Effects of Y-24180, a Long-Acting and Potent Antagonist to Platelet-Activating Factor, on Immediate Asthmatic Response in Guinea Pigs

The effect of Y-24180, a potent antagonist to platelet-activating factor (PAF), was evaluated on the antigen-induced immediate asthmatic response (IAR) in actively sensitized guinea pigs that were pretreated with an antihistaminic agent, pyri-lamine. Then, the effect was compared with that of other antiasthmatic agents. In a dose-dependent manner, Y-24180 (0.01–1 mg/kg, p.o.) suppressed the IAR, and WEB 2086 (0.1–10 mg/kg, p.o.), another PAF antagonist, also suppressed IAR in the same fashion as Y-24180. In contrast, AA-2414 (1–100 mg/kg, p.o.), a thromboxane A2 (TXA2) antagonist, was effective only at the beginning of the IAR and ONO-1078 (1–100 mg/kg, p.o.), a peptide leukotriene (pLT) antagonist, was effective only in the latter period, OKY-046, a TXA2 synthetase inhibitor, showed no significant suppression of the IAR at doses up to 100 mg/kg. Thus, PAF antagonists were more effective than the other agents tested in the present model for IAR. In a subsequent test, Y-24180 (1 mg/kg, p.o.) was confirmed to enhance the suppressive effects of theophylline (10 and 30 mg/kg, p.o.), procaterol (0.1 and 1 µg/kg, i.v.), OKY-046 (100 mg/kg, p.o.) and ONO-1078 (100 mg/kg, p.o.) on the IAR. A combination of three agents, namely Y-24180 with OKY-046 and ONO-1078, completely suppressed the IAR. The results demonstrate that Y-24180 not only suppresses the IAR, but also enhances the suppressive effect of other antiasthmatic agents. Therefore, Y-24180 would be a clinically promising drug for the treatment of bronchial asthma.