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Antimicrobial Agents and Chemotherapy, May 2007, p. 1608-1615, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.00984-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Preclinical Safety Assessments of UC781 Anti-Human Immunodeficiency Virus Topical Microbicide Formulations{triangledown}

D. L. Patton,1* Y. T. Cosgrove Sweeney,1 J. E. Balkus,1 L. C. Rohan,2 B. J. Moncla,2,3 M. A. Parniak,2 and S. L. Hillier2,3

University of Washington, Seattle, Washington,1 University of Pittsburgh, Pittsburgh, Pennsylvania,2 Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania3

Received 7 August 2006/ Returned for modification 21 September 2006/ Accepted 2 March 2007

The nonnucleoside reverse transcriptase inhibitor UC781 is under development as a potential microbicide to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1). Two gel formulations of UC781 (0.1% and 1.0%) were evaluated in a range of preclinical safety assessments, including systemic absorption analysis following topical application in the pig-tailed macaque models for vaginally and rectally applied topical microbicides. High-sensitivity high-performance liquid chromatography analysis of serum samples showed that no systemic absorption of UC781 was detected after repeated vaginal or rectal application of either product. However, high levels of UC781 were detectable in the cervicovaginal lavage samples up to 6 h after product exposure. Both formulations were safe to the vaginal microenvironment, even with repeated daily use, as evidenced by colposcopy, cytokine analysis, and lack of impact on vaginal microflora. By contrast, rectal application of the 1.0% UC781 formulation caused an increased expression of numerous cytokines not observed after rectal application of the 0.1% UC781 formulation. These results provide additional support for the continued development of UC781 formulations as anti-HIV microbicides.

* Corresponding author. Mailing address: Department of Obstetrics and Gynecology, Box 356460, University of Washington, Seattle, WA 98195-6460. Phone: (206) 543-5554. Fax: (206) 616-9479. E-mail: dpatton{at}u.washington.edu

{triangledown} Published ahead of print on 12 March 2007.

Antimicrobial Agents and Chemotherapy, May 2007, p. 1608-1615, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.00984-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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