软坚消瘿颗粒对大鼠血液学、血液生化学的安全性研究

发布时间：2018-11-19 10:24

【摘要】：目的：本课题属于软坚消瘿颗粒的长期毒性研究。基于前期药学实验探明软坚消瘿颗粒的制备工艺、质量标准及稳定性、急性毒性试验和药效学的基础上，本次试验主要观察该制剂对大鼠血液学、血液生化学指标是否出现长期毒性反应，以此预测软坚消瘿颗粒可能引起的临床不良反应，包括不良反应的性质、程度、剂量-反应和时间-反应关系以及可逆性等；推测软坚消瘿颗粒重复给药的临床毒性靶器官或靶组织；预测临床试验的起始剂量和重复用药的安全剂量范围；提示临床试验中需要重点监测的指标；为临床中的解毒或解救措施提供参考信息。最终为新药的研发提供更可靠的理论依据，为软坚消瘿颗粒进入临床试验阶段奠定基础。材料与方法：采用SPF级、体重为120±20g的SD雌雄大鼠各120只，随机分为对照组、低剂量组、中剂量组、高剂量组各60只，灌胃给予指定剂量的软坚消瘿颗粒处方的提取物。每日灌胃2次，间隔8小时。分别于给药后3个月（中期）、6个月（末期）各随机抽取每组1/3数量的大鼠给予25%乌拉坦腹腔注射麻醉，取动脉血进行血液学、血液生化学检测。6个半月（恢复期）将剩余大鼠全部取动脉血做检测。结果： 1各组雌、雄性大鼠在试验期间外观体征、行为活动均无异常变化。 2各组大鼠的体重与摄食量均呈每周递增趋势增加。给药期间软坚消瘿颗粒中、高剂量组大鼠的体重、摄食量分别与生理盐水对照组比较有显著性差异（P＜0.05），考虑与灌胃给药有关。 3血液学指标中，中期低、中剂量组雄性大鼠的WBC、LYMPH、RBC与对照组比较有显著性差异（P＜0.05），中剂量组的MON与对照组比较有显著性差异（P＜0.05），低剂量组的MCV、MCH、RC、雌性大鼠的PT与对照组比较有显著性差异（P＜0.05）。末期中剂量组雄性大鼠的RBC，，高剂量组雌性大鼠的WBC、MCV分别与对照组比较有显著性差异（P＜0.05）。恢复期中剂量组雄性大鼠的HGB、高剂量组的MCH分别与对照组比较有显著性差异（P＜0.05），低、中、高剂量组的RBC与对照组比较有显著性差异（P＜0.05）；中、高剂量组雌性大鼠的Gran、RDW与对照组比较均有显著性差异（P＜0.05），高剂量组的MCV、MCH、PLT分别与对照组比较均有显著性差异（P＜0.05），其余结果显示均无显著性差异（P＞0.05）。 4血液生化指标中，中期低、中、高剂量组雄性大鼠的ALT、AST、雌性大鼠的Cr分别与对照组比较有显著性差异（P＜0.05）。末期中剂量组的TP、ALB与对照组比较有显著性差异（P＜0.05）。恢复期中剂量组雌性大鼠的TP、ALB对照组比较有显著性差异（P＜0.05），中、高剂量组的CR与对照组比较有显著性差异（P＜0.05）。各组雌、雄性大鼠的GLU均高于正常值范围。其余结果显示均无显著性差异（P＞0.05）。结论：软坚消瘿颗粒按试验的剂量服用时安全，对大鼠的血常规、肝肾等功能均无明显的毒副作用。可投入下一步的临床试验阶段。
[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 卤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.
【学位授予单位】：辽宁中医药大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R285.5

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