Chézalviel-Guilbert F, Davy J M, Poirier J M, Weissenburger J
Laboratoire de Pharmacologie, Faculté de Médecine de Saint Antoine, Paris, France.
J Am Coll Cardiol. 1995 Sep;26(3):787-92. doi: 10.1016/0735-1097(95)00234-U.
The arrhythmogenic and electrophysiologic properties of sotalol, a class III antiarrhythmic drug, administered alone and in combination with mexiletine, a class I antiarrhythmic drug, were compared in conscious dogs predisposed to torsade de pointes arrhythmias.
The utility of sotalol is limited by proarrhythmia related to excessive delays in repolarization. The addition of mexiletine may limit the risk of torsade de pointes because it reduced in vitro the sotalol-induced increase in action potential duration.
Two studies were performed in eight hypokalemic dogs (plasma potassium level < or = 3.2 mmol/liter) with chronic atrioventricular block (mean ventricular cycle length, RR 1,100 ms) at 3-day intervals using a crossover protocol. Intravenous sotalol (4.5 + 1.5 mg/kg body weight per h) alone was given for 2 h, or, on another day, an intravenous mexiletine infusion (4.5 + 1.5 mg/kg per h) was begun 30 min before sotalol infusion. Spontaneous ventricular cycle length and QT interval and ventricular effective refractory period at the 1,000-ms pacing cycle length were measured at baseline and 30 min after the onset of each drug infusion. The electrocardiogram (ECG) was continuously monitored for torsade de pointes.
Sotalol plus mexiletine and sotalol alone had a significant (p < or = 0.05) and similar effect on ventricular cycle length (+ 800 +/- 93 vs. + 690 +/- 104 ms [mean +/- SEM]) and ventricular effective refractory period (+ 20 +/- 4 vs. + 25 +/- 4 ms), but sotalol plus mexiletine had a lesser effect on QT interval (+ 20 +/- 6 vs. + 50 +/- 8 ms, p < or = 0.05). Torsade de pointes is less frequent (one of eight dogs vs. six of eight dogs, p = 0.02) with sotalol plus mexiletine than with sotalol alone.
The coadministration of a class Ib agent can reduce the proarrhythmic potential of a class III drug in experimental animals predisposed to torsade de pointes arrhythmias and further suggests the clinical utility of such a strategy.
在易发生尖端扭转型室性心动过速的清醒犬中，比较单独使用Ⅲ类抗心律失常药物索他洛尔以及将其与Ⅰ类抗心律失常药物美西律联合使用时的致心律失常和电生理特性。
索他洛尔的效用受到与复极过度延迟相关的促心律失常作用的限制。加用美西律可能会降低尖端扭转型室性心动过速的风险，因为它在体外可减少索他洛尔诱导的动作电位时程增加。
采用交叉方案，对8只患有慢性房室传导阻滞（平均心室周期长度，RR为1100毫秒）的低钾血症犬（血浆钾水平≤3.2毫摩尔/升）每隔3天进行两项研究。单独静脉注射索他洛尔（每小时4.5 + 1.5毫克/千克体重）2小时，或者在另一天，在注射索他洛尔前30分钟开始静脉输注美西律（每小时4.5 + 1.5毫克/千克）。在基线以及每种药物输注开始后30分钟，测量1000毫秒起搏周期长度时的自发心室周期长度、QT间期和心室有效不应期。持续监测心电图以观察尖端扭转型室性心动过速。
索他洛尔加美西律和单独使用索他洛尔对心室周期长度（分别为+800±93与+690±104毫秒[平均值±标准误]）和心室有效不应期（分别为+20±4与+25±4毫秒）有显著（p≤0.05）且相似的影响，但索他洛尔加美西律对QT间期的影响较小（分别为+20±6与+5 +8毫秒，p≤0.05）。与单独使用索他洛尔相比索他洛尔加美西律时尖端扭转型室性心动过速的发生频率较低（8只犬中有1只发生与8只犬中有只发生，p = 0.02）。
在易发生尖端扭转型室性心动过速的实验动物中，联合使用Ib类药物可降低Ⅲ类药物的促心律失常潜力，并进一步表明了这种策略的临床实用性。
