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

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)

[1]  B. Make,et al.  Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. , 1995, American journal of respiratory and critical care medicine.

[2]  J. Drazen,et al.  Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma. , 1994, The Journal of allergy and clinical immunology.

[3]  E. Israel,et al.  The pivotal role of 5-lipoxygenase products in the reaction of aspirin-sensitive asthmatics to aspirin. , 1993, The American review of respiratory disease.

[4]  S. Holgate,et al.  The protective effect of inhaled leukotriene D4 receptor antagonist ICI 204,219 against exercise-induced asthma. , 1993, The American review of respiratory disease.

[5]  T. Haahtela,et al.  Leukotriene E4 and granulocytic infiltration into asthmatic airways , 1993, The Lancet.

[6]  P. Sterk,et al.  Oral leukotriene inhibitor (MK-886) blocks allergen-induced airway responses. , 1993, The American review of respiratory disease.

[7]  W. Busse,et al.  Bronchodilation with a potent and selective leukotriene D4 (LTD4) receptor antagonist (MK-571) in patients with asthma. , 1992, The American review of respiratory disease.

[8]  E. Riva,et al.  Prevention of exercise-induced bronchoconstriction by a new leukotriene antagonist (SK&F 104353). A double-blind study versus disodium cromoglycate and placebo. , 1992, The American review of respiratory disease.

[9]  S. Findlay,et al.  Effect of the oral leukotriene antagonist, ICI 204,219, on antigen-induced bronchoconstriction in subjects with asthma. , 1992, The Journal of allergy and clinical immunology.

[10]  A. Tattersfield,et al.  Effect of inhaled budesonide on bronchial reactivity to histamine, exercise, and eucapnic dry air hyperventilation in patients with asthma. , 1991, Thorax.

[11]  C. Dollery,et al.  Effect of cysteinyl-leukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects , 1991, The Lancet.

[12]  R. D. Dyer,et al.  5-lipoxygenase inhibitory activity of zileuton. , 1991, The Journal of pharmacology and experimental therapeutics.

[13]  Paul H. Rubin,et al.  Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients. , 1991, Thorax.

[14]  L. Dubé,et al.  Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibitor of 5-lipoxygenase. , 1991, Agents and actions. Supplements.

[15]  P. O'Byrne,et al.  Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. , 1990, The New England journal of medicine.

[16]  Paul H. Rubin,et al.  The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air. , 1990, The New England journal of medicine.

[17]  S. Wenzel,et al.  Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. , 1990, The American review of respiratory disease.

[18]  A. Wardlaw,et al.  Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. , 1989, The American review of respiratory disease.

[19]  A. Wardlaw,et al.  Leukotrienes, LTC4 and LTB4, in bronchoalveolar lavage in bronchial asthma and other respiratory diseases. , 1989, The Journal of allergy and clinical immunology.

[20]  C. Dollery,et al.  URINARY LEUKOTRIENE E4 AFTER ANTIGEN CHALLENGE AND IN ACUTE ASTHMA AND ALLERGIC RHINITIS , 1989, The Lancet.

[21]  E. Israel,et al.  Effect of a leukotriene antagonist, LY171883, on cold air-induced bronchoconstriction in asthmatics. , 1989, The American review of respiratory disease.

[22]  J. Malo,et al.  Theophylline minimally inhibits bronchoconstriction induced by dry cold air inhalation in asthmatic subjects. , 1988, The American review of respiratory disease.

[23]  E. Corey,et al.  Leukotriene B4 action on endothelium mediates augmented neutrophil/endothelial adhesion. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[24]  J. Nowak.  Eicosanoids and the lungs. , 1984, Annals of clinical research.

[25]  N. Thomson,et al.  The protective effect of inhaled chlorpheniramine and atropine on bronchoconstriction stimulated by airway cooling. , 2015, The American review of respiratory disease.

[26]  P. O'Byrne,et al.  Bronchoconstriction stimulated by airway cooling. Better protection with combined inhalation of terbutaline sulphate and cromolyn sodium than with either alone. , 1983, The American review of respiratory disease.

[27]  J. Shelhamer,et al.  Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro. , 2015, The American review of respiratory disease.

[28]  E. R. Mcfadden,et al.  Hyperpnea and heat flux: initial reaction sequence in exercise-induced asthma. , 1979, Journal of applied physiology: respiratory, environmental and exercise physiology.