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

Abstract

Azelastine is a phthalazinone derivative with a wide spectrum of pharmacological activities. Actively sensitized guinea pigs were used to examine the broncholytic effect of azelastine in vivo. Furthermore, the influence of azelastine on the production of arachidonic acid (AA) metabolites was investigated in 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 mumol/l, respectively. Ketotifen exerted only weak inhibitory activity (18% at 100 mumol/l). The arachidonic acid-induced contraction of isolated guinea-pig tracheal rings was also inhibited both by azelastine (IC50 = 92.6 mumol/l) and NDGA (IC50 = 20.4 mumol/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 mumol/l) and NDGA (IC50 = 8.4 mumol/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 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of azelastine on the early allergic response

“…Support for this hypothesis comes from in vitro studies that bave shown that azelastine inhibits antigen-induced production of LTC4 and LTD4 by human and guinea pig lung fragments [10,24,35]. These studies suggest that azelastine achieves its effect by inhibiting the 5-lipoxygenase pathway of arachidonic acid metabolism in these cells [34]. If azelastine truly has 5-lipoxygenase inhibitory properties, then it might also be directly inhibiting that pathway of arachidonic acid metabolism in nasal mast cells without affecting the cyclo-oxygenase pathway or the process of degranulation and histamine release.…”

Effect of azelastine, montelukast, and their combination on allergen-induced bronchoconstriction in asthma

“…In addition to, or as a consequence of their anti-histaminic activity, anti-histamines might also reduce the release of other mediators, including leukotrienes [23,24]. Azelastine shows many of these properties [25][26][27], among which decreased activation of mast cells coupled with decreased release of cysteinyl leukotrienes seems to be of particular relevance for the present study. Table 1 demonstrates that azelastine caused a two-fold reduction of the maximal response of FEV 1 during EAR, and montelukast an about four-fold reduction.…”

Effect of azelastine on substance P content in bronchoalveolar and nasal lavage fluids of patients with allergic asthma

“…Azelastine, a new phthalazinone derivative, is characterized by a long-lasting anti-allergic action and shows a broad spectrum of pharmacological activities promising for the treatment of bronchial asthma and allergic rhinitis [8]. It is a potent histamine HI-receptor antagonist which also inhibits the release of platelet activating factor and leukotrienes [8,9]. It has been suggested that the effect of azelastine may be mediated via suppression of radical generation and inhibition of calcium mobilization [10][11][12].…”