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Interactions of antiretrovirals with drug transporters; role in pharmacokinetics
Řezníček, Josef ; Štaud, František (advisor) ; Chládek, Jaroslav (referee) ; Trejtnar, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Josef Řezníček Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultant: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of antiretrovirals with drug transporters; role in pharmacokinetics Current pharmacotherapy of HIV positive patients consists of co-administration of three or more antiretrovirals from different pharmacotherapeutic groups, so called combination antiretroviral therapy (cART). Using this approach, a significant reduction in viral load, delayed viral resistance progression and prolonged efficacy of therapy is achieved. However, the use of cART often bears the risk of drug-drug interactions, which may result in subtherapeutic or supratherapeutic concentrations of drugs in organism with subsequent failure of therapy, or manifestation of toxic effects. Drug transporters expressed in many tissues of human body are widely responsible for occurrence of drug-drug interactions. Therefore, detailed knowledge on antiretrovirals pharmacokinetics and their interactions with drug transporters is important to ensure safe and effective therapy of HIV infection. The aim of this thesis was to study interactions of drugs used in combination antiretroviral...
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Evaluation of potential Alzheimer's disease drugs as prolyloligopeptidase inhibitors
Soukupová, Andrea ; Trejtnar, František (advisor) ; Cahlíková, Lucie (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Andrea Soukupová Supervisor: doc. PharmDr. František Trejtnar, CSc. Supervisor specialist: plk. doc. PharmDr. Daniel Jun, PhD. Title of Thesis: Evaluation of potential Alzheimer's disease drugs as prolyloligopeptidase inhibitors Alzheimer's disease (AD), which now seems to be one of the most common types of dementia, is alarming health, economic and social threat worldlwide. Despite of significant progression in research during the last decade, casual treatment remains still unknown. Treatment of AD is limited only to suppression of the symptoms by centrally acting inhibitors of acetylcholinesterase and memantine. Enzyme prolyloligopeptidase (POP) plays a role in regulation of neuronal peptides levels and therefore POP has gained attention as one of possible target for the treatment of neuronal disorders. Because effect of POP inhibitors on cognitive functions improvement was reported, the aim of this thesis was to determinate the inhibitory aktivity of newly prepared substabces. These substances were primarily designed as acetylcholinesterase inhibitors with potential N-methyl-D-aspartate (NMDA) receptor antagonism. Additional POP inhibitory potential of novel compounds would even...
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Radiolabelled receprot-specific peptides for cancer diagnosis and therapy
Parýzková, Barbora ; Bárta, Pavel (advisor) ; Trejtnar, František (referee)
Charles University Fakulty of Pharmacy in Hradec Králové Department of Biophysics and Physical Chemistry Candidate: Bc. Barbora Parýzková Supervisor: Mgr. Pavel Bárta, Ph.D. Title of diploma thesis: Radiolabelled receptor-specific peptides for cancer diagnosis and therapy. The presented diploma thesis is based on literature review and it deals with receptor- specific radioactive labeled peptides and their usage in the cancer diagnostic and treatment. It focuses on general knowledge about radiopharmaceuticals, further on the descriptions of either diagnostic or therapeutic radionuclides as well as on currently used chelating agents. The particular attention is paid to peptides like somatostatin and cholecystokinin and their usability in Nuclear Medicine for the imaging and treatment of certain malignancies. The other stated peptides in this diploma thesis are bombesin, vasoactive intestinal peptide and alpha melanocyte stimulating hormone. Keywords: receptor-specific peptides, radiolabelling, radionuclides for diagnosis and therapy, radiotherapy, radiodiagnostics, octreotide.
