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Study of Platinum Cytotoxic Drug Interactions with ABCG2 Membrane Transporter
Bouška, Petr ; Čečková, Martina (advisor) ; Vacková, Zuzana (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Petr Bouška Consultant: PharmDr. Martina Čečková, Ph.D. Title of Thesis: Study of platinum cytotoxic drug interactions with ABCG2 membrane transporter Platinum cytotoxic drugs pertain among most frequently used cytotoxic drugs. However, their usage is complicated with development of resistance which can be caused by few mechanisms. The aim of this study is to evaluate possible interactions of cisplatin, carboplatin and oxaliplatin with ABCG2 membrane efflux transporter which causes resistance to many cytotoxic drugs. Hoechst 33342 assay was performed on cell lines MDCKII (parent cell line) and MDCKII-ABCG2 (cell line genetically modified for expression of human ABCG2 gene). Intracellular concentration of Hoechst 33342 was not increased in presence of any tested cytotoxic drug; significant change of Hoechst 33342 intracellular fluorescence was observed only in presence of ABCG2 control substrate mitoxantron and ABCG2 inhibitor fumitremorgin C. Final results did not demostrate interactions of ABCG2 with any studied platinum cytotoxic. It shows insignificant interaction between ABCG2 and platinum cytotoxic drugs and so improbable effect of this transporter on toxicity reduction...
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Platinum cytostatics in the pharmacotherapy of cancer
Kritman, Gleb ; Čečková, Martina (advisor) ; Štaud, František (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Gleb Kritman Supervisor: PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Platinum cytostatics in the pharmacotherapy of cancer Platinum cytostatics belong currently to the most widely used anticancer drugs. They are involved as a part of chemotherapy regiments in many indications. Cisplatin, as a first substance discovered in this group of cytostatics, was originally registered for the treatment of testicular cancer and ovarian cancer, but it is currently used in many other indications. The limiting factor associated with the administration of cisplatin is represented by adverse effects and the development of resistance in previously sensitive tumor cells. These factors stimulated further research in the field of platinum compounds in order to create a substance with similar mechanism of action, but better properties. To date, more than thirty agents entered clinical trials, but only two of them are used worldwide - carboplatin and oxaliplatin. The aim of this thesis is to create a publication that summarizes current knowledge on platinum cytostatics, which are used in the pharmacotherapy of cancer. This work focuses especially on the comparison between the various representatives...
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Pokračování studie Kuopio 75+: Prevalence ortostatické hypotenze
Henzlová, Veronika ; Čečková, Martina (advisor) ; Štaud, František (referee)
Kuopio study 75+: The prevalence of orthostatic hypotension Veronika Henzlová Abstract This master thesis deals with the prevalence of orthostatic hypotension in home-dwelling elderly. It is a part of the follow-up study Kuopio 75+ conducted in 2003 in Finland. SPSS 14 was used for statistic purpose. The prevalence of orthostatic hypotension was stated to be 23,7%. No difference in prevalence was found in genders, age groups and systolic blood pressure groups.
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Study of the effect of novel antiretroviral drugs on carnitine transport in the placenta
Marková, Eliška ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Eliška Marková Suprevisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Study of the effect of novel antiretroviral drugs on carnitine transport in the placenta Nowadays, the antiretroviral treatment of HIV-positive pregnant women is the standard approach for restriction of transmission of HIV infection from mother to the fetus. In spite of necessity of this pharmacotherapy, it is important to know its safety and risks. For the correct fetal development and function of placenta it is (besides others) essential to ensure the optimal supply of L-carnitine, the key factor for oxidation of fatty acids from mother's blood to the placenta and fetal blood circulation. The deficiency of L-carnitine generally leads to significant metabolic changes in the cells and in it usually demonstrated with cardiomyopathies and myopaties. Published studies indicate higher incidence of cardiovascular diseases and cardiomyopathies in children born to mothers treated with antiretroviral therapy during pregnancy. Optimal transport of carnitine into the placental cells, is ensured due to the presence of functional transport protein OCTN2 in the apical membrane of trophoblast. The aim of this study was...
