関: trimetazidine hydrochloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/12/10 09:39:22」(JST)

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Trimetazidine is a drug for angina pectoris sold under the brand name Vastarel MR. Trimetazidine is described as the first cytoprotective anti-ischemic agent developed and marketed by Les Laboratoires Servier (France). Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, which improves myocardial glucose utilization through inhibition of fatty acid metabolism, also known as fatty acid oxidation inhibitor.

Medical uses

Trimetazidine usually prescribed as a long-term treatment of angina pectoris, and in some countries (including France) for tinnitus and dizziness. It is taken twice a day. In 2012 European Medicines Agency (EMA) finished a review of benefits and risks of trimetazidine and recommended restricting use of trimetazidine-containing medicines just as an additional treatment of angina pectoris in case of inadequate control by or intolerance to first-line antianginal therapies.^[1]

Controlled studies in angina patients have shown that trimetazidine increases coronary flow reserve, thereby delaying the onset of ischemia associated with exercise, limits rapid swings in blood pressure without any significant variations in heart rate, significantly decreases the frequency of angina attacks, and leads to a significant decrease in the use of nitrates.

It improves left ventricular function in diabetic patients with coronary heart disease. Recently, it has been shown to be effective in patients with heart failure of different etiologies.^[2]^[3]

Adverse effects

Trimetazidine has been treated as a drug with a high safety and tolerability profile.^{[citation needed]} It interacts with monoamine oxidase inhibitors.

There is scarce information about trimetazidine's effect on mortality, cardiovascular events or quality of life. Long term randomized controlled trials comparing trimetazidine against standard anti-anginal agents, using clinically important outcomes would be justifiable.^[4] Recently, an international multicentre retrospective cohort study has indeed shown that in patients with heart failure of different etiologies, the addition of trimetazidine on conventional optimal therapy can improve mortality and morbidity.^[5]

EMA recommends that doctors should no longer prescribe trimetazidine for the treatment of patients with tinnitus, vertigo or disturbances in vision.^[1] The recent EMA evaluation also revealed high potential for Parkinsonian (or extrapyramidal) symptoms (such as tremor, rigidity, akinesia, hypertonia), gait instability, restless leg syndrome, other related movement disorders, reversible after treatment discontinuation. As a consequence, doctors are advised not to prescribe the medicine either to patients with Parkinson disease, parkinsonian symptoms, tremors, restless leg syndrome or other related movement disorders, nor to patients with severe renal impairment.^[1]

Mechanism of action

Trimetazidine inhibits beta-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation.^[6] In an ischaemic cell, energy obtained during glucose oxidation requires less oxygen consumption than in the beta-oxidation process. Potentiation of glucose oxidation optimizes cellular energy processes, thereby maintaining proper energy metabolism during ischaemia. By preserving energy metabolism in cells exposed to hypoxia or ischaemia, trimetazidine prevents a decrease in intracellular ATP levels, thereby ensuring the proper functioning of ionic pumps and transmembrane sodium-potassium flow whilst maintaining cellular homeostasis.^[7]

Brand names

Distributed as: Vastarel MR, Vastarel 20 mg, Vastarel LM, Vastarel LP, Preductal MR, Тридуктан, Тридуктан МВ, Flavedon MR, Trivedon MR 35 mg (Cipla Ltd.), Flavedon 20 mg, Cardaptan, Idaptan, Carvidon MR and Trizedon MR. In the Philippines, a local brand is called Vestar. Also Carmetadin for World Medicine company.In Bangladesh, Angirid MR is the local brand by The ACME Laboratories Ltd.

References

^ ^a ^b ^c "European Medicines Agency recommends restricting use of trimetazidine-containing medicines" (pdf). Press release. European Medicines Agency. 2012-06-12.
^ Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A (September 2006). "A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure". J. Am. Coll. Cardiol. 48 (5): 992–8. doi:10.1016/j.jacc.2006.03.060. PMID 16949492.
^ Tuunanen H, Engblom E, Naum A, Någren K, Scheinin M, Hesse B, Juhani Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J (September 2008). "Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy". Circulation 118 (12): 1250–8. doi:10.1161/CIRCULATIONAHA.108.778019. PMID 18765391.
^ Ciapponi A, Pizarro R, Harrison J (2005). "Trimetazidine for stable angina". Cochrane Database Syst Rev (4): CD003614. doi:10.1002/14651858.CD003614.pub2. PMID 16235330.
^ Fragasso G, Rosano G, Baek Hong S, Sisakian H, Di Napoli P, Alberti L, Calori G, Kang SM, Sahakyan A, Vitale C, Marazzi G, Margonato A, Belardinelli R. Effect of partial acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int J Cardiol. 2013;163:320-5.
^ Kantor PF, Lucien A, Kozak R, Lopaschuk GD (March 2000). "The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase". Circ. Res. 86 (5): 580–8. doi:10.1161/01.RES.86.5.580. PMID 10720420.
^ Stanley WC, Marzilli M (April 2003). "Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine". Fundam Clin Pharmacol 17 (2): 133–45. doi:10.1046/j.1472-8206.2003.00154.x. PMID 12667223.

