Study On Hepatotoxicity Factors And Individual Factors Of Blood Stasis Capsules

Zhixue capsule is a kind of pure Chinese medicine compound preparation,by Kushen and Baixianpi two kind of herbs composition,function Indications:Qingrejiedu,cooling blood to stop bleeding.Used to cure the symptoms blood in the stool,anal bulge or fall pain,dry stool or secret embolism caused by ?,? period of hemorrhoids and mixed hemorrhoids.This medicine is contained in the 2004 National Essential Medicines Directory and the National Basic Medical Insurance and Industrial Injury Insurance Medicines Directory.However,in recent years,the National Center of ADR Monitoring has received reports of ADR involving Zhixue capsules,especially the rapid increase in the number of reports in 2008.National drug adverse reaction center seventeenth issue of "adverse drug reactions"reported hemorrhoids capsules caused by liver damage adverse reactions.As of September 25,2008,35 cases of Zhixue capsule were received.Among them,21 cases(60%)of the adverse reactions were described as abnormal liver function,cholestasis hepatitis,drug-induced hepatitis,another 8 cases of abdominal pain,rash in 4 cases,allergic reactions in 1 case,dizziness,headache in 1 case.After analyzing the case system,it cannot rule out the association between Zhixue capsule and liver damage event.In order to study the hepatotoxicity of Zhixue capsules,the causes of hepatotoxicity in hemorrhoid hemorrhage capsules were studied from the factors of drug factors,process factors and individual factors of drug use.Experiment 1:Comparative Study on the hepatotoxicity of Zhixue capsules contained Baixianpi from different producing areas.Objective:observe reaction of hepatotoxicity produced by rats after gave Zhixue capsules contained Baixianpi from different producing areas respectively in a long-term dosage which was divided into low(4.1g·kg-1),medium(8.3g·kg-1)and high(16.5 gkg-1).Methods:Wistar rats were divided randomly into normal group and different doses groups which use high,medium and low dose of Zhixue capsules contained Baixianpi from different producing areas;In gavage method to use distilled water on normal group,high,medium and low dose of Zhixue capsules contained Baixianpi from different producing areas on control groups,all groups are given medication 30d continuously.During given medication,observing rats' common manifestation and change of weight,etc.After final medication,detecting the indicator of serum liver function;Calculating index of viscera;acquire tissues of liver,fix,and observe by microscope after hematoxylin-eosin staining according to the request of pathological examination in liver.Results:Give rats Zhixue capsules contained Baixianpi from different producing areas by gavage 30d continuously,during a given medication,activity,defecating,fur of rats in control groups have no obvious differences with normal groups.After 30d,compared with normal group,biochemistry outcomes ALB,GGT in blood from liver in several groups have increased(P<0.05);Pathological section show that animals' livers which were under influenced by low,medium and high dose of Zhixue capsules contained Baixianpi from five different producing areas respectively both have changed in hyaline cell and hepatic sinusoid expanded.Conclusions:Zhixue capsules contained Baixianpi from five separate producing areas respectively all have obvious hepatotoxicity.Experiment 2:The effect of different extract on the hepatotoxicity of Zhixue CapsuleObjective:To compare the hepatotoxicity of Zhixue Capsule extracts by water and alcohol,so as to discuss the effect of process factors on the safety of traditional Chinese medicine preparation.Method:The 80 Wistar rats were randomly divided into blank control group,and water mention group,and 60%alcohol mention group,and 85%alcohol mention group,The rats in normal group received normal water by gavage,and the rats in other groups received4.1g · kg-1 extraction by gavage,for 30.Orbital venous blood was taken at the last time points after gavage,and the serum was taken by centrifugation.Aspartate aminotransferase(AST)and alkaline phosphatase(ALP),alanine aminotransferase(ALT),total bilirubin(TBIL)in serum were detected to indicate the liver injury.Gather the liver,according to the quality,calculate the viscera index;take liver tissue in the same place of maximum leaves,10%neutral formalin-fixed 48 h,dehydration,paraffin,slicing,HE dyed,pathological examination under the microscope.Result:the ethanol extracts of Zhixue Capsule has clear liver toxicity;Histopathology mainly shows hepatic lobule with liver cells surrounding the small bubble type fatty degeneration;And liver toxicity associated with the ethanol concentration.Conclusion:the effect of processing factors has important influence on the safety of traditional Chinese medicine compound preparations,this prompts new drug research and development should be concerned about the impact of modern technology on safety;there are serious safety risks of overemphasis on composition enrichment.Technology screening should combine the toxin with effect.Experiment 3:Analysis of chemical composition of different extracts of Zhixue capsules.Objective:To analyze the chemical composition of different extracts of Zhixue capsules by HPLC-MS.Methods:Under a unified use of HPLC-MS technology,OPLS-DA analysis was conducted on the main components of the two components.Results:chemical constituents of Zhixue capsules extracted by water,65%alcohol,85%alcohol have obvious content differences,and authenticate its known chemical compounds initially,lay the foundation of a further screening hepatotoxicity's ingredients of Zhixue capsules.Individual factor analysis of Zhixue capsule cause liver damageCompared with syndrome differentiation and treatment of hemorrhoids and attending function of Zhixue capsules and case report review of Zhixue capsules result in liver injury,analyzing individual factors lead to liver injury who used Zhixue capsules.The individual factors of liver injury were analyzed.Found that hemorrhoids capsules appear liver injury in individual factors,including medication is not allowed,medication d does not take into consideration,as well as patients over the course of treatment,overdose and so on.In this study,the long-term toxicity test was conducted in rats by the origin of Baixianpi in Zhixue capsules and the effect of alcohol extraction on the hepatotoxicity of Zhixue capsules.It was clear that one of the principal factors of hemorrhage factor.But whether the dialectical accuracy,whether the use of drugs,and medication has to be in conformity with treatment,dosage and other individual factors,but also hemorrhoids capsules caused by liver injury one of the factors.