Huagongshe화공사 화학 정보 인쇄 보고서 · 연구 참고용
Sertraline
Zoloft · Sertraline for peak identification CRS · Tatig · Gladem · cp51974 · Adjuvin · Sealdin · Atruline
식별자 및 물리적 특성
| CAS No. | 79617-95-1 |
|---|---|
| 분자식 | C17H17Cl2N |
| 평균 분자량 | 306.2 g/mol |
| 단동위원소 질량 | 305.0738049 g/mol |
| SMILES | CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21 |
| InChIKey | VGKDLMBJGBXTGI-SJCJKPOMSA-N |
| PubChem CID | 68617 |
| ChEMBL | CHEMBL809 |
| ChEBI | CHEBI:9123 |
| EC No. | 616-708-3 |
| DTXSID | DTXSID6023577 |
화학 및 물리적 성질
| XLogP | 4.8 |
|---|---|
| 극성 표면적 | 12 |
| 수소 결합 공여자 수 | 1 |
| 수소 결합 수용자 수 | 1 |
| 회전 가능 결합 수 | 2 |
| 무거운 원자 수 | 20 |
| 형식 전하 | 0 |
| 복잡도 | 322 |
| 물질 분류 | Pharmaceutical |
| 의약품 | DEA NFLIS-Drug Category -> AntidepressantsPharmaceuticals -> Synthetic Cannabinoids or Psychoactive CompoundsPharmaceuticals -> Listed in ZINC15Pharmaceuticals -> SSRIs (Selective Serotonin Reuptake Inhibitors)Pharmaceuticals -> Used in Switzerland |
| 용해도 | 3.8mg/mL>45.9 [ug/mL] (The mean of the results at pH 7.4) |
| Human Drugs | Antidepressants -> Selective serotonin reuptake inhibitors (SSRI)Breast FeedingLactationMilk, HumanAntidepressive AgentsSerotonin Uptake InhibitorsPharmaceuticals |
| Endocrine Disruptors | Potential endocrine disrupting compound |
| 끓는 점 | 416.3±45.0 °C416.3±45.0 °C(Predicted) |
| 녹는점 | 245-246 |
| Physical Description | Solid |
| Dissociation Constants | 89.16 |
| Collision Cross Section | 167.7 Ų [M+H]+ [CCS Type: DTBuffer gas: N2Ionization: ESI+Dataset: Antidepressants]166.47 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]167.3 Ų [M+H]+ [CCS Type: DTMethod: single field calibrated] |
| Other Experimental Properties | MW: 342.70. Crystals, mp 243-245 °C. Specific optical rotation at 23 °C = +37.9 deg (c = 2 in methanol). Solubility at room temperature (mg/ml): water 3.80.1N HCl 0.510.1N NaOH 0.002ethanol 15.7isopropyl alcohol 4.3chloroform 110acetone 1.1N,N-dimethylformamide 88dimethylsulfoxide 147ethyl acetate 0.20acetonitrile 0.85methanolic 0.1N HCl 47chloroform/methanol (1:1) 134. pKa (ethanol:water, 1:1 v/v): 8.5. density = 1.37 /Sertraline hydrochloride/ |
| 밀도 | 1.25±0.1 g/cm3(Predicted) |
| pKa(산도 계수) | pKa 9.48±0.04(H2O I > 0)(Approximate) |
| 용해도 | <0.1g/L(상온) |
| InChI | InChI=1S/C17H17Cl2N/c1-20-17-9-7-12(13-4-2-3-5-14(13)17)11-6-8-15(18)16(19)10-11/h2-6,8,10,12,17,20H,7,9H2,1H3/t12-,17-/m0/s1 |
| InChIKey | VGKDLMBJGBXTGI-SJCJKPOMSA-N |
| SMILES | [C@@H]1(NC)C2=C(C=CC=C2)[C@H](C2=CC=C(Cl)C(Cl)=C2)CC1 |
| NIST | Sertraline(79617-96-2) |
| EPA | Sertraline (79617-96-2) |
안전 및 규제
| GHS 분류 | WarningH302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]P264, P270, P273, P301+P317, P330, P391, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 2 reports by companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| 처리 방법 | SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. |
| Treatment | Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. 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 should be administered. Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for sertraline are known. (L1712) |
| 상호 작용 | Examples of drug interactions with serotonin-reuptake inhibitors include potentiation of agents metabolized prominently by CYP1A2 (e.g. beta-adrenergic receptor antagonists, caffeine, several antipsychotic agents, & most tricyclic antidepressants)CYP2C9 (carbamazepine)CYP2C19 (barbiturates, imipramine, propranolol, phenyltoin)CYP2D6 (beta-adrenergic receptor antagonists, some antipsychotics, many antidepressants)CYP3A3/4 (benzodiazepines, carbamazepine, many antidepressants, & several antibiotics). /Serotonin-reuptake inhibitors/Antidepressants potentiate the effects of alcohol & probably other sedatives. The anticholinergic activity of tricyclic antidepressants can add to that of antiparkinsonism agents, antipsychotic drugs of low potency (especially clozapine & thioridazine), or other compounds with antimuscarinic activity to produce toxic effects. Tricyclic antidepressants have prominent & potentially dangerous interactions with biogenic amines, such as norepinephrine, which normally are removed from their site of action by neuronal uptake. However, drugs that inhibit norepinephrine transport also block the effects of indirectly acting amines, such as tyramine, which must be taken up by sympathetic neurons to release norepinephrine. Presumable by a similar mechanism, tricyclic antidepressants prevent the antihypertensive action of adrenergic neuron blocking agents such as guanadrel. Tricyclic agents & trazodone also can block the centrally mediated antihypertensive action of clonidine. /Antidepressants/Serotonin-reuptake inhibitors & virtually any agent with serotonin-potentiating