Effects of a 5-lipoxygenase inhibitor, ABT-761, on exercise-induced bronchoconstriction and urinary LTE4 in asthmatic patients.

Abstract

The novel 5-lipoxygenase (5-LO) inhibitor, ABT-761, was investigated for its effect on exercise-induced bronchoconstriction in asthmatic subjects. The relationship between 5-LO inhibition and effects on the response of the airways to exercise was examined. In a double-blind, randomized, crossover clinical trial, 10 patients with mild to moderate persistent asthma (who exhibited a fall in forced expiratory volume in one second (FEV1) > or = 20% following standardized exercise challenge) received 200 mg ABT-761 or matched placebo, orally, 5 h prior to exercise on two study days, 7-10 days apart. Lung function, urinary leukotriene E4 (LTE4) and ex vivo calcium ionophore-stimulated 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 mean (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). Post-exercise fall in FEV1 was significantly attenuated at 5, 10, 15 and 30 min after exercise and the mean area under curve, representing the overall effect of exercise from 0-45 min post-challenge, was also significantly attenuated by ABT-761 (p<0.001). Ex vivo LTB4 release was inhibited by more than 80% throughout the 4 h post-exercise period, indicating that 5-LO was extensively inhibited at all time points. Urinary LTE4 in the post-exercise period was significantly lower after ABT-761 day than after placebo (40.1 (17.6) versus 89.8 (58.2) pg x mg creatinine(-1); p<0.05). Inhibition of LTB4 release in ABT-761-treated patients correlated positively with the attenuation of post-exercise FEV1 decline (r=0.711; p<0.05). We conclude that ABT-761 is effective in suppressing exercise-induced bronchoconstriction and that this protection is related quantitatively to the degree of 5-lipoxygenase inhibition.

• Authors: B Lehnigk, K F Rabe, G Dent, R S Herst, P J Carpentier, H Magnussen
• Journal: The European respiratory journal (Eur Respir J) Vol. 11 Issue 3 Pg. 617-23 (Mar 1998) ISSN: 0903-1936 [Print] England
• PMID: 9596112 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Enzyme Inhibitors
• Lipoxygenase Inhibitors
• Leukotriene E4
• atreleuton
• Hydroxyurea

Topics

• Adult
• Asthma, Exercise-Induced (drug therapy, physiopathology, urine)
• Bronchoconstriction (drug effects)
• Cross-Over Studies
• Double-Blind Method
• Enzyme Inhibitors (therapeutic use)
• Exercise Test
• Female
• Humans
• Hydroxyurea (analogs & derivatives, therapeutic use)
• Leukotriene E4 (urine)
• Lipoxygenase Inhibitors
• Male