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LC-MS analysis of phase one biotransformation of K1277, a potential drug against Alzheimer's disease
Krchová, Lucie ; Štaud, František (advisor) ; Kučera, Radim (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Krchová Supervisor: Prof. PharmDr. František Štaud, Ph.D. Supervisor - Consultant: Mgr. et Mgr. Rafael Doležal, Ph.D. Title of diploma thesis: LC-MS analysis of phase one biotransformation of K1277, a potential drug against Alzheimer's disease. Alzheimer's disease belongs to the most common neurodegenerative diseases that several milions of people all around the world suffer from. There are few symptomatic drugs, which are able to reduce signs and symptoms of this type of dementia, however none of them is able to completely stop it. The diploma thesis is focused on a metabolomic study of compound K1277, synthesized as a combination of 6-chlortacrine and aminoacid tryptophan, which thanks to its properties belongs to promising potential drugs against Alzheimer's disease and which has not been published yet. The aim of this diploma thesis was to perform in vitro metabolomic screening of the compound K1277 using human liver microsomes focusing on qualitative and quantitative analysis. As intermediate aims of the thesis, necessary conditions for sufficient biotransformation of compound K1277 were investigated, quantity of metabolised compound K1277, identifications of particular metabolites...
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...
LC-MS analysis of phase one biotransformation of K1277, a potential drug against Alzheimer's disease
Krchová, Lucie ; Štaud, František (advisor) ; Kučera, Radim (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Krchová Supervisor: Prof. PharmDr. František Štaud, Ph.D. Supervisor - Consultant: Mgr. et Mgr. Rafael Doležal, Ph.D. Title of diploma thesis: LC-MS analysis of phase one biotransformation of K1277, a potential drug against Alzheimer's disease. Alzheimer's disease belongs to the most common neurodegenerative diseases that several milions of people all around the world suffer from. There are few symptomatic drugs, which are able to reduce signs and symptoms of this type of dementia, however none of them is able to completely stop it. The diploma thesis is focused on a metabolomic study of compound K1277, synthesized as a combination of 6-chlortacrine and aminoacid tryptophan, which thanks to its properties belongs to promising potential drugs against Alzheimer's disease and which has not been published yet. The aim of this diploma thesis was to perform in vitro metabolomic screening of the compound K1277 using human liver microsomes focusing on qualitative and quantitative analysis. As intermediate aims of the thesis, necessary conditions for sufficient biotransformation of compound K1277 were investigated, quantity of metabolised compound K1277, identifications of particular metabolites...
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...
Prediction of tacrine-BQCA derivatives across blood-brain-barrier
Vykoukalová, Nikol ; Štaud, František (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Nikol Vykoukalová Supervisor: prof. PharmDr. František Štaud, Ph.D. Title of diploma thesis: Prediction of tacrine-BQCA derivatives across blood-brain-barrier This master thesis deals with the determination of permeability prediction for tacrine BQCA derivatives, potential drugs for Alzheimer's disease, through the blood-brain barrier (BBB) using the method of parallel artificial membrane penetration (PAMPA). We attempted to predict the central bioavailability by the permeability coefficient, to study the relationship between the solubility of the compounds and their log P (or Log D) and the subsequent significance of these data for the prediction of their passage through the blood-brain-barrier. A solution of 1% Pluronic F-127 in PBS was used to solubilize compounds and to ensure the constant concentration during the measurement. The assay was performed so that the solutions of compounds were applied to the donor part of microtiter plate (so-called sandwich arrangement), the bottom compartment was covered by a solution of a polar brain lipid isolated from pig brain (PBL), which serves as a membrane simulating the phospholipid membrane of the brain capillary endothelium. The solution of the...
Prediction of tacrine-BQCA derivatives across blood-brain-barrier
Vykoukalová, Nikol ; Štaud, František (advisor) ; Čečková, Martina (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Nikol Vykoukalová Supervisor: prof. PharmDr. František Štaud, Ph.D. Title of diploma thesis: Prediction of tacrine-BQCA derivatives across blood-brain-barrier This master thesis deals with the determination of permeability prediction for tacrine BQCA derivatives, potential drugs for Alzheimer's disease, through the blood-brain barrier (BBB) using the method of parallel artificial membrane penetration (PAMPA). We attempted to predict the central bioavailability by the permeability coefficient, to study the relationship between the solubility of the compounds and their log P (or Log D) and the subsequent significance of these data for the prediction of their passage through the blood-brain-barrier. A solution of 1% Pluronic F-127 in PBS was used to solubilize compounds and to ensure the constant concentration during the measurement. The assay was performed so that the solutions of compounds were applied to the donor part of microtiter plate (so-called sandwich arrangement), the bottom compartment was covered by a solution of a polar brain lipid isolated from pig brain (PBL), which serves as a membrane simulating the phospholipid membrane of the brain capillary endothelium. The solution of the...
