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Role of Renal functional reserve (RFR) in developing and recovering from cisplatin-induced renal injury
Hromadová, Pavlína ; Pávek, Petr (advisor) ; Trejtnar, František (referee)
University in Salamanca Faculty of Pharmacy Toxicology Area, Department of physiology and pharmacology Candidate: Pavlína Hromadová Supervisor: Prof. Rosa Laura Vicente, Ph.D. Prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Role of RFR in developing and recovering from cisplatin-induced renal injury The purpose of this study was to find out the role of renal functional reserve (RFR) during development and recovery from cisplatin renal damage. This work focuses on evaluating whether RFR can detect (stages) of kidney damage that are not diagnosed with the clinical reference biomarker: plasma creatinine. To evaluate the RFR, Wistar rats produced in the animal house of the University of Salamanca were used. A protocol was established in which an intravenous perfusion of the amino acid glycine was used as a stressor and the glomerular filtration rate was evaluated through creatinine clearance. The animals received a toxic dose of cisplatin and the RFR was determined in one group two days before the maximum point of toxicity (day 2 of the experiment, evolution of kidney damage), in another one on the day of maximum toxicity (day 4) and in the last group on day 11 (recovery from kidney damage) after drug administration on day 0. The values are compared with those of a control group not treated...
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Drug-related problems as a potential cause of hospitalizations
Očovská, Zuzana ; Vlček, Jiří (advisor) ; Trejtnar, František (referee) ; Urbánek, Karel (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Social and Clinical Pharmacy Doctoral Degree Program Clinical and Social Pharmacy Candidate PharmDr. Zuzana Očovská Supervisor prof. RNDr. Jiří Vlček, CSc. Title of Doctoral Thesis Drug-related problems as a potential cause of hospitalizations Introduction and objectives: A drug-related problem is an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes. Manifested drug-related problems may contribute to hospital admissions of patients. Such hospital admissions, known as drug-related hospital admissions (DRA), represent a significant and potentially preventable burden on health systems. DRA often arise from the combination of multiple medications, making it important to pay increased attention to drug interactions, particularly in older patients who are taking a larger number of medications. DRA can result from inappropriate medication dosing or the selection of medications in the presence of chronic kidney disease. The main objectives of this thesis are: 1) to determine the prevalence and preventability of DRA and to identify medications and clinical manifestations associated with DRA in patients admitted to hospital via the department of emergency...
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Effects of isoflavonoids and their metabolites on vascular smooth muscles in vitro and in vivo
Migkos, Thomas ; Mladěnka, Přemysl (advisor) ; Studenik, Christian (referee) ; Trejtnar, František (referee)
Charles University Faculty of Pharmacy in Hradec Kralove Department of Pharmacology & Toxicology Candidate: Thomas Migkos, M.Sc. Supervisor: Prof. Přemysl Mladěnka, Pharm.D, Ph.D. Consultant: Assoc. Prof. Jana Pourová, Pharm.D, Ph.D. Title of dissertation thesis: Effects of isoflavonoids and their metabolites on vascular smooth muscles in vitro and in vivo The dietary intake of flavonoids seems to be inversely related to cardiovascular mortality, in particular on coronary artery disease. The consumption of isoflavonoids, one class of flavonoids, has been increasing in the general population, especially due to the use of food supplements and a variety of isoflavonoid-rich foods. Although their bioavailability is low, they undergo extensive gastrointestinal metabolism by human bacteria, leading to smaller metabolites with a much higher degree of bioavailability. However, detailed studies on the impact of individual pure isoflavonoids on vascular system were mostly missing and much less was known for the effect of their colonic metabolites in this field. In the present study sixteen isoflavonoids, four metabolites and the racemic mixture of one of them were initially screened ex vivo for their vasorelaxant properties on rat aortas. The most potent of them, biochanin A, glycitein, O-desmethylangolensin...
