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

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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.