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冠心Ⅱ号不同配伍方及不同剂型对丹参素、阿魏酸药代动力学的影响

Effect on the Pharmacokinetics of Danshensu and Ferulic Acid Exerted by Guanxin Ⅱ in Different Compatibility Formulas and in Different Formulations

作者: 专业:药物分析学 导师:李寅超 年度:2010  院校: 郑州大学

Keywords

        方剂配伍规律的现代研究是中医药现代化研究的重点和难点。随着科学进步及中医药现代化进程的加快,利用有效成分及有效组分进行组方配伍已成为方剂配伍规律研究的新模式。本课题为国家973计划项目《方剂配伍规律研究》的一部分,实验选择经典方剂冠心Ⅱ号为工具药,通过对冠心Ⅱ号不同组分配伍和不同剂型中的药效成分——丹参素、阿魏酸在Beagle犬体内药动学过程的较深入研究,获得冠心Ⅱ号全方配伍规律及其科学内涵的诠释,同时就传统汤剂存在的合理性做出评价,为组分配伍模式的完善提供新的例证。目的:研究冠心Ⅱ号不同配伍方和不同剂型的药效成分丹参素、阿魏酸在Beagle犬体内的药代动力学过程,获得对冠心Ⅱ号配伍规律及其科学内涵的合理诠释。方法:1.以色谱柱ZORBAX Eclipse plus C18(2.1×10mm,1.8μm)为固定相,以水-乙腈(v/v=83:17)为流动相,电离源为ESI(-),MRM模式检测,同时优化多种生物样品预处理方法,建立丹参素、阿魏酸在血浆中的液-质联用(LC-MS/MS)检测分析方法。2.将冠心Ⅱ号按功效拆分为不同配伍组:冠心Ⅱ号全方提取物重组方组(A组)、活血药提取物重组方(B组)、理气药提取物重组方组(C组)、丹参提取物组(D组)和川芎提取物组(E组);另设冠心Ⅱ号全方汤剂组(F组)。实验按拉丁方设计法循环6周期(即6次)给Beagle犬灌服冠心Ⅱ号各配伍方及全方汤剂。应用LC-MS/MS检测犬血浆中丹参素、阿魏酸含量。利用药代动力学软件计算各组药代动力学参数:药-时曲线下面积(AUC)、体内平均滞留时间(MRT)、T1/2、表观分布容积(V)、清除率(CL)、峰浓度(Cmax)、达峰时间(Tmax),并比较组间差异。结果:1.建立了灵敏、特异、准确、可靠的丹参素、阿魏酸在Beagle犬血浆中的LC-MS/MS分析方法。2.冠心Ⅱ号不同配伍方的丹参素、阿魏酸在Beagle犬体内的药动学研究显示,与B、D两组比较,A组丹参素的Cmax和AUC呈增高趋势,但无统计学意义;与C、E两组比较,A组阿魏酸的CL呈降低趋势,V呈增高趋势。即冠心Ⅱ号不同配伍方中丹参素、阿魏酸的药动学参数均有差异趋势,但无统计学意义。3.冠心Ⅱ号不同剂型的丹参素、阿魏酸在Beagle犬体内的药动学研究显示,与A组比较,F组丹参素的AUC、Cmax和CL均显著增高(P<0.01或0.05),而V和MRT则显著降低(P<0.01或0.05),F组阿魏酸Tmax和MRT(0→t)均显著增高(P<0.01或0.05),而Cmax、CL和V则显著性降低(P<0.01),T1/2则无显著性差异。即冠心Ⅱ号不同剂型中丹参素、阿魏酸的药动学参数除T1/2外均有统计学意义。结论:1.按功效拆方,冠心Ⅱ号不同配伍方的丹参素和阿魏酸在Beagle犬体内的药代动力学过程基本一致。2.冠心Ⅱ号全方汤剂比全方提取物重组方的丹参素达峰浓度和生物利用度高,比全方提取物重组方的阿魏酸清除慢、体内滞留时间长。3.综合分析冠心Ⅱ号的丹参素、阿魏酸的药代动力学与药效学的结果(全方汤剂优于全方有效组分重组方),可以看出,冠心Ⅱ号疗效的发挥可能是通过活血化瘀来实现的,而行气、理气可助活血化瘀。4.中药传统汤剂有其存在的合理性。本文以药代动力学为手段,首次以功效拆方阐释方剂组合原则,对冠心Ⅱ号有效组分研究方剂配伍规律进行了初步探索;首次通过传统汤剂与全方有效组分重组方的体内过程的比较,验证了中药传统汤剂有其存在的合理性;、并且建立了同时处理含丹参素、阿魏酸两种化学成分的血浆样品的方法,为中药复方多组分的生物样品预处理及药代动力学研究提供了方法学借鉴。
    The modern research for compatibility regularity of Formulas of tradional chinese medicine(TCM) is a key point and difficult point for research of TCM modernization. With the progess of science and the acceleration of the course of TCM modernization, the active component or composition compatibility has become the new model of research for compatibility regularity of formulas of TCM. The research project is a part of the national"973"Project:Investigation in compatibility regularity of Formulas of TCM. In this paper, the recipe of GuanxinⅡwas selected to as a tool. To obtain a scientific illustration to the compatibility principle,and to acquaire an evaluation for the reasonable existance of decoction from the deep research of effectt on the pharmacokinetics of Danshensu(DSS) and Ferulic acid(FA) exerted by GuanxinⅡin different compatibility formulas and in Different Formulations.In brief,the experiment aimed to provide a new example illustration for the perfection of composition compatibility modal.Aim:To obtain a reasonable illustration to compatibility regularity of GuanxinⅡand it’s scientific meaning from the research for pharmacokinetic course of DSS and FA in vivo in different compatibility formulas and in Different formulations of GuanxinⅡ.Methods:1.A ZORBAX Eclipse plus C18(2.1×10mm,1.8μm) column was used as the stationary phase.The mobile phase was composed water and acetonitrile with the volum ratio of 83/17. Taking ESI(-) as ionization source,multiple reaction monitoring.Meanwhile, selecting a reasonable sample pretreatment with the aim of establishing a method to analyze DSS and FA in beagle dog plasma.2.To dismember GuanxinⅡby