네파조돈

네파조돈 · SERZONE · Dutonin · Nefadar · BMY-13754 · NEFAZODONE · MJ-13754-1 · MJ-13754-I

식별자 및 물리적 특성

CAS No.	82752-99-6
분자식	C25H32ClN5O2
평균 분자량	470 g/mol
단동위원소 질량	469.22445294 g/mol
SMILES	CCc1nn(CCCN2CCN(c3cccc(Cl)c3)CC2)c(=O)n1CCOc1ccccc1
InChIKey	VRBKIVRKKCLPHA-UHFFFAOYSA-N
PubChem CID	4449
ChEMBL	CHEMBL623
ChEBI	CHEBI:7494
DTXSID	DTXSID2023357
현지명	네파조돈

화학 및 물리적 성질

XLogP	4.3
극성 표면적	51.6
수소 결합 공여자 수	0
수소 결합 수용자 수	5
회전 가능 결합 수	10
무거운 원자 수	33
형식 전하	0
복잡도	649
의약품	DEA NFLIS-Drug Category -> AntidepressantsPharmaceuticals -> Listed in ZINC15
LogP(분배 계수)	4.74.95
Color/Form	Crystals from 2-propanol/heptane
용해도	6.98e-02 g/L32.6 [ug/mL] (The mean of the results at pH 7.4)DMSO: ~11mg/mL( 60 °C)
Human Drugs	Breast FeedingLactationMilk, HumanAntidepressive AgentsSerotonin and Noradrenaline Reuptake InhibitorsPharmaceuticals
녹는점	83-84 °CCrystals from 2-propanol, with slow cooling yields a polymorph. MP: 186.0-187.0 °C. Also reported as crystals from ethanol. Nonhygroscopic. MP. 175-177 °C. Freely solluble in chloroformsoluble in propylene gylcolslightly soluble in polyethylene glycol, water /Nefazodone hydrchloride/83 - 84 °C180-182°C
Physical Description	Solid
Stability/Shelf Life	Stable under recommended storage conditions. /Nefazodone hydrochloride/
Dissociation Constants	6.5
Collision Cross Section	211.7 Å² [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]
끓는 점	599.6±60.0 °C(Predicted)
밀도	1.23±0.1 g/cm3(Predicted)
저장 조건	2-8°C
물리적 상태	고체
pKa(산도 계수)	pKa 6.5 (Uncertain)
색상	하얀색
NIST	Nefazodone(83366-66-9)

