Distribution of a spermicide containing Nonoxynol-9 in the vaginal canal and the upper female reproductive tract

Topical, intravaginal microbicides and spermicides are greatly needed to prevent transmission of sexually transmitted diseases and/or unwanted pregnancies. The development of such compounds is a high research priority. The presumed method of action of existing, or novel, microbicides/spermicides is to provide a chemical barrier to the vaginal epithelium preventing exposure to micro-organisms. Other intravaginal products are used to treat vaginal bacteria of fungal infections. Little is known, however, about the actual or optimal initial distribution and subsequent spread of medications placed in the vagina. We describe a sensitive new technique to quantify the spread of a gel placed in the vagina using magnetic resonance imaging (MRI). Five millilitres of an over-the-counter spermicide containing Nonoxynol-9 was mixed with Gadolinium. MRI was used to quantify spread of the mixture 10 min after insertion with a standard applicator. We demonstrated contiguous spread of gel throughout the vagina. The coverage of material was thicker in the upper vagina than in the lower vagina. We also demonstrated, for the first time, that spermicidal compounds may migrate from the vaginal canal into the endocervix within 10 min of insertion. This finding suggests that topical microbicides/spermicides may act both in the vaginal canal and in the upper female genital tract.     

Trial participation disclosure and gel use behavior in the CAPRISA 004 tenofovir gel trial

Disclosure, or open communication, by female microbicide trial participants of their trial participation and use of an investigational HIV prevention drug to a sexual partner may affect participants' trial product usage behavior and contribute to poor adherence. With mixed results from recent microbicide clinical trials being linked to differing participant adherence, insights into the communication dynamics between trial participants and their sexual partners are particularly important. We examined the quantitative association between (1) communication of trial participation to a partner and participant adherence to gel and (2) communication of trial participation to a partner and participant HIV status. An in-depth adherence and product acceptability assessment was administered to the women participating in the CAPRISA 004 trial. Additionally, we collected qualitative data related to communication of trial participation and gel use. Qualitatively, among 165 women who had reported that they had discussed trial participation with others, most (68%) stated that they communicated participation to their sexual partner. Most of the women who had communicated study participation with their partners had received a positive/neutral response from their partner. Some of these women stated that gel use was easy; only a small number said that gel use was difficult. Among women who did not communicate their study participation to their partners, difficulty with gel use was more common and some women stated that they feared communicating their participation. Quantitatively, there was no statistically significant difference in the proportions of women who had communicated study participation to a partner across different adherence levels or HIV status. A deeper knowledge of the dynamics surrounding trial participation communication to male partners will be critical to understanding the spectrum of trial product usage behavior, and ultimately to designing tailored strategies to assist trial participants with product adherence.     

杀微生物避孕凝胶剂的抗生育和抗菌作用研究

目的:观察杀微生物避孕凝胶剂的体外杀精、家兔抗生育和抗菌作用。方法:杀精试验采用改良的Sander-Crammer方法;家兔抗生育试验将家兔随机分为高、中、低3个剂量组,分别阴道给予凝胶剂48mg/kg,24mg/kg和12mg/kg,给药后10min与雄兔进行交配,21d后解剖并计算避孕率;抗菌实验用体外试管法观察凝胶剂的抗金黄色葡萄球菌、大肠埃希菌和白色念珠菌的作用。结果:在20s内最低体外杀精浓度为0.5mg/ml;3个剂量组家兔避孕率分别为100%、80%和20%;对金黄色葡萄球菌、大肠埃希菌和白色念珠菌的最低杀菌浓度分别为0.05625%、0.225%和0.45%。结论:研制的凝胶剂有明显的抗生育作用和抗上述3种致病菌作用。     

顶体反应抑制剂4'-乙酰胺苯基4-胍基苯甲酸酯(AGB)具有阻断HIV-1进入细胞的作用

目的:研究4'-乙酰胺苯基4-胍基苯甲酸酯(AGB)抗HIV-1活性及作用靶点。方法:通过AGB对宿主细胞的毒性实验、合胞体抑制实验、融合阻断实验、对HIV-1感染细胞的保护作用实验和对HIV-1急性感染细胞p24抗原产生的抑制作用等试验,观察AGB对HIV-1复制的影响和作用机制。结果:AGB抑制HIV-1IIIB诱导C8166细胞形成合胞体,EC50为39.5μg/ml;抑制HIV-1感染细胞上清中HIV-1p24抗原的表达,EC50为33.36μg/ml;阻断HIV-1慢性感染H9细胞与正常C8166细胞间融合的作用。结论:AGB具有阻断HIV-1进入宿主细胞的作用,是一种有前景的具杀精子作用的杀微生物剂。     

Lesson learned and dispelled myths: three-dimensional imaging of the human vagina

Three-dimensional imaging of the human vagina demonstrates that the cross section can be a "W," rather than an "H," and that intravaginal gel can ascend into the endocervix and presumably into the endometrium.     

