THE EFFECT OF MK-0591, A NOVEL 5-LIPOXYGENASE ACTIVATING PROTEIN INHIBITOR, ON LEUKOTRIENE BIOSYNTHESIS AND ALLERGEN-INDUCED AIRWAY RESPONSES IN ASTHMATIC SUBJECTS IN-VIVO

Background: The 5-lipoxygenase metabolites of arachidonic acid are likely to be involved in the pathophysiology of atopic asthma. We investigated the effect of pretreatment with MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on allergen-induced early asthmatic reactions (EARs) and late asthmatic reactions (LARs), and subsequent airway hyperresponsiveness to histamine. Methods: Eight atopic men with mild to moderate asthma aged 19 to 31 years, (forced expiratory volume in 1 second [FEV(1)] greater than or equal to 67% of predicted value, histamine provocative concentration causing a 20% fall in FEV(1) [PC20] <4 mg/ml) and documented EAR and LAR to house dust mite extract participated in a two-period double-blind placebo-controlled crossover study. During each study period histamine PC20 was measured 2 days before and 1 day after a standardized allergen inhalation challenge test. MK-0591 was administered in 3 oral doses of 250 mg each at 24, 12, and 1.5 hours before inhalation of allergen. Biochemical activity of MK-0591 was determined by calcium ionophore A-23187-stimulated leukotriene (LT)B-4 biosynthesis in whole blood ex vivo and by urinary LTE(4) excretion. Airway response to allergen was measured by FEV(1) (percent fall from baseline). The EAR (0 to 3 hours) and the LAR (3 to 8 hours) were expressed as corresponding areas under the time-response curves. Results: MK-0591 and placebo did not differ in their effects on prechallenge FEV(1) (p = 0.10). As compared with the value before pretreatment, MK-0591 blocked LTB(4) biosynthesis and LTE(4) excretion by a mean of 98% (range, 96% to 99%; p < 0.002) and 87% (range, 84% to 96%; p < 0.046), respectively, from 0 to 24 hours after allergen challenge. Both the EAR and the LAR were significantly reduced after administration of MK-0591 as compared with placebo with a mean inhibition of 79% (p = 0.011) and 39% (p = 0.010), respectively. Allergen-induced airway hyperresponsiveness was not significantly different between the two pretreatment periods (p = 0.37). Conclusions: In this study oral MK-0591 prevented leukotriene biosynthesis after allergen challenge in patients with mild to moderate asthma. The results of our study indicate that 5-lipoxygenase products play an important role during the EAR, whereas their contribution to the pathophysiology of the LAR seems to be of less importance.