화학적 성질

Crystalline Solid

안전 및 규제

규제 정보	3H-1,2,4-Triazol-3-one, 2-3-4-(3-chlorophenyl)-1-piperazinylpropyl-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.
FDA 요건	The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including nefazodone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Nefazodone hydrochloride/
Hazardous Reactivities and Incompatibilities	Incompatible materials: Strong oxidizing agents. /Nefazodone hydrochloride/
Firefighting Hazards	Hazardous decomposition products formed under fire conditions: - Carbon oxides, Nitrogen oxides (NOx), Hydrogen chloride gas. /Nefazodone hydrochloride/
소화 절차	Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Nefazodone hydrochloride/Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Nefazodone hydrochloride/
보관 조건	Store at 20 deg to 25 °C (68 deg to 77 °F). /Nefazodone hydrochloride/Keep container tightly closed in a dry and well-ventilated place. /Nefazodone hydrochloride/
정리 방법	ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Nefazodone hydrochloride/
처리 방법	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. Contaminated packaging: Dispose of as unused product. /Nefazodone hydrochloride/
Preventive Measures	ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains.Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Nefazodone hydrochloride/Appropriate engineering controls: General industrial hygiene practice. /Nefazodone hydrochloride/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. /Nefazodone hydrochloride/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: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Nefazodone hydrochloride/Skin protection: Handle with gloves. /Nefazodone hydrochloride/Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. /Nefazodone hydrochloride/Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Nefazodone hydrochloride/
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 the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for nefazodone are known. (L1712)
상호 작용	Simvastatin is a hydroxymethyl glutaryl coenzyme A reductase inhibitor commonly used to treat patients with hyperlipidemia. It is a safe and effective medication in most patients when used appropriately. A serious side effect known as rhabdomyolysis may rarely occur in patients who take simvastatin, especially at higher doses and with agents that interact and increase the level of simvastatin in the blood. We describe the case of a patient with rhabdomyolysis that occurred after the patient's simvastatin was titrated to 80 mg at approximately the same time that his antidepressant medication was switched to nefazodone. We found only two other similar cases in the literature, both of which were presented as letters to the editor in two different journals. We present this case to add to the literature and to assist practitioners by raising their awareness of this interaction so that it can be monitored.This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and alprazolam after single- and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in 48 healthy male volunteers. A group of 12 subjects received either placebo twice daily, 1 mg of alprazolam twice daily, 200 mg of nefazodone twice daily, or the combination of 1 mg of alprazolam and 200 mg of nefazodone twice daily for 7 days. Serial blood samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determination of alprazolam and its metabolites alpha-hydroxyalprazolam (AOH) and 4-hydroxyalprazolam (4OH) and nefazodone and its metabolites hydroxynefazodone (HO-nefazodone), m-chlorophenylpiperazine (mCPP), and a triazole dione metabolite (dione) by validated high-performance liquid chromatography methods. Steady-state levels in plasma were reached by day 4 for alprazolam, 4OH, nefazodone, HO-nefazodone, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that at steady state, alprazolam Cmax and AUCtau values significantly increased approximately twofold and 4OH Cmax and AUCtau values significantly decreased by 40 and 26%, respectively, when nefazodone was coadministered with alprazolam. There was no effect of alprazolam on the single-dose or steady-state pharmacokinetics of nefazodone, HO-nefazodone, or dione after the coadministration of alprazolam and nefazodone. However, the mean steady-state mCPP Cmax and AUCtau significantly increased by approximately threefold and t1/2 values significantly increased by approximately twofold after the coadministration of alprazolam and nefazodone in comparison to those when nefazodone was given alone. Competitive inhibition between alprazolam and nefazodone metabolism at cytochrome P450 3A4 may be responsible for the pharmacokinetic interaction when alprazolam and nefazodone were coadministered. No adjustment of nefazodone dosage is required when nefazodone and alprazolam are coadministered. Because alprazolam concentrations in plasma are increased in the presence of nefazodone, a reduction in alprazolam dosage is recommended when the two agents are coadministered.Tacrolimus (FK-506) is an important immunosuppressive agent most often given for maintenance immunosuppression to prevent acute cellular organ rejection. A 57-year-old woman with end-stage renal disease presumed secondary to chronic glomerulonephritis underwent a living related renal allograft transplantation. She tolerated the surgery well and was discharged on postoperative day 5. She was stabilized with prednisone, azathioprine, and tacrolimus. Two years after transplantation, nefazodone 50 mg twice/day orally was prescribed due to depression. After 1 week of nefazodone therapy the patient experienced headache, confusion, and "gray areas" in her vision, without abnormal ophthalmologic findings. Her serum creatinine was elevated to 2.2 mg/dL (baseline 1.5 mg/dL), and trough tacrolimus level was markedly elevated (> 30 ng/mL). Both tacrolimus and nefazodone are metabolized by the cytochrome P450 (CYP) 3A4 system. We suspect that nefazodone inhibits metabolism of tacrolimus. Coadministration of antidepressant agents such as nefazodone, or any other drug that inhibits the CYP3A4 isoenzyme subfamily, should be anticipated to interfere with tacrolimus metabolism. Monitoring blood concentrations of tacrolimus is vital, and appropriate dosage adjustments are required when the two drugs are administered concurrently to avoid serious interactions such as nephrotoxicity and neurotoxicity.Depression is a significant post-transplant complication often necessitating drug therapy. Many of the newer selective serotonin reuptake inhibitor (SSRI) antidepressants are metabolized by the same cytochrome P450IIIA isoenzyme system that is responsible for the metabolism of cyclosporine, and these agents pose an interactive risk in transplant patients. We have observed nearly a 10-fold increase in whole blood cyclosporine concentrations in a cardiac transplant patient shortly after the addition of nefazodone antidepressant therapy. We suggest there is a clinically significant drug-drug interaction between nefazodone and cyclosporine due to inhibition of cytochrome P-450 IIIA4 isoenzymes by nefazodone.For more Interactions (Complete) data for Nefazodone (26 total), please visit the HSDB record page.
건강 영향	Serious side effects include an allergic reaction, fainting, or painful/prolonged erection. [Wikipedia]
