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an antidepressant drug (trade name Serzone) (同)Serzone

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/12/06 21:10:26」(JST)

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Nefazodone (Dutonin, Nefadar, Serzone) is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity (liver damage), which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years.^[2] On June 14, 2004, Bristol-Myers Squibb discontinued the sale of Serzone in the United States and Canada.^[3] Several generic formulations of nefazodone are still available.^[4]

Pharmacology[edit]

Nefazodone acts primarily as a potent antagonist at the 5-HT_2A receptors (Kd 26 nM).^[5] It also has moderate affinity for the α₁-adrenergic receptor (Kd 48 nM) and 5-HT_1A receptor (Kd 80 nM), and very low affinity for the α₂-adrenergic receptor (Kd 640 nM) and D₂ receptor (Kd 910 nM).^[5] Nefazodone has low affinity for the serotonin (200 nM), norepinephrine (360 nM), and dopamine (360 nM) transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).^[6] It has negligible affinity for the H₁ receptor (24,000 nM) or muscarinic acetylcholine receptors (11,000 nM), and accordingly lacks any antihistamine or anticholinergic side effects.^[6]

Dosing[edit]

Nefazodone doses for adults typically start at 100 mg twice daily (200 mg/day) to a maximum of 600 mg/day (300 mg twice daily), according to Food and Drug Administration (FDA) regulations. Some patients with severe depression were treated with more than 600 mg/day. Most patients were treated with 300 mg–600 mg daily.

Side effects[edit]

Common and mild side effects of nefazodone reported in clinical trials more often than placebo include dry mouth (25%), sedation/somnolence (25%), nausea (22%), dizziness (17%), blurred/abnormal vision (16%), weakness (11%), lightheadedness (10%), confusion (7%), and orthostatic hypotension (5%).^[7] Rare and serious adverse reactions may include allergic reaction, fainting, priapism (painful/prolonged erection), and jaundice.^[8]

Unlike most serotonin reuptake inhibitors, nefazodone has a low incidence of negative effects on libido or sexual function, and is occasionally used as treatment for SSRI or SNRI-induced impotence and anorgasmia in men.^[9] Additionally, unlike mirtazapine, nefazodone is not especially associated with increased appetite and weight gain either.^[10]

Interactions[edit]

Nefazodone is a potent inhibitor of CYP3A4, an isozyme of the cytochrome P450 system, and may therefore interact adversely with many commonly used medications that are metabolized by CYP3A4.^[1]^[11]

Advantages[edit]

Nefazodone's claimed advantages over other antidepressants include reduced possibility of disturbed sleep or sexual dysfunction, and ability to treat some patients who did not respond to other antidepressant drugs.

Nefazodone, though an antidepressant, may also be beneficial in the prophylaxis of migraines due to its antagonistic effects on the 5-HT_2A^[12] and 5-HT_2C receptors.^[13]^[14] It has a more favorable side effect profile than amitriptyline, a tricyclic antidepressant commonly used for migraine prophylaxis.

Chemistry[edit]

Nefazadone is a piperazine compound incorporating a 1,2,4-triazol-3-one ring. Rxn of the starting propionamide with phosgene leads to the corresponding imino chloride. This intermediate is condensed with hydrazine methylurethane to afford the corresponding guanidine from the displacement of chlorine by basic hydrazine nitrogen. Rxn with sodium methoxide leads first to the ionization of the amine on the side chain; this then cyclizes to a triazolone by displacing the carbamate methoxyl. Alkylation of the anion from rxn of the triazolone with a strong base with chloride affords nefazodone.

References[edit]

^ ^a ^b Lexi-Comp (September 2008). "Nefazodone". The Merck Manual Professional. Retrieved on November 29, 2008.
^ Rxlist.com: "Nefazodone Prescribing Information", accessed 8 January 2007.]
^ Bootie Cosgrove-Mather for CBS News. December 5, 2007 Anti-Depressant Taken Off Market
^ FDA Orange Book, accessed 15 January 2006.
^ ^a ^b Cusack B, Nelson A, Richelson E. (1994). "Binding of Antidepressants to Human Brain Receptors: Focus on Newer Generation Compounds.". Psychopharmacology (Berl). 114 (4): 559–565. doi:10.1007/BF02244985. PMID 7855217.
^ ^a ^b Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997). "Pharmacological Profile of Antidepressants and Related Compounds at Human Monoamine Transporters.". Eur J Pharmacol. 340 (2–3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.
^ "Nefazodone (Serzone) FAQ".
^ http://www.drugs.com/serzone.html
^ http://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_684.html
^ Sussman N, Ginsberg DL, Bikoff J (April 2001). "Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials". The Journal of Clinical Psychiatry 62 (4): 256–60. doi:10.4088/JCP.v62n0407. PMID 11379839.
^ Spina E, Santoro V, D'Arrigo C (July 2008). "Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update". Clin Ther 30 (7): 1206–27. doi:10.1016/S0149-2918(08)80047-1. PMID 18691982.
^ Saper JR, Lake AE, Tepper SJ (May 2001). "Nefazodone for chronic daily headache prophylaxis: an open-label study". Headache 41 (5): 465–74. doi:10.1046/j.1526-4610.2001.01084.x. PMID 11380644.
^ Mylecharane EJ (1991). "5-HT2 receptor antagonists and migraine therapy". J. Neurol. 238 (Suppl 1): S45–52. doi:10.1007/BF01642906. PMID 2045831.
^ Millan MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Therapie 60 (5): 441–60. doi:10.2515/therapie:2005065. PMID 16433010.

