辛热类有毒中药风险-效益阈与效毒机制研究

Chinese herbs with acrid, hot and toxic properties, which have been widely used and proven to have both toxicity and curative effects, are known for their advantages in the treatment of obstinate cold syndrome, but can cause severe safety problems. The toxicity-efficiency characteristics of these herbs are affected by many factors. Therefore, the question of how to measure and control these factors in clinical demands our urgent attention. .Previous studies have revealed the common connections and possibility of quantification between toxicity and efficacy of Chinese herbs with acrid, hot and toxic properties, which would be helpful to elucidate the clinical risks and benefits. This study proposes that there is Yu existing between toxicity and efficacy of Chinese herbs with acrid, hot and toxic properties, which can be quantified and put at the core of the problem. It is the key to estimate risk-benefit clinically and is the precondition to elucidate the mechanisms of efficacy and toxicity. The hypothesis will provide a new perspective for future toxicity studies of Chinese herbs. In this research, Rhizoma Curculiginis, Fructus Cnidii, Radix Aconiti，Radix Aconiti Kusnezoffii，Radix Aconiti Lateralis Praeparata and Radix Aconiti Brachypodi were used as sample drugs，combined with data mining, multi-criteria decision analysis, computer simulation, pathophysiology, molecular biology and other methods to excavate multidimensional Yu of risk-benefit of Chinese herbs with acrid, hot and toxic properties, to screen core conditions of Yu and quantify them. Then, research on the mechanisms of efficacy and toxicity, including targets and signal pathways, will be conducted on the premise of Yu. Finally, sample Chinese herb with same properties would be introduced to verify the results concerning Yu. This study provides a new understanding of the risk and benefit of Chinese herbs with acrid, hot and toxic properties from another perspective, offers a demonstration for studies of Chinese herbs with toxic properties, and provide direct and objective basis for clinical safe use of Chinese herbs.

辛热类有毒中药效毒共存、应用广泛，虽疗痼冷顽疾优势明确，但安全问题突出。其毒、效表征受诸多因素影响，临床如何量化、把控？是亟待解决的困惑。.前期工作发现，辛热药功效、毒性表达有共通联系及量化可能，可为阐释其临床风险-效益提供依据。本次提出假说“辛热类有毒中药的毒与效之间存在可被量化、核心化的‘阈’，是临床风险-效益评价的关键环节，也是效毒机制阐释的前提，可为中药毒性研究提供新认知”。选择辛热类有毒代表性药物仙茅、蛇床子、川乌、草乌、附子及雪上一枝蒿，综合采用数据信息挖掘、多准则决策、计算机模拟、病生理学及分子生物学等方法，挖掘辛热类有毒中药风险-效益多维“阈”，筛选其核心的风险-效益阈并量化，在“阈”前提下开展针对性的效毒机制研究，并以同类辛热有毒药进行“阈”验证。.本研究从新视角认知辛热类有毒中药的风险-效益，为有毒中药研究提供示范，为临床安全用药提供直接、客观的依据。

中药临床“效-毒”表达受复杂因素影响，存在模糊性、不确定性等问题，亟需探索适宜的“效-毒”研究模式，明晰效-毒关系，为临床中药使用提供确切决策依据。为解决这一技术瓶颈，促进中药研究与国际接轨，本项目以辛热类毒性中药为示例，切入优势治疗领域痹证，创新提出以“效益-风险阈”解决毒性中药“效-毒”关系问题，即在效益的前提下评价示例药的风险，并深入挖掘“效-毒”机制，为临床合理用药提供定量的、直观的用药决策依据。. 本研究以乌头类中药、仙茅、蛇床子等作为示例药，以吴茱萸为验证药，基于文献挖掘、风险评价（多准则决策分析、Meta分析、熵权法），及多层次生物学观察、生物信息学研究等方法，开展了三部分研究：. 1. 辛热类毒性中药效益-风险阈研究。集群古今示例药“效-毒”影响因素，界定“效益-风险阈”的范围。基于真实世界报道评价示例药在不同“阈”条件下的风险情形，量化“效益-风险阈”的临界值。如示例药川草乌治疗痹证的效益-风险结果为38.3±9.9，在证候、炮制、剂量“阈”条件下不同用药形式产生差异的概率为100%。结合临床实际，筛选出证候作为核心阈条件，并通过动物实验考察此条件对示例药生物学效应的影响。. 2. 辛热类毒性中药效益-风险阈机制研究。应用生物信息学技术等预测示例药在效的前提下可能的毒性机制。其中产生心毒性机制可能与PKG等靶点有关，并采用体外细胞试验验证得到示例药可通过抑制cGMP-PKG通路活化而表达心脏风险，采用PKG蛋白激动剂亦反证了此机制。. 3. 示例药的效益-风险阈验证。以相似功效的中药吴茱萸验证了“效益-风险阈”的范围及机制，确认了核心阈条件证候对其风险-效益表达的重要影响及cGMP-PKG通路参与其心脏风险的作用机制。. 本项目创新以“效益-风险阈”的视角阐释辛热类毒性中药的效-毒关系，界定“阈”的范围、量化“阈”的临界值、探索“阈”的机制，为临床安全用药提供决策依据，以第一标注发表学术论文17篇（SCI4篇），超额完成任务，突破中药风险评价技术，引领中药“效-毒”关系研究。