THE EFFECT OF INHIBITION OF 5-LIPOXYGENASE BY ZILEUTON IN MILD-TO-MODERATE ASTHMA

Objective: To evaluate the effectiveness of inhibiting the formation o f the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenas e inhibitor zileuton in the treatment of mild-to-moderate asthma. Desi gn: Randomized, double-blind, placebo-controlled study. Setting: Unive rsity hospitals and private allergy and pulmonary practices. Patients: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV1) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. Intervention: Zileuto n, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks. Measurements: Airway fu nction, beta-agonist use, and symptoms; inhibition of 5-lipoxygenase a ssessed by measurement of urinary leukotriene E4 (LTE4). Results: Zile uton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 w ithin 1 hour of administration (P < 0.001 compared with placebo), equi valent to a 14.6% increase from baseline. After 4 weeks of zileuton th erapy, airway function and symptoms improved, with the greatest improv ements occurring in the 2.4 g/d group: This group's FEV1 increased by 0.32 L (CI, 0.16 to 0.48 L), a 13.4% increase, compared with a 0.05-L (CI, -0.10 to 0.20 L) increase in patients taking placebo (P = 0.02). Symptoms and frequency of beta-agonist use also decreased with zileuto n, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creati nine (CI, 18.1 to 60.4 pg/mg creatinine) and 26.5 pg/mg creatinine (CI , 6.6 to 46.5 pg/mg creatinine) in the 2.4 g/d and 1.6 g/d groups, res pectively, compared with a slight increase in the placebo group (P = 0 .007 and P = 0.05). No difference was noted in the number of adverse e vents among treatment groups. Conclusions: Inhibition of 5-lipoxygenas e can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be usefu l therapy for asthma. Also, 5-lipoxygenase products may mediate part o f the baseline airway obstruction in patients with mild-to-moderate as thma.