The Anti-hydatid Pharmacodynamics Evaluate And Safety Evaluation Of Harmine Derivatives In Mice

Objective:the anti-Echinococcus granulosus activity in mice of the Pharmacodynamic evaluation of the 8 harmine derivatives;And in vivo\in vitro safety evaluation of 11Harmine derivatives with anti-Echinococcus granulosusa ctivity.Methods:?Pharmacod-ynamic evaluation of the 8 harmine derivatives first by using mice model with E.g protoscoleces culture in vitro by intraperitoneal injection and applying B ultrasonic examination to modle of success,with albendazole?ABZ?and harmine?HM?as the positive control drugs,LD₅₀ of harmine derivatives were determined by Bliss method,the dose planning was in accordance with LD₅₀,the drug intervention by intraperitoneal injection was 14 days in a row,to observe the effect of harmine derivatives to mean cyst weight and the cyst inhibition rate,the weight scoring method of the number and diameter of sac varied,histopathological changes of the cyst under both optical and electron microscope,histopathological changes in the liver and brain under optical microscope.?in vivo\in vitro safety evaluation of 11 harmine derivatives with anti-Echinococcus granulosus activity.?1?sub-chronic toxicity in mice,with albendazole?ABZ?and harmine?HM?as the positive control drugs,Design the dose according to the Pharmacodynamic effective dose,the drug intervention by intraperitoneal injection was 28 days in a row,to observe the Safety of harmine derivatives to the daily activities were observed,the mice's body weight,food intake,important organization coefficient,hematology and blood biochemistry were measured,and the histopathological changes were examined.?2?Cytotoxicity test,by using PC12cell and NCTC1469 cell,with harmine?HM?as the positive control drugs,MTT assay performed to test the toxicity of different concentrations of harmine derivatives on PC12cell and NCTC1469 cell.Cell apoptosis rate was detected by flow cytometry.Results:The results of anti-hydatid pharmacodynamics evaluate of harmine derivatives in mice as follows,the modle success rate reached to 70%,after pharmacological intervention,the results of mean cyst weight,the TEM and histopathology show inaddition to H-2-3derivative,The other 7 derivatives?DH-082,DH-208,DH-287,DH-274,DH-211,DH-399,H-2-98?on mice have different degrees of inhibition of Echinococcus.and 5derivatives?DH-082,DH-208,DH-287,DH-399,H-2-98?of anti-Echinococcus effect were similar to ABZ and HM of positive drug;the liver histopathology show 7derivatives?DH-082,DH-208,DH-287,DH-274,DH-211,DH-399,H-2-98?could different degrees of improvement in liver tissue of portal area inflammatory cell infiltration,edema and necrosis of liver cells,5 derivatives?DH-082,DH-208,DH-274,DH-399,H-2-98?were similar to HM of positive drug;The weight scoring method of the number and diameter of sac varied results show that 5 derivatives?DH-082,DH-208,DH-287,DH-274,DH-211,DH-399,H-2-98?have different degrees of inhibition of vesiclea and similar to HM of positive drug;The results of anti-hydatid safety evaluation of harmine derivatives in mice as follows,after pharmacological intervention,Compared with blank group,Behaviors,the intake,body weight and Organ coefficient in mice were normal,the results showed that hematology,In addition to ABZ,H-2-98 derivative group mice of hematology indexes had no abnormal The hematological indexes of other groups were abnormal.Blood biochemical results show in addition to ABZ and 4 derivatives DH-004,DH-145,DH-330,H-2-98groups of mice blood biochemistry was normal;the 7derivatives groups of mice e were abnormal.The results of pathological section showed that the heart,spleen,lung and kidney were normal,liver and brain were abnormal.,MTT assay and Apoptosis results show,PC12 cell,The LC₅₀ value of 4 derivatives?DH-004,DH-330,DH-109,H-2-98?is greater than LC₅₀ value of HM and apoptosis rate was less than HM,NCTC1469 cell,The LC₅₀ value of 6 derivatives?DH-145?H-2-98?DH-330?DH-004?DH-109?DH-082?is greater than LC50 value of HM and the apoptosis rate of 6 derivatives was less than HM.Conclusion:Through the comprehensive evaluation and analysis of detection index,the result show that 7derivatives,?DH-082,DH-208,DH-287,DH-274,DH-211,DH-399,H-2-98?had better effective against experimental infected echinocoecsis granulosis cyst in mice,And 5derivatives?DH-082,DH-208,DH-287,DH-399,H-2-98?of E.g effect were similar to ABZ and HM of positive drug.Through the comprehensive evaluation and analysis of detection index,the result show that 11 compounds with higher safety relative to HM are?DH-004,DH-330,DH-109,H-2-98?.This study also lay the foundation for the research and development of the new drug.