Integrated Evaluation And Control Methods For The Quality Of Chinese Herbal Medicines

Quality control is one of the key scientific tissues in the modernization of traditional Chinese medicines （TCM）. Current quality assessment indexes are single and qualitative, lack of systematicness and quantitativity, as well as loose association with clinical efficacy and safety. Thus, we proposed a new integrate evaluation strategy for TCM based on controllability principle, and tried to establish the comprehensive and quantitative evaluation methods for the superior fuzi. On this basis, superiority fuzi detoxicfication products were developed and evaluated. We hope this study could promote the clinical-oriented integration innovation research of TCM, and provide control strategy and technology examples for improving the quality of Chinese medicines and clinical efficacy. The main results and conclusions are as follows:1. Chemical analysisAccording to the requirements of Chinese Pharmacopoeia, the contents of three monoester diterpenoid alkaloids and three diester diterpenoid alkaloids were determined using a HPLC method. Meanwhile, the contents of neoline, songorine, fuziline, and talatisamine were determined using a new established UHPLC/MS-Q-TOF method. The results showed that alkaloids contents in crude fuzi from different regions were different with each other, and these samples from their genuine producing area owned lower toxic ingredients and higher efficacy ingredients. In addition, alkaloids contents in different processed products were also different obviously, which was closely associated with the detoxification technology.2. Toxic constituents index analysisThe minimum lethal dose （MLD） of aconitine, mesaconitine, and hypaconitine were determined and the value was 0.1580,0.1121,0.2919 mg·kg-1, respectively. In which, the toxicity of aconitine was the strongest, which was about 3 times of hypaconitine. Using the reciprocal normalization method, we figured out the toxicity calibration coefficients, and established the equation TCI=100×（0.3387×XMA+ 0.4778×XAC+0.1835×XHA）.Then, ten batches of aconite were selected and their evaluation results of toxic potency （TP）, DDAs, and TCI were compared. Linear regression analysis result suggested that the relevance between TCI and TP was the highest and the correlation coefficient R was 0.954. Prediction error values study also indicated that the evaluation results of TCI was highly consistent with that of TP. These results suggested that TCI is a kind of is rapid, simple, accurate and reliable method, without animals comsumption. In total, TCI is obviously superior to the contents of DDAs recommedation by Ch.P.3. Cardiao activity analysisIn this chapter, the effect of fuzi decoction on the+dp/dt_max in acute heart failure （AHF） rats were investigated to characterize the cardiac activity. After the study of the model drugs, we obtained the modeling method for the AHF rats. Male rats were selected with weight of 250±20g and normal +dp/dt_max of more than 6000, modeling drug solution composed of propafenone hydrochloride and nimodipine injection （1:1） was speed-controlled injected via external jugular vein with the speed of 10ml/h and the amount of 1.0-1.3 ml, at this moment, the +dp/dt_max would decrease more than 50%, and the AHF model was copied successfully. At this point, inj cedilanid, heishunpian decoction, and shenfu injection all can partial restore the heart function of AHF rats, and +dp/dt_max increased significantly, and LVEDP and heart rate improved. Heishunpian was selected as representative and the recovery rate of +dp/dt_max within 15 min was selected as the evaluation index, single factor experiment was designed to test sample preparation method. The results showed that heishunpian was extracted 1-3 times both have cardiao function, however, the cardiao activity weakened with the increase of decoction times; it was extracted 0.5-8h both have cardiao function, however, the cardiao activity did not obviously increase with the extraction time after 1h. Under the conventional dosage （10g/200ml） condition, the best cardiao activity was the extraction of 3 times, and each time for 1h. Further study the cardiao activity of eleven fuzi alkaloids and nine products, the results showed that aconitine and its hydrolysis products were not the cardiao activity substances, neoline, fuziline, songorine, and talatisamine were not the cardiao activity substances.There were obvious activity difference among nine products, and the cardiao activity of Shengfupian was much stronger than others. The above research provides objective and accurate, stable and reliable evaluation method for evaluating the cardiac activity of aconite.4. Preparation and evauation for the fuzi PDPAccording to the conclusion of quality evaluation, we proposed that "reduce water treatment" was the key of fuzi detoxification processing. Condisering active substances retention amount, quality uniformity, and the best extraction, we first designed the specified lengths particles （SLP） based on fresh-processed technology and clinical demands. The results showed that preparing 5 mm SLP by fresh-cutting is rather simple and practicable, with high efficiency and large yield; then, this technology could significantly decrease the ingredients loss and increase the efficacy components; moreover, it was helpful for achieving the quality uniformity and best extraction effects. Based on rat liver mitochondrial thermal model, we found that PDP promoted the energy metabolism was stronger than that of HSP, further studies showed that DDAs inhibit the energy metabolism of mitochondrial, while MDAs promote the energy metabolism. With the heart failure model copyed by adriamycin （ADR）, hemodynamic studies have shown that PDP can significantly improve heart function comparing with HSP. Meanwhile, PDP could improve the content of Na⁺-K⁺-ATPase and Ca²⁺ -Mg²⁺ -ATPase in the myocardial. Pathological study showed that PDP can improve ADR on myocardial injury, reduce myocardial fibers disorder, thinner, dissolved fracture, reduce myocardial cell vacuolar degeneration.To sum up, this paper established the integrated assessment and association efficacy method for the toxicity and efficacy evaluation of fuzi, which provided support for the development of fuzi PDP. This study provides research ideas, methods and examples for the development of other quality of Chinese herbal medicine, also provides the superior quality fuzi processed products for TCM clinical, which was full of important theory value and practice meaning.