Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug–drug interactions

Metformin is used as a probe for OCT2 mediated transport when investigating possible DDIs with new chemical entities. The aim of the current study was to investigate the ability of physiologically-based pharmacokinetic (PBPK) models to simulate the effects of OCT and MATE inhibition by cimetidine on metformin kinetics. PBPK models were developed, incorporating mechanistic kidney and liver sub-models for metformin (OCT and MATE substrate) and a mechanistic kidney sub-model for cimetidine. The models were used to simulate inhibition of the MATE1, MATE2-K, OCT1 and OCT2 mediated transport of metformin by cimetidine. Assuming competitive inhibition and using cimetidine Ki values determined in vitro, the predicted metformin AUC ratio was 1.0 compared to an observed value of 1.46. The observed AUC ratio could only be recovered with this model when the cimetidine Ki for OCT2 was decreased 1000-fold or the Ki's for both OCT1 and OCT2 were decreased 500- fold. An alternative description of metformin renal transport by OCT1 and OCT2, incorporating electrochemical modulation of the rate of metformin uptake together with 8–18-fold decreases in cimetidine Ki's for OCTs and MATEs, allowed recovery of the extent of the observed effect of cimetidine on metformin AUC. While the final PBPK model has limitations, it demonstrates the benefit of allowing for the complexities of passive permeability combined with active cellular uptake modulated by an electrochemical gradient and active efflu

センシ

In Persian; foreword in Japanese and EnglishAdded t.p. in Japanese and Englishجلد 2 published in 2006 before جلد 1Two col. maps on folded leaves of plates inserted in جلد 1"Supported by Grant-in-Aid for Scientific Research (Grant-in-Aid for JSPS Fellows, 17-2387, 2005-2008 and Grant-in-Aid for Young Scientists (B), 21720255, 2009)"--Foreword, جلد 1, p. xviiIncludes bibliographical references and inde

Spectral analysis of spatially resolved 3C295 (sub-arcsecond resolution) with the International LOFAR Telescope

GalaxiesInstrumentatio

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Plant WEE1 Kinase Interacts With a 14-3-3 Protein, GF14w(omega) but a Mutation of WEE1 at S485 Alters Their Spatial Interaction

In animals, 14-3-3 proteins bind two cell cycle proteins WEE1 and CDC25 stabilising their phosphorylated state. We report here for the first time interactions between WEE1 and 14-3-3 proteins both in vitro and in vivo in plants. The Arabidopsis 14-3-3 family partitions into either an Epsilon or Non-Epsilon group. In a yeast 2-hybrid screen Arabidopsis WEE1 interacted with the Non-Epsilon group. Subsequently, we focussed on Non-Epsilon GF1

A SIBLINGS ANALYSIS OF THE EFFECTS OF ALCOHOL CONSUMPTION ONSET ON EDUCATIONAL ATTAINMENT

This article examines the relationship between youthful drinking and educational attainment using data on same-sex siblings pairs from the 1979-90 panels of the National Longitudinal Survey of Youth. We consider different estimators that can be constructed using siblings data, including estimators that adopt key restrictions of the standard regression, family fixed effect, and instrumental variable approaches. We also consider the properties of these estimators under more general conditions and show that under very plausible assumptions the effect of drinking on schooling can be bounded. The study finds that estimates of the schooling consequences of youthful drinking are very sensitive to specification issues. The research concludes that the actual effects of youthful drinking on education are likely to be small. Copyright 2001 Western Economic Association International.

Spectral analysis of spatially resolved 3C295 (sub-arcsecond resolution) with the International LOFAR Telescope

3C295 is a bright, compact steep spectrum source with a well-studied integrated radio spectral energy distribution (SED) from 132 MHz to 15 GHz. However, spatially resolved spectral studies have been limited due to a lack of high resolution images at low radio frequencies. These frequencies are crucial for measuring absorption processes, and anchoring the overall spectral modelling of the radio SED. In this paper, we use International LOw-Frequency ARray (LOFAR) Telescope (ILT) observations of 3C295 to study its spatially resolved spectral properties with sub-arcsecond resolution at 132 MHz. Combining our new 132 MHz observation with archival data at 1.6 GHz, 4.8 GHz, and 15 GHz, we are able to carry out a resolved radio spectral analysis. The spectral properties of the hotspots provides evidence for low frequency flattening. In contrast, the spectral shape across the lobes is consistent with a Jaffe-Perola spectral ageing model. Using the integrated spectral information for each component, we then fitted low-frequency absorption models to the hotspots, finding that both free-free absorption and synchrotron self-absorption models provide a better fit to the data than a standard power law. Although we can say there is low-frequency absorption present in the hotspots of 3C295, future observations with the Low Band Antenna of the ILT at 55 MHz may allow us to distinguish the type of absorption