HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Acitretin
Acetretin · etretin · Acitren · Acitreti · SORIATANE · ACITRETIN · ro10-1670 · NEOTIGASON
Identifikatoren & physikalische Daten
| CAS No. | 54757-46-9 |
|---|---|
| Summenformel | C21H26O3 |
| Durchschnittliche Molmasse | 326,4 g/mol |
| Monoisotopische Masse | 326,18819469 g/mol |
| SMILES | COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)c(C)c1C |
| InChIKey | IHUNBGSDBOWDMA-AQFIFDHZSA-N |
| PubChem CID | 5284513 |
| ChEMBL | CHEMBL1131 |
| ChEBI | CHEBI:50173 |
| EC No. | 259-474-4 |
| DTXSID | DTXSID6022553 |
Chemische & physikalische Eigenschaften
| XLogP | 6,1 |
|---|---|
| Polarare Oberfläche (TPSA) | 46,5 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 3 |
| Frei drehbare Bindungen | 6 |
| Schwere Atome | 24 |
| Formalladung | 0 |
| Komplexität | 539 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | log Kow = 6.405.7 |
| Color/Form | Green-yellow crystalline powderCrystals from hexane |
| Löslichkeit | Practically insoluble in water (<0.1 mg/100 mg)Sparingly soluble in tetrahydrofuranslightly soluble in acetone, alcoholvery slightly soluble in cyclohexane4.78e-04 g/LPractically insoluble in water, sparingly soluble in tetrahydrofuran, slightly soluble in acetone and in ethanol (96 per cent), very slightly soluble in cyclohexane. |
| Human Drugs | Breast FeedingLactationMilk, HumanKeratolytic AgentsRetinoidsFDA approved drugs -> Active ingredient |
| Decomposition | When heated to decomposition it emits acrid smoke and irritating fumes. |
| Schmelzpunkt | 228-230 °C228 - 230 °C228-230°C |
| Physical Description | Solid |
| Stability/Shelf Life | Stable under recommended storage conditions. |
| Siedepunkt | 404.46°C (rough estimate) |
| Dichte | 1.1348 (rough estimate) |
| Brechungsindex | 1.4700 (estimate) |
| Lagerbedingungen | -20°C |
| pKa (Säurekonstante) | 4.72±0.33(Predicted) |
| Aggregatzustand | powder |
| Farbe | Light yellow to yellow |
| Merck | 14,112 |
| Stabilität | LIGHT SENSITIVE |
| InChI | InChI=1S/C21H26O3/c1-14(8-7-9-15(2)12-21(22)23)10-11-19-16(3)13-20(24-6)18(5)17(19)4/h7-13H,1-6H3,(H,22,23)/b9-7+,11-10+,14-8+,15-12+ |
| InChIKey | IHUNBGSDBOWDMA-AQFIFDHZSA-N |
| SMILES | C(O)(=O)/C=C(\C)/C=C/C=C(\C)/C=C/C1=C(C)C=C(OC)C(C)=C1C |
| CAS Datenbank | 55079-83-9(CAS DataBase Reference) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]P203, P264, P264+P265, P273, P280, P302+P352, P305+P351+P338, P318, P321, P332+P317, P337+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 48 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.H315: Causes skin irritation [Warning Skin corrosion/irritation] |
|---|---|
| Regulatorische Informationen | Acitretin: Does not have an individual approval but may be used under an appropriate group standard |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including acitretin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Hazard Classes and Categories | Skin Irrit. 2 (100%) |
| Hazardous Reactivities and Incompatibilities | Incompatible materials: Strong oxidizing agents. |
| Brandbekämpfungsverfahren | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.Advice for firefighters: Wear self-contained breathing apparatus for fire fighting if necessary. |
| Lagerbedingungen | Store at 20 to 25 °C (68 to 77 °F). Protect from light. Avoid exposure to high temperatures and humidity after the bottle is opened.Keep container tightly closed in a dry and well-ventilated place. Light sensitive. Store under inert gas. Moisture sensitive. |
| Reinigungsverfahren | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Contaminated packaging: Dispose of as unused product. |
| Preventive Measures | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker. |
| Personal Protective Equipment (PPE) | Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).Skin protection: Handle with gloves.Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). |
| Wechselwirkungen | Long-term immunosuppression in the organ transplant recipient (OTR) population places these individuals at higher risk of developing skin malignancies. Oral retinoids have become a useful tool for pharmacologic prophylaxis in the OTR population. Immunosuppressants that inhibit mTOR, such as sirolimus, may be used in combination with a systemic retinoid for chemoprophylaxis of cutaneous malignancies. We present the case of a male patient status post second renal transplant who developed an abrupt and unexpected rise in sirolimus levels to supra-therapeutic levels after initiation of prophylactic acitretin for innumerable squamous cell carcinomas (SCC). The sirolimus levels returned to baseline after cessation of acitretin. Systemic drug-drug interactions are an important phenomenon, especially in the solid OTR population. It is postulated that this interaction was mediated by acitretin inhibition of CYP3A4, the primary enzyme responsible for sirolimus metabolism. The Drug Interaction Probability Scale (DIPS) indicates this was a "probable" drug-drug interaction. To date, this interaction has not been reported in the literature. This case accentuates the importance of close monitoring of solid OTRs for adverse medication interactions when multiple medications are taken.Concomitant administration of alcohol and acitretin resulted in formation of etretinate, a known human teratogen with a longer elimination half-life than acitretinthis interaction may increase the duration of teratogenic effects of acitretin. Concomitant use also may result in hepatotoxicity. Concomitant use of alcohol from any source should be avoided during and for 2 months after acitretin therapy cessation in women of childbearing potential.Additive adverse effects (e.g., hypervitaminosis A) are possible in patients concomitantly receiving acitretin with vitamin A. Concomitant use is contraindicated.There is an increased risk of hepatitis in patients concomitantly receiving acitretin and methotrexate. Concomitant use is contraindicated.For more Interactions (Complete) data for Acitretin (15 total), please visit the HSDB record page. |
