三黄方抗内毒素活性的药代动力学和药效学研究
摘要
三黄方首载于《金匮要略》,由大黄、黄连和黄芩三味中药组成,具有清热燥湿、泻火解毒等功效,临床多用于热毒证治疗。热毒证与内毒素血症临床症状相似,而清热解毒法作为治疗热毒证的主法贯穿于治疗的始末。本文在中医药理论的指导下,遵循病证结合、方证关联、药与证对应、理法方药统一的原则,提出三黄方可以治疗内毒素血症的研究思路。
目的:
本文以抗内毒素活性为切入点,开展三黄方抗内毒素血症的药代动力学和药效学实验研究,并对三黄方制剂体外抗内毒素活性进行比较,以揭示三黄方有效组分与药效的关系,阐明其作用机理,为三黄方制剂临床应用提供科学依据。方法:
1三黄方制剂体外抗内毒素活性及其化学指纹图谱研究
采用动态浊度法,对不同处方的十二个厂家三黄方制剂的体外抗内毒素活性进行比较。并对十二个厂家的三黄方制剂进行化学指纹图谱初步研究,确认其共有色谱峰,采用聚类分析和主成(?)分析法进行数据分析,探讨影响三黄方制剂质量差异的因素。然后,运用多元线性回归、双变量相关分析法和主成分分析法,分析三黄方制剂化学指纹图谱和体外抗内毒素活性的相关性。
2一清胶囊抗内毒素血症的药效学和药代动力学研究
根据前期实验结果并结合中医药理论,本实验选择三黄方制剂体外抗内毒素活性较强的制剂一清胶囊,作为三黄方的药效学和药代动力学研究的受试对象。
以血清中内毒素、一氧化氮的含量、外周血流动力学、组织形态学等为指标,进行一清胶囊对LPS致犬内毒素血症模型的药效学研究。
根据预实验和参考文献,以大黄酸和黄芩苷为药代动力学研究的指标,开展一清胶囊在空白给药组和模型给药组中的药代动力学研究,测定黄芩苷、大黄酸经时血药浓度。采用DAS软件分析黄芩苷、大黄酸的药代动力学参数,采用T检验对空白给药组和模型给药组药代动力学参数进行分析。
在一清胶囊抗内毒素血症的药效学和药代动力学实验的基础上,以血流动力学、清除内毒素率、抑制NO率为效应指标,黄芩苷、大黄酸的血药浓度为药代动力学指标,探讨一清胶囊药代动力学指标和药效学指标的相关性。
结果:
1三黄方制剂体外抗内毒素活性及其化学指纹图谱研究
不同三黄方制剂的化学成分差异较大,黄芩苷、大黄酸、大黄素是影响制剂质量的主要因素。三黄方制剂中小檗碱、黄芩苷、大黄酸、大黄素、大黄酚、大黄素甲醚等化学成分和体外抗内毒素活性相关性较大。
2一清胶囊抗内毒素血症的药效学和药代动力学研究
一清胶囊能够清除血清内毒素,抑制NO的过度释放,对外周血流动力学参数具有明显的正性作用,还能够改善LPS致Beagle犬内毒素血症脏器组织形态学的病理变化。总之,一清胶囊能够缓解内毒素血症引起的炎症反应。
对空白给药组和模型给药组药代动力学参数进行比较,其中黄芩苷药代动力学参数t_(1/2ka)、k_a、MRT(0-∞),大黄酸药代动力学参数C_(max)、T_(max)、T_(1/2)、K_a、K都存在显著性差异。模型给药组相对于空白给药组,黄芩苷和大黄酸的吸收、代谢速率明显减慢。
血药浓度-效应曲线均呈现出逆时针滞后环,效应的峰值滞后于血药浓度峰值,效应室不在血液室,出现效应滞后于血药浓度的现象。
结论:
本实验综合采用药效学、化学指纹图谱、药代动力学等多学科研究模式,证明了三黄方能够减轻内毒素引起的炎症反应;黄芩苷、大黄素、大黄酚、大黄酸、大黄素甲醚等是三黄方抗内毒素活性的主要有效组分,其中药理效应明显滞后于血药浓度。
创新点:
1提出了三黄方能够抗内毒素血症的研究思路,这为三黄方治疗内毒素血症提供了科学依据。
2建立化学指纹图谱-药效学(体内和体外)-药代动力学结合的方法评价三黄方质量和药效。
San-Huang Formula was firstly recorded in "Jingui Chamber",composed by Radix et Rhizoma Rhei,Rhizoma Coptidis and Radix Scutellariae,with the function of clearing heat-fire,removing dampness and removing toxin,for the treatment of heat-toxin syndrome,which is similar to endotoxemia.According to the characteristics of the principle of the treatment of heat-toxin syndrome,the method of clearing heat and removing toxin is constantly applied.Under the guidance of TCM theory,this paper is based on the research ideas that San-Huang Formula can treat endotoxemia, obeyed the principles of the combination of disease and syndrome,the relevance of formula and syndrome,the correspondence of drug and syndrome,and the unification of theory,method,formula and drug.
