Prince of Wales Clinical School, Barker Street, Randwick, Sydney, NSW 2063, Australia.
Exp Neurol. 2011 Jan;227(1):120-7. doi: 10.1016/j.expneurol.2010.10.002. Epub 2010 Oct 20.
Oxaliplatin is first-line chemotherapy for colorectal cancer, but produces dose-limiting neurotoxicity. Acute neurotoxicity following infusion produces symptoms including cold-triggered fasciculations and cramps, with subsequent chronic neuropathy developing at higher cumulative doses. Axonal excitability studies were undertaken in 15 oxaliplatin-treated patients before and immediately after oxaliplatin infusion to determine whether the mechanisms underlying acute neurotoxicity altered resting membrane potential or Na(+)/K(+) pump function. Excitability properties were assessed before and after maximal voluntary contraction (MVC) of the abductor pollicis brevis. Following oxaliplatin infusion, abnormalities developed in the recovery cycle with refractoriness markedly increased. Following activity, changes developed consistent with axonal hyperpolarization, with proportional changes pre- and post-oxaliplatin in normalized threshold. However, recovery cycle parameters following activity were significantly and disproportionally enhanced post-oxaliplatin, with partial normalization of the recovery cycle curve post-activity. Patients with the most abnormal change in the recovery cycle after infusion demonstrated the greatest changes post-contraction. Prominent abnormalities developed in Na(+) channel-associated parameters in response to natural activity, without significant alteration in axonal membrane potential or Na(+)/K(+) pump function. Findings from the present series suggest that oxaliplatin affects nerve excitability through voltage-dependent mechanisms, with specific effects mediated through axonal Na(+) channel inactivation.
奥沙利铂是结直肠癌的一线化疗药物，但会产生剂量限制的神经毒性。输注后急性神经毒性会产生症状，包括冷触发的束颤和痉挛，随后在更高的累积剂量下发展为慢性神经病。在奥沙利铂输注前和输注后，对 15 名奥沙利铂治疗患者进行了轴突兴奋性研究，以确定急性神经毒性改变静息膜电位或 Na(+)/K(+)泵功能的机制。兴奋性特性在拇短展肌最大随意收缩（MVC）前后进行评估。奥沙利铂输注后，恢复周期出现异常，不应期明显增加。活动后，变化与轴突超极化一致，奥沙利铂前后的归一化阈值发生比例变化。然而，活动后恢复周期参数显著且不成比例地增强，活动后恢复周期曲线部分正常化。输注后恢复周期变化最异常的患者在收缩后表现出最大的变化。在自然活动的情况下，钠（Na+）通道相关参数出现明显异常，而轴突膜电位或 Na(+)/K(+)泵功能没有明显改变。本系列研究结果表明，奥沙利铂通过电压依赖性机制影响神经兴奋性，通过轴突 Na(+)通道失活介导特定作用。
