EFFECT OF REPEATED APPLICATIONS OF PRO 2000/5 GEL (P) ON INFLAMMATORY MEDIATORS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。局部杀微生物剂是设计用于预防人类免疫缺陷病毒（HIV）和其他性传播感染（STI）传播的产品。开发安全有效的阴道外用杀菌剂可以在降低全球艾滋病毒传播率方面发挥关键作用。其中一种研究产品是PRO 2000/5凝胶(P)，由Indevus制药公司开发。PRO 2000/5是一种聚阴离子聚合物，由2-萘磺酸、钠盐和亚甲基交替组成。它在体外对多种艾滋病毒分离株有活性，阴道凝胶制剂（PRO 2000/5凝胶）已被证明在性传播感染的动物模型中有效。在I期试验中，发现浓度高达4%的PRO 2000/5凝胶在低艾滋病毒感染风险妇女和无症状艾滋病毒血清阳性妇女中是安全且耐受性良好的。很少有产品进入临床试验，只有含壬氧醇-9 （N-9）的产品进入疗效试验。从N-9试验中得到的宝贵教训是，局部使用杀微生物剂可能会改变女性生殖道粘膜水平的先天免疫反应，并增强艾滋病毒的性传播。虽然通过阴道镜监测宫颈阴道病变是临床安全性杀微生物剂试验的常规部分，但对宫颈阴道粘膜屏障的潜在细微变化知之甚少，包括诱导粘膜炎症。在这项研究中，我们将研究PRO 2000/5凝胶对炎症介质的影响。与安慰剂凝胶相比，每天使用0.5% PRO 2000/5凝胶14天后，将测量与阴道炎症相关的细胞群和细胞因子。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Topical microbicides are products designed to prevent the transmission of human immunodeficiency virus (HIV) and other sexually transmitted infections (STI). The development of safe and effective topical microbicides for vaginal use could play a critical role in reducing HIV transmission rates worldwide. One such investigational product is PRO 2000/5 Gel (P), which is being developed by Indevus Pharmaceuticals, Inc. PRO 2000/5 is a polyanionic polymer consisting of alternating 2-naphthalene sulfonic acid, sodium salt and methylene units. It is active against a wide range of HIV isolates in vitro, and a vaginal gel formulation (PRO 2000/5 Gel) has been shown to be effective in animal models for STI. In Phase I trials, PRO 2000/5 Gel at concentrations up to 4% was found to be safe and well tolerated in women at low risk for HIV infection and in asymptomatic HIV-seropositive women. Few products have entered clinical trials and only nonoxynol-9 (N-9)-containing products have advanced to efficacy trials. A valuable lesson learned from the N-9 trials is that the use of topical microbicides may alter innate immune responses of the female genital tract at a mucosal level and enhance sexual transmission of HIV. While monitoring for cervicovaginal lesions by colposcopy has been a routine part of clinical safety microbicide trials, little is known about potential subtle changes in the cervicovaginal mucosal barrier, including induction of mucosal inflammation. In this study, we will examine the effects of PRO 2000/5 Gel on mediators of inflammation. Cell populations and cytokines associated with vaginal inflammation will be measured following 14 days of daily application of 0.5% PRO 2000/5 Gel compared with placebo gel.