| ObjectiveThe basic research on treating AIDS with TCM in China, nowadays in its early stage, is conducted later than that of modern medicine. Research on AIDS with proper animal models is a controllable, reliable and repeatable procedure which can shorten the research process, reduce the confounding factors, and decrease the test risk. Therefore, to some degree, it is much easier to use animal AIDS models to do AIDS research rather than human trial. Although Chinese scholars have done the researches from late1990s, research on animal models with TCM symptoms is still in blank state, which is an obvious barrier to the scientific evaluation of efficacy of TCM on the treatment of AIDS. Rhesus monkey model for AIDS becomes a gold standard for researches on AIDS, and is recommended by WHO. Studies abroad usually use India rhesus monkey. However, due to the fact that the number of the India rhesus monkey deceases and they are expensive and strictly restricted to export, they can no longer meet the increasing needs of the scientific research and inhibits the in-depth research on AIDS. Therefore, more and more scholars use sufficient Chinese rhesus monkey to do their research instead of India rhesus monkey. With the fund by "Eleven-Five" national technology support plans, the study investigated a detailed study on Chinese rhesus monkey model for AIDS, including characteristics of healthy monkeys, characteristics of Chinese rhesus monkey model for AIDS and composite model of Chinese rhesus monkey for AIDS symptoms, treatment of rhesus monkey with TCM, and application of the research results. The targets of this case study include:(1) to study the rhesus monkey AIDS model/Syndrome composite model and deepen the awareness of TCM for AIDS through the basic research of the Chinese rhesus monkey;(2) to explore the significance of the theory of Chinese medicine for AIDS treatment by observing effect of TCM intervention under the guidance of TCM theory through composite model of the monkey AIDS syndromes;(3) to optimize the efficacy of Chinese medicine through monkey AIDS model and provide the experimental basis for the further development of new drugs;(4) to study the metabolic interaction of Chinese and Western medicine and provide some examples and experimental evidence to the reasonability of treating AIDS with the combined TCM and Western medicine.Methods1. Theoretical researches and literature reviewThe software of ENDNOTE was used to collect related literature in mainstream medical journals at home and abroad. After close reading of all the literature, we deleted the duplicate or incomplete information, classified the effective literature, and chose the representative ones to summarize the information to understand the latest researches on AIDS and put forward our own ideas. The literature review mainly focused on the following three aspects: the advancement of research on AIDS in modern medicine, the advancement of research on AIDS in TCM, and the advancement of research on animal models. The overall research design was proposed after the literature review.2. Standardization of experimental basis of Chinese rhesus monkey and research on its backgroundIn this part, the standardization of basic researches was done to ensure that the results are accurate, reliable and repeatable. Meanwhile, the background of Chinese rhesus monkey was studies to strengthen the understanding the research background of animal model. They can be divided into two major parts:the establishment of standard procedures of empirical study on Chinese rhesus monkey model for AIDS (Standard Operating Procedure in the lab), and research on the referrence ranges of indicators about the healthy Chinese rhesus monkey. The former was mainly about the establishment of standard on the experiment, testing, operation and observation of the Chinese rhesus monkey, and the latter was about the normal referrence ranges of various indicators under the condition of this study.3. Research on Chinese rhesus monkey model for AIDSThis part was the detailed study on the Chinese rhesus monkey model and it involved various stages of AIDS. There were mainly four steps in the study: Firstly, we compared the changes of T-lymphocyte subsets and viral load during the acute infectious period; Secondly, we monitored the changes of T-lymphocyte subsets, viral load, hematological variables in TCM-syndrome and clinical symptoms regularly and sequentially; Thirdly, we investigated the survival condition of the Chinese rhesus monkey model and finally we explored the TCM pathogenesis of the disease based on the results of the previous three steps. The purpose of these researches was to find out the characteristics of the changes of the disease and provide some theoretical guidance for treating AIDS with TCM.4. Research on composite model of Chinese rhesus monkey for AIDS symptomsThis part was the detailed study on Chinese rhesus monkey model with TCM symptoms. The key point of the study was to build composite model of Chinese rhesus monkey for AIDS with symptom of spleen-deficiency and composite model of Chinese rhesus monkey for AIDS with symptom of kidney-deficiency and compare the characteristics of the changes of the indicators through experiment. What's more, we compared the therapeutic effects of the