Studies Of The Anti-alzheimer's Disease Compound 9714 On The Long-term Toxicity And Concomitant Toxicokinetics In Beagle Dogs And Toxicogenomics Evaluation

Assessment of drug safety is the necessary part in the course of development of new drugs. The basic means of assessment of drug safety at present are animal experiment, which studied the animals' manifestation, hematology, clinical biochemistry, histopathology etc after medication. People will make these markers the indicator of injured organs for assessment of drug toxicity, and will draw a conclusion from these results of toxicology to treat man—intoxication prototype. Because of species difference between human and animal, there are great pressure for monitoring clinical trial and toxicity of new drugs after go on sale. In recent years, the great development of toxicokinetics and toxicogenomics solved many problems in animal experiments, and consummated the system of assessment of drug safety.9714 is anⅠtype new drug prepared by Institute of Radiation Medicine , Academy of Military Medical Sciences. It's steroid saponin compound. We mainly studied animals' toxic response when they were exposed in the beyond therapy dose of 9714, and simultaneously studied the expose profile of drug in animals. Next, we tried to find the toxic mechanism by DNA micoarray technology, in order to guide the clinical safe medication of drug correctly.First, we had an study of the anti-amentia compound 9714 on the long-term toxicity in beagle dogs. The three dose 10, 30, 90mg.kg-1.d-1 was designed and named big, middle and small dose respectively. A period of medication was 9 months. The following indexes were detected in the period of medication: observation of clinical symptom, detection of elements in blood (white blood count, white blood cell classification count, red blood count, content of hemoglobin, blood platelet count, reticulocyte count), blood coagulation time and platelet aggregation, detection of biochemistry in blood, urinalysis, red blood cell infiltration brittleness experiment, detection of electrocardiogram, pathology observation (system dissection, viscera weight and viscera coefficient, pathological histology observation). It's indicated from results that red blood count in beagle dogs given with 30, 90mg.kg-1.d-1 9714 declined compared with control in medication for 9 months, and have a significant difference in statistics and a dose relativity; At the same time , the MCF of each group have a little increase compared with control. The increase of MCF in animals given with 10,30mg.kg-1.d-1 9714 is approximate, but the increase of MCF in animals given with 90mg.kg-1.d-1 9714 is significant comparatively and have a dose relativity. It shows that 9714 have a little hemolysis trend but not remarkable. The other detection items are all natural during the medication. The pathological histology analysis result shows that there are not any structure abnormality and chatacteristic pathological change in the major target organ liver, kidney and brain tissue.The preliminary concomitant toxicokinetics in beagle dogs is carried at medication for 15 days, 3 months and 9 months. It's indicated that 9714 present in the form of original shape and metabolizable production AⅢ in the body of animals. Following the prolong of medication time, the proportion of AⅢ increased gradually, and at 9 months the drug almost presented in the form of AⅢ completely.In addition, we studied the toxicity function mechanism of 9714 by DNA microarray chip analysis. The reciprocity between drug and cell target protein and cell genome is the function mode of the drug, and the response and the compensation happened in the cell which aroused a series of change of gene expression. This kind of change is earlier than change of cell configuration, so analyses of gene expression have the characteristic of high sensitivity and short detection time. HepG2 cells which are human hepatobalstoma-derived are used in our experiment. The cell line preserves many of the normal functions of the human liver cells, for example, their aldehyde dehydrogenase regulation, their high drug metabolizing capacity and their well-functioning gl...