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Antimicrobial Agents and Chemotherapy, February 2006, p. 713-723, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.713-723.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Preclinical Testing of Nonoxynol-9 as Potential Anti-Human Immunodeficiency Virus Microbicide: a Retrospective Analysis of Results from Five Laboratories

Brigitte E. Beer,^1* Gustavo F. Doncel,² Fred C. Krebs,³ Robin J. Shattock,⁴ Patricia S. Fletcher,⁴ Robert W. Buckheit Jr.,⁵ Karen Watson,⁵ Charlene S. Dezzutti,^6, James E. Cummins,^6,¶ Ena Bromley,⁷ Nicola Richardson-Harman,⁷ Luke A. Pallansch,^1, Carol Lackman-Smith,¹ Clay Osterling,¹ Marie Mankowski,¹ Shendra R. Miller,³ Bradley J. Catalone,^8, Patricia A. Welsh,⁸ Mary K. Howett,⁹ Brian Wigdahl,³ Jim A. Turpin,¹⁰ and Patricia Reichelderfer¹¹

Southern Research Institute, Frederick, Maryland,¹ CONRAD, Eastern Virginia Medical School, Norfolk, Virginia,² Department of Microbiology and Immunology and Institute for Molecular Medicine and Infectious Diseases, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129,³ University of London, London, United Kingdom,⁴ Imquest BioSciences, Inc., Frederick, Maryland,⁵ Centers for Disease Control and Prevention, Atlanta, Georgia,⁶ BioStat Solutions, Inc., Mt. Airy, Maryland,⁷ Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, Pennsylvania 17033,⁸ Department of Bioscience and Biotechnology, Drexel University, Philadelphia, Pennsylvania 19104,⁹ Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,¹⁰ National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, Maryland,¹¹

Received 2 August 2005/ Returned for modification 10 October 2005/ Accepted 21 November 2005

The first product to be clinically evaluated as a microbicide contained the nonionic surfactant nonoxynol-9 (nonylphenoxypolyethoxyethanol; N-9). Many laboratories have used N-9 as a control compound for microbicide assays. However, no published comparisons of the results among laboratories or attempts to establish standardized protocols for preclinical testing of microbicides have been performed. In this study, we compared results from 127 N-9 toxicity and 72 efficacy assays that were generated in five different laboratories over the last six years and were performed with 14 different cell lines or tissues. Intra-assay reproducibility was measured at two-, three-, and fivefold differences using standard deviations. Interassay reproducibility was assessed using general linear models, and interaction between variables was studied using step-wise regression. The intra-assay reproducibility within the same N-9 concentration, cell type, assay duration, and laboratory was consistent at the twofold level of standard deviations. For interassay reproducibility, cell line, duration of assay, and N-9 concentration were all significant sources of variability (P < 0.01). Half-maximal toxicity concentrations for N-9 were similar between laboratories for assays of similar exposure durations, but these similarities decreased with lower test concentrations of N-9. Results for both long (>24 h) and short (<2 h) exposures of cells to N-9 showed variability, while assays with 4 to 8 h of N-9 exposure gave results that were not significantly different. This is the first analysis to compare preclinical N-9 toxicity levels that were obtained by different laboratories using various protocols. This comparative work can be used to develop standardized microbicide testing protocols that will help advance potential microbicides to clinical trials.

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* Corresponding author: Mailing address: Southern Research Institute, 431 Aviation Way, Frederick, MD 21701. Phone: (301) 228-2188. Fax: (301) 694-7223. E-mail: beer{at}sri.org.

Present address: Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA 15213.

^¶ Present address: Southern Research Institute, 431 Aviation Way, Frederick, MD 21701.

Present address: Cell Trends, Inc., 6 North Church Street, Middletown, MD 21769.

Present address: Olympus America, Inc., Two Corporate Center Drive, P.O. Box 9058, Melville, NY 11747-9058.

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Antimicrobial Agents and Chemotherapy, February 2006, p. 713-723, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.713-723.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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