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.

Statin prescribing in Northern Ireland and England pre and post introduction of the quality and outcomes framework

Objective The objective of this research was to examine differences in patterns of statin prescribing between Northern Ireland and England both before and after the introduction of the Quality and Outcomes Framework (QOF). Setting: Primary care practices in Northern Ireland and England. Method Northern Ireland practices were matched with practices in England, statin prescribing data and QOF achievement scores (for the first year post-QOF) were obtained. Crude prescribing data from matched practices were manipulated to provide a data set of Defined Daily Doses (DDDs)/1,000 patients and cost/DDD/1,000 patients for each statin drug entity covering 1 year before and after the introduction of QOF. QOF achievements were converted into percentage scores for matched practices. Main outcome measure Cost per defined daily dose (DDD) per 1,000 patients. Results Significantly less statins (DDD/1,000 patients) were dispensed in Northern Ireland compared with the matched region in England both before and after the introduction of QOF (P

Is naturalisation of the brown hare in Ireland a threat to the endemic Irish hare?

On islands, one of the greatest risks to native wildlife is the establishment of alien species. In Ireland, the Irish hare (Lepus timidus hibernicus), the only native lagomorph, may be at risk from competitive exclusion and hybridisation with naturalised brown hares (L. europaeus) that were introduced during the late nineteenth century. Pre- and post-breeding spotlight surveys during 2005 in the north of Ireland determined that brown hare populations are established in mid-Ulster and west Tyrone. In mid-Ulster, brown hares comprised 53%-62% of the hare population, with an estimated abundance of 700-2000 individuals between pre- and post-breeding periods. Comparison of habitat niches suggest that Irish and brown hares have comparable niche breadths that at times completely overlap, suggesting the potential for strong competition between the species. Anecdotal evidence suggests that both species may hybridise. Further research is urgently required to assess the degree of risk that naturalised brown hares pose to the Irish hare population and what action, if any, is needed to ensure the future ecological security and genetic integrity of the native species.

Signals of need in a cooperatively breeding mammal with mobile offspring

In many bird species with biparental care for young in the nest, hungry chicks beg repeatedly and parents adjust their feeding rate to the call rate of young. Repetitive calling also occurs in fledglings and in some mammals where offspring follow provisioners. It is not yet clear whether, in mobile systems with dispersed young where adults cannot compare the vocal behaviour of all young simultaneously, the calls represent a signal of need. We investigated repetitive begging by cooperatively reared meerkat, Suricata suricatta, pups that foraged with the group. Pups produced two types of begging calls: repeat calls over long periods and high-pitched calls mainly confined to feeding events. Food-deprived pups stayed closer to feeders, and begged for longer and more intensely by calling at a higher rate. Hungry pups increased both the rate of repeat calls, which were given continually, and the number of high-pitched bouts, but adults increased their food allocation only in relation to the rate of repeat calls. Our study indicates that hunger may lead to several changes in vocal behaviour, only some of which may be used by adults to assess need.

Vitamins C and E for prevention of pre-eclampsia in women with type 1 diabetes (DAPIT): a randomised placebo-controlled trial.

Background
Results of several trials of antioxidant use during pregnancy have not shown a reduction in pre-eclampsia, but the eff ect in women with diabetes is unknown. We aimed to assess whether supplementation with vitamins C and E reduced incidence of pre-eclampsia in women with type 1 diabetes.

Methods
We enrolled women from 25 UK antenatal metabolic clinics in a multicentre randomised placebo-controlled trial. Eligibility criteria were type 1 diabetes preceding pregnancy, presentation between 8 weeks’ and 22 weeks’ gestation, singleton pregnancy, and age 16 years or older. Women were randomly allocated in a 1:1 ratio to receive1000 mg vitamin C and 400 IU vitamin E (a-tocopherol) or matched placebo daily until delivery. The randomisation sequence was stratifi ed by centre with balanced blocks of eight patients. All trial personnel and participants were masked to treatment allocation. The primary endpoint was pre-eclampsia, which we defi ned as gestational hypertension with proteinuria. Analysis was by modifi ed intention to treat. This study is registered, ISRCTN27214045.

Findings
Between April, 2003, and June, 2008, 762 women were randomly allocated to treatment groups (379 vitamin supplementation, 383 placebo). The primary endpoint was assessed for 375 women allocated to receive vitamins, and 374 allocated to placebo. Rates of pre-eclampsia did not differ between vitamin (15%, n=57) and placebo (19%, 70)groups (risk ratio 0·81, 95% CI 0·59–1·12). No adverse maternal or neonatal outcomes were reported.

Interpretation
Supplementation with vitamins C and E did not reduce risk of pre-eclampsia in women with type 1 diabetes. However, the possibility that vitamin supplementation might be benefi cial in women with a low antioxidant status at baseline needs further testing.

An exploration of knowledge and attitudes related to pre-pregnancy care in women with diabetes

Aims: Pre-pregnancy care optimizes pregnancy outcome in women with pre-gestational diabetes, yet most women enter pregnancy unprepared. We sought to determine knowledge and attitudes of women with Type 1 and Type 2 diabetes of childbearing age towards pre-pregnancy care.

Methods: Twenty-four women (18 with Type 1 diabetes and six with Type 2 diabetes) aged 17–40 years took part in one of four focus group sessions: young nulliparous women with Type 1 diabetes (Group A), older nulliparous women with Type 1 diabetes (Group B), parous women with Type 1 diabetes (Group C) and women with Type 2 diabetes of mixed parity (Group D).

Results: Content analysis of transcribed focus groups revealed that, while women were well informed about the need to plan pregnancy, awareness of the rationale for planning was only evident in parous women or those who had actively sought pre-pregnancy advice. Within each group, there was uncertainty about what pre-pregnancy advice entailed. Despite many women reporting positive healthcare experiences, frequently cited barriers to discussing issues around family planning included unsupportive staff, busy clinics and perceived social stereotypes held by health professionals.

Conclusions: Knowledge and attitudes reported in this study highlight the need for women with diabetes, regardless of age, marital status or type of diabetes, to receive guidance about planning pregnancy in a motivating, positive and supportive manner. The important patient viewpoints expressed in this study may help health professionals determine how best to encourage women to avail of pre-pregnancy care