Department of Pharmacy, Kyushu University Hospital, Higashi-ku, Fukuoka, Japan.
Pain. 2009 Dec 15;147(1-3):165-74. doi: 10.1016/j.pain.2009.09.003. Epub 2009 Sep 25.
Oxaliplatin is a key drug in the treatment of advanced metastatic colorectal cancer, but it causes acute peripheral neuropathy (acral paresthesias triggered by exposure to cold) and chronic neuropathy (abnormal of sensory and motor dysfunction). Oxaliplatin is metabolized to oxalate and dichloro(1,2-diaminocyclohexane)platinum (Pt(dach)Cl(2)). Although the chelating of Ca(2+) with oxalate eliminated from oxaliplatin is thought as one of the reasons for the neuropathy, there is little behavioral evidence. In this study, we investigated the involvement of oxalate in the oxaliplatin-induced peripheral neuropathy in rats. Oxaliplatin (4mg/kg, i.p., twice a week) induced cold hyperalgesia/allodynia (cold-plate and acetone tests) in the early phase, and mechanical allodynia (von Frey test) in the late phase. Oxalate (1.3mg/kg, i.p., twice a week) induced the cold hyperalgesia/allodynia in the early phase, but did not induce the mechanical allodynia. On the other hand, Pt(dach)Cl(2) (3.8mg/kg, i.p., twice a week) induced the mechanical allodynia in the late phase, but did not induce the cold hyperalgesia/allodynia. The pre-administration of calcium or magnesium (0.5mmol/kg, i.v.) before oxaliplatin or oxalate prevented the cold hyperalgesia but not mechanical allodynia. However, the treatment with calcium or magnesium after the development of neuropathy could not attenuate the cold hyperalgesia or mechanical allodynia. These findings suggest the involvement of oxalate in oxaliplatin-induced cold hyperalgesia but not mechanical allodynia, and usefulness of prophylactic treatments with calcium and magnesium on the acute peripheral neuropathy.
奥沙利铂是治疗晚期转移性结直肠癌的关键药物，但它会引起急性周围神经病变（接触寒冷时出现的肢端感觉异常）和慢性神经病变（感觉和运动功能障碍异常）。奥沙利铂代谢为草酸和二氯（1,2-二氨基环己烷）铂（Pt(dach)Cl(2)）。尽管从奥沙利铂中排出的草酸与 Ca(2+)的螯合被认为是神经病变的原因之一，但行为证据很少。在这项研究中，我们研究了草酸在奥沙利铂诱导的大鼠周围神经病变中的作用。奥沙利铂（4mg/kg，腹腔注射，每周两次）在早期引起冷痛觉过敏/感觉异常（冷板和丙酮测试），在晚期引起机械性痛觉过敏（von Frey 测试）。草酸（1.3mg/kg，腹腔注射，每周两次）在早期引起冷痛觉过敏/感觉异常，但不会引起机械性痛觉过敏。另一方面，Pt(dach)Cl(2)（3.8mg/kg，腹腔注射，每周两次）在晚期引起机械性痛觉过敏，但不会引起冷痛觉过敏/感觉异常。奥沙利铂或草酸给药前给予钙或镁（0.5mmol/kg，静脉注射）可预防冷痛觉过敏，但不能预防机械性痛觉过敏。然而，在神经病变发展后给予钙或镁治疗不能减轻冷痛觉过敏或机械性痛觉过敏。这些发现表明草酸参与了奥沙利铂引起的冷痛觉过敏，但不参与机械性痛觉过敏，并且钙和镁的预防性治疗对急性周围神经病变有用。
