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Immunomodulators
Horká, Zuzana ; Štaud, František (advisor) ; Nachtigal, Petr (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxikology Candidate: Zuzana Horká Supervisor: Doc. PharmDr. František Štaud, Ph.D. Title of master thesis: Immunomodulators The master thesis focuses on modern approaches in the immunomodulatory therapy. The immune system is together with the nervous and endocrine system one of the basic regulating mechanisms of the human body. The main function of the immune system is to maintain its integrity. The disturbances of the immune reactions can lead to the development of various pathologies or diseases. In these cases a therapeutic effect on the immune system with appropriate drugs - immunomodulators is appropriate. These medicaments are capable of inhibiting or stimulating the immune reaction. Immunosuppressive pharmacotherapy is used to treat allergic and autoimmune diseases and in transplantation medicine. Immunosuppressants are a very large group of substances. They differ from each other by their chemical structure and mechanism of its action. Within the frame of immunosuppressives this work elaborates in detail the calcineurin inhibitors, mTOR inhibitors, fingolimod and the theme of monoclonal antibodies. The stimulation of the immune system through appropriate immunomodulator finds its application...
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Implication of the Gabaergic System in Altered Responses to Stress Associated to Maternal Separation
Martišová, Eva ; Pávek, Petr (advisor) ; Štaud, František (referee)
in English language - diploma thesis Implication of the Gabaergic System in Altered Responses to Stress Associated to Maternal Separation Eva Martišová This diploma thesis studied whether the GABA system alters responses to stress induced by maternal separation in rats. The aim was to examine the influence of maternal separation on GABA neurotransmission, in particularly, the biochemical markers of the system (levels of the neurotransmitter GABA, GABA A receptor expression), and to study of gender-related differences in behavioral and neurochemical processes in rats induced by maternal separation. In order to pursue the objectives, it was necessary to develop a model of maternal separation in rats. Rat pups were separated from their mother for three hours a day from postnatal day 2 to postnatal day 21 (in the postnatal period, when the reduced ability to respond to stressful stimuli). At postnatal day 23 pups were removed from mothers, divided into groups of the same sex. Then pups were without significant manipulation left to grow into adulthood. After reaching adulthood (> 60 days) rats were divided into two groups. The first group was killed by decapitation and different brain regions (anterior and temporal cortex, corpus striatum and hippocampus) were used to determine the levels of GABA using...
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Mechanizmy vzniku rezistence vůči platinovým cytostatikům
Bouška, Petr ; Čečková, Martina (advisor) ; Štaud, František (referee)
1. Abstract Although the first platinum drug cisplatin was initially described in 1845, its biological activity was discovered more than 100 years later. Since then are cisplatin and its clinically used analogues carboplatin and oxaliplatin in widespread use for the treatment of variety of human cancers, including ovarian, cervical, head and neck tumors, non-small cell lung, breast, colon, gastric and renal cell carcinoma, sarcoma and relapsed lymphoma. However, the treatment is often accompanied by severe side effects of which nephrotoxicity, peripheral neurotoxicity and myelosuppression are the most serious. Another important obstacle in their clinical use is drug resistance. This thesis evaluates possible mechanisms of the development of platinum drugs resistance. There is a variety of them and they include (i) diminished accumulation of platinum drugs affected by influx transporters (Aquaporin 9, CTR1, OCT1, OCT2) and by efflux transporters (ATP7A, ATP7B,ABCG2); (ii) increased detoxification of drug by thiols glutathione and metallothionein; (iii) improved repair of nuclear lesions affected by NER, MMR, Homologous recombination, and enhanced tolerance to nuclear lesions caused by Replicative bypass, inhibition of pro-apoptic factors (including caspase-3, -8, Fas and other), or by overexpression of...
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Nejnovější přístupy k léčbě Diabetes Mellitus
Hadjiyiangou, Katerina ; Štaud, František (advisor) ; Čečková, Martina (referee)
English abstract Diabetes mellitus (DM) is the best known endocrine disease of the pancreas where the incidence of the affected individuals is increasing rapidly worldwide. It is caused by defects in both the pancreatic islets and in the pancreas to produce enough insulin resulting in impaired glucose homeostasis leading to higher than normal glucose levels in the blood (hyperglycaemia) which is considered to be the hallmark of diabetes. Consequently the main aim of diabetes management is to monitor the glycaemic status. Diabetes mellitus can be subdivided into two classes, type 1 diabetes mellitus (T1DM) which is also known as insulin- dependent diabetes mellitus and type 2 diabetes mellitus (T2DM) which is known as non- insulin-dependent diabetes mellitus. Management of either type of DM requires a number of lifestyle modifications such as increased exercise and decreased weight with the intention of improving metabolic control and enhancing the quality of life. Unfortunately, the majority of patients will eventually require administration of antidiabetic drugs. The present study was performed with the intention of reviewing the currently available scientific literature about both types of DM and discuss the current and novel approaches of treatment, thus giving more emphasis on the novel advances. For...
