Thomas George, Klatt Brian, Blight Andrew
Arch Drug Inf. 2010 Mar;3(1):19-25. doi: 10.1111/j.1753-5174.2009.00027.x.
4-Aminopyridine (fampridine), a potassium channel blocker, has demonstrated efficacy in improving lower extremity strength and walking speed in patients with multiple sclerosis. Since in vitro electrophysiologic studies are recommended for evaluating a drug's potential to prolong the QT interval and induce such cardiac arrhythmias as Torsades de Pointes, we examined the electrophysiologic effects of 4-aminopyridine (0.5, 5.0, 50, and 500 microM) on isolated canine Purkinje fibers. METHODS: Microelectrodes monitored the resting membrane potential, overshoot, amplitude of action potential (AP), and maximal rate of depolarization of the AP upstroke in Purkinje fibers stimulated at 0.5 and 1.0 Hz. RESULTS: None of the above variables were altered in the presence of 4-aminopyridine. The AP duration at 30%, 50%, and 90% repolarization was also monitored, with only the 500-microM concentration at the 1.0-Hz frequency significantly increasing these values with respect to baseline (P < 0.05). However, the small sample size (N = 4) was small. The proportional increases, and their 95% confidence intervals, were 90.8% (-36.4%, 218.0%), 25.8% (11.9%, 39.7%), and 22.0% (14.9%, 29.1%) for APD 30%, 50%, and 90% repolarization, respectively. Reverse rate dependence was not observed, suggesting inhibition of ion channels other than those contributing to QT interval prolongation.
4-氨基吡啶（法吡拉定）是一种钾通道阻滞剂，已证明其在改善多发性硬化症患者下肢力量和步行速度方面具有疗效。由于推荐进行体外电生理研究以评估药物延长QT间期和诱发如尖端扭转型室性心动过速等心律失常的可能性，我们研究了4-氨基吡啶（0.5、5.0、50和500微摩尔）对离体犬浦肯野纤维的电生理作用。方法：微电极监测在0.5和1.0赫兹刺激下浦肯野纤维的静息膜电位、超射、动作电位（AP）幅度和AP上升支的最大去极化速率。结果：在4-氨基吡啶存在的情况下，上述变量均未改变。还监测了复极化30%、50%和90%时的AP持续时间，仅在1.0赫兹频率下500微摩尔浓度相对于基线显著增加了这些值（P<0.05）。然而，样本量较小（N = 4）。复极化30%、50%和90%时APD的比例增加及其95%置信区间分别为90.8%（-36.4%，218.0%）、25.8%（11.9%，39.7%）和22.0%（14.9%，29.1%）。未观察到反向频率依赖性，提示抑制的离子通道不同于导致QT间期延长的离子通道。
