termed: Thermophysiology) have shown that many of the earlier notions of what the terms "warm-blooded" and "cold-blooded" mean, were far from accurate (see below: Definitions). Today scientists realize that body temperature types are not a simple matter of black and white. Most creatures fit more in line with a graded spectrum from one extreme (cold-blooded) to another (warm-blooded).
# Definitions
Cold-bloodedness generally refers to three separate areas of thermoregulation.
- Ectothermy - This refers to creatures that control body temperature through external means , such as the sun, or flowing air/water. For more on this, see below.
- Poikilothermy - This refers to creatures whose internal temperatures vary, often matching the ambient temperature of the immediate environment (Greek: "poikilos" ποικίλος = "varied," "thermia" θερμία = "heat"). (In medicine, loss of normal thermoregulation in humans is referred to as poikilothermia.)
- Bradymetabolism - This term refers to creatures with a high active metabolism and a considerably slower resting metabolism (Greek: "brady" βραδύ = "slow," "metabolia" μεταβολία = "to change"). Bradymetabolic animals can often undergo dramatic changes in metabolic speed, according to food availability and temperature. Many bradymetabolic creatures in deserts and in areas that experience extreme winters are capable of "shutting down" their metabolisms to approach near-death states, until favourable conditions return (see hibernation and estivation).
Few creatures actually fit all three of the above criteria. Most animals use a combination of these three aspects of thermophysiology, along with their counterparts (endothermy, homeothermy & tachymetabolism) to create a broad spectrum of body temperature types. Most of the time, creatures that use any one of the previously defined aspects are usually pigeon-holed into the term cold-blooded.
Physiologists also coined the term heterothermy for creatures that exhibit a unique case of poikilothermy.
# Types of temperature control
Examples of temperature control include:
- Snakes and lizards sunning themselves on rocks.
- Fish changing depths in the water column to find a suitable temperature.
- Desert animals burrowing beneath the sand during the day.
- Insects that warm their flight muscles by vibrating them in place.
- Dilating or constricting peripheral blood vessels to adapt more or less quickly to the ambient temperature.
Many homeothermic, or warm-blooded, animals also make use of these techniques at times. For example, all animals are at risk of hypothermia on cold days, and most homeothermic animals can shiver to get warmer.
Poikilotherms often have more complex metabolisms than homeotherms (homopathics). For an important chemical reaction, poikilotherms may have four to ten enzyme systems that operate at different temperatures. As a result, poikilotherms often have larger, more complex genomes than homeotherms in the same ecological niche. Frogs are a notable example of this effect.
Because their metabolism is so variable, poikilothermic animals do not easily support complex, high-energy organ systems such as brains or wings. Some of the most complex adaptations known involve poikilotherms with such organ systems. One example is the swimming muscles of Tuna, which are warmed by a heat exchanger.
In general, poikilothermic animals do not use their metabolisms to heat or cool themselves. For the same body weight poikilotherms need ⅓ to 1/10 of the energy of homeotherms. They therefore eat only ⅓ to 1/10 of the food needed by homeothermic animals.
Some larger poikilotherms, by virtue of their substantial volume to surface area ratio, are able to maintain relatively high body temperatures and high metabolic rates. This phenomenon, known as gigantothermy (inertial homeothermy), has been observed in sea turtles and great white sharks, and was most likely present in many dinosaurs and ancient sea reptiles (such as ichthyosaurs and plesiosaurs). For example, some species of sea turtles are homeothermic some of the time. They float on the surface of the ocean to absorb heat and then, after submerging again, stay homeothermic for periods of time because of their sheer size. During long periods of time underwater their body temperature may decrease, depending on the temperature of the surrounding water. Their body temperature may also decrease when they float on the surface of the ocean at night, depending on the surrounding temperature.
However, large dinosaurs were probably not poikilotherms, but homeotherms (homeothermic all the time) due to the overwhelming mass of their bodies.
# Ecological niches
It is comparatively easy for a poikilotherm to accumulate enough energy to reproduce. Poikilotherms in the same ecological niche often have much shorter lifetimes than homeotherms: weeks rather than years.
This energy difference also means that a given niche of a given ecology can support three to ten times the number of poikilothermic animals as homeothermic animals. However, in a given niche, homeotherms often drive poikilothermic competitors to extinction because homeotherms can gather food for a greater fraction of each day.
Poikilotherms succeed in some niches, such as islands, or distinct bioregions (such as the small bioregions of the Amazon basin). These often do not have enough food to support a viable breeding population of homeothermic animals. In these niches, poikilotherms such as large lizards, crabs and frogs supplant homeotherms such as birds and mammals. | https://www.wikidoc.org/index.php/Cold-blooded |
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