THE EFFECT OF ABT-761, A NOVEL 5-LIPOXYGENASE INHIBITOR, ON EXERCISE-INDUCED AND ADENOSINE-INDUCED BRONCHOCONSTRICTION IN ASTHMATIC SUBJECTS

Leukotrienes have been implicated in the bronchoconstriction caused by indirect stimuli. In the present study we examined the effect of oral ABT-761, a novel 5-lipoxygenase (5-LO) inhibitor, on exercise-and ade nosine (AMP)-induced bronchoconstriction in nine asthmatics. At the fo ur 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashio n. At study periods 1 and 2 the subjects performed an exercise challen ge and at study periods 3 and 4 an AMP challenge. Pretreatment with AB T-761 caused a significant inhibition of the maximal percentage fall o f FEV(1) from baseline (p = 0.037) and a reduction of the percentage f all in FEV(1) (area under the curve, AUC) of 61.4 +/- 14.1% (mean +/- SEM) after exercise challenge (p = 0.021). Although pretreatment with ABT-761 did not significantly inhibit the maximal fall of FEV(1) after AMP challenge (p = 0.134), the overall bronchoconstriction was signif icantly inhibited, the AUC being reduced by a mean (+/- SEM) of 82.7 /- 7.2% (p = 0.012). There was no significant correlation between the protective effect against exercise and that against AMP for individual patients. The percentage change in urinary leukotriene E(4) (LTE(4)) excretion at exercise was +18.1 +/- 10.9% on placebo and -44.8 +/- 6.2 % after ABT-761 (p = 0.017); changes at adenosine were +38.5 +/- 27.0% on placebo and -36.7 +/- 9.8% after ABT-761 (p = 0.028). On placebo, exercise produced a marked stimulation of the ex vivo LTB(4) productio n, whereas adenosine was associated with only a minor increase; ABT-76 1 caused a greater than 90% inhibition (p < 0.05 for both challenges). We conclude that ABT-761 is a potent and long-acting 5-LO inhibitor w hich significantly attenuates exercise- and adenosine-induced bronchoc onstriction, indicating that leukotrienes are important mediators in b oth challenges.