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Howard J. Schwartz, MD; Thomas Petty, MD; Louise M. Dubé, PhD; Linda J. Swanson, PhD; James F. Lancaster, PhD; for the Zileuton Study Group

Arch Intern Med. 1998;158:141-148.

Background  Zileuton, a leukotriene pathway inhibitor, was compared with slowly absorbed theophylline in a randomized, double-blind study of patients with chronic asthma. The primary efficacy measure was improvement in forced expiratory volume in 1 second (FEV₁).

Methods  Eligibility criteria included FEV₁ of 40% to 80% of predicted, documented reversibility of airway disease, and age 18 to 60 years. Initially, the theophylline dosage was titrated to achieve trough concentrations of 8 to 15 µg/mL. After washout and 1-week placebo lead-in, patients were randomly assigned to 13 weeks of the appropriate theophylline dose or zileuton, 400 or 600 mg 4 times daily. The FEV₁ was measured before the morning dose at 2-week intervals and serially after the dose on days 36 and 92. Patients kept daily diaries of asthma symptoms, -agonist usage, and peak expiratory flow rate; on days 36 and 92, they completed quality-of-life questionnaires.

Results  Of 471 eligible patients at 38 centers, 377 were randomly assigned to the study; 313 completed the study. On first-dose administration, all groups showed 11% to 13% improvement in FEV₁ within 30 minutes. Patients who received zileuton, 400 mg, had significantly greater improvement at several points than did theophylline-treated patients. The range of long-term maximum improvement in FEV₁ in the groups was 30% to 34% (P=.40 for zileuton 600 mg; P=.90 for zileuton 400 mg vs theophylline). Initially, the theophylline group improved significantly more in symptom scores, -agonist usage, and peak expiratory flow rate, but at maximal effect there was no significant difference. All groups showed significant improvement in quality of life. No overall differences were observed between the zileuton dosage groups. Adverse events were comparable in all groups.

Conclusion  Zileuton appears as effective and safe as theophylline in patients with chronic asthma.

From the Department of Medicine, University Hospitals of Cleveland, Cleveland, Ohio (Dr Schwartz); Presbyterian-St Luke's Hospital, Denver, Colo (Dr Petty); and Abbott Laboratories, North Chicago, Ill (Drs Dubé, Swanson, and Lancaster). Members of the Zileuton Study Group are listed at the end of the article.

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