6533b7ddfe1ef96bd1273663

RESEARCH PRODUCT

Action of the racemate and the isomers of the platelet-activating factor antagonist bepafant (WEB 2170) after oral administration to guinea-pigs and rats

subject

description

The aim of the present study was to clarify whether there is a difference in terms of potency and pharmacodynamic half time between the isomers and the racemate of the platelet-activating factor antagonist WEB 2170 (bepafant) after oral administration to guineapigs or rats. The following experiments were performed in the guinea-pig. Infusion of platelet-activating factor at 30 ng/ (kg × min) for 30 min to anaesthetized guinea-pigs induced a decrease of respiratory flow and mean arterial blood pressure. Oral pretreatment with WEB 2170 or isomers, respectively, 60 min before infusion of plateletactivating factor inhibited these changes in a dose-dependent manner. The ED50S for inhibition of respiratory flow were: (−) WEB 2170 = 0.018 (0.009−0.036) mg/kg p.o.; (±) WEB 2170 = 0.021 (0.015–0.03) mg/kg p. o.; (+) WEB 2170 = 1.55 (1.01−3.05) mg/kg p. o. Similar ED50 values were obtained for inhibition of decrease of MAP. Doses of isomers and racemate of WEB 2170 that provided almost complete protection against platelet-activating factor at 1 h after administration were chosen for determination of the duration of the protective effect after oral administration. Oral (−) WEB 2170 or (±) WEB 2170 showed almost identical time-response curves for inhibition (t1/ = 14−17 h; 0.1 mg/kg p. o.) in the guinea-pig, whereas the duration of action of (+) WEB 2170 (3−6 h; 8 mg/kg) was significantly shorter. The following experiments were conducted in the rat. Oral pretreatment with WEB 2170 racemate and isomers resulted in a dose-dependent reversal of plateletactivating factor-induced hypotension. The (−) isomer was more potent than the racemate, whereas the (+) isomer had significantly less platelet-activating factorantagonistic activity. The duration of action of the isomers did not significantly differ from that of the racemate under the experimental conditions used. In conclusion, after oral administration to guinea-pigs there is no relevant difference between the (−) isomer and the racemate of WEB 2170 with respect to their potency to inhibit platelet-activating factor or to their duration of action. In contrast the (+) isomer of WEB 2170 is significantly less potent as a platelet-activating factor-antagonist, with a shorter duration of action. The same applies in principle to the rat, except that (−) WEB 2170 was significantly more potent and there was no difference between isomers and racemate in the duration of action.