虎杖提取物抗病毒物质基础、药理作用及代谢研究
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摘要
为了开发我国的植物资源,实现中药现代化,本文运用现代技术手段和方法对中药虎杖进行了研究。用HPLC-MS技术对灌胃大鼠血清药物化学及尿中排泄成分进行了研究,明确了蒽醌类化合物为虎杖的药效物质基础。初步研究了药代动力学,最高血药浓度在4-6h,初步确定了蒽醌类药效成分的排泄途径是经肾排泄,代谢物为原有结构大黄素和与硫酸、葡萄糖醛酸结合的二相代谢物,为二次开发新药进行深入研究奠定了基础。采用CO2超临界流体萃取技术研究了提取蒽醌的最佳工艺条件。对虎杖蒽醌化合物的抗病毒作用进行了较广泛的研究,并对虎杖蒽醌化合物的抗病毒性心肌炎作用及机制、对阿霉素(ADR)中毒性心肌炎的作用及机制进行了较深入的研究。结果表明,虎杖蒽醌化合物对CoxB3型病毒所感染的细胞病变有明显的抑制作用,能有效抑制CoxB3型病毒在靶器官中的繁殖;能促进模型小鼠自身干扰素产生。能明显降低ADR中毒小鼠心肌酶(LDH、CK、HBDH、CKMB)活性,使中毒小鼠心肌MDA含量明显下降,SOD活性显著升高,使血清iNOS活性下降。
本研究为临床开发抗病毒及治疗病毒性心肌炎药物提供了依据。
Rhizoma et radix polygoni cuspidati is the root and rhizoma of perennial herb Polygonum cuspidatum Sieb. et Zucc., which belongs to Polygonaceae, the genus of Polygonum. It was said to have the function of dispelling wind and eliminating dampness, relieving cough and reducing sputum, clearing away heat and toxic materials, and promoting blood circulation and removing blood stasis. In clinical practice of Traditional Chinese Medicine(TCM) it was used to cure damp-heat jaundice, lung-heat and coughing, carbuncle toxin, menostasis and dysmenorrhea,scald caused by water and fire, traumatic injury, and so on. According to modern researches, the 10% water decoction of Polygonum cuspidatum can inhibit HSV-1, HSV-2, influenza virus A jingKe 68-1 and echoviruses(ECHO) 11, well the 10% water decoction of Polygonum cuspidatum also has highly inhibitory effects on adenoviruse type 3, poliovirus-Ⅱ, ECHO 9,coxsackievirus A9 and B5, and Japanese encephalitis virus. It is reported that Polygonum cuspidatum has better effects of direct killing, proliferation inhibiting and infection blocking than ribavirin on CoxB3 virus.
In this article, researches were done on extractives of Polygonum cuspidatum by using modern technique and approaches, aiming at exploiting Chinese botanical resources and realizing modernization of traditional Chinese medicine.Researches were done on serum medicinal chemistry and compositions of excreted urine of lavaged rats by using HPLC-MS technique, The best process condition of extracting anthraquinone were studied by using CO2 hyper- transition fluid abstraction technique. Penetrating researches were done on Polygounm cuspidatum anthraquinone compound’s antivirus effect, therapic effect and mechanisms in viral myocarditis and toxic myocarditis which caused by ADR. The research contens are as follows:
1 Researches were done on extractives of Polygonum cuspidatum serum medicinal chemistry and compositions by using HPLC-MS technique. The best process condition of extracting anthraquinone were studied by using CO2 hyper- transition fluid abstraction technique.The result showed that after extractives of Polygonum cuspidatum intragastric administration trioxymethylanthraquinone ,physcione and chrysophanol are detected.These are intrinsic ingredients in Polygonum cuspidatum and the component of trioxymethylanthraquinone is component high,so deduction is that anthraquinone is pharmaco dynamic material fundition of Polygonum cuspidatum and trioxymethylanthraquinone is the main pharmacodynamic ingredient. Preliminary research pharmacokinetics, the maximum plasma concentration at 4~6h,for the second development has laid a basis of pharmacokinetic study.
