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Iron-chelating properties of selected novel chelators from 4-acyl-5-pyrazolone group II
Břečková, Anna ; Mladěnka, Přemysl (advisor) ; Hašková, Pavlína (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Anna Břečková Supervisor: Přemysl Mladěnka, Ph.D. Title of Thesis: Iron-chelating properties of selected novel chelators from 4-acyl-5-pyrazolone group II Iron deficiency and iron overload play important roles in the pathophysiology of certain human diseases. Administration of iron chelators is a suitable therapy in iron overload conditions, especially in cases of hematological diseases treated with blood transfusions. Iron- chelating therapy appears as well as a promising tool for other diseases (acute myocardial infarction, tumor, etc.). Several factors should be considered according to expected indications: 1) oral efficiency, 2) activity in acidic environment, 3) ability to reduce ferric ions to ferrous ions (risk of pro-oxidation). The aim of this thesis was to verify the iron-chelating properties of selected novel chelators from 4-acyl-5-pyrazolone group by use of UV-VIS spectrophotometric methods. From this group, p-terc.butyl- and p-nitroderivatives of the basic structure and the derivatives marked as H2Q3Q and H2QPy, which are double molecules of the basic structure, were chosen. All of the tested substances had some potential to chelate ferrous ions and were also devoid of...
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Sulfates as phase II metabolites of natural phenolic compounds
Hetman, Anastasiia ; Mladěnka, Přemysl (advisor) ; Siatka, Tomáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Anastasiia Hetman Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmD., Ph.D. Co-supervisor: Assoc. Prof. Kateřina Valentová, Ph.D. Title of diploma thesis: Sulfates as phase II metabolites of natural phenolic compounds Natural monophenolic compounds, which both occur in plants and are formed during gut microbiota metabolism of polyphenols, are absorbed and pass through phase II metabolism. This results in the formation of various conjugated metabolites, such as sulfates, whose biological activity was not studied as yet. This work focused on the preparation and isolation of pure sulfated metabolites of phenolic compounds, namely 4- methylcatechol, protocatechuic, homoprotocatechuic, and 2,3,4-trihydroxybenzoic acid, and phloroglucinol, using the aryl sulphotransferase from Desulfitobacterium hafniense. As a result, two sulfated products of sufficient purity were prepared, namely 4- methylcatechol-O-sulfate (an inseparable mixture of 4-methylcatechol-2-O-sulfate and 4- methylcatechol-1-O-sulfate) and phloroglucinol-O-sulfate. Their antioxidantactivity was evaluated and compared with the activity of the parent compounds using the following six in vitro tests: DPPH (1-diphenyl-2-picrylhydrazyl) and...
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Rheumatic fever and its pharmacotherapy
Davidová, Kristýna ; Mladěnka, Přemysl (advisor) ; Vokřál, Ivan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Kristýna Davidová Supervisor: Dr. Mladěnka Přemysl, Ph.D. Title of thesis: Rheumatic fever and its pharmacotherapy Rheumatic fever (RH) is a systemic inflammatory disease occurring as a result of untreated tonsillopharyngitis caused by β-haemolytic streptococcus of group A. It is an autoimmune response, which leads to the production of antibodies against bacterial antigens, which also recognize human targets which are similar to M protein in the wall of the β-hemolytic streptococci and thus damage human tissue as well. Disease affects many organs such as joints, central nervous system, subcutaneous tissue and skin, but leaves lasting effects only on the heart. Usually not all symptoms are present, carditis and chorea are more common in children, arthritis in adults. Chronic rheumatic heart disease as a consequence of rheumatic carditis is associated with high morbidity and mortality in developing countries, where its incidence is the highest. There is no specific treatment for RH. We use only symptomatic treatment or preventive tools. Regime measures, including bed rest are also important in the case of acute rheumatic fever (ARH). Symptomatically, we use salicylates for ARH...
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Monitoring the effect of statins and soluble endoglin on markers of endothelial dysfunction in selected cell line and culture.
Vařejčková, Michala ; Nachtigal, Petr (advisor) ; Štěrba, Martin (referee) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Kralove Department of Biological and Medical Sciences Candidate: Mgr. Michala Vařejčková Supervisor: Prof. PharmDr. Petr Nachtigal, Ph.D. Title of Doctoral Thesis: Monitoring the effect of statins and soluble endoglin on markers of endothelial dysfunction in selected cell line and culture. This doctoral thesis studied the effect of soluble endoglin on endothelial dysfunction markers in vitro in primary cell culture HUVEC and cell line HEK293T. Some experiments included in this thesis were made in cooperation in the laboratory of prof. Carmelo Bernabeu in the research center Centro de Investigaciones Biológicas (CIB) in Madrid. Endothelial dysfunction is damage of endothelium when the balance between vasoconstrictor and vasodilatory mechanisms is disrupted, it's leading to platelet aggregation, leukocyte adhesion and increased permeability of the endothelium. All these events represent the first step in the development of atherosclerosis and they are part of other cardiovascular diseases such as preeclampsia, type 2 diabetes mellitus, familial hypercholesterolemia. An important role in these diseases play endoglin, eNOS and soluble endoglin (sEng), which is cleaved by MMP- 14 from the membrane endoglin and released into the circulation. It was found...