TCM therapy like kidney-tonifying therapy, spleen-tonifying therapy and heat-releasing therapy in the treatment of AIDS. The advantages and characteristics of each therapy were analyzed and summarized to put forward an optimized TCM prescription for the treatment of AIDS.5. Application of the research resultsIn this part, we applied the results of previous researches. Based on the summarized basic knowledge on pathogenesis, we selected drugs and tested the effect of TCM intervention in advanced AIDS period. We also tested the synergy of the refined and optimized TCM prescription on single plant chemicals/western medicine in various models and healthy volunteers through metabolic interaction studies on Chinese and Western medicine.Results1. TCM medicine is effective to prevent and treat AIDS, which is unlikely to develop the drug resistance and has a small or mild side effect. Rhesus monkey model for AIDS is the golden standard of the animal models for AIDS, and it is widely used in AIDS research. In the TCM research, animal models are used to establish the TCM-symptoms model, so it is necessary and feasible to establish the Chinese rhesus monkey model to evaluate the efficacy of TCM on the treatment of AIDS. The overall research design consisted of four steps: step1, standardization of experimental basis of Chinese rhesus monkey and research on its background; step2, research on Chinese rhesus monkey model for AIDS; step3, research on composite model of Chinese rhesus monkey for AIDS symptoms; and step4, research on the optimization of anti-AIDS TCM prescription through different animal AIDS model.2. During the standardization of experimental basis of Chinese rhesus monkey and research on its background, the Standard Operating Procedure (SOP) on Chinese rhesus monkey model for AIDS was established. It includes SOP of the rhesus monkey experiment, SOP of the basic experimental testing, SOP of basic experimental observation, SOP of building the animal model, SOP of experimental drug production and use, SOP of disease prevention in rhesus monkey and SOP of data analysis. Furthermore, the normal referrence ranges of36indicators (including13items about routine blood test,4items about liver and kidney function,12items about TCM symptoms and7items about T-lymphocyte subset) were defined after the research on healthy Chinese rhesus monkey.3. A long-term in-depth study on Chinese rhesus monkey model on AIDS was conducted. Analyzing the changes of indicators like T-lymphocyte subset and viral load in acute period, we found plasma viral load reached its peak in10to14days and then exhibited fluctuating decrease trend as a whole, while the percent of CD4+in T-lymphocyte subset decreased and the ratio of CD4+/and CD8+was at its lowest when viral load reached its peak and then the ratio increased. As for the percent of CD8+,it increased during the whole acute period. The18-month-observation to the monkey model indicated that the percent of CD4+and the ratio of CD4+and CD8+exhibited fluctuating decrease trend as the infection progressed, whereas the viral load fluctuated around the set point by0.5logarithmic fluctuations. The variable related to TCM-syndrome like Cor exhibited fluctuating decrease trend as the infection progressed. The analysis of the data about the monkey model between AIDS period and death showed that the CD4+%, CD8+%, the value of CD4+/CD8+, and CD4+counts were closely related to the disease condition, but the decrease of T3was closely related to the deterioration of the disease, while the Cor level increased lto2months before death. The analysis of the survival condition of the animal model indicated that the median survival time of the monkey model infected with SIVmac239was about2years. The exploration of TCM pathogenesis through AIDS model showed that the cause of AIDS was Ai-pathogen, and the pathogenesis manifested as the invasion of Ai-pathogen, the struggle between the Ai-pathogen and healthy qi in acute infection period, then the incubation of Ai-pathogen and injury to the healthy qi in incubation period, then excess of Ai-pathogen and insufficiency of healthy qi in pre-AIDS period, and finally the deficiency of vitality in typical AIDS period.4. The study created two composite model of Chinese rhesus monkey for AIDS with symptoms of spleen-deficiency and two composite model of Chinese rhesus monkey for AIDS with symptoms of kidney-deficiency successfully for the first time. That is spleen-deficiency type I, spleen-deficiency type II, kidney-deficiency type I, and kidney-deficiency type II. The clinical symptoms of spleen-deficiency composite model include decreased food intake, slow growth of the body mass, diarrhea and significant decline of the ratio of hematological indicators like triiodothyronine(T3), CD4+%and CD4+/CD8+,whereas in the kidney-deficiency composite model, the clinical symptoms showed as chills, listlessness, weight loss, diarrhea and significant decline of the ratio of hematological indicators like triiodothyronine (T3), Cor, CD4+%and CD4+/CD8+. Detailed research found that in spleen-deficiency type I, the effect of modeling factors on the disease of AIDS was not significant in the composite model creation stage, but significant after composite model creation stage, which will accelerate the progression