基于生物药剂学研究四逆汤中附子与甘草合煎减毒增效机制
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摘要
旧逆汤是源于《伤寒论》的经典方,由附了、甘草(炙)、干姜组成,是回阳救逆的代表方,现代临床与研究表明四逆汤对缺血再灌滓的心肌损伤具有.显著的保护作用。附子与甘草合煎属中药汤剂摹本要求之一,通过中药复方合煎达到减毒增效的目的。
目的
遵循中医药整体观、辩证观相适宜的整体性、系统性思想,本论文提出四逆汤中附子与甘草合煎达到减毒增效是多成分作用机体,机体产牛棚应应答而实现减毒增效的观点。基于生物药剂学理论,结合LC-MS、GC-MS等分析技术与代谢组学的分忻手段,联合“毒(效)性物质组-减毒-增效物质组-增效”体内体外相应整体代谢特征的研究模式,对四逆汤中附子.与甘草合煎减毒增效机制进行研究。旨在系统探寻四逆汤中附子与甘草合煎达到减毒增效的物质基础和作用机制,以期为整体、系统地研究中药复方合煎配制理论提供新思路。
方法与结果
1.必逆汤制备工艺和质量标准研究：以甘草酸、3种双酯型生物碱(新呜头碱、乌头碱、次乌头碱)、6-姜辣素的含量、干膏量为指标,对比分析传统煎煮工艺与《中国药典》制备方法的差异,结果表明传统制备方法较药典制备方法为优。以3种单酯型生物碱(苯甲酰新乌头原碱、苯甲酰乌头原碱、苯甲酰次乌头原碱)的含量之和、甘草酸的含量及干膏收率为化学指标,以小鼠的抗脑缺氧能力(喘气次数和喘息时间)为药效指标,首先采用L9(34)正交设计试验优选四逆汤的制备工艺；再运用MATLAB建立的前馈型人工神经网络模型进一步优化工艺参数,并进行验证试验。确定最佳制备工艺参数为：加8倍量水,提取3次,每次提取1.5h。四逆汤质量标准研究中,采用薄层色谱法对甘革、干姜两味药材进行攀别,采用HPLC对3种单酯型生物碱及甘草酸进行含量测定,制定本品提取液(0.8g·mL-1)每1mL含3种单酯型生物总量不得少于25.00μg、甘草酸不得少于8.00mg。
2.四逆汤(缺甘草与否)双酯型牛物碱含量变化及次乌头碱药代动力学研究：建立LC-MS测定四逆汤与缺甘草四逆汤(附子和干姜)中3种双酯型生物碱的方法,并对次乌头碱大鼠体内吸收过程影响的对比研究。结果表明四逆汤样品中3种双酯型生物碱含量明显低于缺甘草四逆汤样品的3种双酯型生物碱含量,且存在显著性差异(p<0.01)；四逆汤与缺甘草四逆汤相比次乌头碱的体内吸收速率减慢,吸收总量却增加。
3.四逆汤(缺甘草与否)对MI-RI大鼠心肌细胞代谢组学研究：建立了体外H9c2心肌细胞MI-R1模型,研究四逆汤(缺甘草与否)对模型损伤细胞的毒-效作用,并采用GC-MS联用技术对细胞培养液进行代谢组学研究。结果表明,与缺甘草四逆汤相比,四逆汤对MI-R1模型对H9c2心肌细胞的损伤保护作用更强；四逆汤中附子与甘草合煎减赢增效机制与糖酵解、脂质代谢、三羧酸循环和氨基酸代谢中的氮的代谢等生物代谢途径有关。
4.四逆汤(缺甘草与否)血浆组分GC-MS代谢指纹分析及代谢组学研究：采用GC-MS技术建立大鼠血浆的代谢指纹谱,并进行代谢组学研究,从整体代谢调控模式证实四逆汤中附子与甘草合煎减毒增效的机制与糖酵解、脂质代谢、三羧酸循环和氨基酸代谢等生物代谢途径有关。
结论
本论文基于生物药剂学理论,进一步证实了四逆汤中附子与甘草合煎对附子“毒性成分组”体外结合-体内缓释的“减毒增效”这一传统理论的科学性；通过代谢组学研究,揭示了四逆汤中附子与甘草合煎的减毒增效机制与糖酵解、脂质代谢、三羧酸循环及氨基酸代谢等生物代谢途径有关,为整体、系统地研究中药复方配制理论提供新的思路与方法。
Sini Decoction (SND), a classical Traditional Chinese Medicine formula recorded in Treatise on Febrile Diseases(Shanghan Lim), which is composed of Radix Aconiti Lateralis Preparata. Radix Glycyrrhizae preparata and Rhizoma Zingiberis, is a representative formula, with the function of restoring yang from collapse. Modern clinical and recent researches have shown that SND can protect the myocardium effectively during myocardial ischemia reperfusion injury. Mixed-decoction of Radix Aconiti Lateralis Praeparata and Radix Glycyrrhizae belongs to one of the basic requirements for Chinese decoction, and the purpose of attenuate and synergistic can be reached according to mixed-decoction of Chinese medicine compound.