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Study of interactions of antiviral drugs with selected placental transporters
Karbanová, Sára ; Štaud, František (advisor) ; Kacerovský, Marian (referee) ; Mladěnka, Přemysl (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Sára Karbanová, MSc. Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultant: doc. PharmDr. Lukáš Červený, Ph.D. Title of Dissertation Thesis: Study of interactions of antiviral drugs with selected placental transporters The backbone of HIV treatment in pregnant women is the combination antiretroviral therapy which effectively suppresses the viral proliferation in maternal blood circulation. One of drugs in this therapy regimen should be a molecule with high placental transfer to assure the prophylaxis of viral transfer to fetus. There is no approved guideline for pharmacotherapy of pregnant women infected with hepatitis C (HCV), however recent evidence suggests that lowering the maternal viral load could correlate with lower likelihood of HCV transmission to the fetus. To assure and further develop the effective and safe pharmacotherapeutic approaches for treatment of HIV and HCV in pregnancy with respect to fetal safety, it is essential to understand mechanisms of placental transfer of anti(retro)viral drugs. In this Dissertation thesis we focused on molecules derived from nucleosides (anti-HIV abacavir, emtricitabine, zidovudine, tenofovir disoproxil fumarate and anti-HCV...
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Neurogenetický potenciál kmenových buněk u myší
Slabá, Barbora ; Štaud, František (advisor) ; Červený, Lukáš (referee)
Neural stem cells (NSCs) are present in the mammalian adult nervous system and are found in two specific regions: the subventricular zone of the forebrain and the subgranular zone in the dentate gyrus of the hippocampus. NSCs undergo fate specification, maturation and functional integration before they can take part in neuronal circuits. Less is known about the mechanisms controlling these processes or the function of the newly born neurons in the adult brain. A large number of molecular and environmental factors can regulate various aspects of proliferation, maturation and differentiation of adult stem cells in adult nervous system. NSCs can give rise to three main types of neural cells: neurons, astrocytes and oligodendrocytes. It is suggested that astrocytes may play critical role in regulating neurogenesis in both the intact adult brain and after injury. Therefore, determining how astrocytes regulate adult neurogenesis at the molecular level is an essential step toward understanding the regulation of adult neurogenesis. To find out how genetic alteration of astrocytic intermediate filament will affect neural stem cells of postnatal mice, the neurosphere assay was performed in order to compare the proliferative and differentiation characteristics of neural stem/progenitor cells in GFAP-/- Vim-/-...
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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...
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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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Inaktivace ICAM-1 genu metodou oligonukleotidů modifikovaných lysinem
Kocourková, Aneta ; Štaud, František (advisor) ; Nachtigal, Petr (referee)
Conjugation of ligands to antisense oligonucleotides is a promising approach for enhancing their effects on gene expression. In this study 2'-O-lysylaminohexyl group was linked to the uridine base, which replaces one, two or three thymine bases thus modifies the oligonucleotides. This exchange of bases was tested for improvement of silencing target protein expression. Effectivity of modifications in silencing target protein expression was examined with the alicaforsen sequence (DNA) and siRNA. Alicaforsen, currently in clinical trial 3, is a phosphorothioate targeting ICAM-1, which was the model used to evaluate the influence of modifications. The same target was chosen for siRNA to compare the efficiency of DNA and siRNA substances. For the first time, down-regulation of ICAM-1 was shown on the blood brain barrier cell line ECV304. Unmodified/modified antisense oligonucleotides and siRNA sequences were transfected into ECV304 cells with the help of a transfection agent lipofectamine 2000. After 24 hours of transfection cells were disrupted by a chemical lysis. Protein concentrations were determined by Bradford protein assay. ICAM-1 inhibition was assessed with western blot. The inhibitory effect of ICAM-1 was normalized to the corresponding actin and untreated cells. ICAM-1 protein levels were...
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