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


METHODS
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.


METHODS
Asthma study clinics in university hospitals and private practices.


METHODS
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.


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


METHODS
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.
Israel
E
E
Respiratory and Critical Care Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Cohn
J
J
Dubé
L
L
Drazen
J M
JM
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D000328:Adult; D000704:Analysis of Variance; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005541:Forced Expiratory Volume; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008111:Liver Function Tests; D008297:Male; D010366:Peak Expiratory Flow Rate; D011788:Quality of Life
D000318:Adrenergic beta-Agonists; D005938:Glucocorticoids; D016859:Lipoxygenase Inhibitors; C063449:zileuton; D006918:Hydroxyurea