温经通络法外用对靶向治疗药物相关手足皮肤反应及周围神经病变的干预作用及机理研究

Targeted agents associated hand-foot skin reaction (HFSR) and peripheral neuropathy (PN) are common clinical complications. These complications seriously reduce patients’ quality of life and curative effects of targeted agents. In western medicine, there is still no standard effective treatment. Previous Eleven Five-year National studies showed that wenjing tongluo herbs local administration could effectively relieve HFSR and PN. However, no in vivo experiment to date has investigated effects of herb medicine on targeted agents associated HFSR and PN. In this research, effects of wenjing tongluo herbs local administration are evaluated in animal models of targeted agents associated HFSR and PN. Pain behavior tests and neural electrophysiological observations are performed. Ultra-structural changes of dorsal root ganglia, sciatic nerves and epidermis are observed, related cytokines (FasL, Fas, et al) expression are evaluated. Glia activation and related cytokines(GFAP, TNF-α, et al), neurotransmitters and receptors(CGRP,TRPV1, et al) expression in spinal dorsal horn are evaluated. Targets and mechanisms of local administrated herbs are investigated. This research will provide scientific basis of wenjing tongluo herbs local administration in relieving targeted agents associated HFSR and PN. Traditional Chinese Medicine luobing theory will be enriched and mechanisms of wenjing tongluo herbs will be explored.

靶向治疗药物相关的手足皮肤反应和周围神经病变是临床常见的并发症，严重影响患者的生活质量和治疗疗效，目前西医尚无规范有效防治方法。课题组前期国家“十一五”临床研究表明，温经通络法外用对手足皮肤反应和周围神经病变具有良好的疗效及安全性。但采用动物整体实验研究，目前我国尚属空白。本项研究分别采用靶向药物所致手足皮肤反应和周围神经病变动物模型，通过痛行为学观测、神经电生理学观测、背根神经节、坐骨神经及表皮超微结构改变及相关细胞因子（FasL、Fas等）表达，脊髓胶质细胞激活及相关细胞因子(GFAP、TNF-α等)、神经递质及受体（CGRP、TPRV等）表达，评价温经通络法外用对手足皮肤反应和周围神经病变的干预作用，并探讨外用中药的作用靶点和机理。为临床中医药外用防治手足皮肤反应和周围神经病变提供指导性的科学依据，并进一步丰富中医“络病”理论，探索“温经通络”作用机理。

靶向治疗药物相关的手足皮肤反应和周围神经病变是临床常见的并发症，严重影响患者的生活质量和治疗疗效，目前西医尚缺乏规范有效防治方法。本项研究基于前期国家“十一五”临床研究结果，温经通络法外用对手足皮肤反应和周围神经病变具有良好的疗效和安全性，采用动物整体实验研究评价中药药效并探索作用机理，填补我国空白。研究结果表明温经通络法可明显缓解舒尼替尼所致手足皮肤反应痛觉过敏，逆转表皮超微结构改变及相关细胞因子FasL和Fas表达，中药调节基因富集在趋化因子介导的信号通路；明显缓解硼替佐米或索拉非尼所致的周围神经毒性疼痛，逆转背根神经节神经元核型改变，降低脊髓胶质细胞激活及疼痛相关神经递质CGRP和P物质表达，多组学关联分析表明中药调节基因及代谢物在药物代谢-细胞色素P450及精氨酸和脯氨酸代谢通路等通路显著富集。UPLC-QQQ-MS广靶鉴定获得温络通的213个化合物，网络药理学分析表明君药淫羊藿的6种独有化学成分为温络通防治靶药致HFSR及PN的核心化学成分。研究成果发表期刊论文8篇，形成院内协定处方并在医联体成员单位内推广应用，获得省部级科研奖励2项、滚动省部级科研立项2项。研究成果为临床中医外治手足皮肤反应和周围神经病变提供指导性的科学依据，阐释“温经通络”作用机理。