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• Sexually Transmitted Diseases Prevention—Primate Unit
• Improved Macaque Safety Model for Topical Microbicides: Post-coital Assessments
• Project 4 (LB/CV-N and RC101 Primate Testing) of CV-N Secreting Lactobacilli and
Retrocyclin Microbicides
• Topical Microbicide Safety and Efficacy Evaluation in Nonhuman Primates
• Lactobacilli as a Delivery Vehicle for Microbicides
• Animal Models for Combination Microbicides
Sexually Transmitted Diseases Prevention—Primate Unit
Dorothy L Patton, PhD
The purpose of htis contract is to screen biomedical agents supplied by individual product developers. Screening includes a vaginal safety profile as well as potential for preventing vaginal C. trachomatis or T. vaginalis infection in a non-human primate model.
Funding Source: NIH/NIAID
Contact: Dorothy L Patton, PhD, (206) 543-5554
Ends 4/30/14
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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
Ends 8/31/12
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Project 4 (LB/CV-N and RC101 Primate Testing) of CV-N Secreting Lactobacilli and Retrocyclin Microbicides
Dorothy L Patton, PhD
We have developed a useful model to evaluate the safety of topical microbicide products after vaginal and rectal use in the pigtailed macaque. We have used this model to study the effects of single and repeated applications of microbicides on vaginal and rectal microflora and epithelium.
One of the strengths of this macaque model is the similar vaginal microflora shared by the pigtailed macaque and humans. The presence of the endogenous lactobacilli, and of H2O2-producing lactobacilli in particular, provides for studies which determine a product's influence on vaginal microbiology and more importantly on the production of H2O2 in the vaginal milieu, which is known to have antimicrobial properties.
The specific aims of this project are to document the colonization and cyanovirin secretion of an optimized lactobacillus product in the macaque model. Additionally, we will assess the safety of vaginally and rectally applied products in the macaque model.
Funding Source: NIH
Contact: Dorothy L Patton, PhD, (206) 543-5554
Ends 6/30/09
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Topical Microbicide Safety and Efficacy Evaluation in Nonhuman Primates
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 12/31/08
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Lactobacilli as a Delivery Vehicle for Microbicides
Dorothy L Patton, PhD
Research efforts to develop topical microbicides for intravaginal use for prevention of sexually transmitted infections including HIV have been ongoing for nearly a decade. Topical microbicide products must be tested to ensure that the sexual transmission of HIV and other sexually transmitted infections is prevented, and that repeated use of the product does not harm the cervicovaginal environment.
We have developed a useful model to evaluate the safety of topical microbicide products after vaginal use in the pig-tailed macaque. We have used this model to study the effects of single and repeated applications of microbicides on vaginal microflora and epithelium.
A novel microbicide delivery system will be assessed in these studies. Three separately formulated microbicide products will be enrolled in safety studies to determine effects of multiple vaginal applications in the nonhuman primate model.
Funding Source: NIH
Contact: Dorothy L Patton, PhD, (206) 543-5554
Ends 12/31/08
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Animal Models for Combination Microbicides
Dorothy L Patton, PhD
Topical microbicides represent an important potential strategy for preventing the transmission of HIV/STD. It is desirable that a topical microbicide product effective in preventing HIV and STD infections while not irritating the mucosal surface or adversely affecting normal flora of the vagina or rectum, after single and repeated use. It is essential that the in vivo activity of developing topical microbicidal products be evaluated prior to recommendations for widespread intravaginal or rectal use. Because clinical trials are too cumbersome and expensive for screening purposes, animal models need to be used.
In this new proposal, we plan to screen available SIV and SHIV viruses for their susceptibility to compounds that will be used in the combination microbicide product, before adding viral infection to our existing model. While each compound will have proven activity against HIV (as studied in Projects 1-3), we will ensure that they are active against the particular SIV or SHIV variant which will be evaluated in the animal model. Virus selection will be dependent on in vitro assays targeting compound effectiveness in preventing transmission.
As the proposed combination topical microbicide formulation evolves, we will assess safety of intermediary formulated products in the rectal and vaginal environments using our established animal model for topical microbicide safety testing. When the combination product is formulated, and has been shown to be safe for rectal and cervicovaginal use, this topical microbicide will progress to efficacy testing in the newly developed co-infection model. These proposed studies are key to bridging the gap between laboratory and clinical studies aimed at preventing the spread of HIV/STD.
Funding Source: NIH
Contact: Dorothy L Patton, PhD, (206) 543-5554
Ends 7/31/08
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