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New Possibilities of Cardioprotection in Anthracycline Cardiotoxicity
Kollárová, Petra ; Štěrba, Martin (advisor) ; Fusek, Josef (referee) ; Hrdina, Radomír (referee)
Title: New possibilities of cardioprotection in anthracycline cardiotoxicity This PhD thesis is a commented collection of 3 published original papers describing experimental research into protective effects of bisdioxopiperazine derivatives, including clinically used drug dexrazoxane (DEX), against chronic anthracycline (ANT) cardiotoxicity. In the first part, selected derivatives of DEX with chemical structure modified on dioxopiperazine cycles were studied. In vitro experiments suggested a loss of cardioprotective potential in all derivatives tested including those with the smallest change in the ring structure. This assumption was later confirmed in head-to-head comparison with DEX in vivo on a chronic ANT cardiotoxicity model in rabbits. The loss of cardioprotective effect did not correlate with iron chelating properties of the derivatives' metabolites, but it showed good association with ability of parent compounds to interact with topoisomerase IIβ (TOP2B). These experiments also confirmed that the in vitro assays used in this study are suitable for prediction of cardioprotective effects of these substances against chronic ANT cardiotoxicity in vivo. The other part focused on compound ICRF-193 which differs to DEX by a single methyl attached to the aliphatic linker. This compound showed higher...
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The influence of pH on iron chelation
Hrabalíková, Jitka ; Mladěnka, Přemysl (advisor) ; Hrdina, Radomír (referee)
v angličtině Iron is one of essential elements which are necessary for life of cells. Many important processes are connected with it and its insufficiency can lead to cell death. Iron excess can be dangerous, too; such situation can be triggered not only by acute intoxication, but it appears also chronically due to genetic abnormalities (hereditary hemochromatosis) or by frequent blood transfusions during treatment of thalassaemia, sideroblastic anemia or myelodysplastic syndrome. Iron chelators are used to cure these pathological states, but there have been currently analysed for the treatment of tumors or acute myocardial infarction as well. In pathogenesis of both of these disorders, iron and change of pH play significant roles. In this study, influence of pH on iron chelation abilities of various substances (deferoxamine, synthetic chelator SIH, flavonoids and synthetic coumarin 7,8-dihydroxy-4- methylcoumarin) was measured with the use of ferrozine as an indicator. The stability of complex chelator - iron in various pH was also tested. It was found that chelation activity of all tested substances and the stability of iron- chelator complex is increased with increasing pH. Strong chelators SIH and deferoxamine kept their effectiveness within pH from 7.5 to 5.5, whereas chelating activity of...
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Pharmacotherapy of diabetes mellitus followed up in diabetes clinic
Bradová, Hana ; Pourová, Jana (advisor) ; Hrdina, Radomír (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Mgr. Hana Bradová Supervisor: PharmDr. Jana Pourová, Ph.D. Title of rigorous thesis: Pharmacotherapy of diabetes mellitus followed up in diabetes clinic This rigorous thesis describes current approach to therapy of type 1 and type 2 diabetes mellitus in adult patients. The theoretical part includes subchapters related to evaluation of diabetes mellitus compensation, non-pharmacological measures and especially pharmacological treatment of this disease. Additionally it sums up key information about drugs available on the Czech market (metformin, pioglitazone, sulfonylurea derivatives, repaglinide, acarbose, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 analogs, gliflozines, insulins and insulin analogs) and recommended therapy. Furthermore separate subchapter is dedicated to continuous subcutaneous insulin infusion with an insulin pump. The experimental part introduces therapy of the disease on sample of 100 patients (50 type 1 diabetic patients and 50 type 2 diabetic patients) in a selected diabetes clinic. In addition to the pharmacological treatment and its results, selected patient data (for example age at which a diagnosis was made, duration of the illness, some comorbidities...
