ATTENUATION OF EARLY AND LATE-PHASE ALLERGEN-INDUCED BRONCHOCONSTRICTION IN ASTHMATIC SUBJECTS BY A 5-LIPOXYGENASE ACTIVATING PROTEIN ANTAGONIST, BAYX-1005

Background - The cysteinyl leukotrienes (LTC4, LTD4 and LTE4) have bee n implicated in the pathogenesis of allergen-induced airway responses. The effects of pretreatment with BAYx 1005, an inhibitor of leukotrie ne biosynthesis via antagonism of 5-lipoxygenase activating protein, o n allergen-induced early and late asthmatic responses has been evaluat ed. Methods - Eight atopic subjects with mild asthma participated in a two period, double blind, placebo controlled, crossover trial. Subjec ts were selected on the basis of a forced expiratory volume in one sec ond (FEV1) of > 70% predicted, a methacholine provocative concentratio n causing a 20% fall in FEV1 (PC20) of < 32 mg/ml, a documented allerg en-induced early response (EAR, > 15% fall in FEV1 0-1 hour after alle rgen inhalation) and late response (LAR, > 15% fall in FEV1 3-7 hours after allergen inhalation), and allergen-induced airway hyperresponsiv eness (at least a doubling dose reduction in the methacholine PC20 30 hours after allergen inhalation), During the treatment periods subject s received BAYx 1005 (500 mg twice daily) or placebo for 3.5 days; tre atment periods were separated by at least two weeks. On the third day of treatment, two hours after administration of medication, subjects p erformed an allergen inhalation challenge and FEV1 was measured for se ven hours. Results - Treatment with BAYx 1005 attenuated the magnitude of both the allergen-induced early and late asthmatic responses. The mean (SE) maximal fall in FEV1 during the EAR was 26.6 (3.3)% during p lacebo treatment and 11.4 (3.3)% during treatment with BAYx 1005 (mean difference 15.2 (95% confidence interval (CI) 9.4 to 21.00)) with a m ean protection afforded by BAYx 1005 of 57.1%, The mean (SE) maximal f all in FEV1 during the LAR was 19.8 (5.7)% during placebo treatment an d 10.7 (4.4)% during BAYx 1005 treatment (mean difference 9.2 (95% CI 1.4 to 17.0)) with a mean protection afforded by BAYx 1005 of 46.0%. T he area under the time response curve (AUC(0-3)) was also reduced afte r treatment with BAYx 1005 compared with placebo by 86.5%.h (mean diff erence 26.3 (95% CI 17.1 to 38.5)) and the AUC(3-7) by 59.6%.h (mean d ifference 26.9 (95% CI -3.8 to 57.6)). Conclusions - These results sho w that antagonism of 5-lipoxygenase activating protein can attenuate a llergen-induced bronchoconstrictor responses and support an important role for the cysteinyl leukotrienes in mediating these asthmatic respo nses.