Calzetta Luigino, Matera Maria Gabriella, Cazzola Mario
Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Eur J Pharmacol. 2015 Aug 15;761:168-73. doi: 10.1016/j.ejphar.2015.05.020. Epub 2015 May 14.
Nowadays there is solid clinical information for combining β2-agonists and anti-muscarinic agents, although the nature (additive or synergistic) of the net clinical result obtained by co-administration of these two classes of bronchodilators is not completely elucidated from a pharmacological point of view. Recent preclinical studies demonstrated that combining a long-acting β2-agonist (LABA) with a long-acting anti-muscarinic agent (LAMA) provides synergistic benefit on airway smooth muscle relaxation, which may have major implications for the use of LABA/LAMA combinations in the treatment COPD. Indeed, the LABA/LAMA synergism has been proved also in patients with moderate-to-severe COPD. Nevertheless, there is still a strong medical need for dose-finding clinical trials designed to identify the most favourable doses of LABA/LAMA combinations able to induce a real synergism. We strongly believe that the Bliss Independence theory represents an effective model for investigating the cross-talk between β2-adrenoreceptor and the muscarinic pathways leading to the synergistic interaction between β2-agonists and anti-muscarinic agents. In any case, the possibility of eliciting a synergistic bronchodilator effect when combining a LABA and a LAMA suggests that the therapeutic approach proposed by GOLD recommendations to only use LABA/LAMA combination in more severe COPD patients who are not controlled by a single bronchodilator should be reconsidered. We support the possibility of an early intervention with low doses of LABA/LAMA combination to optimize bronchodilation and reduce the risk of adverse events that characterize both LABAs and LAMAs, especially when administered at the full doses currently approved for the treatment of COPD.
如今，有确凿的临床信息支持β2受体激动剂与抗毒蕈碱药物联合使用，尽管从药理学角度来看，这两类支气管扩张剂联合使用所产生的净临床效果的性质（相加或协同）尚未完全阐明。最近的临床前研究表明，长效β2受体激动剂（LABA）与长效抗毒蕈碱药物（LAMA）联合使用对气道平滑肌松弛具有协同益处，这可能对LABA/LAMA联合制剂用于慢性阻塞性肺疾病（COPD）的治疗具有重要意义。事实上，在中重度COPD患者中也已证实LABA/LAMA具有协同作用。然而，仍然迫切需要进行剂量探索性临床试验，以确定能够产生真正协同作用的LABA/LAMA联合制剂的最适宜剂量。我们坚信，布利斯独立性理论是研究β2肾上腺素能受体与毒蕈碱途径之间相互作用从而导致β2受体激动剂与抗毒蕈碱药物产生协同相互作用的有效模型。无论如何，LABA与LAMA联合使用时产生协同支气管扩张作用的可能性表明，慢性阻塞性肺疾病全球倡议（GOLD）建议仅在单一支气管扩张剂无法控制的更严重COPD患者中使用LABA/LAMA联合制剂的治疗方法应重新考虑。我们支持早期使用低剂量LABA/LAMA联合制剂进行干预的可能性，以优化支气管扩张效果并降低LABA和LAMA所特有的不良事件风险，尤其是在以目前批准用于治疗COPD的全剂量给药时。
