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Analysis of the CYP 1A2 gene polymorphism and its clinical importance
KRŮČKOVÁ, Dominika
The bachelor thesis named Analysis of the CYP1A2 gene polymorphism and its clinical importance focuses on polymorphs in gene CYP1A2 and their benefits to pharmacogenetics. CYP1A2 gene is localized on chromosome 15, it spans around 7,8 kb. CYP1A2 codes one of the P450 cytochrome enzymes. Enzyme CYP1A2 is one of the most important enzymes participating in metabolism of variety of medicines, for instance antipsychotics or anaesthetics. Furthermore, CYP1A2 partakes in metabolism of procarcinogenic and carcinogenic substances and endogenous substances, for example melatonin or oestrogen. Polymorphs in gene partially cause different reactions to medicines. Non-genetic factors also contribute to interindividual variability, for example smoking or taking birth control pills.
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Analýza vybraných genových polymorfismů a její význam pro individualizovanou farmakoterapii
ŘEŽÁBKOVÁ, Kristina
This thesis deals with the metabolism of xenobiotics and the fact that it may be influenced by genetic polymorphisms in pharmacogens. In the experimental part, samples of volunteers and patients were tested by several methods of molecular biology detecting these polymorphisms and the results were interpreted and compared on the basis of available studies. Furthermore, the work highlights methods that would lead to successful individualized pharmacotherapy in similar clinical trials.
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Selected aspects of methotrexate treatment in patients with rheumatoid arthritis
Hloch, Karel ; Pávek, Petr (advisor) ; Souček, Miroslav (referee) ; Tomčík, Michal (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Social and Clinical Pharmacy Doctoral Degree Program Clinical and Social Pharmacy Candidate MSc. Karel Hloch Supervisor prof. PharmD. Petr Pávek, Ph.D. Advisor assoc. prof. MUDr. Tomáš Soukup, Ph.D.; PharmD. Martin Doseděl, Ph.D. Title of Doctoral Thesis: Selected aspects of methotrexate treatment in patients with rheumatoid arthritis Introduction and objectives Rheumatoid arthritis (RA) is an autoimmune disease typically connected with chronic inflammation of the joints, causing their swelling and pain. The prevalence of RA is about 1% in the general population. A crucial role in higher morbidity and mortality in RA patients has been associated with increased inflammatory activity. Methotrexate (MTX), a drug with immunosuppressive activity, is the most frequent drug of choice used in RA therapy. It seems that main anti-inflammatory effect is mediated via release of purine nucleoside adenosine. The status of patients with inflammatory diseases is influenced by activation of A2a and A3 adenosine receptors. High caffeine (adenosine receptor antagonist) consumption may therefore lead to alteration of MTX treatment efficacy. 1) The aim of first study was to determine whether RA patients who had discontinued...
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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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Selected aspects of methotrexate treatment in patients with rheumatoid arthritis
Hloch, Karel ; Pávek, Petr (advisor) ; Souček, Miroslav (referee) ; Tomčík, Michal (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Social and Clinical Pharmacy Doctoral Degree Program Clinical and Social Pharmacy Candidate MSc. Karel Hloch Supervisor prof. PharmD. Petr Pávek, Ph.D. Advisor assoc. prof. MUDr. Tomáš Soukup, Ph.D.; PharmD. Martin Doseděl, Ph.D. Title of Doctoral Thesis: Selected aspects of methotrexate treatment in patients with rheumatoid arthritis Introduction and objectives Rheumatoid arthritis (RA) is an autoimmune disease typically connected with chronic inflammation of the joints, causing their swelling and pain. The prevalence of RA is about 1% in the general population. A crucial role in higher morbidity and mortality in RA patients has been associated with increased inflammatory activity. Methotrexate (MTX), a drug with immunosuppressive activity, is the most frequent drug of choice used in RA therapy. It seems that main anti-inflammatory effect is mediated via release of purine nucleoside adenosine. The status of patients with inflammatory diseases is influenced by activation of A2a and A3 adenosine receptors. High caffeine (adenosine receptor antagonist) consumption may therefore lead to alteration of MTX treatment efficacy. 1) The aim of first study was to determine whether RA patients who had discontinued...
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Pharmacogenetics of peroral antidiabetics
Sichingerová, Ema ; Šeda, Ondřej (advisor) ; Včelák, Josef (referee)
Diabetes mellitus is a summarizing term for chronic metabolic diseases characterized by long- lasting hyperglycemia. The incidence of type 2 diabetes mellitus is rising worldwide, with the predominant characteristics of a global epidemic in recent years. Treatment of diabetes comprises, among other means, oral antidiabetics, whose function and incidence of side effects can also be influenced by genetic factors. Pharmacogenetics, a field on the border between pharmacology and genetics, deals with such interactions. Pharmacogenetic knowledge helps with drug development and deepens the understanding of the physiological causes of the disease, emphasizing the individuality of the patient. This thesis aims to summarize the pharmacogenetic interactions described in the most used oral antidiabetics so far and their mechanisms of action. Key words: pharmacogenetics, diabetes, gene-environment interactions, single nucleotide polymorphisms
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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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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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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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Variability of pharmacokinetics and possibilities for its monitoring.
Světlík, Svatopluk ; Slanař, Ondřej (advisor) ; Čabala, Radomír (referee) ; Paluch, Zoltán (referee)
Backgroun and aims: Pharmacokinetic variability is of paramount importance for sucessfull pharmacotherapy. The main purpose of this work was to study variability of pharmacokinetics in clinical and non-clinical setting with the aim to predict variability in target population. Specifically, three drugs were chosen, sufentanil, with relativelly narrow therapeutic index, and nabumeton and abirateron, both with known high variability. Methods: The study of pharmacokinetic variability of sufentanil was based on clinical samples taken from patients undergoing surgical cardiac procedure, where the sufentanil was used as a part of the drug coctail used during the procedure. New analytical method was necessary to prepare and validate to measure sufentanil concentrations and obtain pharmacokinetic parameters. These were compared between determined genotype groups of MDR1 and OPRM1. Similarly, clinical study was executed with nabumetone, in which nabumetone was administered in a group of 24 subjects on two separate occassions. Plazma samples were obtained and concentrations of nabumetone and its active metabolite, 6-methoxynaphtylacetic acid (6-MNA), were determined. Obtained pharmacokinetic profiles were compared between female and male volunteers, and genotypes for MDR1 and CYP2D6. Finaly for abiraterone,...
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