The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma

E. Israel, P. Rubin, J. P. Kemp, J. Grossman, W. Pierson, S. C. Siegel, D. Tinkelman, J. J. Murray, W. Busse, A. T. Segal, J. Fish, H. B. Kaiser, D. Ledford, S. Wenzel, R. Rosenthal, J. Cohn, C. Lanni, H. Pearlman, P. Karahalios

Research output: Contribution to journalArticle

Abstract

Objective: To evaluate the effectiveness of inhibiting the formation of the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenase inhibitor zileuton in the treatment of mild-to-moderate asthma. Design: Randomized, double-blind, placebo-controlled study. Setting: University 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: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks. Measurements: Airway function, β-agonist use, and symptoms; inhibition of 5-lipoxygenase assessed by measurement of urinary leukotriene E4 (LTE4). Results: Zileuton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 within 1 hour of administration (P < 0.001 compared with placebo), equivalent to a 14.6% increase from baseline. After 4 weeks of zileuton therapy, airway function and symptoms improved, with the greatest improvements 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 β-agonist use also decreased with zileuton, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creatinine (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, respectively, 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 events among treatment groups. Conclusions: Inhibition of 5-lipoxygenase can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be useful therapy for asthma. Also, 5-lipoxygenase products may mediate part of the baseline airway obstruction in patients with mild-to-moderate asthma.

Original languageEnglish (US)
Pages (from-to)1059-1066
Number of pages8
JournalAnnals of internal medicine
Volume119
Issue number11
DOIs
StatePublished - Jan 1 1993

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ASJC Scopus subject areas

  • Internal Medicine

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Israel, E., Rubin, P., Kemp, J. P., Grossman, J., Pierson, W., Siegel, S. C., Tinkelman, D., Murray, J. J., Busse, W., Segal, A. T., Fish, J., Kaiser, H. B., Ledford, D., Wenzel, S., Rosenthal, R., Cohn, J., Lanni, C., Pearlman, H., & Karahalios, P. (1993). The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Annals of internal medicine, 119(11), 1059-1066. https://doi.org/10.7326/0003-4819-119-11-199312010-00001