HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Duloxetine
DULOXETIN · DULOXETINE HCI · DULOXETINE-D3 · (S)-DULOXETINE · (3S)-N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-yl-propan-1-amine · CS-559 · DULOXETINE · (+)-Duloxetine
Identifikatoren & physikalische Daten
| CAS No. | 116539-59-4 |
|---|---|
| Summenformel | C18H19NOS |
| Durchschnittliche Molmasse | 297,4 g/mol |
| Monoisotopische Masse | 297,11873523 g/mol |
| SMILES | CNCC[C@H](Oc1cccc2ccccc12)c1cccs1 |
| InChIKey | ZEUITGRIYCTCEM-KRWDZBQOSA-N |
| PubChem CID | 60835 |
| ChEMBL | CHEMBL1175 |
| ChEBI | CHEBI:36795 |
| EC No. | 601-438-0 |
| DTXSID | DTXSID6048385 |
Chemische & physikalische Eigenschaften
| XLogP | 4,3 |
|---|---|
| Polarare Oberfläche (TPSA) | 49,5 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 3 |
| Frei drehbare Bindungen | 6 |
| Schwere Atome | 21 |
| Formalladung | 0 |
| Komplexität | 312 |
| Stoffklassen | Pharmaceutical |
| Arzneimittel | Pharmaceuticals -> Used in SwitzerlandPharmaceuticals -> AntidepressantPharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | 4 |
| Löslichkeit | 2.96e-03 g/LSoluble in DMSO |
| Flammpunkt | 9.7 °C (49.5 °F) - closed cup |
| Human Drugs | Antidepressants -> Serotonin-noradrenaline reuptake inhibitors (SNRI)Breast FeedingLactationMilk, HumanAntidepressive AgentsSerotonin-Norepinephrine Reuptake InhibitorsEMA approved medicines: Human medicine |
| Physical Description | Solid |
| Stability/Shelf Life | Stable under recommended storage conditions. |
| Dissociation Constants | White to slightly brownish white solid. pKa in dimethylformamide:water (66:34) = 9.6 Slightly soluble in water /Duloxetine hydrochloride/ |
| Collision Cross Section | 171.4 Ų [M+H]+ [CCS Type: DTBuffer gas: N2Ionization: ESI+Dataset: Antidepressants]171 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]170.74 Ų [M+Na]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards] |
| Siedepunkt | 466.2±40.0 °C(Predicted) |
| Dichte | 1.158±0.06 g/cm3(Predicted) |
| Lagerbedingungen | Store at -20°C |
| Aggregatzustand | Oil |
| pKa (Säurekonstante) | 10.02±0.10(Predicted) |
| Farbe | Light brown to yellow |
| BCS Class | 2 |
| InChI | InChI=1/C18H19NOS.ClH/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16/h2-10,13,17,19H,11-12H2,1H31H/t17-/s3 |
| InChIKey | BFFSMCNJSOPUAY-VOPAOICTNA-N |
| SMILES | C1(=CC=CS1)[C@H](CCNC)OC1=CC=CC2=CC=CC=C12.Cl |&1:5,r| |
| EPA chemische Informationen | 2-Thiophenepropanamine, N-methyl-?-(1-naphthalenyloxy)-, (?S)- (116539-59-4) |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH351 (100%): Suspected of causing cancer [Warning Carcinogenicity]P203, P280, P318, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 9 reports by companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.DangerH225: Highly Flammable liquid and vapor [Danger Flammable liquids] |
|---|---|
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including duloxetine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Duloxetine hydrochloride/ |
| Hazard Classes and Categories | Carc. 2 (100%) |
| Hazardous Reactivities and Incompatibilities | Incompatible materials: Acids, Oxidizing agents, Alkali metals, Strong oxidizing agents, Strong acids, Acid chlorides, Acid anhydrides, Reducing agents, Strong reducing agents, Phosphorus halides |
| Brandbekämpfungsverfahren | Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. |
| Lagerbedingungen | Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Recommended storage temperature -20 °C |
| Reinigungsverfahren | ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low areas.Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations. |
| Entsorgungsverfahren | SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.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. |
| Preventive Measures | 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.Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.Precautions for safe handling: Avoid contact with skin and eyes. Avoid inhalation of vapour or mist. Use explosion-proof equipment.Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge. |
| Personal Protective Equipment (PPE) | Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).Body Protection: Complete suit protecting against chemicals, Flame retardant antistatic protective clothing., The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.Skin protection: Handle with gloves.Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). |
| Treatment | There is no specific antidote to Duloxetine, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. (L1712) |
| Wechselwirkungen | Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCt,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued.Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin. |
