Understanding the hepatic disposition of statins to improve predictions of safety and efficacy

Previously held under moratorium in Chemistry Department (GSK) from 03/10/2019 to 14/12/2022To date, little is known about the hepatic transport of statins by the multi resistance proteins MRP2, MRP3 and MRP4 or their inhibitory potential against these same carrier proteins. By inference, the potential clinical consequences of statin transport and inhibition are not fully characterised. This thesis examines seven statins, their transport properties against MRP2, MRP3 and MRP4 and their ability to act as transport inhibitors. The inside-out vesicular model was employed where only a single MRP transporter was transfected. Key findings were; Statins identified as substrates: MRP2: Rosuvastatin MRP3: Pravastatin, rosuvastatin MRP4: Fluvastatin, pitavastatin, pravastatin Statins identified as inhibitors: MRP2: All statins (weak inhibitors except for lovastatin) MRP3: All statins moderate to strong inhibitors especially atorvastatin MRP4: All moderate inhibitors except pravastatin (weak) Notably, our findings imply that statins acting as perpetrators of MRP3 and MRP4 inhibition may be of more clinical relevance than their behaviour as substrates.To date, little is known about the hepatic transport of statins by the multi resistance proteins MRP2, MRP3 and MRP4 or their inhibitory potential against these same carrier proteins. By inference, the potential clinical consequences of statin transport and inhibition are not fully characterised. This thesis examines seven statins, their transport properties against MRP2, MRP3 and MRP4 and their ability to act as transport inhibitors. The inside-out vesicular model was employed where only a single MRP transporter was transfected. Key findings were; Statins identified as substrates: MRP2: Rosuvastatin MRP3: Pravastatin, rosuvastatin MRP4: Fluvastatin, pitavastatin, pravastatin Statins identified as inhibitors: MRP2: All statins (weak inhibitors except for lovastatin) MRP3: All statins moderate to strong inhibitors especially atorvastatin MRP4: All moderate inhibitors except pravastatin (weak) Notably, our findings imply that statins acting as perpetrators of MRP3 and MRP4 inhibition may be of more clinical relevance than their behaviour as substrates

GAELIC/SALIT Interlending Project 2005

The GAELIC Interlending and Document Supply Project was the fortunate recipient of a SALI Trust grant of R15 000 to investigate the performance levels of the ten GAELIC member libraries in supplying and requesting books and articles within the interlending system of South Africa. The duration of the project was from January to September 2005. The Project was led by Heidi Visser of the Academic Information Services at the University of Pretoria

Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disease which is characterized by the presence of extracellular senile plaques mainly composed of amyloid-[beta] peptide (A[beta]), intracellular neurofibrillary tangles, and selective synaptic and neuronal loss. AD brains revealed elevated levels of oxidative stress markers which have been implicated in A[beta]-induced toxicity. In the present work we addressed the hypothesis that oxidative stress occurs early in the development of AD and evaluated the extension of the oxidative stress and the levels of antioxidants in an in vivo model of AD, the triple-transgenic mouse, which develops plaques, tangles, and cognitive impairments and thus mimics AD progression in humans. We have shown that in this model, levels of antioxidants, namely, reduced glutathione and vitamin E, are decreased and the extent of lipid peroxidation is increased. We have also observed increased activity of the antioxidant enzymes glutathione peroxidase and superoxide dismutase. These alterations are evident during the A[beta] oligomerization period, before the appearance of A[beta] plaques and neurofibrillary tangles, supporting the view that oxidative stress occurs early in the development of the disease.http://www.sciencedirect.com/science/article/B6T38-4S575T6-1/1/a8327ebd74cb7baf97f9aa0ac56dbd9

Physical mapping of ribosomal DNA and genome size in diploid and polyploid North African Calligonum species (Polygonaceae)

38 p., tablas, gráf.Most Calligonum species are desert plants, characteristic of the Saharan bioclimatic region. All species karyologically analyzed until present have the basic chromosome number x = 9 and comprise diploids, triploids and tetraploids. The Tunisian flora comprises diploid Calligonum arich and C. azel, of restricted distribution, and the tetraploid C. comosum with wider distribution. Analyses of their karyotypes and polyploidisation-linked rDNA changes by orcein staining, fluorochrome banding with chromomycin A3 and fluorescent in situ hybridisation with 5S and 26S ribosomal DNA probes have been performed. We report the chromosome number for Calligonum arich (2n = 18) as well as the diploid level for C. comosum for the first time. Chromosome counts have also verified the earlier described tetraploid cytotype (2n = 36) of C. comosum. A general pattern of six GC-rich bands as well as two 35S sites and four 5S sites is described for Calligonum species at the diploid level although there is intraspecific variation regarding the site number in a second type of C. comosum, with one pair of 35S rDNA sites and two pairs of 5S rDNA sites. The tetraploid cytotype of C. comosum has undergone locus loss and genome downsizing. Genome size assessments confirmed previous data. Nonetheless, statistically significant differences were found depending on the type of tissue used for estimation. Measurements from seeds had always larger values than from leaves. The presence of cytosolic compounds in leaves, interfering with DNA staining, is discussed as a possible cause of the differences.This work was supported by the Dirección General de Investigación Científica y Técnica, government of Spain (CGL2010-22234-C02-01/BOS and CGL2010-22234-C02-02/BOS) and the Generalitat de Catalunya, government of Catalonia (‘‘Ajuts a grups de recerca consolidats’’, 2009SGR0439). SG and OH benefitted from Juan de la Cierva postdoctoral contracts of the Ministry of Economy and Competitiveness, government of Spain.Peer reviewe