OBJECTIVE
Regarding the anti-toxin activity as the breakthrough point,this article had studied pharmacokinetics and pharmacodynamics of anti-endotoxemia of series of San-Huang preparations,and also compared anti-endotoxin activity,in order to reveal the relationship between effective components and effect of San-Huang Formula, elucidate its mechanism and provide scientific basis for the clinical application.
METHODS
1 San-Huang Formula anti-endotoxin activity in vitro and chemical fingerprints
Compared with the anti-endotoxin activity in vitro of the different prescriptions of 12 manufacturers of San-Huang Formula,and preliminarily studied chemical fingerprints as well,all the major peaks had been confirmed by the method of the dynamic turbidity,with cluster analysis and principal component analysis to process statistical data.
2 the pharmacokinetic and pharmacodyamic research of Yiqing Capsule for anti-endotoxemia
According to preliminary results combined with TCM theory,this experiment had been chosen Yiqing Capsule,one of San-Huang preparations with comparative anti-endotoxin activity in vitro.
With the index of the content of endotoxin in the serum and NO,peripheral hemodynamics,histomorphology and so on,Yiqing Capsule had been studied the pharmacodyamics of LPS-induced Beagle endotoxemia,the pharmacokinetics of treatment group and blank treatment group with baicalin and rhein as the index,and the determination of plasma concentration of baicalin and rhein which the pharmacokinetic parameters of had been analyzed by DAS.Treatment group and blank treatment group had been compared the pharmacokinetic parameters by T-test.
On the basis of the pharmacodynamic experiments of anti-endotoxemia of Yiqing Capsule,the relevance of the pharmacodynamic and pharmacokinetic targets had been investigated with effective index of hemodynamics,the removal rate of anti-endotoxin and the inhibiting rate of NO.
RESULTS
1 San-Huang Formula anti-endotoxin activity in vitro and Chemical fingerprints
The results showed that the chemical compositions of San-Huang preparations were of great difference with the main factors of baicalin,rhein and emodin that affected the quality of preparations.The chemical compositions,such as berberine,, baicalin,rhein,emodin,chrysophanol,and aloe-emodin,were correlated with anti-endo-toxin in vitro.
2 the pharmaeokinetic and pharmacodyamic research of Yiqing Capsule for anti-endotoxemia
Yiqing Capsule removed plasma endotoxin,inhibited the excessive release of NO, positively effected the peripheral hemodynamics parameters,apparently improved the pathologic change of histomorphology of LPS-induced Beagle endotoxemia,and also relieved the inflammation caused by endotoxemia.
Contrasted the pharmacokinetic parameters between treatment group and blank treatment group,t_(1/2ka),K_a and MRT(0-∞) of baicalin and C_(max),T_(max),T_(1/2),K_a and K of rhein were of conspicuous disparity,and the velocity of resorption and metabolism of baicalin and Rhein of treatment group was notablely slower blank treatment group.
Both of blood concentration-effect curve appeared significantly hysteresis loop that the peak of effect apparently lagged behind the peak of blood concentration,and the effect room was not in the blood room which appeared the phenomenon that the effect lagged behind the blood concentration.
