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Pharmacogenetics in rheumatoid arthritis
Kobrlová, Martina ; Pávek, Petr (advisor) ; Doseděl, Martin (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Martina Kobrlová Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Pharmacogenetics in rheumatoid arthritis Based on scientific progress in the research of human genome and the discovery of polymorphisms, which are involved in the interindividual differences in human population, there is also a growing interest in pharmacogenetics. It is a field combining pharmacology and genetics with the aim of identifying specific features that could explain the different responses of patients to treatment by clinically used drugs. Applying this knowledge could contribute to a simpler choice of medication for a particular patient and it could reduce the risk of side effects or poor response. In this diploma thesis I dealt with the latest scientific knowledge on pharmacogenetics in rheumatology, in particular the rheumatoid arthritis. From available studies, reviews, and meta-analyzes that have been published, I summarized current data on the relationship between polymorphisms and disease modifying drugs (DMARDs) used for the treatment of this disease. The largest amount of data was found on the most commonly used methotrexate. Further, the work examines the leflunomide and other...
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Pharmacogenetics in rheumatology - role of miRNAs
Vicherková, Petra ; Pávek, Petr (advisor) ; Doseděl, Martin (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxicology Candidate: Bc. Petra Vicherková Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of master thesis: Pharmacogenetics in rheumatology - role of miRNA Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that causes progressive joint damage and can result in to life-long depreciation of life. The influence on the onset and course of the disease is not only genetic, but due to the heterogeneous character of the disease, it is also strongly influenced by lifestyle. This disease, based on the malfunction of our immune system in RA, is still incurable. The treatment of RA uses conventional synthetic drugs as well as biological treatment. To diagnose the effect of anti-rheumatic therapy, monitoring and evaluating the response to treatment is necessary. Important indicators of RA activity, functional status, quality of life, and structural progression of the disease are important. In clinical practice, we use DAS 28 composite system according to recommendation of ČRS. Recent discoveries in the area of diagnostics raise the question of whether some miRNAs could be appropriate biomarkers of RA progression. In my diploma thesis, I summarize available knowledge in this field, obtained from...
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Pharmacogenetics of statins and metabolic syndrome
Kučera, Miroslav ; Šeda, Ondřej (advisor) ; Schierová, Michaela (referee)
Metabolic syndrome is one of the most prevalent conditions in our population. Among components of the syndrome is a major risk factor of cardiovascular diseases - a change in blood lipid profile presented by alterations in cholesterol and triacylglycerol levels. Statins are currently the drug of choice for therapy of dyslipidemia. This group of drugs is characterized by inhibition of cholesterol synthesis in liver. Pharmacogenetics is a progressive field studying interactions between drugs and genetic background of a patient. There has been described a large amount of genetic variants affecting pharmacokinetic and pharmacodynamic aspects of statin effects. These variants were shown to be important for course of treatment and development of side effects such as statin myopathy. First, this work characterizes pharmacogenetics, metabolic syndrome and statins. Second, it provides a comprehensive summary of genetic polymorphisms underlying important pharmacogenetic interactions with statins.
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Structural biology of the enzymes involved in mercaptopurine metabolism
Soldánová, Anna ; Maloy Řezáčová, Pavlína (advisor) ; Novotný, Marian (referee)
Mercaptopurine (6-mercaptopurine) together with azathioprine and 6-thioguanine belong to a group of widely used chemotherapeutics and immunosuppressants. However, insufficient therapy outcome or severe adverse effects such as myelosuppression are still being reported. Technological progress in DNA and RNA sequencing facilitates effective identification of causative genes responsible for the therapy failure, i.e., description of genetic variants for enzymes involved in metabolism of physiological purines as well as thiopurine drugs. Variants of these enzymes may substantially alter concentrations of cytotoxic forms of thiopurines, which affect therapy success rates. Currently, a number of mutations in genes that play role in thiopurine metabolism have been annotated. Nevertheless, molecular mechanisms underlying the effect of these mutations are not fully elucidated. Knowledge of 3D structure for these enzymes may shed light on the effect of the genetic variants to protein function and mechanisms modulating therapeutic efficacy of thiopurines. This thesis focuses mainly on biochemical and structural characterization of thiopurine-S-methyltransferase, fosfatase NUDT15 and cytosolic 5′-nucleotidase II. It summarizes current state of knowledge and emphasizes the importance of structural biology methods for...
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Cytochrome P450 oxidoreductase: Structurally functional study. Molecular pathology of Antley-Bixler syndrome.
Tomková, Mária ; Martásek, Pavel (advisor) ; Mazura, Ivan (referee) ; Králová, Jarmila (referee)
NADPH-P450 oxidoreductase (POR) is a membrane bound flavoprotein that donates electrons to a wide spectrum of heme-containing proteins, among which are several steroidogenic and many xenobiotics-metabolizing enzymes. Given the important role of POR protein in drug metabolism and pharmacogenomics, there is a particular need to understand the contributions of POR genetic variants to these processes. Mutations in POR gene cause a disorder called POR deficiency, which manifests with a wide phenotypic spectrum ranging from disordered steroidogenesis to skeletal malformation, namely, Antley-Bixler syndrome (ABS). The aim of the present work was to investigate the POR gene in patients suspected to have POR deficiency syndrome from Czech Republic and to perform genotyping in Czech and Jewish control populations. We analyzed 644 alleles in unrelated individuals from the general Czech population and 1128 alleles in Jewish population, where 330 alleles were of Askhenazi and 798 of Sephardic Jews. We have also studied the impact of selected new genetic variants on POR activity and identified fourteen amino acid variations, two of which we have studied in detail to establish their influence on POR activity. Using the available human POR three-dimensional structure, we then modelled the newly identified variants...
