マレイン酸トリミプラミン

関: Surmontil、trimipramine

WordNet

a salt or ester of maleic acid; used as a nontricyclic antidepressant drug for psychomotor activation
tricyclic antidepressant drug (trade name Surmontil) used to treat depression and anxiety and (sometimes) insomnia (同)Surmontil

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/08 23:22:40」(JST)

wiki en

Trimipramine (Surmontil, Rhotrimine, Stangyl) is a tricyclic antidepressant (TCA). It has antidepressant, anxiolytic, antipsychotic and sedative effects.

Medical uses

Trimipramine's primary use in medicine is in the treatment of major depressive disorder,^[5]^[6] especially where sedation is required due to its prominent sedative effects.^[6] Trimipramine also has some weak antipsychotic effects which are less pronounced than with the phenothiazine antipsychotic perazine.^[7]^[8]^[9]

Trimipramine is the only effective drug against insomnia known so far that does not alter the normal sleep architecture (there is evidence in medical journals that refute this last statement^{[weasel words]}^{[citation needed]}). In particular, it does not suppress REM sleep, and dreams are said to brighten during treatment.^[10]

Adverse effects

Common adverse effects include:^[1]^[2]^[3]^[4]^[5]^[6]

Note: Bolded adverse effects are serious ones.

Sedation — especially common with trimipramine compared to the other TCAs

Anticholinergic effects including:

- dry mouth

- blurred vision

- mydriasis

- decreased lacrimation

- constipation

- urinary hesitancy or retention

- reduced GI motility

- Tachycardia (high heart rate)

- anticholinergic delirium (particularly in the elderly and in Parkinson's disease)

Weight gain

Orthostatic hypotension

Sexual dysfunction including impotence, loss of libido and other sexual adverse effects

Tremor

Dizziness

Sweating

Anxiety

Insomnia

Agitation

Rash

whereas adverse effects with an unknown incidence includes:^[1]^[2]^[3]^[4]^[5]^[6]

Confusion

Nausea

Vomiting

Extrapyramidal side effects (e.g. Parkinsonism, dystonia, etc.)

Tinnitus

Paraesthesia

ECG changes

Increased liver function tests

and rare adverse effects include:^[1]^[2]^[3]^[4]^[5]^[6]

Seizures

Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Blood dyscrasias including:

- Agranulocytosis

- Thrombocytopenia

- Eosinophilia

- Leukopaenia

Myocardial infarction

Heart block

QTc interval prolongation

Sudden cardiac death

Depression worsening

Suicidal ideation

Contraindications

Contraindications include:^[1]^[2]^[3]^[4]^[5]^[6]

Recent myocardial infarction

Any degree of heart block or other cardiac arrhythmias

Mania

Severe liver disease

During breast feeding

Hypersensitivity to trimipramine maleate or to any of the excipients

Interactions

Trimipramine should not be given with sympathomimetic agents such as adrenaline, ephedrine, isoprenaline, noradrenaline, phenylephrine and phenylpropanolamine. Barbiturates may increase the rate of metabolism. Trimipramine should be administered with care in patients receiving therapy for hyperthyrodism.^[1]^[2]^[3]^[4]^[5]^[6]

Overdose

Compared to other tricyclic antidepressants trimipramine is relatively safe in overdose, although it is more dangerous than the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) but less dangerous than bupropion in cases of overdose.^[11]

Mechanism of action

Trimipramine's mechanism of action differs from other TCAs. It is a weak^[12] reuptake inhibitor of norepinephrine, and a weak reuptake inhibitor of serotonin and dopamine. Its main effects are due to considerable receptor antagonism as follows:^[9]^[12]^[13]

Extremely strong: H₁
Strong: 5-HT₂, mACh, α₁-adrenergic
Moderate: D₂
Weak: α₂-adrenergic

Transporter/Receptor	K_i (nM)^[9]^[12]^[13]	Species
SERT	149	Human
NET	2450	Human
DAT	3780	Human
H₁	1.4	Human
α₁	24	Rat
α_2A	1380	Rat
α_2B	380	Rat
mAChRs	59	Human
5-HT_2A	19.5	Rat
5-HT_2C	537	Rat
5-HT₃	9120	Rat
D₁	347	Rat
D₂	57.5	Rat

Pharmacokinetics

Trimipramine is a racemic compound with two enantiomers.^[1] CYP2C19 is responsible for the demethylation of (D)- and (L)-trimipramine to (D)- (L)-desmethyltrimipramine, respectively, and CYP2D6 is responsible for the 2-hydroxylation of (D)- and (L)-desmethyltrimipramine to (D)- and (L)-2-hydroxydesmethyltrimipramine, respectively.^[14] CYP2D6 also metabolizes (L)-trimipramine into (L)-2-hydroxytrimipramine.^[14]

Synthesis

Trimipramine is synthesised by treatment of 10,11,Dihydro-5H-dibenz[b,f]azepine and with 3-N,N-Dimethylamino-2-methylpropylchloride in a nucleophilic substition in present of Sodium amide.^[15] Trimipramin was applied as his racemate.^[16]

