Cysteinyl-Leukotriene Receptor Antagonists: Present Situation and Future Opportunities

Abstract

Cysteinlyl-leukotriene receptor antagonists (LTRAs) were introduced as oral preventative anti-asthma medications in the late 1990s and, very recently, montelukast has been approved also for the relief of symptoms of perennial and seasonal allergic rhinitis. Although clinical trials and clinical practice showed LTRAs to be effective in the treatment of asthma patients with a wide range of disease severity, their exact role in the therapy of asthma is not well defined and possibly under-appreciated. As for other anti-asthma drugs, clinical trials with LTRAs uncovered a range of patient responses, so that an understanding of the variability mechanisms (e.g. acquired or genetic factors, etc.) is needed to maximize the probability of a beneficial response. Since the molecular cloning of CysLT receptors (CysLTRs) has been achieved, new roles for cysteinyl-LTs in pathophysiological conditions have been suggested or established from the observed distribution in cells and tissues other than the lung. Cysteinyl-LTs and CysLTRs have been implicated in the pathophysiology of other inflammatory conditions including cancer, atopic dermatitis, idiopathic chronic urticaria, and cardiovascular diseases. As a result, LTRAs might be worth assessing for a therapeutic role in some of these pathologies. This review summarizes and attempts to integrate recent data on the therapeutic efficacy, effectiveness and safety of LTRAs in asthma and allergic rhinitis, and speculates on other therapeutic opportunities.

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…The pathophysiological role of cysteinyl LTs in asthma is well documented (Drazen, 2003;Holgate et al, 2003;Sampson et al, 2003;Arm, 2004;Capra et al, 2007;Hallstrand and Henderson, 2010), and results ob-556 tained from localization studies are consistent with the antibronchoconstrictive and anti-inflammatory activities of CysLT 1 R antagonists (Kemp, 2003;Riccioni et al, 2004;Currie et al, 2005;Capra et al, 2006;Dahlén, 2006;Ducharme et al, 2006;Montuschi et al, 2007;del Giudice et al, 2009). However, the finding of CysLTR expression in other tissues will certainly encourage the discovery of new functions for cysteinyl LTs in other physiological and pathological conditions .…”

Montelukast Is Not Effective in Controlling Allergic Symptoms Outside the Airways

“…Typical manifestations of the atopic syndrome are asthma, rhinitis, conjunctivitis, atopic eczema, and oral symptoms caused by cross-reactivity between pollen allergens and those in fruits or vegetables. Cysteinyl-leukotrienes (cys-LT) are lipid mediators produced by inflammatory cells like eosinophils, basophils, macrophages and mast cells [1]. Cys-LTs play a crucial role in the pathophysiology of atopic inflammation in airways and in other tissues.…”

“…Cys-LTs play a crucial role in the pathophysiology of atopic inflammation in airways and in other tissues. Montelukast, a cys-LT receptor 1 antagonist, is shown to be beneficial in treating allergic asthma and allergic rhinitis, but the role of montelukast in treating other symptoms of the atopic syndrome is controversial [1]. We conducted a randomised, placebo-controlled, double-blind, crossover study to assess the efficacy of montelukast in controlling allergic symptoms in subjects with various manifestations of atopic syndrome.…”

Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils

“…With the possible exception of the effects of corticosteroids on b 2 -receptor expression and function [3][4][5], the clinical benefit of this triad of agents is thought to result from the collective effects of their distinct mechanisms of therapeutic activity, as opposed to meaningful, beneficial interactions between them. Corticosteroids possess broad spectrum antiinflammatory activity, while LABAs and montelukast function primarily as bronchodilators and through antagonism of cysLTRs, respectively [6,7].…”