生大黄“先泻后秘”的“错位效应”与熟大黄“泻敛同步”的“双向调节”作用的物质基础与作用机理探讨

Rhubarb, as a clinical laxative, has significant and curative effect. However, long-term and large doses of using drugs will have a good effect of diarrhea at the beginning; the latter will have more serious constipation. Steamed rhubarb piece does not have these effects. Based on the former research, we hypothesize that: based on the co-effect of anthraquinone and tannin, at the initial time after using raw rhubarb tablet, it will cause one-way diarrhea; at the later time, tannins was hydrolyzed to gallic acid and accumulated in the gut, it will generate strong convergence effect. While steamed rhubarb does not contain tannins, it contains gallic acid which has convergence effect, and it will develop diarrhea and convergence two-way adjustment effect with anthrquinone at the same time. So, it has an easing effect and will not cause constipation, even if long-term using. Therefore, we propose a scientific hypothesis that because of the misplaced effect of raw rhubarb’s constipation after diarrhea it causes poison effect, two-way adjustment effect of cooked rhubarb’s diarrhea and convergence synchronization has a stable curative effect. To confirm this hypothesis, based on the integrated chemical composition and the natural ratio of the extract of rhubarb pieces, combined with raw and steamed rhubarb’s chemical composition and ratio differences, this project study on differences of different components in intestinal absorption, metabolism and multi-level pharmacological effect, systematically, which reveals the scientific connotation of the misplaced effect and two-way adjustment effect. The project may guide the clinical rational use of rhubarb.

大黄，作为临床泻剂，作用显著、疗效确切。但长期、大剂量服用含生大黄的泻剂，初期效果良好，后期则出现更严重的便秘，而熟大黄临床未见此类副作用。基于课题组前期研究推测：由于蒽醌类及复合鞣质类成分的共同作用，生大黄服用初期单向峻泻；服用后期，复合鞣质被水解为没食子酸后在肠道大量累积，才产生强烈的收敛作用。而熟大黄中含微量复合鞣质，富含有收敛作用的没食子酸，与有泻下作用的蒽醌类成分同时发挥泻下与收敛作用，因此泻下作用缓和，即使长期服用，也没有便秘的副作用。综上，我们提出：生大黄因其“先泻后秘”的“错位效应”而产生毒副作用，熟大黄因其“泻敛同步”的“双向调节”而疗效稳定的科学假说。为证实这一假说，本课题拟以生、熟大黄间化学成分组成及量比关系差异为切入点，通过系统考察不同目标成分群肠吸收、代谢及多水平药理作用的差异，揭示大黄“错位效应”、“双向调节”作用的科学内涵，为合理指导大黄临床用药提供科学依据。

大黄，作为临床泻剂，作用显著、疗效确切。但长期、大剂量服用含生大黄的泻剂，初期效果良好，后期则出现更严重的便秘，而熟大黄临床未见此类副作用。为揭示大黄以上作用的相关机制，本课题基于RRLC-QTOF-MS化学模式识别技术，快速鉴定大黄不同饮片中化合物72个，包括蒽醌类27个，二苯乙烯类13个、苯丁酮类10个以及其他类成分22个；建立了一种符合中药特点的含量测定方法-标准叠加法，应用该方法对生、熟大黄提取物及目标成分群中主要特征成分进行了含量测定。发现大黄生片炮制成熟片后，复合鞣质全部分解、苷类成分大幅降低、没食子酸大幅增加。以生、熟大黄间化学成分组成及量比关系差异为切入点，通过系统考察其多水平药理作用，证实生大黄“先泻后秘”的“错位效应”及熟大黄“泻敛同步”的“双向调节”作用；通过研究生、熟大黄不同效应成分与肠道的相互作用的差异，发现生、熟大黄不同效应成分的肠道暴露特征存在显著差异，其发挥泻下与收敛作用的效应物质代谢速率不同步，是生大黄“先泻后秘”的“错位效应”的机制之一。除此之外，长期服用大黄生片可抑制肠道平滑肌的收缩，影响肠道激素及神经递质分泌；造成结肠组织上皮细胞炎性浸润、纤维组织增生；导致肠道的细菌种类总数减少，且使肠道细菌的组成结构发生改变，从而造成继发性便秘。而熟大黄泻下作用缓和，可持续促进肠道平滑肌收缩，未明显造成肠组织上皮细胞炎性反应；且长期服用，未诱导肠道细菌种类总数及组成结构发生显著变化。以上研究工作，初步揭示了生大黄“先泻后秘”的“错位效应”及熟大黄“泻敛同步”的“双向调节”作用机制，为指导大黄临床合理用药提供科学依据。