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Interactions of Antimicrobial Agents with Drug renal Transport Systems in Vitro
Mandíková, Jana ; Trejtnar, František (advisor) ; Pacherník, Jiří (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Jana Mandíková Supervisor doc. PharmDr. František Trejtnar, CSc. Title of Doctoral Thesis Interactions of antimicrobial agents with drug renal transport systems in vitro A number of important and frequently used antimicrobial agents are excreted from the body through the kidneys. During this excretory process drugs may interact with different membrane transport systems (transporters) which are expressed in the renal tissue. These interactions are often the determining factors for both renal excretion, and the toxic effects of these drugs in the kidney. There are highly expressed influx transporter such as organic anion transporters (OATs), organic cation transporters (OCTs) and the concentrative nucleoside transporters (CNTs) and efflux transporter BCRP (breast cancer resistance protein) and P glycoprotein (P-gp) in the kidney. Despite the importance of renal drug transporters for elimination and nephrotoxic effects of drugs and intensive research in this field, interactions of a number of important antimicrobial drugs with transporters in the kidney are not known or sufficiently described. The aim of this study was to investigate the interaction of selected antivirals and...
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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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Frequency of selected genetic polymorphisms of cytochrome P450 in the Czech population and the influence of CYP2C9 genotype on the hypolipidemic effect of fluvastatin
Buzková, Helena ; Perlík, František (advisor) ; Bultas, Jan (referee) ; Mičuda, Stanislav (referee)
55 Abstract Frequency of selected genetic polymorphisms of cytochrome P450 in the Czech population and the influence of CYP2C9 genotype on the hypolipidemic effect of fluvastatin Introduction: One of the main factors of genetically determined variability in response of humans to administered drugs are differences in catalytic activity of metabolizing enzymes, which are caused mainly by genetic polymorphisms in cytochrom P450 family enzymes. This thesis consists of two parts and it is presented as a commentary to the original papers. The first aim was to investigate the frequency of functionally important variant alleles of three main isoenzymes of cytochrome P450 gene: CYP2D6, CYP2C9, CYP2C19, throughout the Czech population, predict the prevalence of poor metabolizer phenotypes, and then to compare the results to the data from other populations. Secondly, we analysed the correlation between the CYP2C9 genotype and cholesterol-lowering effect of fluvastatin in human hypercholesterolemic patients. Methods: Genotypes were determined by PCR-RFLP. The presence of alleles CYP2D6*1, *6, *5, *4, *3, and gene duplication was analysed in 233 healthy volunteers, CYP2C9*1, *2 and*3 in 254 subjects and CYP2C19*1, *2 and *2 in 218 subjects. Eighty seven patients on fluvastatin therapy, and 48 patients on monotherapy...
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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 influence of individual genetic predisposition to the pharmacokinetics and pharmacodynamics of chosen opioids
Matoušková, Olga ; Perlík, František (advisor) ; Votava, Martin (referee) ; Mičuda, Stanislav (referee)
MUDr. Olga Matoušková - the dissertation theses The influence of individual genetic predisposition to the pharmacokinetics and pharmacodynamics of chosen opioids ABSTRACT Introduction: The aim of this thesis is to study the influence of polymorphism of CYP2D6 and MDR1 on the pharmacokinetics and pharmacodynamics of tramadol in healthy volunteers using measurement. A secondary objective is to evaluate these polymorphisms in relation to the analgesic efficacy and side effects of piritramide for acute postoperative pain. Materials and methods: In two prospective work studying the influence of genetic predisposition on the pharmacokinetic and pharmacodynamic parameters of tramadol, we included a total of 90 healthy volunteers. Clinical studies on opioid analgesia and influence of genetic predisposition to the pharmaco-therapeutic effects and side effects in patients with acute postoperative pain, we included a total of 161 patients with acute postoperative pain. Polymorphism genotyping CYP2D6 and MDR1 gene we performed PCR - RFLP analysis, to determine concentrations of tramadol and metabolite, we used gas and liquid chromatography and pharmacodynamic effects of opioids was evaluated by pupilometric measurement and visual analogue scale. Results and conclusion: Variability of the opioid effect is influenced by...
