Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor

Abstract

Background and methods: The clinical importance of leukotrienes in human allergy has not been defined, in part because there have been no selective 5-lipoxygenase inhibitors that have been effective and safe for use in humans. To address the hypothesis that stimulated leukotriene synthesis causes symptoms of immediate-hypersensitivity reactions in vivo, I investigated the effects of a new 5-lipoxygenase inhibitor, A-64077, on provoked allergic nasal symptoms and mediator release in a double-blind, randomized, placebo-controlled study. Eight subjects with allergic rhinitis underwent nasal challenge on two occasions after an oral dose of 800 mg of A-64077 or an identical-appearing placebo.

Results: Allergen-induced nasal congestion was significantly attenuated (P less than 0.02) by A-64077; peak levels of leukotriene B4 (median, 684 pg per milliliter) and 5-hydroxyeicosatetraenoic acid (median, 704 pg per milliliter) in nasal-rinse fluids were markedly reduced (to 67 and 185 pg per milliliter, respectively; P less than 0.01), whereas levels of prostaglandin D2 were not. Histamine release and sneezing were not reduced significantly by A-64077, but there was a significant correlation (P less than 0.01) between the changes in these variables within subjects. The mean (+/- SEM) stimulated synthesis of leukotriene B4 in whole blood ex vivo was markedly reduced by A-64077 (from 153 +/- 19 to 20 +/- 9 ng per milliliter, P less than 0.01), and the specificity of A-64077 for 5-lipoxygenase inhibition was verified by its lack of effect on the synthesis of serum thromboxane B2 or 12-hydroxyeicosatetraenoic acid.

Conclusions: These results provide direct evidence of an important role for the 5-lipoxygenase products of arachidonic acid in allergic rhinitis and support the notion that further experiments in this area may lead to new therapeutic approaches to allergic disorders.