Benefits from adding the 5-lipoxygenase inhibitor Zileuton to conventional therapy in aspirin-intolerant asthmatics

• Published in: American journal of respiratory and critical care medicine 1998-04, Vol.157 (4), p.1187-1194
• Main Authors: DAHLEN, B, NIZANKOWSKA, E, WRIGHT, S, DUBE, L. M, DAHLEN, S.-E, SZCZEKLIK, A, ZETTERSTRÖM, O, BOCHENEK, G, KUMLIN, M, MASTALERZ, L, PINIS, G, SWANSON, L. J, BOODHOO, T. I
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Aspirin - adverse effects; Asthma - drug therapy; Asthma - physiopathology; Biological and medical sciences; Bronchial Hyperreactivity - chemically induced; Bronchial Hyperreactivity - physiopathology; Bronchial Provocation Tests; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Glucocorticoids - administration & dosage; Histamine; Histamine and antagonists. Allergy; Humans; Hydroxyurea - administration & dosage; Hydroxyurea - analogs & derivatives; Leukotriene Antagonists; Leukotriene D4; Lipoxygenase Inhibitors - administration & dosage; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Peak Expiratory Flow Rate; Pharmacology. Drug treatments
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/ajrccm.157.4.9707089

From bronchoprovocation studies and investigations of the acute effects of drugs that inhibit leukotrienes (LT), the hypothesis has emerged that leukotrienes are important mediators of airway obstruction and other symptoms in aspirin-intolerant asthma (AIA). However, it has yet not been shown if subjects with AIA respond favorably to clinical treatment with leukotriene inhibitors. Therefore, in a double-blind placebo-controlled crossover study, we examined the effects of 6 wk of treatment with the leukotriene-pathway inhibitor zileuton (600 mg, four times daily) in 40 patients with well-characterized AIA. The treatment was added to existing therapy, which included medium to high doses of inhaled (average daily dose 1,030 microg of beclomethasone or budesonide) or oral glucocorticosteroids (4 to 25 mg/d) for all but one of the patients. On top of this treated baseline, there were no significant effects of adding placebo, indicating that their asthma was kept relatively stable. However, there was an acute and chronic improvement in pulmonary function after treatment with zileuton, expressed both as increased FEV1 from baseline compared with placebo, and higher morning and evening peak expiratory flow rate (PEFR) values on zileuton treatment compared with placebo. The improvements occurred despite lower use of rescue bronchodilator with zileuton. Zileuton also diminished nasal dysfunction, which is one of the cardinal signs of AIA. There was a remarkable return of smell, less rhinorrhea, and a trend for less stuffiness and higher nasal inspiratory flow during treatment with zileuton. Zileuton caused a small but distinct reduction of bronchial hyperresponsiveness to histamine and inhibited aspirin-induced bronchoconstriction. Zileuton inhibited urinary excretion of LTE4 but did not change airway reactivity to inhaled LTD4, supporting that zileuton specifically inhibited leukotriene biosynthesis. The findings indicate that leukotrienes are important mediators of persistent airway obstruction and chronic nasal dysfunction in AIA. The study also suggests that addition of a leukotriene pathway inhibitor such as zileuton may bring about greater control of asthma than what is achieved by treatment with medium to high doses of glucocorticosteroids alone.