Effect of YM158, a dual lipid mediator antagonist, on immediate and late asthmatic responses, and on airway hyper-responsiveness in guinea pigs

The effects of lipid mediator antagonists: the LTD4-receptor antagonist pra nlukast, the TXA(2)-receptor antagonist seratrodast, and the novel dual LTD 4- and TXA(2)-receptor antagonist YM158 (3-[(4-tert-butylthiazol-2-yl)metho xy]-5'-[3-(4-chlorobenzenesulfonyl)propyl]-2'-(1H-tetrazol-5-ylmethoxy)benz anilide monosodium salt monohydrate) were investigated in animals exhibitin g immediate asthmatic response (IAR), late asthmatic response (LAR) and air way hyper-responsiveness (AHR). Antigen-induced LAR and AHR are inhibited b y orally administered pranlukast (30, 100 mg/kg) and seratrodast (3, 10 mg/ kg). YM158 (30 mg/kg), orally administered before or after IAR induction, a lso inhibited both LAR and AHR. However, while the inhibitory effects of pr anlukast and seratrodast on IAR were marginal, the effects of YM158 (3, 10, 30 mg/kg) were dose-dependent, probably due to its multiple sites of actio n. Additionally, orally administered YM158 (30 mg/kg) inhibited ozone-induc ed AHR in guinea pigs. Thus, an antagonist that inhibits several lipid medi ators might exhibit greater efficacy in treating asthmatic responses than a ntagonists with a single site of action. Therefore, YM158 shows great promi se as a drug that will be able to treat bronchial asthma and related disord ers more potently than currently used single-pathway inhibitors.