2 The best process condition of extracting anthraquinone were studied by using CO2 hyper- transition fluid abstraction technique
3 In this article penetrating researches were done on antivirus effect of Polygounm cuspidatum anthraquinone compound.Studies were carried out on Polygounm cuspidatum anthraquinone compound ,which showed the compound's effects on pathological changes of Hela cells and neonate rat cadiocytes infected by coxsackievirus A9 , HSP-1, adenoviruse type 7,influenza virus H1N1 and ECHO 6 by using vitro infection models of viruses related to viral myocarditis.
By the effects of Polygounm cuspidatum anthraquinone compound, IC50 of Hela infected by coxsackievirus A9 and primary culture neonate rat cadiocytes are 27.02μg/ml and 41.17μg/ml,therapeutic index(TI) are 6.93 and 3.91;IC50 of Hela infected by HSP-1 and primary culture neonate rat cadiocytes are 22.93μg/ml(Hela)and 36.47μg/ml,TI are 8.17 and 4.41;IC50 of Hela infected by adenoviruse type 7 and primary culture neonate rat cadiocytes are 25.35μg/ml and 38.97μg/ml,TI are 7.40 and 4.13;IC50 of MDCK infected by influenza virus H1N1 and primary culture neonate rat cadiocytes are 30.43μg/ml and 34.39μg/ml,TI are 6.16 and 4.68;IC50 of Hela infected by influenza virus H1N1 and primary culture neonate rat cadiocytes are 27.03μg/ml and 40.60μg/ml,TI are 6.93 and 3.97.Results above showed that Polygounm cuspidatum anthraquinone compound had extensive effects of anti-viruses.
4 Effects and mechanisms of Polygounm cuspidatum anthraquinone compound on viral myocarditis caused by CoxB3:①r esults of vitro anti-CoxB3 experiments showed that drugs in different groups have obvious inhibitory effects on Vero infected by CoxB3 virus and primary culture neonate rat cadiocytes and IC50 of Polygounm cuspidatum anthraquinone compound are 27.86μg/m(lVero) and 48.46μg/ml(primary culture neonate rat cadiocytes) and TI are 6.73(Vero) and 4.00(primary culture neonate rat cadiocytes);IC50 of guanidine hydrochloride are both 50μg/ml and TI are 8.02(Vero)and 8.00(primary culture neonate rat cadiocytes).②Virus proliferation inhibiting experiment:Testing virus titer on Vero cell by MTT and calculate TCID50.According to the virus titer test,Polygounm cuspidatum anthraquinone compound had obvious inhibitory effects.③IFN inducing experiments on spleen cells of mouse model and results of IFN dynamic tests in vivo:Polygounm cuspidatum anthraquinone compound could induce IFN in vivo and IFN increased while drug concentration riesd.The same result were gained in mouse serum IFN dynamic change test.④R esults of animal model anti-virus experiments showed that weight of surviving mouse in each drug group increased obviously more than that of mouse in virus infection group(P<0.05),and death rate was also obviously lower than those of virus infection group(P<0.05)and positive drug Rong Xin Wan group.Contents of LDH,AST and CK in mouse serum decreased obviously.⑤Polygounm cuspidatum anthraquinone compound could change the pathological structure of cardiac muscle,relieve pathological changes of myocardial cell caused by CoxB3 virus and lighten symptoms such as myocardial congestion and haemorrhage,hydropic degeneration,myocardial necrosis and inflammatory cell infiltration and so on.
5 In this article the effects and mechanisms of Polygounm cuspidatum anthraquinone compound on protecting toxic myocarditis caused by ADR.The results showed that the compound obviously decreased activity of Enzym(eLD、CK、HBDH、CKMB),then the contents of MDA obviously decreased in toxic mouse cardiac muscle and activity of SOD rised,which lead to decrease of serum iNOS activity.The results of light microscope observation showed that granular degeneration widely occurred in mouse cardiac muscle in model group and local necrosis happened in part of the cardiac muscle,and Polygounm cuspidatum anthraquinone compound could help injured cardiac muscle recover.
