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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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Pharmacological characterization of novel ligands of P2X3 receptor
Balmagambetov, Daulet ; Hyršová, Lucie (advisor) ; Pávek, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxicology Student: Daulet Balmagambetov Supervisors: Prof. Dr. Christa Elisabeth Müller Dr. Aliaa Abdelrahman Mgr. Lucie Hyršová Title of diploma thesis: Pharmacological characterization of novel P2X3 receptor's ligands. The P2X3 receptor takes a part in transferring painful signals through neuronal and non - neuronal cells. The agonist of the receptor, ATP, is released from afferent neurons or from damaged cells or from non-neuronal peripheral tissue by stimuli through various mechanisms including active transport. Before ATP is being degraded, it may activate P2X3 receptors at nociceptive cells endings and stimulate pain pathway. SP2X3 receptor antagonists may therefore be useful for the treatment of severe pain, e.g. in cancer or in chronic pain disorders. Therefore, completely new allosteric antagonists based on a screening hit were synthesized and tested in vitro at the slowly desensitizing P2X3-S15V receptor mutant expressed in human astrocytoma 1321N1 cells. Some of the new compounds have shown promising activity.
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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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Novel approaches for development of in vitro liver cell models
Smutný, Tomáš ; Pávek, Petr (advisor) ; Mičuda, Stanislav (referee) ; Kollár, Peter (referee)
1 Abstract Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Tomáš Smutný, MSc. Supervisor: Prof. PharmDr. Petr Pávek, Ph.D. Title of doctoral thesis: Novel approaches for development of in vitro liver cell models. The liver is a main metabolizing organ in the body. Therefore, the evaluation of hepatic metabolism is a crucial step during drug development. Moreover, a liver damage induced by drugs is another task to be assessed in drug development. In vitro liver cell models allow addressing some of these concerns. Up to date, primary human hepatocytes are considered as a "gold" standard of in vitro liver cell models. Additionally, other liver model systems are used such as liver tissue slices, subcellular fractions, liver cancer cell lines and hepatocytes derived from stem cells. Despite the significant progress towards right estimation of pharmacokinetic and toxicological parameters of drug candidates during drug development, current in vitro systems still suffer from various drawbacks. One of these limitations is their insufficient similarity with in vivo-like phenotype associated with low metabolic capacity of the models. In last several years, we were victims of tremendous effort to improve existing models such as 3D models, co-culture and...
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Nuclear receptors - new ligands study and importance of the genetic variability
Carazo Fernández, Alejandro José ; 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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Anti-inflammatory effects of ursodeoxycholyl lysophosphatidylethanolamide on THP-1 human macrophages via Toll-like receptor 4
Horvátová, Alžbeta ; Pávek, Petr (advisor) ; Nachtigal, Petr (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Alžbeta Horvátová Supervisor: prof. PharmDr. Petr Pávek PhD. Title of diploma thesis: Anti-inflammatory effects of ursodeoxycholyl lysophosphatidylethanolamide on THP-1 human macrophages via Toll-like receptor 4 Nonalcoholic steatohepatitis (NASH) became the most common liver disease in developed countries. It is well-known that the level of protectant phosphatidylcholine (PC) is decreased in NASH. The bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) was designed in order to specifically deliver PC to hepatocytes. However, previous studies have proved that UDCA-LPE possesses its proper hepatoprotectant capacity and exhibits anti-apoptotic, anti-inflammatory, anti-fibrotic properties and also improved steatosis and hyperlipidaemia in various models in vivo. These effects may be mediated secondary through modulation of immune system. Therefore, in order to dissect if UDCA-LPE directly influences immune cells in vitro, release of pro-inflammatory cytokines TNFα, IL-6 and IL-1β in LPS-induced THP-1-derived human macrophages was measured by ELISA. Moreover, effects of UDCA-LPE on MAPK signalling pathways and nuclear translocation of NFκB were...
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Study of interactions of polyfenolic compounds on nuclear receptors
Dubecká, Michaela ; Pávek, Petr (advisor) ; Filipský, Tomáš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Supervisor: Title of diplova thesis: Mgr. Michaela Dubecká Prof. PharmDr. Petr Pávek, Ph.D. Study of interactions of polyfenolic compounds on nuclear receptors The farnesoid X receptor (FXR) is a receptor of primary bile acids in the liver and intestine. FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of cholestasis, metabolic syndrome and diabetes, fatty liver disease, cholesterol gallstone disease and intestinal inflammation. Furthermore, FXR plays an important role in the gut-liver axis feedbacks regulating lipid and glucose homeostasis. The apical sodium dependent bile acid transporter (ASBT; SLC10A2) is a bile acid transporter localized to the apical surface of the terminal ileal enterocytes. ASBT plays an important role in the reabsorption of bile acids in the ileum. In the liver, the hepatocytes take up the bile acids by the sinusoidal sodium-dependent taurocholate co-transporting polypeptide (NTCP; SLC10A1). ASBT and NTCP are regulated in the ileum and liver through FXR receptor by bile acids to control bile acids pool. In the current study, we analyzed whether anthocyanins or...
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