Objective
This thesis is guided by integrally concept and systematic ideas, which are suitable for the whole concept and dialectical view of Traditional Chinese Medicine. The idea that attenuate and synergistic effects of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND are related to a variety of chemical components from effects on organisms and the organisms reply, will be proposed. Based on the theory of biopharmaceutics, the analytical tools of LC-MS, GC-MS and metabonomics, and the research pattern of'toxic substance group-weakened-synergistic materials group-synergy' corresponding metabolic characteristics both in vivo and in vitro will be used together, which are usually preferred in studying the attenuate and synergistic mechanism of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND. We aim to explore the material base and mechanisms of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND, in order to provide a new bunch of ideas for studying preparation theory of mixed-decoction of Chinese medicine compound integrity and systemically.
Method and Result
1.Study preparation technology and quality standard of SND:
The contents of Glycyrrhizic Acid, DDA(Mesaconitine, Aconitine and Hypaconitine),6-gingerol and the value of dry extract were set as indexes for comparative analysising SND prepared by different processes between the traditional method and Chinese Pharmacopoeia (2010,1) method. Then the traditional process of SND were chosen. The content of Monoester Diterpenoid Alkaloids (Benzoylmesaconine, Benzoylaconine, and Benzoylneoline), Glycyrrhizic Acid and the ratio of extractum were used as chemical properties. The function of anti-hypoxia of mice is set as the pharmacodynamic index. Firstly, the optimal technical conditions were selected by orthogonal design L9(34). Then ANN model was established to obtain the optimum extraction parameters, and proved by the experiments. The optimal technical parameters were as follows:extracting3times in all, once1.5h, adding8times amount of water. TLC was used to identify Radix Glycyrrhizae and Rhizoma Zingiberis. and the contents of MDA and Glycyrrhizic Acid in SND were determined by HPLC in the research of the quality standard. It was confirmed that the content of MDA should be more than25.00μg·mL-1in SND (0.8g·mL-1), and the content of Glycyrrhizic Acid should be more than8.00mg·mL-1
2. Compare content change of DDA and pharmacokinetics of hypaconitine between the mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND:
The simultaneous determination method of DDA in supernatant of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND was estimated. The pharmacokinetics of hypaconitine mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND on mice were contracted.The results showed that the content of DDA in SND was lower than the one of SND without Radix Glycyrrhizae, and there were significant differences between them (p<0.01).At the same time, though the absorption rate of hypaconitine was slowed, the total absorption area of hypaconitine was added after mixed-decoction of Radix Glycyrrhizae in SND.
3. Metabonomics research on the effects of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND on MI-RI mouse cardiomyocytes based on GC-MS:
A myocardial ischemia reperfusion injury model of H9c2cardiomyocytes in vitro was established.The effect of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND on myocardial ischemia reperfusion injury in H9c2 cardiomyocytes was studied.and the metabonomic method using GC-MS was developed to research the metabolic profile of extracellular fluid. Compared with the SND without Radix Glycyrrhizae, the protective effect of myocardial ischemia reperfusion injury model of H9c2cardiomyocyte from SND was stronger. The attenuation and synergistic mechanism of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND were related with the glycolysis, lipid metabolism, citrate cycle and nitrogen metabolism of amino acids metabolism.
4.Metabolomic fingerprinting analyze and metabonomics research of mice plasma on mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND based on GC-MS:
Metabolomic fingerprint and metabonomics of mouse plasma based on GC-MS were adopted. From the integrally modes of metabolic regulation,it is proved that the attenuation and synergistic mechanism of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND were related with the glycolysis,lipid metabolism, citrate cycle and some amino acids metabolism.
Conclusion
In this thesis,based on biopharmaceutics theory, we have confirmed that mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND, which is the main toxic component of Radix Aconiti Lateralis Preparata united in vitro firstly, as well as liberated and absorbed slowly while in vivo, and realised the'attenuation and synergistic". It doses not only reveal that the attenuate and synergistic mechanisms of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND are related with the glycolysis, lipid metabolism, citrate cycle and some amino acids metabolism, but also provide a new method and idea for studying preparation theory of mixed-decoction of Chinese medicine compound integrally and systematically.
