Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects

• Published in: American journal of respiratory and critical care medicine Vol. 152; no. 4 Pt 1; p. 1203
• Main Authors: Fischer, A R, McFadden, C A, Frantz, R, Awni, W M, Cohn, J, Drazen, J M, Israel, E
• Format: Journal Article
• Language: English
• Published: United States 01.10.1995
• Subjects: Adult; Arachidonate 5-Lipoxygenase - physiology; Asthma - drug therapy; Asthma - physiopathology; Bronchial Hyperreactivity - drug therapy; Bronchial Hyperreactivity - physiopathology; Bronchial Provocation Tests; Cold Temperature; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Hydroxyurea - analogs & derivatives; Hydroxyurea - pharmacology; Lipoxygenase Inhibitors - pharmacology; Male; Single-Blind Method; Time Factors
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/ajrccm.152.4.7551371

The leukotrienes are known bronchoactive agonists with potential proinflammatory effects that may be involved in mediating airway hyperresponsiveness. We investigated the effects of zileuton, an inhibitor of 5-lipoxygenase (5-LO), on airway responsiveness to cold, dry air in patients with moderate asthma. A group of 10 asthmatic patients underwent cold, dry air hyperventilation challenge; challenges were performed before drug treatment and 1 to 10 d after the completion of treatment with study drugs. The cold air minute ventilation required to cause a 15% decrease in FEV1 (PD15 VE) increased by 58% compared with the response before treatment, 1 to 10 d after the completion of 13 wk of treatment with zileuton. The geometric mean (geometric mean/SEM and geometric mean x SEM) PD15 VE increased from 24.5 (20.4, 29.5) L/min to 38.8 (34.7, 43.7) L/min (p = 0.01). Zileuton treatment inhibited 5-LO as measured ex vivo by ionophore-stimulated LTB4 levels in whole blood. In four of seven subjects, LTB4 levels before zileuton ingestion fell from 110.88 +/- 25.42 to 5.40 +/- 1.95 ng/ml 2 h post-zileuton dosing (p = 0.02, pre- versus 2 h postzileuton ingestion). Consistent with the short half-life of zileuton, 6 h postzileuton dosing the ionophore-stimulated, LTB4 levels in whole blood had increased to 89.68 +/- 35.54 ng/ml (p = 0.41, pre- versus 6 h postzileuton ingestion). Based on the first-order kinetics of zileuton, its effect on 5-LO activity should have been dissipated less than 16 h postingestion. Thus, chronic zileuton treatment decreased airway hyperresponsiveness as determined by reactivity to cold, dry air.