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Study of pharmacokinetic and pharmacodynamic mechanisms of drug resistance and their modulation in non-small cell lung cancer
Zhang, Yu ; Hofman, Jakub (advisor) ; Pešek, Miloš (referee) ; Trejtnar, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Pharmacology and Toxicology Doctoral Degree Program Pharmacology and Toxicology Candidate Yu Zhang Supervisor Assoc. Prof. RNDr. Jakub Hofman, Ph.D. Advisor Title of Doctoral Thesis Study of pharmacokinetic and pharmacodynamic mechanisms of drug resistance and their modulation in non-small cell lung cancer Lung cancer represents one of the most threatening malignancies, which is attributed by its leading morbidity and mortality among all cancer types. Pharmacological interventions have played impressive roles in the clinical management of non-small cell lung cancer (NSCLC) with the outstanding improvements on patients' survival. Nevertheless, the inevitable emergence of drug resistance severely diminishes their efficacies. Traditional chemotherapeutic drugs have been introduced in the treatment of NSCLC decades ago. Countless studies showed that the emergence of multidrug resistance (MDR) is deeply associated with two pharmacokinetic factors: (1) increased drug efflux via ATP-binding cassette (ABC) transporters and (2) enhanced drug deactivation by biotransformation enzymes, e.g., cytochromes P450 (CYPs). Previously, we and others have demonstrated that several novel targeted agents can synergistically...
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Using of genetically modified cells lines to study transport processes in in vitro kidney models.
Mužíková, Michaela ; Smutná, Lucie (advisor) ; Trejtnar, František (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Michaela Mužíková Supervisor: PharmDr. Lucie Smutná, PhD. Title of diploma thesis: Using of genetically modified cells lines to study transport processes in in vitro kidney models Transport processes in renal cells are mostly secured by proximal tubule transporters. These transporters mediate excretion and reabsorption of wide variety of endogenous and exogenous substances, including xenobiotics. Within the broad spectrum of many drug-transporting proteins, we have chosen the glycoprotein megalin (LRP2), a receptor involved in the reabsorption of albumin and other endogenous substances, such as insulin or hemoglobin. Peptide and aminoglycoside antibiotics represented by e.g., gentamicin and belongs between LRP2 ligands. The diploma thesis deals with the development and utilization of the LRP2 knockout cell lines in accumulation studies. The experiments were performed using human cell lines naturally expressing LRP2, the JEG-3 and HK-2. Several genetically modified cell lines expressing unfunctional LRP2 and consequently exerting harmed ability of model ligand internalization were prepared using the CRISPR/Cas9 technique. The effect was confirmed by accumulation studies with FITC-albumin....
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Study of the effect of ABC drug transporters' overexpression on the antiproliferative capacities of selected conventional cytostatics
Malečová, Lucie ; Hofman, Jakub (advisor) ; Trejtnar, František (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Malečová Supervisor: doc. RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Study of the effect of ABC drug transporters' overexpression on the antiproliferative capacities of selected conventional cytostatics Overexpression of ABC drug transporters is one of the mechanisms of multiple drug resistance development, which results in therapy failure in cancer. ABC transporters such as ABCB1, ABCG2 and ABCC1 have a wide range of substrates, including several conventional cytostatics. This study aimed to examine the influence of overexpression of the mentioned transporters on the antiproliferation effects of docetaxel, etoposide, paclitaxel, methotrexate, pemetrexed, topotecan and vinblastin. The results were obtained with the MTT assay in which the MDCKII and A431 cell lines with/without overexpression of mentioned transporters were used. A decrease of cytotoxicity in the presence of at least one of the transporters was observed in five of seven tested cytostatics. Only topotecan has been proven to be the victim of overexpression of all of the tested transporters. To prove the applicability of the obtained results, topotecan was used in the follow-up combination study. Within this study, I have...
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The aspects influencing the therapeutic value of anticoagulants in the Czech Republic
Dvořáčková, Simona ; Kolář, Jozef (advisor) ; Trejtnar, František (referee) ; Tesař, Tomáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Social and Clinical Pharmacy Doctoral Degree Program Clinical and Social Pharmacy Candidate Mgr. Simona Dvořáčková Supervisor doc. RNDr. Jozef Kolář, CSc. Advisor doc. PharmDr. Josef Malý, Ph.D. Title of Doctoral Thesis The aspects influencing the therapeutic value of anticoagulants in the Czech Republic Background and aim: Anticoagulants prevent the onset or maintaining of thromboembolic (TE) diseases. Both long-term used drugs, the disadvantages of which may limit treatment, and newer ones, the benefits of which may be limited by shorter clinical experience, are currently approved. Drug utilization may be an important indicator of trends in drug use, as well as pharmacovigilance surveillance and the benefits and risks assessment in clinical practice. Research related to the evaluation of the therapeutic value of anticoagulants and the factors influencing their use in clinical practice contribute to safer pharmacotherapy, therefore the aims of this thesis were: 1) to analyze the drug utilization of parenteral and oral anticoagulants (OACs) in the Czech Republic (CR) between the years 2007-2020; 2) to evaluate the numbers and characteristics of spontaneously reported suspected adverse drug reactions (ADRs)...