目的
遵循中医药整体观、辩证观相适宜的整体性、系统性思想,本论文提出四逆汤中附子与甘草合煎达到减毒增效是多成分作用机体,机体产牛棚应应答而实现减毒增效的观点。基于生物药剂学理论,结合LC-MS、GC-MS等分析技术与代谢组学的分忻手段,联合“毒(效)性物质组-减毒-增效物质组-增效”体内体外相应整体代谢特征的研究模式,对四逆汤中附子.与甘草合煎减毒增效机制进行研究。旨在系统探寻四逆汤中附子与甘草合煎达到减毒增效的物质基础和作用机制,以期为整体、系统地研究中药复方合煎配制理论提供新思路。
方法与结果
1.必逆汤制备工艺和质量标准研究：以甘草酸、3种双酯型生物碱(新呜头碱、乌头碱、次乌头碱)、6-姜辣素的含量、干膏量为指标,对比分析传统煎煮工艺与《中国药典》制备方法的差异,结果表明传统制备方法较药典制备方法为优。以3种单酯型生物碱(苯甲酰新乌头原碱、苯甲酰乌头原碱、苯甲酰次乌头原碱)的含量之和、甘草酸的含量及干膏收率为化学指标,以小鼠的抗脑缺氧能力(喘气次数和喘息时间)为药效指标,首先采用L9(34)正交设计试验优选四逆汤的制备工艺；再运用MATLAB建立的前馈型人工神经网络模型进一步优化工艺参数,并进行验证试验。确定最佳制备工艺参数为：加8倍量水,提取3次,每次提取1.5h。四逆汤质量标准研究中,采用薄层色谱法对甘革、干姜两味药材进行攀别,采用HPLC对3种单酯型生物碱及甘草酸进行含量测定,制定本品提取液(0.8g·mL-1)每1mL含3种单酯型生物总量不得少于25.00μg、甘草酸不得少于8.00mg。
2.四逆汤(缺甘草与否)双酯型牛物碱含量变化及次乌头碱药代动力学研究：建立LC-MS测定四逆汤与缺甘草四逆汤(附子和干姜)中3种双酯型生物碱的方法,并对次乌头碱大鼠体内吸收过程影响的对比研究。结果表明四逆汤样品中3种双酯型生物碱含量明显低于缺甘草四逆汤样品的3种双酯型生物碱含量,且存在显著性差异(p<0.01)；四逆汤与缺甘草四逆汤相比次乌头碱的体内吸收速率减慢,吸收总量却增加。
3.四逆汤(缺甘草与否)对MI-RI大鼠心肌细胞代谢组学研究：建立了体外H9c2心肌细胞MI-R1模型,研究四逆汤(缺甘草与否)对模型损伤细胞的毒-效作用,并采用GC-MS联用技术对细胞培养液进行代谢组学研究。结果表明,与缺甘草四逆汤相比,四逆汤对MI-R1模型对H9c2心肌细胞的损伤保护作用更强；四逆汤中附子与甘草合煎减赢增效机制与糖酵解、脂质代谢、三羧酸循环和氨基酸代谢中的氮的代谢等生物代谢途径有关。
4.四逆汤(缺甘草与否)血浆组分GC-MS代谢指纹分析及代谢组学研究：采用GC-MS技术建立大鼠血浆的代谢指纹谱,并进行代谢组学研究,从整体代谢调控模式证实四逆汤中附子与甘草合煎减毒增效的机制与糖酵解、脂质代谢、三羧酸循环和氨基酸代谢等生物代谢途径有关。
结论
本论文基于生物药剂学理论,进一步证实了四逆汤中附子与甘草合煎对附子“毒性成分组”体外结合-体内缓释的“减毒增效”这一传统理论的科学性；通过代谢组学研究,揭示了四逆汤中附子与甘草合煎的减毒增效机制与糖酵解、脂质代谢、三羧酸循环及氨基酸代谢等生物代谢途径有关,为整体、系统地研究中药复方配制理论提供新的思路与方法。
Sini Decoction (SND), a classical Traditional Chinese Medicine formula recorded in Treatise on Febrile Diseases(Shanghan Lim), which is composed of Radix Aconiti Lateralis Preparata. Radix Glycyrrhizae preparata and Rhizoma Zingiberis, is a representative formula, with the function of restoring yang from collapse. Modern clinical and recent researches have shown that SND can protect the myocardium effectively during myocardial ischemia reperfusion injury. Mixed-decoction of Radix Aconiti Lateralis Praeparata and Radix Glycyrrhizae belongs to one of the basic requirements for Chinese decoction, and the purpose of attenuate and synergistic can be reached according to mixed-decoction of Chinese medicine compound.
