title: Effect of chronic 5-lipoxygenase inhibition on airway hyperresponsiveness in asthmatic subjects.
abstract: 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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Combined Program in Pulmonary and Critical Care Medicine, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Fischer
authors.forename: C A
authors.initials: CA
authors.lastname: McFadden
authors.forename: R
authors.initials: R
authors.lastname: Frantz
authors.forename: W M
authors.initials: WM
authors.lastname: Awni
authors.forename: J
authors.initials: J
authors.lastname: Cohn
authors.forename: J M
authors.initials: JM
authors.lastname: Drazen
authors.forename: E
authors.initials: E
authors.lastname: Israel
mesh_terms: D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D003080:Cold Temperature; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D016037:Single-Blind Method; D013997:Time Factors
chemical_list: D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea