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Study of drug-drug interactions of antiviral drugs on intestinal transporters
Záboj, Zdeněk ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Zdeněk Záboj Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Study of drugs interactions of antiviral drugs with intestinal transporters Sofosbuvir is an antiviral agent widely used in the treatment of chronic hepatitis C. This orally administered prodrug is a designed substrate of ATP-binding (ABC) efflux transporters, P- glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). ABCB1 and ABCG2 are important determinants of intestinal absorption and are the site of significant pharmacokinetic drug interactions, leading to changes in drug exposure. Pharmacokinetic drug interactions may be undesirable (increasing the toxicity of the treatment) or desirable (allowing dose reduction). Because sofosbuvir is often administered in combination regimens with other anti(retro)virotics, the aim of this thesis was to study the ability to enhance intestinal absorption of sofosbuvir. To study the pharmacokinetic drug interactions on ABCB1 and ABCG2, a widely established in vitro bi-directional transport method through a polarized monolayer formed by the Caco-2 cell line derived from colorectal cancer has been used. We analyzed the drug interactions of sofosbuvir on these efflux...
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Pharmacokinetics of ivermectin in the sheep feces
Sobotová, Dominika ; Vokřál, Ivan (advisor) ; Lamka, Jiří (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Dominika Sobotová Tutor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Pharmacokinetics of ivermectin in the sheep feces Key words: ivermectin, pharmacokinetics, sheep, anthelminthic Infection with internal parasites (endoparasites) is one of the most common diseases in sheep. Infection with these parasites mainly with the barber's pole worm (Haemonchus contortus) causes considerable economic losses and has a significant impact on sheep productivity. Anthelmintics, including ivermectin, are used for treatment. Ivermectin belongs to the class of macrocyclic lactones and is characterised by broad spectrum and low toxicity. On the other hand, it poses a risk to the environment in form of residues that are excreted in feces by treated individuals. The aim of this study was to determine the excretion profile of ivermectin in sheep subcutaneously administered in a standard dose 0,2 mg/kg of body weight. UHPLC/MS/MS method was used for the analysis of ivermectin fecal concentration. Based on the obtained results we determined basic pharmacokinetic parameters which includes time to achieve maximum concentration (tmax), maximum concentration (cmax), area under the curve (AUC) and mean residence...
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Study of drug interactions with OATP family transporters using intestinal tissue slices
Čečková, Patrícia ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Patrícia Čečková Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Study of drug interactions with OATP family transporters using intestinal tissue slices An essential role in the action of orally administered drugs is their absorption through the intestinal barrier. It expresses a variety of transporters, including the OATP2B1 and OATP1A2 influx transporters, belonging to the SLC family. They are located on the apical membrane of enterocytes and allow the flow of endogenous and exogenous substances from the lumen of the intestines to the enterocyte. They affect not only the pharmacokinetics of drugs, but also their safety and efficacy. They represent sites of drug interactions with other drugs/food components that may altered drug efficacy or toxicity. Since FDA (The Food and Drug Administration) and EMA (European Medicines Agency) do not have intestinal OATP transporters included in their guidelines for preclinical studies, there is no single model of interaction study. The limitations of cell models and genetically modified organisms lead to the development of new methods such as the ex vivo method of precision cut intestinal slices (PCIS), which represents a tissue model...
