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c8b757780a562e74fed242ab6b4ce38a0113e9e4 | wikidoc | Ebastine | Ebastine
# Overview
Ebastine (trade names Evastin, Kestine, Ebastel, Aleva, Ebatrol) is a H1 antihistamine with low potential for causing drowsiness.
It does not penetrate the blood–brain barrier to a significant amount and thus combines an effective block of the H1 receptor in peripheral tissue with a low incidence of central side effects, i.e. seldom causing sedation or drowsiness.
The patent in which the structure of ebastine is first mentioned is Template:Patent in Europe and Template:Patent in the US. The substance is often provided in micronised form due to poor water solubility.
# Uses and availability
Ebastine is a second-generation H1 receptor antagonist that is indicated mainly for allergic rhinitis and chronic idiopathic urticaria. It is available in 10 and 20 mg tablets and as fast-dissolving tablets, as well as in pediatric syrup. It has a recommended flexible daily dose of 10 or 20 mg, depending on disease severity.
Ebastine is available in different formulations (tablets, fast dissolving tablets and syrup) and commercialized under different brand names around the world, Ebet, Ebastel FLAS, Kestine, KestineLIO, KestinLYO, EstivanLYO, Evastel Z, Ebatrol, etc.
# Pharmacokinetic profile
After oral administration, ebastine undergoes extensive first-pass metabolism by hepatic cytochrome P450 3A4 into its active carboxylic acid metabolite, carebastine. This conversion is practically complete.
# Efficacy
Data from over 8,000 patients in more than 40 clinical trials and studies suggest efficacy of ebastine in the treatment of intermittent allergic rhinitis, persistent allergic rhinitis and other indications.
# Safety
Ebastine has shown overall safety and tolerability profile with no cognitive/psychomotor impairment and no sedation worse than placebo, and cardiac safety, that is, no QT prolongation. The incidence of most commonly reported adverse events was comparable between the ebastine and placebo groups, which confirms that ebastine has a favourable safety profile.
While experiments in pregnant animals showed no risk for the unborn, no such data are available in humans. It is not known whether ebastine passes into the breast milk. | Ebastine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ebastine (trade names Evastin, Kestine, Ebastel, Aleva, Ebatrol) is a H1 antihistamine with low potential for causing drowsiness.
It does not penetrate the blood–brain barrier to a significant amount and thus combines an effective block of the H1 receptor in peripheral tissue with a low incidence of central side effects, i.e. seldom causing sedation or drowsiness.[1][2][3]
The patent in which the structure of ebastine is first mentioned is Template:Patent in Europe and Template:Patent in the US. The substance is often provided in micronised form due to poor water solubility.
# Uses and availability
Ebastine is a second-generation H1 receptor antagonist that is indicated mainly for allergic rhinitis and chronic idiopathic urticaria.[4] It is available in 10 and 20 mg tablets[5] and as fast-dissolving tablets,[6] as well as in pediatric syrup. It has a recommended flexible daily dose of 10 or 20 mg, depending on disease severity.
Ebastine is available in different formulations (tablets, fast dissolving tablets and syrup) and commercialized under different brand names around the world, Ebet, Ebastel FLAS, Kestine, KestineLIO, KestinLYO, EstivanLYO, Evastel Z, Ebatrol, etc.
# Pharmacokinetic profile
After oral administration, ebastine undergoes extensive first-pass metabolism by hepatic cytochrome P450 3A4 into its active carboxylic acid metabolite, carebastine. This conversion is practically complete.
# Efficacy
Data from over 8,000 patients in more than 40 clinical trials[not in citation given] and studies[3][4][5][7][8][9] suggest efficacy of ebastine in the treatment of intermittent allergic rhinitis, persistent allergic rhinitis and other indications.
# Safety
Ebastine has shown overall safety and tolerability profile with no cognitive/psychomotor impairment[5] and no sedation[5] worse than placebo,[2] and cardiac safety, that is, no QT prolongation.[5] The incidence of most commonly reported adverse events was comparable between the ebastine and placebo groups, which confirms that ebastine has a favourable safety profile.
While experiments in pregnant animals showed no risk for the unborn, no such data are available in humans. It is not known whether ebastine passes into the breast milk.[2] | https://www.wikidoc.org/index.php/Ebastine | |
983dc387f8dfeaf99b3cd949512f61fe7d63af53 | wikidoc | Ecamsule | Ecamsule
Ecamsule (USAN, trade name Mexoryl® SX, INCI Terephthalylidene Dicamphor Sulfonic Acid) is a chemical which is added to many sunscreens to filter out UVA rays. It is a benzylidene camphor derivative, many of which are known for their excellent photostability.
Although there are a few different UV absorbers with the trade name Mexoryl, only two of them are widely used where approved. Mexoryl SX (water soluble) and Mexoryl XL (INCI Drometrizole Trisiloxane, oil soluble). Together they show a synergistic effect in protection. The patents are held by L’Oréal. Sunscreens containing ecamsule are exclusive to L’Oréal and its brands.
# Mode of action
Exposed to UV, ecamsule undergoes reversible photoisomerization, followed by photoexcitation. The absorbed UV is then released as thermal energy, without penetrating the skin.
UVB rays cause short-term sunburn and skin cancer; UVA rays cause wrinkling and may have some role in development of skin cancer. There is no official rating for UVA protection in the US. In Europe, there are several different rating systems that are used to measure effectiveness in blocking UVA rays, including the IPD (immediate pigment darkening assay) and the PPD (persistent pigment darkening assay). The UVB range is 280 to 320 nanometers, and the UVA range is 320 to 400. Ecamsule protects against UV wavelengths in the 290–400 nanometer range, with peak protection at 345 nm. Since ecamsule doesn't cover the entire UV spectrum, it should be combined with other active sunscreen agents to ensure broad-spectrum UV protection. Ecamsule is a photostable organic UVA absorber, meaning it doesn't degrade significantly when exposed to light. This is in contrast to the widely used UVA absorber avobenzone that is not intrinsically photostable and requires photostabilizers to prevent significant degradation in light.
# Efficacy
A 5% ecamsule containing sunscreen can prevent early changes leading to photoaging in humans. A broad spectrum sunscreen with ecamsule, avobenzone and octocrylene significantly reduces the skin damage associated with UV exposure in human subjects.
In studies done in mice it reduces the formation of UV induced pyrimidine dimers and delays the onset of skin cancer. In vitro ecamsule effectively protects against the harmful effects of UV.
# Safety
Ecamsule has little percutaneous absorption and little systemic effects, therefore it is considered relatively safe.
A mouse study shows that it does not increase the probability of promoting skin cancer. Studies done in vitro show that it is not photomutagenic.
Because ecamsule is an acid it needs to be neutralized in order to be used without offsetting the final pH of the sunscreen too much. Usually this is done with triethanolamine.
# Availability
L’Oréal patented ecamsule first in 1982. It was approved in the EU in 1991. Sunscreens based on ecamsule have been available in Europe, Canada and other parts of the world since 1993, and was just recently given approval by the FDA in the U.S. However this approval only extends to ecamsule containing sunscreens registered as New Drug Application, not ecamsule itself. | Ecamsule
Template:OrganicBox small
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Ecamsule (USAN, trade name Mexoryl® SX, INCI Terephthalylidene Dicamphor Sulfonic Acid) is a chemical which is added to many sunscreens to filter out UVA rays. It is a benzylidene camphor derivative, many of which are known for their excellent photostability.[1]
Although there are a few different UV absorbers with the trade name Mexoryl, only two of them are widely used where approved. Mexoryl SX (water soluble) and Mexoryl XL (INCI Drometrizole Trisiloxane, oil soluble). Together they show a synergistic effect in protection.[2] The patents are held by L’Oréal. Sunscreens containing ecamsule are exclusive to L’Oréal and its brands.
# Mode of action
Exposed to UV, ecamsule undergoes reversible photoisomerization, followed by photoexcitation. The absorbed UV is then released as thermal energy, without penetrating the skin.
UVB rays cause short-term sunburn and skin cancer; UVA rays cause wrinkling and may have some role in development of skin cancer. There is no official rating for UVA protection in the US. In Europe, there are several different rating systems that are used to measure effectiveness in blocking UVA rays, including the IPD (immediate pigment darkening assay) and the PPD (persistent pigment darkening assay). The UVB range is 280 to 320 nanometers, and the UVA range is 320 to 400. Ecamsule protects against UV wavelengths in the 290–400 nanometer range, with peak protection at 345 nm.[3][4] Since ecamsule doesn't cover the entire UV spectrum, it should be combined with other active sunscreen agents to ensure broad-spectrum UV protection. Ecamsule is a photostable organic UVA absorber, meaning it doesn't degrade significantly when exposed to light. This is in contrast to the widely used UVA absorber avobenzone that is not intrinsically photostable and requires photostabilizers to prevent significant degradation in light.[5][6][7]
# Efficacy
A 5% ecamsule containing sunscreen can prevent early changes leading to photoaging in humans. A broad spectrum sunscreen with ecamsule, avobenzone and octocrylene significantly reduces the skin damage associated with UV exposure in human subjects.[8]
In studies done in mice it reduces the formation of UV induced pyrimidine dimers and delays the onset of skin cancer. In vitro ecamsule effectively protects against the harmful effects of UV.[9]
# Safety
Ecamsule has little percutaneous absorption and little systemic effects, therefore it is considered relatively safe.[10]
A mouse study shows that it does not increase the probability of promoting skin cancer.[11] Studies done in vitro show that it is not photomutagenic.[12]
Because ecamsule is an acid it needs to be neutralized in order to be used without offsetting the final pH of the sunscreen too much. Usually this is done with triethanolamine.
# Availability
L’Oréal patented ecamsule first in 1982. It was approved in the EU in 1991. Sunscreens based on ecamsule have been available in Europe, Canada and other parts of the world since 1993, and was just recently given approval by the FDA in the U.S.[13] However this approval only extends to ecamsule containing sunscreens registered as New Drug Application, not ecamsule itself.[14][15] | https://www.wikidoc.org/index.php/Ecamsule | |
5ffd1c0a50abfd2773f403645af1377cb2040cb0 | wikidoc | Edoxaban | Edoxaban
# 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
Edoxaban is a factor Xa inhibitor that is FDA approved for the prevention of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). Is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding and anemia in the treatment of NVAF (≥ 5%) and bleeding, rash, abnormal liver function tests and anemia in the treatment of DVT and PE (≥ 1%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
Edoxaban is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).
- Limitation of Use for NVAF
Edoxaban should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin.
- Treatment of Deep Vein Thrombosis and Pulmonary Embolism
Edoxaban is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.
- Nonvalvular Atrial Fibrillation
The recommended dose of Edoxaban is 60 mg taken orally once daily. Assess creatinine clearance, as calculated using the Cockcroft-Gault equation*, before initiating therapy with Edoxaban. Do not use Edoxaban in patients with CrCL > 95 mL/min.
Reduce Edoxaban dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min.
- Treatment of Deep Vein Thrombosis and Pulmonary Embolism
The recommended dose of Edoxaban is 60 mg taken orally once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant.
The recommended dose of Edoxaban is 30 mg once daily in patients with CrCL 15 to 50 mL/min, patients who weigh less than or equal to 60 kg, or patients who are taking certain concomitant P-gp inhibitor medications based on clinical study data in this indication.
- Administration Information
If a dose of Edoxaban is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule. The dose should not be doubled to make up for a missed dose.
Edoxaban can be taken without regard to food.
- Transition to or from Edoxaban
- Transition to Edoxaban
SAVAYSA: Edoxaban tosylate's Brand name
- Transition from Edoxaban
SAVAYSA: Edoxaban tosylate's Brand name
- Discontinuation for Surgery and Other Interventions
Discontinue Edoxaban at least 24 hours before invasive or surgical procedures because of the risk of bleeding.
If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.
Edoxaban can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established noting that the time to onset of pharmacodynamic effect is 1-2 hours. Administer a parenteral anticoagulant and then switch to oral Edoxaban, if oral medication cannot be taken during or after surgical intervention.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
Total arthroplasty of knee - Postoperative deep vein thrombosis (Prophylaxis)
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Edoxaban tosylate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Edoxaban tosylate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Edoxaban tosylate in pediatric patients.
# Contraindications
Edoxaban is contraindicated in patients with active pathological bleeding.
# Warnings
Edoxaban should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AF-TIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with Edoxaban 60 mg daily compared to patients treated with warfarin. In these patients another anticoagulant should be used.
Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If Edoxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance.
Edoxaban increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss.
Discontinue Edoxaban in patients with active pathological bleeding.
Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.
- Reversal of Anticoagulant Effect
There is no established way to reverse the anticoagulant effects of Edoxaban, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of Edoxaban cannot be reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of Edoxaban. The use of prothrombin complex concentrates (PCC), or other procoagulant reversal agents such as activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical outcome studies. When PCCs are used, monitoring for anticoagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or anti-FXa activity is not useful and is not recommended.
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.
The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 12 hours after the last administration of Edoxaban. The next dose of Edoxaban should not be administered earlier than 2 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture.
Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
The safety and efficacy of Edoxaban has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. The use of Edoxaban is not recommended in these patients.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.
- Increased risk of stroke with discontinuation of Edoxaban in patients with NVAF
- Spinal/epidural anesthesia or puncture
The most serious adverse reactions reported with Edoxaban were related to bleeding.
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 Edoxaban was evaluated in the ENGAGE AF-TIMI 48 and Hokusai VTE studies including 11,130 patients exposed to Edoxaban 60 mg and 7002 patients exposed to Edoxaban 30 mg once daily.
- The ENGAGE AF-TIMI 48 Study
In the ENGAGE AF-TIMI 48 study, the median study drug exposure for the Edoxaban and warfarin treatment groups was 2.5 years.
Bleeding was the most common reason for treatment discontinuation. Bleeding led to treatment discontinuation in 3.9% and 4.1% of patients in the Edoxaban 60 mg and warfarin treatment groups, respectively.
In the overall population, Major Bleeding was lower in the Edoxaban group compared to the warfarin group . TABLE 1 shows Major Bleeding events (percentage of patients with at least one bleeding event, per year) for the indicated population (CrCL ≤ 95 mL/min).
- Table 1: Adjudicated Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/min*
SAVAYSA: Edoxaban tosylate's Brand name
The most common site of a Major Bleeding event was the gastrointestinal (GI) tract. TABLE 2 shows the number of and the rate at which patients experienced GI bleeding in the Edoxaban 60 mg and warfarin treatment groups.
- Table 2: Gastrointestinal Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/min*
SAVAYSA: Edoxaban tosylate's Brand name
The rate of anemia-related adverse events was greater with Edoxaban 60 mg than with warfarin (9.6% vs. 6.8%).
The comparative rates of Major Bleeding on Edoxaban and warfarin were generally consistent among subgroups (see FIGURE 1). Bleeding rates appeared higher in both treatment arms (Edoxaban and warfarin) in the following subgroups of patients: those receiving aspirin, those in the United States, those more than 75 years old and those with reduced renal function.
- Figure 1: Adjudicated Major Bleeding in the ENGAGE AF-TIMI 48- Study
SAVAYSA: Edoxaban tosylate's Brand name
- Other Adverse Reactions
The most common non-bleeding adverse reactions (≥ 1%) for Edoxaban 60 mg versus warfarin were rash (4.2% vs. 4.1%), and abnormal liver function tests (4.8% vs. 4.6%), respectively.
Interstitial Lung Disease (ILD) was reported as a serious adverse event on treatment for Edoxaban 60 mg and warfarin in 15 (0.2%) and 7 (0.1%) patients, respectively. Many of the cases in both treatment groups were confounded by the use of amiodarone, which has been associated with ILD, or by infectious pneumonia. In the overall study period, there were 5 and 0 fatal ILD cases in the Edoxaban 60 mg and warfarin groups, respectively.
- The Hokusai VTE Study
In the Hokusai VTE study, the duration of drug exposure for Edoxaban was ≤ 6 months for 1561 (37.9%) of patients, > 6 months for 2557 (62.1%) of patients and 12 months for 1661 (40.3%) of patients.
Bleeding was the most common reason for treatment discontinuation and occurred in 1.4% and 1.4% of patients in the Edoxaban and warfarin arms, respectively.
- Bleeding in Patients with DVT and/or PE in the Hokusai VTE Study
The primary safety endpoint was Clinically Relevant Bleeding, defined as the composite of Major and Clinically Relevant Non-Major (CRNM) Bleeding that occurred during or within three days of stopping study treatment. The incidence of Clinically Relevant Bleeding was lower in Edoxaban than warfarin .
TABLE 3 shows the number of patients experiencing bleeding events in the Hokusai VTE Study.
- Table 3: Bleeding Events in the Hokusai VTE Study
SAVAYSA: Edoxaban tosylate's Brand name
Patients with low body weight (≤ 60 kg), CrCL ≤ 50 mL/min, or concomitant use of select P-gp inhibitors were randomized to receive Edoxaban 30 mg or warfarin. As compared to all patients who received Edoxaban or warfarin in the 60 mg cohort, all patients who received Edoxaban or warfarin in the 30 mg cohort (n= 1452, 17.6% of the entire study population) were older (60.1 vs 54.9 years), more frequently female (66.5% vs 37.7%), more frequently of Asian race (46.0% vs 15.6%) and had more co-morbidities (e.g., history of bleeding, hypertension, diabetes, cardiovascular disease, cancer). Clinically relevant bleeding events occurred in 58/733 (7.9%) of the Edoxaban patients receiving 30 mg once daily and 92/719 (12.8%) of warfarin patients meeting the above criteria.
In the Hokusai VTE study, among all patients the most common bleeding adverse reactions (≥ 1%) are shown in TABLE 4.
- Table 4: Adverse Reactions Occurring in ≥ 1% of Patients Treated in Hokusai VTE
SAVAYSA: Edoxaban tosylate's Brand name
## Postmarketing Experience
There is limited information regarding Edoxaban Postmarketing Experience in the drug label.
# Drug Interactions
- Anticoagulants, Antiplatelets, and Thrombolytics
Co-administration of anticoagulants, antiplatelet drugs, and thrombolytics may increase the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with anticoagulants, aspirin, other platelet aggregation inhibitors, and/or NSAIDs.
Long-term concomitant treatment with Edoxaban and other anticoagulants is not recommended because of increased risk of bleeding. Short term co-administration may be needed for patients transitioning to or from Edoxaban.
In clinical studies with Edoxaban concomitant use of aspirin (low dose ≤ 100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted in increased rates of Clinically Relevant Bleeding. Carefully monitor for bleeding in patients who require chronic treatment with low dose aspirin and/or NSAIDs.
- P-gp Inducers
Avoid the concomitant use of Edoxaban with rifampin.
- P-gp Inhibitors
- Treatment of NVAF
Based on clinical experience from the ENGAGE AF-TIMI 48 study, dose reduction in patients concomitantly receiving P-gp inhibitors resulted in edoxaban blood levels that were lower than in patients who were given the full dose. Consequently, no dose reduction is recommended for concomitant P-gp inhibitor use.
- Treatment of Deep Vein Thrombosis and Pulmonary Embolism
See Clinical Studies
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Risk Summary
There are no adequate and well-controlled studies in pregnant women. Edoxaban should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Human Data
In the Hokusai VTE study there were 10 pregnancy cases reported in patients receiving Edoxaban with exposure in the first trimester and estimated duration of exposure for up to approximately 6 weeks. Among these there were 6 live births (4 full term, 2 pre-term), 1 first-trimester spontaneous abortion, and 3 cases of elective termination of pregnancy.
- Animal Data
Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no teratogenic effects were seen when edoxaban was administered orally at doses up to 300 mg/kg/day, or 49 times the human dose of 60 mg/day normalized to body surface area. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose. In rabbits, no teratogenic effects were seen at doses up to 600 mg/kg/day (49 times the human exposure at a dose of 60 mg/day when based on AUC). Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day, which is equal to or greater than 20 times the human exposure.
In a rat pre- and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to 3 times the human exposure when based on AUC. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Edoxaban in women who are pregnant.
### Labor and Delivery
Safety and effectiveness of Edoxaban during labor and delivery have not been studied in clinical studies. The risks of bleeding should be balanced with the risk of thrombotic events when considering the use of Edoxaban in this setting.
### Nursing Mothers
It is not known if edoxaban is excreted in human milk. Edoxaban was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Edoxaban, a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Of the total patients in the ENGAGE AF-TIMI 48 study, 5182 (74%) were 65 years and older, while 2838 (41%) were 75 years and older. In Hokusai VTE, 1334 (32%) patients were 65 years and older, while 560 (14%) patients were 75 years and older. In clinical trials the efficacy and safety of Edoxaban in elderly (65 years or older) and younger patients were similar.
### Gender
There is no FDA guidance on the use of Edoxaban with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Edoxaban with respect to specific racial populations.
### Renal Impairment
Renal clearance accounts for approximately 50% of the total clearance of edoxaban. Consequently, edoxaban blood levels are increased in patients with poor renal function compared to those with higher renal function. Reduce Edoxaban dose to 30 mg once daily in patients with CrCL 15-50 mL/min. There are limited clinical data with Edoxaban in patients with CrCL < 15 mL/min; Edoxaban is therefore not recommended in these patients. Hemodialysis does not significantly contribute to Edoxaban clearance.
As renal function improves and edoxaban blood levels decrease, the risk for ischemic stroke increases in patients with NVAF.
### Hepatic Impairment
The use of Edoxaban in patients with moderate or severe hepatic impairment (Child-Pugh B and C) is not recommended as these patients may have intrinsic coagulation abnormalities. No dose reduction is required in patients with mild hepatic impairment (Child-Pugh A).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Edoxaban in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Edoxaban in patients who are immunocompromised.
### Low Body Weight Consideration for Patients treated for DVT and/or PE
Based on the clinical experience from the Hokusai VTE study, reduce Edoxaban dose to 30 mg in patients with body weight less than or equal to 60 kg.
# Administration and Monitoring
### Administration
There is limited information regarding Edoxaban Administration in the drug label.
### Monitoring
There is limited information regarding Edoxaban Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Edoxaban and IV administrations.
# Overdosage
A specific reversal agent for edoxaban is not available. Overdose of Edoxaban increases the risk of bleeding.
The following are not expected to reverse the anticoagulant effects of edoxaban: protamine sulfate, vitamin K, and tranexamic acid.
Hemodialysis does not significantly contribute to edoxaban clearance.
# Pharmacology
## Mechanism of Action
Edoxaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Edoxaban inhibits free FXa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation.
## Structure
Edoxaban, a factor Xa inhibitor, is supplied as edoxaban tosylate monohydrate. The chemical name is N-(5-Chloropyridin-2-yl)-N′-thiazolopyridine-2-carboxamido)cyclohexyl] oxamide mono (4-methylbenzenesulfonate) monohydrate. Edoxaban tosylate monohydrate has the empirical formula C24H30ClN7O4SC7H8O3SH2O representing a molecular weight of 738.27. The chemical structure of edoxaban tosylate monohydrate is:
It is a white to pale yellowish-white crystalline powder. The solubility of edoxaban tosylate (pKa 6.7) decreases with increasing pH. It is slightly soluble in water, pH 3 to 5 buffer, very slightly soluble at pH 6 to 7; and practically insoluble at pH 8 to 9.
Edoxaban is available for oral administration as a 60 mg, 30 mg, or 15 mg round shaped, film-coated tablet, debossed with product identification markings. Each 60 mg tablet contains 80.82 mg edoxaban tosylate monohydrate equivalent to 60 mg of edoxaban. Each 30 mg tablet contains 40.41 mg edoxaban tosylate monohydrate equivalent to 30 mg of edoxaban. Each 15 mg tablet contains 20.20 mg edoxaban tosylate monohydrate equivalent to 15 mg of edoxaban. The inactive ingredients are: mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, and carnauba wax. The color coatings contain hypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow (60 mg tablets and 15 mg tablets), and iron oxide red (30 mg tablets and 15 mg tablets).
## Pharmacodynamics
As a result of FXa inhibition, edoxaban prolongs clotting time tests such as prothrombin time (PT), and activated partial thromboplastin time (aPTT). Changes observed in PT, INR, and aPTT at the expected therapeutic dose, however, are small, subject to a high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (Cmax).
- Cardiac Electrophysiology
In a thorough QT study in healthy men and women aged 19-45 years, no QTc interval prolongation was observed with edoxaban (90 mg and 180 mg).
- Effect of PCCs on Pharmacodynamics of Edoxaban
There is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received Edoxaban.
Effects of PCC (50 IU/kg) on the pharmacodynamics of edoxaban were studied in healthy subjects following a punch biopsy. Following administration of a single dose of edoxaban, endogenous thrombin potential (ETP) returned to pre-edoxaban baseline levels in 0.5 hours after the initiation of a 15 minute infusion of 50 IU/kg PCC, compared to more than 24 hours with placebo. Mean ETP levels continued to increase and exceeded pre-edoxaban baseline, reaching maximum elevations (~40% over pre-edoxaban levels) at 22 hours after initiating PCC dose, which was the last observation of ETP. The clinical relevance of this ETP increase is unknown.
- Pharmacodynamic Interactions
- Aspirin
Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
- NSAID (Naproxen)
Co-administration of naproxen (500 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
## Pharmacokinetics
Edoxaban displays approximately dose-proportional pharmacokinetics for doses of 15 to 150 mg and 60 to 120 mg following single and repeat doses, respectively, in healthy subjects.
- Absorption
Following oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%. Food does not affect total systemic exposure to edoxaban. Edoxaban was administered with or without food in the ENGAGE AF-TIMI 48 and Hokusai VTE trials. No data are available regarding the bioavailability upon crushing and/or mixing of edoxaban tablets into food, liquids, or administration through feeding tubes.
- Distribution
Disposition is biphasic. The steady-state volume of distribution (Vdss) is 107 (19.9) L . In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing.
Steady-state concentrations are achieved within 3 days.
- Metabolism
Unchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4.
The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.
- Elimination
Edoxaban is eliminated primarily as unchanged drug in the urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance. The terminal elimination half-life of edoxaban following oral administration is 10 to 14 hours.
- Specific Populations
- Hepatic Impairment
In a dedicated pharmacokinetic study, patients with mild or moderate hepatic impairment (classified as Child-Pugh A or Child-Pugh B) exhibited similar pharmacokinetics and pharmacodynamics to their matched healthy control group. There is no clinical experience with edoxaban in patients with severe hepatic impairment.
- Renal Impairment
In a dedicated pharmacokinetic study, total systemic exposure to edoxaban for subjects with CrCL > 50 to < 80 mL/min, CrCL 30 to 50 mL/min, CrCL < 30 mL/min, or undergoing peritoneal dialysis, were increased by 32%, 74%, 72%, and 93%, respectively, relative to subjects with CrCL ≥ 80 mL/min.
- Hemodialysis
A 4-hour hemodialysis session reduced total edoxaban exposure by less than 7%.
- Age
In a population pharmacokinetic analysis, after taking renal function and body weight into account, age had no additional clinically significant effect on edoxaban pharmacokinetics.
- Weight
In a population pharmacokinetic analysis, total exposure in patients with median low body weight (55 kg) was increased by 13% as compared with patients with median high body weight (84 kg).
- Gender
In a population pharmacokinetic analysis, after accounting for body weight, gender had no additional clinically significant effect on edoxaban pharmacokinetics.
- Race
In a population pharmacokinetic analysis, edoxaban exposures in Asian patients and non-Asian patients were similar.
- Drug Interactions
- In vitro Drug Interactions Studies
In vitro studies indicate that edoxaban does not inhibit the major cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4) and does not induce CYP1A2, CYP3A4 or the P-gp transporter (MDR1). In vitro data also indicate that edoxaban does not inhibit the following transporters at clinically relevant concentrations: P-gp, the organic anion transporters OAT1 or OAT3; the organic cation transporters OCT1 or OCT2; or the organic ion transporting polypeptides OATP1B1 or OATP1B3. Edoxaban is a substrate of P-gp transporter.
- Impact of Other Drugs on Edoxaban
The effect of co-administered amiodarone, cyclosporine, dronedarone, erythromycin, ketoconazole, quinidine, verapamil, and rifampin on edoxaban exposure is shown in FIGURE 2.
- Figure 2: Summary of Drug Interaction Study Results
- Impact of Edoxaban on Other Drugs
Edoxaban increased the Cmax of concomitantly administered digoxin by 28%; however, the AUC was not affected. Edoxaban had no effect on the Cmax and AUC of quinidine.
Edoxaban decreased the Cmax and AUC of concomitantly administered verapamil by 14% and 16%, respectively.
## Nonclinical Toxicology
Edoxaban was not carcinogenic when administered daily to mice and rats by oral gavage for up to 104 weeks. The highest dose tested (500 mg/kg/day) in male and female mice was 3 and 6 times, respectively, the human exposure (AUC) at the human dose of 60 mg/day, and the highest doses tested in male (600/400 mg/kg/day) and female (200 mg/kg/day) rats were 8 and 14 times, respectively, the human exposure at the human dose of 60 mg/day.
Edoxaban and its human-specific metabolite, M-4, were genotoxic in in vitro chromosomal aberration tests but were not genotoxic in the in vitro bacterial reverse mutation (Ames test), in in vitro human lymphocytes micronucleus test, in in vivo rat bone marrow micronucleus test, in in vivo rat liver micronucleus test, and in in vivo unscheduled DNA synthesis tests.
Edoxaban showed no effects on fertility and early embryonic development in rats at doses of up to 1000 mg/kg/day (162 times the human dose of 60 mg/day normalized to body surface area).
# Clinical Studies
- The ENGAGE AF-TIMI 48 Study
The ENGAGE AF-TIMI 48 study was a multi-national, double-blind, non-inferiority study comparing the efficacy and safety of two Edoxaban treatment arms (60 mg and 30 mg) to warfarin (titrated to INR 2.0 to 3.0) in reducing the risk of stroke and systemic embolic events in patients with NVAF. The non-inferiority margin (degree of inferiority of Edoxaban to warfarin that was to be ruled out) was set at 38%, reflecting the substantial effect of warfarin in reducing strokes. The primary analysis included both ischemic and hemorrhagic strokes.
To enter the study, patients had to have one or more of the following additional risk factors for stroke:
- a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or
- 2 or more of the following risk factors:
- age ≥ 75 years,
- hypertension,
- heart failure, or
- diabetes mellitus
A total of 21,105 patients were randomized and followed for a median of 2.8 years and treated for a median of 2.5 years. Patients in the Edoxaban treatment arms had their dose halved (60 mg halved to 30 mg or 30 mg halved to 15 mg) if one or more of the following clinical factors were present: CrCL ≤ 50 mL/min, low body weight (≤ 60 kg) or concomitant use of specific P-gp inhibitors (verapamil, quinidine, dronedarone). Patients on antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) as well as cyclosporine were excluded from the study. Approximately 25% of patients in all treatment groups received a reduced dose at baseline, and an additional 7% were dose-reduced during the study. The most common reason for dose reduction was a CrCL ≤ 50 mL/min at randomization (19% of patients).
Patients were well balanced with respect to demographic and baseline characteristics. The percentages of patients age ≥ 75 years and ≥ 80 years were approximately 40% and 17%, respectively. The majority of patients were Caucasian (81%) and male (62%). Approximately 40% of patients had not taken a Vitamin K Antagonist (VKA) (i.e., never took a VKA or had not taken a VKA for more than 2 months).
The mean patient body weight was 84 kg (185 lbs) and 10% of patients had a body weight of ≤ 60 kg. Concomitant diseases of patients in this study included hypertension (94%), congestive heart failure (58%), and prior stroke or transient ischemic attack (28%). At baseline, approximately 30% of patients were on aspirin and approximately 2% of patients were taking a thienopyridine.
Patients randomized to the warfarin arm achieved a mean TTR (time in therapeutic range, INR 2.0 to 3.0) of 65% during the course of the study.
The primary endpoint of the study was the occurrence of first stroke (either ischemic or hemorrhagic) or of a systemic embolic event (SEE) that occurred during treatment or within 3 days from the last dose taken. In the overall results of the study, shown in TABLE 5, both treatment arms of Edoxaban were non-inferior to warfarin for the primary efficacy endpoint of stroke or SEE. However, the 30 mg (15 mg dose-reduced) treatment arm was numerically less effective than warfarin for the primary endpoint, and was also markedly inferior in reducing the rate of ischemic stroke. Based on the planned superiority analysis (ITT, which required p < 0.01 for success), statistical superiority of the 60 mg (30 mg dose-reduced) treatment arm compared to warfarin was not established in the total study population, but there was a favorable trend .
- Table 5: Strokes and Systemic Embolic Events in the ENGAGE AF-TIMI 48 Study (mITT, on Treatmenta)
SAVAYSA: Edoxaban tosylate's Brand name
FIGURE 3 is a plot of the time from randomization to the occurrence of the first primary endpoint in all patients randomized to 60 mg Edoxaban or warfarin.
- Figure 3: Kaplan-Meier Cumulative Event Rate Estimates for Primary Endpoint (first occurrence of stroke or SEE) (mITT*)
SAVAYSA: Edoxaban tosylate's Brand name
The incidence rate of the primary endpoint of stroke or SEE in patients (N=1776) treated with the 30 mg reduced dose of Edoxaban because of a CrCL level ≤ 50 mL/min, low body weight ≤ 60 kg, or the concomitant use of a P-gp inhibitor drug, was 1.79% per year. Patients with any of these characteristics who were randomized to receive warfarin had an incidence rate of the primary endpoint of 2.21% per year .
In all randomized patients during the overall study period, the rates of CV death with Edoxaban and warfarin were 2.74% per year vs. 3.17% per year, respectively .
The results in the ENGAGE AF-TIMI 48 study for the primary efficacy endpoint for most major subgroups are displayed in FIGURE 4.
- Figure 4: ENGAGE AF-TIMI 48 Study: Primary Efficacy Endpoint by Subgroups (ITT Analysis Set)
SAVAYSA: Edoxaban tosylate's Brand name
Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
The results of the ENGAGE AF-TIMI 48 study show a strong relationship between the blood levels of edoxaban and its effectiveness in reducing the rate of ischemic stroke. There was a 64% increase in the ischemic stroke rate in patients in the 30 mg treatment arm (including patients with dose reduced to 15 mg) compared to the 60 mg treatment arm (including patients with dose reduced to 30 mg). Approximately half of the Edoxaban dose is eliminated by the kidney, and edoxaban blood levels are lower in patients with better renal function, averaging about 30% less in patients with CrCL of > 80 mL/min, and 40% less in patients with CrCL > 95 mL/min when compared to patients with a CrCL of > 50 to ≤ 80 mL/min. Given the clear relationship of dose and blood levels to effectiveness in the ENGAGE AF-TIMI 48 study, it could be anticipated that patients with better renal function would show a smaller effect of Edoxaban compared to warfarin than would patients with mildly impaired renal function, and this was in fact observed.
TABLE 6 shows the results for the study primary efficacy endpoint of first stroke or SEE as well as the effects on ischemic and hemorrhagic stroke in the pre-randomization CrCL subgroups for Edoxaban 60 mg (including 30 mg dose-reduced) and warfarin. There was a decreased rate of ischemic stroke with Edoxaban 60 mg compared to warfarin in patients with CrCL > 50 to ≤ 80 mL/min . In patients with CrCL > 80 to ≤ 95 mL/min the results for ischemic stroke slightly favor warfarin with a confidence interval that crosses 1.0 . The rate of ischemic stroke was higher relative to warfarin in the patients with CrCL > 95 mL/min . Pharmacokinetic data indicate that patients with CrCL > 95 mL/min had lower plasma edoxaban levels, along with a lower rate of bleeding relative to warfarin than patients with CrCL ≤ 95 mL/min. Consequently, Edoxaban should not be used in patients with CrCL > 95 mL/min.
In patients with CrCL ≤ 95 mL/min, the Edoxaban 60 mg (30 mg dose-reduced) treatment arm reduced the risk of Stroke or SEE when compared to warfarin .
In the indicated population (CrCL ≤ 95 mL/min), during the overall study period, the rates of CV death with Edoxaban and warfarin were 2.95% per year vs. 3.59% per year, respectively .
- Table 6: Primary Endpoint, Ischemic and Hemorrhagic Stroke Results in as a Function of Baseline Creatinine Clearance (mITT Population, On Treatment)
SAVAYSA: Edoxaban tosylate's Brand name
- Transition to Other Anticoagulants in the ENGAGE AF-TIMI 48 Study
In the ENGAGE AF-TIMI 48 study, the schemes for transitioning from study medication to open-label warfarin at the end of study were associated with similar rates of stroke and systemic embolism in the Edoxaban 60 mg and warfarin groups. In the Edoxaban 60 mg group 7 (0.2%) of 4529 patients had a stroke or SEE compared to 7 (0.2%) of 4506 patients in the warfarin arm.
- The Hokusai VTE Study
Edoxaban for the treatment of patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) was studied in a multi-national, double-blind study (Hokusai VTE) which compared the efficacy and safety of Edoxaban 60 mg orally once daily to warfarin (titrated to INR 2.0 to 3.0) in patients with acute symptomatic venous thromboembolism (VTE) (DVT or PE with or without DVT). All patients had VTE confirmed by appropriate diagnostic imaging at baseline and received initial heparin therapy with low molecular weight heparin (LMWH) or unfractionated heparin for at least 5 days and until INR (sham or real) was ≥ 2.0 on two measurements. Blinded drug treatment in the warfarin arm was started concurrently with initial heparin therapy and in the Edoxaban arm after discontinuation of initial heparin. Patients randomized to Edoxaban received 30 mg once daily if they met one or more of the following criteria: CrCL 30 to 50 mL/min, body weight ≤ 60 kg, or concomitant use of specific P-gp inhibitors (verapamil and quinidine or the short-term concomitant administration of azithromycin, clarithromycin, erythromycin, oral itraconazole or oral ketoconazole). The edoxaban dosage regimen was to be returned to the regular dosage of 60 mg once daily at any time the subject is not taking the concomitant medication provided no other criteria for dose reduction are met. Other P-gp inhibitors were not permitted in the study. Patients on antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) as well as cyclosporine were excluded from the Hokusai VTE study. The concomitant use of these drugs with Edoxaban has not been studied in patients. The treatment duration was from 3 months up to 12 months, determined by investigator based on patient clinical features. Patients were excluded if they required thrombectomy, insertion of a caval filter, use of a fibrinolytic agent, or use of other P-gp inhibitors, had a creatinine clearance < 30 mL/min, significant liver disease, or active bleeding. The primary efficacy outcome was symptomatic VTE, defined as the composite of recurrent DVT, new non-fatal symptomatic PE, and fatal PE during the 12-month study period.
A total of 8292 patients were randomized to receive Edoxaban or warfarin and were followed for a mean treatment duration of 252 days for Edoxaban and 250 days for warfarin. The mean age was approximately 56 years. The population was 57% male, 70% Caucasian, 21% Asian, and about 4% Black. The presenting diagnosis was PE (with or without DVT) in 40.7% and DVT only in 59.3% of patients. At baseline, 27.6% of patients had temporary risk factors only (e.g., trauma, surgery, immobilization, estrogen therapy). Overall 9.4% had a history of cancer, 17.3% of the patients had an age ≥ 75 years and/or a body weight ≤ 50 kg, and/or a CrCL < 50 mL/min, and 31.4% of patients had NT-ProBNP ≥ 500 pg/mL.
Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 9% of patients in both groups.
In the warfarin group, the median TTR (time in therapeutic range, INR 2.0 to 3.0) was 65.6%.
A total of 8240 patients (n= 4118 for Edoxaban and n = 4122 for warfarin) received study drug and were included in the modified intent-to-treat (mITT) population. Edoxaban was demonstrated to be non inferior to warfarin for the primary endpoint of recurrent VTE (TABLE 7, FIGURE 5).
- Table 7: Primary Composite Efficacy Endpoint Results in Hokusai VTE (mITT Overall Study Period)
SAVAYSA: Edoxaban tosylate's Brand name
- Figure 5: Kaplan-Meier Cumulative Event Rate Estimates for Adjudicated Recurrent VTE (mITT analysis – on treatment)
SAVAYSA: Edoxaban tosylate's Brand name
# How Supplied
Edoxaban tosylate is supplied as:
- 60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60 on one side
- 30 mg, pink round shaped, film-coated tablets, debossed with DSC L30 on one side
- 15 mg, orange round shaped, film-coated tablets, debossed with DSC L15 on one side
## Storage
Store at 20-25°C (68-77°F); excursions permitted to 15°-30°C (59°-86°F).
Keep out of the reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
Advise patients of the following:
- they may bleed more easily, may bleed longer, or bruise more easily when treated with Edoxaban
- to report any unusual bleeding immediately to their healthcare provider
- to take Edoxaban exactly as prescribed
- to not discontinue Edoxaban without talking to the healthcare provider who prescribed it
- to inform their healthcare providers that they are taking Edoxaban before any surgery, medical, or dental procedure is scheduled
- to inform their healthcare providers and dentists if they plan to take, or are taking any prescription medications, over-the-counter drugs or herbal products
- to inform their healthcare provider immediately if they become pregnant or intend to become pregnant or are breastfeeding or intend to breastfeed during treatment with Edoxaban
- that if a dose is missed, take Edoxaban as soon as possible the same day, and resume the normal dosing schedule the following day. The dose should not be doubled to make up for a missing dose
- that if they are having neuraxial anesthesia or spinal puncture, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately.
# Precautions with Alcohol
Alcohol-Edoxaban interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
SAVAYSA™
# Look-Alike Drug Names
There is limited information regarding Edoxaban Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Edoxaban
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
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# Black Box Warning
# Overview
Edoxaban is a factor Xa inhibitor that is FDA approved for the prevention of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). Is also indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant. There is a Black Box Warning for this drug as shown here. Common adverse reactions include bleeding and anemia in the treatment of NVAF (≥ 5%) and bleeding, rash, abnormal liver function tests and anemia in the treatment of DVT and PE (≥ 1%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Reduction in the Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation
Edoxaban is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF).
- Limitation of Use for NVAF
Edoxaban should not be used in patients with CrCL > 95 mL/min because of an increased risk of ischemic stroke compared to warfarin.
- Treatment of Deep Vein Thrombosis and Pulmonary Embolism
Edoxaban is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant.
- Nonvalvular Atrial Fibrillation
The recommended dose of Edoxaban is 60 mg taken orally once daily. Assess creatinine clearance, as calculated using the Cockcroft-Gault equation*, before initiating therapy with Edoxaban. Do not use Edoxaban in patients with CrCL > 95 mL/min.
Reduce Edoxaban dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min.
- Treatment of Deep Vein Thrombosis and Pulmonary Embolism
The recommended dose of Edoxaban is 60 mg taken orally once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant.
The recommended dose of Edoxaban is 30 mg once daily in patients with CrCL 15 to 50 mL/min, patients who weigh less than or equal to 60 kg, or patients who are taking certain concomitant P-gp inhibitor medications based on clinical study data in this indication.
- Administration Information
If a dose of Edoxaban is missed, the dose should be taken as soon as possible on the same day. Dosing should resume the next day according to the normal dosing schedule. The dose should not be doubled to make up for a missed dose.
Edoxaban can be taken without regard to food.
- Transition to or from Edoxaban
- Transition to Edoxaban
SAVAYSA: Edoxaban tosylate's Brand name
- Transition from Edoxaban
SAVAYSA: Edoxaban tosylate's Brand name
- Discontinuation for Surgery and Other Interventions
Discontinue Edoxaban at least 24 hours before invasive or surgical procedures because of the risk of bleeding.
If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.
Edoxaban can be restarted after the surgical or other procedure as soon as adequate hemostasis has been established noting that the time to onset of pharmacodynamic effect is 1-2 hours. Administer a parenteral anticoagulant and then switch to oral Edoxaban, if oral medication cannot be taken during or after surgical intervention.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
Total arthroplasty of knee - Postoperative deep vein thrombosis (Prophylaxis)[1]
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Edoxaban tosylate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Edoxaban tosylate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Edoxaban tosylate in pediatric patients.
# Contraindications
Edoxaban is contraindicated in patients with active pathological bleeding.
# Warnings
Edoxaban should not be used in patients with CrCL > 95 mL/min. In the randomized ENGAGE AF-TIMI 48 study, NVAF patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with Edoxaban 60 mg daily compared to patients treated with warfarin. In these patients another anticoagulant should be used.
Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation increases the risk of ischemic events. If Edoxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant as described in the transition guidance.
Edoxaban increases the risk of bleeding and can cause serious and potentially fatal bleeding. Promptly evaluate any signs or symptoms of blood loss.
Discontinue Edoxaban in patients with active pathological bleeding.
Concomitant use of drugs affecting hemostasis may increase the risk of bleeding. These include aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.
- Reversal of Anticoagulant Effect
There is no established way to reverse the anticoagulant effects of Edoxaban, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of Edoxaban cannot be reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of Edoxaban. The use of prothrombin complex concentrates (PCC), or other procoagulant reversal agents such as activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) may be considered but has not been evaluated in clinical outcome studies. When PCCs are used, monitoring for anticoagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or anti-FXa activity is not useful and is not recommended.
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.
The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 12 hours after the last administration of Edoxaban. The next dose of Edoxaban should not be administered earlier than 2 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture.
Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
The safety and efficacy of Edoxaban has not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. The use of Edoxaban is not recommended in these patients.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.
- Increased risk of stroke with discontinuation of Edoxaban in patients with NVAF
- Spinal/epidural anesthesia or puncture
The most serious adverse reactions reported with Edoxaban were related to bleeding.
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 Edoxaban was evaluated in the ENGAGE AF-TIMI 48 and Hokusai VTE studies including 11,130 patients exposed to Edoxaban 60 mg and 7002 patients exposed to Edoxaban 30 mg once daily.
- The ENGAGE AF-TIMI 48 Study
In the ENGAGE AF-TIMI 48 study, the median study drug exposure for the Edoxaban and warfarin treatment groups was 2.5 years.
Bleeding was the most common reason for treatment discontinuation. Bleeding led to treatment discontinuation in 3.9% and 4.1% of patients in the Edoxaban 60 mg and warfarin treatment groups, respectively.
In the overall population, Major Bleeding was lower in the Edoxaban group compared to the warfarin group [HR 0.80 (0.70, 0.91), p<0.001]. TABLE 1 shows Major Bleeding events (percentage of patients with at least one bleeding event, per year) for the indicated population (CrCL ≤ 95 mL/min).
- Table 1: Adjudicated Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/min*
SAVAYSA: Edoxaban tosylate's Brand name
The most common site of a Major Bleeding event was the gastrointestinal (GI) tract. TABLE 2 shows the number of and the rate at which patients experienced GI bleeding in the Edoxaban 60 mg and warfarin treatment groups.
- Table 2: Gastrointestinal Bleeding Events for NVAF Patients with CrCL ≤ 95 mL/min*
SAVAYSA: Edoxaban tosylate's Brand name
The rate of anemia-related adverse events was greater with Edoxaban 60 mg than with warfarin (9.6% vs. 6.8%).
The comparative rates of Major Bleeding on Edoxaban and warfarin were generally consistent among subgroups (see FIGURE 1). Bleeding rates appeared higher in both treatment arms (Edoxaban and warfarin) in the following subgroups of patients: those receiving aspirin, those in the United States, those more than 75 years old and those with reduced renal function.
- Figure 1: Adjudicated Major Bleeding in the ENGAGE AF-TIMI 48* Study
SAVAYSA: Edoxaban tosylate's Brand name
- Other Adverse Reactions
The most common non-bleeding adverse reactions (≥ 1%) for Edoxaban 60 mg versus warfarin were rash (4.2% vs. 4.1%), and abnormal liver function tests (4.8% vs. 4.6%), respectively.
Interstitial Lung Disease (ILD) was reported as a serious adverse event on treatment for Edoxaban 60 mg and warfarin in 15 (0.2%) and 7 (0.1%) patients, respectively. Many of the cases in both treatment groups were confounded by the use of amiodarone, which has been associated with ILD, or by infectious pneumonia. In the overall study period, there were 5 and 0 fatal ILD cases in the Edoxaban 60 mg and warfarin groups, respectively.
- The Hokusai VTE Study
In the Hokusai VTE study, the duration of drug exposure for Edoxaban was ≤ 6 months for 1561 (37.9%) of patients, > 6 months for 2557 (62.1%) of patients and 12 months for 1661 (40.3%) of patients.
Bleeding was the most common reason for treatment discontinuation and occurred in 1.4% and 1.4% of patients in the Edoxaban and warfarin arms, respectively.
- Bleeding in Patients with DVT and/or PE in the Hokusai VTE Study
The primary safety endpoint was Clinically Relevant Bleeding, defined as the composite of Major and Clinically Relevant Non-Major (CRNM) Bleeding that occurred during or within three days of stopping study treatment. The incidence of Clinically Relevant Bleeding was lower in Edoxaban than warfarin [HR (95% CI): 0.81 (0.71, 0.94); p =0.004].
TABLE 3 shows the number of patients experiencing bleeding events in the Hokusai VTE Study.
- Table 3: Bleeding Events in the Hokusai VTE Study
SAVAYSA: Edoxaban tosylate's Brand name
Patients with low body weight (≤ 60 kg), CrCL ≤ 50 mL/min, or concomitant use of select P-gp inhibitors were randomized to receive Edoxaban 30 mg or warfarin. As compared to all patients who received Edoxaban or warfarin in the 60 mg cohort, all patients who received Edoxaban or warfarin in the 30 mg cohort (n= 1452, 17.6% of the entire study population) were older (60.1 vs 54.9 years), more frequently female (66.5% vs 37.7%), more frequently of Asian race (46.0% vs 15.6%) and had more co-morbidities (e.g., history of bleeding, hypertension, diabetes, cardiovascular disease, cancer). Clinically relevant bleeding events occurred in 58/733 (7.9%) of the Edoxaban patients receiving 30 mg once daily and 92/719 (12.8%) of warfarin patients meeting the above criteria.
In the Hokusai VTE study, among all patients the most common bleeding adverse reactions (≥ 1%) are shown in TABLE 4.
- Table 4: Adverse Reactions Occurring in ≥ 1% of Patients Treated in Hokusai VTE
SAVAYSA: Edoxaban tosylate's Brand name
## Postmarketing Experience
There is limited information regarding Edoxaban Postmarketing Experience in the drug label.
# Drug Interactions
- Anticoagulants, Antiplatelets, and Thrombolytics
Co-administration of anticoagulants, antiplatelet drugs, and thrombolytics may increase the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with anticoagulants, aspirin, other platelet aggregation inhibitors, and/or NSAIDs.
Long-term concomitant treatment with Edoxaban and other anticoagulants is not recommended because of increased risk of bleeding. Short term co-administration may be needed for patients transitioning to or from Edoxaban.
In clinical studies with Edoxaban concomitant use of aspirin (low dose ≤ 100 mg/day) or thienopyridines, and NSAIDs was permitted and resulted in increased rates of Clinically Relevant Bleeding. Carefully monitor for bleeding in patients who require chronic treatment with low dose aspirin and/or NSAIDs.
- P-gp Inducers
Avoid the concomitant use of Edoxaban with rifampin.
- P-gp Inhibitors
- Treatment of NVAF
Based on clinical experience from the ENGAGE AF-TIMI 48 study, dose reduction in patients concomitantly receiving P-gp inhibitors resulted in edoxaban blood levels that were lower than in patients who were given the full dose. Consequently, no dose reduction is recommended for concomitant P-gp inhibitor use.
- Treatment of Deep Vein Thrombosis and Pulmonary Embolism
See Clinical Studies
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Risk Summary
There are no adequate and well-controlled studies in pregnant women. Edoxaban should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Human Data
In the Hokusai VTE study there were 10 pregnancy cases reported in patients receiving Edoxaban with exposure in the first trimester and estimated duration of exposure for up to approximately 6 weeks. Among these there were 6 live births (4 full term, 2 pre-term), 1 first-trimester spontaneous abortion, and 3 cases of elective termination of pregnancy.
- Animal Data
Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no teratogenic effects were seen when edoxaban was administered orally at doses up to 300 mg/kg/day, or 49 times the human dose of 60 mg/day normalized to body surface area. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose. In rabbits, no teratogenic effects were seen at doses up to 600 mg/kg/day (49 times the human exposure at a dose of 60 mg/day when based on AUC). Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day, which is equal to or greater than 20 times the human exposure.
In a rat pre- and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to 3 times the human exposure when based on AUC. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Edoxaban in women who are pregnant.
### Labor and Delivery
Safety and effectiveness of Edoxaban during labor and delivery have not been studied in clinical studies. The risks of bleeding should be balanced with the risk of thrombotic events when considering the use of Edoxaban in this setting.
### Nursing Mothers
It is not known if edoxaban is excreted in human milk. Edoxaban was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Edoxaban, a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Of the total patients in the ENGAGE AF-TIMI 48 study, 5182 (74%) were 65 years and older, while 2838 (41%) were 75 years and older. In Hokusai VTE, 1334 (32%) patients were 65 years and older, while 560 (14%) patients were 75 years and older. In clinical trials the efficacy and safety of Edoxaban in elderly (65 years or older) and younger patients were similar.
### Gender
There is no FDA guidance on the use of Edoxaban with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Edoxaban with respect to specific racial populations.
### Renal Impairment
Renal clearance accounts for approximately 50% of the total clearance of edoxaban. Consequently, edoxaban blood levels are increased in patients with poor renal function compared to those with higher renal function. Reduce Edoxaban dose to 30 mg once daily in patients with CrCL 15-50 mL/min. There are limited clinical data with Edoxaban in patients with CrCL < 15 mL/min; Edoxaban is therefore not recommended in these patients. Hemodialysis does not significantly contribute to Edoxaban clearance.
As renal function improves and edoxaban blood levels decrease, the risk for ischemic stroke increases in patients with NVAF.
### Hepatic Impairment
The use of Edoxaban in patients with moderate or severe hepatic impairment (Child-Pugh B and C) is not recommended as these patients may have intrinsic coagulation abnormalities. No dose reduction is required in patients with mild hepatic impairment (Child-Pugh A).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Edoxaban in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Edoxaban in patients who are immunocompromised.
### Low Body Weight Consideration for Patients treated for DVT and/or PE
Based on the clinical experience from the Hokusai VTE study, reduce Edoxaban dose to 30 mg in patients with body weight less than or equal to 60 kg.
# Administration and Monitoring
### Administration
There is limited information regarding Edoxaban Administration in the drug label.
### Monitoring
There is limited information regarding Edoxaban Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Edoxaban and IV administrations.
# Overdosage
A specific reversal agent for edoxaban is not available. Overdose of Edoxaban increases the risk of bleeding.
The following are not expected to reverse the anticoagulant effects of edoxaban: protamine sulfate, vitamin K, and tranexamic acid.
Hemodialysis does not significantly contribute to edoxaban clearance.
# Pharmacology
## Mechanism of Action
Edoxaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Edoxaban inhibits free FXa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of FXa in the coagulation cascade reduces thrombin generation and reduces thrombus formation.
## Structure
Edoxaban, a factor Xa inhibitor, is supplied as edoxaban tosylate monohydrate. The chemical name is N-(5-Chloropyridin-2-yl)-N′-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl] oxamide mono (4-methylbenzenesulfonate) monohydrate. Edoxaban tosylate monohydrate has the empirical formula C24H30ClN7O4S•C7H8O3S•H2O representing a molecular weight of 738.27. The chemical structure of edoxaban tosylate monohydrate is:
It is a white to pale yellowish-white crystalline powder. The solubility of edoxaban tosylate (pKa 6.7) decreases with increasing pH. It is slightly soluble in water, pH 3 to 5 buffer, very slightly soluble at pH 6 to 7; and practically insoluble at pH 8 to 9.
Edoxaban is available for oral administration as a 60 mg, 30 mg, or 15 mg round shaped, film-coated tablet, debossed with product identification markings. Each 60 mg tablet contains 80.82 mg edoxaban tosylate monohydrate equivalent to 60 mg of edoxaban. Each 30 mg tablet contains 40.41 mg edoxaban tosylate monohydrate equivalent to 30 mg of edoxaban. Each 15 mg tablet contains 20.20 mg edoxaban tosylate monohydrate equivalent to 15 mg of edoxaban. The inactive ingredients are: mannitol, pregelatinized starch, crospovidone, hydroxypropyl cellulose, magnesium stearate, talc, and carnauba wax. The color coatings contain hypromellose, titanium dioxide, talc, polyethylene glycol 8000, iron oxide yellow (60 mg tablets and 15 mg tablets), and iron oxide red (30 mg tablets and 15 mg tablets).
## Pharmacodynamics
As a result of FXa inhibition, edoxaban prolongs clotting time tests such as prothrombin time (PT), and activated partial thromboplastin time (aPTT). Changes observed in PT, INR, and aPTT at the expected therapeutic dose, however, are small, subject to a high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Following oral administration, peak pharmacodynamic effects are observed within 1-2 hours, which correspond with peak edoxaban concentrations (Cmax).
- Cardiac Electrophysiology
In a thorough QT study in healthy men and women aged 19-45 years, no QTc interval prolongation was observed with edoxaban (90 mg and 180 mg).
- Effect of PCCs on Pharmacodynamics of Edoxaban
There is no systematic evaluation of bleeding reversal by 4-factor prothrombin complex concentrate (PCC) products in patients who have received Edoxaban.
Effects of PCC (50 IU/kg) on the pharmacodynamics of edoxaban were studied in healthy subjects following a punch biopsy. Following administration of a single dose of edoxaban, endogenous thrombin potential (ETP) returned to pre-edoxaban baseline levels in 0.5 hours after the initiation of a 15 minute infusion of 50 IU/kg PCC, compared to more than 24 hours with placebo. Mean ETP levels continued to increase and exceeded pre-edoxaban baseline, reaching maximum elevations (~40% over pre-edoxaban levels) at 22 hours after initiating PCC dose, which was the last observation of ETP. The clinical relevance of this ETP increase is unknown.
- Pharmacodynamic Interactions
- Aspirin
Co-administration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
- NSAID (Naproxen)
Co-administration of naproxen (500 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
## Pharmacokinetics
Edoxaban displays approximately dose-proportional pharmacokinetics for doses of 15 to 150 mg and 60 to 120 mg following single and repeat doses, respectively, in healthy subjects.
- Absorption
Following oral administration, peak plasma edoxaban concentrations are observed within 1-2 hours. Absolute bioavailability is 62%. Food does not affect total systemic exposure to edoxaban. Edoxaban was administered with or without food in the ENGAGE AF-TIMI 48 and Hokusai VTE trials. No data are available regarding the bioavailability upon crushing and/or mixing of edoxaban tablets into food, liquids, or administration through feeding tubes.
- Distribution
Disposition is biphasic. The steady-state volume of distribution (Vdss) is 107 (19.9) L [mean (SD)]. In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing.
Steady-state concentrations are achieved within 3 days.
- Metabolism
Unchanged edoxaban is the predominant form in plasma. There is minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation, and oxidation by CYP3A4.
The predominant metabolite M-4, formed by hydrolysis, is human-specific and active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban.
- Elimination
Edoxaban is eliminated primarily as unchanged drug in the urine. Renal clearance (11 L/hour) accounts for approximately 50% of the total clearance of edoxaban (22 L/hour). Metabolism and biliary/intestinal excretion account for the remaining clearance. The terminal elimination half-life of edoxaban following oral administration is 10 to 14 hours.
- Specific Populations
- Hepatic Impairment
In a dedicated pharmacokinetic study, patients with mild or moderate hepatic impairment (classified as Child-Pugh A or Child-Pugh B) exhibited similar pharmacokinetics and pharmacodynamics to their matched healthy control group. There is no clinical experience with edoxaban in patients with severe hepatic impairment.
- Renal Impairment
In a dedicated pharmacokinetic study, total systemic exposure to edoxaban for subjects with CrCL > 50 to < 80 mL/min, CrCL 30 to 50 mL/min, CrCL < 30 mL/min, or undergoing peritoneal dialysis, were increased by 32%, 74%, 72%, and 93%, respectively, relative to subjects with CrCL ≥ 80 mL/min.
- Hemodialysis
A 4-hour hemodialysis session reduced total edoxaban exposure by less than 7%.
- Age
In a population pharmacokinetic analysis, after taking renal function and body weight into account, age had no additional clinically significant effect on edoxaban pharmacokinetics.
- Weight
In a population pharmacokinetic analysis, total exposure in patients with median low body weight (55 kg) was increased by 13% as compared with patients with median high body weight (84 kg).
- Gender
In a population pharmacokinetic analysis, after accounting for body weight, gender had no additional clinically significant effect on edoxaban pharmacokinetics.
- Race
In a population pharmacokinetic analysis, edoxaban exposures in Asian patients and non-Asian patients were similar.
- Drug Interactions
- In vitro Drug Interactions Studies
In vitro studies indicate that edoxaban does not inhibit the major cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4) and does not induce CYP1A2, CYP3A4 or the P-gp transporter (MDR1). In vitro data also indicate that edoxaban does not inhibit the following transporters at clinically relevant concentrations: P-gp, the organic anion transporters OAT1 or OAT3; the organic cation transporters OCT1 or OCT2; or the organic ion transporting polypeptides OATP1B1 or OATP1B3. Edoxaban is a substrate of P-gp transporter.
- Impact of Other Drugs on Edoxaban
The effect of co-administered amiodarone, cyclosporine, dronedarone, erythromycin, ketoconazole, quinidine, verapamil, and rifampin on edoxaban exposure is shown in FIGURE 2.
- Figure 2: Summary of Drug Interaction Study Results
- Impact of Edoxaban on Other Drugs
Edoxaban increased the Cmax of concomitantly administered digoxin by 28%; however, the AUC was not affected. Edoxaban had no effect on the Cmax and AUC of quinidine.
Edoxaban decreased the Cmax and AUC of concomitantly administered verapamil by 14% and 16%, respectively.
## Nonclinical Toxicology
Edoxaban was not carcinogenic when administered daily to mice and rats by oral gavage for up to 104 weeks. The highest dose tested (500 mg/kg/day) in male and female mice was 3 and 6 times, respectively, the human exposure (AUC) at the human dose of 60 mg/day, and the highest doses tested in male (600/400 mg/kg/day) and female (200 mg/kg/day) rats were 8 and 14 times, respectively, the human exposure at the human dose of 60 mg/day.
Edoxaban and its human-specific metabolite, M-4, were genotoxic in in vitro chromosomal aberration tests but were not genotoxic in the in vitro bacterial reverse mutation (Ames test), in in vitro human lymphocytes micronucleus test, in in vivo rat bone marrow micronucleus test, in in vivo rat liver micronucleus test, and in in vivo unscheduled DNA synthesis tests.
Edoxaban showed no effects on fertility and early embryonic development in rats at doses of up to 1000 mg/kg/day (162 times the human dose of 60 mg/day normalized to body surface area).
# Clinical Studies
- The ENGAGE AF-TIMI 48 Study
The ENGAGE AF-TIMI 48 study was a multi-national, double-blind, non-inferiority study comparing the efficacy and safety of two Edoxaban treatment arms (60 mg and 30 mg) to warfarin (titrated to INR 2.0 to 3.0) in reducing the risk of stroke and systemic embolic events in patients with NVAF. The non-inferiority margin (degree of inferiority of Edoxaban to warfarin that was to be ruled out) was set at 38%, reflecting the substantial effect of warfarin in reducing strokes. The primary analysis included both ischemic and hemorrhagic strokes.
To enter the study, patients had to have one or more of the following additional risk factors for stroke:
- a prior stroke (ischemic or unknown type), transient ischemic attack (TIA) or non-CNS systemic embolism, or
- 2 or more of the following risk factors:
- age ≥ 75 years,
- hypertension,
- heart failure, or
- diabetes mellitus
A total of 21,105 patients were randomized and followed for a median of 2.8 years and treated for a median of 2.5 years. Patients in the Edoxaban treatment arms had their dose halved (60 mg halved to 30 mg or 30 mg halved to 15 mg) if one or more of the following clinical factors were present: CrCL ≤ 50 mL/min, low body weight (≤ 60 kg) or concomitant use of specific P-gp inhibitors (verapamil, quinidine, dronedarone). Patients on antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) as well as cyclosporine were excluded from the study. Approximately 25% of patients in all treatment groups received a reduced dose at baseline, and an additional 7% were dose-reduced during the study. The most common reason for dose reduction was a CrCL ≤ 50 mL/min at randomization (19% of patients).
Patients were well balanced with respect to demographic and baseline characteristics. The percentages of patients age ≥ 75 years and ≥ 80 years were approximately 40% and 17%, respectively. The majority of patients were Caucasian (81%) and male (62%). Approximately 40% of patients had not taken a Vitamin K Antagonist (VKA) (i.e., never took a VKA or had not taken a VKA for more than 2 months).
The mean patient body weight was 84 kg (185 lbs) and 10% of patients had a body weight of ≤ 60 kg. Concomitant diseases of patients in this study included hypertension (94%), congestive heart failure (58%), and prior stroke or transient ischemic attack (28%). At baseline, approximately 30% of patients were on aspirin and approximately 2% of patients were taking a thienopyridine.
Patients randomized to the warfarin arm achieved a mean TTR (time in therapeutic range, INR 2.0 to 3.0) of 65% during the course of the study.
The primary endpoint of the study was the occurrence of first stroke (either ischemic or hemorrhagic) or of a systemic embolic event (SEE) that occurred during treatment or within 3 days from the last dose taken. In the overall results of the study, shown in TABLE 5, both treatment arms of Edoxaban were non-inferior to warfarin for the primary efficacy endpoint of stroke or SEE. However, the 30 mg (15 mg dose-reduced) treatment arm was numerically less effective than warfarin for the primary endpoint, and was also markedly inferior in reducing the rate of ischemic stroke. Based on the planned superiority analysis (ITT, which required p < 0.01 for success), statistical superiority of the 60 mg (30 mg dose-reduced) treatment arm compared to warfarin was not established in the total study population, but there was a favorable trend [HR (99% CI): 0.87 (0.71, 1.07)].
- Table 5: Strokes and Systemic Embolic Events in the ENGAGE AF-TIMI 48 Study (mITT, on Treatmenta)
SAVAYSA: Edoxaban tosylate's Brand name
FIGURE 3 is a plot of the time from randomization to the occurrence of the first primary endpoint in all patients randomized to 60 mg Edoxaban or warfarin.
- Figure 3: Kaplan-Meier Cumulative Event Rate Estimates for Primary Endpoint (first occurrence of stroke or SEE) (mITT*)
SAVAYSA: Edoxaban tosylate's Brand name
The incidence rate of the primary endpoint of stroke or SEE in patients (N=1776) treated with the 30 mg reduced dose of Edoxaban because of a CrCL level ≤ 50 mL/min, low body weight ≤ 60 kg, or the concomitant use of a P-gp inhibitor drug, was 1.79% per year. Patients with any of these characteristics who were randomized to receive warfarin had an incidence rate of the primary endpoint of 2.21% per year [HR (95% CI): 0.81 (0.58, 1.13)].
In all randomized patients during the overall study period, the rates of CV death with Edoxaban and warfarin were 2.74% per year vs. 3.17% per year, respectively [HR (95% CI): 0.86 (0.77, 0.97)].
The results in the ENGAGE AF-TIMI 48 study for the primary efficacy endpoint for most major subgroups are displayed in FIGURE 4.
- Figure 4: ENGAGE AF-TIMI 48 Study: Primary Efficacy Endpoint by Subgroups (ITT Analysis Set)
SAVAYSA: Edoxaban tosylate's Brand name
Note: The figure above presents effects in various subgroups all of which are baseline characteristics and most of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
The results of the ENGAGE AF-TIMI 48 study show a strong relationship between the blood levels of edoxaban and its effectiveness in reducing the rate of ischemic stroke. There was a 64% increase in the ischemic stroke rate in patients in the 30 mg treatment arm (including patients with dose reduced to 15 mg) compared to the 60 mg treatment arm (including patients with dose reduced to 30 mg). Approximately half of the Edoxaban dose is eliminated by the kidney, and edoxaban blood levels are lower in patients with better renal function, averaging about 30% less in patients with CrCL of > 80 mL/min, and 40% less in patients with CrCL > 95 mL/min when compared to patients with a CrCL of > 50 to ≤ 80 mL/min. Given the clear relationship of dose and blood levels to effectiveness in the ENGAGE AF-TIMI 48 study, it could be anticipated that patients with better renal function would show a smaller effect of Edoxaban compared to warfarin than would patients with mildly impaired renal function, and this was in fact observed.
TABLE 6 shows the results for the study primary efficacy endpoint of first stroke or SEE as well as the effects on ischemic and hemorrhagic stroke in the pre-randomization CrCL subgroups for Edoxaban 60 mg (including 30 mg dose-reduced) and warfarin. There was a decreased rate of ischemic stroke with Edoxaban 60 mg compared to warfarin in patients with CrCL > 50 to ≤ 80 mL/min [HR (95% CI): 0.63 (0.44, 0.89)]. In patients with CrCL > 80 to ≤ 95 mL/min the results for ischemic stroke slightly favor warfarin with a confidence interval that crosses 1.0 [HR (95% CI): 1.11 (0.58, 2.12)]. The rate of ischemic stroke was higher relative to warfarin in the patients with CrCL > 95 mL/min [HR (95% CI): 2.16 (1.17, 3.97)]. Pharmacokinetic data indicate that patients with CrCL > 95 mL/min had lower plasma edoxaban levels, along with a lower rate of bleeding relative to warfarin than patients with CrCL ≤ 95 mL/min. Consequently, Edoxaban should not be used in patients with CrCL > 95 mL/min.
In patients with CrCL ≤ 95 mL/min, the Edoxaban 60 mg (30 mg dose-reduced) treatment arm reduced the risk of Stroke or SEE when compared to warfarin [HR (95% CI): 0.68 (0.55, 0.84)].
In the indicated population (CrCL ≤ 95 mL/min), during the overall study period, the rates of CV death with Edoxaban and warfarin were 2.95% per year vs. 3.59% per year, respectively [HR (95% CI): 0.82 (0.72, 0.93)].
- Table 6: Primary Endpoint, Ischemic and Hemorrhagic Stroke Results in as a Function of Baseline Creatinine Clearance (mITT Population, On Treatment)
SAVAYSA: Edoxaban tosylate's Brand name
- Transition to Other Anticoagulants in the ENGAGE AF-TIMI 48 Study
In the ENGAGE AF-TIMI 48 study, the schemes for transitioning from study medication to open-label warfarin at the end of study were associated with similar rates of stroke and systemic embolism in the Edoxaban 60 mg and warfarin groups. In the Edoxaban 60 mg group 7 (0.2%) of 4529 patients had a stroke or SEE compared to 7 (0.2%) of 4506 patients in the warfarin arm.
- The Hokusai VTE Study
Edoxaban for the treatment of patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) was studied in a multi-national, double-blind study (Hokusai VTE) which compared the efficacy and safety of Edoxaban 60 mg orally once daily to warfarin (titrated to INR 2.0 to 3.0) in patients with acute symptomatic venous thromboembolism (VTE) (DVT or PE with or without DVT). All patients had VTE confirmed by appropriate diagnostic imaging at baseline and received initial heparin therapy with low molecular weight heparin (LMWH) or unfractionated heparin for at least 5 days [median LMWH/heparin treatment in the Edoxaban 60 mg group was 7 days, and in the warfarin group it was 8.0 days] and until INR (sham or real) was ≥ 2.0 on two measurements. Blinded drug treatment in the warfarin arm was started concurrently with initial heparin therapy and in the Edoxaban arm after discontinuation of initial heparin. Patients randomized to Edoxaban received 30 mg once daily if they met one or more of the following criteria: CrCL 30 to 50 mL/min, body weight ≤ 60 kg, or concomitant use of specific P-gp inhibitors (verapamil and quinidine or the short-term concomitant administration of azithromycin, clarithromycin, erythromycin, oral itraconazole or oral ketoconazole). The edoxaban dosage regimen was to be returned to the regular dosage of 60 mg once daily at any time the subject is not taking the concomitant medication provided no other criteria for dose reduction are met. Other P-gp inhibitors were not permitted in the study. Patients on antiretroviral therapy (ritonavir, nelfinavir, indinavir, saquinavir) as well as cyclosporine were excluded from the Hokusai VTE study. The concomitant use of these drugs with Edoxaban has not been studied in patients. The treatment duration was from 3 months up to 12 months, determined by investigator based on patient clinical features. Patients were excluded if they required thrombectomy, insertion of a caval filter, use of a fibrinolytic agent, or use of other P-gp inhibitors, had a creatinine clearance < 30 mL/min, significant liver disease, or active bleeding. The primary efficacy outcome was symptomatic VTE, defined as the composite of recurrent DVT, new non-fatal symptomatic PE, and fatal PE during the 12-month study period.
A total of 8292 patients were randomized to receive Edoxaban or warfarin and were followed for a mean treatment duration of 252 days for Edoxaban and 250 days for warfarin. The mean age was approximately 56 years. The population was 57% male, 70% Caucasian, 21% Asian, and about 4% Black. The presenting diagnosis was PE (with or without DVT) in 40.7% and DVT only in 59.3% of patients. At baseline, 27.6% of patients had temporary risk factors only (e.g., trauma, surgery, immobilization, estrogen therapy). Overall 9.4% had a history of cancer, 17.3% of the patients had an age ≥ 75 years and/or a body weight ≤ 50 kg, and/or a CrCL < 50 mL/min, and 31.4% of patients had NT-ProBNP ≥ 500 pg/mL.
Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 9% of patients in both groups.
In the warfarin group, the median TTR (time in therapeutic range, INR 2.0 to 3.0) was 65.6%.
A total of 8240 patients (n= 4118 for Edoxaban and n = 4122 for warfarin) received study drug and were included in the modified intent-to-treat (mITT) population. Edoxaban was demonstrated to be non inferior to warfarin for the primary endpoint of recurrent VTE [HR (95% CI): 0.89 (0.70, 1.13)] (TABLE 7, FIGURE 5).
- Table 7: Primary Composite Efficacy Endpoint Results in Hokusai VTE (mITT Overall Study Period)
SAVAYSA: Edoxaban tosylate's Brand name
- Figure 5: Kaplan-Meier Cumulative Event Rate Estimates for Adjudicated Recurrent VTE (mITT analysis – on treatment)
SAVAYSA: Edoxaban tosylate's Brand name
# How Supplied
Edoxaban tosylate is supplied as:
- 60 mg, yellow round shaped, film-coated tablets, debossed with DSC L60 on one side
- 30 mg, pink round shaped, film-coated tablets, debossed with DSC L30 on one side
- 15 mg, orange round shaped, film-coated tablets, debossed with DSC L15 on one side
## Storage
Store at 20-25°C (68-77°F); excursions permitted to 15°-30°C (59°-86°F).
Keep out of the reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
Advise patients of the following:
- they may bleed more easily, may bleed longer, or bruise more easily when treated with Edoxaban
- to report any unusual bleeding immediately to their healthcare provider
- to take Edoxaban exactly as prescribed
- to not discontinue Edoxaban without talking to the healthcare provider who prescribed it
- to inform their healthcare providers that they are taking Edoxaban before any surgery, medical, or dental procedure is scheduled
- to inform their healthcare providers and dentists if they plan to take, or are taking any prescription medications, over-the-counter drugs or herbal products
- to inform their healthcare provider immediately if they become pregnant or intend to become pregnant or are breastfeeding or intend to breastfeed during treatment with Edoxaban
- that if a dose is missed, take Edoxaban as soon as possible the same day, and resume the normal dosing schedule the following day. The dose should not be doubled to make up for a missing dose
- that if they are having neuraxial anesthesia or spinal puncture, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient to contact his or her physician immediately.
# Precautions with Alcohol
Alcohol-Edoxaban interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
SAVAYSA™
# Look-Alike Drug Names
There is limited information regarding Edoxaban Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Edoxaban | |
f21fb1dc9f2c8b09fc91fedc082a91ef3acaf67a | wikidoc | Efficacy | Efficacy
Efficacy is the ability to produce a desired amount of a desired effect.
# Explanation
## Medical
In a medical context it indicates that the therapeutic effect of a given intervention (e.g. intake of a medicine, an operation, or a public health measure) is acceptable. 'Acceptable' in that context refers to a consensus that it is at least as good as other available interventions to which it will have ideally been compared to in a clinical trial. For example, an efficacious vaccine has the ability to prevent or cure a specific illness in an acceptable proportion of exposed individuals. In strict epidemiological language, 'efficacy' refers to the impact of an intervention in a clinical trial, differing from 'effectiveness' which refers to the impact in real world situations.
The concept of 'self-efficacy' is an important one in the self-management of chronic diseases because doctors and patients often do not follow best practice in using a treatment. For instance, a patient using combined oral contraceptive pills to prevent pregnancy may sometimes forget to take a pill at the prescribed time; thus, while the perfect-use failure rate for this form of contraception in the first year of use is just 0.3%, the typical-use failure rate is 8%.
# Pharmacology
In Pharmacology, intrinsic activity or efficacy refers to the ability of a drug to induce a biological response in its molecular target. This must be distinguished from the affinity, which refers to the ability of the drug to bind to its molecular target. The term introduced by Stephenson (1956) to describe the way in which agonists vary in the response they produce even when they occupy the same number of receptors. High-efficacy agonists can produce their maximal response while occupying a relatively low proportion of receptors; agonists of lower efficacy cannot activate the receptors to the same degree and may not be able to produce the same maximal response even when they occupy the entire receptor population, thereby behaving as partial agonists
The term is often used to classify the activity of a drug upon binding to its receptor.
- agonist: affinity and maximum efficacy
- antagonist : affinity without efficacy
- partial agonist: affinity and partial efficacy
# Lighting
In lighting design, "efficacy" refers to the amount of light (luminous flux) produced by a lamp (a light bulb or other light source), usually measured in lumens, as a ratio of the amount of energy consumed to produce it, usually measured in watts. This is not to be confused with efficiency which is always a dimensionless ratio of output divided by input which for lighting relates to the watts of visible energy as a ratio of the energy consumed in watts. The visible energy can be approximated by the area under the Plancks curve between 300 nm and 700 nm for a blackbody at the temperature of the filament as a ratio of the total energy under the blackbody curve. Efficiency values for light from a heat source are typically less than two percent.
## Difference Amplifiers
The efficacy of a differential amplifier is measured by the degree of its rejection of common-mode signals inpreference to differential signals. Refer to common-mode rejection ratio (CMRR). | Efficacy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Efficacy is the ability to produce a desired amount of a desired effect.
# Explanation
## Medical
In a medical context it indicates that the therapeutic effect of a given intervention (e.g. intake of a medicine, an operation, or a public health measure) is acceptable. 'Acceptable' in that context refers to a consensus that it is at least as good as other available interventions to which it will have ideally been compared to in a clinical trial. For example, an efficacious vaccine has the ability to prevent or cure a specific illness in an acceptable proportion of exposed individuals. In strict epidemiological language, 'efficacy' refers to the impact of an intervention in a clinical trial, differing from 'effectiveness' which refers to the impact in real world situations.
The concept of 'self-efficacy' is an important one in the self-management of chronic diseases because doctors and patients often do not follow best practice in using a treatment. For instance, a patient using combined oral contraceptive pills to prevent pregnancy may sometimes forget to take a pill at the prescribed time; thus, while the perfect-use failure rate for this form of contraception in the first year of use is just 0.3%, the typical-use failure rate is 8%.[2]
# Pharmacology
In Pharmacology, intrinsic activity or efficacy refers to the ability of a drug to induce a biological response in its molecular target. This must be distinguished from the affinity, which refers to the ability of the drug to bind to its molecular target. The term introduced by Stephenson (1956)[1] to describe the way in which agonists vary in the response they produce even when they occupy the same number of receptors. High-efficacy agonists can produce their maximal response while occupying a relatively low proportion of receptors; agonists of lower efficacy cannot activate the receptors to the same degree and may not be able to produce the same maximal response even when they occupy the entire receptor population, thereby behaving as partial agonists [2]
The term is often used to classify the activity of a drug upon binding to its receptor.
- agonist: affinity and maximum efficacy
- antagonist : affinity without efficacy
- partial agonist: affinity and partial efficacy
# Lighting
In lighting design, "efficacy" refers to the amount of light (luminous flux) produced by a lamp (a light bulb or other light source), usually measured in lumens, as a ratio of the amount of energy consumed to produce it, usually measured in watts. This is not to be confused with efficiency which is always a dimensionless ratio of output divided by input which for lighting relates to the watts of visible energy as a ratio of the energy consumed in watts. The visible energy can be approximated by the area under the Plancks curve between 300 nm and 700 nm for a blackbody at the temperature of the filament as a ratio of the total energy under the blackbody curve. Efficiency values for light from a heat source are typically less than two percent.
## Difference Amplifiers
The efficacy of a differential amplifier is measured by the degree of its rejection of common-mode signals inpreference to differential signals. Refer to common-mode rejection ratio (CMRR). | https://www.wikidoc.org/index.php/Efficacious | |
101cda8425921ca892d65e1d8ca999e81de957fa | wikidoc | Egg yolk | Egg yolk
An egg yolk is the part of an egg which serves as the food source for the developing embryo inside. Prior to fertilization the yolk together with the germinal disc is a single cell. Mammalian embryos live off their yolk until they implant on the wall of the uterus. The egg yolk is suspended in the egg white (known more formally as albumen or ovalbumin) by one or two spiral bands of tissue called the chalazae.
As a food, yolks are a major source of vitamins and minerals. They contain all of the egg's fat and cholesterol, and almost half of the protein.
If left intact while cooking fried eggs, the yellow yolk surrounded by a flat blob of egg white creates the distinctive sunny-side up form of the food. Mixing the two components together before frying results in the pale yellow form found in omelettes and scrambled eggs.
# Uses
- It is sometimes separated from the egg white and used in cooking (for mayonnaise, custard, hollandaise sauce, crème brûlée, avgolemono, and ovos-moles).
- It is used in painting as a component of traditional egg-tempera.
- It is used in the production of egg-yolk agar plate medium, useful in testing for the presence of Clostridium perfringens.
- Egg yolk also contains an antibody called Immunoglobulin yolk or (IgY). The antibody transfers from the laying hen to the egg yolk by passive immunity to protect both embryo and hatchling from microorganism invasion.
- Egg yolk can be used to make liqueurs such as Advocaat.
# Composition of chicken egg yolk
The yolk makes up about 33% of the liquid weight of the egg; it contains approximately 60 calories, three times the caloric content of the egg white.
All of the fat soluble vitamins, (A, D, E and K) are found in the egg yolk. Egg yolks are one of the few foods naturally containing vitamin D.
The composition (by weight) of the most prevalent fatty acids in egg yolk is typically as follows:
- Unsaturated fatty acids:
Oleic acid 47 %
Linoleic acid 16 %
Palmitoleic acid 5 %
Linolenic acid 2 %
- Oleic acid 47 %
- Linoleic acid 16 %
- Palmitoleic acid 5 %
- Linolenic acid 2 %
- Saturated fatty acids:
Palmitic acid 23 %
Stearic acid 4 %
Myristic acid 1 %
- Palmitic acid 23 %
- Stearic acid 4 %
- Myristic acid 1 %
Egg yolk is a source of lecithin, an emulsifier.
A large yolk contains more than two-thirds of the recommended daily limit of 300mg of cholesterol,which is rather a lot.
The yellow color is caused by lutein and zeaxanthin, which are yellow or orange carotenoids known as xanthophylls.
# Double Egg yolk
Double Yolkers appear when ovulation occurs too rapidly, or when one yolk somehow gets "lost" and is joined by the next yolk. Double yolkers may be by a pullet whose productive cycle is not yet well synchronized. They're occasionally laid by a heavy-breed hen, often as an inherited trait.
# No yolk eggs
No-yolkers are called "dwarf", "wind" eggs. Such an egg is most often a pullet's first effort, produced before her laying mechanism is fully geared up. In a mature hen, a wind egg is unlikely, but can occur if a bit of reproductive tissue breaks away, stimulating the egg producing glands to treat it like a yolk and wrap it in albumen, membranes and a shell as it travels through the egg tube. You can tell this has occurred if, instead of a yolk, the egg contains a small particle of grayish tissue. In the old days, no yolkers were called "cock" eggs. Since they contained no yolk and therefore can't hatch, our forebears believed they were laid by roosters. This type of egg occurs in many varieties of fowl. They have been found in chickens, both standard and bantams, guineas and Coturnix Quail (about the size of a small marble).
These are also the Eggs the turn rotten (green inside) after the hen has laid the eggs and all eggs have hatched.They are mouldy. | Egg yolk
Template:Expert
An egg yolk is the part of an egg which serves as the food source for the developing embryo inside. Prior to fertilization the yolk together with the germinal disc is a single cell. Mammalian embryos live off their yolk until they implant on the wall of the uterus. The egg yolk is suspended in the egg white (known more formally as albumen or ovalbumin) by one or two spiral bands of tissue called the chalazae.
As a food, yolks are a major source of vitamins and minerals. They contain all of the egg's fat and cholesterol, and almost half of the protein.
If left intact while cooking fried eggs, the yellow yolk surrounded by a flat blob of egg white creates the distinctive sunny-side up form of the food. Mixing the two components together before frying results in the pale yellow form found in omelettes and scrambled eggs.
# Uses
- It is sometimes separated from the egg white and used in cooking (for mayonnaise, custard, hollandaise sauce, crème brûlée, avgolemono, and ovos-moles).
- It is used in painting as a component of traditional egg-tempera.
- It is used in the production of egg-yolk agar plate medium, useful in testing for the presence of Clostridium perfringens.
- Egg yolk also contains an antibody called Immunoglobulin yolk or (IgY). The antibody transfers from the laying hen to the egg yolk by passive immunity to protect both embryo and hatchling from microorganism invasion.
- Egg yolk can be used to make liqueurs such as Advocaat.
# Composition of chicken egg yolk
The yolk makes up about 33% of the liquid weight of the egg; it contains approximately 60 calories, three times the caloric content of the egg white.
All of the fat soluble vitamins, (A, D, E and K) are found in the egg yolk. Egg yolks are one of the few foods naturally containing vitamin D.
The composition (by weight) of the most prevalent fatty acids in egg yolk is typically as follows:[1]
- Unsaturated fatty acids:
Oleic acid 47 %
Linoleic acid 16 %
Palmitoleic acid 5 %
Linolenic acid 2 %
- Oleic acid 47 %
- Linoleic acid 16 %
- Palmitoleic acid 5 %
- Linolenic acid 2 %
- Saturated fatty acids:
Palmitic acid 23 %
Stearic acid 4 %
Myristic acid 1 %
- Palmitic acid 23 %
- Stearic acid 4 %
- Myristic acid 1 %
Egg yolk is a source of lecithin, an emulsifier.
A large yolk contains more than two-thirds of the recommended daily limit of 300mg of cholesterol,which is rather a lot.
The yellow color is caused by lutein and zeaxanthin, which are yellow or orange carotenoids known as xanthophylls.
# Double Egg yolk
Double Yolkers appear when ovulation occurs too rapidly, or when one yolk somehow gets "lost" and is joined by the next yolk. Double yolkers may be by a pullet whose productive cycle is not yet well synchronized. They're occasionally laid by a heavy-breed hen, often as an inherited trait.
# No yolk eggs
No-yolkers are called "dwarf", "wind" [or, more commonly, "fart"] eggs. Such an egg is most often a pullet's first effort, produced before her laying mechanism is fully geared up. In a mature hen, a wind egg is unlikely, but can occur if a bit of reproductive tissue breaks away, stimulating the egg producing glands to treat it like a yolk and wrap it in albumen, membranes and a shell as it travels through the egg tube. You can tell this has occurred if, instead of a yolk, the egg contains a small particle of grayish tissue. In the old days, no yolkers were called "cock" eggs. Since they contained no yolk and therefore can't hatch, our forebears believed they were laid by roosters. This type of egg occurs in many varieties of fowl. They have been found in chickens, both standard and bantams, guineas and Coturnix Quail (about the size of a small marble).
These are also the Eggs the turn rotten (green inside) after the hen has laid the eggs and all eggs have hatched.They are mouldy. | https://www.wikidoc.org/index.php/Egg_yolk | |
02758135498e3e4dbe4b69d73ae19a939a0b3375 | wikidoc | Elagolix | Elagolix
# 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
Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist that is FDA approved for the management of moderate to severe pain associated with endometriosis. Common adverse reactions include hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions and mood changes.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Elagolix is indicated for the management of moderate to severe pain associated with endometriosis.
Dosage
- Normal liver function or mild hepatic impairment: 150 mg once daily for up to 24 months or 200 mg twice daily for up to 6 months.
- Moderate hepatic impairment: 150 mg once daily for up to 6 months.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding elagolix Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding elagolix Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of elagolix in patients less than 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding elagolix Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding elagolix Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Elagolix is contraindicated in women:
Who are pregnant. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss.
With known osteoporosis because of the risk of further bone loss.
With severe hepatic impairment because of the risk of bone loss.
With concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil).
- Who are pregnant. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss.
- With known osteoporosis because of the risk of further bone loss.
- With severe hepatic impairment because of the risk of bone loss.
- With concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil).
# Warnings
- Elagolix causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. The impact of these BMD decreases on long-term bone health and future fracture risk are unknown. Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, and do not use in women with known osteoporosis. Limit the duration of use to reduce the extent of bone loss.
- Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.
- Women who take elagolix may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected, and discontinue elagolix if pregnancy is confirmed.
- Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with elagolix in the endometriosis clinical trials. Elagolix subjects had a higher incidence of depression and mood changes compared to placebo, and elagolix subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits. Patients with new or worsening depression, anxiety or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing elagolix if such events occur.
- In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3-times the upper limit of the reference range occurred with elagolix. Use the lowest effective dose of elagolix and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks.
- Based on the mechanism of action of elagolix, estrogen containing contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on the efficacy of elagolix is unknown. Advise women to use non-hormonal contraceptives during treatment with elagolix and for one week after discontinuing elagolix.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of elagolix was evaluated in two six-month, randomized, double-blind, placebo-controlled clinical trials in which a total of 952 adult women with moderate to severe pain associated with endometriosis were treated with elagolix (475 with 150 mg once daily and 477 with 200 mg twice daily) and 734 were treated with placebo. The population age range was 18-49 years old. Women who completed six months of treatment and met eligibility criteria continued treatment in two uncontrolled, blinded six-month extension trials , for a total treatment duration of up to 12 months.
Serious Adverse Events
- Overall, the most common serious adverse events reported for subjects treated with elagolix in the two placebo-controlled clinical trials (Studies EM-1 and EM-2) included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%). In these trials, 0.2% of subjects treated with elagolix 150 mg once daily and 0.2% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to serious adverse reactions compared to 0.5% of those given placebo.
Adverse Reactions Leading to Study Discontinuation
- In the two placebo-controlled clinical trials (Studies EM-1 and EM-2), 5.5% of subjects treated with elagolix 150 mg once daily and 9.6% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to adverse reactions compared to 6.0% of those given placebo. Discontinuations were most commonly due to hot flushes or night sweats (1.1% with 150 mg once daily and 2.5% with 200 mg twice daily) and nausea (0.8% with 150 mg once daily and 1.5% with 200 mg twice daily) and were dose-related. The majority of discontinuations due to hot flushes or night sweats (10 of 17, 59%) and nausea (7 of 11, 64%) occurred within the first 2 months of therapy.
- In the two extension trials (Studies EM-3 and EM-4), discontinuations were most commonly due to decreased bone mineral density and were dose-related. In these trials, 0.3% of subjects treated with elagolix 150 mg once daily and 3.6% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to decreased BMD.
Common Adverse Reactions:
Adverse reactions reported in ≥ 5% of women in the two placebo-controlled trials in either elagolix dose group and at a greater frequency than placebo are noted in the following table.
Less Common Adverse Reactions:
- In Study EM-1 and Study EM-2, adverse reactions reported in ≥ 3% and < 5% in either elagolix dose group and greater than placebo included: decreased libido, diarrhea, abdominal pain, weight gain, dizziness, constipation and irritability.
- The most commonly reported adverse reactions in the extension trials (EM-3 and EM-4) were similar to those in the placebo-controlled trials.
Bone Loss
- The effect of elagolix on bone mineral density was assessed by dual energy X-ray absorptiometry (DXA).
- In Studies EM-1 and EM-2, there was a dose-dependent decrease in BMD in elagolix-treated subjects compared to an increase in placebo-treated subjects.
- In Study EM-1, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -0.9% (95% CI: -1.3, -0.4) with elagolix 150 mg once daily and -3.1% (95% CI: -3.6, -2.6) with elagolix 200 mg twice daily (TABLE 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was 2% with elagolix 150 mg once daily, 7% with elagolix 200 mg twice daily and < 1% with placebo. In the blinded extension Study EM-3, continued bone loss was observed with 12 months of continuous treatment with elagolix. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 8% with continuous elagolix 150 mg once daily and 21% with continuous elagolix 200 mg twice daily.
- In Study EM-2, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -1.3% (95% CI: -1.8, -0.8) with elagolix 150 mg once daily and -3.0% (95% CI: -3.5, -2.6) with elagolix 200 mg twice daily (TABLE 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was < 1% with elagolix 150 mg once daily, 6% with elagolix 200 mg twice daily and 0% with placebo. In the blinded extension Study EM-4, continued bone loss was observed with 12 months of continuous treatment with elagolix. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 2% with continuous elagolix 150 mg once daily and 21% with continuous elagolix 200 mg twice daily.
- To assess for recovery, the change in lumbar spine BMD over time was analyzed for subjects who received continuous treatment with elagolix 150 mg once daily or elagolix 200 mg twice daily for up to 12 months and who were then followed after cessation of therapy for an additional 6 months. Partial recovery of BMD was seen in these subjects (Figure 1).
- In Study EM-3, if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip at the end of treatment, follow-up DXA was required after 6 months off-treatment. In Study EM-4, all subjects were required to have a follow-up DXA 6 months off treatment regardless of change in BMD and if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip after 6 months off treatment, follow-up DXA was required after 12 months off-treatment. Figure 2 shows the change in lumbar spine BMD for the subjects in Study EM-2/EM-4 who completed 12 months of treatment with elagolix and who had a follow-up DXA 12-months off treatment.
Suicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders
- In the placebo-controlled trials (Studies EM-1 and EM-2), elagolix was associated with adverse mood changes (see Table 2 and Table 4), particularly in those with a history of depression.
- A 44-year-old woman received 31 days of elagolix 150 mg once daily then completed suicide 2 days after elagolix discontinuation. She had no relevant past medical history; life stressors were noted.
- Among the 2090 subjects exposed to elagolix in the endometriosis Phase 2 and Phase 3 studies, there were four reports of suicidal ideation. In addition to the two subjects in Table 4, there were two additional reports of suicidal ideation: one subject in EM-3 (150 mg once daily) and one in a Phase 2 study (75 mg once daily, an unapproved dose). Three of these subjects had a history of depression. Two subjects discontinued elagolix and two completed the clinical trial treatment periods.
Hepatic Transaminase Elevations
- In the placebo-controlled clinical trials (Studies EM-1 and EM-2), dose-dependent asymptomatic elevations of serum ALT to at least 3-times the upper limit of the reference range occurred during treatment with elagolix (150 mg once daily – 1/450, 0.2%; 200 mg twice daily – 5/443, 1.1%; placebo – 1/696, 0.1%). Similar increases were seen in the extension trials (Studies EM-3 and EM-4).
Changes in Lipid Parameters
- Dose-dependent increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and serum triglycerides were noted during elagolix treatment in EM-1 and EM-2. In EM-1 and EM-2, 12% and 1% of subjects with mildly elevated LDL-C (130-159 mg/dL) at baseline had an increase in LDL-C concentrations to 190 mg/dL or higher during treatment with elagolix and placebo, respectively. In EM-1 and EM-2, 4% and 1% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an increase in serum triglycerides to at least 500 mg/dL during treatment with elagolix and placebo, respectively. The highest measured serum triglyceride concentration during treatment with elagolix was 982 mg/dL.
- Lipid increases occurred within 1 to 2 months after the start of elagolix and remained stable thereafter over 12 months.
Hypersensitivity Reactions
- In Studies EM-1 and EM-2, non-serious hypersensitivity reactions including rash occurred in 5.8% of elagolix treated-subjects and 6.1% of placebo-treated subjects. These events led to study drug discontinuation in 0.4% of elagolix-treated subjects and 0.5% of placebo-treated subjects.
Endometrial Effects
- Endometrial biopsies were performed in subjects in Study EM-1 and its extension at Month 6 and Month 12. These biopsies showed a dose-dependent decrease in proliferative and secretory biopsy patterns and an increase in quiescent/minimally stimulated biopsy patterns. There were no abnormal biopsy findings on treatment, such as endometrial hyperplasia or cancer.
- Based on transvaginal ultrasound, during the course of a 3-menstrual cycle study in healthy women, elagolix 150 mg once daily and 200 mg twice daily resulted in a dose-dependent decrease from baseline in mean endometrial thickness.
Effects on menstrual bleeding patterns
- The effects of elagolix on menstrual bleeding were evaluated for up to 12 months using an electronic daily diary where subjects classified their flow of menstrual bleeding (if present in the last 24 hours) as spotting, light, medium, or heavy. Elagolix led to a dose-dependent reduction in mean number of bleeding and spotting days and bleeding intensity in those subjects who reported menstrual bleeding.
- Elagolix also demonstrated a dose-dependent increase in the percentage of women with amenorrhea (defined as no bleeding or spotting in a 56-day interval) over the treatment period. The incidence of amenorrhea during the first six months of treatment ranged from 6-17% for elagolix 150 mg once daily, 13-52% for elagolix 200 mg twice daily and less than 1% for placebo. During the second 6 months of treatment, the incidence of amenorrhea ranged from 11-15% for elagolix 150 mg once daily and 46-57% for elagolix 200 mg twice daily.
- After 6 months of therapy with elagolix 150 mg once daily, resumption of menses after stopping treatment was reported by 59%, 87% and 95% of women within 1, 2, and 6 months, respectively. After 6 months of therapy with elagolix 200 mg twice daily, resumption of menses after stopping treatment was reported by 60%, 88%, and 97% of women within 1, 2, and 6 months, respectively.
- After 12 months of therapy with elagolix 150 mg once daily resumption of menses after stopping treatment was reported by 77%, 95% and 98% of women within 1, 2, and 6 months respectively. After 12 months of therapy with elagolix 200 mg twice daily resumption of menses after stopping treatment was reported by 55%, 91% and 96% of women within 1, 2, and 6 months respectively.
## Postmarketing Experience
There is limited information regarding Elagolix Postmarketing Experience in the drug label.
# Drug Interactions
- Elagolix is a weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with elagolix may decrease plasma concentrations of drugs that are substrates of CYP3A.
- Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with elagolix may increase plasma concentrations of drugs that are substrates of P-gp (e.g., digoxin).
- Elagolix is a substrate of CYP3A, P-gp, and OATP1B1.
- Concomitant use of elagolix 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and strong CYP3A inhibitors to 6 months.
- Co-administration of elagolix with drugs that induce CYP3A may decrease elagolix plasma concentrations.
- The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of elagolix is unknown. Co-administration of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Concomitant use of elagolix and strong OATP1B1 inhibitors (e.g., cyclosporine and gemfibrozil) is contraindicated.
- TABLE 7 summarizes the effect of co-administration of elagolix on concentrations of concomitant drugs and the effect of concomitant drugs on elagolix.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Use of elagolix is contraindicated in pregnant women. Discontinue elagolix if pregnancy occurs during treatment.
- The limited human data with the use of elagolix in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with elagolix, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups.
- When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively.
- The background risk for major birth defects and miscarriage in the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Human Data
- There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with elagolix for up to 12 months. These pregnancies occurred while the women were receiving elagolix or within 30 days after stopping elagolix. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with elagolix 150 mg daily and the estimated fetal exposure to elagolix occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with elagolix 150 mg daily and the estimated fetal exposure to elagolix occurred during the first 15 days of pregnancy.
- Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in elagolix clinical trials, there were no apparent decreases in birth weights associated with elagolix in comparison to placebo.
Animal Data
- Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).
- In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD.
- No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.
- In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.
- Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elagolix in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Elagolix during labor and delivery.
### Nursing Mothers
Risk Summary
- There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. There are no adequate animal data on the excretion of elagolix in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for elagolix and any potential adverse effects on the breastfed child from elagolix.
Data
- There are no adequate animal data on excretion of elagolix in milk.
### Pediatric Use
- Safety and effectiveness of elagolix in patients less than 18 years of age have not been established.
### Geriatic Use
There is no FDA guidance on the use of Elagolix in geriatric settings.
### Gender
There is no FDA guidance on the use of Elagolix with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Elagolix with respect to specific racial populations.
### Renal Impairment
- No dose adjustment of elagolix is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis).
### Hepatic Impairment
- No dosage adjustment of elagolix is required for women with mild hepatic impairment (Child-Pugh A). Only the 150 mg once daily regimen is recommended for women with moderate hepatic impairment (Child-Pugh B) and the duration of treatment should be limited to 6 months.
- Elagolix is contraindicated in women with severe hepatic impairment (Child-Pugh C).
### Females of Reproductive Potential and Males
- Based on the mechanism of action, there is a risk of early pregnancy loss if elagolix is administered to a pregnant woman.
Pregnancy Testing
- Exclude pregnancy before initiating treatment with elagolix. Perform pregnancy testing if pregnancy is suspected during treatment with elagolix.
Contraception
- Advise women to use effective non-hormonal contraception during treatment with elagolix and for one week after discontinuing elagolix.
### Immunocompromised Patients
There is no FDA guidance one the use of Elagolix in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Exclude pregnancy before starting elagolix or start elagolix within 7 days from the onset of menses.
- Take elagolix at approximately the same time each day, with or without food.
- Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives.
- Limit the duration of use because of bone loss (Table 1).
- No dosage adjustment of elagolix is required in women with mild hepatic impairment (Child-Pugh A).
- Compared to women with normal liver function, those with moderate hepatic impairment had approximately 3-fold higher elagolix exposures and those with severe hepatic impairment had approximately 7-fold higher elagolix exposures. Because of these increased exposures and risk for bone loss:
Elagolix 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of elagolix 200 mg twice daily is not recommended for women with moderate hepatic impairment.
Elagolix is contraindicated in women with severe hepatic impairment (Child-Pugh C).
- Elagolix 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of elagolix 200 mg twice daily is not recommended for women with moderate hepatic impairment.
- Elagolix is contraindicated in women with severe hepatic impairment (Child-Pugh C).
- Instruct the patient to take a missed dose of elagolix on the same day as soon as she remembers and then resume the regular dosing schedule.
150 mg once daily: take no more than 1 tablet each day.
200 mg twice daily: take no more than 2 tablets each day.
- 150 mg once daily: take no more than 1 tablet each day.
- 200 mg twice daily: take no more than 2 tablets each day.
### Monitoring
There is limited information regarding Elagolix Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Elagolix and IV administrations.
# Overdosage
- In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.
# Pharmacology
## Mechanism of Action
- Elagolix is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.
## Structure
- Elagolix sodium has a molecular formula of C32H29F5N3O5Na and a molecular weight of 653.58. Elagolix free acid has a molecular weight of 631.60.
- Elagolix sodium has the following structural formula:
## Pharmacodynamics
Effect on Ovulation and Estradiol
- In a 3-menstrual cycle study in healthy women, elagolix 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen.
Cardiac Electrophysiology
- The effect of elagolix on the QTc interval was evaluated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.
## Pharmacokinetics
- The pharmacokinetic properties of elagolix in healthy subjects are summarized in TABLE 8. The steady state pharmacokinetic parameters under fasting conditions are summarized in TABLE 9.
Specific Populations
Renal Impairment
- Elagolix exposures (Cmax and AUC) are not altered by renal impairment. The mean exposures are similar for women with moderate to severe or end stage renal disease (including women on dialysis) compared to women with normal renal function.
Hepatic Impairment
- Elagolix exposures (Cmax and AUC) are similar between women with normal hepatic function and women with mild hepatic impairment. Elagolix exposures in women with moderate and severe hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function.
Race/Ethnicity
- No clinically meaningful difference in the pharmacokinetics of elagolix between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of elagolix between Japanese and Han Chinese subjects.
Body weight/Body mass index
- Body weight or body mass index does not affect the pharmacokinetics of elagolix.
Drug Interaction Studies
- Drug interaction studies were performed with elagolix and other drugs that are likely to be co-administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 10 and 11 summarize the pharmacokinetic effects when elagolix was co-administered with these drugs.
- No clinically significant changes in elagolix exposures were observed when co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single dose).
- No clinically significant changes in sertraline or fluconazole exposures were observed when co-administered with elagolix.
## Pharmacogenomics
- Disposition of elagolix involves the OATP 1B1 transporter protein. Higher plasma concentrations of elagolix have been observed in groups of patients who have two reduced function alleles of the gene that encodes OATP 1B1 (SLCO1B1 521T>C). The frequency of this SLCO1B1 521 C/C genotype is generally less than 5% in most racial/ethnic groups. Subjects with this genotype are expected to have a 78% mean increase in elagolix concentrations compared to subjects with normal transporter function (i.e., SLCO1B1 521T/T genotype).
## Nonclinical Toxicology
- Two-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered elagolix by the dietary route revealed no increase in tumors in mice at up to 19-fold the MRHD based on AUC. In the rat, there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (12 to 13-fold the MRHD). The rat tumors were likely species-specific and of negligible relevance to humans.
- Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay.
- In a fertility study conducted in the rat, there was no effect of elagolix on fertility at any dose (50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women compared to the highest dose of 300 mg/kg/day in female rats is approximately 5-fold. However, because elagolix has low affinity for the GnRH receptor in the rat, and because effects on fertility are most likely to be mediated via the GnRH receptor, these data have low relevance to humans.
# Clinical Studies
- The efficacy of elagolix 150 mg once daily and 200 mg twice daily for the management of moderate to severe pain associated with endometriosis was demonstrated in two multinational double-blind, placebo-controlled trials in 1686 premenopausal women . The median age of women in the trials was 32 years; 88% were White, 9% were Black or African American and 3% were other races. Each placebo-controlled trial assessed the reduction in endometriosis-associated pain over 6 months of treatment.
- Moderate to severe pain associated with endometriosis was required for entry into the trials and was assessed during screening using the composite pelvic signs and symptoms score (CPSSS) and other baseline criteria.
- The CPSSS is based on a modified Biberoglu and Behrman scale with five elements: three responses reported by study subjects (dysmenorrhea, dyspareunia, and non-menstrual pelvic pain) and two findings based on investigator assessment during physical examination (rating of pelvic tenderness and induration). Each element is scored from 0 (absent) to 3 (severe) for a maximum total score of 15. A total score of at least 6, with a score of at least 2 for dysmenorrhea and at least 2 for non-menstrual pelvic pain was required to qualify for randomization. Subjects were also required to have non-menstrual pelvic pain for at least four days in the preceding calendar month, defined as 35 days. Other criteria to determine eligibility for randomization included subject responses in a daily electronic diary (Endometriosis Daily Pain Impact Scale, described below) for both dysmenorrhea and non-menstrual pelvic pain in the 35 days prior to randomization.
Dysmenorrhea and Non-Menstrual Pelvic Pain
- The co-primary efficacy endpoints were (1) the proportion of subjects whose dysmenorrhea responded to treatment at Month 3 and (2) the proportion of subjects whose pelvic pain not related to menses (also known as non-menstrual pelvic pain) responded to treatment at Month 3. Dysmenorrhea and non-menstrual pelvic pain were evaluated daily using the Endometriosis Daily Pain Impact Scale that asked subjects to rate their pain severity and its impact on daily activities during the prior 24 hours as none, mild, moderate or severe (correlating with a score of 0 to 3, respectively, where higher scores indicated greater severity). Scores at baseline and at each month were averaged over a 35-day interval.
- Women were defined as responders if they experienced a reduction in dysmenorrhea and non-menstrual pelvic pain as defined in Table 12 with no increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid) for endometriosis-associated pain. The threshold for defining responders was based on a receiver operating characteristic (ROC) analysis using the patient global impression of change as an anchor. A higher proportion of women treated with elagolix 150 mg once daily or 200 mg twice daily were responders for dysmenorrhea and non-menstrual pelvic pain compared to placebo in a dose-dependent manner at Month 3 .
- Women in these studies also provided a daily self-assessment of their endometriosis pain using a numeric rating scale (NRS) that asked subjects to rate their endometriosis pain at its worst over the last 24 hours on a scale from 0 (no pain) to 10 (worst pain ever). In Study EM-1, baseline NRS scores were 5.7 for elagolix 150 mg once daily, 5.5 for elagolix 200 mg twice daily and 5.6 for placebo. In Study EM-2, baseline NRS scores were 5.7 for elagolix 150 mg once daily, 5.3 for elagolix 200 mg twice daily and 5.6 for placebo. Women taking elagolix 150 mg once daily and 200 mg twice daily reported a statistically (p <0.001) significant reduction from baseline in NRS scores compared to placebo at Month 3 in both Studies EM-1 and EM-2 (Study EM-1: 0.7 points for elagolix 150 mg once daily and 1.3 points for elagolix 200 mg twice daily; Study EM-2: 0.6 points for elagolix 150 mg once daily and 1.2 points for elagolix 200 mg twice daily).
- In addition, both elagolix treatment groups showed statistically significantly greater mean decreases from baseline compared to placebo in dysmenorrhea and non-menstrual pelvic pain scores at Month 6. Figures 3 through 6 show the mean scores for dysmenorrhea and non-menstrual pelvic pain over time for Study EM-1 and EM-2.
Dyspareunia
- Dyspareunia associated with endometriosis was evaluated as a secondary endpoint using the Endometriosis Daily Pain Impact Scale that asked subjects to rate their pain during sexual intercourse in the prior 24 hours as none, mild, moderate, severe (correlating with a score of 0 to 3, respectively, where higher scores indicated greater severity), or not applicable. In both Studies EM-1 and EM-2, women treated with elagolix 200 mg twice daily showed statistically significantly greater reduction in dyspareunia from baseline to Month 3 than women given placebo (Study EM-1: 0.2; Study EM-2: 0.3). Figures 7 and 8 show the mean scores over time for Study EM-1 and EM-2.
Use of rescue pain medication
- In EM-1 and EM-2, 59% and 60% of patients used an opioid rescue analgesic for pain at baseline. The opioid rescue analgesics used at baseline were predominantly hydrocodone/acetaminophen (HC/APAP) and codeine/APAP at strengths of 5/300-325 mg and 30/300-500 mg. In EM-1, of all patients on an opioid at baseline, 98% and 2% were on HC/APAP and codeine/APAP, respectively. In EM-2, of all patients on an opioid at baseline, 50% were on HC/APAP and 16% were on codeine/APAP.
- Other data related to opioid rescue analgesic use are summarized in TABLE 13.
- The clinical relevance of these data has not been demonstrated.
# How Supplied
- Elagolix tablets are available in two strengths: 150 mg and 200 mg, which are equivalent to 155.2 mg and 207.0 mg of elagolix sodium, respectively.
- Elagolix 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on one side. Elagolix 150 mg tablets are packaged in weekly blister packs. Each blister pack contains 7 tablets supplying the drug product for one week. Four blister packs (a total of 28 tablets) are packaged into a carton that provides the drug product for 4 weeks (NDC 0074-0038-28).
- Elagolix 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed on one side. The 200 mg tablets are packaged in weekly blister packs. Each blister pack contains 14 tablets supplying the drug product for one week. Four blister packs (a total of 56 tablets) are packaged in a carton that provides the drug product for 4 weeks (NDC 0074-0039-56).
## Storage
- Store at 2°C to 30°C (36°F to 86°F).
- Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash, WWW.FDA.GOV/DRUGDISPOSAL. Do NOT flush down the toilet.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to read the FDA-approved patient labeling (Medication Guide).
- Advise patients on contraceptive options, not to get pregnant while using elagolix, to be mindful that menstrual changes could reflect pregnancy and to discontinue elagolix if pregnancy occurs.
- Inform patients that estrogen containing contraceptives are expected to reduce the efficacy of elagolix.
- Inform patients about the risk of bone loss. Advise adequate intake of calcium and vitamin D.
- Advise patients to seek immediate medical attention for suicidal ideation and behavior. Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention.
- Counsel patients on signs and symptoms of liver injury.
- Instruct patients who miss a dose of elagolix to take the missed dose on the same day as soon as she remembers and then resume the regular dosing schedule:
150 mg once daily: no more than 1 tablet each day should be taken.
200 mg twice daily: no more than 2 tablets each day should be taken.
- 150 mg once daily: no more than 1 tablet each day should be taken.
- 200 mg twice daily: no more than 2 tablets each day should be taken.
- Instruct patients to dispose of unused medication via a take-back option if available or to otherwise follow FDA instructions for disposing of medication in the household trash, WWW.FDA.GOV/DRUGDISPOSAL, and not to flush down the toilet.
# Precautions with Alcohol
Alcohol-Elagolix interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Orilissa
# Look-Alike Drug Names
There is limited information regarding Elagolix Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Elagolix
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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# Overview
Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist that is FDA approved for the management of moderate to severe pain associated with endometriosis. Common adverse reactions include hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions and mood changes.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Elagolix is indicated for the management of moderate to severe pain associated with endometriosis.
Dosage
- Normal liver function or mild hepatic impairment: 150 mg once daily for up to 24 months or 200 mg twice daily for up to 6 months.
- Moderate hepatic impairment: 150 mg once daily for up to 6 months.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding elagolix Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding elagolix Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of elagolix in patients less than 18 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding elagolix Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding elagolix Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Elagolix is contraindicated in women:
Who are pregnant. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss.
With known osteoporosis because of the risk of further bone loss.
With severe hepatic impairment because of the risk of bone loss.
With concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil).
- Who are pregnant. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss.
- With known osteoporosis because of the risk of further bone loss.
- With severe hepatic impairment because of the risk of bone loss.
- With concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil).
# Warnings
- Elagolix causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. The impact of these BMD decreases on long-term bone health and future fracture risk are unknown. Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, and do not use in women with known osteoporosis. Limit the duration of use to reduce the extent of bone loss.
- Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.
- Women who take elagolix may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected, and discontinue elagolix if pregnancy is confirmed.
- Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with elagolix in the endometriosis clinical trials. Elagolix subjects had a higher incidence of depression and mood changes compared to placebo, and elagolix subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits. Patients with new or worsening depression, anxiety or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing elagolix if such events occur.
- In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3-times the upper limit of the reference range occurred with elagolix. Use the lowest effective dose of elagolix and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks.
- Based on the mechanism of action of elagolix, estrogen containing contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on the efficacy of elagolix is unknown. Advise women to use non-hormonal contraceptives during treatment with elagolix and for one week after discontinuing elagolix.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of elagolix was evaluated in two six-month, randomized, double-blind, placebo-controlled clinical trials [EM-1 (NCT01620528) and EM-2 (NCT01931670)] in which a total of 952 adult women with moderate to severe pain associated with endometriosis were treated with elagolix (475 with 150 mg once daily and 477 with 200 mg twice daily) and 734 were treated with placebo. The population age range was 18-49 years old. Women who completed six months of treatment and met eligibility criteria continued treatment in two uncontrolled, blinded six-month extension trials [EM-3 (NCT01760954) and EM-4 (NCT02143713)], for a total treatment duration of up to 12 months.
Serious Adverse Events
- Overall, the most common serious adverse events reported for subjects treated with elagolix in the two placebo-controlled clinical trials (Studies EM-1 and EM-2) included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%). In these trials, 0.2% of subjects treated with elagolix 150 mg once daily and 0.2% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to serious adverse reactions compared to 0.5% of those given placebo.
Adverse Reactions Leading to Study Discontinuation
- In the two placebo-controlled clinical trials (Studies EM-1 and EM-2), 5.5% of subjects treated with elagolix 150 mg once daily and 9.6% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to adverse reactions compared to 6.0% of those given placebo. Discontinuations were most commonly due to hot flushes or night sweats (1.1% with 150 mg once daily and 2.5% with 200 mg twice daily) and nausea (0.8% with 150 mg once daily and 1.5% with 200 mg twice daily) and were dose-related. The majority of discontinuations due to hot flushes or night sweats (10 of 17, 59%) and nausea (7 of 11, 64%) occurred within the first 2 months of therapy.
- In the two extension trials (Studies EM-3 and EM-4), discontinuations were most commonly due to decreased bone mineral density and were dose-related. In these trials, 0.3% of subjects treated with elagolix 150 mg once daily and 3.6% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to decreased BMD.
Common Adverse Reactions:
Adverse reactions reported in ≥ 5% of women in the two placebo-controlled trials in either elagolix dose group and at a greater frequency than placebo are noted in the following table.
Less Common Adverse Reactions:
- In Study EM-1 and Study EM-2, adverse reactions reported in ≥ 3% and < 5% in either elagolix dose group and greater than placebo included: decreased libido, diarrhea, abdominal pain, weight gain, dizziness, constipation and irritability.
- The most commonly reported adverse reactions in the extension trials (EM-3 and EM-4) were similar to those in the placebo-controlled trials.
Bone Loss
- The effect of elagolix on bone mineral density was assessed by dual energy X-ray absorptiometry (DXA).
- In Studies EM-1 and EM-2, there was a dose-dependent decrease in BMD in elagolix-treated subjects compared to an increase in placebo-treated subjects.
- In Study EM-1, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -0.9% (95% CI: -1.3, -0.4) with elagolix 150 mg once daily and -3.1% (95% CI: -3.6, -2.6) with elagolix 200 mg twice daily (TABLE 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was 2% with elagolix 150 mg once daily, 7% with elagolix 200 mg twice daily and < 1% with placebo. In the blinded extension Study EM-3, continued bone loss was observed with 12 months of continuous treatment with elagolix. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 8% with continuous elagolix 150 mg once daily and 21% with continuous elagolix 200 mg twice daily.
- In Study EM-2, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -1.3% (95% CI: -1.8, -0.8) with elagolix 150 mg once daily and -3.0% (95% CI: -3.5, -2.6) with elagolix 200 mg twice daily (TABLE 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was < 1% with elagolix 150 mg once daily, 6% with elagolix 200 mg twice daily and 0% with placebo. In the blinded extension Study EM-4, continued bone loss was observed with 12 months of continuous treatment with elagolix. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 2% with continuous elagolix 150 mg once daily and 21% with continuous elagolix 200 mg twice daily.
- To assess for recovery, the change in lumbar spine BMD over time was analyzed for subjects who received continuous treatment with elagolix 150 mg once daily or elagolix 200 mg twice daily for up to 12 months and who were then followed after cessation of therapy for an additional 6 months. Partial recovery of BMD was seen in these subjects (Figure 1).
- In Study EM-3, if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip at the end of treatment, follow-up DXA was required after 6 months off-treatment. In Study EM-4, all subjects were required to have a follow-up DXA 6 months off treatment regardless of change in BMD and if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip after 6 months off treatment, follow-up DXA was required after 12 months off-treatment. Figure 2 shows the change in lumbar spine BMD for the subjects in Study EM-2/EM-4 who completed 12 months of treatment with elagolix and who had a follow-up DXA 12-months off treatment.
Suicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders
- In the placebo-controlled trials (Studies EM-1 and EM-2), elagolix was associated with adverse mood changes (see Table 2 and Table 4), particularly in those with a history of depression.
- A 44-year-old woman received 31 days of elagolix 150 mg once daily then completed suicide 2 days after elagolix discontinuation. She had no relevant past medical history; life stressors were noted.
- Among the 2090 subjects exposed to elagolix in the endometriosis Phase 2 and Phase 3 studies, there were four reports of suicidal ideation. In addition to the two subjects in Table 4, there were two additional reports of suicidal ideation: one subject in EM-3 (150 mg once daily) and one in a Phase 2 study (75 mg once daily, an unapproved dose). Three of these subjects had a history of depression. Two subjects discontinued elagolix and two completed the clinical trial treatment periods.
Hepatic Transaminase Elevations
- In the placebo-controlled clinical trials (Studies EM-1 and EM-2), dose-dependent asymptomatic elevations of serum ALT to at least 3-times the upper limit of the reference range occurred during treatment with elagolix (150 mg once daily – 1/450, 0.2%; 200 mg twice daily – 5/443, 1.1%; placebo – 1/696, 0.1%). Similar increases were seen in the extension trials (Studies EM-3 and EM-4).
Changes in Lipid Parameters
- Dose-dependent increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and serum triglycerides were noted during elagolix treatment in EM-1 and EM-2. In EM-1 and EM-2, 12% and 1% of subjects with mildly elevated LDL-C (130-159 mg/dL) at baseline had an increase in LDL-C concentrations to 190 mg/dL or higher during treatment with elagolix and placebo, respectively. In EM-1 and EM-2, 4% and 1% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an increase in serum triglycerides to at least 500 mg/dL during treatment with elagolix and placebo, respectively. The highest measured serum triglyceride concentration during treatment with elagolix was 982 mg/dL.
- Lipid increases occurred within 1 to 2 months after the start of elagolix and remained stable thereafter over 12 months.
Hypersensitivity Reactions
- In Studies EM-1 and EM-2, non-serious hypersensitivity reactions including rash occurred in 5.8% of elagolix treated-subjects and 6.1% of placebo-treated subjects. These events led to study drug discontinuation in 0.4% of elagolix-treated subjects and 0.5% of placebo-treated subjects.
