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Study of interactions of antiviral drugs with selected placental transporters
Karbanová, Sára ; Štaud, František (advisor) ; Kacerovský, Marian (referee) ; Mladěnka, Přemysl (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Sára Karbanová, MSc. Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultant: doc. PharmDr. Lukáš Červený, Ph.D. Title of Dissertation Thesis: Study of interactions of antiviral drugs with selected placental transporters The backbone of HIV treatment in pregnant women is the combination antiretroviral therapy which effectively suppresses the viral proliferation in maternal blood circulation. One of drugs in this therapy regimen should be a molecule with high placental transfer to assure the prophylaxis of viral transfer to fetus. There is no approved guideline for pharmacotherapy of pregnant women infected with hepatitis C (HCV), however recent evidence suggests that lowering the maternal viral load could correlate with lower likelihood of HCV transmission to the fetus. To assure and further develop the effective and safe pharmacotherapeutic approaches for treatment of HIV and HCV in pregnancy with respect to fetal safety, it is essential to understand mechanisms of placental transfer of anti(retro)viral drugs. In this Dissertation thesis we focused on molecules derived from nucleosides (anti-HIV abacavir, emtricitabine, zidovudine, tenofovir disoproxil fumarate and anti-HCV...
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The ex vivo effects of selected silymarin flavonolygnans on isolated rat aorta
Sloukgi, Tatiana ; Pourová, Jana (advisor) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Tatiana Sloukgi Supervisor: PharmDr. Jana Pourová, Ph.D. Title of Diploma Thesis: The effect of Silymarin Flavonolignans and their sulfated conjugates on blood vessels ex vivo. Silymarin flavonolignans have recently shown some positive effects on the cardiovascular system. In this work, we studied the vasodilatory effect on rat aorta ex vivo of three silymarin conjugates, silybin A-20-sulfate, silybin B-20-sulfate and 2,3- dehydrosilychristin-19-O-sulfate, and one parent flavonolignan 2,3- dehydrosilychristin. For each substance, a concentration response curve was created and the concentration that produces 50% of maximum relaxation was determined (EC50). All substances exerted very low or no vasodilatory activity. Finally, we focused on the mechanism of action of silybin A. We tested whether its vasorelaxant activity depends on the presence of intact endothelium. The vasorelaxant effect of silybin A on isolated rat aorta ex vivo was clearly endothelium-dependent.
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Preparation of a novel method for screeing of cobalt chelators
Moravcová, Monika ; Mladěnka, Přemysl (advisor) ; Karlíčková, Jana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Monika Moravcová Supervisor: Assoc. Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Title of thesis: Preparation of a Novel Method for Screening of Cobalt Chelators Cobalt as a structural part of the vitamin B12 is an essential microelement for living organisms including humans. However, its excess is associated with pathological conditions. Cobalt poisoning can be caused for example by exposure to cobalt metal dust during the production of hard metals or follow the corrosion of metal hip prosthesis. Patients intoxicated by cobalt can develop different manifestations including neurological impairment, hypothyroidism or cardiomyopathy. The aim of this work is to prepare a standardized, rapid, cheap but precise method for the screening of cobalt chelators. For this purpose, spectrophotometric detection using 1-nitroso-2-nafphhol-3,6-disulfonic acid disodium salt as the indicator was used. Firstly, it was found that the addition of cobalt ions led to a clear bathochromic shift of the maximum absorbance of the indicator. The relationship between the absorbance and cobalt concentration was highly linear from 470 to 560 nm at all 4 tested pH conditions (4.5, 5.5, 6.8 and 7.5). The sensitivity of the method...
