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 pranlukast, the TXA(2)-receptor antagonist seratrodast, and the novel dual LTD4- and TXA(2)-receptor antagonist YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesulfonyl)propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) were investigated in animals exhibiting immediate asthmatic response (IAR), late asthmatic response (LAR) and airway hyper-responsiveness (AHR). Antigen-induced LAR and AHR are inhibited by orally administered pranlukast (30, 100 mg/kg) and seratrodast (3, 10 mg/kg). YM158 (30 mg/kg), orally administered before or after IAR induction, also inhibited both LAR and AHR. However, while the inhibitory effects of pranlukast 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 action. Additionally, orally administered YM158 (30 mg/kg) inhibited ozone-induced AHR in guinea pigs. Thus, an antagonist that inhibits several lipid mediators might exhibit greater efficacy in treating asthmatic responses than antagonists with a single site of action. Therefore, YM158 shows great promise as a drug that will be able to treat bronchial asthma and related disorders more potently than currently used single-pathway inhibitors.