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Spirulina platensis effects on endothelial expression of ICAM-1 in mice
Maxová, Vladimíra ; Nachtigal, Petr (advisor) ; Mičuda, Stanislav (referee)
Vladimíra Maxová Effects of Spirulina platensis on endothelial expression of ICAM-1 in mice Diploma thesis Charles University in Prague, Faculty of Pharmacy in Hradec Králové Pharmacy Background: The aim of this diploma thesis was to identify and describe effects of administration of Spirulina platensis on endothelial expression of ICAM-1 in apoE-deficient mice using immunohistochemical and stereological methods. Methods: We used strain C57BL/6J male mice deficient in apolipoprotein E, in age of 3 months. Mice were randomly divided into two groups, each of which was fed a special diet containing 1% cholesterol for 8 weeks. Spirulina platensis was added daily at a dose 40 mg to Spirulina-group mice. Biochemical analysis was performed in blood, and immunohistochemical and stereological analysis was performed of aorta. Detection of expression of ICAM-1 was carried out by using Avidin-Biotin Complex methodology (ABC) using diaminobenzidine detection (DAB). Results: Biochemical analysis revealed no effect of Spirulina treatment on levels of total cholesterol after 8 weeks when compared with non-treated mice. Immunohistochemical staining showed ICAM-1 expression in all mice in the experiment. The expression was visible in luminal endothelial cells, and also inside atherosclerotic lesions. No difference...
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Spirulina platensis effects on endothelial expression of P-selektin in mice
Králová, Monika ; Nachtigal, Petr (advisor) ; Mičuda, Stanislav (referee)
Monika Králová Spirulina platensis effects on endothelial expression of P-selectin in mice. Diploma thesis Charles University in Prague, Faculty of Pharmacy in Hradec Králové Pharmacy Background: We studied endothelial expression of P-selectin in aorta of apoE-deficient mice after administration of Spirulina platensis. Expression of P-selectin was quantified by using stereological methods. Methods: We used C57BL/6J male mice with deficiency of apolipoprotein E (apoE-/- ) in the experiment. Mice were divided into two groups. The control group was fed by atherogenic diet with 1% of cholesterol for 8 weeks. Mice from the Spirulina platensis group were fed by the same atherogenic diet with the addition of 40 mg Spirulina platensis. We performed a biochemical analysis of blood. Immunohistochemical analysis was performed in a 1 cm aortic sinus and the aortic arch. A series of cross sections with a thickness of 7 µm were cut for the immunohistochemistry and stereology. Detection of expression of P-selectin was performed by avidin-biotic method (ABC) with visualization by diaminobenzidin (DAB). Results: Biochemical analysis did not show significant changes in total cholesterol in mice treated with Spirulina in comparsion with control mice. Expression of P-selectin was observed in all mice. There were no...
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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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Synthesis of Tetrahydroacridine Inhibitors of Acetylcholinesterase
Korábečný, Jan ; Opletalová, Veronika (advisor) ; Vinšová, Jarmila (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Jan Korábečný Supervisor Assoc. prof. RNDr. Veronika Opletalová, Ph. D. Title of Doctoral Thesis Synthesis of tetrahydroacridine inhibitors of acetylcholinesterase Cholinesterase inhibitors have beneficial effects on cognitive, functional, and behavioural symptoms of Alzheimer's disease (AD). Up to date, they represent the only drugs approved by U.S: Food and Drug Administration for AD treatment. These include donepezil, rivastigmine and galantamine. Apart from the above mentioned cholinesterase inhibitors memantine is used for AD treatment as well, acting as N methyl- D-aspartate antagonist drug. Tacrine (9-amino-1,2,3,4-tetrahydroacridine) was the first cholinesterase inhibitor to obtain a marketing authorisation in symptomatic treatment of AD. However, its several side effects (hepatotoxicity and gastrointestinal discomfort) limited tacrine broader usage. Novel tacrine derivatives are extensively investigated in endeavour to find less toxic compounds with "multi-target directed ligand" profile affecting more pathological mechanisms. As a part of these research efforts, 7-methoxytacrine (7-MEOTA) has been prepared as a less toxic derivate compared to tacrine...
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Study of Biological Properties of Hyaluronic Acid Derivatives
Svanovský, Evžen ; Lázníček, Milan (advisor) ; Tilšer, Ivan (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxikology Candidate: Mgr. Evžen Svanovský Supervisor: Prof. PharmDr. Ing. Milan Lázníček, CSc. Title of Doctoral Thesis: Study of biological properties of hyaluronic acid derivatives This PhD thesis, is dealing with physiological properties of Hyaluronic Acid labelled with 111 In isotope. HA is naturally occurring Glycosaminoglycan within organisms with many important functions on the cellular and organ level, including physiological and pathological processes. Its character of physiologically occurring substance makes its tracing in the organism very difficult. Thus preparation of suitable derivative and repeatable procedure of labelling of this molecule became the most important point of the whole work. During the experimental part DTPA-HA molecule created by CPN Dolni Dobrouč has been labelled using well-known method used for labelling of DTPA molecules with 111 In. A reproducible procedure has been created where 0,4 M Acetate buffer pH 5,5 is mixed with an equal volume of DTPA-HA purified by gel filtration and required amount of isotope 111 In and the whole mixture is mixed for 0,5 h. This method was used for labelling of DTPA-HA molecules of three different molecular weights 10, 100 and 400kDa,...
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