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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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Investigation of Drug Interactions on Hepatic and Renal Transport Proteins
Fuksa, Leoš ; Štaud, František (advisor) ; Fusek, Josef (referee) ; Slanař, Ondřej (referee)
STUDY OF DRUG-DRUG INTERACTIONS BASED ON MODULATION OF THE FUNCTION OF LIVER AND KIDNEY ACTIVE TRANSPORTERS Leos Fuksa, M.Sc. ABSTRACT The present thesis focused on closer research of drug-induced changes in the expression and function of the main hepatic and renal transporters and their effects on the pharmacokinetics of the model substrates. The subject of our particular interest were ABC efflux transporters (namely P-gp and Mrp2) localized in the apical membranes of polarized epithelium cells in the excretory organs, and also Oatp2 transporter playing an important role in the basolateral uptake of drugs. Dexamethasone and amiodarone were employed to bring about changes in the active transport. Dexamethasone is a potent corticosteroid that showed capability to increase elimination processes, i.e. to induce enzymes and transporters both in vitro and in vivo. Amiodarone, a life-saving antiarrhythmic, is a well-known inhibitor of drug metabolism. Its direct inhibitory effects on the active transport have recently been reported. The summarized results of the included publications describe various aspects of the pharmacokinetic drug-drug interactions, where the underlying mechanism of the interaction is a modulation (either induction/activation or inhibition) of the active transport. Such modulation is...
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Posttraumatic stress disorder by soldiers comming back from peacekeeping missions
Vaisová, Petra ; Vosečková, Alena (advisor) ; Jirkovský, Daniel (referee) ; Fusek, Josef (referee)
The bachelor's thesis describes the posttraumatic stress disorder by soldier's coming back from peacekeeping missions and the real psychological help provided to concerned soldiers. Theoretically informs about PTSD. More over summarizes the possibilities given within the scope of testing before leaving and after coming back from missions and the psychological care during the execution of a mission. In addition the information about military operations, which the Czech soldiers have taken part recently and are involved nowadays and its characteristics. The key part of this work is the field testing as to discover PTSD symptoms as well as the quality of health care after an accomplishing of missions. The field testing was done by an evaluation of the tested sample which is made of foreign mission participants being deployed during last five years into one or two military operations lasting more than 3 months.
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Study of Pathobiochemistry of Catecholamine Cardiotoxicity: Role of Free Iron Ions and Their Chelation as a Possibility of Pharmacological Cardioprotec-tion.
Hašková, Pavlína ; Šimůnek, Tomáš (advisor) ; Dršata, Jaroslav (referee) ; Fusek, Josef (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Pavlína HAŠKOVÁ Supervisor: doc. PharmDr. Tomáš ŠIMŮNEK, Ph.D. Title of Doctoral Thesis: Study of pathobiochemistry of catecholamine cardiotoxicity: Role of free iron ions and their chelation as a possibility of pharmacological cardioprotec- tion. Catecholamine cardiotoxicity is known for a long time, but its patho- genesis is still incompletely understood. Although traditionally attributed to excessive β-adrenergic stimulation, there is a hypothesis that the catecholamine- induced cardiac cell damage includes involvement of oxidation products of catecholamines, which may arise due to spontaneous oxidation of catechola- mines under aerobic conditions. Spontaneous oxidation of catecholamines is a sequence of redox reactions leading to the formation of numerous reactive in- termediates, such as o-semiquinones and o-quinones, including aminochromes that are subject to redox cyclization generating reactive oxygen species (ROS). The generated ROS and aminochromes are toxic for cells. In addition, the autooxidation may be catalyzed by transition metals, which suggests that free intracellular iron (Fe) ions - the most abundant transition metal in the body - can promote not only the Haber-Weiss...
