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Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2009 Nov; Vol. 331 (2), pp. 740-51. Date of Electronic Publication: 2009 Aug 26. - Publication Year :
- 2009
-
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 dissociated slightly faster from M(2) and M(3) receptors than [(3)H]tiotropium but much more slowly than [(3)H]ipratropium. Its association rate for the M(3) receptor was similar to [(3)H]ipratropium and 2.6 times faster than [(3)H]tiotropium. Residence half-life of [(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 concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t(1/2) = 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.
- Subjects :
- Administration, Inhalation
Anesthesia
Animals
Bronchi drug effects
Bronchoconstriction drug effects
CHO Cells
Carbachol pharmacology
Cricetinae
Cricetulus
Dogs
Guinea Pigs
Heart Rate drug effects
Humans
Ipratropium pharmacology
Male
Muscarinic Agonists pharmacology
Muscarinic Antagonists administration & dosage
Receptors, Muscarinic drug effects
Scopolamine Derivatives pharmacology
Stimulation, Chemical
Tiotropium Bromide
Trachea drug effects
Tropanes administration & dosage
Muscarinic Antagonists pharmacology
Tropanes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 331
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 19710368
- Full Text :
- https://doi.org/10.1124/jpet.109.151639