Objective
This thesis is guided by integrally concept and systematic ideas, which are suitable for the whole concept and dialectical view of Traditional Chinese Medicine. The idea that attenuate and synergistic effects of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND are related to a variety of chemical components from effects on organisms and the organisms reply, will be proposed. Based on the theory of biopharmaceutics, the analytical tools of LC-MS, GC-MS and metabonomics, and the research pattern of'toxic substance group-weakened-synergistic materials group-synergy' corresponding metabolic characteristics both in vivo and in vitro will be used together, which are usually preferred in studying the attenuate and synergistic mechanism of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND. We aim to explore the material base and mechanisms of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND, in order to provide a new bunch of ideas for studying preparation theory of mixed-decoction of Chinese medicine compound integrity and systemically.
Method and Result
1.Study preparation technology and quality standard of SND:
The contents of Glycyrrhizic Acid, DDA(Mesaconitine, Aconitine and Hypaconitine),6-gingerol and the value of dry extract were set as indexes for comparative analysising SND prepared by different processes between the traditional method and Chinese Pharmacopoeia (2010,1) method. Then the traditional process of SND were chosen. The content of Monoester Diterpenoid Alkaloids (Benzoylmesaconine, Benzoylaconine, and Benzoylneoline), Glycyrrhizic Acid and the ratio of extractum were used as chemical properties. The function of anti-hypoxia of mice is set as the pharmacodynamic index. Firstly, the optimal technical conditions were selected by orthogonal design L9(34). Then ANN model was established to obtain the optimum extraction parameters, and proved by the experiments. The optimal technical parameters were as follows:extracting3times in all, once1.5h, adding8times amount of water. TLC was used to identify Radix Glycyrrhizae and Rhizoma Zingiberis. and the contents of MDA and Glycyrrhizic Acid in SND were determined by HPLC in the research of the quality standard. It was confirmed that the content of MDA should be more than25.00μg·mL-1in SND (0.8g·mL-1), and the content of Glycyrrhizic Acid should be more than8.00mg·mL-1
2. Compare content change of DDA and pharmacokinetics of hypaconitine between the mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND:
The simultaneous determination method of DDA in supernatant of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND was estimated. The pharmacokinetics of hypaconitine mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND on mice were contracted.The results showed that the content of DDA in SND was lower than the one of SND without Radix Glycyrrhizae, and there were significant differences between them (p<0.01).At the same time, though the absorption rate of hypaconitine was slowed, the total absorption area of hypaconitine was added after mixed-decoction of Radix Glycyrrhizae in SND.
3. Metabonomics research on the effects of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND on MI-RI mouse cardiomyocytes based on GC-MS:
A myocardial ischemia reperfusion injury model of H9c2cardiomyocytes in vitro was established.The effect of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND on myocardial ischemia reperfusion injury in H9c2 cardiomyocytes was studied.and the metabonomic method using GC-MS was developed to research the metabolic profile of extracellular fluid. Compared with the SND without Radix Glycyrrhizae, the protective effect of myocardial ischemia reperfusion injury model of H9c2cardiomyocyte from SND was stronger. The attenuation and synergistic mechanism of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND were related with the glycolysis, lipid metabolism, citrate cycle and nitrogen metabolism of amino acids metabolism.
4.Metabolomic fingerprinting analyze and metabonomics research of mice plasma on mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae or not in SND based on GC-MS:
Metabolomic fingerprint and metabonomics of mouse plasma based on GC-MS were adopted. From the integrally modes of metabolic regulation,it is proved that the attenuation and synergistic mechanism of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND were related with the glycolysis,lipid metabolism, citrate cycle and some amino acids metabolism.
Conclusion
In this thesis,based on biopharmaceutics theory, we have confirmed that mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND, which is the main toxic component of Radix Aconiti Lateralis Preparata united in vitro firstly, as well as liberated and absorbed slowly while in vivo, and realised the'attenuation and synergistic". It doses not only reveal that the attenuate and synergistic mechanisms of mixed-decoction of Radix Aconiti Lateralis Preparata and Radix Glycyrrhizae in SND are related with the glycolysis, lipid metabolism, citrate cycle and some amino acids metabolism, but also provide a new method and idea for studying preparation theory of mixed-decoction of Chinese medicine compound integrally and systematically.
引文
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