Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group

J Allergy Clin Immunol. 1996 Nov;98(5 Pt 1):859-71. doi: 10.1016/s0091-6749(96)80002-9.


Background: Leukotrienes produced by the 5-lipoxygenase pathway of arachidonic acid metabolism may mediate bronchoconstriction and inflammatory changes important in the pathophysiology of asthma. Leukotriene inhibition may be effective in asthma management.

Objective: This clinical trial was performed to assess the long-term efficacy and safety of zileuton, an inhibitor of 5-lipoxygenase.

Methods: In this multicenter, double-blind, parallel-group, placebo-controlled trial, 600 mg of zileuton, 400 mg of zileuton, or placebo was given orally, each four times daily for 6 months. Patients with mild to moderate asthma (n = 373), 18 to 62 years of age, being managed with regularly inhaled beta-agonist alone, were randomized to the zileuton or placebo groups (n = 122 to 126). Outcome measures included serial spirometry, daily peak expiratory flow rates, daytime and nocturnal symptoms, frequency of beta-agonist use, and number of asthma exacerbations treated with systemic corticosteroids.

Results: An acute bronchodilatory effect was observed 2 to 5 hours after the initial dose of medication in both 400 mg zileuton and 600 mg zileuton groups compared to the placebo group. Both zileuton groups had significantly greater improvements in FEV1 than did the placebo group by day 8. On day 36, FEV1 improved 16% and 12% from baseline for patients treated with 600 mg zileuton and 400 mg zileuton, respectively, compared with an improvement of 6% for the placebo-treated group (p < 0.01, zileuton 600 mg vs placebo). Blood eosinophil levels were significantly reduced in both zileuton-treated groups compared with the placebo group. In the group receiving 600 mg zileuton, morning peak expiratory flow rate improved by 7% to 10%; daytime and nocturnal symptoms decreased by 37% and 31%, respectively; beta-agonist use decreased by 31%; and the proportion of patients requiring steroid rescue medication during the study was reduced by 62% (p < 0.05 for all comparisons of zileuton, 600 mg, vs placebo). Improvements were sustained over 6 months. Adverse events were similar in the three groups with no apparent, dose-related side effects.

Conclusion: Zileuton produces objective and subjective improvements in patients with mild to moderate asthma and is well tolerated.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenergic beta-Agonists / therapeutic use
  • Adult
  • Anti-Asthmatic Agents / administration & dosage
  • Anti-Asthmatic Agents / adverse effects
  • Anti-Asthmatic Agents / pharmacology
  • Anti-Asthmatic Agents / therapeutic use*
  • Asthma / drug therapy*
  • Asthma / enzymology
  • Asthma / physiopathology
  • Bronchoconstriction / drug effects
  • Double-Blind Method
  • Drug Therapy, Combination
  • Eosinophils
  • Female
  • Forced Expiratory Volume
  • Histamine Antagonists / therapeutic use
  • Humans
  • Hydroxyurea / administration & dosage
  • Hydroxyurea / adverse effects
  • Hydroxyurea / analogs & derivatives*
  • Hydroxyurea / pharmacology
  • Hydroxyurea / therapeutic use
  • Leukocyte Count / drug effects
  • Leukotrienes / biosynthesis
  • Lipoxygenase Inhibitors* / administration & dosage
  • Lipoxygenase Inhibitors* / adverse effects
  • Lipoxygenase Inhibitors* / pharmacology
  • Lipoxygenase Inhibitors* / therapeutic use*
  • Liver Function Tests
  • Male
  • Middle Aged
  • Time Factors
  • Treatment Outcome


  • Adrenergic beta-Agonists
  • Anti-Asthmatic Agents
  • Histamine Antagonists
  • Leukotrienes
  • Lipoxygenase Inhibitors
  • zileuton
  • Hydroxyurea