, Volume 24, Issue 3-4, pp 217-223

Inhibition of cysteinyl-leukotriene production by azelastine and its biological significance

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Azelastine is a phthalazinone derivative with a wide spectrum of pharmacological activities. Actively sensitized guinea pigs were used to examine the broncholytic effect of azelastinein vivo. Furthermore, the influence of azelastine on the production of arachidonic acid (AA) metabolites was investigatedin vitro and compared to the effects of nordihydroguaiaretic acid (NDGA), indomethacin and ketotifen.In vivo, azelastine protected actively sensitized guinea-pigs against ovalbumin-induced bronchospasm with an ID50 of 0.08 mg/kg orally. Ketotifen was similarly active (ID50=0.05 mg/kg). Antigen-induced contraction of isolated tracheal rings of sensitized guinea-pigs was concentration-dependently inhibited by azelastine and NDGA with IC50-values of 94.1 and 34.2 μmol/l, respectively. Ketotifen exerted only weak inhibitory activity (18% at 100 μmol/l). The arachidonic acid-induced contraction of isolated guinea-pig tracheal rings was also inhibited both by azelastine (IC50=92.6 μmol/l) and NDGA (IC50=20.4 μmol/l). Ketotifen was inactive on this model. Antigen challenge of chopped lung tissue from sensitized guinea-pigs resulted in the release of cysteinyl-leukotrienes (LT) which were identified by reversed phase high pressure liquid chromatography (HPLC) as LTD4 and LTE4. The release of cysteinyl-LT from sensitized guinea-pig lung tissue induced by antigen challenge was concentration-dependently inhibited by azelastine (IC50=35.2 μmol/l) and NDGA (IC50=8.4 μmol/l) but not by ketotifen and indomethacin. By contrast, indomethacin caused a pronounced augmentation of cysteinyl-LT release. The concentration of indomethacin, which augmented cysteinyl-LT release by 50% was 0.19 μmol/l. At the same concentration, indomethacin inhibited the release of 6-keto-PGF and TXB2 by about 50%. Azelastine negligible influenced 6-keto-PGF and slightly diminished TXB2 release from the chopped lung tissue after challenge. Its IC50-values were >2 mmol/l and 443 μmol/l, respectively. NDGA inhibited the release of 6-keto-PGF and TXB2 with IC50-values of 47.3 and 38.3 μmol/l, respectively. Ketotifen was ineffective in inhibiting the release of cyclo-oxygenase products of AA metabolism. It seems likely that inhibition of release of 5-lipoxygenase-derived products of AA metabolism by azelastine contributes to its antiallergic and antiasthmatic activity.

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