非甾体抗炎药ZLR-8的大鼠胚胎-胎仔发育毒性实验研究

目的在器官发生期对怀孕大鼠连续给予非甾体抗炎药2-(2,6-二氯苯胺基)苯乙酸-4-(4-苯基-1,2,5-噁二唑-2-氧化物-3-)甲氧基苯甲酯(ZLR-8),观察是否有母体毒性和胚胎毒性。方法将ZLR-8按200,100和50 mg.kg-1于鼠妊娠第7~17 d连续灌胃给药,观察孕鼠饮水、摄食、生长等一般状况。每周称体质量2次,妊娠第20 d处死孕鼠,记录黄体数、胎盘质量、着床数、死胎数、活胎数、胎仔性别及体质量等,观察活仔外观异常。各窝1/2胎仔作骨骼畸形检查,另1/2胎仔作内脏检查。结果 ZLR-8高、中、低剂量组,母体未出现临床中毒症状,但高剂量组初期孕鼠体质量增加抑制。各用药组的着床总数、活胎数、死胎数、吸收胎数、子宫总质量、胎盘总质量、黄体数、胎鼠顶臀长、尾长与溶剂对照组相比,无统计学差异。高、中剂量组对胎鼠体质量有影响,骨骼畸形数也较溶剂对照组明显增多,而低剂量组未见统计学差异。结论对母体一般状况和子代发育均安全的剂量为50 mg.kg-1。

Experimental studies on ZLR-8 toxicity to the development of rat embryos-fetus

Objective To study the toxic reaction of pregnant rats and embryos after given the non-steroidal anti-inflammatory drug ZLR-8 continuously in the period of organogenesis. Methods The pregnant rats were administrated ZLR-8 at the dose of 200, 100 and 50mg·kg^-1 at 7 -15 d. The general conditions of the pregnant rats such as food,water intake, and growth were observed. The rats at 20 d were sacrificed to examine the number of corpus luteums, implantations, alive and dead embryos, weight of placentas, fetus and the gender of the embryos. Half of the fetuses were performed skeleton deformity examination and the others were performed organ examination. Results No clinical toxic symptoms were observed in pregnant rats in all the 3 test sample groups. But the body increase of high dose group（ HDG） were significantly inhibited at the early term of administration. The number of total implantation, alive, dead and absorbed fetus, corpus luteums, the weight of uterus, placenta, the length of the fetus in the 3 test sample groups showed no significantly difference comparing with the solvent control group（ SCG）. The HDG and MDG of the ZLR-8 hade significantly effect to the body weight of the fetus, the skeleton deformity also significantly increased comparing with the SCG（ P 〈0.05 ）. While the LDG didn＇t show the effect. Conclusions The safety dose of ZLR-8 to the general conditions of pregnant rats and development of fetus is suggested to be 50 mg·kg^-1.