efficacy,that was, group of GuanxinⅡwhole composition extracts(group A), GuanxinⅡHUOXUE composition extracts(group B), GuanxinⅡLIQI composition extracts(group C), GuanxinⅡDANSHEN extracts(group D) and GuanxinⅡCHUANXIONG extracts(group E).Besides, the group of GuanxinⅡdecoction(group F) was added. Beagle dogs were administrated different GuanxinⅡ compatibility formula and GuanxinⅡdecoction as above. The experiment was performanced according to Latin square design,with 6 cycles to repeat. LC-MS/MS was application to detect the concentration of DSS and FA in plasma. Pharmacokinetic parameters were calculated by related softwares: AUC,MRT,T1/2,Vz/F,CLz/F,Cmax,Tmax and inter-group differences were compared.Results:1.A method which is sensitive, peculiar, precise and reliable to determine the quantities of DSS and FA in Beagle plasma is established.2.In the research of pharmacokinetics of DSS and FA in different GuanxinⅡcompatibility formulas in Beagle dogs,compared with group B and group D, the Cmax and AUC(0→t) of DSS in group A are all on the rise;compared with group C and group E, the CLz/F of FA in group A is decreased,however, the V of FA in group A is increased. On the wholel, the pharmacokinetic parameters of DSS and FA in different GuanxinⅡcompatibility formulas are all the similar,but no significance.3.In the research of pharmacokinetics of DSS and FA in different GuanxinⅡformulations in Beagle dogs, compared with group A, the AUC(0→t),Cmax and CLz/F of DSS in group F are all on the increase(P<0.01 or 0.05), nevertheless, V and MRT(0→t) of DSS in group A are decreased(P<0.01 or 0.05); compared with group A, the Tmax and MRT(0→t) of FA in group F are all on the increase(P<0.01 or 0.05), however, Cmax、CLz/F and V of FA in group A are decreased(P<0.01).That is, the Cmax and bioavailability of DSS in GuanxinⅡdecoction are much higher, the elimination of FA is much slower and the mean residence time of FA is much longer than in GuanxinⅡwhole composition extracts.Conclusions:1. Pharmacokinetics of DSS and FA from different GuanxinⅡcompatibility formulas,dismembered by efficacy, in Beagle dogs are all the same,having no significant difference.2. The maximum concentration and bioavailability of DSS in GuanxinⅡdecoction are much higher, the elimination of FA is much slower and the mean residence time of FA is much longer than in GuanxinⅡwhole composition extracts.3.Comprehensively analysis,combining pharmacokinetics with pharmacodynatics of GuanxinⅡ,shows that the efficacy of GuanxinⅡexerted by activating blood and dissolving stasis,with the help of promoting the circulation of Qi and regulating vital energy.4.The reasonability of decoction’s existence is proved. This study illustrates the principle of compatibility dismembered by efficacy in the light of pharmacokinetics,exploring tentatively the methods by using effective composition to researchIn this article we undertook a preliminary explore in the formulas regularity of TCM by dividing formulas into different components based on their activating blood and regulating vital energy differences; the rationality of existence of chinese traditional decoction is observed by comparing the in vivo process of traditional decoctions and effective components recombination formulation; blood sample treatment procedure containing DSS and FA simultaneously is established which provides a methodology model for biological sample pretreatment and pharmacokinetics research of TCM.
        