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Frequency of occurrence of selected single nucleotide polymorphisms of CYP2C8 and MDR1 in the Czech population and their influence on the effect of amiodarone
Pechandová, Kristina ; Perlík, František (advisor) ; Král, Jiří (referee) ; Anzenbacher, Pavel (referee)
Frequency of occurrence of selected single nucleotide polymorphisms of CYP2C8 and MDR1 in the Czech population and their influence on the effect of amiodarone Introduction: Variability in drug response is sometimes conditioned by genetic differences in the metabolism and the transport of drugs. Interindividual differences are often caused by polymorphisms affecting biotransformation activity of enzymes and expression of transporters. In the thesis we paid attention to the cytochrome P450 CYP2C8 and MDR1. First, we described the frequency of occurrence of selected variant alleles CYP2C8 * 2, CYP2C8 * 3 (2 substitution in exon 3 and 8, CYP2C8 and CYP2C8 * 3G416A * 3A1196G), CYP2C8 * 4, CYP2C8 P404A in the healthy Czech population and MDR1 variant alleles in these exons: 26 C3435T, 21 G2677A/T, 12 C1236T a 17 T-76A. Subsequently, we studied the influence of these polymorphisms on effects of amiodarone in the selected group of patients. Methods: We determined genotypes MDR1 a CYP2C8 by PCR-RFLP by using restriction enzymes and specific primers. We determined the frequency of MDR1 genotypes in 189 healthy volunteers and CYP2C8 in 161 healthy subjects. Further we included into the study 63 patients treated with amiodarone for longer than two months. Their treatment was assessed from medical records and...
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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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Frequency of occurrence of selected single nucleotide polymorphisms of CYP2C8 and MDR1 in the Czech population and their influence on the effect of amiodarone
Pechandová, Kristina ; Perlík, František (advisor) ; Král, Jiří (referee) ; Anzenbacher, Pavel (referee)
Frekvence výskytu vybraných bodových polymorfismů CYP2C8 a MDR1 v české populaci a jejich vliv na působení amiodaronu Úvod: Variabilita lékové odpovědi je někdy podmíněna genetickými rozdíly v metabolismu a transportu léčiv. Interindividuální rozdíly jsou často způsobeny polymorfismy, které ovlivňují biotransformační aktivitu enzymů a expresi transportérů. V disertační práci jsme věnovali pozornost cytochromu P450 izoenzymu CYP2C8 a MDR1. Nejprve jsme popsali frekvenci výskytu vybraných variantních alel CYP2C8*2, CYP2C8*3 (2 substituce v exonu 3 a 8, CYP2C8*3G416A a CYP2C8*3A1196G), CYP2C8*4, CYP2C8 P404A u zdravé české populace a variantních alel MDR1 v exonech: 26 C3435T, 21 G2677A/T, 12 C1236T a 17 T-76A. Následně jsme sledovali vliv těchto polymorfismů na působení amiodaronu u vybraného souboru pacientů. Metody: Genotyp MDR1 a CYP2C8 jsme stanovili pomocí PCR-RFLP za využití specifických restrikčních enzymů a primerů. Frekvence genotypů MDR1jsme určili u 189 zdravých dobrovolníků a CYP2C8 u 161 zdravých osob. Do sledování jsme dále zařadili 63 pacientů užívajících amiodaron déle než dva měsíce. Jejich léčbu jsme posuzovali ze záznamů lékařské dokumentace, s využitím standardních biochemických a hematologických vyšetření a záznamů EKG. Koncentrace amiodaronu a jeho metabolitu N-...
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Interaction of selected anthocyanidins with farnesoid X receptor
Jeřábková, Jana ; Pávek, Petr (advisor) ; Martin, Jan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Jana Jeřábková Supervisor: Doc. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Interaction of selected anthocyanidins with farnesoid X receptor Human farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that act as ligand-activated transcription factors. FXR binds to specific regulatory DNA regions and induces expression of many target genes. These regulated genes are involved in bile acid metabolism and transport, maintaining blood lipids, liporoteins and glucose homeostasis and also contribute to maintain intestinal bacterial balance, hepatoprotection and liver regeneration. The interest of recent studies is to test the range of FXR ligands for treatment and prevention of many diseases such as cholestais, cholesterol gallstone disease, steato-hepatitis, dyslipidemia, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, liver cancer and other forms of cancer such as breast cancer. In this experimental diploma thesis we are focused on testing of potencial ligands of human farnesoid X receptor from the group of natural plant pigments anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin) using the human hepatoma cell line...
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