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Metabolism of flubendazole in human liver subcellular fractions
Holubová, Jana ; Skálová, Lenka (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Jana Holubová Supervisor: prof. RNDr. Lenka Skálová, Ph.D. Title of diploma thesis: Metabolism of flubendazole in human liver subcellular fractions Flubendazole (FLU), a benzimidazole anthelmintic drug with a broad spectrum of activity and low toxicity has been used in veterinary as well as human medicine for a long time. Owing its mechanism of action, based on the specific binding to tubulin, FLU is now considered a promising anti-cancer agent. However, we do not have enough information about its biotransformation in human. In our project, subcellular fractions from the liver of 12 human patients (6 males and 6 females) were used to study the stereospecificity, cellular localization, coenzyme preference and possible inter-individual or sex differences in FLU reduction. In addition, the risk of FLU interaction with other drugs was evaluated. Results showed that FLU is predominantly reduced in cytosol and the NADPH coenzyme is preferred. The strict stereospecificity of FLU carbonyl reduction was proven and carbonyl reductase 1 was identified as the main enzyme of FLU reduction in the human liver. A higher reduction of FLU and a higher level of carbonyl reductase 1 protein was found in males than in...
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Effect of mebendazole on the activity of selected enzymes in tapeworm Hymenolepis diminuta
Lukačiková, Karolína ; Vokřál, Ivan (advisor) ; Skálová, Lenka (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Karolína Lukačiková Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of mebendazole on the activity of selected enzymes in tapeworm Hymenolepis diminuta The resistance of parasitic helminths to anthelmintic drugs is a growing worldwide phenomenon and a concerning issue. Xenobiotic metabolizing enzymes play an important role in drug resistance development as they can lower the concentration of the anthelmintics in the parasite's body and therefore protect the parasite from the anthelmintic effect. The role of drug metabolizing enzymes in drug resistance development has been already described in the group of roundworms and flukes. Limited information is available about this topic in tapeworms. In our study we decided to test the possibility of the anthelmintic mebendazole to affect the activity of these enzymes and possibly to influence the drug resistance development in rat tapeworm (Hymenolepis diminuta). Our first goal was the isolation of adult tapeworms from the definitive host (rat, Rattus norvegicus). We used mealworm beetle (Tenebrio molitor) as an intermediate host. After the successful isolation, adult tapeworms were incubated with the mebendazole (1 and 10µM) in...
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Effect of albendazole on the activity of selected enzymes in tapeworm Hymenolepis diminuta
Krejzová, Andrea ; Vokřál, Ivan (advisor) ; Szotáková, Barbora (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Andrea Krejzová Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of albendazole on the activity of selected enzymes in tapeworm Hymenolepis diminuta The efficacy of anthelmintics used to treat diseases caused by helminths is not always sufficient, and in some cases, we are directly facing resistance to these drugs. Helminths, including tapeworms, are able to defend against the toxic effect of anthelmintics using several mechanisms. Xenobiotic metabolizing enzymes and transport proteins belong to these mechanisms. When xenobiotic metabolizing enzymes are induced, the efficacy of therapy may be significantly reduced. The effect of xenobiotic metabolizing enzymes on the drug resistance development has been already described in number of helminths. In tapeworms this information is still missing. Main aim of this study was to determine effect of drug albendazole on the activity of selected xenobiotic metabolizing enzymes in rat tapeworm (Hymenolepis diminuta). Tapeworms were incubated with albendazole (1 μM and 10 μM) for 24 hours. Then activities of selected enzymes in cytosol-like, microsome-like and mitochondria-like fractions were determined. This study is focused on...
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Involvment of PDA3 in oxidative stress response
Ženklová, Lucie ; Vokřál, Ivan (advisor) ; Jirkovský, Eduard (referee)
Charles University, Faculty of pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Ženklová Supervisors: Prof. Fabio Altieri and PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Involvement of PDIA3 in oxidative stress response PDIA3 is a member of the protein disulfide isomerase family (PDI) and it is a stress- responsive protein. It is also involved in various cellular signalling pathways and has various functions in the cell. The best-known location is in the endoplasmic reticulum where it plays a major role mainly in the proper folding and quality control of glycoproteins, and participation in the assembly of the major histocompatibility complex class I. However, its existence has also been described in many other cell compartments, such as nucleus, mitochondria, cell surface or cytosol, where it interferes in various processes. While in some instances these roles need to be confirmed by further studies, a lot of observations confirmed its involvement in the signal transduction (for example releated with STAT protein) from the cell surface and the regulatory processes in the nucleus. Recent studies have also confirmed its increased expression in various pathological states. The aim of our work was to find out what is its role in the exposure of the MDA-MB 468...
