Microbicides

Improved Macaque Safety Model for Topical Microbicides: Post-coital Assessments

Dorothy L Patton, PhD

Topical microbicides represent an emerging strategy for the prevention of transmission of HIV and other sexually transmitted infections. A successful topical microbicide product could be applied prior to intercourse, and would have activity against a variety of STIs, including HIV. It will be acceptable to potential users in terms of physical characteristics, availability, ease of use, safety and efficacy properties.


We have utilized a macaque vaginal safety model to provide standardized preclinical safety data for numerous topical microbicide products in development. In this model, measures of product safety include cervicovaginal colposcopy, vaginal microbiologic evaluation and vaginal pH monitoring. This model characterizes the vaginal environment's response to repeated topical product applications in the absence of the exogenous factors of intercourse and potentially infectious ejaculate.

While our preclinical evaluations of topical microbicide products have been well-rounded in many aspects, we have yet to investigate the effects of sexual intercourse on the cervicovaginal environment. Mucosal perturbation and potential micro-trauma in the form of epithelial abrasions are likely to result from sexual activity. Additionally, the effects that seminal fluid may induce on the cervicovaginal envirionment, as well as semen's effects on topical microbicide product saftety and efficacy, have not yet received their due attention. It is imperative that these factors be assessed, as they may have significant impact on a topical microbicides's acceptability and efficacy.

We propose to enhance our standardized vaginal safety evaulations conducted in the pigtailed macaque model to include evaluations after sexual activity and with the presence of seminal fluid.

Funding Source: National Institute of Allergy and Infectious Diseases (NIAID)
Contact: Dorothy L Patton, PhD, (206) 543-5554

Topical Microbicide Safety and Efficacy Evaluation in Macaques

Dorothy L Patton, PhD

The objective of these studies is to further the development of topical microbicides aimed at the prevention and control of sexually transmitted infections (STIs) through preclinical testing in nonhuman primates (NHP), utilizing our established models for topical microbicide safety and efficacy evaluations. Macaque models of Chlamydia trachomatis and Trichomonas vaginalis are currently available for efficacy studies in this laboratory.

All test products, provided by NIAID, will first complete safety evaluation with repeated intravaginal product application. If an acceptable safety profile results from these studies, a product will progress (with NIAID approval) to efficacy studies involving one or more STI. Safety measures include microbiologic and pH assessments and documentation of mucosal tissue responses as evidenced by colposcopic evaluation. Efficacy will be determined by a product's ability to prevent infection by the challenge pathogen.

Funding Source: National Institute of Allergy and Infectious Diseases (NIAID)
Contact: Dorothy L Patton, PhD, (206) 543-5554
Ends 5/30/14

Project 2—Nonhuman Primate Studies of Tenofovir and UC781

Dorothy L Patton, PhD

We have developed a useful model to evaluate the safety of topical microbicide products after vaginal use in the pigtailed macaque. We have used this model to study the effects of single and repeated applications of microbicides on vaginal microflora and epithelium. We have conducted preclinical safety and pharmacokinetic studies of vaginal gel formulations containing UC781 (1% and 0.1%) and tenofovir (1%) in this macaque model. In addition, we have the ability to image (MRI) product dispersal and transport in the female reproductive tract.

In this proposed cooperative agreement, a novel delivery system for topical microbicides, vaginal films, will be compared to vaginal gel formulations. We will use our macaque model to assess safety, dispersal and pharmacokinetic characteristics of various film formulations containing UC781 and/or tenofovir, and compare these findings to those compiled for gel formulations. Finally, we will assess the efficacy of each of the developed film products using a macaque model for RT-SHIV infection. These studies will in part guide the optimization of a combination topical microbicide delivery system.

Funding Source: National Institutes of Health (NIH)
Contact: Dorothy L Patton, PhD, (206) 543-5554
Ends 11/30/14