Decreased cervical epithelial sensitivity to nonoxynol-9 N-9 after four daily applications in a murine model of topical vaginal microbicide safetyReport as inadecuate




Decreased cervical epithelial sensitivity to nonoxynol-9 N-9 after four daily applications in a murine model of topical vaginal microbicide safety - Download this document for free, or read online. Document in PDF available to download.

BMC Pharmacology and Toxicology

, 13:9

First Online: 01 October 2012Received: 29 March 2012Accepted: 13 September 2012

Abstract

BackgroundThe disappointing clinical failures of five topical vaginal microbicides have provided new insights into factors that impact microbicide safety and efficacy. Specifically, the greater risk for human immunodeficiency virus type 1 HIV-1 acquisition associated with multiple uses of a nonoxynol-9 N-9-containing product has highlighted the importance of application frequency as a variable during pre-clinical microbicide development, particularly in animal model studies.

MethodsTo evaluate an association between application frequency and N-9 toxicity, experiments were performed using a mouse model of cervicovaginal microbicide safety. In this model system, changes in cervical and vaginal epithelial integrity, cytokine release, and immune cell infiltration were assessed after single and multiple exposures to N-9.

ResultsAfter the initial application of N-9 aqueous, 1%, considerable damage to the cervical epithelium but not the vaginal epithelium was observed as early as 10 min post-exposure and up to 8 h post-exposure. Subsequent daily exposures up to 4 days were characterized by diminished cervical toxicity relative to single exposures of like duration. Levels of pro-inflammatory cytokines released into the cervicovaginal lumen and the degree of CD14-positive immune cell infiltration proximal to the cervical epithelium were also dependent on the number of N-9 exposures.

ConclusionsRather than causing cumulative cervical epithelial damage, repeated applications of N-9 were characterized by decreased sensitivity to N-9-associated toxicity and lower levels of immune cell recruitment. These results provide new insights into the failure of N-9-based microbicides and illustrate the importance of considering multiple exposure protocols in pre-clinical microbicide development strategies.

KeywordsMicrobicide N-9 Cervix Mouse Toxicity Electronic supplementary materialThe online version of this article doi:10.1186-2050-6511-13-9 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Author: Karissa Lozenski - Robert Ownbey - Brian Wigdahl - Tina Kish-Catalone - Fred C Krebs

Source: https://link.springer.com/







Related documents