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Chelation of copper ions by thiol containing chelators
Kladivová, Andrea ; Mladěnka, Přemysl (advisor) ; Carazo Fernández, Alejandro (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Andrea Kladivová Consultant: Václav Tvrdý, MSc. Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of diploma thesis: Chelation of copper ions by thiol containing chelators Copper is an essential trace element that is important for many physiological functions. On the other hand, disruption of copper homeostasis associated with its elevated level is dangerous for the organism, because of the formation of free radicals. Copper chelators can represent an effective tool in the treatment of such conditions. Due to the ability of a thiol group to bind metal ions and form a chelate, thiol containing chelators are promising compounds for the reduction of copper levels. Within this diploma thesis, four compounds containing a thiol group were tested for the ability to chelate copper ions. Spectrophotometric measurement was used for this determination. It is a simple, fast but precise method for determination of the chelation properties in vitro. In addition, the ability of these compounds to reduce cupric ions was examined. When using the basic hematoxylin method, all the tested substances proved they can chelate copper. Their efficacy was practically identical except for the...
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Screening of novel chelators of microbiogenic metals
Catapano, Maria Carmen ; Mladěnka, Přemysl (advisor) ; Hrdina, Radomír (referee) ; Musiol, Robert (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Maria Carmen Catapano, MSc. Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmD., Ph.D. Co-supervisor: Assoc. Prof. Laura Mercolini, Ph.D. Title of Doctoral Thesis: Screening of novel chelators of microbiogenic metals Iron, copper and zinc are microbiogenic elements which play crucial roles in a series of physiological processes in human organism. Homeostasis of these transition metals is strictly regulated since, among others: a) free or loosely bound iron or copper can catalyse the production of hydroxyl radical; b) lack of zinc but also of the previously mentioned metals is associated with significant impairments. Hereditary hemochromatosis, transfusion-induced secondary iron overload and Wilson's disease are known as pathological conditions associated with metal overload in the organism. Chelator agents have vital relevance for the treatment of these impairments. There are also numerous diseases with homeostatic imbalances in iron, copper and or zinc: neurodegenerative diseases, cardiovascular diseases, cancer and diabetes mellitus. Different chelating compounds have been examined for the treatment of these impairments. The aim of this doctoral thesis was to perform a screening of metal...
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The influence of polyphenolic compounds and their metabolites on platelet activation
Applová, Lenka ; Mladěnka, Přemysl (advisor) ; Bultas, Jan (referee) ; Šimůnek, Tomáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Applová Lenka, MSc. Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of Doctoral Thesis: The influence of polyphenolic compounds and their metabolites on platelet activation Blood aggregation is a very difficult and complex process, in which platelets play crucial role. On the other hand, their activation is excessive and therefore undesirable under pathophysiological conditions. Cardiovascular diseases are the most common cause of mortality in developed countries and unfortunately, despite significant advances in treatment, the Czech Republic remains in mortality from these diseases behind most Western European countries. Epidemiological studies suggest, that higher intake of (iso)flavonoids is associated with reduced cardiovascular mortality. It is also worth mentioning, that the Czech Republic is among European countries with the lowest content of flavonoids in diet. The aim of this doctoral thesis was to find out, if polyphenolic compounds, especially (iso)flavonoids and/or their metabolites, are able to influence platelet aggregation and thus indirectly to support epidemiological findings, i.e. whether there may be a link between these substances and possible positive...
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Effect of cholinesterase inhibitors on monoaminergic system and energic metabolism
Nowak, Tereza ; Mladěnka, Přemysl (advisor) ; Štěpánková, Šárka (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Tereza Kalinová Supervisor: Assoc. Prof. Přemysl Mladěnka, Pharm.D., Ph.D. Mentor: Assoc. Prof. Jana Hroudová, Pharm.D., Ph.D. Title of diploma thesis: Effect of cholinesterase inhibitors on monoaminergic system and energy metabolism Cholinesterase (ChE) inhibitors play an essential role in the treatment of Alzheimer's disease (AD). They effect positively cognitive, functional and behavior symptoms of AD. Up to date, donepezil, rivastigmine and galantamine represent the only ChE inhibitors approved for AD treatment. The first ChE inhibitor was tacrine, which was withdrawn from market due to its toxicity and adverse effects. Recently, novel tacrine and 7-methoxytacrine (7-MEOTA) derivatives were synthetized and extensively investigated to find less toxic compounds affecting pathological mechanisms associated with development of AD. There is less known about effects of these drugs on mitochondrial functions and cellular energy metabolism. The aim of this project is to examine in vitro effects of ChE inhibitors on energy metabolism and cellular respiration, specifically on mitochondrial electron transport chain complexes and an enzyme of the citric acid cycle - citrate synthase. Inhibitory effects...