CONCLUSION
Through the combination of in vitro and in vivo,the chemical fingerprints and effects,and pharmacokinetics and efficacy,San-Huang Formula was proved that could remove endotoxins and reduce the inflammatory caused by endotoxins,with the
目的:
本文以抗内毒素活性为切入点,开展三黄方抗内毒素血症的药代动力学和药效学实验研究,并对三黄方制剂体外抗内毒素活性进行比较,以揭示三黄方有效组分与药效的关系,阐明其作用机理,为三黄方制剂临床应用提供科学依据。方法:
1三黄方制剂体外抗内毒素活性及其化学指纹图谱研究
采用动态浊度法,对不同处方的十二个厂家三黄方制剂的体外抗内毒素活性进行比较。并对十二个厂家的三黄方制剂进行化学指纹图谱初步研究,确认其共有色谱峰,采用聚类分析和主成(?)分析法进行数据分析,探讨影响三黄方制剂质量差异的因素。然后,运用多元线性回归、双变量相关分析法和主成分分析法,分析三黄方制剂化学指纹图谱和体外抗内毒素活性的相关性。
2一清胶囊抗内毒素血症的药效学和药代动力学研究
根据前期实验结果并结合中医药理论,本实验选择三黄方制剂体外抗内毒素活性较强的制剂一清胶囊,作为三黄方的药效学和药代动力学研究的受试对象。
以血清中内毒素、一氧化氮的含量、外周血流动力学、组织形态学等为指标,进行一清胶囊对LPS致犬内毒素血症模型的药效学研究。
根据预实验和参考文献,以大黄酸和黄芩苷为药代动力学研究的指标,开展一清胶囊在空白给药组和模型给药组中的药代动力学研究,测定黄芩苷、大黄酸经时血药浓度。采用DAS软件分析黄芩苷、大黄酸的药代动力学参数,采用T检验对空白给药组和模型给药组药代动力学参数进行分析。
在一清胶囊抗内毒素血症的药效学和药代动力学实验的基础上,以血流动力学、清除内毒素率、抑制NO率为效应指标,黄芩苷、大黄酸的血药浓度为药代动力学指标,探讨一清胶囊药代动力学指标和药效学指标的相关性。
结果:
1三黄方制剂体外抗内毒素活性及其化学指纹图谱研究
不同三黄方制剂的化学成分差异较大,黄芩苷、大黄酸、大黄素是影响制剂质量的主要因素。三黄方制剂中小檗碱、黄芩苷、大黄酸、大黄素、大黄酚、大黄素甲醚等化学成分和体外抗内毒素活性相关性较大。
2一清胶囊抗内毒素血症的药效学和药代动力学研究
一清胶囊能够清除血清内毒素,抑制NO的过度释放,对外周血流动力学参数具有明显的正性作用,还能够改善LPS致Beagle犬内毒素血症脏器组织形态学的病理变化。总之,一清胶囊能够缓解内毒素血症引起的炎症反应。
对空白给药组和模型给药组药代动力学参数进行比较,其中黄芩苷药代动力学参数t_(1/2ka)、k_a、MRT(0-∞),大黄酸药代动力学参数C_(max)、T_(max)、T_(1/2)、K_a、K都存在显著性差异。模型给药组相对于空白给药组,黄芩苷和大黄酸的吸收、代谢速率明显减慢。
血药浓度-效应曲线均呈现出逆时针滞后环,效应的峰值滞后于血药浓度峰值,效应室不在血液室,出现效应滞后于血药浓度的现象。
结论:
本实验综合采用药效学、化学指纹图谱、药代动力学等多学科研究模式,证明了三黄方能够减轻内毒素引起的炎症反应;黄芩苷、大黄素、大黄酚、大黄酸、大黄素甲醚等是三黄方抗内毒素活性的主要有效组分,其中药理效应明显滞后于血药浓度。
创新点:
1提出了三黄方能够抗内毒素血症的研究思路,这为三黄方治疗内毒素血症提供了科学依据。
2建立化学指纹图谱-药效学(体内和体外)-药代动力学结合的方法评价三黄方质量和药效。
San-Huang Formula was firstly recorded in "Jingui Chamber",composed by Radix et Rhizoma Rhei,Rhizoma Coptidis and Radix Scutellariae,with the function of clearing heat-fire,removing dampness and removing toxin,for the treatment of heat-toxin syndrome,which is similar to endotoxemia.According to the characteristics of the principle of the treatment of heat-toxin syndrome,the method of clearing heat and removing toxin is constantly applied.Under the guidance of TCM theory,this paper is based on the research ideas that San-Huang Formula can treat endotoxemia, obeyed the principles of the combination of disease and syndrome,the relevance of formula and syndrome,the correspondence of drug and syndrome,and the unification of theory,method,formula and drug.
