Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands.
J Pharmacol Exp Ther. 2014 Feb;348(2):303-10. doi: 10.1124/jpet.113.208439. Epub 2013 Dec 4.
The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.
新型每日一次β₂-激动剂支气管扩张药奥达特罗在过敏哮喘患者中已显示出超过 24 小时的疗效。这些患者常见的胆碱能张力增加可能会降低β₂-激动剂的疗效。这为奥达特罗与长效抗胆碱能药物噻托溴铵联合治疗提供了依据，以实现每日一次的治疗方案。在豚鼠中，我们评估了奥达特罗单独使用和与噻托溴铵联合使用对组胺诱导气道反应性的保护作用，组胺诱导的气道反应性部分由胆碱能反射机制介导。此外，我们使用豚鼠过敏性哮喘模型，研究了这些支气管扩张剂对过敏原诱导的早期（EAR）和晚期（LAR）哮喘反应、对组胺的气道高反应性（AHR）和气道炎症的协同作用。结果表明，在噻托溴铵存在的情况下，奥达特罗对组胺诱导的支气管收缩的保护作用协同增强并延长。此外，噻托溴铵协同增强了奥达特罗逆转 EAR 后 AHR 以及对 AHR 的保护作用。奥达特罗和噻托溴铵在抑制过敏原诱导的 EAR 和 LAR 的程度方面非常有效，并且这两种反应均被这两种药物的联合治疗完全抑制。值得注意的是，这些作用与气道炎症细胞浸润无关。总之，这些结果表明，奥达特罗和噻托溴铵联合治疗可能对治疗过敏原诱导的哮喘反应和 AHR 非常有效。