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The in vitro effects of selected fenolic substances on isolated rat vessels
Rajtmajerová, Iveta ; Pourová, Jana (advisor) ; Hrdina, Radomír (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Iveta Rajtmajerová Supervisor: PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: The in vitro effects of selected fenolic substances on isolated rat vessels Silymarin flavonolignans are endowed with various aspects. Recently their hepatoprotective effect has been discussed widely as well as their positive influence on the cardiovascular system. This diploma thesis is concerned with the vasodilatory effects of silybin-A, silybin-B, silybin-A + B and isosilybin-A on rat aorta. The aim of this study was to test the vasodilatory effect of selected substances. The dependence of aortic relaxation on the increasing concentration of tested substances was measured. Isolated Wistar breed rat aorta was used. DRC curves were created and EC50 values were assessed from the obtained values of vessel tension. The results were evaluated subsequently. The vasodilator potential of silybin-A and isosilybin-A is comparable; hence the position of the substituents may be irrelevant in having any impact on relaxation of the vessels. Different vasodilatory effects of silybin-A and silybin-B have been observed thus, the relaxation could be stereoselective. The testing of the equimolar mixture of silybin-A and...
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Copper chelating properties of 8 - hydroxyquinolines
Bechná, Klára ; Mladěnka, Přemysl (advisor) ; Hrdina, Radomír (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Klára Bechná, MSc. Consultant: Ass Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of Thesis: Copper chelating properties of 8 - hydroxyquinolines Copper is an essential trace element in our body, which is involved in many physiological reactions. Disruption of copper homeostasis is associated with various pathological states. And thus copper chelators represent in these cases an important treatment strategy. Research for new active compounds likes copper chelators can push the boundaries of the treatment of many hardily treatable diseases like Alzheimer's and Wilson's disease or cancer. This thesis presents a study of the chelating properties of a class of compounds derived from 8 - hydroxyquinolines. These substances chelate metal ions including copper ions and have various biological properties ranging from antibacterial to anticancer effects. Clioquinol and other substances from the group of 8 - hydroxyquinolines effectively block the formation of oligomeric β - amyloid associated with the progression of Alzheimer's dementia and can present a potential modern method for the treatment of this disease. In the experimental part of the work we tested the degree of chelation for all...
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Pharmacotherapy of anxiety and sleep disorders
Böhmová, Kateřina ; Hrdina, Radomír (advisor) ; Herink, Josef (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Kateřina Böhmová Supervisor: Prof. MUDr. Hrdina Radomír, CSc. Title of diploma thesis: Pharmacotherapy of anxiety and sleep disorder Anxiety and sleep disorders belong to common medical conditions. Anxiety attacks are recurring unpleasant emotion states. Sleep disorders are characterized by insufficient or excessive amount of sleep or its poor quality, which persist for significant time period. These common disorders represent important medical and socioeconomic problem. Opinions about etiopathogenesis and classification are constantly evolving. Women and elders suffer from these disorders more often. Complex treatment includes mostly removing the cause, life style changes, psychotherapy, and pharmacotherapy of acute attacks relieving anxiety or sleep problem and prophylactic pharmacotherapy slowly lowering frequency, intensity and later on optimally total resolution of symptoms. Antidepressants from SSRI or SNRI group are considered to be the drugs of first choice in frequent anxiety and chronic sleep disorders. Before the full effect of these antidepressants, it is possible to use BZD for acute attacks treatment. For acute sleep disorders treatment, so called "Z" drugs could be...
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The role of TAK1 in neuronal survival
Prokipová, Jana ; Hrdina, Radomír (advisor) ; Lewicka, Sabina (referee)
Charles University in Prague Fakulty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Performed at Institute of Pharmacology Department of Molecular Pharmacology Ruprecht-Karls-University Heidelberg Candidate: Jana Prokipová Supervisor in home University: Doc. MUDr. Radomír Hrdina, CSc. Supervisor in external University: Prof. Dr. Markus Schwaninger Title of diploma thesis: The role of TAK1 in neuronal survival Transforming growth factor-β activated kinase-1 (TAK1) is a serine/threonine kinase and it is part of the mitogen-activated protein kinase (MAPK) signaling. TAK1 is a key modulator of the transcription factors NF-κB and AP1. Recent studies have shown that TAK1 is essential for the survival of different cell types. Here, we focus on the biological role of TAK1 in neurons in vivo. We used DAB immunohistochemistry to evaluate the effect of TAK1 in neuronal survival. Therefore we compared the number of neurons in TAK1 knockout mice and TAK1fl/fl control mice. However, we did not find any significant difference in the number of neurons between both groups of mice.
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