Characterization of Aclidinium Bromide, a Novel Inhaled Muscarinic Antagonist, with Long Duration of Action and a Favorable Pharmacological Profile

Abstract

Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. Aclidinium showed subnanomolar affinity for the five human muscarinic receptors (M 1 -M 5 3 H]aclidinium at the M 2 receptor was shorter than at the M 3 receptor, demonstrating kinetic selectivity for the M 3 receptor. In isolated guinea pig trachea, aclidinium showed comparable potency to ipratropium and tiotropium, faster onset of action than tiotropium, and duration of action similar to tiotropium and significantly longer than ipratropium. Nebulized aclidinium inhibited bronchoconstriction induced by acetylcholine in guinea pigs in a concentrationdependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t 1/2 ϭ 29 h) was much longer than ipratropium (8 h) but shorter than tiotropium (64 h). In dogs, aclidinium induced a smaller and more transient increase in heart rate than tiotropium at comparable supratherapeutic doses. Therefore, under these conditions, aclidinium showed a greater therapeutic index than tiotropium (4.2 versus 1.6). These results indicate that aclidinium is a potent muscarinic antagonist with a fast onset of action, a long duration of effect, and a favorable cardiovascular safety profile.Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease characterized by chronic airflow obstruction attributed to long-term exposure to inhaled noxious gases and particles, most often related to cigarette smoking that is not fully reversible after bronchodilator therapy (www.goldcopd.org) (Rabe et al., 2007). Recent projections from the World Health Organization predict that COPD will become the fourth most common cause of death by 2030 and the third most common cause of chronic disability by 2020 (Lopez et al., 2006;Mathers and Loncar, 2006). Acetylcholine released by parasympathetic nerves regulates airway constriction, mucus secretion, and vasodilation through its interaction with muscarinic receptors localized in smooth muscle, mucosal glands, pulmonary vasculature, and nerve endings of the lungs (Belmonte, 2005).There are five subtypes of the muscarinic receptors, M 1 to M 5 , that are members of the superfamily of G-protein-cou-

Ligand Residence Time at G-protein–Coupled Receptors—Why We Should Take Our Time To Study It

“…Although blocking M 1 /M 3 receptor subtypes would counteract airway limitation in chronic obstructive pulmonary disease patients, blocking presynaptic M 2 autoreceptors would be detrimental for this purpose and systemic M 2 antagonism would increase the risk of tachycardia as side effect. The difficulties in finding muscarinic receptor subtype-selective ligands were successfully overcome by the development of ipratropium, a shortacting muscarinic antagonist, and long-acting muscarinic antagonists (LAMAs) tiotropium (Disse et al, 1993) and the novel aclidinium (Gavaldà et al, 2009) and glycopyrronium (Casarosa et al, 2009) that are particularly indicated for maintenance therapy. All these drugs dissociate more rapidly from M 2 than from M 3 receptors.…”

Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits

“…Nevertheless, we are confident that investigations performed on healthy preparations can provide useful insights into the regulation of the cough reflex as well as hints for further studies on this reflex and possibly for the development of novel antitussive strategies. Preclinical studies have indicated that aclidinium may have a faster onset of action than tiotropium, but comparable protective effects on bronchoconstriction [32,33]. In addition, since it has been reported that the clinical dose of tiotropium 18 mg is very low with respect to the clinical dose of aclidinium 400 mg [14], we made an attempt to find the isoeffective dose of the two drugs as far as bronchodilation is concerned.…”

“…In addition, since it has been reported that the clinical dose of tiotropium 18 mg is very low with respect to the clinical dose of aclidinium 400 mg [14], we made an attempt to find the isoeffective dose of the two drugs as far as bronchodilation is concerned. The potency of these two LAMAs has been previously assessed in guinea pigs [32,33]. Aclidinium 100 mg/mL and tiotropium 10 mg/mL produced 1 h post-administration equi-effective (97e98%) inhibition of acetylcholine-induced bronchoconstriction that lasted several hours.…”

“…1, we found that the adequate concentration of each drug to produce similar decreases in R L (range 90e95%) was 4 mg/mL of aclidinium and 200 mg/mL of tiotropium. Since these muscarinic receptor antagonists are long-acting [33], it was necessary to use one animal for each drug concentration, i.e. three rabbits for each drug.…”

“…In the final solution, the concentration of DMSO was less than 5%. Tiotropium bromide monohydrate (SigmaAldrich) was dissolved in 0.9% NaCl solution at the desired concentrations [7,33]. All drugs were freshly prepared on the day of administration.…”