of AIDS disease. It also turned out that the therapeutic effect of spleen-tonifying therapy was better than that of heat-releasing therapy for this model. As for spleen-deficiency type II, it showed similarity with the spleen-deficiency type I, but the deficiency of the spleen was more serious and the therapeutic effect of spleen-tonifying therapy was not better than that of heat-releasing therapy. The researches on kidney-deficiency type I indicated that the effect of modeling factors on the disease of AIDS was not significant in model creation stage, but significant on treatment and withdrawal period after the model creation period, which will accelerate the progression of AIDS disease.. The therapeutic effect of kidney-tonifying therapy was better than that of heat-releasing therapy, especially the effect of kidney-tonifying therapy8month after withdrawal. With regard to kidney-deficiency type II, it was much serious than kidney-deficiency type I, and the modeling factors had significant effect on AIDS disease during the model creation stage. Meanwhile, the therapeutic effect of kidney-tonifying therapy was better than that of heat-releasing therapy and the disease with this model progressed quickly without treatment. Based on the summary of experience of TCM intervention through animal AIDS model/composite model of Chinese rhesus monkey for AIDS symptoms, we optimized the original kidney-tonifying prescription and put forward the new one (optimized prescription) according to the pathogenesis of AIDS in monkey models.5. The research results can be applied in several aspects. Based on the researches results of the pathogenesis of AIDS, the use of Shenfu injection for treating Chinese rhesus monkey model in the late stage successfully prolonged the survival time of the diseased monkey, alleviated the clinical symptoms and slowed down the progression of the disease. In addition, the results of treating monkey AIDS model with the optimized prescription of combination of single plant chemicals showed that the combination of TCM and single plant chemical E can significantly enhanced the efficacy of single plant chemical E without any obvious side effect. The experimental study on the effect of protease inhibitors indinavir on the plasma concentration in monkey AIDS animal model/healthy volunteers indicated that the combination of optimized prescription and indinavir significantly increased the plasma concentration of indinavir and played a role in slowing down the clearing rate of indinavir in the healthy volunteers.Conclusions1. The literature review shows that TCM has a significant effect on the prevention and treatment of AIDS and indicates that the in-depth research of TCM on AIDS prevention and treatment may make big progress or have a breakthrough. It also clarifies the fact that it is easier to use proper animal AIDS models to do AIDS research rather than human trial and the researches with animal models are controllable, reliable and repeatable procedures which can shorten the research process, reduce the confounding factors, and decrease the test risk, which proves the feasibility of the establishment of composite model for ADIS with TCM symptoms by Chinese rhesus monkey.2. The establishment of standard procedures of empirical study on Chinese rhesus monkey model for AIDS (Standard Operating Procedure in the lab) basically guarantees accuracy and reliability of the research results and lays foundations to the standardization of operation, testing and observation of the experiment on Chinese rhesus monkey. The definition of normal fluctuating ranges of indicators of Chinese rhesus monkey under healthy condition provides related criteria to the correct judgment of the results.3. Chinese rhesus monkey model for AIDS can reflect the changes of disease condition of AIDS, which is applicable in the various researches on AIDS. According to the Chinese rhesus monkey model, the cause of AIDS was Ai-pathogen, and the pathogenesis manifested as the invasion of Ai-pathogen, the struggle between the Ai-pathogen and healthy qi, then the incubation of Ai-pathogen and injury to the healthy qi, then excess of Ai-pathogen and insufficiency of healthy qi, and finally the deficiency of vitality and exhaustion of five zang and six fu (the internal organs), qi blood and ying and yang.4. The composite AIDS model with TCM symptoms varies, and they have different effect on the progression of AIDS and TCM intervention. The study indicates that the disease condition of the composite AIDS model with TCM symptoms is more serious than the simple AIDS model. The comparison of the therapeutic effect indicates that the treatment with TCM is much better than non-treatment, among which kidney-tonifying therapy is better than heat-releasing therapy and the therapeutic effect of spleen-tonifying therapy and heat-releasing therapy is different in different models.5. The application of the results proves the therapeutic effect of TCM on the treatment of AIDS, and also the benefits of treating AIDS with combined drug use of TCM and modern medicine, which theoretically provides some examples and research ideas for the reasonability of treating AIDS with the combined TCM of single plant chemicals and Western medicine.
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