Leukotriene receptor antagonists – novel mechanisms of action
All clinically available LTRAs (montelukast, zafirlukast and pranlukast) act on the cysteinyl leukotriene type 1 receptor (CysLT1) and by competitive antagonism at this receptor are believed to be responsible for the control of airway inflammation, bronchoconstriction, and remodeling.46-48 However, anti-inflammatory activity of LTRAs independent of CysLT1 antagonism has been suggested. LTRAs reduced the eosinophil protease activity,49 and inhibited TNFα-50, or UDP-mediated51,52cytokine expression, as well as NF-κB activation in human mononuclear53 or epithelial cells54through processes that appear to be distinct from CysLT1antagonism. Although, mechanisms of these non-CysLT1-related LTRA activities are not fully understood, concentration dependent inhibition of distinct receptors such as P2Y1, P2Y2, P2Y6 and GPR17 by LTRAs have been reported,51,52,55 suggesting, at least for P2Y receptor, a non-competitive mechanism of action. Interestingly, it was also shown that LTRAs may have a potent inhibitory effect on 5-LOX activity (i.e. LT production)52,56 and transport of LTs by the multidrug resistance protein ABCC4,57suggesting a much broader mechanism of action for these drugs than previously suspected. Indeed, non–CysLT1-related mechanisms of LTRA might represent another level of variability in the response to treatment in patients with asthma and allergy. Some of these activities may be compound-specific or may depend on drug concentration (most non-CysLT1-related effects required micromolar drug concentrations51-53 in contrast to nanomolar levels needed for CysLT1antagonism58-60) or may depend on the presence of a particular inflammatory pathway in patients with asthma (allergy), and therefore, clinically significant effects of treatment may be observed in some, but not all, treated patients. It should be emphasized that initial clinical interventional studies of montelukast in asthma used doses up to 200 mg a day61,62 showing greater lung function improvement than in subsequent studies using recommended dose of 10 mg,63 suggesting that higher doses of currently known LTRAs or new compounds derived from this class of drugs may represent a novel strategy for finding more efficient therapy. The demonstration that the bronchoconstrictive actions of LTE4 in asthma are solely mediated by the CysLT1 receptor further supports that effects on other targets than the CysLT receptors may take place64