activity can interact dangerously or even fatally with MAO inhibitors (particularly long-acting MAO inhibitors). ... The resulting reactions have been referred to as "serotonin syndrome". This syndrome typically includes akasthisia-like restlessness, muscle twitches & myoclonus, hyperreflexia, sweating, penile erection, shivering, & tremor as a prelude to more severe intoxication, with seizures & coma. The reaction is often self-limiting if the diagnosis is made quickly & the offending agents are discontinued. The precise pathophysiological mechanisms underlying these toxic syndromes remain ill-defined. Newer MAO inhibitors (e.g. selegiline, moclobemide) also should be considered to have some risk of such interactions. /Serotonin-reuptake inhibitors/Because of its extensive protein binding. Sertraline may cause a shift in plasma concns of other drugs similarly tightly protein bound (eg, warfarin, propranolol). the risk of using sertraline in combination with other CNS adrenergic drugs has not been systematically evaluated. Sertraline appears to induce hepatic microsomal enzymes. Patients receiving a sertraline reuptake inhibitor drug in combination with a monoamine oxidase inhibitor may develop serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability, & mental changes (extreme agitation, delirium, coma). At least 14 days should be allowed after starting sertraline before starting a MAOI.For more Interactions (Complete) data for SERTRALINE (7 total), please visit the HSDB record page. |
| Hepatotoxicity | Liver test abnormalities have been reported to occur in up to 1% of patients on sertraline, but elevations are usually modest and infrequently 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 sertraline. The onset of injury is usually within 2 to 24 weeks and the pattern of serum enzyme elevations has varied from hepatocellular to mixed and cholestatic. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon. Acute liver failure due to sertraline has been described but is very rare. |
| 유해 작용 | SSRIs, considered a newer class of antidepressants, are better tolerated than tricyclic antidepressants or monoamine oxidase inhibitors. The primary side effects of sertraline include syncope, lightheadedness, diarrhea, nausea, sweating, dizziness, xerostomia, confusion, hallucinations, tremor, somnolence, impotence, a disorder of ejaculation, fatigue, rhinitis, and female sexual disorder. |
| 노출 경로 | The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food. |
| 독성 요약 | IDENTIFICATION: Sertraline is a selective serotonin reuptake inhibitor antidepressant agent. Sertraline hydrochloride is a white solid crystal or powder. It is soluble in water and slightly soluble in isopropyl alcohol. Indications: Psychoanaleptic Antidepressant and bicyclic antidepressant Accepted: Major mental depression and prevention of relapse and recurrence of depression. HUMAN EXPOSURE: Main risks and target organs: Sertraline is a selective serotonin reuptake inhibitor (SSRI). When taken alone it is safer in overdose than most other classes of antidepressants. Patients who ingest a sertraline overdose generally experience only mild neurological and gastroenterological symptomssignificant cardiovascular toxicity is unusual. The serotonergic effects of sertraline may be enhanced when sertraline is combined with tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), carbamazepine, lithium or serotonergic substances. A life threatening serotonin syndrome consisting of hyperthermia, tremor and convulsions can develop when sertraline is ingested with these drugs. Summary of clinical effects: Lightheadedness, drowsiness, tremor in upper extremitiesnausea, vomiting, diarrhea. Diagnosis: Diagnosis of sertraline poisoning is clinical and based on history of overdose and/or access to sertraline and the presence of minor neurological and/or gastroenterological symptoms. Co-ingestion of tricyclic antidepressants and/or MAOIs should be suspected and the diagnosis of the serotonin syndrome should be considered in the presence of three or more of the following symptoms: behavioral change (confusion or hypomania), agitation, myoclonus, ocular clonus, sustained ankle clonus, hyperreflexia, sweating, shivering, tremor, diarrhea, motor incoordination, muscle rigidity, fever. The differential diagnoses include neuroleptic malignant syndrome, acute poisoning with strychnine, acute sepsis, or severe metabolic disturbance. Contraindications: Absolute: Hypersensitivity to sertraline. Children less than 15 years old. Co-administration of sumatriptan, non selective monoamine oxidase inhibitor (MAOI) and MAOI B-selective antidepressants. Relative: Co-administration of MAOI A-selective