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Cardioprotection of trimetazidine and anthracycline-induced acute cardiotoxic effects

2002; Elsevier BV; Volume: 359; Issue: 9312 Linguagem: Inglês

10.1016/s0140-6736(02)08135-7

1474-547X

Claudio Pascale, Paolo Fornengo, Giuseppe Epifani, Albino Claudio Bosio, F Giacometto,

Metal complexes synthesis and properties

Anthracyclines are widely used antineoplastic agents that can induce selective cardiotoxic effects. These effects can be acute, leading to cardiac failure and decrease of the ejection fraction within 48 h, or can be chronic, according to dose, with high mortality rates (30–50%). The mechanisms have been related to free-radical formation with peroxidation of the cell-membrane lipids and interference with sarcoplasmatic reticulum function and cardiomyocyte apoptosis. In addition, the myocardial high-energy phosphate metabolism can be impaired after treatment with anthracyclines. In an attempt to circumvent these toxic effects, various antioxidants have been used in cell culture, animal, and human studies without consistent beneficial effects.1Zhou S Starkov A Froberg MK Leino RL Wallace KB Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin.Cancer Res. 2001; 61: 771-777PubMed Google Scholar, 2Shadle SE Bammel BP Cusack BJ et al.Daunorubicin cardiotoxicity: evidence for the importance of the quinone moiety in a free radical-independent mechanism.Biochem Pharmacol. 2000; 60: 1435-1444Crossref PubMed Scopus (56) Google Scholar The cardiotoxic side-effects are currently treated with dexrazoxane, which works as a chelator agent. Trimetazidine, a 3-keto acyl coenzyme A-thiolase inhibitor, which acts in the myocyte cell metabolism, raising the ATP content in hypoxic conditions and preventing oxygen free-radical cell-membrane damage,3Detry JM Sellier P Pennaforte S Cokkinos D Dargie H Mathes P Trimetazidine: a new concept in the treatment of angina—comparison with propanolol in patients with stable angina.Br J Pharmacol. 1994; 37: 279-288Crossref Scopus (255) Google Scholar has been introduced in ischaemic cardiovascular syndromes. We describe a case of acute anthracycline-induced cardiotoxic effects resistant to dexrazoxane, which improved after treatment with trimetazidine. A woman aged 76 years who had had total right mastectomy for breast cancer in 1995 and a secondary lesion in L3 in 1998 treated with formestane and pamidronic acid, was referred to our division because of a new bone lesion. Electrocardiography was normal and the echocardiogram showed normal cardiac diameters, 58% ejection fraction, normal regional wall motion, and slight aortic insufficiency. We started 90 mg epirubicin intravenously, and dexrazoxane 100 mg. 1 week later she developed dyspnoea with orthopnoea. A new electrocardiogram showed widespread negative T waves and medium-apical segments were strikingly hypokinetic, with a 38% ejection fraction and mitralic insufficiency. Treatment with diuretics and intravenous nitroderivates was ineffective. We purported that trimetazidine could be useful in the acute anthracycline-induced cardiotoxic effects. We began treatment with oral trimetazidine 20 mg three times daily; the patient's signs and symptoms rapidly improved, and T waves normalised on electrocardiography; 24 h later we did another echocardiogram and noted an increase in systolic function, with a 53% ejection fraction and no mitralic insufficiency. The chemotherapy was discontinued. After 5 months the treatment with trimetazidine was stopped. The patient had no further chest pain or dyspnoea. Trimetazidine maintains cellular homoeostasis, preserves electrical and contractile function activity, and limits cytolysis; these effects have been ascribed to a protective action on energy metabolism, limiting intracellular acidosis. There is a protective effect on lipid peroxidation and potassium permeability induced by oxygen free radicals.4Maridonneau-Parin I Harpey C Effects of trimetazidine on membrane damage induced by oxygen free radicals in human red cells.Br J Clin Pharmacol. 1985; 20: 148-151Crossref PubMed Scopus (154) Google Scholar The prevention by trimetazidine of doxorubicin-induced myocardial toxic effects has been studied in rats; it could not prevent the development of long-term effects, but improved substantially the early cardiotoxic signs.5Perletti G Monti E Paracchini L Piccinini F Effect of trimetazidine on early and delayed doxorubicin myocardial toxicity.Int Arch Pharmacodynam Ther. 1989; 302: 280-289PubMed Google Scholar These data need to be confirmed by clinical trials.