【作者】 孙世仁；

【导师】 黄熙；

【作者基本信息】 第四军医大学 ， 中西医结合临床， 2002， 硕士

【摘要】 治疗药物监测(therapeutic drug monitoring,TDM)是近四十年来在治疗学领域内崛起的一门新的边缘学科。它通过监测体液内药物浓度并利用药代动力学原理和公式，实施个体化用药，提高药物的疗效，避免或减少毒性反应。TDM已成为当前临床医学中发展最快的领域之一，TDM的实施大大提高了临床患者用药的安全性、有效性和合理性。受此启迪，黄熙在其“证治药动学”假说和“方剂血清成分谱、靶成分概念”的基础上，提出了“方剂治疗药物监测“raditional Chinese medicine recipe therapeutic drug monitoring,TCMR-TDM)”的设想，旨在通过对方剂制剂学、方剂药动学、方剂药效学、方剂治疗学的全面监测，进行方剂配伍-血清化学成分／靶成分-证效关系的研究，建立可靠的方剂质量控制标准，阐明方剂药效物质、方剂配伍理论，尽可能地实施个体化、量化的辨证施治方案，以提高临床疗效和减轻毒副作用。由于方剂TDM属于方剂药理学、中医治疗学的创新领域，涉及多学科、多领域，因此在有限的时间内全面实施上述四个方面困难很大。故本文首先进行了方剂制剂学监测和方剂临床药动学监测的初步探索。 第四军医大学硕士学位论文 目的 本研究旨在进行方剂治疗药物监测的初步探索。选择研究较为成熟 的川苇复方为工具，以血瘀证患者为对象，在对川穹复方剂制剂学监测的 基础上，首次开展与方剂配伍和证相结合的方剂临床药动学研究。为方剂 制剂学监测和方剂临床药动学监测提供可借鉴的模式，为方剂治疗药物监 测的进一步实践奠定基础，同时也为“证治药动学”假说提供临床依据。 方法 1．）0％复方的制剂学监测：采用临床煎煮方法制备川苇汤、）d％丹参 汤、）；l苇赤芍汤，以新建立的HPLC法测定上述制剂中阿魏酸含量。以完 全随机设计的方差分析和 Dunnett t检验进行数据比较。 2．）0％复方的临床药动学监测：（）采用改良水浴法进行血清样品预 处理，以新建立的HPLC法测定健康人和血瘀证患者口服川穹汤后血清阿 魏酸浓度，以3P97药动学拟合软件拟合药动学参数，比较两组之间的药 动学差别。（2）以HPLC法测定血瘀证患者口服川羊汤、）d ％丹参汤、）0 苇赤芍汤后血清阿魏酸浓度，以3P97药动学拟合软件拟合药动学参数， 用随机单应组设计的方差分析＊——幻J检验进行组间差别比较。 结果 1．）0％复方的制剂学监测：（1）川苇复方制剂中阿魏酸HPLC测定的 方法学：以甲醇：水：冰醋酸（36．4：63：0．6，v八）为流动相，以KromasiL C；s柱 （150minX．6 mm，SPm）为固定相，流速 1．0 mL／min，检测波长： 322 urn。在此色谱条件下，阿魏酸和其他峰分离完全，阿魏酸在 3．378一7．882卜g．mL’范围具有良好的线性关系（r＝0．9971），高、中、｛ 浓度下的 日 内和日 间变异系数均巧％，加样回收率为 94．97t5．40－99．2516．2O，最低检坝限为 0．6756 ng。（2）阿魏酸含量坝定 结果：）4％单煎剂 FA含量为 233．16士 1．62pg／g．mL‘，配伍丹参时，其溶 5 第四军医大学硕士毕位论文 出量明显增加，为引0石6士4．9旭g血”’…＜0刀1卜而与赤芍配伍后，FA 溶出量却明显减少，为1乃．78士5．79呛g．InL”’（p＜0刀）。 二．川苇复方的临床药动学监测：（）人血清中阿魏酸HPLC测定的 方法学：以甲醇：水：醋酸（40：59．7：0．3，v／v）为流动相，Diamonsil（TM） 柱门 mm X 4石 mm，5 u m）为固定相，流速 1刀 mL／min，检测波长： 322 nxn，以香豆素为内标。在此色谱条件下，阿魏酸和内标分离完全，阿 魏酸在8刀449一965．3846ng．mL”‘范围具有良好的线性关系（＊0．9981）。最 低检坝浓度为 8＊44 gng·mL’，最低检狈限为 1＊04 ng。高、中、低浓度的 日内和日间变异系数均＜10％，平均回收率为99．3土5．＊％。Q）健康人和血 瘀证患者口服川穹汤后血清阿魏酸药动学结果：两组的药动学参数均符合 开放性二室模型，血瘀证组和健康组的主要药动学参数分别如下： V厂（c）／un．ml1一0＊064士0＊027和0＊093土0＊042；t；n。／min一24．53士23．85 和12．18士5石3；ti／2。／而＊一2刀．85h06．38和114．47士68．94 TIQk加h一4刀2 士3＊二和4．49上2．45；AUC／ng．min刁．ml＊－12062．＊上2145 ＊5和7112．7022 土二565更多还原