6 Have defined the quinine excretion route of the content of anthracene is excreting through the kidney. Natural ingredients and 3 kinds of metabolins were found in urine by LC/MS-MS test after rats taking Polygounm cuspidatum anthraquinone compound extraction,and they were recoganized as emodin, Emodim glu curonide, Aloe-emodin sulfate and Aloe-emodin glu curonide.Among them,emodin appeared as its original ingredient and emodin bonding with GlcUA was the main metabolism way besides original ingredients. The medicine composition is no less than 24h in internal detention time.
7 Safe pharmacology studies were done.Results showed that after dogs were anesthetized by Polygounm cuspidatum anthraquinone compound via duodenum, blood pressure,heart rate and breathing frequency were not influenced; given to mouse via stomach, its autonomic activities were not influenced,but the compound could raise the rate of mouse falling asleep caused by continal at a subthreshold dose.
本研究为临床开发抗病毒及治疗病毒性心肌炎药物提供了依据。
Rhizoma et radix polygoni cuspidati is the root and rhizoma of perennial herb Polygonum cuspidatum Sieb. et Zucc., which belongs to Polygonaceae, the genus of Polygonum. It was said to have the function of dispelling wind and eliminating dampness, relieving cough and reducing sputum, clearing away heat and toxic materials, and promoting blood circulation and removing blood stasis. In clinical practice of Traditional Chinese Medicine(TCM) it was used to cure damp-heat jaundice, lung-heat and coughing, carbuncle toxin, menostasis and dysmenorrhea,scald caused by water and fire, traumatic injury, and so on. According to modern researches, the 10% water decoction of Polygonum cuspidatum can inhibit HSV-1, HSV-2, influenza virus A jingKe 68-1 and echoviruses(ECHO) 11, well the 10% water decoction of Polygonum cuspidatum also has highly inhibitory effects on adenoviruse type 3, poliovirus-Ⅱ, ECHO 9,coxsackievirus A9 and B5, and Japanese encephalitis virus. It is reported that Polygonum cuspidatum has better effects of direct killing, proliferation inhibiting and infection blocking than ribavirin on CoxB3 virus.
In this article, researches were done on extractives of Polygonum cuspidatum by using modern technique and approaches, aiming at exploiting Chinese botanical resources and realizing modernization of traditional Chinese medicine.Researches were done on serum medicinal chemistry and compositions of excreted urine of lavaged rats by using HPLC-MS technique, The best process condition of extracting anthraquinone were studied by using CO2 hyper- transition fluid abstraction technique. Penetrating researches were done on Polygounm cuspidatum anthraquinone compound’s antivirus effect, therapic effect and mechanisms in viral myocarditis and toxic myocarditis which caused by ADR. The research contens are as follows:
1 Researches were done on extractives of Polygonum cuspidatum serum medicinal chemistry and compositions by using HPLC-MS technique. The best process condition of extracting anthraquinone were studied by using CO2 hyper- transition fluid abstraction technique.The result showed that after extractives of Polygonum cuspidatum intragastric administration trioxymethylanthraquinone ,physcione and chrysophanol are detected.These are intrinsic ingredients in Polygonum cuspidatum and the component of trioxymethylanthraquinone is component high,so deduction is that anthraquinone is pharmaco dynamic material fundition of Polygonum cuspidatum and trioxymethylanthraquinone is the main pharmacodynamic ingredient. Preliminary research pharmacokinetics, the maximum plasma concentration at 4~6h,for the second development has laid a basis of pharmacokinetic study.
2 The best process condition of extracting anthraquinone were studied by using CO2 hyper- transition fluid abstraction technique
3 In this article penetrating researches were done on antivirus effect of Polygounm cuspidatum anthraquinone compound.Studies were carried out on Polygounm cuspidatum anthraquinone compound ,which showed the compound's effects on pathological changes of Hela cells and neonate rat cadiocytes infected by coxsackievirus A9 , HSP-1, adenoviruse type 7,influenza virus H1N1 and ECHO 6 by using vitro infection models of viruses related to viral myocarditis.