| Hepatotoxicity | Liver test abnormalities with ALT elevations above 3 times the upper limit of normal have been reported to occur in ~1% of patients on duloxetine, but elevations were usually self-limited and did not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on duloxetine. The onset of injury is usually within 1 to 6 months and the pattern of serum enzyme elevations is usually hepatocellular, but mixed and cholestatic forms have also been described. Fatal cases have been described but their relatedness to duloxetine has been quesitoned. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8.1X10+4(SRC), determined from a structure estimation method(2), indicates that duloxetine is expected to be immobile in soil(SRC). The estimated pKa of duloxetine is 9.70(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Duloxetine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8.1X10+4(SRC), determined from a structure estimation method(2), indicates that duloxetine is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.70(3) indicates duloxetine will exist almost entirely in the cation or anion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 370(SRC), from an estimated log Kow of 4.68(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data in water were not available(SRC, 2015).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), duloxetine, which has an estimated vapor pressure of 1.2X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase duloxetine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC)the half-life for this reaction in air is estimated to be 25 min(SRC), calculated from its rate constant of 3.13X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase duloxetine may be removed from the air by wet and dry deposition(SRC). Duloxetine contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). |
| Unerwünschte Wirkungen | Duloxetine has a very low anticholinergic side effect profileadverse effects of the cardiovascular, gastrointestinal, and central nervous system, such as headaches, drowsiness, and fatigue, are more common. |
| Expositionspfade | Orally administered duloxetine hydrochloride is well absorbed. |
| Milk Concentrations | It is not known whether duloxetine and/or its metabolites are distributed into breast milk. However, duloxetine and/or its metabolite are distributed into the milk of lactating rats. |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Duloxetine hydrochloride is used for the acute management of generalized anxiety disorder in adults, the management of neuropathic pain associated with diabetic peripheral neuropathy in adults, the management of fibromyalgia in adults, the management of moderate to severe stress urinary incontinence (SUI) in women, and the acute and maintenance treatment of major depressive disorder in adults. HUMAN EXPOSURE AND TOXICITY: Possible risk of severe hepatic toxicityelevated serum transaminase concentrations, sometimes requiring discontinuance of duloxetine, have been reported. In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting. A higher proportion of patients reporting discontinuation-emergent adverse events were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one discontinuation-emergent adverse event differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of discontinuation-emergent adverse events. Abrupt discontinuation of duloxetine is associated with a discontinuation-emergent adverse event profile similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants ANIMAL STUDIES: Duloxetine was administered in the diet to mice for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (6 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/ sq m basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (2 times the MRHD). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (4 times the MRHD). Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (4 times the MRHD) did not alter mating or fertility. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/sq m basis)the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. Duloxetine was not mutagenic in the bacterial reverse mutation assay (Ames test), and not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, it was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA assay in rat hepatocytes, and did not induce in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.Fatal outcomes have occurred with overdoses at as low as 1000 mg. Signs and symptoms of overdose include serotonin syndrome, seizures, coma, somnolence, syncope, tachycardia, autonomic instability, diarrhea, and vomiting. Signs of serotonin syndrome include agitation, restlessness, disorientation, diaphoresis, hyperthermia, tachycardia, nausea, vomiting, tremor, muscle rigidity, hyperreflexia, myoclonus, dilated pupils, dry mucous membranes, and increased bowel sounds. Clonus and hyperreflexia are particularly common in serotonin syndrome.Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. The antidepressant and pain inhibitory actions of duloxetine are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. The mechanism of action of duloxetine in SUI has not been determined, but is thought to be associated with the potentiation of serotonin and norepinephrine activity in the spinal cord, which increases urethral closure forces and thereby reduces involuntary urine loss. |
