Zhang Qianqian, Ye Xiangfeng, Wang Lingzhi, Peng Bangjie, Zhang Yingxue, Bao Jie, Li Wanfang, Wei Jinfeng, Wang Aiping, Jin Hongtao, Chen Shizhong
New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, 100050, China.
Beijing Union-Genious Pharmaceutical Technology Ltd., Beijing, 100176, China.
Regul Toxicol Pharmacol. 2016 Feb;74:117-22. doi: 10.1016/j.yrtph.2015.11.012. Epub 2015 Nov 24.
The aim of this study was to evaluate the embryo-fetal development toxicity of honokiol microemulsion. The drug was intravenously injected to pregnant SD rats at dose levels of 0, 200, 600 and 2000 μg/kg/day from day 6-15 of gestation. All the pregnant animals were observed for body weights and any abnormal changes and subjected to caesarean-section on gestation day (GD) 20; all fetuses obtained from caesarean-section were assessed by external inspection, visceral and skeletal examinations. No treatment-related external alterations as well as visceral and skeletal malformations were observed in honokiol microemulsion groups. There was no significant difference in the body weight gain of the pregnant rats, average number of corpora lutea, and the gravid uterus weight in the honokiol microemulsion groups compared with the vehicle control group. However, at a dose level of 2000 μg/kg/day, there was embryo-fetal developmental toxicity observed, including a decrease in the body length and tail length of fetuses. In conclusion, the no-observed-adverse-effect level (NOAEL) of honokiol microemulsion is 600 μg/kg/day, 75 times above the therapeutic dosage and it has embryo-fetal toxicity at a dose level of 2000 μg/kg/day, which is approximately 250 times above the therapeutic dosage.
本研究旨在评估厚朴酚微乳剂的胚胎-胎儿发育毒性。在妊娠第6至15天，将该药物以0、200、600和2000μg/kg/天的剂量水平静脉注射给妊娠SD大鼠。观察所有妊娠动物的体重及任何异常变化，并在妊娠第20天进行剖宫产；对剖宫产获得的所有胎儿进行外观检查、内脏和骨骼检查。厚朴酚微乳剂组未观察到与治疗相关的外观改变以及内脏和骨骼畸形。与赋形剂对照组相比，厚朴酚微乳剂组妊娠大鼠的体重增加、黄体平均数量和妊娠子宫重量均无显著差异。然而，在2000μg/kg/天的剂量水平下，观察到胚胎-胎儿发育毒性，包括胎儿体长和尾长减少。总之，厚朴酚微乳剂的未观察到不良反应水平（NOAEL）为600μg/kg/天，是治疗剂量的75倍，在2000μg/kg/天的剂量水平下具有胚胎-胎儿毒性，该剂量约为治疗剂量的250倍。
