Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety

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.

Cervical epithelial damage promotes Ureaplasma parvum ascending infection, intrauterine inflammation and preterm birth induction in mice

“…To generate a cervical epithelial damage model during pregnancy, we used the commonly used spermicide N-9. Our findings of epithelial damage and neutrophil infiltration are in agreement with what has been reported in non-pregnant mice 47,48 , rats 49 , rabbits 50 , pigtailed macaques 51 and humans 52 after vaginal N-9 application. Damage has also been described in different epithelial tissues, such as the monkey rectal tissue 53 .…”

A Pilot Study Measuring the Distribution and Permeability of a Vaginal HIV Microbicide Gel Vehicle Using Magnetic Resonance Imaging, Single Photon Emission Computed Tomography/Computed Tomography, and a Radiolabeled Small Molecule

“…While the clinical significance of increased vaginal mucosal permeability resulting from N-9 is not clear, these data are consistent with in vitro, ex vivo, and animal models that have demonstrated disruption of the mucosal barrier by N-9, which may increase the risk of HIV transmission. [17][18][19][20] In comparison with our prior work with the rectal permeability of isotope in the presence of N-9, the median doseadjusted AUC 0-24 and C max were 5-fold and 10-fold lower, respectively, compared to rectal data. 13,15 Similarly, T max was reached several hours later than what was observed with rectal dosing.…”

In silico and in vitro assessment of an optimized QbD-guided myoinositol and metformin-loaded mucus-penetrating particle-based gel for the amelioration of PCOS

“…The prepared slides were visualized and analyzed using an inverted microscope (Olympus IX71 inverted microscope at 10× and 40×, Tokyo, Japan). 38 The effect of the test samples was demonstrated, interpreted, and compared with the control group. Group A: negative control group kept as an untreated group.…”