Synthese von Trimipramin

History

Trimipramine maleate (as Surmontil) oral capsules were first approved by the Food and Drug Administration prior to January 1, 1982 in 25 mg and 50 mg formulations, with the 100 mg formulation having been approved on September 15, 1982. A generic version of all three formulations was given FDA approval on August 2, 2006.^[17]

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "PRODUCT INFORMATION SURMONTIL® Tablets and Capsules" (PDF). TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 28 November 2012. Retrieved 30 November 2013.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "SURMONTIL (trimipramine maleate) capsule [Duramed Pharmaceuticals Inc]". DailyMed. Duramed Pharmaceuticals Inc. December 2012. Retrieved 30 November 2013.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Surmontil, Trimip (trimipramine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 30 November 2013.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Trimipramine 50mg Capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Zentiva. 19 November 2012. Retrieved 30 November 2013.
^ ^a ^b ^c ^d ^e ^f Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. edit
^ ^a ^b ^c ^d ^e ^f ^g Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. edit
^ Bender, S; Olbrich, HM; Fischer, W; Hornstein, C; Schoene, W; Falkai, P; Haarmann, C; Berger, M; Gastpar, M (March–April 2003). "Antipsychotic efficacy of the antidepressant trimipramine: a randomized, double-blind comparison with the phenothiazine perazine". Pharmacopsychiatry 36 (2): 61–69. doi:10.1055/s-2003-39043. PMID 12734763.
^ Eikmeier, G; Berger, M; Lodemann, E; Muszynski, K; Kaumeier, S; Gastpar, M (Winter 1991). "Trimipramine: An atypical neuroleptic?". International Clinical Psychopharmacology 6 (3): 147–153. doi:10.1097/00004850-199100630-00003. PMID 1806621.
^ ^a ^b ^c Gross, G; Xin, X; Gastpar, M (November 1991). "Trimipramine: Pharmacological reevaluation and comparison with clozapine". Neuropharmacology 30 (11): 1159–1166. doi:10.1016/0028-3908(91)90160-D. PMID 1663593.
^ Schredl, M; Berger, M; Riemann, D (May 2009). "The effect of trimipramine on dream recall and dream emotions in depressive outpatients". Psychiatry Research 167 (3): 279–286. doi:10.1016/j.psychres.2008.03.002. PMID 19403177.
^ White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375. edit
^ ^a ^b ^c Roth, BL; Driscol, J (12 January 2011). "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 30 November 2013.
^ ^a ^b Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (in English) (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8. edit
^ ^a ^b Eap CB, Bender S, Gastpar M, et al. (2000). "Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients". Ther Drug Monit 22 (2): 209–14. doi:10.1097/00007691-200004000-00012. PMID 10774635.
^ A. Kleemann, J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications, 4. Auflage (2000), Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9.
^ E. J. Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology, European Journal of Clinical Pharmacology 26 (1984) 663-668.doi:10.1007/BF00541922.
^ "Generic Surmontil Availability". Drugs.com. Retrieved 22 March 2013.

UpToDate Contents

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1. 成人における単極性うつ病と三環系抗うつ剤および四環系抗うつ剤：薬理学、投与、
および副作用 unipolar depression in adults and tricyclic and tetracyclic drugs pharmacology administration and side effects
2. 睡眠の質および睡眠の構造に対する薬剤の効果 the effects of medications on sleep quality and sleep architecture
3. 精神病性特徴を伴う単極性大うつ病：急性期治療 unipolar major depression with psychotic features acute treatment
4. 身体化：治療および予後 somatization treatment and prognosis

English Journal

Identification of small molecules that promote human embryonic stem cell self-renewal.

Kumagai H, Suemori H, Uesugi M, Nakatsuji N, Kawase E.SourceDepartment of Embryonic Stem Cell Research, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Biochemical and biophysical research communications.Biochem Biophys Res Commun.2013 Mar 27. pii: S0006-291X(13)00515-9. doi: 10.1016/j.bbrc.2013.03.061. [Epub ahead of print]
Human embryonic stem cells (hESCs) and induced pluripotent cells have the potential to provide an unlimited source of tissues for regenerative medicine. For this purpose, development of defined/xeno-free culture systems under feeder-free conditions is essential for the expansion of hESCs. Most defin
PMID 23541943

Adsorptive stripping voltammetric determination of imipramine, trimipramine and desipramine employing titanium dioxide nanoparticles and an Amberlite XAD-2 modified glassy carbon paste electrode.

Sanghavi BJ, Srivastava AK.SourceDepartment of Chemistry, University of Mumbai, Vidyanagari, Santacruz (East), Mumbai-400098, India.
The Analyst.Analyst.2013 Mar 7;138(5):1395-404. doi: 10.1039/c2an36330e.
An Amberlite XAD-2 (XAD2) and titanium dioxide nanoparticles (TNPs) modified glassy carbon paste electrode (XAD2-TNP-GCPE) was developed for the determination of imipramine (IMI), trimipramine (TRI) and desipramine (DES). The electrochemical behavior of these molecules was investigated employing cyc
PMID 23324861

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants.

Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Müller DJ, Gaedigk A, Stingl JC.SourceDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Clinical pharmacology and therapeutics.Clin Pharmacol Ther.2013 Jan 16. doi: 10.1038/clpt.2013.2. [Epub ahead of print]
Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metaboli
PMID 23486447

Related Pictures

★リンクテーブル★

リンク元	「トリミプラミン」「Surmontil」
関連記事	「maleate」

「トリミプラミン」

Trimipramine
Systematic (IUPAC) name
	(±)-3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine
Clinical data
Trade names	Surmontil
AHFS/Drugs.com	monograph
MedlinePlus	a602010
Licence data	US FDA:link
Pregnancy cat.	C (AU) C (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral, IM, IV
Pharmacokinetic data
Bioavailability	41%
Protein binding	94.9%
Metabolism	Hepatic
Half-life	23-24 hours
Excretion	Renal
Identifiers
CAS number	739-71-9
ATC code	N06AA10
PubChem	CID 5584
DrugBank	DB00726
ChemSpider	5382
UNII	6S082C9NDT
KEGG	D00394
ChEBI	CHEBI:9738
ChEMBL	CHEMBL644
Chemical data
Formula	C20H26N2
Mol. mass	294.434 g/mol
	SMILES c1cc3c(cc1)CCc2c(cccc2)N3CC(C)CN(C)C;
	InChI InChI=1S/C20H26N2/c1-16(14-21(2)3)15-22-19-10-6-4-8-17(19)12-13-18-9-5-7-11-20(18)22/h4-11,16H,12-15H2,1-3H3 ; Key:ZSCDBOWYZJWBIY-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

英: trimipramine
化: マレイン酸トリミプラミン trimipramine maleate
商: スルモンチール Surmontil
関: 三環系抗うつ薬

「Surmontil」

　　[★]

スルモンチール

関: trimipramine、trimipramine maleate

「maleate」

　　[★]

マレイン酸、マレイン酸塩、マレイン酸エステル

関: maleic acid

maleic acid

[TGA-1] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "PRODUCT INFORMATION SURMONTIL® Tablets and Capsules" (PDF). TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 28 November 2012. Retrieved 30 November 2013.

[DM-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "SURMONTIL (trimipramine maleate) capsule [Duramed Pharmaceuticals Inc]". DailyMed. Duramed Pharmaceuticals Inc. December 2012. Retrieved 30 November 2013.

[MSR-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Surmontil, Trimip (trimipramine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 30 November 2013.

[EMC-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Trimipramine 50mg Capsules - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Zentiva. 19 November 2012. Retrieved 30 November 2013.

[AMH-5] ^ ^a ^b ^c ^d ^e ^f Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. edit

[BNF-6] ^ ^a ^b ^c ^d ^e ^f ^g Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. edit

[7] Bender, S; Olbrich, HM; Fischer, W; Hornstein, C; Schoene, W; Falkai, P; Haarmann, C; Berger, M; Gastpar, M (March–April 2003). "Antipsychotic efficacy of the antidepressant trimipramine: a randomized, double-blind comparison with the phenothiazine perazine". Pharmacopsychiatry 36 (2): 61–69. doi:10.1055/s-2003-39043. PMID 12734763.

[8] Eikmeier, G; Berger, M; Lodemann, E; Muszynski, K; Kaumeier, S; Gastpar, M (Winter 1991). "Trimipramine: An atypical neuroleptic?". International Clinical Psychopharmacology 6 (3): 147–153. doi:10.1097/00004850-199100630-00003. PMID 1806621.

[Gross-9] Gross, G; Xin, X; Gastpar, M (November 1991). "Trimipramine: Pharmacological reevaluation and comparison with clozapine". Neuropharmacology 30 (11): 1159–1166. doi:10.1016/0028-3908(91)90160-D. PMID 1663593.

[10] Schredl, M; Berger, M; Riemann, D (May 2009). "The effect of trimipramine on dream recall and dream emotions in depressive outpatients". Psychiatry Research 167 (3): 279–286. doi:10.1016/j.psychres.2008.03.002. PMID 19403177.

[11] White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375. edit

[PDSP-12] Roth, BL; Driscol, J (12 January 2011). "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 30 November 2013.

[GG-13] Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (in English) (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8. edit

[pmid10774635-14] Eap CB, Bender S, Gastpar M, et al. (2000). "Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients". Ther Drug Monit 22 (2): 209–14. doi:10.1097/00007691-200004000-00012. PMID 10774635.

[Kleemann-15] A. Kleemann, J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications, 4. Auflage (2000), Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9.

[ARIENS-16] E. J. Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology, European Journal of Clinical Pharmacology 26 (1984) 663-668.doi:10.1007/BF00541922.

[17] "Generic Surmontil Availability". Drugs.com. Retrieved 22 March 2013.

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trimipramine maleate