Endometrial Effects
- Endometrial biopsies were performed in subjects in Study EM-1 and its extension at Month 6 and Month 12. These biopsies showed a dose-dependent decrease in proliferative and secretory biopsy patterns and an increase in quiescent/minimally stimulated biopsy patterns. There were no abnormal biopsy findings on treatment, such as endometrial hyperplasia or cancer.
- Based on transvaginal ultrasound, during the course of a 3-menstrual cycle study in healthy women, elagolix 150 mg once daily and 200 mg twice daily resulted in a dose-dependent decrease from baseline in mean endometrial thickness.
Effects on menstrual bleeding patterns
- The effects of elagolix on menstrual bleeding were evaluated for up to 12 months using an electronic daily diary where subjects classified their flow of menstrual bleeding (if present in the last 24 hours) as spotting, light, medium, or heavy. Elagolix led to a dose-dependent reduction in mean number of bleeding and spotting days and bleeding intensity in those subjects who reported menstrual bleeding.
- Elagolix also demonstrated a dose-dependent increase in the percentage of women with amenorrhea (defined as no bleeding or spotting in a 56-day interval) over the treatment period. The incidence of amenorrhea during the first six months of treatment ranged from 6-17% for elagolix 150 mg once daily, 13-52% for elagolix 200 mg twice daily and less than 1% for placebo. During the second 6 months of treatment, the incidence of amenorrhea ranged from 11-15% for elagolix 150 mg once daily and 46-57% for elagolix 200 mg twice daily.
- After 6 months of therapy with elagolix 150 mg once daily, resumption of menses after stopping treatment was reported by 59%, 87% and 95% of women within 1, 2, and 6 months, respectively. After 6 months of therapy with elagolix 200 mg twice daily, resumption of menses after stopping treatment was reported by 60%, 88%, and 97% of women within 1, 2, and 6 months, respectively.
- After 12 months of therapy with elagolix 150 mg once daily resumption of menses after stopping treatment was reported by 77%, 95% and 98% of women within 1, 2, and 6 months respectively. After 12 months of therapy with elagolix 200 mg twice daily resumption of menses after stopping treatment was reported by 55%, 91% and 96% of women within 1, 2, and 6 months respectively.
## Postmarketing Experience
There is limited information regarding Elagolix Postmarketing Experience in the drug label.
# Drug Interactions
- Elagolix is a weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with elagolix may decrease plasma concentrations of drugs that are substrates of CYP3A.
- Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with elagolix may increase plasma concentrations of drugs that are substrates of P-gp (e.g., digoxin).
- Elagolix is a substrate of CYP3A, P-gp, and OATP1B1.
- Concomitant use of elagolix 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and strong CYP3A inhibitors to 6 months.
- Co-administration of elagolix with drugs that induce CYP3A may decrease elagolix plasma concentrations.
- The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of elagolix is unknown. Co-administration of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Concomitant use of elagolix and strong OATP1B1 inhibitors (e.g., cyclosporine and gemfibrozil) is contraindicated.
- TABLE 7 summarizes the effect of co-administration of elagolix on concentrations of concomitant drugs and the effect of concomitant drugs on elagolix.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Use of elagolix is contraindicated in pregnant women. Discontinue elagolix if pregnancy occurs during treatment.
- The limited human data with the use of elagolix in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with elagolix, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups.
- When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively.
- The background risk for major birth defects and miscarriage in the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Human Data
- There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with elagolix for up to 12 months. These pregnancies occurred while the women were receiving elagolix or within 30 days after stopping elagolix. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with elagolix 150 mg daily and the estimated fetal exposure to elagolix occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with elagolix 150 mg daily and the estimated fetal exposure to elagolix occurred during the first 15 days of pregnancy.
- Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in elagolix clinical trials, there were no apparent decreases in birth weights associated with elagolix in comparison to placebo.
Animal Data
- Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).
- In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD.
- No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.
- In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.
- Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elagolix in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Elagolix during labor and delivery.
### Nursing Mothers
Risk Summary
- There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. There are no adequate animal data on the excretion of elagolix in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for elagolix and any potential adverse effects on the breastfed child from elagolix.
Data
- There are no adequate animal data on excretion of elagolix in milk.
### Pediatric Use
- Safety and effectiveness of elagolix in patients less than 18 years of age have not been established.
### Geriatic Use
There is no FDA guidance on the use of Elagolix in geriatric settings.
### Gender
There is no FDA guidance on the use of Elagolix with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Elagolix with respect to specific racial populations.
### Renal Impairment
- No dose adjustment of elagolix is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis).
### Hepatic Impairment
- No dosage adjustment of elagolix is required for women with mild hepatic impairment (Child-Pugh A). Only the 150 mg once daily regimen is recommended for women with moderate hepatic impairment (Child-Pugh B) and the duration of treatment should be limited to 6 months.
- Elagolix is contraindicated in women with severe hepatic impairment (Child-Pugh C).
### Females of Reproductive Potential and Males
- Based on the mechanism of action, there is a risk of early pregnancy loss if elagolix is administered to a pregnant woman.
Pregnancy Testing
- Exclude pregnancy before initiating treatment with elagolix. Perform pregnancy testing if pregnancy is suspected during treatment with elagolix.
Contraception
- Advise women to use effective non-hormonal contraception during treatment with elagolix and for one week after discontinuing elagolix.
### Immunocompromised Patients
There is no FDA guidance one the use of Elagolix in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Exclude pregnancy before starting elagolix or start elagolix within 7 days from the onset of menses.
- Take elagolix at approximately the same time each day, with or without food.
- Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives.
- Limit the duration of use because of bone loss (Table 1).
- No dosage adjustment of elagolix is required in women with mild hepatic impairment (Child-Pugh A).
- Compared to women with normal liver function, those with moderate hepatic impairment had approximately 3-fold higher elagolix exposures and those with severe hepatic impairment had approximately 7-fold higher elagolix exposures. Because of these increased exposures and risk for bone loss:
Elagolix 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of elagolix 200 mg twice daily is not recommended for women with moderate hepatic impairment.
Elagolix is contraindicated in women with severe hepatic impairment (Child-Pugh C).
- Elagolix 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of elagolix 200 mg twice daily is not recommended for women with moderate hepatic impairment.
- Elagolix is contraindicated in women with severe hepatic impairment (Child-Pugh C).
- Instruct the patient to take a missed dose of elagolix on the same day as soon as she remembers and then resume the regular dosing schedule.
150 mg once daily: take no more than 1 tablet each day.
200 mg twice daily: take no more than 2 tablets each day.
- 150 mg once daily: take no more than 1 tablet each day.
- 200 mg twice daily: take no more than 2 tablets each day.
### Monitoring
There is limited information regarding Elagolix Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Elagolix and IV administrations.
# Overdosage
- In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.
# Pharmacology
## Mechanism of Action
- Elagolix is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.
## Structure
- Elagolix sodium has a molecular formula of C32H29F5N3O5Na and a molecular weight of 653.58. Elagolix free acid has a molecular weight of 631.60.
- Elagolix sodium has the following structural formula:
## Pharmacodynamics
Effect on Ovulation and Estradiol
- In a 3-menstrual cycle study in healthy women, elagolix 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen.
Cardiac Electrophysiology
- The effect of elagolix on the QTc interval was evaluated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.
## Pharmacokinetics
- The pharmacokinetic properties of elagolix in healthy subjects are summarized in TABLE 8. The steady state pharmacokinetic parameters under fasting conditions are summarized in TABLE 9.
Specific Populations
Renal Impairment
- Elagolix exposures (Cmax and AUC) are not altered by renal impairment. The mean exposures are similar for women with moderate to severe or end stage renal disease (including women on dialysis) compared to women with normal renal function.
Hepatic Impairment
- Elagolix exposures (Cmax and AUC) are similar between women with normal hepatic function and women with mild hepatic impairment. Elagolix exposures in women with moderate and severe hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function.
Race/Ethnicity
- No clinically meaningful difference in the pharmacokinetics of elagolix between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of elagolix between Japanese and Han Chinese subjects.
Body weight/Body mass index
- Body weight or body mass index does not affect the pharmacokinetics of elagolix.
Drug Interaction Studies
- Drug interaction studies were performed with elagolix and other drugs that are likely to be co-administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 10 and 11 summarize the pharmacokinetic effects when elagolix was co-administered with these drugs.
- No clinically significant changes in elagolix exposures were observed when co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single dose).
- No clinically significant changes in sertraline or fluconazole exposures were observed when co-administered with elagolix.
## Pharmacogenomics
- Disposition of elagolix involves the OATP 1B1 transporter protein. Higher plasma concentrations of elagolix have been observed in groups of patients who have two reduced function alleles of the gene that encodes OATP 1B1 (SLCO1B1 521T>C). The frequency of this SLCO1B1 521 C/C genotype is generally less than 5% in most racial/ethnic groups. Subjects with this genotype are expected to have a 78% mean increase in elagolix concentrations compared to subjects with normal transporter function (i.e., SLCO1B1 521T/T genotype).
## Nonclinical Toxicology
- Two-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered elagolix by the dietary route revealed no increase in tumors in mice at up to 19-fold the MRHD based on AUC. In the rat, there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (12 to 13-fold the MRHD). The rat tumors were likely species-specific and of negligible relevance to humans.
- Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay.
- In a fertility study conducted in the rat, there was no effect of elagolix on fertility at any dose (50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women compared to the highest dose of 300 mg/kg/day in female rats is approximately 5-fold. However, because elagolix has low affinity for the GnRH receptor in the rat, and because effects on fertility are most likely to be mediated via the GnRH receptor, these data have low relevance to humans.
# Clinical Studies
- The efficacy of elagolix 150 mg once daily and 200 mg twice daily for the management of moderate to severe pain associated with endometriosis was demonstrated in two multinational double-blind, placebo-controlled trials in 1686 premenopausal women [Study EM-1 (NCT01620528) and Study EM-2 (NCT01931670)]. The median age of women in the trials was 32 years; 88% were White, 9% were Black or African American and 3% were other races. Each placebo-controlled trial assessed the reduction in endometriosis-associated pain over 6 months of treatment.
- Moderate to severe pain associated with endometriosis was required for entry into the trials and was assessed during screening using the composite pelvic signs and symptoms score (CPSSS) and other baseline criteria.
- The CPSSS is based on a modified Biberoglu and Behrman scale with five elements: three responses reported by study subjects (dysmenorrhea, dyspareunia, and non-menstrual pelvic pain) and two findings based on investigator assessment during physical examination (rating of pelvic tenderness and induration). Each element is scored from 0 (absent) to 3 (severe) for a maximum total score of 15. A total score of at least 6, with a score of at least 2 for dysmenorrhea and at least 2 for non-menstrual pelvic pain was required to qualify for randomization. Subjects were also required to have non-menstrual pelvic pain for at least four days in the preceding calendar month, defined as 35 days. Other criteria to determine eligibility for randomization included subject responses in a daily electronic diary (Endometriosis Daily Pain Impact Scale, described below) for both dysmenorrhea and non-menstrual pelvic pain in the 35 days prior to randomization.
Dysmenorrhea and Non-Menstrual Pelvic Pain
- The co-primary efficacy endpoints were (1) the proportion of subjects whose dysmenorrhea responded to treatment at Month 3 and (2) the proportion of subjects whose pelvic pain not related to menses (also known as non-menstrual pelvic pain) responded to treatment at Month 3. Dysmenorrhea and non-menstrual pelvic pain were evaluated daily using the Endometriosis Daily Pain Impact Scale that asked subjects to rate their pain severity and its impact on daily activities during the prior 24 hours as none, mild, moderate or severe (correlating with a score of 0 to 3, respectively, where higher scores indicated greater severity). Scores at baseline and at each month were averaged over a 35-day interval.
- Women were defined as responders if they experienced a reduction in dysmenorrhea and non-menstrual pelvic pain as defined in Table 12 with no increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid) for endometriosis-associated pain. The threshold for defining responders was based on a receiver operating characteristic (ROC) analysis using the patient global impression of change as an anchor. A higher proportion of women treated with elagolix 150 mg once daily or 200 mg twice daily were responders for dysmenorrhea and non-menstrual pelvic pain compared to placebo in a dose-dependent manner at Month 3 [see TABLE 12].
- Women in these studies also provided a daily self-assessment of their endometriosis pain using a numeric rating scale (NRS) that asked subjects to rate their endometriosis pain at its worst over the last 24 hours on a scale from 0 (no pain) to 10 (worst pain ever). In Study EM-1, baseline NRS scores were 5.7 for elagolix 150 mg once daily, 5.5 for elagolix 200 mg twice daily and 5.6 for placebo. In Study EM-2, baseline NRS scores were 5.7 for elagolix 150 mg once daily, 5.3 for elagolix 200 mg twice daily and 5.6 for placebo. Women taking elagolix 150 mg once daily and 200 mg twice daily reported a statistically (p <0.001) significant reduction from baseline in NRS scores compared to placebo at Month 3 in both Studies EM-1 and EM-2 (Study EM-1: 0.7 points for elagolix 150 mg once daily and 1.3 points for elagolix 200 mg twice daily; Study EM-2: 0.6 points for elagolix 150 mg once daily and 1.2 points for elagolix 200 mg twice daily).
- In addition, both elagolix treatment groups showed statistically significantly greater mean decreases from baseline compared to placebo in dysmenorrhea and non-menstrual pelvic pain scores at Month 6. Figures 3 through 6 show the mean scores for dysmenorrhea and non-menstrual pelvic pain over time for Study EM-1 and EM-2.
Dyspareunia
- Dyspareunia associated with endometriosis was evaluated as a secondary endpoint using the Endometriosis Daily Pain Impact Scale that asked subjects to rate their pain during sexual intercourse in the prior 24 hours as none, mild, moderate, severe (correlating with a score of 0 to 3, respectively, where higher scores indicated greater severity), or not applicable. In both Studies EM-1 and EM-2, women treated with elagolix 200 mg twice daily showed statistically significantly greater reduction in dyspareunia from baseline to Month 3 than women given placebo (Study EM-1: 0.2; Study EM-2: 0.3). Figures 7 and 8 show the mean scores over time for Study EM-1 and EM-2.
Use of rescue pain medication
- In EM-1 and EM-2, 59% and 60% of patients used an opioid rescue analgesic for pain at baseline. The opioid rescue analgesics used at baseline were predominantly hydrocodone/acetaminophen (HC/APAP) and codeine/APAP at strengths of 5/300-325 mg and 30/300-500 mg. In EM-1, of all patients on an opioid at baseline, 98% and 2% were on HC/APAP and codeine/APAP, respectively. In EM-2, of all patients on an opioid at baseline, 50% were on HC/APAP and 16% were on codeine/APAP.
- Other data related to opioid rescue analgesic use are summarized in TABLE 13.
- The clinical relevance of these data has not been demonstrated.
# How Supplied
- Elagolix tablets are available in two strengths: 150 mg and 200 mg, which are equivalent to 155.2 mg and 207.0 mg of elagolix sodium, respectively.
- Elagolix 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on one side. Elagolix 150 mg tablets are packaged in weekly blister packs. Each blister pack contains 7 tablets supplying the drug product for one week. Four blister packs (a total of 28 tablets) are packaged into a carton that provides the drug product for 4 weeks (NDC 0074-0038-28).
- Elagolix 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed on one side. The 200 mg tablets are packaged in weekly blister packs. Each blister pack contains 14 tablets supplying the drug product for one week. Four blister packs (a total of 56 tablets) are packaged in a carton that provides the drug product for 4 weeks (NDC 0074-0039-56).
## Storage
- Store at 2°C to 30°C (36°F to 86°F).
- Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash, WWW.FDA.GOV/DRUGDISPOSAL. Do NOT flush down the toilet.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to read the FDA-approved patient labeling (Medication Guide).
- Advise patients on contraceptive options, not to get pregnant while using elagolix, to be mindful that menstrual changes could reflect pregnancy and to discontinue elagolix if pregnancy occurs.
- Inform patients that estrogen containing contraceptives are expected to reduce the efficacy of elagolix.
- Inform patients about the risk of bone loss. Advise adequate intake of calcium and vitamin D.
- Advise patients to seek immediate medical attention for suicidal ideation and behavior. Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention.
- Counsel patients on signs and symptoms of liver injury.
- Instruct patients who miss a dose of elagolix to take the missed dose on the same day as soon as she remembers and then resume the regular dosing schedule:
150 mg once daily: no more than 1 tablet each day should be taken.
200 mg twice daily: no more than 2 tablets each day should be taken.
- 150 mg once daily: no more than 1 tablet each day should be taken.
- 200 mg twice daily: no more than 2 tablets each day should be taken.
- Instruct patients to dispose of unused medication via a take-back option if available or to otherwise follow FDA instructions for disposing of medication in the household trash, WWW.FDA.GOV/DRUGDISPOSAL, and not to flush down the toilet.
# Precautions with Alcohol
Alcohol-Elagolix interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Orilissa
# Look-Alike Drug Names
There is limited information regarding Elagolix Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Elagolix | |
41260359c71baa6e7243cc1428819b6e32db2c75 | wikidoc | Elastase | Elastase
# Overview
In molecular biology, elastase is an enzyme from the class of proteases (peptidases) that break down proteins.
# Forms and classification
Eight human genes exist for elastase:
Bacterial forms: Organisms such as P. aeruginosa also produce elastase, and is considered a virulence factor.
# Function
Elastase breaks down elastin, an elastic fiber that, together with collagen, determines the mechanical properties of connective tissue. The neutrophil form breaks down the Outer membrane protein A (OmpA) of E. coli and other Gram-negative bacteria. Elastase also has the important immunological role of breaking down Shigella virulence factors. This is accomplished through the cleavage of peptide bonds in the target proteins. The specific peptide bonds cleaved are those on the carboxy side of small, hydrophobic amino acids such as glycine, alanine, and valine. For more on how this is accomplished, see serine protease.
# The role of human elastase in disease
## A1AT
Elastase is inhibited by the acute-phase protein α1-antitrypsin (A1AT), which binds almost irreversibly to the active site of elastase and trypsin. A1AT is normally secreted by the liver cells into the serum. α1-antitryspin deficiency (A1AD) leads to uninhibited destruction of elastic fiber by elastase; the main result is pulmonary emphysema.
## Cyclic hematopoeiesis
The rare disease cyclic hematopoeiesis (also called "cyclic neutropenia") is an autosomal dominant genetic disorder characterised by fluctuating neutrophil granulocyte counts over 21-day periods. During neutropenia, patients are at risk for infections. In 1999, this disease was linked to disorders in the ELA-2 / ELANE gene. Other forms of congenital neutropenia also appear to be linked to ELA-2 mutations.
## Other diseases
Neutrophil elastase is responsible for the blistering in bullous pemphigoid, a skin condition, in the presence of antibodies.
# The role of bacterial elastase in disease
Elastase has been shown to disrupt tight junctions, cause proteolytic damage to tissue, break down cytokines and alpha proteinase inhibitor, cleave immunoglobuline A and G (IgA, IgG), and cleave both C3bi, a component of the complement system, and CR1, a receptor on neutrophils for another complement molecule involved in phagocytosis. The cleavage of IgA, IgG, C3bi, and CR1 contributes to a decrease of the ability of neutrophils to kill bacteria by phagocytosis. Together, all these factors contribute to human pathology. | Elastase
# Overview
In molecular biology, elastase is an enzyme from the class of proteases (peptidases) that break down proteins.[1]
# Forms and classification
Eight human genes exist for elastase:
Bacterial forms: Organisms such as P. aeruginosa also produce elastase, and is considered a virulence factor.
# Function
Elastase breaks down elastin, an elastic fiber that, together with collagen, determines the mechanical properties of connective tissue. The neutrophil form breaks down the Outer membrane protein A (OmpA) of E. coli and other Gram-negative bacteria. Elastase also has the important immunological role of breaking down Shigella virulence factors. This is accomplished through the cleavage of peptide bonds in the target proteins. The specific peptide bonds cleaved are those on the carboxy side of small, hydrophobic amino acids such as glycine, alanine, and valine. For more on how this is accomplished, see serine protease.
# The role of human elastase in disease
## A1AT
Elastase is inhibited by the acute-phase protein α1-antitrypsin (A1AT), which binds almost irreversibly to the active site of elastase and trypsin. A1AT is normally secreted by the liver cells into the serum. α1-antitryspin deficiency (A1AD) leads to uninhibited destruction of elastic fiber by elastase; the main result is pulmonary emphysema.
## Cyclic hematopoeiesis
The rare disease cyclic hematopoeiesis (also called "cyclic neutropenia") is an autosomal dominant genetic disorder characterised by fluctuating neutrophil granulocyte counts over 21-day periods. During neutropenia, patients are at risk for infections. In 1999, this disease was linked to disorders in the ELA-2 / ELANE gene.[2] Other forms of congenital neutropenia also appear to be linked to ELA-2 mutations.[citation needed]
## Other diseases
Neutrophil elastase is responsible for the blistering in bullous pemphigoid, a skin condition, in the presence of antibodies.
# The role of bacterial elastase in disease
Elastase has been shown to disrupt tight junctions, cause proteolytic damage to tissue, break down cytokines and alpha proteinase inhibitor, cleave immunoglobuline A and G (IgA, IgG), and cleave both C3bi, a component of the complement system, and CR1, a receptor on neutrophils for another complement molecule involved in phagocytosis. The cleavage of IgA, IgG, C3bi, and CR1 contributes to a decrease of the ability of neutrophils to kill bacteria by phagocytosis. Together, all these factors contribute to human pathology. | https://www.wikidoc.org/index.php/Elastase | |
0c56ee498d12a7ad1edd6cc17f5a8f91c1a82d80 | wikidoc | Elective | Elective
Elective used as an adjective means that it is optional and chosen, for example, by election. An elective, a noun, chosen by a student means that it is an optional subject or course in a curriculum.
Elective is a term used for an academic course chosen by the student from a set of options, as opposed to a required course. For example, an undergraduate college may require students studying psychology to take six required courses and four electives, chosen from a list of ten options.
The term elective is also used for a period of medical study conducted away from the student's home medical school, often abroad. | Elective
Elective used as an adjective means that it is optional and chosen, for example, by election. An elective, a noun, chosen by a student means that it is an optional subject or course in a curriculum.
Elective is a term used for an academic course chosen by the student from a set of options, as opposed to a required course. For example, an undergraduate college may require students studying psychology to take six required courses and four electives, chosen from a list of ten options.
The term elective is also used for a period of medical study conducted away from the student's home medical school, often abroad.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Elective | |
0a4e4a836011ffd5688f8d8d25c87fab885e1978 | wikidoc | Electron | Electron
# Overview
The electron is a fundamental subatomic particle that carries a negative electric charge. It is a spin ½ lepton that participates in electromagnetic interactions, and its mass is approximately 1/1836 of that of the proton. Together with atomic nuclei, which consist of protons and neutrons, electrons make up atoms. Their interaction with adjacent nuclei is the main cause of chemical bonding.
# History
The name electron comes from the Greek word for amber, ήλεκτρον. This material played an essential role in the discovery of electrical phenomena. The ancient Greeks knew, for example, that rubbing a piece of amber with fur left an electric charge on its surface, which could then create a spark when brought close to a grounded object. For more about the history of the term electricity, see History of electricity.
The electron as a unit of charge in electrochemistry was posited by G. Johnstone Stoney in 1874, who also coined the term electron in 1894.
In this paper an estimate was made of the actual amount of this most remarkable fundamental unit of electricity, for which I have since ventured to suggest the name electron.
During the late 1890s a number of physicists posited that electricity could be conceived of as being made of discrete units, which were given a variety of names, but the reality of these units had not been confirmed in a compelling way.
The discovery that the electron was a subatomic particle was made in 1897 by J.J. Thomson at the Cavendish Laboratory at Cambridge University, while he was studying cathode ray tubes. A cathode ray tube is a sealed glass cylinder in which two electrodes are separated by a vacuum. When a voltage is applied across the electrodes, cathode rays are generated, causing the tube to glow. Through experimentation, Thomson discovered that the negative charge could not be separated from the rays (by the application of magnetism), and that the rays could be deflected by an electric field. He concluded that these rays, rather than being waves, were composed of negatively charged particles he called "corpuscles". He measured their mass-to-charge ratio and found it to be over a thousand times smaller than that of a hydrogen ion, suggesting that they were either very highly charged or very small in mass. Later experiments by other scientists upheld the latter conclusion. Their mass-to-charge ratio was also independent of the choice of cathode material and the gas originally in the vacuum tube. This led Thomson to conclude that they were universal among all materials.
The electron's charge was carefully measured by R. A. Millikan in his oil-drop experiment of 1909.
The periodic law states that the chemical properties of elements largely repeat themselves periodically and is the foundation of the periodic table of elements. The law itself was initially explained by the atomic mass of the element. However, as there were anomalies in the periodic table, efforts were made to find a better explanation for it. In 1913, Henry Moseley introduced the concept of the atomic number and explained the periodic law in terms of the number of protons each element has. In the same year, Niels Bohr showed that electrons are the actual foundation of the table. In 1916, Gilbert Newton Lewis explained the chemical bonding of elements by electronic interactions.
# Classification
The electron is in the class of subatomic particles called leptons, which are believed to be fundamental particles.
As with all particles, electrons can also act as waves. This is called the wave-particle duality, also known by the term complementarity coined by Niels Bohr, and can be demonstrated using the double-slit experiment.
The antiparticle of an electron is the positron, which has positive rather than negative charge. The discoverer of the positron, Carl D. Anderson, proposed calling standard electrons negatrons, and using electron as a generic term to describe both the positively and negatively charged variants. This usage of the term "negatron" is still occasionally encountered today, and it may also be shortened to "negaton".
# Properties and behavior
Electrons have an electric charge of −1.602 × 10−19 C, a mass of 9.11 × 10−31 kg based on charge/mass measurements equivalent to a rest mass of about 0.511 MeV/c². The mass of the electron is approximately 1/1836 of the mass of the proton. The common electron symbol is e−. The electron is thought to be stable on theoretical grounds; the lowest known experimental upper bound for its mean lifetime is 4.6×1026 years, with a 90% confidence interval (see Particle decay).
According to quantum mechanics, electrons can be represented by wavefunctions, from which a calculated probabilistic electron density can be determined. The orbital of each electron in an atom can be described by a wavefunction. Based on the Heisenberg uncertainty principle, the exact momentum and position of the actual electron cannot be simultaneously determined. This is a limitation which, in this instance, simply states that the more accurately we know a particle's position, the less accurately we can know its momentum, and vice versa.
The electron has spin ½ and is a fermion (it follows Fermi-Dirac statistics). In addition to its intrinsic angular momentum, an electron has an intrinsic magnetic moment along its spin axis.
Electrons in an atom are bound to that atom, while electrons moving freely in vacuum, space or certain media are free electrons that can be focused into an electron beam. When free electrons move, there is a net flow of charge, and this flow is called an electric current. The drift velocity of electrons in metal wires is on the order of millimetres per second. However, the speed at which a current at one point in a wire causes a current in other parts of the wire, the velocity of propagation, is typically 75% of light speed.
In some superconductors, pairs of electrons move as Cooper pairs in which their motion is coupled to nearby matter via lattice vibrations called phonons. The distance of separation between Cooper pairs is roughly 100 nm.
A body has an electric charge when that body has more or fewer electrons than are required to balance the positive charge of the nuclei. When there is an excess of electrons, the object is said to be negatively charged. When there are fewer electrons than protons, the object is said to be positively charged. When the number of electrons and the number of protons are equal, their charges cancel each other and the object is said to be electrically neutral. A macroscopic body can develop an electric charge through rubbing, by the phenomenon of triboelectricity.
When electrons and positrons collide, they annihilate each other and produce pairs of high-energy photons or other particles. On the other hand, high-energy photons may transform into an electron and a positron by a process called pair production, but only in the presence of a nearby charged particle, such as a nucleus.
The electron is currently described as a fundamental or elementary particle. It has no known substructure. Hence, for convenience, it is usually defined or assumed to be a point-like mathematical point charge, with no spatial extension. However, when a test particle is forced to approach an electron, we measure changes in its properties (charge and mass). This effect is common to all elementary particles. Current theory suggests that this effect is due to the influence of vacuum fluctuations in its local space, so that the properties measured from a significant distance are considered to be the sum of the bare properties and the vacuum effects (see renormalization).
The "classical electron radius" is 2.8179 × 10−15 m. This is the radius that is inferred from the electron's electric charge, by using the classical theory of electrodynamics alone, ignoring quantum mechanics. (In modern physics, the electron is believed to be a point particle, thus its actual radius is zero.) Classical electrodynamics (Maxwell's electrodynamics) is the older concept that is widely used for practical applications of electricity, electrical engineering, semiconductor physics, and electromagnetics. Quantum electrodynamics, on the other hand, is useful for applications involving modern particle physics and some aspects of optical, laser and quantum physics.
Based on current theory, the speed of an electron can approach, but never reach, c (the speed of light in a vacuum). This limitation is attributed to Einstein's theory of special relativity which defines the speed of light as a constant within all inertial frames. However, when relativistic electrons are injected into a dielectric medium such as water, where the local speed of light is significantly less than c, the electrons (temporarily) travel faster than light in the medium. As they interact with the medium, they generate a faint bluish light called Cherenkov radiation.
The effects of special relativity are based on a quantity known as γ or the Lorentz factor. γ is a function of v, the coordinate velocity of the particle. It is defined as:
The kinetic energy necessary to accelerate an electron is:
For example, the Stanford linear accelerator can accelerate an electron to roughly 51 GeV . This gives a gamma of 100,000, since the mass of an electron is 0.51 MeV/c² (the relativistic momentum of this electron is 100,000 times the classical momentum of an electron at the same speed). Solving the equation above for the speed of the electron (and using an approximation for large γ) gives:
The de Broglie wavelength of a particle is λ=h/p where h is Planck's constant and p is momentum. At low (e.g photoelectron) energies this determines the size of atoms, and at high (e.g. electron microscope) energies this makes the Bragg angles for electron diffraction (co-discovered by J. J. Thomson's son G. P. Thomson) well under one degree. Since momentum is mass times proper-velocity w=γv, we have
For the 51 GeV electron above, proper-velocity is approximately γc, making the wavelength of those electrons small enough to explore structures well below the size of an atomic nucleus.
# Visualisation
The first video images of an electron were captured by a team at Lund University in Sweden in February 2008. To capture this event, the scientists used extremely short flashes of light. To produce this light, newly developed technology for generating short pulses from intense laser light, called attosecond pulses, allowed the team at the university’s Faculty of Engineering to capture the electron's motion for the first time.
"It takes about 150 attoseconds for an electron to circle the nucleus of an atom. An attosecond is related to a second as a second is related to the age of the universe," explained Johan Mauritsson, an assistant professor in atomic physics at the Faculty of Engineering, Lund University.
Video is available here:
# Electrons in chemistry
In 1913, Niels Bohr showed that electrons are the actual foundation of the periodic table of chemical elements, and, in 1916, Gilbert Newton Lewis explained the chemical bonding of elements by electronic interactions. From these discoveries it has become clear that electrons, in particular those orbiting on the outer shell of the atom, play a fundamental part in chemical structure and chemical interactions, and that these interactions form the central part of chemistry, without which it could not even exist.
# In practice
## In the universe
Scientists believe that the number of electrons existing in the known universe is at least 1079. This number amounts to an average density of about one electron per cubic metre of space. Astronomers have estimated that 90% of the mass of atoms in the universe is hydrogen, which is made of one electron and one proton.
## In industry
Electron beams are used in welding, lithography, scanning electron microscopes and transmission electron microscopes. LEED and RHEED are surface-imaging techniques that use electrons.
Electrons are also at the heart of cathode ray tubes, which are used extensively as display devices in laboratory instruments, computer monitors and television sets. In a photomultiplier tube, one photon strikes the photocathode, initiating an avalanche of electrons that produces a detectable current.
## In the laboratory
The uniquely high charge-to-mass ratio of electrons means that they interact strongly with atoms, and are easy to accelerate and focus with electric and magnetic fields. Hence some of today's aberration-corrected transmission electron microscopes use 300keV electrons with velocities greater than the speed of light in water, wavelengths below 2 picometers, transverse coherence-widths over a nanometer, and longitudinal coherence-widths 100 times that. This allows such microscopes to image scattering from individual atomic-nuclei (HAADF) as well as interference-contrast from solid-specimen exit-surface deBroglie-phase (HRTEM) with lateral point-resolutions down to 60 picometers. Magnifications approaching 100 million are needed to make the resulting image detail comfortably visible to the naked eye.
Quantum effects of electrons are also used in the scanning tunneling microscope to study features on solid surfaces with lateral-resolution at the atomic scale (around 200 picometers) and vertical-resolutions much better than that. In such microscopes, the quantum tunneling is strongly dependent on tip-specimen separation, and, precise control of the separation (vertical sensitivity) is made possible with a piezoelectric scanner.
## In medicine
In radiation therapy, electron beams are used for treatment of superficial tumours.
# In theory
In Dirac's model, an electron is defined to be a mathematical point, a point-like, charged "bare" particle surrounded by a sea of interacting pairs of virtual particles and antiparticles. These provide a correction of just over 0.1% to the predicted value of the electron's gyromagnetic ratio from exactly 2 (as predicted by Dirac's single-particle model). The extraordinarily precise agreement of this prediction with the experimentally determined value is viewed as one of the great achievements of modern physics.
In the Standard Model of particle physics, the electron is the first-generation charged lepton. It forms a weak isospin doublet with the electron neutrino; these two particles interact with each other through both the charged and neutral current weak interaction. The electron is very similar to the two more massive particles of higher generations, the muon and the tau lepton, which are identical in charge, spin, and interaction, but differ in mass.
The antimatter counterpart of the electron is the positron. The positron has the same amount of electrical charge as the electron, except that the charge is positive. It has the same mass and spin as the electron. When an electron and a positron meet, they may annihilate each other, giving rise to two gamma-ray photons emitted at roughly 180° to each other. If the electron and positron had negligible momentum, each gamma ray will have an energy of 0.511 MeV. See also Electron-positron annihilation.
Electrons are a key element in electromagnetism, a theory that is accurate for macroscopic systems, and for classical modelling of microscopic systems. | Electron
Template:Infobox Particle
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The electron is a fundamental subatomic particle that carries a negative electric charge. It is a spin ½ lepton that participates in electromagnetic interactions, and its mass is approximately <math>1/1836</math> of that of the proton. Together with atomic nuclei, which consist of protons and neutrons, electrons make up atoms. Their interaction with adjacent nuclei is the main cause of chemical bonding.
# History
The name electron comes from the Greek word for amber, ήλεκτρον. This material played an essential role in the discovery of electrical phenomena. The ancient Greeks knew, for example, that rubbing a piece of amber with fur left an electric charge on its surface, which could then create a spark when brought close to a grounded object. For more about the history of the term electricity, see History of electricity.
The electron as a unit of charge in electrochemistry was posited by G. Johnstone Stoney in 1874, who also coined the term electron in 1894.
In this paper an estimate was made of the actual amount of this most remarkable fundamental unit of electricity, for which I have since ventured to suggest the name electron.
During the late 1890s a number of physicists posited that electricity could be conceived of as being made of discrete units, which were given a variety of names, but the reality of these units had not been confirmed in a compelling way.
The discovery that the electron was a subatomic particle was made in 1897 by J.J. Thomson at the Cavendish Laboratory at Cambridge University, while he was studying cathode ray tubes. A cathode ray tube is a sealed glass cylinder in which two electrodes are separated by a vacuum. When a voltage is applied across the electrodes, cathode rays are generated, causing the tube to glow. Through experimentation, Thomson discovered that the negative charge could not be separated from the rays (by the application of magnetism), and that the rays could be deflected by an electric field. He concluded that these rays, rather than being waves, were composed of negatively charged particles he called "corpuscles". He measured their mass-to-charge ratio and found it to be over a thousand times smaller than that of a hydrogen ion, suggesting that they were either very highly charged or very small in mass. Later experiments by other scientists upheld the latter conclusion. Their mass-to-charge ratio was also independent of the choice of cathode material and the gas originally in the vacuum tube. This led Thomson to conclude that they were universal among all materials.
The electron's charge was carefully measured by R. A. Millikan in his oil-drop experiment of 1909.
The periodic law states that the chemical properties of elements largely repeat themselves periodically and is the foundation of the periodic table of elements. The law itself was initially explained by the atomic mass of the element. However, as there were anomalies in the periodic table, efforts were made to find a better explanation for it. In 1913, Henry Moseley introduced the concept of the atomic number and explained the periodic law in terms of the number of protons each element has. In the same year, Niels Bohr showed that electrons are the actual foundation of the table. In 1916, Gilbert Newton Lewis explained the chemical bonding of elements by electronic interactions.
# Classification
The electron is in the class of subatomic particles called leptons, which are believed to be fundamental particles.
As with all particles, electrons can also act as waves. This is called the wave-particle duality, also known by the term complementarity coined by Niels Bohr, and can be demonstrated using the double-slit experiment.
The antiparticle of an electron is the positron, which has positive rather than negative charge. The discoverer of the positron, Carl D. Anderson, proposed calling standard electrons negatrons, and using electron as a generic term to describe both the positively and negatively charged variants. This usage of the term "negatron" is still occasionally encountered today, and it may also be shortened to "negaton".[1]
# Properties and behavior
Electrons have an electric charge of −1.602 × 10−19 C, a mass of 9.11 × 10−31 kg based on charge/mass measurements equivalent to a rest mass of about 0.511 MeV/c². The mass of the electron is approximately 1/1836 of the mass of the proton. The common electron symbol is e−.[2] The electron is thought to be stable on theoretical grounds; the lowest known experimental upper bound for its mean lifetime is 4.6×1026 years, with a 90% confidence interval (see Particle decay).
According to quantum mechanics, electrons can be represented by wavefunctions, from which a calculated probabilistic electron density can be determined. The orbital of each electron in an atom can be described by a wavefunction. Based on the Heisenberg uncertainty principle, the exact momentum and position of the actual electron cannot be simultaneously determined. This is a limitation which, in this instance, simply states that the more accurately we know a particle's position, the less accurately we can know its momentum, and vice versa.
The electron has spin ½ and is a fermion (it follows Fermi-Dirac statistics). In addition to its intrinsic angular momentum, an electron has an intrinsic magnetic moment along its spin axis.
Electrons in an atom are bound to that atom, while electrons moving freely in vacuum, space or certain media are free electrons that can be focused into an electron beam. When free electrons move, there is a net flow of charge, and this flow is called an electric current. The drift velocity of electrons in metal wires is on the order of millimetres per second. However, the speed at which a current at one point in a wire causes a current in other parts of the wire, the velocity of propagation, is typically 75% of light speed.
In some superconductors, pairs of electrons move as Cooper pairs in which their motion is coupled to nearby matter via lattice vibrations called phonons. The distance of separation between Cooper pairs is roughly 100 nm.
A body has an electric charge when that body has more or fewer electrons than are required to balance the positive charge of the nuclei. When there is an excess of electrons, the object is said to be negatively charged. When there are fewer electrons than protons, the object is said to be positively charged. When the number of electrons and the number of protons are equal, their charges cancel each other and the object is said to be electrically neutral. A macroscopic body can develop an electric charge through rubbing, by the phenomenon of triboelectricity.
When electrons and positrons collide, they annihilate each other and produce pairs of high-energy photons or other particles. On the other hand, high-energy photons may transform into an electron and a positron by a process called pair production, but only in the presence of a nearby charged particle, such as a nucleus.
The electron is currently described as a fundamental or elementary particle. It has no known substructure. Hence, for convenience, it is usually defined or assumed to be a point-like mathematical point charge, with no spatial extension. However, when a test particle is forced to approach an electron, we measure changes in its properties (charge and mass). This effect is common to all elementary particles. Current theory suggests that this effect is due to the influence of vacuum fluctuations in its local space, so that the properties measured from a significant distance are considered to be the sum of the bare properties and the vacuum effects (see renormalization).
The "classical electron radius" is 2.8179 × 10−15 m. This is the radius that is inferred from the electron's electric charge, by using the classical theory of electrodynamics alone, ignoring quantum mechanics. (In modern physics, the electron is believed to be a point particle, thus its actual radius is zero.) Classical electrodynamics (Maxwell's electrodynamics) is the older concept that is widely used for practical applications of electricity, electrical engineering, semiconductor physics, and electromagnetics. Quantum electrodynamics, on the other hand, is useful for applications involving modern particle physics and some aspects of optical, laser and quantum physics.
Based on current theory, the speed of an electron can approach, but never reach, c (the speed of light in a vacuum). This limitation is attributed to Einstein's theory of special relativity which defines the speed of light as a constant within all inertial frames. However, when relativistic electrons are injected into a dielectric medium such as water, where the local speed of light is significantly less than c, the electrons (temporarily) travel faster than light in the medium. As they interact with the medium, they generate a faint bluish light called Cherenkov radiation.
The effects of special relativity are based on a quantity known as γ or the Lorentz factor. γ is a function of v, the coordinate velocity of the particle. It is defined as:
The kinetic energy necessary to accelerate an electron is:
For example, the Stanford linear accelerator can accelerate an electron to roughly 51 GeV [2]. This gives a gamma of 100,000, since the mass of an electron is 0.51 MeV/c² (the relativistic momentum of this electron is 100,000 times the classical momentum of an electron at the same speed). Solving the equation above for the speed of the electron (and using an approximation for large γ) gives:
The de Broglie wavelength of a particle is λ=h/p where h is Planck's constant and p is momentum. At low (e.g photoelectron) energies this determines the size of atoms, and at high (e.g. electron microscope) energies this makes the Bragg angles for electron diffraction (co-discovered by J. J. Thomson's son G. P. Thomson) well under one degree. Since momentum is mass times proper-velocity w=γv, we have
For the 51 GeV electron above, proper-velocity is approximately γc, making the wavelength of those electrons small enough to explore structures well below the size of an atomic nucleus.
# Visualisation
The first video images of an electron were captured by a team at Lund University in Sweden in February 2008. To capture this event, the scientists used extremely short flashes of light. To produce this light, newly developed technology for generating short pulses from intense laser light, called attosecond pulses, allowed the team at the university’s Faculty of Engineering to capture the electron's motion for the first time.
"It takes about 150 attoseconds for an electron to circle the nucleus of an atom. An attosecond is related to a second as a second is related to the age of the universe," explained Johan Mauritsson, an assistant professor in atomic physics at the Faculty of Engineering, Lund University.
[3]
Video is available here: [4]
# Electrons in chemistry
In 1913, Niels Bohr showed that electrons are the actual foundation of the periodic table of chemical elements, and, in 1916, Gilbert Newton Lewis explained the chemical bonding of elements by electronic interactions. From these discoveries it has become clear that electrons, in particular those orbiting on the outer shell of the atom, play a fundamental part in chemical structure and chemical interactions, and that these interactions form the central part of chemistry, without which it could not even exist.
# In practice
## In the universe
Scientists believe that the number of electrons existing in the known universe is at least 1079. This number amounts to an average density of about one electron per cubic metre of space. Astronomers have estimated that 90% of the mass of atoms in the universe is hydrogen, which is made of one electron and one proton.
## In industry
Electron beams are used in welding, lithography, scanning electron microscopes and transmission electron microscopes. LEED and RHEED are surface-imaging techniques that use electrons.
Electrons are also at the heart of cathode ray tubes, which are used extensively as display devices in laboratory instruments, computer monitors and television sets. In a photomultiplier tube, one photon strikes the photocathode, initiating an avalanche of electrons that produces a detectable current.
## In the laboratory
The uniquely high charge-to-mass ratio of electrons means that they interact strongly with atoms, and are easy to accelerate and focus with electric and magnetic fields. Hence some of today's aberration-corrected transmission electron microscopes use 300keV electrons with velocities greater than the speed of light in water, wavelengths below 2 picometers, transverse coherence-widths over a nanometer, and longitudinal coherence-widths 100 times that. This allows such microscopes to image scattering from individual atomic-nuclei (HAADF) as well as interference-contrast from solid-specimen exit-surface deBroglie-phase (HRTEM) with lateral point-resolutions down to 60 picometers. Magnifications approaching 100 million are needed to make the resulting image detail comfortably visible to the naked eye.
Quantum effects of electrons are also used in the scanning tunneling microscope to study features on solid surfaces with lateral-resolution at the atomic scale (around 200 picometers) and vertical-resolutions much better than that. In such microscopes, the quantum tunneling is strongly dependent on tip-specimen separation, and, precise control of the separation (vertical sensitivity) is made possible with a piezoelectric scanner.
## In medicine
In radiation therapy, electron beams are used for treatment of superficial tumours.
# In theory
In Dirac's model, an electron is defined to be a mathematical point, a point-like, charged "bare" particle surrounded by a sea of interacting pairs of virtual particles and antiparticles. These provide a correction of just over 0.1% to the predicted value of the electron's gyromagnetic ratio from exactly 2 (as predicted by Dirac's single-particle model). The extraordinarily precise agreement of this prediction with the experimentally determined value is viewed as one of the great achievements of modern physics.[3]
In the Standard Model of particle physics, the electron is the first-generation charged lepton. It forms a weak isospin doublet with the electron neutrino; these two particles interact with each other through both the charged and neutral current weak interaction. The electron is very similar to the two more massive particles of higher generations, the muon and the tau lepton, which are identical in charge, spin, and interaction, but differ in mass.
The antimatter counterpart of the electron is the positron. The positron has the same amount of electrical charge as the electron, except that the charge is positive. It has the same mass and spin as the electron. When an electron and a positron meet, they may annihilate each other, giving rise to two gamma-ray photons emitted at roughly 180° to each other. If the electron and positron had negligible momentum, each gamma ray will have an energy of 0.511 MeV. See also Electron-positron annihilation.
Electrons are a key element in electromagnetism, a theory that is accurate for macroscopic systems, and for classical modelling of microscopic systems. | https://www.wikidoc.org/index.php/Electron | |
29464a7880869bf592fafec97294a5bbf80811ce | wikidoc | Emulsion | Emulsion
# Overview
An emulsion (IPA: /ɪˈmʌlʃən/) is a mixture of two immiscible (unblendable) substances. One substance (the dispersed phase) is dispersed in the other (the continuous phase). Examples of emulsions include butter and margarine, milk and cream, espresso, mayonnaise, the photo-sensitive side of photographic film, magmas and cutting fluid for metal working. In butter and margarine, oil surrounds droplets of water (a water-in-oil emulsion). In milk and cream, water surrounds droplets of oil (an oil-in-water emulsion). In certain types of magma, globules of liquid NiFe may be dispersed within a continuous phase of liquid silicates. Emulsification is the process by which emulsions are prepared.
Emulsion is also a term used in the oil field as untreated well production that consists primarily of crude oil and water.
# Operation
Emulsions tend to have a cloudy appearance, because the many phase interfaces (the boundary between the phases is called the interface) scatter light that passes through the emulsion. Emulsions are unstable and thus do not form spontaneously. Energy input through shaking, stirring, homogenizers, or spray processes are needed to form an emulsion. Over time, emulsions tend to revert to the stable state of oil separated from water. Surface active substances (surfactants) can increase the kinetic stability of emulsions greatly so that, once formed, the emulsion does not change significantly over years of storage. Homemade oil and vinegar salad dressing is an example of an unstable emulsion that will quickly separate unless shaken continuously. This phenomenon is called coalescence, and happens when small droplets recombine to form bigger ones. Fluid emulsions can also suffer from creaming, the migration of one of the substances to the top of the emulsion under the influence of buoyancy or centripetal force when a centrifuge is used.
Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion tends to imply that both the dispersed and the continuous phase are liquid.
There are three types of emulsion instability: flocculation, where the particles form clumps; creaming, where the particles concentrate towards the surface (or bottom, depending on the relative density of the two phases) of the mixture while staying separated; and breaking and coalescence where the particles coalesce and form a layer of liquid.
# Emulsifier
An emulsifier (also known as an emulgent) is a substance which stabilizes an emulsion, frequently a surfactant. Examples of food emulsifiers are egg yolk (where the main emulsifying chemical is lecithin), honey and mustard, where a variety of chemicals in the mucilage surrounding the seed hull act as emulsifiers; proteins and low-molecular weight emulsifiers are common as well. In some cases, particles can stabilize emulsions as well through a mechanism called Pickering stabilization. Both mayonnaise and hollandaise sauce are oil-in-water emulsions that are stabilized with egg yolk lecithin. Detergents are another class of surfactant, and will chemically interact with both oil and water, thus stabilising the interface between oil or water droplets in suspension. This principle is exploited in soap to remove grease for the purpose of cleaning. A wide variety of emulsifiers are used in pharmacy to prepare emulsions such as creams and lotions.
Whether an emulsion turns into a water-in-oil emulsion or an oil-in-water emulsion depends on the volume fraction of both phases and on the type of emulsifier. Generally, the Bancroft rule applies: emulsifiers and emulsifying particles tend to promote dispersion of the phase in which they do not dissolve very well; for example, proteins dissolve better in water than in oil and so tend to form oil-in-water emulsions (that is they promote the dispersion of oil droplets throughout a continuous phase of water).
# Nanoemulsion
Nanoemulsion is a type of emulsion in which the sizes of the particles in the dispersed phase are defined as less than 1000 nanometers.
In medicine, a nanoemulsion of soybean oil to create drops of 400-600 nanometers in diameter will kill many pathogens such as bacteria and viruses. The process is not chemical, as with other types of anti-pathogenic treatments, but physical. The smaller the droplet, the greater the surface tension and thus the greater the force to merge with other lipids. The oil is emulsified with detergents to stabilize the emulsion (the droplets won't merge with one another), so when they encounter lipids on a bacterial membrane or a virus envelope, they force the lipids to merge with themselves. On a mass scale, this effectively disintegrates the membrane and kills the pathogen.
Remarkably, the soybean oil emulsion does not harm normal human cells nor the cells of most other higher organisms. The exceptions are sperm cells and blood cells, which are vulnerable to nanoemulsions due to their membrane structures. For this reason, nanoemulsions of this type are not yet ready to be used intravenously.
The most effective application of this type of nanoemulsion is for the disinfection of surfaces. Some types of nanoemulsions have been shown to effectively destroy HIV-1 and various tuberculosis pathogens, for example, on non-porous surfaces. | Emulsion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An emulsion (IPA: /ɪˈmʌlʃən/[1]) is a mixture of two immiscible (unblendable) substances. One substance (the dispersed phase) is dispersed in the other (the continuous phase). Examples of emulsions include butter and margarine, milk and cream, espresso, mayonnaise, the photo-sensitive side of photographic film, magmas and cutting fluid for metal working. In butter and margarine, oil surrounds droplets of water (a water-in-oil emulsion). In milk and cream, water surrounds droplets of oil (an oil-in-water emulsion). In certain types of magma, globules of liquid NiFe may be dispersed within a continuous phase of liquid silicates. Emulsification is the process by which emulsions are prepared.
Emulsion is also a term used in the oil field as untreated well production that consists primarily of crude oil and water.
# Operation
Emulsions tend to have a cloudy appearance, because the many phase interfaces (the boundary between the phases is called the interface) scatter light that passes through the emulsion. Emulsions are unstable and thus do not form spontaneously. Energy input through shaking, stirring, homogenizers, or spray processes are needed to form an emulsion. Over time, emulsions tend to revert to the stable state of oil separated from water. Surface active substances (surfactants) can increase the kinetic stability of emulsions greatly so that, once formed, the emulsion does not change significantly over years of storage. Homemade oil and vinegar salad dressing is an example of an unstable emulsion that will quickly separate unless shaken continuously. This phenomenon is called coalescence, and happens when small droplets recombine to form bigger ones. Fluid emulsions can also suffer from creaming, the migration of one of the substances to the top of the emulsion under the influence of buoyancy or centripetal force when a centrifuge is used.
Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion tends to imply that both the dispersed and the continuous phase are liquid.
There are three types of emulsion instability: flocculation, where the particles form clumps; creaming, where the particles concentrate towards the surface (or bottom, depending on the relative density of the two phases) of the mixture while staying separated; and breaking and coalescence where the particles coalesce and form a layer of liquid.
# Emulsifier
An emulsifier (also known as an emulgent) is a substance which stabilizes an emulsion, frequently a surfactant. Examples of food emulsifiers are egg yolk (where the main emulsifying chemical is lecithin), honey and mustard, where a variety of chemicals in the mucilage surrounding the seed hull act as emulsifiers; proteins and low-molecular weight emulsifiers are common as well. In some cases, particles can stabilize emulsions as well through a mechanism called Pickering stabilization. Both mayonnaise and hollandaise sauce are oil-in-water emulsions that are stabilized with egg yolk lecithin. Detergents are another class of surfactant, and will chemically interact with both oil and water, thus stabilising the interface between oil or water droplets in suspension. This principle is exploited in soap to remove grease for the purpose of cleaning. A wide variety of emulsifiers are used in pharmacy to prepare emulsions such as creams and lotions.
Whether an emulsion turns into a water-in-oil emulsion or an oil-in-water emulsion depends on the volume fraction of both phases and on the type of emulsifier. Generally, the Bancroft rule applies: emulsifiers and emulsifying particles tend to promote dispersion of the phase in which they do not dissolve very well; for example, proteins dissolve better in water than in oil and so tend to form oil-in-water emulsions (that is they promote the dispersion of oil droplets throughout a continuous phase of water).
# Nanoemulsion
Nanoemulsion is a type of emulsion in which the sizes of the particles in the dispersed phase are defined as less than 1000 nanometers.
In medicine, a nanoemulsion of soybean oil to create drops of 400-600 nanometers in diameter will kill many pathogens such as bacteria and viruses.[2] The process is not chemical, as with other types of anti-pathogenic treatments, but physical. The smaller the droplet, the greater the surface tension and thus the greater the force to merge with other lipids. The oil is emulsified with detergents to stabilize the emulsion (the droplets won't merge with one another), so when they encounter lipids on a bacterial membrane or a virus envelope, they force the lipids to merge with themselves. On a mass scale, this effectively disintegrates the membrane and kills the pathogen.
Remarkably, the soybean oil emulsion does not harm normal human cells nor the cells of most other higher organisms. The exceptions are sperm cells and blood cells, which are vulnerable to nanoemulsions due to their membrane structures. For this reason, nanoemulsions of this type are not yet ready to be used intravenously.
The most effective application of this type of nanoemulsion is for the disinfection of surfaces. Some types of nanoemulsions have been shown to effectively destroy HIV-1 and various tuberculosis pathogens, for example, on non-porous surfaces. | https://www.wikidoc.org/index.php/Emulsification | |
e6b1069a8dd378447c98b6c6b6c23be6bdf3b27f | wikidoc | Enamelin | Enamelin
Enamelin is a protein that in humans is encoded by the ENAM gene.
Dental enamel is a highly mineralized tissue with 85% of its volume occupied by unusually large, highly organized, hydroxyapatite crystals. This highly organized and unusual structure is thought to be rigorously controlled in ameloblasts through the interaction of a number of organic matrix molecules that include enamelin, amelogenin (AMELX; MIM 300391), ameloblastin (AMBN; MIM 601259), tuftelin (TUFT1; MIM 600087), dentine sialophosphoprotein (DSPP; MIM 125485), and a variety of enzymes. Enamelin is the largest protein in the enamel matrix of developing teeth and comprises approximately 5% of total enamel matrix protein.
Mutations in the ENAM gene can give rise to autosomal dominant amelogenesis imperfecta, indicating a role in amelogenesis. | Enamelin
Enamelin is a protein that in humans is encoded by the ENAM gene.[1][2]
Dental enamel is a highly mineralized tissue with 85% of its volume occupied by unusually large, highly organized, hydroxyapatite crystals. This highly organized and unusual structure is thought to be rigorously controlled in ameloblasts through the interaction of a number of organic matrix molecules that include enamelin, amelogenin (AMELX; MIM 300391), ameloblastin (AMBN; MIM 601259), tuftelin (TUFT1; MIM 600087), dentine sialophosphoprotein (DSPP; MIM 125485), and a variety of enzymes. Enamelin is the largest protein in the enamel matrix of developing teeth and comprises approximately 5% of total enamel matrix protein.[supplied by OMIM][2]
Mutations in the ENAM gene can give rise to autosomal dominant amelogenesis imperfecta,[1][3] indicating a role in amelogenesis. | https://www.wikidoc.org/index.php/Enamelin | |
43948ac9422f8b8cba61430777e2441d527dee7a | wikidoc | Endogeny | Endogeny
The word endogenous means "arising from within", the opposite of exogenous.
# Biology
Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retrovirus are caused by ancient infections of germ cells in humans, mammals and other vertebrates. Their proviruses remain in the genome and are passed on to the next generation.
Endogenous processes include circadian rhythms.
In some biological systems, endogeneity refers to the recipient of DNA (usually in prokaryotes). However, due to homeostasis, discerning between internal and external influences is often difficult.
# Psychology
An emotion or behaviour is endogenous if it is spontaneously generated from an individual's internal state.
# Economics and finance
A variable is called endogenous if it is explained within the model in which it appears. For example, in a supply and demand model of an agricultural market, changes in the weather or in consumer tastes would be exogenous variables that might shift the supply and demand curves; the price and quantity of trade would be the endogenous variables explained by the model.
nl:Endogeen (aardwetenschappen)
fi:Endogeeninen | Endogeny
The word endogenous means "arising from within", the opposite of exogenous.
# Biology
Endogenous substances are those that originate from within an organism, tissue, or cell [1]. Endogenous retrovirus are caused by ancient infections of germ cells in humans, mammals and other vertebrates. Their proviruses remain in the genome and are passed on to the next generation.
Endogenous processes include circadian rhythms.
In some biological systems, endogeneity refers to the recipient of DNA (usually in prokaryotes). However, due to homeostasis, discerning between internal and external influences is often difficult.
# Psychology
An emotion or behaviour is endogenous if it is spontaneously generated from an individual's internal state.
# Economics and finance
A variable is called endogenous if it is explained within the model in which it appears. For example, in a supply and demand model of an agricultural market, changes in the weather or in consumer tastes would be exogenous variables that might shift the supply and demand curves; the price and quantity of trade would be the endogenous variables explained by the model.
nl:Endogeen (aardwetenschappen)
fi:Endogeeninen
Template:Jb1
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Endogenous | |
737cf85cd6a3c7bcdda81c75b482d24c3e8cdc4f | wikidoc | Enoxacin | Enoxacin
# Overview
Enoxacin is an oral broad-spectrum fluoroquinolone antibacterial agent used in the treatment of urinary tract infections and gonorrhea. Insomnia is a common adverse effect. It is no longer available in the United States.
It has been shown recently that it may have cancer inhibiting effect.
# Mechanism of action
Quinolones and fluoroquinolones are bactericidal drugs, eradicating bacteria by interfering with DNA replication.
Like other fluoroquinolones, enoxacin functions by inhibiting bacterial DNA gyrase and topoisomerase IV. The inhibition of these enzymes prevents bacterial DNA replication, transcription, repair and recombination.
Enoxacin is active against many Gram-positive bacteria. The quinolone is also active against Gram-negative bacteria
# Pharmacokinetics
After oral administration enoxacin is rapidly and well absorbed from the gastrointestinal tract. The antibiotic is widely distributed throughout the body and in the different biological tissues. Tissue concentrations often exceed serum concentrations. The binding of enoxacin to serum proteins is 35 to 40%.
The serum elimination half-life, in subjects with normal renal function, is approximately 6 hours. Approximately 60% of an orally administered dose is excreted in the urine as unchanged drug within 24 hours.
A small amount of a dose of drug administered is excreted in the bile. High concentrations of the fluoroquinolone are reached in the urinary tract and this fact ensures an antibacterial effect continued over time, particularly in this district.
# Medical uses
Enoxacin can be used to treat a wide variety of infections, particularly gastroenteritis including infectious diarrhea, respiratory tract infections, gonorrhea and urinary tract infections.
# Adverse effects
Enoxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. The compound should not be administered to patients with epilepsy or a personal history of previous convulsive attacks as may promote the onset of these disorders.
# Contraindications
Enoxacin is contraindicated in subjects with a history of hypersensitivity to the substance or any other member of the quinolone class, or any component of the medicine. Enoxacin, like other fluoroquinolones, can cause degenerative changes in weightbearing joints of young animals. The compound should only be used in children
when the expected benefits are outweigh the risks.
# Interactions
- Fenbufen: co-administration with some quinolones, including enoxacin may increase the risk of seizures. For this reason, concomitant administration of fenbufen and the quinolone should be avoided, as a precaution.
- Theophylline: in patients treated concurrently with theophylline and enoxacin, concentrations of the methylxanthine in plasma arise due to a reduced metabolic clearance of theophylline.
- Ranitidine, sucralfate, antacids containing magnesium or aluminum, supplements containing calcium, iron, or zinc: co-administration with these substances can lead to therapeutic failure of the antibiotic due to decreased absorbment by the intestinal tract. For example magnesium or aluminum antacids turn enoxacin into insoluble salts that are not readily absorbed by the gastroenteric tract. | Enoxacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Enoxacin is an oral broad-spectrum fluoroquinolone antibacterial agent used in the treatment of urinary tract infections and gonorrhea. Insomnia is a common adverse effect.[1][2] It is no longer available in the United States.
It has been shown recently that it may have cancer inhibiting effect.
# Mechanism of action
Quinolones and fluoroquinolones are bactericidal drugs, eradicating bacteria by interfering with DNA replication.
Like other fluoroquinolones, enoxacin functions by inhibiting bacterial DNA gyrase and topoisomerase IV. The inhibition of these enzymes prevents bacterial DNA replication, transcription, repair and recombination.[3][4]
Enoxacin is active against many Gram-positive bacteria.[note 1] The quinolone is also active against Gram-negative bacteria[note 2][5][6]
# Pharmacokinetics
After oral administration enoxacin is rapidly and well absorbed from the gastrointestinal tract. The antibiotic is widely distributed throughout the body and in the different biological tissues. Tissue concentrations often exceed serum concentrations. The binding of enoxacin to serum proteins is 35 to 40%.
The serum elimination half-life, in subjects with normal renal function, is approximately 6 hours. Approximately 60% of an orally administered dose is excreted in the urine as unchanged drug within 24 hours.[7][8]
A small amount of a dose of drug administered is excreted in the bile.[9] High concentrations of the fluoroquinolone are reached in the urinary tract and this fact ensures an antibacterial effect continued over time, particularly in this district.
# Medical uses
Enoxacin can be used to treat a wide variety of infections, particularly gastroenteritis including infectious diarrhea, respiratory tract infections, gonorrhea[10] and urinary tract infections.[11][12]
# Adverse effects
Enoxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold.[13] The compound should not be administered to patients with epilepsy or a personal history of previous convulsive attacks as may promote the onset of these disorders.[14]
# Contraindications
Enoxacin is contraindicated in subjects with a history of hypersensitivity to the substance or any other member of the quinolone class, or any component of the medicine. Enoxacin, like other fluoroquinolones, can cause degenerative changes in weightbearing joints of young animals. The compound should only be used in children
when the expected benefits are outweigh the risks.[15][16]
# Interactions
- Fenbufen: co-administration with some quinolones, including enoxacin may increase the risk of seizures. For this reason, concomitant administration of fenbufen and the quinolone should be avoided, as a precaution.[17][18][19][20]
- Theophylline: in patients treated concurrently with theophylline and enoxacin, concentrations of the methylxanthine in plasma arise due to a reduced metabolic clearance of theophylline.[21][22][23][24]
- Ranitidine, sucralfate, antacids containing magnesium or aluminum, supplements containing calcium, iron, or zinc: co-administration with these substances can lead to therapeutic failure of the antibiotic due to decreased absorbment by the intestinal tract. For example magnesium or aluminum antacids turn enoxacin into insoluble salts that are not readily absorbed by the gastroenteric tract.[25][26][27] | https://www.wikidoc.org/index.php/Enoxacin | |
fd2449b089788d9edaf458db92670eec9b75299a | wikidoc | Enthalpy | Enthalpy
In thermodynamics and molecular chemistry, the enthalpy or heat content (denoted as H, h, or rarely as χ) is a quotient or description of thermodynamic potential of a system, which can be used to calculate the "useful" work obtainable from a closed thermodynamic system under constant pressure and entropy.
The term enthalpy was composed of the prefix en-, meaning to "put into" and the Greek word -thalpein, meaning "to heat", although the original definition is thought to have stemmed from the word "enthalpos" (ἐνθάλπος).
# History
Over the history of thermodynamics, several terms have been used to denote what is now known as the enthalpy of a system. Originally, it was thought that the word "enthalpy" was created by Benoit Paul Émile Clapeyron and Rudolf Clausius through the publishing of the Clausius-Clapeyron relation in "The Mollier Steam Tables and Diagrams" in 1827, but it was later published that the earliest recording of the word was in 1875, by Josiah Willard Gibbs in the publication "Physical Chemistry: an Advanced Treatise", although it is not referenced in Gibbs' works directly. In 1909, Keith Landler discussed Gibbs' work on the 'heat function for constant pressure' and noted that Heike Kamerlingh Onnes had coined its modern name from the Greek word "enthalpos" (ενθαλπος) meaning "to put heat into."
## Original definition
This is the heat change which occurs when 1 mol of a substance reacts completely with oxygen to form products at 298 K and 1 atm.
The function H was introduced by the Dutch physicist Heike Kamerlingh Onnes in early 20th century in the following form:
where E represents the energy of the system. In the absence of an external field, the enthalpy may be defined, as it is generally known, by:
where (all units given in SI)
- H is the enthalpy (joules)
- U is the internal energy, (joules)
- p is the pressure of the system, (pascals)
- V is the volume, (cubic metres)
# Application and extended formula
## Overview
In terms of thermodynamics, enthalpy can be calculated by determining the requirements for creating a system from "nothingness"; the mechanical work required, pV differs, based upon the constancy of conditions present at the creation of the thermodynamic system.
Internal energy, U, must be supplied to remove particles from a surrounding in order to allow space for the creation of a system, providing that environmental variables, such as pressure (p) remain constant. This internal energy also includes the energy required for activation and the breaking of bonded compounds into gaseous species.
This process is calculated within enthalpy calculations as U + pV, to label the amount of energy or work required to "set aside space for" and "create" the system; describing the work done by both the reaction or formation of systems, and the surroundings. For systems at constant pressure, the change in enthalpy is the heat received by the system plus the non-mechanical work that has been done.
Therefore, the change in enthalpy can be devised or represented without the need for compressive or expansive mechanics; for a simple system, with a constant number of particles, the difference in enthalpy is the maximum amount of thermal energy derivable from a thermodynamic process in which the pressure is held constant.
The term pV is the work required to displace the surrounding atmosphere in order to vacate the space to be occupied by the system.
## Relationships
As an expansion of the first law of thermodynamics, enthalpy can be related to several other thermodynamic formulae. As with the original definition of the first law;
As a differentiating expression, the value of H can be defined as
Where
For a process that is not reversible, the second law of thermodynamics states that the increase in heat \delta Q is less than or equal to the product T\mathrm{d}S of temperature T and the increase in entropy \mathrm{d}S; thus
It is seen that, if a thermodynamic process is isobaric (i.e., occurs at constant pressure), then \mathrm{d}p is zero and thus
The difference in enthalpy is the maximum thermal energy attainable from the system in an isobaric process. This explains why it is sometimes called the heat content. That is, the integral of \mathrm{d}H over any isobar in state space is the maximum thermal energy attainable from the system.
If, in addition, the entropy is held constant as well, i.e., \mathrm{d}S = 0, the above equation becomes:
with the equality holding at equilibrium. It is seen that the enthalpy for a general system will continuously decrease to its minimum value, which it maintains at equilibrium.
In a more general form, the first law describes the internal energy with additional terms involving the chemical potential and the number of particles of various types. The differential statement for \mathrm{d}H is then:
where \mu_i is the chemical potential for an i-type particle, and N_i is the number of such particles. It is seen that, not only must the V\mathrm{d}p term be set to zero by requiring the pressures of the initial and final states to be the same, but the \mu_i \mathrm{d}N_i terms must be zero as well, by requiring that the particle numbers remain unchanged. Any further generalization will add even more terms whose extensive differential term must be set to zero in order for the interpretation of the enthalpy to hold.
## Heats of reaction
The total enthalpy of a system cannot be measured directly; the enthalpy change of a system is measured instead. Enthalpy change is defined by the following equation:
where
For an exothermic reaction at constant pressure, the system's change in enthalpy is equal to the energy released in the reaction, including the energy retained in the system and lost through expansion against its surroundings. In a similar manner, for an endothermic reaction, the system's change in enthalpy is equal to the energy absorbed in the reaction, including the energy lost by the system and gained from compression from its surroundings. A relatively easy way to determine whether or not a reaction is exothermic or endothermic is to determine the sign of ΔH. If ΔH is positive, the reaction is endothermic, that is heat is absorbed by the system due to the products of the reaction having a greater enthalpy than the reactants. On the other hand if ΔH is negative, the reaction is exothermic, that is the overall decrease in enthalpy is achieved by the generation of heat.
Although enthalpy is commonly used in engineering and science, it is impossible to measure directly, as enthalpy has no datum (reference point). Therefore enthalpy can only accurately be used in a closed system. However, few real world applications exist in closed isolation, and it is for this reason that two or more closed systems cannot be compared using enthalpy as a basis, although sometimes this is done erroneously.
## Open systems
In thermodynamic open systems, matter may flow in and out of the system boundaries. The first law of thermodynamics for open systems states: the increase in the internal energy of a system is equal to the amount of energy added to the system by matter flowing in and by heating, minus the amount lost by matter flowing out and in the form of work done by the system. The first law for open systems is given by:
where Uin is the average internal energy entering the system and Uout is the average internal energy leaving the system
The region of space enclosed by open system boundaries is usually called a control volume, and it may or may not correspond to physical walls. If we choose the shape of the control volume such that all flow in or out occurs perpendicular to its surface, then the flow of matter into the system performs work as if it were a piston of fluid pushing mass into the system, and the system performs work on the flow of matter out as if it were driving a piston of fluid. There are then two types of work performed: flow work described above which is performed on the fluid (this is also often called pV work) and shaft work which may be performed on some mechanical device.
These two types of work are expressed in the equation:
Substitution into the equation above for the control volume cv yields:
The definition of enthalpy, H, permits us to use this thermodynamic potential to account for both internal energy and pV work in fluids for open systems:
During steady-state operation of a device (see turbine, pump, and engine), the expression above may be set equal to zero. This yields a useful expression for the power generation or requirement for these devices in the absence of chemical reactions:
This expression is described by the diagram above.
# Standard enthalpy changes
Standard enthalpy changes describe the change in enthalpy observed in the constituents of a thermodynamic system when going between different states under standard conditions. The standard enthalpy of vaporization, for example gives the enthaply change when going from liquid and gas, these entalpies are reversible, then enthalpy of going from gas to liquid is negative of the enthalpy of vaporization. A common standard enthalpy change is the standard enthalpy change of formation, which has been determined for a vast number of substances. The enthalpy change of any reaction under any conditions can be computed, given the standard enthalpy change of formation of all of the reactants and products.
## Definitions
### Chemical Properties
Standard enthalpy change of reaction
Standard enthalpy change of formation
Standard enthalpy change of combustion
Standard enthalpy change of hydrogenation
Standard enthalpy change of atomization
### Physical Properties
Standard enthalpy change of solution
Standard enthalpy change of fusion
Standard enthalpy change of vapourization
Standard enthalpy change of denaturation
Lattice enthalpy
# Specific enthalpy
The specific enthalpy of a working mass is a property of that mass used in thermodynamics, defined as h=u+p \cdot v where u is the specific internal energy, p is the pressure, and v is specific volume. In other words, h = H/m where m is the mass of the system. The SI unit for specific enthalpy is joules per kilogram. | Enthalpy
Template:Statistical mechanics
In thermodynamics and molecular chemistry, the enthalpy or heat content (denoted as H, h, or rarely as χ) is a quotient or description of thermodynamic potential of a system, which can be used to calculate the "useful" work obtainable from a closed thermodynamic system under constant pressure and entropy.
The term enthalpy was composed of the prefix en-, meaning to "put into" and the Greek word -thalpein, meaning "to heat", although the original definition is thought to have stemmed from the word "enthalpos" (ἐνθάλπος).[1]
# History
Over the history of thermodynamics, several terms have been used to denote what is now known as the enthalpy of a system. Originally, it was thought that the word "enthalpy" was created by Benoit Paul Émile Clapeyron and Rudolf Clausius through the publishing of the Clausius-Clapeyron relation in "The Mollier Steam Tables and Diagrams" in 1827, but it was later published that the earliest recording of the word was in 1875, by Josiah Willard Gibbs in the publication "Physical Chemistry: an Advanced Treatise"[2], although it is not referenced in Gibbs' works directly[3]. In 1909, Keith Landler discussed Gibbs' work on the 'heat function for constant pressure' and noted that Heike Kamerlingh Onnes had coined its modern name from the Greek word "enthalpos" (ενθαλπος) meaning "to put heat into." [1]
## Original definition
This is the heat change which occurs when 1 mol of a substance reacts completely with oxygen to form products at 298 K and 1 atm.
The function H was introduced by the Dutch physicist Heike Kamerlingh Onnes in early 20th century in the following form:
where E represents the energy of the system. In the absence of an external field, the enthalpy may be defined, as it is generally known, by:
where (all units given in SI)
- H is the enthalpy (joules)
- U is the internal energy, (joules)
- p is the pressure of the system, (pascals)
- V is the volume, (cubic metres)
# Application and extended formula
## Overview
In terms of thermodynamics, enthalpy can be calculated by determining the requirements for creating a system from "nothingness"; the mechanical work required, <math>pV</math> differs, based upon the constancy of conditions present at the creation of the thermodynamic system.
Internal energy, <math>U</math>, must be supplied to remove particles from a surrounding in order to allow space for the creation of a system, providing that environmental variables, such as pressure (<math>p</math>) remain constant. This internal energy also includes the energy required for activation and the breaking of bonded compounds into gaseous species.
This process is calculated within enthalpy calculations as <math>U + pV</math>, to label the amount of energy or work required to "set aside space for" and "create" the system; describing the work done by both the reaction or formation of systems, and the surroundings. For systems at constant pressure, the change in enthalpy is the heat received by the system plus the non-mechanical work that has been done.
Therefore, the change in enthalpy can be devised or represented without the need for compressive or expansive mechanics; for a simple system, with a constant number of particles, the difference in enthalpy is the maximum amount of thermal energy derivable from a thermodynamic process in which the pressure is held constant.
The term <math>p</math><math>V</math> is the work required to displace the surrounding atmosphere in order to vacate the space to be occupied by the system.
## Relationships
As an expansion of the first law of thermodynamics, enthalpy can be related to several other thermodynamic formulae. As with the original definition of the first law;
As a differentiating expression, the value of H can be defined as
Where
For a process that is not reversible, the second law of thermodynamics states that the increase in heat <math>\delta Q</math> is less than or equal to the product <math>T\mathrm{d}S</math> of temperature <math>T</math> and the increase in entropy <math>\mathrm{d}S</math>; thus
It is seen that, if a thermodynamic process is isobaric (i.e., occurs at constant pressure), then <math>\mathrm{d}p</math> is zero and thus
The difference in enthalpy is the maximum thermal energy attainable from the system in an isobaric process. This explains why it is sometimes called the heat content. That is, the integral of <math>\mathrm{d}H</math> over any isobar in state space is the maximum thermal energy attainable from the system.
If, in addition, the entropy is held constant as well, i.e., <math>\mathrm{d}S = 0</math>, the above equation becomes:
with the equality holding at equilibrium. It is seen that the enthalpy for a general system will continuously decrease to its minimum value, which it maintains at equilibrium.
In a more general form, the first law describes the internal energy with additional terms involving the chemical potential and the number of particles of various types. The differential statement for <math>\mathrm{d}H</math> is then:
where <math>\mu_i</math> is the chemical potential for an i-type particle, and <math>N_i</math> is the number of such particles. It is seen that, not only must the <math>V\mathrm{d}p</math> term be set to zero by requiring the pressures of the initial and final states to be the same, but the <math>\mu_i \mathrm{d}N_i</math> terms must be zero as well, by requiring that the particle numbers remain unchanged. Any further generalization will add even more terms whose extensive differential term must be set to zero in order for the interpretation of the enthalpy to hold.
## Heats of reaction
The total enthalpy of a system cannot be measured directly; the enthalpy change of a system is measured instead. Enthalpy change is defined by the following equation:
where
For an exothermic reaction at constant pressure, the system's change in enthalpy is equal to the energy released in the reaction, including the energy retained in the system and lost through expansion against its surroundings. In a similar manner, for an endothermic reaction, the system's change in enthalpy is equal to the energy absorbed in the reaction, including the energy lost by the system and gained from compression from its surroundings. A relatively easy way to determine whether or not a reaction is exothermic or endothermic is to determine the sign of ΔH. If ΔH is positive, the reaction is endothermic, that is heat is absorbed by the system due to the products of the reaction having a greater enthalpy than the reactants. On the other hand if ΔH is negative, the reaction is exothermic, that is the overall decrease in enthalpy is achieved by the generation of heat.
Although enthalpy is commonly used in engineering and science, it is impossible to measure directly, as enthalpy has no datum (reference point). Therefore enthalpy can only accurately be used in a closed system. However, few real world applications exist in closed isolation, and it is for this reason that two or more closed systems cannot be compared using enthalpy as a basis, although sometimes this is done erroneously.
## Open systems
In thermodynamic open systems, matter may flow in and out of the system boundaries. The first law of thermodynamics for open systems states: the increase in the internal energy of a system is equal to the amount of energy added to the system by matter flowing in and by heating, minus the amount lost by matter flowing out and in the form of work done by the system. The first law for open systems is given by:
where Uin is the average internal energy entering the system and Uout is the average internal energy leaving the system
The region of space enclosed by open system boundaries is usually called a control volume, and it may or may not correspond to physical walls. If we choose the shape of the control volume such that all flow in or out occurs perpendicular to its surface, then the flow of matter into the system performs work as if it were a piston of fluid pushing mass into the system, and the system performs work on the flow of matter out as if it were driving a piston of fluid. There are then two types of work performed: flow work described above which is performed on the fluid (this is also often called <math>pV</math> work) and shaft work which may be performed on some mechanical device.
These two types of work are expressed in the equation:
Substitution into the equation above for the control volume cv yields:
The definition of enthalpy, H, permits us to use this thermodynamic potential to account for both internal energy and <math>pV</math> work in fluids for open systems:
During steady-state operation of a device (see turbine, pump, and engine), the expression above may be set equal to zero. This yields a useful expression for the power generation or requirement for these devices in the absence of chemical reactions:
This expression is described by the diagram above.
# Standard enthalpy changes
Standard enthalpy changes describe the change in enthalpy observed in the constituents of a thermodynamic system when going between different states under standard conditions. The standard enthalpy of vaporization, for example gives the enthaply change when going from liquid and gas, these entalpies are reversible, then enthalpy of going from gas to liquid is negative of the enthalpy of vaporization. A common standard enthalpy change is the standard enthalpy change of formation, which has been determined for a vast number of substances. The enthalpy change of any reaction under any conditions can be computed, given the standard enthalpy change of formation of all of the reactants and products.
## Definitions
### Chemical Properties
Standard enthalpy change of reaction
Standard enthalpy change of formation
Standard enthalpy change of combustion
Standard enthalpy change of hydrogenation
Standard enthalpy change of atomization
### Physical Properties
Standard enthalpy change of solution
Standard enthalpy change of fusion
Standard enthalpy change of vapourization
Standard enthalpy change of denaturation
Lattice enthalpy
# Specific enthalpy
The specific enthalpy of a working mass is a property of that mass used in thermodynamics, defined as <math>h=u+p \cdot v</math> where u is the specific internal energy, p is the pressure, and v is specific volume. In other words, <math>h = H/m</math> where <math>m</math> is the mass of the system. The SI unit for specific enthalpy is joules per kilogram. | https://www.wikidoc.org/index.php/Enthalpy | |
8ef946d3791b95dbd72dab2501e4664c0cf04f83 | wikidoc | Enthesis | Enthesis
# Overview
Enthesis (plural: entheses) is the point at which a tendon inserts into bone, where the collagen fibers are mineralized and integrated into bone tissue. These insertion points are commonly called Sharpey's fibers.
# Classification
There are two types:
- Fibrous entheses
- Fibrocartilaginous entheses
In a fibrous enthesis, the collagenous tendon or ligament directly attaches to the bone, whilst the fibrocartilaginous enthesis displays 4 zones during the transition from tendon/ligament to bone:
- i) tendinous area displaying longitudinally oriented fibroblasts and a parallel arrangement of collagen fibres
- ii) a fibrocartilaginous region of variable thickness where the structure of the cells changes to chondrocytes
- iii) an abrupt transition from cartilaginous to calcified fibrocartilage - the so-called 'tidemark' or 'blue line'
- iv) bone
# Pathology
A disease of the entheses is known as an "enthesopathy" or "enthesitis" and is characteristic of spondyloarthropathy but present in other pathology as well. | Enthesis
# Overview
Enthesis (plural: entheses) is the point at which a tendon inserts into bone, where the collagen fibers are mineralized and integrated into bone tissue. These insertion points are commonly called Sharpey's fibers.
# Classification
There are two types:
- Fibrous entheses
- Fibrocartilaginous entheses
In a fibrous enthesis, the collagenous tendon or ligament directly attaches to the bone, whilst the fibrocartilaginous enthesis displays 4 zones during the transition from tendon/ligament to bone:
- i) tendinous area displaying longitudinally oriented fibroblasts and a parallel arrangement of collagen fibres
- ii) a fibrocartilaginous region of variable thickness where the structure of the cells changes to chondrocytes
- iii) an abrupt transition from cartilaginous to calcified fibrocartilage - the so-called 'tidemark' or 'blue line'
- iv) bone
# Pathology
A disease of the entheses is known as an "enthesopathy" or "enthesitis" and is characteristic of spondyloarthropathy but present in other pathology as well.
# External links
- Image of enthesis at Medscape
- Enthesopathy and Soft Tissue Shadows at chiroweb.com
- Resnick D, Niwayama G (1983). "Entheses and enthesopathy. Anatomical, pathological, and radiological correlation". Radiology. 146 (1): 1–9. PMID 6849029..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}
- Template:Medcyclopaedia
- Origin of phrase at rheuma21st.com at rheuma21st.com
Template:Bone and cartilage
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Enthesis | |
e6d7b19a1242b1198c4035f9f3af42ecbe8b172a | wikidoc | Enuresis | Enuresis
# Overview
Enuresis is involuntary urination beyond the age of anticipated control. The two major forms of enuresis are diurnal enuresis (or daytime wetting), and nocturnal enuresis (bedwetting or nighttime wetting). This condition adversely affects the whole family. Enuresis impacts the child's overall development and is mostly associated with poor scholastic performance. It also has a major psychosocial burden on the parents, resulting in poorer quality of life. Treatment of enuresis should be holistic, targeting the management of enuresis in children as well as psychoeducation of the parents.
# Historical Perspective
- Enuresis has been a major social problem since ancient times.
- The term enuresis is derived from the Greek word 'enourein' that means to void urine.
- Initially, enuresis was considered a psychiatric disturbance. It has been followed by the clearer theory of maturation delay along with the major role of hereditary factors.
- After multiple studies, it has been found that enuresis may be the cause and not the result of a psychiatric disorder.
- As early as 1550 BC, the problem of childhood incontinence was described in the Ebers papyrus.
- Prayers were an important component of the treatment options in the middle ages.
- Belladonna, camphor, opium, and ergot were administered to enhance the bladder muscle tone in the eighteenth century.
- In 1948, a direct conditioning-based treatment modality called the alarm or bell-and-pad system was introduced.
- Initially, psychotherapy was accepted as the only possible method to treat enuresis, and there was a lot of skepticism about the conditioning treatment.
- Gradually, the alarm system became one of the most efficacious non-pharmacological management options worldwide.
# Classification
- According to International Children’s Continence Society (ICCS), enuresis consists of wetting by a child who has passed his or her fifth birthday.
- Enuresis is considered significant if it occurs more than once a month and at a frequency of at least three times per three months. Enuresis is termed frequent if there are more than three episodes a week.
- Enuresis is broadly divided into two types: daytime wetting and nighttime wetting.
- Primary enuresis is the condition used for a child that was never continent. On the other hand, the term secondary enuresis is used for new-onset symptoms after a dry period of at least six months.
- If bedwetting and nocturia are the only symptoms, the condition is known as monosymptomatic enuresis (MEN). If there are concomitant daytime voiding symptoms such as incontinence, frequency, urgency, or low voided volume, the condition is termed nonmonosymptomatic enuresis (NMEN).
- MEN occurs without any other symptoms of bladder dysfunction whereas NMEN is associated with dysfunction of the lower urinary tract with or without daytime incontinence.
# Pathophysiology
- Some of the underlying pathophysiological mechanisms for enuresis are:
Altered antidiuretic hormone profile
Sleep arousal failure
Delayed bladder maturation
Abnormal bladder function
Detrusor instability
Excess urine production during sleep
- Altered antidiuretic hormone profile
- Sleep arousal failure
- Delayed bladder maturation
- Abnormal bladder function
- Detrusor instability
- Excess urine production during sleep
- Nocturnal enuresis may be associated with lower urinary tract symptoms such as urgency, and frequency, with an overactive bladder. These may be further associated with constipation.
- Nocturnal enuresis mostly occurs early in the night, mainly in sleep stage 2 and deep sleep. Children with nocturnal enuresis and nocturnal polyuria differ in hemodynamics and autonomic activation at night compared to controls.
- Children with nocturnal enuresis often have sleep-disordered breathing and disturbed sleep due to awakenings and arousal.
- Periodic limb movements (PLM) have also been seen in children with refractory enuresis.
# Differential Diagnosis
Enuresis should be differentiated from other causes
- Medication side effects
- Neurogenic bladder
- Renal diseases
- Constipation
- Diabetes Mellitus
- Detrussor areflexia or overactivity
- Urinary tract infection
- Posterior urethral valve
- Emotional disturbances
- Underlying conditions resulting in polyuria such as sickle cell disease, and diabetes insipidus
- Spinal dysraphism
- Nephronopthisis
- Psychogenic polydipsia
- Pinworm infection
- Upper airway tract obstruction
- Other urological dysfunction
- Other neurological diseases
# Epidemiology and Demographics
## Prevalence
- The prevalence of enuresis is
5,000-10,000 per 100,000 (5%-10%) among children 5 years of age
3,000-5,000 per 100,000 (3%-5%) among children 10 year of age
1,000 per 100,000 (1%) among individuals 15 years of age or older
- 5,000-10,000 per 100,000 (5%-10%) among children 5 years of age
- 3,000-5,000 per 100,000 (3%-5%) among children 10 year of age
- 1,000 per 100,000 (1%) among individuals 15 years of age or older
## Age
- Enuresis is found to be more prevalent in first-born children.
- If enuretic symptoms persist into adulthood, they are less likely to resolve with time.
- Primary nocturnal enuresis in adults may represent a more pronounced form and have a more serious social and psychological effect on affected individuals.
## Gender
- Most studies show a predominance of enuresis in males, whereas some others show no gender predominance.
## Race
- Sickle-cell anemia (SCA) is the most common inherited hemoglobinopathy in the African population. It has been found that children and adolescents with SCA are at increased risk of nocturnal enuresis.
# Risk Factors
- The risk factors for the development of enuresis are
Delayed or lax toilet training
Genetic predisposition
Encopresis
Psychosocial stressors
Family history of enuresis (such as maternal history, and sibling history of bedwetting)
Low socioeconomic status
Snoring
Heavy and late supper
Deep sleeper
Sleepwalking
Being introverted and shy
- Delayed or lax toilet training
- Genetic predisposition
- Encopresis
- Psychosocial stressors
- Family history of enuresis (such as maternal history, and sibling history of bedwetting)
- Low socioeconomic status
- Snoring
- Heavy and late supper
- Deep sleeper
- Sleepwalking
- Being introverted and shy
# Natural History, Complications, and Prognosis
## Natural History
- Most children with enuresis eventually attain bladder control.
- It has been found that the prevalence of nocturnal enuresis gradually decreases with increasing age and many may achieve spontaneous resolution.
- The link between childhood enuresis and adult detrusor instability is observed to be stronger for men than women.
## Complications
- If intranasal desmopressin is used in the treatment of enuresis, some patients may develop seizures or altered mental status within 14 days of starting the medication.
- The accidental poisoning of young children by medications (tricyclic antidepressants) prescribed for enuresis has been reported.
## Prognosis
- The prognosis of secondary nocturnal enuresis due to cystitis, constipation, diabetes mellitus, seizure disorder, acquired urethral obstruction, and hyperthyroidism, is excellent once the underlying cause has been treated successfully.
- Patients with nocturnal enuresis due to psychological causes generally improve over time with psychosocial alterations or psychotherapy.
# Comorbidities
- Enuresis exists with various conditions
Attention-deficit hyperactivity disorder (ADHD)
Obstructive sleep apnea syndrome
Sickle cell anemia
Childhood obesity
Oppositional-defiant disorder (ODD)
Tic disorder
Conduct disorder
Bipolar affective disorder
Post-traumatic stress disorder (PTSD)
- Attention-deficit hyperactivity disorder (ADHD)
- Obstructive sleep apnea syndrome
- Sickle cell anemia
- Childhood obesity
- Oppositional-defiant disorder (ODD)
- Tic disorder
- Conduct disorder
- Bipolar affective disorder
- Post-traumatic stress disorder (PTSD)
# Diagnostic Criteria
## DSM-5 Criteria for Enuresis
- Enuresis is included under the elimination disorders.
- The diagnostic guidelines are
Repeated voiding of urine into bed or clothes, either involuntarily or intentionally.
The behavior is clinically significant manifested as either at least twice a week for a minimum of three consecutive months or with significant impairment of social, occupational, or other areas of functioning.
Chronological age is a minimum of 5 years.
The behavior is not attributable to the physiological effects of a substance (such as a diuretic, an antipsychotic ) or another medical condition (such as diabetes, spina bifida, or seizure disorder).
- Repeated voiding of urine into bed or clothes, either involuntarily or intentionally.
- The behavior is clinically significant manifested as either at least twice a week for a minimum of three consecutive months or with significant impairment of social, occupational, or other areas of functioning.
- Chronological age is a minimum of 5 years.
- The behavior is not attributable to the physiological effects of a substance (such as a diuretic, an antipsychotic ) or another medical condition (such as diabetes, spina bifida, or seizure disorder).
- Specify if:
Nocturnal only: Passage of urine only during nighttime sleep.
Diurnal only: Passage of urine only during waking hours.
Nocturnal and diurnal: A combination of the two subtypes.
- Nocturnal only: Passage of urine only during nighttime sleep.
- Diurnal only: Passage of urine only during waking hours.
- Nocturnal and diurnal: A combination of the two subtypes.
## ICD-10 Criteria
- The criteria for the diagnosis of nonorganic enuresis are described in the section 'F98.0'.
- It emphasizes that enuresis should not be diagnosed in a child under the age of five years or mental age of four years.
- This category includes urinary incontinence of nonorganic origin or functional enuresis.
# Treatment
- The patients are treated by behavioral modifications, medications, or a combination of both.
- Medications are usually avoided in children under seven years of age.
- Parents should be reassured about their child's health and psychoeducated about eliminating guilt, and punishment.
- It is extremely important that the psychosocial consequences of the symptom be addressed with sensitivity during the treatment of enuresis.
## Non-pharmacological management
- Enuresis alarms are effective in patients with primary nocturnal enuresis and should be considered for older, highly motivated children from cooperative families.
- In the long-term follow-up, it has been observed that the enuretic alarm device also provide a full response rate in children with primary nocturnal enuresis.
- Hypnotherapy is found to be an effective alternative or adjunctive treatment for enuresis in children.
- Acupressure administered by the parents could be an alternative non-pharmacological treatment. It has the advantages of being non-invasive, cost-effective, and painless.
## Pharmacological management
- Desmopressin, an antidiuretic hormone (ADH) analog, is also called as arginine vasopressin (AVP). It can resolve primary nocturnal enuresis by reducing urine production at the night.
- It has been found that a structured withdrawal program from sublingual formulation of fast-melting oral desmopressin lyophilisate (MELT) therapy doesn't offer advantages compared to abrupt discontinuation.
- Patients respond rapidly to desmopressin as compared to alarm systems. However, it has been observed that more children improve from psychological (urine alarm) than from pharmacological interventions.
- Tricyclics and desmopressin are effective in reducing the number of wet nights while taking the drugs, but most children relapse after stopping active treatment. On the contrary, relapse rates are lower after alarm treatment.
- Imipramine is useful for enuresis when other treatment options such as desmopressin, alarm, and anticholinergics have failed in older children.
- Oxybutynin has shown partial response in the management of nocturnal enuresis.
## Combined therapy
- Combined pharmacological and non-pharmacological interventions are effective for resistant cases.
- Many studies have found that the combined therapy (enuresis alarm, bladder training, motivational therapy, and pelvic floor muscle training) is more effective than each component used alone.
- The combination of desmopressin and alarm is also helpful for severe cases with other behavioral problems.
- Pharmacotherapy can provide early relief, while behavioral intervention may lead to more long-term benefits. Therefore, the positive effect of achieving dry nights with pharmacotherapy can encourage the patient to sustain behavioral therapy. | Enuresis
Editor(s)-in-Chief: C. Michael Gibson, M.S.,M.D. [1] Phone:617-632-7753; Angela Botts, M.D., Beth Israel Deaconess Medical Center Geriatric Medicine [2]; Associate Editor(s)-in-Chief: Vatsala Sharma, M.B.B.S., M.D. Kiran Singh, M.D. [3]
# Overview
Enuresis is involuntary urination beyond the age of anticipated control. The two major forms of enuresis are diurnal enuresis (or daytime wetting), and nocturnal enuresis (bedwetting or nighttime wetting). This condition adversely affects the whole family. Enuresis impacts the child's overall development and is mostly associated with poor scholastic performance. It also has a major psychosocial burden on the parents, resulting in poorer quality of life. Treatment of enuresis should be holistic, targeting the management of enuresis in children as well as psychoeducation of the parents.
# Historical Perspective
- Enuresis has been a major social problem since ancient times.
- The term enuresis is derived from the Greek word 'enourein' that means to void urine.[1]
- Initially, enuresis was considered a psychiatric disturbance. It has been followed by the clearer theory of maturation delay along with the major role of hereditary factors. [2]
- After multiple studies, it has been found that enuresis may be the cause and not the result of a psychiatric disorder.[3]
- As early as 1550 BC, the problem of childhood incontinence was described in the Ebers papyrus.[4]
- Prayers were an important component of the treatment options in the middle ages.
- Belladonna, camphor, opium, and ergot were administered to enhance the bladder muscle tone in the eighteenth century.[4]
- In 1948, a direct conditioning-based treatment modality called the alarm or bell-and-pad system was introduced.[4]
- Initially, psychotherapy was accepted as the only possible method to treat enuresis, and there was a lot of skepticism about the conditioning treatment. [2]
- Gradually, the alarm system became one of the most efficacious non-pharmacological management options worldwide.
# Classification
- According to International Children’s Continence Society (ICCS), enuresis consists of wetting by a child who has passed his or her fifth birthday.[5]
- Enuresis is considered significant if it occurs more than once a month and at a frequency of at least three times per three months. Enuresis is termed frequent if there are more than three episodes a week.[5]
- Enuresis is broadly divided into two types: daytime wetting and nighttime wetting.[6]
- Primary enuresis is the condition used for a child that was never continent. On the other hand, the term secondary enuresis is used for new-onset symptoms after a dry period of at least six months.[5][7]
- If bedwetting and nocturia are the only symptoms, the condition is known as monosymptomatic enuresis (MEN). If there are concomitant daytime voiding symptoms such as incontinence, frequency, urgency, or low voided volume, the condition is termed nonmonosymptomatic enuresis (NMEN).[5]
- MEN occurs without any other symptoms of bladder dysfunction whereas NMEN is associated with dysfunction of the lower urinary tract with or without daytime incontinence.[8]
# Pathophysiology
- Some of the underlying pathophysiological mechanisms for enuresis are:[5][9][10]
Altered antidiuretic hormone profile
Sleep arousal failure
Delayed bladder maturation
Abnormal bladder function
Detrusor instability
Excess urine production during sleep
- Altered antidiuretic hormone profile
- Sleep arousal failure
- Delayed bladder maturation
- Abnormal bladder function
- Detrusor instability
- Excess urine production during sleep
- Nocturnal enuresis may be associated with lower urinary tract symptoms such as urgency, and frequency, with an overactive bladder. These may be further associated with constipation.[11]
- Nocturnal enuresis mostly occurs early in the night, mainly in sleep stage 2 and deep sleep. Children with nocturnal enuresis and nocturnal polyuria differ in hemodynamics and autonomic activation at night compared to controls.[9]
- Children with nocturnal enuresis often have sleep-disordered breathing and disturbed sleep due to awakenings and arousal.[9]
- Periodic limb movements (PLM) have also been seen in children with refractory enuresis.[9]
# Differential Diagnosis
Enuresis should be differentiated from other causes[12][13][14][15]
- Medication side effects
- Neurogenic bladder
- Renal diseases
- Constipation
- Diabetes Mellitus
- Detrussor areflexia or overactivity
- Urinary tract infection
- Posterior urethral valve
- Emotional disturbances
- Underlying conditions resulting in polyuria such as sickle cell disease, and diabetes insipidus
- Spinal dysraphism
- Nephronopthisis
- Psychogenic polydipsia
- Pinworm infection
- Upper airway tract obstruction
- Other urological dysfunction
- Other neurological diseases
# Epidemiology and Demographics
## Prevalence
- The prevalence of enuresis is[12]
5,000-10,000 per 100,000 (5%-10%) among children 5 years of age
3,000-5,000 per 100,000 (3%-5%) among children 10 year of age
1,000 per 100,000 (1%) among individuals 15 years of age or older
- 5,000-10,000 per 100,000 (5%-10%) among children 5 years of age
- 3,000-5,000 per 100,000 (3%-5%) among children 10 year of age
- 1,000 per 100,000 (1%) among individuals 15 years of age or older
## Age
- Enuresis is found to be more prevalent in first-born children.[16]
- If enuretic symptoms persist into adulthood, they are less likely to resolve with time.[17]
- Primary nocturnal enuresis in adults may represent a more pronounced form and have a more serious social and psychological effect on affected individuals.[17]
## Gender
- Most studies show a predominance of enuresis in males, whereas some others show no gender predominance.[18][19]
## Race
- Sickle-cell anemia (SCA) is the most common inherited hemoglobinopathy in the African population. It has been found that children and adolescents with SCA are at increased risk of nocturnal enuresis.[20]
# Risk Factors
- The risk factors for the development of enuresis are [12][21][1][22][23]
Delayed or lax toilet training
Genetic predisposition
Encopresis
Psychosocial stressors
Family history of enuresis (such as maternal history, and sibling history of bedwetting)
Low socioeconomic status
Snoring
Heavy and late supper
Deep sleeper
Sleepwalking
Being introverted and shy
- Delayed or lax toilet training
- Genetic predisposition
- Encopresis
- Psychosocial stressors
- Family history of enuresis (such as maternal history, and sibling history of bedwetting)
- Low socioeconomic status
- Snoring
- Heavy and late supper
- Deep sleeper
- Sleepwalking
- Being introverted and shy
# Natural History, Complications, and Prognosis
## Natural History
- Most children with enuresis eventually attain bladder control.
- It has been found that the prevalence of nocturnal enuresis gradually decreases with increasing age and many may achieve spontaneous resolution.[24]
- The link between childhood enuresis and adult detrusor instability is observed to be stronger for men than women.[25]
## Complications
- If intranasal desmopressin is used in the treatment of enuresis, some patients may develop seizures or altered mental status within 14 days of starting the medication.[26]
- The accidental poisoning of young children by medications (tricyclic antidepressants) prescribed for enuresis has been reported.[27]
## Prognosis
- The prognosis of secondary nocturnal enuresis due to cystitis, constipation, diabetes mellitus, seizure disorder, acquired urethral obstruction, and hyperthyroidism, is excellent once the underlying cause has been treated successfully.[28]
- Patients with nocturnal enuresis due to psychological causes generally improve over time with psychosocial alterations or psychotherapy.[28]
# Comorbidities
- Enuresis exists with various conditions[29][30][20][31][32]
Attention-deficit hyperactivity disorder (ADHD)
Obstructive sleep apnea syndrome
Sickle cell anemia
Childhood obesity
Oppositional-defiant disorder (ODD)
Tic disorder
Conduct disorder
Bipolar affective disorder
Post-traumatic stress disorder (PTSD)
- Attention-deficit hyperactivity disorder (ADHD)
- Obstructive sleep apnea syndrome
- Sickle cell anemia
- Childhood obesity
- Oppositional-defiant disorder (ODD)
- Tic disorder
- Conduct disorder
- Bipolar affective disorder
- Post-traumatic stress disorder (PTSD)
# Diagnostic Criteria
## DSM-5 Criteria for Enuresis
- Enuresis is included under the elimination disorders.
- The diagnostic guidelines are [12]
Repeated voiding of urine into bed or clothes, either involuntarily or intentionally.
The behavior is clinically significant manifested as either at least twice a week for a minimum of three consecutive months or with significant impairment of social, occupational, or other areas of functioning.
Chronological age is a minimum of 5 years.
The behavior is not attributable to the physiological effects of a substance (such as a diuretic, an antipsychotic ) or another medical condition (such as diabetes, spina bifida, or seizure disorder).
- Repeated voiding of urine into bed or clothes, either involuntarily or intentionally.
- The behavior is clinically significant manifested as either at least twice a week for a minimum of three consecutive months or with significant impairment of social, occupational, or other areas of functioning.
- Chronological age is a minimum of 5 years.
- The behavior is not attributable to the physiological effects of a substance (such as a diuretic, an antipsychotic ) or another medical condition (such as diabetes, spina bifida, or seizure disorder).
- Specify if:
Nocturnal only: Passage of urine only during nighttime sleep.
Diurnal only: Passage of urine only during waking hours.
Nocturnal and diurnal: A combination of the two subtypes.
- Nocturnal only: Passage of urine only during nighttime sleep.
- Diurnal only: Passage of urine only during waking hours.
- Nocturnal and diurnal: A combination of the two subtypes.
## ICD-10 Criteria
- The criteria for the diagnosis of nonorganic enuresis are described in the section 'F98.0'.
- It emphasizes that enuresis should not be diagnosed in a child under the age of five years or mental age of four years.
- This category includes urinary incontinence of nonorganic origin or functional enuresis.
# Treatment
- The patients are treated by behavioral modifications, medications, or a combination of both.
- Medications are usually avoided in children under seven years of age.
- Parents should be reassured about their child's health and psychoeducated about eliminating guilt, and punishment.
- It is extremely important that the psychosocial consequences of the symptom be addressed with sensitivity during the treatment of enuresis.[33]
## Non-pharmacological management
- Enuresis alarms are effective in patients with primary nocturnal enuresis and should be considered for older, highly motivated children from cooperative families.[34]
- In the long-term follow-up, it has been observed that the enuretic alarm device also provide a full response rate in children with primary nocturnal enuresis.[35]
- Hypnotherapy is found to be an effective alternative or adjunctive treatment for enuresis in children.[36]
- Acupressure administered by the parents could be an alternative non-pharmacological treatment. It has the advantages of being non-invasive, cost-effective, and painless.[37]
## Pharmacological management
- Desmopressin, an antidiuretic hormone (ADH) analog, is also called as arginine vasopressin (AVP). It can resolve primary nocturnal enuresis by reducing urine production at the night.[38]
- It has been found that a structured withdrawal program from sublingual formulation of fast-melting oral desmopressin lyophilisate (MELT) therapy doesn't offer advantages compared to abrupt discontinuation.[39]
- Patients respond rapidly to desmopressin as compared to alarm systems. However, it has been observed that more children improve from psychological (urine alarm) than from pharmacological interventions.[34] [40]
- Tricyclics and desmopressin are effective in reducing the number of wet nights while taking the drugs, but most children relapse after stopping active treatment. On the contrary, relapse rates are lower after alarm treatment.[41]
- Imipramine is useful for enuresis when other treatment options such as desmopressin, alarm, and anticholinergics have failed in older children.[42]
- Oxybutynin has shown partial response in the management of nocturnal enuresis.[37]
## Combined therapy
- Combined pharmacological and non-pharmacological interventions are effective for resistant cases.[34]
- Many studies have found that the combined therapy (enuresis alarm, bladder training, motivational therapy, and pelvic floor muscle training) is more effective than each component used alone.[38]
- The combination of desmopressin and alarm is also helpful for severe cases with other behavioral problems.[43]
- Pharmacotherapy can provide early relief, while behavioral intervention may lead to more long-term benefits. Therefore, the positive effect of achieving dry nights with pharmacotherapy can encourage the patient to sustain behavioral therapy.[38] | https://www.wikidoc.org/index.php/Enuresis | |
7fcbd935fdf00c872d14fae0630ccd64b95f7d37 | wikidoc | Ependyma | Ependyma
# Overview
Ependyma is the thin epithelial membrane lining the ventricular system of the brain and the spinal cord. Ependyma is one of the four types of neuroglia in the central nervous system. It is involved in the production of cerebrospinal fluid (CSF).
# Ependymal Cells
The ependyma is made up of ependymal cells. These are the epithelial cells that line the CSF-filled ventricles in the brain and the central canal of the spinal cord. The cells are cuboidal/columnar. Their apical surfaces are covered in a layer of cilia, which circulate CSF around the central nervous system. Their apical surfaces are also covered with microvilli, which absorb CSF. Within the brain's ventricles, a population of modified ependymal cells and capillaries together form a system called the choroid plexus, which produces the CSF.
# Pathology
Ependymoma is a tumor of the ependyma.
# Stem cells
Jonas Frisén and his colleagues at the Karolinska Institute in Stockholm believe that ependyma is the prime candidate for the location of neural stem cells. | Ependyma
Template:Infobox Anatomy
# Overview
Ependyma is the thin epithelial membrane lining the ventricular system of the brain and the spinal cord. Ependyma is one of the four types of neuroglia in the central nervous system. It is involved in the production of cerebrospinal fluid (CSF).
# Ependymal Cells
The ependyma is made up of ependymal cells. These are the epithelial cells that line the CSF-filled ventricles in the brain and the central canal of the spinal cord. The cells are cuboidal/columnar. Their apical surfaces are covered in a layer of cilia, which circulate CSF around the central nervous system. Their apical surfaces are also covered with microvilli, which absorb CSF. Within the brain's ventricles, a population of modified ependymal cells and capillaries together form a system called the choroid plexus, which produces the CSF.
# Pathology
Ependymoma is a tumor of the ependyma.
# Stem cells
Jonas Frisén and his colleagues at the Karolinska Institute in Stockholm believe that ependyma is the prime candidate for the location of neural stem cells.[1] | https://www.wikidoc.org/index.php/Ependyma | |
93bd78e30e7f87b99aa576e4a1179a6c15bc5a71 | wikidoc | Epidemic | Epidemic
In epidemiology, an epidemic (from Greek epi- upon + demos people) is a classification of a disease that appears as new cases in a given human population, during a given period, at a rate that substantially exceeds what is "expected," based on recent experience (the number of new cases in the population during a specified period of time is called the "incidence rate"). (An epizootic is the same thing but for an animal population.)
# Classification
Defining an epidemic can be subjective, depending in part on what is "expected". An epidemic may be restricted to one locale (an outbreak), more general (an "epidemic") or even global (pandemic). Because it is based on what is "expected" or thought normal, a few cases of a very rare disease like rabies may be classified as an "epidemic," while many cases of a common disease (like the common cold) would not.
## Endemic diseases
Common diseases that occur at a constant but relatively high rate in the population are said to be "endemic." An example of an endemic disease is malaria in some parts of Africa (for example, Liberia) in which a large portion of the population is expected to get malaria at some point in their lifetimes.
## Non-infectious disease usage
The term "epidemic" is often used in a sense to refer to widespread and growing societal problems, for example, in discussions of obesity, mental illness or drug addiction.
Famous examples of epidemics include the bubonic plague epidemic of Medieval Europe= known as the Black Death, and the Great Influenza Pandemic which coincided with the end of World War I.
# Factors stimulating new epidemics
Factors that have been described by Mark Woolhouse and Sonya Gowtage-Sequeria to stimulate the rise of new epidemics include:
- Alterations in agricultural practices and land use
- Changes in society and human demographics
- Poor population health (e.g. malnutrition, HIV, ...)
- Hospitals and medical procedures
- Evolution of the pathogen (e.g. increased virulence, antimicrobial drug resistance,)
- Contamination of water supplies and food sources
- International travel
- Failure of public health programs
- International trade
- Climate change
In addition, several other factors have also been mentioned in different reports, such as the report by professor Andy Dobson and the report by professor Akilesh Mishra .These include :
- Reduced levels of biodiversity (e.g. trough environmental destruction)
- Bad urban planning
# Pre-emptive measures
To protect us against the emergence of new epidemics, several preemptive measures have been proposed by professor Nina Marano , and Andy Dobson. These include:
- To eat less food containing animal protein (eg meat, milk, milk-derivates)
- To eat local food
- To eat crops according to the season
- To make agriculture more efficient
- To avoid destruction of the rainforest
- To be prepared to pay a higher price for meat
In addition, certain other measures are known to reduce the beneficial factors found above. As such, the measures would also decrease the possible emergence of new epidemics. These measures are:
- Population control measures
- Improving the urban planning
# Renewed concern
In August 2007, the World Health Organization reported an unprecedented rate of propagation of infectious diseases. | Epidemic
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In epidemiology, an epidemic (from Greek epi- upon + demos people) is a classification of a disease that appears as new cases in a given human population, during a given period, at a rate that substantially exceeds what is "expected," based on recent experience (the number of new cases in the population during a specified period of time is called the "incidence rate"). (An epizootic is the same thing but for an animal population.)
# Classification
Defining an epidemic can be subjective, depending in part on what is "expected". An epidemic may be restricted to one locale (an outbreak), more general (an "epidemic") or even global (pandemic). Because it is based on what is "expected" or thought normal, a few cases of a very rare disease like rabies may be classified as an "epidemic," while many cases of a common disease (like the common cold) would not.
## Endemic diseases
Common diseases that occur at a constant but relatively high rate in the population are said to be "endemic." An example of an endemic disease is malaria in some parts of Africa (for example, Liberia) in which a large portion of the population is expected to get malaria at some point in their lifetimes.
## Non-infectious disease usage
The term "epidemic" is often used in a sense to refer to widespread and growing societal problems, for example, in discussions of obesity, mental illness or drug addiction.
Famous examples of epidemics include the bubonic plague epidemic of Medieval Europe= known as the Black Death, and the Great Influenza Pandemic which coincided with the end of World War I.
# Factors stimulating new epidemics
Factors that have been described by Mark Woolhouse and Sonya Gowtage-Sequeria to stimulate the rise of new epidemics [1] include:
- Alterations in agricultural practices and land use
- Changes in society and human demographics
- Poor population health (e.g. malnutrition, HIV, ...)
- Hospitals and medical procedures
- Evolution of the pathogen (e.g. increased virulence, antimicrobial drug resistance,)
- Contamination of water supplies and food sources
- International travel
- Failure of public health programs
- International trade
- Climate change
In addition, several other factors have also been mentioned in different reports, such as the report by professor Andy Dobson [2] and the report by professor Akilesh Mishra [3].These include :
- Reduced levels of biodiversity (e.g. trough environmental destruction)
- Bad urban planning
# Pre-emptive measures
To protect us against the emergence of new epidemics, several preemptive measures have been proposed by professor Nina Marano [4], and Andy Dobson. These include:
- To eat less food containing animal protein (eg meat, milk, milk-derivates)
- To eat local food
- To eat crops according to the season
- To make agriculture more efficient
- To avoid destruction of the rainforest
- To be prepared to pay a higher price for meat
In addition, certain other measures are known to reduce the beneficial factors found above. As such, the measures would also decrease the possible emergence of new epidemics. These measures are:
- Population control measures
- Improving the urban planning
# Renewed concern
In August 2007, the World Health Organization reported an unprecedented rate of propagation of infectious diseases.[5] | https://www.wikidoc.org/index.php/Epidemic | |
2da3c9d20f0cd5c6d6c6422a33a4f68642e04191 | wikidoc | Epidural | Epidural
# Overview
The term epidural is often short for epidural anesthesia, a form of regional anesthesia involving injection of drugs through a catheter placed into the epidural space. The epidural space (or extradural space or peridural space) is the space inside the spinal canal but outside the membrane called the dura mater (sometimes called the "dura"). In contact with the inner surface of the dura is another membrane called the arachnoid mater ("arachnoid"). The arachnoid encompasses the cerebrospinal fluid that surrounds the spinal cord. Epidural analgesia (pain relief) is a type of Regional Anesthesia which is commonly used to ease the pain of labor and childbirth but can also be used to provide anesthesia for other types of surgeries. A Spanish surgeon named Fidel Pagés Miravé reported the first single-shot thoracolumbar epidural anesthesia in 1921. After a decade, the Italian surgeon Achille M. Dogliotti described a reproducible loss-of-resistance technique to identify the epidural space. Epidural is a technique for perioperative pain management with different applications in anesthesiology and it can be a single shot or a continuous infusion for long term pain relief. Epidural is excellent analgesic, it decreases the side effect of other anesthetics and analgesics and reducing their side effects. Low blood pressure, fever, nausea, difficulty urinating are complications of epidural anesthesia. An epidural is a way of anesthetic which is used for pain relief during labor, it stops pain signals traveling from the spine to the brain. During labor, anesthesiologists injecting a small amount of anesthetic into the epidural space of the spine. The epidural space is filled with fluid and surrounds the spinal cord. Nerves that carry pain signals from the body to the brain (spinal nerves) connect to the spinal cord in certain places. The anesthetic numbs the spinal nerves, blocking the pain signals.
Spinal anesthesia is a technique whereby a local anesthetic drug is injected into the cerebrospinal fluid. This technique has some similarity to epidural anesthesia, and the two techniques may be easily confused with each other.
# History of epidural anesthesia
- In 1921, a Spanish surgeon named Fidel Pages developed the epidural anesthesia technique, he was the pioneer of lumbar epidural anesthesia.
- In 1931, Eugene Aburel, a Romanian obstetrician, performed the lumbar obstetric Epidural analgesia.
- In 1933, an Italian surgen, named Achille M. Dogliotti described a loss-of-resistance technique to identify the epidural space.
- In 1949, Manuel Martinez Curbelo, a Cuban physician reported the first successful continuous lumbar Epidural anaesthesia.
# Epidural anaesthesia and analgesia indication
Indications for epidural anaesthesia and analgesia have expanded over the past decades, a summary of major indications for epidural include:
- For analgesia alone, where surgery is not contemplated. An epidural for pain relief (e.g. in childbirth) is unlikely to cause loss of muscle power but is not usually sufficient for surgery.
- As an adjunct to general anaesthesia. The anesthetist may use epidural analgesia in addition to general anesthesia. This may reduce the patient's requirement for opioid analgesics. This is suitable for a wide variety of surgery, for example gynaecological surgery (e.g. hysterectomy), orthopaedic surgery (e.g. hip replacement), general surgery (e.g. laparotomy) and vascular surgery (e.g. open aortic aneurysm repair). See also caudal epidural, below.
- As a sole technique for surgical anesthesia . Some operations, most frequently Caesarean section, may be performed using an epidural anesthetic as the sole technique. Typically the patient would remain awake during the operation. The dose required for anesthesia is much higher than that required for analgesia.
- For post-operative analgesia, in either of the two situations above. Analgesics are given into the epidural space for a few days after surgery, provided a catheter has been inserted. Through the use of a patient-controlled analgesia (PCA) infusion pump, a patient may be given the ability to control post-surgical pain medications administered through the epidural.
- For the treatment of back pain. Injection of analgesics and steroids into the epidural space may improve some forms of back pain. See below.
- For the treatment of chronic pain or palliation of symptoms in terminal care, usually in the short or medium term.
Because of the nature of epidurals, they are most suitable for analgesia for the abdomen, pelvis or legs. They are much less suitable for analgesia for the chest, neck, or arms and are not possible for the head.
# Cautions
There are circumstances where the risks of an epidural are higher than normal. These circumstances include:
- Anatomical abnormalities, such as spina bifida, meningomyelocele or scoliosis
- Previous spinal surgery (which may cause an acquired tethered spinal cord)
- Certain problems of the central nervous system, including multiple sclerosis or syringomyelia
- Certain heart-valve problems (such as aortic stenosis)
# Contraindications
These are circumstances in which epidurals should not be used:
A relative contraindication to neuraxial anesthesia include:
- Low platelets but no bleeding diathesis
- Infection remote from the site of lumbar puncture
- Progressive neurologic diseases
- Raised intracranial pressure
- Hypovolemia
- Fixed cardiac output (eg, severe aortic stenosis)
Absolute contraindication:
- Patient refusal
- Lack of adequate staff
- Bleeding disorder (coagulopathy) or anticoagulant medication (e.g. warfarin)
- Infection near the point of insertion
- Infection in the bloodstream which may "seed" onto the catheter i.e septicemia which antibiotics must be given prior to anesthesia.
# Anatomy
The diagram at right depicts the various structures of the spinal column. The spinal cord (yellow core) is in intimate contact with the pia mater (blue). The arachnoid (red) exists superficial to the pia mater, and is attached to it by many, many trabeculae, giving it a spider-like appearance. This space (light blue) is filled with cerebrospinal fluid (CSF) and is called the subarachnoid space. Superficial to the arachnoid is the dura mater (pink) and although they are unattached, they are kept firmly pressed against one another because of pressure exerted by the CSF. Superficial to the dura mater is a space (pale green), known as the epidural space, that exists between it and the internal surfaces of the vertebral bones and their supporting ligamentous structures. The vertebral bones (taupe) are attached to one another by the interspinous ligaments (teal), and it is through this ligament that the needle used to place the epidural catheter is put.
# Technique of insertion
Epidural anesthesia should always be performed by a trained anesthetist, using a strict aseptic technique to reduce the risk of infection. American Society of
Anesthesiologists Task Force recommends the following steps on infection control during epidural anesthesia:
- Removal of jewelry from hands
- Handwashing
- Wearing of caps and sterile gloves
- Wearing masks that cover both mouth and nose; masks should be changed between cases
- Individually packaged skin preparation
- Chlorhexidine with alcohol for skin preparation; this must be allowed to dry before needle insertion; povidone-iodine with alcohol is also acceptable
- Sterile draping
- Sterile occlusive dressing
## Position of the patient
The insertion of epidural catheters for analgesia in labor may be carried out with the patient in the sitting or lateral position.
- Epidural block can be performed in the lateral or sitting position, and the decision is usually based on anesthesiologist and patient preferences.
- When the spinous processes are not easily palpable, the sitting position is preferred. In patients with easily identifiable landmarks, neither the lateral nor the sitting position is superior with regard to patient comfort, but heavier patients preferred the sitting position.
- In some patients, the sitting position may be associated with orthostatic hypotension and syncope. For this reason, it is important for an assistant to provide continuous support to the patient during the procedure. Maternal cardiac output can be reduced in the left lateral position if held too tightly in position.
- The sitting patient is asked to slouch and bend forward slightly from the waist to increase the curvature of the spine. The lying patient is asked to draw the knees up to the chin for the same reason. In the sitting position, the midline can be found by drawing a straight line between the vertebra of C7 (palpable in most patients) and the coccygeal cleft.
- Ultrasound identification of the midline may be useful to locate the midline, determine the approximate depth to the epidural space, and to determine the level of puncture.
## Insertion site
The anesthetist palpates the patient's back and identifies a suitable anatomical gap between the bony spinous processes prior to the procedure. Anesthesiologists use ultrasound imaging to detect the anatomic structure of the lumbar spine in order to insert the needle in epidural space.
- The level of the spine at which the catheter is best placed depends mainly on the size and type of an intended operation or the anatomical origin of pain.
- Suboptimal epidural catheter insertion may occur during the block and complications such as paresthesia and venous and subarachnoid cannulation may occur.
- Administration of local anesthetic through the epidural needle before catheter insertion improves the quality of anesthesia, a single-injection dose of local anesthetic (20 mL of 2% lidocaine) through the epidural needle into the epidural space before catheter insertion is used to ease the induction.
- Most commonly, the anesthetist conducting an epidural place the catheter in the mid-lumbar, or lower back region of the spine, although occasionally a catheter is placed in the thoracic (chest) or cervical (neck) region. In adults, the spinal cord terminates at the first lumbar vertebra, below which lies a bundle of nerves known as the cauda equina ("horse's tail"). Hence, lumbar epidurals carry a very low risk of injuring the spinal cord.
## Locating the epidural space
- The skin is infiltrated with a local anesthetic such as lidocaine over the identified space. The insertion point is usually in the midline, although other approaches, such as the paramedian approach, may occasionally be employed.
- A particular type of needle known as a Tuohy needle 16 or 18 gauge is almost invariably used. This needle was specially designed for locating the epidural space safely and has several specific features for this purpose.
- The Tuohy needle is inserted to the interspinous ligament and a loss of resistance to injection technique is used to identify the epidural space. This technique works because the interspinous ligament is extremely dense, and injection into it is almost impossible. The anesthetist attaches a syringe to the Tuohy needle and advances it slowly.
- The syringe may contain air or saline. The principles are the same, but the specifics of the technique are different due to the greater compressibility of air with respect to saline.
