Inhibition of Allergic and Nonallergic Leukotriene C4 Formation and Histamine Secretion by Azelastine: Implication for Its Mechanism of Action

Abstract

Azelastine, an orally effective antiasthmatic agent, has been reported to inhibit antihistamine-resistant, leukotriene-mediated allergic bronchoconstriction in guinea pigs. This suggests that azelastine might act through inhibition of leukotriene (LT) C₄/D₄ synthesis. We have examined the effect of azelastine on allergic and nonallergic histamine secretion and LTC₄ formation. Azelastine and the known 5-lipoxygenase inhibitors, nordihydroguaiaretic acid and AA-861, exerted concentration-dependent inhibition of allergic LTC₄ formation in chopped lung tissue from actively sensitized guinea pigs and calcium ionophore A23187-stimulated LTC₄ synthesis in mixed peritoneal cells from rats. Azelastine also produced concentration-dependent inhibition of allergic and nonallergic histamine secretion from rat peritoneal mast cells. The ability of azelastine to inhibit allergic and nonallergic histamine secretion and LTC₄ generation may contribute to its mode of action and its therapeutic efficacy.