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Transcriptomic analysis of cutaneous inflammatory biomarkers in a mouse model of small fiber neuropathy
Benčová, Simona ; Mladěnka, Přemysl (advisor) ; Smutný, Tomáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Simona Benčová Supervisors: Dr. Claire Demiot, Dr. Aurore Danigo Assoc. Prof. Přemysl Mladěnka, Ph.D Title of diploma thesis: Transcriptomic analysis of cutaneous inflammatory biomarkers in a mouse model of small fiber neuropathy. Peripheral neuropathy is an expanding public health problem conditioned by various diseases and associated with several adverse effects such as the occurrence of chronic pain or increased risk of pressure ulcers (PUs). The aim of this study is to explore, whether the inflammatory state of the skin is modified during peripheral neuropathy and in the course of the formation of a pressure ulcer. The transcriptomic analysis was performed with two different models of mice: PU model and uninjured model, to determine genes that differ in expression and in particular, those involved in inflammation. Small fiber neuropathy was induced in young mice by intraperitoneal injection of resiniferatoxin (50 µg/kg, i.p.) - transient receptor potential vanilloid 1 (TRPV1) agonist. PUs were induced by applying two magnetic plates on the dorsal skin. Gene expression was obtained based on RNA microarray and the results were subsequently verified by qPCR. The transcriptomic analysis of PU...
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Soluble endoglin role in the pathogenesis of endothelial dysfunction
Vitverová, Barbora ; Nachtigal, Petr (advisor) ; Vrablík, Michal (referee) ; Mladěnka, Přemysl (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department of Biological and Medical Sciences Candidate: Msc. Barbora Vitverova Supervisor: prof. PharmDr. Petr Nachtigal, Ph.D. Title of Doctoral Thesis: Soluble endoglin role in the pathogenesis of endothelial dysfunction The endothelium is a major regulator of vascular homeostasis and exerts a number of vasoprotective effects, including production of vasodilating agents, suppression of smooth muscle cell growth, or inhibition of inflammatory responses. Most of these effects are mediated by nitric oxide (NO), the most effective endogenous vasodilator. Decreased NO production or its activity is a hallmark of endothelial dysfunction leading to an impaired endothelial-dependent vasodilation. Endothelial dysfunction is the first and key step in the development of atherosclerosis and can be detected before structural changes in the vessel wall. Atherosclerosis is a complex inflammatory disease underlying many cardiovascular disorders including ischemic heart disease and represents the major cause of morbidity and mortality in developed countries. Statins are drugs of choice in the treatment of atherosclerosis and ischemic heart disease, which have been shown to reduce LDL cholesterol levels and modulate endothelial function with their...
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Interaction of the selected natural substances with conventional drugs
Mottlová, Eliška ; Tůmová, Lenka (advisor) ; Mladěnka, Přemysl (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy Supervisor: Assoc. Prof. PharmDr. Lenka Tůmová, Ph.D. Student: Eliška Mottlová Title of Thesis: Interactions of the selected natural substances with conventional medicine Keywords: medicinal plant, anthraquinones, saponins, tannins, alkaloids, interactions The aim of this diploma thesis is to give an overview of interactions which could occur during simultaneous use of conventional drugs and medicinal plants containing anthraquinones, saponins, tannins or isolated plant alkaloids. Information about herb-drug interactions were obtain and cited mostly from articles of online databases (Web of Science, Science Direct, PubMed, Google scholar) published in period 2000 - 2019. Interactions of 12 medicinal plants and 12 isolated plant alkaloids are mentioned in the thesis. The most significant interactions usually appear in combination of herbal products and drugs with narrow therapeutic index such as warfarin, digoxin, cyclosporin or theophylline. St John's wort affects the metabolism of drugs through induction of CYP450 enzymes (CYP3A4, CYP2C9, CYP2C19) or P- glycoprotein and also St John's wort can increase the risk of serotonin syndrome in combination with SNRI, SSRI or triptanes. Medicinal plants containing...
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