THE RELATIONSHIP BETWEEN WSE, PHARMACOKINETICS, TIONS AND ANTITHROMBOTIC EFFECTS OF NAFAZATROM

Nafazatrom is rapidly and almost completely absorbed after oral administration. However, the plasma levels of unchanged nafazatrom are very low, suggesting an extensive biotransformation during a first passage through the liver. The concentrations of nafazatrom in the plasma therefore, may only reflect indirectly the effective concentration at the receptor site. Concentrations, half-life and distribution of nafazatrom between aqueous and liquid compartments suggest that the cellular membrane may be the site of action. The antithrombotic effects of low oral doses of nafazatrom, 3-methyl-l2-(Z-naphthyloxy)-ethyl -2-pyrazoline-'j-one, have been demonstrated in various experimental thrombosis models (l-3). This effect is not associated with effects on coagulation or fibrinolysis (1,4). Furthermore, nafazatrom has little effect on platelet aggregation in vitro (1,3). In contrast, nafazatrom inhibits platelet aggregation in vivo and ex vivo (3). Thus, in man, platelet aggregation was decreased after venous occlusion in healthy volunteers, who were given 1.2 g nafazatrom daily for 1 week, and ADP-induced platelet aggregation was inhibited after the combined treatment with nafazatrom and dipyridamole (3). In animal studies, Buchanan et al. found that the reduced platelet survival seen in rabbits with an indwelling cannula, was normalized after a 3-day treatment with nafazatrom. ADP-induced maximum aggregation was also significantly inhibited ex vivo in both heparinized and titrated PRP samples after nafazatrom treatment (4). Nafazatrom has also been shown to stimulate prostacyclin synthesis in man (3), rats (5,6), and in vitro (7). Thus, the combined effects of nafazatrom on platelet function and prostacyclin synthesis may contribute to its potent antithrombotic effects.