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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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Antiproliferative and cardioprotective potential of the newly synthetised analogues of dexrazoxane.
Gavurová, Lucie ; Jirkovská, Anna (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Lucie Gavurová Supervisor: PharmDr. Anna Jirkovská, PhD. Title of diploma thesis: Antiproliferative and cardioprotective activity of novel dexrazoxane analogues Anthracycline antibiotics (such as daunorubicin, doxorubicin or epirubicin) forms the basis of anticancer therapy in many hematological malignancies and solid tumors. However, their clinical use is limited by adverse effects. The most serious of these effects is chronic form of anthracycline-induced cardiotoxicity. Dexrazoxane is the only one clinically approved cardioprotective agent against anthracycline cardiotoxicity so far. Despite its well-evidenced cardioprotective effects, dexrazoxane use is very limited due to its possible adverse effects. The the synthesis of novel analogs of might contribute to understanding of the relationship between structure and effects of dexrazoxane. Finally, this approach could lead to the synthesis of structure with better pharmacological properties. The aim of this diploma thesis was to assess the antiproliferative activity of novel analogues of dexrazoxane (JR-281B, JR-311, JR-306A, JR-306B, JR-232 and JR-312B), and the study of the influence on the antiproliferative effect of anthracyclines....
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Study on expression of selected ABC transporters in placenta
Kučerová, Veronika ; Čečková, Martina (advisor) ; Karbanová, Sára (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Veronika Kučerová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: PharmDr. Lenka Ťupová, Ph.D. Title of diploma thesis: Study on expression of selected ABC transporters in placenta The placenta is a temporary organ through which the fetus is supplied with nutrients and oxygen from the mother's blood and conversely waste substances are transferred into the mother's blood during pregnancy. Substance transfer through the placenta is a complex process controlled by a number of physiological mechanisms, including passive diffusion, facilitated diffusion or active transport, which is realized by activity of membrane transporters with energy consumption. Presence of active ABCs efflux transporters in the placenta has been known for a long time and their function is associated primarily with limiting the entry of harmful substances into the placenta and further into the fetus, thus contributing to its protection. Among the best described transporters belong P-glycoprotein (MDR1/ABCB1), breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance protein 2 (MRP2/ABCC2), whose expression has been confirmed in the apical membrane of the placental syncitiotrophoblast facing...
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Intra-amniotic Inflammation in Women with Preterm Labor with Intact Membranes - Clinical and Experimental Aspects
Stráník, Jaroslav ; Kacerovská Musilová, Ivana (advisor) ; Šimetka, Ondřej (referee) ; Čečková, Martina (referee)
Preterm labor with intact membranes (PTL) is responsible for approximately 40% of all preterm deliveries. PTL is frequently complicated by intra-amniotic inflammation (IAI), characterized by the elevation of inflammatory mediators in the amniotic fluid. Based on the presence or absence of microbial invasion of the amniotic cavity (MIAC), two different clinical phenotypes of IAI are distinguished: i) intra-amniotic infection, when microorganisms are present in the amniotic fluid, and ii) sterile IAI, when there are no microorganisms in the amniotic fluid. The clinical severity of both phenotypes of IAI is underlined by their association with adverse neonatal outcomes. In addition to the presence or absence of MIAC, there are also differences between the phenotypes of IAI in terms of their intra-amniotic inflammatory status characteristics. The clinical part of this thesis has addressed these differences in women with PTL. The first specific aim of this clinical study was to determine the concentration of interleukin (IL)-6 in the cervical fluid of women with PTL complicated by intra-amniotic infection and sterile IAI. The second specific aim was to determine the concentration of IgGFc-binding protein (FcgammaBP) in the amniotic and cervical fluids of women with PTL complicated by intra-amniotic...
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Evaluation of the efficacy of new acetylcholinesterase inhibitors by Ellman's method
Mackurová, Michaela ; Čečková, Martina (advisor) ; Pourová, Jana (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Performed at: University of defence in Brno, Faculty of Military Health Sciences in Hradec Králové, Department of Toxicology and Military Pharmacology Candidate: Michaela Mackurová Leader of diploma thesis: Doc. PharmDr. Martina Čečková, Ph.D. Supervisor: mjr. PharmDr. Vendula Hepnarová, Ph.D. Title of diploma thesis: Measurement of the efficacy of new acetylcholinesterase inhibitors using the Ellman method Cholinesterases (ChEs) belong to an important group of enzymes in our body. The best known acetylcholinesterase and butyrylcholinesterase play an important role in the treatment of many diseases, including Alzheimer's disease (AD). It is a neurodegenerative disease that occurs mainly in the elderly. It is one of the most common forms of dementia and its incidence is still increasing. To date, no effective therapy for AD has been developed, only symptomatic treatment is available. It is therefore necessary to look for therapeutics that would be able to stop or cure this serious disease. The aim of this work was to determine the inhibitory contraction of newly synthesized potential drugs AD against both ChEs. A total of 27 tacrine derivatives were tested, which were enriched with substituents...
