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      Development of polyether urethane intravaginal rings for the sustained delivery of hydroxychloroquine

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          Abstract

          Hydroxychloroquine (HCQ) has been shown to demonstrate anti-inflammatory properties and direct anti-HIV activity. In this study, we describe for the first time the fabrication and in vitro evaluation of two types of intravaginal ring (IVR) devices (a surfaced-modified matrix IVR and a reservoir segmental IVR) for achieving sustained delivery (>14 days) of HCQ as a strategy for preventing male-to-female transmission of HIV. Both IVRs were fabricated by hot-melt injection molding. Surface-modified matrix IVRs with polyvinylpyrrolidone or poly(vinyl alcohol) coatings exhibited significantly reduced burst release on the first day (6.45% and 15.72% reduction, respectively). Reservoir IVR segments designed to release lower amounts of HCQ displayed near-zero-order release kinetics with an average release rate of 28.38 μg/mL per day for IVRs loaded with aqueous HCQ and 32.23 μg/mL per day for IVRs loaded with HCQ mixed with a rate-controlling excipient. Stability studies demonstrated that HCQ was stable in coated or noncoated IVRs for 30 days. The IVR segments had no significant effect on cell viability, pro-inflammatory cytokine production, or colony formation of vaginal and ectocervical epithelial cells. Both IVR systems may be suitable for the prevention of HIV transmission and other sexually transmitted infections.

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          Most cited references 52

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          Ecological role of lactobacilli in the gastrointestinal tract: implications for fundamental and biomedical research.

           Jens Walter (2008)
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            Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention.

            Although the balance of recent evidence supports the efficacy of antiretroviral (ARV)-based pre-exposure prophylaxis (PrEP) against HIV-1 infection, recent negative trial results are perplexing. Of seven trials with available HIV endpoints, three different products have been tested: tenofovir 1% vaginal gel, oral tenofovir disoproxil fumarate (TDF) tablets, and TDF/emtricitabine tablets. Six of these trials were conducted exclusively in sub-Saharan Africa; all found the products to be well tolerated, and four demonstrated effectiveness. Furthermore, the HIV Prevention Trial Network (HPTN) 052 trial recently confirmed that antiretroviral treatment leads to 96% reduction in transmission to HIV-negative partners in HIV-serodiscordant couples. These results, along with human and animal data, provide substantial evidence for the efficacy of antiretroviral-based HIV prevention. Yet assessment of oral TDF/emtricitabine in the FEM-PrEP study and of oral and vaginal tenofovir in the Microbicide Trial Network (MTN)-003 trial (VOICE) was stopped for futility. How do we make sense of these discrepant results? We believe that adherence is a key factor, although it cannot be the only factor. Expanding upon a recent editorial in the Lancet, we discuss the impact of suboptimal product adherence on PrEP efficacy in the context of variable drug concentration at the exposure site, integrity of the vaginal epithelium, and the role of acute infection.
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              A distinct cytokine and chemokine profile at the genital mucosa is associated with HIV-1 protection among HIV-exposed seronegative commercial sex workers.

              The predominance of HIV-1 sexual transmission requires a greater understanding of the interaction between HIV-1 and the mucosal immune system. The study of HIV-1-exposed seronegative (HESN) individuals serves as a model to identify the correlates of protection and to aid in microbicide development. A total of 22 cytokines/chemokines were analyzed at the systemic and mucosal compartments in 57 HESN, 51 HIV-1-negative, and 67 HIV-1-infected commercial sex workers from Nairobi, Kenya. HESN individuals had significantly lower expression of monokine induced by interferon-γ (MIG), interferon-γ-induced protein 10 (IP-10), and interleukin-1α (IL-1α) in their genital mucosa compared with controls. HESN cytokine expression also distinctly correlates with mucosal antiproteases, suggesting that HESN individuals have a unique pattern of mucosal chemokine/cytokine expression, which may result in reduced trafficking at the mucosa. These data support the immune quiescence model of protection, whereby lower T-cell activation/recruitment at the mucosal compartment reduces HIV-1 target cell numbers and is an important component of natural protection from HIV-1.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                09 October 2014
                : 8
                : 1801-1815
                Affiliations
                [1 ]Laboratory for Drug Delivery and Biomaterials, Faculty of Pharmacy, University of Manitoba, Winnipeg, MB, Canada
                [2 ]Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
                [3 ]Department of Community Health Sciences, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
                Author notes
                Correspondence: Emmanuel A Ho, Laboratory for Drug Delivery and Biomaterials, Faculty of Pharmacy, University of Manitoba, Apotex Centre, 750 McDermot Ave, Room 329, Winnipeg, MB R3E 0T5, Canada, Tel +1 204 272 3180, Fax +1 204 474 7617, Email emmanuel_ho@ 123456umanitoba.ca
                Article
                dddt-8-1801
                10.2147/DDDT.S71352
                4199968
                © 2014 Chen et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

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