Celiprolol double-peak occurrence and gastric motility: Nonlinear mixed effects modeling of bioavailability data obtained in dogs

Investigation of the underlying mechanism leading to inter- and intrasubject variations in the plasma concentration-time profiles of drugs (1) can considerably benefit rational drug therapy. The significant effect of gastric emptying on the rate and extent of celiprolol absorption and its role with respect to double-peak formation was demonstrated in the present study. In four dogs racemic celiprolol was dosed perorally in a crossover design during four different phases of the fasted-state gastric cycle and gastric motility was recorded simultaneously using a manometric measurement system. Intravenous doses were also given to obtain disposition and bioavailability parameters. The blood samples were assayed by a stereoselective HPLC method (2). The time to onset of the active phase of the gastric cycle showed an excellent correlation with the time to celiprolol peak concentration. Furthermore, bioavailability was increased when celiprolol was administered during the active phase. Double peaks were observed when the first active phase was relatively short, suggesting that a portion of the drug remained in the stomach until the next active phase. Population pharmacokinetic modeling of the data with a two-compartment open model with two lag times incorporating the motility data confirmed the effect of time to gastric empyting on the variability of the oral pharmacokinetics of celiprolol. The fasted-state motility phases determine the rate and extent of celiprolol absorption and influence the occurrence of double peaks. Peak plasma levels of celiprolol exhibit less variability if lag times, and therefore gastric emptying times, are taken into consideration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45049/1/10928_2006_Article_BF02354285.pd

Re-evaluation of blood mercury, lead and cadmium concentrations in the Inuit population of Nunavik (Québec): a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Arctic populations are exposed to mercury, lead and cadmium through their traditional diet. Studies have however shown that cadmium exposure is most often attributable to tobacco smoking. The aim of this study is to examine the trends in mercury, lead and cadmium exposure between 1992 and 2004 in the Inuit population of Nunavik (Northern Québec, Canada) using the data obtained from two broad scale health surveys, and to identify sources of exposure in 2004.</p> <p>Methods</p> <p>In 2004, 917 adults aged between 18 and 74 were recruited in the 14 communities of Nunavik to participate to a broad scale health survey. Blood samples were collected and analysed for metals by inductively coupled plasma mass spectrometry, and dietary and life-style characteristics were documented by questionnaires. Results were compared with data obtained in 1992, where 492 people were recruited for a similar survey in the same population.</p> <p>Results</p> <p>Mean blood concentration of mercury was 51.2 nmol/L, which represent a 32% decrease (p < 0.001) between 1992 and 2004. Mercury blood concentrations were mainly explained by age (partial r²= 0.20; p < 0.0001), and the most important source of exposure to mercury was marine mammal meat consumption (partial r²= 0.04; p < 0.0001). In 2004, mean blood concentration of lead was 0.19 μmol/L and showed a 55% decrease since 1992. No strong associations were observed with any dietary source, and lead concentrations were mainly explained by age (partial r²= 0.20.; p < 0.001). Blood cadmium concentrations showed a 22% decrease (p < 0.001) between 1992 and 2004. Once stratified according to tobacco use, means varied between 5.3 nmol/L in never-smokers and 40.4 nmol/L in smokers. Blood cadmium concentrations were mainly associated with tobacco smoking (partial r²= 0.56; p < 0.0001), while consumption of caribou liver and kidney remain a minor source of cadmium exposure among never-smokers.</p> <p>Conclusion</p> <p>Important decreases in mercury, lead and cadmium exposure were observed. Mercury decrease could be explained by dietary changes and the ban of lead cartridges use likely contributed to the decrease in lead exposure. Blood cadmium concentrations remain high and, underscoring the need for intensive tobacco smoking prevention campaigns in the Nunavik population.</p

Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD

SCADA and related technologies

Presented at SCADA and related technologies for irrigation district modernization, II: a USCID water management conference held on June 6-9, 2007 in Denver, Colorado.Includes bibliographical references.This paper presents an application of Supervisory Control and Data Acquisition (SCADA) in three countries of Central Asia: Uzbekistan, Kyrgyzstan and Tajikistan. The project is financed by the Swiss Development Agency for Cooperation (SDC). The objectives of this project are to stabilize the flows diverted for irrigation downstream from large hydro-power plants and to monitor the equity and reliability of water diverted to secondary canals. This application provides an example of a promising success story in irrigation modernization in developing countries. Three factors may contribute to this success: i) the existence of a regional automation company, ii) the use of factory-made control equipment and iii) the rapid intervention of the local industry when repairs or corrections to control equipment are needed. The project also demonstrates that modernization of irrigation systems can be completed at a reasonable cost. The paper presents the results of the first series of tests of the SCADA system and highlights some of the differences in the design of SCADA projects between developed and developing countries