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March 27, 1996

Effect of Treatment With Zileuton, a 5-Lipoxygenase Inhibitor, in Patients With AsthmaA Randomized Controlled Trial

Author Affiliations

San Antonio, Tex; Encinitas, Calif; Hartford (Conn) Lung Physicians; Allergy Associates, North Dartmouth, Mass; University of California, San Diego; National Jewish Center for Immunology and Respiratory Medicine, Denver, Colo; Mayo Clinic, Rochester, Minn; Prairie Village, Kan; Allergy Research Foundation, Los Angeles, Calif; Montefiore Hospital and Medical Center, Bronx, NY; University of Wisconsin Hospitals and Clinics, Madison; University of California, San Francisco; Allergy and Asthma Center, El Paso, Tex; Allergy Associates, Dallas, Tex; University of Nebraska Medical Center Pulmonary Medicine, Omaha; Washington, DC; University of Arizona Health Science Center, Tucson; University of Chicago (Ill); School of Medicine Tulane University, New Orleans, La; Milwaukee (Wis) Medical Clinic; Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, NJ; Division of Allergy and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn; Allergy and Immunology Research Foundation, Atlanta, Ga; Winthrop Pulmonary Associates Long Island, NY; Allergy and Asthma Specialists PA, Minneapolis, Minn; Endwell (NY) Family Physicians; Albany (NY) Medical College; Division of Pulmonary Medicine, Jefferson Medical Center, Philadelphia, Pa; Austin, Tex; Clinical Research Unit, Tampa, Fla; Allergy and Asthma Consultants PC, Englewood, Colo; Allergy and Asthma Research Center-Toleda, Sylvania, Ohio; Grant Hospital of Chicago (Ill); Grady Hospital Allergy and Asthma Clinic, Atlanta, Ga; St Luke's Roosevelt Hospital, Pulmonary Division, New York, NY; Channing Laboratory, Boston, Mass; Abbott Laboratories, Abbott Park, Ill.
From the Respiratory and Critical Care Division, Brigham and Women's Hospital, Boston, Mass (Drs Israel and Drazen), and Abbott Laboratories, Abbott Park, III (Dr Cohn and Dubé). Dr Cohn is now at Zeneca Pharmaceuticals, Wilmington, Del.

JAMA. 1996;275(12):931-936. doi:10.1001/jama.1996.03530360041036

Objective.  —To study the effect of 3 months of treatment with zileuton, an inhibitor of the enzymatic pathway (5-lipoxygenase) leading to leukotriene formation, on disease control in patients with mild to moderate asthma.

Design.  —Randomized, double-blind, parallel-group study in 401 patients. A 10-day placebo lead-in was followed by a double-blind treatment period of 13 weeks.

Setting.  —Asthma study clinics in university hospitals and private practices.

Patients or Other Participants.  —Patients with mild to moderate asthma (forced expiratory volume in the first second [FEV1], 40% to 80% of predicted) whose only treatment was inhaled β-agonists.

Interventions.  —Treatment with 600 mg or 400 mg of zileuton or placebo (each taken four times daily).

Main Outcome Measures.  —Frequency of asthma exacerbation requiring treatment with corticosteroids, use of inhaled β-agonists, pulmonary function tests, asthma symptom assessment, and quality-of-life evaluation. Safety was evaluated by monitoring adverse events.

Results.  —Only eight (6.1%) of 132 patients receiving 600 mg of zileuton four times a day required corticosteroid treatment for asthma vs 21 (15.6%) of 135 patients receiving placebo (P=.02), giving a relative risk of 2.6. At the time of expected peak drug concentration, the average FEV1 improved 15.7% in the 600-mg zileuton group vs 7.7% in the placebo group (P=.006). Quality-of-life assessments significantly improved in the 600-mg zileuton group and not in the placebo group (P=.007 for the overall score). Elevations in liver function tests (more than three times normal), all of which reversed with drug withdrawal, occurred in five patients (P=.03 vs placebo), three patients (P=.12 vs placebo), and no patients treated with 600 mg of zileuton, 400 mg of zileuton, or placebo, respectively.

Conclusions.  —Three months of 5-lipoxygenase inhibition produced a significant improvement in asthma control. These data indicate that 5-lipoxygenase products of arachidonic acid metabolism are mediators of inflammation with an important role in the biology of asthma.(JAMA. 1996;275:931-936)