Selective voltage-gated sodium channel blockers are of growing interest as treatment for pain. For drug development of such compounds, it would be critical to have a biomarker that can be used for proof-of-mechanism. We aimed to evaluate whether drug-induced changes in sodium conductance can be detected in the peripheral nerve excitability profile in 18 healthy subjects. In a randomized, double-blind, 3-way crossover study, effects of single oral doses of 333 mg mexiletine and 300 mg lacosamide were compared with placebo. On each study visit, motor and sensory nerve excitability measurements of the median nerve were performed (predose; and 3 and 6 hours postdose) using Qtrac. Treatment effects were calculated using an analysis of covariance (ANCOVA) with baseline as covariate. Mexiletine and lacosamide had significant effects on multiple motor and sensory nerve excitability variables. Depolarizing threshold electrotonus (TEd₄₀ (40–60 ms)) decreased by mexiletine (estimated difference (ED) −1.37% (95% confidence interval (CI): −2.20, −0.547; P = 0.002) and lacosamide (ED −1.27%, 95% CI: −2.10, −0.443; P = 0.004) in motor nerves. Moreover, mexiletine and lacosamide decreased superexcitability (less negative) in motor nerves (ED 1.74%, 95% CI: 0.615, 2.87; P = 0.004, and ED 1.47%, 95% CI: 0.341, 2.60; P = 0.013, respectively). Strength-duration time constant decreased after lacosamide in motor- (ED −0.0342 ms, 95% CI: −0.0571, −0.0112; P = 0.005) and sensory nerves (ED −0.0778 ms, 95% CI: −0.116, −0.0399; P < 0.001). Mexiletine and lacosamide significantly decrease excitability of motor and sensory nerves, in line with their suggested mechanism of action. Results of this study indicate that nerve excitability threshold tracking can be an effective pharmacodynamic biomarker. The method could be a valuable tool in clinical drug development.

中文翻译：

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美西律和拉考沙胺对健康受试者神经兴奋性的影响：一项随机、双盲、安慰剂对照、交叉研究

选择性电压门控钠通道阻滞剂作为疼痛治疗越来越受到关注。对于此类化合物的药物开发，拥有可用于机制验证的生物标志物至关重要。我们的目的是评估是否可以在 18 名健康受试者的周围神经兴奋性特征中检测到药物引起的钠电导变化。在一项随机、双盲、3 路交叉研究中，比较了单次口服剂量 333 mg 美西律和 300 mg 拉考沙胺与安慰剂的效果。在每次研究访视时，使用 Qtrac 进行正中神经的运动和感觉神经兴奋性测量（给药前；以及给药后 3 和 6 小时）。使用基线作为协变量的协方差分析 (ANCOVA) 计算治疗效果。美西律和拉考沙胺对多个运动和感觉神经兴奋性变量有显着影响。去极化阈电紧张 (TEd₄₀ (40–60 ms)) 被美西律降低（估计差异 (ED) -1.37%（95% 置信区间 (CI)：-2.20，-0.547；P  = 0.002）和拉考沙胺（ED -1.27%，95% CI : −2.10, −0.443; P  = 0.004) in motor nerves. 此外，美西律和拉考沙胺降低了运动神经的超兴奋性（负性较小）（ED 1.74%，95% CI：0.615, 2.87；P  = 0.004，ED 1.47% , 95% CI: 0.341, 2.60; P  = 0.013, respectively). 运动神经（ED −0.0342 ms, 95% CI: −0.0571, −0.0112; P  = 0.005）和感觉神经中的拉考沙胺后强度-持续时间常数降低（ED -0.0778 毫秒，95% CI：-0.116，-0.0399；P < 0.001)。Mexiletine 和 lacosamide 显着降低运动和感觉神经的兴奋性，这与其建议的作用机制一致。这项研究的结果表明，神经兴奋性阈值追踪可以成为一种有效的药效学生物标志物。该方法可能是临床药物开发中的一个有价值的工具。