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. 2018 Dec 30;38(12):1527-1532.
doi: 10.12122/j.issn.1673-4254.2018.12.21.

[Acute and chronic toxicity of 0.5% podophyllotoxin-loaded nanostructured lipid carriers to vaginal mucosa in rabbits and rats]

[Article in Chinese]
Lishi Liu  1 , Kai Han  1 , Qi Wang  1 , Yan Gao  1 , Jingying Wang  1 , Kang Zeng  1
Affiliations

[Acute and chronic toxicity of 0.5% podophyllotoxin-loaded nanostructured lipid carriers to vaginal mucosa in rabbits and rats]

[Article in Chinese]
Lishi Liu et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To test the acute and chronic toxicity of topical application of 0.5% podophyllotoxin-loaded nanostructured lipid carriers (POD-NLC) to the vaginal mucosa.

Methods: Twelve New Zealand rabbits were randomized into 3 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 graded using the Eckstein scoring system.The acute toxicity of POD-NLC was tested in 20 SD female rats, which received intravaginal administration of POD-NLC or vehicle for 3 times within 24 h; After 14 days of continuous observation, the rats were dissected for calculating the viscera coefficient.For testing the chronic toxicity of POD-NLC, 80 SD female rats were randomized into 4 groups and subjected to daily intravaginal administration of the vehicle or POD-NLC at low, moderate or high doses for 13 consecutive weeks.The rats were weighed once a week and at the end of the experiment, 2/3 of the rats from each group were sacrificed to collect blood samples, calculate the viscera coefficient, and examine the pathological changes in the liver.The remaining 1/3 rats were observed for another 2 weeks without further drug treatment and the same examinations were performed.

Results: In the rabbits, 0.5% POD-NLC elicited only mild irritation while POD-T caused moderate irritation of the vaginal mucosa.In the acute toxicity test, the organ coefficients were comparable between the rats treated with the vehicle and POD-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 chronic toxicity to the vaginal mucosa in rabbits and rats.

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。

Keywords: acute toxicity; chronic toxicity; condyloma acuminate; irritation; nanostructured lipid carrier; podophyllotoxin.

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Figures

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1
新西兰兔给药后阴道黏膜肉眼变化及高倍镜下的HE染色结果 Gross observation of the vaginal mucosa of the New Zealand rabbits in normal saline (A), POD-T (B), and POD-NLC (C) groups and pathological examination of the mucosa in normal saline (D, E), POD-T (F, G), and POD-NLC (H, I) groups (HE staining, original magnification: ×400).
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2
长期毒性试验各分组全部大鼠在第1~13周体质量 Comparison of body weight of the rats in longterm toxicity test at weeks 1-13 (Mean±SD).
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3
大鼠肝脏HE染色病理切片在高倍镜下的结果 Pathological section of the liver of the rats in the control (A) and high-dose (B) groups (×400).
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