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Zinc induced activation of breast cancer cell lines and the involvement of Map kinase
Králová, Jarmila ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Jarmila Králová Supervisor: Dr. Kathryn Taylor, Ph.D., PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Zinc induced activation of breast cancer cell lines and the involvement of MAP kinase The aim of this work was to investigate the effect of zinc on various signalling pathways in breast carcinoma cell lines MCF7 and TamR cells. The differences between signalling pathways in MCF7 cell line and TamR cells were evaluated with a special focus on a role of MAP kinase, which activation is believed to be linked with malignant diseases. An effect of zinc on various cellular kinases in 0, 2, 5, 10, 15 and 20 minute of zinc treatment was analyzed in MCF7 cells transfected by wild and mutant type of ZIP 7, TamR cells and TamR cells pre-treated with MAP kinase inhibitor (PD) using the methods of western blotting and fluorescent microscopy. We show here the dependence of activation of pMAP kinase and other important oncogenic kinases (such as Lyn, Src and STAT3) on zinc release into cytoplasm. According to our results, MAP kinase is activated very upstream and it can stimulate many important protein kinases as Src Y418 , STAT3 S727 and Lyn Y396 in tamoxifen-resistant breast cancer...
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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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Pharmacological and physiological characteristics of organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs)
Gregorová, Pavla ; Štaud, František (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Pavla Gregorová Supervisor: Prof. PharmDr. František Štaud, Ph.D. Title of diploma thesis: Pharmacological and physiological characteristics of organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) Abstract: Membrane transporters are important and life-enabling proteins of the body, which facilitate the absorption, distribution, and elimination of nutrients, metabolic waste products, drugs, and xenobiotics. Multidrug and toxin extrusion proteins (MATEs) and organic cation transporters (OCTs) belong to polyspecific transporters of the solute carrier (SLC) family and form a cooperating system of excretion in the kidney and liver. The transporters are expressed in many tissues throughout the body primarily in the kidneys, liver, heart, brain, small intestine, and placenta and transmit countless molecules from the natural neurotransmitters and hormones to exogenous compounds, such as metformine, cimetidine, 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA) or acyclovir. Furthermore, there are described the most recent studies in knockout mice models and genetic polymorphisms that help identify transporters activity and pharmacokinetics with altered...
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Study of effects of antiretroviral drugs on transmembrane transport of tenofofovir disoproxil fumarate across MDCKII-ABCB1 cell monolayer
Repeľová, Beáta ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Beáta Repeľová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of effects of antiretroviral drugs on transmembrane transport of tenofovir disoproxil fumarate across MDCKII - ABCB1 cell monolayer Tenofovir disoproxil fumarate (TDF) - ester prodrug of tenofovir is considered as one of the most frequently used component of combination antiretroviral therapy. Several ways of application and good patients' tolerability is typical for this compound. TDF is a substrate of dug transporter such as P-glycoprotein (P-gp) therefore its efflux activity may limit the bioavailability after oral administration and distribution of TDF. As many of antiretroviral drugs are also substrates or inhibitors of P-gp, drug - drug interactions with TDF at the level of transmembrane transport could be expected. The aim of the diploma thesis was to describe effects of co-administered antiretroviral drugs on transfer of TDF across MDCKII cell monolayer by using bidirectional transport and concentration equilibrium setups. The results of experiments confirmed that TDF is a substrate of P-gp. High values of efflux ratio describing transmembrane transport of TDF across parental cells have been observed. This...
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Principy transportu léčiv přes placentu: nové aspekty pro farmakoterapii v těhotenství
Schönwälderová, Denisa ; Čečková, Martina (advisor) ; Pávek, Petr (referee)
7.SUMMARY After thalidomide-induced birth defects affair, the view of uterus as pharmacologically unconquerable site dramatically changed. Subsequently it was accepted that any chemical substance permeates across the placenta. As there was a continuing need for many mothers to continue to receive medications for chronic disease states, extensive research was launched to gain an appropriate rationale. Progressive investigation of placental barrier compounds allowed the emergence of in vitro and in vivo models, which enabled particularly drug transport studies. Syncytiotrophoblast plays an important role as a rate-limiting component of the barrier. Detailed understanding of pharmacokinetic changes that occur during gestation offered a rationale for pharmacotherapy in pregnancy (large charged molecule, excessive protein-binding, short elimination half-life, volume of distribution, fetal-maternal serum pH gradient). The mechanism of passive diffusion is most important way of drug transport. Perfusion studies clarified the crucial role of active efflux transporters, members of ABC protein family, namely P-glycoprotein, multidrug resistence-associated proteins a ABCG2. As P- gp was first to be discovered, is the most studied until now. Its substrates and inhibitors are well defined and their interactions are...
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