A phase I comparative study of three contraceptive vaginal films containing nonoxynol-9

Mauck, Christine; Baker, Jay M.; Barr, Susan P.; Johanson, Wendy; Archer, David F.

doi:10.1016/s0010-7824(97)00099-1

Cited by 24 publications

(12 citation statements)

References 4 publications

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“…This might be one of the reasons underlying the poor dose-discriminating power of the standard rabbit vaginal irritation model. Of greater clinical relevance, these findings could explain why N-9-containing products passed phase I clinical safety trials [44,45], showing no major macroscopic alteration of the cervicovaginal mucosa, but dramatically failed to prevent HIV transmission [4,46,47].…”

Section: Discussionmentioning

confidence: 99%

Interleukin (IL)-1, IL-6, and IL-8 Predict Mucosal Toxicity of Vaginal Microbicidal Contraceptives1

Fichorova

Bajpai

Chandra

et al. 2004

Biology of Reproduction

139

143

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Inflammation of the female reproductive tract increases susceptibility to HIV-1 and other viral infections and, thus, it becomes a serious liability for vaginal products. Excessive release of proinflammatory cytokines may alter the mucosal balance between tissue destruction and repair and be linked to enhanced penetration and replication of viral pathogens upon chemical insult. The present study evaluates four surface-active microbicide candidates, nonoxynol-9 (N-9), benzalkonium chloride (BZK), sodium dodecyl sulfate, and sodium monolaurate for their activity against human sperm and HIV, and their capacity to induce an inflammatory response on human vaginal epithelial cells and by the rabbit vaginal mucosa. Spermicidal and virucidal evaluations ranked N-9 as the most potent compound but were unable to predict the impact of the compounds on vaginal cell viability. Interleukin (IL)-1 release in vitro reflected their cytotoxicity profiles more accurately. Furthermore, IL-1 concentrations in vaginal washings correlated with cumulative mucosal irritation scores after single and multiple applications (P < 0.01), showing BZK as the most damaging agent for the vaginal mucosa. BZK induced rapid cell death, IL-1 release, and IL-6 secretion. The other compounds required either more prolonged or repeated contact with the vaginal epithelium to induce a significant inflammatory reaction. Increased IL-8 levels after multiple applications in vivo identified compounds with the highest cumulative mucosal toxicity (P < 0.01). In conclusion, IL-1, IL-6, and IL-8 in the vaginal secretions are sensitive indicators of compound-induced mucosal toxicity. The described evaluation system is a valuable tool in identifying novel vaginal contraceptive microbicides, selecting out candidates that may enhance, rather than decrease, HIV transmission.

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Section: Discussionmentioning

confidence: 99%

Interleukin (IL)-1, IL-6, and IL-8 Predict Mucosal Toxicity of Vaginal Microbicidal Contraceptives1

Fichorova

Bajpai

Chandra

et al. 2004

Biology of Reproduction

139

143

View full text Add to dashboard Cite

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“…Early studies indicated that N9 was active against a range of bacteria and enveloped viruses in vitro, including HIV-1 and herpes simplex virus (HSV), and various N9 products, including COL-1492, were defined to be generally safe by colposcopic examination in phase I and phase II clinical trials (30,40,41). However, clinical trials to evaluate the efficacy of COL-1492 (containing 52.5 mg N9) in protecting against HIV-1 infection have generated disappointing outcomes.…”

mentioning

confidence: 99%

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

Zhong

Yang

et al. 2012

Antimicrob Agents Chemother

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A major obstacle thwarting preclinical development of microbicides is the lack of a validated biomarker of cervicovaginal inflammation. Therefore, the present study aims to identify novel noninvasive soluble markers in a murine model for assessment of microbicide mucosal safety. By performing cytokine antibody array analysis, we identified two adhesion molecules, L-selectin and P-selectin, which significantly increased when mucosal inflammation was triggered by nonoxynol-9 (N9), an anti-HIV-1 microbicide candidate that failed clinical trials, in a refined murine model of agent-induced cervicovaginal inflammation. We found that patterns of detection of L-selectin and P-selectin were obviously different from those of the two previously defined biomarkers of cervicovaginal inflammation, monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6). The levels of these two soluble selectins correlated better than those of MCP-1 and IL-6 with the duration and severity of mucosal inflammation triggered by N9 and two approved proinflammatory compounds, benzalkonium chloride (BZK) and sodium dodecyl sulfate (SDS), but not by two nonproinflammatory compounds, carboxymethyl celluose (CMC; microbicide excipients) and tenofovir (TFV; microbicide candidate). These data indicated that L-selectin and P-selectin can serve as additional novel cervicovaginal inflammation biomarkers for preclinical mucosal safety evaluation of candidate microbicides for the prevention of infection with HIV and other sexually transmitted pathogens.

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“…Although its frequent use has been associated with vaginal irritation and ulceration [4][5][6][7], various N-9 products, including COL-1492, have been found generally safe by colposcopic examination in phase 1 and 2 clinical trials [8][9][10].…”

mentioning

confidence: 99%

The Molecular Basis of Nonoxynol‐9–Induced Vaginal Inflammation and Its Possible Relevance to Human Immunodeficiency Virus Type 1 Transmission

2001

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Topical microbicides are being sought to prevent sexually transmitted diseases by inactivating pathogens while preserving or enhancing the natural mucosal barrier. Serious public health concerns were raised by a recent phase 3 clinical trial that showed that nonoxynol-9 (N-9), a leading microbicide candidate widely used as an over-the-counter spermicide, may actually increase human immunodeficiency virus type 1 (HIV-1) transmission. The present study links N-9-induced vaginal inflammation to increased risk of HIV-1 infection. Analysis of molecular and cellular components in cervicovaginal secretions, as well as results from in vitro activation of cervicovaginal epithelial cells and U1/HIV promonocytic cells, showed that multiple N-9 use can promote HIV-1 transmission through interleukin-1-mediated NF-kappaB activation, which leads to chemokine-induced recruitment of HIV-1 host cells and increased HIV-1 replication in infected cells. Furthermore, this study identifies in vitro and in vivo model systems for monitoring undesirable proinflammatory effects of microbicides and other vaginal products.

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A phase I comparative study of three contraceptive vaginal films containing nonoxynol-9

Cited by 24 publications

References 4 publications

Interleukin (IL)-1, IL-6, and IL-8 Predict Mucosal Toxicity of Vaginal Microbicidal Contraceptives1

Interleukin (IL)-1, IL-6, and IL-8 Predict Mucosal Toxicity of Vaginal Microbicidal Contraceptives1

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

The Molecular Basis of Nonoxynol‐9–Induced Vaginal Inflammation and Its Possible Relevance to Human Immunodeficiency Virus Type 1 Transmission

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