【Abstract】 Therapeutic drug monitoring(TDM) is a novel discipline of therapeutics. It formulates individual plans of treatment to enhance therapeutic effects or decrease adverse effects by motoring drug concentration in body fluids and pharmacokinetics (PK) analysis. TDM is one of the most rapidly progess fields in clinical medicine. The safety, efficiency and rationality of drugs have been improved greatly since TDM was applied. Professor Huang Xi brought forward the hypothesis of traditional Chinese medicine recipe therapeutic drug monitoring (TCMR桾DM), which includes TCM recipe pharmaceutics monitoring, TCM recipe PK monitoring, TCM recipe pharmacodynamics and TCM recipe therapeutics monitoring. If the TCM recipe TDM is carried out, it is possible to clarify the theory of combination and substances of pharmacological effects in TCM recipe and formulate individual plan of treatment with TCM recipe to enhance therapeutic effects or diminish adverse effects. TCM recipe TDM belongs to a new field in TCM recipepharmacology and TCM therapeutics. It is a complex science, so it is impossible for all the four aspects of TCM recipe TDM to progress. This experiment explored the TCM recipe pharmaceutics monitoring and TCM recipe pharmacokinetics monitoring. ObjectiveThis experiment is to monitor the pharmaceutics of Ligusticum Wallichii recipe (LWR) and PK of Ferulic Acid (FA) following LWR decoction in patients with blood stasis and healthy volunteers. Its aim is to explore the TCM recipe pharmaceutics monitoring and TCM recipe clinical PK monitoring of TCMR-TDM. Meanwhile, the results of this experiment can provide further clinical evidence in support of the hypothesis of "syndrome and TCM recipe pharmacokinetics". Method1. Pharmaceutics monitoring of LWR: The quantites of ferulic acid (FA) were detected by HPLC in Ligusticum wallichii decoction (LWD), Ligusticum \vallichi & Radix salviave miltiorrhizae decoction(Z,7?D) and Ligusticum wallichi & Paeonia veitchii Lyunch decoction ( LPD), which were prepared by clinic decoction method.2. Clinical PK monitoring of LWR: (1) The serum samples in healthy volunteers and patients with blood stasis were pretreated with improved boiling water method and the concentration of FA in samples were respectively detected by HPLC. The pharmacokinetic parameters were fitted in 3P97 software respectively, and compare them between two groups. (2) The serum FA concentrations were determined by HPLC in patients with blood stasis following oral administration of LWD, LRD and LPD. The pharmacokinetic parameters were fitted in 3P97 software, and compare theirvariances analysis in SPSS statistics software. Result1. Pharmaceutics monitoring of LWR: (1) Methodological results of HPLC determination of FA concentration in LWR decoction: Methanol-water-acetic acid (36.4:63:0.6, v/v) was used as the mobile phase, while the KromasiL Cjg (150 mm X 4.6 mm, 5 y m) as a fixed phase. FA was detected at the wavelength of 322 nm. Flow rate was l.OmL/min. FA was separated on the baseline under the condition described as above, the linearity in the range of 3.378-7.882ug.mL"’ was good (r=0.9971). The intra-assay and inter-assay precisions were less than 5 %; the recovery rates ranged from 94.97+5.4% to 99.25?.2%, and the lowest limit was 0.6756ng. (2) The results of FA determination: the concentrations of FA in LWD, LRD and LPD were 233.16 ?l^ug/g.mL’1, 310.66 ?4.9|ig/g.mL’1 and 178.78 ?5.79jj.g/g.mL" respectively. Compare with LWD group, the concentration of FA in LRD increased distinctly, while the concentration of FA in LPD decreased significantly.2. Clinical PK monitoring of LWR: (1) Methodological results of HPLC determination of FA concentration in serum: Methanol- water- acetic acid (40:59.7:0.3, v/v) was used as the mobile phase, while the Diamonsil(TM) (150 mm X 4.6 mm, 5 u m ) as a fixed phase. FA was detected at the wavelength of 322 nm. Flow rate was l.OmL/min. FA and internal standard were separate更多还原