Hepatotoxicity	Liver test abnormalities occur in a proportion of patients on nefazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. Soon after its general availability, nefazodone was linked to several instances of acute, clinically apparent liver injury, some of which were fatal. The onset of injury varied from 6 weeks to 8 months and the pattern of serum enzyme elevations was typically hepatocellular. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were uncommon. Liver biopsy usually demonstrated an acute hepatitis with cholestasis and variable degrees of centrolobular (zone 3) necrosis. Systematic reviews suggested that the incidence of hepatic failure due to nefazodone is 1 per 250,000 to 300,000 patient-years of exposure. Because of this complication, nefazodone was withdrawn from use in many countries. Nefazodone, however, can be effective in patients with otherwise resistant forms of severe depression. For this reason, it remains available in the United States with the recommendation that it be used only if other antidepressants have been found to be ineffective and after full disclosure and discussion of the risks. It has a “black box” warning for hepatotoxicity.
환경 거동	TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+5(SRC), determined from a structure estimation method(2), indicates that nefazodone is expected to be immobile in soil(SRC). Volatilization of nefazodone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.5X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Nefazodone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.2X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+5(SRC), determined from a structure estimation method(2), indicates that nefazodone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.5X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(65), an estimated BCF of 9(SRC), from an estimated log Kow of 5.00(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2018).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), nefazodone, which has aan estimated vapor pressure of 5.2X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase. Particulate-phase nefazodone may be removed from the air by wet and dry deposition(SRC). Nefazodone does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).
노출 경로	Nefazodone is rapidly and completely absorbed. Its absolute bioavailability is low (about 20%).
독성 요약	IDENTIFICATION AND USE: Nefazodone is a solid. It is used as an antidepressive agent. HUMAN STUDIES: In postmarketing experience, overdose with nefazodone alone and in combination with alcohol and/or other substances has been reported. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established. In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. None of these patients died. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One patient took 2000 to 3000 mg of nefazodone with methocarbamol and alcohol, and this person reportedly experienced a convulsion. Nefazodone therapy has been associated with liver abnormalities ranging from asymptomatic reversible serum transaminase increases to cases of liver failure resulting in transplant and/or death. At present, there is no way to predict who is likely to develop liver failure. Ordinarily, patients with active liver disease should not be treated with nefazodone. The drug does not increase the rates of major human malformations during pregnancy above the baseline rate of 1% to 3%. ANIMAL STUDIES: There is no evidence of carcinogenicity with nefazodone. The dietary administration of nefazodone to rats and mice for 2 years at daily doses of up to 200 mg/kg and 800 mg/kg, respectively, produced no increase in tumors. Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively. No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality, and decreased pup weights were seen in rats. A fertility study in rats showed a slight decrease in fertility at 200 mg/kg/day. Nefazodone has been shown to have no genotoxic effects based on the following assays: bacterial mutation assays, a DNA repair assay in cultured rat hepatocytes, a mammalian mutation assay in Chinese hamster ovary cells, an in vivo cytogenetics assay in rat bone marrow cells, and a rat dominant lethal study.Within the serotonergic system, nefazodone acts as an antagonist at type 2 serotonin (5-HT<sub>2</sub>) post-synaptic receptors and, like fluoxetine-type antidepressants, inhibits pre-synaptic serotonin (5-HT) reuptake. These mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally. Nefazodone also antagonizes alpha(1)-adrenergic receptors, producing sedation, muscle relaxation, and a variety of cardiovascular effects. Nefazodone's affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, and beta or alpha(2)-adrenergic receptors is not significant.
Signs and Symptoms	Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone.
Soil Adsorption/Mobility	Using a structure estimation method based on molecular connectivity indices(1), the Koc of nefazodone can be estimated to be 1.0X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that nefazodone is expected to be immobile in soil. Freundlich adsorption isotherms for nefazodone in primary sludge, secondary long sludge and secondary short sludge were reported as 2.7, 0.96 and 3.0X10-2 L/g, respectively. The average Kd value at pH 6-8 was 6.4(3).
Human Toxicity Excerpts	/SIGNS AND SYMPTOMS/ Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone hydrochloride tablets. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone hydrochloride treatment. The total patient-years is a summation of each patient's duration of exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc. Ordinarily, treatment with nefazodone hydrochloride tablets should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. There is no evidence that pre-existing liver disease increases the likelihood of developing liver failure, however, baseline abnormalities can complicate patient monitoring. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur. Nefazodone hydrochloride tablets should be discontinued if clinical signs or symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels = 3 times the upper limit of NORMAL, while on nefazodone hydrochloride tablets should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone hydrochloride is reintroduced. Accordingly, such patients should not be considered for re-treatment./SIGNS AND SYMPTOMS/ In postmarketing experience, overdose with nefazodone alone and in combination with alcohol and/or other substances has been reported. Commonly reported symptoms were similar to those reported from overdose in premarketing experience. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established./SIGNS AND SYMPTOMS/ In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One nonstudy participant took 2000 to 3000 mg of nefazodone with methocarbamol and alcoholthis person reportedly experienced a convulsion (type not documented). None of these patients died./SIGNS AND SYMPTOMS/ Patients should be informed that nefazodone therapy has been associated with liver abnormalities ranging from asymptomatic reversible serum transaminase increases to cases of liver failure resulting in transplant and/or death. At present, there is no way to predict who is likely to develop liver failure. Ordinarily, patients with active liver disease should not be treated with nefazodone. Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur.For more Human Toxicity Excerpts (Complete) data for Nefazodone (17 total), please visit the HSDB record page.
Artificial Pollution Sources	Nefazodone's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC).
Carcinogen Classification	No indication of carcinogenicity to humans (not listed by IARC).
수질 위해 등급(WGK)	3
안전 문구(S)	22-24/25
유해 물질 데이터	83366-66-9(Hazardous Substances Data)

용도

A selective serotonin 5-HT2 receptor antagonist. An antidepressant