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Effect of epigallocatechin gallate on bile production
Hiršová, Petra ; Mičuda, Stanislav (advisor) ; Slanař, Ondřej (referee) ; Trejtnar, František (referee)
Effect of epigallocatechin gallate Epigallocatechin gallate (EGCG), the major green tea catechin, has been shown to be protective in various experimental models of liver injury. Since its effect on biliary physiology and liver cholesterol homeostasis has not been thoroughly studied, the present study investigated effect of EGCG on bile flow, bile acid homeostasis and cholesterol metabolism in healthy and ethinylestradiol-treated rats. Compared to controls, EGCG treatment in rats decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter at the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. Interestingly, EGCG markedly enhanced biliary excretion of cholesterol and phospholipids. These changes tightly correlated with increased expression of ATP- binding cassette transporter G5 and G8 (Abcg5/8) and scavenger receptor class B type 1 and with decreased expression of acyl-CoA:cholesterol acyltransferase (Acat2). EGCG administration to rats also doubled plasma bile acid concentrations compared to controls. While protein expression of the main...
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The study of the potential importance of pravastatin in the prevention of the cholestatic liver impairment
Karlasová, Gabriela ; Mičuda, Stanislav (advisor) ; Slanař, Ondřej (referee) ; Večeřa, Rostislav (referee)
The study of the potential importance of pravastatin in the prevention of the cholestatic liver impairment. Obstructive cholestasis is a clinical syndrome accompanying numerous liver diseases. Early diagnosis and appropriate treatment of obstructive jaundice is very important because untreated condition leads to irreparable changes in the liver. This gives rise to liver fibrosis, which later passes into biliary cirrhosis with all its consequences (portal hypertension, esophageal varices, liver failure). The causal therapy such as surgical removal of the obstruction is quite often impossible. Therefore it is necessary to search for pharmacotherapeutic approaches that can positively modulate the developing disease. In the present thesis, the effect of pravastatin on the liver damage during chronic obstructive cholestasis was investigated in rats. Pravastatin, belonging to a group of widely used inhibitors of HMG-CoA reductase, possesses not only lipid-lowering action but also anti-inflammatory and antioxidant effects, so called pleiotropic effects. The decisive fact for choosing pravastatin as a suitable substance for our study was that pravastatin has already shown positive effects in several patients with cholestasis and its hydrophilic nature does not require metabolism in impaired liver and allows...
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The study of the potential importance of pravastatin in the prevention of the cholestatic liver impairment
Karlasová, Gabriela ; Mičuda, Stanislav (advisor) ; Slanař, Ondřej (referee) ; Večeřa, Rostislav (referee)
The study of the potential importance of pravastatin in the prevention of the cholestatic liver impairment. Obstructive cholestasis is a clinical syndrome accompanying numerous liver diseases. Early diagnosis and appropriate treatment of obstructive jaundice is very important because untreated condition leads to irreparable changes in the liver. This gives rise to liver fibrosis, which later passes into biliary cirrhosis with all its consequences (portal hypertension, esophageal varices, liver failure). The causal therapy such as surgical removal of the obstruction is quite often impossible. Therefore it is necessary to search for pharmacotherapeutic approaches that can positively modulate the developing disease. In the present thesis, the effect of pravastatin on the liver damage during chronic obstructive cholestasis was investigated in rats. Pravastatin, belonging to a group of widely used inhibitors of HMG-CoA reductase, possesses not only lipid-lowering action but also anti-inflammatory and antioxidant effects, so called pleiotropic effects. The decisive fact for choosing pravastatin as a suitable substance for our study was that pravastatin has already shown positive effects in several patients with cholestasis and its hydrophilic nature does not require metabolism in impaired liver and allows...
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Intracellular Concentration of Methotrexate in Erytrocytes and MTHFR Polymorphisms: Possible Association with Methotrexate Efficasy and Toxicity in Patients with Juvenile Idiopathic Arthritis
Tuková, Jana ; Doležalová, Pavla (advisor) ; Slanař, Ondřej (referee) ; Pavelka, Karel (referee)
Objective: To investigate whether methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and erythrocyte concentration of methotrexate (EMTX) could serve as predictors of methotrexate (MTX) efficacy and toxicity in patients with juvenile idiopathic arthritis (JIA). Methods: Genetic analyses and EMTX and folate assessment were performed in 69 JIA patients treated with MTX and classified as full responders (n=51, disease inactivity) or nonresponders (n=18, less than 30 % improvement in paediatric ACR30 criteria while on 15 mg/m2/week parenteral MTX for at least 3 months). Results: Nonresponders were treated with the higher median MTX dose (17.2 vs 12.6 mg/m2/week, P<0.0001), and accumulated more EMTX (217 nmol/L vs 106 nmol/L, P<0.02) and erythrocyte folates (763 nmol/L vs 592 nmol/L, P=0.052) than responders. Analysis of MTHFR allele and genotype frequencies in relation to response failed to detect association. The frequency of any adverse effect was 29.4 % in responders and 33.3 % in nonresponders (P=0.77). The frequency of 677T allele was elevated in patients with adverse effects (52.4 % vs 20.9%, OR=3.88; 95% CI: 1.8-8.6; p<0.002). The probability of any adverse effect was significantly higher in patients with 677TT when compared to 677CC genotype (OR=55.5; 95-% CI: 2.9-1080;...
