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Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts
Gala, Viktor ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Viktor Gala Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts The nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC) is now the mainstay of combination antiretroviral therapy (cART) for HIV in pregnant women. The introduction of cART, along with several other measures, has reduced mother-to-fetus transmission of HIV to less than 1% in recent years. The placenta is a key organ for the health of both the fetus and the mother. Imbalances in placental development can result in adaptive changes and fetal programming errors. cART recommended in pregnancy is known for its good safety profile, but some epidemiological studies suggest a higher risk of reduced fetal weight, preterm birth, etc. The placenta is a rapidly growing organ dependent on the supply of building materials that resembles tumor growth in certain aspects. Nucleosides are promoters of tumor proliferation and are involved in the development of immunotolerance. The placenta is complexly equipped for nucleoside synthesis, uptake,...
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Changes of internal organs after percutaneous exposure to sulfur mustard
Šulová, Veronika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Šulová Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. External supervisor: pplk. doc. MUDr. Jaroslav Pejchal, Ph.D. et Ph.D. Title of diploma thesis: Changes of internal organs after percutaneous exposure to sulfur mustard Sulfur mustard is a chemical warfare agent belonging to the group of blistering agents. The theoretical section of the thesis is mainly focused on the description of acute toxic effects, the mechanism of action, and deals with the current possibilities of poisoning therapy. The experimental section is focused on monitoring the effect of sulfur mustard poisoning in the liver, lung, and kidney of female C57BL/6J mice after the percutaneous administration. This work aimed to evaluate markers of oxidative stress and histopathological changes of the selected organs at 3, 5, and 7 days after the poisoning. Ferric reducing antioxidant power (FRAP) and thiobarbituric acid reactive substances (TBARS) methods were used to determine markers of oxidative stress. Histopathological changes were evaluated microscopically using the hematoxylin-eosin staining method. The airness of the lung parenchyma was also assessed by computer image analysis. First, the LD50 of sulfur mustard was...
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Effect of darunavir and atazanavir on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Hradecká, Tereza ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Student: Tereza Hradecká Department of Pharmacology & Toxicology Supervisor: PharmDr. Vokřál Ivan, Ph.D. Oral administration of drugs is currently the most common and most convenient method of drug administration. Most drugs administered in this way are subsequently absorbed in the intestine and enter the systemic circulation. The absorption of drugs in the intestine can be influenced by a number of factors. Factors influencing drug absorption include, for example, efflux transporters or biotransformation enzymes. Currently, the most studied intestinal transporter is P-glycoprotein (P-gg), which is able to transport various substances back into the lumen of the intestine. Another factor affecting the absorption of drugs is intestinal metabolism, which in the first phase often takes place through enzymes from the cytochrome P450 family, while most drugs are metabolized through CYP3A4, which is also widely represented in the intestine. The activity of efflux transporters and biotransformation enzymes can be reduced (inhibition) or, conversely, increased (induction) by some drugs. This can subsequently lead to a whole range of drug interactions. The possible pharmacokinetic consequences of enzyme or transporter induction depend on the specific...
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Interactions of antiretroviral drugs with membrane transporters
Martinec, Ondřej ; Červený, Lukáš (advisor) ; Boušová, Iva (referee) ; Chládek, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Ondřej Martinec Supervisor: Assoc. Prof. PharmDr. Lukáš Červený, Ph.D. Title of doctoral thesis: Interactions of antiretroviral drugs with membrane transporters Oral delivery is the most common, convenient, and economical form of drug administration. Absorption of orally administered drugs occurs mainly in the intestine. Intestinal absorption can be reduced by the activity of efflux drug ABC transporters, mainly p-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), located in the apical membrane of the intestinal epithelium. HIV-infected patients are dependent on lifelong pharmacotherapy, which includes a combination of three or more antiretroviral drugs. Hepatitis C (HCV) is a common co-infection of HIV. In addition, the HIV-positive population is aging, which is associated with burden of other comorbidities. This results in an indication of polypharmacy and thus an increased risk of drug-drug interactions. Many antiretroviral drugs used are substrates, inhibitors and /or inducers of ABCB1, so they might quantitatively affect the intestinal absorption of co-administered drugs (ABCB1 substrates), thereby affecting the efficacy/safety of treatment. As part of this...
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Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts
Gala, Viktor ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Viktor Gala Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts The nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC) is now the mainstay of combination antiretroviral therapy (cART) for HIV in pregnant women. The introduction of cART, along with several other measures, has reduced mother-to-fetus transmission of HIV to less than 1% in recent years. The placenta is a key organ for the health of both the fetus and the mother. Imbalances in placental development can result in adaptive changes and fetal programming errors. cART recommended in pregnancy is known for its good safety profile, but some epidemiological studies suggest a higher risk of reduced fetal weight, preterm birth, etc. The placenta is a rapidly growing organ dependent on the supply of building materials that resembles tumor growth in certain aspects. Nucleosides are promoters of tumor proliferation and are involved in the development of immunotolerance. The placenta is complexly equipped for nucleoside synthesis, uptake,...