antidepressants. Pregnancy and breast feeding. Routes of exposure: Oral: Sertraline is available as capsules, thus ingestion is the most common route of exposure. Kinetics: Absorption by route of exposure: Sertraline is slowly and completely absorbed from the gastrointestinal tract. Peak plasma concentrations (Cmax) occur between 4.5 and 8.5 hours after ingestion of a single dose. The presence of food slightly increases sertraline bioavailability and Cmax increases by 25%. Sertraline undergoes extensive first pass metabolism in the liver. Distribution by route of exposure: Widely distributed throughout body tissues and highly bound to plasma proteins (about 98 %). The apparent volume of distribution is 20 L/kg. The plasma sertraline level was reported to be 20 to 48 ug/L after at least 1 week of treatment with 100 mg sertraline daily, and it ranged from 40 to 187 ug/L after 200 mg. Plasma sertraline concentrations increase proportionally to the administered dose, unlike fluoxetine and paroxetine. Cmax and area under the plasma concentration-time curve values are increased, and elimination half-life is prolonged in elderly patients but these changes do not appear to warrant dose adjustment in this patient group. Biological half-life by route of exposure: After oral doses, plasma half-life is 24 to 26 hours. Metabolism: Sertraline is extensively metabolized in the liver to N-desmethylsertraline, whose half-life is 2 to 3 times longer than sertraline. N-desmethylsertraline is 10 times less active as an inhibitor of serotonin re-uptake in vitro, and has almost no activity in animal models. Elimination and excretion: N-desmethylsertraline is oxidatively deaminated to desmethylsertraline ketone which, in turn, undergoes hydroxylation to an alpha-hydroxyketone and alcoholthese metabolites are then conjugated and excreted in equal amounts in the urine and fecesa small amount of unchanged drug (less than 0.2 %) is excreted in the urine. There are few data about the excretion of sertraline and its metabolites in breast milk did not detect sertraline in the serum of an infant exclusively breastfed by his mother, after 3 weeks and 7 weeks of treatment, although sertraline could be detected in breast milk. Pharmacology and toxicology: Mode of action: Toxicodynamics: Sertraline is a potent inhibitor of serotonin re-uptake by central nervous system neurones and may interact with other drugs or circumstances which cause serotonin release. The enhancement of the serotonergic effects may produce a life-threatening serotonin syndrome. Sertraline, like the other SSRIs fluoxetine and paroxetine, can inhibit in vivo and in vitro, the hepatic isoenzyme 2D6 of the cytochrome P450 system (CYP2D6), which is involved in the oxidative metabolism of numerous drugs. Caution should be used when combining sertraline with CYP2D6 substrates (desipramine, nortriptyline, haloperidol, thioridazine, flecainide, codeine, propranolol, metoprolol), as sertraline can cause a significant increase in the serum concentrations of these drugs. In vitro studies suggest that sertraline may be a substrate for, but does not inhibit another hepatic iso-enzyme of the cytochrome P450 system, CYP3A3/4, which is involved in the metabolism of carbamazepine. A study performed in healthy volunteers showed no evidence of a pharmacodynamic drug-drug interaction between sertraline and carbamazepine. Pharmacodynamics: Sertraline specifically inhibits central nervous system neuronal re-uptake of serotonin, thus increasing the concentration of the serotonin at the synapse and enhancing of serotonergic neuronal transmission. The increased availability of serotonin is thought to be linked with the improvement in depression accounted for by sertraline treatment. Sertraline has no direct effect on the re-uptake of noradrenaline, dopamine or GABA. Unlike most tricyclic antidepressants, it has no significant affinity for alpha1-adrenergic, H1-histamine, and muscarinic receptors. Furthermore, sertraline does not show significant affinity for D1 and D2 dopaminergic, alpha2 and adrenergic, benzodiazepine and opioid receptors. The selectivity of sertraline may account for the lower incidence of some adverse effects such as sedation, orthostatic hypotension and anticholinergic effects. Like tricyclic antidepressants, MAOIs, and other SSRIs, sertraline significantly reduces REM (rapid eye movement) sleep density, REM time and the REM percentage of total sleep time in patients with major depression. Adults: Overdoses up to 4500 mg of sertraline alone produced mild drowsiness and serious toxicity did not develop in the 48 patients. Children: In a case series of pediatric overdoses, sertraline caused no symptoms in 10 