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Applications of chiral and achiral chromatography in pharmacology and toxicology
Chytil, Lukáš ; Slanař, Ondřej (advisor) ; Bultas, Jan (referee) ; Coufal, Pavel (referee)
Development and validation of methods for analysis of several drugs or their metabolites are decribed in this thesis. The document is presented as a commentary to the original papers, which were published in peer reviewed journals. Discussion on the optimization of each method is presented and covers also method development and influence of preanalytical aspects. Additionally, examples of the application of the developed methods in clinical pharmacology and toxicology are shown. This dissertation consists of three parts: enantiomeric determination of tramadol and its metabolite, determination of some antihypertensive drugs, and qualitative analysis of benzodiazepines. Development of a method for chiral analysis of tramadol and its desmethylated metabolite O- desmethyltramadol (ODT) in human urine and plasma is described in the first part of the thesis. Tramadol is a centrally acting analgetic drug, which is used as racemate in clinical practise. Each enantiomer displays different binding properties for various receptors: (+)-tramadol preferentially inhibits serotonin reuptake while (-)-tramadol mainly inhibits noradrenalin reuptake. (+)-tramadol is considered 10-times more potent than (-)-tramadol. Major active metabolite (ODT), which is considered to be the main agent responsible for the...
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Investigation of Drug Interactions on Hepatic and Renal Transport Proteins
Fuksa, Leoš ; Štaud, František (advisor) ; Fusek, Josef (referee) ; Slanař, Ondřej (referee)
STUDY OF DRUG-DRUG INTERACTIONS BASED ON MODULATION OF THE FUNCTION OF LIVER AND KIDNEY ACTIVE TRANSPORTERS Leos Fuksa, M.Sc. ABSTRACT The present thesis focused on closer research of drug-induced changes in the expression and function of the main hepatic and renal transporters and their effects on the pharmacokinetics of the model substrates. The subject of our particular interest were ABC efflux transporters (namely P-gp and Mrp2) localized in the apical membranes of polarized epithelium cells in the excretory organs, and also Oatp2 transporter playing an important role in the basolateral uptake of drugs. Dexamethasone and amiodarone were employed to bring about changes in the active transport. Dexamethasone is a potent corticosteroid that showed capability to increase elimination processes, i.e. to induce enzymes and transporters both in vitro and in vivo. Amiodarone, a life-saving antiarrhythmic, is a well-known inhibitor of drug metabolism. Its direct inhibitory effects on the active transport have recently been reported. The summarized results of the included publications describe various aspects of the pharmacokinetic drug-drug interactions, where the underlying mechanism of the interaction is a modulation (either induction/activation or inhibition) of the active transport. Such modulation is...
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Genetic variability of drug metabolizing enzymes
Slanař, Ondřej ; Perlík, František (advisor) ; Průša, Richard (referee) ; Lukáš, Milan (referee)
Drug metabolism is one of the key processes allowing to eliminate the administered dose. High interindividual variability of the activity of drug metabolizing enzymes is caused by many genetic and epigenetic factors. This variation can result in substantial differences in clinical response to the drug, ranging from failure of the therapy to appearance of toxic side effects or frequent onset of drug-drug interactions. The aim of the thesis was to evaluate the influence of genetically determined variability in drug metabolizing enzymes activity on the drug pharmacokinetics, pharmacodynemics and to asses whether either phenotyping or genotyping can be effectively applied under the naturalistic conditions of routine clinical practice, for e.g. as a prediction tool during to asses individual risk of development and progress of a disease or to forecast the drug response. The thesis mainly summarizes previously published articles on the topic. We have studied genetically determined variability of tramadol pharmacokinetics as well as drug-induced miosis in healthy volunteers with known CYP2D6 status. The lowest blood concentrations of principal active metabolite O-demethyltramadol accompanied by the highest levels of the parent compound at all sampling intervals up to 12 hours post-dose were found in the...
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