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CHARACTERIZATION OF GILTERITINIB-RESISTANT LEUKEMIC CELL LINE
Zlesáková, Lucie ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Zlesáková Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Consultant: Mgr. Simona Suchá, Ph.D. Title of diploma thesis: Characterization of gilteritinib-resistant leukemic cell line Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis for which therapy failure is often responsible. Development of drug resistance is among the most common causes of treatment failure. The exact mechanisms leading to the resistance are not known, especially for drugs recently introduced into the clinical practice such as gilteritinib. Therefore, the gilteritinib-resistant leukemic cell line (referred to as HL-60 g75) has been established in our lab and further characterized. The aim of this study was to evaluate the sensitivity of HL-60 g75 cells to gilteritinib and to clarify the stability of acquired resistance. We revealed that the resistance of HL-60 g75 cells is transient, since only after 4 weeks of gilteritinib-free cell culture, sensitivity of these cells was restored. While gilteritinib induced apoptosis similarly in both gilteritinib-sensitive (HL-60 wt) and -resistant cells, cell cycle analysis revealed lower responsiveness of HL-60 g75 to gilteritinib than HL-60 wt....
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Effect of darunavir and atazanavir on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Hradecká, Tereza ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Student: Tereza Hradecká Department of Pharmacology & Toxicology Supervisor: PharmDr. Vokřál Ivan, Ph.D. Oral administration of drugs is currently the most common and most convenient method of drug administration. Most drugs administered in this way are subsequently absorbed in the intestine and enter the systemic circulation. The absorption of drugs in the intestine can be influenced by a number of factors. Factors influencing drug absorption include, for example, efflux transporters or biotransformation enzymes. Currently, the most studied intestinal transporter is P-glycoprotein (P-gg), which is able to transport various substances back into the lumen of the intestine. Another factor affecting the absorption of drugs is intestinal metabolism, which in the first phase often takes place through enzymes from the cytochrome P450 family, while most drugs are metabolized through CYP3A4, which is also widely represented in the intestine. The activity of efflux transporters and biotransformation enzymes can be reduced (inhibition) or, conversely, increased (induction) by some drugs. This can subsequently lead to a whole range of drug interactions. The possible pharmacokinetic consequences of enzyme or transporter induction depend on the specific...
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Expression of ABC transporters in cell cultures of non-small cell lung cancer: effect of selected targeted drugs
Žofajová, Barbora ; Hofman, Jakub (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Barbora Žofajová Supervisor: doc. RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Expression of ABC transporters in non-small cell lung carcinoma cell cultures: effect of selected targeted drugs ABC transporters form a special family of transmembrane proteins, their function is the active efflux of substrates into the extracellular environment. These transporters are expressed in normal tissues and tumor cells. Thus, they influence drug pharmacokinetics and play a role in the development of multidrug resistance (MDR). Tyrosine kinases have essential functions ranging from proliferation to differentiation and cell death, their mutation can cause carcinogenesis. Finding, exploring, and inhibiting the functions of these targets is a promising strategy to treat cancer. This work aimed to determine whether the selected drugs are involved in pharmacokinetic interactions that are based on inductions of ABC efflux transporter genes and whether they have the potential to affect MDR phenotype of tumor cells. The drugs, which we studied, were three targeted anticancer drugs (capmatinib, pralsetinib, and tazemetostat) and two well- known chemotherapeutic drugs (pemetrexed and methotrexate). First, we...
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New strategies in pharmacotherapy and prevention of migraine
Kovaříková, Gabriela ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Gabriela Kovaříková Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: New strategies for the treatment and prevention of migraine Abstract: Migraine is a severe neurological disease, which has many subtypes. Migraine affects patient's physical and mental well-being and also work and family relationships. Migraine manifests as characteristic pain accompanied by vomiting and nausea or other symptoms. The first part of this paper deals with the current knowledge on pathophysiology of migraine, factors which affect migraine, degree of heritability, and specifics of chronic migraine. Diagnosis of migraine is also included and that based on MIDAS questionnaire are addressed in the diploma thesis. The second part is devoted to the therapy of acute attacks and prophylaxis of migraine, describes drugs used in these indications, characterizes them in more detail and lists their limitations. This section also outlines new pathophysiological findings and molecules that may receive future attention. New biological therapies and progress in terms of monoclonal antibody registration are also described. Nonpharmacological strategies for migraine treatment are mentioned as well. In addition, the...
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Modulation of cholesterol and bile acid metabolism via soluble endoglin and pharmacotherapy
Igreja e Sá, Ivone Cristina ; Nachtigal, Petr (advisor) ; Vítek, Libor (referee) ; Červený, Lukáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Biological and Medical Sciences Doctoral Degree Program Pharmacology and Toxicology Candidate M.Sc. Ivone Cristina Igreja e Sá Supervisor prof. PharmD. Petr Nachtigal, Ph.D. Advisor Title of Doctoral Thesis Modulation of cholesterol and bile acid metabolism via soluble endoglin and pharmacotherapy Endoglin (Eng, CD105) is a transmembrane glycoprotein and co-receptor of the Transforming growth factor-β (TGFβ) receptor complex. Upregulated expression of Eng has been implicated in endothelial dysfunction, liver impairment, and hepatic fibrosis development. When Eng is cleaved by the matrix metalloproteinase-14 (MMP14), its soluble form termed soluble endoglin (sEng, sCD105) is released into the circulation. Increased plasma levels of sEng have not only been observed in patients with cardiovascular and metabolic diseases associated with hypercholesterolemia (e.g., atherosclerosis) but have also been reported to promote conditions of the metabolic syndrome (e.g., hypertension). However, the direct role of sEng in the modulation of hepatic metabolism and liver functions under physiologic or pathological conditions has not been previously explored. Therefore, this doctoral thesis aimed to test the hypothesis that...
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