Safety and Pharmacokinetics of Dapivirine Delivery From Matrix and Reservoir Intravaginal Rings to HIV-Negative Women

Vaginal microbicides for the prevention of HIV transmission may be an important option for protecting women from infection. Incorporation of dapivirine, a lead candidate nonnucleoside reverse transcriptase inhibitor, into intravaginal rings (IVRs) for sustained mucosal delivery may increase microbicide product adherence and efficacy compared with conventional vaginal formulations. Twentyfour
healthy HIV-negative women 18–35 years of age were randomly assigned (1:1:1) to dapivirine matrix IVR, dapivirine reservoir IVR, or placebo IVR. Dapivirine concentrations were measured in plasma
and vaginal fluid samples collected at sequential time points over the 33-day study period (28 days of IVR use, 5 days of follow-up). Safety was assessed by pelvic/colposcopic examinations, clinical laboratory tests, and adverse events. Both IVR types were safe and well tolerated with similar adverse events observed in the placebo and dapivirine groups. Dapivirine from both IVR types was successfully distributed throughout the lower genital tract at concentrations over 4 logs greater than the EC50 against wild-type HIV-1 (LAI) in MT4 cells. Maximum concentration (Cmax) and area under the concentration–time curve (AUC) values were significantly higher with the matrix than reservoir IVR. Mean plasma concentrations of dapivirine were ,2 ng/mL. These findings suggest that IVR delivery of microbicides is a viable option meriting further study.

Archaeology and the "New" British Museum.

Malone , C. Archaeology and the "New" British Museum. . in Dia Internacional de los Museuos, 2002. Museuo Nacional de Arte Romano Merida: Museuo Nacional de Arte Romano Merida.

Advances in microbicide vaginal rings

Vaginal ring devices capable of providing sustained/controlled release of incorporated actives are already marketed for steroidal contraception and estrogen replacement therapy. In recent years, there has been considerable interest in developing similar ring devices for the administration of microbicidal compounds to prevent vaginal HIV transmission. Intended to be worn continuously, such coitally independent micro- bicide rings are being developed to maintain effective vaginal microbicide concentrations over many weeks or months, thereby overcoming issues around timing of product application, user compliance and acceptability associated with more conventional semi-solid formulations. In this article, an overview of vaginal ring technologies is presented, followed by a review of recent advances and issues pertaining to their application for the delivery of HIV microbicides. This article forms part of a special supplement on presentations covering intravaginal rings, based on the symposium “Trends in Microbicide Formulations”, held on 25 and 26 January 2010, Arlington, VA.

beta-1,2,3-Triazolyl-Nucleosides as Nicotinamide Riboside Mimics

The synthesis of a series of pyridine- and piperidine-substituted 1,2,3-triazolides linked to a riboside moiety is described. The presence of a triazolide substituent on the pyridine moiety permitted the facile reduction of the latter under mild hydrogenation conditions. These analogues were modelled as to define their similarity to nicotinamide riboside and quantify their ability to bind NAD-dependent protein deacetylases.