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Study of Novel FXR Ligands
Jeřábková, Jana ; Pávek, Petr (advisor) ; Schreiberová, Jolana (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Mgr. Jana Jeřábková Consultant: prof. PharmDr. Petr Pávek, Ph.D. Title of Thesis: Study of Novel FXR Ligands Human farnesoid X receptor (FXR) is ligand-activated transcription factor that belongs to the nuclear receptor superfamily. FXR binds to its response element (FXRE) as monomer or heterodimer with retinoid X receptor (RXR) resulting to activation of transcription of target genes. FXR positively or negatively regulates a wide range of target genes involved in maintaining the homeostasis of bile acids, cholesterol, lipid and glucose metabolism. Furthermore, FXR transcriptionally regulates genes involved in regulation of the immune response, in the development of inflammation and maintaining the intestinal barrier function and genes controlling coagulation and remodeling of the vessel wall. The interest of current scientific studies is to find the new ligands of FXR, which would be suitable for therapeutic use. Besides the natural bile acids, the first medicinal product containing semi- synthetic FXR ligand, obeticholic acid (6-ECDCA) as active substance was registered last year for the treatment of primary biliary cholangitis. In this experimental rigorosum thesis we focused on...
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ZIP7, hlavní místo intracelulární signalizace zinku: studium prostřednictvím mutageneze
Manišová, Michaela ; Pávek, Petr (advisor) ; Skálová, Lenka (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Michaela Manišová Supervisors: Dr. Kathryn Taylor, Ph.D. Doc. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: ZIP7, a hub for intracellular zinc signalling. Functional investigation by site-directed mutagenesis. Zinc is essential for many cellular processes. It is cofactor for enzymes, important for normall cell growth and can be classified as a second messenger. A significant role of zinc is ability to inhibit protein tyrosine phosphatases activity, resulting in activation of mitogen-activated protein kinases. Zinc is unable passively cross over the cell membranes and need special transporters. Zinc transporters have a main role in intracellular zinc homoeostasis, aberrations of which could lead to diseases such as cancer. The zinc transporter solute carrier family 39, member 7 (SLC39A7, commonly referred to as ZIP7) releases zinc from the endoplasmic reticulum into the cytoplasm and might be required for tyrosine kinases activation. ZIP7 is encoded by 1407 nucleotide pairs which fit into 469 amino acids. ZIP7 contains 8 transmembrane domains and two predicted phosphorylation residues one at serine 275 and one at serine 276. The presence of these phosphorylation sites is an...
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Interactions of new compounds with constitutive androstane receptor
Lágnerová, Jitka ; Pávek, Petr (advisor) ; Trejtnar, František (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Jitka Lágnerová Supervisor: Doc. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Interactions of new compounds with constitutive androstane receptor Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of genes involved in a broad range of biological processes. Pregnan X receptor (PXR) and constitutive androstane receptor (CAR) are members of the orphan NR subfamily, that were originally defined as xenobiotic sensors regulating the expression of drug-metabolizing enzymes in order to protect the body from toxic chemicals. Alteration in CAR function may impact not only pharmacokinetics, efficacy, and toxicity of drugs but also endocrine homeostasis, energy metabolism, and cell proliferation. The aim of this study was to verified interactions of newly synthesized compounds with human CAR. Using the methods of gene-reporter assay and two- hybrid assay we tested 40 agents in various concentrations in HepG2 and LS174T cell lines. As the direct ligands of hCAR with significant transcriptional activity we have identified two substances, namely 2 - (3-methoxyphenyl)quinazoline-4-thiol, resp. -ol used in concentration of 10 µM. In the future, the...
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Molecular mechanisms of interactions- interactions of constitutive androstane receptor with selected stilbene compounds
Linhartová, Lenka ; Pávek, Petr (advisor) ; Smutná, Lucie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lenka Linhartová Supervisor: Prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Molecular mechanisms of intractions - interactions of constitutive androstane receptor with selected stilbene compounds Constitutive androstane receptor (CAR), member of nuclear receptors family, is a major regulator of gene expression of phase I and II enzymes metabolizing endobiotics and xenobiotics. Changes in its activity can lead to pharmacokinetic drug interactions, ineffective treatment or higher toxicity of drugs simultaneously administered with CAR ligands. Recently another effects of this receptor, especially in homeostasis of bile acids, lipids and glucose have been discovered and CAR is now considered as a potential drug target for the treatment of metabolic diseases. Stilbenes represent a small group of plant polyphenols with typical 1,2-diphenylethylene nucleus. The most famous member is resveratrol, which has attracted great attention thanks to its antioxidant, anti-inflammatory, antiproliferative and cardioprotective effects. Others stilbene compounds such as pterostilben, piceatannol or pinosylvin have shown similar health beneficial effects as well. The aim of this diploma thesis was...
