Antileukotriene drugs in the management of asthma.

Abstract

1the mortality and morbidity associated with this disease have not appreciably declined. 2 It continues to be imperative to develop new approaches to asthma therapy. Antileukotriene drugs are a novel form of asthma pharmacotherapy and the first new treatment strategy for chronic asthma in 20 years. In experimental studies, cysteinyl leukotrienes (LTC4, LTD4, and LTE4, together known formerly as slow-reacting substance of anaphylaxis or SRS-A) were found to be extremely potent bronchoconstrictors and to attract inflammatory cells, increase mucous production, and alter vascular permeability. 3 LTB4 was found to be a potent chemoattractant for neutrophils and eosinophils, but not to have a bronchoconstrictive effect. 3 The cysteinyl leukotrienes were also shown to be produced by activated inflammatory cells (eosinophils, basophils, and mast cells) known to be present in the airways of patients with asthma, 3 and were recovered in increased amounts at baseline, after allergen challenge, and during asthma exacerbations from bronchoalveolar lavage fluid and urine of patients with asthma. 3-5 These observations suggested that leukotrienes could be important in the clinical symptoms and physiologic changes of asthma, but confirmation of that concept required the development of drugs that either blocked the synthesis of leukotrienes from arachidonic acid (5-lipoxygenase [5-LO] inhibitors and 5-lipoxygenase activating protein [FLAP] inhibitors) or antagonized the activity of the cysteinyl leukotrienes at their receptor, cysLT1 (leukotriene receptor antagonists). Four oral antileukotriene drugs are now available for the treatment of asthma: 3 leukotriene receptor antagonists, montelukast, zafirlukast, and pranlukast (not available in the United States), and a 5-LO inhibitor, zileuton. Although 5-LO inhibitors inhibit the synthesis of LTB4 as well as the cysteinyl leukotrienes, it remains to be seen whether this broader spectrum of activity produces greater efficacy in the treatment of asthma. These antileukotriene drugs have been extensively studied in clinical trials, but longterm data on effectiveness and adverse effects are lacking. Efficacy Studies indicate that antileukotriene drugs directly inhibit bronchoconstriction and have anti-inflammatory effects as well, a combination of actions that has not been demonstrated as clearly in other classes of asthma drugs. Early in their development, the leukotriene receptor antagonists and FLAP inhibitors, in single doses, were found to almost completely eliminate the immediate bronchoconstriction response to allergen challenge and to reduce the later bronchoconstriction response by approximately 50%. 6 Antileukotriene drugs also abolished the bronchoconstriction response that is observed after the administration of very small doses of aspirin in patients with aspirinsensitive asthma. 7 Further, they reduced exercise-induced bronchoconstriction by 40% to 60%, 8 and recent evidence suggests that this protective effect has no tachyphylaxis, unlike that reported with the use of the long-acting b2-agonist salmeterol. 9,10 Studies of the anti-inflammatory effects of the antileukotriene drugs have shown significant reductions from baseline in the number and proportion of airway and circulating eosinophils in patients with asthma treated with these drugs compared with those who received placebo. 11-13