The effect of trimetazidine, 1‐(2, 3, 4 trimethoxybenzyl)piperazine di‐ hydrochloride, on membrane damage induced by oxygen free radicals in red cells was studied in seven healthy volunteers after oral administration. Red cells collected prior to and after a 7 day treatment period with trimetazidine were incubated in the presence of phenazine methosulphate (an intracellular oxygen free radical generator) and diethyldithiocarbamate (a Cu‐Zn superoxide dismutase inhibitor). The loss of intracellular K+ induced by oxygen free radicals and the membrane content of peroxidated lipids were significantly reduced in red cells collected after the period of treatment. These results indicate a potent antioxidant activity of trimetazidine which could explain its cardioprotective role during ischaemic and reperfusion phases in which oxygen free radicals are generated and probably implicated in the genesis of cardiac cell injury.

Trimetazidine (S 50 16), a molecule developed by the Servier Research Institute, is a cellular anti-ischemic agent. Its chemical name is I -(2,3,4-trimethoxybenzyl)-piperazine dihydrochloride (Fig. I ). Initial pharmacological studies have indicated that trimetazidine prevents cellular changes associated with ischemia or hypoxia, but it has no effect under normoxic conditions ( I ,2).Trimetazidine is freely soluble in water (80%), sparingly soluble in methanol, but insoluble in other organic solvents. Trimetazidine solution is slightly sensitive to light although substantially less than dihydropyridines. The molecular weight of tnmetazidine is, as a dihydrochloride, 339.27 and, in basic form, 266.34. The molecule has two pKa values (4.32 and 8.95) and the pH value of an aqueous solution (5 mg/ml) is 3; this aqueous solution is stable at room temperature. PHARMACOLOGY Effects on the Hypoxic Cell and on the Ischemic TissueIschemia is defined as a deficiency of blood supply in a given tissue, and consequently of oxygen supply to the cells. Ischemia results in a decrease of oxidative metabolism that is responsible for the various functional disorders observed in the cell: reduction in the production of energetic compounds, accumulation of protons, and increase in the generation of oxygen-derived free radicals. The aggression of oxygenderived free radicals towards living tissues is therefore superimposed on the energy disorders and added to the effects of acidosis, which severely alters cellular homeostasis and results in accumulation of calcium within the cell. This considerable excess of intracellular calcium blocks all vital enzymatic functions, leading to necrosis.Despite hypoxia or induced ischemia, trimetazidine maintains homeostasis and cellular functions and inhibits cytolysis. This activity has been evidenced in vivo, by Camilleri and Joseph (3), Fitoussi et al. (4), and Catroux et al. ( 5 ) , using different models of ischemia. After induction of left ventricular infarction in the rat by coro-

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Free radicals have been implicated in several aspects of cellular injury, both during ischemia and reperfusion of the myocardium. In this study, formation of free radicals in the isolated rat heart was measured a) directly using electron paramagnetic resonance (EPR) spectroscopy and b) indirectly using the generation of thiobarbituric acid reactants as an index of lipid peroxidation. EPR spectra of frozen heart powder recorded at 100 degrees K show several lines and consist of different components separated by temperature studies: signal C disappears after warming the sample 1 minute at 190 degrees K and is suggestive of a triplet signal g = 2.001, aN = 25 Gauss; signal B g parallel = 2.034, g perpendicular = 2.007, disappears after 1 min at 240 degrees K, and is similar to those previously reported for oxygen alkylperoxyl free radical; the remaining signal, signal A with g = 2.004 is identical to that of a carbon-centered ubiquinone free radical. The total free radical concentration in isolated rat heart perfused at a constant flow rate of 12 ml/min was increased by 44% compared with control (p less than 0.05) after 10 minutes of normothermic global ischemia with a 10% residual flow, and by only 31% compared with control after 20 seconds of reflow with oxygenated perfusate (p less than 0.05). Compared with the reperfused group, trimetazidine 10(-5) M administered 15 minutes before the ischemic period decreased the free radical concentration (-20%). However, this free radical generation in heart was not associated with a concomitant increase of lipid peroxides.