Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics.

Abstract

We defined the contribution of histamine and leukotrienes to allergen-induced airway obstruction in asthmatics; 12 subjects with allergic asthma underwent identical allergen bronchoprovocations on four occasions. At a control session, all subjects displayed early (EAR) and late asthmatic (LAR) reactions. The mean (+/- SE) drop in FEV1 during EAR (0-2 h) and LAR (2-12 h) was 29 +/- 2% and 28 +/- 4%, respectively. Thereafter, the influence of 1 wk randomized pretreatment with the leukotriene receptor antagonist zafirlukast (Accolate) (80 mg twice daily), the antihistamine loratadine (10 mg twice daily), and the combination of both antagonists was assessed. Expressed as AUC FEV1 in percent of the control reaction, zafirlukast reduced the response during EAR and LAR by 62 +/- 11% and 55 +/- 12%, respectively (p < 0.05 versus control). Loratadine inhibited EAR and LAR by 25 +/- 14% and 40 +/- 16%, respectively (p < 0.05 versus control). Zafirlukast was significantly more effective than loratadine during EAR but not during LAR. The combination of zafirlukast and loratadine reduced the AUC FEV1 during EAR and LAR further, by 75 +/- 8% and 74 +/- 14%, respectively (p < 0.05 versus control). The combination was significantly (p < 0.05) more effective than either drug alone during the LAR. The findings indicate that leukotrienes and histamine together mediate the major part of both the EAR and the LAR following exposure of asthmatics to allergen. Combination of leukotriene antagonism and antihistamines may represent a new strategy for treatment of airway obstruction in asthma.

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

“…The protection provided by all three types of treatment during LAR was about the same as that observed previously using loratadine and zafirlukast [17], but there seemed to be stronger effects during EAR. This was true particularly for the antihistamines.…”

“…As the protection is not complete, ranging from 50 to 75%, the question is raised whether the combination with an anti-histamine can further attenuate allergen responses. Indeed, concurrent treatment with zafirlukast and the anti-histamine loratadine was capable of enhancing the protection against allergen-induced bronchoconstriction, compared to the individual agents [17]. However, the dose of the anti-leukotriene employed in this study was four-times greater than that recommended for clinical use.…”

“…However, the protection achieved by the compounds used, either alone or in combination, was at least as high as that achieved previously, probably due to the different potency of the compounds used. Compared to zafirlukast and loratadine [17], the stronger protection by azelastine on the EAR was also observed when combined with montelukast. Whether the combination of an anti-leukotriene and an anti-histamine is a realistic therapeutic option in patients with allergic airway diseases, remains, however, to be proven [7,28,29].…”

“…At present, one other study is available which has investigated the effect of combined treatment with an anti-histamine and an anti-leukotriene on EAR and LAR in asthma [17]. Treatment was performed for one week with zafirlukast 80 mg twice daily, loratadine 10 mg twice daily, or a combination of the two.…”

Asma e rinite alérgica como expressão de uma única doença: um paradigma em construção

“…Este efeito sinérgico também foi observado agregando-se anti-histamínicos a antileucotrienos 25,26 . Outro reforço a essas evidências indiretas foi proporcionado pelo estudo conhecido pela sigla ETAC (Early Treatment of Atopic Child), que envolveu um expressivo número de crianças, cujos resultados animadores indicaram que o uso contínuo de anti-histamínicos foi capaz de reduzir o surgimento subseqüente de asma 27 .…”