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Nefazodone, an antagonist for the 5-hydroxytryptanine receptor, has been used for the treatment of depression. Acute liver injury has been documented to be associated with the use of nefazodone; however, the mechanisms of nefazodone-induced liver toxicity are not well defined. In this report, using
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Lee DJ1,2, Schnitzlein CW3,4, Wolf JP5, Vythilingam M6, Rasmusson AM7,8,9, Hoge CW10.
Depression and anxiety.Depress Anxiety.2016 Sep;33(9):792-806. doi: 10.1002/da.22511. Epub 2016 Apr 29.
BACKGROUND: Current clinical practice guidelines (CPGs) for posttraumatic stress disorder (PTSD) offer contradictory recommendations regarding use of medications or psychotherapy as first-line treatment. Direct head-to-head comparisons are lacking.METHODS: Systemic review of Medline, EMBASE, PILOTS,
PMID 27126398

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「ネファゾドン」

Nefazodone
Systematic (IUPAC) name
	1-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-3-ethyl-4-(2-phenoxyethyl)-1H-1,2,4-triazol-5(4H)-one
Clinical data
Trade names	Dutonin, Nefadar, Rulivan, Serzone
AHFS/Drugs.com	monograph
MedlinePlus	a695005
Pregnancy cat.	C
Legal status	Prescription Only (S4) (AU) ℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	20% (variable)
Protein binding	>99%
Metabolism	Hepatic (active metabolites, including mCPP)
Half-life	2–4 hours
Excretion	Urine (55%), Feces (20–30%)
Identifiers
CAS number	83366-66-9
ATC code	N06AX06
PubChem	CID 4449
DrugBank	DB01149
ChemSpider	4294
UNII	59H4FCV1TF
KEGG	D08257
ChEBI	CHEBI:7494
ChEMBL	CHEMBL623
Chemical data
Formula	C25H32ClN5O2
Mol. mass	470.01 g/mol
	SMILES Clc4cccc(N3CCN(CCCN1/N=C(\N(C1=O)CCOc2ccccc2)CC)CC3)c4;
	InChI InChI=1S/C25H32ClN5O2/c1-2-24-27-31(25(32)30(24)18-19-33-23-10-4-3-5-11-23)13-7-12-28-14-16-29(17-15-28)22-9-6-8-21(26)20-22/h3-6,8-11,20H,2,7,12-19H2,1H3 ; Key:VRBKIVRKKCLPHA-UHFFFAOYSA-N ;
(what is this?) (verify);

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英: nefazodone
関: 抗うつ薬

販売停止となっている。

[Lexi-Comp-1] Lexi-Comp (September 2008). "Nefazodone". The Merck Manual Professional. Retrieved on November 29, 2008.

[pi-2] Rxlist.com: "Nefazodone Prescribing Information", accessed 8 January 2007.]

[3] Bootie Cosgrove-Mather for CBS News. December 5, 2007 Anti-Depressant Taken Off Market

[fdaob-4] FDA Orange Book, accessed 15 January 2006.

[pmid7855217-5] Cusack B, Nelson A, Richelson E. (1994). "Binding of Antidepressants to Human Brain Receptors: Focus on Newer Generation Compounds.". Psychopharmacology (Berl). 114 (4): 559–565. doi:10.1007/BF02244985. PMID 7855217.

[pmid9537821-6] Tatsumi M, Groshan K, Blakely RD, Richelson E. (1997). "Pharmacological Profile of Antidepressants and Related Compounds at Human Monoamine Transporters.". Eur J Pharmacol. 340 (2–3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.

[urlNefazodone_.28Serzone.29_FAQ-7] "Nefazodone (Serzone) FAQ".

[8] ttp://www.drugs.com/serzone.html

[9] ttp://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_684.html

[pmid11379839-10] Sussman N, Ginsberg DL, Bikoff J (April 2001). "Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials". The Journal of Clinical Psychiatry 62 (4): 256–60. doi:10.4088/JCP.v62n0407. PMID 11379839.

[11] Spina E, Santoro V, D'Arrigo C (July 2008). "Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update". Clin Ther 30 (7): 1206–27. doi:10.1016/S0149-2918(08)80047-1. PMID 18691982.

[12] Saper JR, Lake AE, Tepper SJ (May 2001). "Nefazodone for chronic daily headache prophylaxis: an open-label study". Headache 41 (5): 465–74. doi:10.1046/j.1526-4610.2001.01084.x. PMID 11380644.

[13] Mylecharane EJ (1991). "5-HT2 receptor antagonists and migraine therapy". J. Neurol. 238 (Suppl 1): S45–52. doi:10.1007/BF01642906. PMID 2045831.

[14] Millan MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Therapie 60 (5): 441–60. doi:10.2515/therapie:2005065. PMID 16433010.

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