Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group.

Abstract

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 beta-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 beta-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.

• Authors: E Israel, J Cohn, L Dubé, J M Drazen
• Journal: JAMA (JAMA) Vol. 275 Issue 12 Pg. 931-6 (Mar 27 1996) ISSN: 0098-7484 [Print] United States
• PMID: 8598621 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Agonists
• Glucocorticoids
• Lipoxygenase Inhibitors
• zileuton
• Hydroxyurea

Topics

• Adrenergic beta-Agonists (therapeutic use)
• Adult
• Analysis of Variance
• Asthma (drug therapy, physiopathology)
• Double-Blind Method
• Drug Administration Schedule
• Drug Monitoring
• Female
• Forced Expiratory Volume
• Glucocorticoids (therapeutic use)
• Humans
• Hydroxyurea (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
• Lipoxygenase Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Liver (drug effects, enzymology)
• Liver Function Tests
• Male
• Peak Expiratory Flow Rate
• Quality of Life