吴茱萸“陈久者良”的科学内涵研究

The parlance “Liuchen” in Traditional Chinese medicine (TCM) has been best known for thousands of years, and Chinese have been using the long-stored TCM following the ancient saying. But what is the reason and scientific basis? No explicit conclusions have ever been given. The previous methods are insufficient with less comparability, less evaluation index and insular analysis, and the novel research idea and approaches are imperative for long-stored TCM. Euodiae Fructus, a commonly used TCM, is toxic and rich in volatile oil, and has a definite analgesic, dispelling-cold, preventing-vomiting effect. So it is a good example to explore the scientific connotation of “the older the better” with representativeness and feasibility. Based on the previous research experience and the recent progress of the research methods of TCM, Euodiae Fructus was taking as model herb to explore the scientific connotations of “the older the better”, the theory and technology of various disicipline were integrated, and the experiment methods such as spectrum-effect relationship and acceleration test were introduced in the aging experiments. The specific procedures are as follows: Firstly, find the bioactive compounds according to the spectrum-toxicity-effect relationship; Secondly, the dynamic change law of the bioactive compound group was the research focus with the effect and toxic data as the complementary parameters. The aging process of Euodiae Fructus was investigated with the acceleration test and normal storing. and the results from the two aging experiments may complement and validate each other; Thirdly, the quality changes of the herbs during the process of aging were comprehensively evaluated according to the appearance properties, component, efficacy and toxicity indexes, and the scientific connotations of “Euodiae Fructus, the older the better” were elucidated. The research method shows the holistic characteristics. The implementation of the project can provide a research paradigm for the scientific basis of long-stored TCM.

中药“六陈”之说，历经千载，多遵古炮制，然其道理何在，有无科学依据，仍无定论。文献方法多存在缺乏可比性、评价手段和指标单一、缺乏动态分析等不足，中药陈用研究需要新的研究思路与方法。吴茱萸为临床常用中药，有小毒，富含挥发油，具有明确的散寒止痛、降逆止呕功效，以其为例探讨中药“陈久者良”的科学内涵，兼具代表性和可行性。基于先前的研究经验和新近的中药研究方法进展，本项目拟以吴茱萸为研究对象，融合多学科研究成果，引入谱效学和加速试验方法，从谱-效-毒关系入手，发现其活性成分群；继以活性成分的动态变化规律为主线，辅以药效、毒性数据，采用加速试验和正常贮藏两种陈化方法，相互补充、验证；再整合药材性状、挥发油总量、组分、药效和毒性等指标全面评价吴茱萸陈化过程中的质量变化，结合中药陈用理论阐述“陈久者良”的科学道理。研究方法具有整体思辨的特点，项目的实施能为中药陈用理论的现代研究提供一个较好的研究范例。

陈用理论属于中医药传统理论，历代本草均有论述，至今仍为中医临床所沿用。然而，中药是否“陈久者良”尚且存疑，其科学依据更少深究。中药陈用的现代研究踟蹰不前，关键在于缺乏有效研究方法，无法应对陈药研究的时间特点。吴茱萸为临床常用中药，效毒兼具，富含挥发油，以其为例探讨中药“陈久者良”的科学内涵，兼具代表性和可行性。本项目整合谱-效学、质量标志物、网络药理学和加速试验等技术手段，提出并验证了系统的陈药研究方法，追踪活性成分群的动态变化规律，综合性状、组分、药效/毒性等指标，全面评价陈化过程中的质量属性，系统剖析“陈久者良”的科学内涵。.主要内容与结果：.1. 引入谱-效学思路，三元关联“谱-效-毒”，发现了21个镇痛活性成分，11个止呕成分和18个肝毒性物质，辩证分析了吴茱萸的功效/毒性物质基础。.2. 解码“组-效-动”以明确物质基础，探讨网络药理学以分析作用机制，辅以可测性分析，基本明确了吴茱萸的功效/毒性Q-marker，并建立了基于Q-Marker的吴茱萸质量控制方法.3. 提出了系统的中药陈药研究思路，设计并验证了能应对时间维度的陈药研究的整体研究方法。模拟自然条件精心设计陈化实验：正常陈化、加速陈化和冰冻陈化互为补充、验证，确保了可比性和可靠性。采用台阶型升温法加速试验，推算加速试验的折算系数。.4. 基于指纹图谱半定量与多指标定量方法，追踪活性成分群的动态变化规律，综合外观性状、常规检查、组分、药效/毒性等指标，全面评价陈化过程中的质量变化，系统剖析了吴茱萸“陈久者良”的科学内涵。研究发现：①吴茱萸的质量属性比较稳定，陈化后毒副作用减轻，吴茱萸确实“陈久者良”；②陈化过程中，活性组分发生了含量变化和转化，这是“陈久者良”的内在原因；③吴茱萸质量稳定，有最佳陈化期限。.项目的实施为中药陈药的研究提供了系统的研究思路与方法，有助于提升吴茱萸的质量标准，可用于指导吴茱萸的包装、储存等生产过程。