children less than 5 year oldeight of these received gastrointestinal decontamination. Interactions: Coadministration of drugs increasing the level of serotonin: tricyclic antidepressants, other SSRIs, MAOIs, reversible inhibitors of monoamine oxidase (RIMAs), lithium, may cause a serotonin syndrome. At least 2 weeks should elapse after discontinuing a MAOI before starting therapy with sertraline. Sertraline should be stopped at least 1 week before beginning MAOI therapy. Sertraline should not be concomitantly used with sumatriptan, which is a selective agonist at serotonin type 1D receptors, because of possible hypertensive crises and severe coronary vasoconstriction, and advises a washout period of 1 week after cessation of sertraline. A clinical study involving 103 episodes of migraine in patients taking any SSRIs, did not show evidence of significant adverse effects. Cimetidine inhibits the metabolism of sertraline, leading to increased plasma concentrationsclose clinical monitoring and/or reduced sertraline doses are recommended. By extrapolation from data available for fluoxetine, drug interactions with oral anticoagulants and carbamazepine might occur, though in vitro and in vivo studies performed with carbamazepine did not show evidence of interactions and though no cases have been reported to date. Treatment with sertraline was associated with worsening and/or recurrence of the lysergide (LSD) flashbacks in two adolescents with a long history of polydrug abuse. They had stopped taking LSD 10 months before sertraline therapy. Main adverse effects: The most common adverse effects reported with therapeutic doses of sertraline are primarily nausea, diarrhea, dyspepsia, dry mouth, insomnia, somnolence, tremor, dizziness, headache and male sexual dysfunction (delayed ejaculation). These adverse effects are reported to occur in 10 to 20 % of patients, and they cause patients to stop therapy in approximately 1 to 4 % of cases. Manic episodes may be provoked in patients with bipolar disorders. If this occurs, sertraline should be discontinued and a sedative antipsychotic drug should be administered. Less common adverse effects include, pruritus, alopecia, and extrapyramidal symptoms. Several cases of hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have been reported, mainly in elderly patients. Galactorrhea developed in a 40 year old woman receiving sertraline 150 mg/day during 11 week of dosing. Several cases of stuttering have been described. Bruxism causing significant physical consequences was associated with sertraline and other SSRIs in a case series reported. A case of anisocoria was reported. Increase in serum AST and ALT levels has occurred, and returned to normal after treatment was stopped. Sertraline caused prolonged bleeding time in one patientagranulocytosis was also reported. ANIMAL/PLANT STUDIES: Symptomatology: decreased food intake, hyperactivity, muscular weakness, convulsions. Chronic toxicity: oral doses of serataline for 6 and 12 monthsseveral adverse effects occurred during the first weeks, including hypersalivation, abnormal movements of the head, disorientation, agitationresulted in convulsions in 2 dogsall of these effects where temporary and resolved spontaneously despite continuation of sertraline administration. An increase of liver weight associated with a rise in plasma alkaline phosphatase enzymes was noted, due to the properties of enzyme induction of sertraline. Carcinogenicity: Animal studies: In rats a slight increase in the number of follicular and thyroid adenomas was observed in relation with hepatic enzyme inductionthese findings cannot be extrapolated to man, because of species differences in the metabolic mechanisms. Teratogenicity: Animal studies: Fertility in rats was not affected. Sertraline did not show embryotoxic or teratogenic properties in rat and rabbit models. However, in the rat, sertraline caused a delay in fetal ossification and a delay in apparition of teeth in the young. A decrease in food intake inducing a delay in growth in the young, proportional to the administered dose, sometimes associated with hyperactivity, was also observed. Mutagenicity: In vitro and in vivo: sertraline did not show mutagenicity for chromosomes and genes.The overdose of sertraline is generally well-tolerated. Sertraline toxicity may result in serotonin syndrome, resulting in myoclonus, muscle rigidity, diaphoresis, tremor, hyperreflexia, agitated delirium, and hyperthermia. Treatment of serotonin syndrome requires discontinuing the medication and supportive care. Consider antiemetics (non-serotonergic), benzodiazepines, and standard cooling measures for symptom relief. The patient can also receive serotonin antagonists such as cyproheptadine. If severe toxicity and the patient develops muscular rigidity and hyperthermia with body temperatures higher than 41 degrees C, consider sedation, endotracheal intubation, external cooling, and neuromuscular paralysis. It is important to note that antipyretics are likely not beneficial to patients experiencing hyperthermia due to serotonin syndrome.The exact mechanism of action sertraline is not fully known, but the drug appears to selectively inhibit the reuptake of serotonin at the presynaptic membrane. