Antileukotriene therapy. Future directions.

Abstract

In the early 1990s, numerous clinical trials with antileukotriene drugs confirmed Brocklehurst's hypothesis that slow-reacting substance of anaphylaxis (SRS-A) is an important bronchoconstrictor agent in asthma (1). Bronchoprovocation studies showed that inhibition of the synthesis of leukotrienes (LTs) or antagonism of cysteinyl-LT receptors partly or wholly blocks constrictor responses to a wide range of asthma triggers, including allergen, platelet-activating factor (PAF), exercise, cold air, sulfur dioxide, adenosine 5'-monophosphate, and nonsteroidal antiinflammatory drugs (NSAIDs) (2). Multiple-dose studies of patients with allergic and nonallergic asthma commonly report 10-15% improvements in baseline lung function, with 25-60% improvements in secondary outcome measures, including symptom scores, night-time awakenings, use of rescue medication (β 2 -agonists and glucocorticoids), and days lost from work and school (3). To many researchers, the clinical improvements observed after blockade of this single family of inflammatory mediators were surprising, in view of the widely accepted model that airway narrowing is caused by numerous agents acting as components of a mediator soup. Indeed, the efficacy of antileukotriene drugs is highlighted by the relative failure in clinical trials of other mediator antagonists such as histamine H 1 antagonists, thromboxane antagonists, and PAF antagonists (4), The antibronchoconstrictor efficacy of antileukotriene drugs provided the main impetus behind their introduction as the first novel class of asthma therapy in more than 20 yr. However, clinical trials also provided surprising evidence for a hitherto unsuspected role of cysteinyl-leukotrienes in promoting persistent eosinophilia in the airway and blood of patients with asthma, and possibly influencing pathways involved in airway wall remodeling (5). A better understanding of these actions of antileukotriene drugs will influence their place in asthma management.