- When the tip of the needle enters a space of negative or neutral pressure (such as the epidural space), there will be a "loss of resistance" and it will be possible to inject through the syringe. There is now a high likelihood that the tip of the needle has entered the epidural space. A sensation of "pop" or "click" may be felt as the needle breaches the ligamentum flavum just before entering the epidural space.
- Traditionally anesthetists have used either air or saline for identifying the epidural space, depending on their personal preference. however, the evidence is accumulating that saline may result in a more rapid and satisfactory quality of analgesia.
- In addition to the loss of resistance technique, realtime observation of the progress of the needle is becoming more common. This may be done using a portable ultrasound scanner, or with fluoroscopy (moving X-ray pictures).
- The position of an epidural catheter and the distribution of local anesthetic drugs in the epidural space are two of the most important determining factors for successful epidural analgesia.
## Feeding the catheter
- After placement of the tip of the Tuohy needle into the epidural space the catheter is threaded through the needle. The needle is then withdrawn over the catheter. Generally, the catheter is then withdrawn slightly so that 4-6 cm remains in the epidural space. The catheter has depth markings on it (see photo) so that the length of the catheter in the epidural space can be estimated.
- The catheter is a fine plastic tube, down which anesthetics may be given into the epidural space. Early catheters had a hole at the end ("end-hole catheters"), but were prone to blockage. More modern catheters ("side-hole catheters") have a blind end but three or more side-holes along the shaft near the tip. This not only disperses the anesthetic more widely around the catheter but lessens the likelihood of blockage.
- The catheter is typically secured to the skin with adhesive tape or dressings to prevent it from becoming dislodged.
- In some unusual instances, it may not be required to insert a catheter into the epidural space, e.g. for steroid injections; see below. The anesthesiologist may inject medication into the epidural space through the needle, then remove the needle.
- complications including abscess, spinal hematoma, radiculopathy, breakage, migration may occur during insertion of the catheter.
## Anaesthetic drugs
- A patient receiving an epidural for pain relief typically receives a combination of local anesthetics and opioids. This combination works better than either type of drug used alone. This combination helps to reduce the dose of the local anesthetic agent.
- Local anesthetic agents are combined with morphine, fentanyl or clonidine to prolong the epidural effect or to stabilize the blood pressure. Common local anesthetics include lidocaine, bupivacaine, ropivacaine, and chloroprocaine. Common opioids include morphine, fentanyl, sufentanil, and pethidine (known as meperidine in the U.S.). These are injected in relatively small doses.
- Occasionally other agents may be used, such as clonidine or ketamine.
## Bolus or infusion?
- For a short procedure, the anesthetist may introduce a single dose of medication (the "bolus" technique). This will eventually wear off. Thereafter, the anesthetist may repeat the bolus provided the catheter remains undisturbed.
- For a prolonged effect, a continuous infusion of drugs may be employed. A common solution for epidural infusion in childbirth or for post-operative analgesia is 0.2% ropivacaine or 0.125% bupivacaine, with 2 μg/mL of fentanyl added. This solution is infused at a rate between 4 and 14 mL/hour, following a loading dose to initiate the nerve block.
- There is some evidence that an intermittent bolus technique provides better analgesia than a continuous infusion technique when the total doses are identical.
## Removing the catheter
- The catheter should be withdrawn when it is no longer used. An epidural catheter is likely to be safe if left in for up to 72 hours.
- The risk of problems such as infection rises sharply after this time. Subcutaneously tunneled epidural catheters may be left in place for longer periods, without as much risk of infection.
- If prolonged analgesics are needed, tunneled epidural catheters can be used. This might reduce the risk of infection including epidural abscess formation.
# Other types of epidural
## Combined spinal-epidurals
Combined spinal and epidural anaesthesia (CSE) is a regional anaesthetic technique, which combines the rapid spinal block with the flexibility of continuous epidural to extend the duration of analgesia. This is an effective way to reduce the total drug dosage required for anaesthesia or analgesia.
- For some procedures, the anaesthetist may choose to combine the rapid onset and reliable, dense block of a spinal anaesthetic with the post-operative analgesic effects of an epidural. This is called combined spinal and epidural anaesthesia (CSE).
- The anaesthetist may insert the spinal anaesthetic at one level, and the epidural at an adjacent level. Alternatively, after locating the epidural space with the Tuohy needle, a spinal needle may be inserted through the Tuohy needle into the subarachnoid space. The spinal dose is then given, the spinal needle withdrawn, and the epidural catheter inserted as normal. This method, known as the "needle-through-needle" technique, may be associated with a slightly higher risk of placing the catheter into the subarachnoid space.
- Many studies have confirmed that low-dose CSE with local anaesthetic and opioid, or low-dose epidural block alone, will provide effective analgesia with minimal motor and proprioceptive block.
## Caudal epidurals
- It is performed by inserting a standard 21G needle through the sacral hiatus to gain entrance into the sacral epidural space. Injecting a volume of local anesthetic here provides good analgesia of the perineum and genital areas. This is typically a single-injection technique and a catheter is not normally placed. This is known as a caudal epidural or "caudal".
- It is performed by inserting a needle through the sacral hiatus to gain entrance into the sacral epidural space.
- The caudal epidural is an effective and safe analgesic technique in children undergoing pelvic or perineal surgery. It is usually combined with general anesthesia.
- A well-documented epidural complication, a “wet tap,” results in a headache and possible total spinal anesthesia/block, requiring immediate maintenance of the patient’s airway and blood pressure.
## Techniques of Caudal Epidural Block
There are different techniques to perform caudal epidural block during anesthesia, by advances in diagnostic imaging tools, anesthesiologists can use ultrasound-guided block rather than the blind technique.
Blind Caudal Epidural Block:
- In blind caudal block, the patient can be placed in prone or lateral decubitus position, a line is drawn to connect the bilateral posterior superior iliac crests and used as one side of an equilateral triangle; then the location of the sacral hiatus should be approximated.
- By palpating the sacral cornua as 2 bony prominences, the sacral hiatus could be identified as a dimple in between. A needle is inserted at 45 degrees to the sacrum and redirected if the posterior surface of the sacral bone is contacted.
Fluoroscopy-Guided Caudal Epidural Block:
- In this technique, the patient is usually placed in a prone position for the fluoroscopy-guided caudal epidural block. In lateral view of fluoroscopy, the sacral hiatus could be identified as an abrupt drop off at the end of S4 lamina.
- The block needle trajectory can be visualized and navigated accordingly into the sacral canal.
- By injecting contrast medium under fluoroscopy, the placement of needle tip within the sacral epidural space can be verified, and intravascular or intrathecal needle tip placement can be detected.
Ultrasound-Guided Caudal Epidural Block:
- In 2003, Klocke and colleagues first described the ultrasound-guided caudal block, thereafter use of ultrasound-guided epidural gained popularity.
- The ultrasound transducer is placed at the midline to have the transverse view of sacral hiatus.
- The two sacral cornua appear as two hyperechoic structures on ultrasound. Between the sacral cornua are two band-like hyperechoic structures; the superficial one is the SCL, and the deep one is the dorsal surface of sacral bone.
- At this level, the ultrasound transducer is rotated 90 degrees to obtain the longitudinal view of sacral hiatus (Figure 5). Under longitudinal view, the block needle is inserted using the “in-plane” technique. The block needle can be visualized in real-time, piercing the SCL, entering the sacral hiatus, but cannot be visualized beyond the apex of sacral hiatus.
## Epidural steroid injections
- An epidural injection, or epidural steroid injection, may be used to help reduce the pain caused by a herniated disc, degenerative disc disease, or spinal stenosis. These spinal disorders often affect the cervical (neck) and lumbar (lower back) areas of the spine.
- The medicine used in the injection is usually a combination of a local anesthetic (e.g. bupivacaine) and a steroid (e.g. triamcinolone).
- The technique and risks of the procedure are similar to those for standard epidural analgesia. The effects of an epidural steroid injection vary, but the permanent benefit is unlikely
- Some patients who have some residual pain after the first injection may receive a second or third epidural steroid injection. Patients who do not receive any relief from the first injection are unlikely to benefit from a second injection.
# Benefits of epidural analgesia after surgery
Epidural analgesia has been demonstrated to have several benefits after surgery. These include:
- Effective analgesia without the need for systemic opioids .
- The incidence of postoperative respiratory problems and chest infections is reduced .
- The incidence of postoperative myocardial infarction ("heart attack") is reduced .
- The stress response to surgery is reduced .
- Motility of the intestines is improved by blockade of the sympathetic nervous system .
- Use of epidural analgesia during surgery reduces blood transfusion requirements .
Despite these benefits, no survival benefit has been proven for high-risk patients .
# Potential problems
## Side effects
In addition to blocking the nerves which carry pain, local anesthetic drugs in the epidural space will block other types of nerves as well, in a dose-dependent manner. Depending on the drug and dose used, the effects may last only a few minutes or up to several hours. This results in three main effects:
- Loss of other modalities of sensation (including touch, and proprioception)
- Loss of muscle power
- Loss of function of the sympathetic nervous system, which controls blood pressure
- The leak of spinal fluid can cause headache in less than 1% of patients and it is corrected by using blood patch( injecting blood into epidural space).
- Very large doses of epidural anesthetic can cause paralysis of the intercostal muscles and diaphragm (which are responsible for breathing), and loss of sympathetic function to the heart itself, causing a profound drop in heart rate and blood pressure. This requires emergency treatment, and in severe cases may require airway support. This happens because the epidural is blocking the heart's sympathetic nerves, as well as the phrenic nerves, which supply the diaphragm.
## Complications of epidural use
These include:
- Block failure (about 1 in 20). Partial failure may still give satisfactory pain relief. However, if pain relief is inadequate, another epidural may have to be performed.
- Bloody tap (about 1 in 30-50). It is easy to injure an epidural vein with the needle. In patients who have normal blood clotting, it is extremely rare (e.g. 1 in 100,000) for problems to develop. However, in a patient who has a coagulopathy, the patient may be at risk of epidural hematoma. If blood comes back down the needle, the anesthesiologist will normally site the epidural at another level.
- Accidental dural puncture with headache (common, about 1-3 in 100 insertions) The epidural space in the adult lumbar spine is only 3-5mm deep, which means it is comparatively easy to cross it and accidentally puncture the dura (and arachnoid) with the needle. This may cause cerebrospinal fluid (CSF) to leak out into the epidural space, which may, in turn, cause the post dural puncture headache (PDPH). This can be severe and last several days and in some cases weeks or months. It is caused by a reduction in CSF pressure and is characterized by postural exacerbation when the patient raises their head above the lying position. If severe it may be successfully treated with a epidural blood patch (a small amount of the patient's own blood given into the epidural space via another epidural needle). Most cases resolve spontaneously with time.
- Catheter misplaced into a vein (uncommon, less than 1 in 300). Occasionally the catheter may be misplaced into an epidural vein, which results in all the anaesthetic being injected intravenously, where it can be toxic in large doses (about 1 in 10,000 insertions). This also results in block failure.
- High block, as described above (uncommon, less than 1 in 500).
- Catheter misplaced into the subarachnoid space (rare, less than 1 in 1000). If the catheter is accidentally misplaced into the subarachnoid space (e.g. after an unrecognized accidental dural puncture), normally cerebrospinal fluid can be freely aspirated from the catheter (which would usually prompt the anesthetist to withdraw the catheter and resite it elsewhere). If, however, this is not recognized, large doses of anesthetic may be delivered directly into the cerebrospinal fluid. This may result in a high block, or, more rarely, a total spinal, where the anesthetic is delivered directly to the brainstem, causing unconsciousness and sometimes seizures.
- Neurological injury lasting less than 1 year (rare, about 1 in 6,700).
- Epidural abscess formation (very rare, about 1 in 145,000). The risk increases greatly with catheters which are left in place longer than 72 hours.
- Epidural haematoma formation (very rare, about 1 in 168,000).
- Neurological injury lasting longer than 1 year (extremely rare, about 1 in 240,000).
- Paraplegia (extremely rare, less than 1 in 100,000).
- Arachnoiditis (extremely rare, fewer than 1000 cases in the past 50 years)
- Death (extremely rare, less than 1 in 100,000)) .
The figures above relate to epidurals in healthy individuals.
There is no evidence to support the concern that epidural analgesia increases the risk of anastomotic breakdown following bowel surgery.
# Epidural analgesia in childbirth
## Safety and efficacy
Epidural analgesia is a relatively safe method of relieving pain in labor. It provides rapid pain relief in most cases. It is more effective than nitrous oxide, opioids, TENS, and other common modalities of analgesia in childbirth.
## Prolonged labour and risk of instrumental delivery
- Epidural analgesia is associated with a longer labor, some researchers claim that it is correlated with an increased chance of operational intervention. The clinical research data on this topic are conflicting. For example, a study in Australia (Roberts, Tracy, Peat, 2000) concluded that having an epidural reduced the woman's chances of having a vaginal birth, without further interventions (such as episiotomy, forceps, ventouse or caesarean section) from 71.4% to 37.8%. Conversely, a 2001 study by researchers at the National Institute of Child Health and Human Development and a 2002 study by researchers at Cornell University and the University of Ontario demonstrated that epidurals do not increase the likelihood of a cesarean section. In 2005, a meta-analysis of 21 studies also showed that epidurals do not increase the likelihood of cesarean section, but they do increase the chance of a forceps or ventouse delivery by 40% (Anim-Somuah, Cochrane Review, 2005). The COMET Study, published in The Lancet in 2001 (vol358, No9275 p19-23) showed that a combined spinal-epidural in labor may speed up the labor process by a few minutes, although those women receiving an epidural had a cesarean rate of 28% and only 35% had a normal birth without instrument-assisted delivery.
These differing outcomes may be explained by data that demonstrates that the likelihood of increased intervention is directly related to the quality of the institution or practitioner providing the care: epidurals administered at top-rated institutions do not generally result in a clinically significant increase in cesarean rates, whereas the risk of cesarean delivery at poorly ranked facilities seems to increase with the use of epidural
An alternative explanation is that women having difficult labors are more likely to request epidurals, and are also less likely to have an unassisted vaginal birth.
## Effects on the baby
- Some mothers worry that epidural analgesia may harm their newborn. However, although epidural labor analgesia may be associated with slower progression of labor, it has no adverse effect on perinatal outcome and perinatal complications.
- One study concluded that women whose epidurals contain the drug fentanyl were less likely to fully breastfeed their infant in the few days after birth and more likely to stop breastfeeding in the first 24 weeks. However, this study has been criticized for several reasons, one of which is that the original patient records were not examined in this study, and so many of the epidurals were assumed to contain fentanyl when almost certainly they would not have.
- In addition, all patients who used epidurals in labor had also used systemic pethidine, which would be much more likely to be the cause of any effect on breastfeeding due to the higher amounts of medication used via that route. If that were the case, then early epidurals which avoided the need for pethidine may actually improve breastfeeding outcomes, not worsen them.
# Historical notes
- Prior to 1943, there were few methods of relieving pain in childbirth without risk of harm to the baby. Caesarean sections under general anesthesia was used only as an emergency measure. Dr. Robert A. Hingson, Dr. Waldo B. Edwards, and Dr. James L. Southworth working at the United States Marine Hospital at Stapleton, on Staten Island, New York, developed the technique of continuous caudal anesthesia.
- In 1912, German physicians had found that the injection of an anesthetic, at the base of the spinal cord, would prevent pain impulses from reaching the brain. Doctors in the United States developed the technique further. For expectant mothers, the injection "only reduced the pangs of childbirth; it did not eliminate them," wrote Dr. Morris Fishbein in the March 1943 issue of Hygeia, and a single nerve-blocking injection was used only toward the end of labor.
- Drs. Hingson and Southworth combined the concepts of caudal analgesia and the spinal injection in an operation to strip the varicose veins of a Scottish merchant seaman. The surgeons experimented with a continuous infusion of the local anesthetic, rather than removing the needle after the injection, to originate "continuous caudal analgesia". Dr. Hingson then collaborated with Dr. Edwards, the chief obstetrician at the Marine Hospital, to study the use of this technique in childbirth. The two studied the caudal region to determine where a needle could be safely placed to deliver anesthesia to the spinal nerves without placing the drugs into the spinal fluid.
- Testing on a human being did not occur until January 6, 1942, when the wife of a Coast Guardsman was brought into the Marine Hospital for delivery. Because the woman suffered from rheumatic heart disease, general anesthesia could not be safely used for an emergency Caesarean section, and it was believed that she would not survive the stress of labor. With the use of continuous local anesthesia, the woman and her baby survived. According to Dr. Fishbein's article in Hygeia, a total of 589 women in more than twenty participating hospitals gave birth relatively painlessly in 1942.
- The results were published in the January 23, 1943, issue of the Journal of the American Medical Association. | Epidural
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2]
# Overview
The term epidural is often short for epidural anesthesia, a form of regional anesthesia involving injection of drugs through a catheter placed into the epidural space. The epidural space (or extradural space or peridural space) is the space inside the spinal canal but outside the membrane called the dura mater (sometimes called the "dura"). In contact with the inner surface of the dura is another membrane called the arachnoid mater ("arachnoid"). The arachnoid encompasses the cerebrospinal fluid that surrounds the spinal cord. Epidural analgesia (pain relief) is a type of Regional Anesthesia which is commonly used to ease the pain of labor and childbirth but can also be used to provide anesthesia for other types of surgeries. A Spanish surgeon named Fidel Pagés Miravé reported the first single-shot thoracolumbar epidural anesthesia in 1921. After a decade, the Italian surgeon Achille M. Dogliotti described a reproducible loss-of-resistance technique to identify the epidural space. Epidural is a technique for perioperative pain management with different applications in anesthesiology and it can be a single shot or a continuous infusion for long term pain relief. Epidural is excellent analgesic, it decreases the side effect of other anesthetics and analgesics and reducing their side effects. Low blood pressure, fever, nausea, difficulty urinating are complications of epidural anesthesia. An epidural is a way of anesthetic which is used for pain relief during labor, it stops pain signals traveling from the spine to the brain. During labor, anesthesiologists injecting a small amount of anesthetic into the epidural space of the spine. The epidural space is filled with fluid and surrounds the spinal cord. Nerves that carry pain signals from the body to the brain (spinal nerves) connect to the spinal cord in certain places. The anesthetic numbs the spinal nerves, blocking the pain signals.
Spinal anesthesia is a technique whereby a local anesthetic drug is injected into the cerebrospinal fluid. This technique has some similarity to epidural anesthesia, and the two techniques may be easily confused with each other.
# History of epidural anesthesia
- In 1921, a Spanish surgeon named Fidel Pages developed the epidural anesthesia technique, he was the pioneer of lumbar epidural anesthesia.[1]
- In 1931, Eugene Aburel, a Romanian obstetrician, performed the lumbar obstetric Epidural analgesia.[2]
- In 1933, an Italian surgen, named Achille M. Dogliotti described a loss-of-resistance technique to identify the epidural space.[3]
- In 1949, Manuel Martinez Curbelo, a Cuban physician reported the first successful continuous lumbar Epidural anaesthesia.[2]
# Epidural anaesthesia and analgesia indication
Indications for epidural anaesthesia and analgesia have expanded over the past decades, a summary of major indications for epidural include:[4][5][6][7]
- For analgesia alone, where surgery is not contemplated. An epidural for pain relief (e.g. in childbirth) is unlikely to cause loss of muscle power but is not usually sufficient for surgery.
- As an adjunct to general anaesthesia. The anesthetist may use epidural analgesia in addition to general anesthesia. This may reduce the patient's requirement for opioid analgesics. This is suitable for a wide variety of surgery, for example gynaecological surgery (e.g. hysterectomy), orthopaedic surgery (e.g. hip replacement), general surgery (e.g. laparotomy) and vascular surgery (e.g. open aortic aneurysm repair). See also caudal epidural, below.
- As a sole technique for surgical anesthesia . Some operations, most frequently Caesarean section, may be performed using an epidural anesthetic as the sole technique. Typically the patient would remain awake during the operation. The dose required for anesthesia is much higher than that required for analgesia.
- For post-operative analgesia, in either of the two situations above. Analgesics are given into the epidural space for a few days after surgery, provided a catheter has been inserted. Through the use of a patient-controlled analgesia (PCA) infusion pump, a patient may be given the ability to control post-surgical pain medications administered through the epidural.
- For the treatment of back pain. Injection of analgesics and steroids into the epidural space may improve some forms of back pain. See below.
- For the treatment of chronic pain or palliation of symptoms in terminal care, usually in the short or medium term.
Because of the nature of epidurals, they are most suitable for analgesia for the abdomen, pelvis or legs. They are much less suitable for analgesia for the chest, neck, or arms and are not possible for the head.
# Cautions
There are circumstances where the risks of an epidural are higher than normal. These circumstances include:
- Anatomical abnormalities, such as spina bifida, meningomyelocele or scoliosis
- Previous spinal surgery (which may cause an acquired tethered spinal cord)
- Certain problems of the central nervous system, including multiple sclerosis or syringomyelia
- Certain heart-valve problems (such as aortic stenosis)
# Contraindications
These are circumstances in which epidurals should not be used:
A relative contraindication to neuraxial anesthesia include:[8]
- Low platelets but no bleeding diathesis
- Infection remote from the site of lumbar puncture
- Progressive neurologic diseases
- Raised intracranial pressure
- Hypovolemia
- Fixed cardiac output (eg, severe aortic stenosis)
Absolute contraindication:[8]
- Patient refusal
- Lack of adequate staff
- Bleeding disorder (coagulopathy) or anticoagulant medication (e.g. warfarin)
- Infection near the point of insertion
- Infection in the bloodstream which may "seed" onto the catheter i.e septicemia which antibiotics must be given prior to anesthesia.
# Anatomy
The diagram at right depicts the various structures of the spinal column. The spinal cord (yellow core) is in intimate contact with the pia mater (blue). The arachnoid (red) exists superficial to the pia mater, and is attached to it by many, many trabeculae, giving it a spider-like appearance. This space (light blue) is filled with cerebrospinal fluid (CSF) and is called the subarachnoid space. Superficial to the arachnoid is the dura mater (pink) and although they are unattached, they are kept firmly pressed against one another because of pressure exerted by the CSF. Superficial to the dura mater is a space (pale green), known as the epidural space, that exists between it and the internal surfaces of the vertebral bones and their supporting ligamentous structures. The vertebral bones (taupe) are attached to one another by the interspinous ligaments (teal), and it is through this ligament that the needle used to place the epidural catheter is put.
# Technique of insertion
Epidural anesthesia should always be performed by a trained anesthetist, using a strict aseptic technique to reduce the risk of infection. American Society of
Anesthesiologists Task Force recommends the following steps on infection control during epidural anesthesia:[9]
- Removal of jewelry from hands
- Handwashing
- Wearing of caps and sterile gloves
- Wearing masks that cover both mouth and nose; masks should be changed between cases
- Individually packaged skin preparation
- Chlorhexidine with alcohol for skin preparation; this must be allowed to dry before needle insertion; povidone-iodine with alcohol is also acceptable
- Sterile draping
- Sterile occlusive dressing
## Position of the patient
The insertion of epidural catheters for analgesia in labor may be carried out with the patient in the sitting or lateral position.[10][8]
- Epidural block can be performed in the lateral or sitting position, and the decision is usually based on anesthesiologist and patient preferences.[11]
- When the spinous processes are not easily palpable, the sitting position is preferred. In patients with easily identifiable landmarks, neither the lateral nor the sitting position is superior with regard to patient comfort, but heavier patients preferred the sitting position.
- In some patients, the sitting position may be associated with orthostatic hypotension and syncope. For this reason, it is important for an assistant to provide continuous support to the patient during the procedure. Maternal cardiac output can be reduced in the left lateral position if held too tightly in position. [12]
- The sitting patient is asked to slouch and bend forward slightly from the waist to increase the curvature of the spine. The lying patient is asked to draw the knees up to the chin for the same reason. In the sitting position, the midline can be found by drawing a straight line between the vertebra of C7 (palpable in most patients) and the coccygeal cleft.
- Ultrasound identification of the midline may be useful to locate the midline, determine the approximate depth to the epidural space, and to determine the level of puncture.[13]
## Insertion site
The anesthetist palpates the patient's back and identifies a suitable anatomical gap between the bony spinous processes prior to the procedure. Anesthesiologists use ultrasound imaging to detect the anatomic structure of the lumbar spine in order to insert the needle in epidural space.[14][15]
- The level of the spine at which the catheter is best placed depends mainly on the size and type of an intended operation or the anatomical origin of pain.
- Suboptimal epidural catheter insertion may occur during the block and complications such as paresthesia and venous and subarachnoid cannulation may occur.
- Administration of local anesthetic through the epidural needle before catheter insertion improves the quality of anesthesia, a single-injection dose of local anesthetic (20 mL of 2% lidocaine) through the epidural needle into the epidural space before catheter insertion is used to ease the induction.
- Most commonly, the anesthetist conducting an epidural place the catheter in the mid-lumbar, or lower back region of the spine, although occasionally a catheter is placed in the thoracic (chest) or cervical (neck) region. In adults, the spinal cord terminates at the first lumbar vertebra, below which lies a bundle of nerves known as the cauda equina ("horse's tail"). Hence, lumbar epidurals carry a very low risk of injuring the spinal cord.
## Locating the epidural space
- The skin is infiltrated with a local anesthetic such as lidocaine over the identified space. The insertion point is usually in the midline, although other approaches, such as the paramedian approach, may occasionally be employed. [16][17]
- A particular type of needle known as a Tuohy needle 16 or 18 gauge is almost invariably used. This needle was specially designed for locating the epidural space safely and has several specific features for this purpose.
- The Tuohy needle is inserted to the interspinous ligament and a loss of resistance to injection technique is used to identify the epidural space. This technique works because the interspinous ligament is extremely dense, and injection into it is almost impossible. The anesthetist attaches a syringe to the Tuohy needle and advances it slowly.
- The syringe may contain air or saline. The principles are the same, but the specifics of the technique are different due to the greater compressibility of air with respect to saline.
- When the tip of the needle enters a space of negative or neutral pressure (such as the epidural space), there will be a "loss of resistance" and it will be possible to inject through the syringe. There is now a high likelihood that the tip of the needle has entered the epidural space. A sensation of "pop" or "click" may be felt as the needle breaches the ligamentum flavum just before entering the epidural space.
- Traditionally anesthetists have used either air or saline for identifying the epidural space, depending on their personal preference. however, the evidence is accumulating that saline may result in a more rapid and satisfactory quality of analgesia.[18]
- In addition to the loss of resistance technique, realtime observation of the progress of the needle is becoming more common. This may be done using a portable ultrasound scanner, or with fluoroscopy (moving X-ray pictures).
- The position of an epidural catheter and the distribution of local anesthetic drugs in the epidural space are two of the most important determining factors for successful epidural analgesia.
## Feeding the catheter
- After placement of the tip of the Tuohy needle into the epidural space the catheter is threaded through the needle. The needle is then withdrawn over the catheter. Generally, the catheter is then withdrawn slightly so that 4-6 cm remains in the epidural space. The catheter has depth markings on it (see photo) so that the length of the catheter in the epidural space can be estimated.
- The catheter is a fine plastic tube, down which anesthetics may be given into the epidural space. Early catheters had a hole at the end ("end-hole catheters"), but were prone to blockage. More modern catheters ("side-hole catheters") have a blind end but three or more side-holes along the shaft near the tip. This not only disperses the anesthetic more widely around the catheter but lessens the likelihood of blockage.
- The catheter is typically secured to the skin with adhesive tape or dressings to prevent it from becoming dislodged.
- In some unusual instances, it may not be required to insert a catheter into the epidural space, e.g. for steroid injections; see below. The anesthesiologist may inject medication into the epidural space through the needle, then remove the needle.
- complications including abscess, spinal hematoma, radiculopathy, breakage, migration may occur during insertion of the catheter. [19]
## Anaesthetic drugs
- A patient receiving an epidural for pain relief typically receives a combination of local anesthetics and opioids. This combination works better than either type of drug used alone. This combination helps to reduce the dose of the local anesthetic agent.
- Local anesthetic agents are combined with morphine, fentanyl or clonidine to prolong the epidural effect or to stabilize the blood pressure. Common local anesthetics include lidocaine, bupivacaine, ropivacaine, and chloroprocaine. Common opioids include morphine, fentanyl, sufentanil, and pethidine (known as meperidine in the U.S.). These are injected in relatively small doses.
- Occasionally other agents may be used, such as clonidine or ketamine.
## Bolus or infusion?
- For a short procedure, the anesthetist may introduce a single dose of medication (the "bolus" technique). This will eventually wear off. Thereafter, the anesthetist may repeat the bolus provided the catheter remains undisturbed.
- For a prolonged effect, a continuous infusion of drugs may be employed. A common solution for epidural infusion in childbirth or for post-operative analgesia is 0.2% ropivacaine or 0.125% bupivacaine, with 2 μg/mL of fentanyl added. This solution is infused at a rate between 4 and 14 mL/hour, following a loading dose to initiate the nerve block.
- There is some evidence that an intermittent bolus technique provides better analgesia than a continuous infusion technique when the total doses are identical.
## Removing the catheter
- The catheter should be withdrawn when it is no longer used. An epidural catheter is likely to be safe if left in for up to 72 hours.[20]
- The risk of problems such as infection rises sharply after this time. Subcutaneously tunneled epidural catheters may be left in place for longer periods, without as much risk of infection.
- If prolonged analgesics are needed, tunneled epidural catheters can be used. This might reduce the risk of infection including epidural abscess formation.
# Other types of epidural
## Combined spinal-epidurals
Combined spinal and epidural anaesthesia (CSE) is a regional anaesthetic technique, which combines the rapid spinal block with the flexibility of continuous epidural to extend the duration of analgesia. This is an effective way to reduce the total drug dosage required for anaesthesia or analgesia.[21]
- For some procedures, the anaesthetist may choose to combine the rapid onset and reliable, dense block of a spinal anaesthetic with the post-operative analgesic effects of an epidural. This is called combined spinal and epidural anaesthesia (CSE).
- The anaesthetist may insert the spinal anaesthetic at one level, and the epidural at an adjacent level. Alternatively, after locating the epidural space with the Tuohy needle, a spinal needle may be inserted through the Tuohy needle into the subarachnoid space. The spinal dose is then given, the spinal needle withdrawn, and the epidural catheter inserted as normal. This method, known as the "needle-through-needle" technique, may be associated with a slightly higher risk of placing the catheter into the subarachnoid space.
- Many studies have confirmed that low-dose CSE with local anaesthetic and opioid, or low-dose epidural block alone, will provide effective analgesia with minimal motor and proprioceptive block.
## Caudal epidurals
- It is performed by inserting a standard 21G needle through the sacral hiatus to gain entrance into the sacral epidural space. Injecting a volume of local anesthetic here provides good analgesia of the perineum and genital areas. This is typically a single-injection technique and a catheter is not normally placed. This is known as a caudal epidural or "caudal".[22]
- It is performed by inserting a needle through the sacral hiatus to gain entrance into the sacral epidural space.
- The caudal epidural is an effective and safe analgesic technique in children undergoing pelvic or perineal surgery. It is usually combined with general anesthesia.
- A well-documented epidural complication, a “wet tap,” results in a headache and possible total spinal anesthesia/block, requiring immediate maintenance of the patient’s airway and blood pressure.
## Techniques of Caudal Epidural Block
There are different techniques to perform caudal epidural block during anesthesia, by advances in diagnostic imaging tools, anesthesiologists can use ultrasound-guided block rather than the blind technique. [23]
Blind Caudal Epidural Block:
- In blind caudal block, the patient can be placed in prone or lateral decubitus position, a line is drawn to connect the bilateral posterior superior iliac crests and used as one side of an equilateral triangle; then the location of the sacral hiatus should be approximated.
- By palpating the sacral cornua as 2 bony prominences, the sacral hiatus could be identified as a dimple in between. A needle is inserted at 45 degrees to the sacrum and redirected if the posterior surface of the sacral bone is contacted.
Fluoroscopy-Guided Caudal Epidural Block:
- In this technique, the patient is usually placed in a prone position for the fluoroscopy-guided caudal epidural block. In lateral view of fluoroscopy, the sacral hiatus could be identified as an abrupt drop off at the end of S4 lamina.
- The block needle trajectory can be visualized and navigated accordingly into the sacral canal.
- By injecting contrast medium under fluoroscopy, the placement of needle tip within the sacral epidural space can be verified, and intravascular or intrathecal needle tip placement can be detected.
Ultrasound-Guided Caudal Epidural Block:
- In 2003, Klocke and colleagues first described the ultrasound-guided caudal block, thereafter use of ultrasound-guided epidural gained popularity.[24]
- The ultrasound transducer is placed at the midline to have the transverse view of sacral hiatus.
- The two sacral cornua appear as two hyperechoic structures on ultrasound. Between the sacral cornua are two band-like hyperechoic structures; the superficial one is the SCL, and the deep one is the dorsal surface of sacral bone.
- At this level, the ultrasound transducer is rotated 90 degrees to obtain the longitudinal view of sacral hiatus (Figure 5). Under longitudinal view, the block needle is inserted using the “in-plane” technique. The block needle can be visualized in real-time, piercing the SCL, entering the sacral hiatus, but cannot be visualized beyond the apex of sacral hiatus.
## Epidural steroid injections
- An epidural injection, or epidural steroid injection, may be used to help reduce the pain caused by a herniated disc, degenerative disc disease, or spinal stenosis. These spinal disorders often affect the cervical (neck) and lumbar (lower back) areas of the spine.
- The medicine used in the injection is usually a combination of a local anesthetic (e.g. bupivacaine) and a steroid (e.g. triamcinolone).
- The technique and risks of the procedure are similar to those for standard epidural analgesia. The effects of an epidural steroid injection vary, but the permanent benefit is unlikely
- Some patients who have some residual pain after the first injection may receive a second or third epidural steroid injection. Patients who do not receive any relief from the first injection are unlikely to benefit from a second injection.
# Benefits of epidural analgesia after surgery
Epidural analgesia has been demonstrated to have several benefits after surgery. These include:
- Effective analgesia without the need for systemic opioids [25].
- The incidence of postoperative respiratory problems and chest infections is reduced [26].
- The incidence of postoperative myocardial infarction ("heart attack") is reduced [27].
- The stress response to surgery is reduced [28].
- Motility of the intestines is improved by blockade of the sympathetic nervous system [29].
- Use of epidural analgesia during surgery reduces blood transfusion requirements [30].
Despite these benefits, no survival benefit has been proven for high-risk patients [31].
# Potential problems
## Side effects
In addition to blocking the nerves which carry pain, local anesthetic drugs in the epidural space will block other types of nerves as well, in a dose-dependent manner. Depending on the drug and dose used, the effects may last only a few minutes or up to several hours. This results in three main effects:[8]
- Loss of other modalities of sensation (including touch, and proprioception)
- Loss of muscle power
- Loss of function of the sympathetic nervous system, which controls blood pressure
- The leak of spinal fluid can cause headache in less than 1% of patients and it is corrected by using blood patch( injecting blood into epidural space).
- Very large doses of epidural anesthetic can cause paralysis of the intercostal muscles and diaphragm (which are responsible for breathing), and loss of sympathetic function to the heart itself, causing a profound drop in heart rate and blood pressure. This requires emergency treatment, and in severe cases may require airway support. This happens because the epidural is blocking the heart's sympathetic nerves, as well as the phrenic nerves, which supply the diaphragm.
## Complications of epidural use
These include:
- Block failure (about 1 in 20). Partial failure may still give satisfactory pain relief. However, if pain relief is inadequate, another epidural may have to be performed.
- Bloody tap (about 1 in 30-50). It is easy to injure an epidural vein with the needle. In patients who have normal blood clotting, it is extremely rare (e.g. 1 in 100,000) for problems to develop. However, in a patient who has a coagulopathy, the patient may be at risk of epidural hematoma. If blood comes back down the needle, the anesthesiologist will normally site the epidural at another level.
- Accidental dural puncture with headache (common, about 1-3 in 100 insertions[32][33][34]) The epidural space in the adult lumbar spine is only 3-5mm deep, which means it is comparatively easy to cross it and accidentally puncture the dura (and arachnoid) with the needle. This may cause cerebrospinal fluid (CSF) to leak out into the epidural space, which may, in turn, cause the post dural puncture headache (PDPH). This can be severe and last several days and in some cases weeks or months. It is caused by a reduction in CSF pressure and is characterized by postural exacerbation when the patient raises their head above the lying position. If severe it may be successfully treated with a epidural blood patch (a small amount of the patient's own blood given into the epidural space via another epidural needle). Most cases resolve spontaneously with time.
- Catheter misplaced into a vein (uncommon, less than 1 in 300). Occasionally the catheter may be misplaced into an epidural vein, which results in all the anaesthetic being injected intravenously, where it can be toxic in large doses (about 1 in 10,000 insertions[35]). This also results in block failure.
- High block, as described above (uncommon, less than 1 in 500).
- Catheter misplaced into the subarachnoid space (rare, less than 1 in 1000). If the catheter is accidentally misplaced into the subarachnoid space (e.g. after an unrecognized accidental dural puncture), normally cerebrospinal fluid can be freely aspirated from the catheter (which would usually prompt the anesthetist to withdraw the catheter and resite it elsewhere). If, however, this is not recognized, large doses of anesthetic may be delivered directly into the cerebrospinal fluid. This may result in a high block, or, more rarely, a total spinal, where the anesthetic is delivered directly to the brainstem, causing unconsciousness and sometimes seizures.
- Neurological injury lasting less than 1 year (rare, about 1 in 6,700).[3]
- Epidural abscess formation (very rare, about 1 in 145,000).[4] The risk increases greatly with catheters which are left in place longer than 72 hours.
- Epidural haematoma formation (very rare, about 1 in 168,000).[5]
- Neurological injury lasting longer than 1 year (extremely rare, about 1 in 240,000).[6]
- Paraplegia (extremely rare, less than 1 in 100,000)[36].
- Arachnoiditis (extremely rare, fewer than 1000 cases in the past 50 years)[37]
- Death (extremely rare, less than 1 in 100,000)[38]) .
The figures above relate to epidurals in healthy individuals.
There is no evidence to support the concern that epidural analgesia increases the risk of anastomotic breakdown following bowel surgery[39].
# Epidural analgesia in childbirth
## Safety and efficacy
Epidural analgesia is a relatively safe method of relieving pain in labor. It provides rapid pain relief in most cases. It is more effective than nitrous oxide, opioids, TENS, and other common modalities of analgesia in childbirth.[7]
## Prolonged labour and risk of instrumental delivery
- Epidural analgesia is associated with a longer labor, some researchers claim that it is correlated with an increased chance of operational intervention. The clinical research data on this topic are conflicting. For example, a study in Australia (Roberts, Tracy, Peat, 2000) concluded that having an epidural reduced the woman's chances of having a vaginal birth, without further interventions (such as episiotomy, forceps, ventouse or caesarean section) from 71.4% to 37.8%. Conversely, a 2001 study by researchers at the National Institute of Child Health and Human Development and a 2002 study by researchers at Cornell University and the University of Ontario demonstrated that epidurals do not increase the likelihood of a cesarean section. In 2005, a meta-analysis of 21 studies also showed that epidurals do not increase the likelihood of cesarean section, but they do increase the chance of a forceps or ventouse delivery by 40% (Anim-Somuah, Cochrane Review, 2005). The COMET Study, published in The Lancet in 2001 (vol358, No9275 p19-23) showed that a combined spinal-epidural in labor may speed up the labor process by a few minutes, although those women receiving an epidural had a cesarean rate of 28% and only 35% had a normal birth without instrument-assisted delivery.
These differing outcomes may be explained by data that demonstrates that the likelihood of increased intervention is directly related to the quality of the institution or practitioner providing the care: epidurals administered at top-rated institutions do not generally result in a clinically significant increase in cesarean rates, whereas the risk of cesarean delivery at poorly ranked facilities seems to increase with the use of epidural[40]
An alternative explanation is that women having difficult labors are more likely to request epidurals, and are also less likely to have an unassisted vaginal birth.
## Effects on the baby
- Some mothers worry that epidural analgesia may harm their newborn. However, although epidural labor analgesia may be associated with slower progression of labor, it has no adverse effect on perinatal outcome and perinatal complications.[41]
- One study concluded that women whose epidurals contain the drug fentanyl were less likely to fully breastfeed their infant in the few days after birth and more likely to stop breastfeeding in the first 24 weeks.[42] However, this study has been criticized for several reasons, one of which is that the original patient records were not examined in this study, and so many of the epidurals were assumed to contain fentanyl when almost certainly they would not have.[43]
- In addition, all patients who used epidurals in labor had also used systemic pethidine, which would be much more likely to be the cause of any effect on breastfeeding due to the higher amounts of medication used via that route. If that were the case, then early epidurals which avoided the need for pethidine may actually improve breastfeeding outcomes, not worsen them.
# Historical notes
- Prior to 1943, there were few methods of relieving pain in childbirth without risk of harm to the baby. Caesarean sections under general anesthesia was used only as an emergency measure. Dr. Robert A. Hingson, Dr. Waldo B. Edwards, and Dr. James L. Southworth working at the United States Marine Hospital at Stapleton, on Staten Island, New York, developed the technique of continuous caudal anesthesia.[44]
- In 1912, German physicians had found that the injection of an anesthetic, at the base of the spinal cord, would prevent pain impulses from reaching the brain. Doctors in the United States developed the technique further. For expectant mothers, the injection "only reduced the pangs of childbirth; it did not eliminate them," wrote Dr. Morris Fishbein in the March 1943 issue of Hygeia, and a single nerve-blocking injection was used only toward the end of labor.[44]
- Drs. Hingson and Southworth combined the concepts of caudal analgesia and the spinal injection in an operation to strip the varicose veins of a Scottish merchant seaman. The surgeons experimented with a continuous infusion of the local anesthetic, rather than removing the needle after the injection, to originate "continuous caudal analgesia". Dr. Hingson then collaborated with Dr. Edwards, the chief obstetrician at the Marine Hospital, to study the use of this technique in childbirth. The two studied the caudal region to determine where a needle could be safely placed to deliver anesthesia to the spinal nerves without placing the drugs into the spinal fluid.
- Testing on a human being did not occur until January 6, 1942, when the wife of a Coast Guardsman was brought into the Marine Hospital for delivery. Because the woman suffered from rheumatic heart disease, general anesthesia could not be safely used for an emergency Caesarean section, and it was believed that she would not survive the stress of labor. With the use of continuous local anesthesia, the woman and her baby survived. According to Dr. Fishbein's article in Hygeia, a total of 589 women in more than twenty participating hospitals gave birth relatively painlessly in 1942.[45]
- The results were published in the January 23, 1943, issue of the Journal of the American Medical Association.[46] | https://www.wikidoc.org/index.php/Epidural | |
b9aa8cd8c9655146daf44a44cc8c087c389f89ea | wikidoc | HER2/neu | HER2/neu
Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene isolated from avian genome. It is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.
HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.
# Name
HER2 is so named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Molecular cloning of the gene showed that HER2, Neu, and ErbB-2 are all encoded by the same orthologs.
# Gene
ERBB2, a known proto-oncogene, is located at the long arm of human chromosome 17 (17q12).
# Function
The ErbB family consists of four plasma membrane-bound receptor tyrosine kinases. One of which is erbB-2, and the other members being epidermal growth factor receptor, erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4. All four contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules and exhibit both ligand-dependent and ligand-independent activity. Notably, no ligands for HER2 have yet been identified. HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.
Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.
## Signal transduction
Signaling pathways activated by HER2 include:
- mitogen-activated protein kinase (MAPK)
- phosphoinositide 3-kinase (PI3K/Akt)
- phospholipase C γ
- protein kinase C (PKC)
- Signal transducer and activator of transcription (STAT)
In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.
# Clinical significance
## Cancer
Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers. It is strongly associated with increased disease recurrence and a poor prognosis. Over-expression is also known to occur in ovarian, stomach, adenocarcinoma of the lung and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma, e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer and in 30% of salivary duct carcinomas.
HER2 is colocalised and most of the time, coamplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.
HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.
Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.
## Mutations
Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerisation of this protein in the absence of a ligand.
HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.
# As a drug target
HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2 is over-expressed. One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy. Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12. Trastuzumab is administered intravenously weekly or every 3 weeks.
An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation. Another monoclonal antibody, Pertuzumab, which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.
As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. margetuximab.
Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.
It has been found that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.
Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.
The expression of HER2 is regulated by signaling through eostrogen receptors. Normally, estradiol and tamoxifen acting through the eostrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.
# Diagnostics
## Cancer biopsy
HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy. It is important that trastuzumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity. For HER2-negative tumours, the risks of trastuzumab clearly outweigh the benefits.
Tests are usually performed on biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision. Immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Examples of this assay include HercepTest, Dako, Glostrup, and Denmark. The sample is given a score based on the cell membrane staining pattern. Specimens with equivocal IHC results should then be validated using fluorescence in situ hybridisation (FISH). FISH can be used to measure the number of copies of the gene which are present and is thought to be more reliable than IHC.
## Serum
The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy. However, its ability to determine eligibility for trastuzumab therapy is less clear.
# Interactions
HER2/neu has been shown to interact with:
- CTNNB1,
- DLG4,
- Erbin,
- GRB2,
- HSP90AA1,
- IL6ST,
- MUC1,
- PICK1 and
- PIK3R2,
- PLCG1, and
- SHC1. | HER2/neu
Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene isolated from avian genome. It is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.[1][2][3]
HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.[4]
# Name
HER2 is so named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ErbB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Molecular cloning of the gene showed that HER2, Neu, and ErbB-2 are all encoded by the same orthologs.[5]
# Gene
ERBB2, a known proto-oncogene, is located at the long arm of human chromosome 17 (17q12).
# Function
The ErbB family consists of four plasma membrane-bound receptor tyrosine kinases. One of which is erbB-2, and the other members being epidermal growth factor receptor, erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4. All four contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules and exhibit both ligand-dependent and ligand-independent activity. Notably, no ligands for HER2 have yet been identified.[6][7] HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.[8]
Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.
## Signal transduction
Signaling pathways activated by HER2 include:[9]
- mitogen-activated protein kinase (MAPK)
- phosphoinositide 3-kinase (PI3K/Akt)
- phospholipase C γ
- protein kinase C (PKC)
- Signal transducer and activator of transcription (STAT)
In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.
# Clinical significance
## Cancer
Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.[4][10] It is strongly associated with increased disease recurrence and a poor prognosis.[11] Over-expression is also known to occur in ovarian,[12] stomach, adenocarcinoma of the lung[13] and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma,[14][15] e.g. HER-2 is over-expressed in approximately 7-34% of patients with gastric cancer[16][17] and in 30% of salivary duct carcinomas.[18]
HER2 is colocalised and most of the time, coamplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.
HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.[19][20]
Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[21]
## Mutations
Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerisation of this protein in the absence of a ligand.[22]
HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.[23]
# As a drug target
HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2 is over-expressed. One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy.[24] Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12. Trastuzumab is administered intravenously weekly or every 3 weeks.[25]
An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.[26] Another monoclonal antibody, Pertuzumab, which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.
As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. margetuximab.[27]
Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.
It has been found that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.[28]
Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.
The expression of HER2 is regulated by signaling through eostrogen receptors. Normally, estradiol and tamoxifen acting through the eostrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.[29][30]
# Diagnostics
## Cancer biopsy
HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy. It is important that trastuzumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity.[31] For HER2-negative tumours, the risks of trastuzumab clearly outweigh the benefits.
Tests are usually performed on biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision. Immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Examples of this assay include HercepTest, Dako, Glostrup, and Denmark. The sample is given a score based on the cell membrane staining pattern. Specimens with equivocal IHC results should then be validated using fluorescence in situ hybridisation (FISH). FISH can be used to measure the number of copies of the gene which are present and is thought to be more reliable than IHC.[32]
## Serum
The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy.[33] However, its ability to determine eligibility for trastuzumab therapy is less clear.[34]
# Interactions
HER2/neu has been shown to interact with:
- CTNNB1,[35][36][37]
- DLG4,[38]
- Erbin,[39][40][41]
- GRB2,[42][43][44]
- HSP90AA1,[45][46]
- IL6ST,[47]
- MUC1,[48][49]
- PICK1[39] and
- PIK3R2,[50]
- PLCG1,[51][52] and
- SHC1.[42][44][53] | https://www.wikidoc.org/index.php/ErbB-2_receptor | |
e426eddc2f03835c077c7fbfff8c478afde7c360 | wikidoc | Erection | Erection
# Overview
The erection of the penis, clitoris or a nipple is its enlarged and firm state. It depends on a complex interaction of psychological, neural, vascular and endocrine factors.
The ability to maintain the erectile state is key to the reproductive system and many forms of life could not reproduce in a natural way without this ability.
# Penis erection
A penis erection occurs when two tubular structures that run the length of the penis, the corpora cavernosa, become engorged with venous blood. This may result from any of various physiological stimuli, also known as sexual arousal. The corpus spongiosum is a single tubular structure located just below the corpora cavernosa, which contains the urethra, through which urine and semen pass during urination and ejaculation, respectively. This may also become slightly engorged with blood, but less so than the corpora cavernosa. After a man has ejaculated during sexual encounter or masturbation, his erection usually ends, but this may take time depending on the length and thickness of the penis.
Penis erection usually results from exposure to sexual stimulation from sexual arousal, but can also occur by such causes as a full urinary bladder or spontaneously during the course of a day or at night, often during REM sleep (see "nocturnal penile tumescence"). An erection results in swelling, hardening and enlargement of the penis. Erection enables sexual intercourse and other sexual activities (sexual functions), though it is not essential for all sexual activities. An erection may also occur once woken up, called nocturnal penile tumescence. The scrotum may also become tightened during an erection.
## Autonomic control
In the presence of mechanical stimulation, erection is initiated by the parasympathetic division of the autonomic nervous system (ANS) with minimal input from the central nervous system. Parasympathetic branches extend from the sacral plexus into the arteries supplying the erectile tissue; upon stimulation, these nerve branches initiate the release of nitric oxide, a vasodilating agent, in the target arteries. The arteries dilate, filling the corpora spongiosum and cavernosa with blood. Erection subsides when parasympathetic stimulation is discontinued; baseline stimulation from the sympathetic division of the ANS causes constriction of the penile arteries, forcing blood out of the erectile tissue.
The cerebral cortex can initiate erection in the absence of direct mechanical stimulation (in response to visual, auditory, olfactory, imagined, or tactile stimuli) acting through erectile centers in the lumbar and sacral regions of the spinal cord. The cortex can suppress erection even in the presence of mechanical stimulation, as can other psychological, emotional, and environmental factors.
The opposite term is detumescence.
## Shape and size
An erect penis can take on a number of different shapes and angles, ranging from a straight tube angled at a 45-90 degree angle, to a curvature to the left or right (see image), up or down. A tightly curved penis, known as Peyronie's disease, is identified by a severe curve in the erect penis. This may cause physical and psychological effects for the affected individual, which could include erectile dysfunction or pain during erection. Treatments include oral medication (such as Vitamin E) or surgery, which is most often reserved as a last resort.
Generally the size of an erect penis is fixed throughout post-pubescent life. Its size may be increased by surgery, although the procedure is controversial, and mostly the results are disappointing. Penile enlargement is a controversial subject. See Penis enlargement.
## Erectile dysfunction
Erectile dysfunction (also known as ED or '(male) impotence') is a sexual dysfunction characterized by the inability to develop or maintain an erection. It can occur due to both physiological and psychological reasons, most of which are amenable to treatment. Common physiological reasons include cardiovascular leakage and diabetes. Some drugs also may cause erectile dysfunction in patients who received them such as lithium, paroxetine, etc.
Erectile dysfunction, tied closely as it is to cultural notions of potency, success and masculinity, can have devastating psychological consequences including feelings of shame, loss or inadequacy; often unnecessary since in most cases the matter can be helped. There is a strong culture of silence and inability to discuss the matter. In fact around 1 in 10 men will experience recurring impotence problems at some point in their lives.
The study of erectile dysfunction within medicine is covered by andrology, a sub-field within urology.
# Clitoral erection
Clitoral erection is a part of sexual arousal in women. The clitoris is the anatomically homologous counterpart of the penis, and the physiological mechanism of its erection is similar.
Swelling and enlargement may also occur during a clitoral erection but because a large proportion of the clitoris is within the body and its drastically reduced size, it is often not as obvious.
# Nipple erection
Nipple erection may result from three kinds of response. It happens in females during breast feeding. It is also an early part of the sexual response in females and males. Both of these are caused by the release of oxytocin. Nipple erection can also be caused by a tactile response to cold temperature in both males and females. The erection of nipples is not due to erectile tissue, but due to the contraction of smooth muscle under the control of the autonomic nervous system. It is more akin to a hair follicle standing on end than to a sexual erection. | Erection
# Overview
The erection of the penis, clitoris or a nipple is its enlarged and firm state. It depends on a complex interaction of psychological, neural, vascular and endocrine factors.
The ability to maintain the erectile state is key to the reproductive system and many forms of life could not reproduce in a natural way without this ability.
# Penis erection
A penis erection occurs when two tubular structures that run the length of the penis, the corpora cavernosa, become engorged with venous blood. This may result from any of various physiological stimuli, also known as sexual arousal. The corpus spongiosum is a single tubular structure located just below the corpora cavernosa, which contains the urethra, through which urine and semen pass during urination and ejaculation, respectively. This may also become slightly engorged with blood, but less so than the corpora cavernosa. After a man has ejaculated during sexual encounter or masturbation, his erection usually ends, but this may take time depending on the length and thickness of the penis.[1]
Penis erection usually results from exposure to sexual stimulation from sexual arousal, but can also occur by such causes as a full urinary bladder or spontaneously during the course of a day or at night, often during REM sleep (see "nocturnal penile tumescence"). An erection results in swelling, hardening and enlargement of the penis. Erection enables sexual intercourse and other sexual activities (sexual functions), though it is not essential for all sexual activities. An erection may also occur once woken up, called nocturnal penile tumescence. The scrotum may also become tightened during an erection.
## Autonomic control
In the presence of mechanical stimulation, erection is initiated by the parasympathetic division of the autonomic nervous system (ANS) with minimal input from the central nervous system. Parasympathetic branches extend from the sacral plexus into the arteries supplying the erectile tissue; upon stimulation, these nerve branches initiate the release of nitric oxide, a vasodilating agent, in the target arteries. The arteries dilate, filling the corpora spongiosum and cavernosa with blood. Erection subsides when parasympathetic stimulation is discontinued; baseline stimulation from the sympathetic division of the ANS causes constriction of the penile arteries, forcing blood out of the erectile tissue.[2]
The cerebral cortex can initiate erection in the absence of direct mechanical stimulation (in response to visual, auditory, olfactory, imagined, or tactile stimuli) acting through erectile centers in the lumbar and sacral regions of the spinal cord. The cortex can suppress erection even in the presence of mechanical stimulation, as can other psychological, emotional, and environmental factors.
The opposite term is detumescence.
## Shape and size
An erect penis can take on a number of different shapes and angles, ranging from a straight tube angled at a 45-90 degree angle, to a curvature to the left or right (see image), up or down. A tightly curved penis, known as Peyronie's disease, is identified by a severe curve in the erect penis. This may cause physical and psychological effects for the affected individual, which could include erectile dysfunction or pain during erection. Treatments include oral medication (such as Vitamin E) or surgery, which is most often reserved as a last resort.
Generally the size of an erect penis is fixed throughout post-pubescent life. Its size may be increased by surgery[3], although the procedure is controversial, and mostly the results are disappointing.[4] Penile enlargement is a controversial subject. See Penis enlargement.
## Erectile dysfunction
Erectile dysfunction (also known as ED or '(male) impotence') is a sexual dysfunction characterized by the inability to develop or maintain an erection.[5][6] It can occur due to both physiological and psychological reasons, most of which are amenable to treatment. Common physiological reasons include cardiovascular leakage and diabetes. Some drugs also may cause erectile dysfunction in patients who received them such as lithium, paroxetine, etc.[7][6]
Erectile dysfunction, tied closely as it is to cultural notions of potency, success and masculinity, can have devastating psychological consequences including feelings of shame, loss or inadequacy[8]; often unnecessary since in most cases the matter can be helped. There is a strong culture of silence and inability to discuss the matter. In fact around 1 in 10 men will experience recurring impotence problems at some point in their lives.[9]
The study of erectile dysfunction within medicine is covered by andrology, a sub-field within urology.[10]
# Clitoral erection
Clitoral erection is a part of sexual arousal in women. The clitoris is the anatomically homologous counterpart of the penis, and the physiological mechanism of its erection is similar.
Swelling and enlargement may also occur during a clitoral erection but because a large proportion of the clitoris is within the body and its drastically reduced size, it is often not as obvious.
# Nipple erection
Nipple erection may result from three kinds of response. It happens in females during breast feeding. It is also an early part of the sexual response in females and males. Both of these are caused by the release of oxytocin. Nipple erection can also be caused by a tactile response to cold temperature in both males and females. The erection of nipples is not due to erectile tissue, but due to the contraction of smooth muscle under the control of the autonomic nervous system. It is more akin to a hair follicle standing on end than to a sexual erection. | https://www.wikidoc.org/index.php/Erect | |
1a4f204a9c58c1b594332dc57c8d45a9ade2ab13 | wikidoc | Erenumab | Erenumab
# Disclaimer
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# Overview
Erenumab is a calcitonin gene-related peptide receptor antagonist that is FDA approved for the preventive treatment of migraine in adults. Common adverse reactions include injection site reactions and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Erenumab is indicated for the preventive treatment of migraine in adults.
- The recommended dosage of Erenumab is 70 mg injected subcutaneously once monthly. Some patients may benefit from a dosage of 140 mg injected subcutaneously once monthly, which is administered as two consecutive subcutaneous injections of 70 mg each.
- If a dose of Erenumab is missed, administer as soon as possible. Thereafter, Erenumab can be scheduled monthly from the date of the last dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Erenumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Erenumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Erenumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Erenumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Erenumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
There is limited information regarding Erenumab Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of Erenumab has been evaluated in 2,537 patients with migraine who received at least one dose of Erenumab, representing 2,310 patient-years of exposure. Of these, 2,057 patients were exposed to 70 mg or 140 mg once monthly for at least 6 months, 1,198 patients were exposed for at least 12 months, and 287 patients were exposed for at least 18 months.
- In placebo-controlled clinical studies (Studies 1, 2, and 3) of 2,184 patients, 787 patients received at least one dose of Erenumab 70 mg once monthly, 507 patients received at least one dose of Erenumab 140 mg once monthly, and 890 patients received placebo during 3 months or 6 months of double-blind treatment. Approximately 84% were female, 91% were white, and the mean age was 42 years at study entry.
- The most common adverse reactions (incidence ≥ 3% and more often than placebo) in the migraine studies were injection site reactions and constipation. Table 1 summarizes the adverse reactions that occurred during the first 3 months in the migraine studies (Studies 1, 2, and 3).
- In Studies 1, 2, and 3, 1.3% of patients treated with Erenumab discontinued double-blind treatment because of adverse events. The most frequent injection site reactions were injection site pain, injection site erythema, and injection site pruritus.
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation, including neutralizing antibodies, 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 Erenumab-aooe in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- The immunogenicity of Erenumab has been evaluated using an immunoassay for the detection of binding anti-Erenumab-aooe antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
- In controlled studies with Erenumab, the incidence of anti-Erenumab-aooe antibody development was 6.2% (48/778) in patients receiving Erenumab 70 mg once monthly (2 of whom had in vitro neutralizing activity) and 2.6% (13/504) in patients receiving Erenumab 140 mg once monthly (none of whom had in vitro neutralizing activity). The neutralizing anti-Erenumab-aooe antibody positive rate may be underestimated because of limitations of the assay. Although these data do not demonstrate an impact of anti-Erenumab-aooe antibody development on the efficacy or safety of Erenumab in these patients, the available data are too limited to make definitive conclusions.
## Postmarketing Experience
There is limited information regarding Erenumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Erenumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no adequate data on the developmental risk associated with the use of Erenumab in pregnant women. No adverse effects on offspring were observed when pregnant monkeys were administered Erenumab-aooe throughout gestation. Serum Erenumab-aooe exposures in pregnant monkeys were greater than those in humans at clinical doses.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The estimated rate of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
- Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.
Data (Animal)
- In a study in which female monkeys were administered Erenumab-aooe (0 or 50 mg/kg) twice weekly by subcutaneous injection throughout pregnancy (gestation day 20-22 to parturition), no adverse effects on offspring were observed. Serum Erenumab-aooe exposures (AUC) in pregnant monkeys were approximately 20 times that in humans at a dose of 140 mg once monthly.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Erenumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Erenumab during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of Erenumab-aooe in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Erenumab and any potential adverse effects on the breastfed infant from Erenumab or from the underlying maternal condition.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of Erenumab did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Erenumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Erenumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Erenumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Erenumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Erenumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Erenumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Erenumab is for subcutaneous use only.
- The needle shield within the white cap of the Erenumab prefilled autoinjector and gray needle cap of the Erenumab prefilled syringe contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
- Erenumab is intended for patient self-administration. Prior to use, provide proper training to patients and/or caregivers on how to prepare and administer Erenumab using the single-dose prefilled autoinjector or single-dose prefilled syringe, including aseptic technique.
- Prior to subcutaneous administration, allow Erenumab to sit at room temperature for at least 30 minutes protected from direct sunlight . Do not warm by using a heat source such as hot water or a microwave.
- Do not shake the product.
- Inspect visually for particulate matter and discoloration prior to administration . Do not use if the solution is cloudy or discolored or contains flakes or particles.
- Administer Erenumab in the abdomen, thigh, or upper arm subcutaneously. Do not inject into areas where the skin is tender, bruised, red, or hard.
- Both prefilled autoinjector and prefilled syringe are single-dose and deliver the entire contents.
### Monitoring
There is limited information regarding Erenumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Erenumab and IV administrations.
# Overdosage
There is limited information regarding Erenumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Erenumab-aooe is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function.
## Structure
There is limited information regarding Erenumab Structure in the drug label.
## Pharmacodynamics
- In a randomized, double-blind, placebo-controlled study in healthy volunteers, concomitant administration of Erenumab-aooe (140 mg intravenous, single-dose) with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) had no effect on resting blood pressure compared with sumatriptan alone. Erenumab is for subcutaneous use only.
## Pharmacokinetics
- Erenumab-aooe exhibits non-linear kinetics as a result of binding to the CGRP receptor. The Cmax mean and AUClast mean following subcutaneous administration of a 70 mg once monthly and a 140 mg once monthly dose in healthy volunteers or migraine patients are included in Table 2.
- Less than 2-fold accumulation was observed in trough serum concentrations (Cmin) for episodic and chronic migraine patients following subcutaneous administration of 70 mg once monthly and 140 mg once monthly doses (see Table 2). Serum trough concentrations approached steady state by 3 months of dosing. The effective half-life of Erenumab-aooe is 28 days.
Absorption
- Following a single subcutaneous dose of 70 mg or 140 mg Erenumab-aooe administered to healthy adults, median peak serum concentrations were attained in approximately 6 days, and estimated absolute bioavailability was 82%.
Distribution
- Following a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminal phase (Vz) was estimated to be 3.86 (0.77) L.
Metabolism and Excretion
- Two elimination phases were observed for Erenumab-aooe. At low concentrations, the elimination is predominantly through saturable binding to target (CGRP receptor), while at higher concentrations the elimination of Erenumab-aooe is largely through a non-specific, non-saturable proteolytic pathway.
Specific Populations
- The pharmacokinetics of Erenumab-aooe were not affected by age, gender, race, or subtypes of migraine spectrum (episodic or chronic migraine) based on population pharmacokinetics analysis.
Patients with Renal or Hepatic Impairment
- Population pharmacokinetic analysis of integrated data from the Erenumab clinical studies did not reveal a difference in the pharmacokinetics of Erenumab-aooe in patients with mild or moderate renal impairment relative to those with normal renal function. Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) have not been studied. No dedicated clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of Erenumab-aooe. Renal or hepatic impairment is not expected to affect pharmacokinetics of Erenumab-aooe.
Drug Interaction Studies
P450 Enzymes
- Erenumab-aooe is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
Oral Contraceptives
- In an open-label drug interaction study in healthy female volunteers, Erenumab-aooe (140 mg subcutaneous, single-dose) did not affect the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate.
Sumatriptan
- In a study in healthy volunteers, concomitant administration of Erenumab-aooe with sumatriptan had no effect on the pharmacokinetics of sumatriptan.
## Nonclinical Toxicology
Carcinogenesis
- The carcinogenic potential of Erenumab-aooe has not been assessed.
Mutagenesis
- Genetic toxicology studies of Erenumab-aooe have not been conducted.
Impairment of Fertility
- Mating studies have not been conducted on Erenumab-aooe. No histopathological changes in male or female reproductive organs were observed in monkeys administered Erenumab-aooe (0, 25, or 150 mg/kg) by subcutaneous injection twice weekly for up to 6 months. Serum Erenumab-aooe exposures (AUC) at the higher dose tested were more than 100 times that in humans at a dose of 140 mg once monthly.
# Clinical Studies
- The efficacy of Erenumab was evaluated as a preventive treatment of episodic or chronic migraine in three randomized, double-blind, placebo-controlled studies: two studies in patients with episodic migraine (4 to 14 migraine days per month) (Study 1 and Study 2) and one study in patients with chronic migraine (≥ 15 headache days per month with ≥ 8 migraine days per month) (Study 3). The studies enrolled patients with a history of migraine, with or without aura, according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria.
- Study 1 (NCT 02456740) was a randomized, multi-center, 6-month, placebo-controlled, double-blind study evaluating Erenumab for the preventive treatment of episodic migraine. A total of 955 patients with a history of episodic migraine were randomized to receive either Erenumab 70 mg (N = 317), Erenumab 140 mg (N = 319), or placebo (N = 319) by subcutaneous injection once monthly (QM) for 6 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.
- The study excluded patients with medication overuse headache as well as patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening.
- The primary efficacy endpoint was the change from baseline in mean monthly migraine days over months 4 to 6. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in mean monthly migraine days over months 4 to 6 (“≥ 50% MMD responders”), the change from baseline in mean monthly acute migraine-specific medication days over months 4 to 6, and the change from baseline in mean Migraine Physical Function Impact Diary (MPFID) over months 4 to 6. The MPFID measures the impact of migraine on everyday activities (EA) and physical impairment (PI) using an electronic diary administered daily. Monthly MPFID scores are averaged over 28 days, including days with and without migraine; scores are scaled from 0 to 100. Higher scores indicate worse impact on EA and PI. Reductions from baseline in MPFID scores indicate improvement.
- A total of 858 (90%) patients completed the 6-month double-blind study. Patients had a median age of 42 years (range: 18 to 65 years), 85% were female, and 89% were white. Three percent of patients were taking concomitant preventive treatments for migraine. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups.
- Erenumab treatment demonstrated statistically significant improvements for key efficacy endpoints compared to placebo, as summarized in Table 3.
- Figure 2 shows the distribution of change from baseline in mean monthly migraine days over months 4 to 6 in bins of 2 days by treatment group. A treatment benefit over placebo for both doses of Erenumab is seen across a range of changes from baseline in monthly migraine days.
- Compared to placebo, patients treated with Erenumab 70 mg once monthly and 140 mg once monthly showed greater reductions from baseline in mean monthly MPFID everyday activity scores averaged over months 4 to 6 , and in mean monthly MPFID physical impairment scores averaged over months 4 to 6 .
- Study 2 (NCT 02483585) was a randomized, multi-center, 3-month, placebo-controlled, double-blind study evaluating Erenumab for the preventive treatment of episodic migraine. A total of 577 patients with a history of episodic migraine were randomized to receive either Erenumab 70 mg (N = 286) or placebo (N = 291) by subcutaneous injection once monthly for 3 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.
- The study excluded patients with medication overuse headache as well as patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening.
- The primary efficacy endpoint was the change from baseline in monthly migraine days at month 3. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in monthly migraine days (“≥ 50% MMD responders”), the change from baseline in monthly acute migraine-specific medication days at month 3, and the proportion of patients with at least a 5-point score reduction from baseline in MPFID at month 3.
- A total of 546 (95%) patients completed the 3-month double-blind study. Patients had a median age of 43 years (range: 18 to 65 years), 85% were female, and 90% were white. Six to seven percent of patients were taking concomitant preventive migraine treatment. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar between treatment groups.
- Erenumab treatment demonstrated statistically significant improvements for key efficacy endpoints compared to placebo, as summarized in Table 4.
- Figure 4 shows the distribution of change from baseline in monthly migraine days at month 3 in bins of 2 days by treatment group. A treatment benefit over placebo for Erenumab is seen across a range of changes from baseline in monthly migraine days.
- The pre-specified analysis for the MPFID was based on at least a 5-point reduction within-patient responder definition. Erenumab 70 mg once monthly was not significantly better than placebo for the proportion of responders for everyday activity and physical impairment . In an exploratory analysis of the change from baseline in the mean MPFID scores at month 3, patients treated with Erenumab 70 mg, as compared to placebo, showed nominally greater reductions of physical impairment scores , but not of everyday activities scores .
Chronic Migraine
- Study 3 (NCT 02066415) was a randomized, multi-center, 3-month, placebo-controlled, double-blind study evaluating Erenumab as a preventive treatment of chronic migraine. A total of 667 patients with a history of chronic migraine with or without aura were randomized to receive Erenumab 70 mg (N = 191), Erenumab 140 mg (N = 190), or placebo (N = 286) by subcutaneous injections once monthly for 3 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.
- The study excluded patients with medication overuse headache caused by opiate overuse and patients with concurrent use of migraine preventive treatments. Patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening were also excluded.
- The primary efficacy endpoint was the change from baseline in monthly migraine days at month 3. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in monthly migraine days (“≥ 50% MMD responders”) and change from baseline in monthly acute migraine-specific medication days at month 3.
- A total of 631 (95%) patients completed the 3-month double-blind study. Patients had a median age of 43 years (range: 18 to 66 years), 83% were female, and 94% were white. The mean migraine frequency at baseline was approximately 18 migraine days per month and was similar across treatment groups.
- Erenumab treatment demonstrated statistically significant improvements for key efficacy outcomes compared to placebo, as summarized in Table 5.
- Figure 6 shows the distribution of change from baseline in monthly migraine days at month 3 in bins of 3 days by treatment group. A treatment benefit over placebo for both doses of Erenumab is seen across a range of changes from baseline in migraine days.
# How Supplied
- Erenumab (Erenumab-aooe) injection is a sterile, clear to opalescent, colorless to light yellow solution for subcutaneous administration.
- The needle shield within the white cap of the Erenumab prefilled autoinjector and gray needle cap of the Erenumab prefilled syringe contain dry natural rubber (a derivative of latex). Each single-dose prefilled SureClick® autoinjector or single-dose prefilled syringe of Erenumab contains a Type 1 glass syringe and stainless steel needle and delivers 1 mL of 70 mg/mL solution.
- Erenumab is supplied as follows:
SureClick® Autoinjector
- Pack of 1 autoinjector: 70 mg/mL single-dose prefilled autoinjector NDC 55513-841-01.
- Pack of 2 autoinjectors: 140 mg/2 mL (2 x 70 mg/mL single-dose prefilled autoinjectors) NDC 55513-841-02
Syringe
- Pack of 1 syringe: 70 mg/mL single-dose prefilled syringe NDC 55513-840-01
- Pack of 2 syringes: 140 mg/2 mL (2 x 70 mg/mL single-dose prefilled syringes) NDC 55513-840-02
## Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use.
- If removed from the refrigerator, Erenumab should be kept at room temperature (up to 25°C ) in the original carton and must be used within 7 days. Throw away Erenumab that has been left at room temperature for more than 7 days.
- Do not freeze.
- Do not shake.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information on Preparation and Administration:
- Provide guidance to patients and caregivers on proper subcutaneous administration technique, including aseptic technique, and how to use the single-dose prefilled autoinjector or single-dose prefilled syringe. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use Erenumab.
- Instruct patients prescribed 140 mg to administer the once monthly dosage as two separate subcutaneous injections of 70 mg each.
- Advise latex-sensitive patients that the needle shield within the white cap of the Erenumab prefilled autoinjector and gray needle cap of the Erenumab prefilled syringe contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex.
# Precautions with Alcohol
Alcohol-Erenumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Aimovig
# Look-Alike Drug Names
There is limited information regarding Erenumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Erenumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2];
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# Overview
Erenumab is a calcitonin gene-related peptide receptor antagonist that is FDA approved for the preventive treatment of migraine in adults. Common adverse reactions include injection site reactions and constipation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Erenumab is indicated for the preventive treatment of migraine in adults.
- The recommended dosage of Erenumab is 70 mg injected subcutaneously once monthly. Some patients may benefit from a dosage of 140 mg injected subcutaneously once monthly, which is administered as two consecutive subcutaneous injections of 70 mg each.
- If a dose of Erenumab is missed, administer as soon as possible. Thereafter, Erenumab can be scheduled monthly from the date of the last dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Erenumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Erenumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Erenumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Erenumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Erenumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
There is limited information regarding Erenumab Warnings' in the drug label.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- The safety of Erenumab has been evaluated in 2,537 patients with migraine who received at least one dose of Erenumab, representing 2,310 patient-years of exposure. Of these, 2,057 patients were exposed to 70 mg or 140 mg once monthly for at least 6 months, 1,198 patients were exposed for at least 12 months, and 287 patients were exposed for at least 18 months.
- In placebo-controlled clinical studies (Studies 1, 2, and 3) of 2,184 patients, 787 patients received at least one dose of Erenumab 70 mg once monthly, 507 patients received at least one dose of Erenumab 140 mg once monthly, and 890 patients received placebo during 3 months or 6 months of double-blind treatment. Approximately 84% were female, 91% were white, and the mean age was 42 years at study entry.
- The most common adverse reactions (incidence ≥ 3% and more often than placebo) in the migraine studies were injection site reactions and constipation. Table 1 summarizes the adverse reactions that occurred during the first 3 months in the migraine studies (Studies 1, 2, and 3).
- In Studies 1, 2, and 3, 1.3% of patients treated with Erenumab discontinued double-blind treatment because of adverse events. The most frequent injection site reactions were injection site pain, injection site erythema, and injection site pruritus.
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation, including neutralizing antibodies, 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 Erenumab-aooe in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- The immunogenicity of Erenumab has been evaluated using an immunoassay for the detection of binding anti-Erenumab-aooe antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
- In controlled studies with Erenumab, the incidence of anti-Erenumab-aooe antibody development was 6.2% (48/778) in patients receiving Erenumab 70 mg once monthly (2 of whom had in vitro neutralizing activity) and 2.6% (13/504) in patients receiving Erenumab 140 mg once monthly (none of whom had in vitro neutralizing activity). The neutralizing anti-Erenumab-aooe antibody positive rate may be underestimated because of limitations of the assay. Although these data do not demonstrate an impact of anti-Erenumab-aooe antibody development on the efficacy or safety of Erenumab in these patients, the available data are too limited to make definitive conclusions.
## Postmarketing Experience
There is limited information regarding Erenumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Erenumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no adequate data on the developmental risk associated with the use of Erenumab in pregnant women. No adverse effects on offspring were observed when pregnant monkeys were administered Erenumab-aooe throughout gestation. Serum Erenumab-aooe exposures in pregnant monkeys were greater than those in humans at clinical doses.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The estimated rate of major birth defects (2.2%-2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
- Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.
Data (Animal)
- In a study in which female monkeys were administered Erenumab-aooe (0 or 50 mg/kg) twice weekly by subcutaneous injection throughout pregnancy (gestation day 20-22 to parturition), no adverse effects on offspring were observed. Serum Erenumab-aooe exposures (AUC) in pregnant monkeys were approximately 20 times that in humans at a dose of 140 mg once monthly.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Erenumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Erenumab during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of Erenumab-aooe in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Erenumab and any potential adverse effects on the breastfed infant from Erenumab or from the underlying maternal condition.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of Erenumab did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Erenumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Erenumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Erenumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Erenumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Erenumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Erenumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Erenumab is for subcutaneous use only.
- The needle shield within the white cap of the Erenumab prefilled autoinjector and gray needle cap of the Erenumab prefilled syringe contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
- Erenumab is intended for patient self-administration. Prior to use, provide proper training to patients and/or caregivers on how to prepare and administer Erenumab using the single-dose prefilled autoinjector or single-dose prefilled syringe, including aseptic technique.
- Prior to subcutaneous administration, allow Erenumab to sit at room temperature for at least 30 minutes protected from direct sunlight [see How Supplied/Storage and Handling (16.2)]. Do not warm by using a heat source such as hot water or a microwave.
- Do not shake the product.
- Inspect visually for particulate matter and discoloration prior to administration [see Dosage Forms and Strengths (3)]. Do not use if the solution is cloudy or discolored or contains flakes or particles.
- Administer Erenumab in the abdomen, thigh, or upper arm subcutaneously. Do not inject into areas where the skin is tender, bruised, red, or hard.
- Both prefilled autoinjector and prefilled syringe are single-dose and deliver the entire contents.
### Monitoring
There is limited information regarding Erenumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Erenumab and IV administrations.
# Overdosage
There is limited information regarding Erenumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Erenumab-aooe is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function.
## Structure
There is limited information regarding Erenumab Structure in the drug label.
## Pharmacodynamics
- In a randomized, double-blind, placebo-controlled study in healthy volunteers, concomitant administration of Erenumab-aooe (140 mg intravenous, single-dose) with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) had no effect on resting blood pressure compared with sumatriptan alone. Erenumab is for subcutaneous use only.
## Pharmacokinetics
- Erenumab-aooe exhibits non-linear kinetics as a result of binding to the CGRP receptor. The Cmax mean and AUClast mean following subcutaneous administration of a 70 mg once monthly and a 140 mg once monthly dose in healthy volunteers or migraine patients are included in Table 2.
- Less than 2-fold accumulation was observed in trough serum concentrations (Cmin) for episodic and chronic migraine patients following subcutaneous administration of 70 mg once monthly and 140 mg once monthly doses (see Table 2). Serum trough concentrations approached steady state by 3 months of dosing. The effective half-life of Erenumab-aooe is 28 days.
Absorption
- Following a single subcutaneous dose of 70 mg or 140 mg Erenumab-aooe administered to healthy adults, median peak serum concentrations were attained in approximately 6 days, and estimated absolute bioavailability was 82%.
Distribution
- Following a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminal phase (Vz) was estimated to be 3.86 (0.77) L.
Metabolism and Excretion
- Two elimination phases were observed for Erenumab-aooe. At low concentrations, the elimination is predominantly through saturable binding to target (CGRP receptor), while at higher concentrations the elimination of Erenumab-aooe is largely through a non-specific, non-saturable proteolytic pathway.
Specific Populations
- The pharmacokinetics of Erenumab-aooe were not affected by age, gender, race, or subtypes of migraine spectrum (episodic or chronic migraine) based on population pharmacokinetics analysis.
Patients with Renal or Hepatic Impairment
- Population pharmacokinetic analysis of integrated data from the Erenumab clinical studies did not reveal a difference in the pharmacokinetics of Erenumab-aooe in patients with mild or moderate renal impairment relative to those with normal renal function. Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) have not been studied. No dedicated clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of Erenumab-aooe. Renal or hepatic impairment is not expected to affect pharmacokinetics of Erenumab-aooe.
Drug Interaction Studies
P450 Enzymes
- Erenumab-aooe is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
Oral Contraceptives
- In an open-label drug interaction study in healthy female volunteers, Erenumab-aooe (140 mg subcutaneous, single-dose) did not affect the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate.
Sumatriptan
- In a study in healthy volunteers, concomitant administration of Erenumab-aooe with sumatriptan had no effect on the pharmacokinetics of sumatriptan.
## Nonclinical Toxicology
Carcinogenesis
- The carcinogenic potential of Erenumab-aooe has not been assessed.
Mutagenesis
- Genetic toxicology studies of Erenumab-aooe have not been conducted.
Impairment of Fertility
- Mating studies have not been conducted on Erenumab-aooe. No histopathological changes in male or female reproductive organs were observed in monkeys administered Erenumab-aooe (0, 25, or 150 mg/kg) by subcutaneous injection twice weekly for up to 6 months. Serum Erenumab-aooe exposures (AUC) at the higher dose tested were more than 100 times that in humans at a dose of 140 mg once monthly.
# Clinical Studies
- The efficacy of Erenumab was evaluated as a preventive treatment of episodic or chronic migraine in three randomized, double-blind, placebo-controlled studies: two studies in patients with episodic migraine (4 to 14 migraine days per month) (Study 1 and Study 2) and one study in patients with chronic migraine (≥ 15 headache days per month with ≥ 8 migraine days per month) (Study 3). The studies enrolled patients with a history of migraine, with or without aura, according to the International Classification of Headache Disorders (ICHD-III) diagnostic criteria.
- Study 1 (NCT 02456740) was a randomized, multi-center, 6-month, placebo-controlled, double-blind study evaluating Erenumab for the preventive treatment of episodic migraine. A total of 955 patients with a history of episodic migraine were randomized to receive either Erenumab 70 mg (N = 317), Erenumab 140 mg (N = 319), or placebo (N = 319) by subcutaneous injection once monthly (QM) for 6 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.
- The study excluded patients with medication overuse headache as well as patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening.
- The primary efficacy endpoint was the change from baseline in mean monthly migraine days over months 4 to 6. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in mean monthly migraine days over months 4 to 6 (“≥ 50% MMD responders”), the change from baseline in mean monthly acute migraine-specific medication days over months 4 to 6, and the change from baseline in mean Migraine Physical Function Impact Diary (MPFID) over months 4 to 6. The MPFID measures the impact of migraine on everyday activities (EA) and physical impairment (PI) using an electronic diary administered daily. Monthly MPFID scores are averaged over 28 days, including days with and without migraine; scores are scaled from 0 to 100. Higher scores indicate worse impact on EA and PI. Reductions from baseline in MPFID scores indicate improvement.
- A total of 858 (90%) patients completed the 6-month double-blind study. Patients had a median age of 42 years (range: 18 to 65 years), 85% were female, and 89% were white. Three percent of patients were taking concomitant preventive treatments for migraine. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups.
- Erenumab treatment demonstrated statistically significant improvements for key efficacy endpoints compared to placebo, as summarized in Table 3.
- Figure 2 shows the distribution of change from baseline in mean monthly migraine days over months 4 to 6 in bins of 2 days by treatment group. A treatment benefit over placebo for both doses of Erenumab is seen across a range of changes from baseline in monthly migraine days.
- Compared to placebo, patients treated with Erenumab 70 mg once monthly and 140 mg once monthly showed greater reductions from baseline in mean monthly MPFID everyday activity scores averaged over months 4 to 6 [difference from placebo: -2.2 for Erenumab 70 mg and -2.6 for Erenumab 140 mg; p-value < 0.001 for both], and in mean monthly MPFID physical impairment scores averaged over months 4 to 6 [difference from placebo: -1.9 for Erenumab 70 mg and -2.4 for Erenumab 140 mg; p-value < 0.001 for both].
- Study 2 (NCT 02483585) was a randomized, multi-center, 3-month, placebo-controlled, double-blind study evaluating Erenumab for the preventive treatment of episodic migraine. A total of 577 patients with a history of episodic migraine were randomized to receive either Erenumab 70 mg (N = 286) or placebo (N = 291) by subcutaneous injection once monthly for 3 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.
- The study excluded patients with medication overuse headache as well as patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening.
- The primary efficacy endpoint was the change from baseline in monthly migraine days at month 3. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in monthly migraine days (“≥ 50% MMD responders”), the change from baseline in monthly acute migraine-specific medication days at month 3, and the proportion of patients with at least a 5-point score reduction from baseline in MPFID at month 3.
- A total of 546 (95%) patients completed the 3-month double-blind study. Patients had a median age of 43 years (range: 18 to 65 years), 85% were female, and 90% were white. Six to seven percent of patients were taking concomitant preventive migraine treatment. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar between treatment groups.
- Erenumab treatment demonstrated statistically significant improvements for key efficacy endpoints compared to placebo, as summarized in Table 4.
- Figure 4 shows the distribution of change from baseline in monthly migraine days at month 3 in bins of 2 days by treatment group. A treatment benefit over placebo for Erenumab is seen across a range of changes from baseline in monthly migraine days.
- The pre-specified analysis for the MPFID was based on at least a 5-point reduction within-patient responder definition. Erenumab 70 mg once monthly was not significantly better than placebo for the proportion of responders for everyday activity [difference from placebo: 4.7%; odds ratio = 1.2; p-value = 0.26] and physical impairment [difference from placebo: 5.9%; odds ratio = 1.3; p-value = 0.13]. In an exploratory analysis of the change from baseline in the mean MPFID scores at month 3, patients treated with Erenumab 70 mg, as compared to placebo, showed nominally greater reductions of physical impairment scores [difference from placebo: -1.3; p-value = 0.021], but not of everyday activities scores [difference from placebo: -1.1; p-value = 0.061].
Chronic Migraine
- Study 3 (NCT 02066415) was a randomized, multi-center, 3-month, placebo-controlled, double-blind study evaluating Erenumab as a preventive treatment of chronic migraine. A total of 667 patients with a history of chronic migraine with or without aura were randomized to receive Erenumab 70 mg (N = 191), Erenumab 140 mg (N = 190), or placebo (N = 286) by subcutaneous injections once monthly for 3 months. Patients were allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.
- The study excluded patients with medication overuse headache caused by opiate overuse and patients with concurrent use of migraine preventive treatments. Patients with myocardial infarction, stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months prior to screening were also excluded.
- The primary efficacy endpoint was the change from baseline in monthly migraine days at month 3. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in monthly migraine days (“≥ 50% MMD responders”) and change from baseline in monthly acute migraine-specific medication days at month 3.
- A total of 631 (95%) patients completed the 3-month double-blind study. Patients had a median age of 43 years (range: 18 to 66 years), 83% were female, and 94% were white. The mean migraine frequency at baseline was approximately 18 migraine days per month and was similar across treatment groups.
- Erenumab treatment demonstrated statistically significant improvements for key efficacy outcomes compared to placebo, as summarized in Table 5.
- Figure 6 shows the distribution of change from baseline in monthly migraine days at month 3 in bins of 3 days by treatment group. A treatment benefit over placebo for both doses of Erenumab is seen across a range of changes from baseline in migraine days.
# How Supplied
- Erenumab (Erenumab-aooe) injection is a sterile, clear to opalescent, colorless to light yellow solution for subcutaneous administration.
- The needle shield within the white cap of the Erenumab prefilled autoinjector and gray needle cap of the Erenumab prefilled syringe contain dry natural rubber (a derivative of latex). Each single-dose prefilled SureClick® autoinjector or single-dose prefilled syringe of Erenumab contains a Type 1 glass syringe and stainless steel needle and delivers 1 mL of 70 mg/mL solution.
- Erenumab is supplied as follows:
SureClick® Autoinjector
- Pack of 1 autoinjector: 70 mg/mL single-dose prefilled autoinjector NDC 55513-841-01.
- Pack of 2 autoinjectors: 140 mg/2 mL (2 x 70 mg/mL single-dose prefilled autoinjectors) NDC 55513-841-02
Syringe
- Pack of 1 syringe: 70 mg/mL single-dose prefilled syringe NDC 55513-840-01
- Pack of 2 syringes: 140 mg/2 mL (2 x 70 mg/mL single-dose prefilled syringes) NDC 55513-840-02
## Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use.
- If removed from the refrigerator, Erenumab should be kept at room temperature (up to 25°C [77°F]) in the original carton and must be used within 7 days. Throw away Erenumab that has been left at room temperature for more than 7 days.
- Do not freeze.
- Do not shake.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information on Preparation and Administration:
- Provide guidance to patients and caregivers on proper subcutaneous administration technique, including aseptic technique, and how to use the single-dose prefilled autoinjector or single-dose prefilled syringe. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use Erenumab.
- Instruct patients prescribed 140 mg to administer the once monthly dosage as two separate subcutaneous injections of 70 mg each.
- Advise latex-sensitive patients that the needle shield within the white cap of the Erenumab prefilled autoinjector and gray needle cap of the Erenumab prefilled syringe contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex.
# Precautions with Alcohol
Alcohol-Erenumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Aimovig
# Look-Alike Drug Names
There is limited information regarding Erenumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Erenumab | |
84bf5cb14d491ac98db17b79ac7be7fe37b1fde1 | wikidoc | Ergoline | Ergoline
Ergoline is a chemical compound whose structural skeleton is contained in a diverse range of alkaloids and a few psychedelic drugs (ololiuhqui, LSD). Ergoline derivitives are used clinically for the purpose of vasoconstriction (5-HT 1 Agonists - Ergotamine) and in the treatment of migraine (used with caffeine) and Parkinson's disease, some are implicated in the disease ergotism. Ergometrine and ergotamine are listed as Table I precursors under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.
# Chemistry
There are three main classes of ergoline derivatives, the water-soluble amides of lysergic acid, the water-insoluble ergopeptines (i.e., ergopeptides), and the clavine group.
## Lysergic acid amides
- Ergine (LSA, D-lysergic acid amide, LAA, LA-111)
IUPAC name: 9,10-didehydro-6-methylergoline-8beta-carboxamide
CAS number: 478-94-4
- IUPAC name: 9,10-didehydro-6-methylergoline-8beta-carboxamide
- CAS number: 478-94-4
- Ergonovine (ergobasine)
INN: ergometrine
IUPAC name: (8beta(S))−9,10-didehydro-N-(2-hydroxy-1-methylethyl)−6-methyl-ergoline-8-carboxamide
CAS number: 60-79-7
- INN: ergometrine
- IUPAC name: (8beta(S))−9,10-didehydro-N-(2-hydroxy-1-methylethyl)−6-methyl-ergoline-8-carboxamide
- CAS number: 60-79-7
- Methergine (ME-277)
INN: methylergometrine
IUPAC name: (8beta(S))−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−6-methyl-ergoline-8-carboxamide
CAS number: 113-42-8
- INN: methylergometrine
- IUPAC name: (8beta(S))−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−6-methyl-ergoline-8-carboxamide
- CAS number: 113-42-8
- Methysergide (UML-491)
INN: methysergide
IUPAC name: (8beta)−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−1,6-dimethyl-ergoline-8-carboxamide
CAS number: 361-37-5
- INN: methysergide
- IUPAC name: (8beta)−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−1,6-dimethyl-ergoline-8-carboxamide
- CAS number: 361-37-5
- LSD (D-lysergic acid diethylamide, LSD-25)
INN: lysergide
IUPAC name: (8beta)−9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-carboxamide
CAS number: 50-37-3
- INN: lysergide
- IUPAC name: (8beta)−9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-carboxamide
- CAS number: 50-37-3
The relationship between these compounds is summarized in the following structural formula and table of substitutions.
## Peptide alkaloids
These compounds have a tripeptide structure attached to the basic ergoline ring, in the same location as the amide group of the lysergic acid derivatives. This tripeptide moiety contains an unusual cyclol bond >N-C(OH)< at the juncture between the two lactam rings. Some of the important ergopeptines (also known as ergopeptides) are summarized below. In addition to the following ergopeptines, a commonly encountered term is ergotoxine, which refers to a mixture of equal proportions of ergocristine, ergocornine and ergocryptine.
- Ergotamine
IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-, (5'-alpha)- (9CI)
CAS number: 113-15-5
- IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-, (5'-alpha)- (9CI)
- CAS number: 113-15-5
- Ergocristine
IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(phenylmethyl)-, (5'-alpha)-
CAS number: 511-08-0
- IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(phenylmethyl)-, (5'-alpha)-
- CAS number: 511-08-0
- Ergocornine
IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2',5'-bis(1-methylethyl)-, (5'-alpha)-
CAS number: 564-36-3
- IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2',5'-bis(1-methylethyl)-, (5'-alpha)-
- CAS number: 564-36-3
- Ergocryptine
IUPAC name:Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(2-methylpropyl)-, (5'alpha)- (9CI)
CAS number: 511-09-1
- IUPAC name:Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(2-methylpropyl)-, (5'alpha)- (9CI)
- CAS number: 511-09-1
- Bromocriptine (INN)
IUPAC name: Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)−5'-(2-methylpropyl)-, (5'alpha)-
CAS number: 25614-03-3
- IUPAC name: Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)−5'-(2-methylpropyl)-, (5'alpha)-
- CAS number: 25614-03-3
- Ergovaline
IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylethyl)-, (5'alpha)-
CAS number: 2873-38-3
- IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylethyl)-, (5'alpha)-
- CAS number: 2873-38-3
## Clavines
A variety of modifications to the basic ergoline are seen in nature, for example agroclavine, elymoclavine, lysergol. Those deriving from dimethylergoline are referred to as clavines.
## Others
Some synthetic ergoline derivatives do not fall easily into any of the above groups. Some examples are:
- Pergolide (INN)
IUPAC name: (8beta)−8-((methylthio)methyl)−6-propyl-ergoline
CAS number: 66104-22-1
- IUPAC name: (8beta)−8-((methylthio)methyl)−6-propyl-ergoline
- CAS number: 66104-22-1
- Lisuride (INN)
IUPAC name: 3-(9,10-didehydro-6-methylergolin-8alpha-yl)−1,1-diethylurea
CAS number: 18016-80-3
- IUPAC name: 3-(9,10-didehydro-6-methylergolin-8alpha-yl)−1,1-diethylurea
- CAS number: 18016-80-3
# History & Uses
Ergoline alkaloids were first isolated from ergot, a fungus that infects grain and causes the disease ergotism. Ergot also has a long history of medicinal use, which led to attempts to characterize its activity chemically. This began in 1907 with the isolation by G. Barger and F. H. Carrin of ergotoxine, so-named since it appeared to exhibit more of the toxicity of ergot than its therapeutic qualities. With the isolation of ergotamine in 1918 by A. Stoll came the first therapeutic use of isolated ergoline alkaloids.
With the determination of the basic chemical structure of the ergot alkaloids in the early 1930s, an era of intensive exploration of synthetic derivatives began. In addition to the naturally occurring ergonovine (used as an oxytocic) and ergotamine (an analgesic used to control migraine), synthetic derivatives of continuing importance today are the oxytocic methergine, the anti-migraine drugs dihydroergotamine and methysergide, Hydergine™ (a mixture of dihydroergotoxine mesylates, INN: ergoline mesylates), and bromocriptine, used for numerous purposes including treatment of Parkinson's disease. Newer synthetic ergolines used for Parkinson's disease include pergolide and lisuride. Perhaps the most famous ergoline derivative of all is the psychedelic drug LSD.
In 1960, Albert Hofmann (discoverer of methergine, dihydroergotamine, Hydergine and LSD) delivered a speech that was to cause shockwaves of incredulity and disbelief in the scientific community. Ergoline alkaloids, previously only known from the lower fungi, had been found in two species of flowering plants. These were the Mexican species Rivea corymbosa and Ipomoea violacea of the Convolvulaceae (morning glory) family, the seeds of which were identified as the psychedelic plant drugs known as "ololiuhqui" and "tlitliltzin". Hofmann's result was later confirmed by other studies. The principal alkaloids in the seeds are ergine and its optical isomer isoergine, with several other lysergic acid derivatives and clavines present in lesser amounts. The Hawaiian species Argyreia nervosa was later found to include similar alkaloids. It is possible, though not proven, that ergine or isoergine are responsible for the hallucinogenic effects. However, while Hofmann's discovery is an important landmark in the research of ergot alkaloids, a recent study has provided evidence for a fungal origin of the ergoline alkaloids also in the Convolvulaceae. Like the ergot alkaloids in some monocot plants, the ergoline alkaloids found in the plant Ipomoea asarifolia (Convolvulaceae) are produced by a seed-transmitted epiphytic clavicipitaceous fungus. | Ergoline
Ergoline is a chemical compound whose structural skeleton is contained in a diverse range of alkaloids and a few psychedelic drugs (ololiuhqui, LSD). Ergoline derivitives are used clinically for the purpose of vasoconstriction (5-HT 1 Agonists - Ergotamine) and in the treatment of migraine (used with caffeine) and Parkinson's disease, some are implicated in the disease ergotism. Ergometrine and ergotamine are listed as Table I precursors under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[1]
# Chemistry
Template:Splitsection
There are three main classes of ergoline derivatives, the water-soluble amides of lysergic acid, the water-insoluble ergopeptines (i.e., ergopeptides), and the clavine group.[2]
## Lysergic acid amides
- Ergine (LSA, D-lysergic acid amide, LAA, LA-111)
IUPAC name: 9,10-didehydro-6-methylergoline-8beta-carboxamide
CAS number: 478-94-4
- IUPAC name: 9,10-didehydro-6-methylergoline-8beta-carboxamide
- CAS number: 478-94-4
- Ergonovine (ergobasine)
INN: ergometrine
IUPAC name: (8beta(S))−9,10-didehydro-N-(2-hydroxy-1-methylethyl)−6-methyl-ergoline-8-carboxamide
CAS number: 60-79-7
- INN: ergometrine
- IUPAC name: (8beta(S))−9,10-didehydro-N-(2-hydroxy-1-methylethyl)−6-methyl-ergoline-8-carboxamide
- CAS number: 60-79-7
- Methergine (ME-277)
INN: methylergometrine
IUPAC name: (8beta(S))−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−6-methyl-ergoline-8-carboxamide
CAS number: 113-42-8
- INN: methylergometrine
- IUPAC name: (8beta(S))−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−6-methyl-ergoline-8-carboxamide
- CAS number: 113-42-8
- Methysergide (UML-491)
INN: methysergide
IUPAC name: (8beta)−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−1,6-dimethyl-ergoline-8-carboxamide
CAS number: 361-37-5
- INN: methysergide
- IUPAC name: (8beta)−9,10-didehydro-N-(1-(hydroxymethyl)propyl)−1,6-dimethyl-ergoline-8-carboxamide
- CAS number: 361-37-5
- LSD (D-lysergic acid diethylamide, LSD-25)
INN: lysergide
IUPAC name: (8beta)−9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-carboxamide
CAS number: 50-37-3
- INN: lysergide
- IUPAC name: (8beta)−9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8-carboxamide
- CAS number: 50-37-3
The relationship between these compounds is summarized in the following structural formula and table of substitutions.
## Peptide alkaloids
These compounds have a tripeptide structure attached to the basic ergoline ring, in the same location as the amide group of the lysergic acid derivatives. This tripeptide moiety contains an unusual cyclol bond >N-C(OH)< at the juncture between the two lactam rings. Some of the important ergopeptines (also known as ergopeptides) are summarized below. In addition to the following ergopeptines, a commonly encountered term is ergotoxine, which refers to a mixture of equal proportions of ergocristine, ergocornine and ergocryptine.
- Ergotamine
IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-, (5'-alpha)- (9CI)
CAS number: 113-15-5
- IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(phenylmethyl)-, (5'-alpha)- (9CI)
- CAS number: 113-15-5
- Ergocristine
IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(phenylmethyl)-, (5'-alpha)-
CAS number: 511-08-0
- IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(phenylmethyl)-, (5'-alpha)-
- CAS number: 511-08-0
- Ergocornine
IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2',5'-bis(1-methylethyl)-, (5'-alpha)-
CAS number: 564-36-3
- IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2',5'-bis(1-methylethyl)-, (5'-alpha)-
- CAS number: 564-36-3
- Ergocryptine
IUPAC name:Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(2-methylpropyl)-, (5'alpha)- (9CI)
CAS number: 511-09-1
- IUPAC name:Ergotaman-3',6',18-trione, 12'-hydroxy-2'-(1-methylethyl)−5'-(2-methylpropyl)-, (5'alpha)- (9CI)
- CAS number: 511-09-1
- Bromocriptine (INN)
IUPAC name: Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)−5'-(2-methylpropyl)-, (5'alpha)-
CAS number: 25614-03-3
- IUPAC name: Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)−5'-(2-methylpropyl)-, (5'alpha)-
- CAS number: 25614-03-3
- Ergovaline
IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylethyl)-, (5'alpha)-
CAS number: 2873-38-3
- IUPAC name: Ergotaman-3',6',18-trione, 12'-hydroxy-2'-methyl-5'-(1-methylethyl)-, (5'alpha)-
- CAS number: 2873-38-3
## Clavines
A variety of modifications to the basic ergoline are seen in nature, for example agroclavine, elymoclavine, lysergol. Those deriving from dimethylergoline are referred to as clavines.
## Others
Some synthetic ergoline derivatives do not fall easily into any of the above groups. Some examples are:
- Pergolide (INN)
IUPAC name: (8beta)−8-((methylthio)methyl)−6-propyl-ergoline
CAS number: 66104-22-1
- IUPAC name: (8beta)−8-((methylthio)methyl)−6-propyl-ergoline
- CAS number: 66104-22-1
- Lisuride (INN)
IUPAC name: 3-(9,10-didehydro-6-methylergolin-8alpha-yl)−1,1-diethylurea
CAS number: 18016-80-3
- IUPAC name: 3-(9,10-didehydro-6-methylergolin-8alpha-yl)−1,1-diethylurea
- CAS number: 18016-80-3
# History & Uses
Ergoline alkaloids were first isolated from ergot, a fungus that infects grain and causes the disease ergotism. Ergot also has a long history of medicinal use, which led to attempts to characterize its activity chemically. This began in 1907 with the isolation by G. Barger and F. H. Carrin of ergotoxine, so-named since it appeared to exhibit more of the toxicity of ergot than its therapeutic qualities. With the isolation of ergotamine in 1918 by A. Stoll came the first therapeutic use of isolated ergoline alkaloids.
With the determination of the basic chemical structure of the ergot alkaloids in the early 1930s, an era of intensive exploration of synthetic derivatives began. In addition to the naturally occurring ergonovine (used as an oxytocic) and ergotamine (an analgesic used to control migraine), synthetic derivatives of continuing importance today are the oxytocic methergine, the anti-migraine drugs dihydroergotamine and methysergide, Hydergine™ (a mixture of dihydroergotoxine mesylates, INN: ergoline mesylates), and bromocriptine, used for numerous purposes including treatment of Parkinson's disease. Newer synthetic ergolines used for Parkinson's disease include pergolide and lisuride. Perhaps the most famous ergoline derivative of all is the psychedelic drug LSD.
In 1960, Albert Hofmann (discoverer of methergine, dihydroergotamine, Hydergine and LSD) delivered a speech that was to cause shockwaves of incredulity and disbelief in the scientific community. Ergoline alkaloids, previously only known from the lower fungi, had been found in two species of flowering plants. These were the Mexican species Rivea corymbosa and Ipomoea violacea of the Convolvulaceae (morning glory) family, the seeds of which were identified as the psychedelic plant drugs known as "ololiuhqui" and "tlitliltzin". Hofmann's result was later confirmed by other studies. The principal alkaloids in the seeds are ergine and its optical isomer isoergine, with several other lysergic acid derivatives and clavines present in lesser amounts. The Hawaiian species Argyreia nervosa was later found to include similar alkaloids. It is possible, though not proven, that ergine or isoergine are responsible for the hallucinogenic effects. However, while Hofmann's discovery is an important landmark in the research of ergot alkaloids, a recent study has provided evidence for a fungal origin of the ergoline alkaloids also in the Convolvulaceae. Like the ergot alkaloids in some monocot plants, the ergoline alkaloids found in the plant Ipomoea asarifolia (Convolvulaceae) are produced by a seed-transmitted epiphytic clavicipitaceous fungus.[3] | https://www.wikidoc.org/index.php/Ergoline | |
6b8b7c570c2fe16fcc6386861d08ed69bdb64202 | wikidoc | Ergoloid | Ergoloid
# Overview
Ergoloid mesylates (USAN), co-dergocrine mesilate (BAN) or dihydroergotoxine mesylate, trade name Hydergine, is a mixture of the methanesulfonate salts of three dihydrogenated ergot alkaloids (dihydroergocristine, dihydroergocornine, and alpha- and beta-dihydroergocryptine).
It was developed by Albert Hofmann (the inventor of LSD) for Sandoz (now part of Novartis).
# Uses
It has been used to treat dementia and age-related cognitive impairment (such as in Alzheimer disease), as well as to aid in recovery after stroke.
There is some evidence suggesting that potentially effective doses may be higher than those currently approved in dementia treatment.
Ergoloids are also used by many people as a nootropic. It may be used in conjunction with other cerebral enhancers like piracetam, with which it may act synergistically.
Ergoloid Mesylate Tablets USP for sublingual use contain 1 mg of Ergoloid Mesylates USP, a mixture of the methanesulfonate salt of the following hydrogenated alkaloids: Dihydroergocornine mesylate 0.333 mg, Dihydroergocristine mesylate 0.333 mg, Dihydroergocryptine mesylate 0.333 mg.
# Mechanism of action
Despite the fact that hydergine has been used in the treatment of dementia for many years, its mechanism of action is still not clear. It stimulates dopaminergic and serotonergic receptors and blocks alpha-adrenoreceptors. Current studies imply that the major effect of hydergine may be the modulation of synaptic neurotransmission rather than solely increasing blood flow as was once thought. A prominent feature that accompanies aging is an increase in monoamine oxidase (MAO) levels. This results in decreased availability of catecholamines in the synaptic cleft. In one study, an interaction between age and hydergine treatment was observed in the hypothalamus, hippocampus and cerebellum. The hydergine effect was more pronounced in the aged group in the hypothalamus and cerebellum, and more pronounced in the adult in the hippocampus. These findings imply that increased brain MAO activity in aging can be modified by hydergine treatment in some brain regions.
# Contraindications
Ergoloid is contraindicated in individuals who have previously shown hypersensitivity to the drug. They are also contraindicated in patients who have psychosis, acute or chronic, regardless of etiology. Specific drug interactions are unknown but it has been claimed that there are multiple potential interactions.
# Adverse reactions
Adverse effects are minimal. The most common include transient, dose dependent nausea and gastrointestinal disturbances, and sublingual irritation with SL tablets. Other common side effects include:
- Cardiovascular: orthostatic hypotension, bradycardia
- Dermatologic: skin rash, flushing
- Ocular: blurred vision
- Respiratory: nasal congestion
- Increased risk of fibrosis and ergotism.
As a result of the last-mentioned effects, the use of ergot derivatives for the treatment of blood circulation disorders, memory problems, sensation problems and the treatment of migraine is no longer permitted in some EU countries because the risks are believed to outweigh any benefits.
# Chemistry
The four constituents differ only in which of four proteinogenic amino acids is used in biosynthesis:
# Trade names
Hydergine, Hydergina, Gerimal, Niloric, Redizork, Alkergot, Cicanol, Redergin. | Ergoloid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ergoloid mesylates (USAN), co-dergocrine mesilate (BAN) or dihydroergotoxine mesylate, trade name Hydergine, is a mixture of the methanesulfonate salts of three dihydrogenated ergot alkaloids (dihydroergocristine, dihydroergocornine, and alpha- and beta-dihydroergocryptine).
It was developed by Albert Hofmann (the inventor of LSD) for Sandoz (now part of Novartis).
# Uses
It has been used to treat dementia and age-related cognitive impairment (such as in Alzheimer disease),[1] as well as to aid in recovery after stroke.
There is some evidence suggesting that potentially effective doses may be higher than those currently approved in dementia treatment.[2]
Ergoloids are also used by many people as a nootropic. It may be used in conjunction with other cerebral enhancers like piracetam, with which it may act synergistically.[3]
Ergoloid Mesylate Tablets USP for sublingual use contain 1 mg of Ergoloid Mesylates USP, a mixture of the methanesulfonate salt of the following hydrogenated alkaloids: Dihydroergocornine mesylate 0.333 mg, Dihydroergocristine mesylate 0.333 mg, Dihydroergocryptine mesylate 0.333 mg.[4]
# Mechanism of action
Despite the fact that hydergine has been used in the treatment of dementia for many years, its mechanism of action is still not clear.[5] It stimulates dopaminergic and serotonergic receptors and blocks alpha-adrenoreceptors.[6] Current studies imply that the major effect of hydergine may be the modulation of synaptic neurotransmission rather than solely increasing blood flow as was once thought.[7] A prominent feature that accompanies aging is an increase in monoamine oxidase (MAO) levels.[8] This results in decreased availability of catecholamines in the synaptic cleft. In one study, an interaction between age and hydergine treatment was observed in the hypothalamus, hippocampus and cerebellum. The hydergine effect was more pronounced in the aged group in the hypothalamus and cerebellum, and more pronounced in the adult in the hippocampus. These findings imply that increased brain MAO activity in aging can be modified by hydergine treatment in some brain regions.
# Contraindications
Ergoloid is contraindicated in individuals who have previously shown hypersensitivity to the drug. They are also contraindicated in patients who have psychosis, acute or chronic, regardless of etiology.[9] Specific drug interactions are unknown but it has been claimed that there are multiple potential interactions.[9]
# Adverse reactions
Adverse effects are minimal. The most common include transient, dose dependent nausea and gastrointestinal disturbances,[5] and sublingual irritation with SL tablets. Other common side effects include:[9][10]
- Cardiovascular: orthostatic hypotension, bradycardia
- Dermatologic: skin rash, flushing
- Ocular: blurred vision
- Respiratory: nasal congestion
- Increased risk of fibrosis and ergotism.[11][12]
As a result of the last-mentioned effects, the use of ergot derivatives for the treatment of blood circulation disorders, memory problems, sensation problems and the treatment of migraine is no longer permitted in some EU countries because the risks are believed to outweigh any benefits.[11]
# Chemistry
The four constituents differ only in which of four proteinogenic amino acids is used in biosynthesis:[13]
# Trade names
Hydergine, Hydergina, Gerimal, Niloric, Redizork, Alkergot, Cicanol, Redergin. | https://www.wikidoc.org/index.php/Ergoloid | |
4eddc4225980987d70302f855e6351dd66ea6536 | wikidoc | Ergotism | Ergotism
Ergotism is the effect of long-term ergot poisoning, classically due to the ingestion of the alkaloids produced by the Claviceps purpurea fungus which infects rye and other cereals, and more recently by the action of a number of ergoline-based drugs. It is also known as ergotoxicosis, ergot poisoning and St Anthony's fire. In Italy and in Malta, shingles is also known as St. Anthony's fire.
# Causes
The toxic ergoline derivatives are found in ergot-based drugs (such as methylergometrine, ergotamine or, previously, ergotoxine). The deleterious side-effects occur either under high dose or when moderate doses interact with potentiators such as azithromycin.
Classically, eating grain products contaminated with the fungus Claviceps purpurea also caused ergotism.
Finally, the alkaloids can also pass through lactation from mother to child, causing ergotism in infants.
# Symptoms
The symptoms can be roughly divided into convulsive symptoms and gangrenous symptoms.
## Convulsive symptoms
Convulsive symptoms include painful seizures and spasms, diarrhea, paresthesias, itching, headaches, nausea and vomiting. Usually the gastrointestinal effects precede central nervous system effects. As well as seizures there can be hallucinations resembling those produced by LSD (lysergic acid diethylamide), and mental effects including mania or psychosis. The convulsive symptoms are caused by clavine alkaloids.
## Gangrenous symptoms
The dry gangrene is a result of vasoconstriction induced by the ergotamine-ergocristine alkaloids of the fungus. It affects the more poorly vascularized distal structures, such as the fingers and toes. Symptoms include desquamation, weak peripheral pulse, loss of peripheral sensation, edema and ultimately the death and loss of affected tissues.
# History
Epidemics of the disease were identified throughout history, though the references in classical writers are inconclusive. Rye, the main vector for transmitting ergotism, was not grown much around the Mediterranean. When Fuchs 1834 separated references to ergotism from erysipelas and other afflictions he found the earliest reference to ergotism in the Annales Xantenses for the year 857: "a Great plague of swollen blisters consumed the people by a loathsome rot, so that their limbs were loosened and fell off before death."
In the Middle Ages the gangrenous poisoning was known as ignis sacer ("holy fire") or "Saint Anthony's fire", named after monks of the Order of St. Anthony who were particularly successful at treating this ailment. The 12th century chronicler Geoffroy du Breuil of Vigeois recorded the mysterious outbreaks in the Limousin region of France, where the gangrenous form of ergotism was associated with the local Saint Martial as much as Saint Anthony.
The blight, named from the cock's spur it forms on grasses, was identified and named by Denis Dodart who reported the relation between ergotized rye and bread poisoning in a letter to the French Royal Academy of Sciences in 1676 (John Ray mentioning ergot for the first time in English the next year), but "ergotism" in this modern sense was first recorded in 1853.
Research by Linda Caporael (1976) suggests that many of the people whose accusations resulted in the 1692 Salem witch trials in Massachusetts were genuinely suffering hallucinations and other symptoms of convulsive ergotism.
Similar eruptions of ergotism also occurred in Essex and Fairfield counties in Connecticut that damp and cool season, though in Connecticut no one went to the gallows. Notable epidemics of ergotism, at first seen as a punishment from God, occurred up into the 19th century. Fewer outbreaks have occurred since then, because in developed countries rye is carefully monitored.
When milled the ergot is reduced to a red powder, obvious in lighter grasses but easy to miss in dark rye flour. In less wealthy countries ergotism still occurs: there was an outbreak in Ethiopia in mid-2001 from contaminated barley. Whenever there is a combination of moist weather, cool temperatures, delayed harvest in lowland crops and rye consumption an outbreak is possible. Russia has been particularly afflicted.
Poisonings due to consumption of seeds treated with mercury compounds are sometimes misidentified as ergotism, such as the case of mass-poisoning in the French village Pont-Saint-Esprit in 1951: The incident is described in John Grant Fuller's book The Day of St Anthony's Fire. | Ergotism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Ergotism is the effect of long-term ergot poisoning, classically due to the ingestion of the alkaloids produced by the Claviceps purpurea fungus which infects rye and other cereals, and more recently by the action of a number of ergoline-based drugs. It is also known as ergotoxicosis, ergot poisoning and St Anthony's fire. In Italy and in Malta, shingles is also known as St. Anthony's fire.[1]
# Causes
The toxic ergoline derivatives are found in ergot-based drugs (such as methylergometrine, ergotamine or, previously, ergotoxine). The deleterious side-effects occur either under high dose or when moderate doses interact with potentiators such as azithromycin.
Classically, eating grain products contaminated with the fungus Claviceps purpurea also caused ergotism.
Finally, the alkaloids can also pass through lactation from mother to child, causing ergotism in infants.
# Symptoms
The symptoms can be roughly divided into convulsive symptoms and gangrenous symptoms.
## Convulsive symptoms
Convulsive symptoms include painful seizures and spasms, diarrhea, paresthesias, itching, headaches, nausea and vomiting. Usually the gastrointestinal effects precede central nervous system effects. As well as seizures there can be hallucinations resembling those produced by LSD (lysergic acid diethylamide), and mental effects including mania or psychosis. The convulsive symptoms are caused by clavine alkaloids.
## Gangrenous symptoms
The dry gangrene is a result of vasoconstriction induced by the ergotamine-ergocristine alkaloids of the fungus. It affects the more poorly vascularized distal structures, such as the fingers and toes. Symptoms include desquamation, weak peripheral pulse, loss of peripheral sensation, edema and ultimately the death and loss of affected tissues.
# History
Epidemics of the disease were identified throughout history, though the references in classical writers are inconclusive. Rye, the main vector for transmitting ergotism, was not grown much around the Mediterranean. When Fuchs 1834 separated references to ergotism from erysipelas and other afflictions he found the earliest reference to ergotism in the Annales Xantenses for the year 857: "a Great plague of swollen blisters consumed the people by a loathsome rot, so that their limbs were loosened and fell off before death."
In the Middle Ages the gangrenous poisoning was known as ignis sacer ("holy fire") or "Saint Anthony's fire", named after monks of the Order of St. Anthony who were particularly successful at treating this ailment. The 12th century chronicler Geoffroy du Breuil of Vigeois recorded the mysterious outbreaks in the Limousin region of France, where the gangrenous form of ergotism was associated with the local Saint Martial as much as Saint Anthony.
The blight, named from the cock's spur it forms on grasses, was identified and named by Denis Dodart who reported the relation between ergotized rye and bread poisoning in a letter to the French Royal Academy of Sciences in 1676 (John Ray mentioning ergot for the first time in English the next year), but "ergotism" in this modern sense was first recorded in 1853.
Research by Linda Caporael (1976) suggests that many of the people whose accusations resulted in the 1692 Salem witch trials in Massachusetts were genuinely suffering hallucinations and other symptoms of convulsive ergotism.
Similar eruptions of ergotism also occurred in Essex and Fairfield counties in Connecticut that damp and cool season, though in Connecticut no one went to the gallows. Notable epidemics of ergotism, at first seen as a punishment from God, occurred up into the 19th century. Fewer outbreaks have occurred since then, because in developed countries rye is carefully monitored.
When milled the ergot is reduced to a red powder, obvious in lighter grasses but easy to miss in dark rye flour. In less wealthy countries ergotism still occurs: there was an outbreak in Ethiopia in mid-2001 from contaminated barley. Whenever there is a combination of moist weather, cool temperatures, delayed harvest in lowland crops and rye consumption an outbreak is possible. Russia has been particularly afflicted.
Poisonings due to consumption of seeds treated with mercury compounds are sometimes misidentified as ergotism, such as the case of mass-poisoning in the French village Pont-Saint-Esprit in 1951: The incident is described in John Grant Fuller's book The Day of St Anthony's Fire. | https://www.wikidoc.org/index.php/Ergotism | |
f871c3a3083cac1a6c1560c10284eaf02ff3a648 | wikidoc | Eribulin | Eribulin
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# Overview
Eribulin is an antineoplastic agent and mitotic Inhibitor that is FDA approved for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.. Common adverse reactions include alopecia, weight loss, constipation, anorexia, nausea, anemia, neutropenia, ALT/SGPT elevation, arthralgia, myalgia, asthenia, headache, peripheral neuropathy, fatigue, fever..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Recommended Dose
- The recommended dose of Eribulin is 1.4 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.
### Dose Modification
- Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.
Do not administer Eribulin on Day 1 or Day 8 for any of the following:
- ANC < 1,000/mm3
- Platelets < 75,000/mm3
- Grade 3 or 4 non-hematological toxicities.
The Day 8 dose may be delayed for a maximum of 1 week.
- If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.
- If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer Eribulin at a reduced dose and initiate the next cycle no sooner than 2 weeks later.
- If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume Eribulin at a reduced dose as set out in Table 1.
- Do not re-escalate Eribulin dose after it has been reduced.
### Instructions for Preparation and Administration
- Aseptically withdraw the required amount of Eribulin from the single-use vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.
- Do not dilute in or administer through an intravenous line containing solutions with dextrose.
- Do not administer in the same intravenous line concurrent with the other medicinal products.
- Store undiluted Eribulin in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C). Store diluted solutions of Eribulin for up to 4 hours at room temperature or up to 24 hours under refrigeration.
- Discard unused portions of the vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eribulin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eribulin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Eribulin 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 Eribulin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eribulin in pediatric patients.
# Contraindications
- None
# Warnings
### Neutropenia
- Severe neutropenia (ANC 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.
- Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of Eribulin and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of Eribulin did not include patients with baseline neutrophil counts below 1,500/mm3.
### Peripheral Neuropathy
- Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1.
- Peripheral neuropathy was the most common toxicity leading to discontinuation of Eribulin (5% of patients; 24/503).
- Neuropathy lasting more than one year occurred in 5% (26/503) of patients.
- Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days).
- Monitor patients closely for signs of peripheral motor neuropathy and sensory neuropathy.
- Withhold Eribulin in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.
### Embryo-Fetal Toxicity
- There are no adequate and well-controlled studies of Eribulin in pregnant women.
- Eribulin is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman.
- Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area.
- If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.
### Prolongation
- In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia antiarrhythmics and Class III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating Eribulin and monitor these electrolytes periodically during therapy. Avoid Eribulin in patients with congenital long QT syndrome.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are discussed in detail in other sections of the labeling:
- Neutropenia.
- Peripheral neuropathy.
- QT interval prolongation.
- The most common adverse reactions (≥25%) reported in patients receiving Eribulin were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving Eribulin were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of Eribulin was peripheral neuropathy (5%).
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
- In clinical trials, Eribulin has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to Eribulin for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).
- The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either Eribulin (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received Eribulin and 247 patients in the control group received therapy consisting of chemotherapy or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving Eribulin and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.
### Cytopenias
- Grade 3 neutropenia occurred in 28% (143/503) of patients who received Eribulin in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received Eribulin.
### Peripheral Neuropathy
- In Study 1, 17 % of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received Eribulin.
- Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.
### Liver Function Test Abnormalities
- Among patients with Grade 0 or 1 ALT levels at baseline, 18% of Eribulin-treated patients experienced Grade 2 or greater ALT elevation. *One Eribulin-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to Eribulin.
### Less Common Adverse Reactions
The following additional adverse reactions were reported in ≥5% to <10% of the Eribulin-treated group:
- Eye Disorders: increased lacrimation
- Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth
- General Disorders and Administration Site Conditions: peripheral edema
- Infections and Infestations: upper respiratory tract infection
- Metabolism and Nutrition Disorders: hypokalemia
- Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness
- Nervous System Disorders: dysgeusia, dizziness
- Psychiatric Disorders: insomnia, depression
- Skin and Subcutaneous Tissue Disorders: rash
## Postmarketing Experience
The following adverse drug reactions have been identified during post-approval of Eribulin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and Lymphatic System Disorders: lymphopenia
- Gastrointestinal Disorders: pancreatitis
- Hepatobiliary Disorders: hepatotoxicity
- Immune System Disorders: drug hypersensitivity
- Infections and Infestations: pneumonia, sepsis/neutropenic sepsis
- Metabolism and Nutrition Disorders: hypomagnesemia, dehydration
- Respiratory, thoracic and mediastinal disorders: interstitial lung disease
- Skin and Subcutaneous Tissue Disorders: pruritus
# Drug Interactions
### Effects of Other Drugs on Eribulin
- No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when Eribulin was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when Eribulin was administered with or without rifampin (a CYP3A4 inducer).
