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

Abstract

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 [FEV1] > or = 67% of predicted value, histamine provocative concentration causing a 20% fall in FEV1 [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)B4 biosynthesis in whole blood ex vivo and by urinary LTE4 excretion. Airway response to allergen was measured by FEV1 (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 FEV1 (p = 0.10). As compared with the value before pretreatment, MK-0591 blocked LTB4 biosynthesis and LTE4 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 = 0.040), 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.