基于化学信息、整合PK-PD相关性的茅苍术“生燥熟补”麸炒机理研究

AAtractylodes lancea(AL) can reach the effects of depriving the evil wetness and regulating the function of the spleen. It has been commonly used for digestive disorders. Gastric ulcer belongs to spleen and stomach deficiency syndrome in TCM. It had been reported that AL had the effect of treating gastric ulcer. Currently, stir-baking with wheat bran is the most commonly used in all the processing methods. AL is a typical representative of stir-baking with wheat bran. It was traditionally believed that the dryness of the crude AL was larger than that of the processed AL, and the effect of invigorating spleen and stomach was enhanced after processing. There was no information available in literature about comparing anti-ulcer activities of the crude AL and processed AL and the study on the change of dryness effect in gastric ulcer rats after processing in China and abroad..Response surface methodology will be used to optimize and obtain the optimal stir-baking with wheat bran technology of AL. Quality will be evaluated based on quantitative analysis of multi-components by single marker(QAMS). Changes of chemical information of AL will be observed by fingerprint comparison and multiple pattern recognition analysis. Effects of the crude AL and processed AL on water metabolism in normal rats and gastric ulcer rats will be investigated in order to compare the dryness changes. We will compare the anti-ulcer effects between the crude AL and AL processed with bran and preliminarily evaluate the mechanisms in the aspects of the anti-inflammatory properties, the gastroprotective effects and improving gastric motility. The traditionally processing theory “the crude AL was dry and the processed AL was tonic ” will be proved. Information of the integrated pharmacokinetics in gastric ulcer rats and the correlation of integrated PK- anti gastric ulcer PD will be analized. Above all, we will discuss the material basis of the effect changes of AL, and deeply explain the processing mechanisms of the stir-baking with wheat bran.

茅苍术具有燥湿健脾等功效,常用于治疗消化系统疾病。胃溃疡属中医“脾虚”、“胃虚”等范畴。曾有报道茅苍术具有抗胃溃疡的作用。茅苍术的炮制最常用的为麸炒法，其为麸炒的典型代表，传统认为生品燥性较大，炮制后燥性降低，补脾健胃作用增强。关于茅苍术炮制后抗胃溃疡的作用以及对胃溃疡大鼠的燥性变化研究，目前国内外未见相关报道。.本研究采用响应面法优化茅苍术的麸炒工艺；基于“一测多评”技术进行质量评价；通过指纹图谱比较、多种模式识别分析考察茅苍术化学信息的变化；考察麸炒前后对正常大鼠及胃溃疡大鼠水液代谢的影响，以比较其燥性变化；比较生品和麸炒品抗胃溃疡的作用，从抗炎、胃黏膜保护和提高胃动力等方面初步探讨其作用机制, 验证茅苍术“生燥熟补”的炮制理论；分析麸炒茅苍术多效应指标在胃溃疡大鼠体内的整合药代动力学及整合PK-抗胃溃疡PD的相关性，探讨其药效变化的物质基础，全面深入地阐释茅苍术麸炒的炮制机理。

茅苍术具有燥湿健脾等功效，传统认为生品燥性较大，炮制后燥性降低，补脾健胃作用增强，即“生燥熟补”。现代对茅苍术炮制的研究多集中在炮制后对脾虚动物的作用方面，关于炮制后对胃溃疡大鼠的燥性变化，以及抗胃溃疡、抗溃疡性结肠炎和抗心肌缺血的作用研究，目前国内外未见相关报道，且麸炒茅苍术炮制机理和物质基础研究尚不够深入。.中医认为胃溃疡属于“脾虚”、“胃虚”等范畴，病机主要有脾失健运，胃失和降等方面；溃疡性结肠炎（UC）总属本虚标实、虚实夹杂之证，其病机以脾胃虚损为本；心肌缺氧/复氧（H/R）损伤为脾虚失健，气血生化无源，无力养心，认为当“从脾论治”。以上三种疾病治疗上常以补脾健胃为主。.本研究采用Box-Behnken设计-响应面法优化了茅苍术的麸炒工艺；基于“一测多评”技术进行质量评价；选取了三个以脾虚为主要病机的疾病药效试验，即抗胃溃疡、体外抗UC、体外抗心肌H/R损伤试验，结果茅苍术具有抗胃溃疡的作用，其机制为抗炎、胃黏膜保护和提高胃动力；具有抗试验性UC的作用，其机制为调控IKK/NF-κB信号通路；具有抗心肌细胞H/R损伤的作用，其机制为抗氧化应激和抗凋亡。麸炒后的作用均增强，即麸炒后补脾健胃作用增强。另外通过对正常大鼠、胃溃疡大鼠的水液代谢调节作用比较，验证了茅苍术具有燥性，能够促进水液代谢，而麸炒后该作用减弱，即燥性降低。即验证了茅苍术“生燥熟补”的炮制理论。.本研究从体内外化学成分的变化初步探讨了茅苍术抗胃溃疡作用增强的物质基础。通过指纹图谱比较考察了茅苍术化学信息的变化，结果麸炒后化学成分发生了量变；分析了麸炒茅苍术中苍术素在胃溃疡大鼠体内PK-PD的相关性，以EGF、TFF2、IL-8、TNF-a含量为效应指标，构建PK-PD模型，结果麸炒能够影响苍术素在体内的药代动力学行为，该行为与其抗胃溃疡作用紧密关联。本研究可为茅苍术的临床合理应用提供实验依据，为中药材的麸炒工艺和理论研究提供参考，对揭示茅苍术麸炒的科学内涵，指导临床合理用药，是十分有意义的。..