title: A comprehensive murine model to evaluate topical vaginal microbicides: mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety.
abstract: A critical gap in microbicide development is the absence of surrogate safety markers. The objective of the present study was to develop a murine model to examine the mucosal response to microbicides and to assess the functional implication of observed changes. Mice received 14 daily intravaginal doses of nonoxynol-9, PRO 2000, or placebo gel. Nonoxynol-9 induced an inflammatory response characterized by increases in levels of cytokines and chemokines, recruitment of neutrophils and monocytes into the genital tract, and activation of the transcription factors NF- kappa B and activator protein-1. Minimal inflammation was observed in response to 2% PRO 2000. Nonoxynol-9-treated mice were significantly more susceptible to challenge with a low dose of herpes simplex virus type 2; the response of PRO 2000-treated mice was similar to the response to placebo. These findings suggest that PRO 2000 has little deleterious effect on mucosal immunity and, if validated by clinical experiences, support the inclusion of this model in the preclinical evaluation of future candidate microbicides.
authors.affiliation: Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Galen
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Martin
authors.forename: Ehsan
authors.initials: E
authors.lastname: Hazrati
authors.forename: Alexandre
authors.initials: A
authors.lastname: Garin
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Guzman
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Wilson
authors.forename: David D
authors.initials: DD
authors.lastname: Porter
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.forename: Marla J
authors.initials: MJ
authors.lastname: Keller
authors.forename: Betsy C
authors.initials: BC
authors.lastname: Herold
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004198:Disease Susceptibility; D005260:Female; D006558:Herpes Genitalis / Q000517:prevention & control* / Q000635:transmission / Q000821:virology; D051379:Mice; D023421:Models, Animal; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D017137:Nonoxynol / Q000008:administration & dosage* / Q000009:adverse effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015229:Sexually Transmitted Diseases, Viral / Q000517:prevention & control / Q000635:transmission / Q000821:virology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics; D014621:Vagina / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000009:adverse effects; D014627:Vaginitis / Q000139:chemically induced / Q000473:pathology
chemical_list: D000890:Anti-Infective Agents; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014622:Vaginal Creams, Foams, and Jellies; D017137:Nonoxynol