### Effects of Eribulin on Other Drugs
- Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- There are no adequate and well-controlled studies with Eribulin in pregnant women. Eribulin is a microtubule inhibitor, therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.
- Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eribulin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eribulin during labor and delivery.
### Nursing Mothers
- It is not known whether Eribulin is excreted into human milk. No studies in humans or animals were conducted to determine if Eribulin is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from Eribulin, a decision should be made whether to discontinue nursing or to discontinue Eribulin taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of Eribulin in pediatric patients below the age of 18 years have not been established.
### Geriatic Use
- Study 1 did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 827 subjects who received the recommended dose and schedule of Eribulin in clinical studies, 15% (121/827) were 65 and older, and 2% (17/827) patients were 75 and older. No overall differences in safety were observed between these subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Eribulin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eribulin with respect to specific racial populations.
### Renal Impairment
- For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of Eribulin was not studied in patients with severe renal impairment (CrCl < 30 mL/min)
### Hepatic Impairment
- Administration of Eribulin at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). Eribulin was not studied in patients with severe hepatic impairment (Child-Pugh C)
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eribulin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eribulin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Eribulin Administration in the drug label.
### Monitoring
There is limited information regarding Eribulin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Eribulin and IV administrations.
# Overdosage
- Overdosage of Eribulin has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for Eribulin overdose.
# Pharmacology
## Mechanism of Action
- Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.
## Structure
- It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C40H59NO11CH4O3S. Eribulin mesylate has the following structural formula:
## Pharmacodynamics
There is limited information regarding Eribulin Pharmacodynamics in the drug label.
## Pharmacokinetics
- The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2. The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65% Eribulin exposure after multiple dosing is comparable to that following a single dose. No accumulation of eribulin is observed with weekly administration.
- Unchanged eribulin was the major circulating species in plasma following administration of 14C‑eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro.
- Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of the dose in feces and urine, respectively.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with eribulin mesylate.
Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.
The effects of Eribulin on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.
# Clinical Studies
- Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast cancer who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen. Patients were required to receive prior anthracycline- and taxane- based chemotherapy for adjuvant or metastatic disease. Patients were randomized (2:1) to receive Eribulin (n=508) or a single agent therapy selected prior to randomization (control arm, n=254). Randomization was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. Eribulin was administered at a dose of 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle. Eribulin-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal therapy. The main efficacy outcome was overall survival.
- Patient demographic and baseline characteristics were comparable between the treatment arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER-,PR-,HER2/neu-: 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in the Eribulin and control arms. Patients received a median of four prior chemotherapy regimens in both arms.
- In Study 1, a statistically significant improvement in overall survival was observed in patients randomized to the Eribulin arm compared to the control arm (see Table 3). An updated, unplanned survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent with the primary analysis. In patients randomized to Eribulin, the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months).
# How Supplied
- Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial. One vial per carton.
## Storage
- Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F). Do not freeze. Store the vials in their original cartons.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Eribulin Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Eribulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Halaven
# Look-Alike Drug Names
There is limited information regarding Eribulin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Eribulin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
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# Overview
Eribulin is an antineoplastic agent and mitotic Inhibitor that is FDA approved for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.. Common adverse reactions include alopecia, weight loss, constipation, anorexia, nausea, anemia, neutropenia, ALT/SGPT elevation, arthralgia, myalgia, asthenia, headache, peripheral neuropathy, fatigue, fever..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Recommended Dose
- The recommended dose of Eribulin is 1.4 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.
### Dose Modification
- Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.
Do not administer Eribulin on Day 1 or Day 8 for any of the following:
- ANC < 1,000/mm3
- Platelets < 75,000/mm3
- Grade 3 or 4 non-hematological toxicities.
The Day 8 dose may be delayed for a maximum of 1 week.
- If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.
- If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer Eribulin at a reduced dose and initiate the next cycle no sooner than 2 weeks later.
- If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume Eribulin at a reduced dose as set out in Table 1.
- Do not re-escalate Eribulin dose after it has been reduced.
### Instructions for Preparation and Administration
- Aseptically withdraw the required amount of Eribulin from the single-use vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.
- Do not dilute in or administer through an intravenous line containing solutions with dextrose.
- Do not administer in the same intravenous line concurrent with the other medicinal products.
- Store undiluted Eribulin in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration (40°F or/ 4°C). Store diluted solutions of Eribulin for up to 4 hours at room temperature or up to 24 hours under refrigeration.
- Discard unused portions of the vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Eribulin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eribulin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Eribulin 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 Eribulin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Eribulin in pediatric patients.
# Contraindications
- None
# Warnings
### Neutropenia
- Severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.
- Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of Eribulin and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of Eribulin did not include patients with baseline neutrophil counts below 1,500/mm3.
### Peripheral Neuropathy
- Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1.
- Peripheral neuropathy was the most common toxicity leading to discontinuation of Eribulin (5% of patients; 24/503).
- Neuropathy lasting more than one year occurred in 5% (26/503) of patients.
- Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days).
- Monitor patients closely for signs of peripheral motor neuropathy and sensory neuropathy.
- Withhold Eribulin in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.
### Embryo-Fetal Toxicity
- There are no adequate and well-controlled studies of Eribulin in pregnant women.
- Eribulin is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman.
- Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area.
- If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.
### Prolongation
- In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia antiarrhythmics and Class III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating Eribulin and monitor these electrolytes periodically during therapy. Avoid Eribulin in patients with congenital long QT syndrome.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are discussed in detail in other sections of the labeling:
- Neutropenia.
- Peripheral neuropathy.
- QT interval prolongation.
- The most common adverse reactions (≥25%) reported in patients receiving Eribulin were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving Eribulin were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of Eribulin was peripheral neuropathy (5%).
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
- In clinical trials, Eribulin has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to Eribulin for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).
- The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either Eribulin (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received Eribulin and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving Eribulin and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.
### Cytopenias
- Grade 3 neutropenia occurred in 28% (143/503) of patients who received Eribulin in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received Eribulin.
### Peripheral Neuropathy
- In Study 1, 17 % of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received Eribulin.
- Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.
### Liver Function Test Abnormalities
- Among patients with Grade 0 or 1 ALT levels at baseline, 18% of Eribulin-treated patients experienced Grade 2 or greater ALT elevation. *One Eribulin-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to Eribulin.
### Less Common Adverse Reactions
The following additional adverse reactions were reported in ≥5% to <10% of the Eribulin-treated group:
- Eye Disorders: increased lacrimation
- Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth
- General Disorders and Administration Site Conditions: peripheral edema
- Infections and Infestations: upper respiratory tract infection
- Metabolism and Nutrition Disorders: hypokalemia
- Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness
- Nervous System Disorders: dysgeusia, dizziness
- Psychiatric Disorders: insomnia, depression
- Skin and Subcutaneous Tissue Disorders: rash
## Postmarketing Experience
The following adverse drug reactions have been identified during post-approval of Eribulin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Blood and Lymphatic System Disorders: lymphopenia
- Gastrointestinal Disorders: pancreatitis
- Hepatobiliary Disorders: hepatotoxicity
- Immune System Disorders: drug hypersensitivity
- Infections and Infestations: pneumonia, sepsis/neutropenic sepsis
- Metabolism and Nutrition Disorders: hypomagnesemia, dehydration
- Respiratory, thoracic and mediastinal disorders: interstitial lung disease
- Skin and Subcutaneous Tissue Disorders: pruritus
# Drug Interactions
### Effects of Other Drugs on Eribulin
- No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when Eribulin was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when Eribulin was administered with or without rifampin (a CYP3A4 inducer).
### Effects of Eribulin on Other Drugs
- Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- There are no adequate and well-controlled studies with Eribulin in pregnant women. Eribulin is a microtubule inhibitor, therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.
- Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eribulin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Eribulin during labor and delivery.
### Nursing Mothers
- It is not known whether Eribulin is excreted into human milk. No studies in humans or animals were conducted to determine if Eribulin is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from Eribulin, a decision should be made whether to discontinue nursing or to discontinue Eribulin taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of Eribulin in pediatric patients below the age of 18 years have not been established.
### Geriatic Use
- Study 1 did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 827 subjects who received the recommended dose and schedule of Eribulin in clinical studies, 15% (121/827) were 65 and older, and 2% (17/827) patients were 75 and older. No overall differences in safety were observed between these subjects and younger subjects.
### Gender
There is no FDA guidance on the use of Eribulin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Eribulin with respect to specific racial populations.
### Renal Impairment
- For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of Eribulin was not studied in patients with severe renal impairment (CrCl < 30 mL/min)
### Hepatic Impairment
- Administration of Eribulin at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). Eribulin was not studied in patients with severe hepatic impairment (Child-Pugh C)
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Eribulin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Eribulin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Eribulin Administration in the drug label.
### Monitoring
There is limited information regarding Eribulin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Eribulin and IV administrations.
# Overdosage
- Overdosage of Eribulin has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for Eribulin overdose.
# Pharmacology
## Mechanism of Action
- Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.
## Structure
- It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C40H59NO11•CH4O3S. Eribulin mesylate has the following structural formula:
## Pharmacodynamics
There is limited information regarding Eribulin Pharmacodynamics in the drug label.
## Pharmacokinetics
- The pharmacokinetics (PK) of eribulin is linear with a mean elimination half-life of approximately 40 hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of 1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2. The human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65% Eribulin exposure after multiple dosing is comparable to that following a single dose. No accumulation of eribulin is observed with weekly administration.
- Unchanged eribulin was the major circulating species in plasma following administration of 14C‑eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin. Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro.
- Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine. Unchanged eribulin accounted for approximately 88% and 91% of the dose in feces and urine, respectively.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with eribulin mesylate.
Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.
The effects of Eribulin on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.
# Clinical Studies
- Study 1 was an open-label, randomized, multicenter trial of 762 patients with metastatic breast cancer who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen. Patients were required to receive prior anthracycline- and taxane- based chemotherapy for adjuvant or metastatic disease. Patients were randomized (2:1) to receive Eribulin (n=508) or a single agent therapy selected prior to randomization (control arm, n=254). Randomization was stratified by geographic region, HER2/neu status, and prior capecitabine exposure. Eribulin was administered at a dose of 1.4 mg/m2 on Days 1 and 8 of a 21-day cycle. Eribulin-treated patients received a median of 5 cycles (range: 1 to 23 cycles) of therapy. Control arm therapy consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3% hormonal therapy. The main efficacy outcome was overall survival.
- Patient demographic and baseline characteristics were comparable between the treatment arms. The median age was 55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients were enrolled in North America/Western Europe/Australia, 25% in Eastern Europe/Russia, and 11% in Latin America/South Africa. Ninety-one percent of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic characteristics, including estrogen receptor status (positive: 67%, negative: 28%), progesterone receptor status (positive: 49%, negative: 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple negative status (ER-,PR-,HER2/neu-: 19%), presence of visceral disease (82%, including 60% liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater than two: 50%), were also similar in the Eribulin and control arms. Patients received a median of four prior chemotherapy regimens in both arms.
- In Study 1, a statistically significant improvement in overall survival was observed in patients randomized to the Eribulin arm compared to the control arm (see Table 3). An updated, unplanned survival analysis, conducted when 77% of events had been observed (see Figure 1), was consistent with the primary analysis. In patients randomized to Eribulin, the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months).
# How Supplied
- Eribulin mesylate injection, 1 mg/2 mL, in a single-use vial. One vial per carton.
## Storage
- Store at 25°C (77°F); excursions permitted to 15° – 30° C (59° -86° F). Do not freeze. Store the vials in their original cartons.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Eribulin Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Eribulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Halaven
# Look-Alike Drug Names
There is limited information regarding Eribulin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Eribulin | |
fdac9b627f4b4aed214beff596986bc6f60f369a | wikidoc | Erythema | Erythema
# Overview
Erythema is redness of the skin caused by capillary congestion.
It can be caused by infection, massage, electrical treatments, acne medication, allergies, exercise or solar radiation (sunburn), and waxing and plucking of the hairs any of which can cause the capillaries to dilate, resulting in redness. Erythema is a common side effect of radiotherapy treatment due to patient exposure to ionizing radiation.
# Causes
It can be caused by infection, massage, electrical treatment, acne medication, allergies, exercise, solar radiation (sunburn), cutaneous radiation syndrome, niacin administration, vitamin A toxicity, or waxing and tweezing of the hairs—any of which can cause the capillaries to dilate, resulting in redness. Erythema is a common side effect of radiotherapy treatment due to patient exposure to ionizing radiation. Circumoral erythema has been described as a typical sign of acute oleander poisoning by ingestion.
## Common Causes
- Atopic dermatitis
- Chickenpox
- Contact dermatitis
- Fifth disease
- Hand-foot-mouth disease
- Impetigo
- Insect bites or stings
- Kawasaki disease
- Lupus erythematosus
- Measles
- Psoriasis
- Roseola
- Rheumatoid arthritis
- Rubella
- Scarlet fever
- Seborrheic dermatitis
- Shingles
- Perianal abscess
## Causes by Organ System
## Causes in Alphabetical Order
# Associated conditions
- Erythema ab igne
- Erythema annulare centrifugum
- Erythema chromicum figuratum
- Erythema chronicum migrans
- Erythema craquele
- Erythema dyschromicum perstans
- Erythema elevatum diutinum
- Erythema gyratum perstans
- Erythema gyratum repens
- Erythema induratum
- Erythema infectiosum
- Erythema marginatum
- Erythema migrans
- Erythema multiforme
- Erythema nodosum
- Erythema toxicum neonatorum
In about 30-50% of cases, the cause of Erythema is unknown.
# Differentiating Erythema from Other Diseases
Different rash-like conditions can be confused with erythema and are thus included in its differential diagnosis. The various conditions that should be differentiated from erythema include: | Erythema
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Erythema is redness of the skin caused by capillary congestion.
It can be caused by infection, massage, electrical treatments, acne medication, allergies, exercise or solar radiation (sunburn), and waxing and plucking of the hairs any of which can cause the capillaries to dilate, resulting in redness. Erythema is a common side effect of radiotherapy treatment due to patient exposure to ionizing radiation.
# Causes
It can be caused by infection, massage, electrical treatment, acne medication, allergies, exercise, solar radiation (sunburn), cutaneous radiation syndrome, niacin administration, vitamin A toxicity, or waxing and tweezing of the hairs—any of which can cause the capillaries to dilate, resulting in redness. Erythema is a common side effect of radiotherapy treatment due to patient exposure to ionizing radiation. Circumoral erythema has been described as a typical sign of acute oleander poisoning by ingestion.
## Common Causes
- Atopic dermatitis
- Chickenpox
- Contact dermatitis
- Fifth disease
- Hand-foot-mouth disease
- Impetigo
- Insect bites or stings
- Kawasaki disease
- Lupus erythematosus
- Measles
- Psoriasis
- Roseola
- Rheumatoid arthritis
- Rubella
- Scarlet fever
- Seborrheic dermatitis
- Shingles
- Perianal abscess
## Causes by Organ System
## Causes in Alphabetical Order
# Associated conditions
- Erythema ab igne
- Erythema annulare centrifugum
- Erythema chromicum figuratum
- Erythema chronicum migrans
- Erythema craquele
- Erythema dyschromicum perstans
- Erythema elevatum diutinum
- Erythema gyratum perstans
- Erythema gyratum repens
- Erythema induratum
- Erythema infectiosum
- Erythema marginatum
- Erythema migrans
- Erythema multiforme
- Erythema nodosum
- Erythema toxicum neonatorum
In about 30-50% of cases, the cause of Erythema is unknown.
# Differentiating Erythema from Other Diseases
Different rash-like conditions can be confused with erythema and are thus included in its differential diagnosis. The various conditions that should be differentiated from erythema include:[1][2][3][4][5][6][7] | https://www.wikidoc.org/index.php/Erythema | |
8bb37a4b3ca9188f753ca2ab80f0c1f767887cc7 | wikidoc | Eskatrol | Eskatrol
Eskatrol was an amphetamine weight loss agent which was removed by the
Food and Drug Administration in 1981 after its manufacturer,
SmithKline & French, was unable to prove the drug's effectiveness. At the time it was among the 200 most widely prescribed drugs in the United States. Another was Dexamyl tablets. Eskatrol contained dextroamphetamine sulfate.
In August 1970 the F.D.A. sought to limit the use of pep pills by calling for changes in labeling which decreased the number of allowable claims and intensified the warnings about possible hazards. F.D.A. Commissioner,
Charles C. Edwards, criticized the drug industry for not helping to prevent the abuse of amphetamines. Thomas M. Rauch, president of SmithKline & French laboratories, responded that his company had long promoted stricter drug abuse legislation and tighter controls
-n production and distribution. SmithKline & French also made Dexedrine and Benzedrine. The F.D.A. began to restrict amphetamine manufacturer claims to only three medical uses, two of them uncommon. The two rare conditions specified were narcolepsy
and hyperactivity. The third permitted use was for suppressing appetite among persons who needed to lose weight. However, this would only be allowed for a total of a few weeks, and as a part of
treatment for obesity. | Eskatrol
Eskatrol was an amphetamine weight loss agent which was removed by the
Food and Drug Administration in 1981 after its manufacturer[1],
SmithKline & French,[2] was unable to prove the drug's effectiveness. At the time it was among the 200 most widely prescribed drugs in the United States. Another was Dexamyl tablets.[1] Eskatrol contained dextroamphetamine sulfate.[3]
In August 1970 the F.D.A. sought to limit the use of pep pills by calling for changes in labeling which decreased the number of allowable claims and intensified the warnings about possible hazards. F.D.A. Commissioner,
Charles C. Edwards, criticized the drug industry for not helping to prevent the abuse of amphetamines. Thomas M. Rauch, president of SmithKline & French laboratories, responded that his company had long promoted stricter drug abuse legislation and tighter controls
on production and distribution. SmithKline & French also made Dexedrine and Benzedrine. The F.D.A. began to restrict amphetamine manufacturer claims to only three medical uses, two of them uncommon. The two rare conditions specified were narcolepsy
and hyperactivity. The third permitted use was for suppressing appetite among persons who needed to lose weight. However, this would only be allowed for a total of a few weeks, and as a part of
treatment for obesity.[4] | https://www.wikidoc.org/index.php/Eskatrol | |
f9479ef85d5dc50f1bd101ccc6ac7be006663c33 | wikidoc | Estrogen | Estrogen
# Overview
Estrogens (alternative spellings: oestrogens or œstrogens) are a group of steroid compounds, named for their importance in the estrous cycle, and functioning as the primary female sex hormone.
Estrogens are used as part of some oral contraceptives, in estrogen replacement therapy of postmenopausal women, and in hormone replacement therapy for transwomen.
Like all steroid hormones, estrogens readily diffuse across the cell membrane; inside the cell, they interact with estrogen receptors.
# Types of estrogen
The three major naturally occurring estrogens in women are estradiol, estriol, and estrone. In the body these are all produced from androgens through actions of enzymes.
- From menarche to menopause the primary estrogen is 17β-estradiol. In postmenopausal women more estrone is present than estradiol.
- Estradiol is produced from testosterone and estrone from androstenedione.
- Estrone is weaker than estradiol.
Premarin, a commonly prescribed estrogenic drug, contains the steroidal estrogens equilin and equilenin, in addition to estrone sulfate.
A range of synthetic and natural substances have been identified that also possess estrogenic activity. Synthetic substances of this kind are known as xenoestrogens, plant products with estrogenic activity are called phytoestrogens, and those produced by fungi are known as mycoestrogens. Unlike estrogens produced by mammals, these substances are not necessarily steroids.
# Estrogen production
Testosterone is synthesized during steroidogenesis, with cholesterol as the starting molecule.
Estrogen is produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the production of estrogen in the ovaries. Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts. These secondary sources of estrogen are especially important in postmenopausal women.
Synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of moderate androgenic activity. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted to estrone or estradiol, either immediately or through testosterone. The conversion of testosterone to estradiol, and of androstenedione to estrone, is catalyzed by the enzyme aromatase.
Estradiol levels vary through the menstrual cycle, with levels highest just before ovulation.
# Functions
While estrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. They promote the development of female secondary sex characteristics, such as breasts, and are also involved in the thickening of the endometrium and other aspects of regulating the menstrual cycle. In males estrogen regulates certain functions of the reproductive system important to the maturation of sperm and may be necessary for a healthy libido.. Furthermore, there are several other structural changes induced by estrogen, in addition to other functions.
- Structural
promote formation of female secondary sex characteristics
accelerate height growth
accelerate metabolism (burn fat)
reduce muscle mass
stimulate endometrial growth
increase uterine growth
maintenance of vessel and skin
reduce bone resorption, increase bone formation
morphic change (endomorphic -> mesomorphic -> ectomorphic)
- promote formation of female secondary sex characteristics
- accelerate height growth
- accelerate metabolism (burn fat)
- reduce muscle mass
- stimulate endometrial growth
- increase uterine growth
- maintenance of vessel and skin
- reduce bone resorption, increase bone formation
- morphic change (endomorphic -> mesomorphic -> ectomorphic)
- protein synthesis
increase hepatic production of binding proteins
- increase hepatic production of binding proteins
- coagulation
increase circulating level of factors 2, 7, 9, 10, antithrombin III, plasminogen
increase platelet adhesiveness
- increase circulating level of factors 2, 7, 9, 10, antithrombin III, plasminogen
- increase platelet adhesiveness
- Lipid
increase HDL, triglyceride, height growth
decrease LDL, fat depositition
- increase HDL, triglyceride, height growth
- decrease LDL, fat depositition
- Fluid balance
salt (sodium) and water retention
increase growth hormone
increase cortisol, SHBG
- salt (sodium) and water retention
- increase growth hormone
- increase cortisol, SHBG
- gastrointestinal tract
reduce bowel motility
increase cholesterol in bile
- reduce bowel motility
- increase cholesterol in bile
- Melanin
increase pheomelanin, reduce eumelanin
- increase pheomelanin, reduce eumelanin
- Cancer
support hormone-sensitive breast cancers (see section below)
- support hormone-sensitive breast cancers (see section below)
- Lung function
promotes lung function by supporting alveoli (in rodents but probably in humans) .
- promotes lung function by supporting alveoli (in rodents but probably in humans) .
On the other hand, sexual desire rather depend on androgen levels than for estrogen levels.
## Role in cancer
About 80% of breast cancers, once established, rely on supplies of the hormone estrogen to grow: they are known as hormone-sensitive or hormone-receptor-positive cancers. Suppression of production in the body of estrogen is a treatment for these cancers.
# Medical applications
Since estrogen circulating in the blood can negatively feed-back to reduce circulating levels of FSH and LH, most oral contraceptives contain a synthetic estrogen, along with a synthetic progestin. Even in men, the major hormone involved in LH feedback is estradiol, not testosterone.
As more fully discussed in the article on Hormone replacement therapy , estrogen and other hormones are given to postmenopausal women in order to prevent osteoporosis as well as treat the symptoms of menopause such as hot flashes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. Fractures of the spine, wrist, and hips decrease by 50-70% and spinal bone density increases by ~5% in those women treated with estrogen within 3 years of the onset of menopause and for 5-10 years thereafter.
Before the specific dangers of conjugated equine estrogens were well understood, standard therapy was 0.625 mg/day of conjugated equine estrogens (such as Premarin). There are, however, risks associated with conjugated equine estrogen therapy. Among the older postmenopausal women studied as part of the Women's Health Initiative (WHI), an orally-administered conjugated equine estrogen supplement was found to be associated with an increased risk of dangerous blood clotting. The WHI studies used one type of estrogen supplement, a high oral dose of conjugated equine estrogens (Premarin alone and with medroxyprogesterone acetate as PremPro).
In a study by the NIH, esterified estrogens were not proven to pose the same risks to health as conjugated equine estrogens. Hormone replacement therapy has favorable effects on serum cholesterol levels, and when initiated immediately upon menopause reduces the incidence of cardiovascular disease. Estrogen has a protector effect on atherosclerosis : it lowers LDL and triglycerides, it raises HDL levels and has endothelial vasodilatation properties plus an anti-inflammatory component.
Research is underway to determine if risks of estrogen supplement use are the same for all methods of delivery. In particular, estrogen applied topically may have a different spectrum of side-effects than when administered orally, and transdermal oestrogens do not affect clotting as they are absorbed directly into the systemic circulation, avoiding first-pass metabolism in the liver. This route of administration is thus preferred in women with a history of thrombo-embolic disease.
Estrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a result of hypogonadism, castration, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Estrogens can also be used to suppress lactation after child birth.
Hormone-receptor-positive breast cancers are treated with drugs which suppress production in the body of estrogen. This technique, in the context of treatment of breast cancer, is known variously as hormonal therapy, hormone therapy, or anti-estrogen therapy (not to be confused with hormone replacement therapy). Certain foods such as soy may also suppress the effects of estrogen and are used as an alternative to hormone therapy.
In humans and mice, estrogen promotes wound healing.
At one time, estrogen was used to induce growth attenuation in tall girls. Recently, estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size.
Under certain circumstances, estrogen may also be used in males for treatment of prostate cancer.
Most recently, estrogen has been used in experimental research as a way to treat patients suffering from bulimia nervosa, in addition to Cognitive Behavioral Therapy, which is the established standard for treatment in bulimia cases. The estrogen research hypothesizes that the disease may be linked to a hormonal imbalance in the brain.
Estrogen has also been used in studies which indicate that it may be an effective drug for use in the treatment of traumatic liver injury.
# Health risks and warning labels
The labeling of estrogen-only products in the U.S. includes a boxed warning that unopposed estrogen (without progestagen) therapy increases the risk of endometrial cancer.
Based on a review of data from the WHI, on January 8, 2003 the FDA changed the labeling of all estrogen and estrogen with progestin products for use by postmenopausal women to include a new boxed warning about cardiovascular and other risks. The estrogen-alone substudy of the WHI reported an increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using 0.625 mg of Premarin conjugated equine estrogens (CEE). The estrogen-plus-progestin substudy of the WHI reported an increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and DVT in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using PremPro, which is 0.625 mg of CEE with 2.5 mg of the progestin medroxyprogesterone acetate (MPA).
# Estrogens in cosmetics
Some hair shampoos on the market include estrogens and placental extracts; others contain phytoestrogens. There are case reports of young children developing breasts after exposure to these shampoos. These products are often marketed to African-American consumers.
On September 9, 1993, the FDA determined that not all topically-applied hormone-containing drug products for OTC human use are generally recognized as safe and effective and are misbranded. An accompanying proposed rule deals with cosmetics, concluding that any use of natural estrogens in a cosmetic product makes the product an unapproved new drug and that any cosmetic using the term "hormone" in the text of its labeling or in its ingredient statement makes an implied drug claim, subjecting such a product to regulatory action.
In addition to being considered misbranded drugs, products claiming to contain placental extract may also be deemed to be misbranded cosmetics if the extract has been prepared from placentas from which the hormones and other biologically active substances have been removed and the extracted substance consists principally of protein. The FDA recommends that this substance be identified by a name other than "placental extract" and describing its composition more accurately because consumers associate the name "placental extract" with a therapeutic use of some biological activity.
# History
The existence and effects of estrogen were established from 1923 to 1938 in which the formulation was led by a group of scientists instead of pharmaceutical companies. Thereafter, the market for hormonal drug research opened up.
The “first orally effective estrogen”, Emmenin, derived from the late-pregnancy urine of Canadian women, was introduced in 1930 by Collip and Ayerst Laboratories . Estrogens are not water-soluble and cannot be given orally, but the urine was found to contain estriol glucuronide which is water soluble and becomes active in the body after hydrolization.
Scientists continued to search for new sources of estrogen because of concerns associated with the practicality of introducing the drug into the market. At the same time, a German pharmaceutical drug company, formulated a similar product as Emmenin that was introduced to German women to treat menopausal symptoms.
In 1938, British scientists obtained a patent on a newly formulated nonsteroidal estrogen, Diethylstilbestrol (DES), that was cheaper and more powerful than the previously manufactured estrogens. Soon after, concerns over the side effects of DES were raised in scientific journals while the drug manufacturers came together to lobby for governmental approval of DES. It was only until 1941 when estrogen therapy was finally approved by the Food and Drug Administration (FDA) for the treatment of menopausal symptoms. | Estrogen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Estrogens (alternative spellings: oestrogens or œstrogens) are a group of steroid compounds, named for their importance in the estrous cycle, and functioning as the primary female sex hormone.
Estrogens are used as part of some oral contraceptives, in estrogen replacement therapy of postmenopausal women, and in hormone replacement therapy for transwomen.
Like all steroid hormones, estrogens readily diffuse across the cell membrane; inside the cell, they interact with estrogen receptors.[1]
# Types of estrogen
The three major naturally occurring estrogens in women are estradiol, estriol, and estrone. In the body these are all produced from androgens through actions of enzymes.
- From menarche to menopause the primary estrogen is 17β-estradiol. In postmenopausal women more estrone is present than estradiol.
- Estradiol is produced from testosterone and estrone from androstenedione.
- Estrone is weaker than estradiol.
Premarin, a commonly prescribed estrogenic drug, contains the steroidal estrogens equilin and equilenin, in addition to estrone sulfate.
A range of synthetic and natural substances have been identified that also possess estrogenic activity.[2] Synthetic substances of this kind are known as xenoestrogens, plant products with estrogenic activity are called phytoestrogens, and those produced by fungi are known as mycoestrogens. Unlike estrogens produced by mammals, these substances are not necessarily steroids.
# Estrogen production
Testosterone is synthesized during steroidogenesis, with cholesterol as the starting molecule.
Estrogen is produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the production of estrogen in the ovaries. Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts. These secondary sources of estrogen are especially important in postmenopausal women.
Synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of moderate androgenic activity. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted to estrone or estradiol, either immediately or through testosterone. The conversion of testosterone to estradiol, and of androstenedione to estrone, is catalyzed by the enzyme aromatase.
Estradiol levels vary through the menstrual cycle, with levels highest just before ovulation.
# Functions
While estrogens are present in both men and women, they are usually present at significantly higher levels in women of reproductive age. They promote the development of female secondary sex characteristics, such as breasts, and are also involved in the thickening of the endometrium and other aspects of regulating the menstrual cycle. In males estrogen regulates certain functions of the reproductive system important to the maturation of sperm [3] [4] and may be necessary for a healthy libido.[5]. Furthermore, there are several other structural changes induced by estrogen, in addition to other functions.
- Structural
promote formation of female secondary sex characteristics
accelerate height growth
accelerate metabolism (burn fat)
reduce muscle mass
stimulate endometrial growth
increase uterine growth
maintenance of vessel and skin
reduce bone resorption, increase bone formation
morphic change (endomorphic -> mesomorphic -> ectomorphic)
- promote formation of female secondary sex characteristics
- accelerate height growth
- accelerate metabolism (burn fat)
- reduce muscle mass
- stimulate endometrial growth
- increase uterine growth
- maintenance of vessel and skin
- reduce bone resorption, increase bone formation
- morphic change (endomorphic -> mesomorphic -> ectomorphic)
- protein synthesis
increase hepatic production of binding proteins
- increase hepatic production of binding proteins
- coagulation
increase circulating level of factors 2, 7, 9, 10, antithrombin III, plasminogen
increase platelet adhesiveness
- increase circulating level of factors 2, 7, 9, 10, antithrombin III, plasminogen
- increase platelet adhesiveness
- Lipid
increase HDL, triglyceride, height growth
decrease LDL, fat depositition
- increase HDL, triglyceride, height growth
- decrease LDL, fat depositition
- Fluid balance
salt (sodium) and water retention
increase growth hormone
increase cortisol, SHBG
- salt (sodium) and water retention
- increase growth hormone
- increase cortisol, SHBG
- gastrointestinal tract
reduce bowel motility
increase cholesterol in bile
- reduce bowel motility
- increase cholesterol in bile
- Melanin
increase pheomelanin, reduce eumelanin
- increase pheomelanin, reduce eumelanin
- Cancer
support hormone-sensitive breast cancers (see section below)
- support hormone-sensitive breast cancers (see section below)
- Lung function
promotes lung function by supporting alveoli (in rodents but probably in humans) [6].
- promotes lung function by supporting alveoli (in rodents but probably in humans) [6].
On the other hand, sexual desire rather depend on androgen levels than for estrogen levels.[7]
## Role in cancer
About 80% of breast cancers, once established, rely on supplies of the hormone estrogen to grow: they are known as hormone-sensitive or hormone-receptor-positive cancers.[8] Suppression of production in the body of estrogen is a treatment for these cancers.
# Medical applications
Since estrogen circulating in the blood can negatively feed-back to reduce circulating levels of FSH and LH, most oral contraceptives contain a synthetic estrogen, along with a synthetic progestin. Even in men, the major hormone involved in LH feedback is estradiol, not testosterone.
As more fully discussed in the article on Hormone replacement therapy , estrogen and other hormones are given to postmenopausal women in order to prevent osteoporosis as well as treat the symptoms of menopause such as hot flashes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. Fractures of the spine, wrist, and hips decrease by 50-70% and spinal bone density increases by ~5% in those women treated with estrogen within 3 years of the onset of menopause and for 5-10 years thereafter.
Before the specific dangers of conjugated equine estrogens were well understood, standard therapy was 0.625 mg/day of conjugated equine estrogens (such as Premarin). There are, however, risks associated with conjugated equine estrogen therapy. Among the older postmenopausal women studied as part of the Women's Health Initiative (WHI), an orally-administered conjugated equine estrogen supplement was found to be associated with an increased risk of dangerous blood clotting. The WHI studies used one type of estrogen supplement, a high oral dose of conjugated equine estrogens (Premarin alone and with medroxyprogesterone acetate as PremPro).[9]
In a study by the NIH, esterified estrogens were not proven to pose the same risks to health as conjugated equine estrogens. Hormone replacement therapy has favorable effects on serum cholesterol levels, and when initiated immediately upon menopause reduces the incidence of cardiovascular disease. Estrogen has a protector effect on atherosclerosis : it lowers LDL and triglycerides, it raises HDL levels and has endothelial vasodilatation properties plus an anti-inflammatory component.
Research is underway to determine if risks of estrogen supplement use are the same for all methods of delivery. In particular, estrogen applied topically may have a different spectrum of side-effects than when administered orally,[10] and transdermal oestrogens do not affect clotting as they are absorbed directly into the systemic circulation, avoiding first-pass metabolism in the liver. This route of administration is thus preferred in women with a history of thrombo-embolic disease.
Estrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a result of hypogonadism, castration, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Estrogens can also be used to suppress lactation after child birth.
Hormone-receptor-positive breast cancers are treated with drugs which suppress production in the body of estrogen.[11] This technique, in the context of treatment of breast cancer, is known variously as hormonal therapy, hormone therapy, or anti-estrogen therapy (not to be confused with hormone replacement therapy). Certain foods such as soy may also suppress the effects of estrogen and are used as an alternative to hormone therapy.[12]
In humans and mice, estrogen promotes wound healing.[13]
At one time, estrogen was used to induce growth attenuation in tall girls.[14] Recently, estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size.[15]
Under certain circumstances, estrogen may also be used in males for treatment of prostate cancer.[16]
Most recently, estrogen has been used in experimental research as a way to treat patients suffering from bulimia nervosa, in addition to Cognitive Behavioral Therapy, which is the established standard for treatment in bulimia cases. The estrogen research hypothesizes that the disease may be linked to a hormonal imbalance in the brain.[17]
Estrogen has also been used in studies which indicate that it may be an effective drug for use in the treatment of traumatic liver injury.[18]
# Health risks and warning labels
The labeling of estrogen-only products in the U.S. includes a boxed warning that unopposed estrogen (without progestagen) therapy increases the risk of endometrial cancer.
Based on a review of data from the WHI, on January 8, 2003 the FDA changed the labeling of all estrogen and estrogen with progestin products for use by postmenopausal women to include a new boxed warning about cardiovascular and other risks. The estrogen-alone substudy of the WHI reported an increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using 0.625 mg of Premarin conjugated equine estrogens (CEE). The estrogen-plus-progestin substudy of the WHI reported an increased risk of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli and DVT in postmenopausal women 50 years of age or older and an increased risk of dementia in postmenopausal women 65 years of age or older using PremPro, which is 0.625 mg of CEE with 2.5 mg of the progestin medroxyprogesterone acetate (MPA).[19][20][21]
# Estrogens in cosmetics
Some hair shampoos on the market include estrogens and placental extracts; others contain phytoestrogens. There are case reports of young children developing breasts after exposure to these shampoos. [22] These products are often marketed to African-American consumers.[23]
On September 9, 1993, the FDA determined that not all topically-applied hormone-containing drug products for OTC human use are generally recognized as safe and effective and are misbranded. An accompanying proposed rule deals with cosmetics, concluding that any use of natural estrogens in a cosmetic product makes the product an unapproved new drug and that any cosmetic using the term "hormone" in the text of its labeling or in its ingredient statement makes an implied drug claim, subjecting such a product to regulatory action.[24]
In addition to being considered misbranded drugs, products claiming to contain placental extract may also be deemed to be misbranded cosmetics if the extract has been prepared from placentas from which the hormones and other biologically active substances have been removed and the extracted substance consists principally of protein. The FDA recommends that this substance be identified by a name other than "placental extract" and describing its composition more accurately because consumers associate the name "placental extract" with a therapeutic use of some biological activity.[24]
# History
The existence and effects of estrogen were established from 1923 to 1938 in which the formulation was led by a group of scientists instead of pharmaceutical companies. Thereafter, the market for hormonal drug research opened up.
The “first orally effective estrogen”, Emmenin, derived from the late-pregnancy urine of Canadian women, was introduced in 1930 by Collip and Ayerst Laboratories . Estrogens are not water-soluble and cannot be given orally, but the urine was found to contain estriol glucuronide which is water soluble and becomes active in the body after hydrolization.
Scientists continued to search for new sources of estrogen because of concerns associated with the practicality of introducing the drug into the market. At the same time, a German pharmaceutical drug company, formulated a similar product as Emmenin that was introduced to German women to treat menopausal symptoms.
In 1938, British scientists obtained a patent on a newly formulated nonsteroidal estrogen, Diethylstilbestrol (DES), that was cheaper and more powerful than the previously manufactured estrogens. Soon after, concerns over the side effects of DES were raised in scientific journals while the drug manufacturers came together to lobby for governmental approval of DES. It was only until 1941 when estrogen therapy was finally approved by the Food and Drug Administration (FDA) for the treatment of menopausal symptoms. [25] | https://www.wikidoc.org/index.php/Estrogen | |
7cc37c508a34458d6cbd2074efe82239ee742366 | wikidoc | Ethotoin | Ethotoin
# 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
Ethotoin is an anticonvulsant that is FDA approved for the treatment of tonic-clonic (grand mal) and complex partial (psychomotor) seizures. Common adverse reactions include stevens-johnson syndrome, disorder of hematopoietic structure, megaloblastic anemia, lymphadenopathy, systemic lupus erythematosus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ethotoin is indicated for the control of tonic-clonic (grand mal) and complex partial (psychomotor) seizures.
- Ethotoin is administered orally in 4 to 6 divided doses daily. The drug should be taken after food, and doses should be spaced as evenly as practicable. Initial dosage should be conservative. For adults, the initial daily dose should be 1 g or less, with subsequent gradual dosage increases over a period of several days. The optimum dosage must be determined on the basis of individual response. The usual adult maintenance dose is 2 to 3 g daily. Less than 2 g daily has been found ineffective in most adults.
- Pediatric dosage depends upon the age and weight of the patient. The initial dose should not exceed 750 mg daily. The usual maintenance dose in children ranges from 500 mg to 1 g daily, although occasionally 2 or (rarely) 3 g daily may be necessary.
- If a patient is receiving another antiepileptic drug, it should not be discontinued when PEGANONE therapy is begun. The dosage of the other drug should be reduced gradually as that of PEGANONE is increased. PEGANONE may eventually replace the other drug or the optimal dosage of both antiepileptics may be established.
- In tonic-clonic (grand mal) seizures, use of the drug with phenobarbital may be beneficial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethotoin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethotoin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ethotoin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethotoin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethotoin in pediatric patients.
# Contraindications
- Ethotoin is contraindicated in patients with hepatic abnormalities or hematologic disorders.
# Warnings
- Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including PEGANONE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. TABLE 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing PEGANONE or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
- Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Use in Pregnancy: ethotoin can cause fetal harm when administered to a pregnant woman. There are multiple reports in the clinical literature which indicate that the use of antiepileptic drugs during pregnancy results in an increased incidence of birth defects in the offspring. Although data are more extensive with respect to phenytoin and phenobarbital, reports indicate a possible similar association with the use of other antiepileptic drugs. Therefore, antiepileptic drugs should be administered to women of child-bearing potential only if they are clearly shown to be essential in the management of their seizures.
- Antiepileptic drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risk to both mother and the unborn child. Consideration should, however, be given to discontinuation of antiepileptics prior to and during pregnancy when the nature, frequency and severity of the seizures do not pose a serious threat to the patient. It is not, however, known whether even minor seizures constitute some risk to the developing embryo or fetus.
- Reports have suggested that the maternal ingestion of antiepileptic drugs, particularly barbiturates, is associated with a neonatal coagulation defect that may cause bleeding during the early (usually within 24 hours of birth) neonatal period. The possibility of the occurrence of this defect with the use of PEGANONE should be kept in mind. The defect is characterized by decreased levels of vitamin k-dependent clotting factors, and prolongation of either the prothrombin time or the partial thromboplastin time, or both. It has been suggested that vitamin k be given prophylactically to the mother one month prior to and during delivery, and the infant, intravenously, immediately after birth.
- If PEGANONE 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.
- To provide information regarding the effects of in utero exposure to PEGANONE, physicians are advised to recommend that pregnant patients taking PEGANONE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Ethotoin in the drug label.
## Postmarketing Experience
- Adverse reactions associated with PEGANONE, in decreasing order of severity, are:
- Isolated cases of lymphadenopathy and systemic lupus erythematosus have been reported in patients taking hydantoin compounds, and lymphadenopathy has occurred with PEGANONE. Withdrawal of therapy has resulted in remission of the clinical and pathological findings. Therefore, if a lymphoma-like syndrome develops, the drug should be withdrawn and the patient should be closely observed for regression of signs and symptoms before treatment is resumed.
- Ataxia and gum hypertrophy have occurred only rarely—usually only in patients receiving an additional hydantoin derivative. It is of interest to note that ataxia and gum hypertrophy have subsided in patients receiving other hydantoins when ethotoin was given as a substitute antiepileptic.
- Occasionally, vomiting or nausea after ingestion of PEGANONE has been reported, but if the drug is administered after meals, the incidence of gastric distress is reduced. Other side effects have included chest pain, nystagmus, diplopia, fever, dizziness, diarrhea, headache, insomnia, fatigue, numbness, skin rash, and Stevens-Johnson syndrome.
# Drug Interactions
There is limited information regarding Ethotoin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- ethotoin can cause fetal harm when administered to a pregnant woman. There are multiple reports in the clinical literature which indicate that the use of antiepileptic drugs during pregnancy results in an increased incidence of birth defects in the offspring. Although data are more extensive with respect to phenytoin and phenobarbital, reports indicate a possible similar association with the use of other antiepileptic drugs.
- Therefore, antiepileptic drugs should be administered to women of child-bearing potential only if they are clearly shown to be essential in the management of their seizures.
- Antiepileptic drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risk to both mother and the unborn child. Consideration should, however, be given to discontinuation of antiepileptics prior to and during pregnancy when the nature, frequency and severity of the seizures do not pose a serious threat to the patient. It is not, however, known whether even minor seizures constitute some risk to the developing embryo or fetus.
- Reports have suggested that the maternal ingestion of antiepileptic drugs, particularly barbiturates, is associated with a neonatal coagulation defect that may cause bleeding during the early (usually within 24 hours of birth) neonatal period. The possibility of the occurrence of this defect with the use of PEGANONE should be kept in mind. The defect is characterized by decreased levels of vitamin k-dependent clotting factors, and prolongation of either the prothrombin time or the partial thromboplastin time, or both. It has been suggested that vitamin k be given prophylactically to the mother one month prior to and during delivery, and the infant, intravenously, immediately after birth.
- If PEGANONE 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.
- Reports have suggested that the maternal ingestion of antiepileptic drugs, particularly barbiturates, is associated with a neonatal coagulation defect that may cause bleeding during the early (usually within 24 hours of birth) neonatal period. The possibility of the occurrence of this defect with the use of PEGANONE should be kept in mind.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ethotoin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ethotoin during labor and delivery.
### Nursing Mothers
- Ethotoin is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from ethotoin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Ethotoin with respect to pediatric patients.
### Geriatic Use
- Clinical studies of PEGANONE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Ethotoin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ethotoin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ethotoin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ethotoin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ethotoin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ethotoin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
# IV Compatibility
There is limited information regarding IV Compatibility of Ethotoin in the drug label.
# Overdosage
- Symptoms of acute overdosage include drowsiness, visual disturbance, nausea and ataxia. Coma is possible at very high dosage.
- Treatment should be begun by inducing emesis; gastric lavage may be considered as an alternative. General supportive measures will be necessary. A careful evaluation of blood-forming organs should be made following recovery.
# Pharmacology
## Mechanism of Action
- Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges.
## Structure
- Ethotoin is an oral antiepileptic of the hydantoin series and is chemically identified as 3-ethyl-5-phenyl-2,4-imidazolidinedione. It is represented by the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ethotoin in the drug label.
## Pharmacokinetics
- Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ethotoin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ethotoin in the drug label.
# How Supplied
- Ethotoin 250 mg grooved, white tablets bearing the letters OV on one side and the number 61 on the other and are supplied in bottles of 100 (NDC 55292-601-01).
## Storage
Recommended storage: Store at 20-25ºC (68-77ºF).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Read this Medication Guide before you start taking PEGANONE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
- What is the most important information I should know about PEGANONE?
- Do not stop taking PEGANONE without first talking to your healthcare provider.
- Stopping PEGANONE suddenly can cause serious problems.
- PEGANONE can cause serious side effects, including:
- Like other antiepileptic drugs, PEGANONE may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
- Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- Thoughts about suicide or dying
- Attempts to commit suicide
- New or worse depression
- New or worse anxiety
- Feeling agitated or restless
- Panic attacks
- Trouble sleeping (insomnia)
- New or worse irritability
- Acting aggressive, being angry, or violent
- Acting on dangerous impulses
- An extreme increase in activity and talking (mania)
- Other unusual changes in behavior or mood
- How can I watch for early symptoms of suicidal thoughts and actions?
- Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
- Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Do not stop PEGANONE without first talking to a healthcare provider.
- Stopping PEGANONE suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
- Suicidal thoughts or actions can be caused by things other than medicines. - If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- What is PEGANONE?
- PEGANONE is a prescription medicine used to treat tonic-clonic (grand mal) and complex partial (psychomotor) seizures.
- It is not known if PEGANONE is safe or effective in children younger than 1 year old.
- Who should not take PEGANONE?
- Do not take PEGANONE if you have:
- Liver problems
- Blood problems
- What should I tell my healthcare provider before taking PEGANONE?
- Before you take PEGANONE, tell your healthcare provider if you:
- Have or have had depression, mood problems, or suicidal thoughts or behavior
- Have any other medical conditions
- Are pregnant or plan to become pregnant. PEGANONE may harm your unborn baby and cause birth defects. Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
- Tell your healthcare provider right away if you become pregnant while taking PEGANONE. You and your healthcare provider should decide if you will take PEGANONE while you are pregnant.
- If you become pregnant while taking PEGANONE, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
- Are breastfeeding or plan to breastfeed. PEGANONE can pass into breast milk.
- You and your healthcare provider should decide if you will take PEGANONE or breast feed. You should not do both. Talk to your healthcare provider about the best way to feed your baby if you take PEGANONE.
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Taking PEGANONE with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
- Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
- Especially tell your healthcare provider if you take medicines that affect blood clotting.
- How should I take PEGANONE?
- Take PEGANONE exactly as your healthcare provider tells you. Your healthcare provider will tell you how much PEGANONE to take.
- Your healthcare provider may change your dose. Do not change your dose of PEGANONE without talking to your healthcare provider.
- Do not stop taking PEGANONE without first talking to your healthcare provider. Stopping PEGANONE suddenly can cause serious problems.
- Take PEGANONE after eating, and space doses out evenly.
- If you take too much PEGANONE, call your healthcare provider or local Poison Control Center right away.
- What are the possible side effects of PEGANONE?
- See “What is the most important information I should know about PEGANONE?”.
- PEGANONE may cause other rare, but serious side effects. These include:
- Blood problems – symptoms may include: not feeling well, sore throat, fever, bruising easily, red or purple spots on your body, nose bleed
- Liver problems – symptoms may include: yellowing of your skin or the whites of your eyes (jaundice), dark urine, nausea or vomiting, loss of appetite, pain on the right side of your stomach, bruising easily.
- Swollen glands (enlarged lymph nodes)
- Lupus – symptoms may include: a rash on your cheeks or other parts of your body, sensitivity to the sun, new joint or muscle pains, chest pain or shortness of breath, swelling of your feet, ankles, and legs.
- Serious rash – symptoms may include: skin rash, hives, sore throat, sores in your mouth, your skin blisters and peels, swelling of your face,eyes, lips, tongue, or throat.
- Call your healthcare provider right away if you have any of the symptoms listed above.
- The most common side effects of PEGANONE include:
- Nausea or vomiting
- Tiredness
- Rash
- Dizziness
- Jerky eye movements
- Problems with walking and balance
- Double vision
- Overgrowth of gum tissue
- These are not all the possible side effects of PEGANONE. For more information, ask your healthcare provider or pharmacist.
- Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How should I store PEGANONE?
- Store at 20-25°C (68-77°F).
- Keep PEGANONE in a tightly closed container, and keep PEGANONE out of the light.
- Keep PEGANONE and all medicines out of the reach of children.
- General Information about PEGANONE
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PEGANONE for a condition for which it was not prescribed. Do not give PEGANONE to other people, even if they have the same symptoms that you have. It may harm them.
- This Medication Guide summarizes the most important information about PEGANONE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about PEGANONE that is written for health professionals.
- For more information, go to www.recordatirarediseases.com or call 1-888-575-8344.
# Precautions with Alcohol
- Alcohol-Ethotoin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PEGANONE ®
# Look-Alike Drug Names
There is limited information regarding Ethotoin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ethotoin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
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# Overview
Ethotoin is an anticonvulsant that is FDA approved for the treatment of tonic-clonic (grand mal) and complex partial (psychomotor) seizures. Common adverse reactions include stevens-johnson syndrome, disorder of hematopoietic structure, megaloblastic anemia, lymphadenopathy, systemic lupus erythematosus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ethotoin is indicated for the control of tonic-clonic (grand mal) and complex partial (psychomotor) seizures.
- Ethotoin is administered orally in 4 to 6 divided doses daily. The drug should be taken after food, and doses should be spaced as evenly as practicable. Initial dosage should be conservative. For adults, the initial daily dose should be 1 g or less, with subsequent gradual dosage increases over a period of several days. The optimum dosage must be determined on the basis of individual response. The usual adult maintenance dose is 2 to 3 g daily. Less than 2 g daily has been found ineffective in most adults.
- Pediatric dosage depends upon the age and weight of the patient. The initial dose should not exceed 750 mg daily. The usual maintenance dose in children ranges from 500 mg to 1 g daily, although occasionally 2 or (rarely) 3 g daily may be necessary.
- If a patient is receiving another antiepileptic drug, it should not be discontinued when PEGANONE therapy is begun. The dosage of the other drug should be reduced gradually as that of PEGANONE is increased. PEGANONE may eventually replace the other drug or the optimal dosage of both antiepileptics may be established.
- In tonic-clonic (grand mal) seizures, use of the drug with phenobarbital may be beneficial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethotoin in adult patients.
### Non–Guideline-Supported Use
=
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethotoin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ethotoin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ethotoin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethotoin in pediatric patients.
# Contraindications
- Ethotoin is contraindicated in patients with hepatic abnormalities or hematologic disorders.
# Warnings
- Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including PEGANONE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. TABLE 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing PEGANONE or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.
- Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Use in Pregnancy: ethotoin can cause fetal harm when administered to a pregnant woman. There are multiple reports in the clinical literature which indicate that the use of antiepileptic drugs during pregnancy results in an increased incidence of birth defects in the offspring. Although data are more extensive with respect to phenytoin and phenobarbital, reports indicate a possible similar association with the use of other antiepileptic drugs. Therefore, antiepileptic drugs should be administered to women of child-bearing potential only if they are clearly shown to be essential in the management of their seizures.
- Antiepileptic drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risk to both mother and the unborn child. Consideration should, however, be given to discontinuation of antiepileptics prior to and during pregnancy when the nature, frequency and severity of the seizures do not pose a serious threat to the patient. It is not, however, known whether even minor seizures constitute some risk to the developing embryo or fetus.
- Reports have suggested that the maternal ingestion of antiepileptic drugs, particularly barbiturates, is associated with a neonatal coagulation defect that may cause bleeding during the early (usually within 24 hours of birth) neonatal period. The possibility of the occurrence of this defect with the use of PEGANONE should be kept in mind. The defect is characterized by decreased levels of vitamin k-dependent clotting factors, and prolongation of either the prothrombin time or the partial thromboplastin time, or both. It has been suggested that vitamin k be given prophylactically to the mother one month prior to and during delivery, and the infant, intravenously, immediately after birth.
- If PEGANONE 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.
- To provide information regarding the effects of in utero exposure to PEGANONE, physicians are advised to recommend that pregnant patients taking PEGANONE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Ethotoin in the drug label.
## Postmarketing Experience
- Adverse reactions associated with PEGANONE, in decreasing order of severity, are:
- Isolated cases of lymphadenopathy and systemic lupus erythematosus have been reported in patients taking hydantoin compounds, and lymphadenopathy has occurred with PEGANONE. Withdrawal of therapy has resulted in remission of the clinical and pathological findings. Therefore, if a lymphoma-like syndrome develops, the drug should be withdrawn and the patient should be closely observed for regression of signs and symptoms before treatment is resumed.
- Ataxia and gum hypertrophy have occurred only rarely—usually only in patients receiving an additional hydantoin derivative. It is of interest to note that ataxia and gum hypertrophy have subsided in patients receiving other hydantoins when ethotoin was given as a substitute antiepileptic.
- Occasionally, vomiting or nausea after ingestion of PEGANONE has been reported, but if the drug is administered after meals, the incidence of gastric distress is reduced. Other side effects have included chest pain, nystagmus, diplopia, fever, dizziness, diarrhea, headache, insomnia, fatigue, numbness, skin rash, and Stevens-Johnson syndrome.
# Drug Interactions
There is limited information regarding Ethotoin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- ethotoin can cause fetal harm when administered to a pregnant woman. There are multiple reports in the clinical literature which indicate that the use of antiepileptic drugs during pregnancy results in an increased incidence of birth defects in the offspring. Although data are more extensive with respect to phenytoin and phenobarbital, reports indicate a possible similar association with the use of other antiepileptic drugs.
- Therefore, antiepileptic drugs should be administered to women of child-bearing potential only if they are clearly shown to be essential in the management of their seizures.
- Antiepileptic drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risk to both mother and the unborn child. Consideration should, however, be given to discontinuation of antiepileptics prior to and during pregnancy when the nature, frequency and severity of the seizures do not pose a serious threat to the patient. It is not, however, known whether even minor seizures constitute some risk to the developing embryo or fetus.
- Reports have suggested that the maternal ingestion of antiepileptic drugs, particularly barbiturates, is associated with a neonatal coagulation defect that may cause bleeding during the early (usually within 24 hours of birth) neonatal period. The possibility of the occurrence of this defect with the use of PEGANONE should be kept in mind. The defect is characterized by decreased levels of vitamin k-dependent clotting factors, and prolongation of either the prothrombin time or the partial thromboplastin time, or both. It has been suggested that vitamin k be given prophylactically to the mother one month prior to and during delivery, and the infant, intravenously, immediately after birth.
- If PEGANONE 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.
- Reports have suggested that the maternal ingestion of antiepileptic drugs, particularly barbiturates, is associated with a neonatal coagulation defect that may cause bleeding during the early (usually within 24 hours of birth) neonatal period. The possibility of the occurrence of this defect with the use of PEGANONE should be kept in mind.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ethotoin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ethotoin during labor and delivery.
### Nursing Mothers
- Ethotoin is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from ethotoin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Ethotoin with respect to pediatric patients.
### Geriatic Use
- Clinical studies of PEGANONE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Ethotoin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ethotoin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ethotoin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ethotoin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ethotoin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ethotoin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
# IV Compatibility
There is limited information regarding IV Compatibility of Ethotoin in the drug label.
# Overdosage
- Symptoms of acute overdosage include drowsiness, visual disturbance, nausea and ataxia. Coma is possible at very high dosage.
- Treatment should be begun by inducing emesis; gastric lavage may be considered as an alternative. General supportive measures will be necessary. A careful evaluation of blood-forming organs should be made following recovery.
# Pharmacology
## Mechanism of Action
- Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges.
## Structure
- Ethotoin is an oral antiepileptic of the hydantoin series and is chemically identified as 3-ethyl-5-phenyl-2,4-imidazolidinedione. It is represented by the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ethotoin in the drug label.
## Pharmacokinetics
- Ethotoin exerts an antiepileptic effect without causing general central nervous system depression. The mechanism of action is probably very similar to that of phenytoin. The latter drug appears to stabilize rather than to raise the normal seizure threshold, and to prevent the spread of seizure activity rather than to abolish the primary focus of seizure discharges.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ethotoin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Ethotoin in the drug label.
# How Supplied
- Ethotoin 250 mg grooved, white tablets bearing the letters OV on one side and the number 61 on the other and are supplied in bottles of 100 (NDC 55292-601-01).
## Storage
Recommended storage: Store at 20-25ºC (68-77ºF).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Read this Medication Guide before you start taking PEGANONE and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
- What is the most important information I should know about PEGANONE?
- Do not stop taking PEGANONE without first talking to your healthcare provider.
- Stopping PEGANONE suddenly can cause serious problems.
- PEGANONE can cause serious side effects, including:
- Like other antiepileptic drugs, PEGANONE may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.
- Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
- Thoughts about suicide or dying
- Attempts to commit suicide
- New or worse depression
- New or worse anxiety
- Feeling agitated or restless
- Panic attacks
- Trouble sleeping (insomnia)
- New or worse irritability
- Acting aggressive, being angry, or violent
- Acting on dangerous impulses
- An extreme increase in activity and talking (mania)
- Other unusual changes in behavior or mood
- How can I watch for early symptoms of suicidal thoughts and actions?
- Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled.
- Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Do not stop PEGANONE without first talking to a healthcare provider.
- Stopping PEGANONE suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).
- Suicidal thoughts or actions can be caused by things other than medicines. * If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
- What is PEGANONE?
- PEGANONE is a prescription medicine used to treat tonic-clonic (grand mal) and complex partial (psychomotor) seizures.
- It is not known if PEGANONE is safe or effective in children younger than 1 year old.
- Who should not take PEGANONE?
- Do not take PEGANONE if you have:
- Liver problems
- Blood problems
- What should I tell my healthcare provider before taking PEGANONE?
- Before you take PEGANONE, tell your healthcare provider if you:
- Have or have had depression, mood problems, or suicidal thoughts or behavior
- Have any other medical conditions
- Are pregnant or plan to become pregnant. PEGANONE may harm your unborn baby and cause birth defects. Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
- Tell your healthcare provider right away if you become pregnant while taking PEGANONE. You and your healthcare provider should decide if you will take PEGANONE while you are pregnant.
- If you become pregnant while taking PEGANONE, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.
- Are breastfeeding or plan to breastfeed. PEGANONE can pass into breast milk.
- You and your healthcare provider should decide if you will take PEGANONE or breast feed. You should not do both. Talk to your healthcare provider about the best way to feed your baby if you take PEGANONE.
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Taking PEGANONE with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
- Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
- Especially tell your healthcare provider if you take medicines that affect blood clotting.
- How should I take PEGANONE?
- Take PEGANONE exactly as your healthcare provider tells you. Your healthcare provider will tell you how much PEGANONE to take.
- Your healthcare provider may change your dose. Do not change your dose of PEGANONE without talking to your healthcare provider.
- Do not stop taking PEGANONE without first talking to your healthcare provider. Stopping PEGANONE suddenly can cause serious problems.
- Take PEGANONE after eating, and space doses out evenly.
- If you take too much PEGANONE, call your healthcare provider or local Poison Control Center right away.
- What are the possible side effects of PEGANONE?
- See “What is the most important information I should know about PEGANONE?”.
- PEGANONE may cause other rare, but serious side effects. These include:
- Blood problems – symptoms may include: not feeling well, sore throat, fever, bruising easily, red or purple spots on your body, nose bleed
- Liver problems – symptoms may include: yellowing of your skin or the whites of your eyes (jaundice), dark urine, nausea or vomiting, loss of appetite, pain on the right side of your stomach, bruising easily.
- Swollen glands (enlarged lymph nodes)
- Lupus – symptoms may include: a rash on your cheeks or other parts of your body, sensitivity to the sun, new joint or muscle pains, chest pain or shortness of breath, swelling of your feet, ankles, and legs.
- Serious rash – symptoms may include: skin rash, hives, sore throat, sores in your mouth, your skin blisters and peels, swelling of your face,eyes, lips, tongue, or throat.
- Call your healthcare provider right away if you have any of the symptoms listed above.
- The most common side effects of PEGANONE include:
- Nausea or vomiting
- Tiredness
- Rash
- Dizziness
- Jerky eye movements
- Problems with walking and balance
- Double vision
- Overgrowth of gum tissue
- These are not all the possible side effects of PEGANONE. For more information, ask your healthcare provider or pharmacist.
- Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
- How should I store PEGANONE?
- Store at 20-25°C (68-77°F).
- Keep PEGANONE in a tightly closed container, and keep PEGANONE out of the light.
- Keep PEGANONE and all medicines out of the reach of children.
- General Information about PEGANONE
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use PEGANONE for a condition for which it was not prescribed. Do not give PEGANONE to other people, even if they have the same symptoms that you have. It may harm them.
- This Medication Guide summarizes the most important information about PEGANONE. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about PEGANONE that is written for health professionals.
- For more information, go to www.recordatirarediseases.com or call 1-888-575-8344.
# Precautions with Alcohol
- Alcohol-Ethotoin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PEGANONE ®[1]
# Look-Alike Drug Names
There is limited information regarding Ethotoin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ethotoin | |
d45ccaf2e546f4b9c1ddaee7203a9c749498ab57 | wikidoc | Etizolam | Etizolam
# Overview
Etizolam (marketed under the brand name Etilaam, Etizest, Etidev,Etizola, Sedekopan, Pasaden or Depas) is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring, making the drug a thienodiazepine. It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.
# Indications
- Short-term treatment of insomnia
- Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required
# Dosage
- Anxiety disorders associated with depression : 1 mg two to three times a day (maximum 3 mg per day)
- For panic disorder (associated with agoraphobia): 0.5 mg two times per day (maximum 1 mg per day)
- For insomnia: 1–2 mg once daily before bedtime
A 1 mg dose of etizolam is approximately equivalent to a 10 mg dose of diazepam, see List of benzodiazepines.
# Side effects
- Blepharospasms with long term use
Very Rare
- Erythema annulare centrifugum skin lesions
# Tolerance, dependence and withdrawal
Abrupt or rapid withdrawal from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia. Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.
In a study that compared the effectiveness of etizolam, alprazolam, and bromazepam for the treatment of generalized anxiety disorder, all three drugs retained their effectiveness over 2 weeks, but etizolam became more effective from 2 weeks to 4 weeks, a type of reverse tolerance. Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.
When multiple doses of etizolam, or lorazepam, were administered to rat neurons, lorazepam caused downregulation of alpha-1 benzodiazepine binding sites (tolerance/dependence), while etizolam caused an increase in alpha-2 benzodiazepine binding sites (reverse tolerance to anti-anxiety effects). Tolerance to the anticonvulsant effects of lorazepam were observed, but no significant tolerance to the anticonvulsant effects of etizolam were observed. Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classical benzodiazepines.
# Contraindications and special caution
Etizolam is metabolised by the liver and is contraindicated in those with severely impaired hepatic function. It may impair the ability to drive and operate machinery so caution should be applied. Elderly patients should start on a lower dose as they are more susceptible to the sedative effects of etizolam. It is not recommended to be taken during pregnancy or breastfeeding.
Etizolam can increase the sedative and antidepressant actions of other medication such as neuroleptics, analgesics, anaesthetics, antiepileptics, sedatives and first-generation antihistamines. Co-administration with these medications should be avoided unless instructed by a medical professional. Alcohol should also be avoided.
Drugs inhibiting the enzymes CYP2C19 and CYP3A4, such as fluvoxamine, should not be taken concurrently as etizolam can increase the plasma levels of these enzymes.
# Pharmacology
Etizolam, a thienodiazepine derivative, is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half life of about 3.5 hours. Etizolam possesses potent hypnotic properties, and is comparable with other short-acting benzodiazepines. Etizolam acts as a full agonist at the benzodiazepine receptor to produce its range of therapeutic and adverse effects. Similar to other benzodiazepines, etizolam binds non-selectively to benzodiazepine receptor subtypes.
In addition, etizolam, unlike most other benzodiazepines (some of which can increase levels of estradiol), has prolactogenic effects, leading to an increase in blood levels of prolactin.
According to the Italian P.I. sheet, etizolam belongs to a new class of diazepines, thienotriazolodiazepines. This new class is easily oxidized, rapidly metabolized, and has a lower risk of accumulation, even after prolonged treatment. Etizolam has an anxiolytic action about 6 times greater than that of diazepam. Etizolam produces, especially at higher dosages, a reduction in time taken to fall asleep, an increase in total sleep time, and a reduction in the number of awakenings. During tests, there were not substantial changes in deep sleep; however, it may reduce REM sleep. In EEG tests of healthy volunteers, etizolam showed some characteristics of tricyclic antidepressants.
# Legal status
## United States
Etizolam is not authorized for medical use in the U.S. However, it currently remains unscheduled and is legal for research purposes. As it is a thienodiazepine, an analog of benzodiazepines, which are Schedule IV drug under Federal Scheduling Guidelines, it does not fall under the Federal Analog Act, which only applies to Schedule I and II drugs.
Etizolam is a controlled substance in the following states: Alabama, Arkansas and Mississippi.
## United Kingdom
Unlike other thienodiazepines such as brotizolam and clotiazepam, etizolam is not controlled under the Misuse of Drugs Act 1971 or licensed as a medicine in the United Kingdom.
## Germany
Etizolam was controlled in Germany in July 2013.
## Poland
Etizolam may be scheduled under the Act on Counteracting Drug Addiction and the State Sanitary Inspection -Article 27c
# Interactions
Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects. Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.
Etizolam, similarly to other GABAergic agonists including the benzodiazepines has a strong synergistic effect with ethanol and the consequences of co-ingestion of the two drugs can drastically compound the side effects of either drug.Template:Medcn This can result in (among other effects) anterograde amnesia (blackouts) and severe respiratory depression which in extreme cases can lead to death.Template:Medcn
# Overdose
Cases of intentional suicide by overdose using etizolam have been reported. Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose. Many lethal etizolam overdoses were due to drug interactions.
# Abuse
Etizolam is a drug of potential abuse. However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.
According to the Journal of the American Medical Association, benzodiazepines — either alone or mixed with other drugs — were involved in nearly 30 percent of fatal overdoses in the United States in 2010. A Japanese study published in Forensic Science International revealed that metabolic traces of etizolam were detected in two people who died of lethal drug overdoses. Fast-acting benzodiazepines may produce side effects very quickly, especially if the user is taking other drugs. | Etizolam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Etizolam (marketed under the brand name Etilaam, Etizest, Etidev,Etizola, Sedekopan, Pasaden or Depas) is a benzodiazepine analog.[1] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring, making the drug a thienodiazepine.[2] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.[3]
# Indications
- Short-term treatment of insomnia[4]
- Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required[5]
# Dosage
- Anxiety disorders associated with depression : 1 mg two to three times a day (maximum 3 mg per day)
- For panic disorder (associated with agoraphobia): 0.5 mg two times per day (maximum 1 mg per day)
- For insomnia: 1–2 mg once daily before bedtime[6]
A 1 mg dose of etizolam is approximately equivalent to a 10 mg dose of diazepam, see List of benzodiazepines.
# Side effects
- Blepharospasms with long term use[7]
Very Rare
- Erythema annulare centrifugum skin lesions[8]
# Tolerance, dependence and withdrawal
Abrupt or rapid withdrawal from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.[9] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.[10]
In a study that compared the effectiveness of etizolam, alprazolam, and bromazepam for the treatment of generalized anxiety disorder, all three drugs retained their effectiveness over 2 weeks, but etizolam became more effective from 2 weeks to 4 weeks, a type of reverse tolerance.[11] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.[12]
When multiple doses of etizolam, or lorazepam, were administered to rat neurons, lorazepam caused downregulation of alpha-1 benzodiazepine binding sites (tolerance/dependence), while etizolam caused an increase in alpha-2 benzodiazepine binding sites (reverse tolerance to anti-anxiety effects).[13] Tolerance to the anticonvulsant effects of lorazepam were observed, but no significant tolerance to the anticonvulsant effects of etizolam were observed.[13] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classical benzodiazepines.[13]
# Contraindications and special caution
Etizolam is metabolised by the liver and is contraindicated in those with severely impaired hepatic function. It may impair the ability to drive and operate machinery so caution should be applied. Elderly patients should start on a lower dose as they are more susceptible to the sedative effects of etizolam. It is not recommended to be taken during pregnancy or breastfeeding.[6]
Etizolam can increase the sedative and antidepressant actions of other medication such as neuroleptics, analgesics, anaesthetics, antiepileptics, sedatives and first-generation antihistamines. Co-administration with these medications should be avoided unless instructed by a medical professional. Alcohol should also be avoided.[6]
Drugs inhibiting the enzymes CYP2C19 and CYP3A4, such as fluvoxamine, should not be taken concurrently as etizolam can increase the plasma levels of these enzymes.[6]
# Pharmacology
Etizolam, a thienodiazepine derivative, is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half life of about 3.5 hours.[14] Etizolam possesses potent hypnotic properties,[15] and is comparable with other short-acting benzodiazepines.[14] Etizolam acts as a full agonist at the benzodiazepine receptor to produce its range of therapeutic and adverse effects.[16] Similar to other benzodiazepines, etizolam binds non-selectively to benzodiazepine receptor subtypes.[dubious – discuss][17]
In addition, etizolam, unlike most other benzodiazepines (some of which can increase levels of estradiol), has prolactogenic effects, leading to an increase in blood levels of prolactin.[18]
According to the Italian P.I. sheet[citation needed], etizolam belongs to a new class of diazepines, thienotriazolodiazepines. This new class is easily oxidized, rapidly metabolized, and has a lower risk of accumulation, even after prolonged treatment. Etizolam has an anxiolytic action about 6 times greater than that of diazepam. Etizolam produces, especially at higher dosages, a reduction in time taken to fall asleep, an increase in total sleep time, and a reduction in the number of awakenings. During tests, there were not substantial changes in deep sleep; however, it may reduce REM sleep. In EEG tests of healthy volunteers, etizolam showed some characteristics of tricyclic antidepressants.[5]
# Legal status
## United States
Etizolam is not authorized for medical use in the U.S. However, it currently remains unscheduled and is legal for research purposes. As it is a thienodiazepine, an analog of benzodiazepines, which are Schedule IV drug under Federal Scheduling Guidelines, it does not fall under the Federal Analog Act, which only applies to Schedule I and II drugs.[19]
Etizolam is a controlled substance in the following states: Alabama, Arkansas[20] and Mississippi.[21]
## United Kingdom
Unlike other thienodiazepines such as brotizolam and clotiazepam, etizolam is not controlled under the Misuse of Drugs Act 1971 or licensed as a medicine in the United Kingdom.[22]
## Germany
Etizolam was controlled in Germany in July 2013.[23]
## Poland
Etizolam may be scheduled under the Act on Counteracting Drug Addiction and the State Sanitary Inspection -Article 27c
# Interactions
Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.[24][25] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.[26]
Etizolam, similarly to other GABAergic agonists including the benzodiazepines has a strong synergistic effect with ethanol and the consequences of co-ingestion of the two drugs can drastically compound the side effects of either drug.Template:Medcn This can result in (among other effects) anterograde amnesia (blackouts) and severe respiratory depression which in extreme cases can lead to death.Template:Medcn
# Overdose
Cases of intentional suicide by overdose using etizolam have been reported.[27] Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose. Many lethal etizolam overdoses were due to drug interactions.[citation needed]
# Abuse
Etizolam is a drug of potential abuse. However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.[28]
According to the Journal of the American Medical Association, benzodiazepines — either alone or mixed with other drugs — were involved in nearly 30 percent of fatal overdoses in the United States in 2010. A Japanese study published in Forensic Science International revealed that metabolic traces of etizolam were detected in two people who died of lethal drug overdoses. Fast-acting benzodiazepines may produce side effects very quickly, especially if the user is taking other drugs. | https://www.wikidoc.org/index.php/Etizolam | |
a8b454c36ed020933c431b1a40f697093fa2fcab | wikidoc | Etodolac | Etodolac
# 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
Etodolac is an analgesic, anti-inflammatory agent that is FDA approved for the treatment of juvenile arthritis, rheumatoid arthritis, osteoarthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, abdominal pain, diarrhea, flatulance, indigestion, nausea, increased liver function test, dizziness, headache, malaise.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- For the relief of the signs and symptoms of osteoarthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day.
- As with other NSAID s, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.
- Dosing Information
- Immediate release, 200 to 400 mg ORALLY every 6 to 8 h as needed; max 1200 mg/day
- Dosing Information
- For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day.
- As with other NSAIDs, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Gout
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Etodolac in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- For the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 6 to 16 years of age, the recommended dose given orally once per day should be based on body weight, according to the following table:
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Etodolac in pediatric patients.
### Non–Guideline-Supported Use
- Rheumatoid arthritis
# Contraindications
- Etodolac extended-release tablets are contraindicated in patients with known hypersensitivity to etodolac.
- Etodolac extended-release tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
- Etodolac extended-release tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
# Warnings
Cardiovascular Effects
Cardiovascular Thrombotic Events
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see GI WARNINGS).
- Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
- NSAIDs, including etodolac extended-release tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including etodolac extended-release tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
- Fluid retention and edema have been observed in some patients taking NSAIDs. Etodolac extended-release tablets should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
- NSAIDs, including etodolac extended-release tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
- No information is available from controlled clinical studies regarding the use of etodolac extended-release tablets in patients with advanced renal disease. Therefore, treatment with etodolac extended-release tablets is not recommended in these patients with advanced renal disease. If etodolac extended-release tablet therapy must be initiated, close monitoring of the patient's renal function is advisable.
Anaphylactoid Reactions
- As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to etodolac extended-release tablets. Etodolac extended-release tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
- NSAIDs, including etodolac extended-release tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
- In late pregnancy, as with other NSAIDs, etodolac extended-release tablets should be avoided because it may cause premature closure of the ductus arteriosus.
### PRECAUTIONS
General
- Etodolac extended-release tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
- The pharmacological activity of etodolac extended-release tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
- Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including etodolac extended-release tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
- A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with etodolac extended-release tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), etodolac extended-release tablets should be discontinued.
Hematological Effects
- Anemia is sometimes seen in patients receiving NSAIDs, including etodolac extended-release tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including etodolac extended-release tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving etodolac extended-release tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
- Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, etodolac extended-release tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Etodolac extended-release tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
- Etodolac extended-release tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
- Etodolac extended-release tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
- In late pregnancy, as with other NSAIDs, etodolac extended-release tablets should be avoided because it will cause premature closure of the ductus arteriosus.
Laboratory Tests
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, etodolac extended-release tablets should be discontinued.
# Adverse Reactions
## Clinical Trials Experience
- A total of 1552 patients were exposed to etodolac extended-release tablets in controlled clinical studies of at least 4 weeks in length and using daily doses in the range of 400 to 1200 mg. In the tabulations below, adverse event rates are generally categorized based on the incidence of events in the first 30 days of treatment with etodolac extended-release tablets. As with other NSAIDs, the cumulative adverse event rates may increase significantly over time with extended therapy.
- In patients taking NSAIDs, including etodolac extended-release tablets, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are:
- gastrointestinal experiences including:
- Adverse events that were observed in < 1% of patients in the first 30 days of treatment with etodolac extended-release tablets in clinical trials.
- Additional NSAID Adverse Experiences Reported Occasionally with NSAIDs or Etodolac Extended-Release Tablets Include
- Body as a whole - allergic reaction, anaphylactic/anaphylactoid reactions (including shock), chills, fever, sepsis
- Cardiovascular system - congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic)
- Digestive system - anorexia, cholestatic hepatitis, cholestatic jaundice, dry mouth, duodenitis, eructation, esophagitis, gastritis, gastric/peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis
- Hemic and lymphatic system - agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia
- Metabolic and nutritional - hyperglycemia in previously controlled diabetic patients
- Nervous system - anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo
- Respiratory system - asthma, dyspnea, pulmonary infiltration with eosinophilia
- Skin and appendages - angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash
- Special senses - blurred vision, photophobia, transient visual disturbances
- Urogenital system - dysuria, elevated BUN, oliguria/polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency
- Other NSAID Adverse Reactions, Which Occur Rarely Are
- Body as a whole - anaphylactic reactions, appetite changes, death
- Cardiovascular system - arrhythmia, cerebrovascular accident, hypotension, myocardial infarction
- Digestive system - colitis, esophagitis with or without stricture or cardiospasm, thirst, ulcerative stomatitis
- Hemic and lymphatic system - aplastic anemia, lymphadenopathy
- Metabolic and nutritional - change in weight
- Nervous system - coma, convulsions, hallucinations, meningitis
- Respiratory - bronchitis, pneumonia, respiratory depression, sinusitis
- Skin and appendages - alopecia, exfoliative dermatitis, maculopapular rash, photosensitivity, skin peeling, Stevens-Johnson syndrome, toxic epidermal necrosis
- Special senses - conjunctivitis, deafness, hearing impairment, taste perversion
- Urogenital system - cystitis, hematuria, interstitial nephritis, leukorrhea, renal calculus, uterine bleeding irregularities
## Postmarketing Experience
There is limited information regarding Etodolac Postmarketing Experience in the drug label.
# Drug Interactions
Drug Interactions
ACE-inhibitors
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
Aspirin
- When etodolac extended-release tablets are administered with aspirin, its protein binding is reduced, although the clearance of free etodolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of etodolac extended-release tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
Cyclosporine and Digoxin
- Etodolac extended-release tablets, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs, leading to elevated serum levels of cyclosporine and digoxin and increased toxicity. Nephrotoxicity associated with cyclosporine may also be enhanced. Patients receiving these drugs who are given etodolac extended-release tablets, or any other NSAID, and particularly those patients with altered renal function, should be observed for the development of the specific toxicities of these drugs.
Furosemide
- Clinical studies, as well as post marketing observations, have shown that etodolac extended-release tablets can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Methotrexate
- NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
Phenylbutazone
- Phenylbutazone causes an increase (by about 80%) in the free fraction of etodolac. Although in vivo studies have not been done to see if etodolac clearance is changed by coadministration of phenylbutazone, it is not recommended that they be coadministered.
Warfarin
- The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Drug/Laboratory Test Interactions
- The urine of patients who take etodolac can give a false-positive reaction for urinary bilirubin (urobilin) due to the presence of phenolic metabolites of etodolac. Diagnostic dip-stick methodology, used to detect ketone bodies in urine, has resulted in false-positive findings in some patients treated with etodolac. Generally, this phenomenon has not been associated with other clinically significant events. No dose relationship has been observed.
- Etodolac treatment is associated with a small decrease in serum uric acid levels. In clinical trials, mean decreases of 1 to 2 mg/dL were observed in arthritic patients receiving etodolac (600 mg to 1000 mg/day) after 4 weeks of therapy. These levels then remained stable for up to 1 year of therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects
Pregnancy category C
- Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.
Nonteratogenic Effects
- Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etodolac in women who are pregnant.
### Labor and Delivery
- In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of etodolac extended-release tablets on labor and delivery in pregnant women are unknown.
### 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 etodolac extended-release tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 6 years have not been established.
### Geriatic Use
- As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
### Gender
- There is no FDA guidance on the use of Etodolac with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Etodolac with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Etodolac in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Etodolac in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Etodolac in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Etodolac in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Carefully consider the potential benefits and risks of etodolac extended-release tablets and other treatment options before deciding to use etodolac extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
- After observing the response to initial therapy with etodolac extended-release tablets, the dose and frequency should be adjusted to suit an individual patient's needs.
Juvenile Rheumatoid Arthritis
- For the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 6 to 16 years of age, the recommended dose given orally once per day should be based on body weight, according to the following table:
Rheumatoid Arthritis and Osteoarthritis
- For the relief of the signs and symptoms of osteoarthritis or rheumatoid arthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day.
- As with other NSAIDs, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.
### Monitoring
- Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- If etodolac extended-release tablet therapy must be initiated, close monitoring of the patient's renal function is advisable.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving etodolac extended-release tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, etodolac extended-release tablets should be discontinued.
# IV Compatibility
- There is limited information regarding IV Compatibility of Etodolac in the drug label.
# Overdosage
- Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
- Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of the urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
# Pharmacology
## Mechanism of Action
There is limited information regarding Etodolac Mechanism of Action in the drug label.
## Structure
- Etodolac extended-release tablets contain etodolac, which is a member of the pyranocarboxylic acid group of non-steroidal anti-inflammatory drugs (NSAIDs). Each tablet contains etodolac for oral administration. Etodolac is a racemic mixture of S and R-enantiomers. It is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol.
- The chemical name is (±) 1,8-diethyl-1,3,4,9-tetrahydropyrano-indole-1-acetic acid. It has the following structural formula:
- The inactive ingredients in etodolac extended-release tablets are calcium phosphate dibasic anhydrous, carbomer 934P, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide. In addition, the following colorants are used: 400 mg tablets - D&C Yellow #10 Lake, FD&C Red #40, and FD&C Yellow #6; 500 mg tablets - D&C Yellow #10 Lake, FD&C Blue No. 2 Indigo Carmine Aluminum Lake, and iron oxide black; 600 mg tablets - FD&C Blue No. 2 Indigo Carmine Lake, iron oxide black, and iron oxide yellow.
## Pharmacodynamics
- Etodolac extended-release tablets are a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac extended-release tablets, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.
## Pharmacokinetics
Absorption
- Etodolac extended-release tablets and etodolac tablets both contain etodolac, but differ in their release characteristics. The systemic availability of etodolac from etodolac extended-release tablets is generally greater than 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. After oral administration of etodolac extended-release tablets in doses up to 800 mg once daily, peak concentrations occur approximately 6 hours after dosing and are dose proportional for both total and free etodolac.
- Table 1 shows the comparison of etodolac pharmacokinetic parameters after the administration of etodolac tablets and etodolac extended-release tablets.
- Table 2 shows the etodolac pharmacokinetic parameters in various populations. The data from patients with renal and hepatic impairment were obtained following administration of (immediate-release) etodolac tablets.
Food/Antacid Effects
- Food has no significant effect on the extent of etodolac extended-release tablets absorption, however, food significantly increased Cmax (54%) following a 600 mg dose.
- The extent of absorption of etodolac is not affected when etodolac is administered with antacid. Coadministration, with an antacid, decreases the peak concentration reached by about 15 to 20% with no measurable effect on time-to-peak.
Distribution
- The mean apparent volume of distribution (Vd/F) of etodolac following administration of etodolac extended-release tablets is 566 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin, and is independent of etodolac concentration over the dose range studied. It is not known whether etodolac is excreted in human milk. However, based on its physical-chemical properties, excretion into breast milk is expected.
Metabolism
- Etodolac metabolites do not contribute significantly to the pharmacological activity of etodolac extended-release tablets.
- Following administration of immediate-release etodolac, several metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8-hydroxylated etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolites do not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.
Excretion
- The mean oral clearance of etodolac following oral etodolac extended-release tablets dosing is 47 (±17) mL/h/kg. The terminal half-life (t1/2) of etodolac after etodolac extended-release tablets administration is 8.4 hours compared to 6.4 hours for etodolac tablets. Approximately 1% of an etodolac tablet dose is excreted unchanged in the urine, with 72% of the dose excreted into the urine as parent drug plus metabolites:
- Fecal excretion accounted for 16% of the dose.
Special Populations
Geriatric
- In clinical studies, age was not shown to have any effect on half-life or protein binding, and demonstrated no change in expected drug accumulation. No dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics. The elderly may need dosage adjustment, however, as they may be more sensitive to antiprostaglandin effects than younger patients.
Pediatric
- The pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12 week clinical trial which included plasma sampling for population pharmacokinetics. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 13.3 to 21.3 mg/kg given as 400 to 1000 mg once daily. The results from a population pharmacokinetic analysis based on the 59 subjects who completed the trial are as follows:
- While similar, the pharmacokinetic parameters for children with juvenile rheumatoid arthritis did not directly correlate with adult pharmacokinetic data in rheumatoid arthritis. In the population pharmacokinetic analysis, body weights below 50 kg were found to correlate with CL/F.
Race
- Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion.
Hepatic Insufficiency
- The pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with hepatic insufficiency. Following administration of etodolac tablets, the plasma protein binding and disposition of total and free etodolac were unchanged in the presence of compensated hepatic cirrhosis. Although no dosage adjustment is generally required in patients with chronic hepatic diseases, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure.
Renal Insufficiency
- The pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with renal insufficiency. Etodolac renal clearance following administration of etodolac tablets was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance, 37 to 88 mL/min). Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. Etodolac plasma protein binding decreases in patients with severe renal deficiency. Etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenic effect of etodolac was observed in mice or rats receiving oral doses of 15 mg/kg/day (45 to 89 mg/m2, respectively) or less for periods of 18 months or 2 years, respectively. Etodolac was not mutagenic in in vitro tests performed with S. typhimurium and mouse lymphoma cells as well as in an in vivo mouse micronucleus test. However, data from the in vitro human peripheral lymphocyte test showed an increase in the number of gaps (3% to 5% unstained regions in the chromatid without dislocation) among the etodolac-treated cultures (50 to 200 g/mL) compared to negative controls (2%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of fertility in male and female rats up to oral doses of 16 mg/kg (94 mg/m2). However, reduced implantation of fertilized eggs occurred in the 8 mg/kg group.
# Clinical Studies
Arthritis
- The use of etodolac extended-release tablets in managing the signs and symptoms of osteoarthritis of the knee and rheumatoid arthritis was assessed in double-blind, randomized, parallel, controlled clinical trials in 1552 patients. In these trials, etodolac extended-release tablets, given once daily, provided efficacy comparable to immediate-release etodolac.
- The safety, efficacy, and pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12 week clinical trial. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 400 to 1000 mg (13.3 to 21.3 mg/kg body weight) once daily. At these doses, etodolac extended-release tablets controlled the signs and symptoms of juvenile rheumatoid arthritis. Based on the results of this study, the safety profile of etodolac extended-release tablets (at doses not exceeding 20 mg/kg) appeared to be similar to that observed in the adult arthritic patients in clinical trials.
# How Supplied
Etodolac extended-release tablets, 400 mg, are available as orange, film-coated, oval-shaped tablets, debossed “1122” on one side and “93” on the other. They are available in bottles of 100.
- Etodolac extended-release tablets, 500 mg, are available as gray, film-coated, oval-shaped tablets, debossed “7172” on one side and “93” on the other. They are available in bottles of 100.
- Etodolac extended-release tablets, 600 mg, are available as light blue, film-coated, oval-shaped tablets, debossed “1118” on one side and “93” on the other. They are available in bottles of 100.
## Storage
- Store at 20° to 25°C (68° to 77°F) .
- Protect from excessive heat and humidity.
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Etodolac extended-release tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
- Etodolac extended-release tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
- Etodolac extended-release tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
- In late pregnancy, as with other NSAIDs, etodolac extended-release tablets should be avoided because it will cause premature closure of the ductus arteriosus.
# Precautions with Alcohol
- Alcohol-Etodolac interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Lodine,
Lodine XL
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Etodolac
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Black Box Warning
# Overview
Etodolac is an analgesic, anti-inflammatory agent that is FDA approved for the treatment of juvenile arthritis, rheumatoid arthritis, osteoarthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, abdominal pain, diarrhea, flatulance, indigestion, nausea, increased liver function test, dizziness, headache, malaise.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- For the relief of the signs and symptoms of osteoarthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day.
- As with other NSAID s, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.
- Dosing Information
- Immediate release, 200 to 400 mg ORALLY every 6 to 8 h as needed; max 1200 mg/day
- Dosing Information
- For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day.
- As with other NSAIDs, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Gout
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Etodolac in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- For the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 6 to 16 years of age, the recommended dose given orally once per day should be based on body weight, according to the following table:
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Etodolac in pediatric patients.
### Non–Guideline-Supported Use
- Rheumatoid arthritis
# Contraindications
- Etodolac extended-release tablets are contraindicated in patients with known hypersensitivity to etodolac.
- Etodolac extended-release tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
- Etodolac extended-release tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
# Warnings
Cardiovascular Effects
Cardiovascular Thrombotic Events
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see GI WARNINGS).
- Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
- NSAIDs, including etodolac extended-release tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including etodolac extended-release tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
- Fluid retention and edema have been observed in some patients taking NSAIDs. Etodolac extended-release tablets should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
- NSAIDs, including etodolac extended-release tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Renal Effects
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
- No information is available from controlled clinical studies regarding the use of etodolac extended-release tablets in patients with advanced renal disease. Therefore, treatment with etodolac extended-release tablets is not recommended in these patients with advanced renal disease. If etodolac extended-release tablet therapy must be initiated, close monitoring of the patient's renal function is advisable.
Anaphylactoid Reactions
- As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to etodolac extended-release tablets. Etodolac extended-release tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Skin Reactions
- NSAIDs, including etodolac extended-release tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy
- In late pregnancy, as with other NSAIDs, etodolac extended-release tablets should be avoided because it may cause premature closure of the ductus arteriosus.
### PRECAUTIONS
General
- Etodolac extended-release tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
- The pharmacological activity of etodolac extended-release tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hepatic Effects
- Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including etodolac extended-release tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
- A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with etodolac extended-release tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), etodolac extended-release tablets should be discontinued.
Hematological Effects
- Anemia is sometimes seen in patients receiving NSAIDs, including etodolac extended-release tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including etodolac extended-release tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving etodolac extended-release tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
- Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, etodolac extended-release tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for Patients
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Etodolac extended-release tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
- Etodolac extended-release tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
- Etodolac extended-release tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
- In late pregnancy, as with other NSAIDs, etodolac extended-release tablets should be avoided because it will cause premature closure of the ductus arteriosus.
Laboratory Tests
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, etodolac extended-release tablets should be discontinued.
# Adverse Reactions
## Clinical Trials Experience
- A total of 1552 patients were exposed to etodolac extended-release tablets in controlled clinical studies of at least 4 weeks in length and using daily doses in the range of 400 to 1200 mg. In the tabulations below, adverse event rates are generally categorized based on the incidence of events in the first 30 days of treatment with etodolac extended-release tablets. As with other NSAIDs, the cumulative adverse event rates may increase significantly over time with extended therapy.
- In patients taking NSAIDs, including etodolac extended-release tablets, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are:
- gastrointestinal experiences including:
- Adverse events that were observed in < 1% of patients in the first 30 days of treatment with etodolac extended-release tablets in clinical trials.
- Additional NSAID Adverse Experiences Reported Occasionally with NSAIDs or Etodolac Extended-Release Tablets Include
- Body as a whole - allergic reaction, anaphylactic/anaphylactoid reactions (including shock), chills, fever, sepsis
- Cardiovascular system - congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic)
- Digestive system - anorexia, cholestatic hepatitis, cholestatic jaundice, dry mouth, duodenitis, eructation, esophagitis, gastritis, gastric/peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis
- Hemic and lymphatic system - agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia
- Metabolic and nutritional - hyperglycemia in previously controlled diabetic patients
- Nervous system - anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo
- Respiratory system - asthma, dyspnea, pulmonary infiltration with eosinophilia
- Skin and appendages - angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash
- Special senses - blurred vision, photophobia, transient visual disturbances
- Urogenital system - dysuria, elevated BUN, oliguria/polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency
- Other NSAID Adverse Reactions, Which Occur Rarely Are
- Body as a whole - anaphylactic reactions, appetite changes, death
- Cardiovascular system - arrhythmia, cerebrovascular accident, hypotension, myocardial infarction
- Digestive system - colitis, esophagitis with or without stricture or cardiospasm, thirst, ulcerative stomatitis
- Hemic and lymphatic system - aplastic anemia, lymphadenopathy
- Metabolic and nutritional - change in weight
- Nervous system - coma, convulsions, hallucinations, meningitis
- Respiratory - bronchitis, pneumonia, respiratory depression, sinusitis
- Skin and appendages - alopecia, exfoliative dermatitis, maculopapular rash, photosensitivity, skin peeling, Stevens-Johnson syndrome, toxic epidermal necrosis
- Special senses - conjunctivitis, deafness, hearing impairment, taste perversion
- Urogenital system - cystitis, hematuria, interstitial nephritis, leukorrhea, renal calculus, uterine bleeding irregularities
## Postmarketing Experience
There is limited information regarding Etodolac Postmarketing Experience in the drug label.
# Drug Interactions
Drug Interactions
ACE-inhibitors
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
Aspirin
- When etodolac extended-release tablets are administered with aspirin, its protein binding is reduced, although the clearance of free etodolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of etodolac extended-release tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
Cyclosporine and Digoxin
- Etodolac extended-release tablets, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs, leading to elevated serum levels of cyclosporine and digoxin and increased toxicity. Nephrotoxicity associated with cyclosporine may also be enhanced. Patients receiving these drugs who are given etodolac extended-release tablets, or any other NSAID, and particularly those patients with altered renal function, should be observed for the development of the specific toxicities of these drugs.
Furosemide
- Clinical studies, as well as post marketing observations, have shown that etodolac extended-release tablets can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.
Lithium
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
Methotrexate
- NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
Phenylbutazone
- Phenylbutazone causes an increase (by about 80%) in the free fraction of etodolac. Although in vivo studies have not been done to see if etodolac clearance is changed by coadministration of phenylbutazone, it is not recommended that they be coadministered.
Warfarin
- The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Drug/Laboratory Test Interactions
- The urine of patients who take etodolac can give a false-positive reaction for urinary bilirubin (urobilin) due to the presence of phenolic metabolites of etodolac. Diagnostic dip-stick methodology, used to detect ketone bodies in urine, has resulted in false-positive findings in some patients treated with etodolac. Generally, this phenomenon has not been associated with other clinically significant events. No dose relationship has been observed.
- Etodolac treatment is associated with a small decrease in serum uric acid levels. In clinical trials, mean decreases of 1 to 2 mg/dL were observed in arthritic patients receiving etodolac (600 mg to 1000 mg/day) after 4 weeks of therapy. These levels then remained stable for up to 1 year of therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects
Pregnancy category C
- Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.
Nonteratogenic Effects
- Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etodolac in women who are pregnant.
### Labor and Delivery
- In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of etodolac extended-release tablets on labor and delivery in pregnant women are unknown.
### 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 etodolac extended-release tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 6 years have not been established.
### Geriatic Use
- As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).
### Gender
- There is no FDA guidance on the use of Etodolac with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Etodolac with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Etodolac in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Etodolac in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Etodolac in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Etodolac in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Carefully consider the potential benefits and risks of etodolac extended-release tablets and other treatment options before deciding to use etodolac extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
- After observing the response to initial therapy with etodolac extended-release tablets, the dose and frequency should be adjusted to suit an individual patient's needs.
Juvenile Rheumatoid Arthritis
- For the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 6 to 16 years of age, the recommended dose given orally once per day should be based on body weight, according to the following table:
Rheumatoid Arthritis and Osteoarthritis
- For the relief of the signs and symptoms of osteoarthritis or rheumatoid arthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day.
- As with other NSAIDs, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.
### Monitoring
- Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- If etodolac extended-release tablet therapy must be initiated, close monitoring of the patient's renal function is advisable.
- NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving etodolac extended-release tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, etodolac extended-release tablets should be discontinued.
# IV Compatibility
- There is limited information regarding IV Compatibility of Etodolac in the drug label.
# Overdosage
- Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
- Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of the urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
# Pharmacology
## Mechanism of Action
There is limited information regarding Etodolac Mechanism of Action in the drug label.
## Structure
- Etodolac extended-release tablets contain etodolac, which is a member of the pyranocarboxylic acid group of non-steroidal anti-inflammatory drugs (NSAIDs). Each tablet contains etodolac for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. It is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol.
- The chemical name is (±) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid. It has the following structural formula:
- The inactive ingredients in etodolac extended-release tablets are calcium phosphate dibasic anhydrous, carbomer 934P, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide. In addition, the following colorants are used: 400 mg tablets - D&C Yellow #10 Lake, FD&C Red #40, and FD&C Yellow #6; 500 mg tablets - D&C Yellow #10 Lake, FD&C Blue No. 2 Indigo Carmine Aluminum Lake, and iron oxide black; 600 mg tablets - FD&C Blue No. 2 Indigo Carmine Lake, iron oxide black, and iron oxide yellow.
## Pharmacodynamics
- Etodolac extended-release tablets are a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac extended-release tablets, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.
## Pharmacokinetics
Absorption
- Etodolac extended-release tablets and etodolac tablets both contain etodolac, but differ in their release characteristics. The systemic availability of etodolac from etodolac extended-release tablets is generally greater than 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. After oral administration of etodolac extended-release tablets in doses up to 800 mg once daily, peak concentrations occur approximately 6 hours after dosing and are dose proportional for both total and free etodolac.
- Table 1 shows the comparison of etodolac pharmacokinetic parameters after the administration of etodolac tablets and etodolac extended-release tablets.
- Table 2 shows the etodolac pharmacokinetic parameters in various populations. The data from patients with renal and hepatic impairment were obtained following administration of (immediate-release) etodolac tablets.
Food/Antacid Effects
- Food has no significant effect on the extent of etodolac extended-release tablets absorption, however, food significantly increased Cmax (54%) following a 600 mg dose.
- The extent of absorption of etodolac is not affected when etodolac is administered with antacid. Coadministration, with an antacid, decreases the peak concentration reached by about 15 to 20% with no measurable effect on time-to-peak.
Distribution
- The mean apparent volume of distribution (Vd/F) of etodolac following administration of etodolac extended-release tablets is 566 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin, and is independent of etodolac concentration over the dose range studied. It is not known whether etodolac is excreted in human milk. However, based on its physical-chemical properties, excretion into breast milk is expected.
Metabolism
- Etodolac metabolites do not contribute significantly to the pharmacological activity of etodolac extended-release tablets.
- Following administration of immediate-release etodolac, several metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8-hydroxylated etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolites do not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.
Excretion
- The mean oral clearance of etodolac following oral etodolac extended-release tablets dosing is 47 (±17) mL/h/kg. The terminal half-life (t1/2) of etodolac after etodolac extended-release tablets administration is 8.4 hours compared to 6.4 hours for etodolac tablets. Approximately 1% of an etodolac tablet dose is excreted unchanged in the urine, with 72% of the dose excreted into the urine as parent drug plus metabolites:
- Fecal excretion accounted for 16% of the dose.
Special Populations
Geriatric
- In clinical studies, age was not shown to have any effect on half-life or protein binding, and demonstrated no change in expected drug accumulation. No dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics. The elderly may need dosage adjustment, however, as they may be more sensitive to antiprostaglandin effects than younger patients.
Pediatric
- The pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12 week clinical trial which included plasma sampling for population pharmacokinetics. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 13.3 to 21.3 mg/kg given as 400 to 1000 mg once daily. The results from a population pharmacokinetic analysis based on the 59 subjects who completed the trial are as follows:
- While similar, the pharmacokinetic parameters for children with juvenile rheumatoid arthritis did not directly correlate with adult pharmacokinetic data in rheumatoid arthritis. In the population pharmacokinetic analysis, body weights below 50 kg were found to correlate with CL/F.
Race
- Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion.
Hepatic Insufficiency
- The pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with hepatic insufficiency. Following administration of etodolac tablets, the plasma protein binding and disposition of total and free etodolac were unchanged in the presence of compensated hepatic cirrhosis. Although no dosage adjustment is generally required in patients with chronic hepatic diseases, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure.
Renal Insufficiency
- The pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with renal insufficiency. Etodolac renal clearance following administration of etodolac tablets was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance, 37 to 88 mL/min). Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. Etodolac plasma protein binding decreases in patients with severe renal deficiency. Etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenic effect of etodolac was observed in mice or rats receiving oral doses of 15 mg/kg/day (45 to 89 mg/m2, respectively) or less for periods of 18 months or 2 years, respectively. Etodolac was not mutagenic in in vitro tests performed with S. typhimurium and mouse lymphoma cells as well as in an in vivo mouse micronucleus test. However, data from the in vitro human peripheral lymphocyte test showed an increase in the number of gaps (3% to 5% unstained regions in the chromatid without dislocation) among the etodolac-treated cultures (50 to 200 g/mL) compared to negative controls (2%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of fertility in male and female rats up to oral doses of 16 mg/kg (94 mg/m2). However, reduced implantation of fertilized eggs occurred in the 8 mg/kg group.
# Clinical Studies
Arthritis
- The use of etodolac extended-release tablets in managing the signs and symptoms of osteoarthritis of the knee and rheumatoid arthritis was assessed in double-blind, randomized, parallel, controlled clinical trials in 1552 patients. In these trials, etodolac extended-release tablets, given once daily, provided efficacy comparable to immediate-release etodolac.
- The safety, efficacy, and pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12 week clinical trial. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 400 to 1000 mg (13.3 to 21.3 mg/kg body weight) once daily. At these doses, etodolac extended-release tablets controlled the signs and symptoms of juvenile rheumatoid arthritis. Based on the results of this study, the safety profile of etodolac extended-release tablets (at doses not exceeding 20 mg/kg) appeared to be similar to that observed in the adult arthritic patients in clinical trials.
# How Supplied
Etodolac extended-release tablets, 400 mg, are available as orange, film-coated, oval-shaped tablets, debossed “1122” on one side and “93” on the other. They are available in bottles of 100.
- Etodolac extended-release tablets, 500 mg, are available as gray, film-coated, oval-shaped tablets, debossed “7172” on one side and “93” on the other. They are available in bottles of 100.
- Etodolac extended-release tablets, 600 mg, are available as light blue, film-coated, oval-shaped tablets, debossed “1118” on one side and “93” on the other. They are available in bottles of 100.
## Storage
- Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
- Protect from excessive heat and humidity.
- Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- Etodolac extended-release tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
- Etodolac extended-release tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
- Etodolac extended-release tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
- In late pregnancy, as with other NSAIDs, etodolac extended-release tablets should be avoided because it will cause premature closure of the ductus arteriosus.
# Precautions with Alcohol
- Alcohol-Etodolac interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Lodine,
Lodine XL
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Etodolac | |
c47a2c9a74a65d36232624800c83471779cf417c | wikidoc | Euphoria | Euphoria
# Overview
Euphoria or euphoric may refer to:
- Euphoria (emotion), a state of very intense happiness and feelings of well-being
- 4-Methyl-aminorex (commonly known as "Euphoria" or "U4EA"), a stimulant drug with effects comparable to methamphetamine
- Euphoria (beetle), genus of scarab beetles
- New York Euphoria (formerly "Team Euphoria"), a team in the Lingerie Football League
An album:
- Euphoria (Def Leppard album)
- Euphoria (compilations), a number of trance compilations on the Telstar Records label
- Euphoric, a 1991 album by Delerium
A song:
- "Euphoria", a song by DJ Tiësto from his album Parade of the Athletes
- "Euphoria", by Kyle Ward from the video game In the Groove
- "Euphoria", by Collide from the 2003 album Some Kind of Strange
- "Euphoria (Definite Mix)", by André Schneider from the 2004 album Lover's Space
- "Euphoria", by Sirenia from the 2004 album An Elixir for Existence
- "Euphoria (Firefly)", by Delerium from the 1997 album Karma
A musical group:
- EUPHORIA (American Band), a 1960s American Sunshine Pop band
- Euphoria (Australian band), a 1990s Australian pop/dance trio
- Euphoria (Indian band), an active Indian rock group formed in 1989.
- Euphoria (music project), an active Canadian dance music project formed in the 1990s
In film and television:
- Euphoria (film), a Russian 2006 dramatic film by Ivan Vyrypayev
- "Euphoria, Part 1" and "Euphoria, Part 2" (2006), a two-part episode of the American television series House
In computing:
- Euphoria (software), game animation engine software by NaturalMotion
- Euphoria (programming language), an interpreted programming language
Euphoria may also be:
- a propaganda technique meant to induce the emotion euphoria in order to boost morale or acceptance | Euphoria
Template:Wiktionarypar
# Overview
Euphoria or euphoric may refer to:
- Euphoria (emotion), a state of very intense happiness and feelings of well-being
- 4-Methyl-aminorex (commonly known as "Euphoria" or "U4EA"), a stimulant drug with effects comparable to methamphetamine
- Euphoria (beetle), genus of scarab beetles
- New York Euphoria (formerly "Team Euphoria"), a team in the Lingerie Football League
An album:
- Euphoria (Def Leppard album)
- Euphoria (compilations), a number of trance compilations on the Telstar Records label
- Euphoric, a 1991 album by Delerium
A song:
- "Euphoria", a song by DJ Tiësto from his album Parade of the Athletes
- "Euphoria", by Kyle Ward from the video game In the Groove
- "Euphoria", by Collide from the 2003 album Some Kind of Strange
- "Euphoria (Definite Mix)", by André Schneider from the 2004 album Lover's Space
- "Euphoria", by Sirenia from the 2004 album An Elixir for Existence
- "Euphoria (Firefly)", by Delerium from the 1997 album Karma
A musical group:
- EUPHORIA (American Band), a 1960s American Sunshine Pop band
- Euphoria (Australian band), a 1990s Australian pop/dance trio
- Euphoria (Indian band), an active Indian rock group formed in 1989.
- Euphoria (music project), an active Canadian dance music project formed in the 1990s
In film and television:
- Euphoria (film), a Russian 2006 dramatic film by Ivan Vyrypayev
- "Euphoria, Part 1" and "Euphoria, Part 2" (2006), a two-part episode of the American television series House
In computing:
- Euphoria (software), game animation engine software by NaturalMotion
- Euphoria (programming language), an interpreted programming language
Euphoria may also be:
- a propaganda technique meant to induce the emotion euphoria in order to boost morale or acceptance | https://www.wikidoc.org/index.php/Euphoria | |
f3ec015cfc9061198073bccb1dbedd8964094701 | wikidoc | Eutheria | Eutheria
# Overview
Eutheria is a taxon containing the placental mammals, such as humans. The sister group of Eutheria is Metatheria, which includes marsupials and their extinct relatives.
# Origin of the word
The name Eutheria comes from the Greek words eu- "well" and ther "beast". When Eutheria was introduced by Thomas Henry Huxley in 1880, he meant it to be broader in definition than its precursor Placentalia. Some use Eutheria as a total group which includes the crown group Placentalia and extinct mammals which are closer to Placentalia than to Marsupialia.
# Characteristics of eutherians
Nevertheless, all living eutherians are placental mammals. This means that a eutherian fetus is nourished during gestation by a placenta. Eutherians are also viviparous, meaning that the offspring are carried in the mother's uterus until fully developed.
# Differences from other mammals
Because of this, eutherians are different from other mammal groups such as monotremes and marsupials which are not placental. Monotremes, for instance, lay eggs which protect developing young until they are fully developed. Marsupials give birth to partially-developed young who then migrate to a special pouch in the mother's body in which the young continue their development. (Some exceptions do exist. Bandicoots for instance, which are marsupials, develop small placenta-like structures during gestation.)
# Earliest example
The earliest known eutherian species is the extinct Eomaia scansoria from the Lower Cretaceous of China. It is a member of Eutheria, but the hips of the animal were too narrowly built to have allowed the birth of well-developed young. Thus it is unlikely that a placenta greatly contributed to the development of E. scansoria's young before they were born.
Members of Eutheria are found on all continents and in all oceans. | Eutheria
# Overview
Eutheria[2] is a taxon containing the placental mammals, such as humans. The sister group of Eutheria is Metatheria, which includes marsupials and their extinct relatives.
# Origin of the word
The name Eutheria comes from the Greek words eu- "well[-developed]" and ther "beast". When Eutheria was introduced by Thomas Henry Huxley in 1880, he meant it to be broader in definition than its precursor Placentalia. Some use Eutheria as a total group which includes the crown group Placentalia and extinct mammals which are closer to Placentalia than to Marsupialia.
# Characteristics of eutherians
Nevertheless, all living eutherians are placental mammals. This means that a eutherian fetus is nourished during gestation by a placenta. Eutherians are also viviparous, meaning that the offspring are carried in the mother's uterus until fully developed.
# Differences from other mammals
Because of this, eutherians are different from other mammal groups such as monotremes and marsupials which are not placental. Monotremes, for instance, lay eggs which protect developing young until they are fully developed. Marsupials give birth to partially-developed young who then migrate to a special pouch in the mother's body in which the young continue their development. (Some exceptions do exist. Bandicoots for instance, which are marsupials, develop small placenta-like structures during gestation.)
# Earliest example
The earliest known eutherian species is the extinct Eomaia scansoria from the Lower Cretaceous of China. It is a member of Eutheria, but the hips of the animal were too narrowly built to have allowed the birth of well-developed young. Thus it is unlikely that a placenta greatly contributed to the development of E. scansoria's young before they were born.
Members of Eutheria are found on all continents and in all oceans. | https://www.wikidoc.org/index.php/Eutheria | |
05b7af6c1935417cc0e6b9db23955ef26b30128c | wikidoc | Exanthem | Exanthem
# Overview
An exanthem is a widespread rash, usually of viral origin, and usually occurring in children. It represents either a reaction to a toxin produced by the organism, damage to the skin by the organism or an immune response. Exanthems may also be due to a drug, most commonly antibiotics.
Historically, five "classical" childhood exanthems have been recognized: they are rubeola (measles), varicella (chicken pox), rubella, scarlet fever and "fifth disease". Roseola (aka exanthem subitum or "sixth disease") was later added to these. Vaccinations now exist against measles, rubella and chickenpox; scarlet fever is a streptococcal disease easily treated with antibiotics and the remaining two viral syndromes are considered benign.
A "new" exanthem was identified in 1992, unilateral laterothoracic exanthem (ULE), later also known as asymmetric periflexural exanthem of childhood. | Exanthem
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An exanthem is a widespread rash, usually of viral origin, and usually occurring in children. It represents either a reaction to a toxin produced by the organism, damage to the skin by the organism or an immune response. Exanthems may also be due to a drug, most commonly antibiotics.
Historically, five "classical" childhood exanthems have been recognized: they are rubeola (measles), varicella (chicken pox), rubella, scarlet fever and "fifth disease". Roseola (aka exanthem subitum or "sixth disease") was later added to these. Vaccinations now exist against measles, rubella and chickenpox; scarlet fever is a streptococcal disease easily treated with antibiotics and the remaining two viral syndromes are considered benign.[1]
A "new" exanthem was identified in 1992, unilateral laterothoracic exanthem (ULE), later also known as asymmetric periflexural exanthem of childhood.[2] | https://www.wikidoc.org/index.php/Exanthem | |
257f6b277a1d3969e0c038c0ab742daadfca47fb | wikidoc | Excavate | Excavate
# Overview
The excavates are a major assemblage of protists, often known as Excavata. The phylogenetic category Excavata contains a variety of free-living and symbiotic forms, and includes some important parasites of humans. Many excavates lack 'classical' mitochondria - these organisms are often referred to as 'amitochondriate', although, most, perhaps all, retain a mitochondrial organelle in greatly modified form. Others have mitochondria with tubular, discoidal, or in some cases, flat cristae. Most excavates have two, four, or more flagella and many have a conspicuous ventral feeding groove with a characteristic ultrastructure, supported by microtubules. However, various groups that lack these traits may be considered excavates based on genetic evidence (primarily phylogenetic trees of molecular sequences). Most excavates fall into one of four groups, which may be treated as phyla:
Of these, the Percolozoa (Heterolobosea) and Euglenozoa appear to be particularly close relatives, and are united by the presence of discoid cristae within the mitochondria. Most jakobids have tubular cristae, like most other protists, while the metamonads are unusual in having lost classical mitochondria - instead they have 'hydrogenosomes', 'mitosomes' or uncharacterised organelles. Excavate relationships are still uncertain; it is possible that they are not a monophyletic group.
Certain excavates are often considered among the most primitive eukaryotes, based partly on their placement in many evolutionary trees. This could encourage proposals that excavates are a paraphyletic grade that includes the ancestors of other living eukaryotes. However, the placement of certain excavates as 'early branches' may be an analysis artifact caused by long branch attraction, as has been seen with some other groups, for example, microsporidia. | Excavate
# Overview
The excavates are a major assemblage of protists, often known as Excavata. The phylogenetic category Excavata contains a variety of free-living and symbiotic forms, and includes some important parasites of humans. Many excavates lack 'classical' mitochondria - these organisms are often referred to as 'amitochondriate', although, most, perhaps all, retain a mitochondrial organelle in greatly modified form. Others have mitochondria with tubular, discoidal, or in some cases, flat cristae. Most excavates have two, four, or more flagella and many have a conspicuous ventral feeding groove with a characteristic ultrastructure, supported by microtubules. However, various groups that lack these traits may be considered excavates based on genetic evidence (primarily phylogenetic trees of molecular sequences). Most excavates fall into one of four groups, which may be treated as phyla:
Of these, the Percolozoa (Heterolobosea) and Euglenozoa appear to be particularly close relatives, and are united by the presence of discoid cristae within the mitochondria. Most jakobids have tubular cristae, like most other protists, while the metamonads are unusual in having lost classical mitochondria - instead they have 'hydrogenosomes', 'mitosomes' or uncharacterised organelles. Excavate relationships are still uncertain; it is possible that they are not a monophyletic group.
Certain excavates are often considered among the most primitive eukaryotes, based partly on their placement in many evolutionary trees. This could encourage proposals that excavates are a paraphyletic grade that includes the ancestors of other living eukaryotes. However, the placement of certain excavates as 'early branches' may be an analysis artifact caused by long branch attraction, as has been seen with some other groups, for example, microsporidia. | https://www.wikidoc.org/index.php/Excavata | |
0ef2de64807651dc6db37819ac9be4fcfe35832d | wikidoc | Exertion | Exertion
Exertion is a concept describing the use of physical or perceived energy. It normally connotates a strenuous or costly effort related to physical, philosophical actions and work.
# Concept
In psychological terms exertion is a perceived measure of expenditure or cost.
Conceptually it is also used to describe the use of power (sociological or mental) - like in (violent) force or will (philosophy), but also in economics as in cost. Philosophically it is used as a concept or percept for something different than rest - i.e activity, indicating some sort of decision making or motivation - like instinctal drive.
# Physical
In physics exertion is use of energy against, or for, inertia as described by Isaac Newton's First Law of Motion. In mechanics it describes use of force against a body in direction of its motion (see vector).
# Medical
In medical terms exertion is the expenditure of energy by skeletal muscles. The intensity of this action can be measured by the rate of which oxygen is expended, heat is produced and heart rate.
A frequently used term is rating of perceived exertion or RPE-scale which is use of a scale to indicate a quantitive feeling of fatigue.
# Cybernetics
Exertion can be proxied or extended when applied to various human-machine interfaces, like prosthesis, remote control - even for games. | Exertion
Exertion is a concept describing the use of physical or perceived energy. It normally connotates a strenuous or costly effort related to physical, philosophical actions and work.
# Concept
In psychological terms exertion is a perceived measure of expenditure or cost.
Conceptually it is also used to describe the use of power (sociological or mental) - like in (violent) force or will (philosophy), but also in economics as in cost. Philosophically it is used as a concept or percept for something different than rest - i.e activity, indicating some sort of decision making or motivation - like instinctal drive.
# Physical
In physics exertion is use of energy against, or for, inertia as described by Isaac Newton's First Law of Motion. In mechanics it describes use of force against a body in direction of its motion (see vector).
Template:Sect-stub
# Medical
In medical terms exertion is the expenditure of energy by skeletal muscles. The intensity of this action can be measured by the rate of which oxygen is expended, heat is produced and heart rate.
A frequently used term is rating of perceived exertion or RPE-scale which is use of a scale to indicate a quantitive feeling of fatigue.
Template:Sect-stub
# Cybernetics
Exertion can be proxied or extended when applied to various human-machine interfaces, like prosthesis, remote control - even for games. | https://www.wikidoc.org/index.php/Exertion | |
32d0a8ed53a14693b3691f53e98ea94f4d32252f | wikidoc | Exotoxin | Exotoxin
An exotoxin is a soluble protein excreted by a microorganism, including bacteria, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism.
Both gram negative and gram positive bacteria produce exotoxins. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell.
Most exotoxins can be destroyed by heating. They may exert their effect locally or produce systemic effects. (Nester, 2007). Well known exotoxins include the botulinum toxin produced by Clostridium botulinum, the Corynebacterium diphtheriae exotoxin which is produced during life threatening symptoms of diphtheria.
Exotoxins are susceptible to antibodies produced by the immune system, but many exotoxins are so toxic that they may be fatal to the host before the immune system has a chance to mount defenses against it (Nester, 2007).
# Types
Although many exotoxins can be categorized by their mode of action on target cells, rigid classification of some toxins is not possible or appropriate.
## Type I toxins: toxins that act from the cell surface
Type I toxins bind to a receptor on the cell surface and stimulate intracellular signaling pathways. Two examples are described below.
Superantigens are produced by several bacteria. The best characterized superantigens are those produced by the strains of Staphylococcus aureus and Streptococcus pyogenes that cause toxic shock syndrome. Superantigens bridge the MHC class II protein on antigen presenting cells with the T cell receptor on the surface of T cells with a particular Vβ chain. Consequently, up to 20% of all T cells are activated, leading to massive secretion of proinflammatory cytokines, which produce the symptoms of toxic shock.
Some strains of E. coli produce heat-stable enterotoxins (ST), which are small peptides that are able to withstand heat treatment at 100oC. Different STs recognize distinct receptors on the cell surface and thereby affect different intracellular signaling pathways. For example, STa enterotoxins bind and activate membrane-bound guanylate cyclase, which leads to the intracellular accumulation of cyclic GMP and downstream effects on several signaling pathways. These events lead to the loss of electrolytes and water from intestinal cells.
## Type II toxins: membrane damaging toxins
Membrane damaging toxins exhibit hemolysin or cytolysin activity in vitro. However, induction of cell lysis may not be the primary function of the toxins during infection. At low concentrations of toxin, more subtle effects such as modulation of host cell signal transduction may be observed in the absence of cell lysis. Membrane-damaging toxins can be divided into two categories, the channel-forming toxins and toxins that function as enzymes that act on the membrane.
Most channel-forming toxins, which form pores in the target cell membrane, can be classified into two families, the cholesterol-dependent toxins and the RTX toxins.
- Cholesterol-dependent cytolysins
Formation of pores by cholesterol-dependent cytolysins (CDC) such as the α toxin of Staphylococcus aureus requires the presence of cholesterol in the target cell. The size of the pores formed by members of this family is extremely large: 25-30 nm in diameter. A conserved 11 amino acid sequence is found at the C-terminus of all family members. Moreover, all CDCs are secreted by the type II secretion system. The exception is pneumolysin, which is released from the cytoplasm of Streptococcus pneumoniae when the bacteria lyse. Pneumolysin, Clostridium perfringens perfringolysin, and Listeria monocytogenes listeriolysin O cause specific modifications of histones in the host cell nucleus, resulting in down-regulation of several genes encoding proteins involved in the inflammatory resopnse. Histone modification does not involve the pore-forming activity of the CDCs.
- RTX toxins
RTX (repeats in toxin) cytolysins can be identified by the presence of a specific tandemly-repeated nine amino acid residue sequence in the protein. The prototype RTX member is the HlyA hemolysin of E. coli.
One example is the α toxin of Clostridium perfringens, which causes gas gangrene. α toxin has phospholipase activity.
## Type III toxins: intracellular toxins
Intracellular toxins must be able to gain access to the cytoplasm of the target cell to exert their effects.
One group of intracellular toxins is the AB toxins. The 'B'-subunit attaches to target regions on cell membranes, the 'A'-subunit enters through the membrane and possesses enzymatic function that affects internal cellular bio-mechanisms. The structure of these toxins allows for the development specific vaccines and treatments. Certain compounds can be attached to the B unit, which is not generally harmful, which the body learns to recognize, and which elicits an immune response. This allows the body to detect the harmful toxin if it is encountered later, and to eliminate it before it can cause harm to the host. Toxins of this type include cholera toxin, pertussis toxin, Shiga toxin and heat-labile enterotoxin from E. coli.
