Atrial-specific drug AVE0118 is free of torsades de pointes in anesthetized dogs with chronic complete atrioventricular block.
BACKGROUND
The novel compound AVE0118 has been shown to prevent and terminate persistent atrial fibrillation. AVE0118 blocks I(Kur), I(KAch), and I(to), leading to prolongation of atrial repolarization with no change in ventricular repolarization. This finding suggests that AVE0118 may be devoid of proarrhythmic side effects. Experimentally, AVE0118 has been antiarrhythmic against some specific ventricular arrhythmias.


OBJECTIVE
The purpose of this study was to investigate the proarrhythmic and antiarrhythmic effects of AVE0118 in anesthetized dogs with chronic complete AV block, known for a high proclivity for torsades de pointes (TdP).


METHODS
AVE0118 was administered intravenously as a fast infusion (0.5 mg/kg/5 min) and a slow infusion (3 or 10 mg/kg/60 min). Dofetilide was given to induce TdP. ECG and monophasic action potentials were recorded. Short-term beat-to-beat variability (STV) of the left ventricular monophasic action potential duration (MAPD) was calculated. We examined whether AVE0118 (1) caused ventricular proarrhythmia (both infusions), (2) prevented dofetilide-induced TdP (slow infusion + dofetilide after 30 minutes), and (3) abolished TdP (fast infusion).


RESULTS
At 0.55 +/- 0.10 microg/mL (fast infusion at 10 minutes), AVE0118 did not increase ventricular repolarization or induce TdP; however, right atrial MAPD(50) and MAPD(90) were significantly increased by 26% +/- 9% and 10% +/- 5%, respectively (P <.05 vs baseline). At 1.9 +/- 0.5 microg/mL and 6.1 +/- 1.2 microg/mL (30 minutes of 3 or 10 mg/kg/h), AVE0118 did not induce TdP (0/6 and 0/4) nor prevent dofetilide-induced TdP (6/6 and 2/2). Dofetilide significantly increased all repolarization parameters, including STV from 2.1 +/- 0.4 ms to 4.6 +/- 1.8 ms (P <.05 vs baseline), which were not changed by AVE0118 (to 2.1 +/- 0.3 ms after 30 minutes). Rapid infusion of AVE0118 did not suppress dofetilide-induced TdP.


CONCLUSIONS
In the anesthetized chronic complete AV block dog, the atrial-specific drug AVE0118 is free of TdP and has no antiarrhythmic properties against dofetilide-induced torsades de pointes.
Oros
Avram
A
Department of Medical Physiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. aoros@hotmail.com
Volders
Paul G A
PG
Beekman
Jet D M
JD
van der Nagel
Theo
T
Vos
Marc A
MA
D000200:Action Potentials / Q000187:drug effects*; D000768:Anesthesia, General; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006327:Heart Block / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D010627:Phenethylamines / Q000633:toxicity; D013449:Sulfonamides / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced / Q000517:prevention & control; D016896:Treatment Outcome
C501729:AVE 0118; D001713:Biphenyl Compounds; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide