Cazzola Mario, Calzetta Luigino, Rogliani Paola, Puxeddu Ermanno, Facciolo Francesco, Matera Maria Gabriella
University of Rome Tor Vergata, Department of Systems Medicine, Chair of Respiratory Medicine, Rome, Italy; University of Rome Tor Vergata, Department of Systems Medicine, Respiratory Pharmacology Research Unit, Rome, Italy; University Hospital Tor Vergata, Division of Respiratory Medicine, Rome, Italy.
University of Rome Tor Vergata, Department of Systems Medicine, Respiratory Pharmacology Research Unit, Rome, Italy.
Pulm Pharmacol Ther. 2016 Feb;36:1-9. doi: 10.1016/j.pupt.2015.11.004. Epub 2015 Nov 30.
To date there is emerging clinical evidence to add long-acting anti-muscarinic agents (LAMAs) with inhaled corticosteroid (ICSs) in asthma, but the pharmacological rationale that supports the use of such a combination has not yet been explained. The aim of this study was to pharmacologically investigate the interaction between the ICS beclomethasone and the LAMA glycopyrronium on the human airway smooth muscle (ASM) tone.
We investigated the rapid non-genomic bronchorelaxant effect of beclomethasone and glycopyrronium, administered alone and in combination, in human isolated bronchi and bronchioles. Experiments were carried out also in passively sensitized airways and the pharmacological analysis of drug interaction was performed by Bliss Independence method.
The acute administration of beclomethasone and glycopyrronium induced a significant relaxation of passively sensitized ASM pre-contracted with histamine, by causing submaximal/maximal inhibition of the contractile tone in both medium bronchi and bronchioles. Beclomethasone was characterized by a rapid non-genomic and epithelium independent bronchorelaxant effect. In passively sensitized airways, this effect seemed to be dependent by the activation of a Gsα--cyclic adenosine monophosphate (cAMP)--protein kinase A cascade. While no synergistic interaction was detected in non-sensitized bronchi, the beclomethasone/glycopyrronium combination synergistically enhanced the relaxation of passively sensitized medium and small bronchi. The synergistic interaction between beclomethasone and glycopyrronium was associated with an increase of cAMP concentrations.
Our study provides for the first time the pharmacological rationale for combining low doses of an ICS plus a LAMA.
迄今为止，有新出现的临床证据表明在哮喘治疗中可将长效抗毒蕈碱药物（LAMA）与吸入性糖皮质激素（ICS）联用，但支持使用这种联合用药的药理学原理尚未得到解释。本研究的目的是从药理学角度研究ICS倍氯米松与LAMA格隆溴铵对人气道平滑肌（ASM）张力的相互作用。
我们研究了倍氯米松和格隆溴铵单独及联合给药对人离体支气管和细支气管的快速非基因组支气管舒张作用。还在被动致敏气道中进行了实验，并采用布利斯独立法对药物相互作用进行了药理学分析。
倍氯米松和格隆溴铵急性给药可使预先用组胺预收缩的被动致敏ASM显著舒张，在中等大小支气管和细支气管中均引起收缩张力的次最大/最大抑制。倍氯米松的特点是具有快速非基因组且不依赖上皮的支气管舒张作用。在被动致敏气道中，这种作用似乎依赖于Gsα - 环磷酸腺苷（cAMP） - 蛋白激酶A级联反应的激活。虽然在未致敏支气管中未检测到协同相互作用，但倍氯米松/格隆溴铵组合可协同增强被动致敏的中、小支气管的舒张作用。倍氯米松和格隆溴铵之间的协同相互作用与cAMP浓度的增加有关。
我们的研究首次为低剂量ICS加LAMA联合用药提供了药理学依据。
