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 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.
Lehnigk
B
B
Krankenhaus Grosshansdorf, Zentrum für Pneumologie und Thoraxchirurgie, LVA Hamburg, Germany.
Rabe
K F
KF
Dent
G
G
Herst
R S
RS
Carpentier
P J
PJ
Magnussen
H
H
D000328:Adult; D001250:Asthma, Exercise-Induced / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005080:Exercise Test; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017999:Leukotriene E4 / Q000652:urine*; D016859:Lipoxygenase Inhibitors; D008297:Male
D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D017999:Leukotriene E4; C096921:atreleuton; D006918:Hydroxyurea