| Title | Preclinical evaluation of Long Acting Muscarinic Antagonists (LAMAs): comparison of tiotropium and investigational drugs. | | Author(s) | Casarosa P, Bouyssou T, Germeyer S, Schnapp A, Gantner F, Pieper MP | | Institution | BI Pharma GmbH & Co KG. | | Source | J Pharmacol Exp Ther 2009 May 28. | | Abstract | Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation due to 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 M3 receptor (hM3) subtype. Tiotropium bromide (Spiriva((R))) 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 i) affinity towards the different human muscarinic receptor subtypes expressed in CHO cells and kinetics of receptor dissociation, ii) potency in inhibiting the agonist-induced activation of muscarinic receptors through measurement of second messengers, and iii) efficacy and duration of bronchoprotection, as tested in a model of acetylcholine-induced bronchoconstriction in anaesthetized dogs over a time period of 24 hours. All the tested LAMAs showed high affinity and potency towards the hM3 receptor (tiotropium: pA2=10.4; aclidinium: pA2=9.6 and glycopyrrolate: pA2=9.7). However, dissociation half-lives of the LAMAs from the hM3 receptor differed significantly (tiotropium: t1/2=27h, aclidinium: t1/2=10.7h and glycopyrrolate: t1/2=6.1h). In line with their kinetic properties at the hM3, the tested LAMAs provided different levels of bronchoprotection in the in vivo setting 24h after administration (tiotropium=35%, aclidinium=21% and glycopyrrolate=0% at 24h), when applied at equieffective doses. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19478135 |
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