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Using of genetically modified cells lines to study transport processes in in vitro kidney models.
Mužíková, Michaela ; Smutná, Lucie (advisor) ; Trejtnar, František (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Michaela Mužíková Supervisor: PharmDr. Lucie Smutná, PhD. Title of diploma thesis: Using of genetically modified cells lines to study transport processes in in vitro kidney models Transport processes in renal cells are mostly secured by proximal tubule transporters. These transporters mediate excretion and reabsorption of wide variety of endogenous and exogenous substances, including xenobiotics. Within the broad spectrum of many drug-transporting proteins, we have chosen the glycoprotein megalin (LRP2), a receptor involved in the reabsorption of albumin and other endogenous substances, such as insulin or hemoglobin. Peptide and aminoglycoside antibiotics represented by e.g., gentamicin and belongs between LRP2 ligands. The diploma thesis deals with the development and utilization of the LRP2 knockout cell lines in accumulation studies. The experiments were performed using human cell lines naturally expressing LRP2, the JEG-3 and HK-2. Several genetically modified cell lines expressing unfunctional LRP2 and consequently exerting harmed ability of model ligand internalization were prepared using the CRISPR/Cas9 technique. The effect was confirmed by accumulation studies with FITC-albumin....
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Study of the effect of ABC drug transporters' overexpression on the antiproliferative capacities of selected conventional cytostatics
Malečová, Lucie ; Hofman, Jakub (advisor) ; Trejtnar, František (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Malečová Supervisor: doc. RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Study of the effect of ABC drug transporters' overexpression on the antiproliferative capacities of selected conventional cytostatics Overexpression of ABC drug transporters is one of the mechanisms of multiple drug resistance development, which results in therapy failure in cancer. ABC transporters such as ABCB1, ABCG2 and ABCC1 have a wide range of substrates, including several conventional cytostatics. This study aimed to examine the influence of overexpression of the mentioned transporters on the antiproliferation effects of docetaxel, etoposide, paclitaxel, methotrexate, pemetrexed, topotecan and vinblastin. The results were obtained with the MTT assay in which the MDCKII and A431 cell lines with/without overexpression of mentioned transporters were used. A decrease of cytotoxicity in the presence of at least one of the transporters was observed in five of seven tested cytostatics. Only topotecan has been proven to be the victim of overexpression of all of the tested transporters. To prove the applicability of the obtained results, topotecan was used in the follow-up combination study. Within this study, I have...
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The effect of natural compounds on transport by OATP drug transporters
Zemčíková, Lucie ; Trejtnar, František (advisor) ; Mičuda, Stanislav (referee) ; Szotáková, Barbora (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: MSc. Lucie Zemčíková Supervisor: Assoc. Prof. PharmDr. František Trejtnar, CSc. Title of doctoral thesis: The effect of natural compounds on transport by OATP drug transporters OATP membrane transporters belong to carrier proteins responsible for transporting certain drugs (e.g. hypolipidemics from the group of statins) and other xenobiotics across the biological membranes and tissue barriers within the body. These transport proteins play an important role in pharmacokinetic processes such as absorption, distribution and elimination. The potential modulation of their transport function by natural compounds commonly present in plant food or food supplements may result in the changes of the concentration of their substrate (drug) in the cells and body fluids, that may affect the effect and toxicity of these drugs. The aim of this study was to obtain data on the interactions of selected natural compounds with human transporters OATP2B1 and OATP1A2 and their ability to affect drug transport mediated by these transporters. These two OATP transporters are involved in the drug uptake especially in organ barriers important for pharmacokinetics. For the study natural compounds from the group of...
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