0.5%鬼臼毒素纳米脂质载体在阴道黏膜的毒性试验

目的考察0.5%鬼臼毒素纳米脂质载体在阴道黏膜的安全性。方法（1）刺激性试验：将12只新西兰兔均分为3组，分别予生理盐水（NS）、0.5%鬼臼毒素酊剂（POD-T）和0.5%鬼臼毒素纳米脂质载体（POD-NLC），阴道给药10 d后取阴道组织行病理检查，根据Eckstein评分标准进行评估。（2）急性毒性试验：将20只SD雌性大鼠均分2 组，分别予赋形剂和POD-NLC，以300倍临床剂量在24 h内分3次阴道给药，连续观察14 d后解剖并计算脏器系数。（3）长期毒性试验：80只SD雌性大鼠均分4组，分别予赋形剂、低剂量POD-NLC（15倍临床剂量）、中剂量POD-NLC（30倍临床剂量）和高剂量POD-NLC（60倍临床剂量）。连续13周每日阴道给药1次，每周记录体质量，给药结束后对每组2/3的大鼠进行抽血化验、解剖并计算脏器系数和肝脏组织病理学检查。为观察药物延迟毒性，每组剩余1/3的大鼠停药观察2周后做同前处理。结果（1）刺激性试验：0.5% POD-NLC对阴道黏膜为极轻刺激性，0.5% POD-T为中度刺激性；（2）急性毒性试验：赋形剂组与POD-NLC组大鼠相比，各器官的脏器系数的差异无统计学意义（P>0.05）；（3）长期毒性试验：赋形剂组与POD-NLC各剂量组大鼠的一般表现、行为活动、体质量变化、血常规、血生化、重要器官脏器系数及肝脏病理未见明显异常，且组间差异无统计学意义（P>0.05）。结论POD-NLC在阴道黏膜用药刺激性较小，对机体无明显的急性及长期毒性，有较高的安全性。

Acute and chronic toxicity of 0.5% podophyllotoxin-loaded nanostructured lipid carriersto vaginal mucosa in rabbits and rats

Objective To test the acute and chronic toxicity of topical application of 0.5% podophyllotoxin-loadednanostructured lipid carriers (POD-NLC) to the vaginal mucosa. Methods Twelve New Zealand rabbits were randomized into3 groups and subjected to daily topical applications of normal saline (control group), 0.5% podophyllotoxin tincture (POD-T)or 0.5% POD-NLC on the vaginal mucosa for 10 consecutive days, and the pathological changes in the mucosa were gradedusing the Eckstein scoring system. The acute toxicity of POD-NLC was tested in 20 SD female rats, which received intravaginaladministration of POD-NLC or vehicle for 3 times within 24 h; After 14 days of continuous observation, the rats were dissectedfor calculating the viscera coefficient. For testing the chronic toxicity of POD-NLC, 80 SD female rats were randomized into 4groups and subjected to daily intravaginal administration of the vehicle or POD-NLC at low, moderate or high doses for 13consecutive weeks. The rats were weighed once a week and at the end of the experiment, 2/3 of the rats from each group weresacrificed to collect blood samples, calculate the viscera coefficient, and examine the pathological changes in the liver. Theremaining 1/3 rats were observed for another 2 weeks without further drug treatment and the same examinations wereperformed. Results In the rabbits, 0.5% POD-NLC elicited only mild irritation while POD-T caused moderate irritation of thevaginal mucosa. In the acute toxicity test, the organ coefficients were comparable between the rats treated with the vehicle andPOD-NLC (P>0.05). Long-term intravaginal administration of POD-NLC did not produce significant changes in the behavior,activity, body weight, blood biochemical profiles or organ coefficient as compared with the vehicle control group (P>0.05).Conclusions Intravaginal administration of 0.5% POD-NLC causes very mild irritation without obvious acute or chronictoxicity to the vaginal mucosa in rabbits and rats.