Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.
Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.
Pulm Pharmacol Ther. 2019 Jun;56:39-50. doi: 10.1016/j.pupt.2019.03.004. Epub 2019 Mar 12.
Combining a long-acting β-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the LAMA tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.
联合长效β-激动剂（LABA）和长效抗胆碱能药物（LAMA）是治疗慢性阻塞性肺疾病（COPD）患者的基石。在这项研究中，我们研究了 LAMA 噻托溴铵与 LABA 奥达特罗在人中型支气管和小气道收缩张力方面的相互作用。在乙酰胆碱诱导的亚最大收缩张力下评估噻托溴铵和奥达特罗联合的反应。通过跨壁刺激研究组织收缩时，研究了作用持续时间。支气管张力的松弛以对罂粟碱最大反应的百分比表示。通过 Bliss 独立性方法和统一理论分析药物相互作用。噻托溴铵/奥达特罗联合在由乙酰胆碱预收缩的中型支气管和小气道中诱导出显著的协同松弛反应（P <0.05 与预期的相加效应相比），分别增强松弛+22.13 ± 4.42%和+26.31 ± 12.39%。噻托溴铵和奥达特罗的联合还降低了由跨壁刺激引起的气道平滑肌收缩性，降低了 73.60 ± 3.10%。协同作用的程度是强到非常强的，这得到了神经元乙酰胆碱的释放、环磷酸腺苷水平的增加以及对 iberiotoxin 敏感的 KCa 通道的激活的支持。相反，噻托溴铵和奥达特罗之间的相互作用与 M 毒蕈碱受体的活性无关。这些结果表明，噻托溴铵/奥达特罗联合导致人中型支气管和小气道的强大而持久的协同松弛。需要进一步的药理学研究来确认这些结果在临床环境中的适用性。