| Signs and Symptoms | Symptoms of overdose include tremors, convulsions, reduced activity, slow pupillary response, intermittent tremors, and rigidity. |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of duloxetine can be estimated to be 8.1X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that duloxetine is expected to be immobile in soil. The estimated pKa of duloxetine is 9.70(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Duloxetine, present at 0.08 ug/L, exhibited Kd values of 1.3X10+4, 3.2X10+3 and 2.9X10+3 in primary, secondary sludge (short age) and secondary sludge (long age), respectively(5). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting./SIGNS AND SYMPTOMS/ Possible risk of severe hepatic toxicityelevated serum transaminase concentrations, sometimes requiring discontinuance of duloxetine, have been reported. Laboratory findings suggestive of severe liver injury (e.g., increased serum transaminase, bilirubin, and alkaline phosphatase concentrations) with evidence of obstruction were reported in 3 patients who received duloxetine in clinical studies. Because there was evidence of substantial alcohol use in these patients that may have contributed to the abnormalities, duloxetine should not ordinarily be prescribed to patients with a history of excessive alcohol consumption./EPIDEMIOLOGY STUDIES/ Data were obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder (MDD). In a pooled analysis of 6 short-term treatment trials, in which treatment was stopped abruptly, discontinuation-emergent adverse events (DEAEs) were reported by 44.3% and 22.9% of duloxetine- and placebo-treated patients, respectively (p<0.05). Among duloxetine-treated patients reporting at least 1 discontinuation-emergent adverse event, the mean number of symptoms was 2.4. discontinuation-emergent adverse events reported significantly more frequently on abrupt discontinuation of duloxetine compared with placebo were dizziness (12.4%), nausea (5.9%), headache (5.3%), paresthesia (2.9%), vomiting (2.4%), irritability (2.4%), and nightmares (2.0%). Dizziness was also the most frequently reported discontinuation-emergent adverse event in the analyses of 3 long-term duloxetine studies. Across the short- and long-term data sets, 45.1% of discontinuation-emergent adverse events had resolved in the duloxetine-treated populations by the end of the respective studies, and the majority of these (65.0%) resolved within 7 days. Most patients rated the severity of their symptoms as mild or moderate. A higher proportion of patients reporting discontinuation-emergent adverse events were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one discontinuation-emergent adverse event differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of discontinuation-emergent adverse events. Abrupt discontinuation of duloxetine is associated with a discontinuation-emergent adverse event profile similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. It is recommended that, whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment./SIGNS AND SYMPTOMS/ The most frequently observed adverse reactions in the clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as CYMBALTA.For more Human Toxicity Excerpts (Complete) data for DULOXETINE (8 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Duloxetine's production and adminsitration as a medication(1) may result in its release to the environment through various waste streams(SRC). |
| Gefahrstoffdaten | 116539-59-4(Hazardous Substances Data) |
Anwendungen & Verwendung
History
Duloxetine is a second-generation antidepressant. Its mechanism of action involves inhibiting the reuptake of serotonin and norepinephrine by neurons, thereby increasing the concentration of these two neurotransmitters in the synaptic cleft, thus improving mood and relieving pain.Initial Approval (2004): Cymbalta was initially approved for the treatment of major depressive disorder (MDD). In the same year, it also received approval for the treatment of diabetic peripheral neuropathy (DPNP), making it a unique drug capable of simultaneously addressing two common and frequently co-occurring conditions: depression and neuropathic pain.Expansion of Indications: Subsequently, Eli Lilly expanded its indications through clinical trials, making it a multi-functional drug. The most significant expansions include generalized anxiety disorder (GAD) (2007), fibromyalgia (2008), and chronic musculoskeletal pain (2010). The approval of these indications secured Cymbalta a significant position in the pain management market, making it one of Eli Lilly's blockbuster drugs.Patent Expiration (2013): In December 2013, Cymbalta's primary patent in the United States expired, a phenomenon known as the "patent cliff." Following the patent expiration, the FDA quickly approved several generic versions (generic name: duloxetine), leading to a significant drop in sales, but also enabling wider use of the drug at a lower price.
Verwenden
Antidepressant.