| Hepatotoxicity | Liver test abnormalities occur in up to one third of patients on acitretin, although marked elevations above three times the upper limit of normal occur in only 1% to 5%. These abnormalities are typically transient, not accompanied by symptoms and can resolve even with continuation of acitretin, but they may be associated with mild symptoms and require drug discontinuation in up to 4% of patients. |
| Unerwünschte Wirkungen | A high amount of vitamin A produces a broad spectrum of signs and symptoms, primarily of the musculoskeletal, mucocutaneous, neuropsychiatric, central nervous, and hepatic systems. Many adverse reactions reported using acitretin capsules resemble those of the hypervitaminosis A syndrome. The following adverse reactions are reported in clinical trials and post-marketing experience. |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Acitretin is a keratolytic agent indicated for the treatment of severe psoriasis in adults. Acitretin has been used in a limited number of patients for the management of discoid lupus erythematosus. HUMAN STUDIES: Symptoms of overdose are identical to acute hypervitaminosis A, including headache and vertigo. Lipid elevations were reported in 25-50% of acitretin recipients. Elevations of triglycerides to concentrations associated with fatal fulminant pancreatitis are rarehowever, cases have been reported with acitretin. Rare cases of pancreatitis without hypertriglyceridemia also have been reported. The case of a female psoriatic patient with angioedema (without urticaria) due to oral acitretin was reported. Acitretin should be considered as a possible cause of thrombotic stroke. n one reported case of overdose, a 32 year old male with Darier's disease took 525 mg single dose. He vomited several hours later but experienced no other ill effects. No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of keratinization, and 6 healthy volunteers) given 30 to 50 mg per day of acitretin for at least 12 weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in any of the 31 men. No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured. Acitretin is a known human teratogen, and there is a very high risk of severe birth defects if a patient becomes pregnant while receiving acitretin or upon drug discontinuance (birth defects have been reported 2 years or longer after the last dose of acitretin). Teratogenicity generally is characterized by malformations involving craniofacial, cardiovascular, skeletal, and CNS structures. Acitretin was evaluated for mutagenic potential in unscheduled DNA synthesis assay in human fibroblasts. No evidence of mutagenicity of acitretin was observed in this assay. ANIMAL STUDIES: An 80-week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice. A carcinogenesis study of acitretin in rats, at doses up to 2 mg per kg per day administered 7 days per week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin. Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg per day). In a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of acitretin tested, 3 mg per kg per day. Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat hepatocytes and in an in vivo mouse micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays.Acitretin must be withdrawn at once in overdose cases. Overdose symptoms are similar to acute hypervitaminosis A (headache and vertigo). In mice and rats, the acute oral toxicity (LD50) of acitretin was only observed at greater than 4,000 mg/kg dose. In one reported overdose, a 32-year-old man with Darier disease took a 525 mg single dose. Later, he vomited for several hours but did not experience any other ill effects. One case of fulminant hepatic failure following an intentional overdose of 600 mg of acitretin was reported, where the patient demonstrated a rapid recovery and did not require liver transplantation. |
| Ongoing Test Status | EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPAICSS Dashboard ApplicationAvailable from, as of February 4, 2019: http://actor.epa.gov/dashboard/] |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Symptoms of overdose are identical to acute hypervitaminosis A, ie, headache and vertigo./SIGNS AND SYMPTOMS/ Lipid elevations were reported in 25-50% of acitretin recipients. Elevations of triglycerides to concentrations associated with fatal fulminant pancreatitis are rarehowever, cases have been reported with acitretin. Rare cases of pancreatitis without hypertriglyceridemia also have been reported./CASE REPORTS/ The efficacy of oral acitretin in the systemic treatment of severe and recalcitrant dermatoses has been established in a large number of clinical trials. Its mucocutaneous and ocular adverse reactions are common or relatively common, whereas systemic side effects are either uncommon or rare and include teratogenesis, hyperlipidemia, hepatotoxicity, intracranial hypertension, myopathy, and peripheral neuropathy. Angioedema is a term used to describe an acute, solitary or multiple, circumscribed, and non-pitting mucocutaneous swelling