By the effects of Polygounm cuspidatum anthraquinone compound, IC50 of Hela infected by coxsackievirus A9 and primary culture neonate rat cadiocytes are 27.02μg/ml and 41.17μg/ml,therapeutic index(TI) are 6.93 and 3.91;IC50 of Hela infected by HSP-1 and primary culture neonate rat cadiocytes are 22.93μg/ml(Hela)and 36.47μg/ml,TI are 8.17 and 4.41;IC50 of Hela infected by adenoviruse type 7 and primary culture neonate rat cadiocytes are 25.35μg/ml and 38.97μg/ml,TI are 7.40 and 4.13;IC50 of MDCK infected by influenza virus H1N1 and primary culture neonate rat cadiocytes are 30.43μg/ml and 34.39μg/ml,TI are 6.16 and 4.68;IC50 of Hela infected by influenza virus H1N1 and primary culture neonate rat cadiocytes are 27.03μg/ml and 40.60μg/ml,TI are 6.93 and 3.97.Results above showed that Polygounm cuspidatum anthraquinone compound had extensive effects of anti-viruses.
4 Effects and mechanisms of Polygounm cuspidatum anthraquinone compound on viral myocarditis caused by CoxB3:①r esults of vitro anti-CoxB3 experiments showed that drugs in different groups have obvious inhibitory effects on Vero infected by CoxB3 virus and primary culture neonate rat cadiocytes and IC50 of Polygounm cuspidatum anthraquinone compound are 27.86μg/m(lVero) and 48.46μg/ml(primary culture neonate rat cadiocytes) and TI are 6.73(Vero) and 4.00(primary culture neonate rat cadiocytes);IC50 of guanidine hydrochloride are both 50μg/ml and TI are 8.02(Vero)and 8.00(primary culture neonate rat cadiocytes).②Virus proliferation inhibiting experiment:Testing virus titer on Vero cell by MTT and calculate TCID50.According to the virus titer test,Polygounm cuspidatum anthraquinone compound had obvious inhibitory effects.③IFN inducing experiments on spleen cells of mouse model and results of IFN dynamic tests in vivo:Polygounm cuspidatum anthraquinone compound could induce IFN in vivo and IFN increased while drug concentration riesd.The same result were gained in mouse serum IFN dynamic change test.④R esults of animal model anti-virus experiments showed that weight of surviving mouse in each drug group increased obviously more than that of mouse in virus infection group(P<0.05),and death rate was also obviously lower than those of virus infection group(P<0.05)and positive drug Rong Xin Wan group.Contents of LDH,AST and CK in mouse serum decreased obviously.⑤Polygounm cuspidatum anthraquinone compound could change the pathological structure of cardiac muscle,relieve pathological changes of myocardial cell caused by CoxB3 virus and lighten symptoms such as myocardial congestion and haemorrhage,hydropic degeneration,myocardial necrosis and inflammatory cell infiltration and so on.
5 In this article the effects and mechanisms of Polygounm cuspidatum anthraquinone compound on protecting toxic myocarditis caused by ADR.The results showed that the compound obviously decreased activity of Enzym(eLD、CK、HBDH、CKMB),then the contents of MDA obviously decreased in toxic mouse cardiac muscle and activity of SOD rised,which lead to decrease of serum iNOS activity.The results of light microscope observation showed that granular degeneration widely occurred in mouse cardiac muscle in model group and local necrosis happened in part of the cardiac muscle,and Polygounm cuspidatum anthraquinone compound could help injured cardiac muscle recover.
6 Have defined the quinine excretion route of the content of anthracene is excreting through the kidney. Natural ingredients and 3 kinds of metabolins were found in urine by LC/MS-MS test after rats taking Polygounm cuspidatum anthraquinone compound extraction,and they were recoganized as emodin, Emodim glu curonide, Aloe-emodin sulfate and Aloe-emodin glu curonide.Among them,emodin appeared as its original ingredient and emodin bonding with GlcUA was the main metabolism way besides original ingredients. The medicine composition is no less than 24h in internal detention time.
7 Safe pharmacology studies were done.Results showed that after dogs were anesthetized by Polygounm cuspidatum anthraquinone compound via duodenum, blood pressure,heart rate and breathing frequency were not influenced; given to mouse via stomach, its autonomic activities were not influenced,but the compound could raise the rate of mouse falling asleep caused by continal at a subthreshold dose.
引文
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