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Analysis of the Biological Behavior of Receptor-Specific Radiopharmaceuticals in Vitro
Melicharová, Ludmila ; Lázníček, Milan (advisor) ; Pávek, Petr (referee) ; Komárek, Pavel (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Kralove Department of: Pharmacology and Toxicology Candidate: PharmDr. Ludmila Melicharová Supervisor: Prof. PharmDr. Ing. Milan Lázníček, PhD. Title of Doctoral Thesis: Analysis of the biological behavior of receptor-specific radiopharmaceuticals in vitro In the present work were studied receptor-specific radiopharmaceuticals and their biological behavior. Studies were performed with radiolabelled somatostatin and gastrin analogues. All of these substances are potentially useful in the diagnosis and therapy of neuroendocrine tumors. Somatostatin analogues under study: DOTA-TATE and DOTA-NOC labelled with 111 indium, 177 lutetium, 90 yttrium and 125 iodine. The studies were performed on AR42J cell line (rat pancreatic tumour cells). Internalization rate of these analogues and their specific binding to the cells with high density of appropriate receptors were determined. The data were compared with values obtained after intravenous administration of the same peptides to rats. The uptake of radioactive peptides in tissues with high density of somatostatin receptors in vivo were correlated with the results obtained in vitro conditions. We have compared four 111 In labelled gastrin analogues (so called minigastrins /MG/, namely MG11, MG45,...
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Nukleární receptory - studium nových ligandů a význam genové variability
Carazo Fernández, Alejandro ; Pávek, Petr (advisor) ; Mičuda, Stanislav (referee) ; Vrzal, Radim (referee)
IN ENGLISH LANGUAGE Candidate: Mgr. Alejandro Carazo Fernández Supervisor: Prof. PharmDr. Petr Pávek, PhD. Title of the doctoral thesis: Nuclear receptors - new ligands study and importance of the genetic variability Nuclear receptors (NRs) constitute a superfamily of transcription factors, which regulate the expression of target genes upon the binding of a ligand. These receptors can be classified in steroid receptors, "orphan receptors" and "adopted orphan receptors" depending on the affinity to an endogenous ligand. Nuclear receptors play important roles in physiological processes and are widely distributed in the human body. Thus, adipogenesis, lipolysis, insulin sensitivity, oxidative metabolism, fatty acid homeostasis, cholesterol homeostasis, gluconeogenesis, glycogen homeostasis, triglyceride metabolism among other processes, are regulated by nuclear receptors. During my study, we have tested several sets of drugs, endogenous, natural and synthetic, in several nuclear receptors, focusing mainly on constitutive androstane receptor (CAR) and to a lesser extent on pregnane X receptor (PXR). My main aim was to find a new and reliable ligand or activator for human CAR. In addition, I aimed to study the mechanism of action by which these compounds interact with the receptor and how they trigger...
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Alterations in gene expression of hepatobiliary transporters as potential mechanisms for drug-induced cholestasis by amoxicillin and clavulanic acid
Řepová, Veronika ; Pávek, Petr (advisor) ; Mičuda, Stanislav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Řepová Supervisor: Prof. PharmDr. Petr Pávek, Ph.D., Prof. Ramiro Jover Atienza, Ph.D. Title of diploma thesis: Alterations in gene expression of hepatobiliary transporters as potential mechanisms for drug-induced cholestasis by amoxicillin and clavulanic acid The combination of amoxicillin and clavulanic acid (AMO/CLA) represents one of the most frequent causes of the idiosyncratic type of drug-induced liver injury (DILI) nowadays. Despite difficulties in diagnosis and causality assessment, the clinical features have already been reported and in most of the cases categorized as cholestatic damages. Number of descriptions of the molecular mechanisms of drug-induced cholestasis has been rising recently and the role of hepatobiliary transporters has turned out to be crucial in the pathogenesis. However, the mechanisms of AMO/CLA-induced DILI at the molecular level still remain indistinct. In order to investigate the hepatotoxic effects of AMO/CLA and AMO alone in vitro, HepG2 and human Upcyte hepatocytes were used as hepatocellular models. The mRNA levels of key bile acid (BA) transporters, enzymes and nuclear receptors (NRs) were measured by quantitative real-time polymerase chain...
