EFFECTS OF A 5-LIPOXYGENASE INHIBITOR, ABT-761, ON EXERCISE-INDUCED BRONCHOCONSTRICTION AND URINARY LTE4 IN ASTHMATIC-PATIENTS

The novel 5-lipoxygenase (5-LO) inhibitor, ABT-761, was investigated f or its effect on exercise-induced bronchoconstriction in asthmatic sub jects. The relationship between 5-LO inhibition and effects on the res ponse of the airways to exercise was examined. In a double-blind, rand omized, crossover clinical trial, 10 patients with mild to moderate pe rsistent asthma (who exhibited a fall in forced expiratory volume in o ne second (FEV1) greater than or equal to 20% following standardized e xercise challenge) received 200 mg ABT-761 or matched placebo, orally, 5 h prior to exercise on two study days, 7-10 days apart. Lung functi on, urinary leukotriene E-4 (LTE4) and ex vivo calcium ionophore-stimu lated LTB4 release in whole blood were measured prior to dosing, prior to exercise and at various time points up to 4 h post-exercise. The m ean (SD) maximal percentage fall in FEV1 after exercise was 27.1 (12)% on placebo and 19.9 (10)% on ABT-761 days, respectively (p < 0.05). P ost-exercise fall in FEV1 was significantly attenuated at 5, 10, 15 an d 30 min after exercise and the mean area under curve, representing th e overall effect of exercise from 0-45 min post-challenge, was also si gnificantly attenuated by ABT-761 (p < 0.001). Ex vivo LTB4 release wa s inhibited by more than 80% throughout the 4 h post-exercise period, indicating that 5-LO was extensively inhibited at all time points. Uri nary LTE4 in the post-exercise period was significantly lower after AB T-761 day than after placebo (40.1 (17.6) versus 89.8 (58.2) pg.mg cre atinine(-1); p < 0.05). Inhibition of LTB4 release in ABT-761-treated patients correlated positively with the attenuation of post-exercise F EV1 decline (r = 0.711;p < 0.05). We conclude that ABT-761 is effectiv e in suppressing exercise-induced bronchoconstriction and that this pr otection is related quantitatively to the degree of 5-lipoxygenase inh ibition.