A Study On The Relationship Between Substitution - Effect And Toxicity Based On The Thought Of "No Death"

Acoitumn carmchaili Debx.(Fuzi) are heat, toxic, and are the first choice drug of "Yang deficiency". Because of the strong toxicity of Fuzi, some doctors fear theirs toxicity, so they called them tigers and do not dare to use. But in Sichuan, the doctors of "Huoshen faction" are the representative of use of large dose of Fuzi, and often obtain wonders. The clinical usage of Fuzi often exceeds100g even to300g. The clinical usage of Fuzi has great difference. However, the research of dose-effect-toxicity relationship of Fuzi is insufficient.In this study, the thought of "YOU-GU-WU-YUN" was used as the guidance. The dose-effect-toxicity relationship of Fuzi was investigated in the normal animals and model models (Heart failure model). Through this study, we could clarify the objective truth of dose-effect-toxicity relationship of Fuzi, provide recommendations for clinical rational drug, to interpret the feasibility and scientific nature of dialectical attenuated of Traditional Chinese Medicine (TCM), and set an example for the study of dose-effect-toxicity relationship of toxic TCM. The main findings are as follows:1. Acute toxicity and sub-acute toxicity test of FuziAcute toxicity test of Fuzi:The extract of Fuzi was intragastric administrated to normal mice as maximum concentration and volume (equivalent crude drug100g/kg), administered three times a day, and observed the acute toxicity of the normal mice. The results showed that:no death occurred in mice, but toxic reactions significantly occurred.Sub-acute toxicity test of Fuzi:the doses of Fuzi were80g/kg,12g/kg,1.75g/kg, administered (ig) to normal rat three weeks, and observed the sub-acute toxicity of the normal rat. The results showed that:cardiac index all increased in rats of medicated group. Rats appeared part of death in the high dose group. Weight gain of rats in the doses of80g/kg,12g/kg was significantly inhibited.2. Dose-toxicity relationship of Fuzi based on normal animalFuzi extract were administered (ig) to normal rats three weeks as doses of80g/kg, 26g/kg,6.74g/kg,1.75g/kg. Through a series of indicators detected in rats, the response of normal rats in different doses could be evaluated. The results showed that: compared with the normal group, the rats treated with different concentrations of Fuzi occurring toxic reaction, and the toxicity appeared a dose-dependent manner.3. Dose-effect-toxicity relationship of Fuzi based on model animalWe established the rat model of heart failure, and Fuzi extract were administered (ig) to these model rats three weeks as doses of80g/kg,26g/kg,6.74g/kg,1.75g/kg. Through a series of indicators detected in rats, the response of model rats in different doses could be evaluated. The results showed that:compared with the model group, the general condition, blood biochemical parameters, histopathology etc. have improved in the group of the rats treated with different concentrations of Fuzi (1.75g/kg,6.74g/kg,26g/kg), however, the rats administered Fuzi of80g/kg decreased, and increased cardio-toxicity of the model rats.4. A preliminary study on Fuzi treating the heart failure model.Fuzi were given to the heart failure rats with different doses, and observe the changes of myocardial cell apoptosis. The results showed that:compared with normal rats, activity of Casepase-3was significantly increased in the myocardial tissue of model group, and Bcl-2expression decreased. Compared with model rats, activity of Casepase-3was significantly decreased, and Bcl-2expression increased in the group of the rats treated with different concentrations of Fuzi (1.75g/kg,6.74g/kg,26g/kg), however, the rats administered Fuzi of80g/kg decreased has not difference, and Bcl-2expression decreased.5. Comprehensive analysisIn the levels of experimental animal, dose-effect-toxicity relationship of Fuzi test and verify the thought of "You Gu Wu Yun". In the doses of1.75～26g/kg, Fuzi was toxic to the healthy animals, however, produced therapeutic effect to the model rats. These indicated that different status of body leads to different effects. Therefore, accurate differentiation, it will not produce toxic when Fuzi was used in the large doses, and will improve the efficacy.Dose-effect-toxicity relationship of Fuzi to the model rats, and its possible "therapeutic window" range:dose-effect-toxicity relationship of Fuzi to the model rats exists objectively. In the dose range of1.75-26g/kg, Fuzi mainly occurred the treatment, within26～80g/kg range, the damage of the heart failure rats was increased. Based on this,"therapeutic window" of Fuzi in treating heart failure may be possible in the range of1.75～26g/kg.