冠心Ⅱ号不同配伍方及不同剂型对丹参素、阿魏酸药代动力学的影响

摘要4-6
Abstract6-8
英文缩略词11-12
第一章 引言12-23
    1 中药复方配伍规律研究12-15
    2 中药复方传统剂型的研究15-16
    3 中药复方药代动力学16-18
    4 冠心Ⅱ号方的相关研究18-23
        4.1 历史背景18
        4.2 冠心Ⅱ号化学成分及药效学研究18-20
        4.3 冠心Ⅱ号药味药代动力学研究20-23
第二章 实验部分23-50
    1 LC-MS/MS法测定犬血浆中丹参素、阿魏酸的方法学建立23-31
        1.1 实验动物23
        1.2 药品与试剂23-24
        1.3 仪器24
        1.4 给药及采血24-25
        1.5 方法学的建立与验证25-30
        1.6 小结30-31
    2 冠心Ⅱ号不同配伍方中丹参素、阿魏酸在Beagle犬体内的药代动力学研究31-41
        2.1 实验动物31
        2.2 受试药与试剂31-32
        2.3 仪器32
        2.4 剂量设计32
        2.5 给药及采血32-33
        2.6 生物样品处理及测定33
        2.7 结果33-40
        2.8 小结40-41
    3 冠心Ⅱ号不同剂型中丹参素、阿魏酸在Beagle犬体内的药代动力学研究41-50
        3.1 实验动物41
        3.2 药品与试剂41
        3.3 仪器41-42
        3.4 剂量设计42
        3.5 给药及采血42
        3.6 生物样品处理及测定42
        3.7 结果42-49
        3.8 小结49-50
第三章 讨论与总结50-58
    1 讨论50-56
        1.1 方法学建立51-54
        1.2 冠心Ⅱ号不同配伍方对丹参素、阿魏酸药代动力学的影响54-55
        1.3 冠心Ⅱ号不同剂型对丹参素、阿魏酸药代动力学的影响55-56
    2 结论56
    3 创新56
    4 展望56-58
参考文献58-61
致谢61-62
个人简历62-63
附录A63-67
附录B67-74
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