新型天麻素衍生物对大鼠的功能观察组合试验及长期毒性研究

Study on the functional observation battery and long-term toxicity of novel gastrodin derivatives in rats

目的评价新型天麻素衍生物(Gas-D)的安全性。方法根据功能观察组合试验(FOB)方法,单次ig给予大鼠30、100、300 mg·kg^(-1)Gas-D、20 mg·kg^(-1)氯丙嗪及溶媒。观察给药前及给药后0.5、1.5、3、24 h大鼠机体行为、感觉、反射等功能。每天ig给予大鼠150、450、900 mg·kg^(-1)(为临床拟用剂量的10、30、60倍)Gas-D,给药30 d,观察给药期间大鼠长期毒性实验的一般状况及体质量、血液学、血液生化学、脏器系数及病理组织学变化。结果与空白对照组比较,低、中、高剂量Gas-D组大鼠在FOB实验中进食、手指接近、头部接触、唤醒、体温等40余项观察指标均未见异常,氯丙嗪阳性对照组大鼠出现明显的中枢神经抑制(包括行动减少、嗜睡、意识反应变慢、肌张力减小)。与空白对照组比较,连续给药30 d后,低、中、高剂量Gas-D组大鼠的一般状况及体质量、组织病理学未见差异;与空白对照组比较,低、中、高剂量Gas-D组大鼠的血液学(16项)、血液生化学(11项)、脏器系数(8项)均未出现显著性差异。结论单次ig 30、100、300 mg·kg^(-1)Gas-D未见大鼠神经行为发生明显改变。30 d连续ig给予150、450、900 mg·kg^(-1)Gas-D的大鼠长期用药未见明显毒性,按临床拟用剂量、用药途径和疗程是安全的。

OBJECTIVE To evaluate safety of novel gastrodin derivatives(Gas-D).METHODS Rats were given 30,100 and 300 mg·kg^(-1) Gas-D,chlorpromazine 20 mg·kg^(-1) and vehicle in a single intragastric administration.According to the functional observation battery(FOB)test method,the change of behavior,feeling and reflection of rats were observed after administration 0.5,1.5,3 and 24 h post administration.Long-term toxicity test was conducted.Rats were intragastrically administered with Gas-D 150,450 and 900 mg·kg^(-1)(10,30 and 60 times as much as the clinical dosage),and respectively daily for 30 d.The general condition of rats and body weight,the hematology index,blood biochemistry index,viscera coefficient and histopathological changes during administration were observed.RESULTS Compared with the blank control group,the low-,medium-,and high-dose rats in the Gas-D group had no abnormalities in more than 40 observation indexes such as eating,finger approaching,head contact,arousal,and body temperature in the FOB experiment.Significant central nervous system depression(including decreased action,lethargy,slower conscious response,and decreased muscle tone)was observed in the azine-positive control animals.After continuous administration for 30 days,the general condition,body weight and histopathology of the Gas-D low,medium and high dose rats were not different from those of the vehicle control group.Compared with the vehicle control group,there were no significant differences in hematology(16 items),blood biochemistry(11 items),and main organ coefficient(8 items)in the low-,medium-,and high-dose groups of Gas-D.CONCLUSION In the functional observation battery,no obvious changes in central nervous system of rats have been found after intragastric administration.Gas-D has no obvious toxicity in rats for long-term administration according to the clinical dose,route of administration and course of treatment.