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Modulation of biotransformation and antioxidant enzymes by selected natural compounds
Lněničková, Kateřina ; Szotáková, Barbora (advisor) ; Anzenbacherová, Eva (referee) ; Trejtnar, František (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Kateřina LNĚNIČKOVÁ Supervisor: prof. Ing. Barbora SZOTÁKOVÁ, Ph.D. Title of Doctoral Thesis: MODULATION OF BIOTRANSFORMATION AND ANTIOXIDANT ENZYMES BY SELECTED NATURAL COMPOUNDS Public interest in various dietary supplements containing herbs, herbal extracts or isolated active compounds has increased significantly over past decades. Consumption of these supplements increases worldwide and they are often consumed in unreasonably high doses, as they are generally considered as safe. Upon the intake to organism, these compounds are, as other xenobiotics, modified mostly by xenobiotic-metabolizing enzymes and they could influence these enzymes at the same time. Potential modulation of xenobiotic-metabolizing enzymes' activity (induction or inhibition) can seriously affect pharmacokinetics of concomitantly administered drugs. Knowledge of the possible impact of natural compounds on the xenobiotic-metabolizing enzymes is essential for their safe use. The aim of this doctoral thesis was to study the effects of selected herbal extracts and their active chemical constituents on the activity and expression of xenobiotic-metabolizing and antioxidant enzymes. We have focused on the study of effects of...
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Effect of epigallocatechin gallate on bile production
Hiršová, Petra ; Čečková, Martina (advisor) ; Trejtnar, František (referee) ; Slanař, Ondřej (referee)
Effect of epigallocatechin gallate Epigallocatechin gallate (EGCG), the major green tea catechin, has been shown to be protective in various experimental models of liver injury. Since its effect on biliary physiology and liver cholesterol homeostasis has not been thoroughly studied, the present study investigated effect of EGCG on bile flow, bile acid homeostasis and cholesterol metabolism in healthy and ethinylestradiol-treated rats. Compared to controls, EGCG treatment in rats decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter at the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. Interestingly, EGCG markedly enhanced biliary excretion of cholesterol and phospholipids. These changes tightly correlated with increased expression of ATP- binding cassette transporter G5 and G8 (Abcg5/8) and scavenger receptor class B type 1 and with decreased expression of acyl-CoA:cholesterol acyltransferase (Acat2). EGCG administration to rats also doubled plasma bile acid concentrations compared to controls. While protein expression of the main...
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Effect of Synthetic Magnolol Derivatives on Activity of Nuclear Receptors PPARγ and RXRα
Dymáková, Andrea ; Szotáková, Barbora (advisor) ; Trejtnar, František (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences University of Vienna Faculty of Life Sciences Department of Pharmacognosy Candidate: Andrea Dymáková Supervisors: Mag. Simone Latkolik, doc. Ing. Barbora Szotáková, Ph. D. Title of diploma thesis: Effect of Synthetic Magnolol Derivatives on Activity of Nuclear Receptors PPARγ and RXRα The nuclear receptors, peroxisome proliferator-activated receptor γ (PPARγ) and its heterodimerization partner retinoid X receptor α (RXRα) are drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. The effort has been made to develop new agonists for PPARγ to obtain ligands with more favourable properties than currently used drugs (Berger et al. 2002, Berger et al. 2005). Magnolol was previously described as a dual agonist of PPARγ and RXRα (Fakhrudin et al. 2010, Zhang et al. 2011). Based on the bi- aryl structure of magnolol, the effort has been made to design and synthesize linked magnolol dimers. The aim of this thesis was to investigate the agonistic potential of these compounds with respect of the nuclear receptors PPARγ and RXRα in comparison to magnolol. We evaluated the ligand binding properties of the compounds and their functionality as PPARγ agonists in vitro...
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Elimination of alcohol in blood of patients treated with coumarin drugs
Kahounová, Jana ; Vopršalová, Marie (advisor) ; Trejtnar, František (referee)
CHARLES UNIVERSITY Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Jana Kahounová Supervizor: Doc. PharmDr. Marie Vopršálová, Ph.D. Ing. Jaroslav Procházka Title of diploma thesis: ELIMINATION OF ALKOHOL IN BLOOD OF PATIENTS TREATED WITH COUMARIN DRUGS Coumarin preparations are the most commonly used oral anticoagulants. The main representative is Warfarin. The most important function of warfarin is to reduce the formation of K-dependent coagulation factors in the liver. Alcohol is the oldest and most widely used addictive substance. Alcohol is the oldest and most commonly used substance. Society is tolerated and regular use of small doses of alcohol is considered "beneficial to health". The aim of my thesis was to find out how the concomitant use of coumarin drugs and alcohol interacts. There were tested 62 people (33 men and 29 women), of whom 27 people (14 men and 13 women) were treated with coumarin drugs, 35 people (19 men and 16 women) formed the control group of individuals without treatment with coumarin drugs. All people were given a standard dose of alcohol. The blood alcohol level (COBAS INTEGRA 400 plus) and INR (SYSMEX CA 1500) were measured in the time-0 (before administration), 1½ and 3 hours (after administration). The data obtained was...
