In vitro and in vivo evaluation of sunitinib eluting beads

Background: Chemoembolization is used to treat liver malignancies. However recurrence occurs frequently, possibly because of neoangiogenesis triggered by ischemia caused by the embolic agent. In this context, the combination of an embolic agent with an anti-angiogenic drug seems appealing. This study characterizes the in vitro loading and release profile of sunitinib eluting beads of different sizes and their pharmacokinetic profile in a rabbit model. Methods: 70-150 μm and 100-300 μm drug eluting beads (DC Bead, Biocompatibles UK) were loaded by incubation in a sunitinib hydrochloride solution. Drug was quantified by spectrophotometry at 430 nm. Drug release was measured over one-week periods and normalized using an internal standard in 30% ethanol in NaCl 0.9%. New-Zealand white rabbits were used. Eight animals received 0.2 ml of 100-300 μm DC Bead loaded with 6 mg of sunitinib in the hepatic artery (group 1) and 4 animals received 6 mg of sunitinib p.o. (group 2). Half of the animals were sacrificed after 6 hours and half after24 hours. Liver enzymes were measured at 0, 6 and 24 hours in both groups. Plasmatic sunitinib concentration was determined by tandem mass spectroscopy (LC MS/MS) at 0, 1, 2, 3, 4, 5, 6 and 24 hours. At sacrifice, the livers were harvested and sunitinib concentration in liver tissue was assessed by LC MS/MS. Results: High drug loading was obtained for both microsphere bead sizes. Particle shrinking was observed with adsorption of sunitinib. Almost complete release of sunitinib was detected under physiological conditions, with very similar release for 70-150 μm and 100-300 μm (t50%=1.2 h) DC Bead. Conclusions: Sunitinib eluting beads are well tolerated by rabbits when administered in the hepatic artery. No unexpected toxicity was observed. Very high drug concentration can be obtained at the site of embolization with minimal systemic passage.

Distribution of metals exposure and associations with cardiometabolic risk factors in the "Modeling the Epidemiologic Transition Study".

BACKGROUND: Metals are known endocrine disruptors and have been linked to cardiometabolic diseases via multiple potential mechanisms, yet few human studies have both the exposure variability and biologically-relevant phenotype data available. We sought to examine the distribution of metals exposure and potential associations with cardiometabolic risk factors in the "Modeling the Epidemiologic Transition Study" (METS), a prospective cohort study designed to assess energy balance and change in body weight, diabetes and cardiovascular disease risk in five countries at different stages of social and economic development. METHODS: Young adults (25-45 years) of African descent were enrolled (N = 500 from each site) in: Ghana, South Africa, Seychelles, Jamaica and the U.S.A. We randomly selected 150 blood samples (N = 30 from each site) to determine concentrations of selected metals (arsenic, cadmium, lead, mercury) in a subset of participants at baseline and to examine associations with cardiometabolic risk factors. RESULTS: Median (interquartile range) metal concentrations (μg/L) were: arsenic 8.5 (7.7); cadmium 0.01 (0.8); lead 16.6 (16.1); and mercury 1.5 (5.0). There were significant differences in metals concentrations by: site location, paid employment status, education, marital status, smoking, alcohol use, and fish intake. After adjusting for these covariates plus age and sex, arsenic (OR 4.1, 95% C.I. 1.2, 14.6) and lead (OR 4.0, 95% C.I. 1.6, 9.6) above the median values were significantly associated with elevated fasting glucose. These associations increased when models were further adjusted for percent body fat: arsenic (OR 5.6, 95% C.I. 1.5, 21.2) and lead (OR 5.0, 95% C.I. 2.0, 12.7). Cadmium and mercury were also related with increased odds of elevated fasting glucose, but the associations were not statistically significant. Arsenic was significantly associated with increased odds of low HDL cholesterol both with (OR 8.0, 95% C.I. 1.8, 35.0) and without (OR 5.9, 95% C.I. 1.5, 23.1) adjustment for percent body fat. CONCLUSIONS: While not consistent for all cardiometabolic disease markers, these results are suggestive of potentially important associations between metals exposure and cardiometabolic risk. Future studies will examine these associations in the larger cohort over time.

The nine-year sustained cost-containment impact of swiss pilot physicians-pharmacists quality circles.

