Effect of Azelastine on the Release and Action of Leukotriene C4 and D4

Abstract

The effect of azelastine on the release of leukotriene C₄ and D₄ (LTC₄ and LTD₄), and the antagonistic action of the drug against the leukotrienes were determined by using in vitro tests and compared with those of ketotifen and chlorpheniramine. Azelastine inhibited LTC₄ and LTD₄ release from guinea pig lung fragments passively sensitized with homologous anti-ovalbumin IgG1-b antibody. The 50% inhibitory concentration (IC₅₀) of azelastine was 6.4 × 10^––5M for a 15-min preincubation or 4.7 × 10^––5M for a 30-min preincubation. Ketotifen and chlorpheniramine were inhibitory only at the highest concentration tested (3 × 10^––4M), giving inhibitions of 35.6 and 21.3%, respectively. Azelastine also inhibited calcium ionophore A23187-induced release of leukotrienes from human polymorphonuclear leukocytes; the IC₅₀ values were 3.6 × 10^––5M for 15 min and 2.3 × 10^––6M for 30 min of preincubation. Ketotifen and chlorpheniramine were inhibitory only after a 30-min preincubation, with IC₅₀ values of 2.1 × 10^––5 and 5.9 × 10^––5M, respectively. The potent inhibition by azelastine might be partly a result of the inhibition of 5-lipoxygenase, since 5-hydroxyeicosatetraenoic acid formation in rat basophilic leukemia cell homogenate was inhibited by azelastine. Pretreatment of guinea pig ileum with azelastine antagonized LTC₄- and LTT-Vinduced contraction of the ileum with IC₅₀ values of 7.0 × 10^––6 and 1.1 × 10^––5M, respectively. Azelastine (with a 50% relaxation concentration of 6.0 × 10^––6M) relaxed the ileum contracted by LTC₄. These antagonistic actions of azelastine were 2–3 times more potent than those of ketotifen. The present results suggest that the anti-allergic action of azelastine may be based on not only inhibition of the release of mediators (including LTC₄/D₄ and histamine), but also antagonism against leukotrienes and histamine.