Experimental Study For New Carbazole Aminoalcohol Nanometer Preparation In The Treatment Of Alveolar Echinococcosis Mice

Objective: To evaluate the efficacy of carbazole aminoalcohol H1424 active drug and its new nanometer preparation in the treatment of Alveolar echinococcosis mice by oral gavage.At the same time,immunohistochemistry and metabonomics experiments were used to explore the mechanism of drug action on Alveolar echinococcosis mice in vivo.Methods:The 60 female kunming mice abdominal cavity injection method is adopted to establish the bubble type spines ball larva mouse model,after 16 weeks,randomly divided into 6 groups,each group,10 mice carbazole alcohols H1424 technical and nano preparation(high and low dose group respectively according to the100 mg/kg/d,50 mg/kg/d,albendazole technical group according to 50 mg/kg/d),model group give every day 0.2 ml carboxymethyl cellulose(CMC)solution to fill the stomach,another take 10 female kunming mice do blank control group,one day to 0.2ml CMC lavage solution,put in the same culture,for 30 days.Two weeks after the end of treatment,the mice were examined to observe the therapeutic effect of each group.Pharmacodynamic evaluation indexes are as follows :(1)observation of the general morphology of pathological tissue;(2)the wet weight of tomont and the rate of cyst inhibition;(3)The ultrastructural changes of tomont were observed.(4)Changes of toxicological and biochemical indexes in mice.At the same time,through Dab diaminobezidin(DAB)on vascular endothelial growth factor(VEGF)and microvascular density(MVD)in tumor two indicators of immunohistochemical experiment,through the liquid chromatography-mass spectrometry technology in model group,the H1424 technical group and its carrier drug group of metabonomics experiments,combined as a result,to explore the mechanism of drug action.Results: 1.The cyst weight of each drug group decreased compared with the model group.The cyst inhibition rates of H1424 low-dose,high-dose active drug groups and carrier drugs low-dose and high-dose groups were 76.67%,79.63%,86.04% and86.60%,respectively,which were higher than 61.89% of albendazole active drug group.2.The ultrastructure of echinococcosis cysts of mice in each drug group and model group was observed by transmission electron microscopy.The corneum,germinal layer and microvillus structure in each drug group were damaged to different degrees.3.All biochemical indexes of the blood of the mice were normal,and no obvious abnormalities were found in the pathological examination of the organs.4.VEGF and MVD-CD34 were strongly expressed in both the model group and each drug experimental group,and the two indexes in each drug experimental group were decreased to different degrees compared with the model group,but the expression difference between each group was not significant,which was not statistically significant.5.Based on LC-MS non-targeted metabonomics,18 metabolites with significant differences were identified,including a series of metabolites such as choline,phosphatidic acid,DHA,linoleic acid and long-chain acid.Conclusions:1.The active drug carbazole aminoalcohol H1424 and its new nanocarrier-based preparation are significantly effective in vivo for the treatment of Alveolar echinococcosis mice,and have no obvious side effects.It is expected to become a new drug for the treatment of Alveolar echinococcosis.2.A total of 18 metabolites were screened out by LC-MS non-targeted metabolomics technology,which could well distinguish AE individuals from those with outcomes.These metabolites are mainly involved in glycerolipid metabolism,linoleic acid metabolism and arachidonic acid metabolism,and the changes of these metabolites and the metabolic pathways involved can provide new ideas for the development of AE drug targets in the future.3.5.The combination model of 10 metabolites,such as PE(22:6)and 13R-Hode,has the potential to distinguish the disinfected mouse model from the recovered mouse model after intervention,which also indicates that these different metabolites may play a potential role in the recovery process of AE.4.In the disease development process of AE,abnormal Th2 response will be induced in the body,and the Th1 response will be inhibited,so that the ratio between Th1 and Th2 is unbalanced.The new carbazole amino-alcohol nanoagents will make the immune response of the body tend to return to normal.