Some bacteria deliver toxins directly from their cytoplasm to the cytoplasm of the target cell through a needle-like structure. The effector proteins injected by the type III secretion apparatus of Yersinia into target cells are one example.
## Toxins that damage the extracellular matrix
These toxins allow the further spread of bacteria and consequently deeper tissue infections. Examples are hyaluronidase and collagenase. | Exotoxin
An exotoxin is a soluble protein excreted by a microorganism, including bacteria, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism.
Both gram negative and gram positive bacteria produce exotoxins. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell.
Most exotoxins can be destroyed by heating. They may exert their effect locally or produce systemic effects. (Nester, 2007). Well known exotoxins include the botulinum toxin produced by Clostridium botulinum, the Corynebacterium diphtheriae exotoxin which is produced during life threatening symptoms of diphtheria.
Exotoxins are susceptible to antibodies produced by the immune system, but many exotoxins are so toxic that they may be fatal to the host before the immune system has a chance to mount defenses against it (Nester, 2007).
# Types
Although many exotoxins can be categorized by their mode of action on target cells, rigid classification of some toxins is not possible or appropriate.
## Type I toxins: toxins that act from the cell surface
Type I toxins bind to a receptor on the cell surface and stimulate intracellular signaling pathways. Two examples are described below.
Superantigens are produced by several bacteria. The best characterized superantigens are those produced by the strains of Staphylococcus aureus and Streptococcus pyogenes that cause toxic shock syndrome. Superantigens bridge the MHC class II protein on antigen presenting cells with the T cell receptor on the surface of T cells with a particular Vβ chain. Consequently, up to 20% of all T cells are activated, leading to massive secretion of proinflammatory cytokines, which produce the symptoms of toxic shock.
Some strains of E. coli produce heat-stable enterotoxins (ST), which are small peptides that are able to withstand heat treatment at 100oC. Different STs recognize distinct receptors on the cell surface and thereby affect different intracellular signaling pathways. For example, STa enterotoxins bind and activate membrane-bound guanylate cyclase, which leads to the intracellular accumulation of cyclic GMP and downstream effects on several signaling pathways. These events lead to the loss of electrolytes and water from intestinal cells.
## Type II toxins: membrane damaging toxins
Membrane damaging toxins exhibit hemolysin or cytolysin activity in vitro. However, induction of cell lysis may not be the primary function of the toxins during infection. At low concentrations of toxin, more subtle effects such as modulation of host cell signal transduction may be observed in the absence of cell lysis. Membrane-damaging toxins can be divided into two categories, the channel-forming toxins and toxins that function as enzymes that act on the membrane.
Most channel-forming toxins, which form pores in the target cell membrane, can be classified into two families, the cholesterol-dependent toxins and the RTX toxins.
- Cholesterol-dependent cytolysins
Formation of pores by cholesterol-dependent cytolysins (CDC) such as the α toxin of Staphylococcus aureus requires the presence of cholesterol in the target cell. The size of the pores formed by members of this family is extremely large: 25-30 nm in diameter. A conserved 11 amino acid sequence is found at the C-terminus of all family members. Moreover, all CDCs are secreted by the type II secretion system.[1] The exception is pneumolysin, which is released from the cytoplasm of Streptococcus pneumoniae when the bacteria lyse. Pneumolysin, Clostridium perfringens perfringolysin, and Listeria monocytogenes listeriolysin O cause specific modifications of histones in the host cell nucleus, resulting in down-regulation of several genes encoding proteins involved in the inflammatory resopnse.[2] Histone modification does not involve the pore-forming activity of the CDCs.
- RTX toxins
RTX (repeats in toxin) cytolysins can be identified by the presence of a specific tandemly-repeated nine amino acid residue sequence in the protein. The prototype RTX member is the HlyA hemolysin of E. coli.
One example is the α toxin of Clostridium perfringens, which causes gas gangrene. α toxin has phospholipase activity.
## Type III toxins: intracellular toxins
Intracellular toxins must be able to gain access to the cytoplasm of the target cell to exert their effects.
One group of intracellular toxins is the AB toxins. The 'B'-subunit attaches to target regions on cell membranes, the 'A'-subunit enters through the membrane and possesses enzymatic function that affects internal cellular bio-mechanisms. The structure of these toxins allows for the development specific vaccines and treatments. Certain compounds can be attached to the B unit, which is not generally harmful, which the body learns to recognize, and which elicits an immune response. This allows the body to detect the harmful toxin if it is encountered later, and to eliminate it before it can cause harm to the host. Toxins of this type include cholera toxin, pertussis toxin, Shiga toxin and heat-labile enterotoxin from E. coli.
Some bacteria deliver toxins directly from their cytoplasm to the cytoplasm of the target cell through a needle-like structure. The effector proteins injected by the type III secretion apparatus of Yersinia into target cells are one example.
## Toxins that damage the extracellular matrix
These toxins allow the further spread of bacteria and consequently deeper tissue infections. Examples are hyaluronidase and collagenase. | https://www.wikidoc.org/index.php/Exotoxin | |
4aeb840774d783331587868796bb0d8e4fc2d228 | wikidoc | Eye bank | Eye bank
Eye banks retrieve and store eyes for cornea transplants and research. US eye banks provide tissue for about 46,000 cornea transplants a year to treat conditions such as keratoconus and cornea scarring. The cornea is the only part of the eye that can currently undergo transplantation. In contrast to other organs, there is an adequate supply of corneas for transplants.
When an organ donor dies, certified eye bank technicians are dispatched to the hospital to collect the donor's eyes. The whole eye, called a globe, is enucleated from the donor and taken back to the eye bank for processing. A sample of the donor's blood is also collected to test for any pathogens. Back at the eye bank, the cornea and part of the white sclera are cut away from the rest of the eye and placed in a container with preservation medium. The corneas undergo visual examination underneath a slit-lamp and endothelial cell counts underneath a specular microscope.
There is a wide variety of storage media used in eye banking. The most popular is Optisol GS, which can preserve cornea tissue for up to 14 days if kept refrigerated. Eusol-C is another commonly used media. Organ culture media can also preserve corneas and does not require refrigeration. | Eye bank
Eye banks retrieve and store eyes for cornea transplants and research. US eye banks provide tissue for about 46,000 cornea transplants a year to treat conditions such as keratoconus and cornea scarring. The cornea is the only part of the eye that can currently undergo transplantation. In contrast to other organs, there is an adequate supply of corneas for transplants.
When an organ donor dies, certified eye bank technicians are dispatched to the hospital to collect the donor's eyes. The whole eye, called a globe, is enucleated from the donor and taken back to the eye bank for processing. A sample of the donor's blood is also collected to test for any pathogens. Back at the eye bank, the cornea and part of the white sclera are cut away from the rest of the eye and placed in a container with preservation medium. The corneas undergo visual examination underneath a slit-lamp and endothelial cell counts underneath a specular microscope.
There is a wide variety of storage media used in eye banking. The most popular is Optisol GS, which can preserve cornea tissue for up to 14 days if kept refrigerated. Eusol-C is another commonly used media. Organ culture media can also preserve corneas and does not require refrigeration. | https://www.wikidoc.org/index.php/Eye_bank | |
8715132c51bc73bbe1bb34148773d8c839b67131 | wikidoc | FAM114A2 | FAM114A2
FAM114A2 (chromosome 5 open reading frame 3) is a gene on chromosome 5 in humans that encodes a protein FAM114A2. The protein function is not well known. FAM114A2 is, however, highly conserved in mammals with homologs both in fungi and plants.
# Protein
The FAM114A2 protein is 505 amino acids long with a molecular weight of 55.5 kdal and an isoelectric point of 4.66. It is predicted to stay in the nucleus after translation
There is evidence that c5orf3 interacts with another protein of unknown function from chromosome 5, c5orf4
This protein is thought to include a P loop that suggests a role in ATP- and/or GTP-binding
# Gene
The FAM114A2 gene is located on chromosome 5 (5q31-33). This gene has 14 exons spanning through its sequence. The coding sequence is 2886 base pairs with a 5’ UTR of 94 base pairs and a 3’ UTR of 1273 base pairs. It is expressed at high levels in most tissues of the human body. It is also highly expressed in tissues in the human brain | FAM114A2
FAM114A2 (chromosome 5 open reading frame 3) is a gene on chromosome 5 in humans that encodes a protein FAM114A2. The protein function is not well known. FAM114A2 is, however, highly conserved in mammals with homologs both in fungi and plants.
# Protein
The FAM114A2 protein is 505 amino acids long[1] with a molecular weight of 55.5 kdal and an isoelectric point of 4.66.[2] It is predicted to stay in the nucleus after translation [3]
There is evidence that c5orf3 interacts with another protein of unknown function from chromosome 5, c5orf4 [4]
This protein is thought to include a P loop [5] that suggests a role in ATP- and/or GTP-binding [6]
# Gene
The FAM114A2 gene is located on chromosome 5 (5q31-33).[7] This gene has 14 exons spanning through its sequence.[1] The coding sequence is 2886 base pairs with a 5’ UTR of 94 base pairs and a 3’ UTR of 1273 base pairs.[1] It is expressed at high levels in most tissues of the human body.[7] It is also highly expressed in tissues in the human brain [8] | https://www.wikidoc.org/index.php/FAM114A2 | |
569ffad4b7384b1142d16eea5644dc60565db1b5 | wikidoc | FAM149B1 | FAM149B1
The Family with sequence similarity 149 member B1 is an uncharacterized protein encoded by the human FAM149B1 gene, with one alias KIAA0974. The protein resides in the nucleus of the cell. The predicted secondary structure of the gene contains multiple alpha-helices, with a few beta-sheet structures. The gene is conserved in mammals, birds, reptiles, fish, and some invertebrates. The protein encoded by this gene contains a DUF3719 protein domain, which is conserved across its orthologues. The protein is expressed at slightly below average levels in most human tissue types, with high expression in brain, kidney, and testes tissues, while showing relatively low expression levels in pancreas tissues.
# Gene
This gene has a possible 14 exons. It is located on the forward strand of chromosome 10 at 10q22.2 on the positive strand. The total span of the gene, including 5' and 3' UTR, is 3149 base pairs. The gene is flanked on the left by NUDT13 (nudix hydrolase 13) and on the right by DNAJC9-AS1 (DNAJC9 antisense RNA 1).
## Isoforms
The FAM149B1 protein has a possible 10 isoforms, which are determined through alternative splicing of the gene.
# Protein
## General Properties
The primary protein encoded by the FAM149B1 gene is 583 amino acids in length and has a molecular weight of 64 kDal. The protein contains a conserved protein domain, DUF3719 located at the amino acids 115-179. The isoelectric point of the protein before post-translational modifications is 6.3, and this isoelectric point is relatively conserved in the protein's isoforms, especially in those with the most similar composition of exons. This protein is considered serine rich, in that it expresses a higher serine composition relative to the composition of other human proteins. This high serine composition is also seen in the gene's orthologues.
## Splice Variants
The splice variants of the protein demonstrate some shared qualities of the protein that is translated from the primary transcript. Because each isoform is a different length and contains various combinations of the available exons, there are variances in the isoelectric point and molecular weight. The isoforms closest to the weight and exon composition to the primary transcript generally share these characteristics. The protein isoforms missing the conserved DUF3719 domain are isoforms X5 and X6 because this domain is contained between exons 3-6.
## Structure
There is a negative charge cluster from amino acids 212 to 239. Negative charge clusters often coordinate calcium, or magnesium or zinc ions, mannose-binding protein, or aminopeptidase. The protein contains no positive or mixed charge clusters. The secondary structure of the protein is predicted to be a combination of mostly alpha-helices with a few predicted beta-sheet structures.
## Subcellular Localization
The subcellular location of the protein is the nucleus. There is a leucine zipper pattern in the protein beginning at amino acid 347.
## Post-Translational Modifications
### Acetylation
The third amino acid in the protein sequence, serine, is predicted to be acetylated.
### Phosphorylation
There are multiple predicted phosphorylation sites on various serine, tyrosine, and threonine amino acids are predicted for this protein sequence. The conserved DUF3719 domain contains 7 predicted phosphorylation sites.
### Sumoylation
One predicted sumoylation site was identified in the protein sequence at K267.
# Expression
Overall in the human body, this gene is expressed at levels slightly below the average human gene expression level. The protein is expressed in most cell types of the human body. Most experimentation shows a higher expression of this protein in kidney, testes, and brain tissues, with very low expression seen in pancreas tissues. The gene is expressed at lower levels than its normal expression in most cancerous tissues. The gene is also seen to be expressed most highly in fetal and infantile tissues.
## DNA Microarray Data
DNA microarray analysis experiments show expression patterns of FAM149B1 compared to multiple other genes in a sample. FAM149B1 is shown to be at a lower expression level than most other genes in a multiple myeloma cell line and was shown to increase to close to average gene expression levels after the beta-catenin was depleted from the sample.
FAM149B1 expression was also shown to decrease to lower than average gene expression levels in an ovarian cancer cell line after the use of an anticancer drug named NSC319726.
# Transcriptional Regulation
The gene has 9 different identified promoter regions, which correlate to the various isoforms of the gene. The promoter for the primary transcript of the gene has binding sites for a variety of different transcription factors.
# Interacting Proteins
Current data supports the FAM149B1 protein interactions with 6 different proteins.
One protein was determined to be an interacting protein with FAM149B1 through affinity chromatography techniques.
- The TBC1D32 protein has a role in many biological processes including determination of left/right symmetry, embryonic digit morphogenesis, heart development, lens development in camera-type eye, non-motile cilium assembly, protein localization to cilium, retinal pigment epithelium development, and smoothened signaling pathway involved in dorsal/ventral neural tube patterning. This protein is classified as a developmental protein.
The other five proteins that have been predicted to interact with FAM149B1 protein were found through the process of textmining.
- The human ABHD8 (Alpha/Beta Hydrolase Domain-Containing Protein 8) protein is a hydrolase protein found in the extracellular exosome.
METTL16 (Methyltransferase 10 Domain Containing) protein is a methyltransferase found in the nucleus and cytosol of the cell. This protein was experimentally determined to interact with YARS protein (tyrosyl-tRNA synthetase), which catalyzes attachment of tyrosine to tRNA, and MEPCE (Methylphosphate Capping Enzyme) which adds a methylphosphate cap at the 5-end of 7SK snRNA.
- METTL16 (Methyltransferase 10 Domain Containing) protein is a methyltransferase found in the nucleus and cytosol of the cell. This protein was experimentally determined to interact with YARS protein (tyrosyl-tRNA synthetase), which catalyzes attachment of tyrosine to tRNA, and MEPCE (Methylphosphate Capping Enzyme) which adds a methylphosphate cap at the 5-end of 7SK snRNA.
- SLC6A17 (Solute Carrier Family 6 Member 17) is a sodium-dependent vesicular transporter that is selective for proline, glycine, leucine, and alanine, and is not chloride-dependent as are most other transporters in its family.
- The TM2D1 (Beta-Amyloid-Binding Protein) gene is thought to participate in beta-amyloid-induced apoptosis with its interaction with beta-APP42, and also has G-protein coupled receptor activity. This protein is found mainly in the nucleus and plasma membrane of the cell.
- The DNAJc9 (DnaJ Heat Shock Protein Family (Hsp40) Member C9) protein may play a role as co-chaperone of the Hsp70 family proteins HSPA1A, HSPA1B and HSPA8. This protein is found extracellularly, and in the nucleus, plasma membrane, and cytosol.
# Homology/Evolution
## Paralog
There is one known paralog, FAM149A. It is located on the human chromosome 4 at 4q35.1. The function of the protein encoded by this gene is not well understood, but it also contains the DUF3719 protein domain. The protein translated by this gene shares a 21.2% identity with the FAM149B1 protein. The protein sequence is 482 amino acids in length.
## Orthologs
This gene has orthologues across mammals, birds, reptiles, fish, and some invertebrates. There is a high conservation in mammals, moderate conservation in many of the other vertebrate orthologues, and a low conservation in its few invertebrate orthologues.
# Clinical Significance
While the gene is largely not well understood by scientists, it is shown to be associated with a wide range of various cancerous tumors.
The FAM149B1 gene is also included in a region of 11 genes that comprises one of 15 regions containing mutations associated with the African Pygmy phenotype. | FAM149B1
The Family with sequence similarity 149 member B1 is an uncharacterized protein[1] encoded by the human FAM149B1 gene, with one alias KIAA0974.[2][3] The protein resides in the nucleus of the cell. The predicted secondary structure of the gene contains multiple alpha-helices, with a few beta-sheet structures. The gene is conserved in mammals, birds, reptiles, fish, and some invertebrates. The protein encoded by this gene contains a DUF3719 protein domain, which is conserved across its orthologues.[3] The protein is expressed at slightly below average levels in most human tissue types, with high expression in brain, kidney, and testes tissues, while showing relatively low expression levels in pancreas tissues.[4][5]
# Gene
This gene has a possible 14 exons. It is located on the forward strand of chromosome 10 at 10q22.2 on the positive strand.[6] The total span of the gene, including 5' and 3' UTR, is 3149 base pairs. The gene is flanked on the left by NUDT13 (nudix hydrolase 13) and on the right by DNAJC9-AS1 (DNAJC9 antisense RNA 1).
## Isoforms
The FAM149B1 protein has a possible 10 isoforms, which are determined through alternative splicing of the gene.
# Protein
## General Properties
The primary protein encoded by the FAM149B1 gene is 583 amino acids in length and has a molecular weight of 64 kDal. The protein contains a conserved protein domain, DUF3719[8][6] located at the amino acids 115-179. The isoelectric point of the protein before post-translational modifications is 6.3,[9] and this isoelectric point is relatively conserved in the protein's isoforms, especially in those with the most similar composition of exons. This protein is considered serine rich, in that it expresses a higher serine composition relative to the composition of other human proteins.[10][11] This high serine composition is also seen in the gene's orthologues.
## Splice Variants
The splice variants of the protein demonstrate some shared qualities of the protein that is translated from the primary transcript. Because each isoform is a different length and contains various combinations of the available exons, there are variances in the isoelectric point and molecular weight. The isoforms closest to the weight and exon composition to the primary transcript generally share these characteristics. The protein isoforms missing the conserved DUF3719 domain are isoforms X5 and X6 because this domain is contained between exons 3-6.
## Structure
There is a negative charge cluster from amino acids 212 to 239. Negative charge clusters often coordinate calcium, or magnesium or zinc ions, mannose-binding protein, or aminopeptidase.[12] The protein contains no positive or mixed charge clusters. The secondary structure of the protein is predicted to be a combination of mostly alpha-helices with a few predicted beta-sheet structures.
## Subcellular Localization
The subcellular location of the protein is the nucleus.[13] There is a leucine zipper pattern in the protein beginning at amino acid 347.[14]
## Post-Translational Modifications
### Acetylation
The third amino acid in the protein sequence, serine, is predicted to be acetylated.[15]
### Phosphorylation
There are multiple predicted phosphorylation sites on various serine, tyrosine, and threonine amino acids are predicted for this protein sequence.[16] The conserved DUF3719 domain contains 7 predicted phosphorylation sites.
### Sumoylation
One predicted sumoylation site was identified in the protein sequence at K267.[17]
# Expression
Overall in the human body, this gene is expressed at levels slightly below the average human gene expression level.[18] The protein is expressed in most cell types of the human body.[19] Most experimentation shows a higher expression of this protein in kidney, testes, and brain tissues, with very low expression seen in pancreas tissues.[4][5] The gene is expressed at lower levels than its normal expression in most cancerous tissues. The gene is also seen to be expressed most highly in fetal and infantile tissues.[20]
## DNA Microarray Data
DNA microarray analysis experiments show expression patterns of FAM149B1 compared to multiple other genes in a sample. FAM149B1 is shown to be at a lower expression level than most other genes in a multiple myeloma cell line and was shown to increase to close to average gene expression levels after the beta-catenin was depleted from the sample.[21]
FAM149B1 expression was also shown to decrease to lower than average gene expression levels in an ovarian cancer cell line after the use of an anticancer drug named NSC319726.[13]
# Transcriptional Regulation
The gene has 9 different identified promoter regions, which correlate to the various isoforms of the gene. The promoter for the primary transcript of the gene has binding sites for a variety of different transcription factors.
# Interacting Proteins
Current data supports the FAM149B1 protein interactions with 6 different proteins.
One protein was determined to be an interacting protein with FAM149B1 through affinity chromatography techniques.
- The TBC1D32 protein has a role in many biological processes including determination of left/right symmetry, embryonic digit morphogenesis, heart development, lens development in camera-type eye, non-motile cilium assembly, protein localization to cilium, retinal pigment epithelium development, and smoothened signaling pathway involved in dorsal/ventral neural tube patterning. This protein is classified as a developmental protein.[22]
The other five proteins that have been predicted to interact with FAM149B1 protein were found through the process of textmining.
- The human ABHD8 (Alpha/Beta Hydrolase Domain-Containing Protein 8) protein is a hydrolase protein found in the extracellular exosome.[23]
METTL16 (Methyltransferase 10 Domain Containing) protein is a methyltransferase found in the nucleus and cytosol of the cell.[24] This protein was experimentally determined to interact with YARS protein (tyrosyl-tRNA synthetase), which catalyzes attachment of tyrosine to tRNA, and MEPCE (Methylphosphate Capping Enzyme) which adds a methylphosphate cap at the 5-end of 7SK snRNA.
- METTL16 (Methyltransferase 10 Domain Containing) protein is a methyltransferase found in the nucleus and cytosol of the cell.[24] This protein was experimentally determined to interact with YARS protein (tyrosyl-tRNA synthetase), which catalyzes attachment of tyrosine to tRNA, and MEPCE (Methylphosphate Capping Enzyme) which adds a methylphosphate cap at the 5-end of 7SK snRNA.
- SLC6A17 (Solute Carrier Family 6 Member 17) is a sodium-dependent vesicular transporter that is selective for proline, glycine, leucine, and alanine, and is not chloride-dependent as are most other transporters in its family.[25]
- The TM2D1 (Beta-Amyloid-Binding Protein) gene is thought to participate in beta-amyloid-induced apoptosis with its interaction with beta-APP42, and also has G-protein coupled receptor activity. This protein is found mainly in the nucleus and plasma membrane of the cell.[26]
- The DNAJc9 (DnaJ Heat Shock Protein Family (Hsp40) Member C9) protein may play a role as co-chaperone of the Hsp70 family proteins HSPA1A, HSPA1B and HSPA8. This protein is found extracellularly, and in the nucleus, plasma membrane, and cytosol.
# Homology/Evolution
## Paralog
There is one known paralog, FAM149A.[27] It is located on the human chromosome 4 at 4q35.1. The function of the protein encoded by this gene is not well understood, but it also contains the DUF3719 protein domain. The protein translated by this gene shares a 21.2% identity[28] with the FAM149B1 protein. The protein sequence is 482 amino acids in length.
## Orthologs
This gene has orthologues across mammals, birds, reptiles, fish, and some invertebrates.[3] There is a high conservation in mammals, moderate conservation in many of the other vertebrate orthologues, and a low conservation in its few invertebrate orthologues.[29][28]
# Clinical Significance
While the gene is largely not well understood by scientists, it is shown to be associated with a wide range of various cancerous tumors.[31][32]
The FAM149B1 gene is also included in a region of 11 genes that comprises one of 15 regions containing mutations associated with the African Pygmy phenotype.[33][34] | https://www.wikidoc.org/index.php/FAM149B1 | |
8eaa04fdf9605e78c80e817ee62c25ed225b0eef | wikidoc | FGFR1OP2 | FGFR1OP2
Fibroblast growth factor receptor oncogene partner 2 (FGFR1OP2) was identified in a study on myeloproliferative syndrome (EMS). The study aimed to identify the partner genes to the fibroblast growth factor receptor 1 (FGFR1) involved in the syndrome. Using the 5'-RACE PCR technique, FGFR1OP2 was identified as a novel gene with no known function.
# Function
FGFR1OP2, when fused with the fibroblast growth factor receptor 1 (FGFR1), is shown to cause myeloproliferative syndrome. The protein encoded by the FGFR1 gene belongs to the fibroblast growth factor receptor family. FGFRs usually contain an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. The extracellular domain specifies which ligand the receptor will bind to and mediates ligand-induced receptor dimerization. When FGFR1OP2 is fused to FGFR1, it may exhibit constitutive kinase activity. Furthermore, FGFR1OP2 is possibly involved in some steps of the wound healing pathway.
# Evolutionary Biology
The following tables compare the Homo sapiens FGFR1OP2 gene and protein to orthologs. In both of the following tables, the divergence from the Homo sapiens FGFR1OP2 gene or protein to the ortholog was found using TimeTree. Ortholog mRNA and protein sequences were found using NCBI's BLAST and UCSC's BLAT Tool. The accession numbers, as well as the sequence length and the sequence similarity were compiled using BLAST.
The mRNA orthologs sequence similarity to Homo sapiens FGFR1OP2 was graphed as a function of time in order to show how the FGFR1OP2 gene has changed over time. The graph is depicted on the right.
The table below shows the protein orthologs to the Homo sapiens FGFR1OP2 protein. FGFR1OP2 is conserved in all clades of the animal kingdom, as seen in the table below.
# Gene
There are three transcript variants for the FGFR1OP2 gene, with the first being the longest. FGFR1OP2 is also known as HSPC123-like protein (HSPC123L) and wound inducible transcript 3.0 (wit3.0).
## Locus
The Homo sapiens FGFR1OP2 gene is located on chromosome 12, with its specific locus being 12p11.23. The Homo sapiens asunder spermatogenesis regulator (ASUN) gene (NCBI Reference Sequence NM_018164.2) is located directly upstream from FGFR1OP2. The ASUN gene is a regulator of development and the mitotic cell cycle. The Homo sapiens transmembrane 7 superfamily member 3 (TM7SF3) gene is located slightly downstream from FGFR1OP2.
## Promoter
# Protein
There are three isoforms of the FGFR1OP2 protein. Transcript variant 1 consists of 253 amino acids and weighs 29.4 kilodaltons. FGFR1OP2's isoelectric point is 5.61. The FGFR1OP2 protein does not have a signal sequences, and therefore is not secreted.
## Domains
FGFR1OP2 has a domain of unknown function, designated DUF837.
## Protein Structure
Using the PELE program of Biology WorkBench the protein sequence of FGFR1OP2 was analyzed, and FGFR1OP2 appears to be completely composed of alpha helices. No structural models for the Homo sapiens FGFR1OP2 protein could be found, but the Mus musculus FGFR1OP2 protein's structure can be seen below.
# Expression
The expression of FGFR1OP2 was analyzed via the Gene Expression Omnibus at NCBI. The following are findings from the Gene Expression Onmibus database:
- There is a slightly elevated expression level of FGFR1OP2 in pulmonary sarcoidosis, suggesting FGFR1OP2 operates in part of the wound healing pathway.
- FGFR1OP2 is strongly upregulated when compared to the control in an increased immune response triggered by the VAF347 ligand. FGFR1OP2 is upregulated in the monocyte derived dendritic cell response to the VAF347 ligand. VAF347 activates the aryl hydrocarbon receptor and acts on monocytes and naive CD4+ Th cells to promote development of IL-22 secreting Th cells.
- Langerhans cells show decreased expression of FGFR1OP2 with the null aryl hydrocarbon receptor (ligand is VAF347) in Mus musculus.
- The gene is also highly expressed compared to control samples in monocytopenia.
- It is expressed in cases of leukemia; it may have a linkage to the disease.
- FGFR1OP2 shows low expression levels in septic splenocytes in Mus musculus.
- FGFR1OP2 is expressed in fetal reticulocytes but not adult reticulocytes, suggesting it may play a role in the development of red blood cells.
# Interactions
Using the STRING database and Gene Cards, proteins that possibly interact with FGFR1OP2 were identified, and they are shown in the table below.
# Clinical Significance
Single-nucleotide polymorphisms (SNPs) in the FGFR1OP2 gene were found to lead to edentulism in the mandible of a small Korean population (134 subjects aged 60–80 years). Also, when FGFR1OP2 is fused to FGFR1, 8p11 myeloproliferative syndrome can result. | FGFR1OP2
Fibroblast growth factor receptor oncogene partner 2 (FGFR1OP2) was identified in a study on myeloproliferative syndrome (EMS). The study aimed to identify the partner genes to the fibroblast growth factor receptor 1 (FGFR1) involved in the syndrome. Using the 5'-RACE PCR technique, FGFR1OP2 was identified as a novel gene with no known function.[1]
# Function
FGFR1OP2, when fused with the fibroblast growth factor receptor 1 (FGFR1), is shown to cause myeloproliferative syndrome.[1] The protein encoded by the FGFR1 gene belongs to the fibroblast growth factor receptor family.[2] FGFRs usually contain an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. The extracellular domain specifies which ligand the receptor will bind to and mediates ligand-induced receptor dimerization.[3] When FGFR1OP2 is fused to FGFR1, it may exhibit constitutive kinase activity.[4] Furthermore, FGFR1OP2 is possibly involved in some steps of the wound healing pathway.[5]
# Evolutionary Biology
The following tables compare the Homo sapiens FGFR1OP2 gene and protein to orthologs. In both of the following tables, the divergence from the Homo sapiens FGFR1OP2 gene or protein to the ortholog was found using TimeTree.[6] Ortholog mRNA and protein sequences were found using NCBI's BLAST [7] and UCSC's BLAT Tool.[8] The accession numbers, as well as the sequence length and the sequence similarity were compiled using BLAST.[7]
The mRNA orthologs sequence similarity to Homo sapiens FGFR1OP2 was graphed as a function of time in order to show how the FGFR1OP2 gene has changed over time. The graph is depicted on the right.
The table below shows the protein orthologs to the Homo sapiens FGFR1OP2 protein. FGFR1OP2 is conserved in all clades of the animal kingdom, as seen in the table below.
# Gene
There are three transcript variants for the FGFR1OP2 gene, with the first being the longest.[9] FGFR1OP2 is also known as HSPC123-like protein (HSPC123L) and wound inducible transcript 3.0 (wit3.0).[9]
## Locus
The Homo sapiens FGFR1OP2 gene is located on chromosome 12, with its specific locus being 12p11.23.[9] The Homo sapiens asunder spermatogenesis regulator (ASUN) gene (NCBI Reference Sequence NM_018164.2) is located directly upstream from FGFR1OP2.[11] The ASUN gene is a regulator of development and the mitotic cell cycle.[12] The Homo sapiens transmembrane 7 superfamily member 3 (TM7SF3) gene is located slightly downstream from FGFR1OP2.[13]
## Promoter
# Protein
There are three isoforms of the FGFR1OP2 protein. Transcript variant 1 consists of 253 amino acids and weighs 29.4 kilodaltons.[9] FGFR1OP2's isoelectric point is 5.61.[14] The FGFR1OP2 protein does not have a signal sequences, and therefore is not secreted.[15]
## Domains
FGFR1OP2 has a domain of unknown function, designated DUF837.[9]
## Protein Structure
Using the PELE program of Biology WorkBench the protein sequence of FGFR1OP2 was analyzed, and FGFR1OP2 appears to be completely composed of alpha helices.[14] No structural models for the Homo sapiens FGFR1OP2 protein could be found, but the Mus musculus FGFR1OP2 protein's structure can be seen below.
# Expression
The expression of FGFR1OP2 was analyzed via the Gene Expression Omnibus at NCBI.[16] The following are findings from the Gene Expression Onmibus database:
- There is a slightly elevated expression level of FGFR1OP2 in pulmonary sarcoidosis, suggesting FGFR1OP2 operates in part of the wound healing pathway.
- FGFR1OP2 is strongly upregulated when compared to the control in an increased immune response triggered by the VAF347 ligand. FGFR1OP2 is upregulated in the monocyte derived dendritic cell response to the VAF347 ligand. VAF347 activates the aryl hydrocarbon receptor and acts on monocytes and naive CD4+ Th cells to promote development of IL-22 secreting Th cells.[17]
- Langerhans cells show decreased expression of FGFR1OP2 with the null aryl hydrocarbon receptor (ligand is VAF347) in Mus musculus.
- The gene is also highly expressed compared to control samples in monocytopenia.
- It is expressed in cases of leukemia; it may have a linkage to the disease.
- FGFR1OP2 shows low expression levels in septic splenocytes in Mus musculus.
- FGFR1OP2 is expressed in fetal reticulocytes but not adult reticulocytes, suggesting it may play a role in the development of red blood cells.
# Interactions
Using the STRING database and Gene Cards, proteins that possibly interact with FGFR1OP2 were identified, and they are shown in the table below.[5][18]
# Clinical Significance
Single-nucleotide polymorphisms (SNPs) in the FGFR1OP2 gene were found to lead to edentulism in the mandible of a small Korean population (134 subjects aged 60–80 years).[19] Also, when FGFR1OP2 is fused to FGFR1, 8p11 myeloproliferative syndrome can result.[1] | https://www.wikidoc.org/index.php/FGFR1OP2 | |
36a0e4709bc6f5eb4881811a1af30e5f806c3671 | wikidoc | FTO gene | FTO gene
Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified. Certain variants of the FTO gene appear to be correlated with obesity in humans.
# Function
The amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA. FTO is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylase, which are non-heme iron-containing proteins. Recombinant FTO protein was first discovered to catalyze demethylation of 3-methylthymine in single-stranded DNA, and 3-methyluridine in single-stranded RNA, with low efficiency. The nucleoside N6-methyladenosine, an abundant modification in RNA, was then found to be a major substrate of FTO. The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexigenic galanin-like peptide which is involved in the stimulation of food intake.
Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.
People with two copies of the risk allele for the rs9939609 single nucleotide polymorphism (SNP) showed differing neural responses to food images via fMRI. However, rs9939609's association with FTO is controversial, and may actually affect another gene, called iroquious homeobox protein 3 (IRX3).
# FTO demethylates RNA
N6-methyladenosine (m6A) is an abundant modification in mRNA and is found within some viruses, and most eukaryotes including mammals, insects, plants, and yeast. It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist. Adenosine methylation is directed by a large m6A methyltransferase complex containing METTL3 as the SAM-binding sub-unit. In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA and in bovine prolactin mRNA. In plants, the majority of the m6A is found within 150 nucleotides before the start of the poly(A) tail.
Mapping of m6A in human and mouse RNA has identified over 18,000 m6A sites in the transcripts of more than 7,000 human genes with a consensus sequence of m6AC consistent with the previously identified motif. Sites preferentially appear in two distinct landmarks—around stop codons and within long internal exons—and are highly conserved between human and mouse. A subset of stimulus-dependent, dynamically modulated sites has been identified. Silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis.
FTO has been demonstrated to efficiently demethylate the related modified ribonucleotide, N6,2'-O-dimethyladenosine, and to an equal or lesser extent, m6A, in vitro . FTO knockdown with siRNA led to increased amounts of m6A in polyA-RNA, whereas overexpression of FTO resulted in decreased amounts of m6A in human cells. FTO partially co-localizes with nuclear speckles, which supports the notion that in the nucleus, m6A can be a substrate of FTO. Function of FTO could affect the processing of pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative demethylation of RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA, and identification of RNA substrates for which FTO has the highest affinity.
# Tissue distribution
The FTO gene is widely expressed in both fetal and adult tissues.
# Clinical significance
## Association with obesity
38,759 Europeans were studied for variants of FTO obesity risk allele. In particular, carriers of one copy of the allele weighed on average 1.2 (Expression error: Missing operand for *. ) more than people with no copies. Carriers of two copies (16% of the subjects) weighed 3 (Expression error: Missing operand for *. ) more and had a 1.67-fold higher rate of obesity than those with no copies. The association was observed in ages 7 and upwards. This gene is not directly associated with diabetes; however, increased body-fat also increases the risk of developing type 2 diabetes.
Simultaneously, a study in 2,900 affected individuals and 5,100 controls of French descent, together with 500 trios (confirming an association independent of population stratification) found association of SNPs in the very same region of FTO (rs1421085). The authors found that this variation, or a variation in strong LD with this variation explains 1% of the population BMI variance and 22% of the population attributable risk of obesity. The authors of this study claim that while obesity was already known to have a genetic component (from twin studies), no replicated previous study has ever identified an obesity risk allele that was so common in the human population. The risk allele is a cluster of 10 single nucleotide polymorphism in the first intron of FTO called rs9939609. According to HapMap, it has population frequencies of 45% in the West/Central Europeans, 52% in Yorubans (West African natives) and 14% in Chinese/Japanese. Furthermore, morbid obesity is associated with a combination of FTO and INSIG2 single nucleotide polymorphisms.
In 2009, variants in the FTO gene were further confirmed to associate with obesity in two very large genome wide association studies of body mass index (BMI).
In adult humans, it was shown that adults bearing the at risk AT and AA alleles at rs9939609 consumed between 500 and 1250 kJ more each day than those carrying the protective TT genotype (equivalent to between 125 and 280 kcal per day more intake). The same study showed that there was no impact of the polymorphism on energy expenditure. This finding of an effect of the rs9939609 polymorphism on food intake or satiety has been independently replicated in five subsequent studies (in order of publication). Three of these subsequent studies also measured resting energy expenditure and confirmed the original finding that there is no impact of the polymorphic variation at the rs9939609 locus on energy expenditure. A different study explored the effects of variation in two different SNPs in the FTO gene (rs17817449 and rs1421085) and suggested there might be an effect on circulating leptin levels and energy expenditure, but this latter effect disappeared when the expenditure was normalised for differences in body composition. The accumulated data across seven independent studies therefore clearly implicates the FTO gene in humans as having a direct impact on food intake but no effect on energy expenditure.
The obesity-associated noncoding region within the FTO gene interacts directly with the promoter of IRX3, a homeobox gene, and IRX5, another homeobox gene. The noncoding region of FTO interacts with the promoters of IRX3 and FTO in human, mouse and zebrafish, and with IRX5. Results suggest that IRX3 and IRX5 are linked with obesity and determine body mass and composition. This is further supported by the fact that obesity-associated single nucleotide polymorphisms, in which cytosine is substituted for thymine, are involved in the expression of IRX3 and IRX5 (not FTO) in human brains. The enhanced expression of IRX3 and IRX5 resulting from this single nucleotide alteration promoted a shift from energy-dissipating beige adipocytes to energy-storing white adipocytes and a subsequent reduction in mitochondrial thermogenesis by a factor of 5. Another study found indications that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner, and that there is a pathway for adipocyte thermoregulation which involves the proteine ARID5B, the single-nucleotide variant rs1421085, and the IRX3 and IRX5 genes.
## Association with Alzheimer's disease
Recent studies revealed that carriers of common FTO gene polymorphisms show both a reduction in frontal lobe volume of the brain and an impaired verbal fluency performance. Fittingly, a population-based study from Sweden found that carriers of the FTO rs9939609 A allele have an increased risk for incident Alzheimer disease.
## Association with other diseases
The presence of the FTO rs9939609 A allele was also found to be positively correlated with other symptoms of the metabolic syndrome, including higher fasting insulin, glucose, and triglycerides, and lower HDL cholesterol. However all these effects appear to be secondary to weight increase since no association was found after correcting for increases in body mass index. Similarly, the association of rs11076008 G allele with the increased risk for degenerative disc disease was reported.
# Model organisms
Model organisms have been used in the study of FTO function. In contrast to the findings in humans deletion, analysis of the Fto gene in mice showed loss of function is associated with no differences in energy intake but greater energy expenditure and this results in a reduction of body weight and fatness.
Another conditional knockout mouse line, called Ftotm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals from this line underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and only significant skeletal abnormalities were observed, including kyphosis and abnormal vertebral transverse processes, and only in female homozygous mutant animals.
The reasons for the differences in FTO phenotype between humans and different lines of mice is presently uncertain. However, many other genes involved in regulation of energy balance exert effects on both intake and expenditure.
# Origin of name
By exon trapping, Peters et al. (1999) cloned a novel gene from a region of several hundred kb deleted by the mouse 'fused toes' (FT) mutation. They named the gene 'fatso' (Fto) due to its large size. | FTO gene
Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified.[1] Certain variants of the FTO gene appear to be correlated with obesity in humans.[2]
# Function
The amino acid sequence of the transcribed FTO protein shows high similarity with the enzyme AlkB which oxidatively demethylates DNA.[3][4] FTO is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylase, which are non-heme iron-containing proteins. Recombinant FTO protein was first discovered to catalyze demethylation of 3-methylthymine in single-stranded DNA, and 3-methyluridine in single-stranded RNA, with low efficiency.[3] The nucleoside N6-methyladenosine, an abundant modification in RNA, was then found to be a major substrate of FTO.[1][5] The FTO gene expression was also found to be significantly upregulated in the hypothalamus of rats after food deprivation and strongly negatively correlated with the expression of orexigenic galanin-like peptide which is involved in the stimulation of food intake.[6]
Increases in hypothalamic expression of FTO are associated with the regulation of energy intake but not feeding reward.[7]
People with two copies of the risk allele for the rs9939609 single nucleotide polymorphism (SNP) showed differing neural responses to food images via fMRI.[8] However, rs9939609's association with FTO is controversial, and may actually affect another gene, called iroquious homeobox protein 3 (IRX3).[9]
# FTO demethylates RNA
N6-methyladenosine (m6A) is an abundant modification in mRNA and is found within some viruses,[10][11] and most eukaryotes including mammals,[12][13][14][15] insects,[16] plants,[17][18][19] and yeast.[20][21] It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.[5][22] Adenosine methylation is directed by a large m6A methyltransferase complex containing METTL3 as the SAM-binding sub-unit.[23] In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU[24] and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA[25] and in bovine prolactin mRNA.[26] In plants, the majority of the m6A is found within 150 nucleotides before the start of the poly(A) tail.[27]
Mapping of m6A in human and mouse RNA has identified over 18,000 m6A sites in the transcripts of more than 7,000 human genes with a consensus sequence of [G/A/U][G>A]m6AC[U>A/C][5][22] consistent with the previously identified motif.[24] Sites preferentially appear in two distinct landmarks—around stop codons and within long internal exons—and are highly conserved between human and mouse.[5][22] A subset of stimulus-dependent, dynamically modulated sites has been identified. Silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis.
FTO has been demonstrated to efficiently demethylate the related modified ribonucleotide, N6,2'-O-dimethyladenosine, and to an equal or lesser extent, m6A, in vitro .[1][28] FTO knockdown with siRNA led to increased amounts of m6A in polyA-RNA, whereas overexpression of FTO resulted in decreased amounts of m6A in human cells.[5] FTO partially co-localizes with nuclear speckles, which supports the notion that in the nucleus, m6A can be a substrate of FTO. Function of FTO could affect the processing of pre-mRNA, other nuclear RNAs, or both. The discovery of the FTO-mediated oxidative demethylation of RNA may initiate further investigations on biological regulation based on reversible chemical modification of RNA, and identification of RNA substrates for which FTO has the highest affinity.[1][5][28]
# Tissue distribution
The FTO gene is widely expressed in both fetal and adult tissues.[29]
# Clinical significance
## Association with obesity
38,759 Europeans were studied for variants of FTO obesity risk allele.[29] In particular, carriers of one copy of the allele weighed on average 1.2 (Expression error: Missing operand for *. ) more than people with no copies. Carriers of two copies (16% of the subjects) weighed 3 (Expression error: Missing operand for *. ) more and had a 1.67-fold higher rate of obesity than those with no copies. The association was observed in ages 7 and upwards. This gene is not directly associated with diabetes; however, increased body-fat also increases the risk of developing type 2 diabetes.[30]
Simultaneously, a study in 2,900 affected individuals and 5,100 controls of French descent, together with 500 trios (confirming an association independent of population stratification) found association of SNPs in the very same region of FTO (rs1421085).[31] The authors found that this variation, or a variation in strong LD with this variation explains 1% of the population BMI variance and 22% of the population attributable risk of obesity. The authors of this study claim that while obesity was already known to have a genetic component (from twin studies), no replicated previous study has ever identified an obesity risk allele that was so common in the human population. The risk allele is a cluster of 10 single nucleotide polymorphism in the first intron of FTO called rs9939609. According to HapMap, it has population frequencies of 45% in the West/Central Europeans, 52% in Yorubans (West African natives) and 14% in Chinese/Japanese. Furthermore, morbid obesity is associated with a combination of FTO and INSIG2 single nucleotide polymorphisms.[32]
In 2009, variants in the FTO gene were further confirmed to associate with obesity in two very large genome wide association studies of body mass index (BMI).[33][34]
In adult humans, it was shown that adults bearing the at risk AT and AA alleles at rs9939609 consumed between 500 and 1250 kJ more each day than those carrying the protective TT genotype (equivalent to between 125 and 280 kcal per day more intake).[35] The same study showed that there was no impact of the polymorphism on energy expenditure. This finding of an effect of the rs9939609 polymorphism on food intake or satiety has been independently replicated in five subsequent studies (in order of publication).[36][37][38][39][40] Three of these subsequent studies also measured resting energy expenditure and confirmed the original finding that there is no impact of the polymorphic variation at the rs9939609 locus on energy expenditure. A different study explored the effects of variation in two different SNPs in the FTO gene (rs17817449 and rs1421085) and suggested there might be an effect on circulating leptin levels and energy expenditure, but this latter effect disappeared when the expenditure was normalised for differences in body composition.[41] The accumulated data across seven independent studies therefore clearly implicates the FTO gene in humans as having a direct impact on food intake but no effect on energy expenditure.
The obesity-associated noncoding region within the FTO gene interacts directly with the promoter of IRX3, a homeobox gene, and IRX5, another homeobox gene. The noncoding region of FTO interacts with the promoters of IRX3 and FTO in human, mouse and zebrafish, and with IRX5. Results suggest that IRX3 and IRX5 are linked with obesity and determine body mass and composition. This is further supported by the fact that obesity-associated single nucleotide polymorphisms, in which cytosine is substituted for thymine, are involved in the expression of IRX3 and IRX5 (not FTO) in human brains. The enhanced expression of IRX3 and IRX5 resulting from this single nucleotide alteration promoted a shift from energy-dissipating beige adipocytes to energy-storing white adipocytes and a subsequent reduction in mitochondrial thermogenesis by a factor of 5.[42][43] Another study found indications that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner, and that there is a pathway for adipocyte thermoregulation which involves the proteine ARID5B, the single-nucleotide variant rs1421085, and the IRX3 and IRX5 genes.[44]
## Association with Alzheimer's disease
Recent studies revealed that carriers of common FTO gene polymorphisms show both a reduction in frontal lobe volume of the brain[45] and an impaired verbal fluency performance.[46] Fittingly, a population-based study from Sweden found that carriers of the FTO rs9939609 A allele have an increased risk for incident Alzheimer disease.[47]
## Association with other diseases
The presence of the FTO rs9939609 A allele was also found to be positively correlated with other symptoms of the metabolic syndrome, including higher fasting insulin, glucose, and triglycerides, and lower HDL cholesterol. However all these effects appear to be secondary to weight increase since no association was found after correcting for increases in body mass index.[48] Similarly, the association of rs11076008 G allele with the increased risk for degenerative disc disease was reported.[49]
# Model organisms
Model organisms have been used in the study of FTO function. In contrast to the findings in humans deletion, analysis of the Fto gene in mice showed loss of function is associated with no differences in energy intake but greater energy expenditure and this results in a reduction of body weight and fatness.[50]
Another conditional knockout mouse line, called Ftotm1a(EUCOMM)Wtsi[56][57] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[58][59][60] Male and female animals from this line underwent a standardized phenotypic screen to determine the effects of deletion.[54][61] Twenty five tests were carried out on mutant mice and only significant skeletal abnormalities were observed, including kyphosis and abnormal vertebral transverse processes, and only in female homozygous mutant animals.[54]
The reasons for the differences in FTO phenotype between humans and different lines of mice is presently uncertain. However, many other genes involved in regulation of energy balance exert effects on both intake and expenditure.
# Origin of name
By exon trapping, Peters et al. (1999) cloned a novel gene from a region of several hundred kb deleted by the mouse 'fused toes' (FT) mutation. They named the gene 'fatso' (Fto) due to its large size.[62][63] | https://www.wikidoc.org/index.php/FTO_gene | |
674a730282a6e72602e5abe22026603ee36ca259 | wikidoc | Frataxin | Frataxin
Frataxin is a protein that in humans is encoded by the FXN gene.
# Function
Frataxin is localized to the mitochondrion. The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters. It has been proposed to act as either an iron chaperone or an iron storage protein.
Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin.).
# Clinical significance
Reduced expression of frataxin is the cause of Friedreich's ataxia (FRDA), a lethal neurodegenerative disease. The reduction in frataxin gene expression may be attributable from either the silencing of transcription of the frataxin gene because of epigenetic modifications in the chromosomal entity or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in Bacteria and Human cells or both. The expansion of intronic trinucleotide repeat GAA results in Friedreich's ataxia. This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression.
# Animal studies
An overexpression of frataxin in Drosophila has shown an increase in antioxidant capability, resistance to oxidative stress insults and longevity.
Fibroblasts from a mouse model of Friedreich’s ataxia and Friedreich’s ataxia patient fibroblasts show increased levels of DNA double-strand breaks. A lentivirus gene delivery system was used to deliver the frataxin gene to the Friedreich’s ataxia mouse model and human patient cells, and this resulted in long-term restored expression of frataxin mRNA and frataxin protein. This restored expression of the frataxin gene was accompanied by a substantial reduction in the number of DNA double-strand breaks. The impaired frataxin in Friedreich’s ataxia cells appears to cause reduced capacity for repair of DNA damage and this may contribute to neurodegeneration.
# Interactions
Frataxin has been shown to biologically interact with the enzyme PMPCB. | Frataxin
Frataxin is a protein that in humans is encoded by the FXN gene.[1][2]
# Function
Frataxin is localized to the mitochondrion. The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters. It has been proposed to act as either an iron chaperone or an iron storage protein.[3]
Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin.).[1][4][5]
# Clinical significance
Reduced expression of frataxin is the cause of Friedreich's ataxia (FRDA), a lethal neurodegenerative disease. The reduction in frataxin gene expression may be attributable from either the silencing of transcription of the frataxin gene because of epigenetic modifications in the chromosomal entity[6] or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in Bacteria[7] and Human cells[8] or both. The expansion of intronic trinucleotide repeat GAA results in Friedreich's ataxia.[9] This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression.[10]
# Animal studies
An overexpression of frataxin in Drosophila has shown an increase in antioxidant capability, resistance to oxidative stress insults and longevity.[11]
Fibroblasts from a mouse model of Friedreich’s ataxia and Friedreich’s ataxia patient fibroblasts show increased levels of DNA double-strand breaks.[12] A lentivirus gene delivery system was used to deliver the frataxin gene to the Friedreich’s ataxia mouse model and human patient cells, and this resulted in long-term restored expression of frataxin mRNA and frataxin protein. This restored expression of the frataxin gene was accompanied by a substantial reduction in the number of DNA double-strand breaks.[12] The impaired frataxin in Friedreich’s ataxia cells appears to cause reduced capacity for repair of DNA damage and this may contribute to neurodegeneration.[12]
# Interactions
Frataxin has been shown to biologically interact with the enzyme PMPCB.[13] | https://www.wikidoc.org/index.php/FXN | |
16f695854631de24daeed23f87ed73af533944c2 | wikidoc | Thrombin | Thrombin
Thrombin (EC 3.4.21.5, fibrinogenase, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, blood-coagulation factor IIa, factor IIa, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.
# History
After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.
# Physiology
## Synthesis
Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is co-translationally modified in a vitamin K-dependent reaction that converts 10-12 glutamic acids in the N terminus of the molecule to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.
In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.
## Mechanism of action
In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa.
Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin.
As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet.
## Negative feedback
Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor.
# Structure
The molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da. Structurally, it is a member of the large PA clan of proteases.
Prothrombin is composed of four domains; an N-terminal Gla domain, two kringle domains and a C-terminal trypsin-like serine protease domain.
Factor Xa with factor V as a cofactor leads to cleavage of the Gla and two Kringle domains (forming together a fragment called fragment 1.2) and leave thrombin, consisting solely of the serine protease domain.
As is the case for all serine proteases, prothrombin is converted to active thrombin by proteolysis of an internal peptide bond, exposing a new N-terminal Ile-NH3. The historic model of activation of serine proteases involves insertion of this newly formed N-terminus of the heavy chain into the β-barrel promoting the correct conformation of the catalytic residues. Contrary to crystal structures of active thrombin, hydrogen-deuterium exchange mass spectrometry studies indicate that this N-terminal Ile-NH3 does not become inserted into the β-barrel in the apo form of thrombin. However, binding of the active fragment of thrombomodulin appears to allosterically promote the active conformation of thrombin by inserting this N-terminal region.
# Gene
The thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12).
There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency, which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.
Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e., Crohn's disease or ulcerative colitis) and prothrombin G20210A or factor V Leiden mutation have been contradicted by research.
# Role in disease
Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant also known as (antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation.
Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke).
Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.
Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted.
# Applications
## Research tool
Due to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Following purification of the fusion protein, thrombin can be used to selectively cleave between the Arginine and Glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity.
## Medicine and surgery
Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin.
Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site.
Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding.
## Food production
Thrombin is sold under the brand name Fibrimex for use as a binding agent for meat. The thrombin in Fibrimex derives from porcine or bovine blood. According to the manufacturer it can be used to produce new kinds of mixed meats (for example combining beef and fish seamlessly). The manufacturer also states that it can be used to combine whole muscle meat, form and portion these thus cutting down on production costs without a loss in quality.
General secretary Jan Bertoft of Swedish Consumers' Association has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat" | Thrombin
Thrombin (EC 3.4.21.5, fibrinogenase, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, blood-coagulation factor IIa, factor IIa, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease, an enzyme that, in humans, is encoded by the F2 gene.[1][2] Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.
# History
After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.[3]
# Physiology
## Synthesis
Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is co-translationally modified in a vitamin K-dependent reaction that converts 10-12 glutamic acids in the N terminus of the molecule to gamma-carboxyglutamic acid (Gla).[4] In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.
In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.[5]
## Mechanism of action
In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa.
Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin.[6][7]
As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet.
## Negative feedback
Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor.
# Structure
The molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da. Structurally, it is a member of the large PA clan of proteases.
Prothrombin is composed of four domains; an N-terminal Gla domain, two kringle domains and a C-terminal trypsin-like serine protease domain.
Factor Xa with factor V as a cofactor leads to cleavage of the Gla and two Kringle domains (forming together a fragment called fragment 1.2) and leave thrombin, consisting solely of the serine protease domain.[9]
As is the case for all serine proteases, prothrombin is converted to active thrombin by proteolysis of an internal peptide bond, exposing a new N-terminal Ile-NH3. The historic model of activation of serine proteases involves insertion of this newly formed N-terminus of the heavy chain into the β-barrel promoting the correct conformation of the catalytic residues.[10] Contrary to crystal structures of active thrombin, hydrogen-deuterium exchange mass spectrometry studies indicate that this N-terminal Ile-NH3 does not become inserted into the β-barrel in the apo form of thrombin. However, binding of the active fragment of thrombomodulin appears to allosterically promote the active conformation of thrombin by inserting this N-terminal region.[11]
# Gene
The thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12).[1]
There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency,[12] which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.[13]
Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e., Crohn's disease or ulcerative colitis) and prothrombin G20210A or factor V Leiden mutation have been contradicted by research.[14]
# Role in disease
Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant also known as (antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation.
Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke).
Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.[15][16][17]
Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted.[18]
# Applications
## Research tool
Due to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Following purification of the fusion protein, thrombin can be used to selectively cleave between the Arginine and Glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity.
## Medicine and surgery
Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin.
Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site.
Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding.[19][20][21]
## Food production
Thrombin is sold under the brand name Fibrimex for use as a binding agent for meat. The thrombin in Fibrimex derives from porcine or bovine blood.[22] According to the manufacturer it can be used to produce new kinds of mixed meats (for example combining beef and fish seamlessly). The manufacturer also states that it can be used to combine whole muscle meat, form and portion these thus cutting down on production costs without a loss in quality.[23]
General secretary Jan Bertoft of Swedish Consumers' Association has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat"[22] | https://www.wikidoc.org/index.php/Factor_2 | |
424d220393dd98464d26e8151a12cc596e931f78 | wikidoc | Factor D | Factor D
Factor D (EC 3.4.21.46, C3 proactivator convertase, properdin factor D esterase, factor D (complement), complement factor D, CFD, adipsin) a protein which in humans is encoded by the CFD gene. Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B.
# Function
The protein encoded by this gene is a member of the trypsin family of peptidases. The encoded protein is a component of the alternative complement pathway best known for its role in humoral suppression of infectious agents. This protein is also a serine protease that is secreted by adipocytes into the bloodstream. Finally, the encoded protein has a high level of expression in fat, suggesting a role for adipose tissue in immune system biology.
Factor D is a serine protease that stimulates glucose transport for triglyceride accumulation in fats cells and inhibits lipolysis.
# Clinical significance
The level of Factor D is decreased in the obese, this reduction may be due to high activity or resistance but exact cause is not totally known.
# Structure
All members of the chymotrypsin family of serine proteases have very similar structures. In all cases, including factor D, there are two antiparallel β-barrel domains with each barrel containing six β-strands with the same typology in all enzymes. The major difference in backbone structure between Factor D and the other serine proteases of the chymotrpsin family is in the surface loops connecting the secondary structural elements. Factor D displays different conformations of major catalytic and substrate-binding residues typically found in the chrotrypsin family. These features suggest the catalytic activity of factor D is prohibited unless conformational changes are induced by a realignment. | Factor D
Factor D (EC 3.4.21.46, C3 proactivator convertase, properdin factor D esterase, factor D (complement), complement factor D, CFD, adipsin) a protein which in humans is encoded by the CFD gene.[3] Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B.
# Function
The protein encoded by this gene is a member of the trypsin family of peptidases. The encoded protein is a component of the alternative complement pathway best known for its role in humoral suppression of infectious agents. This protein is also a serine protease that is secreted by adipocytes into the bloodstream. Finally, the encoded protein has a high level of expression in fat, suggesting a role for adipose tissue in immune system biology.[3]
Factor D is a serine protease that stimulates glucose transport for triglyceride accumulation in fats cells and inhibits lipolysis.[4]
# Clinical significance
The level of Factor D is decreased[5] in the obese, this reduction may be due to high activity or resistance but exact cause is not totally known.
# Structure
All members of the chymotrypsin family of serine proteases have very similar structures. In all cases, including factor D, there are two antiparallel β-barrel domains with each barrel containing six β-strands with the same typology in all enzymes. The major difference in backbone structure between Factor D and the other serine proteases of the chymotrpsin family is in the surface loops connecting the secondary structural elements. Factor D displays different conformations of major catalytic and substrate-binding residues typically found in the chrotrypsin family. These features suggest the catalytic activity of factor D is prohibited unless conformational changes are induced by a realignment.[6] | https://www.wikidoc.org/index.php/Factor_D | |
a58bba0356981b6ade18c47f0c661c2df84dfe83 | wikidoc | Factor H | Factor H
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large (155 kilodaltons), soluble glycoprotein that circulates in human plasma (at typical concentrations of 200–300 micrograms per milliliter). Its principal function is to regulate the alternative pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the Factor I mediated C3b cleavage, and decay accelerating activity against the alternative pathway C3-convertase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses. This is thought to be the result of Factor H having the ability to adopt conformations with lower or higher activities as a cofactor for C3 cleavage or decay accelerating activity. The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification. The more active conformation is thought to be induced when Factor H binds to glycosaminoglycans (GAGs) and or sialic acids that are generally present on host cells but not, normally, on pathogen surfaces ensuring that self surfaces are protected whilst complement proceeds unabated on foreign surfaces.
# Structure
The molecule is made up of 20 complement control protein (CCP) modules (also referred to as Short Consensus Repeats or sushi domains) connected to one another by short linkers (of between three and eight amino acid residues) and arranged in an extended head to tail fashion. Each of the CCP modules consists of around 60 amino acids with four cysteine residues disulfide bonded in a 1-3 2-4 arrangement, and a hydrophobic core built around an almost invariant tryptophan residue. The CCP modules are numbered from 1-20 (from the N-terminus of the protein); CCPs 1-4 and CCPs 19-20 engage with C3b while CCPs 7 and CCPs 19-20 bind to GAGs and sialic acid. To date atomic structures have been determined for CCPs 1-3, CCP 5, CCP 7 (both 402H & 402Y), CCPs 10-11 and CCPs 11-12, CCPs 12-13, CCP 15, CCP 16, CCPs 15-16, CCPs 18-20, and CCPs 19-20. The atomic structure for CCPs 6-8 (402H) bound to the GAG mimic sucrose octasulfate, CCPs 1-4 in complex with C3b and CCPs 19-20 in complex with C3d (that corresponds to the thioster domain of C3b) have also been determined. Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution. Information available to date indicates that CCP modules 1-4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or GAG or sialic acid binding to 19-20.
# Clinical significance
Due to the central role that factor H plays in the regulation of complement, there are a number of clinical implications arising from aberrant factor H activity. Overactive factor H may result in reduced complement activity on pathogenic cells - increasing susceptibility to microbial infections. Underactive factor H may result in increased complement activity on healthy host cells - resulting in autoimmune diseases. It is not surprising therefore that mutations or single nucleotide polymorphisms (SNPs) in factor H often result in pathologies. Moreover, the complement inhibitory activities of factor H, and other complement regulators, are often used by pathogens to increase virulence.
## Age-related macular degeneration
Recently it was discovered that about 35% of individuals carry an at-risk Single Nucleotide Polymorphism in one or both copies of their factor H gene. Homozygous individuals have an approximately sevenfold increased chance of developing age-related macular degeneration, while heterozygotes have a two-to-threefold increased likelihood of developing the disease. This SNP, located in CCP module 7 of factor H, has been shown to affect the interaction between factor H and heparin indicating a causal relationship between the SNP and disease.
Deletion of two adjacent genes with a high degree of homology to complement factor H, named complement factor H-related 3 and complement factor H-related 1, protects against age-related macular degeneration because of reduced competition for binding of CFH to vascular surface binding sites.
## Schizophrenia
Alterations in the immune response are involved in pathogenesis of many neuropsychiatric disorders including schizophrenia. Recent studies indicated alterations in the complement system, including hyperactivation of the alternative complement pathway in patients with schizophrenia. It was investigated functional single nucleotide polymorphisms (SNPs) of gene encoding factor H (CFH), and found CFH rs424535 (2783-526T >A) SNP was positively associated with schizophrenia, so rs424535*A minor allele of the CFH gene may represent a risk factor for schizophrenia.
## Ischemic stroke
It was found that rs800292(184G >A) SNP was positively associated with stroke and rs800912 minor allele of the CFH gene might be considered as a risk factor for ischemic stroke.
## Atypical haemolytic uraemic syndrome
Haemolytic uraemic syndrome (HUS) is a disease associated with microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure. A rare subset of this disease (referred to as atypical haemolytic uraemic syndrome, aHUS), has been strongly linked to mutations in genes of the complement system (including factor H, factor I and membrane cofactor protein), with the factor H mutations being the most numerous. These factor H mutations tend to congregate towards the C-terminus of factor H—a region responsible for discriminating self from non-self—and have been shown to disrupt heparin (a model compound for glycosaminoglycans) and C3d (equivalent to the thioester domain of C3b) binding.
## Recruitment by pathogens
Given the central role of factor H in protecting cells from complement, it is not surprising that several important human pathogens have evolved mechanisms for recruiting factor H. This recruitment of factor H by pathogens provides significant resistance to complement attack, and therefore increased virulence. Pathogens that have been shown to recruit factor H include: Aspergillus spp.; Borrelia burgdorferi; B. duttonii; B. recurrentis; Candida albicans; Francisella tularensis; Haemophilus influenzae; Neisseria meningitidis; Streptococcus Pneumoniae; and Streptococcus pyogenes.
The Gram-negative bacterium B.burgdorferi has five Factor H binding proteins: CRASP-1, CRASP-2, CRASP-3, CRASP-4 and CRASP-5. Each CRASP protein also binds plasminogen.
# Interactions
Factor H has been shown to interact with Complement component 3.
# Recombinant production
Biologically active Factor H has been produced by Ralf Reski and coworkers in the moss bioreactor, in a process called molecular farming. Large quantities of biologically active human Factor H, potentially suitable for therapeutic purposes, were produced using a synthetic codon-optimised gene expressed in the yeast expression host, Pichia pastoris. | Factor H
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large (155 kilodaltons), soluble glycoprotein that circulates in human plasma (at typical concentrations of 200–300 micrograms per milliliter[1][2][3]). Its principal function is to regulate the alternative pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the Factor I mediated C3b cleavage, and decay accelerating activity against the alternative pathway C3-convertase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses. This is thought to be the result of Factor H having the ability to adopt conformations with lower or higher activities as a cofactor for C3 cleavage or decay accelerating activity.[4] The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification. The more active conformation is thought to be induced when Factor H binds to glycosaminoglycans (GAGs) and or sialic acids that are generally present on host cells but not, normally, on pathogen surfaces ensuring that self surfaces are protected whilst complement proceeds unabated on foreign surfaces.[5][6]
# Structure
The molecule is made up of 20 complement control protein (CCP) modules (also referred to as Short Consensus Repeats or sushi domains) connected to one another by short linkers (of between three and eight amino acid residues) and arranged in an extended head to tail fashion. Each of the CCP modules consists of around 60 amino acids with four cysteine residues disulfide bonded in a 1-3 2-4 arrangement, and a hydrophobic core built around an almost invariant tryptophan residue. The CCP modules are numbered from 1-20 (from the N-terminus of the protein); CCPs 1-4 and CCPs 19-20 engage with C3b while CCPs 7 and CCPs 19-20 bind to GAGs and sialic acid.[7] To date atomic structures have been determined for CCPs 1-3,[8] CCP 5,[9] CCP 7 (both 402H & 402Y),[10] CCPs 10-11 and CCPs 11-12,[11] CCPs 12-13,[12] CCP 15, CCP 16,[13] CCPs 15-16,[14] CCPs 18-20,[15] and CCPs 19-20.[16][17] The atomic structure for CCPs 6-8 (402H) bound to the GAG mimic sucrose octasulfate,[18] CCPs 1-4 in complex with C3b[19] and CCPs 19-20 in complex with C3d (that corresponds to the thioster domain of C3b)[20][21] have also been determined. Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution.[22] Information available to date indicates that CCP modules 1-4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or GAG or sialic acid binding to 19-20.[22][23]
# Clinical significance
Due to the central role that factor H plays in the regulation of complement, there are a number of clinical implications arising from aberrant factor H activity. Overactive factor H may result in reduced complement activity on pathogenic cells - increasing susceptibility to microbial infections. Underactive factor H may result in increased complement activity on healthy host cells - resulting in autoimmune diseases. It is not surprising therefore that mutations or single nucleotide polymorphisms (SNPs) in factor H often result in pathologies. Moreover, the complement inhibitory activities of factor H, and other complement regulators, are often used by pathogens to increase virulence.
## Age-related macular degeneration
Recently it was discovered that about 35% of individuals carry an at-risk Single Nucleotide Polymorphism in one or both copies of their factor H gene. Homozygous individuals have an approximately sevenfold increased chance of developing age-related macular degeneration, while heterozygotes have a two-to-threefold increased likelihood of developing the disease. This SNP, located in CCP module 7 of factor H, has been shown to affect the interaction between factor H and heparin indicating a causal relationship between the SNP and disease.[10][24]
Deletion of two adjacent genes with a high degree of homology to complement factor H, named complement factor H-related 3 and complement factor H-related 1, protects against age-related macular degeneration because of reduced competition for binding of CFH to vascular surface binding sites.[25][26]
## Schizophrenia
Alterations in the immune response are involved in pathogenesis of many neuropsychiatric disorders including schizophrenia. Recent studies indicated alterations in the complement system, including hyperactivation of the alternative complement pathway in patients with schizophrenia. It was investigated functional single nucleotide polymorphisms (SNPs) of gene encoding factor H (CFH), and found CFH rs424535 (2783-526T >A) SNP was positively associated with schizophrenia, so rs424535*A minor allele of the CFH gene may represent a risk factor for schizophrenia.[27]
## Ischemic stroke
It was found that rs800292(184G >A) SNP was positively associated with stroke and rs800912 minor allele of the CFH gene might be considered as a risk factor for ischemic stroke.[27]
## Atypical haemolytic uraemic syndrome
Haemolytic uraemic syndrome (HUS) is a disease associated with microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure. A rare subset of this disease (referred to as atypical haemolytic uraemic syndrome, aHUS), has been strongly linked to mutations in genes of the complement system (including factor H, factor I and membrane cofactor protein), with the factor H mutations being the most numerous. These factor H mutations tend to congregate towards the C-terminus of factor H—a region responsible for discriminating self from non-self—and have been shown to disrupt heparin (a model compound for glycosaminoglycans) and C3d (equivalent to the thioester domain of C3b) binding.[28][29]
## Recruitment by pathogens
Given the central role of factor H in protecting cells from complement, it is not surprising that several important human pathogens have evolved mechanisms for recruiting factor H. This recruitment of factor H by pathogens provides significant resistance to complement attack, and therefore increased virulence. Pathogens that have been shown to recruit factor H include: Aspergillus spp.; Borrelia burgdorferi; B. duttonii; B. recurrentis; Candida albicans;[30] Francisella tularensis; Haemophilus influenzae; Neisseria meningitidis; Streptococcus Pneumoniae;[4] and Streptococcus pyogenes.
The Gram-negative bacterium B.burgdorferi has five Factor H binding proteins: CRASP-1, CRASP-2, CRASP-3, CRASP-4 and CRASP-5.[31] Each CRASP protein also binds plasminogen.[31]
# Interactions
Factor H has been shown to interact with Complement component 3.[32][33]
# Recombinant production
Biologically active Factor H has been produced by Ralf Reski and coworkers in the moss bioreactor,[34] in a process called molecular farming. Large quantities of biologically active human Factor H, potentially suitable for therapeutic purposes, were produced using a synthetic codon-optimised gene expressed in the yeast expression host, Pichia pastoris.[35] | https://www.wikidoc.org/index.php/Factor_H | |
78fa828b299f2c3ef131f23f5722469bd2bb72f8 | wikidoc | Factor V | Factor V
Factor V (pronounced factor five) is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations (most notably factor V Leiden) predispose for thrombosis.
# Genetics
The gene for factor V is located on the first chromosome (1q23). It is genomically related to the family of multicopper oxidases, and is homologous to coagulation factor VIII. The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330kDa.
# Structure
Factor V protein consists of six domains: A1-A2-B-A3-C1-C2.
The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin, and form a triangular as in that protein. A copper ion is bound in the A1-A3 interface, and A3 interacts with the plasma.
The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding. The B domain C-terminus acts as a cofactor for the anticoagulant protein C activation by protein S.
Activation of factor V to factor Va is done by cleavage and release of the B domain, after which the protein no longer assists in activating protein C. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor Va.
# Physiology
Factor V synthesis occurs in the liver, principally. The molecule circulates in plasma as a single-chain molecule with a plasma half-life of 12–36 hours.
Factor V is able to bind to activated platelets and is activated by thrombin. On activation, factor V is spliced in two chains (heavy and light chain with molecular masses of 110000 and 73000, respectively) which are noncovalently bound to each other by calcium. The thereby activated factor V (now called FVa) is a cofactor of the prothrombinase complex: The activated factor X (FXa) enzyme requires calcium and activated factor V to convert prothrombin to thrombin on the cell surface membrane.
Factor Va is degraded by activated protein C, one of the principal physiological inhibitors of coagulation. In the presence of thrombomodulin, thrombin acts to decrease clotting by activating Protein C; therefore, the concentration and action of protein C are important determinants in the negative feedback loop through which thrombin limits its own activation.
# Role in disease
Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form of hemophilia (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an autosomal recessive fashion.
Other mutations of factor V are associated with venous thrombosis. They are the most common hereditary causes for thrombophilia (a tendency to form blood clots). The most common one of these, factor V Leiden, is due to the replacement of an arginine residue with glutamine at amino acid position 506 (R506Q). All prothrombotic factor V mutations (factor V Leiden, factor V Cambridge, factor V Hong Kong) make it resistant to cleavage by activated protein C ("APC resistance"). It therefore remains active and increases the rate of thrombin generation.
# History
Until the discovery of factor V, coagulation was regarded as a product of four factors: calcium (IV) and thrombokinase (III) together acting on prothrombin (II) to produce fibrinogen (I); this model had been outlined by Paul Morawitz in 1905.
The suggestion that an additional factor might exist was made by Dr Paul Owren (1905–1990), a Norwegian physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered from nosebleeds and menorrhagia (excessive menstrual blood loss) for most her life, and was found to have a prolonged prothrombin time, suggesting either vitamin K deficiency or chronic liver disease leading to prothrombin deficiency. However, neither were the case, and Owren demonstrated this by correcting the abnormality with plasma from which prothrombin had been removed. Using Mary's serum as index, he found that the "missing" factor, which he labeled V (I-IV having been used in Morawitz' model), had particular characteristics. Most investigations were performed during the Second World War, and while Owren published his results in Norway in 1944, he could not publish them internationally until the war was over. They appeared finally in The Lancet in 1947.
The possibility of an extra coagulation factor was initially resisted on methodological grounds by Drs Armand Quick and Walter Seegers, both world authorities in coagulation. Confirmatory studies from other groups led to their final approval several years later.
Owren initially felt that factor V (labile factor or proaccelerin) activated another factor, which he named VI. VI was the factor that accelerated the conversion from prothrombin to thrombin. It was later discovered that factor V was "converted" (activated) by thrombin itself, and later still that factor VI was simply the activated form of factor V.
The complete amino acid sequence of the protein was published in 1987. In 1994 factor V Leiden, resistant to inactivation by protein C, was described; this abnormality is the most common genetic cause for thrombosis.
# Interactions
Factor V has been shown to interact with Protein S. | Factor V
Factor V (pronounced factor five) is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations (most notably factor V Leiden) predispose for thrombosis.
# Genetics
The gene for factor V is located on the first chromosome (1q23). It is genomically related to the family of multicopper oxidases, and is homologous to coagulation factor VIII. The gene spans 70 kb, consists of 25 exons, and the resulting protein has a relative molecular mass of approximately 330kDa.
# Structure
Factor V protein consists of six domains: A1-A2-B-A3-C1-C2.
The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin, and form a triangular as in that protein. A copper ion is bound in the A1-A3 interface, and A3 interacts with the plasma.[1]
The C domains belong to the phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding. The B domain C-terminus acts as a cofactor for the anticoagulant protein C activation by protein S.[2]
[3]
Activation of factor V to factor Va is done by cleavage and release of the B domain, after which the protein no longer assists in activating protein C. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor Va.[2]
# Physiology
Factor V synthesis occurs in the liver, principally. The molecule circulates in plasma as a single-chain molecule with a plasma half-life of 12–36 hours.[4]
Factor V is able to bind to activated platelets and is activated by thrombin. On activation, factor V is spliced in two chains (heavy and light chain with molecular masses of 110000 and 73000, respectively) which are noncovalently bound to each other by calcium. The thereby activated factor V (now called FVa) is a cofactor of the prothrombinase complex: The activated factor X (FXa) enzyme requires calcium and activated factor V to convert prothrombin to thrombin on the cell surface membrane.
Factor Va is degraded by activated protein C, one of the principal physiological inhibitors of coagulation. In the presence of thrombomodulin, thrombin acts to decrease clotting by activating Protein C; therefore, the concentration and action of protein C are important determinants in the negative feedback loop through which thrombin limits its own activation.
# Role in disease
Various hereditary disorders of factor V are known. Deficiency is associated with a rare mild form of hemophilia (termed parahemophilia or Owren parahemophilia), the incidence of which is about 1:1,000,000. It inherits in an autosomal recessive fashion.
Other mutations of factor V are associated with venous thrombosis. They are the most common hereditary causes for thrombophilia (a tendency to form blood clots). The most common one of these, factor V Leiden, is due to the replacement of an arginine residue with glutamine at amino acid position 506 (R506Q). All prothrombotic factor V mutations (factor V Leiden, factor V Cambridge, factor V Hong Kong) make it resistant to cleavage by activated protein C ("APC resistance"). It therefore remains active and increases the rate of thrombin generation.
# History
Until the discovery of factor V, coagulation was regarded as a product of four factors: calcium (IV) and thrombokinase (III) together acting on prothrombin (II) to produce fibrinogen (I); this model had been outlined by Paul Morawitz in 1905.[5]
The suggestion that an additional factor might exist was made by Dr Paul Owren (1905–1990), a Norwegian physician, during his investigations into the bleeding tendency of a lady called Mary (1914–2002). She had suffered from nosebleeds and menorrhagia (excessive menstrual blood loss) for most her life, and was found to have a prolonged prothrombin time, suggesting either vitamin K deficiency or chronic liver disease leading to prothrombin deficiency. However, neither were the case, and Owren demonstrated this by correcting the abnormality with plasma from which prothrombin had been removed. Using Mary's serum as index, he found that the "missing" factor, which he labeled V (I-IV having been used in Morawitz' model), had particular characteristics. Most investigations were performed during the Second World War, and while Owren published his results in Norway in 1944, he could not publish them internationally until the war was over. They appeared finally in The Lancet in 1947.[5][6]
The possibility of an extra coagulation factor was initially resisted on methodological grounds by Drs Armand Quick and Walter Seegers, both world authorities in coagulation. Confirmatory studies from other groups led to their final approval several years later.[5]
Owren initially felt that factor V (labile factor or proaccelerin) activated another factor, which he named VI. VI was the factor that accelerated the conversion from prothrombin to thrombin. It was later discovered that factor V was "converted" (activated) by thrombin itself, and later still that factor VI was simply the activated form of factor V.[5]
The complete amino acid sequence of the protein was published in 1987.[7] In 1994 factor V Leiden, resistant to inactivation by protein C, was described; this abnormality is the most common genetic cause for thrombosis.[8]
# Interactions
Factor V has been shown to interact with Protein S.[9][10] | https://www.wikidoc.org/index.php/Factor_V | |
4a2ffaee8fae8a44a2b73821e9a834181a94c1b4 | wikidoc | Farnesol | Farnesol
Farnesol is a natural organic compound which is a sesquiterpene alcohol found as a colorless liquid. It is insoluble in water, but miscible with oils.
It is present in many essential oils such as citronella, neroli, cyclamen, lemon grass, tuberose, rose, musk, balsam and tolu. It is used in perfumery to emphasize the odors of sweet floral perfumes.
Farnesol is also a natural pesticide for mites and is a pheromone for several other insects.
In a 1994 report released by five top cigarette companies, farnesol was listed as one of 599 additives to cigarettes. It is a flavoring ingredient.
# Health & Safety information
Farnesol should be avoided by people with perfume allergy. | Farnesol
Farnesol is a natural organic compound which is a sesquiterpene alcohol found as a colorless liquid. It is insoluble in water, but miscible with oils.
It is present in many essential oils such as citronella, neroli, cyclamen, lemon grass, tuberose, rose, musk, balsam and tolu. It is used in perfumery to emphasize the odors of sweet floral perfumes.
Farnesol is also a natural pesticide for mites and is a pheromone for several other insects.
In a 1994 report released by five top cigarette companies, farnesol was listed as one of 599 additives to cigarettes. [1] It is a flavoring ingredient.
# Health & Safety information
Farnesol should be avoided by people with perfume allergy[1]. | https://www.wikidoc.org/index.php/Farnesol | |
cc64c02f79f5679197db9b0ae83afae7c102c611 | wikidoc | Fat choy | Fat choy
Fat choy, Nostoc flagelliforme, also known as faat choy, black moss, hair moss or hair weed is a terrestrial cyanobacterium (a type of photosynthetic bacteria) that is used as a vegetable in Chinese cuisine. When dried, the product has the appearance of black hair. For that reason, its name in Chinese means "hair vegetable". When soaked, this vegetable has a very soft texture which is like very fine vermicelli, and an appearance very similar to long, black human hair.
# Production
Fat choy grows on the ground in the Gobi Desert and the Qinghai plateau. Over-harvesting on the Mongolian steppes has furthered erosion and desertification in those areas. The Chinese government has limited its harvesting, which has caused its price to increase. This may be one reason why some commercially available fat choy has been found to be adulterated with strands of a non-cellular starchy material, with other additives and dyes. Real fat choy is dark green in color, while the counterfeit fat choy appears black.
# Chinese culture
The last two syllables of this name in Cantonese sound the same as another Cantonese saying meaning "struck it rich" (though the second syllable, choi, has a different tone) -- this is found, for example, in the Cantonese saying, "Gung1 hei2 faat3 choi4" (恭喜发财, meaning "congratulations and be prosperous"), which is often proclaimed during Chinese New Year. For that reason, this product is a popular ingredient in dishes used for the Chinese New Year. It is enjoyed as an alternative to cellophane noodles. It is mostly used in Cantonese cuisine and Buddhist cuisine. It is sometimes used as a hot pot ingredient.
# Health effects
A research team from the biochemistry department of the Chinese University of Hong Kong said that international research has shown that fat choy, besides having no nutritional value, has also been found to contain Beta-methylamino L-alanine (BMAA), a toxic amino acid that could affect the normal functions of nerve cells. Professor Chan King-ming of the team told the media that eating fat choy could lead to degenerative diseases such as Alzheimer's, Parkinson's, and dementia.
# Notes
- ↑ ijs.sgmjournals.org
- ↑ Jump up to: 2.0 2.1 2.2 The standard.com.hk
- ↑ Waynesword | Fat choy
Template:Chinese
Template:Otheruses4
Fat choy, Nostoc flagelliforme, also known as faat choy, black moss, hair moss or hair weed is a terrestrial cyanobacterium (a type of photosynthetic bacteria) that is used as a vegetable in Chinese cuisine. When dried, the product has the appearance of black hair. For that reason, its name in Chinese means "hair vegetable". When soaked, this vegetable has a very soft texture which is like very fine vermicelli, and an appearance very similar to long, black human hair.
# Production
Fat choy grows on the ground in the Gobi Desert and the Qinghai plateau. Over-harvesting on the Mongolian steppes has furthered erosion and desertification in those areas. The Chinese government has limited its harvesting, which has caused its price to increase. This may be one reason why some commercially available fat choy has been found to be adulterated with strands of a non-cellular starchy material, with other additives and dyes.[2][3] Real fat choy is dark green in color, while the counterfeit fat choy appears black.[2]
# Chinese culture
The last two syllables of this name in Cantonese sound the same as another Cantonese saying meaning "struck it rich" (though the second syllable, choi, has a different tone) -- this is found, for example, in the Cantonese saying, "Gung1 hei2 faat3 choi4" (恭喜发财, meaning "congratulations and be prosperous"), which is often proclaimed during Chinese New Year. For that reason, this product is a popular ingredient in dishes used for the Chinese New Year. It is enjoyed as an alternative to cellophane noodles.[citation needed] It is mostly used in Cantonese cuisine and Buddhist cuisine. It is sometimes used as a hot pot ingredient.
# Health effects
A research team from the biochemistry department of the Chinese University of Hong Kong said that international research has shown that fat choy, besides having no nutritional value, has also been found to contain Beta-methylamino L-alanine (BMAA), a toxic amino acid that could affect the normal functions of nerve cells. Professor Chan King-ming of the team told the media that eating fat choy could lead to degenerative diseases such as Alzheimer's, Parkinson's, and dementia.[2]
# Notes
- ↑ ijs.sgmjournals.org
- ↑ Jump up to: 2.0 2.1 2.2 The standard.com.hk
- ↑ Waynesword | https://www.wikidoc.org/index.php/Fat_choy | |
326c1753df8c30d8ed16b366ca15619b2a1d1222 | wikidoc | Fecaloma | Fecaloma
Synonyms and keywords: a tumor made of feces; fecalith; coprolith; stones made of feces
# Overview
A fecaloma is a hardening of feces into stones of varying size inside the colon.
# Pathophysiology
A fecaloma occurs in the setting of chronic obstruction of fecal transit.
# Causes
- Chagas disease
- Hirschsprung's disease
- Megacolon and chronic constipation
- Destruction of the autonomic nervous system inside the colon's mucosa (Auerbach's plexus)
# Natural History, Complications and Prognosis
Fecal impaction may have severe and even lethal effects, such as the rupture of the colon's walls by acute angles of the fecalomas (stercoral perforation), followed by septicemia. A fecolith is also usually the cause of acute appendicitis.
# Treatment
Extremely large (giant) fecalomas, which must be surgically removed (disimpaction). Normally, however, fecalomas can be manually disimpacted or by passing colonic tubes (catheters which carry a flow of disimpaction fluid (solvent). | Fecaloma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: a tumor made of feces; fecalith; coprolith; stones made of feces
# Overview
A fecaloma is a hardening of feces into stones of varying size inside the colon.
# Pathophysiology
A fecaloma occurs in the setting of chronic obstruction of fecal transit.
# Causes
- Chagas disease
- Hirschsprung's disease
- Megacolon and chronic constipation
- Destruction of the autonomic nervous system inside the colon's mucosa (Auerbach's plexus)
# Natural History, Complications and Prognosis
Fecal impaction may have severe and even lethal effects, such as the rupture of the colon's walls by acute angles of the fecalomas (stercoral perforation), followed by septicemia. A fecolith is also usually the cause of acute appendicitis.[1]
# Treatment
Extremely large (giant) fecalomas, which must be surgically removed (disimpaction). Normally, however, fecalomas can be manually disimpacted or by passing colonic tubes (catheters which carry a flow of disimpaction fluid (solvent). | https://www.wikidoc.org/index.php/Fecalith | |
89d7543e8bf9fdc1dd70fade635f096e6490b5ad | wikidoc | Feedback | Feedback
Feedback is a process whereby some proportion of the output signal of a system is passed (fed back) to the input. This is often used to control the dynamic behavior of the system. Examples of feedback can be found in most complex systems, such as engineering, architecture, economics, thermodynamics, and biology. An example of a complex feedback system is the steering system of an automobile. While driving, a person receives signals from the environment, such as signs and hazards. The driver’s brain processes the information and sends signals to the automobile via the steering wheel and pedals. The automobile responds by changing direction or speed accordingly.
Negative feedback was applied by Harold Stephen Black to electrical amplifiers in 1927, but he could not get his idea patented until 1937. Arturo Rosenblueth, a Mexican researcher and physician, co-authored a seminal 1943 paper Behavior, Purpose and Teleology that, according to Norbert Wiener (another co-author of the paper), set the basis for the new science of cybernetics. Rosenblueth proposed that behavior controlled by negative feedback, whether in animal, human or machine, was a determinative, directive principle in nature and human creations.. This kind of feedback is studied in cybernetics and control theory.
In organizations, feedback is a process of sharing observations, concerns and suggestions between persons or divisions of the organization with an intention of improving both personal and organizational performance. Feedback can be unilateral, but experience suggests that bi-directional feedback is more effective in achieving continuous improvement in an organization.
# Overview
Feedback is both a mechanism, process and signal that is looped back to control a system within itself. This loop is called the feedback loop. A control system usually has input and output to the system; when the output of the system is fed back into the system as part of its input, it is called the "feedback."
Feedback and regulation are self related. The negative feedback helps to maintain stability in a system in spite of external changes. It is related to homeostasis. Positive feedback amplifies possibilities of divergences (evolution, change of goals); it is the condition to change, evolution, growth; it gives the system the ability to access new points of equilibrium.
For example, in an organism, most positive feedback provide for fast autoexcitation of elements of endocrine and nervous systems (in particular, in stress responses conditions) and play a key role in regulation of morphogenesis, growth, and development of organs, all processes which are in essence a rapid escape from the initial state. Homeostasis is especially visible in the nervous and endocrine systems when considered at organism level.
# Types of feedback
Types of feedback are:
- negative feedback: which tends to reduce output (but in amplifiers, stabilizes and linearizes operation),
- positive feedback: which tends to increase output, or
- bipolar feedback: which can either increase or decrease output.
Systems which include feedback are prone to hunting, which is oscillation of output resulting from improperly tuned inputs of first positive then negative feedback. Audio feedback typifies this form of oscillation.
Bipolar feedback is present in many natural and human systems. Feedback is usually bipolar—that is, positive and negative—in natural environments, which, in their diversity, furnish synergic and antagonistic responses to the output of any system.
# Applications
## In biology
In biological systems such as organisms, ecosystems, or the biosphere, most parameters must stay under control within a narrow range around a certain optimal level under certain environmental conditions. The deviation of the optimal value of the controlled parameter can result from the changes in internal and external environments. A change of some of the environmental conditions may also require change of that range to change for the system to function. The value of the parameter to maintain is recorded by a reception system and conveyed to a regulation module via an information channel.
Biological systems contain many types of regulatory circuits, both positive and negative. As in other contexts, Positive and negative don't imply consequences of the feedback have good or bad final effect. A negative feedback loop is one that tends to slow down a process, while the positive feedback loop tends to accelerate it.
The mirror neurons are part of a social feedback system, when an observed action is ´mirrored´ by the brain - like a self performed action.
Feedback is also central to the operations of genes and gene regulatory networks. Repressor (see Lac repressor) and activator proteins are used to create genetic operons, which were identified by Francois Jacob and Jacques Monod in 1961 as feedback loops. These feedback loops may be positive
(as in the case of the coupling between a sugar molecule and the proteins that import sugar into a bacterial cell), or negative (as is often the case in metabolic consumption). Interactive models for interplay between positive and negative feedback loop in metabolism is presented
here.
Any self-regulating natural process involves feedback and is prone to hunting. A well known example in ecology is the oscillation of the population of snowshoe hares due to predation from lynxes.
In zymology, feedback serves as regulation of activity of an enzyme by its direct product(s) or downstream metabolite(s) in the metabolic pathway (see Allosteric regulation).
There is an ice-albedo positive feedback loop whereby melting snow exposes more dark ground (of lower albedo), which in turn absorbs heat and causes more snow to melt. This is part of the evidence of the danger of global warming.
## In economics and finance
A system prone to hunting (oscillating) is the stock market, which has both positive and negative feedback mechanisms. This is due to cognitive and emotional factors belonging to the field of behavioral finance. For example,
- When stocks are rising (a bull market), the belief that further rises are probable gives investors an incentive to buy (positive feedback, see also stock market bubble); but the increased price of the shares, and the knowledge that there must be a peak after which the market will fall, ends up deterring buyers (negative feedback).
- Once the market begins to fall regularly (a bear market), some investors may expect further losing days and refrain from buying (positive feedback), but others may buy because stocks become more and more of a bargain (negative feedback).
George Soros used the word "reflexism" to describe feedback in the financial markets and developed an investment theory based on this principle.
The conventional economic equilibrium model of supply and demand supports only ideal linear negative feedback and was heavily criticized by Paul Ormerod in his book "The Death of Economics" which in turn was criticized by traditional economists. This book was part of a change of perspective as economists started to recognise that Chaos Theory applied to nonlinear feedback systems including financial markets.
## In education
Young students will often look up to instructors as experts in the field and take to heart most of the things instructors say. Thus, it is believed that spending a fair amount of time and effort thinking about how to respond to students may be a worthwhile time investment. Here are some general types of feedback that can be used in many types of student assessment:
(Adapted from Flemming and Levie.)
A different application of feedback in education is the system for "continuous improvement" of engineering curricula monitored by the .
## In electronic engineering
The processing and control of feedback is engineered into many electronic devices and may also be embedded in other technologies.
If the signal is inverted on its way round the control loop, the system is said to have negative feedback; otherwise, the feedback is said to be positive. Negative feedback is often deliberately introduced to increase the stability and accuracy of a system. This scheme can fail if the input changes faster than the system can respond to it. When this happens, the lag in arrival of the feedback signal results in positive feedback, causing the output to oscillate or hunt Positive feedback is usually an unwanted consequence of system behaviour.
Harry Nyquist contributed the Nyquist plot for assessing the stability of feedback systems. An easier assessment, but less general, is based upon gain margin and phase margin using Bode plots (contributed by Hendrik Bode). Design to insure stability often involves frequency compensation, one method of compensation being pole splitting.
## In control theory
Feedback is extensively used in control theory, using a variety of methods including state space (controls), pole placement and so forth.
The most common general-purpose controller using a control-loop feedback mechanism is a proportional-integral-derivative (PID) controller. Each term of the PID controller copes with time. The proportional term handles the present state of the system, the integral term handles its past, and the derivative or slope term tries to predict and handle the future.
## In mechanical engineering
In ancient times, the float valve was used to regulate the flow of water in Greek and Roman water clocks; similar float valves are used to regulate fuel in a carburetor and also used to regulate tank water level in the flush toilet.
The windmill was enhanced in 1745 by blacksmith Edmund Lee who added a fantail to keep the face of the windmill pointing into the wind. In 1787 Thomas Mead regulated the speed of rotation of a windmill by using a centrifugal pendulum to adjust the distance between the bedstone and the runner stone (i.e. to adjust the load).
The use of the centrifugal governor by James Watt in 1788 to regulate the speed of his steam engine was one factor leading to the Industrial Revolution. Steam engines also use float valves and pressure release valves as mechanical regulation devices. A mathematical analysis of Watt's governor was done by James Clerk Maxwell in 1868.
The Great Eastern was one of the largest steamships of its time and employed a steam powered rudder with feedback mechanism designed in 1866 by J.McFarlane Gray. Joseph Farcot coined the word servo in 1873 to describe steam powered steering systems. Hydraulic servos were later used to position guns. Elmer Ambrose Sperry of the Sperry Corporation designed the first autopilot in 1912. Nicolas Minorsky published a theoretical analysis of automatic ship steering in 1922 and described the PID controller.
Internal combustion engines of the late 20th century employed mechanical feedback mechanisms such as vacuum advance (see: Ignition timing) but mechanical feedback was replaced by electronic engine management systems once small, robust and powerful single-chip microcontrollers became affordable.
## In organizations
As an organization seeks to improve its performance, feedback helps it to make required adjustments.
Examples of feedback in organizations:
- Financial audit
- Performance appraisal
- Shareholders' meetings
- Marketing research
- 360-degree feedback
- Walkouts
- Lockouts
## In government
Examples of feedback in government are:
- Elections
- Mass media
- Revolution
- Curfews | Feedback
Feedback is a process whereby some proportion of the output signal of a system is passed (fed back) to the input. This is often used to control the dynamic behavior of the system. Examples of feedback can be found in most complex systems, such as engineering, architecture, economics, thermodynamics, and biology. An example of a complex feedback system is the steering system of an automobile. While driving, a person receives signals from the environment, such as signs and hazards. The driver’s brain processes the information and sends signals to the automobile via the steering wheel and pedals. The automobile responds by changing direction or speed accordingly.
Negative feedback was applied by Harold Stephen Black to electrical amplifiers in 1927, but he could not get his idea patented until 1937.[1] Arturo Rosenblueth, a Mexican researcher and physician, co-authored a seminal 1943 paper Behavior, Purpose and Teleology[2] that, according to Norbert Wiener (another co-author of the paper), set the basis for the new science of cybernetics. Rosenblueth proposed that behavior controlled by negative feedback, whether in animal, human or machine, was a determinative, directive principle in nature and human creations.[citation needed]. This kind of feedback is studied in cybernetics and control theory.
In organizations, feedback is a process of sharing observations, concerns and suggestions between persons or divisions of the organization with an intention of improving both personal and organizational performance. Feedback can be unilateral, but experience suggests that bi-directional feedback is more effective in achieving continuous improvement in an organization.
# Overview
Feedback is both a mechanism, process and signal that is looped back to control a system within itself. This loop is called the feedback loop. A control system usually has input and output to the system; when the output of the system is fed back into the system as part of its input, it is called the "feedback."
Feedback and regulation are self related. The negative feedback helps to maintain stability in a system in spite of external changes. It is related to homeostasis. Positive feedback amplifies possibilities of divergences (evolution, change of goals); it is the condition to change, evolution, growth; it gives the system the ability to access new points of equilibrium.
For example, in an organism, most positive feedback provide for fast autoexcitation of elements of endocrine and nervous systems (in particular, in stress responses conditions) and play a key role in regulation of morphogenesis, growth, and development of organs, all processes which are in essence a rapid escape from the initial state.[citation needed] Homeostasis is especially visible in the nervous and endocrine systems when considered at organism level.
# Types of feedback
Types of feedback are:
- negative feedback: which tends to reduce output (but in amplifiers, stabilizes and linearizes operation),
- positive feedback: which tends to increase output, or
- bipolar feedback: which can either increase or decrease output.
Systems which include feedback are prone to hunting, which is oscillation of output resulting from improperly tuned inputs of first positive then negative feedback. Audio feedback typifies this form of oscillation.
Bipolar feedback is present in many natural and human systems. Feedback is usually bipolar—that is, positive and negative—in natural environments, which, in their diversity, furnish synergic and antagonistic responses to the output of any system.
# Applications
## In biology
In biological systems such as organisms, ecosystems, or the biosphere, most parameters must stay under control within a narrow range around a certain optimal level under certain environmental conditions. The deviation of the optimal value of the controlled parameter can result from the changes in internal and external environments. A change of some of the environmental conditions may also require change of that range to change for the system to function. The value of the parameter to maintain is recorded by a reception system and conveyed to a regulation module via an information channel.
Biological systems contain many types of regulatory circuits, both positive and negative. As in other contexts, Positive and negative don't imply consequences of the feedback have good or bad final effect. A negative feedback loop is one that tends to slow down a process, while the positive feedback loop tends to accelerate it.
The mirror neurons are part of a social feedback system, when an observed action is ´mirrored´ by the brain - like a self performed action.
Feedback is also central to the operations of genes and gene regulatory networks. Repressor (see Lac repressor) and activator proteins are used to create genetic operons, which were identified by Francois Jacob and Jacques Monod in 1961 as feedback loops. These feedback loops may be positive
(as in the case of the coupling between a sugar molecule and the proteins that import sugar into a bacterial cell), or negative (as is often the case in metabolic consumption). Interactive models for interplay between positive and negative feedback loop in metabolism is presented
here.
Any self-regulating natural process involves feedback and is prone to hunting. A well known example in ecology is the oscillation of the population of snowshoe hares due to predation from lynxes.
In zymology, feedback serves as regulation of activity of an enzyme by its direct product(s) or downstream metabolite(s) in the metabolic pathway (see Allosteric regulation).
There is an ice-albedo positive feedback loop whereby melting snow exposes more dark ground (of lower albedo), which in turn absorbs heat and causes more snow to melt. This is part of the evidence of the danger of global warming.
## In economics and finance
A system prone to hunting (oscillating) is the stock market, which has both positive and negative feedback mechanisms. This is due to cognitive and emotional factors belonging to the field of behavioral finance. For example,
- When stocks are rising (a bull market), the belief that further rises are probable gives investors an incentive to buy (positive feedback, see also stock market bubble); but the increased price of the shares, and the knowledge that there must be a peak after which the market will fall, ends up deterring buyers (negative feedback).
- Once the market begins to fall regularly (a bear market), some investors may expect further losing days and refrain from buying (positive feedback), but others may buy because stocks become more and more of a bargain (negative feedback).
George Soros used the word "reflexism" to describe feedback in the financial markets and developed an investment theory based on this principle.
The conventional economic equilibrium model of supply and demand supports only ideal linear negative feedback and was heavily criticized by Paul Ormerod in his book "The Death of Economics" which in turn was criticized by traditional economists. This book was part of a change of perspective as economists started to recognise that Chaos Theory applied to nonlinear feedback systems including financial markets.
## In education
Young students will often look up to instructors as experts in the field and take to heart most of the things instructors say. Thus, it is believed that spending a fair amount of time and effort thinking about how to respond to students may be a worthwhile time investment. Here are some general types of feedback that can be used in many types of student assessment:
(Adapted from Flemming and Levie[3].)
A different application of feedback in education is the system for "continuous improvement" of engineering curricula monitored by the [Accreditation Board for Engineering and Technology (ABET)] .[4]
## In electronic engineering
The processing and control of feedback is engineered into many electronic devices and may also be embedded in other technologies.
If the signal is inverted on its way round the control loop, the system is said to have negative feedback; otherwise, the feedback is said to be positive. Negative feedback is often deliberately introduced to increase the stability and accuracy of a system. This scheme can fail if the input changes faster than the system can respond to it. When this happens, the lag in arrival of the feedback signal results in positive feedback, causing the output to oscillate or hunt[5] Positive feedback is usually an unwanted consequence of system behaviour.
Harry Nyquist contributed the Nyquist plot for assessing the stability of feedback systems. An easier assessment, but less general, is based upon gain margin and phase margin using Bode plots (contributed by Hendrik Bode). Design to insure stability often involves frequency compensation, one method of compensation being pole splitting.
## In control theory
Feedback is extensively used in control theory, using a variety of methods including state space (controls), pole placement and so forth.
The most common general-purpose controller using a control-loop feedback mechanism is a proportional-integral-derivative (PID) controller. Each term of the PID controller copes with time. The proportional term handles the present state of the system, the integral term handles its past, and the derivative or slope term tries to predict and handle the future.
## In mechanical engineering
In ancient times, the float valve was used to regulate the flow of water in Greek and Roman water clocks; similar float valves are used to regulate fuel in a carburetor and also used to regulate tank water level in the flush toilet.
The windmill was enhanced in 1745 by blacksmith Edmund Lee who added a fantail to keep the face of the windmill pointing into the wind. In 1787 Thomas Mead regulated the speed of rotation of a windmill by using a centrifugal pendulum to adjust the distance between the bedstone and the runner stone (i.e. to adjust the load).
The use of the centrifugal governor by James Watt in 1788 to regulate the speed of his steam engine was one factor leading to the Industrial Revolution. Steam engines also use float valves and pressure release valves as mechanical regulation devices. A mathematical analysis of Watt's governor was done by James Clerk Maxwell in 1868.
The Great Eastern was one of the largest steamships of its time and employed a steam powered rudder with feedback mechanism designed in 1866 by J.McFarlane Gray. Joseph Farcot coined the word servo in 1873 to describe steam powered steering systems. Hydraulic servos were later used to position guns. Elmer Ambrose Sperry of the Sperry Corporation designed the first autopilot in 1912. Nicolas Minorsky published a theoretical analysis of automatic ship steering in 1922 and described the PID controller.
Internal combustion engines of the late 20th century employed mechanical feedback mechanisms such as vacuum advance (see: Ignition timing) but mechanical feedback was replaced by electronic engine management systems once small, robust and powerful single-chip microcontrollers became affordable.
## In organizations
As an organization seeks to improve its performance, feedback helps it to make required adjustments.
Examples of feedback in organizations:
- Financial audit
- Performance appraisal
- Shareholders' meetings
- Marketing research
- 360-degree feedback
- Walkouts
- Lockouts
## In government
Examples of feedback in government are:
- Elections
- Mass media
- Revolution
- Curfews | https://www.wikidoc.org/index.php/Feedback | |
dac1cc46742426b35152706688e489de266d4912 | wikidoc | Feldsher | Feldsher
Feldsher (Russian/Cyrillic: Фельдшер) was the name of medical/healthcare professional that provided many medical services in the Soviet Union, mainly in rural areas. Trained in undergraduate medical / health professions schools, they were supposed to work on preventive and primary care work and refer most serious cases to higher-level institutions. Feldsher actually means barber, and was based on the surgeons-barbers in the Russian Army going back to the 1600s. This system of rural primary care provided some of the inspiration for China's program of Barefoot doctors.
The name Feldsher was derived from the German term Feldscher, which was coined in the 15th century. Feldscher means Field doctor (Feld = Field, Scher = doctor), and was the name of medieval barber-surgeons. They worked as army field surgeons for the German and Swiss Landsknecht until real military medical services were established by Prussia in the early 18th century. The term was then exported with Prussian officers and nobility to Russia.
Feldsher(Фельдшер), as healthcare profession in the Soviet Union, is an equivalent to Physician Assistant or Nurse Practitioners in the USA.
de:Feldscher
nl:Feldsjer | Feldsher
Feldsher (Russian/Cyrillic: Фельдшер) was the name of medical/healthcare professional that provided many medical services in the Soviet Union, mainly in rural areas. Trained in undergraduate medical / health professions schools, they were supposed to work on preventive and primary care work and refer most serious cases to higher-level institutions. Feldsher actually means barber, and was based on the surgeons-barbers in the Russian Army going back to the 1600s. This system of rural primary care provided some of the inspiration for China's program of Barefoot doctors.
The name Feldsher was derived from the German term Feldscher, which was coined in the 15th century. Feldscher means Field doctor (Feld = Field, Scher = doctor), and was the name of medieval barber-surgeons. They worked as army field surgeons for the German and Swiss Landsknecht until real military medical services were established by Prussia in the early 18th century. The term was then exported with Prussian officers and nobility to Russia.
Feldsher(Фельдшер), as healthcare profession in the Soviet Union, is an equivalent to Physician Assistant or Nurse Practitioners in the USA.
de:Feldscher
nl:Feldsjer
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Feldsher | |
323165cfffbd11946048af6aa4ef2f7349de8062 | wikidoc | Fen-phen | Fen-phen
Fen-phen was an anti-obesity medication (an anorectic) which consisted of two drugs: fenfluramine and phentermine. Fenfluramine, and later, a related drug, dexfenfluramine, was marketed by American Home Products, now known as Wyeth.
After reports of valvular heart disease and pulmonary hypertension, primarily in women who had been undergoing treatment with Fen-phen, the Food and Drug Administration (FDA) requested its withdrawal from the market in September 1997.
The action was based on findings from doctors who had evaluated patients taking these two drugs with echocardiograms, a special procedure that can test the functioning of heart valves. These findings indicated that approximately 30 percent of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms. This percentage of abnormal test results was much higher than would be expected from a comparatively-sized sample of the population who had not been exposed to either fenfluramine or dexfenfluramine.
In July 1997, researchers at the Mayo Clinic and Mayo Foundation reported 24 cases of rare valvular disease in women who took the Fen-phen combination therapy. The FDA alerted medical doctors that it had received nine additional reports of the same type, and requested all health care professionals to report any such cases to the agency’s MedWatch program, or to their respective pharmaceutical manufacturers.
The FDA subsequently received 66 additional reports of heart valve disease, all primarily associated with Fen-phen. There were also reports of documented heart-valve problems in patients taking only either fenfluramine or dexfenfluramine. The FDA requested that the manufacturers of fenfluramine and dexfenfluramine stress the potential risk to the heart in the drugs' labeling and in patient package inserts. As of 1997, the FDA was continuing to receive reports of cardiac valvular disease in persons who have taken these drugs. This valvular disease typically involves the aortic and mitral valves.
As of 2004, Fen-phen is no longer widely available. In April 2005, American Lawyer magazine ran a cover story on the Fen-phen mass tort crisis, reporting that more than 50,000 product liability lawsuits had been filed by alleged Fen-phen victims. Estimates of total liability run as high as $14 billion. | Fen-phen
Fen-phen was an anti-obesity medication (an anorectic) which consisted of two drugs: fenfluramine and phentermine. Fenfluramine, and later, a related drug, dexfenfluramine, was marketed by American Home Products, now known as Wyeth.
After reports of valvular heart disease and pulmonary hypertension, primarily in women who had been undergoing treatment with Fen-phen, the Food and Drug Administration (FDA) requested its withdrawal from the market in September 1997.
The action was based on findings from doctors who had evaluated patients taking these two drugs with echocardiograms, a special procedure that can test the functioning of heart valves. These findings indicated that approximately 30 percent of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms. This percentage of abnormal test results was much higher than would be expected from a comparatively-sized sample of the population who had not been exposed to either fenfluramine or dexfenfluramine.
In July 1997, researchers at the Mayo Clinic and Mayo Foundation reported 24 cases of rare valvular disease in women who took the Fen-phen combination therapy. The FDA alerted medical doctors that it had received nine additional reports of the same type, and requested all health care professionals to report any such cases to the agency’s MedWatch program, or to their respective pharmaceutical manufacturers.
The FDA subsequently received 66 additional reports of heart valve disease, all primarily associated with Fen-phen. There were also reports of documented heart-valve problems in patients taking only either fenfluramine or dexfenfluramine. The FDA requested that the manufacturers of fenfluramine and dexfenfluramine stress the potential risk to the heart in the drugs' labeling and in patient package inserts. As of 1997, the FDA was continuing to receive reports of cardiac valvular disease in persons who have taken these drugs. This valvular disease typically involves the aortic and mitral valves.
As of 2004, Fen-phen is no longer widely available. In April 2005, American Lawyer magazine ran a cover story on the Fen-phen mass tort crisis, reporting that more than 50,000 product liability lawsuits had been filed by alleged Fen-phen victims. Estimates of total liability run as high as $14 billion.
# External links
- U.S. FDA Fen-Phen information
sh:Fen-phen
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Fen-Phen | |
593b41919e06970ed699852071690e75e63a906c | wikidoc | Fioricet | Fioricet
Fioricet and Esgic are brand name drugs made from a combination of acetaminophen (325 mg), butalbital (a barbiturate, 50 mg), and caffeine (40 mg). They are indicated for the treatment of tension headaches and muscle contraction headaches. Although not indicated, they are commonly used to treat migraines and other pain related ailments.
# Usage and dosage
Fioricet is indicated for the treatment of complex and muscle contraction headaches. It is also commonly prescribed for migraines although it is not FDA indicated for this use. The usual adult dose is 1-2 tablets every four hours as needed, not exceeding six tablets in a 24 hour period.
# Mechanism of action
Butalbital has generalized depressant effect on central nervous system and, in very high doses, has peripheral effects. Acetaminophen has analgesic and antipyretic effects; its analgesic effects may be mediated through inhibition of prostaglandin synthetase enzyme complex. Caffeine is thought to produce constriction of cerebral blood vessels.
Butalbital has half-life of about 35 hours. Acetaminophen half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Caffeine half-life is about 3 hours.
# Side effects
Side effects for any drug are difficult to predict, but commonly reported side effects for Fioricet include:
- Dizziness
- Drowsiness
- Intoxicated feeling
- Light-headedness
- Nausea
- Vomiting
- Sedation
- Addiction
- Shortness of breath
- Abdominal pain
# Variations
- Phrenilin is an equivalent combination of butalbital and acetaminophen, without the caffeine (325/50).
- Esgic Plus and Phrenilin Forte contains 500 and 650 miligrams of acetaminophen respectively, instead of 325 milligrams. Additionally, Esgic Plus contains 40 milligrams of caffeine.
- Fiorinal contains aspirin instead of acetaminophen.
- Fiorinal and Fioricet also come as a combination drug with codeine called Fiorinal with Codeine and Fioricet with Codeine which adds 30 milligrams of codeine phosphate to each mixture. | Fioricet
Fioricet and Esgic are brand name drugs made from a combination of acetaminophen (325 mg), butalbital (a barbiturate, 50 mg), and caffeine (40 mg). They are indicated for the treatment of tension headaches and muscle contraction headaches. Although not indicated, they are commonly used to treat migraines and other pain related ailments.
# Usage and dosage
Fioricet is indicated for the treatment of complex and muscle contraction headaches. It is also commonly prescribed for migraines although it is not FDA indicated for this use. The usual adult dose is 1-2 tablets every four hours as needed, not exceeding six tablets in a 24 hour period.
# Mechanism of action
Butalbital has generalized depressant effect on central nervous system and, in very high doses, has peripheral effects. Acetaminophen has analgesic and antipyretic effects; its analgesic effects may be mediated through inhibition of prostaglandin synthetase enzyme complex. Caffeine is thought to produce constriction of cerebral blood vessels.
Butalbital has half-life of about 35 hours. Acetaminophen half-life is 1.25 to 3 hours, but may be increased by liver damage and following overdosage. Caffeine half-life is about 3 hours.
# Side effects
Side effects for any drug are difficult to predict, but commonly reported side effects for Fioricet include:
- Dizziness
- Drowsiness
- Intoxicated feeling
- Light-headedness
- Nausea
- Vomiting
- Sedation
- Addiction
- Shortness of breath
- Abdominal pain
# Variations
- Phrenilin is an equivalent combination of butalbital and acetaminophen, without the caffeine (325/50).
- Esgic Plus and Phrenilin Forte contains 500 and 650 miligrams of acetaminophen respectively, instead of 325 milligrams. Additionally, Esgic Plus contains 40 milligrams of caffeine.
- Fiorinal contains aspirin instead of acetaminophen.
- Fiorinal and Fioricet also come as a combination drug with codeine called Fiorinal with Codeine and Fioricet with Codeine which adds 30 milligrams of codeine phosphate to each mixture.
# External links
- Fioricet - drugs.com
- Fiorinal & Fioricet - National Headache Foundation
Template:Treatment-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Fioricet | |
c4935222fd59335948897f399ce513850a03eb48 | wikidoc | Fire ant | Fire ant
Fire ants, sometimes referred to as simply red ants, are stinging ants with over 280 species worldwide. They have several common names including Ginger Ants and Tropical Fire Ants (English), aka-kami-ari (Japanese), and Feuerameise (German).
# Appearance
The bodies of fire ants, like all insects' bodies, are broken up into three sections: the head, the thorax, and the abdomen, with three pairs of legs and a pair of antennae. Fire ants can be distinguished from other ants by their copper brown head and body with a darker abdomen. The worker ants are blackish to reddish, and their size varies from 2mm to 6 mm (0.12 in to 0.24 in). These different sizes of the ants can all exist in the same nest.
# Behavior
A typical fire ant colony produces large mounds in open areas, and feeds mostly on young plants, seeds, and sometimes crickets. Fire ants often attack small animals and can kill them. Unlike many other ants, which bite and then spray acid on the wound, fire ants only bite to get a grip and then sting (from the abdomen) and inject a toxic alkaloid venom called Solenopsin, a compound from the class of piperidines. For humans, this is a painful sting, a sensation similar to what one feels when burned by fire — hence the name fire ant — and the aftereffects of the sting can be deadly to sensitive individuals. Although fire ants do not typically seek out and attack the face, they are as likely to attack an exposed and vulnerable face as any other body part. The venom is both insecticidal and antibiotic. Researchers have proposed that nurse workers will spray their brood to protect them from microorganisms.
Fire ants nest in the soil, often near moist areas, such as river banks, pond edges, watered lawns and highway edges. Usually the nest will not be visible as it will be built under objects such as timber, logs, rocks, pavers, bricks, etc. If there is no cover for nesting, dome-shaped mounds will be constructed, but this is usually only found in open spaces such as fields, parks and lawns. These mounds can reach heights of 40 cm (15.7 in).
Colonies are founded by small groups of queens or single queens. Even if only one queen survives, within a month or so the colony can expand to thousands of individuals. Some colonies may be polygynous (having multiple queens per nest).
In the Klang Valley of Malaysia, fire ants build nests in leaves by folding the leaf sideways and downwards over itself, with the queen inside, and then excreting a sticky white substance with which they bond and seal the fold. The excretion is also used inside the folded leaf to cover the queen and the eggs, like a kind of translucent duvet. It should also be noted that fire ants commonly construct their nests out of dug-out mounds and complex tunnel systems.
The ants guard the nest and fiercely attack intruders. Even the lightest touch brings them out in a fury.
# Roles
## Queens
A queen is generally the largest individual in the colony. The primary function of the queen is reproduction; she may live for 6-7 years and produce up to 1,500 eggs per day. Many fire ant colonies will have more than one queen.
## Males
Mate with the queen ant in order to produce eggs. Also defend their queen in the event of an attack or structural damage of the colony/mound.
## Workers
The workers are sterile females who build and repair the nest, care for the young, defend the nest, and feed both young and adult ants.
# Introduced species
Although most fire ant species do not bother people and are not invasive due to biological factors, Solenopsis invicta, commonly known as the Red imported fire ant (or RIFA) is an invasive pest in many areas of the world, notably the United States, Australia, the Philippines, China and Taiwan. The RIFA was accidentally introduced into the United States due to a South American cargo ship coming to an Alabama port in 1918, but now infests the majority of the Southern and Southwestern United States.
In the US, the FDA estimates that more than US$5 billion is spent annually on medical treatment, damage, and control in RIFA-infested areas. Furthermore, the ants cause approximately US$750 million in damage annually to agricultural assets, including veterinarian bills and livestock loss as well as crop loss. Since September 2004, Taiwan has been seriously affected by the red fire ant.
The US, Taiwan and Australia all have ongoing national efforts to control or eradicate the species, but, other than Australia, none have been especially effective. In Australia an intensive program costing A$175 million has, at February 2007, eradicated 99% of fire ants from the sole infestation occurring in South East Queensland.
# Symptoms and First aid
The venom of a fire ant sting causes stinging and swells into a bump. This can cause much pain and irritation at times, especially when stung repeatedly by several at once. The bump often forms into a white pustule, which is at risk of becoming infected. The pustules are unattractive and uncomfortable while active and, if the bite sites become infected, can turn into scars. Additionally, some people are allergic to the venom and, as with many allergies, may experience anaphylaxis, which requires emergency treatment. An antihistamine or topical corticosteroids may help reduce the itching.
First aid for fire ant bites includes external treatments and oral medicines.
- External treatments: a topical steroid cream (hydrocortisone), or one containing aloe vera.
- Oral medicines: antihistamines
Patients who experience severe or life threatening allergic reactions to fire ant insect stings should visit a doctor or hospital immediately upon contact as these reactions can result in death.
# Other names
In Spanish, fire ants are known as hormiga colorada/roja (red ant) or hormiga brava (fierce ant). In Puerto Rico there is a native, very small and slow-moving kind of fire ant called abayarde. In Portuguese, they are called formiga de fogo (fire ant) and formiga lava-pé (wash foot ant).
# Species
This species list is incomplete.
# Trivia
In CSI's episode Grave Danger, Nick Stokes a CSI member was attacked by a Solenopsis
In an episode of Bones, Season 2, Episode 15 "Bodies in the Book" one of the victims was killed by a Solenopsis | Fire ant
Fire ants, sometimes referred to as simply red ants, are stinging ants with over 280 species worldwide. They have several common names including Ginger Ants and Tropical Fire Ants (English), aka-kami-ari (Japanese), and Feuerameise (German).
# Appearance
The bodies of fire ants, like all insects' bodies, are broken up into three sections: the head, the thorax, and the abdomen, with three pairs of legs and a pair of antennae. Fire ants can be distinguished from other ants by their copper brown head and body with a darker abdomen. The worker ants are blackish to reddish, and their size varies from 2mm to 6 mm (0.12 in to 0.24 in). These different sizes of the ants can all exist in the same nest.
# Behavior
A typical fire ant colony produces large mounds in open areas, and feeds mostly on young plants, seeds, and sometimes crickets. Fire ants often attack small animals and can kill them. Unlike many other ants, which bite and then spray acid on the wound, fire ants only bite to get a grip and then sting (from the abdomen) and inject a toxic alkaloid venom called Solenopsin, a compound from the class of piperidines. For humans, this is a painful sting, a sensation similar to what one feels when burned by fire — hence the name fire ant — and the aftereffects of the sting can be deadly to sensitive individuals. Although fire ants do not typically seek out and attack the face, they are as likely to attack an exposed and vulnerable face as any other body part. The venom is both insecticidal and antibiotic. Researchers have proposed that nurse workers will spray their brood to protect them from microorganisms.
Fire ants nest in the soil, often near moist areas, such as river banks, pond edges, watered lawns and highway edges. Usually the nest will not be visible as it will be built under objects such as timber, logs, rocks, pavers, bricks, etc. If there is no cover for nesting, dome-shaped mounds will be constructed, but this is usually only found in open spaces such as fields, parks and lawns. These mounds can reach heights of 40 cm (15.7 in).
Colonies are founded by small groups of queens or single queens. Even if only one queen survives, within a month or so the colony can expand to thousands of individuals. Some colonies may be polygynous (having multiple queens per nest)[1].
In the Klang Valley of Malaysia, fire ants build nests in leaves by folding the leaf sideways and downwards over itself, with the queen inside, and then excreting a sticky white substance with which they bond and seal the fold. The excretion is also used inside the folded leaf to cover the queen and the eggs, like a kind of translucent duvet. It should also be noted that fire ants commonly construct their nests out of dug-out mounds and complex tunnel systems.
The ants guard the nest and fiercely attack intruders. Even the lightest touch brings them out in a fury.
# Roles
## Queens
A queen is generally the largest individual in the colony. The primary function of the queen is reproduction; she may live for 6-7 years and produce up to 1,500 eggs per day. Many fire ant colonies will have more than one queen.
## Males
Mate with the queen ant in order to produce eggs. Also defend their queen in the event of an attack or structural damage of the colony/mound.
## Workers
The workers are sterile females who build and repair the nest, care for the young, defend the nest, and feed both young and adult ants.
# Introduced species
Although most fire ant species do not bother people and are not invasive due to biological factors, Solenopsis invicta, commonly known as the Red imported fire ant (or RIFA) is an invasive pest in many areas of the world, notably the United States, Australia, the Philippines, China and Taiwan. The RIFA was accidentally introduced into the United States due to a South American cargo ship coming to an Alabama port in 1918, but now infests the majority of the Southern and Southwestern United States.
In the US, the FDA estimates that more than US$5 billion is spent annually on medical treatment, damage, and control in RIFA-infested areas. Furthermore, the ants cause approximately US$750 million in damage annually to agricultural assets, including veterinarian bills and livestock loss as well as crop loss.[2] Since September 2004, Taiwan has been seriously affected by the red fire ant.
The US, Taiwan and Australia all have ongoing national efforts to control or eradicate the species, but, other than Australia, none have been especially effective. In Australia an intensive program costing A$175 million has, at February 2007, eradicated 99% of fire ants from the sole infestation occurring in South East Queensland.