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The impact of apixaban on overall hemostatic potential.
Cablíková, Ladislava ; Pávek, Petr (advisor) ; Carazo Fernández, Alejandro (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Bc. Ladislava Cablíková Supervisors: Ass. Prof. Mojca Božič-Mijovski, Ph.D., prof. PharmDr. Petr Pávek, Ph.D., RNDr. Jana Nekvindová, Ph.D. Thesis title: The Impact of Apixaban on Overall Hemostatic Potential Disorders at certain levels of the complicated haemostatic system can lead to either bleeding or excessive blood coagulation. These pathological conditions are treated with anticoagulants, which aim to correct excessive coagulation. However, traditional anticoagulant therapy has many limitations, which initiated efforts to develop oral anticoagulants with a better profile. These new-generation anticoagulants are called DOAC - Direct Oral AntiCoagulans. Apixaban, as one of xabans, has predictable pharmacokinetics and pharmacodynamics and therefore does not require a routine laboratory monitoring of the treatment effect. Nevertheless, it still requires evaluation in urgent clinical situations. Standard coagulation screening assays, e.g., PT (prothrombin test) and APTT (activated partial thromboplastin test), do not fully reflect the actual status of the drug. Therefore, researchers aim is to find a relatively simple and fast hemostatic assay that would correlate with the actual condition...
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Principy transportu léčiv přes placentu: nové aspekty pro farmakoterapii v těhotenství
Schönwälderová, Denisa ; Čečková, Martina (advisor) ; Pávek, Petr (referee)
7.SUMMARY After thalidomide-induced birth defects affair, the view of uterus as pharmacologically unconquerable site dramatically changed. Subsequently it was accepted that any chemical substance permeates across the placenta. As there was a continuing need for many mothers to continue to receive medications for chronic disease states, extensive research was launched to gain an appropriate rationale. Progressive investigation of placental barrier compounds allowed the emergence of in vitro and in vivo models, which enabled particularly drug transport studies. Syncytiotrophoblast plays an important role as a rate-limiting component of the barrier. Detailed understanding of pharmacokinetic changes that occur during gestation offered a rationale for pharmacotherapy in pregnancy (large charged molecule, excessive protein-binding, short elimination half-life, volume of distribution, fetal-maternal serum pH gradient). The mechanism of passive diffusion is most important way of drug transport. Perfusion studies clarified the crucial role of active efflux transporters, members of ABC protein family, namely P-glycoprotein, multidrug resistence-associated proteins a ABCG2. As P- gp was first to be discovered, is the most studied until now. Its substrates and inhibitors are well defined and their interactions are...
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Troxerutin and its therapeutic use
Zuranová, Jana ; Mladěnka, Přemysl (advisor) ; Pávek, Petr (referee)
This diploma thesis is aimed at description characteristics and use of troxerutin in the clinical and the experimental practice. The first part of this thesis describes flavonoids as original substance. It includes theirs classification, chemical structure, common and potentionally beneficial pharmacodynamics properties. The main part of this thesis characterizes troxerutin. Troxerutin is a semisynthetic derivate of rutin. Its pharmacodynamics activities has been used therapeutically in the treatment of chronic venous insufficiency for more 30 years. Its positive is based on its antithrombotic, fibrinolytic, odemaprotective, blood viscosity and leukocyte endothelium-wall adherence decresing properties. Troxerutin directly affects erythrocytic aggregation particullary marked at high doses and it facilitation higher afflux of blood to the microcirculation. Its antioxidative effect is important too. The main indications of troxerutin at the present are chronic venous insufficiency and hemorrhoids. Simultaneously is experimentaly examined in a range of disorder, for example in the therapy of common cold, diabetic retinopathy and lymphoedema. In the Czech republic, troxerutin is available perorally in the form (Cilkanol® , Ginkor fort® and Venoruton® ) and locally as gel in Venoruton® gel.
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