De Grandis Domenico
Divisione di Neurologia, Ospedale Civile di Rovigo, Rovigo, Italy.
CNS Drugs. 2007;21 Suppl 1:39-43; discussion 45-6. doi: 10.2165/00023210-200721001-00006.
Peripheral neurotoxicity is a major complication associated with the use of chemotherapeutic agents such as platinum compounds, taxanes and vinca alkaloids. The neurotoxicity of chemotherapy depends not only on the anticancer agent(s) used, the cumulative dose and the delivery method, but also on the capacity of the nerve to cope with the nerve-damaging process. The sensory and motor symptoms and signs of neurotoxicity are disabling, and have a significant impact on the quality of life of cancer patients. Moreover, the risk of cumulative toxicity may limit the use of highly effective chemotherapeutic agents. Therefore, prophylaxis and treatment of peripheral neurotoxicity secondary to chemotherapy are major clinical issues. Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism. Some of the properties exhibited by ALC include neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including chemotherapy-induced peripheral neuropathy (CIPN). In several experimental settings, the prophylactic administration of ALC prevented the occurrence of peripheral neurotoxicity commonly induced by chemotherapeutic agents. In animal models of CIPN, ALC administration promoted the recovery of nerve conduction velocity, restored the mechanical nociceptive threshold, and induced analgesia by up-regulating the expression of type-2 metabotropic glutamate receptors in dorsal root ganglia. These results, plus the favourable safety profile of ALC in neuropathies of other aetiologies, have led to the effects of ALC on CIPN being investigated in cancer patients. Preliminary results have confirmed the reasonably good tolerability profile and the efficacy of ALC on CIPN. The present studies support the use of ALC in cancer patients with persisting neurotoxicity induced by paclitaxel or cisplatin treatment.
外周神经毒性是与使用铂类化合物、紫杉烷类和长春花生物碱等化疗药物相关的主要并发症。化疗的神经毒性不仅取决于所使用的抗癌药物、累积剂量和给药方式，还取决于神经应对神经损伤过程的能力。神经毒性的感觉和运动症状及体征会使人丧失能力，并对癌症患者的生活质量产生重大影响。此外，累积毒性的风险可能会限制高效化疗药物的使用。因此，预防和治疗化疗继发的外周神经毒性是主要的临床问题。乙酰左旋肉碱（ALC）是左旋肉碱的乙酰酯，在中间代谢中起重要作用。ALC表现出的一些特性包括神经保护和神经营养作用、抗氧化活性、对线粒体代谢的积极作用以及细胞内膜的稳定作用。ALC已证明在治疗各种病因的神经病变（包括化疗引起的外周神经病变（CIPN））方面具有疗效且耐受性良好。在多个实验环境中，预防性给予ALC可预防化疗药物常见引起的外周神经毒性的发生。在CIPN的动物模型中，给予ALC可促进神经传导速度的恢复，恢复机械性痛觉阈值，并通过上调背根神经节中2型代谢型谷氨酸受体的表达诱导镇痛。这些结果，加上ALC在其他病因神经病变中的良好安全性，促使人们对癌症患者中ALC对CIPN的影响进行研究。初步结果已证实ALC对CIPN具有相当良好的耐受性和疗效。目前的研究支持在接受紫杉醇或顺铂治疗后仍存在神经毒性的癌症患者中使用ALC。
