...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Current medicinal chemistry. Anti-infective agents >Preclinical Overview of WHI-07, A Novel Nucleoside Analog-based Dual-Function Microbicide
【24h】

Preclinical Overview of WHI-07, A Novel Nucleoside Analog-based Dual-Function Microbicide

机译：新型核苷类似物双功能杀菌剂WHI-07的临床前概述

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The current pandemic of sexually transmitted HIV/AiDS has created an urgent need for a new type of microbicide, one that is both a spermicide and a virucide. WHI-07 is a novel 5-bromo 6-methoxy aryl phosphoramidate derivative of 3'-azido-3'-deoxythymidine (zidovudine, ZDV/AZT) with potent anti-HIV and spermicidal activities. WHI-07 was rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions, WHI-07 was formulated via a nontoxic gel-microemulsion for intravaginal use as a potential candidate anti-HIV spermicide. The in vivo efficacy as well as safety studies of WHI-07 included: (i) vaginal as well as rectal microbicide efficacy studies in the feline immunodeficiency virus (FIV)/domestic cat model for AIDS; (ii) in vivo retention of anti-HIV activity in the nonhuman primate; (iii) vaginal contraceptive efficacy studies in rabbits; (iv) single- and/or multiple-dose toxicity studies in mice, rabbits, cats as well as monkeys; (v) mucosal, reproductive, and developmental toxicity studies in mice and rabbits; (vi) cytotoxicity, mutagenicity, and genotoxicy tests using human and yeast cells; and (vii) long-term carcinogenicity studies in mice. WHI-07 which exhibited nanomolar in vitro anti-HIV IC_50 and low micromolar spermicidal EC_50 values was significantly less active against genital epithelial cells and did not induce primary DNA damage in human and yeast cells. WHI-07 retained full activity in TK-deficient cells, the main carriers of HIV in semen. Both vaginal as well as rectal instillation of WHI-07 gel-microemulsion, either alone or in combination with a vanadocene dithiocarbamate, effectively protected domestic cats from a subsequent vaginal or rectal exposure to feline T cells chronically infected with a mucosally transmissible FIV strain. WHI-07 gel-microemulsion was a potent vaginal contraceptive in the rabbit model. Both short-term (up to 90 days) and long-term (2-yr) repetitive intravaginal administrations of WHI-07 at concentrations as high as 5.7 X10~6 times its in vitro anti-HIV IC_50 and 5700-times its spermicidal EC_50 were not associated with mucosal, systemic, reproductive or developmental toxicity in mice and rabbits and did not produce increased carcinogenicity in mice. WHI-07 has clinical potential as a safe prophylactic contraceptive anti-HIV microbicide for sexually active women.
机译：当前性传播艾滋病毒/艾滋病的大流行已经迫切需要一种新型杀微生物剂，既是杀精剂又是杀病毒剂。 WHI-07是3'-叠氮基3'-脱氧胸苷（齐多夫定，ZDV / AZT）的新型5-溴6-甲氧基芳基氨基磷酸酯衍生物，具有强大的抗HIV和杀精子活性。 WHI-07经过合理设计，可以绕过生殖道分泌物中ZDV激活对胸苷激酶的依赖性，WHI-07通过无毒凝胶微乳剂制成，可在阴道内使用，作为潜在的候选抗HIV杀精子剂。 WHI-07的体内疗效和安全性研究包括：（i）在猫免疫缺陷病毒（FIV）/家猫对AIDS的模型中阴道和直肠杀菌剂的功效研究; （ii）在非人类灵长类动物体内体内保留抗HIV活性; （iii）兔子的阴道避孕药效研究; （iv）在小鼠，兔子，猫和猴子中的单剂量和/或多剂量毒性研究; （v）在小鼠和兔子中的粘膜，生殖和发育毒性研究; （vi）使用人和酵母细胞的细胞毒性，诱变性和遗传毒性测试; （vii）小鼠长期致癌性研究。 WHI-07表现出纳摩尔的体外抗HIV IC_50和低的微摩尔的杀精子EC_50值，对生殖器上皮细胞的活性明显较低，并且不会在人和酵母细胞中引起原发性DNA损伤。 WHI-07在TK缺陷细胞（精液中HIV的主要携带者）中保留了全部活性。阴道或直肠滴注WHI-07凝胶微乳液（单独或与钒二烯二硫代氨基甲酸酯联用）可有效保护家猫免于随后的阴道或直肠暴露于慢性感染通过粘膜可传播的FIV株感染的猫T细胞。 WHI-07凝胶微乳剂在兔子模型中是有效的阴道避孕药。 WHI-07的短期（最多90天）和长期（2年）重复性阴道内给药，其浓度分别是其体外抗HIV IC_50的5.7 X10〜6倍和杀精剂EC_50的5700倍在小鼠和兔子中与粘膜，全身，生殖或发育毒性无关，并且在小鼠中不产生增加的致癌性。 WHI-07具有临床潜力，可作为性活跃妇女的安全预防性避孕抗HIV杀菌剂。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号