Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile.
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.
Gavaldà
Amadeu
A
Almirall, Biology Department, R&D Center, Sant Feliu de Llobregat, Barcelona, Spain.
Miralpeix
Montserrat
M
Ramos
Israel
I
Otal
Raquel
R
Carreño
Cristina
C
Viñals
Marisa
M
Doménech
Teresa
T
Carcasona
Carla
C
Reyes
Blanca
B
Vilella
Dolors
D
Gras
Jordi
J
Cortijo
Julio
J
Morcillo
Esteban
E
Llenas
Jesús
J
Ryder
Hamish
H
Beleta
Jorge
J
D000280:Administration, Inhalation; D000758:Anesthesia; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D009241:Ipratropium / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects; D012602:Scopolamine Derivatives / Q000494:pharmacology; D013268:Stimulation, Chemical; D000069447:Tiotropium Bromide; D014132:Trachea / Q000187:drug effects; D014326:Tropanes / Q000008:administration & dosage / Q000494:pharmacology*
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D014326:Tropanes; D002217:Carbachol; D009241:Ipratropium; C542859:aclidinium bromide; D000069447:Tiotropium Bromide