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. It is suggested that these modifications are responsible for the antidepressant action observed during long term administration of antidepressants. It has also been hypothesized that obsessive-compulsive disorder is caused by the dysregulation of serotonin, as it is treated by sertraline, and the drug corrects this imbalance. |
| Signs and Symptoms | Symptoms of toxicity include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome. |
| Human Toxicity Excerpts | A 23 yr old woman with a past history of depression ingested an overdose of 700-1000 mga 28 yr old man took an overdose of 2100 mg. Both received gastric lavage & recovered fully with no sequelae. A 43 yr old woman with a past history of depression took an overdose of 1400 mg together with unsuspected amounts of mefenamic acid, temazepam, & alcoholthe patient was discharged the next day with no sequelae. None of the 4 cases of overdose reported to the manufacturer with a max ingestion of 2.6 g of sertraline (equivalent to 13 times the max daily dose) required intensive monitoring & there were no significant changes in vital signs, cardiovascular function, or level of consciousness. ... Up to 4500 mg my be tolerated without profound toxicity.In a U.S. series of 6 cases of overdose, all experienced lethargy & 4 had sinus tachycardia. All recovered within 24 hr of gastric lavage, activated charcoal, & supportive care. The quantity of sertraline ingested & the time before symptoms were noted were not provided in the report. Sertraline does produce the classic toxic syndrome associated with cyclic antidepressants.Sertraline has a wide margin of safety in overdose. However, deaths have occurred in overdoses involving sertraline in combination with other drugs and/or alcohol. Symptoms of overdose resemble the side/adverse effects occurring with therapeutic doses, but may be more intense or several symptoms may occur together. The following effects have been selected on the basis of their potential clinical significance ... not necessary inclusive: Anxietydrowsinesselectrocardiogram (ECG) changesmydriasis (unusually large pupils)nauseatachycardia (unusually fast heartbeat)vomiting. NOTE: Some patients may develop the serotonin syndrome, a potentially fatal symptom complex, in response to acute overdose with sertraline. The serotonin syndrome may be manifested by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and/or fever.Limited data are available regarding the use of sertraline (Zoloft) during pregnancy. The California Teratogen Information Service prospectively ascertained 112 pregnant women taking sertraline and compared outcomes to those of 191 women ascertained for nonteratogenic exposures. The rate of major anomalies did not differ significantly between the groups (3.8% vs. 1.9%). Anomalies in the sertraline group included bilateral choanal atresia, valvular pulmonic stenosis with an atrial septal aneurysm, unilateral clubfoot, and Down Syndrome in a pregnancy that was terminated. Among the 158 infants who received a dysmorphological examination, the frequency of minor anomalies was similar in the two groups. There was a nonsignificant excess of spontaneous abortions in the sertraline group (16.7% vs. 10.9%, p = 0.17). Infants exposed to sertraline in the third trimester compared to those with earlier exposure or controls were more often premature (16.3%, 9.3%, 7.5%, trend p = 0.10), had neonatal transition difficulty (adj OR 10.3, 95% CI 3.9, 27.1), or were admitted to a special care nursery (adj OR 6.9, 95% CI 2.5, 25.9). Furthermore, there was evidence of a dose response relationship for the latter two endpoints. These data confirm previous findings indicating that sertraline is not a structural teratogen. They provide further evidence that neonatal complications are more common in infants born to women who take SSRI's late in pregnancy.For more Human Toxicity Excerpts (Complete) data for SERTRALINE (6 total), please visit the HSDB record page. |
| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
| Drug Induced Liver Injury | Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)sertralineZoloft®Antidepressants3less-DILI-concern drugs |