that affects the dermis and the subcutaneous tissue, lasts 24 to 72 hours, and may become potentially life-threatening when the pharynx and/or the larynx are involved. We report here the case of a 51-year old female psoriatic patient with angioedema (without urticaria) due to oral acitretin, confirmed by a positive oral provocation test. To the best of our knowledge, this is the second description of such an adverse reaction to acitretin./CASE REPORTS/ The retinoic acid derivatives are used for disorders of keratinization such as psoriasis. Retinoic acid syndrome is a cytokine release syndrome, commonly encountered in patients with acute promyelocytic leukaemia (APL). It is very rarely described in psoriasis seconday to use of retoind derivatives. Here we report a case of elderly male with psoriasis presenting with acitretin induced retinoic acid syndrome.For more Human Toxicity Excerpts (Complete) data for Acitretin (22 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Acitretin's production and administration as a psoriasis medication and veterinary dermatology medication(1) may result in its release to the environment through various waste streams(SRC). |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)AcitretinvMost-DILI-concern5Box warningDOI:10.1016/j.drudis.2016.02.015 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ An 80-week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice at doses approximately one-half the maximum recommended human therapeutic dose based on a mg/sq m comparison. /Etretinate//LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg per kg per day administered 7 days per week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg per day)./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ The present study determines the relative developmental toxicity potencies of retinoids in the embryonic stem (ES)-D3 cell differentiation assay of the embryonic stem cell test, and compares the outcomes with their relative potencies in in vivo and two other in vitro assays for developmental toxicity. The results reveal that the potency ranking obtained in the ES-D3 cell differentiation assay is similar to the reported potency rankings in the two other in vitro assays for developmental toxicity. TTNPB ((E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid) was the most potent retinoid, whereas etretinate and retinol had the lowest potency. All-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and acitretin showed an intermediate potency. In vivo potency rankings of the developmental toxicity of retinoids appear to be dependent on the species and/or exposure regimens used. The obtained in vitro potency ranking does not completely correspond with the in vivo potency rankings, although TTNPB is correctly predicted to be the most potent and retinol the least potent congener. The lack of in vivo kinetic processes in the ES-D3 cell differentiation assay might explain the deviating potency predictions of some retinoids. Therefore, knowledge on the species-dependent in vivo kinetics is essential when using in vitro toxicity data for the estimation of in vivo developmental toxicity potencies within series of related compounds.For more Non-Human Toxicity Excerpts (Complete) data for Acitretin (10 total), please visit the HSDB record page. |
| Populations at Special Risk | Acitretin is contraindicated in patients with severely impaired renal or hepatic function. The drug also is contraindicated in patients with chronic, abnormally elevated blood lipids.There is an increased risk of hypertriglyceridemia in patients with diabetes mellitus, obesity, increased alcohol intake, lipid metabolism disorder, or familial history of these conditions. Close monitoring of serum lipid and/or glucose in these patients and in patients receiving long-term therapy is recommended. Acitretin is contraindicated in patients with chronic, abnormally elevated blood lipid concentrations. |
| Antidote and Emergency Treatment | /SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B//SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B//SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/ |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| F | 8-10-21 |
| Wassergefährdungsklasse (WGK) | 3 |
| UN-Transportnummer | UN 3077 9/PG 3 |
| Zollcode | 2918992090 |
| RTECS-Nr. | RA8460000 |
| R-Sätze (R) | 61-36/38-50/53 |
| Toxizität | LD50 i.p. in mice (mg/kg): >4000 (1 day), 700 (10 days), 700 (20 days) (Bollag, 1978) |
| Gefahrensymbole | T,N |
| Sicherheitshinweise (S) | 53-26-45-60-61-37/39 |
| Gefahrenklasse | 9Aquatic Acute 1Aquatic Chronic 1Eye Irrit. 2Repr. 1BSkin Irrit. 2 |
| Verpackungsgruppe | III |
| Lagerklasse | 6.1C - Combustible, acute toxic Cat.3toxic compounds or compounds which causing chronic effects |
| Gefahrstoffdaten | 55079-83-9(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Acitretin is the free acid form of etretinate useful in the treatment of severe psoriasis and other disorders of keratinization. Although the two compounds have virtually the same efficacy and teratogenic side-effects, acitretin is advantageous for child-bearing women, as its shorter half-life reduces the necessary contraception period from two years to only one month after treatment ceases.
Verwenden
Acitretin, a retinoid that binds to nuclear receptors and regulates gene expression, is a potent activator of the α-secretase ADAM10 gene expression and apoptosis inducer via the CD95 signalling pathway. Acitretin is a systemic retinoid drug used in the treatment of severe psoriasis.