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Prediction of the penetration of new drugs through the blood-brain barrier
Kobrlová, Tereza ; Soukup, Ondřej (advisor) ; Čečková, Martina (referee) ; Fusek, Josef (referee)
and keywords The dissertation thesis deals with problem of insufficient penetration of antidotes for treatment of organophosphorus poisonings. Methods for evaluating the ability of compounds to penetrate the central nervous system (CNS) were developed and compared to each other. These methods were subsequently used for the standard and newly synthesized potential drugs from this group to evaluate their penetration to the brain. Furthermore, the strategies that could improve CNS penetration were investigated. Highly toxic organophosphorus compounds represent a big threat due to possible misuse in the military of for terrorist purposes. These compounds affecting cholinergic neurotransmission by inhibition of the enzyme acetylcholinesterase (AChE). For this reason, they are called nerve agents (NAs). NAs are extremely toxic, relatively easily obtainable and the therapy of intoxication is insufficiently effective. One of the major obstacles of AChE reactivators, causal antidote used in the treatment, is to overcome the blood-brain barrier in therapeutic concentration and restore the function of AChE in the CNS. Thus, research and development of new drug candidates for such antidotes requires appropriate methods for evaluation of their biological properties even in the in vitro stage. Selection,...
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Interaction of Organophosphorus Poisoning Antidotes with Muscarinic and Nitotinic Receptors
Soukup, Ondřej ; Fusek, Josef (advisor) ; Trejtnar, František (referee) ; Anzenbacher, Pavel (referee)
1 Summary in English Currently, organophosphorus (OP) poisoning is a threat particularly in war conflicts in connection with terrorism or a poisoning caused by OP pesticides in agriculture. The poisoning is caused by inhibition of the enzyme acetylcholinesterase (AChE), which, under physiological conditions, cleaves acetylcholine (ACh) and regulates the transmission of nerve signals. The inhibition of AChE leads to excessive stimulation of cholinergic receptors and clinically it manifests as so-called cholinergic syndrome. According to the structures affected, symptoms are divided into nicotinic, muscarinic and central. Organophosphates are lethal compounds, when death is caused by suffocation. Current treatment is mainly based on the application of anticholinergics (atropine) and /or on the application of AChE oxime reactivators (HI-6, obidoxime, pralidoxime etc.) Atropine inhibits excessive neural transmission by blocking muscarinic receptors. However, it is only symptomatic cure not causal. Whereas oximes, which represent a causal therapy, are able to unbind an OP compound from the AChE and restore its splitting function. Using reactivators has two major drawbacks; there is no universal reactivator against all types of OP compounds (soman, sarin, paraoxon etc.) and reactivation is possible only within a...
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Pharmacological cardioprotection with iron chelators and anthracycline cardiotoxicity
Popelová, Olga ; Geršl, Vladimír (advisor) ; Fusek, Josef (referee) ; Kolář, František (referee)
In this Ph.D. thesis, following aims were addressed: 1) potentially cardioprotective effects of deferiprone on the model of daunorubicin-induced chronic cardiotoxicity in rabbits, 2) the role of apoptotic cell death in the development of anthracycline cardiotoxicity, 3) cardioprotective effects of dexrazoxane against chronic anthracycline cardiotoxicity with a focus on rescue of cardiac myocytes from programmed cell death and oxidative stress, and 4) staging of myocardial changes in the time-course of chronic anthracycline cardiotoxicity development. First, using the leukemic cell line, deferiprone (1-300 µmol/L) was shown not to blunt the antiproliferative effect of daunorubicin. Instead, at higher concentrations of deferiprone, the augmentation of antiproliferative actions of both agents was observed. However, in the cardioprotective study deferiprone failed to afford significant protection against daunorubicin-induced mortality, cardiac dysfunction, morphological cardiac deteriorations, plasma cardiac troponin T rise as well as myocardial lipoperoxidation. This finding contrasted with previous positive outcomes of in vitro studies. Hence, this study changes the current view on deferiprone as a potential cardioprotectant against anthracycline cardiotoxicity. In addition, these results, together...
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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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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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