EFFECT OF A NOVEL 5-LIPOXYGENASE ACTIVATING PROTEIN INHIBITOR, BAYX-1005, ON ASTHMA INDUCED BY COLD DRY AIR

Background - Leukotrienes have been implicated in the mediation of air way obstruction induced by hyperventilation of cold dry air in asthmat ic subjects. The effect of a novel inhibitor of 5-lipoxygenase activat ing protein, BAYx 1005, on the bronchospastic response to cold dry air hyperventilation was investigated in asthmatic patients. Methods - Af ter a screening cold dry air hyperventilation challenge to document co ld air responsiveness, 16 asthmatic subjects (baseline forced expirato ry volume in one second (FEV1) >60% of predicted) underwent cold air c hallenge three hours after receiving 750 mg of BAYx 1005 or placebo us ing a randomised, double blind, crossover design. Leukotriene synthesi s inhibition was estimated by measuring the concentration of leukotrie ne B-4 in whole blood stimulated with calcium ionophore A21387. Result s - Treatment with BAYx 1005 produced a 34% (95% CI 11 to 63) increase in the amount of cold air minute ventilation required for a 10% decre ase in FEV1 (PD10(V)over dot E) compared with placebo (mean (SE) 37.6 (1.12) l/min compared with 28.0 (1.13) l/min, p<0.006). The PD20(V)ove r dot E increased 19% (95% CI 8 to 31) after treatment with BAYx 1005 compared with placebo (57.3 (1.10) l/min versus 48.1 (1.10) l/min, p<0 .002). Treatment with BAYx 1005 produced a 15.4% decrease in ionophore -stimulated LTB4 production, while treatment with placebo produced a 7 .1% increase in ex vivo LTB4 (p<0.02). Conclusions - Treatment with BA Yx 1005, a novel inhibitor of leukotriene synthesis, produced a signif icant blunting of cold dry air responsiveness consistent with the hypo thesis that leukotrienes mediate part of the bronchoconstriction induc ed by hyperventilation of cold dry air.