Trimetazidine, A Cellular Anti‐ischemic Agent

Abstract

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-

Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group.

“…In patients undergoing coronary artery bypass surgery, oral pre-treatment with trimetazidine and addition of trimetazidine to the cardioplegic solution decreased release of malondialdehyde and myosin in the coronary sinus after reflow. Trimetazidine has also been shown to preserve energy balance, prevent intracellular acidosis and reduce free-radical-induced injury in numerous experimental models of ischaemia (see review by Harpey et al [12]). However, the precise mechanisms by which trimetazidine exerts its effects remain to be determined [1].…”

The first histopathological evidence of trimetazidine for the prevention of contrast-induced nephropathy

“…During hypoxia and ischemia TMZ maintains cellular functions by decreasing cellular acidosis and increasing ATP production. 26,27 TMZ was shown to have antioxidant properties. 28,29 Under ischemic conditions TMZ reduces the loss of intracellular K + induced by oxygen free radicals and protects cellular membrane.…”

Role of Trimetazidine in Coronary Artery Bypass Graft Surgery

“…TMZ decreases oxidative damage to mitochondria and protects hearts from I/R-induced damage to mitochondrial respiration [31]. TMZ also showed a cytoprotective effect in several models of myocardial infarction [32] [33]. Recently, it has been shown that TMZ protected post-ischemic hearts by inhibiting the activation of neutrophils [34].…”