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Biotransformation of monepantel in plant (Campanula rotundifolia, Plantago lanceolata)
Crhová, Anna ; Raisová Stuchlíková, Lucie (advisor) ; Vokřál, Ivan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Anna Crhová Supervisor: RNDr. Lucie Stuchlíková Raisová, Ph.D. Title of diploma thesis: Biotransformation of monepantel in plants (Campanula rotundifolia, Plantago lanceolata) Anthelmintics are veterinary drugs used to eliminate disease caused by parasitic worms. Monepantel (MOP) is a representative of amino-acetonitrile derivatives. This relatively new group of drugs is effective on helminthic strains, which are resistant to classic therapy (benzimidazoles, makrocyklic lactones, imidazothiazoles). Due to high consuption of these drugs, it is important to find out their fate in the exposed organisms. Anthelmintics are in contact with the environment and they can affect terrestrial and aquatic organisms. Their various forms can be accumulate in plants. These plants can be eaten by the animal, which may lead to development of resistance in helminths. In addition, the physiology of plants and animals may be disrupt and, consequently, biodiversity loss may occur. The aim of this study was to determine the biotransformation processes occurring in ribwort plantain (Plantago lanceolata) and harebell (Campanula rotundifolia) after low concentrations of MOP. Suspensions of both plants cells...
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Constitutive expression of UDP-glucosyltransferases from Haemonchus contortus
Nekovová, Lucie ; Matoušková, Petra (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Lucie Nekovová Supervisor: Ing. Petra Matoušková, Ph.D. Title of diploma thesis: Constitutive expression of UDP-glucosyltransferases from Haemonchus contortus Haemonchosis is one of the most frequent parasitic disease on small ruminants caused by gastrointestinal nematode Haemonchus contortus. Attack of this blood sucking parasite does not mean only serious health damage but also lower productivity and economic losses. Anthelmintics are used as a medical treatment of haemonchosis however they are often insufficient because of worlwide developing resistence. Knowledge of mechanisms causing resistence is still not sufficient, therefore much effort is spent in order to find the factors which could be their source. It appears that changes of biotransformation enzymes and their expression might be one of the reason for resistence. At H. contortus more than 40 genes which code a different types of UDP- glucosyltransferases (UGTs) have been found. UGTs are the main enzymes in nematode which are connected with a deactivation of drugs (glycosylation). Therefore this thesis is focused especially on UGT family with the main goal to analyse changes in expression of these genes of susceptible (ISE) and...
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Evaluation of photodynamic activity of tetrapyridoporphyrazine derivatives for treatment of tumorous diseases.
Půlkrábková, Martina ; Macháček, Miloslav (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Martina Půlkrábková Supervisor: Mgr. Miloslav Macháček, Ph.D. Title of diploma thesis: Evaluation of photodynamic activity of tetrapyridoporphyrazine derivatives for treatment of tumorous diseases. Cancerous diseases are one of the most common causes of death, especially in industrialized countries. Their more effective treatment requires development of new potential anti-tumor agents and therapeutic methods. Photodynamic therapy (PDT) is a clinically approved method for the treatment of both tumorous and some other diseases. Its main advantages are non-invasiveness and potential for high selectivity to target cells, which distinguishes it from current conventional anticancer treatments (chemotherapy, radiotherapy). The effect of PDT is based on a combination of three effective components - molecular oxygen, light and photosensitiser (PS). These substances are inherently non-toxic, but they can form reactive oxygen species (ROS) if combined. Then, ROS significantly damages cellular structures in target cells, which can result in cell death. PS is a substance capable of absorbing light of suitable wavelength and transferring the received energy to surrounding molecules, to molecular oxygen in...
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