OBJECTIVE
Regarding the anti-toxin activity as the breakthrough point,this article had studied pharmacokinetics and pharmacodynamics of anti-endotoxemia of series of San-Huang preparations,and also compared anti-endotoxin activity,in order to reveal the relationship between effective components and effect of San-Huang Formula, elucidate its mechanism and provide scientific basis for the clinical application.
METHODS
1 San-Huang Formula anti-endotoxin activity in vitro and chemical fingerprints
Compared with the anti-endotoxin activity in vitro of the different prescriptions of 12 manufacturers of San-Huang Formula,and preliminarily studied chemical fingerprints as well,all the major peaks had been confirmed by the method of the dynamic turbidity,with cluster analysis and principal component analysis to process statistical data.
2 the pharmacokinetic and pharmacodyamic research of Yiqing Capsule for anti-endotoxemia
According to preliminary results combined with TCM theory,this experiment had been chosen Yiqing Capsule,one of San-Huang preparations with comparative anti-endotoxin activity in vitro.
With the index of the content of endotoxin in the serum and NO,peripheral hemodynamics,histomorphology and so on,Yiqing Capsule had been studied the pharmacodyamics of LPS-induced Beagle endotoxemia,the pharmacokinetics of treatment group and blank treatment group with baicalin and rhein as the index,and the determination of plasma concentration of baicalin and rhein which the pharmacokinetic parameters of had been analyzed by DAS.Treatment group and blank treatment group had been compared the pharmacokinetic parameters by T-test.
On the basis of the pharmacodynamic experiments of anti-endotoxemia of Yiqing Capsule,the relevance of the pharmacodynamic and pharmacokinetic targets had been investigated with effective index of hemodynamics,the removal rate of anti-endotoxin and the inhibiting rate of NO.
RESULTS
1 San-Huang Formula anti-endotoxin activity in vitro and Chemical fingerprints
The results showed that the chemical compositions of San-Huang preparations were of great difference with the main factors of baicalin,rhein and emodin that affected the quality of preparations.The chemical compositions,such as berberine,, baicalin,rhein,emodin,chrysophanol,and aloe-emodin,were correlated with anti-endo-toxin in vitro.
2 the pharmaeokinetic and pharmacodyamic research of Yiqing Capsule for anti-endotoxemia
Yiqing Capsule removed plasma endotoxin,inhibited the excessive release of NO, positively effected the peripheral hemodynamics parameters,apparently improved the pathologic change of histomorphology of LPS-induced Beagle endotoxemia,and also relieved the inflammation caused by endotoxemia.
Contrasted the pharmacokinetic parameters between treatment group and blank treatment group,t_(1/2ka),K_a and MRT(0-∞) of baicalin and C_(max),T_(max),T_(1/2),K_a and K of rhein were of conspicuous disparity,and the velocity of resorption and metabolism of baicalin and Rhein of treatment group was notablely slower blank treatment group.
Both of blood concentration-effect curve appeared significantly hysteresis loop that the peak of effect apparently lagged behind the peak of blood concentration,and the effect room was not in the blood room which appeared the phenomenon that the effect lagged behind the blood concentration.
CONCLUSION
Through the combination of in vitro and in vivo,the chemical fingerprints and effects,and pharmacokinetics and efficacy,San-Huang Formula was proved that could remove endotoxins and reduce the inflammatory caused by endotoxins,with the
引文
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