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UpToDate Contents

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1. 狭心症の新しい治療法 new therapies for angina pectoris
2. 新生児におけるチアノーゼ性心疾患の診断および初期マネージメント diagnosis and initial management of cyanotic heart disease in the newborn
3. Identifying newborns with critical congenital heart disease
4. 新生児におけるチアノーゼの心臓の原因 cardiac causes of cyanosis in the newborn
5. 造影剤誘発性腎症の予防 prevention of contrast induced nephropathy

English Journal

Trimetazidine and cardioprotection: facts and perspectives.

Tsioufis K1, Andrikopoulos G2, Manolis A3.
Angiology.Angiology.2015 Mar;66(3):204-10. doi: 10.1177/0003319714530040. Epub 2014 Apr 8.
Trimetazidine (TMZ) is a metabolic agent used in cardiology for more than 40 years. Several studies assessed the cardioprotective effects of TMZ in patients with chronic coronary heart disease (CHD) as well as in patients with heart failure (HF). In light of the inclusion of TMZ in the current guide
PMID 24719262

Trimetazidine Decreases Risk of Contrast-Induced Nephropathy in Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials.

Nadkarni GN1, Konstantinidis I2, Patel A3, Yacoub R2, Kumbala D2, Patel RA4, Annapureddy N5, Pakanati KC6, Simoes PK7, Javed F4, Benjo AM4.
Journal of cardiovascular pharmacology and therapeutics.J Cardiovasc Pharmacol Ther.2015 Feb 24. pii: 1074248415573320. [Epub ahead of print]
OBJECTIVES: We sought to synthesize and analyze the available data from randomized controlled trials (RCTs) for trimetazidine (TMZ) in the prevention of contrast-induced nephropathy (CIN).BACKGROUND: Contrast-induced nephropathy after coronary angiography is associated with poor outcomes. Trimetazid
PMID 25715308

Sirtuin 1 in rat orthotopic liver transplantation: An IGL-1 preservation solution approach.

Pantazi E1, Zaouali MA1, Bejaoui M1, Folch-Puy E1, Ben Abdennebi H1, Varela AT1, Rolo AP1, Palmeira CM1, Roselló-Catafau J1.
World journal of gastroenterology : WJG.World J Gastroenterol.2015 Feb 14;21(6):1765-74. doi: 10.3748/wjg.v21.i6.1765.
AIM: To investigate the possible involvement of Sirtuin 1 (SIRT1) in rat orthotopic liver transplantation (OLT), when Institute Georges Lopez 1 (IGL-1) preservation solution is enriched with trimetazidine (TMZ).METHODS: Male Sprague-Dawley rats were used as donors and recipients. Livers were stored
PMID 25684941

Japanese Journal

Crystal Structure of 1-(2,3,4-Trimethoxybenzyl)piperazine monohydrochloride

X-ray Structure Analysis Online 28, 5-6, 2012
NAID 130004544288

The protective effects of trimetazidine on testicular ischemia and reperfusion injury in rats

Pediatric surgery international 23(11), 1113-1118, 2007-11-01
NAID 10027859325

Sensitive determination of trimetazidine in spiked human plasma by HPLC with fluorescence detection after pre-column derivatization with 9-fluorenylmethyl chloroformate

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 856(1), 337-342, 2007-09-01
NAID 10025808206

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Trimetazidine
Systematic (IUPAC) name
	1-(2,3,4-trimethoxybenzyl)piperazine
Clinical data
Trade names	Vastarel
AHFS/Drugs.com	International Drug Names
Legal status	UK: CD (Schedule I);
Routes	Oral
Pharmacokinetic data
Bioavailability	completely absorbed at around 5 hours, steady state is reached by 60th hour
Protein binding	low (16%)
Metabolism	minimal
Half-life	7 to 12 hours
Excretion	mainly renal (unchanged), exposure is increased in renal impairment - on average by 4-fold in subjects with severe renal impairment (CrCl <30 ml/min)
Identifiers
CAS number	5011-34-7
ATC code	C01EB15
PubChem	CID 21109
ChemSpider	19853
UNII	N9A0A0R9S8
ChEMBL	CHEMBL203266
Chemical data
Formula	C14H22N2O3
Mol. mass	266.336 g/mol
	SMILES O(c1ccc(c(OC)c1OC)CN2CCNCC2)C;
	InChI InChI=1S/C14H22N2O3/c1-17-12-5-4-11(13(18-2)14(12)19-3)10-16-8-6-15-7-9-16/h4-5,15H,6-10H2,1-3H3 ; Key:UHWVSEOVJBQKBE-UHFFFAOYSA-N ;
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