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Europace 2004 6(5):384-391; doi:10.1016/j.eupc.2004.05.006
© 2004 by European Society of Cardiology
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Evaluation of KCB-328, a new IKr blocking antiarrhythmic agent in pacing induced canine atrial fibrillation

Parag Chandraa,b, Tove S. Rosenc, Zi-Ho Yeomd, Kiho Leed, Hak-Yeop Kimd, Peter Danilo, Jra,b and Michael R. Rosena,b,c,*

aDepartment of Pharmacology, College of Physicians and Surgeons of Columbia University New York, USA; bThe Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University New York, USA; cDepartment of Pediatrics, College of Physicians and Surgeons of Columbia University New York, USA; dC&C Research Laboratories, 146-141, Annyung-ri, Taean-ub, Hwasung-si Kyunggi-do 445-970, South Korea

HYPOTHESIS: 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.

CONCLUSION: 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.

Key Words: chronic heart block, antiarrhythmic drugs, potassium channel blockade, proarrhythmia, effective refractory period, atrial fibrillation

*Corresponding author. College of Physicians & Surgeons of Columbia University, Department of Pharmacology, 630 West 168 Street, PH7W-321, New York, NY 10032, USA. Tel.: +1-212-305-8754; fax: +1-212-305-8351. E-mail address: mrr1{at}columbia.edu (M.R. Rosen).


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