Evaluation of KCB-328, a new IKr blocking antiarrhythmic agent in pacing induced canine atrial fibrillation.
OBJECTIVE
KCB-328 is a new potassium channel blocker, which prolongs action potential duration with exhibition of minimal reverse use dependence. We tested the efficacy and proarrhythmic potential of KCB-328, dofetilide and propafenone in the pacing induced canine model of atrial fibrillation (AF).


METHODS
Mongrel dogs in complete heart block were paced for 1-6 weeks to produce AF, and given KCB-328 or dofetilide. A subset then received propafenone 14+/-3 days after testing the first drug.


RESULTS
KCB-328 prolonged right and left atrial (RA and LA) activation times and AF cycle length (CL), terminating AF in 3 of 6 dogs. RA effective refractory period (ERP) and ventricular ERP and QT interval were prolonged. Dofetilide terminated AF in 1/6 dogs, and increased AF CL and ventricular ERP and QT interval. Dofetilide's reverse use dependency on the QT interval was greater than KCB-328. Propafenone prolonged RA and LA activation times and AF CL and terminated AF in 8 of 9 dogs. One death occurred with dofetilide, none with KCB-328 or propafenone.


CONCLUSIONS
The spectrum of effect of the three drugs differed significantly: propafenone showed the greatest success in AF termination, and both propafenone and KCB-328 appeared less proarrhythmic than dofetilide in this model.
Chandra
Parag
P
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Rosen
Tove S
TS
Yeom
Zi-Ho
ZH
Lee
Kiho
K
Kim
Hak-Yeop
HY
Danilo
Peter
P
Rosen
Michael R
MR
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D010627:Phenethylamines / Q000008:administration & dosage*; D026902:Potassium Channel Blockers / Q000008:administration & dosage; D011405:Propafenone / Q000008:administration & dosage*; D011897:Random Allocation; D026941:Sodium Channel Blockers / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage*
C112304:1-(2-amino-4-methanesulfonamidophenoxy)-2-(N-(3,4-dimethoxyphenethyl)-N-methylamino)ethane; D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D011405:Propafenone; C063533:dofetilide