Comparative Safety Evaluation of the Candidate Vaginal Microbicide C31G

Abstract

C31G is currently the focus of clinical trials designed to evaluate this agent as a microbicidal and spermicidal agent. In the following studies, the in vivo safety of C31G was assessed with a Swiss Webster mouse model of cervicovaginal toxicity and correlated with results from in vitro cytotoxicity experiments and published clinical observations. A single exposure of unformulated 1% C31G resulted in mild-to-moderate epithelial disruption and inflammation at 2 and 4 h postapplication. The columnar epithelium of the cervix was the primary site of damage, while no perturbation of the vaginal mucosa was observed. In contrast, application of unformulated 1.7% C31G resulted in greater levels of inflammation in the cervical epithelium at 2 h postapplication and severe epithelial disruption that persisted to 8 h postapplication. Application of a nonionic aqueous gel formulation containing 1% C31G resulted in no apparent cervicovaginal toxicity at any time point evaluated. However, formulation of 1.7% C31G did not substantially reduce the toxicity associated with unformulated C31G at that concentration. These observations correlate with findings gathered during a recent clinical trial, in which once-daily applications resulted in no adverse events in women receiving the formulation containing 1% C31G, compared to moderate-to-severe adverse events in 30% of women receiving the 1.7% C31G formulation. The Swiss Webster mouse model was able to effectively discriminate between concentrations and formulations of C31G that produced distinct clinical effects in human trials. The Swiss Webster animal model may be a highly valuable tool for preclinical evaluation of candidate vaginal microbicides.

L-Selectin and P-Selectin Are Novel Biomarkers of Cervicovaginal Inflammation for Preclinical Mucosal Safety Assessment of Anti-HIV-1 Microbicide

“…Our study also agreed with two other previous studies (9,16). Despite some discrepancy, our study and the studies of Catalone et al (7,8) also had some agreements: N9-associated damage peaked at about 2 to 4 h postapplication and was resolved by 24 to 48 h postexposure. The present study and the previous studies all showed that the murine model is useful for assessment of the mucosal safety of microbicide candidates.…”

“…A few studies examined the mucosal inflammatory response to intravaginally administered N9 and SDS in the mouse model and found exfoliation of epithelia, infiltration of neutrophils and macrophages into the genital lumen and tissue, increases in cytokines and chemokines, and activation of the transcription factor NF-B (7-9, 16, 32). Catalone and colleagues found that the cervix was the site of N9-and C31G-associated damage and inflammation, while the vaginal epithelium was resistant to the damaging effects of these surfactants (7,8). However, our study found that the cervix (data not shown) and the vaginal epithelium are both sensitive to N9 irritation.…”

Short Communication: Expression of Transporters and Metabolizing Enzymes in the Female Lower Genital Tract: Implications for Microbicide Research

“…11,33,34 It has been shown that the toxicity profile of a number of microbicide candidates in progesterone synchronized mice correlated well with clinical trial results. 12,35,36 Nevertheless, our finding suggests that caution is needed when interpreting data from mouse studies.…”

N,N'–Dithiobisphthalimide, a disulfide aromatic compound, is a potent spermicide agent in humans

“…N-9 is known to inhibit the growth of Lactobacillus [Krebs et al 2002;Ojha et al 2003] and to irritate the cervical-vaginal epithelium. This effect perhaps causes the observed increased susceptibility to HIV infection by providing a direct subcutaneous entry for the virus [Catalon et al 2005].…”