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目的观察连续6个月重复灌胃给予SY-1对大鼠产生的毒性作用,判断毒性的性质、程度、剂量反应关系和可逆性,提供毒副反应的靶器官,确定无毒反应剂量,为拟定人用安全剂量提供参考。方法 SD大鼠,144只,SPF级,实验设置4个组,分别为SY-1 5.0,15.0和33.6 g生药/kg组及生理对照组,每组36只动物,雌雄各半。连续灌胃给药6个月,每周给药6次,每天1次,周六停药,停药恢复观察1个月。检查指标包括:每天对大鼠进行1次一般观察,每周至少进行1次体重和进食量检查,给药3个月、给药6个月和恢复期结束,进行血液学、血清生化及电解质、凝血功能、解剖检查、脏器统计和组织病理学检查,综合分析供试品对大鼠各项检查指标的影响。结果 SY-1大鼠灌胃给药6个月,主要毒性反应表现为:①一般观察可见各给药剂量组部分动物药后出现短时间流涎症状,分析认为可能是药物的特殊味道对动物的直接刺激引起,非药物全身毒性反应,而各组动物的精神状态、外观体征、行为活动、呼吸等均未见药物相关性异常改变;②一般检查可见中、高剂量组雄性大鼠进食量明显减少,相应剂量组大鼠体重增长缓慢,停药后体重增长和进食量均可逐渐恢复;③临床检验、解剖检查及组织病理学检查各剂量组大鼠各项检查均未见明显异常变化,停药后也未见明显延迟毒性反应;④脏器统计可见中、高剂量组大鼠肝、肾重量或系数轻度升高,变化幅度均在本实验室历史数据正常范围内。结论 SY-1大鼠灌胃给药6个月,可能由于药物的特殊味道引起大鼠出现短时间流涎症状,同时引起中、高剂量组雄性大鼠进食量明显减少,进而导致相应剂量组大鼠体重增长缓慢;SY-1在中、高剂量下可引起大鼠肝、肾重量或系数轻度升高;停药后上述变化均可逐渐恢复。33.6 g生药/kg下虽然可引起大鼠肝、肾重量或系数升高,但变化幅度均在本实验室历史数据正常范围内,且对肝、肾功能和组织结构均无任何异常影响,因此无明显毒理学意义。SY-1灌胃给药6个月大鼠的安全剂量为33.6 g生药/kg(临床拟用剂量的50.1倍),临床长期使用的安全性较好,但实验结果提示临床使用中应注意监测肝、肾相关指标。
Objective To observe the toxic effect of SY-1 on rats after repeated gavage for 6 months, determine the nature, degree, dose-response relationship and reversibility of toxicity, provide target organs for toxic side effects and determine the dose of non-toxic reaction as Proposed to use safe dose for reference. Methods SD rats (144 rats) were randomly divided into 4 groups: SY-1 5.0, 15.0 and 33.6 g crude drug / kg group and physiological control group, with 36 animals in each group. Continuous gavage for 6 months, 6 times a week, once daily, withdrawal on Saturdays, withdrawal observed for 1 month. Checkpoints include: 1 daily observation of rats, weekly body weight and food intake at least once, 3 months, 6 months and convalescence, hematology, serum biochemistry and electrolytes , Coagulation function, anatomy, organ statistics and histopathological examination, a comprehensive analysis of the test for the various indicators of rats. Results The main toxicities of SY-1 rats after 6 months of gavage were as follows: (1) The general observation showed that short-time salivary symptoms appeared after some animal drugs in each dosage group, which may be the special taste of the drugs Directly stimulate, non-drug systemic toxicity, and each group of animals mental state, appearance signs, behavioral activities, breathing and other drug-related abnormalities were no change; ② general examination shows that high-dose group of male rats eating significantly The body weight of rats in the corresponding dose group increased slowly, and the body weight gain and the food intake in the corresponding dose group could be recovered gradually. ③The clinical examination, anatomic examination and histopathological examination showed no obvious abnormal changes in various doses of rats, No obvious delay after stopping the drug toxicity; ④ organ statistics, medium and high dose group rats liver, kidney weight or coefficient of mild increase, the magnitude of change in the laboratory within the normal range of historical data. Conclusion Gavage administration of SY-1 for 6 months may cause short-time salivary symptoms in rats due to the special taste of the drugs. At the same time, the food intake of male rats in medium and high dose groups is obviously decreased, Rat weight growth slow; SY-1 in medium and high doses can cause liver, kidney weight or coefficient of mild increase; after stopping the above changes can be gradually restored. 33.6 g crude drug / kg can cause liver and kidney weight or coefficient increase in rats, but the magnitude of change is within the normal range of the laboratory historical data, and has no abnormal effect on the liver, kidney function and tissue structure, therefore No obvious toxicological significance. The safety dose of SY-1 administered intragastrically for 6 months was 33.6 g crude drug / kg (50.1 times of the clinical dose), and the safety of long-term clinical use was better, but the experimental results indicated that the monitoring should be monitored in clinical use Liver, kidney related indicators.