Regulation of leukotrienes in the management of asthma: Biology and clinical therapy

Leukotrienes (LTs) are the ultimate synthetic product resulting from the in tracellular hydrolysis of membrane phospholipid at the nuclear envelope in inflammatory cells. Activated cytosolic phospholipase (cPLA(2)) catalyzes t he production of arachidonic acid, which is converted by cyclooxygenases in to leukotriene A(4) (LTA(4)) and subsequently into the chemotaxin LTB4, whi ch has no direct bronchoconstrictor activity. In certain inflammatory cells , LTA4 is converted into the cysteinyl leukotriene (cysLT) LTC4, which is c onverted into LTD4 and finally to LTE4 after extracellular transport. All c ysLTs occupy the same receptors and are extremely potent bronchoconstrictin g agents that are pathogenetic in both asthma and allergy. With the identif ication of the structure of the cysLT receptor, antileukotriene therapies h ave been developed that either (a) inhibit synthesis of leukotriene (throug h 5-lipoxygenase inhibition) or (b) block the cysLT receptor. Preliminary i nvestigations indicate that corticosteroids also may partially block the sy nthesis of cysLT and that cysLTs may be chemotactic for other inflammatory cells, e.g, eosinophils, by a mechanism that has not yet been defined, Curr ently, anti-LT therapies are approved by the US Food and Drug Administratio n (FDA) only for patients with asthma. These drugs generally are moderately efficacious agents, although they are highly efficacious in aspirin-induce d asthma (AIA). In other forms of asthma, inhaled corticosteroid (ICS) ther apy has been more effective than anti-LT therapy in improving air flow obst ruction. However, anti-LT agents are additive to beta-adrenoceptor and ICS in their effects. Accordingly, anti-LT therapies are used frequently as sup plemental treatments in asthmatic patients whose asthma is not optimally co ntrolled by a combination of other drugs, including long-acting beta-adreno ceptor drugs and ICS agents. The growth of leukotriene receptor antagonists (LTRAs) has been extraordinary in the United States. The exceptional safet y of these agents and their ease of administration as tablets taken once or twice daily has spurred this growth. In the past year, the high-affinity c ysLT receptor has been cloned. This holds forth the promise of a second gen eration of LTRA agents of even greater efficacy and possibly greater durati on of action.