Contraceptive activity of a spermicidal aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07) in rabbits

OBJECTIVE: To determine the vaginal contraceptive activity of WHI-07 in the rabbit model. DESIGN: Prospective, controlled study. SETTING: Center for advanced preclinical sciences. ANIMAL(S): Subgroups of 15, 16, or 24 New Zealand White does and 24 bucks per experiment. INTERVENTION(S): Ex vivo (Experiment 1) and in vivo (Experiments 2 and 3) treatment of semen with WHI-07 or Nonoxynol-9 (N-9). In Experiment I, ovulated does in subgroups of 15 were artificially inseminated with semen mixed with WHI-07 or vehicle. In Experiment 2, ovulated does in subgroups of 24 were artificially inseminated within 2 min after intravaginal administration of 2% WHI-07 gel-microemulsion or 2% N-9 gel and allowed to complete term pregnancy. In Experiment 3, ovulated does in subgroups of 16 were artificially inseminated at 15, 30, or 60 minutes. MAIN OUTCOME MEASURE(S): The numbers of implanted embryos on postinsemination day 8 or the proportion of does that became pregnant and delivered newborn rabbits; the litter size, weight, growth, and viability of pups until lactation day 5. RESULT(S): Exposure of semen to WHI-07 at the time of artificial insemination completely inhibited pregnancy rates (WHI-07-pretreated, 0%, vs. control, 60%) and embryo implantation (WHI-07-pretreated, 0/175 vs. control, 68/170). Intravaginal administration of a 2% WHI-07 gel-microemulsion or 2% N-9 gel before artificial insemination significantly inhibited pregnancy rates (81% and 85% inhibition, respectively) when compared with control. Furthermore, the 2% WHI-07 gel-microemulsion provided >90% inhibition of fertility even when insemination was delayed until 60 minutes after intravaginal application. Rabbits that delivered litters despite intravaginal application of 2% WHI-07 gel-microemulsion had healthy offsprings with no perinatal or postnatal repercussions. CONCLUSION(S): WHI-07 is a potent contraceptive agent in vivo. Intravaginal use of WHI-07 gel-microemulsion has clinical potential as a safe prophylactic contraceptive, in addition to its microbicide activity to curb the sexual transmission of HIV.     

Use of mandelic acid condensation polymer (SAMMA), a new antimicrobial contraceptive agent,for vaginal prophylaxis

OBJECTIVE: To assess the contraceptive properties, antimicrobial activity, and safety of mandelic acid condensation polymer (SAMMA). DESIGN: Experimental study of SAMMA's in vitro and in vivo properties. SETTING: Academic research laboratories. PATIENT(S): Healthy volunteers for semen donation in an academic research environment. INTERVENTION(S): Inhibition of sperm function indicators, conception, sexually transmitted infection-causing pathogens (including HIV), and lactobacilli was evaluated. Safety indicators were studied. MAIN OUTCOME MEASURE(S): Quantitation of SAMMA's effect on microbial infectivity or multiplication and on sperm function in vitro; evaluation of contraceptive efficacy in vivo; assessment of safety in vitro and in vivo. RESULT(S): Mandelic acid condensation polymer is not cytotoxic toward lactobacilli, microbial host cells, and spermatozoa. The compound inhibits hyaluronidase and acrosin, induces sperm acrosomal loss, and is contraceptive in the rabbit model. Mandelic acid condensation polymer prevents infectivity of HIV and herpesviruses 1 and 2 and, to a lesser extent, of Chlamydia trachomatis. It inhibits the multiplication of Neisseria gonorrhoeae. Mandelic acid condensation polymer is not mutagenic, has low acute oral toxicity, and is safe in the rabbit vaginal irritation assay. CONCLUSION(S): Mandelic acid condensation polymer inhibits sperm function, is contraceptive, has broad-spectrum antimicrobial activity, and is highly safe. Further development as a microbicide is warranted.     