| Non-Human Toxicity Excerpts | Reproduction studies in rats & rabbits did not reveal teratogenicity, but delayed ossification of the fetuses occurred that was thought to be secondary to effects on the mothers. A probable direct effect on the fetuses resulting in decreased neonatal survival was observed with maternal doses as low as 5 times the max human mg/kg dose.In lifetime carcinogenicity studies, there was a dose-related increase in the incidence of liver adenomas in male CD-1 mice receiving sertraline at doses of 10 to 40 mg/kg body weight per day (less than and equal to the maximum recommended human dose (MRHD) on a mg per square meter of body surface area basis). However, liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse, and the significance of this finding to use in humans is unknown. No increases in live adenomas was seen in Long-Evans rats or in female CD-1 mice receiving doses of up to 40 mg/kg. No increase in the incidence of hepatocellular carcinomas was seen in studies. Female rats receiving 40 mg/kg (two times the MRHD on a mg/sq m basis) had an increase in follicular adenomas of the thyroid, unaccompanied by thyroid hyperplasia. Rats receiving 10 to 40 mg/kg (0.5 to 2 times the MRHD on a mg/sq m basis) showed an increase in uterine adenocarcinomas compared with placebo controls, but this effect was not clearly drug-related.A decrease in fertility was seen in one of two studies in rats that received 80 mg/kg of sertraline per day (four times the MRHD on a mg/sq m basis).The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drug-treated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk.Recent studies suggest that serotonin (5-HT) may play a role in morphogenesis in the mouse embryo. The possible involvement of 5-HT in early development suggests that substances which interfere with serotonergic activities may have teratogenic potential. Therefore, the ability of sertraline, a selective 5-HT uptake inhibitor, to cause developmental defects was investigated. Mouse embryos, in whole embryo culture, were exposed during gastrulation (day 8plug day = day 1) or neurulation (day 9) to 5-20 uM sertraline and examined for malformations after 48-60 hours. Dose dependent effects were observed on growth and expansion of the prosencephalon and on development of the first visceral arch, following exposure at both stages. Exposure to 20 uM sertraline at day 9 caused a high incidence of embryolethality which was not observed after treatment with the same dose at a later stage (day 9.5). These results lend further support to a functional role for 5-HT during these stages of development and for the teratogenic potential of 5-HT uptake inhibitors, which include a number of clinically relevant antidepressant compounds. |
| Antidote and Emergency Treatment | Treatment of overdose is largely symptomatic & supportive. Patients should be hospitalized where adequate oxygen, cardiac monitoring, & a central line are available. An airway should be established & maintained, & adequate oxygenation & ventilation ensured. Cardiac function & vital signs must be monitored. The possibility of multiple-drug involvement should be considered. Activated charcoal, used with sorbitol, may be as or more effective than emesis. ... Because of the large volume of distribution & extensive protein binding of sertraline, forced diuresis, dialysis, hemoperfusion, & exchange transfusion are not likely to be of benefit. There is no specific antidote. Patients should remain under observation for at least 48 hr after an overdose (the metabolite has a half-life of several days)./SRP:/ Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison 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 respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ |
| 위험 문구(R) | 36/37/38 |
| 위험 표시 | Xi |
| 안전 문구(S) | 26-36 |
| 유해 물질 데이터 | 79617-96-2(Hazardous Substances Data) |
용도
역사
The history of sertraline dates back to the early 1970s when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds, including lometraline, based on the structures of the neuroleptics thiothixene and pinoxepin. Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. A few years later, in 1977, pharmacologist Kenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated several potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer[a] was taken into further development and eventually named sertraline.
용도
Antidepressant;5-HT uptake inhibitor
일반 설명
Inspection of sertraline (Zoloft) (1S,4S) reveals the pharmacophorefor SERT inhibition. The Cl substituents alsopredict tropism for a 5-HT system. The depicted stereochemistryis important for activity.