鱼腥草注射剂的超分子结构特征及其（类）致敏性研究

The elucidation of mechanisms of (anaphylactoid) hypersensibility for the TCM injection is to build the cornerstone to securely assess the Chinese medicine injection, on which the TCM fields have being focused. Based on the previous studies of immunotoxicities and systematical screening technologies of (anaphylactoid) allergens for TCM injections, after analyses of the significant differences of (anaphylactoid) hypersensibilities between "injection" and "oral" administration of traditional Chinese medicine and combination of supramolecular chemistry, it was inferred out the hypothesis: "In Chinese medicine injections the supramolecular structures can independently be generated, and shown the overall apparent (anaphylactoid) hypersensibility, whose strength depended on the structure features, whose(anaphylactoid) hypersensitive critical supramolecular structure was existed. When it was administrated by "injection", it’s structure was not easy to be destroyed, and took place more stronger apparent immunogenicity, whereas by "oral", the structure would be destroyed owning to absorptionof the gastrointestinal tract, and did weaker lower apparent immunogenicity, even disappeared in case”. This project, as a model drug as Houttuynia cordatain jection, by studying on it’s supramolecular structure features, on influences of (anaphylactoid) hypersensibility on supramolecular structures features, on the prediction of (anaphylactoid) hypersensibility with supramolecular structure, and on the hypersensibility differences between "injection" and "oral" administration of it, clarifies it’s supramolecular structures features and it’s (anaphylactoid) special hypersensitive mechanisms, to establish predictive model of (anaphylactoid) hypersensibility to supramolecular structure features, to determine their (anaphylactoid) sensitized critical supramolecular structure, in order to build the foundations for TCM injections safe medication barrier, and for promotion of it’s technologic research.

中药注射剂的（类）致敏性机理阐明是构筑其安全性评价方法的基石，中医药研究领域瞩目。在前期中药注射剂免疫毒性与（类）致敏原综合筛查技术等研究基础上，针对中药“注射”与“口服”给药（类）致敏性的差异，结合超分子化学，推理出：“中药注射剂可自主产生超分子结构，呈现整体表观（类）致敏性，强度决定其结构特征，存在（类）致敏临界超分子结构。“注射”给药其结构难被破坏，易呈表观免疫原性；而“口服”给药，其结构将被胃肠道破坏，表观免疫原性弱或消失”假说。本项目以鱼腥草注射剂为模型药物，通过对其超分子结构特征、超分子结构特征对（类）致敏性的影响、超分子结构的（类）致敏性预测、“注射”与“口服”给药（类）致敏性差异等研究，阐明其超分子结构特征及其产生（类）致敏反应的特殊机理，建立其（类）致敏性超分子结构的预测模型，确定其（类）致敏临界超分子结构，为构筑中药注射剂安全用药屏障，促进其工艺研究奠定基础。

本项目运用生物超分子化学，以鱼腥草注射剂为模型药物，展开了指纹图谱、超分子结构与（类）致敏性的关系、“注射 ”与“口服”给药（类）致敏性差异等研究，建立了GC/MS指纹图谱、超分子结构表征及其微量热滴定、胶束品红染色、核磁、紫外、质谱等测定方法；结合信息熵、总量统地矩法分析，发现了模型药物的基于“印迹模板”特征及修饰的“三稳”和“三不稳”成分作用规律；发现了在吐温-80增溶下，模型药物成分分散在中，镶嵌在其内、吸附在其外，共同组成超分子胶束，决定表面积大小和“化学决定簇”的复杂性程度；进行了不同注射用辅料、浓度、给药方式的（类）致敏毒性研究，确定了吐温-80增溶浓度为0.17%-0.3%；建立了免疫指纹图谱的（类）致敏原筛查（类）法，筛查出65种疑似（类）致敏原；采用网络药理学法构成了29个（类）致敏靶点与80个原、代谢成分的拓扑网络，并对其中15个成分进行了网络动力学验证，根据平衡常数矩阵特征值和特征向量作用大小确定了6个单萜或高级脂肪醇的高（类）致敏原。本项目验证原假说，阐明了中药注射剂产生（类）致敏性机理，共发论文52篇，其中本行业高水平期刊论文28篇，8篇为封面论文，3项专利，1项省部级奖励，培养博士生2名，硕士生9名。