Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study

Article (PDF Available)inContraception 74(2):133-40 · September 2006with72 Reads
DOI: 10.1016/j.contraception.2006.02.008 · Source: PubMed
Topical microbicides against the human immunodeficiency virus (HIV) 1 that are nonirritating to the female genital epithelium are urgently needed to slow the heterosexual spread of HIV infection. Products that are also effective contraceptives provide additional benefits. Cellulose sulfate (CS) is a noncytotoxic antifertility agent that exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV. We performed a multicenter, Phase I, placebo-controlled, randomized study to evaluate the genital toxicity of CS. Two cohorts of healthy women used 3.5 ml of 6% CS gel or 3.5 ml of K-Y Jelly, vaginally, bid, for 14 days. The first cohort was sexually abstinent, and the second cohort was sexually active. CS was associated with only a slightly higher odds ratio (OR) of symptoms of minor urogenital irritation compared to the inactive lubricant K-Y Jelly (OR=2.02, 95% confidence interval=0.90-4.53). In addition, there were minor shifts in some genital flora, but there was no evidence of greater inflammation as evidenced by few colposcopic findings, decreased influx of polymorphonuclear cells and minimal changes in proinflammatory cytokines. Moreover, both products appeared acceptable to most women. Product leakage was identified as more of a problem in sexually abstinent women, but less so in women using the product for sexual intercourse, as would be the case in actual practice. CS was safe for twice-daily use for 14 days. CS is appropriate for future studies in effectiveness trials.

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    • "Hydroxyethylcellulose (HEC) is even used as the base of the " universal placebo " gel that is commonly used in efficacy and safety trials of new microbicides [38,39]. The " universal placebo " gel is an isotonic get that is proven not to cause mucosal irritation in the standard rabbit vaginal irritation test assay [38], in the slug mucosal irritation assay [40] as well as in humans [39]. Whereas tonicity has been shown to be important to prevent epithelial swelling or dehydration [40], dry formulations seems to be less irritating on the vaginal mucosa15161718, unless they contain materials that are irritating as such. "
    [Show abstract] [Hide abstract] ABSTRACT: Different non-ionic cellulose ethers (methyl cellulose, MC; hydroxyethyl cellulose, HEC; hydroxypropyl cellulose, HPC; hydroxypropylmethyl cellulose, HPMC) and microcrystalline cellulose (MCC) were investigated as matrix formers for preparation of mini-tablets targeting vaginal drug delivery. Hexyl aminolevulinat hydrochloridum (HAL) was used as a model drug. The mini-tablets were characterized with respect to their mechanical strength, bioadhesion towards cow vaginal tissue in two independent tests (rotating cylinder test, detachment test using texture analyzer), and dissolution rate in two media mimicking the pH levels of fertile, healthy and post-menopausal women (vaginal fluid simulant pH 4.5, phosphate buffer pH 6.8). Mini-tablets with a matrix of either HPMC or HPC were found to possess adequate mechanical strength, superior bioadhesive behavior towards vaginal tissue, and pH independent controlled release of the model drug, suggesting that both systems would be suited for the treatment of women regardless of age, i.e., respective of their vaginal pH levels. Bioadhesive mini-tablets offer a potential for improved residence time in the vaginal cavity targeting contact with mucosal tissue and prolonged release of the drug.
    Full-text · Article · Sep 2014
    • "Even worse, nonoxynol-9 caused toxic side effects and even enhanced HIV-1 infection and transmission, so that it was no longer pursued as a potential HIV-1 preventive agent [86]. The microbicide cellulose sulfate (CS) was found safe in a phase I safety study [87], however, a phase III clinical trial was interrupted because preliminary results indicated an increased risk of HIV transmission/infection in CS-treated women [88]. So, it is important that microbicidal agents are safe and effective following vaginal or rectal administration, and they should cause minimal, if any, genital side effects by long-term and repeated administration. "
    [Show abstract] [Hide abstract] ABSTRACT: The development and use of topical microbicides potentially offers an additional strategy to reduce the spread of the Human Immunodeficiency Virus (HIV). Carbohydrate-binding agents (CBAs) that show specificity for high mannose carbohydrates on the surface of the heavily glycosylated envelope of HIV are endowed with potent anti-HIV activity. In fact, a number of algal lectins such as cyanovirin-N, microvirin, microcystis viridis lectin, scytovirin, Oscillatoria agardhii agglutinin and griffithsin are considered as potential microbicide candidates to prevent the sexual transmission of HIV through topical applications. They not only inhibit infection of cells by cell-free virus but they can also efficiently prevent virus transmission from virus-infected cells to uninfected CD4(+) target T-lymphocytes and DC-SIGN-directed capture of HIV-1 and transmission to CD4(+) T lymphocytes. This review focuses on the structural properties and carbohydrate specificity of these algal lectins, their antiviral activity against HIV and several other enveloped viruses, their safety profile and viral resistance patterns.
    Full-text · Article · Jul 2012
    • "Therefore, our findings are relevant to locations outside of North America. Most other studies have used gel formulated microbicides (Patton et al., 2006, Patton et al., 2007, Schwartz et al., 2006) and we encountered sampling difficulties with these formulations. In our studies we observed killing by gel formulations. "
    [Show abstract] [Hide abstract] ABSTRACT: The development of topical microbicides for intravaginal use to prevent HIV infection requires that the drugs and formulated products be nontoxic to the endogenous vaginal Lactobacillus. In 30min exposure tests we found dapivirine, tenofovir and UC781 (reverse transcriptase inhibitor anti-HIV drugs) as pure drugs or formulated as film or gel products were not deleterious to Lactobacillus species; however, PSC-RANTES (a synthetic CCR5 antagonist) killed 2 strains of Lactobacillus jensenii. To demonstrate the toxicity of formulated products a new assay was developed for use with viscous and non-viscous samples that we have termed the Lactobacillus toxicity test. We found that the vortex mixing of vaginal Lactobacillus species can lead to reductions in bacterial viability. Lactobacillus can survive briefly, about 2s, but viability declines with increased vortex mixing. The addition of heat inactivated serum or bovine serum albumin, but not glycerol, prevented the decrease in bacterial viability. Bacillus atrophaeus spores also demonstrated loss of viability upon extended mixing. We observed that many of the excipients used in film formulation and the films themselves also afford protection from the killing during vortex mixing. This method is of relevance for toxicity for cidal activities of viscous products.
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