AZELASTINE - A NOVEL IN-VIVO INHIBITOR OF LEUKOTRIENE BIOSYNTHESIS - A POSSIBLE MECHANISM OF ACTION - A MINI REVIEW

Leukotrienes have been proposed as important chemical mediators of allergic inflammation, and there is evidence that azelastine (Astelin(R)) can affect leukotriene-mediated allergic responses. One of the enzymes required for the synthesis of leukotrienes from arachidonic acid is 5-lipoxygenase (5-LO). Azelastine, which is preferentially taken up by the lung and alveolar macrophages, inhibits leukotriene generation in the airways. This property of azelastine may contribute to its therapeutic efficacy in the long-term treatment and management of rhinitis and asthma. Azelastine does not directly inhibit 5-LO in disrupted murine peritoneal cel Is and rat basophilic leukemia cells (IC50 > 100 mu M), but does have moderate 5-LO inhibitory activity in intact murine peritoneal cells (IC50 = 10 mu M, 5 min) and in chopped guinea pig liver IC50 = 14 mu M, 2 hr). The generation and release of leukotrienes in human neutrophils and eosinophils is also inhibited by azelastine (IC50 = 0.9-1.1 mu M). Furthermore, azelastine is a potent and specific inhibitor of allergen-induced generation of leukotrienes in the nose of the guinea pig (ID50 < 100 mu g/kg, im, 20 min) as well as in patients with rhinitis (2 mg, po, 4 hr; ID50 < 30 mu g/kg). Azelastine also in hi bits allergen-induced, leukotriene-mediated, pyrilamine-resistant bronchoconstriction (oral ID50 = 60 mu g/kg, 2 hr and 120 mu g/kg, 24 hr). This profile suggests that azelastine may be a novel inhibitor of Ca2+-dependent translocation of 5-lipoxygenase from cytosol to the nuclear envelope or a FLAP inhibitor rather than a direct 5-LO inhibitor.