PT  - JOURNAL ARTICLE
AU  - Amadeu Gavaldà
AU  - Montserrat Miralpeix
AU  - Israel Ramos
AU  - Raquel Otal
AU  - Cristina Carreño
AU  - Marisa Viñals
AU  - Teresa Doménech
AU  - Carla Carcasona
AU  - Blanca Reyes
AU  - Dolors Vilella
AU  - Jordi Gras
AU  - Julio Cortijo
AU  - Esteban Morcillo
AU  - Jesús Llenas
AU  - Hamish Ryder
AU  - Jorge Beleta
TI  - Characterization of Aclidinium Bromide, a Novel Inhaled Muscarinic Antagonist, with Long Duration of Action and a Favorable Pharmacological Profile
AID  - 10.1124/jpet.109.151639
DP  - 2009 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 740--751
VI  - 331
IP  - 2
4099  - http://jpet.aspetjournals.org/content/331/2/740.short
4100  - http://jpet.aspetjournals.org/content/331/2/740.full
SO  - J Pharmacol Exp Ther2009 Nov 01; 331
AB  - 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 (M1–M5). [3H]Aclidinium dissociated slightly faster from M2 and M3 receptors than [3H]tiotropium but much more slowly than [3H]ipratropium. Its association rate for the M3 receptor was similar to [3H]ipratropium and 2.6 times faster than [3H]tiotropium. Residence half-life of [3H]aclidinium at the M2 receptor was shorter than at the M3 receptor, demonstrating kinetic selectivity for the M3 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 concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t1/2 = 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. © 2009 by The American Society for Pharmacology and Experimental Therapeutics