Influence of inflammation modulation on excretory mechanisms during intrahepatic cholestasis
Kadová, Zuzana ; Štaud, František (advisor) ; Večeřa, Rostislav (referee) ; Kučera, Otto (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Zuzana Kadová Supervisor: Prof. PharmDr. František Štaud, PhD. Consultant: Prof. MUDr. Stanislav Mičuda, PhD. Title of doctoral thesis: Influence of inflammation modulation on excretory mechanisms during intrahepatic cholestasis Intrahepatic cholestasis accompanies several systemic diseases, and can be induced by several drugs. All of its forms are associated with a certain degree of inflammation. The aim of this research was therefore to study changes in hepatic and renal elimination pathways during different forms of cholestasis, especially endotoxin-induced, and to characterize their modulation by administration of currently used or potential anti-inflammatory agents. One of the most significant alteration of excretory mechanisms develops during sepsis. The status induces acute renal injury through activation of immune response activated by lipopolysaccharides (LPS) on their surface. In this study, we examined the possibilities to prevent such damage by two potent anti-inflammatory drugs, dexamethasone and anakinra, an IL-1 receptor antagonist. Biochemical and molecular signs of renal impairment were observed in rats administered the LPS from Salmonellatyphimurium, after...
TRANSPORT OF NSAIDs ACROSS A BLOOD-BRAIN BARRIER IN VITRO MODEL BASED ON CELL LINE PBMEC/C1-2
Nováková, Iveta ; Štaud, František (advisor) ; Červený, Lukáš (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Iveta Nováková Consultant: Prof. PharmDr. František Štaud, Ph.D. Title of Thesis: Transport of NSAIDS across a blood-brain barrier in vitro model based on cell line PBMEC/C1-2 The blood-brain barrier (BBB) has a prominent role in regulation of the transport of substances into and out of the central nervous system (CNS). Partly, the BBB inhibits the entrance of substances harmful for the brain, it regulates the delivery of needed substances and it takes part in efflux of useless substances as well. The equilibrium of these regulation systems is essential for the correct function of the CNS, without which the homeostasis would be disturbed. Non-steroidal anti-inflammatory drugs (NSAIDs) are very well known for their anti- inflammatory effect, for reduction of fever and pain. Due to their bright, everyday usage, some side effects on the brain were observed (sleepiness, giddiness, nausea). This has evoked the question, how NSAIDs can cross the BBB. PBMEC/C1-2 cell monolayer was used as an in vitro model of the BBB. The transport of following NSAIDs was investigated: celecoxib, diclofenac, ibuprofen, lornoxicam, meloxicam, piroxicam and tenoxicam. The experiments were carried out...
Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy
Číhalová, Daniela ; Štaud, František (advisor) ; Kollár, Peter (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Daniela Číhalová Supervisor: Prof. PharmDr. František Štaud, PhD. Consultant: PharmDr. Martina Čečková, PhD. Title of doctoral thesis: Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy Cyclin-dependent kinases play an important role in cell cycle regulation and their enhanced activity can lead to the development of various malignancies. Therefore, these kinases have become a rational target for inhibition in cancer therapy and many compounds from the group of cyclin-dependent kinase inhibitors (CDKIs) are being evaluated in clinical trials. ABC efflux transporters are expressed in physiological tissues, where they influence the absorption, distribution and elimination of their substrates including drugs and determine their pharmacokinetic properties. On the other hand, overexpression of ABC transporters in cancer cells can contribute to the development of multidrug resistance (MDR) against structurally and functionally diverse compounds. Three members of the ABC transporter family play the most prominent role in the development of MDR: ABCB1 (P-glycoprotein), ABCG2 (breast cancer...
Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy
Číhalová, Daniela ; Štaud, František (advisor) ; Kollár, Peter (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Daniela Číhalová Supervisor: Prof. PharmDr. František Štaud, PhD. Consultant: PharmDr. Martina Čečková, PhD. Title of doctoral thesis: Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy Cyclin-dependent kinases play an important role in cell cycle regulation and their enhanced activity can lead to the development of various malignancies. Therefore, these kinases have become a rational target for inhibition in cancer therapy and many compounds from the group of cyclin-dependent kinase inhibitors (CDKIs) are being evaluated in clinical trials. ABC efflux transporters are expressed in physiological tissues, where they influence the absorption, distribution and elimination of their substrates including drugs and determine their pharmacokinetic properties. On the other hand, overexpression of ABC transporters in cancer cells can contribute to the development of multidrug resistance (MDR) against structurally and functionally diverse compounds. Three members of the ABC transporter family play the most prominent role in the development of MDR: ABCB1 (P-glycoprotein), ABCG2 (breast cancer...

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