In Vitro Comparison of Topical Microbicides for Prevention of Human Immunodeficiency Virus Type 1 Transmission

Dezzutti, Charlene S.; James, V. Nicole; Ramos, Artur; Sullivan, Sharon T.; Siddig, Aladin; Bush, Timothy J.; Grohskopf, Lisa A.; Paxton, Lynn A.; Subbarao, Shambavi; Hart, Clyde E.

doi:10.1128/aac.48.10.3834-3844.2004

Cited by 127 publications

(113 citation statements)

References 55 publications

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“…We evaluated the safety and efficacy of the PYD gel formulation using reconstructed VEC-100 tissue (MatTek Corp.) and human polarized ectocervical tissue. The VEC-100 tissue recapitulates only the morphological characteristics of the stratified squamous epithelial layer, whereas the polarized ectocervical explants contains both epithelium and relevant immune cells (2,7,8,26). In an in vitro HIV-1 entry inhibition assay the 3.0% HEC gel with 0.25% IQP-0528 demonstrated a 50% effective concentration (EC 50 ) of 0.14 g/ml of gel in culture media, corresponding to ϳ0.001 M IQP-0528, and showed complete protection of the human polarized ectocervical tissue against HIV infection.…”

mentioning

confidence: 99%

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Mahalingam

Simmons

Ugaonkar

et al. 2011

Antimicrob Agents Chemother

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Pyrimidinediones, a novel class of compounds, have previously been shown to possess antiviral activity at nanomolar concentrations. One member of this class of compounds, IQP-0528, was selected as the lead molecule for formulation development owing to its stability at physiologically relevant conditions, wide therapeutic window, and antiviral activity in the nanomolar range. Here, we report the development of two vaginal gels-3.0% hydroxyethyl cellulose (HEC) formulation and a 0.65% Carbopol formulation-for the sustained delivery of IQP-0528. Stability studies under accelerated conditions confirmed the chemical stability of IQP-0528 and mechanical stability of the gel formulation for 3 months. In vitro release studies revealed that diffusion-controlled release of IQP-0528 occurred over 6 h, with an initial lag time of approximately 1 h. Based on the drug release profile, the 3.0% HEC gel was selected as the lead formulation for safety and activity evaluations. The in vitro and ex vivo safety evaluations showed no significant loss in cell viability or significant inflammatory response after treatment with a 3.0% HEC gel containing 0.25% IQP-0528. In an in vitro HIV-1 entry inhibition assay, the lead formulation showed an 50% effective concentration of 0.14 g/ml for gel in culture media, which corresponds to ϳ0.001 M IQP-0528. The antiviral activity was further confirmed by using polarized cervical explants, in which the formulation showed complete protection against HIV infection. In summary, these results are encouraging and warrant further evaluation of IQP-0528 gel formulations in in vivo models, as well as the development of alternative formulations for the delivery of IQP-0528 as a microbicide.

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mentioning

confidence: 99%

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Mahalingam

Simmons

Ugaonkar

et al. 2011

Antimicrob Agents Chemother

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“…In addition, placebos can modify the immune activation status of the reproductive tract, and evidence suggests that some placebos planned for use may have HIV activity that offers unintended protection. 59 Thus, a condom only arm allows assessment of the protective effect of the placebo, which may be essential. Much progress has been made in developing an inert placebo product, with HEC (hydroxyethylcellulose) now available for effectiveness trials.…”

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confidence: 99%

Effectiveness of female controlled barrier methods in preventing sexually transmitted infections and HIV: current evidence and future research directions

Minnis

Padian²

2005

Sexually Transmitted Infections

100

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Objectives: To evaluate evidence for the effectiveness of female controlled physical and chemical barrier methods in preventing STI/HIV transmission, to examine recent reviews on microbicide development, and to highlight promising research directions. To discuss challenges in conducting effectiveness research and in translating results to public health intervention. Methods: Systematic review of articles that examined the disease prevention effectiveness of at least one female controlled barrier method. Review of conference abstracts that presented clinical and preclinical microbicide data. Results: Randomised controlled trials provide evidence that female condoms confer as much protection from STIs as male condoms. Observational studies suggest that the diaphragm protects against STI pathogens. Several microbicide effectiveness studies are under way and new directions, such as adaptation of therapeutic agents as preventive products, are being examined. Substantial attention is now given to product formulation and novel delivery strategies. Combining microbicide products with different mechanisms of action as well as combining chemical and physical barriers will be necessary to maximise prevention effectiveness. Conclusions: Increased investment in the development and identification of female controlled barrier methods offers promise that additional products will be available in the years ahead. Generalising trial results to a community setting, promoting products that may be less effective than male condoms, and bringing an effective product to scale introduce public health challenges that warrant attention. The need for female controlled barrier methods that provide women with the opportunity to take an active role in reducing their STI/HIV risk are urgently needed and constitute an essential tool to prevent continued spread of these infections.

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“…The detergent Nonoxynol 9 is a topical microbicide that was initially thought to be effective in inhibiting HIV infection, but its toxicity to the epithelial cells resulted in breaches of the barrier and may have led to an increase in HIV infection by users [44]. Measuring epithelial barrier function by TER or permeability is one way to ascertain if a proposed topical microbicide is cytotoxic [45]. In addition, TER can be measured to test the potential cytotoxic effects of antimicrobial peptides on tight junctions prior to use in clinical situations [46].…”

Section: Tight Junctions With Microbicides and Vaccinesmentioning

confidence: 99%

Innate Immunity in the Female Reproductive Tract: Role of Sex Hormones in Regulating Uterine Epithelial Cell Protection Against Pathogens

Ochiel

Fahey²,

Ghosh³

et al. 2008

CWHR

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The mucosal immune system in the upper female reproductive tract is uniquely prepared to maintain a balance between the presence of commensal bacteria, sexually transmitted bacterial and viral pathogens, allogeneic spermatozoa, and an immunologically distinct fetus. At the center of this dynamic system are the epithelial cells that line the Fallopian tubes, uterus, cervix and vagina. Epithelial cells provide a first line of defense that confers continuous protection, by providing a physical barrier as well as secretions containing bactericidal and virucidal agents. In addition to maintaining a state of ongoing protection, these cells have evolved to respond to pathogens, in part through Toll-like receptors (TLRs), to enhance innate immune protection and, when necessary, to contribute to the initiation of an adaptive immune response. Against this backdrop, epithelial cell innate and adaptive immune function is modulated to meet the constraints of procreation. The overall goal of this review is to focus on the dynamic role of epithelial cells in the upper reproductive tract, with special emphasis on the uterus, to define the unique properties of these cells as they maintain homeostasis in preparation for successful fertilization and pregnancy while at the same time confer protection against sexually transmitted infections, which threaten to compromise women's reproductive health and survival. By understanding the nature of this protection and the ways in which innate and adaptive immunity are regulated by sex hormones, these studies provide the opportunity to contribute to the foundation of information essential for ensuring reproductive health.

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In Vitro Comparison of Topical Microbicides for Prevention of Human Immunodeficiency Virus Type 1 Transmission

Cited by 127 publications

References 55 publications

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Effectiveness of female controlled barrier methods in preventing sexually transmitted infections and HIV: current evidence and future research directions

Innate Immunity in the Female Reproductive Tract: Role of Sex Hormones in Regulating Uterine Epithelial Cell Protection Against Pathogens

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