Hamamatsu Pharma Research, Inc. Hamamatsu Shizuoka Japan.
Pharmacol Res Perspect. 2016 Feb 8;4(1):e00216. doi: 10.1002/prp2.216. eCollection 2016 Feb.
Oxaliplatin is a first-line treatment for colorectal cancer. However, shortly following treatment, cold-evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin-induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy-induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water ("cold hypersensitivity") was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin-induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin-treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin-induced peripheral neuropathy.
奥沙利铂是结直肠癌的一线治疗药物。然而，在治疗后不久，四肢会出现冷诱发过敏，随着时间的推移，疼痛会导致奥沙利铂的剂量需要大幅减少甚至停止。目前，对于奥沙利铂引起的周围神经病变还没有有效的治疗方法，这部分是由于将临床前啮齿动物化疗诱导周围神经病变模型中的发现转化为临床有用的治疗方法存在困难。非人类灵长类动物（NHP）与啮齿动物相比在进化上更接近人类，可能会表现出与人类相似的药物反应。在食蟹猴中，静脉注射奥沙利铂（5mg/kg）后 3 天，观察到尾巴撤回潜伏期对 10°C 水的显著降低（“冷过敏”）。单次给予度洛西汀（30mg/kg，po）可改善奥沙利铂引起的冷过敏，而普瑞巴林（30mg/kg，po）和曲马多（30mg/kg，po）则没有。相比之下，在大鼠中，在首次注射奥沙利铂（5mg/kg，ip，每天一次，两次注射）后 3 天，未观察到明显的冷过敏或对后爪施加丙酮的反应性增加。因此，在大鼠中，在首次治疗后 17 天，进行了 6 次奥沙利铂治疗后进行了测试。所有镇痛药（30mg/kg，po）均显著改善了大鼠的冷过敏。奥沙利铂处理的猕猴中的镇痛药活性与临床发现一致。目前的结果表明，NHP 可以作为一种桥梁物种，提高将临床前发现转化为奥沙利铂引起的周围神经病变的临床有用治疗方法的可翻译性。
