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The effect of ABT-761, a novel 5-lipoxygenase inhibitor, on exercise- and adenosine-induced bronchoconstriction in asthmatic subjects.

Abstract：

: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 adenosine (AMP)-induced bronchoconstriction in nine asthmatics. At the four 1-d, single-dose treatment periods, ABT-761 (200 mg) or placebo (P) was ingested 5 h before challenge in a double-blind, crossover fashion. At study periods 1 and 2 the subjects performed an exercise challenge and at study periods 3 and 4 an AMP challenge. Pretreatment with ABT-761 caused a significant inhibition of the maximal percentage fall of FEV1 from baseline (p = 0.037) and a reduction of the percentage fall in FEV1 (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 FEV1 after AMP challenge (p = 0.134), the overall bronchoconstriction was significantly 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 E4 (LTE4) 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 LTB4 production, whereas adenosine was associated with only a minor increase; ABT-761 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 which significantly attenuates exercise- and adenosine-induced bronchoconstriction, indicating that leukotrienes are important mediators in both challenges.

journal_name

Am J Respir Crit Care Med

journal_title

American journal of respiratory and critical care medicine

authors

Van Schoor J,Joos GF,Kips JC,Drajesk JF,Carpentier PJ,Pauwels RA

doi

10.1164/ajrccm.155.3.9117020

subject

Has Abstract

pub_date

1997-03-01 00:00:00

pages

875-80

issue

eissn

1073-449X

issn

1535-4970

journal_volume

155

pub_type

临床试验,杂志文章,随机对照试验

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The effect of ABT-761, a novel 5-lipoxygenase inhibitor, on exercise- and adenosine-induced bronchoconstriction in asthmatic subjects.