# Symptoms and First aid
The venom of a fire ant sting causes stinging and swells into a bump. This can cause much pain and irritation at times, especially when stung repeatedly by several at once. The bump often forms into a white pustule, which is at risk of becoming infected. The pustules are unattractive and uncomfortable while active and, if the bite sites become infected, can turn into scars. Additionally, some people are allergic to the venom and, as with many allergies, may experience anaphylaxis, which requires emergency treatment.[3] An antihistamine or topical corticosteroids may help reduce the itching.
First aid for fire ant bites includes external treatments and oral medicines.
- External treatments: a topical steroid cream (hydrocortisone), or one containing aloe vera.
- Oral medicines: antihistamines
Patients who experience severe or life threatening allergic reactions to fire ant insect stings should visit a doctor or hospital immediately upon contact as these reactions can result in death.
# Other names
In Spanish, fire ants are known as hormiga colorada/roja (red ant) or hormiga brava (fierce ant). In Puerto Rico there is a native, very small and slow-moving kind of fire ant called abayarde. In Portuguese, they are called formiga de fogo (fire ant) and formiga lava-pé (wash foot ant).
# Species
This species list is incomplete.
# Trivia
In CSI's episode Grave Danger, Nick Stokes a CSI member was attacked by a Solenopsis
In an episode of Bones, Season 2, Episode 15 "Bodies in the Book" one of the victims was killed by a Solenopsis | https://www.wikidoc.org/index.php/Fire_ant | |
c3b34e7f53d124b4fd4cd54022a7a68d50cf5880 | wikidoc | Fish oil | Fish oil
Fish oil is oil derived from the tissues of oily fish.
Fish oil is recommended for a healthy diet because it contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors to eicosanoids that reduce inflammation throughout the body
However, fish do not actually produce omega-3 fatty acids, but instead accumulate them from either consuming microalgae that produce these fatty acids, as is the case with prey fish like herring and sardines, or, as is the case with fatty predatory fish, by eating prey fish that have accumulated omega-3 fatty acids from microalgae. Such fatty predatory fish like mackerel, lake trout, albacore tuna and salmon may be high in omega-3 fatty acids, but due to their position at the top of the food chain, these species can accumulate toxic substances (See biomagnification). For this reason, the FDA recommends limiting consumption of certain (predatory) fish species (e.g. albacore tuna) due to high levels of toxic contaminants such as mercury, dioxin, PCBs and chlordane.
Due to this limitation, many people have turned to fish oil supplements to get adequate omega-3 fatty acids.
Fish oil supplements have sometimes come under scrutiny in recent years. In early 2006, government agencies such as the Food Standards Agency in the UK and the Food Safety Authority of Ireland reported PCB levels that exceeded the strict new European maximum limits in several fish oil brands,
which required temporary withdrawal of these brands. To address the growing concern over contaminated fish oil supplements, the International Fish Oil Standards program, a voluntary review process, was created at University of Guelph.
Patented production purification processes do however exist in order to remove pollutants and dioxins from fish oil to levels far below the EU limits. This is called stripping technology.
Most of the fish oils used for Omega purposes are originating from Peru, Chile and Morocco because the Omega 3 levels in the fish caught in these areas are higher (around 30%) than in Scandinavian and other fish oils (around 20%). Fish oils are being used in the Omega 3 industry to produce nutraceuticals and pharmaceuticals. However the largest off-takers of the Omega 3 fish oils are still the feeding buyers with the big fish feed companies such as Ewos, Skretting and Biomar in the lead.
# Benefits of fish oil
Some experts believe that taking fish oil (in any form) can help regulate cholesterol in the body,Template:Who because fish oil has high levels of omega-3 fatty acids. The regulation occurs through effects of the EPA and DHA constituents on Peroxisome proliferator-activated receptor alpha (PPARα). Besides cholesterol regulation, benefits include anti-inflammatory properties and positive effects on body composition. However, the preferred source of Omega 3 should be from the fish's body, not the liver. The liver and liver products (such as cod liver oil) of fish and many animals (such as seals and whales) contain Omega-3, but also the active form of vitamin A. At high levels, this form of the vitamin can be dangerous. Early explorers to the land of the Inuit were given raw liver by the natives, which contained a toxic overdose of vitamin A for the white explorers; however, the same amount was harmless to the Inuit, who had no other source of Vitamin A except animal livers.
Studies
were conducted on prisoners in England where the inmates were fed seafood which contains Omega-3 Fatty acids. The higher consumption of these fatty acids led to a drop in the assault rates. Another Finnish study found that prisoners who were convicted of violence had lower levels of omega–3 fatty acids than prisoners convicted of nonviolent offenses. It was suggested that these kinds of fatty acids are responsible for the neuronal growth of the frontal cortex of the brain which, it is further alleged, is the seat of personal behavior.
The American Heart Association recommends the consumption of 1g of fish oil daily, preferably by eating fish, for patients with coronary heart disease.
The US National Institutes of Health lists three conditions for which fish oil and other omega-3 sources are most highly recommended: hypertriglyceridemia, secondary cardiovascular disease prevention and high blood pressure. It then lists 27 other conditions for which there less evidence. It also lists possible safety concerns: "Intake of 3 grams per day or greater of omega-3 fatty acids may increase the risk of bleeding, although there is little evidence of significant bleeding risk at lower doses. Very large intakes of fish oil/omega-3 fatty acids ("Eskimo" amounts) may increase the risk of hemorrhagic (bleeding) stroke."
According to a study from Louisiana State University in September 2005, fish oil may help protect the brain from cognitive problems associated with Alzheimer's disease.
Fish oil has also been shown to aid in the treatment of people suffering with depression.
For purchasing fish oil dietary supplements, it is highly recommended to seek a label certifying the product to be "molecularly distilled", USP Certified, and therefore free of mercury and other metal toxins. | Fish oil
Fish oil is oil derived from the tissues of oily fish.
Fish oil is recommended for a healthy diet because it contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors to eicosanoids that reduce inflammation throughout the body
However, fish do not actually produce omega-3 fatty acids, but instead accumulate them from either consuming microalgae that produce these fatty acids, as is the case with prey fish like herring and sardines, or, as is the case with fatty predatory fish, by eating prey fish that have accumulated omega-3 fatty acids from microalgae. Such fatty predatory fish like mackerel, lake trout, albacore tuna and salmon may be high in omega-3 fatty acids, but due to their position at the top of the food chain, these species can accumulate toxic substances (See biomagnification). For this reason, the FDA recommends limiting consumption of certain (predatory) fish species (e.g. albacore tuna) due to high levels of toxic contaminants such as mercury, dioxin, PCBs and chlordane.[1]
Due to this limitation, many people have turned to fish oil supplements to get adequate omega-3 fatty acids.
Fish oil supplements have sometimes come under scrutiny in recent years. In early 2006, government agencies such as the Food Standards Agency in the UK and the Food Safety Authority of Ireland reported PCB levels that exceeded the strict new European maximum limits in several fish oil brands,[2]
[3]
which required temporary withdrawal of these brands. To address the growing concern over contaminated fish oil supplements, the International Fish Oil Standards program, a voluntary review process, was created at University of Guelph.
Patented production purification processes do however exist in order to remove pollutants and dioxins from fish oil to levels far below the EU limits. This is called stripping technology.
Most of the fish oils used for Omega purposes are originating from Peru, Chile and Morocco because the Omega 3 levels in the fish caught in these areas are higher (around 30%) than in Scandinavian and other fish oils (around 20%). Fish oils are being used in the Omega 3 industry to produce nutraceuticals and pharmaceuticals. However the largest off-takers of the Omega 3 fish oils are still the feeding buyers with the big fish feed companies such as Ewos, Skretting and Biomar in the lead.
# Benefits of fish oil
Some experts believe that taking fish oil (in any form) can help regulate cholesterol in the body,Template:Who because fish oil has high levels of omega-3 fatty acids. The regulation occurs through effects of the EPA and DHA constituents on Peroxisome proliferator-activated receptor alpha (PPARα). Besides cholesterol regulation, benefits include anti-inflammatory properties and positive effects on body composition. However, the preferred source of Omega 3 should be from the fish's body, not the liver. The liver and liver products (such as cod liver oil) of fish and many animals (such as seals and whales) contain Omega-3, but also the active form of vitamin A. At high levels, this form of the vitamin can be dangerous. Early explorers to the land of the Inuit were given raw liver by the natives, which contained a toxic overdose of vitamin A for the white explorers; however, the same amount was harmless to the Inuit, who had no other source of Vitamin A except animal livers.
Studies[4][5]
were conducted on prisoners in England where the inmates were fed seafood which contains Omega-3 Fatty acids. The higher consumption of these fatty acids led to a drop in the assault rates. Another Finnish study found that prisoners who were convicted of violence had lower levels of omega–3 fatty acids than prisoners convicted of nonviolent offenses. It was suggested that these kinds of fatty acids are responsible for the neuronal growth of the frontal cortex of the brain which, it is further alleged, is the seat of personal behavior.
The American Heart Association recommends the consumption of 1g of fish oil daily, preferably by eating fish, for patients with coronary heart disease.[6]
The US National Institutes of Health lists three conditions for which fish oil and other omega-3 sources are most highly recommended: hypertriglyceridemia, secondary cardiovascular disease prevention and high blood pressure. It then lists 27 other conditions for which there less evidence. It also lists possible safety concerns: "Intake of 3 grams per day or greater of omega-3 fatty acids may increase the risk of bleeding, although there is little evidence of significant bleeding risk at lower doses. Very large intakes of fish oil/omega-3 fatty acids ("Eskimo" amounts) may increase the risk of hemorrhagic (bleeding) stroke."[7]
According to a study from Louisiana State University in September 2005, fish oil may help protect the brain from cognitive problems associated with Alzheimer's disease.
[8]
Fish oil has also been shown to aid in the treatment of people suffering with depression.[9]
For purchasing fish oil dietary supplements, it is highly recommended to seek a label certifying the product to be "molecularly distilled", USP Certified, and therefore free of mercury and other metal toxins.[citation needed] | https://www.wikidoc.org/index.php/Fish_oil | |
9cccd13b8020aa945e945c2bb823b360db1ffc91 | wikidoc | Flatworm | Flatworm
The flatworms (Phylum Platyhelminthes from the Greek platy, meaning "flat" and helminth, meaning worm) are a phylum of relatively simple soft-bodied invertebrate animals. With about 25,000 known species they are the largest phylum of acoelomates. Flatworms are found in marine, freshwater, and even damp terrestrial environments. A troublesome terrestrial example is the New Zealand flatworm, Arthurdendyus triangulatus, which rapidly colonized large areas of Ireland and Scotland since its unintentional introduction in the 1960s and has since destroyed most of the indigenous earthworms . Most flatworms are free-living, but many are parasitic. There are four classes: Trematoda (flukes), Cestoda (tapeworms), Monogenea, and Turbellaria.
# Description
The flatworm’s cephalized soft body is ribbon-shaped, flattened dorso-ventrally (from top to bottom), and bilaterally symmetric. Flatworms are the simplest triploblastic animals with organs. This means their organ systems form out of three germ layers: an outer ectoderm and an inner endoderm with a mesoderm between them. Turbellarians generally have a ciliated epidermis. There is also no true body cavity (coelom) except the gut; hence, flatworms are classified as acoelomates. The interior of the acoelomate body is filled with somewhat loosely spaced mesodermal tissue called parenchyma tissue.
Flatworms have a hydrostatic skeleton, which consists of a water filled body cavity that is controlled by muscles.
Flatworms exhibit an undulating form of locomotion.
Depending on species and age, individuals can range in size from almost microscopic to over 20 m long. The longest ever recorded flatworm was a tapeworm over 90 ft (27 m) long.
## Haptor
The haptor is a part of Platyhelminthes used to attach to its host. These differ between the prohaptor which is on the anterior end of the body and the opisthaptor, which is part of the posterior end of the body.
The prohaptor has various adhesive and feeding structures. In some species, the prohaptor may have a number of cephalic or head glands that secrete a sticky adhesive substance, and shallow muscular suckers, all used for attachment. In other species there is an oral sucker, with various degrees of muscularisation that surrounds the mouth.
The opisthaptor is primarily responsible for the attachment of the monogeneans to the host. The morphology of the opisthaptor is highly variable. It may have suckers in various degrees of development, large hooks called anchors (or hamuli), small hooks that are remnants from the larval stage, or complex clamps that may be either muscular or sclerotised.
# Circulation and nervous system
There is no true circulatory or respiratory system, but like all other animals, flatworms do take in oxygen. Extracellular body fluids (interstitial fluids) percolate between cells to help distribute nutrients, gases, and waste products.
Flatworms respire at their integument; gasses diffuse directly across their moist outer surface. This type of system is called integumentary exchange.
However, flatworms do have a bilateral nervous system; they are the simplest animals to have one. Two cordlike nerves branch repeatedly in an array resembling a ladder. The head end of some species even has a collection of ganglia acting as a rudimentary brain to integrate signals from sensory organs such as eyespots.
# Feeding
Usually the digestive tract has one opening, so the animal can feed, digest, and eliminate undigested particles of food simultaneously, as most animals with tubular guts are able to do. This blind-ended gastrovascular cavity functions similarly to that of the Cnidaria. However, in a few particularly long flatworms or those with highly branched guts, there may be one or more anuses. A small group where the gut is absent or non-permanent, called acoel flatworms, appear to be unrelated to the other Platyhelminthes (see below).They eat rarely, maybe a few times per year(once or twice). Their diet includes small bugs found in soils and other types of worms, smaller then itself.
Despite the simplicity of the digestive chamber, they are significantly more complex than cnidarians in that they possess numerous organs, and are therefore said to show an organ level of organization. Mesoderm allows for the development of these organs, and true muscle. Major sense organs are concentrated in the front end of the animals for species who possess these organs.
Muscular contraction in the gut causes a strong sucking force which allows flatworms to ingest food.
# Reproduction
Flatworm reproduction is hermaphroditic, meaning each individual produces eggs and sperm. When two flatworms mate, they exchange sperm so both become fertilized. Some flatworms, such as Pseudobiceros hancockanus engage in penis fencing, in which two individuals fight, trying to pierce the skin of the other with their penises; the first to succeed inseminates the other, which must then carry and nourish the fertilized eggs. Flatworms usually do not fertilize their own eggs.
Turbellarians classified as planarians (usually freshwater, non-parasitic) can also reproduce asexually by transverse fission. The body constricts at the midsection, and the posterior end grips a substrate. After a few hours of tugging, the body rips apart at the constriction. Each half grows replacements of the missing pieces to form two whole flatworms. This also means that if one of these planarian flatworms is cut in half, each half will regenerate, forming two separate, fully-functioning flatworms.
# Classes
Flatworms were formerly consider to be basal among the protostomes. Molecular evidence suggests that this is only true of the orders Acoela and Nemertodermatida, which are thus given their own phylum Acoelomorpha. These findings, however, are still not accepted by all biologists. The systematic position of Catenulida seems uncertain, although Donoghue and Cracraft would place it as a sister group to all other non-Acoelomorpha flatworms. Xenoturbella was at first believed to be a flatworm as well, but it is now obvious that it belongs in its own phyla. The remaining and true flatworms form a monophyletic group that developed from more complex ancestors, and grouped with several other phyla as the Platyzoa. The traditional classifications of flatworms is primarily based on differing degrees of parasitism and divided into three monophyletic classes:
- Trematoda - flukes, probably paraphyletic to Cestoda.
- Cestoda - tapeworms
- Monogenea - ectoparasitic flukes with simpler life cycles than Trematode flukes. They live an exclusively parasitic existence.
The remaining flatworms are grouped together for convenience as the class Turbellaria, now comprising the following orders:
- Catenulida
- Macrostomida
- Lecithoepitheliata
- Rhabdocoela
- Prolecithophora
- Proseriata
- Tricladida
- Polycladida - Marine flatworms
Most of these groups include free-living forms. The flukes and tapeworms, though, are parasitic, and a few cause massive damage to humans and other animals.
# Biochemical memory experiments
In 1955, Thompson and James V. McConnell conditioned planarian flatworms by pairing a bright light with an electric shock. After repeating this several times they took away the electric shock, and only exposed them to the bright light. The flatworms would react to the bright light as if they had been shocked. Thompson and McConnell found that if they cut the worm in two, and allowed both worms to regenerate each half would develop the light-shock reaction. In 1962, McConnell repeated the experiment, but instead of cutting the trained flatworms in two he ground them into small pieces and fed them to other flatworms. Incredibly these flatworms learned to associate the bright light with a shock much faster than flatworms who had not been fed trained worms.
This experiment intended to show that memory could perhaps be transferred chemically. The experiment was repeated with mice, fish, and rats, but it always failed to produce the same results, . The perceived explanation was that rather than memory being transferred to the other animals, it was the hormones in the ingested ground animals that changed its behaviour. McConnell believed that this was evidence of a chemical basis for memory, which he identified as memory RNA. McConnell's results are now attributed to observer bias. No double-blind experiment has ever reproduced his results. | Flatworm
Template:Wikispecies
The flatworms (Phylum Platyhelminthes from the Greek platy, meaning "flat" and helminth, meaning worm) are a phylum of relatively simple soft-bodied invertebrate animals. With about 25,000 known species[1] they are the largest phylum of acoelomates. Flatworms are found in marine, freshwater, and even damp terrestrial environments. A troublesome terrestrial example is the New Zealand flatworm, Arthurdendyus triangulatus, which rapidly colonized large areas of Ireland and Scotland since its unintentional introduction in the 1960s and has since destroyed most of the indigenous earthworms[2] . Most flatworms are free-living, but many are parasitic. There are four classes: Trematoda (flukes), Cestoda (tapeworms), Monogenea, and Turbellaria.
# Description
The flatworm’s cephalized soft body is ribbon-shaped, flattened dorso-ventrally (from top to bottom), and bilaterally symmetric. Flatworms are the simplest triploblastic animals with organs. This means their organ systems form out of three germ layers: an outer ectoderm and an inner endoderm with a mesoderm between them. Turbellarians generally have a ciliated epidermis. There is also no true body cavity (coelom) except the gut; hence, flatworms are classified as acoelomates. The interior of the acoelomate body is filled with somewhat loosely spaced mesodermal tissue called parenchyma tissue.
Flatworms have a hydrostatic skeleton, which consists of a water filled body cavity that is controlled by muscles.
Flatworms exhibit an undulating form of locomotion.
Depending on species and age, individuals can range in size from almost microscopic to over 20 m long. The longest ever recorded flatworm was a tapeworm over 90 ft (27 m) long.[3]
## Haptor
The haptor is a part of Platyhelminthes used to attach to its host. These differ between the prohaptor which is on the anterior end of the body and the opisthaptor, which is part of the posterior end of the body.
The prohaptor has various adhesive and feeding structures. In some species, the prohaptor may have a number of cephalic or head glands that secrete a sticky adhesive substance, and shallow muscular suckers, all used for attachment. In other species there is an oral sucker, with various degrees of muscularisation that surrounds the mouth.
The opisthaptor is primarily responsible for the attachment of the monogeneans to the host. The morphology of the opisthaptor is highly variable. It may have suckers in various degrees of development, large hooks called anchors (or hamuli), small hooks that are remnants from the larval stage, or complex clamps that may be either muscular or sclerotised.
# Circulation and nervous system
There is no true circulatory or respiratory system, but like all other animals, flatworms do take in oxygen. Extracellular body fluids (interstitial fluids) percolate between cells to help distribute nutrients, gases, and waste products.
Flatworms respire at their integument; gasses diffuse directly across their moist outer surface. This type of system is called integumentary exchange.
However, flatworms do have a bilateral nervous system; they are the simplest animals to have one. Two cordlike nerves branch repeatedly in an array resembling a ladder. The head end of some species even has a collection of ganglia acting as a rudimentary brain to integrate signals from sensory organs such as eyespots.
# Feeding
Usually the digestive tract has one opening, so the animal can feed, digest, and eliminate undigested particles of food simultaneously, as most animals with tubular guts are able to do. This blind-ended gastrovascular cavity functions similarly to that of the Cnidaria. However, in a few particularly long flatworms or those with highly branched guts, there may be one or more anuses. A small group where the gut is absent or non-permanent, called acoel flatworms, appear to be unrelated to the other Platyhelminthes (see below).They eat rarely, maybe a few times per year(once or twice). Their diet includes small bugs found in soils and other types of worms, smaller then itself.
Despite the simplicity of the digestive chamber, they are significantly more complex than cnidarians in that they possess numerous organs, and are therefore said to show an organ level of organization. Mesoderm allows for the development of these organs, and true muscle. Major sense organs are concentrated in the front end of the animals for species who possess these organs.
Muscular contraction in the gut causes a strong sucking force which allows flatworms to ingest food.
# Reproduction
Flatworm reproduction is hermaphroditic, meaning each individual produces eggs and sperm. When two flatworms mate, they exchange sperm so both become fertilized. Some flatworms, such as Pseudobiceros hancockanus engage in penis fencing, in which two individuals fight, trying to pierce the skin of the other with their penises; the first to succeed inseminates the other, which must then carry and nourish the fertilized eggs.[4] Flatworms usually do not fertilize their own eggs.
Turbellarians classified as planarians (usually freshwater, non-parasitic) can also reproduce asexually by transverse fission. The body constricts at the midsection, and the posterior end grips a substrate. After a few hours of tugging, the body rips apart at the constriction. Each half grows replacements of the missing pieces to form two whole flatworms. This also means that if one of these planarian flatworms is cut in half, each half will regenerate, forming two separate, fully-functioning flatworms.
# Classes
Flatworms were formerly consider to be basal among the protostomes. Molecular evidence suggests that this is only true of the orders Acoela and Nemertodermatida, which are thus given their own phylum Acoelomorpha. These findings, however, are still not accepted by all biologists. The systematic position of Catenulida seems uncertain, although Donoghue and Cracraft would place it as a sister group to all other non-Acoelomorpha flatworms.[5] Xenoturbella was at first believed to be a flatworm as well, but it is now obvious that it belongs in its own phyla. The remaining and true flatworms form a monophyletic group that developed from more complex ancestors, and grouped with several other phyla as the Platyzoa. The traditional classifications of flatworms is primarily based on differing degrees of parasitism and divided into three monophyletic classes:
- Trematoda - flukes, probably paraphyletic to Cestoda.
- Cestoda - tapeworms
- Monogenea - ectoparasitic flukes with simpler life cycles than Trematode flukes. They live an exclusively parasitic existence.
The remaining flatworms are grouped together for convenience as the class Turbellaria, now comprising the following orders:
- Catenulida
- Macrostomida
- Lecithoepitheliata
- Rhabdocoela
- Prolecithophora
- Proseriata
- Tricladida
- Polycladida - Marine flatworms
Most of these groups include free-living forms. The flukes and tapeworms, though, are parasitic, and a few cause massive damage to humans and other animals.
# Biochemical memory experiments
In 1955, Thompson and James V. McConnell conditioned planarian flatworms by pairing a bright light with an electric shock. After repeating this several times they took away the electric shock, and only exposed them to the bright light. The flatworms would react to the bright light as if they had been shocked. Thompson and McConnell found that if they cut the worm in two, and allowed both worms to regenerate each half would develop the light-shock reaction. In 1962, McConnell repeated the experiment, but instead of cutting the trained flatworms in two he ground them into small pieces and fed them to other flatworms. Incredibly these flatworms learned to associate the bright light with a shock much faster than flatworms who had not been fed trained worms.
This experiment intended to show that memory could perhaps be transferred chemically. The experiment was repeated with mice, fish, and rats, but it always failed to produce the same results, . The perceived explanation was that rather than memory being transferred to the other animals, it was the hormones in the ingested ground animals that changed its behaviour.[6] McConnell believed that this was evidence of a chemical basis for memory, which he identified as memory RNA. McConnell's results are now attributed to observer bias.[7] No double-blind experiment has ever reproduced his results. | https://www.wikidoc.org/index.php/Flatworm | |
8ffb3288c74093161296431dca9649b4a1ceb924 | wikidoc | Flavones | Flavones
# Overview
Flavones are a class of flavonoids based on the backbone of 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) shown on the right.
Natural flavones include Apigenin (4',5,7-trihydroxyflavone, Luteolin (3',4',5,7-tetrahydroxyflavone) and Tangeritin (4',5,6,7,8-pentamethoxyflavone). Synthetic flavones are Diosmin and Flavoxate
# Organic chemistry
In organic chemistry several methods exist for the synthesis of flavones:
- the Allan-Robinson reaction
- the Auwers synthesis
- the Baker-Venkataraman rearrangement
- the Algar-Flynn-Oyamada reaction
Another method is the dehydrative cyclization of certain 1,3-diaryl diketones
this particular study making use of an ionic liquid solvent and microwave irradiation.
## Wessely-Moser rearrangement
The Wessely-Moser rearrangement (1930) has been an important tool in structure elucidation of flavonoids. It involves the conversion of 5,7,8-trimethoxyflavone into 5,6,7-trihydroxyflavone on hydrolysis of the methoxy groups to phenol groups. It also has synthetic potential for example:
This rearrangement reaction takes place in several steps: A ring opening to the diketone, B bond rotation with formation of a favorable acetylacetone-like phenyl-ketone interaction and C hydrolysis of two methoxy groups and ring closure. | Flavones
# Overview
Flavones are a class of flavonoids based on the backbone of 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) shown on the right.
Natural flavones include Apigenin (4',5,7-trihydroxyflavone, Luteolin (3',4',5,7-tetrahydroxyflavone) and Tangeritin (4',5,6,7,8-pentamethoxyflavone). Synthetic flavones are Diosmin and Flavoxate
# Organic chemistry
In organic chemistry several methods exist for the synthesis of flavones:
- the Allan-Robinson reaction
- the Auwers synthesis
- the Baker-Venkataraman rearrangement
- the Algar-Flynn-Oyamada reaction
Another method is the dehydrative cyclization of certain 1,3-diaryl diketones [1]
this particular study making use of an ionic liquid solvent and microwave irradiation.
## Wessely-Moser rearrangement
The Wessely-Moser rearrangement (1930) [2] has been an important tool in structure elucidation of flavonoids. It involves the conversion of 5,7,8-trimethoxyflavone into 5,6,7-trihydroxyflavone on hydrolysis of the methoxy groups to phenol groups. It also has synthetic potential for example[3]:
This rearrangement reaction takes place in several steps: A ring opening to the diketone, B bond rotation with formation of a favorable acetylacetone-like phenyl-ketone interaction and C hydrolysis of two methoxy groups and ring closure.
# External links
- Flavones at the US National Library of Medicine Medical Subject Headings (MeSH) | https://www.wikidoc.org/index.php/Flavone | |
842a30b0a0e7b7626f28019c1f05d4e60871a27b | wikidoc | Flunixin | Flunixin
# Overview
Flunixin is a non-steroidal anti-inflammatory drug (NSAID), analgesic, and antipyretic used in horses, cattle and pigs. It is often formulated as the meglumine salt. In the United States, it is regulated by the U.S. Food and Drug Administration (FDA), and may only be lawfully distributed by order of a licensed veterinarian. There are many trade names for the product, as stated below.
# Dosage and uses in horses
Flunixin is administered at a dose of 1.1 mg/kg. The full analgesic and antipyretic effects usually occur 1-2 hours following treatment, but there is often an effective analgesic effect within approximately 15 minutes. Despite its short plasma half life of 1.6-2.5 hours, effects can persist for up to 30 hours, with maximal effects occurring between 2 and 16 hours. This is likely due to accumulation of the drug as an inflammatory foci.
Because it targets the inflamed tissue, flunixin is mainly used for colic pain, muscle pain, and joint disease, as well as to alleviate fevers and pain, and prevent endotoxemia. It is also effective in injuries of the eye.
# Side effects and precautions
Flunixin should not be given for more than five days. Like most NSAIDs, it can produce gastrointestinal (GI) side effects if the drug is given in high doses or over several days. GI ulceration is the most common side effect, especially in the animal's large colon or stomach, and is most likely to occur if the drug is given for a prolonged period. Other side effects include kidney damage and bleeding problems. It should be used with caution in horses with kidney or liver disease.
Flunixin does not treat the underlying problem causing the fever or pain, only the symptoms. Additionally, pain is often useful for a veterinarian to diagnose a horse's condition, and masking it with flunixin may do more harm than good. For this reason, there are many veterinarians who do not wish for the animal to be given flunixin if colic is suspected, instead preferring to withhold the drug until the need for colic surgery has been determined. It is therefore advisable to ask the horse's veterinarian before giving the drug.
Flunixin is a prohibited class A drug under International Federation for Equestrian Sports rules, and its use is prohibited or restricted by many other equestrian organizations. It can be detected in the blood for 2-3 days, and in the urine up to 15 days following administration.
# Combining with other drugs
Flunixin should not be combined with other NSAIDs or corticosteriods, as this increases the risk of gastric ulcers, right dorsal colitis, and kidney disease. Additionally, veterinarians should use caution when combining it with anticoagulants or aminoglycoside antibiotics. Flunixin is commonly used with omeprazole, sucralfate, and cimetidine to protect the gastrointestinal tract.
# Administration
Flunixin may be given orally as a paste or as granules in feed. It can also be used intramuscularly or intravenously, although because it is very irritating to tissue, the IV route is preferred, and in cattle it is the labeled route of administration.
Dosages are usually reduced for ponies, who are more at-risk for NSAID side effects, as well as horses with decreased liver or kidney function (such as older horses).
# Trade names
In the USA the trade names are Banamine, Flunixamine, Citation, Equileve, and Meflosyl Solution. In the UK the trade names are Flunixin (Licensed by Norbrook), Finadyne and Cronyxin. In South Africa and Australia a common trade name is Finadyne. In India, its " Megludyne" by Virbac(veterinary), commonly used brand.
# Sources
- Forney, Barbara C, MS, VMD.Equine Medications, Revised Edition. Blood Horse Publications. Lexington, KY. Copyright 2007. | Flunixin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Flunixin is a non-steroidal anti-inflammatory drug (NSAID), analgesic, and antipyretic used in horses, cattle and pigs. It is often formulated as the meglumine salt. In the United States, it is regulated by the U.S. Food and Drug Administration (FDA), and may only be lawfully distributed by order of a licensed veterinarian. There are many trade names for the product, as stated below.
# Dosage and uses in horses
Flunixin is administered at a dose of 1.1 mg/kg.[1] The full analgesic and antipyretic effects usually occur 1-2 hours following treatment, but there is often an effective analgesic effect within approximately 15 minutes. Despite its short plasma half life of 1.6-2.5 hours, effects can persist for up to 30 hours,[2] with maximal effects occurring between 2 and 16 hours. This is likely due to accumulation of the drug as an inflammatory foci.
Because it targets the inflamed tissue, flunixin is mainly used for colic pain, muscle pain, and joint disease, as well as to alleviate fevers and pain, and prevent endotoxemia. It is also effective in injuries of the eye.
# Side effects and precautions
Flunixin should not be given for more than five days. Like most NSAIDs, it can produce gastrointestinal (GI) side effects if the drug is given in high doses or over several days. GI ulceration is the most common side effect, especially in the animal's large colon or stomach, and is most likely to occur if the drug is given for a prolonged period. Other side effects include kidney damage and bleeding problems. It should be used with caution in horses with kidney or liver disease.
Flunixin does not treat the underlying problem causing the fever or pain, only the symptoms. Additionally, pain is often useful for a veterinarian to diagnose a horse's condition, and masking it with flunixin may do more harm than good. For this reason, there are many veterinarians who do not wish for the animal to be given flunixin if colic is suspected, instead preferring to withhold the drug until the need for colic surgery has been determined. It is therefore advisable to ask the horse's veterinarian before giving the drug.
Flunixin is a prohibited class A drug under International Federation for Equestrian Sports rules, and its use is prohibited or restricted by many other equestrian organizations. It can be detected in the blood for 2-3 days, and in the urine up to 15 days following administration.
# Combining with other drugs
Flunixin should not be combined with other NSAIDs or corticosteriods, as this increases the risk of gastric ulcers, right dorsal colitis, and kidney disease. Additionally, veterinarians should use caution when combining it with anticoagulants or aminoglycoside antibiotics. Flunixin is commonly used with omeprazole, sucralfate, and cimetidine to protect the gastrointestinal tract.
# Administration
Flunixin may be given orally as a paste or as granules in feed. It can also be used intramuscularly or intravenously, although because it is very irritating to tissue, the IV route is preferred, and in cattle it is the labeled route of administration.
Dosages are usually reduced for ponies, who are more at-risk for NSAID side effects, as well as horses with decreased liver or kidney function (such as older horses).
# Trade names
In the USA the trade names are Banamine, Flunixamine, Citation, Equileve, and Meflosyl Solution. In the UK the trade names are Flunixin (Licensed by Norbrook), Finadyne and Cronyxin. In South Africa and Australia a common trade name is Finadyne. In India, its " Megludyne" by Virbac(veterinary), commonly used brand.
# Sources
- Forney, Barbara C, MS, VMD.Equine Medications, Revised Edition. Blood Horse Publications. Lexington, KY. Copyright 2007. | https://www.wikidoc.org/index.php/Flunixin | |
126e17d56013fd8de5cc50f04191287dfeb3e2f9 | wikidoc | Fluorene | Fluorene
Fluorene, or 9H-fluorene, is a polycyclic aromatic hydrocarbon. It has the form of odorless white crystals. It is combustible. It has a violet fluorescence, which gave it its name. It is manufactured artificially, although it occurs in the higher boiling fractions of coal tar. It is insoluble in water and soluble in benzene and ether.
Fluorene is used to make dyes, plastics, and pesticides. It can be found in corn silk and engine exhaust gas. It is used for production of fluorenone and fluorene-9-methanol.
Poly(fluorene) is commonly used as a luminophore in organic light-emitting diodes. Fluorene copolymers are being investigated as materials for solar cells.
The protons in the 9-position of the fluorene ring are acidic (pKa = 22.6 in DMSO) and removal of one of them with a strong base, such as n-butyllithium, leads to the stable fluorenyl anion, which is aromatic and has an intense orange colour. The anion is a nucleophile and most electrophiles react with it by adding to the 9-position.
The carbamate ester of 9-hydroxymethylfluorene, 9-fluorenylmethyl carbamate (FMOC), is used a N-terminal protective group in peptide synthesis.
Fluorene should not be confused with fluorone, nor with the element fluorine. | Fluorene
Fluorene, or 9H-fluorene, is a polycyclic aromatic hydrocarbon. It has the form of odorless white crystals. It is combustible. It has a violet fluorescence, which gave it its name. It is manufactured artificially, although it occurs in the higher boiling fractions of coal tar. It is insoluble in water and soluble in benzene and ether.
Fluorene is used to make dyes, plastics, and pesticides. It can be found in corn silk and engine exhaust gas. It is used for production of fluorenone and fluorene-9-methanol.
Poly(fluorene) is commonly used as a luminophore in organic light-emitting diodes. Fluorene copolymers are being investigated as materials for solar cells.
The protons in the 9-position of the fluorene ring are acidic (pKa = 22.6 in DMSO[1]) and removal of one of them with a strong base, such as n-butyllithium, leads to the stable fluorenyl anion, which is aromatic and has an intense orange colour. The anion is a nucleophile and most electrophiles react with it by adding to the 9-position.
The carbamate ester of 9-hydroxymethylfluorene, 9-fluorenylmethyl carbamate (FMOC), is used a N-terminal protective group in peptide synthesis.
Fluorene should not be confused with fluorone, nor with the element fluorine. | https://www.wikidoc.org/index.php/Fluorene | |
4ee771c02ec1951681976ddeb8a8a53fd9a3ab04 | wikidoc | Fluoride | Fluoride
# Overview
Fluoride is the ionic form of fluorine. Fluorides are organic and inorganic compounds containing the element fluorine. As a halogen, fluorine forms a monovalent ion (−1 charge). Fluoride forms a binary compound with another element or radical. Examples of fluoride compounds include hydrofluoric acid (HF), sodium fluoride (NaF) and calcium fluoride (CaF2), and uranium hexafluoride (UF6).
# Occurrence
Fluoride compounds, usually calcium fluoride, are naturally found in low concentration in drinking water and some foods, such as tea, seaweed, and fish bones (as in fish soup).
Water with underground sources are more likely to have higher levels of fluoride, while the total concentration in seawater has an average concentration of 1.3 parts per million(ppm). Fresh water supplies generally contain between 0.01-0.3 ppm, while the ocean contains between 1.2 and 1.5 ppm.
# Applications
Hydrofluoric acid is used in the etching of glass and other industrial applications, including integrated circuit manufacturing.
Fluoride, as a concentrated gel, foam, or varnish, is used as a prescription drug. Fluorine is also part of certain drug molecules to resist detoxification in the liver by the Cytochrome P450 oxidase because the strong C-F bonds are not easily broken. This is to ensure that orally administered medication are not inactivated before reaching the blood stream.
Fluoride ion has a very significant use in synthetic organic chemistry. The silicon-fluorine chemical bond is quite strong. Silyl ether protecting groups can be easily removed by the addition of fluoride ion. Sodium fluoride or tetra-n-butylammonium fluoride (TBAF) are the most common reagents used.
In biochemistry, fluoride salts are commonly used to inhibit the activity of serine/threonine phosphatases.
Sulfur hexafluoride is a nearly-inert, non-toxic propellant. Uranium hexafluoride is used in the separation of isotopes of uranium between the fissile isotope U-235 and the non-fissile isotope U-238 in preparation of nuclear reactor fuel and atomic bombs.
## Water fluoridation
Fluoride containing compounds such as sodium fluoride, calcium fluoride, and sodium monofluorophosphate are commonly added to toothpaste, drinking water, prescribed treatments, and other commercially available oral hygiene products because fluoride increases the resistance of the enamel to decay. Originally, sodium fluoride was used to fluoridate water; however, hexafluorosilicic acid (H2SiF6) and its salt sodium hexafluorosilicate (Na2SiF6) are more commonly used, especially in the United States.
Some studies suggest that fluoridation is associated with a median decline in the number of children with cavities of 12.5%, and a median decline of 2.25 teeth with cavities. The fluoridation of water is not without critics, however (see Water fluoridation controversy).
## Salt fluoridation
In countries where large, centralized water systems are uncommon, salt fluoridation is sometimes used as an alternative to water fluoridation. In countries where salt fluoridation is common, such as Switzerland, France, and Jamaica, among many others, caries experience has also decreased in groups using fluoridated salt compared to groups using salt without fluoride.
# Toxicology
## Acute
In high concentrations, fluoride compounds are toxic and can cause death. In mice, the LD50 is estimated to be 184 milligrams of stannous fluoride per kilogram of body mass. An individual report involving fatality following the accidental administration of fluoride ion to a child at 5 mg/kg was cited by G. M. Whitford in 1987. While experimenting on himself in 1899, Herbert H Baldwin reported that symptoms of acute toxicity (e.g. gastrointestinal upset) occurred at doses as low as 0.1-0.3 mg/kg.
When ingested directly, fluoride compounds are readily absorbed by the intestines. Over time, the compound is excreted through the urine, and the half life for concentration of fluorine compounds is on an order of hours. It is thought that fluoride is taken out of circulation by the body and trace amounts become bound in bone. Urine tests are a good indication of high exposure to fluoride compounds in the recent past.
Skin or eye contact with many fluoride compounds in high concentrations is dangerous. In case of accidental swallowing, milk, calcium carbonate, or milk of magnesia is given to slow absorption. Eye or skin contact is treated by removing any contaminated clothing and flushing with water.
## Chronic
Fluoride ions replace hydroxide ions in calcium hydroxyapatite, Ca5, in teeth, forming calcium fluoroapatite, Ca5, which is more chemically stable and dissolves at a pH of 4.5, compared to 5.5 pH for calcium hydroxyapatite. This is generally believed to lead to fewer cavities, since stronger acids are needed to attack the tooth enamel. In 1951, Joseph C. Muhler and Harry G. Day of Indiana University reported their research results on stannous fluoride as a tooth decay preventive and the university first sold the technology to Procter & Gamble to use in Crest toothpaste. Groups that have evaluated available studies and support water fluoridation include The American Dental Association (ADA), World Health Organization (WHO), and some other health organizations which recommend raising the fluoride level of municipal water supplies to a level between 0.7 and 1.2 ppm.
The most widely accepted adverse effect of excessive fluorine intake at this time is fluorosis. It is a condition caused by 'excessive' intake of fluorine compounds over an extended period of time, and can cause yellowing of teeth. The definition of 'excessive' in the context of fluorosis falls on the order of parts per million and is generally accepted to mean significantly higher than the 0.7 to 1.2 ppm amounts recommended for fluoridated water. However, some believe that any water fluoridation is detrimental to human health.
Dosage is crucial to adverse effects, and therefore, what concentration is problematic will depend on the amount of fluoride ingested, how much is absorbed, and the weight of the person ingesting it. The ADA currently recommends using low- or non-fluoridated water to make up formula for infants.
## Contested claims
Some opponents of fluoridation have expressed concern that fluoride damages body function. One of the key concerns is that fluoride can weaken bone strength, leading to an increase in hip and wrist fracture. Additional concerns of fluoridation opponents include the potential for fluoride to damage the brain, reduce thyroid function, and cause bone cancer in adolescent boys. While a recent review from the US National Research Council supports concerns that fluoride may cause some of these effects, at least at high doses, more than 100 national and international health service agencies and professional organizations continue to accept that there are benefits of community water fluoridation in preventing tooth decay. | Fluoride
# For patient information, click here
# Overview
Fluoride is the ionic form of fluorine. Fluorides are organic and inorganic compounds containing the element fluorine. As a halogen, fluorine forms a monovalent ion (−1 charge). Fluoride forms a binary compound with another element or radical. Examples of fluoride compounds include hydrofluoric acid (HF), sodium fluoride (NaF) and calcium fluoride (CaF2), and uranium hexafluoride (UF6).
# Occurrence
Fluoride compounds, usually calcium fluoride, are naturally found in low concentration in drinking water and some foods, such as tea, seaweed, and fish bones (as in fish soup).
Water with underground sources are more likely to have higher levels of fluoride, while the total concentration in seawater has an average concentration of 1.3 parts per million(ppm).[1] Fresh water supplies generally contain between 0.01-0.3 ppm, while the ocean contains between 1.2 and 1.5 ppm.[2]
# Applications
Hydrofluoric acid is used in the etching of glass and other industrial applications, including integrated circuit manufacturing.
Fluoride, as a concentrated gel, foam, or varnish, is used as a prescription drug.[3] Fluorine is also part of certain drug molecules to resist detoxification in the liver by the Cytochrome P450 oxidase because the strong C-F bonds are not easily broken. This is to ensure that orally administered medication are not inactivated before reaching the blood stream.
Fluoride ion has a very significant use in synthetic organic chemistry. The silicon-fluorine chemical bond is quite strong. Silyl ether protecting groups can be easily removed by the addition of fluoride ion. Sodium fluoride or tetra-n-butylammonium fluoride (TBAF) are the most common reagents used.
In biochemistry, fluoride salts are commonly used to inhibit the activity of serine/threonine phosphatases.
Sulfur hexafluoride is a nearly-inert, non-toxic propellant. Uranium hexafluoride is used in the separation of isotopes of uranium between the fissile isotope U-235 and the non-fissile isotope U-238 in preparation of nuclear reactor fuel and atomic bombs.
## Water fluoridation
Fluoride containing compounds such as sodium fluoride, calcium fluoride, and sodium monofluorophosphate are commonly added to toothpaste, drinking water, prescribed treatments, and other commercially available oral hygiene products because fluoride increases the resistance of the enamel to decay. Originally, sodium fluoride was used to fluoridate water; however, hexafluorosilicic acid (H2SiF6) and its salt sodium hexafluorosilicate (Na2SiF6) are more commonly used, especially in the United States.
Some studies suggest that fluoridation is associated with a median decline in the number of children with cavities of 12.5%, and a median decline of 2.25 teeth with cavities.[4] The fluoridation of water is not without critics, however (see Water fluoridation controversy).
## Salt fluoridation
In countries where large, centralized water systems are uncommon, salt fluoridation is sometimes used as an alternative to water fluoridation. In countries where salt fluoridation is common, such as Switzerland, France, and Jamaica, among many others, caries experience has also decreased in groups using fluoridated salt compared to groups using salt without fluoride.[5][6]
# Toxicology
## Acute
In high concentrations, fluoride compounds are toxic and can cause death. In mice, the LD50 is estimated to be 184 milligrams of stannous fluoride per kilogram of body mass.[7] An individual report involving fatality following the accidental administration of fluoride ion to a child at 5 mg/kg was cited by G. M. Whitford in 1987.[8] While experimenting on himself in 1899, Herbert H Baldwin reported that symptoms of acute toxicity (e.g. gastrointestinal upset) occurred at doses as low as 0.1-0.3 mg/kg.[9]
When ingested directly, fluoride compounds are readily absorbed by the intestines. Over time, the compound is excreted through the urine, and the half life for concentration of fluorine compounds is on an order of hours. It is thought that fluoride is taken out of circulation by the body and trace amounts become bound in bone. Urine tests are a good indication of high exposure to fluoride compounds in the recent past.
Skin or eye contact with many fluoride compounds in high concentrations is dangerous. In case of accidental swallowing, milk, calcium carbonate, or milk of magnesia is given to slow absorption. Eye or skin contact is treated by removing any contaminated clothing and flushing with water.
## Chronic
Fluoride ions replace hydroxide ions in calcium hydroxyapatite, Ca5[(PO4)3OH], in teeth, forming calcium fluoroapatite, Ca5[(PO4)3F], which is more chemically stable and dissolves at a pH of 4.5, compared to 5.5 pH for calcium hydroxyapatite. This is generally believed to lead to fewer cavities, since stronger acids are needed to attack the tooth enamel. In 1951, Joseph C. Muhler and Harry G. Day of Indiana University reported their research results on stannous fluoride as a tooth decay preventive and the university first sold the technology to Procter & Gamble to use in Crest toothpaste. Groups that have evaluated available studies and support water fluoridation include The American Dental Association (ADA), World Health Organization (WHO), and some other health organizations which recommend raising the fluoride level of municipal water supplies to a level between 0.7 and 1.2 ppm.
The most widely accepted adverse effect of excessive fluorine intake at this time is fluorosis.[4] It is a condition caused by 'excessive' intake of fluorine compounds over an extended period of time, and can cause yellowing of teeth. The definition of 'excessive' in the context of fluorosis falls on the order of parts per million and is generally accepted to mean significantly higher than the 0.7 to 1.2 ppm amounts recommended for fluoridated water. However, some believe that any water fluoridation is detrimental to human health.
Dosage is crucial to adverse effects, and therefore, what concentration is problematic will depend on the amount of fluoride ingested, how much is absorbed, and the weight of the person ingesting it. The ADA currently recommends using low- or non-fluoridated water to make up formula for infants.[10]
## Contested claims
Some opponents of fluoridation have expressed concern that fluoride damages body function. One of the key concerns is that fluoride can weaken bone strength, leading to an increase in hip and wrist fracture.[11] Additional concerns of fluoridation opponents include the potential for fluoride to damage the brain,[12] reduce thyroid function,[13] and cause bone cancer in adolescent boys.[14] While a recent review from the US National Research Council supports concerns that fluoride may cause some of these effects, at least at high doses,[15] more than 100 national and international health service agencies and professional organizations continue to accept that there are benefits of community water fluoridation in preventing tooth decay.[16] | https://www.wikidoc.org/index.php/Fluoride | |
ed45cf1f0bf112ea6d3b0b307d593d6fc832cceb | wikidoc | Forehead | Forehead
In human anatomy, the forehead or brow is the bony part of the head above the eyes.
# Anatomy
In modern humans it is roughly vertical, ending at the hairline where the head flattens out. Muscles of the forehead include the frontalis, which moves and contracts the forehead's scalp.
# Pronunciation
Historically, the word has rhymed with "horrid" RP: Template:IPA, General American: Template:IPA, but the spelling pronunciation RP: Template:IPA, GenAm: Template:IPA has become more common in recent years. | Forehead
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In human anatomy, the forehead or brow is the bony part of the head above the eyes.
# Anatomy
In modern humans it is roughly vertical, ending at the hairline where the head flattens out. Muscles of the forehead include the frontalis, which moves and contracts the forehead's scalp.
# Pronunciation
Historically, the word has rhymed with "horrid" RP: Template:IPA, General American: Template:IPA, but the spelling pronunciation RP: Template:IPA, GenAm: Template:IPA has become more common in recent years.
# External links
- Template:EMedicineDictionary
Template:Human anatomical features
Template:Head and neck general
ang:Forhēafod
ar:جبهة
br:Tal
de:Stirn
dv:ނިއްކުރި
eo:Frunto
gd:Bathais
id:Dahi
it:Fronte (anatomia)
ln:Eboló
nl:Voorhoofd
simple:Forehead
fi:Otsa
tl:Noo
uk:Чоло
diq:Çare
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Forehead | |
f904c0e0b7ded59469199951b559424c31704158 | wikidoc | Foreskin | Foreskin
The foreskin or prepuce (a technically broader term that also includes the clitoral hood, the homologous structure in women) is a retractable double-layered fold of skin and mucous membrane that covers the glans penis and protects the urinary meatus when the penis is not erect. Almost all mammals have foreskins, although in these non-human cases the foreskin is usually a sheath into which the whole penis is retracted. Only monotremes (the platypus and the echidna) lack foreskins.
# The human foreskin
## Description
In humans, the outside of the foreskin is like the skin on the shaft of the penis but the inner foreskin is a mucous membrane like the inside of the eyelid or the mouth. Like the eyelid, the foreskin is free to move. Smooth muscle fibres keep it close to the glans but make it highly elastic. The foreskin is attached to the glans with a frenulum which helps retract the foreskin over the glans. At the end of foreskin there is a band of tissue called the ridged band which, according to one study, is rich in nerve endings called Meissner's corpuscles. According to a NOCIRC-funded study by Sorrells et al., the five most sensitive areas of the penis are on the foreskin.
In children, the foreskin normally covers the glans completely but in adults this need not be so. Schöberlein found that about 50% of young men had full coverage of the glans, 42% had partial coverage, and in the remaining 8%, the glans was uncovered. After adjusting for circumcision, he stated that in 4% of the young men the foreskin had spontaneously atrophied (shrunk). See also : foreskin coverage index
## Development
Eight weeks after fertilization, the foreskin begins to grow over the head of the penis, covering it completely by 16 weeks. At this stage the foreskin and glans share an epithilium (mucous layer) that fuses the two together. It remains this way until the foreskin separates from the glans.
At birth, the foreskin is usually still fused with the glans. As childhood progresses the foreskin and the glans gradually separate, a process that may not be complete until the age of 17. Thorvaldsen and Meyhoff reported that average age of first foreskin retraction in Denmark is 10.4 years. Wright argues that forcible retraction of the foreskin should be avoided and that the child himself should be the first one to retract his own foreskin. Premature retraction may be painful, and may result in infection.
## Functions
Some researchers believe that the foreskin facilitates intercourse. In her book Sex as Nature Intended It, Kristen O'Hara argues that foreskin is a natural gliding stimulator of the vaginal walls during intercourse, increasing a woman's overall clitoral stimulation and helping a woman achieve orgasm more often and more quickly. She therefore believes that the absence of the foreskin and gliding action makes it more difficult for a woman to achieve orgasm during intercourse.
Taylor et al described the foreskin in detail, documenting a ridged band of mucosal tissue. They stated "This ridged band contains more Meissner's corpuscles than does the smooth mucosa and exhibits features of specialized sensory mucosa." The AAP noted that the work of Taylor et al "suggests that there may be a concentration of specialized sensory cells in specific ridged areas of the foreskin." In 1999, Cold and Taylor stated "The prepuce is primary, erogenous tissue necessary for normal sexual function." Moses and Bailey (1998}, however, describe the evidence as "indirect," and state that "aside from anecdotal reports, it has not been demonstrated that this is associated with increased male sexual pleasure."
Gairdner (1949) states that the foreskin protects the glans but some studies show that inflammation of the glans is more common when the foreskin is present.
Shen (China) found a statistically significant *(p = 0.001) increase in erectile dysfunction following circumcision. Pang and Kim (South Korea) reported "Of those who were circumcised long after they had been sexually active, > 80% reported no noticeable difference in sexuality, but a man was twice as likely to have experienced diminished sexuality than improved sexuality." In another study by Kim and Pang (2006) of 255 men circumcised after the age of 20 and 118 who were not circumcised, they reported that masturbatory pleasure decreased in 48% of the respondents and increased in 8%. Masturbatory difficulty increased in 63% but was easier in 37%. 20% reported that their sex life was worse after circumcision and 6% reported that it had improved (the abstract is silent about the other 74%). "There were no significant differences in sexual drive, erection, ejaculation, and ejaculation latency time between circumcised and uncircumcised men." They concluded, "There was a decrease in masturbatory pleasure and sexual enjoyment after circumcision, indicating that adult circumcision adversely affects sexual function in many men, possibly because of complications of the surgery and a loss of nerve endings." Sorrells et al. (2007), in a study funded by NOCIRC, compared penile sensitivity in 91 circumcised and 68 uncircumcised men and concluded, "The transitional region from the external to the internal prepuce is the most sensitive region of the uncircumcised penis and more sensitive than the most sensitive region of the circumcised penis."
Fink's study of American men also found significantly worsened erectile function *(p = 0.01) Other studies came to different conclusions. Collins (USA), Senkul (Turkey), and Masood (Britain) found no significant difference in erectile function. Senkul found that the circumcised men took significantly longer to ejaculate after circumcision *(P = 0.02). Laumann's study of American-born men found "little difference between circumcision status and sexual dysfunction for the two younger cohorts" (18-29 and 30-44). However, older men (45-59) with foreskins in his sample were significantly more likely to suffer from erectile dysfunction overall *(p < 0.05) and trouble achieving and maintaining an erection *(p. < 0.05). Premature ejaculation and performance anxiety were also noted *(both p. < 0.10). Circumcision rates were also significantly different in different ethnic groups (less common in Blacks and Hispanics) and they varied with the education level of the mother (less common in those with less education).
Fink's study reported less sensitivity after circumcision, though this only bordered on statistical significance *(p = 0.08). In contrast, Masood et al. reported improved sensation in 38% of men following circumcision and less sensation in 18%. 61% expressed greater satisfaction following removal of the foreskin, less satisfaction in 17%, and no change in 22%.
Interpretation of these findings vary. For example, Masood said, "Penile sensitivity had variable outcomes after circumcision. The poor outcome of circumcision considered by overall satisfaction rates suggests that when we circumcise men, these outcome data should be discussed during the informed consent process." Hill and Denniston listed Senkul's finding of an increased ejaculatory time as a "demonstrated adverse effect" of circumcision However, Senkul stated: "Adult circumcision does not adversely affect sexual function. The increase in the ejaculatory latency time can be considered an advantage rather than a complication. However, concerning the cause of that increase, in a Muslim community, the psychological influence of circumcision may be more pronounced than the organic effect."
Some do not accept that the presence or absence of the foreskin makes any difference and as such has no sexual effect.
The fold of the prepuce maintains sub-preputial wetness, which mixes with exfoliated skin to form smegma. Some authors believe that smegma contains antibacterial enzymes, though their theory has been challenged. Inferior hygiene has been associated with balanitis, though excessive washing can cause non-specific dermatatis.
The term 'gliding action' is used in some papers to describe the way the foreskin moves during sexual intercourse. A foreskin that covers the glans penis may move back and forth over the glans. This gliding movement may reduce friction during sexual intercourse. The gliding action was described by Lakshamanan & Prakash in 1980 The outer layer of the prepuce in common with the skin of the shaft of the penis glides freely in a to and fro fashion...
Several genital integrity activists have argued that the gliding movement of the foreskin is important during sexual intercourse:
- Warren & Bigelow claim that gliding action would help to reduce vaginal dryness and that restoration of the gliding action is an important advantage of foreskin restoration.
- A survey by Bensley & Boyle provides some confirmation that gliding action provides protection of vaginal lubrication. The authors explain, however, that their subjects were self-selected and a larger sample size is needed.
- O'Hara describes the gliding action:
- Fleiss and Hodges claim: The foreskin's double-layered sheath enables the penile shaft skin to glide back and forth over the penile shaft. (p.24) and The foreskin enables the penis to slip in and out of the vagina nonabrasively inside its own slick sheath of self-lubricating movable skin. (p.26)
- Taylor suggests that the gliding action, where it occurs, may stimulate the nerves of the ridged band , and speculates that the stretching of the frenulum by the rearward gliding action during penetration triggers ejaculation.
Taves used a single subject to test the actual force required to penetrate a measuring apparatus. When the foreskin was retracted a more than tenfold increase in force was needed. He argued that this confirms the belief of Morgan (1967) that the foreskin makes sexual penetration easier during sexual intercourse. Whiddon (1953) and Foley (1966) also believed that the presence of the foreskin made sexual penetration easier
A 2002 study into changing circumcision practices in Tanzania Africa, found that there was a significant move towards popularizing circumcision, mostly for perceived health reasons, but that participants (unclear whether male focus groups or female as well) reported it also led to improved sexual pleasure for men and women alike. Some participants in this context, compared the presence of a foreskin to a condom.
## Conditions
Frenulum breve is where the frenulum is insufficiently long to allow the foreskin to fully retract, which may lead to discomfort during intercourse. The frenulum may also tear during intercourse. Phimosis is a condition when the foreskin of an adult cannot be retracted properly. (Before adulthood, the foreskin may still be separating from the glans.) Phimosis can be treated by gently stretching the foreskin, by changing masturbation habits, using topical steroid ointments, preputioplasty, or by circumcision. See phimosis for more information.
A condition called paraphimosis may occur if a tight foreskin becomes trapped behind the glans and swells as a restrictive ring. This can cut off the blood supply, resulting in ischaemia of the glans penis.
Aposthia is a rare condition in which the foreskin is not present at birth.
## Surgical and other modifications of the foreskin
Circumcision is the removal of the foreskin, either partially or completely. It may be done for religious, aesthetic, health, or hygiene reasons, or to treat disease.
Preputioplasty is a procedure to relieve a tight foreskin without resorting to circumcision.
Other practices include genital piercings involving the foreskin and slitting the foreskin.
## Research use
Foreskins obtained from circumcision procedures are frequently used by biochemical and micro-anatomical researchers to study the structure and proteins of human skin. In particular, foreskins obtained from newborns have been found to be useful in the manufacturing of more human skin.
## Langerhans cells
Langerhans cells are immature dendritic cells that are found in all areas of the penile epitelium, but are most superficial in the inner surface of the foreskin. The recent Szabo and Short (2000) study targets Langerhans cells as receptors of HIV, and states that these cells "must be regarded as the most probable sites for viral entry in primary HIV infection in men." Langerhans cells are also known to express the c-type lectin langerin, which may play a role in transmission of HIV to nearby lymph nodes. However, de Witte et al. (2007) reported that langerin, produced by Langerhans cells, blocks the transmission of HIV.
# Foreskin in non-human species
In koalas the foreskin contains naturally occurring bacteria that play an important role in fertilization. | Foreskin
Template:Infobox Anatomy
The foreskin or prepuce (a technically broader term that also includes the clitoral hood, the homologous structure in women) is a retractable double-layered fold of skin and mucous membrane that covers the glans penis and protects the urinary meatus when the penis is not erect. Almost all mammals have foreskins, although in these non-human cases the foreskin is usually a sheath into which the whole penis is retracted. Only monotremes (the platypus and the echidna) lack foreskins.[1]
# The human foreskin
## Description
In humans, the outside of the foreskin is like the skin on the shaft of the penis but the inner foreskin is a mucous membrane like the inside of the eyelid or the mouth. Like the eyelid, the foreskin is free to move. Smooth muscle fibres keep it close to the glans but make it highly elastic.[2] The foreskin is attached to the glans with a frenulum which helps retract the foreskin over the glans. At the end of foreskin there is a band of tissue called the ridged band which, according to one study, is rich in nerve endings called Meissner's corpuscles.[3] According to a NOCIRC-funded study by Sorrells et al., the five most sensitive areas of the penis are on the foreskin.[4]
In children, the foreskin normally covers the glans completely but in adults this need not be so. Schöberlein [5] found that about 50% of young men had full coverage of the glans, 42% had partial coverage, and in the remaining 8%, the glans was uncovered. After adjusting for circumcision, he stated that in 4% of the young men the foreskin had spontaneously atrophied (shrunk). See also : foreskin coverage index
## Development
Eight weeks after fertilization, the foreskin begins to grow over the head of the penis, covering it completely by 16 weeks. At this stage the foreskin and glans share an epithilium (mucous layer) that fuses the two together. It remains this way until the foreskin separates from the glans.[6]
At birth, the foreskin is usually still fused with the glans.[6] As childhood progresses the foreskin and the glans gradually separate, a process that may not be complete until the age of 17.[7] Thorvaldsen and Meyhoff reported that average age of first foreskin retraction in Denmark is 10.4 years.[8] Wright argues that forcible retraction of the foreskin should be avoided and that the child himself should be the first one to retract his own foreskin.[9] Premature retraction may be painful, and may result in infection.
## Functions
Some researchers believe that the foreskin facilitates intercourse. In her book Sex as Nature Intended It, Kristen O'Hara argues that foreskin is a natural gliding stimulator of the vaginal walls during intercourse, increasing a woman's overall clitoral stimulation and helping a woman achieve orgasm more often and more quickly. [2] She therefore believes that the absence of the foreskin and gliding action makes it more difficult for a woman to achieve orgasm during intercourse.
Taylor et al described the foreskin in detail, documenting a ridged band of mucosal tissue. They stated "This ridged band contains more Meissner's corpuscles than does the smooth mucosa and exhibits features of specialized sensory mucosa."[10] The AAP noted that the work of Taylor et al "suggests that there may be a concentration of specialized sensory cells in specific ridged areas of the foreskin."[11] In 1999, Cold and Taylor stated "The prepuce is primary, erogenous tissue necessary for normal sexual function."[3] Moses and Bailey (1998}, however, describe the evidence as "indirect," and state that "aside from anecdotal reports, it has not been demonstrated that this is associated with increased male sexual pleasure."[12]
Gairdner (1949) states that the foreskin protects the glans[6] but some studies show that inflammation of the glans is more common when the foreskin is present.[13]
Shen (China) found a statistically significant *(p = 0.001) increase in erectile dysfunction following circumcision.[14] Pang and Kim (South Korea) reported "Of those who were circumcised long after they had been sexually active, > 80% reported no noticeable difference in sexuality, but a man was twice as likely to have experienced diminished sexuality than improved sexuality."[15] In another study by Kim and Pang (2006) of 255 men circumcised after the age of 20 and 118 who were not circumcised, they reported that masturbatory pleasure decreased in 48% of the respondents and increased in 8%. Masturbatory difficulty increased in 63% but was easier in 37%. 20% reported that their sex life was worse after circumcision and 6% reported that it had improved (the abstract is silent about the other 74%). "There were no significant differences in sexual drive, erection, ejaculation, and ejaculation latency time between circumcised and uncircumcised men." They concluded, "There was a decrease in masturbatory pleasure and sexual enjoyment after circumcision, indicating that adult circumcision adversely affects sexual function in many men, possibly because of complications of the surgery and a loss of nerve endings." [3] [4] Sorrells et al. (2007), in a study funded by NOCIRC, compared penile sensitivity in 91 circumcised and 68 uncircumcised men and concluded, "The transitional region from the external to the internal prepuce is the most sensitive region of the uncircumcised penis and more sensitive than the most sensitive region of the circumcised penis."[5]
Fink's study of American men also found significantly worsened erectile function *(p = 0.01)[16] Other studies came to different conclusions. Collins (USA), Senkul (Turkey), and Masood (Britain) found no significant difference in erectile function.[17][18][19] Senkul found that the circumcised men took significantly longer to ejaculate after circumcision *(P = 0.02).[19] Laumann's study of American-born men found "little difference between circumcision status and sexual dysfunction for the two younger cohorts" (18-29 and 30-44). However, older men (45-59) with foreskins in his sample were significantly more likely to suffer from erectile dysfunction overall *(p < 0.05) and trouble achieving and maintaining an erection *(p. < 0.05). Premature ejaculation and performance anxiety were also noted *(both p. < 0.10). Circumcision rates were also significantly different in different ethnic groups (less common in Blacks and Hispanics) and they varied with the education level of the mother (less common in those with less education).[20][21]
Fink's study reported less sensitivity after circumcision, though this only bordered on statistical significance *(p = 0.08).[16] In contrast, Masood et al. reported improved sensation in 38% of men following circumcision and less sensation in 18%. 61% expressed greater satisfaction following removal of the foreskin, less satisfaction in 17%, and no change in 22%.[22]
Interpretation of these findings vary. For example, Masood said, "Penile sensitivity had variable outcomes after circumcision. The poor outcome of circumcision considered by overall satisfaction rates suggests that when we circumcise men, these outcome data should be discussed during the informed consent process."[22] Hill and Denniston listed Senkul's finding of an increased ejaculatory time as a "demonstrated adverse effect" of circumcision[23] However, Senkul stated: "Adult circumcision does not adversely affect sexual function. The increase in the ejaculatory latency time can be considered an advantage rather than a complication. However, concerning the cause of that increase, in a Muslim community, the psychological influence of circumcision may be more pronounced than the organic effect."
Some do not accept that the presence or absence of the foreskin makes any difference and as such has no sexual effect.
The fold of the prepuce maintains sub-preputial wetness, which mixes with exfoliated skin to form smegma. Some authors believe that smegma contains antibacterial enzymes,[24] though their theory has been challenged.[25] Inferior hygiene has been associated with balanitis,[26] though excessive washing can cause non-specific dermatatis.[27]
The term 'gliding action' is used in some papers to describe the way the foreskin moves during sexual intercourse. A foreskin that covers the glans penis may move back and forth over the glans. This gliding movement may reduce friction during sexual intercourse. The gliding action was described by Lakshamanan & Prakash in 1980 [6]The outer layer of the prepuce in common with the skin of the shaft of the penis glides freely in a to and fro fashion...
Several genital integrity activists have argued that the gliding movement of the foreskin is important during sexual intercourse:
- Warren & Bigelow claim that gliding action would help to reduce vaginal dryness and that restoration of the gliding action is an important advantage of foreskin restoration. [7]
- A survey by Bensley & Boyle provides some confirmation that gliding action provides protection of vaginal lubrication.[8] The authors explain, however, that their subjects were self-selected and a larger sample size is needed.
- O'Hara describes the gliding action:
- Fleiss and Hodges claim: The foreskin's double-layered sheath enables the penile shaft skin to glide back and forth over the penile shaft. (p.24) and The foreskin enables the penis to slip in and out of the vagina nonabrasively inside its own slick sheath of self-lubricating movable skin. (p.26)
- Taylor suggests that the gliding action, where it occurs, may stimulate the nerves of the ridged band [9], and speculates that the stretching of the frenulum by the rearward gliding action during penetration triggers ejaculation. [10]
Taves used a single subject to test the actual force required to penetrate a measuring apparatus. When the foreskin was retracted a more than tenfold increase in force was needed. [11] He argued that this confirms the belief of Morgan (1967) that the foreskin makes sexual penetration easier during sexual intercourse.[12] Whiddon (1953) and Foley (1966) also believed that the presence of the foreskin made sexual penetration easier [13] [14]
A 2002 study into changing circumcision practices in Tanzania Africa, found that there was a significant move towards popularizing circumcision, mostly for perceived health reasons, but that participants (unclear whether male focus groups or female as well) reported it also led to improved sexual pleasure for men and women alike. Some participants in this context, compared the presence of a foreskin to a condom.[28]
## Conditions
Frenulum breve is where the frenulum is insufficiently long to allow the foreskin to fully retract, which may lead to discomfort during intercourse. The frenulum may also tear during intercourse. Phimosis is a condition when the foreskin of an adult cannot be retracted properly. (Before adulthood, the foreskin may still be separating from the glans.[29]) Phimosis can be treated by gently stretching the foreskin, by changing masturbation habits,[30] using topical steroid ointments, preputioplasty, or by circumcision. See phimosis for more information.
A condition called paraphimosis may occur if a tight foreskin becomes trapped behind the glans and swells as a restrictive ring. This can cut off the blood supply, resulting in ischaemia of the glans penis.
Aposthia is a rare condition in which the foreskin is not present at birth.
## Surgical and other modifications of the foreskin
Circumcision is the removal of the foreskin, either partially or completely. It may be done for religious, aesthetic, health, or hygiene reasons, or to treat disease.
Preputioplasty is a procedure to relieve a tight foreskin without resorting to circumcision.
Other practices include genital piercings involving the foreskin and slitting the foreskin.[31]
## Research use
Foreskins obtained from circumcision procedures are frequently used by biochemical and micro-anatomical researchers to study the structure and proteins of human skin. In particular, foreskins obtained from newborns have been found to be useful in the manufacturing of more human skin.[15]
## Langerhans cells
Langerhans cells are immature dendritic cells that are found in all areas of the penile epitelium,[16] but are most superficial in the inner surface of the foreskin.[17] The recent Szabo and Short (2000) study targets Langerhans cells as receptors of HIV, and states that these cells "must be regarded as the most probable sites for viral entry in primary HIV infection in men."[18] Langerhans cells are also known to express the c-type lectin langerin, which may play a role in transmission of HIV to nearby lymph nodes.[19] However, de Witte et al. (2007) reported that langerin, produced by Langerhans cells, blocks the transmission of HIV.[20]
# Foreskin in non-human species
In koalas the foreskin contains naturally occurring bacteria that play an important role in fertilization.[32] | https://www.wikidoc.org/index.php/Foreskin | |
fe2ab88684e3446f2f6dd0f77e2c8733ae266a6d | wikidoc | Fortisip | Fortisip
Fortisip™ is a nutritional supplement, a palatable, ready-made milkshake style drink made by the company Nutricia, for the dietary management of disease related malnutrition.
Fortisip is designed to provide the essential nutrients that you usually obtain from a varied diet. So, it is made for people who can not consume enough solid food, which may be due to a variety of different causes: when appetite is poor and nutritional requirements are not being met through ordinary food, many people find it easier to drink than to eat and Fortisip drink help increase nutritional intake. It is suitable for use as the sole source of nutrition for most people over 6 years of age.
Fortisip Bottle is often useful to reduce the amount of weight loss in people with cancer, helping them build up their strength and withstand the effects of the cancer and its treatment.
Each 200ml Fortisip bottle contains 300 Kcal or 1260 kj. Fortisip bottle also contains proteins and all of the vitamins, minerals and trace elements you need for a nutritionally complete diet.
While Fortisip is gluten and lactose free, it is suitable also for use for people with coeliac disease or lactose intolerance. It is not suitable for people with the condition galactosemia, or as a partial source of nutrition for children under the age of 3.
Fortisip Bottle is available in various flavours: neutral, vanilla, strawberry, orange, banana, tropical fruits, chocolate and toffee. | Fortisip
Fortisip™ is a nutritional supplement, a palatable, ready-made milkshake style drink made by the company Nutricia, for the dietary management of disease related malnutrition.
Fortisip is designed to provide the essential nutrients that you usually obtain from a varied diet. So, it is made for people who can not consume enough solid food, which may be due to a variety of different causes: when appetite is poor and nutritional requirements are not being met through ordinary food, many people find it easier to drink than to eat and Fortisip drink help increase nutritional intake. It is suitable for use as the sole source of nutrition for most people over 6 years of age.
Fortisip Bottle is often useful to reduce the amount of weight loss in people with cancer, helping them build up their strength and withstand the effects of the cancer and its treatment.
Each 200ml Fortisip bottle contains 300 Kcal or 1260 kj. Fortisip bottle also contains proteins and all of the vitamins, minerals and trace elements you need for a nutritionally complete diet.
While Fortisip is gluten and lactose free, it is suitable also for use for people with coeliac disease or lactose intolerance. It is not suitable for people with the condition galactosemia, or as a partial source of nutrition for children under the age of 3.
Fortisip Bottle is available in various flavours: neutral, vanilla, strawberry, orange, banana, tropical fruits, chocolate and toffee. | https://www.wikidoc.org/index.php/Fortisip | |
c40b2ad79af0556a4f5b2e6573b14958401ba546 | wikidoc | Humorism | Humorism
# Overview
Humorism, or humoralism, was a theory of the makeup and workings of the human body adopted by ancient Greek and Roman physicians and philosophers. From Hippocrates onward, the humor theory was the most commonly held view of the human body among European physicians until the advent of modern medical research in the nineteenth century.
Essentially, this theory held that the human body was filled with four basic substances, called four humours, or humors, which are in balance when a person is healthy. All diseases and disabilities resulted from an excess or deficit of one of these four humors. The four humors were identified as black bile, yellow bile, phlegm, and blood. Greeks and Romans, and the later Western European medical establishments that adopted and adapted classical medical philosophy, believed that each of these humors would wax and wane in the body, depending on diet and activity. When a patient was suffering from a surplus or imbalance of one fluid, then his or her personality and physical health would be affected.
Theophrastus and others developed a set of characters based on the humors. Those with too much blood were sanguine. Those with too much phlegm were phlegmatic. Those with too much yellow bile were choleric, and those with too much black bile were melancholic. The idea of human personality based on humors contributed to the character comedies of Menander and, later, Plautus.
Through the neo-classical revival in Europe, the humor theory dominated medical practice, and the theory of humoral types made periodic appearances in drama. Such typically "eighteenth-century" practices as bleeding a sick person or applying hot cups to a person were, in fact, based on the humor theory of surpluses of fluids (blood and bile in those cases). Ben Jonson wrote humor plays, where types were based on their humoral complexion.
Additionally, because people believed that there were finite amounts of humors in the body, there were folk/medical beliefs that the loss of fluids was a form of death.
# History and the connection with temperament theory
Although modern medical science has thoroughly discredited humorism, this "wrong-headed theory dominated medical thinking... until at least the middle of the 20th century, and in certain ways continues to influence modern-day diagnosis and therapy."
The concept was developed by ancient Greek thinkers around 400 BC and was directly linked with the popular theory of the four elements earth, fire, water, and air (Empedocles). Paired qualities were associated with each humour and its season. The word humour derives from the Greek χυμός, chymos (literally juice or sap, metaphorically flavor).
The four humours, their corresponding elements, seasons, sites of formation, and resulting temperaments alongside their modern equivalents are: Template:Temperament
Hippocrates is the one credited for applying this idea to medicine. Humoralism, or the doctrine of the four temperaments, as a medical theory retained its popularity for centuries largely through the influence of the writings of Galen (131-201 AD) and was decisively displaced only in 1858 by Rudolf Virchow's newly published theories of cellular pathology. While Galen thought that humours were formed in the body, rather than ingested, he believed that different foods had varying potential to be acted upon by the body to produce different humours. Warm foods, for example, tended to produce yellow bile, while cold foods tended to produce phlegm. Seasons of the year, periods of life, geographic regions and occupations also influenced the nature of the humours formed.
The imbalance of humours, or dyscrasia, was thought to be the direct cause of all diseases. Health was associated with a balance of humours, or eucrasia. The qualities of the humours, in turn, influenced the nature of the diseases they caused. Yellow bile caused warm diseases and phlegm caused cold diseases.
In On the Temperaments, Galen further emphasized the importance of the qualities. An ideal temperament involved a balanced mixture of the four qualities. Galen identified four temperaments in which one of the qualities, warm, cold, moist or dry, predominated and four more in which a combination of two, warm and moist, warm and dry, cold and dry or cold and moist, dominated. These last four, named for the humours with which they were associated—that is, sanguine, choleric, melancholic and phlegmatic, eventually became better known than the others. While the term temperament came to refer just to psychological dispositions, Galen used it to refer to bodily dispositions, which determined a person's susceptibility to particular diseases as well as behavioral and emotional inclinations.
Methods of treatment like blood letting, emetics and purges were aimed at expelling a harmful surplus of a humour. They remained part of mainstream Western medicine into the 16th century when William Harvey investigated the circulatory system. Other methods used herbs and foods associated with a particular humour to counter symptoms of disease, for instance: people who had a fever and were sweating were considered hot and wet and therefore given substances associated with cold and dry.
There are still remnants of the theory of the four humours in the current medical language. For example, we refer to humoral immunity or humoral regulation to mean substances like hormones and antibodies that are circulated throughout the body, or use the term blood dyscrasia to refer to any blood disease or abnormality. The associated food classification survives in adjectives that are still used for food, as when we call some spices "hot" and some wine "dry". When the chilli pepper was first introduced to Europe in the sixteenth century, dieticians disputed whether it was hot or cold.
The humours can be found in Elizabethan works, such as in Taming of the Shrew, in which the character Petruchio pretends to be irritable and angry to show Katherina what it is like being around a disagreeable person. He yells at the servants for them serving mutton, a "choleric" food, to two people who are already choleric.
Foods in Elizabethan times were believed all to have an affinity with one of these four humours. A person suffering from a sickness in which they were coughing up phlegm were believed to be too phlegmatic and might have been served wine (a choleric drink and the direct opposite humour to phlegmatic) to balance it out.
The theory was a modest advance over the previous views on human health that tried to explain disease in terms of evil spirits. Since then, practitioners have started to look for natural causes of disease and to provide natural treatments.
The Unani school of Indian medicine, still apparently practiced in India, is very similar to Galenic medicine in its emphasis on the four humours and in treatments based on controlling intake, general environment, and the use of purging as a way of relieving humoral imbalances. | Humorism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Otheruses4
Humorism, or humoralism, was a theory of the makeup and workings of the human body adopted by ancient Greek and Roman physicians and philosophers. From Hippocrates onward, the humor theory was the most commonly held view of the human body among European physicians until the advent of modern medical research in the nineteenth century.
Essentially, this theory held that the human body was filled with four basic substances, called four humours, or humors, which are in balance when a person is healthy. All diseases and disabilities resulted from an excess or deficit of one of these four humors. The four humors were identified as black bile, yellow bile, phlegm, and blood. Greeks and Romans, and the later Western European medical establishments that adopted and adapted classical medical philosophy, believed that each of these humors would wax and wane in the body, depending on diet and activity. When a patient was suffering from a surplus or imbalance of one fluid, then his or her personality and physical health would be affected.
Theophrastus and others developed a set of characters based on the humors. Those with too much blood were sanguine. Those with too much phlegm were phlegmatic. Those with too much yellow bile were choleric, and those with too much black bile were melancholic. The idea of human personality based on humors contributed to the character comedies of Menander and, later, Plautus.
Through the neo-classical revival in Europe, the humor theory dominated medical practice, and the theory of humoral types made periodic appearances in drama. Such typically "eighteenth-century" practices as bleeding a sick person or applying hot cups to a person were, in fact, based on the humor theory of surpluses of fluids (blood and bile in those cases). Ben Jonson wrote humor plays, where types were based on their humoral complexion.
Additionally, because people believed that there were finite amounts of humors in the body, there were folk/medical beliefs that the loss of fluids was a form of death.
# History and the connection with temperament theory
Although modern medical science has thoroughly discredited humorism, this "wrong-headed theory dominated medical thinking... until at least the middle of the 20th century, and in certain ways continues to influence modern-day diagnosis and therapy." [1]
The concept was developed by ancient Greek thinkers around 400 BC and was directly linked with the popular theory of the four elements earth, fire, water, and air (Empedocles). Paired qualities were associated with each humour and its season. The word humour derives from the Greek χυμός, chymos (literally juice or sap, metaphorically flavor).
The four humours, their corresponding elements, seasons, sites of formation, and resulting temperaments alongside their modern equivalents are: Template:Temperament
Hippocrates is the one credited for applying this idea to medicine. Humoralism, or the doctrine of the four temperaments, as a medical theory retained its popularity for centuries largely through the influence of the writings of Galen (131-201 AD) and was decisively displaced only in 1858 by Rudolf Virchow's newly published theories of cellular pathology. While Galen thought that humours were formed in the body, rather than ingested, he believed that different foods had varying potential to be acted upon by the body to produce different humours. Warm foods, for example, tended to produce yellow bile, while cold foods tended to produce phlegm. Seasons of the year, periods of life, geographic regions and occupations also influenced the nature of the humours formed.
The imbalance of humours, or dyscrasia, was thought to be the direct cause of all diseases. Health was associated with a balance of humours, or eucrasia. The qualities of the humours, in turn, influenced the nature of the diseases they caused. Yellow bile caused warm diseases and phlegm caused cold diseases.
In On the Temperaments, Galen further emphasized the importance of the qualities. An ideal temperament involved a balanced mixture of the four qualities. Galen identified four temperaments in which one of the qualities, warm, cold, moist or dry, predominated and four more in which a combination of two, warm and moist, warm and dry, cold and dry or cold and moist, dominated. These last four, named for the humours with which they were associated—that is, sanguine, choleric, melancholic and phlegmatic, eventually became better known than the others. While the term temperament came to refer just to psychological dispositions, Galen used it to refer to bodily dispositions, which determined a person's susceptibility to particular diseases as well as behavioral and emotional inclinations.
Methods of treatment like blood letting, emetics and purges were aimed at expelling a harmful surplus of a humour. They remained part of mainstream Western medicine into the 16th century when William Harvey investigated the circulatory system. Other methods used herbs and foods associated with a particular humour to counter symptoms of disease, for instance: people who had a fever and were sweating were considered hot and wet and therefore given substances associated with cold and dry.
There are still remnants of the theory of the four humours in the current medical language. For example, we refer to humoral immunity or humoral regulation to mean substances like hormones and antibodies that are circulated throughout the body, or use the term blood dyscrasia to refer to any blood disease or abnormality. The associated food classification survives in adjectives that are still used for food, as when we call some spices "hot" and some wine "dry". When the chilli pepper was first introduced to Europe in the sixteenth century, dieticians disputed whether it was hot or cold.
The humours can be found in Elizabethan works, such as in Taming of the Shrew, in which the character Petruchio pretends to be irritable and angry to show Katherina what it is like being around a disagreeable person. He yells at the servants for them serving mutton, a "choleric" food, to two people who are already choleric.
Foods in Elizabethan times were believed all to have an affinity with one of these four humours. A person suffering from a sickness in which they were coughing up phlegm were believed to be too phlegmatic and might have been served wine (a choleric drink and the direct opposite humour to phlegmatic) to balance it out.
The theory was a modest advance over the previous views on human health that tried to explain disease in terms of evil spirits. Since then, practitioners have started to look for natural causes of disease and to provide natural treatments.
The Unani school of Indian medicine, still apparently practiced in India, is very similar to Galenic medicine in its emphasis on the four humours and in treatments based on controlling intake, general environment, and the use of purging as a way of relieving humoral imbalances. | https://www.wikidoc.org/index.php/Four_humours | |
54788ddeab6030bf517e0ec1102c39477ad4752c | wikidoc | Freckles | Freckles
Freckles are clusters of concentrated melanin which are most often visible on people with a fair complexion. A freckle is also called an "ephelis."
# Biology
Having freckles is genetic and is related to the presence of the melanocortin-1 receptor MC1R gene variant, which is dominant. Freckles are often found in people with fair hair such as blonde, strawberry blonde, dishwater blonde, or most commonly red hair. The formation of freckles is triggered by exposure to sunlight. The exposure to UV-B radiation activates melanocytes to increase the melanin production, which causes freckles to become darker and more numerous.
Freckles are predominantly found on the face, although they may appear on any skin exposed to the sun. Freckles are rare on infants, and more common on children before puberty; they are less common on adults.
Upon exposure to the sun, freckles will reappear if they have been altered with creams or lasers and not protected from the sun, but do however fade with age in some cases.
Freckles are not a skin disorder. People with freckles usually have a lower concentration of photoprotective melanin and are therefore more susceptible to the harmful effects of UV-radiation. An overexposure of UV-radiation should be avoided. However due to the debate about the safety of sunscreen, protective clothing should be the preferred method.
Sunscreens and Cancer by Hans R Larsen
# Two types of freckles
Ephelides is a genetic trait. It’s used to describe a freckle that is flat, light brown or red, and fades in the winter. Ephelides are more common in those with light complexions and with the regular use of sunblock, can be suppressed.
Liver spots (also known as sun spots and Lentigines) are freckles that sometimes do not fade in the winter. Rather, they form after years of exposure to the sun. Lentigines are more common in older people. | Freckles
Freckles are clusters of concentrated melanin which are most often visible on people with a fair complexion. A freckle is also called an "ephelis."
## Biology
Having freckles is genetic and is related to the presence of the melanocortin-1 receptor MC1R gene variant, which is dominant.[1] Freckles are often found in people with fair hair such as blonde, strawberry blonde, dishwater blonde, or most commonly red hair. The formation of freckles is triggered by exposure to sunlight. The exposure to UV-B radiation activates melanocytes to increase the melanin production, which causes freckles to become darker and more numerous.
Freckles are predominantly found on the face, although they may appear on any skin exposed to the sun. Freckles are rare on infants, and more common on children before puberty; they are less common on adults.
Upon exposure to the sun, freckles will reappear if they have been altered with creams or lasers and not protected from the sun, but do however fade with age in some cases.
Freckles are not a skin disorder. People with freckles usually have a lower concentration of photoprotective melanin and are therefore more susceptible to the harmful effects of UV-radiation. An overexposure of UV-radiation should be avoided. However due to the debate about the safety of sunscreen, protective clothing should be the preferred method. [2]
[3]
Sunscreens and Cancer by Hans R Larsen
## Two types of freckles
Ephelides is a genetic trait. It’s used to describe a freckle that is flat, light brown or red, and fades in the winter. Ephelides are more common in those with light complexions and with the regular use of sunblock, can be suppressed.
Liver spots (also known as sun spots and Lentigines) are freckles that sometimes do not fade in the winter. Rather, they form after years of exposure to the sun. Lentigines are more common in older people. | https://www.wikidoc.org/index.php/Freckles | |
d35eff44d292adea449d29a5554d09f53df22c5f | wikidoc | FreeLife | FreeLife
FreeLife International is a multi-level marketing company established in 1995 by Ray Faltinsky that supplies health food supplements. FreeLife is best known for promoting Himalayan Goji Juice, made from goji berries.
# Products
FreeLife’s product line initially consisted of nutritional supplements, weight loss products, shampoo and personal care products. FreeLife has since changed its product lines and now focuses on a juice made from wolfberry and sold under the name of Himalayan Goji Juice. FreeLife operates as an international multi-level marketing company where commissions are paid on multiple levels for recruiting others to buy and sell the product. Getting started includes an initial financial investment plus getting set up on a monthly 4-pack shipment of Himalayan Goji Juice for about $129.95 +taxes & shipping (about $200.00 per month). By recruiting others to buy and sell the product, an individual can reduce their product expenses and earn additional revenue.
# History
FreeLife was backed by investors, including Anson Beard of Morgan Stanley/Dean Witter, and with nutritionist and author of the nutritional book, the Vitamin Bible, Earl Mindell. FreeLife has since grown into a large multi-million dollar international company.
FreeLife's spokesperson, Earl Mindell, has made several claims about the health benefits of the goji brand of wolfberry juice, including that it has anti-aging properties.. Several unpublished studies have been made linking the juice with benefits for cancer patients, a claim which has caused controversy because the Goji Juice is an antioxidant, which can interfere with existing cancer treatments. A seller of Goji Juice, was warned about making unsubstantiated claims about the juice's health benefits by the United States Food and Drug Administration.
In a hidden-camera investigation and an interview by Wendy Mesley on the CBC consumer television program Marketplace (aired 24 January, 2007), H. Leon Bradlow, the author of a study that Mindell cites as support for this anti-cancer claim, says that his original research does not, in fact, show that goji juice has any anti-cancer properties, and states "I don't have proof that it would have that effect in a tumor in a mouse, let alone a person."
In addition, Bradlow's study was carried out at Hackensack University Medical Center, not the "prestigious" Memorial Sloan-Kettering Cancer Center as Mindell had repeatedly claimed.Template:Who
Mesley then went on to confront Mindell, whom FreeLife refers to as "Dr. Mindell" about the validity of his Ph.D from Pacific Western University and whether or not he is a medical doctor. Mindell asserted that his degree is "accredited in every state in the Union", a claim that is clearly contrary to fact . Shortly after this comment, he ejected Mesley and her crew from his house and threatened to call the police. | FreeLife
Template:Infobox Company
FreeLife International is a multi-level marketing[citation needed] company established in 1995 by Ray Faltinsky that supplies health food supplements. FreeLife is best known for promoting Himalayan Goji Juice, made from goji berries.
# Products
FreeLife’s product line initially consisted of nutritional supplements, weight loss products, shampoo and personal care products. FreeLife has since changed its product lines and now focuses on a juice made from wolfberry and sold under the name of Himalayan Goji Juice. FreeLife operates as an international multi-level marketing company where commissions are paid on multiple levels for recruiting others to buy and sell the product. Getting started includes an initial financial investment plus getting set up on a monthly 4-pack shipment of Himalayan Goji Juice for about $129.95 +taxes & shipping (about $200.00 per month). By recruiting others to buy and sell the product, an individual can reduce their product expenses and earn additional revenue.
# History
FreeLife was backed by investors, including Anson Beard of Morgan Stanley/Dean Witter, and with nutritionist and author of the nutritional book, the Vitamin Bible, Earl Mindell. FreeLife has since grown into a large multi-million dollar international company.[1]
FreeLife's spokesperson, Earl Mindell, has made several claims about the health benefits of the goji brand of wolfberry juice, including that it has anti-aging properties.[2]. Several unpublished studies have been made linking the juice with benefits for cancer patients, a claim which has caused controversy because the Goji Juice is an antioxidant, which can interfere with existing cancer treatments.[2] A seller of Goji Juice, was warned about making unsubstantiated claims about the juice's health benefits by the United States Food and Drug Administration.[3]
In a hidden-camera investigation and an interview by Wendy Mesley on the CBC consumer television program Marketplace (aired 24 January, 2007), H. Leon Bradlow, the author of a study that Mindell cites as support for this anti-cancer claim, says that his original research does not, in fact, show that goji juice has any anti-cancer properties, and states "I don't have proof that it would have that effect in a tumor in a mouse, let alone a person."
In addition, Bradlow's study was carried out at Hackensack University Medical Center, not the "prestigious" Memorial Sloan-Kettering Cancer Center as Mindell had repeatedly claimed.Template:Who
Mesley then went on to confront Mindell, whom FreeLife refers to as "Dr. Mindell" about the validity of his Ph.D from Pacific Western University and whether or not he is a medical doctor. Mindell asserted that his degree is "accredited in every state in the Union", a claim that is clearly contrary to fact [4]. Shortly after this comment, he ejected Mesley and her crew from his house and threatened to call the police.[5] | https://www.wikidoc.org/index.php/FreeLife | |
9939018a9984114c648c55c80a4a71c9add17eaa | wikidoc | Freezing | Freezing
In physics and chemistry, freezing is the process whereby a liquid turns to a solid when cold enough. The freezing point is the temperature at which this happens. Melting, the process of turning a solid to a liquid, is almost the exact opposite of freezing. All known liquids undergo freezing when the temperature is lowered with the sole exception of helium, which remains fluid at absolute zero and can only be solidified under pressure. For most substances, the melting and freezing points are the same temperature, however, certain substances possess differing solid-liquid transition temperatures. For example, agar melts at 85 °C (185 °F) and solidifies from 31 °C to 40 °C (89.6 °F to 104 °F); this process is known as thermal hysteresis.
# Crystallization
Most liquids freeze by crystallization, formation of crystalline solid from the uniform liquid. This is a first-order thermodynamic phase transition, which means that as long as solid and liquid coexist, the equilibrium temperature of the system remains constant and equal to the melting point. Crystallization consists of two major events, nucleation and crystal growth. Nucleation is the step where the molecules start to gather into clusters, on the nanometer scale, arranging in a defined and periodic manner that defines the crystal structure. The crystal growth is the subsequent growth of the nuclei that succeed in achieving the critical cluster size.
# Supercooling
In spite of the second law of thermodynamics, crystallization of pure liquids usually begins at lower temperature than the melting point, due to high activation energy of homogeneous nucleation. The creation of a nucleus implies the formation of an interface at the boundaries of the new phase. Some energy is expended to form this interface, based on the surface energy of each phase. If a hypothetical nucleus is too small, the energy that would be released by forming its volume is not enough to create its surface, and nucleation does not proceed. Freezing does not start until the temperature is low enough to provide enough energy to form stable nuclei. In presence of irregularities on the surface of the containing vessel, solid or gaseous impurities, pre-formed solid crystals, or other nucleators, heterogeneous nucleation may occur, where some energy is released by the partial destruction of the previous interface, rising the supercooling point to be near or equal to the melting point. The melting point of water at 1 atmosphere of pressure is very close to 0 °C (32 °F, 273.15 K), and in the presence of nucleating substances the freezing point of water is close to the melting point, but in the absence of nucleators water can super cool to −42 °C (−43.6 °F, 231 K) before freezing. Under high pressure (2,000 atmospheres) water will super cool to as low as −70°C (−94°F, 203 K) before freezing.
# Vitrification
Certain materials, such as glass or glycerol, may harden without crystallizing; these are called amorphous solids. Amorphous materials as well as some polymers do not have a true freezing point as there is no abrupt phase change at any specific temperature. Instead, there is a gradual change in their viscoelastic properties over a range of temperatures. Such materials are characterized by a glass transition temperature which may be roughly defined as the "knee" point of the material's density vs. temperature graph.
# Freezing of biological fluids
Most living organisms accumulate cryoprotectants such as anti-nucleating proteins, polyols, and glucose to protect themselves against frost damage by sharp ice crystals. Most plants, in particular, can safely reach temperatures of −4°C to −12°C. Certain bacteria, notably Pseudomonas syringae, produce specialized proteins that serve as potent ice nucleators, which they use to force ice formation on the surface of various fruits and plants at about −2°C. The freezing causes injuries in the epithelia and makes the nutrients in the underlying plant tissues available to the bacteria.
# Food preservation
Freezing is a common method of food preservation which slows both food decay and the growth of micro-organisms. Besides the effect of lower temperatures on reaction rates, freezing makes water less available for bacterial growth. | Freezing
In physics and chemistry, freezing is the process whereby a liquid turns to a solid when cold enough. The freezing point is the temperature at which this happens. Melting, the process of turning a solid to a liquid, is almost the exact opposite of freezing. All known liquids undergo freezing when the temperature is lowered with the sole exception of helium, which remains fluid at absolute zero and can only be solidified under pressure. For most substances, the melting and freezing points are the same temperature, however, certain substances possess differing solid-liquid transition temperatures. For example, agar melts at 85 °C (185 °F) and solidifies from 31 °C to 40 °C (89.6 °F to 104 °F); this process is known as thermal hysteresis.
# Crystallization
Most liquids freeze by crystallization, formation of crystalline solid from the uniform liquid. This is a first-order thermodynamic phase transition, which means that as long as solid and liquid coexist, the equilibrium temperature of the system remains constant and equal to the melting point. Crystallization consists of two major events, nucleation and crystal growth. Nucleation is the step where the molecules start to gather into clusters, on the nanometer scale, arranging in a defined and periodic manner that defines the crystal structure. The crystal growth is the subsequent growth of the nuclei that succeed in achieving the critical cluster size.
# Supercooling
In spite of the second law of thermodynamics, crystallization of pure liquids usually begins at lower temperature than the melting point, due to high activation energy of homogeneous nucleation. The creation of a nucleus implies the formation of an interface at the boundaries of the new phase. Some energy is expended to form this interface, based on the surface energy of each phase. If a hypothetical nucleus is too small, the energy that would be released by forming its volume is not enough to create its surface, and nucleation does not proceed. Freezing does not start until the temperature is low enough to provide enough energy to form stable nuclei. In presence of irregularities on the surface of the containing vessel, solid or gaseous impurities, pre-formed solid crystals, or other nucleators, heterogeneous nucleation may occur, where some energy is released by the partial destruction of the previous interface, rising the supercooling point to be near or equal to the melting point. The melting point of water at 1 atmosphere of pressure is very close to 0 °C (32 °F, 273.15 K), and in the presence of nucleating substances the freezing point of water is close to the melting point, but in the absence of nucleators water can super cool to −42 °C (−43.6 °F, 231 K) before freezing. Under high pressure (2,000 atmospheres) water will super cool to as low as −70°C (−94°F, 203 K) before freezing[1].
# Vitrification
Certain materials, such as glass or glycerol, may harden without crystallizing; these are called amorphous solids. Amorphous materials as well as some polymers do not have a true freezing point as there is no abrupt phase change at any specific temperature. Instead, there is a gradual change in their viscoelastic properties over a range of temperatures. Such materials are characterized by a glass transition temperature which may be roughly defined as the "knee" point of the material's density vs. temperature graph.
# Freezing of biological fluids
Most living organisms accumulate cryoprotectants such as anti-nucleating proteins, polyols, and glucose to protect themselves against frost damage by sharp ice crystals. Most plants, in particular, can safely reach temperatures of −4°C to −12°C. Certain bacteria, notably Pseudomonas syringae, produce specialized proteins that serve as potent ice nucleators, which they use to force ice formation on the surface of various fruits and plants at about −2°C[2]. The freezing causes injuries in the epithelia and makes the nutrients in the underlying plant tissues available to the bacteria. [3]
# Food preservation
Freezing is a common method of food preservation which slows both food decay and the growth of micro-organisms. Besides the effect of lower temperatures on reaction rates, freezing makes water less available for bacterial growth. | https://www.wikidoc.org/index.php/Freezing | |
75e4fc6b5617aec84fbdc771e32d2a80429c2482 | wikidoc | Fremitus | Fremitus
Fremitus is a palpable vibration on the human body. In common medical usage, it usually refers to (tactile) vocal fremitus, although there are several other types.
# Bronchial fremitus
See rhonchal fremitus below.
# Hepatic fremitus
Hepatic fremitus is a vibration felt over the patient's liver. It is thought to be caused by a severely inflamed and necrotic liver rubbing up against the peritoneum. The name 'Monash sign' has been suggested for this clinical sign, after the Monash Medical Centre in Melbourne, Australia (Nagappan et al, 2001).
# Hydatid fremitus
Hydatid fremitus is a vibratory sensation felt on palpating a hydatid cyst.
# Pectoral fremitus
See vocal fremitus below.
# Pericardial fremitus
Pericardial fremitus is a vibration felt on the chest wall due to the friction of the surfaces of the pericardium over each other. See pericardial friction rub for the auditory analog of this sign.
# Periodontal fremitus
Periodontal fremitus occurs in either of the alveolar bones when an individual sustains trauma from occlusion. It is a result of teeth exhibiting at least slight mobility rubbing against the adjacent walls of their sockets, the volume of which has been expanded ever so slightly by inflammatory responses, bone resorption or both. As a test to determine the severity of periodontal disease, a patient is told to close his or her mouth into maximum intercuspation and is asked to grind his or her teeth ever so slightly. Fingers placed in the labial vestibule against the alveolar bone can detect fremitus.
# Pleural fremitus
Pleural fremitus is a palpable vibration of the wall of the thorax caused by friction between the parietal and visceral pleura of the lungs. See pleural friction rub for the auditory analog of this sign.
# Rhonchal fremitus
Rhonchal fremitus, also known as bronchial fremitus, is a palpable vibration produced during breathing caused by partial airway obstruction. The obstruction can be due to mucus or other secretions in the airway, bronchial hyperreactivity, or tumors. See rhonchus (rhonchi) for the auditory analog of this sign.
# Subjective fremitus
Subjective fremitus is a vibration felt by the patient on humming with the mouth closed.
# Tactile fremitus
See vocal fremitus below.
# Tussive fremitus
Tussive fremitus is a vibration felt on the chest when the patient coughs.
# Vocal fremitus
Vocal Fremitus, also called pectoral fremitus, or tactile vocal fremitus, is a vibration felt on the patient's chest during low frequency vocalization. Commonly, the patient is asked to repeat the phrase 'boy oh boy' (or any other diphthong such as 'toy boat' and 'blue balloons') while the examiner attempts to detect vibrations on the chest wall. The phrase 'ninety-nine' is also commonly used. The German language equivalent neun und neunzig, is a diphthong, and is appropriate.
Vocal fremitus is normally more intense in the right second intercostal space, as well as in the interscapular region, as these areas are closest to the bronchial bifurcation. Vocal fremitus is pathologically increased over areas of consolidation and decreased or absent over areas of pleural effusion or pneumothorax (collapsed lung).
The reason for increased fremitus in a consolidated lung is the fact that the sound waves travel quicker through liquid (the consolidation) than air. Conversely, the reason for decreased fremitus in a pleural effusion (or any pathology separating the pleura), is that this increased space between the pleura acts as a barrier to the sound waves.
It has recently been suggested that the artifacts caused by eliciting vocal fremitus during breast ultrasonography can be used to differentiate between benign and malignant tumors (Sohn and Baudendistel, 1995). | Fremitus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Fremitus is a palpable vibration on the human body. In common medical usage, it usually refers to (tactile) vocal fremitus, although there are several other types.
# Bronchial fremitus
See rhonchal fremitus below.
# Hepatic fremitus
Hepatic fremitus is a vibration felt over the patient's liver. It is thought to be caused by a severely inflamed and necrotic liver rubbing up against the peritoneum. The name 'Monash sign' has been suggested for this clinical sign, after the Monash Medical Centre in Melbourne, Australia (Nagappan et al, 2001).
# Hydatid fremitus
Hydatid fremitus is a vibratory sensation felt on palpating a hydatid cyst.
# Pectoral fremitus
See vocal fremitus below.
# Pericardial fremitus
Pericardial fremitus is a vibration felt on the chest wall due to the friction of the surfaces of the pericardium over each other. See pericardial friction rub for the auditory analog of this sign.
# Periodontal fremitus
Periodontal fremitus occurs in either of the alveolar bones when an individual sustains trauma from occlusion. It is a result of teeth exhibiting at least slight mobility rubbing against the adjacent walls of their sockets, the volume of which has been expanded ever so slightly by inflammatory responses, bone resorption or both. As a test to determine the severity of periodontal disease, a patient is told to close his or her mouth into maximum intercuspation and is asked to grind his or her teeth ever so slightly. Fingers placed in the labial vestibule against the alveolar bone can detect fremitus.[1]
# Pleural fremitus
Pleural fremitus is a palpable vibration of the wall of the thorax caused by friction between the parietal and visceral pleura of the lungs. See pleural friction rub for the auditory analog of this sign.
# Rhonchal fremitus
Rhonchal fremitus, also known as bronchial fremitus, is a palpable vibration produced during breathing caused by partial airway obstruction. The obstruction can be due to mucus or other secretions in the airway, bronchial hyperreactivity, or tumors. See rhonchus (rhonchi) for the auditory analog of this sign.
# Subjective fremitus
Subjective fremitus is a vibration felt by the patient on humming with the mouth closed.
# Tactile fremitus
See vocal fremitus below.
# Tussive fremitus
Tussive fremitus is a vibration felt on the chest when the patient coughs.
# Vocal fremitus
Vocal Fremitus, also called pectoral fremitus, or tactile vocal fremitus, is a vibration felt on the patient's chest during low frequency vocalization. Commonly, the patient is asked to repeat the phrase 'boy oh boy' (or any other diphthong such as 'toy boat' and 'blue balloons') while the examiner attempts to detect vibrations on the chest wall. The phrase 'ninety-nine' is also commonly used. The German language equivalent neun und neunzig, is a diphthong, and is appropriate.
Vocal fremitus is normally more intense in the right second intercostal space, as well as in the interscapular region, as these areas are closest to the bronchial bifurcation. Vocal fremitus is pathologically increased over areas of consolidation and decreased or absent over areas of pleural effusion or pneumothorax (collapsed lung).
The reason for increased fremitus in a consolidated lung is the fact that the sound waves travel quicker through liquid (the consolidation) than air. Conversely, the reason for decreased fremitus in a pleural effusion (or any pathology separating the pleura), is that this increased space between the pleura acts as a barrier to the sound waves.
It has recently been suggested that the artifacts caused by eliciting vocal fremitus during breast ultrasonography can be used to differentiate between benign and malignant tumors (Sohn and Baudendistel, 1995). | https://www.wikidoc.org/index.php/Fremitus | |
48fcff923ea82915b817fa0c0f3bbded0dd5c4d9 | wikidoc | Frenulum | Frenulum
# Overview
A frenulum (or frenum, plural: frenula or frena, from the Latin frēnulum, "little bridle", the diminutive of frēnum ) is a small fold of tissue that secures or restricts the motion of a mobile organ in the body. A short frenulum may require a frenectomy or frenuloplasty to achieve normal mobility.
Frenula on the human body include several in the mouth, some in the digestive tract, and some connected to the external genitalia:
- Oral tissue: Frenula of the mouth include the frenulum linguae under the tongue, the f. labii superioris inside the upper lip, the f. labii inferioris inside the lower lip, and the buccal frena which connect the cheeks to the gum. These can easily be torn by violent blows to the face or mouth, and thus a torn frenulum is sometimes a warning sign of physical abuse.
- Vulvular tissue: In females, genital frenula include the frenulum clitoridis of the clitoris and the frenulum labiorum pudendi (aka. fourchette) where the labia minora meet at the back.
- Penile tissue: The word frenulum on its own is often used for the frenulum of prepuce of penis or frenulum preputii penis, which is an elastic band of tissue under the glans penis that connects to the prepuce, or foreskin to the vernal mucosa, and helps contract the prepuce over the glans.
- Brain: Frenulum veli
The word frenulum also refers to a bristle present at the root of the hindwing of most moths which engages with a small hook on the forewing to join the wings together. | Frenulum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A frenulum (or frenum, plural: frenula or frena, from the Latin frēnulum, "little bridle", the diminutive of frēnum ) is a small fold of tissue that secures or restricts the motion of a mobile organ in the body. A short frenulum may require a frenectomy or frenuloplasty to achieve normal mobility.
Frenula on the human body include several in the mouth, some in the digestive tract, and some connected to the external genitalia:
- Oral tissue: Frenula of the mouth include the frenulum linguae under the tongue, the f. labii superioris inside the upper lip, the f. labii inferioris inside the lower lip, and the buccal frena which connect the cheeks to the gum. These can easily be torn by violent blows to the face or mouth, and thus a torn frenulum is sometimes a warning sign of physical abuse.
- Vulvular tissue: In females, genital frenula include the frenulum clitoridis of the clitoris and the frenulum labiorum pudendi (aka. fourchette) where the labia minora meet at the back.
- Penile tissue: The word frenulum on its own is often used for the frenulum of prepuce of penis or frenulum preputii penis, which is an elastic band of tissue under the glans penis that connects to the prepuce, or foreskin to the vernal mucosa, and helps contract the prepuce over the glans.
- Brain: Frenulum veli
The word frenulum also refers to a bristle present at the root of the hindwing of most moths which engages with a small hook on the forewing to join the wings together.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Frenar_band | |
db18efeda9eaf3a104deddf2fc6064369fdf3a17 | wikidoc | Friction | Friction
# Overview
Friction is the force resisting the relative motion of two surfaces in contact or a surface in contact with a fluid (e.g. air on an aircraft or water in a pipe). It is not a fundamental force, as it is derived from electromagnetic forces between atoms and electrons, and so cannot be calculated from first principles, but instead must be found empirically. When contacting surfaces move relative to each other, the friction between the two objects converts kinetic energy into thermal energy, or heat. Friction between solid objects is often referred to as dry friction or sliding friction and between a solid and a gas or liquid as fluid friction. Both of these types of friction are called kinetic friction. Contrary to popular credibility, sliding friction is not caused by surface roughness, but by chemical bonding between the surfaces. Surface roughness and contact area, however, do affect sliding friction for micro- and nano-scale objects where surface area forces dominate inertial forces. Internal friction is the motion- resisting force between the surfaces of the particles making up the substance.
# Coulomb friction
One model of friction is called Coulomb friction after Charles-Augustin de Coulomb. It is described by the equation:
- F_\mathrm{f} is either the force exerted by friction, or, in the case of equality, the maximum possible magnitude of this force.
- \mu is the coefficient of friction, which is an empirical property of the contacting materials,
- F_\mathrm{n} is the normal force exerted between the surfaces, and
For surfaces at rest relative to each other, \mu is the coefficient of static friction (generally larger than its kinetic counterpart), the Coulomb friction may take any value from zero up to F_\mathrm{f}, and the direction of the frictional force against a surface is opposite to the motion that surface would experience in the absence of friction. Thus, in the static case, the frictional force is exactly what it must be in order to prevent motion between the surfaces; it balances the net force tending to cause such motion. In this case, rather than providing an estimate of the actual frictional force, the Coulomb approximation provides a threshold value for this force, above which sliding would commence.
For surfaces in relative motion, \mu is the coefficient of kinetic friction (see below), the Coulomb friction is equal to F_f, and the frictional force on each surface is exerted in the direction opposite to its motion relative to the other surface.
This approximation mathematically follows from the assumptions that surfaces are in atomically close contact only over a small fraction of their overall area, that this contact area is proportional to the normal force (until saturation, which takes place when all area is in atomic contact), and that frictional force is proportional to the applied normal force, independently of the contact area (you can see the experiments on friction from Leonardo Da Vinci). Such reasoning aside, however, the approximation is fundamentally an empirical construction. It is a rule of thumb describing the approximate outcome of an extremely complicated physical interaction. The strength of the approximation is its simplicity and versatility – though in general the relationship between normal force and frictional force is not exactly linear (and so the frictional force is not entirely independent of the contact area of the surfaces), the Coulomb approximation is an adequate representation of friction for the analysis of many physical systems.
## Coefficient of friction
The coefficient of friction (also known as the frictional coefficient) is a dimensionless scalar value which describes the ratio of the force of friction between two bodies and the force pressing them together. The coefficient of friction depends on the materials used; for example, ice on steel has a low coefficient of friction (the two materials slide past each other easily), while rubber on pavement has a high coefficient of friction (the materials do not slide past each other easily). Coefficients of friction range from near zero to greater than one–under good conditions, a tire on concrete may have a coefficient of friction of 1.7.
When the surfaces are conjoined, Coulomb friction becomes a very poor approximation (for example, Scotch tape resists sliding even when there is no normal force, or a negative normal force). In this case, the frictional force may depend strongly on the area of contact. Some drag racing tires are adhesive in this way.
The force of friction is always exerted in a direction that opposes movement (for kinetic friction) or potential movement (for static friction) between the two surfaces. For example, a curling stone sliding along the ice experiences a kinetic force slowing it down. For an example of potential movement, the drive wheels of an accelerating car experience a frictional force pointing forward; if they did not, the wheels would spin, and the rubber would slide backwards along the pavement. Note that it is not the direction of movement of the vehicle they oppose, it is the direction of (potential) sliding between tire and road.
The coefficient of friction is an empirical measurement–it has to be measured experimentally, and cannot be found through calculations. Rougher surfaces tend to have higher effective values. Most dry materials in combination have friction coefficient values between 0.3 and 0.6. Values outside this range are rarer, but Teflon, for example, can have a coefficient as low as 0.04. A value of zero would mean no friction at all, an elusive property–even Magnetic levitation vehicles have drag. Rubber in contact with other surfaces can yield friction coefficients from 1.0 to 2.
## Static friction
Static friction is the force between two objects that are not moving relative to each other. For example, static friction can prevent an object from sliding down a sloped surface. The coefficient of static friction, typically denoted as μs, is usually higher than the coefficient of kinetic friction. The initial force to get an object moving is often dominated by static friction.
Another important example of static friction is the force that prevents a car wheel from slipping as it rolls on the ground. Even though the wheel is in motion, the patch of the tire in contact with the ground is stationary relative to the ground, so it is static rather than kinetic friction.
The maximum value of static friction, when motion is impending, is sometimes referred to as limiting friction,
although this term is not used universally.
The value is given by the product of the normal force and coefficient of static friction.
## Kinetic friction
Kinetic (or dynamic) friction occurs when two objects are moving relative to each other and rub together (like a sled on the ground). The coefficient of kinetic friction is typically denoted as μk, and is usually less than the coefficient of static friction.
Since friction is exerted in a direction that opposes movement, kinetic friction usually does negative work, typically slowing something down. There are exceptions, for instance if the surface itself is under acceleration. One can see this by placing a heavy box on a rug, then pulling on the rug quickly. In this case, the box slides backwards relative to the rug, but moves forward relative to the floor. Thus, the kinetic friction between the box and rug accelerates the box in the same direction that the box moves, doing positive work.
Examples of kinetic friction:
- Sliding friction (also called dry friction) is when two objects are rubbing against each other. Putting a book flat on a desk and moving it around is an example of sliding friction
- Fluid friction is the friction between a solid object as it moves through a liquid or a gas. The drag of air on an airplane or of water on a swimmer are two examples of fluid friction.
# Other types of friction
## Rolling resistance
Rolling resistance is the force that resists the rolling of a wheel or other circular objects along a surface. Generally the force of rolling resistance is less than that associated with kinetic friction. Typical values for the coefficient of rolling resistance are 0.001.
One of the most common examples of rolling resistance is the movement of motor vehicle tires on a road, a process which generates heat and sound as by-products.
## Triboelectric effect
Rubbing dissimilar materials against one another can cause a build-up of electrostatic charge, which can be hazardous if flammable gases or vapours are present. When the static build-up discharges, explosions can be caused by ignition of the flammable mixture.
# Reducing friction
## Devices
Devices such as tires, ball bearings, air cushion or roller bearing can change sliding friction into a much smaller type of rolling friction. Many thermoplastic materials such as nylon, HDPE and PTFE are commonly used for low friction bearings. They are especially useful because the coefficient of friction falls with increasing imposed load.
## Techniques
One technique used by railroad engineers is to back up the train to create slack in the linkages between cars. This allows the train engine to pull forward and only take on the static friction of one car at a time, instead of all cars at once, thus spreading the static frictional force out over time.
## Lubricants
A common way to reduce friction is by using a lubricant, such as oil, water, or grease, which is placed between the two surfaces, often dramatically lessening the coefficient of friction. The science of friction and lubrication is called tribology. Lubricant technology is when lubricants are mixed with the application of science, especially to industrial or commercial objectives.
Superlubricity, a recently-discovered effect, has been observed in graphite: it is the substantial decrease of friction between two sliding objects, approaching zero levels. A very small amount of frictional energy would still be dissipated.
Lubricants to overcome friction need not always be thin, turbulent fluids or powdery solids such as graphite and talc; acoustic lubrication actually uses sound as a lubricant.
# Energy of friction
According to the law of conservation of energy, no energy is destroyed due to friction, though it may be lost to the system of concern. Energy is transformed from other forms into heat. A sliding hockey puck comes to rest because friction converts its kinetic energy into heat. Since heat quickly dissipates, many early philosophers, including Aristotle, wrongly concluded that moving objects lose energy without a driving force.
When an object is pushed along a surface, the energy converted to heat is given by:
where
Physical deformation is associated with friction. While this can be beneficial, as in polishing, it is often a problem, as the materials are worn away, and may no longer hold the specified tolerances.
The work done by friction can translate into deformation, wear, and heat that can affect the contact surface's material properties (and even the coefficient of friction itself). The work done by friction can also be used to mix materials such as in the technique of friction welding. | Friction
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Friction is the force resisting the relative motion of two surfaces in contact or a surface in contact with a fluid (e.g. air on an aircraft or water in a pipe). It is not a fundamental force, as it is derived from electromagnetic forces between atoms and electrons, and so cannot be calculated from first principles, but instead must be found empirically. When contacting surfaces move relative to each other, the friction between the two objects converts kinetic energy into thermal energy, or heat. Friction between solid objects is often referred to as dry friction or sliding friction and between a solid and a gas or liquid as fluid friction. Both of these types of friction are called kinetic friction. Contrary to popular credibility, sliding friction is not caused by surface roughness, but by chemical bonding between the surfaces.[1] Surface roughness and contact area, however, do affect sliding friction for micro- and nano-scale objects where surface area forces dominate inertial forces.[2] Internal friction is the motion- resisting force between the surfaces of the particles making up the substance.
# Coulomb friction
One model of friction is called Coulomb friction after Charles-Augustin de Coulomb. It is described by the equation:
- <math>F_\mathrm{f}</math> is either the force exerted by friction, or, in the case of equality, the maximum possible magnitude of this force.
- <math>\mu</math> is the coefficient of friction, which is an empirical property of the contacting materials,
- <math>F_\mathrm{n}</math> is the normal force exerted between the surfaces, and
For surfaces at rest relative to each other, <math>\mu</math> is the coefficient of static friction (generally larger than its kinetic counterpart), the Coulomb friction may take any value from zero up to <math>F_\mathrm{f}</math>, and the direction of the frictional force against a surface is opposite to the motion that surface would experience in the absence of friction. Thus, in the static case, the frictional force is exactly what it must be in order to prevent motion between the surfaces; it balances the net force tending to cause such motion. In this case, rather than providing an estimate of the actual frictional force, the Coulomb approximation provides a threshold value for this force, above which sliding would commence.
For surfaces in relative motion, <math>\mu</math> is the coefficient of kinetic friction (see below), the Coulomb friction is equal to <math>F_f</math>, and the frictional force on each surface is exerted in the direction opposite to its motion relative to the other surface.
This approximation mathematically follows from the assumptions that surfaces are in atomically close contact only over a small fraction of their overall area, that this contact area is proportional to the normal force (until saturation, which takes place when all area is in atomic contact), and that frictional force is proportional to the applied normal force, independently of the contact area (you can see the experiments on friction from Leonardo Da Vinci). Such reasoning aside, however, the approximation is fundamentally an empirical construction. It is a rule of thumb describing the approximate outcome of an extremely complicated physical interaction. The strength of the approximation is its simplicity and versatility – though in general the relationship between normal force and frictional force is not exactly linear (and so the frictional force is not entirely independent of the contact area of the surfaces), the Coulomb approximation is an adequate representation of friction for the analysis of many physical systems.
## Coefficient of friction
The coefficient of friction (also known as the frictional coefficient) is a dimensionless scalar value which describes the ratio of the force of friction between two bodies and the force pressing them together. The coefficient of friction depends on the materials used; for example, ice on steel has a low coefficient of friction (the two materials slide past each other easily), while rubber on pavement has a high coefficient of friction (the materials do not slide past each other easily). Coefficients of friction range from near zero to greater than one–under good conditions, a tire on concrete may have a coefficient of friction of 1.7.
When the surfaces are conjoined, Coulomb friction becomes a very poor approximation (for example, Scotch tape resists sliding even when there is no normal force, or a negative normal force). In this case, the frictional force may depend strongly on the area of contact. Some drag racing tires are adhesive in this way.
The force of friction is always exerted in a direction that opposes movement (for kinetic friction) or potential movement (for static friction) between the two surfaces. For example, a curling stone sliding along the ice experiences a kinetic force slowing it down. For an example of potential movement, the drive wheels of an accelerating car experience a frictional force pointing forward; if they did not, the wheels would spin, and the rubber would slide backwards along the pavement. Note that it is not the direction of movement of the vehicle they oppose, it is the direction of (potential) sliding between tire and road.
The coefficient of friction is an empirical measurement–it has to be measured experimentally, and cannot be found through calculations. Rougher surfaces tend to have higher effective values. Most dry materials in combination have friction coefficient values between 0.3 and 0.6. Values outside this range are rarer, but Teflon, for example, can have a coefficient as low as 0.04. A value of zero would mean no friction at all, an elusive property–even Magnetic levitation vehicles have drag. Rubber in contact with other surfaces can yield friction coefficients from 1.0 to 2.
## Static friction
Static friction is the force between two objects that are not moving relative to each other. For example, static friction can prevent an object from sliding down a sloped surface. The coefficient of static friction, typically denoted as μs, is usually higher than the coefficient of kinetic friction. The initial force to get an object moving is often dominated by static friction.
Another important example of static friction is the force that prevents a car wheel from slipping as it rolls on the ground. Even though the wheel is in motion, the patch of the tire in contact with the ground is stationary relative to the ground, so it is static rather than kinetic friction.
The maximum value of static friction, when motion is impending, is sometimes referred to as limiting friction,[3]
although this term is not used universally.[4]
The value is given by the product of the normal force and coefficient of static friction.
## Kinetic friction
Kinetic (or dynamic) friction occurs when two objects are moving relative to each other and rub together (like a sled on the ground). The coefficient of kinetic friction is typically denoted as μk, and is usually less than the coefficient of static friction.
Since friction is exerted in a direction that opposes movement, kinetic friction usually does negative work, typically slowing something down. There are exceptions, for instance if the surface itself is under acceleration. One can see this by placing a heavy box on a rug, then pulling on the rug quickly. In this case, the box slides backwards relative to the rug, but moves forward relative to the floor. Thus, the kinetic friction between the box and rug accelerates the box in the same direction that the box moves, doing positive work.
Examples of kinetic friction:
- Sliding friction (also called dry friction) is when two objects are rubbing against each other. Putting a book flat on a desk and moving it around is an example of sliding friction
- Fluid friction is the friction between a solid object as it moves through a liquid or a gas. The drag of air on an airplane or of water on a swimmer are two examples of fluid friction.
# Other types of friction
## Rolling resistance
Rolling resistance is the force that resists the rolling of a wheel or other circular objects along a surface. Generally the force of rolling resistance is less than that associated with kinetic friction.[5] Typical values for the coefficient of rolling resistance are 0.001.[6]
One of the most common examples of rolling resistance is the movement of motor vehicle tires on a road, a process which generates heat and sound as by-products.[7]
## Triboelectric effect
Rubbing dissimilar materials against one another can cause a build-up of electrostatic charge, which can be hazardous if flammable gases or vapours are present. When the static build-up discharges, explosions can be caused by ignition of the flammable mixture.
