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

• Published in: American journal of respiratory and critical care medicine Vol. 155; no. 3; p. 875
• Main Authors: Van Schoor, J, Joos, G F, Kips, J C, Drajesk, J F, Carpentier, P J, Pauwels, R A
• Format: Journal Article
• Language: English
• Published: United States 01.03.1997
• Subjects: Adenosine - pharmacology; Adult; Asthma - physiopathology; Bronchi - drug effects; Bronchial Provocation Tests; Bronchoconstriction - drug effects; Bronchoconstriction - physiology; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors - pharmacology; Exercise - physiology; Female; Forced Expiratory Volume; Humans; Hydroxyurea - analogs & derivatives; Hydroxyurea - pharmacology; Leukotriene B4 - blood; Leukotriene B4 - metabolism; Leukotriene B4 - urine; Lipoxygenase Inhibitors; Male; Middle Aged; Vasodilator Agents - pharmacology
• ISSN: 1073-449X
• DOI: 10.1164/ajrccm.155.3.9117020

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.