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Effect of CDK and FLT3 inhibitors on activity of ABC efflux transporters in vitro, relation to multidrug resistance
Poráč, Jakub ; Čečková, Martina (advisor) ; Hofman, Jakub (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Jakub Poráč Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Effect of CDK and FLT3 inhibitors on activity of ABC efflux transporters in vitro, relation to multidrug resistance P-gp and BCRP are transmembrane proteins that form part of a large family of ABC transporters. These are ATP-driven transporters, which main task is to eliminate exogenous and endogenous substances and their metabolites from cells of both, healthy and tumour tissues. This activity is often associated with the expulsion of administered therapeutics and multiple drug resistance (MDR) in tumour cells. A promising therapy of cancer represents a newer class of drugs target the tyrosine kinase (TK), and cyclin-dependent kinases (CDK), which are cell enzymes responsible for the processes of proliferation, apoptosis and differentiation. Cyclin- dependent kinase inhibitors (CDKI) are used in the treatment of breast cancer, but at the same time they form a new group of drugs with the potential for use in hematological malignancies. In the treatment of AML, a new successful approach is TK inhibitors (TKI), which target the mutated FLT3 receptor, specifically the recently approved drugs midostaurin and...
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Crime relating to the abuse of addictive substances
Pacovský, Josef ; Bohuslav, Lukáš (referee)
Crime relating to the abuse of addictive substances The abuse of addictive substances is an issue of the whole society, which in current globalized world, considering continuous development of drug scene, still remains topical. The abuse of addictive substances, as a significant criminogenic need, relates to all kinds of different criminal offences, both those committed by addicts and those committed against them. This includes for example property crimes, crimes against life, person and health, or endangerment. Because of such wide scope of crimes related to the abuse of addictive substances, the focus of my work is on substantive regulation of so-called drug offences, which is stated in the articles 283 - 287 of the Criminal Code. The purpose of this thesis is to analyse constituent elements of the particular drug offences, coherent case-law, as well as some questionable issues related with this kind of criminal offences. It is for instance, the issue of determining the term "greater than the small amount" and regulation of making cannabis accessible for medical use. Higher consideration is given to the questions of so called growshops and the issues of the distribution of drug addiction. The thesis is divided into general part and special part. In the general part, there is a definition of some...
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Membrane endoglin and its role in pathogenesis of endothelial dysfunction in vitro
Vicen, Matej ; Nachtigal, Petr (advisor) ; Mladěnka, Přemysl (referee) ; Štěrba, Martin (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department of Biological and Medical Sciences Candidate: M. Sc. Matej Vicen Supervisor: Prof. PharmDr. Petr Nachtigal, Ph.D. Title of Doctoral Thesis: Membrane endoglin and its role in pathogenesis of endothelial dysfunction in vitro Membrane endoglin (Eng) is a transmembrane glycoprotein that acts as a co-receptor in the transforming growth factor β (TGFβ) signalling cascade. Its expression and function have been extensively studied predominantly in relation to endothelial function under various pathological conditions, including hypercholesterolemia and atherogenesis. However, its role in the development of endothelial dysfunction remains controversial. Eng contributes to the formation of nitric oxide (NO) and is crucial in in vivo conditions for the development of the cardiovascular system and especially the heart. On the other hand, it may play an important role in inflammatory adhesion and transmigration of leukocytes to the endothelium, thus contributing to the development of endothelial dysfunction as the first stage of atherogenesis. Experiments on endothelial cells isolated from various blood vessels are used to study short-term effects of substances and drugs on the endothelium. One of the effects studied in endothelial cell...