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In vitro evaluation of novel Toll-like receptor ligands II.
Machalová, Vanda ; Trejtnar, František (advisor) ; Janočková, Jana (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Vanda Machalová Supervisor: doc. PharmDr. František Trejtnar, CSc. Title of diploma thesis: In vitro evaluation of novel Toll-like receptor ligands II. The aim of this diploma thesis was to test the new substances at Toll-like receptors (TLR), namely TLR4 and TLR8 subtypes, as potential vaccine adjuvants. Adjuvants are required for new subunit vaccines to promote stimulation of a sufficient immune response. Stimulation of TLR receptors is safe and leads to the activation of both innate and adaptive immunity and to subsequent specific immune response. Testing was carried out on cell lines stable co-expressing the respective receptors, with colorimetric activity detection. In this work, both agonist and antagonist activity at TLR4 and TLR8 receptors was investigated and a half maximal effective concentration (EC50) of resiquimod was determined. Based on the results, the respective substances cannot be considered as potential adjuvants to the TLR8 receptor and DM014 exhibits the potential for agonist activity on the TLR4 receptor, whereas the substance DM015 can be used on further investigation of immunosuppression in autoimmune diseases and diseases associated with excessive activation of the...
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In vitro evaluation of novel Toll-like receptor ligands I.
Hudáková, Kristína ; Trejtnar, František (advisor) ; Soukup, Ondřej (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Kristína Hudáková Supervisor: doc. PharmDr. František Trejtnar, CSc. Title of diploma thesis: In vitro evaluation of novel Toll-like receptor ligands I Vaccination against preventable infections prevents millions of deaths each year. Their immunity enhancing activity is strengthened by the presence of vaccine adjuvants. Development of vaccine adjuvants leads to improved safety profile and also can play a vital role in the research of new vaccines against pathogens against which the vaccines currently do not exist. The main aim of this diploma thesis was to verify the ability of rationally developed small molecule ligands to influence Toll-like receptors and thus their potential to be utilized as vaccine adjuvants. The assay was carried out using modified cell lines continually expressing the human TLR4 or TLR8 whose activation leads to production of secreted embryonic alkaline phosphatase. Ten analyzed substances labelled as DM 001 - DM 010 were examined for their agonistic and also antagonistic properties while interacting with the TLRs. Immunomodulatory activity of these tested samples was then determined by quantification of secreted alkaline phosphatase with the help of a colorimetric...
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Modulation of biotransformation and antioxidant enzymes by selected natural compounds
Lněničková, Kateřina ; Szotáková, Barbora (advisor) ; Anzenbacherová, Eva (referee) ; Trejtnar, František (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Kateřina LNĚNIČKOVÁ Supervisor: prof. Ing. Barbora SZOTÁKOVÁ, Ph.D. Title of Doctoral Thesis: MODULATION OF BIOTRANSFORMATION AND ANTIOXIDANT ENZYMES BY SELECTED NATURAL COMPOUNDS Public interest in various dietary supplements containing herbs, herbal extracts or isolated active compounds has increased significantly over past decades. Consumption of these supplements increases worldwide and they are often consumed in unreasonably high doses, as they are generally considered as safe. Upon the intake to organism, these compounds are, as other xenobiotics, modified mostly by xenobiotic-metabolizing enzymes and they could influence these enzymes at the same time. Potential modulation of xenobiotic-metabolizing enzymes' activity (induction or inhibition) can seriously affect pharmacokinetics of concomitantly administered drugs. Knowledge of the possible impact of natural compounds on the xenobiotic-metabolizing enzymes is essential for their safe use. The aim of this doctoral thesis was to study the effects of selected herbal extracts and their active chemical constituents on the activity and expression of xenobiotic-metabolizing and antioxidant enzymes. We have focused on the study of effects of...
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