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

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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.