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Interactions of selected antiretroviral drugs and methylmercury with placental membrane transporters
Ťupová, Lenka ; Čečková, Martina (advisor) ; Fusek, Josef (referee) ; Kacerovský, Marian (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Lenka Ťupová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of selected antiretroviral drugs and methylmercury with placental membrane transporters. Pregnant women are especially in developed countries exposed to high amount of various xenobiotic including environmental pollutants and drugs. Antiretroviral therapy (ART) is administered to HIV positive pregnant women for the purpose of prevention of HIV mother- to-child-transmission. Pharmacokinetics of many antiretrovirals is limited or enhanced by activity of ATP-binding cassette (ABC) or Solute carrier's transporters, of which many are expressed also in placental tissue. ART therapy usually consists of combination of 3 - 4 antiretroviral drugs, thereby leading to higher risk for development of drug-drug interactions on ABC and SLC transporters. In this study we described influence of non-nucleoside reverse transcriptase inhibitors etravirin and rilpivirin on BCRP- and MDR1-mediated transport of tenofovir disoproxil fumarate (TDF) and/or abacavir. Etravirin showed potent inhibition of BCRP transporter significantly changing transport of both, TDF and abacavir, across monolayers of MDCKII-BCRP...
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Cardiovascular risc factors and complications associated with atherosclerosis - their prevalence and control in seniors in the EUROAGEISM H2020 project
Kubíková, Veronika ; Fialová, Daniela (advisor) ; Kostřiba, Jan (referee)
INTRODUCTION Cardiovascular diseases (CVD) are currently on the first place among the causes of death worldwide and also in the Czech Republic (CR). The most common causes of death among CVDs are disorders associated with atherosclerosis (ATS) and the prevalence of atherosclerosis and their complications increases with increasing age. The aim of this diploma thesis was to document CVS morbidity in geriatric patients in the sample of FIP7 program of the EUROAGEISM H2020 project, mainly the prevalence of CVS disorders associated with ATS, and to evaluate the controll of risk factors associatedwith general risks of progression of ATS. METHODS The data collection for this theses was carried out in the CR from September 2018 to January 2019 in patients in acute care at the age of 65 and older at geriatric wards in Hradec Králové (HK) and Brno. Patients involved in the study were those admitted to hospitalization at the time of data collection, were complying with inclusion criteria and undersigned the informed consent. The Ethics committee of the Faculy of Pharmacy, Charles University and ethics committee of participating healthcare facilities approved the project. Information have been obtained using the questionnaire for comprehensive geriatric assessment which is the secured instrument of the...
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Intracellular pH homeostasis in pathogenic yeast Candida albicans and Candida glabrata
Winterová, Lucie ; Štaud, František (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Winterová Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultants: RNDr. Marie Kodedová, Ph.D., RNDr. Hana Sychrová, DrSc. Title of diploma thesis: Intracellular pH homeostasis in pathogenic yeast Candida albicans and Candida glabrata The thesis examines the influence of culture conditions on intracellular pH homeostasis in Candida albicans and Candida glabrata yeast strains with deletions of alkali- metal-cation membrane transporters, Cacnh1Δ and Cgtrk1Δ. Intracellular pH was measured with the use of pHluorin: a variant of a green fluorescent protein which had been expressed in the cytosol of both yeast species. Fluorescence of the expressed pHluorin was confirmed by a fluorescence microscopy and a calibration curve was created to determine the dependence of fluorescence intensity of pHluorin on intracellular pH. This thesis further demonstrates impact of medium composition (especially different nitrogen sources) and antifungal agents (fluconazole, clotrimazole, amphotericin B and terbinafine) on intracellular pH values in both yeasts. The effects of Cacnh1Δ and Cgtrk1Δ mutations were established on certain physiological parameters, such as the growth speed under different culture...
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Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases
Odvárková, Anna ; Hofman, Jakub (advisor) ; Novotná, Eva (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Anna Odvárková Supervisor: RNDr. Jakub Hofman, Ph.D. Consultants: Carina Lemke Prof. Dr. Michael Gütschow Title of diploma thesis: Kinetic Evaluation of Potential Inhibitors for Selected Cysteine Proteases Cysteine cathepsins are proteases which are naturally present in the human body, taking part in various physiological processes such as cell signaling, proliferation or bone remodeling. However, their dysregulation leads to serious disorders. An aberrant activity of cysteine cathepsins is present in diseases like cancer, osteoporosis, neurodegenerative disorders or autoimmune diseases. Therefore, these enzymes can serve as valuable diagnostic or therapeutic targets. Rhodesain is a parasitic protease produced by Trypanosoma brucei rhodesiense and essential for its survival. This enzyme shares a high homology with human cysteine cathepsin L. Inhibition of rhodesain can be a potential treatment of African trypanosomiasis, also known as sleeping sickness. Inhibitory potency of several compounds against the target enzymes was assayed spectrophotometrically or fluorometrically and the results were evaluated by using linear or non-linear regression. Determination of a Michaelis- Menten constant...
