THE INHIBITORY EFFECT OF TMK688, A NOVEL ANTIALLERGIC DRUG HAVING BOTH 5-LIPOXYGENASE INHIBITORY ACTIVITY AND ANTIHISTAMINE ACTIVITY, AGAINST BRONCHOCONSTRICTION, LEUKOTRIENE PRODUCTION AND INFLAMMATORY CELL INFILTRATION IN SENSITIZED GUINEA-PIGS

Background TMK688 is being developed as an anti-allergic drug having b oth 5-lipoxygenase inhibitory activity and anti-histamine activity. Me thod We compared the inhibition of the late asthmatic responses by TMK 688 with that by other anti-allergic agents in actively sensitized gui nea pigs, and examined the relationship between 5-lipoxygenase inhibit ion and the late asthmatic responses. Results At 1-3.2 mg/kg, TMK688 i nhibited the increases in respiratory resistance, leukotriene (LT) B-4 and C-4 production in the lungs and eosinophil infiltration into the alveoli during the late asthmatic response, whereas the effects tended to lessen at the dose of 10 mg/kg. These effects are thought to be ca used by the 5-lipoxygenase inhibitory activity of TMK688 because Azela stine, an anti-allergic drug having potent antihistamine activity, exh ibited no effect. ONO-1078, a peptide LT antagonist, inhibited the lat e-phase bronchoconstriction at a dose of 100 mg/kg p.o., but not the i ncrease in the infiltration of inflammatory cells into the alveoli, su ggesting that the late-phase bronchoconstriction is induced, in part, by peptide LTs, i.e. LT C-4, D-4 and E(4) and that the inflammatory ce ll infiltration may be caused by LTB(4). TMK688 inhibited the immediat e bronchoconstriction dose-dependently, and the effect was significant at a dose of 10 mg/kg orally. Since Azelastine, Ketotifen and Oxatomi de suppressed the bronchoconstriction at far lower doses than did TMK6 88, the inhibitory effect was mainly caused by its antihistamine activ ity. Conclusions TMK688 appears to be a novel anti-allergic drug havin g inhibitory effects on both the bronchoconstriction and the infiltrat ion of inflammatory cells during late asthmatic responses.