阴道用尼非韦罗凝胶的大、小鼠急性毒性和家兔刺激性研究

摘要

目的:研究阴道用尼非韦罗凝胶的大、小鼠急性毒性和家兔刺激性.方法:取60只小鼠腹腔注射不同浓度( 199、229、263、302、348、400 mg·kg-1)的尼非韦罗凝胶进行全身急性毒性实验,计算半数致死量(LD50),观察14d内小鼠死亡数；对30只大鼠进行阴道急性毒性实验,分别阴道内给予尼非韦罗凝胶（5 mg·kg-1）、空白凝胶,并设阴性对照,观察14d内大鼠体重变化、死亡数及生殖道形态学变化；对12只性成熟家兔进行阴道刺激性实验,分组为机械刺激组（生理盐水）、参比对照组（3％壬苯醇醚）、尼非韦罗凝胶组(1 mg· kg-1)、空白凝胶组,阴道给予相应药物,连续给药10d,按Eckstein刺激性评价标准,以充血、水肿、炎性细胞浸润及上皮脱落为指标进行阴道刺激性评分.结果:尼非韦罗凝胶的小鼠LD50为303.37 mg· kg-1,95％可信限为278.7～333.29mg·kg-1；大鼠14d内无死亡,体重无明显变化,生殖道未见异常分泌物；4组家兔阴道刺激性总分值比较无显著差异,刺激程度均在轻度以下.结论:尼非韦罗凝胶的全身急性毒性属中等毒性,阴道急性毒性和刺激性均在可接受范围内,总体评价较为安全,可作为阴道凝胶剂进行临床试验.%OBJECTIVE: To study the acute toxicity of Nifeviroc vaginal gel in rats and mice and vaginal irritation of it in rabbits. METHODS: In systematic acute toxicity test, 60 mice were selected and intraperitoneal administered with different concentration of Nifeviroc vaginal gel (199, 229, 263, 302, 348, 400 mg·kg-1) to test the median lethal doses (LDs50o), and the number of dead mice were followed for 14 days. In vaginal acute toxicity test, 30 rats were given Nifeviroc vaginal gels 5 mg·kg-1 and blank gel respectively with negative control; the body weight, mortality and morphology of vaginal tract were recorded for 14 days. By Eckstein method, vaginal irritation was study on 12 mature rabbits for continuous 10 days, and they were divided into mechanical irritation group (normal saline), reference control group (3% nonoxynol), Nifeviroc vaginal gel group (1 mg·kg-1), blank gel group; according to Eckstein irritation score, regions of vagina were examined for epithelial ulceration, edema, leukocyte infiltration, and vascular congestion. RESULTS: LD60 of Nefiviroc vaginal gel was 303.37 mg·kg-1 and the 95% creditability was 278.7- 333.29 mg·kg-1 in mice. There was no rat dead in 14 d and no significant change occurred in body weight; no abnormal secretion was observed in vaginal tract. There was no significant difference in vaginal irritation score of the gels in rabbits. Irritation degree of vaginal tract was below slight level. CONCLUSION: In the experimental dose, LD50 of the gels belongs to moderate toxicity,the vaginal acute toxicity and irritation are acceptable. Nefiviroc vaginal gel is safe on the whole and can be used for clinical study of vaginal gel.