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Expongement and related institutions
Mráz, Miroslav ; Bohuslav, Lukáš (advisor) ; Pelc, Vladimír (referee)
1 Expungement and related institutions Abstract This work deals with the definition of the terms of expungement of criminal records and also analyzes related institutes, especially the extract from the criminal record (in Czech: výpis z rejstříku trestů) and a copy from the criminal record (in Czech: opis z rejstříku trestů) and the definition of legal integrity in the Czech legal system. Over 120 effective pieces of legislation that establish the right to demand proof of criminal integrity have been analyzed in detail. According to the author's knowledge, such an analysis is also a newly elaborated topic. In addition to the analysis of the regulations that establish the right to demand proof of criminal integrity, the development of the institute of expungement of criminal records from the oldest sources to the present have also been analyzed. Furthermore, the softening trend of the legislator is indicated, precisely in this historical comparison and also in the adoption of new legislation. The analysis of the topic was supplemented by an overview of case law and foreign comparisons, specifically with Slovakia, Germany and the United Kingdom. A pleasant surprise was the precise editing in Germany, where the author thinks we could be inspired. A chapter was devoted to protective measures imposed by the...
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Copper reducin properties of a series of xanthe-3-ones
Kopková, Nikola ; Mladěnka, Přemysl (advisor) ; Němečková, Ivana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Nikola Kopková, MSc Consultant: Assoc. Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of diploma thesis: Copper reducing properties of a series of xanthen-3-ones Key words: copper, reduction, xanthene-3-one, homeostasis Copper is present as a trace element in all tissues and is essential in cellular respiration, in the biosynthesis of neurotransmitters, for the scavening of reactive oxygen species, and is also a cofactor for various enzymes. Disruption of homeostasis can lead to liver and CNS damage, and tumor formation. Typical examples of an imbalance in copper homeostasis represents Wilson and Menkes disease. Xanthene derivatives are biologically active compounds with a possible broad therapeutic spectrum. Some of these derivatives have antitumor, antipyretic, immunomodulatory, antioxidant and other positive biological activities. The aim of this work was to determine whether 2,6,7-trihydroxyxanthen-3-one derivatives have the ability to reduce cupric ions and possibly to detect the effect of various substituents on this ability. As a methodology, a spectrophotometric method based on bathocuproindisulfonic acid as an indicator was used. Ten compounds were tested at different pH values. All...
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Detection of submicroscopic chromosomal aberrations in phenotypically abnormal carriers of apparently balanced rearrangements using array CGH
Slámová, Zuzana
Carriers of apparently balanced chromosomal aberrations (BCA) are usually phenotypically normal. However, it has been estimated that up to 27% of these BCA may be associated with an abnormal phenotype, most often caused by cryptic imbalances at the breakpoints, gene disruption by the breakpoint or via the position effect. In contrast to conventional karyotyping, molecular cytogenetic techniques enable more detailed BCA characterization and better correlation between genotype and phenotype of the patient. The aim of this thesis was to evaluate the presence of copy number variants (CNVs) at breakpoints or elsewhere in the genome in patients with abnormal phenotype who carry de novo or inherited BCA. 54 BCA were investigated using array CGH (20 de novo cases, 27 inherited and 7 cases of unknown origin) including 32 reciprocal translocations, 6 robertsonian translocations, 12 inversions and 4 complex chromosomal rearrangements. If possible, the parents were also examined to ascertain the inheritance of the relevant CNVs. In order to specify microarray findings or exclude gene disruption, FISH was used in selected patients. Among the patients included, in 31,5% (17/54) at least one (in 8 patients more than one) significant CNV was detected. Four cases carried cryptic imbalances only at the breakpoints,...
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