BACKGROUND: Six pioneer physicians-pharmacists quality circles (PPQCs) located in the Swiss canton of Fribourg (administratively corresponding to a state in the US) were under the responsibility of 6 trained community pharmacists moderating the prescribing process of 24 general practitioners (GPs). PPQCs are based on a multifaceted collaborative process mediated by community pharmacists for improving compliance with clinical guidelines within GPs' prescribing practices. OBJECTIVE: To assess, over a 9-year period (1999-2007), the cost-containment impact of the PPQCs. METHODS: The key elements of PPQCs are a structured continuous quality improvement and education process; local networking; feedback of comparative and detailed data regarding costs, drug choice, and frequency of prescribed drugs; and structured independent literature review for interdisciplinary continuing education. The data are issued from the community pharmacy invoices to the health insurance companies. The study analyzed the cost-containment impact of the PPQCs in comparison with GPs working in similar conditions of care without particular collaboration with pharmacists, the percentage of generic prescriptions for specific cardiovascular drug classes, and the percentage of drug costs or units prescribed for specific cardiovascular drugs. RESULTS: For the 9-year period, there was a 42% decrease in the drug costs in the PPQC group as compared to the control group, representing a $225,000 (USD) savings per GP only in 2007. These results are explained by better compliance with clinical and pharmacovigilance guidelines, larger distribution of generic drugs, a more balanced attitude toward marketing strategies, and interdisciplinary continuing education on the rational use of drugs. CONCLUSIONS: The PPQC work process has yielded sustainable results, such as significant cost savings, higher penetration of generics and reflection on patient safety, and the place of "new" drugs in therapy. The PPQCs may also constitute a solid basis for implementing more comprehensive collaborative programs, such as medication reviews, adherence-enhancing interventions, or disease management approaches.

A mixed ecologic-cohort comparison of physical activity & weight among young adults from five populations of African origin.

BACKGROUND: Examination of patterns and intensity of physical activity (PA) across cultures where obesity prevalence varies widely provides insight into one aspect of the ongoing epidemiologic transition. The primary hypothesis being addressed is whether low levels of PA are associated with excess weight and adiposity. METHODS: We recruited young adults from five countries (500 per country, 2500 total, ages 25-45 years), spanning the range of obesity prevalence. Men and women were recruited from a suburb of Chicago, Illinois, USA; urban Jamaica; rural Ghana; peri-urban South Africa; and the Seychelles. PA was measured using accelerometry and expressed as minutes per day of moderate-to-vigorous activity or sedentary behavior. RESULTS: Obesity (BMI ≥ 30) prevalence ranged from 1.4% (Ghanaian men) to 63.8% (US women). South African men were the most active, followed by Ghanaian men. Relatively small differences were observed across sites among women; however, women in Ghana accumulated the most activity. Within site-gender sub-groups, the correlation of activity with BMI and other measures of adiposity was inconsistent; the combined correlation across sites was -0.17 for men and -0.11 for women. In the ecological analysis time spent in moderate-to-vigorous activity was inversely associated with BMI (r = -0.71). CONCLUSION: These analyses suggest that persons with greater adiposity tend to engage in less PA, although the associations are weak and the direction of causality cannot be inferred because measurements are cross-sectional. Longitudinal data will be required to elucidate direction of association.

Atorvastatin-loaded hydrogel affects the smooth muscle cells of human veins.

Intimal hyperplasia (IH) is the major cause of stenosis of vein grafts. Drugs such as statins prevent stenosis, but their systemic administration has limited effects. We developed a hyaluronic acid hydrogel matrix, which ensures a controlled release of atorvastatin (ATV) at the site of injury. The release kinetics demonstrated that 100% of ATV was released over 10 hours, independent of the loading concentration of the hydrogel. We investigated the effects of such a delivery on primary vascular smooth muscle cells isolated from human veins. ATV decreased the proliferation, migration, and passage of human smooth muscle cells (HSMCs) across a matrix barrier in a similar dose-dependent (5-10 µM) and time-dependent manner (24-72 hours), whether the drug was directly added to the culture medium or released from the hydrogel. Expression analysis of genes known to be involved in the development of IH demonstrated that the transcripts of both the gap junction protein connexin43 (Cx43) and plasminogen activator inhibitor-1 (PAI-1) were decreased after a 24-48-hour exposure to the hydrogel loaded with ATV, whereas the transcripts of the heme oxygenase (HO-1) and the inhibitor of tissue plasminogen activator were increased. At the protein level, Cx43, PAI-1, and metalloproteinase-9 expression were decreased, whereas HO-1 was upregulated in the presence of ATV. The data demonstrate that ATV released from a hydrogel has effects on HSMCs similar to the drug being freely dissolved in the environment.