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Comparison of iron-chelating properties of synthetic iron chelators
Zárubová, Pavla ; Mladěnka, Přemysl (advisor) ; Pourová, Jana (referee)
in English Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxicology Candidate: Pavla Zárubová Tutor: Přemysl Mladěnka, Ph.D. Name of thesis: Comparison of iron-chelating properties of synthetic iron chelators Iron is an essential element for living cells. Both lack of iron (sideropenia) and iron overload can be dangerous for the organism. Thus, iron homeostasis is maintained on the cellular and whole body levels. Sideropenia may occur as a consequence of increased blood loss/ increased iron need (menarche, gravidity, lactation), lack of iron in food or in derangements of gastrointestinal tract. Iron excess can be caused by acute intoxication, dangerous mainly in children, and also in chronic poisoning, caused by hereditary disorders or especially by frequent blood transfusions during the treatment of some haematological diseases. Iron chelators are a wide group of chemical substances with very variable structure. They have been used therapeutically in different indications for many years and other indications are being researched recently. Traditionally, they are used for chelation therapy in acute intoxication and in chronic iron overload, nowadays they are in the center of research attention in association with cancer and neurodegenerative...
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Ability of copper chelators to interact with iron and zinc
Hanuščinová, Lucia ; Mladěnka, Přemysl (advisor) ; Čonka, Patrik (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Lucia Hanuščinová Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmDr., PhD. Title of diploma thesis: Ability of copper chelators to interact with iron and zinc Copper plays in the human organism a role of an element with indispensable significance, whose biological influence and effects depend on its quantity. With elevated concentrations in the human body, copper becomes toxic, resulting in pathological conditions. The most well-known diseases is the Wilson's disease, whose treatment consists of oral administration of chelators, i.e. chemical compounds, which are capable of binding copper ions in various proportions and eliminating them from the organism. Chelation therapy is currently the first choice after confirmation of the diagnosis. Chelation toxicity results from several factors, e.g. inhibition of copper dependent enzymes or low selectivity to metals. And precisely the selectivity of chelators is being discussed in this diploma thesis. An ideal chelator should not interact with any of the other physiological ions, that are necessary for the proper functioning of the organism. Five of the most frequently therapeutically or experimentally used substances /trientine, D-penicillamine,...
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Pharmacological characterization of human monoglyceride lipase cystein mutants
Kařízková, Julie ; Pourová, Jana (advisor) ; Mladěnka, Přemysl (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Julie Kařízková Supervisors: Docent Jarmo T. Laitinen, Ph.D., Juha R. Savinainen, Ph.D., PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Pharmacological characterization of human monoglyceride lipase cystein mutants The therapeutic and psychotropic potential of Cannabis Sativa has been known for ages but the biochemical basis of physiological processes behind the scene was only recently revealed. The most psychotropic constituent of the plant, tetrahydrocannabinol (Δ 9 -THC), hits the function of the endocannabinoid system which includes the endocannabinoids, metabolic enzymes for the biosynthesis and degradation, and cannabinoid receptors which all were discovered and described quite recently. Through the past 20 years, more and more chemical compounds are being classified or at least studied as the endogenous ligands of the cannabinoid receptors, although the two most famous, explored and plentiful compounds are anandamide (AEA) and the primary endocannabinoid 2-arachidonoylglycerol (2-AG). The most frequent manner of 2-AG-degradation is enzymatic hydrolysis by monoglyceride lipase (MGL) and α/β-hydrolase domain-containing proteins ABHD6 and ABHD12. MGL has several critical...
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Patophysiological value of rat myocardium after acute exposition of isoprenaline.
Kostinková, Veronika ; Semecký, Vladimír (advisor) ; Mladěnka, Přemysl (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Candidate: Veronika Kostinková Supervisor: Doc. RNDr. Vladimír Semecký, CSc. Title of thesis: Patophysiological values of rat myocardium after acute exposition of isoprenaline Cardiovascular diseases remain one of the main causes of mortality despite advances in medicine. Isoprenaline (ISO) model of myocardial injury in laboratory animals is used to clarify the pathogenesis of acute myocardial infarction (AIM) and to research cardioprotective substances. The monitoring of early histopathological changes that occur in the rat myocardium at 2 hours after application of 100 mg.kg-1 s.c. ISO, was the main aim of this experiment. Histological results were completed in collaboration with the Department of Pharmacology and Toxicology which provided the data about functional parameters and biochemical markers also after 2 hours from application. Detected changes were compared against the control group to which the solvent was administered. Histopathological analysis revealed more frequent and intense changes in the subendocardial area. Some interstitial dilatation with oedema, cardiomyocytes fragmentation and presence of inflammatory infiltration were observed in the myocardium, especially in...
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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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