尼非韦罗微乳热敏凝胶对小型猪阴道黏膜炎症刺激性的研究  

Vaginal inflammatory irritation of nifeviroc microemulsion thermosensitive gel in mini-pigs

作　　者：田芳[1] 王玉柱[1] 黄超[1] 夏敏杰[1] 职瑞娜 孙冰[1,2] 丁训诚[1] 周新初[3] 李卫华[1] 

机构地区：[1]上海市计划生育科学研究所国家计划生育药具重点实验室,上海200032 [2]复旦大学公共卫生学院,上海200032 [3]上海交通大学农业与生物学院,上海200032

出　　处：《中国新药杂志》2017年第19期2328-2333,共6页Chinese Journal of New Drugs

基　　金：国家重点研发计划资助项目(2016YFC1000905);上海市科委项目(1514091200);上海市环境卫生和劳动卫生学重点学科建设项目(15GWZK0201);国家科技部中青年科技创新领军人才项目(万人计划)(新型外用避孕药和杀微生物剂的研究)

摘　　要：目的:研究尼非韦罗微乳热敏凝胶(NFVR/ME-TISG)对小型猪阴道黏膜的炎症刺激性。方法:将9只雌性小型猪随机分为基质凝胶组、NFVR/ME-TISG组(25 mg·d^(-1))和壬苯醇醚-9(N-9)凝胶组(25 mg·d^(-1))。肌注苯甲酸雌二醇后12 d,开始阴道给药5 m L·d^(-1),连续7 d,给药前和末次给药后24与72 h,收集阴道灌洗液(cervicovaginal lavages,CVL),流式细胞仪检测CVL中的中性粒细胞,末次给药后72 h收集阴道组织,苏木素伊红染色法(hematoxylin&eosin,HE)评价小型猪阴道黏膜组织溃疡、坏死、细胞浸润、出血、充血、水肿等指标,免疫组织化学法(immuno-histochemical,IHC)检测阴道黏膜组织中CD_(45)^+表达的分布。结果:与基质凝胶组相比,N-9凝胶组CVL中炎性细胞的中性粒细胞数目明显增加(P<0.01),阴道黏膜出现上皮局部脱落、炎性细胞增多、出血和水肿,CD_(45)^+累积光密度(integrated optical density,IOD)值(33.95±6.69)显著增高(P<0.05);而NFVR/ME-TISG组未见明显变化。结论:NFVR/ME-TISG未明显引起小型猪阴道黏膜的炎症刺激性,安全性较好,有望作为阴道外用杀微生物剂候选物进一步研发。Objective： To evaluate the inflammatory irritation of nifeviroc microemulsion thermosensitive gel （NFVR/ME-TISG） in the vaginal mucosa of mini-pigs.Methods： Nine female pigs were randomly divided into matrix gel group,NFVR/ME-TISG group （25 mg·d^（-1）） and nonoxynol-9 （N-9） jelly group （25 mg·d^（-1））.Twelve days after estradiol benzoate intramuscular injection,5 m L of gel was administered intravaginally once daily to the mini-pigs for 7 days.Cervicovaginal lavages （CVLs） were collected predose and at 24,72 h after the final administration.The numbers of neutrophilic granulocytes were analyzed by flow cytometry.Vaginal tissue was collected at 72 h after the final administration.Vaginal sections from each specimen were assessed after hematoxylin eosin （HE） staining,and scored for the following histological features： epithelial ulceration/erosion,necrosis,cell infiltration,hemorrhage,congestion and edema.The CD_（45）~＋ expression in the vaginal mucosa was examined by the im-munohistochemical （IHC） assay.Results： Compared to the matrix gel group,the number of neutrophilic granulocytes of the N-9 jelly group was significantly increased （P 0.01）.The vaginal mucosa of the N-9 jelly group showed obvious histopathological changes including epithelium loss,inflammation,bleeding and edema.CD_（45）~＋ expression in the vaginal mucosa in N-9 jelly group was increased significantly （P 0.05）.However,NFVR/METISG group showed no obvious changes.Conslusion： NFVR/ME-TISG did not induce the inflammatory irritation in the vaginal mocusa of mini-pigs,so they are promising to be developed into a topical microbicide.

关 键 词：小型猪 尼非韦罗 微乳热敏凝胶 炎症 

分 类 号：R994.1[医药卫生—毒理学]