【摘要】：目的： 本課題屬于軟堅消癭顆粒的長期毒性研究�；谇捌谒帉W實驗探明軟堅消癭顆粒的制備工藝、質量標準及穩(wěn)定性、急性毒性試驗和藥效學的基礎上，本次試驗主要觀察該制劑對大鼠血液學、血液生化學指標是否出現(xiàn)長期毒性反應，以此預測軟堅消癭顆�？赡芤鸬呐R床不良反應，包括不良反應的性質、程度、劑量-反應和時間-反應關系以及可逆性等；推測軟堅消癭顆粒重復給藥的臨床毒性靶器官或靶組織；預測臨床試驗的起始劑量和重復用藥的安全劑量范圍；提示臨床試驗中需要重點監(jiān)測的指標；為臨床中的解毒或解救措施提供參考信息。最終為新藥的研發(fā)提供更可靠的理論依據(jù)，為軟堅消癭顆粒進入臨床試驗階段奠定基礎。 材料與方法： 采用SPF級、體重為120±20g的SD雌雄大鼠各120只，隨機分為對照組、低劑量組、中劑量組、高劑量組各60只，灌胃給予指定劑量的軟堅消癭顆粒處方的提取物。每日灌胃2次，間隔8小時。分別于給藥后3個月（中期）、6個月（末期）各隨機抽取每組1/3數(shù)量的大鼠給予25%烏拉坦腹腔注射麻醉，取動脈血進行血液學、血液生化學 檢測。6個半月（恢復期）將剩余大鼠全部取動脈血做檢測。結果： 1各組雌、雄性大鼠在試驗期間外觀體征、行為活動均無異常變化。 2各組大鼠的體重與攝食量均呈每周遞增趨勢增加。給藥期間軟堅消癭顆粒中、高劑量組大鼠的體重、攝食量分別與生理鹽水對照組比較有顯著性差異（P＜0.05），考慮與灌胃給藥有關。 3血液學指標中，中期低、中劑量組雄性大鼠的WBC、LYMPH、RBC與對照組比較有顯著性差異（P＜0.05），中劑量組的MON與對照組比較有顯著性差異（P＜0.05），低劑量組的MCV、MCH、RC、雌性大鼠的PT與對照組比較有顯著性差異（P＜0.05）。末期中劑量組雄性大鼠的RBC，，高劑量組雌性大鼠的WBC、MCV分別與對照組比較有顯著性差異（P＜0.05）�；謴推谥袆┝拷M雄性大鼠的HGB、高劑量組的MCH分別與對照組比較有顯著性差異（P＜0.05），低、中、高劑量組的RBC與對照組比較有顯著性差異（P＜0.05）；中、高劑量組雌性大鼠的Gran、RDW與對照組比較均有顯著性差異（P＜0.05），高劑量組的MCV、MCH、PLT分別與對照組比較均有顯著性差異（P＜0.05），其余結果顯示均無顯著性差異（P＞0.05）。 4血液生化指標中，中期低、中、高劑量組雄性大鼠的ALT、AST、雌性大鼠的Cr分別與對照組比較有顯著性差異（P＜0.05）。末期中劑量組的TP、ALB與對照組比較有顯著性差異（P＜0.05）�；謴推谥袆┝拷M雌性大鼠的TP、ALB對照組比較有顯著性差異（P＜0.05），中、高劑量組的CR與對照組比較有顯著性差異（P＜0.05）。各組雌、雄性大鼠的GLU均高于正常值范圍。其余結果顯示均無顯著性差異（P＞0.05）。 結論： 軟堅消癭顆粒按試驗的劑量服用時安全，對大鼠的血常規(guī)、肝腎等功能均無明顯的毒副作用�？赏度胂乱徊降呐R床試驗階段。
[Abstract]:Objective: to study the long-term toxicity of Ruanjian Xiaoying granules. Based on the previous pharmacological experiments, the preparation process, quality standard and stability, acute toxicity test and pharmacodynamics of Ruangjian Xiaoying granule, this experiment mainly observed the effect of the preparation on rat hematology. Whether there is long-term toxic reaction in blood biochemistry index, so as to predict the possible clinical adverse reactions caused by Ruangjian Xiaoying granule, including the nature, degree, dose-response, time-response relationship and reversibility of the adverse reactions. The clinical toxic target organ or target tissue of repeated administration of Ruangjian Xiaoying granule was inferred, the initial dose of clinical trial and the safe dose range of repeated administration were predicted, and the key monitoring indexes in clinical trial were suggested. To provide reference information for clinical detoxification or rescue measures. Finally, it provides a more reliable theoretical basis for the research and development of new drugs, and lays the foundation for Ruanjian Xiaoying granules to enter the clinical trial stage. Materials and methods: 120 male and female SD rats of SPF grade, weight 120 鹵20g, were randomly divided into control group, low dose group, middle dose group and high dose group (60 rats). Two times a day, 8 hours interval. At the end of 6 months and 3 months after administration, rats in each group were randomly selected for intraperitoneal injection of 25% uratan, and arterial blood was taken for hematology, and a third of the rats in each group were given intraperitoneal anaesthesia. Blood biochemical examination. 6 and a half months (convalescence) the remaining rats were collected for arterial blood test. Results: 1 there were no abnormal changes in appearance signs and behavioral activities of female and male rats in each group during the experiment. 2 the body weight and food intake of rats in each group increased weekly. There were significant differences in body weight and food intake between the high dose group and the saline control group (P < 0.05). 3There was a significant difference in WBC,LYMPH,RBC between the middle dose group and the control group (P < 0. 05), and the difference between the middle dose group and the control group (P < 0. 05), and the difference between the middle dose group and the control group was significant (P < 0. 05), and there was a significant difference between the middle dose group and the control group (P < 0. 05). The PT of MCV,MCH,RC, female rats in low dose group was significantly different from that of control group (P < 0. 05). The WBC,MCV of female rats in RBC, high dose group was significantly higher than that in control group (P < 0. 05). There was significant difference in MCH between the high dose group and the control group in the middle dose group and the control group in the recovery period (P < 0. 05). The RBC in the middle and high dose group was significantly higher than that in the control group (P < 0. 05), while that in the middle and high dose group was significantly higher than that in the control group (P < 0. 05). The Gran,RDW of female rats in high dose group was significantly different from that of control group (P < 0. 05), and the MCV,MCH,PLT of high dose group was significantly different from that of control group (P < 0. 05). The other results showed no significant difference (P > 0.05). (4) the Cr of ALT,AST, female rats in the middle, middle and high dose groups were significantly different from those in the control group (P < 0. 05). There was a significant difference in TP,ALB between the middle dose group and the control group (P < 0. 05). There was a significant difference in the TP,ALB control group between the middle dose group and the high dose group (P < 0. 05), while the CR in the high dose group was significantly higher than that in the control group (P < 0. 05). The GLU of female and male rats in each group was higher than the normal range. The other results showed no significant difference (P > 0.05). Conclusion: Ruangjian Xiaoying granule is safe to take according to the dosage of test, and has no obvious side effect on blood routine, liver and kidney function of rats. It can be put into the next clinical trial stage.
【學位授予單位】：遼寧中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R285.5

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