# Reducing friction
## Devices
Devices such as tires, ball bearings, air cushion or roller bearing can change sliding friction into a much smaller type of rolling friction. Many thermoplastic materials such as nylon, HDPE and PTFE are commonly used for low friction bearings. They are especially useful because the coefficient of friction falls with increasing imposed load.
## Techniques
One technique used by railroad engineers is to back up the train to create slack in the linkages between cars. This allows the train engine to pull forward and only take on the static friction of one car at a time, instead of all cars at once, thus spreading the static frictional force out over time.
## Lubricants
A common way to reduce friction is by using a lubricant, such as oil, water, or grease, which is placed between the two surfaces, often dramatically lessening the coefficient of friction. The science of friction and lubrication is called tribology. Lubricant technology is when lubricants are mixed with the application of science, especially to industrial or commercial objectives.
Superlubricity, a recently-discovered effect, has been observed in graphite: it is the substantial decrease of friction between two sliding objects, approaching zero levels. A very small amount of frictional energy would still be dissipated.
Lubricants to overcome friction need not always be thin, turbulent fluids or powdery solids such as graphite and talc; acoustic lubrication actually uses sound as a lubricant.
# Energy of friction
According to the law of conservation of energy, no energy is destroyed due to friction, though it may be lost to the system of concern. Energy is transformed from other forms into heat. A sliding hockey puck comes to rest because friction converts its kinetic energy into heat. Since heat quickly dissipates, many early philosophers, including Aristotle, wrongly concluded that moving objects lose energy without a driving force.
When an object is pushed along a surface, the energy converted to heat is given by:
where
Physical deformation is associated with friction. While this can be beneficial, as in polishing, it is often a problem, as the materials are worn away, and may no longer hold the specified tolerances.
The work done by friction can translate into deformation, wear, and heat that can affect the contact surface's material properties (and even the coefficient of friction itself). The work done by friction can also be used to mix materials such as in the technique of friction welding. | https://www.wikidoc.org/index.php/Friction | |
bec5404a06f6f96da5a00617d3863277b0895072 | wikidoc | Frizzled | Frizzled
# Overview
Frizzled is a family of G protein-coupled receptor proteins that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol. Frizzled proteins and the genes that encode them have been identified in an array of animals, from sponges to humans. Frizzled proteins also play key roles in governing cell polarity, embryonic development, formation of neural synapses, cell proliferation, and many other processes in developing and adult organisms. Mutations in the human frizzled-4 receptor have been linked to familial exudative vitreoretinopathy, a rare disease affecting the retina at the back of the eye, and the vitreous, the clear fluid inside the eye.
The frizzled (fz) locus of Drosophila coordinates the cytoskeletons of epidermal cells, producing a parallel array of cuticular hairs and bristles. In fz mutants, the orientation of individual hairs with respect both to their neighbours and to the organism as a whole is altered. In the wild-type wing, all hairs point towards the distal tip.
In the developing wing, Fz has 2 functions: it is required for the proximal-distal transmission of an intracellular polarity signal; and it is required for cells to respond to the polarity signal. Fz produces an mRNA that encodes an integral membrane protein with 7 putative transmembrane (TM) domains. This protein should contain both extracellular and cytoplasmic domains, which could function in the transmission and interpretation of polarity information. This signature is usually found downstream of the Fz domain (InterPro: IPR000024)
# Group members
The following is a list of the ten known human frizzled receptors:
- FZD1 (FZD1)
- FZD2 (FZD2)
- FZD3 (FZD3)
- FZD4 (FZD4)
- FZD5 (FZD5)
- FZD6 (FZD6)
- FZD7 (FZD7)
- FZD8 (FZD8)
- FZD9 (FZD9)
- FZD10 (FZD10) | Frizzled
# Overview
Frizzled is a family of G protein-coupled receptor proteins[1] that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol. Frizzled proteins and the genes that encode them have been identified in an array of animals, from sponges to humans. Frizzled proteins also play key roles in governing cell polarity, embryonic development, formation of neural synapses, cell proliferation, and many other processes in developing and adult organisms.[2] Mutations in the human frizzled-4 receptor have been linked to familial exudative vitreoretinopathy, a rare disease affecting the retina at the back of the eye, and the vitreous, the clear fluid inside the eye.
The frizzled (fz) locus of Drosophila coordinates the cytoskeletons of epidermal cells, producing a parallel array of cuticular hairs and bristles[3][4]. In fz mutants, the orientation of individual hairs with respect both to their neighbours and to the organism as a whole is altered. In the wild-type wing, all hairs point towards the distal tip[4].
In the developing wing, Fz has 2 functions: it is required for the proximal-distal transmission of an intracellular polarity signal; and it is required for cells to respond to the polarity signal. Fz produces an mRNA that encodes an integral membrane protein with 7 putative transmembrane (TM) domains. This protein should contain both extracellular and cytoplasmic domains, which could function in the transmission and interpretation of polarity information[4]. This signature is usually found downstream of the Fz domain (InterPro: IPR000024)
# Group members
The following is a list of the ten known human frizzled receptors:
- FZD1 (FZD1)
- FZD2 (FZD2)
- FZD3 (FZD3)
- FZD4 (FZD4)
- FZD5 (FZD5)
- FZD6 (FZD6)
- FZD7 (FZD7)
- FZD8 (FZD8)
- FZD9 (FZD9)
- FZD10 (FZD10) | https://www.wikidoc.org/index.php/Frizzled | |
da29b45f1aa3b8332aad5c2b986c01a352d6e69a | wikidoc | Fucoidan | Fucoidan
Fucoidan is a sulfated polysaccharide (MW: average 20,000) found mainly in various species of brown seaweed such as kombu, limu moui, bladderwrack, wakame, mozuku, and hijiki (variant forms of fucoidan have also been found in animal species, including the sea cucumber).
Substantial pharmaceutical research has been done on fucoidan, focusing primarily on two distinct forms: F-fucoidan, which is >95% composed of sulfated esters of fucose, and U-fucoidan, which is approximately 20% glucuronic acid. As a consequence of this research, U-fucoidan and F-fucoidan are now being marketed as a nutraceutical, a supposed "miracle drug", and a food supplement.
Researchers began studying fucoidan around 1970, and since that time fucoidan has been cited in approximately 700 studies published in the National Library of Medicine's database. The overall findings of this large body of research, coupled with anecdotal evidence provided by a long history of use of fucoidan-bearing seaweed in areas such as Japan, Hawaii and Tonga, indicate that fucoidan demonstrates great potential as a safe nutritional answer for a wide variety of health complaints.
A study released in 2005 by Japanese researchers have indicated that F-fucoidan can induce apoptosis in human lymphoma cell lines; as well, French researchers showed in 2002 that F-fucoidan can inhibit hyperplasia in rabbits. | Fucoidan
Fucoidan is a sulfated polysaccharide (MW: average 20,000) found mainly in various species of brown seaweed such as kombu, limu moui, bladderwrack, wakame, mozuku, and hijiki (variant forms of fucoidan have also been found in animal species, including the sea cucumber).
Substantial pharmaceutical research has been done on fucoidan, focusing primarily on two distinct forms: F-fucoidan, which is >95% composed of sulfated esters of fucose, and U-fucoidan, which is approximately 20% glucuronic acid. As a consequence of this research, U-fucoidan and F-fucoidan are now being marketed as a nutraceutical, a supposed "miracle drug", and a food supplement.[1]
Researchers began studying fucoidan around 1970, and since that time fucoidan has been cited in approximately 700 studies published in the National Library of Medicine's database. The overall findings of this large body of research, coupled with anecdotal evidence provided by a long history of use of fucoidan-bearing seaweed in areas such as Japan, Hawaii and Tonga, indicate that fucoidan demonstrates great potential as a safe nutritional answer for a wide variety of health complaints.[citation needed]
A study [2] released in 2005 by Japanese researchers have indicated that F-fucoidan can induce apoptosis in human lymphoma cell lines; as well, French researchers showed in 2002 [3] that F-fucoidan can inhibit hyperplasia in rabbits. | https://www.wikidoc.org/index.php/Fucoidan | |
1d8f31e2d8ee90ff63bf554e59b2065f89881611 | wikidoc | Fumarase | Fumarase
Fumarase (or fumarate hydratase) is an enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial isoenzyme is involved in the Krebs Cycle (also known as the Tricarboxylic Acid Cycle or the Citric Acid Cycle), and the cytosolic isoenzyme is involved in the metabolism of amino acids and fumarate. Subcellular localization is established by the presence of a signal sequence on the amino terminus in the mitochondrial form, while subcellular localization in the cytosolic form is established by the absence of the signal sequence found in the mitochondrial variety.
This enzyme participates in 2 metabolic pathways: citric acid cycle, reductive citric acid cycle (CO2 fixation), and is also important in renal cell carcinoma. Mutations in this gene have been associated with the development of leiomyomas in the skin and uterus in combination with renal cell carcinoma.
# Nomenclature
This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. The systematic name of this enzyme class is (S)-malate hydro-lyase (fumarate-forming). Other names in common use include:
- fumarase
- L-malate hydro-lyase
- (S)-malate hydro-lyase
# Structure
## Gene
The FH gene is localized to the chromosomal position 1q42.3-q43. The FH gene contains 10 exons.
## Protein
Crystal structures of fumarase C from Escherichia coli have been observed to have two occupied dicarboxylate binding sites. These are known as the active site and the B site. The active site and B site are both identified as having areas unoccupied by a bound ligand. This so-called ‘free’ crystal structure demonstrates conservation of the active-site water. Similar orientation has been discovered in other fumarase C crystal structures. Crystallographic research on the B site of the enzyme has observed that there is a shift on His129. This information suggests that water is a permanent component of the active site. It also suggests that the use of an imidazole-imidazolium conversion controls access to the allosteric B site.
# Function
## Mechanism
Figure 2 depicts the fumarase reaction mechanism. Two acid-base groups catalyze proton transfer, and the ionization state of these groups is in part defined by two forms of the enzyme E1 and E2. In E1, the groups exist in an internally neutralized A-H/B: state, while in E2, they occur in a zwitterionic A-/BH+ state. E1 binds fumarate and facilitates its transformation into malate, and E2 binds malate and facilitates its transformation into fumarate. The two forms must undergo isomerization with each catalytic turnover.
Despite its biological significance, the reaction mechanism of fumarase is not completely understood. The reaction itself can be monitored in either direction; however, it is the formation of fumarate from S-malate in particular that is less understood due to the high pKa value of the HR (Fig. 1) atom that is removed without the aid of any cofactors or coenzymes. However, the reaction from fumarate to L-malate is better understood, and involves a stereospecific hydration of fumarate to produce S-malate by trans-addition of a hydroxyl group and a hydrogen atom through a trans 1,4 addition of a hydroxyl group. Early research into this reaction suggested that the formation of fumarate from S-malate involved dehydration of malate to a carbocationic intermediate, which then loses the alpha proton to form fumarate. This led to the conclusion that in the formation of S-Malate from fumarate E1 elimination, protonation of fumarate to the carbocation was followed by the additional of a hydroxyl group from H2O. However, more recent trials have provided evidence that the mechanism actually takes place through an acid-base catalyzed elimination by means of a carbanionic intermediate E1CB elimination (Figure 2).
## Biochemical pathway
The function of fumarase in the citric acid cycle is to facilitate a transition step in the production of energy in the form of NADH. In the cytosol the enzyme functions to metabolize fumarate, which is a byproduct of the urea cycle as well as amino acid catabolism. Studies have revealed that the active site is composed of amino acid residues from three of the four subunits within the tetrameric enzyme.
The primary binding site on fumarase is known as catalytic site A. Studies have revealed that catalytic site A is composed of amino acid residues from three of the four subunits within the tetrameric enzyme. Two potential acid-base catalytic residues in the reaction include His 188 and Lys 324.
## Subtypes
There are two classes of fumarases. Classifications depend on the arrangement of their relative subunit, their metal requirement, and their thermal stability. These include class I and class II. Class I fumarases are able to change state or become inactive when subjected to heat or radiation, are sensitive to superoxide anion, are Iron II (Fe2+) dependent, and are dimeric proteins consisting of around 120 kD. Class II fumarases, found in prokaryotes as well as in eukaryotes, are tetrameric enzymes of 200,000 D that contain three distinct segments of significantly homologous amino acids. They are also iron-independent and thermal-stable. Prokaryotes are known to have three different forms of fumarase: Fumarase A, Fumarase B, and Fumarase C. Fumarase C is a part of the class II fumarases, whereas Fumarase A and Fumarase B from Escherichia coli (E. coli) are classified as class I.
# Clinical significance
Fumarase deficiency is characterized by polyhydramnios and fetal brain abnormalities. In the newborn period, findings include severe neurologic abnormalities, poor feeding, failure to thrive, and hypotonia. Fumarase deficiency is suspected in infants with multiple severe neurologic abnormalities in the absence of an acute metabolic crisis. Inactivity of both cytosolic and mitochondrial forms of fumarase are potential causes. Isolated, increased concentration of fumaric acid on urine organic acid analysis is highly suggestive of fumarase deficiency. Molecular genetic testing for fumarase deficiency is currently available.
Fumarase is prevalent in both fetal and adult tissues. A large percentage of the enzyme is expressed in the skin, parathyroid, lymph, and colon. Mutations in the production and development of fumarase have led to the discovery of several fumarase-related diseases in humans. These include benign mesenchymal tumors of the uterus, leiomyomatosis and renal cell carcinoma, and fumarase deficiency. Germinal mutations in fumarase are associated with two distinct conditions. If the enzyme has missense mutation and in-frame deletions from the 3’ end, fumarase deficiency results. If it contains heterozygous 5’ missense mutation and deletions (ranging from one base pair to the whole gene), then leiomyomatosis and renal cell carcinoma/Reed’s syndrome (multiple cutaneous and uterine leiomyomatosis) could result.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..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} | Fumarase
Fumarase (or fumarate hydratase) is an enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate. Fumarase comes in two forms: mitochondrial and cytosolic. The mitochondrial isoenzyme is involved in the Krebs Cycle (also known as the Tricarboxylic Acid Cycle [TCA] or the Citric Acid Cycle), and the cytosolic isoenzyme is involved in the metabolism of amino acids and fumarate. Subcellular localization is established by the presence of a signal sequence on the amino terminus in the mitochondrial form, while subcellular localization in the cytosolic form is established by the absence of the signal sequence found in the mitochondrial variety.[1]
This enzyme participates in 2 metabolic pathways: citric acid cycle, reductive citric acid cycle (CO2 fixation), and is also important in renal cell carcinoma. Mutations in this gene have been associated with the development of leiomyomas in the skin and uterus in combination with renal cell carcinoma.
# Nomenclature
This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. The systematic name of this enzyme class is (S)-malate hydro-lyase (fumarate-forming). Other names in common use include:
- fumarase
- L-malate hydro-lyase
- (S)-malate hydro-lyase
# Structure
## Gene
The FH gene is localized to the chromosomal position 1q42.3-q43. The FH gene contains 10 exons.
## Protein
Crystal structures of fumarase C from Escherichia coli have been observed to have two occupied dicarboxylate binding sites. These are known as the active site and the B site. The active site and B site are both identified as having areas unoccupied by a bound ligand. This so-called ‘free’ crystal structure demonstrates conservation of the active-site water. Similar orientation has been discovered in other fumarase C crystal structures. Crystallographic research on the B site of the enzyme has observed that there is a shift on His129. This information suggests that water is a permanent component of the active site. It also suggests that the use of an imidazole-imidazolium conversion controls access to the allosteric B site.[2]
# Function
## Mechanism
Figure 2 depicts the fumarase reaction mechanism. Two acid-base groups catalyze proton transfer, and the ionization state of these groups is in part defined by two forms of the enzyme E1 and E2. In E1, the groups exist in an internally neutralized A-H/B: state, while in E2, they occur in a zwitterionic A-/BH+ state. E1 binds fumarate and facilitates its transformation into malate, and E2 binds malate and facilitates its transformation into fumarate. The two forms must undergo isomerization with each catalytic turnover.[3]
Despite its biological significance, the reaction mechanism of fumarase is not completely understood. The reaction itself can be monitored in either direction; however, it is the formation of fumarate from S-malate in particular that is less understood due to the high pKa value of the HR (Fig. 1) atom that is removed without the aid of any cofactors or coenzymes. However, the reaction from fumarate to L-malate is better understood, and involves a stereospecific hydration of fumarate to produce S-malate by trans-addition of a hydroxyl group and a hydrogen atom through a trans 1,4 addition of a hydroxyl group. Early research into this reaction suggested that the formation of fumarate from S-malate involved dehydration of malate to a carbocationic intermediate, which then loses the alpha proton to form fumarate. This led to the conclusion that in the formation of S-Malate from fumarate E1 elimination, protonation of fumarate to the carbocation was followed by the additional of a hydroxyl group from H2O. However, more recent trials have provided evidence that the mechanism actually takes place through an acid-base catalyzed elimination by means of a carbanionic intermediate E1CB elimination (Figure 2).[3][4][5]
## Biochemical pathway
The function of fumarase in the citric acid cycle is to facilitate a transition step in the production of energy in the form of NADH.[6] In the cytosol the enzyme functions to metabolize fumarate, which is a byproduct of the urea cycle as well as amino acid catabolism. Studies have revealed that the active site is composed of amino acid residues from three of the four subunits within the tetrameric enzyme.[7]
The primary binding site on fumarase is known as catalytic site A. Studies have revealed that catalytic site A is composed of amino acid residues from three of the four subunits within the tetrameric enzyme. Two potential acid-base catalytic residues in the reaction include His 188 and Lys 324.[3][4][5]
## Subtypes
There are two classes of fumarases.[8] Classifications depend on the arrangement of their relative subunit, their metal requirement, and their thermal stability. These include class I and class II. Class I fumarases are able to change state or become inactive when subjected to heat or radiation, are sensitive to superoxide anion, are Iron II (Fe2+) dependent, and are dimeric proteins consisting of around 120 kD. Class II fumarases, found in prokaryotes as well as in eukaryotes, are tetrameric enzymes of 200,000 D that contain three distinct segments of significantly homologous amino acids. They are also iron-independent and thermal-stable. Prokaryotes are known to have three different forms of fumarase: Fumarase A, Fumarase B, and Fumarase C. Fumarase C is a part of the class II fumarases, whereas Fumarase A and Fumarase B from Escherichia coli (E. coli) are classified as class I.[7]
# Clinical significance
Fumarase deficiency is characterized by polyhydramnios and fetal brain abnormalities. In the newborn period, findings include severe neurologic abnormalities, poor feeding, failure to thrive, and hypotonia. Fumarase deficiency is suspected in infants with multiple severe neurologic abnormalities in the absence of an acute metabolic crisis. Inactivity of both cytosolic and mitochondrial forms of fumarase are potential causes. Isolated, increased concentration of fumaric acid on urine organic acid analysis is highly suggestive of fumarase deficiency. Molecular genetic testing for fumarase deficiency is currently available.[8]
Fumarase is prevalent in both fetal and adult tissues. A large percentage of the enzyme is expressed in the skin, parathyroid, lymph, and colon. Mutations in the production and development of fumarase have led to the discovery of several fumarase-related diseases in humans. These include benign mesenchymal tumors of the uterus, leiomyomatosis and renal cell carcinoma, and fumarase deficiency. Germinal mutations in fumarase are associated with two distinct conditions. If the enzyme has missense mutation and in-frame deletions from the 3’ end, fumarase deficiency results. If it contains heterozygous 5’ missense mutation and deletions (ranging from one base pair to the whole gene), then leiomyomatosis and renal cell carcinoma/Reed’s syndrome (multiple cutaneous and uterine leiomyomatosis) could result.[7][8]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "TCACycle_WP78"..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/Fumarase | |
d4933c480abd40709410ea818cca4c0f180548db | wikidoc | Fusarium | Fusarium
Fusarium is a large genus of filamentous fungi widely distributed in soil and in association with plants. Most species are harmless saprobes and are relatively abundant members of the soil microbial community. Some species produce mycotoxins in cereal crops that can affect human and animal health if they enter the food chain. The main toxins produced by these Fusarium species are fumonisins and trichothecenes.
# Pathogens
The genus includes a number of economically important plant pathogenic species. The genome of the wheat and maize pathogen, Fusarium graminearum, has been sequenced. In addition, some species may cause a range of opportunistic infections in humans. In humans with normal immune systems, fusarial infections may occur in the nails (onychomycosis) and in the cornea (keratomycosis or mycotic keratitis). In humans whose immune systems are weakened in a particular way (neutropenia, i.e., very low count of the white blood cell type called neutrophils), aggressive fusarial infections penetrating the entire body and bloodstream (disseminated infections) may be caused by members of the Fusarium solani complex, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum and rarely other fusarial species. The neutropenia in such cases is almost always the result of chemotherapy against certain kinds of leukemia or else heavy use of immunosuppressive drugs in problematic cases of major organ transplant surgery.
# Crop Damage
## Barley
Fusarium graminearum commonly infects barley if there is rain late in the season. It is of economic impact to the Malting and Brewing industries as well as feed barley. Fusarium contamination in barley can result in head blight and in extreme contaminations the barley can appear pink.
Fusarium graminearum can also cause root rot and seedling blight. The total losses in the US of barley and wheat crops between 1991 and 1996 have been estimated at $3 billion.
# Use as human food
Fusarium venenatum is produced industrially for use as a human food by Marlow Foods, Ltd., and is marketed under the name Quorn in Europe and North America.
# Biological warfare
Mass casualties occurred in the Soviet Union in the 1930s and 1940s when Fusarium-contaminated wheat flour was baked into bread, causing alimentary toxic aleukia with a 60% mortality rate. Symptoms began with abdominal pain, diarrhea, vomiting, and prostration. Within days fever, chills, myalgias and bone marrow depression with granulocytopenia and secondary sepsis. Further symptoms included pharyngeal or laryngeal ulceration and diffuse bleeding into the skin (petechiae and ecchymoses), melena, bloody diarrhea, hematuria, hematemesis, epistaxis, vaginal bleeding, Pancytopenia and gastrointestinal ulceration. Fusarium sporotrichoides contamination was found in affected grain in 1932, spurring research for medical purposes and for use in biological warfare. The active ingredient was found to be trichothecene T-2 mycotoxin, and was produced in quantity and weaponized prior to the passage of the Biological Weapons Convention in 1972. The Soviets were accused of using the agent, dubbed "yellow rain", to cause 6,300 deaths in Laos, Kampuchea, and Afghanistan between 1975 and 1981.
Following an outbreak of Fusarium oxysporum that affected coca plantations in Peru, and other crops planted in the area, the United States has proposed the use of the agent as a mycoherbicide in drug eradication. In 2000, a proposal was passed to use the agent as part of Plan Colombia. In response to concerns that use of the fungus could be perceived as biological warfare, the Clinton Administration "waived" this use of Fusarium. A subsequent law passed in 2006 has mandated the testing of mycoherbicide agents - either Fusarium oxysporum or Pleospora papaveracea - in field trials in U.S. territory. Use of Fusarium oxysporum for these tests has raised concerns because resistant coca from the previous outbreak has been widely cultivated, and the fungus has been implicated in the birth of 31 anencephalic children in the Rio Grande region of Texas in 1991, the loss of palm trees in Los Angeles, and eye infections from contact lens solutions. The alternative Pleospora papaveracea is less well-known; despite decades of study in the Soviet biowarfare lab in Tashkent, Uzbekistan, the relevant mycotoxins reportedly have not yet been isolated, named, or studied. | Fusarium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Fusarium is a large genus of filamentous fungi widely distributed in soil and in association with plants. Most species are harmless saprobes and are relatively abundant members of the soil microbial community. Some species produce mycotoxins in cereal crops that can affect human and animal health if they enter the food chain. The main toxins produced by these Fusarium species are fumonisins and trichothecenes.
# Pathogens
The genus includes a number of economically important plant pathogenic species. The genome of the wheat and maize pathogen, Fusarium graminearum, has been sequenced. In addition, some species may cause a range of opportunistic infections in humans. In humans with normal immune systems, fusarial infections may occur in the nails (onychomycosis) and in the cornea (keratomycosis or mycotic keratitis).[1] In humans whose immune systems are weakened in a particular way (neutropenia, i.e., very low count of the white blood cell type called neutrophils), aggressive fusarial infections penetrating the entire body and bloodstream (disseminated infections) may be caused by members of the Fusarium solani complex, Fusarium oxysporum, Fusarium verticillioides, Fusarium proliferatum and rarely other fusarial species.[2] The neutropenia in such cases is almost always the result of chemotherapy against certain kinds of leukemia or else heavy use of immunosuppressive drugs in problematic cases of major organ transplant surgery.
# Crop Damage
## Barley
Fusarium graminearum commonly infects barley if there is rain late in the season. It is of economic impact to the Malting and Brewing industries as well as feed barley. Fusarium contamination in barley can result in head blight and in extreme contaminations the barley can appear pink. [3]
Fusarium graminearum can also cause root rot and seedling blight. The total losses in the US of barley and wheat crops between 1991 and 1996 have been estimated at $3 billion. [3]
# Use as human food
Fusarium venenatum is produced industrially for use as a human food by Marlow Foods, Ltd., and is marketed under the name Quorn in Europe and North America.
# Biological warfare
Mass casualties occurred in the Soviet Union in the 1930s and 1940s when Fusarium-contaminated wheat flour was baked into bread, causing alimentary toxic aleukia with a 60% mortality rate. Symptoms began with abdominal pain, diarrhea, vomiting, and prostration. Within days fever, chills, myalgias and bone marrow depression with granulocytopenia and secondary sepsis. Further symptoms included pharyngeal or laryngeal ulceration and diffuse bleeding into the skin (petechiae and ecchymoses), melena, bloody diarrhea, hematuria, hematemesis, epistaxis, vaginal bleeding, Pancytopenia and gastrointestinal ulceration. Fusarium sporotrichoides contamination was found in affected grain in 1932, spurring research for medical purposes and for use in biological warfare. The active ingredient was found to be trichothecene T-2 mycotoxin, and was produced in quantity and weaponized prior to the passage of the Biological Weapons Convention in 1972. The Soviets were accused of using the agent, dubbed "yellow rain", to cause 6,300 deaths in Laos, Kampuchea, and Afghanistan between 1975 and 1981.[3][4]
Following an outbreak of Fusarium oxysporum that affected coca plantations in Peru, and other crops planted in the area, the United States has proposed the use of the agent as a mycoherbicide in drug eradication. In 2000, a proposal was passed to use the agent as part of Plan Colombia. In response to concerns that use of the fungus could be perceived as biological warfare, the Clinton Administration "waived" this use of Fusarium. A subsequent law passed in 2006 has mandated the testing of mycoherbicide agents - either Fusarium oxysporum or Pleospora papaveracea - in field trials in U.S. territory.[5] Use of Fusarium oxysporum for these tests has raised concerns because resistant coca from the previous outbreak has been widely cultivated, and the fungus has been implicated in the birth of 31 anencephalic children in the Rio Grande region of Texas in 1991, the loss of palm trees in Los Angeles, and eye infections from contact lens solutions. The alternative Pleospora papaveracea is less well-known; despite decades of study in the Soviet biowarfare lab in Tashkent, Uzbekistan, the relevant mycotoxins reportedly have not yet been isolated, named, or studied.[5] | https://www.wikidoc.org/index.php/Fusarium | |
36687038bdbb05c618dc9cc73fa69391cc9acbc0 | wikidoc | Oncogene | Oncogene
# Overview
An oncogene is a modified gene, or a set of nucleotides that codes for a protein and is believed to cause cancer. Genetic mutations resulting in the activation of oncogenes increase the chance that a normal cell will develop into a tumor cell. Since the 1970s, dozens of oncogenes have been identified in human cancer. Oncogenes are figuratively thought to be in a perpetual tug-of-war with tumor suppressor genes which act to prevent DNA damage and keep the cell's activities under control. There is much evidence to support the notion that loss of tumor suppressors or gain of oncogenes can lead to cancer.
# History
The first oncogene was discovered in 1970 and was termed src (pronounced SARK). Src was in fact first discovered as an oncogene in a chicken retrovirus. Experiments performed by Dr G. Steve Martin of the University of California, Berkeley demonstrated that the SRC was indeed the oncogene of the virus.
In 1976 Drs. J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were defective proto-oncogenes, found in many organisms including humans. For this discovery Bishop and Varmus were awarded the Nobel Prize in 1989.
# Proto-oncogene
proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (or its product) becomes a tumor inducing agent, an oncogene. Examples of proto-oncogenes include RAS, WNT, MYC, ERK and TRK.
## Activation
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic activation types:
- A mutation within a proto-oncogene can cause a change in the protein structure, causing
an increase in protein (enzyme) activity
a loss of regulation
- an increase in protein (enzyme) activity
- a loss of regulation
- An increase in protein concentration, caused by
an increase of protein expression (through misregulation)
an increase of protein stability, prolonging its existence and thus its activity in the cell
a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
- an increase of protein expression (through misregulation)
- an increase of protein stability, prolonging its existence and thus its activity in the cell
- a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
- A chromosomal translocation (another type of chromosome abnormality), causing
an increased gene expression in the wrong cell type or at wrong times
the expression of a constitutively active hybrid protein. This type of aberration in a dividing stem cell in the bone marrow leads to adult leukemia
- an increased gene expression in the wrong cell type or at wrong times
- the expression of a constitutively active hybrid protein. This type of aberration in a dividing stem cell in the bone marrow leads to adult leukemia
Mutations in microRNAs can lead to activation of oncogenes. New research indicates that small RNAs 21-25 nucleotides in length called microRNAs (miRNAs) can control expression of these genes by downregulating them.
# Oncogene
There are several systems for classifying oncogenes, but there is not yet a widely accepted standard. They are sometimes grouped both spatially (moving from outside the cell inwards) and chronologically (parallelling the "normal" process of signal transduction). There are several categories that are commonly used: | Oncogene
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An oncogene is a modified gene, or a set of nucleotides that codes for a protein and is believed to cause cancer. Genetic mutations resulting in the activation of oncogenes increase the chance that a normal cell will develop into a tumor cell. Since the 1970s, dozens of oncogenes have been identified in human cancer. Oncogenes are figuratively thought to be in a perpetual tug-of-war with tumor suppressor genes which act to prevent DNA damage and keep the cell's activities under control. There is much evidence to support the notion that loss of tumor suppressors or gain of oncogenes can lead to cancer.[1]
# History
The first oncogene was discovered in 1970 and was termed src (pronounced SARK). Src was in fact first discovered as an oncogene in a chicken retrovirus. Experiments performed by Dr G. Steve Martin of the University of California, Berkeley demonstrated that the SRC was indeed the oncogene of the virus.
In 1976 Drs. J. Michael Bishop and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were defective proto-oncogenes, found in many organisms including humans. For this discovery Bishop and Varmus were awarded the Nobel Prize in 1989.
# Proto-oncogene
proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression. Proto-oncogenes code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often involved in signal transduction and execution of mitogenic signals, usually through their protein products. Upon activation, a proto-oncogene (or its product) becomes a tumor inducing agent, an oncogene.[2] Examples of proto-oncogenes include RAS, WNT, MYC, ERK and TRK.
## Activation
The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic activation types:
- A mutation within a proto-oncogene can cause a change in the protein structure, causing
an increase in protein (enzyme) activity
a loss of regulation
- an increase in protein (enzyme) activity
- a loss of regulation
- An increase in protein concentration, caused by
an increase of protein expression (through misregulation)
an increase of protein stability, prolonging its existence and thus its activity in the cell
a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
- an increase of protein expression (through misregulation)
- an increase of protein stability, prolonging its existence and thus its activity in the cell
- a gene duplication (one type of chromosome abnormality), resulting in an increased amount of protein in the cell
- A chromosomal translocation (another type of chromosome abnormality), causing
an increased gene expression in the wrong cell type or at wrong times
the expression of a constitutively active hybrid protein. This type of aberration in a dividing stem cell in the bone marrow leads to adult leukemia
- an increased gene expression in the wrong cell type or at wrong times
- the expression of a constitutively active hybrid protein. This type of aberration in a dividing stem cell in the bone marrow leads to adult leukemia
Mutations in microRNAs can lead to activation of oncogenes.[3] New research indicates that small RNAs 21-25 nucleotides in length called microRNAs (miRNAs) can control expression of these genes by downregulating them.[4]
# Oncogene
There are several systems for classifying oncogenes,[5][6] but there is not yet a widely accepted standard. They are sometimes grouped both spatially (moving from outside the cell inwards) and chronologically (parallelling the "normal" process of signal transduction). There are several categories that are commonly used: | https://www.wikidoc.org/index.php/Fusion_oncogene_protein | |
335f74446ed972e4746a81e8d776819f96277e20 | wikidoc | GPATCH11 | GPATCH11
GPATCH11 is a protein that in humans is encoded by the G-patch domain containing protein 11 gene. The gene has four transcript variants encoding two functional protein isoforms and is expressed in most human tissues. The protein has been found to interact with several other proteins, including two from a splicing pathway. In addition, GPATCH11 has orthologs in all taxa of the eukarya domain.
# Gene
G-patch domain containing protein 11 is a protein that in humans is encoded by the gene GPATCH11 and located on chromosome 2, location 2p22.2. It also contains several aliases including CCDC75, and CENPY. The gene is 14,484 bp long and contains 9 exons. Though the function of the protein is not yet known, it is predicted to serve in nucleic acid binding and protein binding.
# mRNA
GPATCH11 has four predicted transcript variants, though only two are known to code for functional protein. Its longest form is unspliced and contains 9 exons whereas the second functional variant has 7 exons with exons 3 and 4 cut out.
# Protein
GPATCH11 has a molecular weight of about 33.3 kdal and is 285 amino acids long. It also comes in a second isoform that is 156 amino acids long. The gene contains a G-patch domain and the DUF 4138 domain. The G-patch domain itself is a novel domain found only in eukarya. BLAST searches of the human gene against bacteria, archaea, and viruses, support this finding.
## Primary structure
The following is the primary sequence of the long form of GPATCH11:
The protein is rich in glutamic acid and is very highly charged. In addition, it is low in amino acids such as valine, threonine, phenylalanine, and proline. It is a soluble protein and has a nuclear export signal and bipartite nuclear import signal implying that it is localized in the nucleus.
## Secondary structure
The conserved areas of the protein have a secondary structure composed only of alpha-helices and coiled-coil regions.
## Tertiary structure
The image to the right is the predicted tertiary structure of GPATCH11 based on results obtained from I-tasser. The confidence score was very low though, so reliability is uncertain. However, it does match up with the secondary structure prediction of the protein being composed primarily of alpha-helices and coiled coils.
# Protein expression
Protein expression has been found in the endocrine and nervous system, along with the eye, breast, colon, liver, ovary, and 55 other tissues. Gene expression is found to be about 1.1 times the average. The highest expression is found in the brain and spinal cord, followed by the spleen. There are six areas in the brain where GPATCH11 is expressed above average including the olfactory areas, hippocampus, midbrain, pons, medulla, and cerebellum. In addition, expression levels increase in cancerous tissue compared to normal tissue.
# Predicted Post-Translational Modification
Using various tools at ExPASy the following are possible post-translational modifications for GPATCH11.
- 3 possible CK2 phosphorylation sites
- 6 possible PKC phosphorylation sites
- 2 possible N-mirystoylation sites
- 6 possible glycation sites
# Protein Interaction
The interaction between GPATCH11 and BAI3 was found via PSICQUIC, mentha, and STRING. The confidence score given by mentha is only .454, however, according to STRING the interaction between the two proteins has been experimentally determined by a validated two-hybrid approach. The two proteins are thought to have a direct physical interaction. BAI3 is a transmembrane protein and a p53 target gene. BAI3 may regulate the number of excitatory synapses that are formed on the hippocampus neurons, and may be involved in angiogenesis inhibition and suppression of glioblastoma. As GPATCH11does have higher expression than the average gene in the hippocampus and the spinal cord, this could be a real interaction.
The interaction between GPATCH11 and JUN could be real as JUN is both localized in the nucleus and associated with cancers. GPATCH11 tends to have higher expression in cancerous tissue compared to normal tissue, so interaction with other proteins highly expressed in cancers seems plausible.
Finally, the interactions between GPATCH11 and ZRSR2 and GPATCH11 and U2AF1 appear to be real due to the fact that ZRSR2 and U2AF1 are known to interact with each other, and all three proteins are localized in the nucleus.
# Evolutionary History
The protein is found in all taxa of the domain eukarya, including unicellular organisms. Aligning the human gene with the various taxids revealed high conservation in the G-patch domain area and the DUF 4187 area. Alignments with closely related taxids such as birds and reptiles revealed conservation over the majority of the sequence. However, alignments with more distantly related taxids such as fungi and plants had less conservation with identities of less than 40%, thoug the G-patch domain and the DUF domain still had high conservation. Overall, the protein is composed mainly of charged amino acids, both acidic and basic. There were no regions of sustained non-polarity. This implies that this is not a transmembrane protein as that requires a long region of non-polarity.
When comparing the rate of evolution of GPATCH11 to known proteins such as fibrinogen and cytochrome c, GPATCH11 is evolving quite rapidly, similar to the rate of the fibrinogen protein. An unrooted evolutionary tree can be seen to the right including representatives of species ranging from invertebrates to mammals. This shows the hypothetical relationship of the GPATCH11 sequence among the different taxa, and is supported by divergence time of the taxa from humans as well as sequence identity/similarity.
## Homology
The protein is highly conserved among the domain eukarya. The table below lists a number of species from all different taxids whose GPATCH11 sequence was compared to the human GPATCH11 sequence. Protein sequence lengths, similarities, and identities are represented, including divergence in millions of years.
# Clinical significance
Clinical significance is not yet known, however, GPATCH11 is present in much higher amounts in cancerous tissue than normal tissue, and has shown possible protein interaction with oncogenes, so might somehow be involved in cancer. | GPATCH11
GPATCH11 is a protein that in humans is encoded by the G-patch domain containing protein 11 gene. The gene has four transcript variants encoding two functional protein isoforms and is expressed in most human tissues. The protein has been found to interact with several other proteins, including two from a splicing pathway. In addition, GPATCH11 has orthologs in all taxa of the eukarya domain.
# Gene
G-patch domain containing protein 11 is a protein that in humans is encoded by the gene GPATCH11 and located on chromosome 2, location 2p22.2.[1] It also contains several aliases including CCDC75, and CENPY.[2] The gene is 14,484 bp long and contains 9 exons. Though the function of the protein is not yet known, it is predicted to serve in nucleic acid binding and protein binding.[2][3]
# mRNA
GPATCH11 has four predicted transcript variants, though only two are known to code for functional protein. Its longest form is unspliced and contains 9 exons whereas the second functional variant has 7 exons with exons 3 and 4 cut out.
# Protein
GPATCH11 has a molecular weight of about 33.3 kdal and is 285 amino acids long.[2][5] It also comes in a second isoform that is 156 amino acids long. The gene contains a G-patch domain and the DUF 4138 domain. The G-patch domain itself is a novel domain found only in eukarya. BLAST searches of the human gene against bacteria, archaea, and viruses, support this finding.[2]
## Primary structure
The following is the primary sequence of the long form of GPATCH11:
The protein is rich in glutamic acid and is very highly charged. In addition, it is low in amino acids such as valine, threonine, phenylalanine, and proline. It is a soluble protein and has a nuclear export signal and bipartite nuclear import signal implying that it is localized in the nucleus.
## Secondary structure
The conserved areas of the protein have a secondary structure composed only of alpha-helices and coiled-coil regions.
## Tertiary structure
The image to the right is the predicted tertiary structure of GPATCH11 based on results obtained from I-tasser. The confidence score was very low though, so reliability is uncertain. However, it does match up with the secondary structure prediction of the protein being composed primarily of alpha-helices and coiled coils.
# Protein expression
Protein expression has been found in the endocrine and nervous system, along with the eye, breast, colon, liver, ovary, and 55 other tissues. Gene expression is found to be about 1.1 times the average. The highest expression is found in the brain and spinal cord, followed by the spleen. There are six areas in the brain where GPATCH11 is expressed above average including the olfactory areas, hippocampus, midbrain, pons, medulla, and cerebellum.[6] In addition, expression levels increase in cancerous tissue compared to normal tissue.
# Predicted Post-Translational Modification
Using various tools at ExPASy[7] the following are possible post-translational modifications for GPATCH11.
- 3 possible CK2 phosphorylation sites
- 6 possible PKC phosphorylation sites
- 2 possible N-mirystoylation sites
- 6 possible glycation sites
# Protein Interaction
The interaction between GPATCH11 and BAI3 was found via PSICQUIC,[9] mentha,[9] and STRING.[8] The confidence score given by mentha is only .454, however, according to STRING the interaction between the two proteins has been experimentally determined by a validated two-hybrid approach. The two proteins are thought to have a direct physical interaction. BAI3 is a transmembrane protein and a p53 target gene. BAI3 may regulate the number of excitatory synapses that are formed on the hippocampus neurons, and may be involved in angiogenesis inhibition and suppression of glioblastoma. As GPATCH11does have higher expression than the average gene in the hippocampus and the spinal cord, this could be a real interaction.
The interaction between GPATCH11 and JUN could be real as JUN is both localized in the nucleus and associated with cancers. GPATCH11 tends to have higher expression in cancerous tissue compared to normal tissue, so interaction with other proteins highly expressed in cancers seems plausible.
Finally, the interactions between GPATCH11 and ZRSR2 and GPATCH11 and U2AF1 appear to be real due to the fact that ZRSR2 and U2AF1 are known to interact with each other, and all three proteins are localized in the nucleus.
# Evolutionary History
The protein is found in all taxa of the domain eukarya, including unicellular organisms. Aligning the human gene with the various taxids revealed high conservation in the G-patch domain area and the DUF 4187 area.[2] Alignments with closely related taxids such as birds and reptiles revealed conservation over the majority of the sequence. However, alignments with more distantly related taxids such as fungi and plants had less conservation with identities of less than 40%, thoug the G-patch domain and the DUF domain still had high conservation.[10] Overall, the protein is composed mainly of charged amino acids, both acidic and basic. There were no regions of sustained non-polarity. This implies that this is not a transmembrane protein as that requires a long region of non-polarity.
When comparing the rate of evolution of GPATCH11 to known proteins such as fibrinogen and cytochrome c, GPATCH11 is evolving quite rapidly, similar to the rate of the fibrinogen protein. An unrooted evolutionary tree[10] can be seen to the right including representatives of species ranging from invertebrates to mammals. This shows the hypothetical relationship of the GPATCH11 sequence among the different taxa, and is supported by divergence time of the taxa from humans as well as sequence identity/similarity.
## Homology
The protein is highly conserved among the domain eukarya. The table below lists a number of species from all different taxids whose GPATCH11 sequence was compared to the human GPATCH11 sequence. Protein sequence lengths, similarities, and identities are represented, including divergence in millions of years.
# Clinical significance
Clinical significance is not yet known, however, GPATCH11 is present in much higher amounts in cancerous tissue than normal tissue, and has shown possible protein interaction with oncogenes, so might somehow be involved in cancer. | https://www.wikidoc.org/index.php/GPATCH11 | |
7058abec35766899a5fb2b7bc53d264b0d1d6687 | wikidoc | Galbanum | Galbanum
Galbanum is an aromatic gum resin, the product of certain Persian plant species, chiefly Ferula gummosa, syn. galbaniflua and Ferula rubricaulis. Galbanum-yielding plants grow plentifully on the slopes of the mountain ranges of northern Iran. It occurs usually in hard or soft, irregular, more or less translucent and shining lumps, or occasionally in separate tears, of a light-brown, yellowish or greenish-yellow colour, and has a disagreeable, bitter taste, a peculiar, somewhat musky odour, and a specific gravity of 1.212. It contains about 8% of terpene; about 65% of a resin which contains sulphur; about 20% of gum; and a very small quantity of the colourless crystalline substance umbelliferone.
Galbanum is one of the oldest of drugs. In the Book of Exodus 30:34, it is mentioned as a sweet spice, to be used in the making of a perfume for the tabernacle. However, Rabbi Shelomo ben Yitschak of the 1100s comments on this passage that galabanum is bitter and was included in the incense as a reminder of deliberate and unrepentant sinners.
It is occasionally used in the making of modern perfume, and is the ingredient which gives the distinctively unique smell to the fragrance "Must" by Cartier. Hippocrates employed it in medicine, and Pliny the Elder (Nat. Hist. xxiv. 13) ascribes to it extraordinary curative powers, concluding his account of it with the assertion that "the very touch of it mixed with oil of spondylium is sufficient to kill a serpent." The drug is occasionally given in modern medicine, in doses of from five to fifteen grains. It has the actions common to substances containing a resin and a volatile oil. Its use in medicine is, however, obsolescent.
de:Galbanharz | Galbanum
Galbanum is an aromatic gum resin, the product of certain Persian plant species, chiefly Ferula gummosa, syn. galbaniflua and Ferula rubricaulis. Galbanum-yielding plants grow plentifully on the slopes of the mountain ranges of northern Iran. It occurs usually in hard or soft, irregular, more or less translucent and shining lumps, or occasionally in separate tears, of a light-brown, yellowish or greenish-yellow colour, and has a disagreeable, bitter taste, a peculiar, somewhat musky odour, and a specific gravity of 1.212. It contains about 8% of terpene; about 65% of a resin which contains sulphur; about 20% of gum; and a very small quantity of the colourless crystalline substance umbelliferone.
Galbanum is one of the oldest of drugs. In the Book of Exodus 30:34, it is mentioned as a sweet spice, to be used in the making of a perfume for the tabernacle. However, Rabbi Shelomo ben Yitschak of the 1100s comments on this passage that galabanum is bitter and was included in the incense as a reminder of deliberate and unrepentant sinners.
It is occasionally used in the making of modern perfume, and is the ingredient which gives the distinctively unique smell to the fragrance "Must" by Cartier. Hippocrates employed it in medicine, and Pliny the Elder (Nat. Hist. xxiv. 13) ascribes to it extraordinary curative powers, concluding his account of it with the assertion that "the very touch of it mixed with oil of spondylium is sufficient to kill a serpent." The drug is occasionally given in modern medicine, in doses of from five to fifteen grains. It has the actions common to substances containing a resin and a volatile oil. Its use in medicine is, however, obsolescent.
Template:1911
de:Galbanharz
Template:WikiDoc Sources
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Galbanum | |
e00d50389811537860c3c0f0262739af1539155e | wikidoc | Gambling | Gambling
Gambling has a specific
Edit this pageeconomic definition, referring to wagering money or something of material value on an event with an uncertain outcome with the primary intent of winning additional money and/or material goods. Typically, the outcome of the wager is evident within a short period of time.
The term gaming in this context typically refers to instances in which the activity has been specifically permitted by law. The two words are not mutually exclusive; i.e., a “gaming” company offers (legal) “gambling” activities to the public. (This distinction is not universally observed in the English-speaking world, however. For instance, in the UK, the regulator of gambling activities is called the Gambling Commission (not the Gaming Commission.)
# Legal aspects
Both the Catholic and Jewish traditions traditionally set aside days for gambling, although religious authorities generally disapprove of gambling to some extent. Gambling can have adverse social consequences. For these social and religious reasons, most legal jurisdictions limit gambling. Some Islamic nations prohibit gambling; most other countries regulate it.
Many jurisdictions, local as well as national, either ban or heavily control (by licensing) gambling. Such regulation generally leads to gambling tourism and illegal gambling. The involvement of governments, through regulation and taxation, has led to a close connection between many governments and gaming organizations, where legal gambling provides significant government revenue, such as in Monaco or Macau.
Under US federal law, gambling is legal in the United States, and states are free to regulate or prohibit the practice. Gambling has been legal in Nevada since 1931, forming the backbone of the state's economy, Las Vegas is perhaps the best known gambling destination in the world. In 1976, gambling was legalized in Atlantic City, New Jersey, and in 1990, it was legalized in Tunica, Mississippi; both of those cities have developed extensive casino and resort areas since then. Since a favorable US Supreme Court decision in 1987, many Native American tribes have built their own casinos on tribal lands as a way to provide revenue for the tribe. Because the tribes are considered sovereign nations, they are often exempt from state laws banning gambling, and are instead regulated under federal law. Additionally almost all states have legalized gambling in the form of a lottery.
Because contracts of insurance have many features in common with wagers, insurance contracts are often distinguished under law as agreements in which either party has an interest in the "bet-upon" outcome beyond the specific financial terms. E.g.: a “bet” with an insurer on whether one's house will burn down is not gambling, but rather insurance — as the homeowner has an obvious interest in the continued existence of his/her home independent of the purely financial aspects of the "bet" (i.e., the insurance policy).
There is generally legislation requiring that the odds in gaming devices are statistically random, to prevent manufacturers from making some high-payoff results impossible. Since these high-payoffs have very low probability, a house bias can quite easily be missed unless checking the odds carefully.
# Gambling variables
There are three variables common to all forms of gambling:
- How much is being wagered, the initial stake (in money or material goods).
- The predictability of the event.
In mechanical or electronic gambling such as lotteries, slot machines and bingo, the results are random and unpredictable; no amount of skill or knowledge (assuming machinery is functioning as intended) can give an advantage in predictability to anyone.
However, for sports events such as horse racing and soccer matches there is some predictability to the outcome; thus a person with greater knowledge and/or skill will have an advantage over others.
- In mechanical or electronic gambling such as lotteries, slot machines and bingo, the results are random and unpredictable; no amount of skill or knowledge (assuming machinery is functioning as intended) can give an advantage in predictability to anyone.
- However, for sports events such as horse racing and soccer matches there is some predictability to the outcome; thus a person with greater knowledge and/or skill will have an advantage over others.
- The odds agreed between the two (or more) parties to the wager; where there is a house or a bookmaker, the odds are (quite legally) arranged in favor of the house.
The expected value, positive or negative, is a mathematical calculation using these three variables. The amount wagered determines the scale of an individual wager (bet); the odds and the amount wagered determine the payout if successful; the predictability determines the frequency of success. Finally the frequency of success times the payout minus the amount wagered equals the "expected value"
The skill of a gambler lies in understanding and maneuvering the three variables so that the "actual value" is positive over a series of wagers.
# Types of gambling
## Casino games
While almost any game can be played for money, and any game typically played for money can also be played just for fun, some games are generally offered in a casino setting.
### Table games
- Blackjack
- Pai Gow Poker and Tiles
- Poker
- Spanish 21
- 3-card poker
- Baccarat (punto banco)
- Caribbean Stud Poker
- Casino war
- Craps
- Fan-Tan
- Faro
- Let It Ride
- Pachinko
- Pyramid Poker
- 4-card poker
- Red Dog
- Sic Bo
- Texas Hold'em Bonus Poker
- Roulette
### Electronic gaming
- Slot machine
- Video poker
### Other gambling
- Sports betting
- Arbitrage betting
- Keno
- Bingo
## Non-casino gambling games
Gambling games that take place outside of casinos include Bingo (as played in the US and UK), dead pool, lotteries, pull-tab games and scratchcards, and Mahjong.
Other non-casino gambling games include:
- Card games, such as Liar's poker, Bridge, Basset, Lansquenet, Piquet, Put, Teen patti
- Coin-tossing games such as Head and Tail, Two-up*
- Confidence tricks such as Three-card Monte or the Shell game
- Carnival Games such as The Razzle or Hanky Pank
- Dice-based games, such as Backgammon, Liar's dice, Passe-dix, Hazard, Threes, Pig, or Mexico
*Although coin tossing isn't usually played in a casino, it has been known to be an official gambling game in some Australian casinos
## Fixed-odds gambling
Fixed-odds gambling and Parimutuel betting frequently occur at many types of sporting events. In addition many bookmakers offer fixed odds on a number of non-sports related outcomes, for example the direction and extent of movement of various financial indices, the winner of television competitions such as Big Brother, election results,. Interactive prediction markets also offer trading on these outcomes, with "shares" of results trading on an open market.
### Parimutuel betting
One of the most widespread forms of gambling involves betting on horse or greyhound racing. Wagering may take place through parimutuel pools, or bookmakers may take bets personally. Parimutuel wagers pay off at prices determined by support in the wagering pools, while bookmakers pay off either at the odds offered at the time of accepting the bet; or at the median odds offered by track bookmakers at the time the race started.
### Sports betting
Betting on team sports has become an important service industry in many countries. For example, millions of Britons play the football pools every week.
## Arbitrage betting
Arbitrage betting is a theoretically risk-free betting system in which every outcome of an event is bet upon so that a known profit will be made by the bettor upon completion of the event, regardless of the outcome. Arbitrage betting is a combination of the ancient art of arbitrage trading and gambling, which has been made possible by the large numbers of bookmakers in the marketplace, creating occasional opportunities for arbitrage.
## Other types of betting
One can also bet with another person that a statement is true or false, or that a specified event will happen (a "back bet") or will not happen (a "lay bet") within a specified time. This occurs in particular when two people have opposing but strongly-held views on truth or events. Not only do the parties hope to gain from the bet, they place the bet also to demonstrate their certainty about the issue. Some means of determining the issue at stake must exist. Sometimes the amount bet remains nominal, demonstrating the outcome as one of principle rather than of financial importance.
Betting exchanges allow consumers to both back and lay at odds of their choice. Similar in some ways to a stock exchange, a better may want to back a horse (hoping it will win) or lay a horse (hoping it will lose, effectively acting as bookmaker)
# Staking systems
Many betting systems have been created in an attempt to "beat the bookie" but most still accept that no system can make an unprofitable bet profitable over time. Widely-used systems include:
- Fixed stakes – a traditional system of staking the same amount on each selection.
- Fixed profits – the stakes vary based on the odds to ensure the same profit from each winning selection.
- Due-column betting – A variation on fixed profits betting in which the bettor sets a target profit and then calculates a bet size that will make this profit, adding any losses to the target.
- Card counting - Many systems exist for Blackjack to keep track of the ratio of ten values to all others; when this ratio is high the player has an advantage and should increase the amount of their bets. Keeping track of cards dealt confers an advantage in other games as well.
- Pot odds vs. true odds - In poker, the ratio of the size of the current pot to the bet a player is considering is called "pot odds", which can be compared to the "true odds" of a player completing a winning hand from the cards remaining to be dealt to determine whether to make the bet.
- Kelly – the optimum level to bet to maximize your future median bank level.
- Martingale – A system based on staking enough each time to recover losses from previous bet(s) until one wins.
# Other uses of the term "gambling"
Many risk-return choices are sometimes referred to colloquially as "gambling." Whether this terminology is acceptable is a matter of debate, but generally the following activities are not considered gambling:
- Emotional or physical risk-taking, where the risk-return ratio is not quantifiable (e.g., skydiving, campaigning for political office, asking someone for a date, etc.)
- Insurance is a method of shifting risk from one party to another. Insurers use actuarial methods to calculate appropriate premiums, which could be considered similar to calculating gambling odds. However, insurers can set their premiums to obtain a long term positive expected return.
- Situations where the possible return is a secondary reason for the wager/purchase (e.g. buying a raffle ticket to support a charitable cause)
Investments are also usually not considered gambling, although some investments can involve significant risk. Examples of investments include stocks, bonds and real estate. Starting a business can also be considered a form of investment. Investments are generally not considered gambling when they meet the following criteria:
- Positive expected returns (at least in the long term)
- Economic utility
- Underlying value independent of the risk being undertaken
Some speculative investment activities are particularly risky, but are still usually considered separately from gambling:
- Securities derivatives, such as options or futures, where the value of the derivative is dependent on the value of the underlying asset at a specific point in time (typically the derivative's associated expiration date)
- Foreign currency exchange (forex) transactions
- Prediction markets
# Psychological aspects
Studies show that though many people participate in gambling as a form of recreation or even as a means to gain an income, gambling, like any behavior which involves variation in brain chemistry, can become a psychologically addictive and harmful behavior in some people. Reinforcement schedules may also make gamblers persist in gambling even after repeated losses.
The Russian writer Dostoevsky (himself a problem gambler) portrays in his novella The Gambler the psychological implications of gambling and how gambling can affect gamblers. He also associates gambling and the idea of "getting rich quick", suggesting that Russians may have a particular affinity for gambling. Dostoevsky shows the effect of betting money for the chance of gaining more in 19th-century Europe. The association between Russians and gambling has fed legends of the origins of Russian roulette.
# By country
- Gambling in Japan
- Gambling in Macau (PRC)
- Gambling in the United Kingdom
- Gambling in the United States | Gambling
Gambling has a specific http://en.wikipedia.org/w/index.php?title=Gambling&action=edit
Edit this pageeconomic definition, referring to wagering money or something of material value on an event with an uncertain outcome with the primary intent of winning additional money and/or material goods. Typically, the outcome of the wager is evident within a short period of time.
The term gaming[1] in this context typically refers to instances in which the activity has been specifically permitted by law. The two words are not mutually exclusive; i.e., a “gaming” company offers (legal) “gambling” activities to the public.[2] (This distinction is not universally observed in the English-speaking world, however. For instance, in the UK, the regulator of gambling activities is called the Gambling Commission (not the Gaming Commission.[3])
# Legal aspects
Both the Catholic and Jewish traditions traditionally set aside days for gambling,[4] although religious authorities generally disapprove of gambling to some extent. Gambling can have adverse social consequences. For these social and religious reasons, most legal jurisdictions limit gambling. Some Islamic nations prohibit gambling; most other countries regulate it.[5]
Many jurisdictions, local as well as national, either ban or heavily control (by licensing) gambling. Such regulation generally leads to gambling tourism and illegal gambling. The involvement of governments, through regulation and taxation, has led to a close connection between many governments and gaming organizations, where legal gambling provides significant government revenue, such as in Monaco or Macau.
Under US federal law, gambling is legal in the United States, and states are free to regulate or prohibit the practice. Gambling has been legal in Nevada since 1931, forming the backbone of the state's economy, Las Vegas is perhaps the best known gambling destination in the world. In 1976, gambling was legalized in Atlantic City, New Jersey, and in 1990, it was legalized in Tunica, Mississippi; both of those cities have developed extensive casino and resort areas since then. Since a favorable US Supreme Court decision in 1987, many Native American tribes have built their own casinos on tribal lands as a way to provide revenue for the tribe. Because the tribes are considered sovereign nations, they are often exempt from state laws banning gambling, and are instead regulated under federal law. Additionally almost all states have legalized gambling in the form of a lottery.
Because contracts of insurance have many features in common with wagers, insurance contracts are often distinguished under law as agreements in which either party has an interest in the "bet-upon" outcome beyond the specific financial terms. E.g.: a “bet” with an insurer on whether one's house will burn down is not gambling, but rather insurance — as the homeowner has an obvious interest in the continued existence of his/her home independent of the purely financial aspects of the "bet" (i.e., the insurance policy).
There is generally legislation requiring that the odds in gaming devices are statistically random, to prevent manufacturers from making some high-payoff results impossible. Since these high-payoffs have very low probability, a house bias can quite easily be missed unless checking the odds carefully.[6]
# Gambling variables
There are three variables common to all forms of gambling:
- How much is being wagered, the initial stake (in money or material goods).
- The predictability of the event.
In mechanical or electronic gambling such as lotteries, slot machines and bingo, the results are random and unpredictable; no amount of skill or knowledge (assuming machinery is functioning as intended) can give an advantage in predictability to anyone.
However, for sports events such as horse racing and soccer matches there is some predictability to the outcome; thus a person with greater knowledge and/or skill will have an advantage over others.
- In mechanical or electronic gambling such as lotteries, slot machines and bingo, the results are random and unpredictable; no amount of skill or knowledge (assuming machinery is functioning as intended) can give an advantage in predictability to anyone.
- However, for sports events such as horse racing and soccer matches there is some predictability to the outcome; thus a person with greater knowledge and/or skill will have an advantage over others.
- The odds agreed between the two (or more) parties to the wager; where there is a house or a bookmaker, the odds are (quite legally) arranged in favor of the house.
The expected value, positive or negative, is a mathematical calculation using these three variables. The amount wagered determines the scale of an individual wager (bet); the odds and the amount wagered determine the payout if successful; the predictability determines the frequency of success. Finally the frequency of success times the payout minus the amount wagered equals the "expected value"
The skill of a gambler lies in understanding and maneuvering the three variables so that the "actual value" is positive over a series of wagers.
# Types of gambling
## Casino games
While almost any game can be played for money, and any game typically played for money can also be played just for fun, some games are generally offered in a casino setting.
### Table games
- Blackjack
- Pai Gow Poker and Tiles
- Poker
- Spanish 21
- 3-card poker
- Baccarat (punto banco)
- Caribbean Stud Poker
- Casino war
- Craps
- Fan-Tan
- Faro
- Let It Ride
- Pachinko
- Pyramid Poker
- 4-card poker
- Red Dog
- Sic Bo
- Texas Hold'em Bonus Poker
- Roulette
### Electronic gaming
- Slot machine
- Video poker
### Other gambling
- Sports betting
- Arbitrage betting
- Keno
- Bingo
## Non-casino gambling games
Gambling games that take place outside of casinos include Bingo (as played in the US and UK), dead pool, lotteries, pull-tab games and scratchcards, and Mahjong.
Other non-casino gambling games include:
- Card games, such as Liar's poker, Bridge, Basset, Lansquenet, Piquet, Put, Teen patti
- Coin-tossing games such as Head and Tail, Two-up*
- Confidence tricks such as Three-card Monte or the Shell game
- Carnival Games such as The Razzle or Hanky Pank
- Dice-based games, such as Backgammon, Liar's dice, Passe-dix, Hazard, Threes, Pig, or Mexico
*Although coin tossing isn't usually played in a casino, it has been known to be an official gambling game in some Australian casinos[7]
## Fixed-odds gambling
Fixed-odds gambling and Parimutuel betting frequently occur at many types of sporting events. In addition many bookmakers offer fixed odds on a number of non-sports related outcomes, for example the direction and extent of movement of various financial indices, the winner of television competitions such as Big Brother, election results,[8]. Interactive prediction markets also offer trading on these outcomes, with "shares" of results trading on an open market.
### Parimutuel betting
One of the most widespread forms of gambling involves betting on horse or greyhound racing. Wagering may take place through parimutuel pools, or bookmakers may take bets personally. Parimutuel wagers pay off at prices determined by support in the wagering pools, while bookmakers pay off either at the odds offered at the time of accepting the bet; or at the median odds offered by track bookmakers at the time the race started.
### Sports betting
Betting on team sports has become an important service industry in many countries. For example, millions of Britons play the football pools every week.
## Arbitrage betting
Arbitrage betting is a theoretically risk-free betting system in which every outcome of an event is bet upon so that a known profit will be made by the bettor upon completion of the event, regardless of the outcome. Arbitrage betting is a combination of the ancient art of arbitrage trading and gambling, which has been made possible by the large numbers of bookmakers in the marketplace, creating occasional opportunities for arbitrage.
## Other types of betting
One can also bet with another person that a statement is true or false, or that a specified event will happen (a "back bet") or will not happen (a "lay bet") within a specified time. This occurs in particular when two people have opposing but strongly-held views on truth or events. Not only do the parties hope to gain from the bet, they place the bet also to demonstrate their certainty about the issue. Some means of determining the issue at stake must exist. Sometimes the amount bet remains nominal, demonstrating the outcome as one of principle rather than of financial importance.
Betting exchanges allow consumers to both back and lay at odds of their choice. Similar in some ways to a stock exchange, a better may want to back a horse (hoping it will win) or lay a horse (hoping it will lose, effectively acting as bookmaker)
# Staking systems
Many betting systems have been created in an attempt to "beat the bookie" but most still accept that no system can make an unprofitable bet profitable over time. Widely-used systems include:
- Fixed stakes – a traditional system of staking the same amount on each selection.
- Fixed profits – the stakes vary based on the odds to ensure the same profit from each winning selection.
- Due-column betting – A variation on fixed profits betting in which the bettor sets a target profit and then calculates a bet size that will make this profit, adding any losses to the target.
- Card counting - Many systems exist for Blackjack to keep track of the ratio of ten values to all others; when this ratio is high the player has an advantage and should increase the amount of their bets. Keeping track of cards dealt confers an advantage in other games as well.
- Pot odds vs. true odds - In poker, the ratio of the size of the current pot to the bet a player is considering is called "pot odds", which can be compared to the "true odds" of a player completing a winning hand from the cards remaining to be dealt to determine whether to make the bet.
- Kelly – the optimum level to bet to maximize your future median bank level.
- Martingale – A system based on staking enough each time to recover losses from previous bet(s) until one wins.
# Other uses of the term "gambling"
Many risk-return choices are sometimes referred to colloquially as "gambling." Whether this terminology is acceptable is a matter of debate, but generally the following activities are not considered gambling:
- Emotional or physical risk-taking, where the risk-return ratio is not quantifiable (e.g., skydiving, campaigning for political office, asking someone for a date, etc.)
- Insurance is a method of shifting risk from one party to another. Insurers use actuarial methods to calculate appropriate premiums, which could be considered similar to calculating gambling odds. However, insurers can set their premiums to obtain a long term positive expected return.
- Situations where the possible return is a secondary reason for the wager/purchase (e.g. buying a raffle ticket to support a charitable cause)
Investments are also usually not considered gambling, although some investments can involve significant risk. Examples of investments include stocks, bonds and real estate. Starting a business can also be considered a form of investment. Investments are generally not considered gambling when they meet the following criteria:
- Positive expected returns (at least in the long term)
- Economic utility
- Underlying value independent of the risk being undertaken
Some speculative investment activities are particularly risky, but are still usually considered separately from gambling:
- Securities derivatives, such as options or futures, where the value of the derivative is dependent on the value of the underlying asset at a specific point in time (typically the derivative's associated expiration date)
- Foreign currency exchange (forex) transactions
- Prediction markets
# Psychological aspects
Studies show that though many people participate in gambling as a form of recreation or even as a means to gain an income, gambling, like any behavior which involves variation in brain chemistry, can become a psychologically addictive and harmful behavior in some people. Reinforcement schedules may also make gamblers persist in gambling even after repeated losses.
The Russian writer Dostoevsky (himself a problem gambler) portrays in his novella The Gambler the psychological implications of gambling and how gambling can affect gamblers. He also associates gambling and the idea of "getting rich quick", suggesting that Russians may have a particular affinity for gambling. Dostoevsky shows the effect of betting money for the chance of gaining more in 19th-century Europe. The association between Russians and gambling has fed legends of the origins of Russian roulette.
# By country
- Gambling in Japan
- Gambling in Macau (PRC)
- Gambling in the United Kingdom
- Gambling in the United States | https://www.wikidoc.org/index.php/Gambling | |
3a950af5e7a536d3b16c7121dc3e2b07ba3e5d0b | wikidoc | Ganglion | Ganglion
# Overview
In anatomy, a ganglion (pl. ganglia) is a tissue mass, composed mainly of somata and dendritic structures, that often interconnects with other ganglia to form a complex system of ganglia known as a plexus. Ganglia provide relay points and intermediary connections between different neurological structures in the body, such as the peripheral and central nervous systems.
There are two major groups of ganglia: dorsal root ganglia (also known as the spinal ganglia) and autonomic ganglia. The former contains the cell bodies of sensory (afferent) nerves and the latter contains the cell bodies of autonomic nerves.
In the autonomic nervous system, fibers from the central nervous system to the ganglion are known as preganglionic fibers, while those from the ganglion to the effector organ are called postganglionic fibers.
In the brain, basal ganglia is a group of nuclei interconnected with the cerebral cortex, thalamus and brainstem, associated with a variety of functions: motor control, cognition, emotions and learning.
# Related Chapters
- Dorsal root ganglion
- Ganglion cell
- Ganglion cyst
- Nervous system
- Neuron | Ganglion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In anatomy, a ganglion (pl. ganglia) is a tissue mass, composed mainly of somata and dendritic structures, that often interconnects with other ganglia to form a complex system of ganglia known as a plexus. Ganglia provide relay points and intermediary connections between different neurological structures in the body, such as the peripheral and central nervous systems.
There are two major groups of ganglia: dorsal root ganglia (also known as the spinal ganglia) and autonomic ganglia. The former contains the cell bodies of sensory (afferent) nerves and the latter contains the cell bodies of autonomic nerves.
In the autonomic nervous system, fibers from the central nervous system to the ganglion are known as preganglionic fibers, while those from the ganglion to the effector organ are called postganglionic fibers.
In the brain, basal ganglia is a group of nuclei interconnected with the cerebral cortex, thalamus and brainstem, associated with a variety of functions: motor control, cognition, emotions and learning.
# Related Chapters
- Dorsal root ganglion
- Ganglion cell
- Ganglion cyst
- Nervous system
- Neuron
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ganglia | |
54024b0625d58a5d618b28485be1c02804232b73 | wikidoc | Gargling | Gargling
Gargling is a common method of cleansing the throat, especially if one has a sore throat or upper-respiratory virus or infection. The physical act of gargling usually requires that one tilts the head back, allowing a mouthful of liquid to sit in the upper throat. Air is then expelled from the lungs, causing the liquid to bubble and undulate throughout the throat and mouth region.
Gargling may be done with water or green tea (as it has been used in Asia1 2), but there are also many specific medicines designed to be used, either readily available at a supermarket or drug store or requiring a prescription from a licensed medical doctor. Home remedies for gargling include a hyper-tonic saline solution of table salt (ratio of solid to liquid varies; suggestion: 1/4 teaspoon of table salt in 8 oz. warm water) and various types of vinegar. Gargling with a solution of table salt is known to provide relief for a sore throat because as a natural dehydrator, salt draws water from the inflammations in the throat by osmosis.
Antiseptic mouthwash can be also gargled to remove bacteria from the throat.
According to modern western etiquette, gargling is a fairly impolite activity during a social occasion or mealtime. It is typically performed in a bathroom at a sink so the refused liquid may be disposed of properly. | Gargling
Gargling is a common method of cleansing the throat, especially if one has a sore throat or upper-respiratory virus or infection. The physical act of gargling usually requires that one tilts the head back, allowing a mouthful of liquid to sit in the upper throat. Air is then expelled from the lungs, causing the liquid to bubble and undulate throughout the throat and mouth region.
Gargling may be done with water or green tea (as it has been used in Asia1 2), but there are also many specific medicines designed to be used, either readily available at a supermarket or drug store or requiring a prescription from a licensed medical doctor. Home remedies for gargling include a hyper-tonic saline solution of table salt (ratio of solid to liquid varies; suggestion: 1/4 teaspoon of table salt in 8 oz. warm water) and various types of vinegar. Gargling with a solution of table salt is known to provide relief for a sore throat because as a natural dehydrator, salt draws water from the inflammations in the throat by osmosis.
Antiseptic mouthwash can be also gargled to remove bacteria from the throat.
According to modern western etiquette, gargling is a fairly impolite activity during a social occasion or mealtime. It is typically performed in a bathroom at a sink so the refused liquid may be disposed of properly. | https://www.wikidoc.org/index.php/Gargling | |
04e810f332811198506c4b298f8591693a34ea2d | wikidoc | Gaviscon | Gaviscon
Gaviscon is a non-prescription medication for the treatment of heartburn and GERD (acid reflux). It is produced and distributed in the UK by Reckitt Benckiser and by GlaxoSmithKline in the US and Canada.
The active antacid ingredients in the Gaviscon UK formula are aluminum hydroxide and either magnesium carbonate or magnesium trisillicate.
In addition to the acid-neutralizing ingredients, Gaviscon contains "alginate" (alginic acid + sodium bicarbonate). When taken by mouth the combination of the alginic acid and bicarbonate creates a protective barrier which prevents stomach acid from refluxing back up into the esophagus.
This protective barrier helps reduce the number of reflux episodes and provides up to 4 hours action against heartburn. If reflux occurs, this protective barrier is the first to contact the esophageal mucosa, and thus provides protection against the gastric contents.
It may be helpful to combine treatment with lifestyle modifications such as loss of weight, raising the head of the bed at night, reduction in alcohol consumption and cessation of smoking.
Gaviscon works in a non-systemic way, so the treatment doesn't enter the bloodstream. | Gaviscon
Template:Advert
Gaviscon is a non-prescription medication for the treatment of heartburn and GERD (acid reflux). It is produced and distributed in the UK by Reckitt Benckiser and by GlaxoSmithKline in the US and Canada.
The active antacid ingredients in the Gaviscon UK formula are aluminum hydroxide and either magnesium carbonate or magnesium trisillicate.
In addition to the acid-neutralizing ingredients, Gaviscon contains "alginate" (alginic acid + sodium bicarbonate). When taken by mouth the combination of the alginic acid and bicarbonate creates a protective barrier which prevents stomach acid from refluxing back up into the esophagus.
This protective barrier helps reduce the number of reflux episodes and provides up to 4 hours action against heartburn. If reflux occurs, this protective barrier is the first to contact the esophageal mucosa, and thus provides protection against the gastric contents.
It may be helpful to combine treatment with lifestyle modifications such as loss of weight, raising the head of the bed at night, reduction in alcohol consumption and cessation of smoking[1].
Gaviscon works in a non-systemic way, so the treatment doesn't enter the bloodstream.
# External links
- Official "Gaviscon US" website
- Official "Gaviscon Canada" website
Template:WikiDoc Sources
- ↑ Kumar & Clark: Clinical Medicine 6e p.276 Elsevier 2005 | https://www.wikidoc.org/index.php/Gaviscon | |
f9fb84e0759d613a6cecad494c9becd9b16f5610 | wikidoc | Gelsolin | Gelsolin
Gelsolin is an actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/villin superfamily, as it severs with nearly 100% efficiency. Gelsolin is located intracellularly (in cytosol and mitochondria) and extracellularly (in blood plasma).
# Structure
Gelsolin is an 82-kD protein with six homologous subdomains, referred to as S1-S6. Each subdomain is composed of a five-stranded β-sheet, flanked by two α-helices, one positioned perpendicular with respect to the strands and one positioned parallel. The N-terminal (S1-S3) forms an extended β-sheet, as does the C-terminal (S4-S6).
# Regulation
Among the lipid binding actin regulatory proteins, gelsolin (along with cofilin) is one of the few that exhibit preferential binding towards polyphosphoinositide (PPIs). The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.
Gelsolin's activity is stimulated by calcium ions (Ca2+). Although the protein retains its overall structural integrity in both activated and deactivated states, the S6 helical tail moves like a latch depending on the concentration of calcium ions. The C-terminal end detects the calcium concentration within the cell. When there is no Ca2+ present, the tail of S6 shields the actin-binding sites on one of S2's helices. When a calcium ion attaches to the S6 tail, however, it straightens, exposing the S2 actin-binding sites. The N-terminal is directly involved in the severing of actin. S2 and S3 bind to the actin before the binding of S1 severs actin-actin bonds and caps the barbed end.
Gelsolin can be inhibited by a local rise in the concentration of phosphatidylinositol (4,5)-bisphosphate (PIP2), a PPI. This is a two step process. Firstly, (PIP2) binds to S2 and S3, inhibiting gelsolin from actin side binding. Then, (PIP2) binds to gelsolin’s S1, preventing gelsolin from severing actin, although (PIP2) does not bind directly to gelsolin's actin-binding site.
Gelsolin's severing of actin, in contrast to the severing of microtubules by katanin, does not require any extra energy input.
# Cellular Function
As an important actin regulator, gelsolin plays a role in podosome formation (along with Arp3, cortactin, and Rho GTPases).
Gelsolin also inhibits apoptosis by stabilizing the mitochondria . Prior to cell death, mitochondria normally lose membrane potential and become more permeable. Gelsolin can impede the release of cytochrome C, obstructing the signal amplification that would have led to apoptosis.
Actin can be cross-linked into a gel by actin cross-linking proteins. Gelsolin can turn this gel into a sol, hence the name gelsolin.
# Organismal Relevance
Research in mice suggests that gelsolin, like other actin-severing proteins, is not expressed to a significant degree until after the early embryonic stage--approximately 2 weeks in murine embryos. In adult specimens, however, gelsolin is particularly important in motile cells, such as blood platelets. Mice with null gelsolin-coding genes undergo normal embryonic development, but the deformation of their blood platelets reduced their motility, resulting in a slower response to wound healing.
An insufficiency of gelsolin in mice has also been shown to cause increased permeability of the vascular pulmonary barrier, suggesting that gelsolin is important in the response to lung injury. | Gelsolin
Gelsolin is an actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/villin superfamily, as it severs with nearly 100% efficiency.[1] Gelsolin is located intracellularly (in cytosol and mitochondria) and extracellularly (in blood plasma).[2]
# Structure
Gelsolin is an 82-kD protein with six homologous subdomains, referred to as S1-S6. Each subdomain is composed of a five-stranded β-sheet, flanked by two α-helices, one positioned perpendicular with respect to the strands and one positioned parallel. The N-terminal (S1-S3) forms an extended β-sheet, as does the C-terminal (S4-S6).[3]
# Regulation
Among the lipid binding actin regulatory proteins, gelsolin (along with cofilin) is one of the few that exhibit preferential binding towards polyphosphoinositide (PPIs).[4] The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.[4]
Gelsolin's activity is stimulated by calcium ions (Ca2+).[1] Although the protein retains its overall structural integrity in both activated and deactivated states, the S6 helical tail moves like a latch depending on the concentration of calcium ions.[5] The C-terminal end detects the calcium concentration within the cell. When there is no Ca2+ present, the tail of S6 shields the actin-binding sites on one of S2's helices.[3] When a calcium ion attaches to the S6 tail, however, it straightens, exposing the S2 actin-binding sites.[5] The N-terminal is directly involved in the severing of actin. S2 and S3 bind to the actin before the binding of S1 severs actin-actin bonds and caps the barbed end.[4]
Gelsolin can be inhibited by a local rise in the concentration of phosphatidylinositol (4,5)-bisphosphate (PIP2), a PPI. This is a two step process. Firstly, (PIP2) binds to S2 and S3, inhibiting gelsolin from actin side binding. Then, (PIP2) binds to gelsolin’s S1, preventing gelsolin from severing actin, although (PIP2) does not bind directly to gelsolin's actin-binding site.[4]
Gelsolin's severing of actin, in contrast to the severing of microtubules by katanin, does not require any extra energy input.
# Cellular Function
As an important actin regulator, gelsolin plays a role in podosome formation (along with Arp3, cortactin, and Rho GTPases).[6]
Gelsolin also inhibits apoptosis by stabilizing the mitochondria [2]. Prior to cell death, mitochondria normally lose membrane potential and become more permeable. Gelsolin can impede the release of cytochrome C, obstructing the signal amplification that would have led to apoptosis.
Actin can be cross-linked into a gel by actin cross-linking proteins. Gelsolin can turn this gel into a sol, hence the name gelsolin.
# Organismal Relevance
Research in mice suggests that gelsolin, like other actin-severing proteins, is not expressed to a significant degree until after the early embryonic stage--approximately 2 weeks in murine embryos.[7] In adult specimens, however, gelsolin is particularly important in motile cells, such as blood platelets. Mice with null gelsolin-coding genes undergo normal embryonic development, but the deformation of their blood platelets reduced their motility, resulting in a slower response to wound healing.[7]
An insufficiency of gelsolin in mice has also been shown to cause increased permeability of the vascular pulmonary barrier, suggesting that gelsolin is important in the response to lung injury.[8] | https://www.wikidoc.org/index.php/Gelsolin | |
21bffb9bc7db3d1f7fe683b49c2c41b4172a99ab | wikidoc | GemIdent | GemIdent
GemIdent is an interactive image processing program that identifies regions of interest. It is specifically designed for images with few colors, where the objects of interest look alike with small variation. For example, color image segmentation of:
- Oranges from a tree
- Stained cells from microscopic images
GemIdent also packages data analysis tools to investigate spatial relationships among the objects identified.
# History
GemIdent was developed at Stanford University by Adam Kapelner from June, 2006 until January, 2007 in the lab of Dr. Peter Lee under the tutelage of Professor Susan Holmes. The concept was inspired by data from Ref. publication concerning immune profiles of lymph nodes in breast cancer patients. Hence, GemIdent works well when identifying cells in IHC-stained tissue imaged via automated light microscopy when the nuclear background stain and membrane/cytoplasmic stain are well-defined.
# Methodology
GemIdent uses supervised learning to perform automated
identification of regions of interest in the images. Therefore, the user must do a substantial amount of work first supplying the relevant colors, then pointing out examples of the objects or regions themselves as well as negatives (training set creation).
When a user clicks on a pixel, many scores are generated using the surrounding color information via Mahalanobis Ring Score attribute generation. These scores are then used to build a random forest machine-learning classifier which will then classify pixels in any given image.
After classification, there may be mistakes. The user can return to training and point out the specific mistakes and then reclassify. These training-classifying-retraining-reclassifying iterations (considered interactive boosting) can result in a highly accurate segmentation.
# Source code
The source code for GemIdent is available to noncommercial users in pure Java 6. The code is licensed under the "GemIdent license" - a license written by Stanford's Office of Technology and Licensing that is not an open source license or a free software license because commercial redistribution is prohibited and distribution of derivative works is highly restricted.
# Examples
The raw photograph (left), a superimposed mask showing the pixel classification results (center), and finally the photograph is marked with the centroids of the object of interest - the oranges (right)
The raw microscopic image of a stained lymph node (left) from the Kohrt study, a superimposed mask showing the pixel classification results (center), and finally the image is marked with the centroids of the object of interest - the cancer nuclei (right)
This example illustrates GemIdent's ability to find multiple phenotypes in the same image: the raw microscopic image of a stained lymph node (top left) from the Kohrt study, a superimposed mask showing the pixel classification results (top right), and finally the image marked with the centroids of the objects of interest - the cancer nuclei (in green stars), the T-cells (in yellow stars), and non-specific background nuclei (in cyan stars).
The command-line data analysis and visualization interface in action analyzing results of a classification of a lymph node from the Kohrt study. The histogram displays the distribution of distances from T-cells to neighboring cancer cells. The binary image of cancer membrane is the result of a pixel-only classification. The open PDF document is the autogenerated report of the analysis which includes a thumbnail view of the entire lymph node, counts and Type I error rates for all phenotypes, as well as a transcript of the analyses performed.
# Notes and references
- ↑ Kapelner, Adam (2007-07). "An Interactive Statistical Image Segmentation and Visualization System". medivis. IEEE Computer Society. 0: 81–86. ISSN 0-7695-2904-6 Check |issn= value (help). Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 2.2 2.3 Kohrt, Holbrook E (2005-09). "Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer". PLoS medicine. 2 (9): e284. doi:10.1371/journal.pmed.0020284. ISSN 1549-1676. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help) | GemIdent
GemIdent is an interactive image processing program that identifies regions of interest. It is specifically designed for images with few colors, where the objects of interest look alike with small variation. For example, color image segmentation of:
- Oranges from a tree
- Stained cells from microscopic images
GemIdent also packages data analysis tools to investigate spatial relationships among the objects identified.
# History
GemIdent was developed at Stanford University by Adam Kapelner from June, 2006 until January, 2007 in the lab of Dr. Peter Lee under the tutelage of Professor Susan Holmes.[1] The concept was inspired by data from Ref. [2] publication concerning immune profiles of lymph nodes in breast cancer patients. Hence, GemIdent works well when identifying cells in IHC-stained tissue imaged via automated light microscopy when the nuclear background stain and membrane/cytoplasmic stain are well-defined.
# Methodology
GemIdent uses supervised learning to perform automated
identification of regions of interest in the images. Therefore, the user must do a substantial amount of work first supplying the relevant colors, then pointing out examples of the objects or regions themselves as well as negatives (training set creation).
When a user clicks on a pixel, many scores are generated using the surrounding color information via Mahalanobis Ring Score attribute generation. These scores are then used to build a random forest machine-learning classifier which will then classify pixels in any given image.
After classification, there may be mistakes. The user can return to training and point out the specific mistakes and then reclassify. These training-classifying-retraining-reclassifying iterations (considered interactive boosting) can result in a highly accurate segmentation.
# Source code
The source code for GemIdent is available to noncommercial users in pure Java 6. The code is licensed under the "GemIdent license" - a license written by Stanford's Office of Technology and Licensing that is not an open source license or a free software license because commercial redistribution is prohibited and distribution of derivative works is highly restricted.
# Examples
The raw photograph (left), a superimposed mask showing the pixel classification results (center), and finally the photograph is marked with the centroids of the object of interest - the oranges (right)
The raw microscopic image of a stained lymph node (left) from the Kohrt study[2], a superimposed mask showing the pixel classification results (center), and finally the image is marked with the centroids of the object of interest - the cancer nuclei (right)
This example illustrates GemIdent's ability to find multiple phenotypes in the same image: the raw microscopic image of a stained lymph node (top left) from the Kohrt study[2], a superimposed mask showing the pixel classification results (top right), and finally the image marked with the centroids of the objects of interest - the cancer nuclei (in green stars), the T-cells (in yellow stars), and non-specific background nuclei (in cyan stars).
The command-line data analysis and visualization interface in action analyzing results of a classification of a lymph node from the Kohrt study[2]. The histogram displays the distribution of distances from T-cells to neighboring cancer cells. The binary image of cancer membrane is the result of a pixel-only classification. The open PDF document is the autogenerated report of the analysis which includes a thumbnail view of the entire lymph node, counts and Type I error rates for all phenotypes, as well as a transcript of the analyses performed.
# Notes and references
- ↑ Kapelner, Adam (2007-07). "An Interactive Statistical Image Segmentation and Visualization System". medivis. IEEE Computer Society. 0: 81–86. ISSN 0-7695-2904-6 Check |issn= value (help). Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 2.2 2.3 Kohrt, Holbrook E (2005-09). "Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer". PLoS medicine. 2 (9): e284. doi:10.1371/journal.pmed.0020284. ISSN 1549-1676. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
# External links
- GemIdent's homepage
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/GemIdent | |
fc16b8807bee136093db5d068c3d29f863ce0f67 | wikidoc | Genogram | Genogram
# Overview
A genogram is a pictorial display of a person's family relationships and medical history. It goes beyond a traditional family tree by allowing the user to visualize hereditary patterns and psychological factors that punctuate relationships. It can be used to identify repetitive patterns of behavior and to recognize hereditary tendencies.
Genograms were first developed and popularized in clinical settings by Monica McGoldrick and Randy Gerson through the publication of a book titled Genograms: Assessment and Intervention in 1985. Genograms are now used by various groups of people in a variety of fields such as genealogy, medicine, psychiatry, psychology, social work, genetic research, education, and many more. Some practitioners in personal and family therapy use genograms for personal records and/ or to explain family dynamics to the client. Few if any genealogists use them.
# Genogram symbols
A genogram is created with simple symbols representing the gender, with various lines to illustrate family relationships. Figure 1 illustrates basic genogram symbols with various types of individuals. Some genogram users also put circles around members who live in the same living spaces. Genograms can be prepared by using a complex word processor, or a computer drawing program. There are also computer programs that are custom designed for genograms.
Basic Genogram Symbols
Genogram symbols will usually have the date of birth (and date of death if applicable) above, and the name of the individual underneath. The inside of the symbol will hold the person’s current age or various codes for genetic diseases or user-defined properties: abortions, still-births, SIDS, cohabitations, etc.
# Genogram content
A genogram can contain a wealth of information on the families represented. It will not only show you the names of people who belong to your family lineage, but how these relatives relate to each other. For example, a genogram will not only tell you that your uncle Paul and his wife Lily have three children, but that their eldest child was sent to boarding school, that their middle child is always in conflict with her mother, that their youngest has juvenile diabetes, that Uncle Paul suffered from depression, was an alcoholic, and a philosopher, while Aunt Lily has not spoken to her brother for years, has breast cancer and has a history of quitting her jobs. Figure 2 illustrates that genogram.
Sample Genogram
# Family relationships
One of the advantages of a genogram is the ability to use colour-coded lines to define different types of relationships such as family relationships, emotional relationships and social relationships. Within family relationships, you can illustrate if a couple is married, divorced, common-law, engaged, etc. Figure 3 illustrates the symbols commonly used for family relationships.
Family Relationship Symbols in a Genogram
# Emotional relationships
Genograms usually also include emotional relationships. These provide an in-depth analysis of how individuals relate to one another. Colour-coded lines represent various emotional relationships that bond individuals together. In Figure 2, the double dotted line between Lily and Natalie illustrates discord, the line with red stripes illustrates distrust between Paul and his son Andrew, and the broken line between Lily and Frank illustrates a cut-off relationship. Figure 4 illustrates the symbols commonly used for emotional relationships
Emotional Relationship Symbols in a Genogram
# Social relationships
Another component of genograms is social relationships. These allow users to link individuals who are not related to one another, but who have a connection in society-at-large, such as neighbor, co-worker, boss-employee, pastor-church member, teacher-student, etc. Social relationships can also illustrate an individual’s relation to a social entity like Andrew and the boarding school in Figure 2. The use of social relationships links allows the genogram to be used in a business environment to create organizational charts or floor plan layouts of the employees.
A genogram looks like a family tree, but with all the different types of relationships, it contains a significantly more detailed and complete picture of the family or group it illustrates.
# Purpose of the Genogram
## Genealogy
In genealogy, genograms are used to record family history through the lives of each of its members. Genograms allow the genealogist to graphically portray complex family trees that show marriages and divorces, reconstituted families, adoptions, strained relationships, family cohesion, etc. Genealogists can use genograms to discover and analyze interesting facts about their family history, such as a naming pattern, sibling rivalry, or significant events like immigration.
## Medicine
In medicine, medical genograms provide a quick and useful context in which to evaluate an individual's health risks. Knowledge of diseases and conditions that occur within a family can give a health care team invaluable information that may aid in a swift, accurate diagnosis and treatment of health problems. And, a knowledge of diseases and illnesses that "run" in families can give individuals an important head start in pursuing effective preventive measures. A medical genogram is helpful in determining patterns of disease or illness within a family. Medical genograms can include many generations, however four generations may prove to be enough detail. Figure 5 illustrates a user-defined legend for a medical genogram.
Medical Genogram Lege
## Psychology
In psychology, genograms are used by psychologists to gather objective and consistent information from the clients and their family, helping them to view the client’s issues in the larger context of their marital relationship, family relationships and culture of origin and underlining key issues to discuss in client counseling. Genograms portray emotional relationships, which allow psychologists to see and evaluate possible conflicts within the family.
## Social work
In social work, genograms are used to display emotional bonds between individuals composing a family or social unit. A genogram will help social workers to make an assessment of the level of cohesiveness within a family or a group and to evaluate if proper care is available within that unit. Genograms also allow displaying social relationships that illustrate the places people attend such as schools, churches, youth facilities, associations or retirement homes.
## Family Therapy
In family therapy, genograms are used to study and record relationship patterns between family members and the individual characteristics that make up these patterns that occur. A genogram will help family therapists to make an appropriate assessment of the those relationship patterns and where intervention may be needed to assist the family reduce their dysfunction and/or problematic situation that brought them into therapy.
## Research
In research, genograms allow researchers to understand multi generational processes within various plant and animal species, such as the development of mutations. Genograms can also illustrate rates of renewal, mechanisms of survival, or processes involved in the regulation of tolerance, among other things.
## Education
In education, genograms can be used by teachers and students for illustrating book reviews, or family trees of a famous politician, philosopher, scientist, musician, etc. They allow them to focus their attention on specific details and also see the big picture of the books and individuals they are studying.
# Creating Genograms
Genograms can be useful in almost any profession that deals with social interaction. Genograms can help to visualize complex interactions between individuals and to study patterns of behaviors or diseases. Genograms are best created with genealogy software, as advanced software allows the user to include tremendous amounts of data. Genealogy software also allows the user to create detailed reports containing analysis of the information stored in each person’s individual properties. Genograms are often drawn by hand, sketched working right with the client. It is also possible to create a Genogram using MS Word. | Genogram
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A genogram is a pictorial display of a person's family relationships and medical history. It goes beyond a traditional family tree by allowing the user to visualize hereditary patterns and psychological factors that punctuate relationships. It can be used to identify repetitive patterns of behavior and to recognize hereditary tendencies.
Genograms were first developed and popularized in clinical settings by Monica McGoldrick and Randy Gerson through the publication of a book titled Genograms: Assessment and Intervention in 1985. Genograms are now used by various groups of people in a variety of fields such as genealogy, medicine, psychiatry, psychology, social work, genetic research, education, and many more. Some practitioners in personal and family therapy use genograms for personal records and/ or to explain family dynamics to the client. Few if any genealogists use them.
# Genogram symbols
A genogram is created with simple symbols representing the gender, with various lines to illustrate family relationships. Figure 1 illustrates basic genogram symbols with various types of individuals. Some genogram users also put circles around members who live in the same living spaces. Genograms can be prepared by using a complex word processor, or a computer drawing program. There are also computer programs that are custom designed for genograms.
Basic Genogram Symbols
Genogram symbols will usually have the date of birth (and date of death if applicable) above, and the name of the individual underneath. The inside of the symbol will hold the person’s current age or various codes for genetic diseases or user-defined properties: abortions, still-births, SIDS, cohabitations, etc.
# Genogram content
A genogram can contain a wealth of information on the families represented. It will not only show you the names of people who belong to your family lineage, but how these relatives relate to each other. For example, a genogram will not only tell you that your uncle Paul and his wife Lily have three children, but that their eldest child was sent to boarding school, that their middle child is always in conflict with her mother, that their youngest has juvenile diabetes, that Uncle Paul suffered from depression, was an alcoholic, and a philosopher, while Aunt Lily has not spoken to her brother for years, has breast cancer and has a history of quitting her jobs. Figure 2 illustrates that genogram.
Sample Genogram
# Family relationships
One of the advantages of a genogram is the ability to use colour-coded lines to define different types of relationships such as family relationships, emotional relationships and social relationships. Within family relationships, you can illustrate if a couple is married, divorced, common-law, engaged, etc. Figure 3 illustrates the symbols commonly used for family relationships.
Family Relationship Symbols in a Genogram
# Emotional relationships
Genograms usually also include emotional relationships. These provide an in-depth analysis of how individuals relate to one another. Colour-coded lines represent various emotional relationships that bond individuals together. In Figure 2, the double dotted line between Lily and Natalie illustrates discord, the line with red stripes illustrates distrust between Paul and his son Andrew, and the broken line between Lily and Frank illustrates a cut-off relationship. Figure 4 illustrates the symbols commonly used for emotional relationships
Emotional Relationship Symbols in a Genogram
# Social relationships
Another component of genograms is social relationships. These allow users to link individuals who are not related to one another, but who have a connection in society-at-large, such as neighbor, co-worker, boss-employee, pastor-church member, teacher-student, etc. Social relationships can also illustrate an individual’s relation to a social entity like Andrew and the boarding school in Figure 2. The use of social relationships links allows the genogram to be used in a business environment to create organizational charts or floor plan layouts of the employees.
A genogram looks like a family tree, but with all the different types of relationships, it contains a significantly more detailed and complete picture of the family or group it illustrates.
# Purpose of the Genogram
## Genealogy
In genealogy, genograms are used to record family history through the lives of each of its members. Genograms allow the genealogist to graphically portray complex family trees that show marriages and divorces, reconstituted families, adoptions, strained relationships, family cohesion, etc. Genealogists can use genograms to discover and analyze interesting facts about their family history, such as a naming pattern, sibling rivalry, or significant events like immigration.
## Medicine
In medicine, medical genograms provide a quick and useful context in which to evaluate an individual's health risks. Knowledge of diseases and conditions that occur within a family can give a health care team invaluable information that may aid in a swift, accurate diagnosis and treatment of health problems. And, a knowledge of diseases and illnesses that "run" in families can give individuals an important head start in pursuing effective preventive measures. A medical genogram is helpful in determining patterns of disease or illness within a family. Medical genograms can include many generations, however four generations may prove to be enough detail. Figure 5 illustrates a user-defined legend for a medical genogram.
Medical Genogram Lege
## Psychology
In psychology, genograms are used by psychologists to gather objective and consistent information from the clients and their family, helping them to view the client’s issues in the larger context of their marital relationship, family relationships and culture of origin and underlining key issues to discuss in client counseling. Genograms portray emotional relationships, which allow psychologists to see and evaluate possible conflicts within the family.
## Social work
In social work, genograms are used to display emotional bonds between individuals composing a family or social unit. A genogram will help social workers to make an assessment of the level of cohesiveness within a family or a group and to evaluate if proper care is available within that unit. Genograms also allow displaying social relationships that illustrate the places people attend such as schools, churches, youth facilities, associations or retirement homes.
## Family Therapy
In family therapy, genograms are used to study and record relationship patterns between family members and the individual characteristics that make up these patterns that occur. A genogram will help family therapists to make an appropriate assessment of the those relationship patterns and where intervention may be needed to assist the family reduce their dysfunction and/or problematic situation that brought them into therapy.
## Research
In research, genograms allow researchers to understand multi generational processes within various plant and animal species, such as the development of mutations. Genograms can also illustrate rates of renewal, mechanisms of survival, or processes involved in the regulation of tolerance, among other things.
## Education
In education, genograms can be used by teachers and students for illustrating book reviews, or family trees of a famous politician, philosopher, scientist, musician, etc. They allow them to focus their attention on specific details and also see the big picture of the books and individuals they are studying.
# Creating Genograms
Genograms can be useful in almost any profession that deals with social interaction. Genograms can help to visualize complex interactions between individuals and to study patterns of behaviors or diseases. Genograms are best created with genealogy software, as advanced software allows the user to include tremendous amounts of data. Genealogy software also allows the user to create detailed reports containing analysis of the information stored in each person’s individual properties. Genograms are often drawn by hand, sketched working right with the client. It is also possible to create a Genogram using MS Word.
# External links
- Introduction to the Genogram
- Genogram & Eco-Map assignment, created in MS Word for SOWK 460
- WinGeno, a computer program to create diagrams of family constellations in form of genograms.
de:Genogramm
eo:Genogramo
it:Genogramma
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Genogram | |
859b83fa2e6135013ac50495f474c723f0d61892 | wikidoc | Genomics | Genomics
Genomics is the study of an organism's entire genome. The field includes intensive efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping efforts. The field also includes studies of intragenomic phenomena such as heterosis, epistasis, pleiotropy and other interactions between loci and alleles within the genome. In contrast, the investigation of single genes, their functions and roles, something very common in today's medical and biological research, and a primary focus of molecular biology, does not fall into the definition of genomics, unless the aim of this genetic, pathway, and functional information analysis is to elucidate its effect on, place in, and response to the entire genome's networks.
# History of the field
Genomics can be said to have appeared in the 1980s, and took off in the 1990s with the initiation of genome projects for several biological species. A major branch of genomics is still concerned with sequencing the genomes of various organisms, but the knowledge of full genomes has created the possibility for the field of functional genomics, mainly concerned with patterns of gene expression during various conditions. The most important tools here are microarrays and bioinformatics. Study of the full set of proteins in a cell type or tissue, and the changes during various conditions, is called proteomics.
In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University of Ghent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene for Bacteriophage MS2 coat protein.
In 1976, the team determined the complete nucleotide-sequence of bacteriophage MS2-RNA.
The first DNA-based genome to be sequenced in its entirety was that of bacteriophage Φ-X174; (5,368 bp), sequenced by Frederick Sanger in 1977.
The first free-living organism to be sequenced was that of Haemophilus influenzae (1.8 Mb) in 1995, and since then genomes are being sequenced at a rapid pace. A rough draft of the human genome was completed by the Human Genome Project in early 2001, creating much fanfare.
As of September 2007, the complete sequence was known of about 1879 viruses , 577 bacterial species and roughly 23 eukaryote organisms, of which about half are fungi.
Most of the bacteria whose genomes have been completely sequenced are problematic disease-causing agents, such as Haemophilus influenzae. Of the other sequenced species, most were chosen because they were well-studied model organisms or promised to become good models. Yeast (Saccharomyces cerevisiae) has long been an important model organism for the eukaryotic cell, while the fruit fly Drosophila melanogaster has been a very important tool (notably in early pre-molecular genetics). The worm Caenorhabditis elegans is an often used simple model for multicellular organisms. The zebrafish Brachydanio rerio is used for many developmental studies on the molecular level and the flower Arabidopsis thaliana is a model organism for flowering plants. The Japanese pufferfish (Takifugu rubripes) and the spotted green pufferfish (Tetraodon nigroviridis) are interesting because of their small and compact genomes, containing very little non-coding DNA compared to most species.
The mammals dog (Canis familiaris),
brown rat (Rattus norvegicus), mouse (Mus musculus), and chimpanzee (Pan troglodytes) are all important model animals in medical research.
# Bacteriophage Genomics
Bacteriophages have played and continue to play a key role in bacterial genetics and molecular biology. Historically, they were used to define gene structure and gene regulation. Also the first genome to be sequenced was a bacteriophage. However, bacteriophage research did not lead the genomics revolution, which is clearly dominated by bacterial genomics. Only very recently has the study of bacteriophage genomes become prominent, thereby enabling researchers to understand the mechanisms underlying phage evolution. Bacteriophage genome sequences can be obtained through direct sequencing of isolated bacteriophages, but can also be derived as part of microbial genomes. Analysis of bacterial genomes has shown that a substantial amount of microbial DNA consists of prophage sequences and prophage-like elements. A detailed database mining of these sequences offers insights into the role of prophages in shaping the bacterial genome.
# Cyanobacteria Genomics
At present there are 24 cyanobacteria for which a total genome sequence is available. 15 of these cyanobacteria come from the marine environment. These are six Prochlorococcus strains, seven marine Synechococcus strains, Trichodesmium erythraeum IMS101 and Crocosphaera watsonii | Genomics
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Genomics is the study of an organism's entire genome. The field includes intensive efforts to determine the entire DNA sequence of organisms and fine-scale genetic mapping efforts. The field also includes studies of intragenomic phenomena such as heterosis, epistasis, pleiotropy and other interactions between loci and alleles within the genome. In contrast, the investigation of single genes, their functions and roles, something very common in today's medical and biological research, and a primary focus of molecular biology, does not fall into the definition of genomics, unless the aim of this genetic, pathway, and functional information analysis is to elucidate its effect on, place in, and response to the entire genome's networks.
# History of the field
Genomics can be said to have appeared in the 1980s, and took off in the 1990s with the initiation of genome projects for several biological species. A major branch of genomics is still concerned with sequencing the genomes of various organisms, but the knowledge of full genomes has created the possibility for the field of functional genomics, mainly concerned with patterns of gene expression during various conditions. The most important tools here are microarrays and bioinformatics. Study of the full set of proteins in a cell type or tissue, and the changes during various conditions, is called proteomics.
In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University of Ghent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene for Bacteriophage MS2 coat protein.[1]
In 1976, the team determined the complete nucleotide-sequence of bacteriophage MS2-RNA.[2]
The first DNA-based genome to be sequenced in its entirety was that of bacteriophage Φ-X174; (5,368 bp), sequenced by Frederick Sanger in 1977[3].
The first free-living organism to be sequenced was that of Haemophilus influenzae (1.8 Mb) in 1995, and since then genomes are being sequenced at a rapid pace. A rough draft of the human genome was completed by the Human Genome Project in early 2001, creating much fanfare.
As of September 2007, the complete sequence was known of about 1879 viruses [4], 577 bacterial species and roughly 23 eukaryote organisms, of which about half are fungi.
[5]
Most of the bacteria whose genomes have been completely sequenced are problematic disease-causing agents, such as Haemophilus influenzae. Of the other sequenced species, most were chosen because they were well-studied model organisms or promised to become good models. Yeast (Saccharomyces cerevisiae) has long been an important model organism for the eukaryotic cell, while the fruit fly Drosophila melanogaster has been a very important tool (notably in early pre-molecular genetics). The worm Caenorhabditis elegans is an often used simple model for multicellular organisms. The zebrafish Brachydanio rerio is used for many developmental studies on the molecular level and the flower Arabidopsis thaliana is a model organism for flowering plants. The Japanese pufferfish (Takifugu rubripes) and the spotted green pufferfish (Tetraodon nigroviridis) are interesting because of their small and compact genomes, containing very little non-coding DNA compared to most species.
[6]
[7]
The mammals dog (Canis familiaris),
[8]
brown rat (Rattus norvegicus), mouse (Mus musculus), and chimpanzee (Pan troglodytes) are all important model animals in medical research.
# Bacteriophage Genomics
Bacteriophages have played and continue to play a key role in bacterial genetics and molecular biology. Historically, they were used to define gene structure and gene regulation. Also the first genome to be sequenced was a bacteriophage. However, bacteriophage research did not lead the genomics revolution, which is clearly dominated by bacterial genomics. Only very recently has the study of bacteriophage genomes become prominent, thereby enabling researchers to understand the mechanisms underlying phage evolution. Bacteriophage genome sequences can be obtained through direct sequencing of isolated bacteriophages, but can also be derived as part of microbial genomes. Analysis of bacterial genomes has shown that a substantial amount of microbial DNA consists of prophage sequences and prophage-like elements. A detailed database mining of these sequences offers insights into the role of prophages in shaping the bacterial genome.[9]
# Cyanobacteria Genomics
At present there are 24 cyanobacteria for which a total genome sequence is available. 15 of these cyanobacteria come from the marine environment. These are six Prochlorococcus strains, seven marine Synechococcus strains, Trichodesmium erythraeum IMS101 and Crocosphaera watsonii [[WH8501. Several studies have demonstrated how these sequences could be used very successfully to infer important ecological and physiological characteristics of marine cyanobacteria. However, there are many more genome projects currently in progress, amongst those there are further Prochlorococcus and marine Synechococcus isolates, Acaryochloris and Prochloron, the N2-fixing filamentous cyanobacteria Nodularia spumigena, Lyngbya aestuarii and Lyngbya majuscula, as well as bacteriophages infecting marine cyanobaceria. Thus, the growing body of genome information can also be tapped in a more general way to address global problems by applying a comparative approach. Some new and exciting examples of progress in this field are the identification of genes for regulatory RNAs, insights into the evolutionary origin of photosynthesis, or estimation of the contribution of horizontal gene transfer to the genomes that have been analyzed.[10] | https://www.wikidoc.org/index.php/Genomic | |
7893f9e2bedf00241c7d5d33baabc23c676c0a5f | wikidoc | Gephyrin | Gephyrin
Gephyrin is a protein that in humans is encoded by the GPHN gene.
This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperekplexia and also lead to molybdenum cofactor deficiency.
# Gene
Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. The production of alternatively spliced variants is affected by noncoding regions within the gene. A ‘yin-yang’ noncoding sequence pair encompassing gephyrin has been identified. These sequences are opposites of each other - consisting of hundreds of divergent nucleotide states. Both of these patterns are uniquely human and evolved rapidly after splitting from their ancestral DNA pattern. The gephyrin yin and yang sequences are prevalent today in populations representing every major human ancestry.
# Function
Gephyrin is a 93kDa multi-functional protein that is a component of the postsynaptic protein network of inhibitory synapses. It consists of 3 domains: N terminal G domain, C terminal E domain, and a large unstructured linker domain which connects the two. Although there are structures available for trimeric G and dimeric E domains, there is no structure available for the full length protein, which may be due to the large unstructured region which makes the protein hard to crystallize. But a recent study of the full length gephyrin by small-angle X-ray scattering shows that it predominantly forms trimers, and that because of its long linker region, it can exist in either a compact state or either of two extended states.
Positive antibody staining for gephyrin at a synapse is most of the time consistent with the presence of glycine and/or GABAA receptors. Nevertheless, some exceptions can occur like in neurons of Dorsal Root Ganglions where gephyrin is absent despite the presence of GABAA receptors. Gephyrin is considered a major scaffolding protein at inhibitory synapses, analogous in its function to that of PSD-95 at glutamatergic synapses. Gephyrin was identified by its interaction with the glycine receptor, the main receptor protein of inhibitory synapses in the spinal cord and brainstem. In addition to its interaction with the glycine receptor, recent publications have shown that gephyrin also interacts with the intracellular loop between the transmembrane helices TM3 and TM4 of alpha and beta subunits of the GABAA receptor.
Gephyrin displaces GABA receptors from the GABARAP/P130 complex, then brings the receptors to the synapse. Once at the synapse, the protein binds to collybistin and neuroligin 2. In cells, gephyrin appears to form oligomers of at least three subunits. Several splice variants have been described that prevent this oligomerization without influencing the affinity for receptors. They nevertheless affect the composition of inhibitory synapses and can even play a role in diseases like epilepsy.
The gephyrin protein is also required during molybdenum cofactor assembly for insertion of molybdenum.
As aforementioned, gephyrin also catalyzes terminal two steps of Moco biosynthesis. In the penultimate step, N-terminal G domain adenylate the apo form of the molybdopterin to form the intermediate adenylated molybdopterin. In the terminal step, the C-terminal E domain catalyzes the deadenylation and also the metal insertion mechanism.
# Clinical significance
Humans with temporal lobe epilepsy have been found to have abnormally low levels of gephyrin in their temporal lobes. In animal models, a total lack of gephyrin results in stiff muscles and death immediately after birth. Stiff muscles are also a symptom of startle disease, that can be caused by a mutation in the gephyrin gene. And if a person produces auto-antibodies against gephyrin, this can even result in stiff person syndrome.
# Yin-yang sequences
At some point in human history, there was a DNA sequence encompassing gephyrin that split and followed two divergent evolutionary paths. These types of splits can occur when two populations become isolated from each other or when a chromosomal region does not experience recombination events. The two sequences that split from the ancestral sequence each acquired more than a hundred mutations that subsequently became common. This happened in a relatively short time on an evolutionary scale, as hundreds of mutations were fixed in distinct ‘yin’ and ‘yang’ sequences prior to human migration to Asia. It has been reported that currently Asians carry nearly equal numbers of yin and yang sequences and global populations representing every major human ancestry possess both yin and yang sequences. The existence of this massive yin-yang pattern suggests that two completely divergent evolutionary paths rapidly progressed during human history, presumably achieving the common goal of enhancing regulation of gephyrin.
# Interactions
GPHN has been shown to interact with Mammalian target of rapamycin and ARHGEF9. | Gephyrin
Gephyrin is a protein that in humans is encoded by the GPHN gene.[1][2][3][4][5]
This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperekplexia and also lead to molybdenum cofactor deficiency.
# Gene
Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known.[4] The production of alternatively spliced variants is affected by noncoding regions within the gene. A ‘yin-yang’ noncoding sequence pair encompassing gephyrin has been identified.[6] These sequences are opposites of each other - consisting of hundreds of divergent nucleotide states. Both of these patterns are uniquely human and evolved rapidly after splitting from their ancestral DNA pattern. The gephyrin yin and yang sequences are prevalent today in populations representing every major human ancestry.
# Function
Gephyrin is a 93kDa multi-functional protein that is a component of the postsynaptic protein network of inhibitory synapses. It consists of 3 domains: N terminal G domain, C terminal E domain, and a large unstructured linker domain which connects the two. Although there are structures available for trimeric G and dimeric E domains, there is no structure available for the full length protein, which may be due to the large unstructured region which makes the protein hard to crystallize. But a recent study of the full length gephyrin by small-angle X-ray scattering shows that it predominantly forms trimers, and that because of its long linker region, it can exist in either a compact state or either of two extended states.[7]
Positive antibody staining for gephyrin at a synapse is most of the time consistent with the presence of glycine and/or GABAA receptors. Nevertheless, some exceptions can occur like in neurons of Dorsal Root Ganglions where gephyrin is absent despite the presence of GABAA receptors.[5] Gephyrin is considered a major scaffolding protein at inhibitory synapses, analogous in its function to that of PSD-95 at glutamatergic synapses.[8][9] Gephyrin was identified by its interaction with the glycine receptor, the main receptor protein of inhibitory synapses in the spinal cord and brainstem. In addition to its interaction with the glycine receptor, recent publications have shown that gephyrin also interacts with the intracellular loop between the transmembrane helices TM3 and TM4 of alpha and beta subunits of the GABAA receptor.[10]
Gephyrin displaces GABA receptors from the GABARAP/P130 complex, then brings the receptors to the synapse.[11] Once at the synapse, the protein binds to collybistin[12] and neuroligin 2.[13] In cells, gephyrin appears to form oligomers of at least three subunits. Several splice variants have been described that prevent this oligomerization without influencing the affinity for receptors. They nevertheless affect the composition of inhibitory synapses and can even play a role in diseases like epilepsy.[14]
The gephyrin protein is also required during molybdenum cofactor assembly for insertion of molybdenum.[15]
As aforementioned, gephyrin also catalyzes terminal two steps of Moco biosynthesis. In the penultimate step, N-terminal G domain adenylate the apo form of the molybdopterin to form the intermediate adenylated molybdopterin. In the terminal step, the C-terminal E domain catalyzes the deadenylation and also the metal insertion mechanism.
# Clinical significance
Humans with temporal lobe epilepsy have been found to have abnormally low levels of gephyrin in their temporal lobes.[16] In animal models, a total lack of gephyrin results in stiff muscles and death immediately after birth. Stiff muscles are also a symptom of startle disease, that can be caused by a mutation in the gephyrin gene. And if a person produces auto-antibodies against gephyrin, this can even result in stiff person syndrome.[14]
# Yin-yang sequences
At some point in human history, there was a DNA sequence encompassing gephyrin that split and followed two divergent evolutionary paths.[6] These types of splits can occur when two populations become isolated from each other or when a chromosomal region does not experience recombination events. The two sequences that split from the ancestral sequence each acquired more than a hundred mutations that subsequently became common. This happened in a relatively short time on an evolutionary scale, as hundreds of mutations were fixed in distinct ‘yin’ and ‘yang’ sequences prior to human migration to Asia. It has been reported that currently Asians carry nearly equal numbers of yin and yang sequences and global populations representing every major human ancestry possess both yin and yang sequences.[6] The existence of this massive yin-yang pattern suggests that two completely divergent evolutionary paths rapidly progressed during human history, presumably achieving the common goal of enhancing regulation of gephyrin.
# Interactions
GPHN has been shown to interact with Mammalian target of rapamycin[2] and ARHGEF9.[12] | https://www.wikidoc.org/index.php/Gephyrin | |
e3139351635a46a711bdbd5eae9351114d4c5e0a | wikidoc | Geraniol | Geraniol
Geraniol, also called rhodinol, is a monoterpenoid and an alcohol. It is the primary part of oil-of-rose, palmarosa oil, and citronella oil (Java type). It also occurs in small quantities in geranium, lemon, and many other essential oils. It appears as a clear to pale-yellow oil which is insoluble in water, but soluble in most common organic solvents. It has a rose-like odor, for which it is commonly used in perfumes. It is used in flavors such as peach, raspberry, grapefruit, red apple, plum, lime, orange, lemon, watermelon, pineapple and blueberry.
Research has shown geraniol to be an effective plant based insect repellent.
Although,it is also produced by the scent glands of honey bees to help them mark nectar-bearing flowers and locate the entrances to their hives.
In a 1994 report released by five top cigarette companies, geraniol is listed as one of the 599 additives to cigarettes, to improve their flavor. Geraniol and other flavor compounds are found naturally in well aged tobacco.
In acidic solutions, geraniol is converted to the cyclic terpene alpha-terpineol.
# Health and safety information
Geraniol should be avoided by people with perfume allergy. | Geraniol
Template:Chembox new
Geraniol, also called rhodinol, is a monoterpenoid and an alcohol. It is the primary part of oil-of-rose, palmarosa oil, and citronella oil (Java type). It also occurs in small quantities in geranium, lemon, and many other essential oils. It appears as a clear to pale-yellow oil which is insoluble in water, but soluble in most common organic solvents. It has a rose-like odor, for which it is commonly used in perfumes. It is used in flavors such as peach, raspberry, grapefruit, red apple, plum, lime, orange, lemon, watermelon, pineapple and blueberry.
Research has shown geraniol to be an effective plant based insect repellent.[1][2]
Although,it is also produced by the scent glands of honey bees to help them mark nectar-bearing flowers and locate the entrances to their hives.
In a 1994 report released by five top cigarette companies, geraniol is listed as one of the 599 additives to cigarettes, to improve their flavor.[1] Geraniol and other flavor compounds are found naturally in well aged tobacco.
In acidic solutions, geraniol is converted to the cyclic terpene alpha-terpineol.
# Health and safety information
Geraniol should be avoided by people with perfume allergy[3]. | https://www.wikidoc.org/index.php/Geraniol | |
50cd2b98d374170d892f0b8f7db48602e7e8edef | wikidoc | Germaben | Germaben
Germaben II is a clear, viscous liquid used to inhibit microbial, yeast and mould growth in cosmetics and other personal products. It contains propylene glycol, propylparaben, methylparaben, and diazolidinyl urea. It is a Registered Trademark of International Specialty Products.
Germaben II is used primarily by small businesses or home hobbyists who make soap, lotions, shampoos and other body care products.
Germaben II contains parabens which are known carcinogens, causing breast tumors by mimicking the body's hormone estrogen. | Germaben
Germaben II[1] is a clear, viscous liquid used to inhibit microbial, yeast and mould growth in cosmetics and other personal products. It contains propylene glycol, propylparaben, methylparaben, and diazolidinyl urea. It is a Registered Trademark of International Specialty Products.
Germaben II is used primarily by small businesses or home hobbyists who make soap, lotions, shampoos and other body care products.
Germaben II contains parabens which are known carcinogens, causing breast tumors[2][3] by mimicking the body's hormone estrogen. | https://www.wikidoc.org/index.php/Germaben | |
507f79f3666f3236037cc6e96a05f534e51a2763 | wikidoc | Gibbsite | Gibbsite
Gibbsite, Al(OH)3, is one of the mineral forms of aluminium hydroxide. It is often designated as γ-Al(OH)3 (but sometimes as α-Al(OH)3 .). It is also sometimes called hydrargillite (or hydrargyllite).
Gibbsite is an important ore of aluminium in that it is one of three main phases that make up the rock bauxite. Bauxite is often thought of as a mineral but it is really a rock composed of hydroxide and oxyhydroxide minerals such as gibbsite, boehmite (γ-AlO(OH)), and diaspore (α-AlO(OH)), as well as clays, silt, and iron oxides and hydroxides.
Gibbsite has three named structural polymorphs or polytypes: bayerite (designated often as α-Al(OH)3, but sometimes as β-Al(OH)3), doyleite, and nordstrandite. Gibbsite and bayerite are monoclinic, whereas doyleite and nordstrandite are triclinic forms.
# Structure
The structure of gibbsite is interesting and analogous to the basic structure of the micas. The basic structure forms stacked sheets of linked octahedrons of aluminium hydroxide. The octahedrons are composed of aluminium ions with a +3 charge bonded to six octahedrally coordinated hydroxides with a -1 charge. Each of the hydroxides is bonded to only two aluminium atoms because one third of the octahedrons are vacant a central aluminium. The result is a neutral sheet since +3/6 = +1/2 (+3 charge on the aluminiums divided by six hydroxide bonds times the number of aluminiums) and -1/2 = -1/2 (-1 charge on the hydroxides divided between only two aluminiums); thus the charges cancel. The lack of a charge on the gibbsite sheets means that there is no charge to retain ions between the sheets and act as a "glue" to keep the sheets together. The sheets are only held together by weak residual bonds and this results in a very soft easily cleaved mineral.
Gibbsite's structure is closely related to the structure of brucite, Mg(OH)2. However the lower charge in brucite's magnesium (+2) as opposed to gibbsite's aluminium (+3) does not require that one third of the octahedrons be vacant of a central ion in order to maintain a neutral sheet. The different symmetry of gibbsite and brucite is due to the different way that the layers are stacked.
It is the gibbsite layer that in a way forms the "floor plan" for the mineral corundum, Al2O3. The basic structure of corundum is identical to gibbsite except the hydroxides are replaced by oxygen. Since oxygen has a charge of -2 the layers are not neutral and require that they must be bonded to other aluminiums above and below the initial layer producing the framework structure that is the structure of corundum.
Gibbsite is interesting for another reason because it is often found as a part of the structure of other minerals. The neutral aluminium hydroxide sheets are found sandwiched between silicate sheets in important clay groups: the illite, kaolinite, and montmorillonite/smectite groups. The individual aluminium hydroxide layers are identical to the individual layers of gibbsite and are referred to as the gibbsite layers.
# Etymology
Gibbsite is named after George Gibbs (1776-1833), an American mineral collector. G. Gibbs' collection was acquired by Yale University early in the nineteenth century.
# Further reading
- Hurlbut, Cornelius S.; Klein, Cornelis, 1985, Manual of Mineralogy, 20th ed., ISBN 0-471-80580-7
- Webmineral Gibbsite | Gibbsite
Gibbsite, Al(OH)3, is one of the mineral forms of aluminium hydroxide. It is often designated as γ-Al(OH)3 (but sometimes as α-Al(OH)3 [1].). It is also sometimes called hydrargillite (or hydrargyllite).
Gibbsite is an important ore of aluminium in that it is one of three main phases that make up the rock bauxite. Bauxite is often thought of as a mineral but it is really a rock composed of hydroxide and oxyhydroxide minerals such as gibbsite, boehmite (γ-AlO(OH)), and diaspore (α-AlO(OH)), as well as clays, silt, and iron oxides and hydroxides.
Gibbsite has three named structural polymorphs or polytypes: bayerite (designated often as α-Al(OH)3, but sometimes as β-Al(OH)3), doyleite, and nordstrandite. Gibbsite and bayerite are monoclinic, whereas doyleite and nordstrandite are triclinic forms.