Comparisons of intensity-duration patterns of physical activity in the US, Jamaica and 3 African countries.

BACKGROUND: This difference in how populations living in low-, middle or upper-income countries accumulate daily PA, i.e. patterns and intensity, is an important part in addressing the global PA movement. We sought to characterize objective PA in 2,500 participants spanning the epidemiologic transition. The Modeling the Epidemiologic Transition Study (METS) is a longitudinal study, in 5 countries. METS seeks to define the association between physical activity (PA), obesity and CVD risk in populations of African origin: Ghana (GH), South Africa (SA), Seychelles (SEY), Jamaica (JA) and the US (suburban Chicago). METHODS: Baseline measurements of objective PA, SES, anthropometrics and body composition, were completed on 2,500 men and women, aged 25-45 years. Moderate and vigorous PA (MVPA, min/d) on week and weekend days was explored ecologically, by adiposity status and manual labor. RESULTS: Among the men, obesity prevalence reflected the level of economic transition and was lowest in GH (1.7%) and SA (4.8%) and highest in the US (41%). SA (55%) and US (65%) women had the highest levels of obesity, compared to only 16% in GH. More men and women in developing countries engaged in manual labor and this was reflected by an almost doubling of measured MPVA among the men in GH (45 min/d) and SA (47 min/d) compared to only 28 min/d in the US. Women in GH (25 min/d), SA (21 min/d), JA (20 min/d) and SEY (20 min/d) accumulated significantly more MPVA than women in the US (14 min/d), yet this difference was not reflected by differences in BMI between SA, JA, SEY and US. Moderate PA constituted the bulk of the PA, with no study populations except SA men accumulating > 5 min/d of vigorous PA. Among the women, no sites accumulated >2 min/d of vigorous PA. Overweight/obese men were 22% less likely to engage in manual occupations. CONCLUSION: While there is some association for PA with obesity, this relationship is inconsistent across the epidemiologic transition and suggests that PA policy recommendations should be tailored for each environment.

25-Hydroxyvitamin D in African-origin populations at varying latitudes challenges the construct of a physiologic norm.

BACKGROUND: The vitamin D-endocrine system is thought to play a role in physiologic processes that range from mineral metabolism to immune function. Serum 25-hydroxyvitamin D [25(OH)D] is the accepted biomarker for vitamin D status. Skin color is a key determinant of circulating 25(OH)D concentrations, and genes responsible for melanin content have been shown to be under strong evolutionary selection in populations living in temperate zones. Little is known about the effect of latitude on mean concentrations of 25(OH)D in dark-skinned populations. OBJECTIVE: The objective was to describe the distribution of 25(OH)D and its subcomponents in 5 population samples of African origin from the United States, Jamaica, Ghana, South Africa, and the Seychelles. DESIGN: Participants were drawn from the Modeling of the Epidemiologic Transition Study, a cross-sectional observational study in 2500 adults, ages 25-45 y, enrolled between January 2010 and December 2011. Five hundred participants, ∼50% of whom were female, were enrolled in each of 5 study sites: Chicago, IL (latitude: 41°N); Kingston, Jamaica (17°N); Kumasi, Ghana (6°N); Victoria, Seychelles (4°S); and Cape Town, South Africa (34°S). All participants had an ancestry primarily of African origin; participants from the Seychelles trace their history to East Africa. RESULTS: A negative correlation between 25(OH)D and distance from the equator was observed across population samples. The frequency distribution of 25(OH)D in Ghana was almost perfectly normal (Gaussian), with progressively lower means and increasing skewness observed at higher latitudes. CONCLUSIONS: It is widely assumed that lighter skin color in populations outside the tropics resulted from positive selection, driven in part by the relation between sun exposure, skin melanin content, and 25(OH)D production. Our findings show that robust compensatory mechanisms exist that create tolerance for wide variation in circulating concentrations of 25(OH)D across populations, suggesting a more complex evolutionary relation between skin color and the vitamin D pathway. This trial was registered at clinicaltrials.gov as NCT02111902.