Pre-treatment with Depo-Provera modifies the pharmacokinetics of CMPD167 in rhesus macaques following vaginal ring administration

BACKGROUND: Vaginal ring devices are being developed to provide sustained release of HIV microbicides. To date, only limited pharmacokinetic data is available from animal or human studies. Here we report the effect of Depo-Provera (DP) pre- treatment, commonly used to thin the vaginal epithelium in challenge experiments, on the pharmacokinetic profile of CMPD167 (a small molecule CCR5 co-receptor antagonist) in rhesus macaques following vaginal ring administration.

METHODS: A single 400mg CMPD167 silicone elastomer vaginal ring was inserted into each of twelve female rhesus macaques. Six macaques were treated with (DP) 30 days before ring placement; the other six macaques were untreated. Blood, vaginal fluid and vaginal biopsies were collected prior to and at various times during 28 days of ring placement and assayed for CMPD167 levels by HPLC. Rings were assayed for residual CMPD167 at the end of the study and the calculated amount of CMPD167 released in vivo compared with in vitro release data.

RESULTS: Vaginal fluid, plasma and tissue levels of CMPD167 were detectable throughout ring placement. Significant differences were observed in mean daily vaginal fluid levels between the DP-treated (16–56 mcg/mL) and untreated groups (48–181 mcg/mL). Plasma CMPD167 levels were significantly higher peaking at 4 ng/mL and maintaining levels of 1–2 nM throughout the 14 days of testing in animals pre-treated with DP compared to non DP-treated macaques (<1 ng/mL maintained). Tissue levels were varied between 2–10 g/mL CMPD167 with no significant difference between the DP-treated and untreated macaques.

CONCLUSIONS: The study demonstrates that clinically relevant, and possibly protective doses of CMPD167 are released in the vaginal vault of rhesus macaques from vaginal rings through 28 days duration. DP is known to induce vaginal epithelial thinning and lower vaginal fluid levels, which accounts for the increased plasma levels of CMPD167. In contrast, macaques not treated with DP had minimal absorption into plasma compartments and significantly higher levels of CMPD167 in the vagina, similar to those previously shown to be protective against vaginal challenge.

Preaching to Princes: John Burgess and George Hakewill in the Royal Pulpit

This article examines a previously unnoticed link between the Puritan John Burgess and the Calvinist conformist George Hakewill. In 1604 Burgess preached a court sermon so outspoken and critical of James I’s religious policy that he was imprisoned. Nearly twenty years later, however, Hakewill chose to incorporate extended passages from Burgess’s sermon into the series of sermons, King David’s vow (1621), preached to Prince Charles’s household. This article considers why Burgess’s sermon became so resonant for Hakewill in the early 1620s and also demonstrates how Hakewill deliberately sought to moderate Burgess’s strident polemic. In so doing the article provides important new evidence for the politically attuned sermon culture at Prince Charles’s court in the early 1620s and also suggests how, as the parameters for clerical conformity shifted in the latter years of James’s reign, Calvinist conformists found a new appeal in the works of moderate Puritans. I

"Producers and Consumers in EU E-Commerce Law by John Dickie, Oxford: Hart Publishing, 2005 (ISBN 1-841-13454-6)"

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