Oros Avram, Volders Paul G A, Beekman Jet D M, van der Nagel Theo, Vos Marc A
Department of Medical Physiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.
Heart Rhythm. 2006 Nov;3(11):1339-45. doi: 10.1016/j.hrthm.2006.07.017. Epub 2006 Jul 20.
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.
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).
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).
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.
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.
新型化合物AVE0118已被证明可预防和终止持续性心房颤动。AVE0118可阻断I(Kur)、I(KAch)和I(to)，导致心房复极延长，而心室复极无变化。这一发现表明AVE0118可能没有促心律失常的副作用。在实验中，AVE0118对某些特定的室性心律失常具有抗心律失常作用。
本研究的目的是调查AVE0118在患有慢性完全性房室传导阻滞且已知有较高尖端扭转型室性心动过速（TdP）倾向的麻醉犬中的促心律失常和抗心律失常作用。
静脉快速输注（0.5mg/kg/5分钟）和缓慢输注（3或10mg/kg/60分钟）AVE0118。给予多非利特以诱发TdP。记录心电图和单相动作电位。计算左心室单相动作电位时程（MAPD）的短期逐搏变异性（STV）。我们检查了AVE0118是否（1）引起室性心律失常（两种输注方式），（2）预防多非利特诱发的TdP（缓慢输注+30分钟后给予多非利特），以及（3）终止TdP（快速输注）。
在0.55±0.10μg/mL（10分钟时快速输注）时，AVE0118未增加心室复极或诱发TdP；然而，右心房MAPD(50)和MAPD(90)分别显著增加26%±9%和10%±5%（与基线相比，P<.05）。在1.9±0.5μg/mL和6.1±1.2μg/mL（3或10mg/kg/h输注30分钟）时，AVE0118未诱发TdP（0/6和0/4），也未预防多非利特诱发的TdP（6/6和2/2）。多非利特显著增加了所有复极参数，包括STV从2.1±0.4ms增加到4.6±1.8ms（与基线相比，P<.05），而AVE0118未改变这些参数（30分钟后为2.1±0.3ms）。快速输注AVE0118未抑制多非利特诱发的TdP。
在麻醉的慢性完全性房室传导阻滞犬中，心房特异性药物AVE0118无TdP，且对多非利特诱发的尖端扭转型室性心动过速没有抗心律失常特性。
