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Antimicrobial Agents and Chemotherapy, May 2004, p. 1837-1847, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1837-1847.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mouse Model of Cervicovaginal Toxicity and Inflammation for Preclinical Evaluation of Topical Vaginal Microbicides

Bradley J. Catalone,^1, Tina M. Kish-Catalone,^1, Lynn R. Budgeon,² Elizabeth B. Neely,¹ Maelee Ferguson,¹ Fred C. Krebs,³ Mary K. Howett,⁴ Mohamed Labib,⁵ Robert Rando,⁵ and Brian Wigdahl^3*

Department of Microbiology and Immunology,¹ Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033,² Department of Microbiology and Immunology and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129,³ Department of Bioscience and Biotechnology, Drexel University, Philadelphia, Pennsylvania 19104,⁴ Novaflux Biosciences, Inc., Princeton, New Jersey 08540⁵

Received 9 December 2002/ Returned for modification 20 February 2003/ Accepted 25 November 2003

Clinical trials evaluating the efficacy of nonoxynol-9 (N-9) as a topical microbicide concluded that N-9 offers no in vivo protection against human immunodeficiency virus type 1 (HIV-1) infection, despite demonstrated in vitro inactivation of HIV-1 by N-9. These trials emphasize the need for better model systems to determine candidate microbicide effectiveness and safety in a preclinical setting. To that end, time-dependent in vitro cytotoxicity, as well as in vivo toxicity and inflammation, associated with N-9 exposure were characterized with the goal of validating a mouse model of microbicide toxicity. In vitro studies using submerged cell cultures indicated that human cervical epithelial cells were inherently more sensitive to N-9-mediated damage than human vaginal epithelial cells. These results correlated with in vivo findings obtained by using Swiss Webster mice in which intravaginal inoculation of 1% N-9 or Conceptrol gel (containing 4% N-9) resulted in selective and acute disruption of the cervical columnar epithelial cells 2 h postapplication accompanied by intense inflammatory infiltrates within the lamina propria. Although damage to the cervical epithelium was apparent out to 8 h postapplication, these tissues resembled control tissue by 24 h postapplication. In contrast, minimal damage and infiltration were associated with both short- and long-term exposure of the vaginal mucosa to either N-9 or Conceptrol. These analyses were extended to examine the relative toxicity of polyethylene hexamethylene biguanide (PEHMB), a polybiguanide compound under evaluation as a candidate topical microbicide. In similar studies, in vivo exposure to 1% PEHMB caused minimal damage and inflammation of the genital mucosa, a finding consistent with the demonstration that PEHMB was >350-fold less cytotoxic than N-9 in vitro. Collectively, these studies highlight the murine model of toxicity as a valuable tool for the preclinical assessment of toxicity and inflammation associated with exposure to candidate topical microbicides.

Present address: Chesapeake Biological Laboratories, Inc., Baltimore, MD 21230.

Present address: Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, MD 21201

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