Proarrhythmia of azimilide and other class III antiarrhythmic agents in the adrenergically stimulated rabbit.
The ventricular proarrhythmic actions of five class III antiarrhythmic agents were compared in the Carlsson rabbit model. In adrenergically stimulated anesthetized rabbits, azimilide, clofilium, dofetilide, sematilide, and d,l-sotalol caused premature ventricular contractions and nonsustained and sustained ventricular tachyarrhythmias (NSVT and SVT) at pharmacologically equivalent intravenous doses that increased QTc intervals 20% (ED20). There were no significant differences between agents in the percentage of rabbits with serious arrhyhthmias at the ED20 doses of 5.2, 0.033, 0.015, 0.66, and 2.8 mg/kg i.v., respectively. Proarrhythmia was dose-dependent. Linear regression analysis of arrhythmia score versus log dose estimated the NSVT doses as 6.2, 0.055, 0.0089, 1.5, and 5.7, respectively. Analysis of arrhythmia states during a 10-min window after infusion when QTc prolongation was 20% showed that the compounds differed significantly in the proportion of time treated rabbits spent in SVT and combined NSVT and SVT. Rabbits treated with azimilide spent significantly less time in SVT and combined NSVT and SVT, followed in order of increasing time by d,l-sotalol, sematilide, clofilium, and dofetilide.
Brooks
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RR
Procter & Gamble Pharmaceuticals, Cincinnati, Ohio 45253-8707, USA. brooks.rr@pg.com
Drexler
A P
AP
Maynard
A E
AE
Al-Khalidi
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H
Kostreva
D R
DR
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011342:Procainamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011817:Rabbits; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010627:Phenethylamines; D010879:Piperazines; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C062818:sematilide; C086123:azimilide; C022799:clofilium; D013015:Sotalol; D008729:Methoxamine; D011342:Procainamide; C063533:dofetilide