# Structure
The structure of gibbsite is interesting and analogous to the basic structure of the micas. The basic structure forms stacked sheets of linked octahedrons of aluminium hydroxide. The octahedrons are composed of aluminium ions with a +3 charge bonded to six octahedrally coordinated hydroxides with a -1 charge. Each of the hydroxides is bonded to only two aluminium atoms because one third of the octahedrons are vacant a central aluminium. The result is a neutral sheet since +3/6 = +1/2 (+3 charge on the aluminiums divided by six hydroxide bonds times the number of aluminiums) and -1/2 = -1/2 (-1 charge on the hydroxides divided between only two aluminiums); thus the charges cancel. The lack of a charge on the gibbsite sheets means that there is no charge to retain ions between the sheets and act as a "glue" to keep the sheets together. The sheets are only held together by weak residual bonds and this results in a very soft easily cleaved mineral.
Gibbsite's structure is closely related to the structure of brucite, Mg(OH)2. However the lower charge in brucite's magnesium (+2) as opposed to gibbsite's aluminium (+3) does not require that one third of the octahedrons be vacant of a central ion in order to maintain a neutral sheet. The different symmetry of gibbsite and brucite is due to the different way that the layers are stacked.
It is the gibbsite layer that in a way forms the "floor plan" for the mineral corundum, Al2O3. The basic structure of corundum is identical to gibbsite except the hydroxides are replaced by oxygen. Since oxygen has a charge of -2 the layers are not neutral and require that they must be bonded to other aluminiums above and below the initial layer producing the framework structure that is the structure of corundum.
Gibbsite is interesting for another reason because it is often found as a part of the structure of other minerals. The neutral aluminium hydroxide sheets are found sandwiched between silicate sheets in important clay groups: the illite, kaolinite, and montmorillonite/smectite groups. The individual aluminium hydroxide layers are identical to the individual layers of gibbsite and are referred to as the gibbsite layers.[2]
# Etymology
Gibbsite is named after George Gibbs (1776-1833), an American mineral collector[3]. G. Gibbs' collection was acquired by Yale University early in the nineteenth century[4].
# Further reading
- Hurlbut, Cornelius S.; Klein, Cornelis, 1985, Manual of Mineralogy, 20th ed., ISBN 0-471-80580-7
- Webmineral Gibbsite | https://www.wikidoc.org/index.php/Gibbsite | |
520446be7bc0a29bb114b9d1f090b5bc0286b6a1 | wikidoc | Gillenia | Gillenia
Gillenia (syn. Porteranthus) is a genus of two species of perennial herbs in the Rosaceae family. Common names for plants in this genus include: Bowman's root, indian-physic, American ipecac. This genus is endemic to dry open woods with acidic soils in eastern North America. Both plants are subshrubs with exposed semi-woody branches and serrated leaves; the larger lower leaves are divided into palmately arranged leaflets. Plants bloom in May, June, or July; blooms are composed of five slender white petals which are loosely arranged and typically appear slightly twisted and limp as if they were wilted. The flowers mature into small capsules. These plants are often planted as ornamentals and used medicinally as an herbal remedy.
# Classification and name
Traditionally this genus is considered a member of subfamily Spiraeoideae. However, this genus is sometimes included in the subfamily Maloideae (or Pomoideae). This is somewhat controversial since members of this subfamily typically include only woody pome bearing plants with a haploid chromosome number of 17, and Gillenia is herbaceous and has a haploid chromosome number of 9.
It is not totally clear whether Gillenia (Moench) or Porteranthus (Britton ex Small) is the best name to use for this genus. Most current North American scholarly sources use the latter synonym Porteranthus citing that Gillenia is already occupied by way of quasi-synonymy: Gillena was used by Michel Adanson as a synonym for Clethra (The ICBN rules that "similar names that can be confused" should be treated as synonyms). A proposal to formally conserve Gillenia was mooted after a vote determined that Gillena was not validly published and that it and Gillenia were not likely to be confused. Several sources continue to use Porteranthus: Missouri Botanical Gardens 2007, Moerman 2003, Gleason & Cronquist 1991, and Magee and Ahles 1999. The Flora of North America volume containing this genus is not yet published.
# Species
The two similar species can be distinguished by their stipules. In G. stipulata, the stipules at the base of the leaves, which are round and deeply toothed, persist throughout the life of the plant. In G. trifoliata the long slender stipules are quickly deciduous, this species also tends to have longer leaves and petals.
- G. trifoliata or Porteranthus trifoliatus -- mountain indian physic
- G. stipulata or Porteranthus stipulatus -- indian physic | Gillenia
Gillenia (syn. Porteranthus) is a genus of two species of perennial herbs in the Rosaceae family. Common names for plants in this genus include: Bowman's root, indian-physic, American ipecac. This genus is endemic to dry open woods with acidic soils in eastern North America. Both plants are subshrubs with exposed semi-woody branches and serrated leaves; the larger lower leaves are divided into palmately arranged leaflets. Plants bloom in May, June, or July; blooms are composed of five slender white petals which are loosely arranged and typically appear slightly twisted and limp as if they were wilted. The flowers mature into small capsules. These plants are often planted as ornamentals and used medicinally as an herbal remedy.
# Classification and name
Traditionally this genus is considered a member of subfamily Spiraeoideae. However, this genus is sometimes included in the subfamily Maloideae (or Pomoideae). This is somewhat controversial since members of this subfamily typically include only woody pome bearing plants with a haploid chromosome number of 17, and Gillenia is herbaceous and has a haploid chromosome number of 9.
It is not totally clear whether Gillenia (Moench) or Porteranthus (Britton ex Small) is the best name to use for this genus. Most current North American scholarly sources use the latter synonym Porteranthus citing that Gillenia is already occupied by way of quasi-synonymy: Gillena was used by Michel Adanson as a synonym for Clethra[1] (The ICBN rules that "similar names that can be confused" should be treated as synonyms).[2] A proposal to formally conserve Gillenia[1] was mooted after a vote determined that Gillena was not validly published and that it and Gillenia were not likely to be confused.[3] Several sources continue to use Porteranthus: Missouri Botanical Gardens 2007,[4] Moerman 2003,[5] Gleason & Cronquist 1991,[6] and Magee and Ahles 1999.[7] The Flora of North America volume containing this genus is not yet published.[8]
# Species
The two similar species can be distinguished by their stipules. In G. stipulata, the stipules at the base of the leaves, which are round and deeply toothed, persist throughout the life of the plant. In G. trifoliata the long slender stipules are quickly deciduous, this species also tends to have longer leaves and petals.
- G. trifoliata or Porteranthus trifoliatus -- mountain indian physic
- G. stipulata or Porteranthus stipulatus -- indian physic | https://www.wikidoc.org/index.php/Gillenia | |
b5c4895a318f22750b667b4aead35b76d42920d3 | wikidoc | Gingerol | Gingerol
Gingerol, or sometimes -gingerol, is the active constituent of fresh ginger. Chemically, gingerol is a relative of capsaicin, the compound that gives chile peppers their spiciness. It is normally found as a pungent yellow oil, but also can form a low-melting crystalline solid.
Cooking ginger transforms gingerol into zingerone, which is less pungent and has a spicy-sweet aroma.
Gingerol may reduce nausea caused by motion sickness or pregnancy and may also relieve migraine. | Gingerol
Gingerol, or sometimes [6]-gingerol, is the active constituent of fresh ginger. Chemically, gingerol is a relative of capsaicin, the compound that gives chile peppers their spiciness. It is normally found as a pungent yellow oil, but also can form a low-melting crystalline solid.
Cooking ginger transforms gingerol into zingerone, which is less pungent and has a spicy-sweet aroma.
Gingerol may reduce nausea caused by motion sickness or pregnancy[1] and may also relieve migraine.[2] | https://www.wikidoc.org/index.php/Gingerol | |
b1878c8258d35b0039a25f6b0af0eacf237ff17f | wikidoc | Glanders | Glanders
# Overview
Glanders (from Middle English glaundres or Old French glandres, both meaning glands) (Latin: Malleus German: Rotz) is an infectious disease that occurs primarily in horses, mules, and donkeys. It can be contracted by other animals such as dogs, cats and goats. It is caused by infection by the bacterium Burkholderia mallei, usually by ingestion of contaminated food or water. Symptoms of glanders include the formation of nodular lesions in the lungs and ulceration of the mucous membranes in the upper respiratory tract. The acute form results in coughing, fever and the release of infectious nasal discharge, followed by septicemia and death within days. In the chronic form, nasal and subcutaneous nodules develop, eventually ulcerating. Death can occur within months, while survivors act as carriers.
Glanders is endemic in Africa, Asia, the Middle East, Central and South America. It has been eradicated from North America, Australia and most of Europe through surveillance and destruction of affected animals, and import restrictions.
Burkholderia mallei, is able to infect humans and is therefore classed as a zoonotic agent. Transmission occurs by direct contact with infected animals and entry is through skin abrasions, nasal and oral mucosal surfaces, or by inhalation.
# Biological warfare use
Due to the high mortality rate in humans and the small number of organisms required to establish infection, Burkholderia mallei is regarded as a potential biological warfare (BW) or bioterrorism agent, as is the closely related organism, Burkholderia pseudomallei, the causative agent of melioidosis. During World War I, glanders was believed to have been spread deliberately by German agents to infect large numbers of Russian horses and mules on the Eastern Front. This had an effect on troop and supply convoys as well as on artillery movement, which were dependent on horses and mules. Human cases in Russia increased with the infections during and after WWI. The Japanese deliberately infected horses, civilians, and prisoners of war with B. mallei at the Pinfang (China) Institute during World War II. The U.S. studied this agent as a possible BW weapon in 1943–44 but did not weaponize it. The Soviet Union is also believed to have been interested in B. mallei as a potential BW agent after World War II.
# Gallery
- Colonial morphology displayed by Gram-negative Burkholderia mallei bacteria, on a medium of sheep’s blood agar (SBA). From Public Health Image Library (PHIL).
- Colonial morphology displayed by Gram-negative Burkholderia mallei bacteria, grown on a medium of chocolate agar. From Public Health Image Library (PHIL).
- Colonial morphology displayed by Gram-negative Burkholderia mallei bacteria, grown on a medium of chocolate agar. From Public Health Image Library (PHIL).
- Colonial morphology colonial morphology displayed by Gram-negative Burkholderia thailandensis bacteria, grown on a medium of sheep’s blood agar (SBA). From Public Health Image Library (PHIL).
# Treatment
## Antimicrobial regimen
- Glanders
- Preferred regimen: Ceftazidime OR Gentamicin OR Imipenem OR Doxycycline OR Ciprofloxacin is recommended based on in vitro susceptibility | Glanders
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Glanders (from Middle English glaundres or Old French glandres, both meaning glands)[1] (Latin: Malleus German: Rotz) is an infectious disease that occurs primarily in horses, mules, and donkeys. It can be contracted by other animals such as dogs, cats and goats. It is caused by infection by the bacterium Burkholderia mallei, usually by ingestion of contaminated food or water. Symptoms of glanders include the formation of nodular lesions in the lungs and ulceration of the mucous membranes in the upper respiratory tract. The acute form results in coughing, fever and the release of infectious nasal discharge, followed by septicemia and death within days. In the chronic form, nasal and subcutaneous nodules develop, eventually ulcerating. Death can occur within months, while survivors act as carriers.
Glanders is endemic in Africa, Asia, the Middle East, Central and South America. It has been eradicated from North America, Australia and most of Europe through surveillance and destruction of affected animals, and import restrictions.
Burkholderia mallei, is able to infect humans and is therefore classed as a zoonotic agent. Transmission occurs by direct contact with infected animals and entry is through skin abrasions, nasal and oral mucosal surfaces, or by inhalation.
# Biological warfare use
Due to the high mortality rate in humans and the small number of organisms required to establish infection, Burkholderia mallei is regarded as a potential biological warfare (BW) or bioterrorism agent, as is the closely related organism, Burkholderia pseudomallei, the causative agent of melioidosis. During World War I, glanders was believed to have been spread deliberately by German agents to infect large numbers of Russian horses and mules on the Eastern Front.[2] This had an effect on troop and supply convoys as well as on artillery movement, which were dependent on horses and mules. Human cases in Russia increased with the infections during and after WWI. The Japanese deliberately infected horses, civilians, and prisoners of war with B. mallei at the Pinfang (China) Institute during World War II. The U.S. studied this agent as a possible BW weapon in 1943–44 but did not weaponize it. The Soviet Union is also believed to have been interested in B. mallei as a potential BW agent after World War II.
# Gallery
- Colonial morphology displayed by Gram-negative Burkholderia mallei bacteria, on a medium of sheep’s blood agar (SBA). From Public Health Image Library (PHIL). [3]
- Colonial morphology displayed by Gram-negative Burkholderia mallei bacteria, grown on a medium of chocolate agar. From Public Health Image Library (PHIL). [3]
- Colonial morphology displayed by Gram-negative Burkholderia mallei bacteria, grown on a medium of chocolate agar. From Public Health Image Library (PHIL). [3]
- Colonial morphology colonial morphology displayed by Gram-negative Burkholderia thailandensis bacteria, grown on a medium of sheep’s blood agar (SBA). From Public Health Image Library (PHIL). [3]
# Treatment
## Antimicrobial regimen
- Glanders[4]
- Preferred regimen: Ceftazidime OR Gentamicin OR Imipenem OR Doxycycline OR Ciprofloxacin is recommended based on in vitro susceptibility | https://www.wikidoc.org/index.php/Glanders | |
5282d4b8bad2eaf95703d44309f4acb884328f62 | wikidoc | Imatinib | Imatinib
- Content
- For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).
- For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron.
- Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.
- Newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase.
- Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
- The recommended dose of Imatinib is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.
- In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.
- Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia.
- The recommended dose of Imatinib is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.
- Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements.
- The recommended dose of Imatinib is 400 mg/day for adult patients with MDS/MPD.
- Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.
- The recommended dose of Imatinib is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Imatinib 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
- Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.
- The recommended dose of Imatinib is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
- Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.
- The recommended dose of Imatinib is 800 mg/day for adult patients with DFSP.
- Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.
- The recommended dose of Imatinib is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.
- Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.
- The recommended dose of Imatinib is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials one year of Imatinib and three years of Imatinib were studied. In the patient population defined in Study 2, three years of Imatinib is recommended. The optimal treatment duration with Imatinib is not known.
- Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Imatinib should be increased by at least 50%, and clinical response should be carefully monitored.
- Hepatic Impairment: Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.
- Renal Impairment: Patients with moderate renal impairment (CrCL=20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL=40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended.
- Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two patients with severe renal impairment.
- If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur, Imatinib should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels to <2.5 x IULN. In adults, treatment with Imatinib may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day.
- If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Imatinib should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
- Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.
- The recommended dose of Imatinib for children with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600 mg).
- The recommended dose of Imatinib to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340mg/m2/day (not to exceed 600mg).
- Imatinib is often associated with edema and occasionally serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Imatinib dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Imatinib, and in 2%-6% of other adult CML patients taking Imatinib. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Imatinib, and in 2%-6% of other adult CML patients taking Imatinib. Severe fluid retention was reported in 9% to 13.1% of patients taking Imatinib for GIST.
- Treatment with Imatinib is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy.
- Severe congestive heart failure and left ventricular dysfunction have been reported in patients taking Imatinib. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Imatinib compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.
- Hepatotoxicity, occasionally severe, may occur with Imatinib. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Imatinib. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Imatinib interruption and/or dose reduction.
- When Imatinib is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.
- In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. Patients should therefore be monitored for gastrointestinal symptoms at the start of therapy.
- Imatinib is sometimes associated with GI irritation. Imatinib should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.
- In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of Imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Imatinib. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Imatinib should be considered at the initiation of therapy.
- Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Imatinib. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Imatinib therapy after resolution or improvement of the bullous reaction. In these instances, Imatinib was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.
- Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Imatinib. TSH levels should be closely monitored in such patients.
- It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.
- Imatinib can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. Sexually active female patients of reproductive potential taking Imatinib should use highly effective contraception. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- Growth retardation has been reported in children and pre-adolescents receiving Imatinib. The long term effects of prolonged treatment with Imatinib on growth in children are unknown. Therefore, close monitoring of growth in children under Imatinib treatment is recommended.
- Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Imatinib. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Imatinib.
- Reports of motor vehicle accidents have been received in patients receiving Imatinib. While most of these reports are not suspected to be caused by Imatinib, patients should be advised that they may experience undesirable effects such as dizziness,blurred vision or somnolence during treatment with Imatinib. Therefore, caution should be recommended when driving a car or operating machinery.
- The majority of Imatinib-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% in blast crisis.
- The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 for newly diagnosed CML, Table 3 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Imatinib. The frequency of severe superficial edema was 1.5%-6%.
- A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Imatinib treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure.
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Imatinib treated patients are shown in Tables 2 and 3.
- Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.
- In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 4 and 5). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.
- These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Imatinib, but in rare cases require permanent discontinuation of treatment.
- Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.
- Single agent therapy
- The overall safety profile of pediatric patients treated with Imatinib in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low.
- In combination with multi-agent chemotherapy
- Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n=92) were assigned to receive Imatinib and treated in 5 successive cohorts. Imatinib exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.
- The safety of Imatinib given in combination with intensive chemotherapy was evaluated by comparing the incidence of grade 3 and 4 adverse events, neutropenia (<750/µL) and thrombocytopenia (<75,000/ µL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive Imatinib. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without Imatinib. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with Imatinib and 647 without Imatinib. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included Imatinib are presented in Table 6.
- In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.
## Acute Lymphoblastic Leukemia=
- The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps and rash, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Imatinib.
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Imatinib for MDS/MPD in the phase 2 study, are shown in Table 7.
- All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and lower respiratory tract infection. None of the 5 patients in the phase 2 study with ASM discontinued Imatinib due to drug-related adverse reactions or abnormal laboratory values.
- The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of Imatinib observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Imatinib for DFSP in the phase 2 study are shown in Table 8.
- Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Imatinib for DFSP in the phase 2 study are presented in Table 9.
- In the Phase 3 trials the majority of Imatinib-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Imatinib. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Imatinib are shown in Table 10.
- Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.
- Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 11.
- In Study 1, the majority of both Imatinib and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Imatinib and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.
- In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the Imatinib 12-month and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Imatinib are shown in Table 12 (Study 1) and Table 13 (Study 2). There were no deaths attributable to Imatinib treatment in either trial.
The following adverse reactions have been reported during clinical trials of Imatinib.
- Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema
- Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion
- Estimated 1%-10%: flushing, hemorrhage
- Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynaud's phenomenon, hematoma, subdural hematoma
- Estimated 0.1%-1%: blood CPK increased, blood LDH increased
- Estimated 0.01%-0.1%: blood amylase increased
- Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction
- Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae
- Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, erythema multiforme, leucocytoclastic vasculitis
- Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis
- Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis
- Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease
- Estimated 1%-10%: weakness, anasarca, chills
- Estimated 0.1%-1%: malaise
- Estimated 1%-10%: pancytopenia, febrile neutropenia
- Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy
- Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia
- Estimated 0.1%-1%: hepatitis, jaundice
- Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1
- Estimated 0.01%-0.1%: angioedema
- Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis
- Estimated 0.01%-0.1%: fungal infection
Metabolic and Nutritional:
- Estimated 1%-10%: weight decreased
- Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia
- Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia
- Estimated 1%-10%: joint swelling
- Estimated 0.1%-1%: joint and muscle stiffness
- Estimated 0.01%-0.1%: muscular weakness, arthritis
- Estimated 1%-10%: paresthesia, hypesthesia
- Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor
- Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis
- Estimated 0.1%-1%: acute renal failure, urinary frequency increased, hematuria, renal pain
- Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema
- Estimated 1%-10%: epistaxis
- Estimated 0.1%-1%: pleural effusion
- Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage
- Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye
- Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss
- Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract.
- Cerebral edema
- Vitreous hemorrhage
- Pericarditis, cardiac tamponade
- Thrombosis/embolism, anaphylactic shock
- Acute respiratory failure, interstitial lung disease
- Ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation, diverticulitis
- Lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)
- Avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children
- Hemorrhagic corpus luteum/hemorrhagic ovarian cyst
- Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Imatinib, increased Imatinib oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC.
- Similar findings were observed in patients receiving 400-1200 mg/day Imatinib concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED.
Concomitant administration of Imatinib and St. John’s Wort led to a 30% reduction in the AUC of imatinib.
Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Imatinib doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers.
- There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Imatinib was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Imatinib with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations.
- Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Imatinib. Particular caution is recommended when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).
- Imatinib will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).
Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.
- Imatinib increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Imatinib has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.
- In vitro, Imatinib inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 µM). Co-administration of Imatinib (400 mg/day for eight days) with acetaminophen (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Imatinib pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of Imatinib at doses >400 mg/day or the chronic use of concomitant acetaminophen and Imatinib.
- Imatinib can cause fetal harm when administered to a pregnant woman. There have been post-market reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Imatinib was teratogenic in animals. Women should be advised not to become pregnant when taking Imatinib. 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.
- Animal Data
- Imatinib mesylate was teratogenic in rats when administered orally during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg).
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imatinib in women who are pregnant.
- As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m2 in children vs. 10.0 L/hr/m2 in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m2 and 340 mg/m2 achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m2 and 340 mg/m2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose.
- Based on pooled population pharmacokinetic analysis in pediatric patients with hematological disorders (CML, Ph+ ALL, or other hematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in pediatric patients receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily.
- In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.
- In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Imatinib was similar in patients older than 65 years and younger patients.
- Monitoring of hepatic function is recommended.
## Signs and Symptoms
- Adult Overdose
- 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
- 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain.
- 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.
- 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.
- A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Imatinib daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Imatinib daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Imatinib on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy.
- Pediatric Overdose
- One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3 year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea.
## Management
- In the event of overdosage, the patient should be observed and appropriate supportive treatment given.
# Chronic Overdose
There is limited information regarding Chronic Overdose of Imatinib in the drug label.
- In vivo, imatinib inhibits tumor growth of bcr-abl transfected murine myeloid cells as well as bcr-abl positive leukemia lines derived from CML patients in blast crisis.
- Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation.
- Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. Its molecular formula is C29H31N7O - CH4SO3 and its molecular weight is 589.7. Imatinib mesylate is soluble in aqueous buffers ≤pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol, and ethanol, but is insoluble in n-octanol, acetone, and acetonitrile.
- Inactive Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); hydroxypropyl methylcellulose (USP); magnesium stearate (NF); and microcrystalline cellulose (NF). Tablet coating: ferric oxide, red (NF); ferric oxide, yellow (NF); hydroxypropyl methylcellulose (USP); polyethylene glycol (NF) and talc (USP).
- CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound. Human liver microsome studies demonstrated that Imatinib is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with Ki values of 27, 7.5, and 8 µM, respectively.
- Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.
- Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.
- In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. Neoplastic lesions were not seen at: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known.
- Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay.
- In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on body surface area. This was not seen at doses ≤20 mg/kg (one-fourth the maximum human dose of 800 mg). The fertility of male and female rats was not affected.
- In a pre- and post-natal development study in female rats dosed with imatinib mesylate at 45 mg/kg (approximately one-half the maximum human dose of 800 mg/day, based on body surface area) from gestational Day 6 until the end of lactation, red vaginal discharge was noted on either gestational Day 14 or 15. In the first generation offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice. First generation offspring fertility was not affected but reproductive effects were noted at 45 mg/kg/day including an increased number of resorptions and a decreased number of viable fetuses.
- Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In the preclinical pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by Imatinib.
- Human studies on male patients receiving Imatinib and its affect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on Imatinib treatment should consult with their physician.
- Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. This study compared treatment with either single-agent Imatinib or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C). Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR. Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC). In the Imatinib arm, patients were treated initially with 400 mg daily. Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily. In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m2/day subcutaneously in combination with subcutaneous Ara-C 20 mg/m2/day for 10 days/month.
- A total of 1,106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range 18-70 years), with 21.9% of patients ≥60 years of age. There were 59% males and 41% females; 89.9% Caucasian and 4.7% Black patients. At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the Imatinib and IFN arm, respectively. The median duration of second-line treatment with Imatinib was 64 months. Sixty percent of patients randomized to Imatinib are still receiving first-line treatment. In these patients, the average dose of Imatinib was 403 mg ± 57 mg. Overall, in patients receiving first line Imatinib, the average daily dose delivered was 406 mg ± 76 mg. Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the Imatinib arm was severe intolerance to treatment (26%) and progression (14%).
- The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive Imatinib were compared with patients randomized to receive IFN. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 84 months in the ITT population was 81.2 % in the Imatinib arm and 60.6 % in the IFN arm (p<0.0001, log-rank test), (Figure 1). With 7 years follow up there were 93 (16.8%) progression events in the Imatinib arm: 37(6.7%) progression to AP/BC, 31(5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC and 10 (1.8%) CML unrelated deaths. In contrast, there were 165 (29.8%) events in the IFN+Ara-C arm of which 130 occurred during first-line treatment with IFN-Ara-C. The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 84 months was 92.5% in the Imatinib arm compared to the 85.1%, (p≤0.001) in the IFN arm, (Figure 2). The annual rates of any progression events have decreased with time on therapy. The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (≥3 log reduction in Bcr-Abl transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in complete cytogenetic response but without a major molecular response and 70% in patients who were not in complete cytogenetic response at this time point (p<0.001).
- A total of 71 (12.8%) and 85 (15.4%) patients died in the Imatinib and IFN+Ara-C group, respectively. At 84 months the estimated overall survival is 86.4% (83, 90) vs. 83.3% (80, 87) in the randomized Imatinib and the IFN+Ara-C group, respectively (p=0.073 log-rank test). The hazard ratio is 0.750 with 95% CI 0.547-1.028. This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to Imatinib. Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints. Response data are shown in Table 16. Complete hematologic response, major cytogenetic response and complete cytogenetic response were also statistically significantly higher in the Imatinib arm compared to the IFN + Ara-C arm (no cross-over data considered for evaluation of responses). Median time to CCyR in the 454 responders was 6 months (range 2-64 months, 25th to 75th percentiles=3 to 11 months) with 10% of responses seen only after 22 months of therapy).
- Molecular response was defined as follows:
- In the peripheral blood, after 12 months of therapy, reduction of ≥3 logarithms in the amount of bcr-abl transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a standardized baseline. Molecular response was only evaluated in a subset of patients who had a complete cytogenetic response by 12 months or later (N=333). The molecular response rate in patients who had a complete cytogenetic response in the Imatinib arm was 59% at 12 months and 72% at 24 months.
- Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase. After one month of therapy to six months of therapy, there was a 13%-21% decrease in median index from baseline in patients treated with IFN, consistent with increased symptoms of IFN toxicity. There was no apparent change from baseline in median index for patients treated with Imatinib.
- Late Chronic Phase CML and Advanced Stage CML:
- Three international, open-label, single-arm phase 2 studies were conducted to determine the safety and efficacy of Imatinib in patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2) in accelerated phase disease, or 3) in myeloid blast crisis. About 45% of patients were women and 6% were Black. In clinical studies 38%-40% of patients were ≥60 years of age and 10%-12% of patients were ≥70 years of age.
- Chronic Phase, Prior Interferon-Alpha Treatment:
- 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed. The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%). Patients had received a median of 14 months of prior IFN therapy at doses ≥25 x 106 IU/week and were all in late chronic phase, with a median time from diagnosis of 32 months. Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or complete cytogenetic response (0% Ph+ metaphases). Median duration of treatment was 29 months with 81% of patients treated for ≥24 months (maximum = 31.5 months). Efficacy results are reported in Table 16. Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%). Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients.
- Accelerated Phase:
- 235 patients with accelerated phase disease were enrolled. These patients met one or more of the following criteria: ≥15%-<30% blasts in PB or BM; ≥30% blasts + promyelocytes in PB or BM; ≥20% basophils in PB; and <100 x 109/L platelets. The first 77 patients were started at 400 mg, with the remaining 158 patients starting at 600 mg.
- Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. Cytogenetic responses were also evaluated. Median duration of treatment was 18 months with 45% of patients treated for ≥24 months (maximum=35 months). Efficacy results are reported in Table 17. Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs. 64%), confirmed and unconfirmed major cytogenetic response (31% vs. 19%).
- Myeloid Blast Crisis:
- 260 patients with myeloid blast crisis were enrolled. These patients had ≥30% blasts in PB or BM and/or extramedullary involvement other than spleen or liver; 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg; the remaining 223 patients were started at 600 mg.
- Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase. Cytogenetic responses were also assessed. Median duration of treatment was 4 months with 21% of patients treated for ≥12 months and 10% for ≥24 months (maximum=35 months). Efficacy results are reported in Table 17. The hematologic response rate was higher in untreated patients than in treated patients (36% vs. 22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs. 16%). The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600 mg dose group than for the 400 mg dose group (17% vs. 8%).
- The median time to hematologic response was 1 month. In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to AP or BC, and estimated overall survival was 90.8% . In accelerated phase, median duration of hematologic response was 28.8 months for patients with an initial dose of 600 mg (16.5 months for 400 mg). An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response. The median survival was 20.9 months for the 400 mg group and was not yet reached for the 600 mg group (p=0.0097). An estimated 46.2% vs. 65.8% of patients were still alive after 2 years of treatment in the 400 mg vs. 600 mg dose groups, respectively. In blast crisis, the estimated median duration of hematologic response is 10 months. An estimated 27.2% of hematologic responders maintained their response 2 years after achieving their initial response. Median survival was 6.9 months, and an estimated 18.3% of all patients with blast crisis were alive 2 years after start of study.
- Efficacy results were similar in men and women and in patients younger and older than age 65. Responses were seen in Black patients, but there were too few Black patients to allow a quantitative comparison.
- A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single arm phase 2 trial. Patients were treated with Imatinib 340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy. The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16%. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 6.74 months. Patients were allowed to be removed from protocol therapy to undergo alternative therapy including hematopoietic stem cell transplantation. Thirty one children received stem cell transplantation. Of the 31 children, 5 were transplanted after disease progression on study and 1 withdrew from study during first week treatment and received transplant approximately 4 months after withdrawal. Twenty five children withdrew from protocol therapy to undergo stem cell transplant after receiving a median of 9 twenty-eight day courses (range 4 to 24). Of the 25 patients 13 (52%) had CCyR and 5 (20%) had PCyR at the end of protocol therapy.
- One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy. These patients had not previously received Imatinib and ranged in age from 3-20 years old; 3 were 3-11 years old, 9 were 12-18 years old, and 2 were >18 years old. Patients were treated at doses of 260 mg/m2/day (n=3), 340 mg/m2/day (n=4), 440 mg/m2/day (n=5) and 570 mg/m2/day (n=2). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had a minimal cytogenetic response.
- In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a complete cytogenetic response at doses of 242 and 257 mg/m2/day.
- A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended Imatinib dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received Imatinib 600 mg/day in a phase 1 study.
- Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ALL phase 2 study patients and for the 2 phase 1 patients are shown in Table 18. The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months.
- Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol.
- The safety and effectiveness of Imatinib (340 mg/m2/day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL. The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor. There were 92 eligible patients with Ph+ ALL enrolled. The median age was 9.5 years (1 to 21 years), 64% were male, 75% were white, 9% were Asian/Pacific Islander, and 5% were black. In 5 successive cohorts of patients, Imatinib exposure was systematically increased by earlier introduction and prolonged duration. Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of Imatinib exposure.
- There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received Imatinib plus chemotherapy; 30 were treated exclusively with chemotherapy and Imatinib and 20 received chemotherapy plus Imatinib and then underwent hematopoietic stem cell transplant, followed by further Imatinib treatment. Patients in cohort 5 treated with chemotherapy received continuous daily exposure to Imatinib beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy. During maintenance cycles 5 through 12 Imatinib was administered 28 days out of the 56 day cycle. Patients who underwent hematopoietic stem cell transplant received 42 days of Imatinib prior to HSCT, and 28 weeks (196 days) of Imatinib after the immediate post transplant period. The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81). The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months.
- An open label, multicenter, phase 2 clinical trial was conducted testing Imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD. These patients were treated with Imatinib 400 mg daily. The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received Imatinib at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a complete cytogenetic response). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1(7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12.9 months (0.8-26.7) in the 7 patients treated within the phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 19. Response durations of phase 2 study patients ranged from 141+ days to 457+ days.
- One open-label, multicenter, phase 2 study was conducted testing Imatinib in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5 patients with aggressive systemic mastocytosis (ASM) treated with 100 mg to 400 mg of Imatinib daily. These 5 patients ranged from 49 to 74 years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of Imatinib in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of Imatinib daily.
- Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with Imatinib from the published reports and in the phase 2 study. Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to Imatinib), one with concomitant CML.
- Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (61% overall response rate). Median duration of Imatinib therapy for the 5 ASM patients in the phase 2 study was 13 months (range 1.4-22.3 months) and between 1 month and more than 30 months in the responding patients described in the published medical literature. A summary of the response rates to Imatinib in ASM is provided in Table 20. Response durations of literature patients ranged from 1+ to 30+ months.
- Imatinib has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). Imatinib is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that harbor the D816V mutation of c-Kit are not sensitive to Imatinib and should not receive Imatinib.
- One open-label, multicenter, phase 2 study was conducted testing Imatinib in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100 mg to 1000 mg of Imatinib daily. The ages of these patients ranged from 16 to 64 years. A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series. These patients received Imatinib at doses of 75 mg to 800 mg daily. Hematologic response rates are summarized in Table 21. Response durations for literature patients ranged from 6+ weeks to 44 months.
- Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene.
- An open-label, multicenter, phase 2 study was conducted testing Imatinib in a diverse population of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 12 patients with DFSP who were treated with Imatinib 800 mg daily (age range 23 to 75 years). DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry. A further 6 DFSP patients treated with Imatinib are reported in 5 published case reports, their ages ranging from 18 months to 49 years. The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) Imatinib daily. A single pediatric patient received 400 mg/m2/daily, subsequently increased to 520 mg/m2/daily. Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities. Responses to treatment are described in Table 22.
- Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%). For the 10 study patients with the PDGF B gene rearrangement there were 4 complete and 6 partial responses. The median duration of response in the phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months.
- Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST). The two study designs were similar allowing a predefined combined analysis of safety and efficacy. A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally daily continuously until disease progression or unacceptable toxicity. Patients in the 400 mg daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily. The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 years. Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST.
- The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 23.
- Median follow up for the combined studies was 37.5 months. There were no observed differences in overall survival between the treatment groups (p=0.98). Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n=347) had a 3.4 month median and a 7.7 month mean exposure to Imatinib following crossover.
- One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally q.d. for up to 36 months. The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. There were no differences in response rates between the 2 dose groups. The response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group. The median time to response was 12 weeks (range was 3-98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached).
- In the adjuvant setting, Imatinib was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1). Patients were randomized one to one to Imatinib at 400 mg/day or matching placebo for 12 months. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size ≥3 cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration.
- Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause. In a planned interim analysis, the median follow up was 15 months in patients without a RFS event; there were 30 RFS events in the 12-month Imatinib arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95% CI: 0.259, 0.610), p<0.0001. After the interim analysis of RFS, 79 of the 354 patients initially randomized to the placebo arm were eligible to cross over to the 12-month Imatinib arm. Seventy-two of these 79 patients subsequently crossed over to Imatinib therapy. In an updated analysis, the median follow-up for patients without a RFS event was 50 months. There were 74 (21%) RFS events in the 12-month Imatinib arm compared to 98 (28%) events in the placebo arm with a hazard ratio of 0.718 (95% CI: 0.531-0.971) (Figure 3). The median follow-up for OS in patients still living was 61 months. There were 26 (7%) and 33 (9%) deaths in the 12-month Imatinib and placebo arms, respectively with a hazard ratio of 0.816 (95% CI: 0.488-1.365).
- A second randomized, multicenter, open label, phase 3 trial in the adjuvant setting (Study 2) compared 12 months of Imatinib treatment to 36 months of Imatinib treatment at 400 mg/day in adult patients with KIT (CD117) positive GIST after surgical resection with one of the following: tumor diameter >5 cm and mitotic count >5/50 high power fields (HPF), or tumor diameter >10 cm and any mitotic count, or tumor of any size with mitotic count >10/50 HPF, or tumors ruptured into the peritoneal cavity. There were a total of 397 patients randomized in the trial with 199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm. The median age was 61 years (range 22 to 84 years).
- RFS was defined as the time from date of randomization to the date of recurrence or death from any cause. The median follow-up for patients without a RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of Imatinib treatment significantly prolonged RFS compared to 12 months of Imatinib treatment with a hazard ratio of 0.46 (95% CI: 0.32, 0.65), p<0.0001 (Figure 4).
- The median follow-up for overall survival (OS) in patients still living was 48 months. There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six months of Imatinib treatment significantly prolonged OS compared to 12 months of Imatinib treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p=0.0187 (Figure 5).
- 100 mg Tablets
- Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side.
- Bottles of 90 tablets………………………………….NDC 0078-0401-34
- 400 mg Tablets
- Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side with score on the other side, and “SL” on each side of the score.
- Bottles of 30 tablets…………………………………NDC 0078-0438-15
- Storage and Handling
- Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Protect from moisture.
- Dispense in a tight container, USP.
- Imatinib is an antineoplastic product. Follow special handling and disposal procedures1
- Imatinib tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed tablets.
- Patients should be informed to take Imatinib exactly as prescribed, not to change their dose or to stop taking Imatinib unless they are told to do so by their doctor. If patients miss a dose they should be advised to take their dose as soon as possible unless it is almost time for their next dose in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. Patients should be advised to take Imatinib with a meal and a large glass of water.
- Pregnancy and Breast-Feeding
- Patients should be advised to inform their doctor if they are or think they may be pregnant. Women of reproductive potential should be advised to avoid becoming pregnant while taking Imatinib. Sexually active female patients taking Imatinib should use highly effective contraception. Patients should also be advised not to breast feed while taking Imatinib.
- Adverse Reactions
- Patients should be advised to tell their doctor if they experience side effects during Imatinib therapy including fever, shortness of breath, blood in their stools, jaundice, sudden weight gain, symptoms of cardiac failure, or if they have a history of cardiac disease or risk factors for cardiac failure.
- Drug Interactions
- Patients should be advised not to take any other medications, including over-the-counter medications such as herbal products without talking to their doctor or pharmacist first. Examples of other medications that should not be taken with Imatinib are warfarin, erythromycin, and phenytoin. Patients should also be advised to tell their doctor if they are taking or plan to take iron supplements. Patients should also avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking Imatinib.
- Pediatric
- Patients should be advised that growth retardation has been reported in children and pre-adolescents receiving Imatinib. The long term effects of prolonged treatment with Imatinib on growth in children are unknown. Therefore, close monitoring of growth in children under Imatinib treatment is recommended.
- Driving and Using Machines
- Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with Imatinib. Therefore, caution patients about driving a car or operating machinery.
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- Content
- For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).
- For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron.
- Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.
- Newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase.
- Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
- The recommended dose of Imatinib is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.
- In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.
- Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia.
- The recommended dose of Imatinib is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.
- Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements.
- The recommended dose of Imatinib is 400 mg/day for adult patients with MDS/MPD.
- Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.
- The recommended dose of Imatinib is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Imatinib 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
- Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.
- The recommended dose of Imatinib is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
- Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.
- The recommended dose of Imatinib is 800 mg/day for adult patients with DFSP.
- Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.
- The recommended dose of Imatinib is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.
- Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.
- The recommended dose of Imatinib is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials one year of Imatinib and three years of Imatinib were studied. In the patient population defined in Study 2, three years of Imatinib is recommended. The optimal treatment duration with Imatinib is not known.
- Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Imatinib should be increased by at least 50%, and clinical response should be carefully monitored.
- Hepatic Impairment: Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.
- Renal Impairment: Patients with moderate renal impairment (CrCL=20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL=40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended.
- Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two patients with severe renal impairment.
- If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur, Imatinib should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels to <2.5 x IULN. In adults, treatment with Imatinib may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day.
- If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Imatinib should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
- Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.
- The recommended dose of Imatinib for children with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600 mg).
- The recommended dose of Imatinib to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340mg/m2/day (not to exceed 600mg).
- Imatinib is often associated with edema and occasionally serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Imatinib dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Imatinib, and in 2%-6% of other adult CML patients taking Imatinib. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Imatinib, and in 2%-6% of other adult CML patients taking Imatinib. Severe fluid retention was reported in 9% to 13.1% of patients taking Imatinib for GIST.
- Treatment with Imatinib is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy.
- Severe congestive heart failure and left ventricular dysfunction have been reported in patients taking Imatinib. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Imatinib compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.
- Hepatotoxicity, occasionally severe, may occur with Imatinib. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Imatinib. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Imatinib interruption and/or dose reduction.
- When Imatinib is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.
- In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. Patients should therefore be monitored for gastrointestinal symptoms at the start of therapy.
- Imatinib is sometimes associated with GI irritation. Imatinib should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation.
- In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of Imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Imatinib. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Imatinib should be considered at the initiation of therapy.
- Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Imatinib. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Imatinib therapy after resolution or improvement of the bullous reaction. In these instances, Imatinib was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.
- Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Imatinib. TSH levels should be closely monitored in such patients.
- It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.
- Imatinib can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. Sexually active female patients of reproductive potential taking Imatinib should use highly effective contraception. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- Growth retardation has been reported in children and pre-adolescents receiving Imatinib. The long term effects of prolonged treatment with Imatinib on growth in children are unknown. Therefore, close monitoring of growth in children under Imatinib treatment is recommended.
- Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Imatinib. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Imatinib.
- Reports of motor vehicle accidents have been received in patients receiving Imatinib. While most of these reports are not suspected to be caused by Imatinib, patients should be advised that they may experience undesirable effects such as dizziness,blurred vision or somnolence during treatment with Imatinib. Therefore, caution should be recommended when driving a car or operating machinery.
- The majority of Imatinib-treated patients experienced adverse reactions at some time. Most reactions were of mild-to-moderate grade, but drug was discontinued for drug-related adverse reactions in 2.4% of newly diagnosed patients, 4% of patients in chronic phase after failure of interferon-alpha therapy, 4% in accelerated phase and 5% in blast crisis.
- The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 for newly diagnosed CML, Table 3 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Imatinib. The frequency of severe superficial edema was 1.5%-6%.
- A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Imatinib treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure.
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Imatinib treated patients are shown in Tables 2 and 3.
- Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses ≥750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.
- In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 4 and 5). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.
- These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Imatinib, but in rare cases require permanent discontinuation of treatment.
- Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 4 and 5) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.
- Single agent therapy
- The overall safety profile of pediatric patients treated with Imatinib in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low.
- In combination with multi-agent chemotherapy
- Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n=92) were assigned to receive Imatinib and treated in 5 successive cohorts. Imatinib exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.
- The safety of Imatinib given in combination with intensive chemotherapy was evaluated by comparing the incidence of grade 3 and 4 adverse events, neutropenia (<750/µL) and thrombocytopenia (<75,000/ µL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive Imatinib. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without Imatinib. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with Imatinib and 647 without Imatinib. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included Imatinib are presented in Table 6.
- In older patients (≥65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.
### Acute Lymphoblastic Leukemia=
- The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps and rash, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Imatinib.
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Imatinib for MDS/MPD in the phase 2 study, are shown in Table 7.
- All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and lower respiratory tract infection. None of the 5 patients in the phase 2 study with ASM discontinued Imatinib due to drug-related adverse reactions or abnormal laboratory values.
- The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of Imatinib observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Imatinib for DFSP in the phase 2 study are shown in Table 8.
- Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Imatinib for DFSP in the phase 2 study are presented in Table 9.
- In the Phase 3 trials the majority of Imatinib-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Imatinib. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%).
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Imatinib are shown in Table 10.
- Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group.
- Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 11.
- In Study 1, the majority of both Imatinib and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Imatinib and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation.
- In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the Imatinib 12-month and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain.
- Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Imatinib are shown in Table 12 (Study 1) and Table 13 (Study 2). There were no deaths attributable to Imatinib treatment in either trial.
The following adverse reactions have been reported during clinical trials of Imatinib.
- Estimated 0.1%-1%: congestive cardiac failure, tachycardia, palpitations, pulmonary edema
- Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion
- Estimated 1%-10%: flushing, hemorrhage
- Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynaud's phenomenon, hematoma, subdural hematoma
- Estimated 0.1%-1%: blood CPK increased, blood LDH increased
- Estimated 0.01%-0.1%: blood amylase increased
- Estimated 1%-10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction
- Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, nail disorder, purpura, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae
- Estimated 0.01%-0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, erythema multiforme, leucocytoclastic vasculitis
- Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis
- Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis
- Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease
- Estimated 1%-10%: weakness, anasarca, chills
- Estimated 0.1%-1%: malaise
- Estimated 1%-10%: pancytopenia, febrile neutropenia
- Estimated 0.1%-1%: thrombocythemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy
- Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia
- Estimated 0.1%-1%: hepatitis, jaundice
- Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1
- Estimated 0.01%-0.1%: angioedema
- Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis
- Estimated 0.01%-0.1%: fungal infection
Metabolic and Nutritional:
- Estimated 1%-10%: weight decreased
- Estimated 0.1%-1%: hypophosphatemia, dehydration, gout, increased appetite, decreased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia
- Estimated 0.01%-0.1%: hyperkalemia, hypomagnesemia
- Estimated 1%-10%: joint swelling
- Estimated 0.1%-1%: joint and muscle stiffness
- Estimated 0.01%-0.1%: muscular weakness, arthritis
- Estimated 1%-10%: paresthesia, hypesthesia
- Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor
- Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis
- Estimated 0.1%-1%: acute renal failure, urinary frequency increased, hematuria, renal pain
- Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema
- Estimated 1%-10%: epistaxis
- Estimated 0.1%-1%: pleural effusion
- Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage
- Estimated 1%-10%: conjunctivitis, vision blurred, eyelid edema, conjunctival hemorrhage, dry eye
- Estimated 0.1%-1%: vertigo, tinnitus, eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss
- Estimated 0.01%-0.1%: papilledema1, glaucoma, cataract.
- Cerebral edema
- Vitreous hemorrhage
- Pericarditis, cardiac tamponade
- Thrombosis/embolism, anaphylactic shock
- Acute respiratory failure, interstitial lung disease
- Ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation, diverticulitis
- Lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)
- Avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children
- Hemorrhagic corpus luteum/hemorrhagic ovarian cyst
- Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Imatinib, increased Imatinib oral-dose clearance by 3.8-fold, which significantly (p<0.05) decreased mean Cmax and AUC.
- Similar findings were observed in patients receiving 400-1200 mg/day Imatinib concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED.
Concomitant administration of Imatinib and St. John’s Wort led to a 30% reduction in the AUC of imatinib.
Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Imatinib doses up to 1200 mg/day (600 mg BID) have been given to patients receiving concomitant strong CYP3A4 inducers.
- There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when Imatinib was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering Imatinib with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations.
- Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by Imatinib. Particular caution is recommended when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus or tacrolimus).
- Imatinib will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).
Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.
- Imatinib increased the mean Cmax and AUC of metoprolol by approximately 23% suggesting that Imatinib has a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.
- In vitro, Imatinib inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 µM). Co-administration of Imatinib (400 mg/day for eight days) with acetaminophen (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Imatinib pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of Imatinib at doses >400 mg/day or the chronic use of concomitant acetaminophen and Imatinib.
- Imatinib can cause fetal harm when administered to a pregnant woman. There have been post-market reports of spontaneous abortions and infant congenital anomalies from women who have taken Imatinib. Imatinib was teratogenic in animals. Women should be advised not to become pregnant when taking Imatinib. 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.
- Animal Data
- Imatinib mesylate was teratogenic in rats when administered orally during organogenesis at doses ≥100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤30 mg/kg (one-third the maximum human dose of 800 mg).
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Imatinib in women who are pregnant.
- As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m2 in children vs. 10.0 L/hr/m2 in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m2 and 340 mg/m2 achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m2 and 340 mg/m2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose.
- Based on pooled population pharmacokinetic analysis in pediatric patients with hematological disorders (CML, Ph+ ALL, or other hematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in pediatric patients receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily.
- In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.
- In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Imatinib was similar in patients older than 65 years and younger patients.
- Monitoring of hepatic function is recommended.
### Signs and Symptoms
- Adult Overdose
- 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
- 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain.
- 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.
- 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.
- A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Imatinib daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Imatinib daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Imatinib on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy.
- Pediatric Overdose
- One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3 year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea.
### Management
- In the event of overdosage, the patient should be observed and appropriate supportive treatment given.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Imatinib in the drug label.
- In vivo, imatinib inhibits tumor growth of bcr-abl transfected murine myeloid cells as well as bcr-abl positive leukemia lines derived from CML patients in blast crisis.
- Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation.
- Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. Its molecular formula is C29H31N7O • CH4SO3 and its molecular weight is 589.7. Imatinib mesylate is soluble in aqueous buffers ≤pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol, and ethanol, but is insoluble in n-octanol, acetone, and acetonitrile.
- Inactive Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); hydroxypropyl methylcellulose (USP); magnesium stearate (NF); and microcrystalline cellulose (NF). Tablet coating: ferric oxide, red (NF); ferric oxide, yellow (NF); hydroxypropyl methylcellulose (USP); polyethylene glycol (NF) and talc (USP).
- CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound. Human liver microsome studies demonstrated that Imatinib is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with Ki values of 27, 7.5, and 8 µM, respectively.
- Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.
- Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.
- In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. Neoplastic lesions were not seen at: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known.
- Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay.
- In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on body surface area. This was not seen at doses ≤20 mg/kg (one-fourth the maximum human dose of 800 mg). The fertility of male and female rats was not affected.
- In a pre- and post-natal development study in female rats dosed with imatinib mesylate at 45 mg/kg (approximately one-half the maximum human dose of 800 mg/day, based on body surface area) from gestational Day 6 until the end of lactation, red vaginal discharge was noted on either gestational Day 14 or 15. In the first generation offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice. First generation offspring fertility was not affected but reproductive effects were noted at 45 mg/kg/day including an increased number of resorptions and a decreased number of viable fetuses.
- Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In the preclinical pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by Imatinib.
- Human studies on male patients receiving Imatinib and its affect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on Imatinib treatment should consult with their physician.
- Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. This study compared treatment with either single-agent Imatinib or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C). Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR. Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC). In the Imatinib arm, patients were treated initially with 400 mg daily. Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily. In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m2/day subcutaneously in combination with subcutaneous Ara-C 20 mg/m2/day for 10 days/month.
- A total of 1,106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range 18-70 years), with 21.9% of patients ≥60 years of age. There were 59% males and 41% females; 89.9% Caucasian and 4.7% Black patients. At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the Imatinib and IFN arm, respectively. The median duration of second-line treatment with Imatinib was 64 months. Sixty percent of patients randomized to Imatinib are still receiving first-line treatment. In these patients, the average dose of Imatinib was 403 mg ± 57 mg. Overall, in patients receiving first line Imatinib, the average daily dose delivered was 406 mg ± 76 mg. Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the Imatinib arm was severe intolerance to treatment (26%) and progression (14%).
- The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive Imatinib were compared with patients randomized to receive IFN. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 84 months in the ITT population was 81.2 % [95% CI: 78, 85] in the Imatinib arm and 60.6 % [56, 65] in the IFN arm (p<0.0001, log-rank test), (Figure 1). With 7 years follow up there were 93 (16.8%) progression events in the Imatinib arm: 37(6.7%) progression to AP/BC, 31(5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC and 10 (1.8%) CML unrelated deaths. In contrast, there were 165 (29.8%) events in the IFN+Ara-C arm of which 130 occurred during first-line treatment with IFN-Ara-C. The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 84 months was 92.5%[90, 95] in the Imatinib arm compared to the 85.1%, [82, 89] (p≤0.001) in the IFN arm, (Figure 2). The annual rates of any progression events have decreased with time on therapy. The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response (CCyR) with molecular response (≥3 log reduction in Bcr-Abl transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in complete cytogenetic response but without a major molecular response and 70% in patients who were not in complete cytogenetic response at this time point (p<0.001).
- A total of 71 (12.8%) and 85 (15.4%) patients died in the Imatinib and IFN+Ara-C group, respectively. At 84 months the estimated overall survival is 86.4% (83, 90) vs. 83.3% (80, 87) in the randomized Imatinib and the IFN+Ara-C group, respectively (p=0.073 log-rank test). The hazard ratio is 0.750 with 95% CI 0.547-1.028. This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to Imatinib. Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints. Response data are shown in Table 16. Complete hematologic response, major cytogenetic response and complete cytogenetic response were also statistically significantly higher in the Imatinib arm compared to the IFN + Ara-C arm (no cross-over data considered for evaluation of responses). Median time to CCyR in the 454 responders was 6 months (range 2-64 months, 25th to 75th percentiles=3 to 11 months) with 10% of responses seen only after 22 months of therapy).
- Molecular response was defined as follows:
- In the peripheral blood, after 12 months of therapy, reduction of ≥3 logarithms in the amount of bcr-abl transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a standardized baseline. Molecular response was only evaluated in a subset of patients who had a complete cytogenetic response by 12 months or later (N=333). The molecular response rate in patients who had a complete cytogenetic response in the Imatinib arm was 59% at 12 months and 72% at 24 months.
- Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase. After one month of therapy to six months of therapy, there was a 13%-21% decrease in median index from baseline in patients treated with IFN, consistent with increased symptoms of IFN toxicity. There was no apparent change from baseline in median index for patients treated with Imatinib.
- Late Chronic Phase CML and Advanced Stage CML:
- Three international, open-label, single-arm phase 2 studies were conducted to determine the safety and efficacy of Imatinib in patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2) in accelerated phase disease, or 3) in myeloid blast crisis. About 45% of patients were women and 6% were Black. In clinical studies 38%-40% of patients were ≥60 years of age and 10%-12% of patients were ≥70 years of age.
- Chronic Phase, Prior Interferon-Alpha Treatment:
- 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed. The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%). Patients had received a median of 14 months of prior IFN therapy at doses ≥25 x 106 IU/week and were all in late chronic phase, with a median time from diagnosis of 32 months. Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or complete cytogenetic response (0% Ph+ metaphases). Median duration of treatment was 29 months with 81% of patients treated for ≥24 months (maximum = 31.5 months). Efficacy results are reported in Table 16. Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%). Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients.
- Accelerated Phase:
- 235 patients with accelerated phase disease were enrolled. These patients met one or more of the following criteria: ≥15%-<30% blasts in PB or BM; ≥30% blasts + promyelocytes in PB or BM; ≥20% basophils in PB; and <100 x 109/L platelets. The first 77 patients were started at 400 mg, with the remaining 158 patients starting at 600 mg.
- Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. Cytogenetic responses were also evaluated. Median duration of treatment was 18 months with 45% of patients treated for ≥24 months (maximum=35 months). Efficacy results are reported in Table 17. Response rates in accelerated phase CML were higher for the 600 mg dose group than for the 400 mg group: hematologic response (75% vs. 64%), confirmed and unconfirmed major cytogenetic response (31% vs. 19%).
- Myeloid Blast Crisis:
- 260 patients with myeloid blast crisis were enrolled. These patients had ≥30% blasts in PB or BM and/or extramedullary involvement other than spleen or liver; 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg; the remaining 223 patients were started at 600 mg.
- Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase. Cytogenetic responses were also assessed. Median duration of treatment was 4 months with 21% of patients treated for ≥12 months and 10% for ≥24 months (maximum=35 months). Efficacy results are reported in Table 17. The hematologic response rate was higher in untreated patients than in treated patients (36% vs. 22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs. 16%). The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600 mg dose group than for the 400 mg dose group (17% vs. 8%).
- The median time to hematologic response was 1 month. In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to AP or BC, and estimated overall survival was 90.8% [88.3, 93.2]. In accelerated phase, median duration of hematologic response was 28.8 months for patients with an initial dose of 600 mg (16.5 months for 400 mg). An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response. The median survival was 20.9 [13.1, 34.4] months for the 400 mg group and was not yet reached for the 600 mg group (p=0.0097). An estimated 46.2% [34.7, 57.7] vs. 65.8% [58.4, 73.3] of patients were still alive after 2 years of treatment in the 400 mg vs. 600 mg dose groups, respectively. In blast crisis, the estimated median duration of hematologic response is 10 months. An estimated 27.2% [16.8, 37.7] of hematologic responders maintained their response 2 years after achieving their initial response. Median survival was 6.9 [5.8, 8.6] months, and an estimated 18.3% [13.4, 23.3] of all patients with blast crisis were alive 2 years after start of study.
- Efficacy results were similar in men and women and in patients younger and older than age 65. Responses were seen in Black patients, but there were too few Black patients to allow a quantitative comparison.
- A total of 51 pediatric patients with newly diagnosed and untreated CML in chronic phase were enrolled in an open-label, multicenter, single arm phase 2 trial. Patients were treated with Imatinib 340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Complete hematologic response (CHR) was observed in 78% of patients after 8 weeks of therapy. The complete cytogenetic response rate (CCyR) was 65%, comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16%. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 6.74 months. Patients were allowed to be removed from protocol therapy to undergo alternative therapy including hematopoietic stem cell transplantation. Thirty one children received stem cell transplantation. Of the 31 children, 5 were transplanted after disease progression on study and 1 withdrew from study during first week treatment and received transplant approximately 4 months after withdrawal. Twenty five children withdrew from protocol therapy to undergo stem cell transplant after receiving a median of 9 twenty-eight day courses (range 4 to 24). Of the 25 patients 13 (52%) had CCyR and 5 (20%) had PCyR at the end of protocol therapy.
- One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy. These patients had not previously received Imatinib and ranged in age from 3-20 years old; 3 were 3-11 years old, 9 were 12-18 years old, and 2 were >18 years old. Patients were treated at doses of 260 mg/m2/day (n=3), 340 mg/m2/day (n=4), 440 mg/m2/day (n=5) and 570 mg/m2/day (n=2). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had a minimal cytogenetic response.
- In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a complete cytogenetic response at doses of 242 and 257 mg/m2/day.
- A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended Imatinib dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received Imatinib 600 mg/day in a phase 1 study.
- Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ALL phase 2 study patients and for the 2 phase 1 patients are shown in Table 18. The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months.
- Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol.
- The safety and effectiveness of Imatinib (340 mg/m2/day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL. The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor. There were 92 eligible patients with Ph+ ALL enrolled. The median age was 9.5 years (1 to 21 years), 64% were male, 75% were white, 9% were Asian/Pacific Islander, and 5% were black. In 5 successive cohorts of patients, Imatinib exposure was systematically increased by earlier introduction and prolonged duration. Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of Imatinib exposure.
- There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received Imatinib plus chemotherapy; 30 were treated exclusively with chemotherapy and Imatinib and 20 received chemotherapy plus Imatinib and then underwent hematopoietic stem cell transplant, followed by further Imatinib treatment. Patients in cohort 5 treated with chemotherapy received continuous daily exposure to Imatinib beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy. During maintenance cycles 5 through 12 Imatinib was administered 28 days out of the 56 day cycle. Patients who underwent hematopoietic stem cell transplant received 42 days of Imatinib prior to HSCT, and 28 weeks (196 days) of Imatinib after the immediate post transplant period. The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81). The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months.
- An open label, multicenter, phase 2 clinical trial was conducted testing Imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD. These patients were treated with Imatinib 400 mg daily. The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received Imatinib at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a complete cytogenetic response). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1(7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12.9 months (0.8-26.7) in the 7 patients treated within the phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 19. Response durations of phase 2 study patients ranged from 141+ days to 457+ days.
- One open-label, multicenter, phase 2 study was conducted testing Imatinib in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5 patients with aggressive systemic mastocytosis (ASM) treated with 100 mg to 400 mg of Imatinib daily. These 5 patients ranged from 49 to 74 years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of Imatinib in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of Imatinib daily.
- Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with Imatinib from the published reports and in the phase 2 study. Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to Imatinib), one with concomitant CML.
- Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (61% overall response rate). Median duration of Imatinib therapy for the 5 ASM patients in the phase 2 study was 13 months (range 1.4-22.3 months) and between 1 month and more than 30 months in the responding patients described in the published medical literature. A summary of the response rates to Imatinib in ASM is provided in Table 20. Response durations of literature patients ranged from 1+ to 30+ months.
- Imatinib has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). Imatinib is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that harbor the D816V mutation of c-Kit are not sensitive to Imatinib and should not receive Imatinib.
- One open-label, multicenter, phase 2 study was conducted testing Imatinib in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100 mg to 1000 mg of Imatinib daily. The ages of these patients ranged from 16 to 64 years. A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series. These patients received Imatinib at doses of 75 mg to 800 mg daily. Hematologic response rates are summarized in Table 21. Response durations for literature patients ranged from 6+ weeks to 44 months.
- Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene.
- An open-label, multicenter, phase 2 study was conducted testing Imatinib in a diverse population of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 12 patients with DFSP who were treated with Imatinib 800 mg daily (age range 23 to 75 years). DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry. A further 6 DFSP patients treated with Imatinib are reported in 5 published case reports, their ages ranging from 18 months to 49 years. The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) Imatinib daily. A single pediatric patient received 400 mg/m2/daily, subsequently increased to 520 mg/m2/daily. Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities. Responses to treatment are described in Table 22.
- Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%). For the 10 study patients with the PDGF B gene rearrangement there were 4 complete and 6 partial responses. The median duration of response in the phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months.
- Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST). The two study designs were similar allowing a predefined combined analysis of safety and efficacy. A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally daily continuously until disease progression or unacceptable toxicity. Patients in the 400 mg daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily. The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 years. Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST.
- The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 23.
- Median follow up for the combined studies was 37.5 months. There were no observed differences in overall survival between the treatment groups (p=0.98). Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n=347) had a 3.4 month median and a 7.7 month mean exposure to Imatinib following crossover.
- One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally q.d. for up to 36 months. The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. There were no differences in response rates between the 2 dose groups. The response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group. The median time to response was 12 weeks (range was 3-98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached).
- In the adjuvant setting, Imatinib was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1). Patients were randomized one to one to Imatinib at 400 mg/day or matching placebo for 12 months. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size ≥3 cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration.
- Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause. In a planned interim analysis, the median follow up was 15 months in patients without a RFS event; there were 30 RFS events in the 12-month Imatinib arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95% CI: 0.259, 0.610), p<0.0001. After the interim analysis of RFS, 79 of the 354 patients initially randomized to the placebo arm were eligible to cross over to the 12-month Imatinib arm. Seventy-two of these 79 patients subsequently crossed over to Imatinib therapy. In an updated analysis, the median follow-up for patients without a RFS event was 50 months. There were 74 (21%) RFS events in the 12-month Imatinib arm compared to 98 (28%) events in the placebo arm with a hazard ratio of 0.718 (95% CI: 0.531-0.971) (Figure 3). The median follow-up for OS in patients still living was 61 months. There were 26 (7%) and 33 (9%) deaths in the 12-month Imatinib and placebo arms, respectively with a hazard ratio of 0.816 (95% CI: 0.488-1.365).
- A second randomized, multicenter, open label, phase 3 trial in the adjuvant setting (Study 2) compared 12 months of Imatinib treatment to 36 months of Imatinib treatment at 400 mg/day in adult patients with KIT (CD117) positive GIST after surgical resection with one of the following: tumor diameter >5 cm and mitotic count >5/50 high power fields (HPF), or tumor diameter >10 cm and any mitotic count, or tumor of any size with mitotic count >10/50 HPF, or tumors ruptured into the peritoneal cavity. There were a total of 397 patients randomized in the trial with 199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm. The median age was 61 years (range 22 to 84 years).
- RFS was defined as the time from date of randomization to the date of recurrence or death from any cause. The median follow-up for patients without a RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of Imatinib treatment significantly prolonged RFS compared to 12 months of Imatinib treatment with a hazard ratio of 0.46 (95% CI: 0.32, 0.65), p<0.0001 (Figure 4).
- The median follow-up for overall survival (OS) in patients still living was 48 months. There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six months of Imatinib treatment significantly prolonged OS compared to 12 months of Imatinib treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p=0.0187 (Figure 5).
- 100 mg Tablets
- Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side.
- Bottles of 90 tablets………………………………….NDC 0078-0401-34
- 400 mg Tablets
- Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side with score on the other side, and “SL” on each side of the score.
- Bottles of 30 tablets…………………………………NDC 0078-0438-15
- Storage and Handling
- Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Protect from moisture.
- Dispense in a tight container, USP.
- Imatinib is an antineoplastic product. Follow special handling and disposal procedures1
- Imatinib tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed tablets.
- Patients should be informed to take Imatinib exactly as prescribed, not to change their dose or to stop taking Imatinib unless they are told to do so by their doctor. If patients miss a dose they should be advised to take their dose as soon as possible unless it is almost time for their next dose in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose. Patients should be advised to take Imatinib with a meal and a large glass of water.
- Pregnancy and Breast-Feeding
- Patients should be advised to inform their doctor if they are or think they may be pregnant. Women of reproductive potential should be advised to avoid becoming pregnant while taking Imatinib. Sexually active female patients taking Imatinib should use highly effective contraception. Patients should also be advised not to breast feed while taking Imatinib.
- Adverse Reactions
- Patients should be advised to tell their doctor if they experience side effects during Imatinib therapy including fever, shortness of breath, blood in their stools, jaundice, sudden weight gain, symptoms of cardiac failure, or if they have a history of cardiac disease or risk factors for cardiac failure.
- Drug Interactions
- Patients should be advised not to take any other medications, including over-the-counter medications such as herbal products without talking to their doctor or pharmacist first. Examples of other medications that should not be taken with Imatinib are warfarin, erythromycin, and phenytoin. Patients should also be advised to tell their doctor if they are taking or plan to take iron supplements. Patients should also avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking Imatinib.
- Pediatric
- Patients should be advised that growth retardation has been reported in children and pre-adolescents receiving Imatinib. The long term effects of prolonged treatment with Imatinib on growth in children are unknown. Therefore, close monitoring of growth in children under Imatinib treatment is recommended.
- Driving and Using Machines
- Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with Imatinib. Therefore, caution patients about driving a car or operating machinery.
- ↑ "Gleevec (imatinib mesylate) tablet"..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/Gleevec | |
04c0eb0ac85de7445f0c2b6a5c0879e5e8168f0e | wikidoc | Glisodin | Glisodin
Glisodin is a nutritional supplement based on two constituents:
- Cantaloupe extract, which typically contains high quantities of the enzyme superoxide dismutase (SOD)
- Gliadin, a wheat protein designed to protect SOD during the digestive process
# Background
As oxygen metabolizes in the body, potentially harmful reactive oxygen species (ROS) are created. The human body implements an antioxidant defense system to protect against ROS. In the event that these defenses are overpowered by the ROS, cell damage results (which is a major cause of aging in the body).
Superoxide dismutase (SOD) helps to slow the creation of ROS, ultimately playing a key role in the defense against cell damage. However, due to a very fragile molecular structure, it is particularly prone to damage from stomach acids and digestive enzymes when taken orally. Gliadin, which is well-known as a carrier protein for controlled drug release, helps to protect SOD. The union of the two is known as GliSODin, and is "the only proven orally effective delivery of SOD."
# Research
A wide range of clinical research has been undertaken to study glisodin's antioxidant capacities. This has extended into a wide range of applications, including protection from ultraviolet radiation, athletic performance, cardiovascular health, ischemia and reperfusion injury.
A group of researchers in France and Germany led by Dr. Claus Muth concluded that glisodin is helpful in protecting against DNA damage caused by hyperbaric oxidation. A 2005 study at Rutgers University also concluded that glisodin is helpful in enhancing athletic performance while minimizing fatigue. | Glisodin
Glisodin is a nutritional supplement based on two constituents:
- Cantaloupe extract, which typically contains high quantities of the enzyme superoxide dismutase (SOD)
- Gliadin, a wheat protein designed to protect SOD during the digestive process
# Background
As oxygen metabolizes in the body, potentially harmful reactive oxygen species (ROS) are created. The human body implements an antioxidant defense system to protect against ROS. In the event that these defenses are overpowered by the ROS, cell damage results (which is a major cause of aging in the body).
Superoxide dismutase (SOD) helps to slow the creation of ROS, ultimately playing a key role in the defense against cell damage. However, due to a very fragile molecular structure, it is particularly prone to damage from stomach acids and digestive enzymes when taken orally. Gliadin, which is well-known as a carrier protein for controlled drug release, helps to protect SOD. The union of the two is known as GliSODin, and is "the only proven orally effective delivery of SOD."[1]
# Research
A wide range of clinical research has been undertaken to study glisodin's antioxidant capacities. This has extended into a wide range of applications, including protection from ultraviolet radiation, athletic performance, cardiovascular health, ischemia and reperfusion injury.
A group of researchers in France and Germany led by Dr. Claus Muth concluded that glisodin is helpful in protecting against DNA damage caused by hyperbaric oxidation.[2] A 2005 study at Rutgers University also concluded that glisodin is helpful in enhancing athletic performance while minimizing fatigue.[3] | https://www.wikidoc.org/index.php/Glisodin | |
b86ca42b5fd92b5c27161d6626a7b3f9419a5898 | wikidoc | Globulin | Globulin
# Overview
Globulin is one of the two types of serum proteins, the other being albumin. This generic term encompasses a heterogeneous series of families of proteins, with larger molecules and less soluble in pure water than albumin, which migrate less than albumin during serum electrophoresis.
It is sometimes used synonymously with Globular protein. However, albumin is also a globular protein, but not a globulin. All other serum globular proteins are globulins.
Protein electrophoresis is used to categorize globulins into the following four categories:
- Alpha 1 globulins
- Alpha 2 globulins
- Beta globulins
- Gamma globulins (one group of gamma globulins are immunoglobulins, that function as antibodies) | Globulin
# Overview
Globulin is one of the two types of serum proteins, the other being albumin. This generic term encompasses a heterogeneous series of families of proteins, with larger molecules and less soluble in pure water than albumin, which migrate less than albumin during serum electrophoresis.
It is sometimes used synonymously with Globular protein. However, albumin is also a globular protein, but not a globulin. All other serum globular proteins are globulins.
Protein electrophoresis is used to categorize globulins into the following four categories:
- Alpha 1 globulins
- Alpha 2 globulins
- Beta globulins
- Gamma globulins (one group of gamma globulins are immunoglobulins, that function as antibodies)
# External links
- Serum Proteins
- Cornell
- Understanding and interpreting serum protein electrophoresis
de:Globuline
mk:Глобулин
sl:Globulin
fi:Globuliini
sv:Globulin
th:กลอบูลิน
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Globin_protein_family | |
1ede370c49ed68975e9d0da4fa4188d867127e65 | wikidoc | Inhalant | Inhalant
# Overview
Inhalants are drugs that are inhaled as a gas, vapor, or
aerosol. Some inhalants are used for medical purposes, such as
anesthesia and the delivery of medication to the lungs (for example
by an inhaler or nebulizer to administer asthma medication.)
Other inhalants are used recreationally, such as
-rganic solvents and propellant gases. Some inhalants, such as ether and alkyl nitrites,
have been widely used both medically and recreationally.
Effects of recreational solvent inhalation can range from an alcohol-like
intoxication and euphoria to hallucinations. Toxicity and death may also result. Nonmedical inhalant use is restricted and even criminalized in some jurisdictions.
# Non-medical inhalants
## Solvents and propellants
Solvents and propellants used as inhalants are found in a range of inexpensive, legally-available household, office, industrial, and automotive products.
A number of household and office products contain solvents that are used as inhalants, such as toluene and acetone. These products include correction fluids such as Liquid Paper, nail polish removers (acetone), and permanent markers (xylene). Propellant gases used as inhalants in household and office products include freon and compressed hydrofluorocarbons, which are used in various household and office products that come in aerosol spraycans, such as air freshener, computer keyboard cleaner spray (canned air), non-stick cooking spray, aerosol insecticides, and aerosol hairspray. Another household product which contains propellant gases that are used as an inhalant is aerosol whipped cream cans, which contain nitrous oxide gas. Various insecticides such as Raid are also used.
Industrial and automotive products also contain solvents and propellant gases that are used as inhalants. Solvents such as toluene are found in turpentine, gasoline, paint, spraypaint, an a range of quick-drying adhesives and cements (e.g., rubber cement and plastic cement). The solvent diethyl ether is used in an aerosol product called automotive starting fluid, which is used to help carburetor engines start in frigid weather. Canisters of butane are used in inexpensive home welding kits.
## Nitrites
Several nitrite drugs called "poppers" are used for their euphoric effect in the gay subculture and in the rave dance scene. While nitrite drugs are regulated by a variety of federal and local regulations and legal restrictions, several nitrite products can be found in legally-available products. Amyl nitrite is available as an over-the-counter drug in some areas; butyl nitrite is sold as a room deodorizers under trade names as "RUSH" and "Locker Room"; and alkyl nitrite is an ingredient in video head cleaner or some brands of nail polish remover.
# Mechanisms of action
Inhalants are a large class of drugs and therefore exhibit a variety of mechanisms of action.
The mechanisms of action of many non-medical inhalants has not been well elucidated.
Anesthetic gases used for surgery, such as nitrous oxide or enflurane, are believed to induce anesthesia primarily by acting as NMDA antagonists, open channel blockers which bind to the inside of the calcium channels on the outer surface of the neuron, and provide high levels of NMDA receptor blockade for a short period of time.
This makes inhaled anesthetic gases different to other NMDA antagonists such as ketamine, which bind to a regulatory site on the NMDA-sensitive calcium transporter complex and provide slightly lower levels of NMDA blockade, but for a longer and much more predictable duration. This makes a deeper level of anesthesia achievable more easily using anaesthetic gases, but can also make them more dangerous than other drugs used for this purpose.
Alcohol is known to act as a GABA agonist, and it is likely that other solvents also act here to produce additional depressant effects. The solvent diethyl ether, for instance, has seen historical episodes of both inhalation and drinking, and produces effects suggestive of both kinds of activity. The particular mix of NMDA antagonist vs GABA agonist properties will vary between solvents depending on molecular size or shape, and so the effects of particular solvents will differ, although all tend to share a similar profile
# Methods of Psychoactive Inhalant use and effects
Inhalant users inhale vapors or aerosol propellant gases using plastic bags held over the mouth or by breathing from an open container of solvents, such as gasoline or paint thinner. Nitrous oxide gases from whipped cream aerosol cans and aerosol hairspray or non-stick frying spray is sprayed into plastic bags; some users may filter the aerosolized particles out with a rag. Some gases such as propane and butane gases are inhaled directly from the canister.
Once these solvents or gases are inhaled, the extensive capillary surface of the lungs rapidly absorb the solvent or gas, and blood levels peak rapidly. The intoxication effects occur so quickly that the effects of inhalation can resemble the intensity of effects produced by intravenous injection of other psychoactive drugs.
The effects of solvent intoxication can vary widely depending on the dose and what type of solvent or gas is inhaled. A person who has inhaled a small amount of rubber cement or paint thinner vapour may be impaired in a manner resembling alcohol inebriation - stimulation, a sense of euphoria and intoxication, followed by a period of depression. A person who has inhaled a larger quantity of solvents or gases, or a stronger chemical may experience to stronger effects such as distortion in perceptions of time and space, hallucinations, and emotional disturbances.
In the short term, many users experience headache, nausea and vomiting, slurred speech, loss of motor coordination, and wheezing. A characteristic "glue sniffer's rash" around the nose and mouth is sometimes seen after prolonged use. An odor of paint or solvents on clothes, skin, and breath is sometimes a sign of inhalant abuse, and paint or solvent residues can sometimes emerge in sweat.
# Dangers associated with psychoactive inhalants
Psychoactive inhalant users can be injured or killed due to the effects of inhaling these solvents or gases, which can cause hypoxia (lack of oxygen), pneumonia, cardiac failure or arrest, or aspiration of vomit. Other inhalant users are injured due to the harmful effects of other chemicals used in these products (e.g., tetraethyl lead used in some fuels) or due to dangerous behavior while they are intoxicated.
The inhaling of some solvents can cause irreversible effects such as hearing loss, limb spasms, and damage to the central nervous system and brain. Serious but potentially reversible effects include liver and kidney damage and blood oxygen depletion. Death from inhalants is usually caused by a very high concentration of fumes. Deliberately inhaling from an attached paper or plastic bag or in a closed area greatly increases the chances of suffocation.
Of more concern from a toxicological perspective, or from the point of view of an individual considering the recreational use of solvents, is the additional toxicity resulting from either the physical properties of the compound itself, or additional ingredients present in a product. Many solvents of abuse are fairly toxic compounds which often produce liver and brain damage after prolonged use. This is particularly bad with chlorinated compounds such as carbon tetrachloride or chloroform, or when products containing mixtures of many substances such as glue or paint is inhaled.
Toxicity may also result from the pharmacological properties of the drug; excess NMDA antagonism can completely block calcium influx into neurons and provoke cell death through apoptosis, although this is more likely to be a long term result of chronic solvent abuse than a consequence of short term use.
## Solvents
Use of inhalants can cause brain, nerve, liver and other damage to the body. In the short term, death from solvent abuse occurs most commonly from aspiration of vomit while unconscious, or from a combination of respiratory depression and hypoxia, the second cause being especially a risk with heavier than air vapors such as butane or gasoline vapor. Deaths typically occur from complications related to excessive sedation and vomiting. Actual overdose from the drug does occur, however, and indeed inhaled solvent abuse is statistically more likely to result in life-threatening respiratory depression than intravenous use of opiates such as heroin.
Most deaths from solvent abuse could be prevented if individuals were resuscitated quickly when they stopped breathing and their airway cleared if they vomited. However, most inhalant abuse takes place when people inhale solvents by themselves or in groups of people who are intoxicated. Certain solvents are more hazardous than others, such as gasoline or refrigerant gases.
Hypoxia can occur when inhalant users are huffing from a plastic bag over their face, which means that they are not breathing enough fresh air. However, some inhalants are heavier-than-air gases or vapors, and, if regular breathing is not maintained, they will remain in the lungs instead of being naturally expelled. Also, since many solvents are highly flammable (e.g., gasoline, paint thinner), some users have suffered burn injuries and deaths due to fires.
Female inhalant users who become pregnant may have adverse effects on the fetus. The baby may be smaller, and may need additional health care. There is some evidence of birth defects and disabilities in babies born to women who sniffed solvents such as gasoline. Driving while using solvents presents the same dangers as other types of impaired driving, because many solvents cause an alcohol-type intoxication. In 1999, five high school girls were killed in a car accident outside Philadelphia after the driver and three of the passengers had inhaled computer keyboard cleaner.
## Other inhalants
Inhaling butane gas can cause drowsiness, narcosis, asphyxia, cardiac arrhythmia and frostbite. Butane is the most commonly misused volatile solvent in the UK, and caused 52% of solvent related deaths in 2000. By spraying butane directly into the throat, the jet of fluid can cool rapidly to –20 °C by expansion, causing prolonged laryngospasm.
Some inhalants can also indirectly cause sudden death by cardiac arrest, in a syndrome known as Sudden Sniffing Death Syndrome. The anesthetic gases present in the inhalants appear to sensitize the user to adrenaline. In this state a sudden surge of adrenaline (e.g., from a frightening hallucination or run in with the law), can cause a fatal cardiac arrhythmia.
Nitrous oxide gas can cause death by asphyxiation if a user inhales directly from a large tank using a mask or tube. Normally with recreational use, users get oxygen because they continue to breathe after inhaling the nitrous oxide from a bag or balloon. However, if a mask is attached to the tank, then the user gets pure nitrous oxide with no way to take in any oxygen. The rapidly-expanding gas causes very cold temperatures which can freeze the lips and throat if the gas is inhaled directly from a tank or "whippit" aerosol container. Releasing the gas into a balloon first allows the gas to expand and warm before it is inhaled.
## Death statistics
Precise statistics on deaths caused by inhalant abuse are difficult to determine, as it is considered a dramatically under-reported cause of death due to the common result of a cause-of-death determination being attributed to the side-effects of inhalant abuse (such as a blood vessel rupture in the brain or a heart attack) rather than to the abuse itself.
Inhalant use or abuse was mentioned on 144 death certificates in Texas during the period 1988-1998 and was reported in 39 deaths in Virginia between 1987 and 1996 from acute voluntary exposure to abused inhalants.
# Socioeconomics of inhalant abuse
Inhalant drugs are often used by children, teenagers, incarcerated or institutionalized people, and impoverished people, because these solvents and gases are ingredients in hundreds of legally-available, inexpensive products, such as aerosol spray cans, adhesives and rubber cements, deodorant sprays, hair spray, air fresheners, gasoline, lighter fluid, paint, and paint thinner.
Inhalants are used by a wide cross section of society, including children, teenagers, and adults, in lower-income, middle-income, and even upper-income settings, because inhalant drugs are a legal and easily available source of a "high." However, most users tend to be "...adolescents (between the ages of 13 and 17)" In some countries, chronic, heavy inhalant use is concentrated in marginalized, impoverished communities
Young people who become chronic, heavy inhalant abusers are also more likely to be those who are isolated from their families and community. The article Epidemiology of Inhalant Abuse: An International Perspective notes that "he most serious form of obsession with inhalant use probably occurs in countries other than the United States where young children live on the streets completely without family ties. These groups almost always use inhalants at very high levels (Leal et al. 1978). This isolation can make it harder to keep in touch with the sniffer and encourage him or her to stop sniffing." The article also states that "...high rates among barrio Hispanics almost undoubtedly are
related to the poverty, lack of opportunity, and social dysfunction that
-ccur in barrios", and states that the "...same general tendency appears for Native-American youth", because "...Indian reservations are among the most disadvantaged environments in the
United States; there are high rates of unemployment, little opportunity, and high rates of alcoholism and other health problems."
There is a wide range of social problems associated with inhalant use such as feelings of distress, anxiety and grief for the community; violence and damage to property, violent crime, stresses on the juvenile justice system, and stresses on youth agencies and support services.
# History of inhalants
Solvents such as chloroform and diethyl ether and gases such as nitrous oxide were first used for medical purposes, such as providing anesthesia. These solvents' psychoactive and hallucinogenic effects at sub-anesthetic levels was also noted, which led to recreational use. Nitrous oxide particularly was popularised by the scientist Sir Humphry Davy who held nitrous oxide parties where users could enjoy the euphoric properties of the gas. Davy, noting the anesthetic effects, proposed that the gas could be used for operations, although this was not tried for another half century.
Chloroform was used as an anaesthetic, but it fell into disuse due to its high toxicity and narrow dose margin. Nitrous oxide and diethyl ether were adopted by the medical mainstream and became the standard anesthetics in use for many years. Other gases such as cyclopropane were also used for anesthesia. Non-flammable gases such as halothane replaced flammable anaesthetics such as ether.
Halothane is now rarely used in humans due to problems with liver damage and a rare condition called malignant hyperthermia, but it is still widely used in veterinary medicine.
In modern times newer anesthetics such as isoflurane and sevoflurane have been developed for medical use which lack both the flammability of ether and the toxicity of halothane, and research in the area is ongoing. Nitrous oxide is still widely used as a dental anaesthetic, to reduce patient anxiety during dental work and minor dental surgery. Other medical anesthetics and inhaled medicinal drugs include xenon, enflurane, isoflurane, sevoflurane, desflurane, methoxyflurane, salbutamol, and fluticasone.
# Legal issues
Most inhalant solvents and gases are not regulated under illegal drug laws such as the United States' Controlled Substances Act. However, many US states and Canadian cities have placed restrictions on the sale of some solvent-containing products to minors, particularly for products widely associated with "sniffing", such as model cement. The practice of inhaling such substances is sometimes colloquially referred to as huffing, sniffing (or "glue-sniffing"), dusting, or chroming.
# Patterns of Psychoactive Inhalant usage
## Africa
Dung sniffing has also been seen in some African countries (see Jenkem). Glue sniffing is also a problem in these countries, with dung sniffing generally being a last resort by people too poor to afford
glue.
## Asia
### India and South Asia
In India and South Asia, three of the most widely abused inhalants are the Dendrite brand and other forms of contact adhesives and rubber cements manufactured in Kolkata, toluenes in paint thinners and Iodex - a muscle stress relieving balm. Another very common inhalant is Erase-X, a correction fluid which contains toluene. It has become very common for school and college students to use it because it is easily available in stationery shops in India.
### South East Asia
Dung sniffing has been noted as a problem in several countries in South East Asia such as Thailand and Malaysia among poor and homeless people. Animal or human dung is placed into a plastic bag or tin and left out in the sun where it starts to decompose, releasing methane gas, which has narcotic properties. Police were unsure of what action could be taken, given that dung is not illegal and would be problematic to restrict supplies.
## UK
Generally exists in party cultures (using poppers)
### Russia and Eastern Europe
Gasoline sniffing became common on Russian ships following attempts to limit the supply of alcohol to ship crews in the 1980s. The documentary Children Underground depicts the huffing of a solvent called Aurolac by Romanian homeless children. Gasoline sniffing also occurs in some remote indigenous communities in developed countries.
## North America
### Canada
Native children in the isolated Northern Labrador community of Davis Inlet were the focus of national concern in 1993 when many were found to be sniffing gasoline. The federal Canadian and provincial Newfoundland and Labrador governments intervened on a number of occasions, sending many children away for treatment. Despite being moved to the new community of Natuashish in 2002, serious inhalant abuse problems have continued. Similar problems were also reported in Sheshatshiu in 2000.
### Mexico
The inhaling of a mixture of gasoline and/or industrial solvents, known locally as "Activo" or "Chemo", has risen in popularity among the homeless and among the street children of Mexico City in recent years. The mixture is poured onto a handkerchief and inhaled while held in one's fist.
The chemicals in most common use are cements (trichloroethylene, tetrachloroethylene), lubricants (toluene, ethyl acetate and other acetones), thinners (petroleum distillants, benzene, acetone, tetrachloroethylene) and paint strippers (acetone, toluene, benzene, methylene chloride).
### United States
Ether was used as a recreational drug during the 1930s Prohibition era, when alcohol was made illegal in the USA for over 10 years. Ether was either sniffed or drunk, and in some towns replaced alcohol entirely. However, the risk of death from excessive sedation or overdose is greater than that with alcohol, and ether drinking is associated with damage to the stomach and gastrointestinal tract.
Use of glue, paint and gasoline was little known before the 1950s. Later, glue sniffing became a worldwide phenomenon; however, it is not known if this popularity was caused by government anti-inhalant campaigns. Drug educators argue that the advertising campaigns designed to prevent drug use may instead promote such use. Abuse of aerosol sprays became more common in the 1980s as older propellants such as CFCs were phased out and replaced by more environmentally friendly compounds such as propane and butane.
Abuse of solvents is widespread in impoverished communities, both in developing countries or in poor communities in developed countries (e.g., Aboriginal communities in northern Canada or in Australia). Because solvents and inhalant gases are legally available and inexpensive, there has long been incidents of teenagers using inhalants recreationally. However, most of the long term abuse, or use by older adults tends to be limited to extremely poor or marginalised groups in society.
## South Pacific
### Australia
Although some sources argue that sniffing was introduced by US servicemen stationed in the nation's Top End during World War II, or through experimentation by 1940s-era Coburg Peninsula sawmill workers, other sources claim that inhalant abuse (such as glue inhalation) emerged in Australia in the late 1960s. Chronic, heavy gasoline sniffing appears mainly to occur among remote, impoverished indigenous communities, where the ready accessibility of gasoline has helped to make it a common substance for abuse.
In Australia, gasoline sniffing now occurs widely throughout remote communities of the Northern Territory, Western Australia, northern parts of South Australia and Queensland. The number of people sniffing gasoline goes up and down over time as young people experiment or sniff occasionally. 'Boss' or chronic sniffers may move in and out of communities; they are often responsible for encouraging young people to take it up.
A 1983 survey of 4,165 secondary students in New South Wales showed that solvents and aerosols ranked just after analgesics (e.g., codeine pills) and alcohol for drugs that were abused. This 1983 study did not find any common usage patterns or social class factors.
In Australia between 1981-1991, there were 60 Aboriginal males and three Aboriginal females whose deaths were associated with gasoline sniffing
. They ranged in age from 11 to 32. The causes of death included pneumonia, cardiac failure/arrest, aspiration of vomit, and burns. In 1985, there were 14 communities in Central Australia reporting young people sniffing. In July 1997, it was estimated that there were around 200 young people sniffing gasoline across 10 communities in Central Australia. Approximately 40 were classified as 'chronic' sniffers.
In some communities many children and youths might try gasoline sniffing at least once or twice. Most of these 'experimental' users will not become regular or long-term sniffers. Recently, there have been reports of young Aboriginal people sniffing gasoline in the urban areas around Darwin and Alice Springs. Substitution of gasoline by non-sniffable Opal fuel (which is much less likely to cause a "high") has made a difference in some communities.
## Elsewhere
In several parts of the world where glue-sniffing is widespread, terms for glue-sniffers have arisen based on brand-names of substances, such as aurolaci in Romania from the brand name Aurolac, or resistoleros in Brazil from the brand name Resistol. These terms are often used even in English-language writing about substance abuse in those regions.
# Popular culture references
## Music and musical culture
- The Ramones sang "Now I Want to Sniff Some Glue" about adolescent ennui.
- The punk fanzine "Sniffin' Glue" takes its name from the song but, the fanzine is not about inhalants.
- In the Nirvana song "Dumb", Kurt Cobain sings "my heart is broke/But I have some glue/ help me inhale /And mend it with you".
- The Beck song "Fume" from his cassette "Fresh Meat and Old Slabs" is entirely about doing nitrous oxide. He sings: "Had a can of nitrous/we rolled the windows up/Now we're breathing deeply/breathing deeply." The lyrics have a humorous tone throughout, particularly in the chorus: "There's a fume/in this truck/and I don't know if we're dead or what the fuck?"
- Primus's 1998 song "Lacquer Head" is about adolescents who use inhalants to get high.
- In the Sum 41 song "Fat Lip", one part of the song is "...you don't make sense from all the gas you be huffing..."
- The Dead Milkmen song, "Life is Shit" from their album "Beelzebubba" is almost entirely about two friends hallucinating after sniffing glue. The only direct reference is in the first verse, as every verse following it details their hallucinations: "He said 'Yes I do believe this is true, would you like to come and sniff some glue? And we'll fly to where the skies are blue, and look for things both bright and new'".
- The Eminem song, "Bad Meets Evil" contains the lyric: "I breathe ether in three lethal amounts"
- The L7 song, "Scrap" is about a skinhead, Scrap, who regularly inhales spraypaint fumes. The first verse describes Scrap thusly: "I met a skinhead named Scrap, he lived in my friend's garage, everyday he's shaking that spraypaint can, and comes out seeing stars," The chorus describes the general use of spraypaint as an inhalant: " Grab a paper bag like an oxygen mask, until your mind starts to gel, because the ball in the can has a crazy beat, the funky dyin' brain cell"
## Films and books
- In the 1996 film Citizen Ruth, the character Ruth sniffs patio sealant from a paper bag.
- In the movie Love Liza, the main character, played by Philip Seymour Hoffman, develops a gasoline addiction.
- In the David Lynch film Blue Velvet, Dennis Hopper's character uses a mask to inhale nitrous oxide.
- In Little Shop of Horrors, Steve Martin's character dies from nitrous oxide inhalation.
- In The Cider House Rules, Michael Caine's character is an ether addict.
- In the film thirteen, the main character uses computer cleaner to get high.
- Harmony Korine's 1997 film Gummo features two adolescent boys who often huff glue.
- In the book Fear and Loathing in Las Vegas and in the film version, the two main characters inhale Diethyl Ether and Amyl Nitrite, two of several recreational drugs they take on their trip.
- In the movie Shooter, Mark Wahlburg inhales gases from a Whip-It! whipped cream canister to knock himself out.
- In the 1980 Film Airplane!, McCroskey (played by Lloyd Bridges) delivers the famous quote I picked the wrong week to stop sniffing glue. | Inhalant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Inhalants are drugs that are inhaled as a gas, vapor, or
aerosol. Some inhalants are used for medical purposes, such as
anesthesia and the delivery of medication to the lungs (for example
by an inhaler or nebulizer to administer asthma medication.)
Other inhalants are used recreationally, such as
organic solvents and propellant gases. Some inhalants, such as ether and alkyl nitrites,
have been widely used both medically and recreationally.
Effects of recreational solvent inhalation can range from an alcohol-like
intoxication and euphoria to hallucinations. Toxicity and death may also result. Nonmedical inhalant use is restricted and even criminalized in some jurisdictions.
# Non-medical inhalants
## Solvents and propellants
Solvents and propellants used as inhalants are found in a range of inexpensive, legally-available household, office, industrial, and automotive products.
A number of household and office products contain solvents that are used as inhalants, such as toluene and acetone. These products include correction fluids such as Liquid Paper, nail polish removers (acetone), and permanent markers (xylene). Propellant gases used as inhalants in household and office products include freon and compressed hydrofluorocarbons, which are used in various household and office products that come in aerosol spraycans, such as air freshener, computer keyboard cleaner spray (canned air), non-stick cooking spray, aerosol insecticides, and aerosol hairspray. Another household product which contains propellant gases that are used as an inhalant is aerosol whipped cream cans, which contain nitrous oxide gas. Various insecticides such as Raid are also used.
Industrial and automotive products also contain solvents and propellant gases that are used as inhalants. Solvents such as toluene are found in turpentine, gasoline, paint, spraypaint, an a range of quick-drying adhesives and cements (e.g., rubber cement and plastic cement). The solvent diethyl ether is used in an aerosol product called automotive starting fluid, which is used to help carburetor engines start in frigid weather. Canisters of butane are used in inexpensive home welding kits.
## Nitrites
Several nitrite drugs called "poppers" are used for their euphoric effect in the gay subculture and in the rave dance scene. While nitrite drugs are regulated by a variety of federal and local regulations and legal restrictions, several nitrite products can be found in legally-available products. Amyl nitrite is available as an over-the-counter drug in some areas; butyl nitrite is sold as a room deodorizers under trade names as "RUSH" and "Locker Room"; and alkyl nitrite is an ingredient in video head cleaner or some brands of nail polish remover.
# Mechanisms of action
Inhalants are a large class of drugs and therefore exhibit a variety of mechanisms of action.
The mechanisms of action of many non-medical inhalants has not been well elucidated.
Anesthetic gases used for surgery, such as nitrous oxide or enflurane, are believed to induce anesthesia primarily by acting as NMDA antagonists, open channel blockers which bind to the inside of the calcium channels on the outer surface of the neuron, and provide high levels of NMDA receptor blockade for a short period of time.
This makes inhaled anesthetic gases different to other NMDA antagonists such as ketamine, which bind to a regulatory site on the NMDA-sensitive calcium transporter complex and provide slightly lower levels of NMDA blockade, but for a longer and much more predictable duration. This makes a deeper level of anesthesia achievable more easily using anaesthetic gases, but can also make them more dangerous than other drugs used for this purpose.
Alcohol is known to act as a GABA agonist, and it is likely that other solvents also act here to produce additional depressant effects. The solvent diethyl ether, for instance, has seen historical episodes of both inhalation and drinking, and produces effects suggestive of both kinds of activity. The particular mix of NMDA antagonist vs GABA agonist properties will vary between solvents depending on molecular size or shape, and so the effects of particular solvents will differ, although all tend to share a similar profile
# Methods of Psychoactive Inhalant use and effects
Inhalant users inhale vapors or aerosol propellant gases using plastic bags held over the mouth or by breathing from an open container of solvents, such as gasoline or paint thinner. Nitrous oxide gases from whipped cream aerosol cans and aerosol hairspray or non-stick frying spray is sprayed into plastic bags; some users may filter the aerosolized particles out with a rag. Some gases such as propane and butane gases are inhaled directly from the canister.
Once these solvents or gases are inhaled, the extensive capillary surface of the lungs rapidly absorb the solvent or gas, and blood levels peak rapidly. The intoxication effects occur so quickly that the effects of inhalation can resemble the intensity of effects produced by intravenous injection of other psychoactive drugs.[1]
The effects of solvent intoxication can vary widely depending on the dose and what type of solvent or gas is inhaled. A person who has inhaled a small amount of rubber cement or paint thinner vapour may be impaired in a manner resembling alcohol inebriation - stimulation, a sense of euphoria and intoxication, followed by a period of depression. A person who has inhaled a larger quantity of solvents or gases, or a stronger chemical may experience to stronger effects such as distortion in perceptions of time and space, hallucinations, and emotional disturbances.
In the short term, many users experience headache, nausea and vomiting, slurred speech, loss of motor coordination, and wheezing. A characteristic "glue sniffer's rash" around the nose and mouth is sometimes seen after prolonged use. An odor of paint or solvents on clothes, skin, and breath is sometimes a sign of inhalant abuse, and paint or solvent residues can sometimes emerge in sweat.[2]
# Dangers associated with psychoactive inhalants
Psychoactive inhalant users can be injured or killed due to the effects of inhaling these solvents or gases, which can cause hypoxia (lack of oxygen), pneumonia, cardiac failure or arrest[2], or aspiration of vomit. Other inhalant users are injured due to the harmful effects of other chemicals used in these products (e.g., tetraethyl lead used in some fuels[3][4]) or due to dangerous behavior while they are intoxicated.
The inhaling of some solvents can cause irreversible effects such as hearing loss, limb spasms, and damage to the central nervous system and brain[5]. Serious but potentially reversible effects include liver and kidney damage and blood oxygen depletion. Death from inhalants is usually caused by a very high concentration of fumes. Deliberately inhaling from an attached paper or plastic bag or in a closed area greatly increases the chances of suffocation.
Of more concern from a toxicological perspective, or from the point of view of an individual considering the recreational use of solvents, is the additional toxicity resulting from either the physical properties of the compound itself, or additional ingredients present in a product. Many solvents of abuse are fairly toxic compounds which often produce liver and brain damage after prolonged use. This is particularly bad with chlorinated compounds such as carbon tetrachloride or chloroform, or when products containing mixtures of many substances such as glue or paint is inhaled.
Toxicity may also result from the pharmacological properties of the drug; excess NMDA antagonism can completely block calcium influx into neurons and provoke cell death through apoptosis, although this is more likely to be a long term result of chronic solvent abuse than a consequence of short term use.
## Solvents
Use of inhalants can cause brain, nerve, liver and other damage to the body. In the short term, death from solvent abuse occurs most commonly from aspiration of vomit while unconscious, or from a combination of respiratory depression and hypoxia, the second cause being especially a risk with heavier than air vapors such as butane or gasoline vapor. Deaths typically occur from complications related to excessive sedation and vomiting. Actual overdose from the drug does occur, however, and indeed inhaled solvent abuse is statistically more likely to result in life-threatening respiratory depression than intravenous use of opiates such as heroin.
Most deaths from solvent abuse could be prevented if individuals were resuscitated quickly when they stopped breathing and their airway cleared if they vomited. However, most inhalant abuse takes place when people inhale solvents by themselves or in groups of people who are intoxicated. Certain solvents are more hazardous than others, such as gasoline or refrigerant gases.
Hypoxia can occur when inhalant users are huffing from a plastic bag over their face, which means that they are not breathing enough fresh air. However, some inhalants are heavier-than-air gases or vapors, and, if regular breathing is not maintained, they will remain in the lungs instead of being naturally expelled. Also, since many solvents are highly flammable (e.g., gasoline, paint thinner), some users have suffered burn injuries and deaths due to fires.
Female inhalant users who become pregnant may have adverse effects on the fetus. The baby may be smaller, and may need additional health care. There is some evidence of birth defects and disabilities in babies born to women who sniffed solvents such as gasoline. Driving while using solvents presents the same dangers as other types of impaired driving, because many solvents cause an alcohol-type intoxication. In 1999, five high school girls were killed in a car accident outside Philadelphia after the driver and three of the passengers had inhaled computer keyboard cleaner[6][7].
## Other inhalants
Inhaling butane gas can cause drowsiness, narcosis, asphyxia, cardiac arrhythmia and frostbite. Butane is the most commonly misused volatile solvent in the UK, and caused 52% of solvent related deaths in 2000. By spraying butane directly into the throat, the jet of fluid can cool rapidly to –20 °C by expansion, causing prolonged laryngospasm.
Some inhalants can also indirectly cause sudden death by cardiac arrest, in a syndrome known as Sudden Sniffing Death Syndrome. The anesthetic gases present in the inhalants appear to sensitize the user to adrenaline. In this state a sudden surge of adrenaline (e.g., from a frightening hallucination or run in with the law), can cause a fatal cardiac arrhythmia.[3]
Nitrous oxide gas can cause death by asphyxiation if a user inhales directly from a large tank using a mask or tube. Normally with recreational use, users get oxygen because they continue to breathe after inhaling the nitrous oxide from a bag or balloon. However, if a mask is attached to the tank, then the user gets pure nitrous oxide with no way to take in any oxygen. The rapidly-expanding gas causes very cold temperatures which can freeze the lips and throat if the gas is inhaled directly from a tank or "whippit" aerosol container. Releasing the gas into a balloon first allows the gas to expand and warm before it is inhaled.
## Death statistics
Precise statistics on deaths caused by inhalant abuse are difficult to determine, as it is considered a dramatically under-reported cause of death due to the common result of a cause-of-death determination being attributed to the side-effects of inhalant abuse (such as a blood vessel rupture in the brain or a heart attack) rather than to the abuse itself[8].
Inhalant use or abuse was mentioned on 144 death certificates in Texas during the period 1988-1998 and was reported in 39 deaths in Virginia between 1987 and 1996 from acute voluntary exposure to abused inhalants[9].
# Socioeconomics of inhalant abuse
Inhalant drugs are often used by children, teenagers, incarcerated or institutionalized people, and impoverished people, because these solvents and gases are ingredients in hundreds of legally-available, inexpensive products, such as aerosol spray cans, adhesives and rubber cements, deodorant sprays, hair spray, air fresheners, gasoline, lighter fluid, paint, and paint thinner.
Inhalants are used by a wide cross section of society, including children, teenagers, and adults, in lower-income, middle-income, and even upper-income settings, because inhalant drugs are a legal and easily available source of a "high." However, most users tend to be "...adolescents (between the ages of 13 and 17)"[4] In some countries, chronic, heavy inhalant use is concentrated in marginalized, impoverished communities[5][6]
).
Young people who become chronic, heavy inhalant abusers are also more likely to be those who are isolated from their families and community. The article Epidemiology of Inhalant Abuse: An International Perspective notes that "[t]he most serious form of obsession with inhalant use probably occurs in countries other than the United States where young children live on the streets completely without family ties. These groups almost always use inhalants at very high levels (Leal et al. 1978). This isolation can make it harder to keep in touch with the sniffer and encourage him or her to stop sniffing."[7] The article also states that "...high [inhalant use] rates among barrio Hispanics almost undoubtedly are
related to the poverty, lack of opportunity, and social dysfunction that
occur in barrios", and states that the "...same general tendency appears for Native-American youth", because "...Indian reservations are among the most disadvantaged environments in the
United States; there are high rates of unemployment, little opportunity, and high rates of alcoholism and other health problems."[8]
There is a wide range of social problems associated with inhalant use such as feelings of distress, anxiety and grief for the community; violence and damage to property, violent crime, stresses on the juvenile justice system, and stresses on youth agencies and support services.
# History of inhalants
Solvents such as chloroform and diethyl ether and gases such as nitrous oxide were first used for medical purposes, such as providing anesthesia. These solvents' psychoactive and hallucinogenic effects at sub-anesthetic levels was also noted, which led to recreational use. Nitrous oxide particularly was popularised by the scientist Sir Humphry Davy who held nitrous oxide parties where users could enjoy the euphoric properties of the gas. Davy, noting the anesthetic effects, proposed that the gas could be used for operations, although this was not tried for another half century.
Chloroform was used as an anaesthetic, but it fell into disuse due to its high toxicity and narrow dose margin. Nitrous oxide and diethyl ether were adopted by the medical mainstream and became the standard anesthetics in use for many years. Other gases such as cyclopropane were also used for anesthesia. Non-flammable gases such as halothane replaced flammable anaesthetics such as ether.
Halothane is now rarely used in humans due to problems with liver damage and a rare condition called malignant hyperthermia, but it is still widely used in veterinary medicine.
In modern times newer anesthetics such as isoflurane and sevoflurane have been developed for medical use which lack both the flammability of ether and the toxicity of halothane, and research in the area is ongoing. Nitrous oxide is still widely used as a dental anaesthetic, to reduce patient anxiety during dental work and minor dental surgery. Other medical anesthetics and inhaled medicinal drugs include xenon, enflurane, isoflurane, sevoflurane, desflurane, methoxyflurane, salbutamol, and fluticasone.
# Legal issues
Most inhalant solvents and gases are not regulated under illegal drug laws such as the United States' Controlled Substances Act. However, many US states and Canadian cities have placed restrictions on the sale of some solvent-containing products to minors, particularly for products widely associated with "sniffing", such as model cement. The practice of inhaling such substances is sometimes colloquially referred to as huffing, sniffing (or "glue-sniffing"), dusting, or chroming.
# Patterns of Psychoactive Inhalant usage
## Africa
Dung sniffing has also been seen in some African countries (see Jenkem). Glue sniffing is also a problem in these countries, with dung sniffing generally being a last resort by people too poor to afford
glue.[9][10]
## Asia
### India and South Asia
In India and South Asia, three of the most widely abused inhalants are the Dendrite brand and other forms of contact adhesives and rubber cements manufactured in Kolkata, toluenes in paint thinners and Iodex - a muscle stress relieving balm. Another very common inhalant is Erase-X, a correction fluid which contains toluene. It has become very common for school and college students to use it because it is easily available in stationery shops in India.
### South East Asia
Dung sniffing has been noted as a problem in several countries in South East Asia such as Thailand and Malaysia among poor and homeless people. Animal or human dung is placed into a plastic bag or tin and left out in the sun where it starts to decompose, releasing methane gas, which has narcotic properties. Police were unsure of what action could be taken, given that dung is not illegal and would be problematic to restrict supplies.[11]
## UK
Generally exists in party cultures (using poppers)
### Russia and Eastern Europe
Gasoline sniffing became common on Russian ships following attempts to limit the supply of alcohol to ship crews in the 1980s. The documentary Children Underground depicts the huffing of a solvent called Aurolac by Romanian homeless children. Gasoline sniffing also occurs in some remote indigenous communities in developed countries.
## North America
### Canada
Native children in the isolated Northern Labrador community of Davis Inlet were the focus of national concern in 1993 when many were found to be sniffing gasoline. The federal Canadian and provincial Newfoundland and Labrador governments intervened on a number of occasions, sending many children away for treatment. Despite being moved to the new community of Natuashish in 2002, serious inhalant abuse problems have continued. Similar problems were also reported in Sheshatshiu in 2000.
### Mexico
The inhaling of a mixture of gasoline and/or industrial solvents, known locally as "Activo" or "Chemo", has risen in popularity among the homeless and among the street children of Mexico City in recent years. The mixture is poured onto a handkerchief and inhaled while held in one's fist.
The chemicals in most common use are cements (trichloroethylene, tetrachloroethylene), lubricants (toluene, ethyl acetate and other acetones), thinners (petroleum distillants, benzene, acetone, tetrachloroethylene) and paint strippers (acetone, toluene, benzene, methylene chloride)[10].
### United States
Ether was used as a recreational drug during the 1930s Prohibition era, when alcohol was made illegal in the USA for over 10 years. Ether was either sniffed or drunk, and in some towns replaced alcohol entirely. However, the risk of death from excessive sedation or overdose is greater than that with alcohol, and ether drinking is associated with damage to the stomach and gastrointestinal tract.[12]
Use of glue, paint and gasoline was little known before the 1950s. Later, glue sniffing became a worldwide phenomenon; however, it is not known if this popularity was caused by government anti-inhalant campaigns. Drug educators argue that the advertising campaigns designed to prevent drug use may instead promote such use. Abuse of aerosol sprays became more common in the 1980s as older propellants such as CFCs were phased out and replaced by more environmentally friendly compounds such as propane and butane.
Abuse of solvents is widespread in impoverished communities, both in developing countries or in poor communities in developed countries (e.g., Aboriginal communities in northern Canada or in Australia). Because solvents and inhalant gases are legally available and inexpensive, there has long been incidents of teenagers using inhalants recreationally. However, most of the long term abuse, or use by older adults tends to be limited to extremely poor or marginalised groups in society.
## South Pacific
### Australia
Although some sources argue that sniffing was introduced by US servicemen stationed in the nation's Top End during World War II,[13] or through experimentation by 1940s-era Coburg Peninsula sawmill workers,[14] other sources claim that inhalant abuse (such as glue inhalation) emerged in Australia in the late 1960s.[15] Chronic, heavy gasoline sniffing appears mainly to occur among remote, impoverished indigenous communities, where the ready accessibility of gasoline has helped to make it a common substance for abuse.
In Australia, gasoline sniffing now occurs widely throughout remote communities of the Northern Territory, Western Australia, northern parts of South Australia and Queensland. The number of people sniffing gasoline goes up and down over time as young people experiment or sniff occasionally. 'Boss' or chronic sniffers may move in and out of communities; they are often responsible for encouraging young people to take it up.[16]
A 1983 survey of 4,165 secondary students in New South Wales showed that solvents and aerosols ranked just after analgesics (e.g., codeine pills) and alcohol for drugs that were abused. This 1983 study did not find any common usage patterns or social class factors.[17]
In Australia between 1981-1991, there were 60 Aboriginal males and three Aboriginal females whose deaths were associated with gasoline sniffing[18]
. They ranged in age from 11 to 32. The causes of death included pneumonia, cardiac failure/arrest, aspiration of vomit, and burns. In 1985, there were 14 communities in Central Australia reporting young people sniffing. In July 1997, it was estimated that there were around 200 young people sniffing gasoline across 10 communities in Central Australia. Approximately 40 were classified as 'chronic' sniffers.
In some communities many children and youths might try gasoline sniffing at least once or twice. Most of these 'experimental' users will not become regular or long-term sniffers. Recently, there have been reports of young Aboriginal people sniffing gasoline in the urban areas around Darwin and Alice Springs. Substitution of gasoline by non-sniffable Opal fuel (which is much less likely to cause a "high") has made a difference in some communities.
## Elsewhere
In several parts of the world where glue-sniffing is widespread, terms for glue-sniffers have arisen based on brand-names of substances, such as aurolaci in Romania from the brand name Aurolac, or resistoleros in Brazil from the brand name Resistol. These terms are often used even in English-language writing about substance abuse in those regions.
# Popular culture references
Template:Trivia
## Music and musical culture
- The Ramones sang "Now I Want to Sniff Some Glue" about adolescent ennui.
- The punk fanzine "Sniffin' Glue" takes its name from the song but, the fanzine is not about inhalants.
- In the Nirvana song "Dumb", Kurt Cobain sings "my heart is broke/But I have some glue/ help me inhale /And mend it with you".
- The Beck song "Fume" from his cassette "Fresh Meat and Old Slabs" is entirely about doing nitrous oxide. He sings: "Had a can of nitrous/we rolled the windows up/Now we're breathing deeply/breathing deeply." The lyrics have a humorous tone throughout, particularly in the chorus: "There's a fume/in this truck/and I don't know if we're dead or what the fuck?"
- Primus's 1998 song "Lacquer Head" is about adolescents who use inhalants to get high.
- In the Sum 41 song "Fat Lip", one part of the song is "...you don't make sense from all the gas you be huffing..."
- The Dead Milkmen song, "Life is Shit" from their album "Beelzebubba" is almost entirely about two friends hallucinating after sniffing glue. The only direct reference is in the first verse, as every verse following it details their hallucinations: "He said 'Yes I do believe this is true, would you like to come and sniff some glue? And we'll fly to where the skies are blue, and look for things both bright and new'".
- The Eminem song, "Bad Meets Evil" contains the lyric: "I breathe ether in three lethal amounts"
- The L7 song, "Scrap" is about a skinhead, Scrap, who regularly inhales spraypaint fumes. The first verse describes Scrap thusly: "I met a skinhead named Scrap, he lived in my friend's garage, everyday he's shaking that spraypaint can, and comes out seeing stars," The chorus describes the general use of spraypaint as an inhalant: " Grab a paper bag like an oxygen mask, until your mind starts to gel, because the ball in the can has a crazy beat, the funky dyin' brain cell"
## Films and books
- In the 1996 film Citizen Ruth, the character Ruth sniffs patio sealant from a paper bag.
- In the movie Love Liza, the main character, played by Philip Seymour Hoffman, develops a gasoline addiction.
- In the David Lynch film Blue Velvet, Dennis Hopper's character uses a mask to inhale nitrous oxide.
- In Little Shop of Horrors, Steve Martin's character dies from nitrous oxide inhalation.
- In The Cider House Rules, Michael Caine's character is an ether addict.
- In the film thirteen, the main character uses computer cleaner to get high.
- Harmony Korine's 1997 film Gummo features two adolescent boys who often huff glue.
- In the book Fear and Loathing in Las Vegas and in the film version, the two main characters inhale Diethyl Ether and Amyl Nitrite, two of several recreational drugs they take on their trip.
- In the movie Shooter, Mark Wahlburg inhales gases from a Whip-It! whipped cream canister to knock himself out.
- In the 1980 Film Airplane!, McCroskey (played by Lloyd Bridges) delivers the famous quote I picked the wrong week to stop sniffing glue. | https://www.wikidoc.org/index.php/Glue_sniffing | |
aa1ae8c4e04e6b8ee559e19bf9e49313f3c9513e | wikidoc | Glutelin | Glutelin
# Overview
Glutelins are soluble in dilute acids or bases, detergents, chaotropic or reducing agents. They are generally prolamin-like proteins in certain grass seeds. glutenin is the most common glutelin as it is found in wheat and is responsible from some of the refined baking properties in bread wheat. The glutelins of barley and rye have also been identified.
Typically there are HMW and LMW glutelins in these species, they crosslink with themselves and other proteins during baking via disulfide bonds.
A HMW glutelin (glutenin) of the grass tribe Triticeae can be sensitizing agents for coeliac disease in individuals who possess the HLA-DQ8 class II antigen receptor gene. (not yet characterized to the epitope level) | Glutelin
# Overview
Glutelins are soluble in dilute acids or bases, detergents, chaotropic or reducing agents. They are generally prolamin-like proteins in certain grass seeds. glutenin is the most common glutelin as it is found in wheat and is responsible from some of the refined baking properties in bread wheat. The glutelins of barley and rye[1] have also been identified.
Typically there are HMW and LMW glutelins in these species, they crosslink with themselves and other proteins during baking via disulfide bonds.
A HMW glutelin (glutenin) of the grass tribe Triticeae can be sensitizing agents for coeliac disease in individuals who possess the HLA-DQ8 class II antigen receptor gene.[2] (not yet characterized to the epitope level) | https://www.wikidoc.org/index.php/Glutelin | |
85f40119f0e2bc32532901a626d39fbaa327320b | wikidoc | Gluttony | Gluttony
Derived from the Latin gluttire, meaning to gulp down or swallow, gluttony is the over-indulgence and over-consumption of food, drink, or intoxicants to the point of waste. In some Christian denominations, it is considered one of the seven deadly sins—a misplaced desire of food or its withholding from the needy.
Depending on the culture, it can be seen as either a vice or a sign of status. The relative affluence of the society can affect this view both ways. A wealthy group might take pride in the security of having enough food to eat to show it off, but it could also result in a moral backlash when confronted with the reality of those less fortunate.
Early Church leaders (e.g., Thomas Aquinas) took a more expansive view of gluttony (Okholm 2000), arguing that it could also include an obsessive anticipation of meals, and the constant eating of delicacies and excessively costly foods. He went so far as to prepare a list of five ways to commit gluttony, including:
- Praepropere - eating too soon
- Laute - eating too expensively
- Nimis - eating too much
- Ardenter - eating too eagerly
- Studiose - eating too daintily
Innocent XI has condemned the proposition which asserts,
that it is not a sin to eat or to drink from
the sole motive of satisfying the palate. However,
it is not a fault to feel pleasure in eating:
for it is, generally speaking, impossible to eat
without experiencing the delight which food
naturally produces. But, it is a defect to eat,
like beasts, through the sole motive of sensual
gratification, and without any reasonable object.
Hence, the most delicious meats may
be eaten without sin, if the motive be good and
worthy of a rational creature; and, in taking
the coarsest food through attachment to pleasure,
there may be a fault.
# Gluttony in the Bible
Gluttony is addressed by the Biblical teachings of moderation (Ecclesiastes 7:18) and self-control (Galatians 5:23; Titus 2:12). It is mentioned most in the book of Proverbs, e.g.,
- “Do not join those who drink too much wine or gorge themselves on meat, for drunkards and gluttons become poor, and drowsiness clothes them in rags.” (Proverbs 23:20-21)
- “He who keeps the law is a discerning son, but a companion of gluttons disgraces his father.” (Proverbs 28:7)
- “When you sit to dine with a ruler, note well what is before you, and put a knife to your throat if you are given to gluttony.” (Proverbs 23:2)
The view of gluttony as one of the Seven Deadly Sins is rooted in the physical destructiveness of excess consumption of food or drink. At the same time, gluttony can cause an individual to focus so intensely on physical desires that the life of the spirit is stunted or forgotten. As a case in point, Emperor Claudius of Rome was, according to Suetonius, a notorious glutton who would bathe in food and gulp down priceless pearls dissolved in vinegar. This self-indulgent personality, never checked by parent or court, led to excesses of violence as well.1
Also See Lewis Welt for examples
# Glorified gluttony
In some social groups gluttony has become glorified, for example, competitive eating competitions. These competitions are often overt displays which are televised.
A famous example is Nathan's Hot Dog Eating Contest.
# In the media
- InCharmed , Piper Halliwell Gluttony
- In Charlie and the Chocolate Factory, Augustus Gloop represents gluttony.
- In Se7en the first murder victim represents gluttony
- In Garth Nix's The Keys to the Kingdom series, gluttony is embodied by Drowned Wednesday, who appropriately takes the form of an enormous Leviathan.
- In Fullmetal Alchemist, Gluttony is one of seven homunculi. He has the ability to eat literally anything, and is always seen around another homunculus, Lust.
- In the Archie Comics newspaper comic for August 14, 2007, it is stated that Jughead is listed in Wikipedia under "Glutton".
1 Suetonius, The Lives of the Twelve Caesars | Gluttony
Derived from the Latin gluttire, meaning to gulp down or swallow, gluttony is the over-indulgence and over-consumption of food, drink, or intoxicants to the point of waste. In some Christian denominations, it is considered one of the seven deadly sins—a misplaced desire of food or its withholding from the needy.[1]
Depending on the culture, it can be seen as either a vice or a sign of status. The relative affluence of the society can affect this view both ways. A wealthy group might take pride in the security of having enough food to eat to show it off, but it could also result in a moral backlash when confronted with the reality of those less fortunate.
Early Church leaders (e.g., Thomas Aquinas) took a more expansive view of gluttony (Okholm 2000), arguing that it could also include an obsessive anticipation of meals, and the constant eating of delicacies and excessively costly foods.[2] He went so far as to prepare a list of five ways to commit gluttony, including:
- Praepropere - eating too soon
- Laute - eating too expensively
- Nimis - eating too much
- Ardenter - eating too eagerly
- Studiose - eating too daintily
Innocent XI has condemned the proposition which asserts,
that it is not a sin to eat or to drink from
the sole motive of satisfying the palate. However,
it is not a fault to feel pleasure in eating:
for it is, generally speaking, impossible to eat
without experiencing the delight which food
naturally produces. But, it is a defect to eat,
like beasts, through the sole motive of sensual
gratification, and without any reasonable object.
Hence, the most delicious meats may
be eaten without sin, if the motive be good and
worthy of a rational creature; and, in taking
the coarsest food through attachment to pleasure,
there may be a fault.[3]
# Gluttony in the Bible
Gluttony is addressed by the Biblical teachings of moderation (Ecclesiastes 7:18) and self-control (Galatians 5:23; Titus 2:12). It is mentioned most in the book of Proverbs, e.g.,
- “Do not join those who drink too much wine or gorge themselves on meat, for drunkards and gluttons become poor, and drowsiness clothes them in rags.” (Proverbs 23:20-21)
- “He who keeps the law is a discerning son, but a companion of gluttons disgraces his father.” (Proverbs 28:7)
- “When you sit to dine with a ruler, note well what is before you, and put a knife to your throat if you are given to gluttony.” (Proverbs 23:2)
The view of gluttony as one of the Seven Deadly Sins is rooted in the physical destructiveness of excess consumption of food or drink. At the same time, gluttony can cause an individual to focus so intensely on physical desires that the life of the spirit is stunted or forgotten. As a case in point, Emperor Claudius of Rome was, according to Suetonius, a notorious glutton who would bathe in food and gulp down priceless pearls dissolved in vinegar. This self-indulgent personality, never checked by parent or court, led to excesses of violence as well.1
Also See Lewis Welt for examples
# Glorified gluttony
In some social groups gluttony has become glorified, for example, competitive eating competitions. These competitions are often overt displays which are televised.
A famous example is Nathan's Hot Dog Eating Contest.
# In the media
- InCharmed , Piper Halliwell Gluttony
- In Charlie and the Chocolate Factory, Augustus Gloop represents gluttony.
- In Se7en the first murder victim represents gluttony
- In Garth Nix's The Keys to the Kingdom series, gluttony is embodied by Drowned Wednesday, who appropriately takes the form of an enormous Leviathan.
- In Fullmetal Alchemist, Gluttony is one of seven homunculi. He has the ability to eat literally anything, and is always seen around another homunculus, Lust.
- In the Archie Comics newspaper comic for August 14, 2007, it is stated that Jughead is listed in Wikipedia under "Glutton".
1 Suetonius, The Lives of the Twelve Caesars | https://www.wikidoc.org/index.php/Gluttony |
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