Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 µg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ~10(6)-fold greater than the 50% inhibitory concentrations (IC(50)s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β

Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor ?B signaling that represses tumor invasion and metastasis. Glycogen synthase kinase-3ß (GSK3ß) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. Here, we show that RKIP binds GSK3 proteins and maintains GSK3ß protein levels and its active form. Depletion of RKIP augments oxidative stress-mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3ß by phosphorylating it at the inhibitory T390 residue. This pathway de-represses GSK3ß inhibition of oncogenic substrates causing stabilization of cyclin D, which induces cell-cycle progression and ß-catenin, SNAIL, and SLUG, which promote epithelial to mesenchymal transition. RKIP levels in human colorectal cancer positively correlate with GSK3ß expression. These findings reveal the RKIP/GSK3 axis as both a potential therapeutic target and a prognosis-based predictor of cancer progression.

Politics, ethics, and the search for a just international order:symposium in honour of Stanley Hoffmann

Published symposium with Stanley Hoffmann (Harvard), Suzanne Berger (MIT), Michael Doyle (Columbia), Peter Gourevitch (California San Diego), Robert Keohane (Princeton), Andrew Moravcsik (Princeton). Ed. James Shields, French Politics, 7 (3/4) 2009, 359-436. ISSN 1476-3419 (print) 1476-3427 (online)

Case Comment : Jones v Kernott:which road to Rome?

Jones v Kernott [2011] UKSC 53 (SC) Stack v Dowden [2007] UKHL 17; [2007] 2 A.C. 432 (HL). Casenote explores the implications of the ruling in Jones v Kernott by the Supreme Court and assesses its implications for English Property Law. Building on the commonwealth experience the casenote calls for the intorduction of a statutory scheme so as to allow courts to reallocate property rights to unmarried cohabitants in the event of relationship breakdown.

Assessing the motivation of MDs to use computer-based support at the point-of-care in the emergency department

A significant body of research investigates the acceptance of computer-based support (including devices and applications ranging from e-mail to specialized clinical systems, like PACS) among clinicians. Much of this research has focused on measuring the usability of systems using characteristics related to the clarity of interactions and ease of use. We propose that an important attribute of any clinical computer-based support tool is the intrinsic motivation of the end-user (i.e. a clinician) to use the system in practice. In this paper we present the results of a study that investigated factors motivating medical doctors (MDs) to use computer-based support. Our results demonstrate that MDs value computer-based support, find it useful and easy to use, however, uptake is hindered by perceived incompetence, and pressure and tension associated with using technology.