FAME‐04: A Phase 1 trial to assess the safety,acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir

Introduction

Fast‐dissolving vaginal film formulations release antiretroviral drugs directly into vaginal fluid and may be as efficient at drug delivery yet more acceptable to women than gels. In this Phase 1 vaginal film study, the safety, acceptability, pharmacokinetics and pharmacodynamics of two doses of tenofovir (TFV) film and TFV 1% gel were compared to corresponding placebo formulations.

Methods

Seventy‐eight healthy HIV negative women were randomized to self‐insert daily vaginal film (10 mg TFV, 40 mg TFV or placebo) or 4 mL of vaginal gel (TFV 1% [40 mg] or placebo) for seven days. Grade 2 and higher adverse events (AEs) related to study product were compared across study arms using Fisher's exact test. Plasma TFV concentrations were measured before and 2 hours after last product use. Paired cervical and vaginal tissue biopsies obtained 2 hours after the last dose were measured to determine tenofovir diphosphate (TFV‐DP) concentrations and exposed to HIV in an ex vivo challenge assay. Acceptability was assessed through questionnaire.

Results

There was only one grade 2 or higher related AE, the primary endpoint; it occurred in the placebo gel arm. AEs occurred in 90% of participants; the majority (91%) were grade 1. AEs were similar across study arms. TFV concentrations in plasma and TFV‐DP concentrations in cervical and vaginal tissues were comparable between 40 mg TFV film and the TFV gel groups. There was a significant relationship between reduced viral replication and TFV‐DP concentrations in cervical tissues. Film users were less likely to report product leakage than gel users (66% vs. 100%, p < 0.001).

Conclusions

Films were safe and well tolerated. Furthermore, films delivered TFV to mucosal tissues at concentrations similar to gel and were sufficient to block HIV infection of genital tissue ex vivo.

     

Hepatitis C virus NS5A anchor peptide disrupts human immunodeficiency virus

In the absence of an effective vaccine, there is an urgent need for safe and effective antiviral agents to prevent transmission of HIV. Here, we report that an amphipathic alpha-helical peptide derived from the hepatitis C virus NS5A anchor domain (designated C5A in this article) that has been shown to be virocidal for the hepatitis C virus (HCV) also has potent antiviral activity against HIV. C5A exhibits a broad range of antiviral activity against HIV isolates, and it prevents infection of the three in vivo targets of HIV: CD4(+) T lymphocytes, macrophages, and dendritic cells by disrupting the integrity of the viral membrane and capsid core while preserving the integrity of host membranes. C5A can interrupt an ongoing T cell infection, and it can prevent transmigration of HIV through primary genital epithelial cells, infection of mucosal target cells and transfer from dendritic cells to T cells ex vivo, justifying future experiments to determine whether C5A can prevent HIV transmission in vivo.     

Targeted Delivery of PSC-RANTES for HIV-1 Prevention using Biodegradable Nanoparticles

Purpose  Nanoparticles formulated from the biodegradable co-polymer poly(lactic-co-glycolic acid) (PLGA), were investigated as a drug delivery system to enhance tissue uptake, permeation, and targeting for PSC-RANTES anti-HIV-1 activity. Materials and Methods  PSC-RANTES nanoparticles formulated via a double emulsion process and characterized in both in vitro and ex vivo systems to determine PSC-RANTES release rate, nanoparticle tissue permeation, and anti-HIV bioactivity. Results  Spherical, monodisperse (PDI = 0.098 ± 0.054) PSC-RANTES nanoparticles (d = 256.58 ± 19.57 nm) with an encapsulation efficiency of 82.23 ± 8.35% were manufactured. In vitro release studies demonstrated a controlled release profile of PSC-RANTES (71.48 ± 5.25% release). PSC-RANTES nanoparticle maintained comparable anti-HIV activity with unformulated PSC-RANTES in a HeLa cell-based system with an IC₅₀ of approximately 1pM. In an ex vivo cervical tissue model, PSC-RANTES nanoparticles displayed a fivefold increase in tissue uptake, enhanced tissue permeation, and significant localization at the basal layers of the epithelium over unformulated PSC-RANTES. Conclusions  These results indicate that PSC-RANTES can readily be encapsulated into a PLGA nanoparticle drug delivery system, retain its anti-HIV-1 activity, and deliver PSC-RANTES to the target tissue. This is crucial for the success of this drug candidate as a topical microbicide product.