Preclinical Evaluation of Long-Acting Muscarinic Antagonists: Comparison of Tiotropium and Investigational Drugs
Preclinical Evaluation of Long-Acting Muscarinic Antagonists: Comparison of Tiotropium and Investigational Drugs
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DOI：
10.1124/jpet.109.152470
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发表时间：
2009-08-01
影响因子：
3.5
通讯作者：
Pieper, Michael
中科院分区：
文献类型：
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作者：
Casarosa, Paola;Bouyssou, Thierry;Pieper, Michael
慢性阻塞性肺疾病(COPD)的特征是由于呼吸道持续的炎症过程导致进行性气流受限。增加的胆碱能张力主要通过激活人M受体(HM(3))亚型介导COPD不同的病理生理特征，如支气管收缩和粘液高分泌。噻托溴铵(Spiriva)是一种公认的毒鼠碱拮抗剂，用于慢性阻塞性肺疾病的药理治疗，每天一次。噻托溴铵具有持续的支气管扩张作用，其原理在于它与HM3受体的缓慢解离。在这项研究中，我们进行了一项全面的临床前比较，硫托品与其他长效毒碱拮抗剂(LAMA)目前在临床上开发，即阿立溴铵和甘草次酸。不同的M受体拮抗剂的特点是：1)与中国仓鼠卵巢细胞表达的不同的人M受体亚型的亲和力和受体解离动力学；2)通过测量第二信使抑制激动剂诱导的M受体的激活；3)保护支气管的有效性和持续时间，在麻醉狗的乙酰胆碱诱导的支气管收缩模型中进行了测试。所有受试LAMA对HM3受体都表现出高亲和力和效力(硫托溴铵，pA(2)=10.4；acliddium，pA(2)=9.6；和甘草酸，pA(2)=9.7)。然而，LAMAS与HM3受体的解离半衰期有显著差异(噻托溴铵，t1/2=27h；acliddium，t1/2=10.7h；和甘草次酸，t1/2=6.1h)。根据它们在HM3中的动力学特性，受试LAMA在体内环境中提供了不同程度的支气管保护作用，当应用相同剂量时，给药后24小时(噻托溴铵=35%，aclidine=21%，24 h时甘草次酸=0%)。
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation caused by persistent inflammatory processes in the airways. An increased cholinergic tone mediates different pathophysiological features of COPD, such as bronchoconstriction and mucus hypersecretion, mostly through activation of the human muscarinic M 3 receptor (hM(3)) subtype. Tiotropium bromide (Spiriva) is a well established muscarinic antagonist in the pharmacological management of COPD with a once-daily posology. The rationale behind the sustained bronchodilation obtained with tiotropium consists in its slow dissociation from hM3 receptors. In this study, we performed a comprehensive preclinical comparison of tiotropium with other long-acting muscarinic antagonists (LAMAs) currently in clinical development, namely aclidinium bromide and glycopyrrolate. The different muscarinic antagonists were characterized for their 1) affinity toward the different human muscarinic receptor subtypes expressed in Chinese hamster ovary cells and kinetics of receptor dissociation, 2) potency in inhibiting the agonist-induced activation of muscarinic receptors through measurement of second messengers, and 3) efficacy and duration of bronchoprotection, as tested in a model of acetylcholine-induced bronchoconstriction in anesthetized dogs over a period of 24 h. All of the tested LAMAs showed high affinity and potency toward the hM3 receptor (tiotropium, pA(2) = 10.4; aclidinium, pA(2) = 9.6; and glycopyrrolate, pA(2) = 9.7). However, dissociation half-lives of the LAMAs from the hM3 receptor differed significantly (tiotropium, t1/2 = 27 h; aclidinium, t1/2 = 10.7 h; and glycopyrrolate, t1/2 = 6.1 h). In line with their kinetic properties at the hM3, the tested LAMAs provided different levels of bronchoprotection in the in vivo setting 24 h after administration (tiotropium = 35%, aclidinium = 21%, and glycopyrrolate = 0% at 24 h) when applied at equieffective doses.