J. Vanschoor et al., THE EFFECT OF ABT-761, A NOVEL 5-LIPOXYGENASE INHIBITOR, ON EXERCISE-INDUCED AND ADENOSINE-INDUCED BRONCHOCONSTRICTION IN ASTHMATIC SUBJECTS, American journal of respiratory and critical care medicine, 155(3), 1997, pp. 875-880
Citations number
35
Categorie Soggetti
Emergency Medicine & Critical Care","Respiratory System
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.