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Interactions of Antimicrobial Agents with Drug renal Transport Systems in Vitro
Mandíková, Jana ; Trejtnar, František (advisor) ; Pacherník, Jiří (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Jana Mandíková Supervisor doc. PharmDr. František Trejtnar, CSc. Title of Doctoral Thesis Interactions of antimicrobial agents with drug renal transport systems in vitro A number of important and frequently used antimicrobial agents are excreted from the body through the kidneys. During this excretory process drugs may interact with different membrane transport systems (transporters) which are expressed in the renal tissue. These interactions are often the determining factors for both renal excretion, and the toxic effects of these drugs in the kidney. There are highly expressed influx transporter such as organic anion transporters (OATs), organic cation transporters (OCTs) and the concentrative nucleoside transporters (CNTs) and efflux transporter BCRP (breast cancer resistance protein) and P glycoprotein (P-gp) in the kidney. Despite the importance of renal drug transporters for elimination and nephrotoxic effects of drugs and intensive research in this field, interactions of a number of important antimicrobial drugs with transporters in the kidney are not known or sufficiently described. The aim of this study was to investigate the interaction of selected antivirals and...
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The role of melatonin in SIRT1 and p-AMPK regulation in HT-29 cell line
Shkut, Anastasiya ; Ramos Mandíková, Jana (advisor) ; Svobodová, Hana (referee)
Charles University in Prague Pharmaceutical Faculty in Hradec Králové Department of Pharmacology and Toxicology Student: Anastasiya Shkut Supervisors: Mgr. Jana Mandíková, Virginia Motilva Ph.D. Title of diploma thesis: The role of melatonin in SIRT1 and p-AMPK regulation in HT-29 cell line. Sirituin 1 (SIRT1) is NAD+ dependent deacetylase present in wide range of organisms including mammals. It was found to extend life span in yeasts during calorie restriction (CR) conditions. SIRT1 deacetylates many regulator proteins and thus control metabolic status of cell as well as AMP-activated kinase (AMPK), which is also energy regulator enzyme depending on NAD+ levels in cell. Both of them play roles in cancer and could influence autophagy, although the exact mechanism remains unclear. We focused our study on hormone melatonin, which has anti-inflammatory and anti-cancer effects, to study its influence on human colon cancer cell line HT-29. If it has impact on SIRT1 and AMPK and what is hierarchic relationship between SIRT1 and AMPK. Also we observed its possible influence on autophagy. We used Western blotting (WB) technique and from our results it seems that melatonin has significant effect on SIRT1, which might activate AMPK as well as autophagy. Nevertheless some of results did not have sufficient...
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Study of plasma protein binding of radiopharmaceuticals
Hafinec, Václav Matyáš ; Lázníček, Milan (advisor) ; Ramos Mandíková, Jana (referee)
Study of Plasma Protein Binding of Radiopharmaceuticals Summary The purpose of this work is the study of binding of substances (177 Lu-DOTA- [Lys3]bombesin, 177 Lu-NOTA-[Lys3]bombesin, 177 Lu-PCTA-[Lys3]bombesin, and 177 Lu- DOTA-MG47) to plasma proteins by equilibrum dialysis in 37řC, particularly using plasma samples of beef, rabbit, rat and human. Within this group, these substances were compared interspecifically. The substances 177 Lu-DOTA-[Lys3]bombesin, 177 Lu-NOTA-[Lys3]bombesin, 177 Lu- PCTA-[Lys3]bombesin, and 177 Lu-DOTA-MG47 are the newly developed receptor- specific radiolabeled peptides. For all the newly collected data, the interspecific comparison and subsequent statistical evaluation was performed. The indicated bombesin derivates were compared and statistically analyzed even between themselves. During the interspecies comparisons and the determination of the statistical significance of the data, there were found statistically significant and statistically highly significant differences between some of the examined samples. A highly significant difference was found during comparing with samples of 177 Lu-NOTA- [Lys3]bombesin and statistical evaluation, there was found a statistically highly significant difference. Despite the differences found, it is clear that the plasma binding concerning...
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Permeation studies of a set antihistaminic drugs and the influence of verapamil in an in vitro Blood-brain barrier model
Mandíková, Jana ; Šimůnek, Tomáš (advisor) ; Trejtnar, František (referee)
Studies of drug permeation across the blood-brain barrier (BBB) are an indispensable part of the drug development strategy. Recent in vitro studies have suggested that P-gP and passive membrane permeability may influence the brain concentrations of non-sedating (second generation) H1-antagonists. The purpose of this thesis was to determine the importance of P-gP mediated efflux of the first and the second generation of H1-antagonists in an in vitro BBB model and the influence of P-gP inhibitor verapamil. CNS adverse effects of the first generation of H1-antagonists are linked with their ability to penetrate the BBB and cause sedation and drowsiness. The second and the third generation of H1-antagonists are relatively free of sedation and their limited brain penetration has been suggested to arise from P-gP mediated effux (Obradovic, Dobson et al. 2006). In our in vitro PBMEC/C1-2 model, three H1-antagonists (promethazine, fexofenadine and cetirizine) and a known P-gP substrate rhodamine 123 were tested for their permeation properties. Firstly, P-gP experiments in PBMEC/C1-2 was proven by western blotting. The functional activity of P-gP was assessed by the permeation experiments with an established Transwell in vitro model. The resulting drug quantificantion were evaluated by RP-HPLC and fluorescence...
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Study of cytotoxicity of potential antituberculotics using selected methods on liver and kidney cell line
Katrnošková, Simona ; Ramos Mandíková, Jana (advisor) ; Bárta, Pavel (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Mgr. Simona Katrnošková Supervisor: PharmDr. Jana Ramos Mandíková, Ph.D. Title of Thesis: Study of cytotoxicity of potential antituberculotics using selected methods on liver and kidney cell line During pharmacologic therapy, tissues of liver and kidney are frequently exposed to high doses of xenobiotics. Via in vitro assays during preclinical testing, we are able to predict potential toxicity which helps to prevent the possible serious adverse drug reactions in clinical practice. The aim of this rigorous thesis was to state the cytotoxic profile of 4 potential antituberculotic drug candidates using appropriate cell models and in vitro assays. Another aim was to compare the cytotoxic effect of the tested compounds among themselves and to 4-aminosalicylic acid (PAS) which antituberculotic activity is known for many years. The tested substances were 3 salicylanilide diethyl phosphate-based derivatives and 4-(trifluormethyl)benzoic acid. For the cytotoxic potential assessment, we used the parameter half maximal inhibitory concentration IC50. We have used methods determining the cell metabolic activity, aminopeptidase activity, lactate dehydrogenase leakage and activity of 3/7 caspases in this...
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