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Interaction of gilteritinib with OCT1 and OCT2 transporters; relation to conventional therapy of acute myeloid leukemia.
Novotná, Kateřina ; Čečková, Martina (advisor) ; Hofman, Jakub (referee)
Univerzita Karlova Farmaceutická fakulta v Hradci Králové Katedra Farmakologie a toxikologie Student: Kateřina Novotná Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Interaction of gilteritinib with OCT1 and OCT2 transporters; relation to conventional therapy of acute myeloid leukemia. Gilteritinib is one of the recently approved drugs which is primarily used in the treatment of relapsed/refractory acute myeloid leukemia (AML) with mutated FMS-like tyrosine kinase 3 (FLT3) receptor. In this project, gilteritinib was investigated in terms of its ability to interact with solute carrier (SLC) membrane transporters, namely with OCT1 and OCT2. These membrane proteins play a role in uptake of endogenous compounds and also drugs into the cells of main elimination organs (liver, kidney), but also to cancer cells. In particular, we wanted to examine potential interaction with daunorubicin and mitoxantrone, drugs traditionally used in AML therapy. First, we performed accumulation study and evaluated, whether gilteritinib is potential inhibitor of OCT1 and OCT2 studying differential uptake of daunorubicin and mitoxantrone into MDCKII-OCT1 and MDCKII-OCT2 cells based on OCT1 and OCT2 inhibition by gilteritinib. Secondly, the study evaluating the transfer of gilteritinib across the...
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Role of selected ABC and SLC transporters in transmembrane permeability of maraviroc: effect on transport in placenta
Matiašková, Zuzana ; Čečková, Martina (advisor) ; Vopršalová, Marie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and toxikology Student: Zuzana Matiašková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Role of selected ABC and SLC transporters in transmembrane permeability of maraviroc: effect on transport in placenta Antiretroviral drug maraviroc is an inhibitor of CCR5-trophic HIV virus and belongs to the group of entry inhibitors. Nowadays, maraviroc is administered as part of combination antiretroviral therapy (cART) primarily in adults, children over the age of two and pregnant women to reduce the risk of transmission of HIV to the fetus. The knowledge of interactions of maraviroc with drug transporters in placenta is crucial for optimizing the therapy during pregnancy, both in terms of efficacy and potential adverse effects. Maraviroc is known substrate of ABCB1 transporter, which plays a protective role to the fetus by its efflux activity in the apical membrane of trophoblast. However, the results of recent study employing dually perfused human placenta suggest involvement of other transport mechanisms in the maraviroc transplacental pharmaocokinetics, especially those operating in the opposite direction to ABCB1. The aim of this study was to evaluate in vitro studies whether, besides ABCB1,...
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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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Precisation prediction of therapeutic response to cancer immunotherapy
Novotná, Jana ; Malý, Josef (advisor) ; Čečková, Martina (referee)
Precisation prediction of therapeutic response to cancer immunotherapy Author: Mgr. Jana Novotná Consultant: doc. PharmDr. Josef Malý, Ph.D. Department of Social and Clinical Pharamcy Faculty of Pharmacy in Hradec Králové, Charles University Introduction and aims: Over the last few years, anticancer immunotherapy has increasingly become an important agent in treatment of oncologic patients. The aim of this thesis was to assess the clinical parameters and to find any biological markers that would predict efficacy of pembrolizumab and nivolumab. Methods: The research was based on retrospective data analysis of patients treated with pembrolizumab or nivolumab during 2015-2020 at Oncology Clinic of General Uviersity Hospital in Prague. The patients were divided into responder or non-responder groups based on their treatment response. Subsequently the analysis of clinical parameters, adverse events, panel gene sequencing of tumor DNA and RNA was performed. Finally, the obtained data were tested to find any correlations between biological markers and the treatment outcomes by the descriptive statistic method. Results: The data of 70 patients (60 % men, between 42-86 years old) were analysed. The most frequent patient profile was man in age 70-79 years with non- small cell lung cancer diagnosis. In...
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