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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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COVID-19 and kidney diseases
Stanovský, Samuel ; Čertíková-Chábová, Věra (advisor) ; Zahrádka, Ivan (referee)
In clinical practice, SARS-CoV-2 virus infection and COVID-19 disease are mainly associated with dominant respiratory disorders of varying severity, from minor events such as upper respiratory tract infections to life-threatening respiratory failure. However, COVID-19 can not only be seen as a respiratory infection, but the possibility of systemic involvement should also be considered. One of the internal organs that can be directly affected by the virus is the kidneys. Renal damage from the SARS-CoV-2 virus can occur in completely intact kidneys or can affect kidneys with pre-existing nephropathy. In addition, patients with manifest renal disease are considered at higher risk for the COVID-19 than healthy population due to the often-significant immunosuppressive pharmacotherapy that might be a part of various nephropathy treatment regimens.
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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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Study of the effect of novel antiretroviral drugs on carnitine transport in the placenta
Marková, Eliška ; Čečková, Martina (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Eliška Marková Suprevisor: doc. PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: Study of the effect of novel antiretroviral drugs on carnitine transport in the placenta Nowadays, the antiretroviral treatment of HIV-positive pregnant women is the standard approach for restriction of transmission of HIV infection from mother to the fetus. In spite of necessity of this pharmacotherapy, it is important to know its safety and risks. For the correct fetal development and function of placenta it is (besides others) essential to ensure the optimal supply of L-carnitine, the key factor for oxidation of fatty acids from mother's blood to the placenta and fetal blood circulation. The deficiency of L-carnitine generally leads to significant metabolic changes in the cells and in it usually demonstrated with cardiomyopathies and myopaties. Published studies indicate higher incidence of cardiovascular diseases and cardiomyopathies in children born to mothers treated with antiretroviral therapy during pregnancy. Optimal transport of carnitine into the placental cells, is ensured due to the presence of functional transport protein OCTN2 in the apical membrane of trophoblast. The aim of this study was...
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In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters
Halodová, Veronika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Halodová Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters Tenofovir (TFV) is the first-line agent in the treatment of hepatitis B virus (HBV) infection for patients aged over 12 years and one of the first-line choices for the combination antiretroviral therapy (cART) of infections caused by human immunodeficiency virus (HIV). Two commercially available prodrugs have been developed for oral administration of TFV, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). These prodrugs increase TFV membrane permeability and oral bioavailability. One of the factors that can affect the bioavailability of orally administrated drugs is active transport mediated by efflux transporters, mainly by P-glycoprotein (ABCB1, P-gp) and Breast cancer resistance protein (ABCG2, BCRP). It has been already proved that TDF and TAF are substrates of both of these transporters. The goal of this diploma thesis was to use in vitro and ex vivo models of intestinal barrier to assess the impact of the efflux transporters on TDF and TAF transport in the intestine and on their...
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The influence of solubility and adsorption on plastic materials on transport experiments
Šilhanová, Marie ; Kučera, Radim (advisor) ; Váňová, Nela (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Marie Šilhanová Supervisor: doc. PharmDr. Radim Kučera, Ph.D. Title of diploma thesis: The influence of solubility and adsorption on plastic materials on transport experiments From transport experiments on cell culture models we get valuable information about transport mechanism of drugs in organism. In vitro experiments are conducted for example on Transwell type inserts. During the experiment it was discovered that the results are not homogeneous, and the quantity of a substance in the solution decreases apparently, the reason behind this is inadequate solubility of lipophilic substances or their adsorption on the surface of plastic materials used in the experiment. Due to these problems we experience significant bias. This thesis is focused on antivirotics that did not perform well during transport experiments. First, HPLC/MS methods were developed, and they were used for concentration measurement of samples containing individual antivirotics. The drugs were tested under wide range of conditions so possible changes in effects of adsorption on plastic surfaces and solubility of drugs could be observed. The substances were divided into groups based on...
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Synthesis of novel types of acyclic nucleoside phosphonates and preparation of prodrugs and drug delivery systems
Kalčic, Filip ; Janeba, Zlatko (advisor) ; Míšek, Jiří (referee) ; Krečmerová, Marcela (referee)
First part of this thesis was focused on the previously overlooked field of C1'-branched acyclic nucleoside phosphonates (ANPs). Five diverse synthetic approaches were developed/optimized affording key 6-chloropurine intermediates bearing N9 -phosphonomethoxyethyl (PME) branched at C1' position in 2-4 steps. It was demonstrated that these intermediates can be further vastly diversified into ANPs bearing both natural and unnatural nucleobases. Single enantiomers as well as racemates of final C1'-branched ANPs (overall 48 final compounds) were prepared and selected compounds were evaluated with respect to their biological properties. The aforementioned ANPs showed no antiviral potency against studied viruses and only weak to moderate cytostatic activity. Adenine C1'-branched ANPs proved to be the most potent currently known inhibitors of Trypanosoma brucei adenine phosphoribosyl transferase (TbrAPRT), an enzyme involved in purine salvage pathway (PSP) of T. brucei. Further biological evaluation of prepared compounds is in progress. Second part of this thesis was focused on development of novel prodrug moieties with higher selectivity index (i.e. toxicity/potency ratio - SI) based on so-called ProTide prodrugs where phenol (present in ProTides) was replaced by tyrosine derivatives. Tenofovir was...
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Fungal secondary metabollites with antiviral activity
Besedová, Alena ; Čmoková, Adéla (advisor) ; Kolařík, Miroslav (referee)
The past year 2020 has clearly shown how quickly some viral infections can reach pandemic proportions. Thus, there is still a need to discover new substances with antiviral activity. Such substances (eg. asteltoxin E, cytosporaquinone B) have been discovered in the past in several groups of fungi, however, their potential as a source of virostatic chemotherapeutics has not been much explored. The possible use of fungi as a source of substances with antiviral activity is also indicated by the use of some species (eg. Ganoderma linghzi, Lentinula edoles) in the alleviation or prevention of viral diseases in traditional medicine. In most cases, however, it was not possible to find substances responsible for this effect. Therefore, in my bachelor's thesis I will first analyse kinds of fungi traditionally used as treatment of viral infections in traditional medicine. I will also summarize the most important fungal substances for which antiviral activity has been demonstrated. The bachelor's thesis will provide a comprehensive overview of currently known secondary metabolites of fungi and their virostatic effects. The information summarized in the work may point to possible candidates in the fight against viral infections.
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DNA/RNA intercalating agents as antivirotics: possible mechanisms of action
Kropáček, Václav ; Španielová, Hana (advisor) ; Šmahelová, Jana (referee)
DNA/RNA intercalating agents are compounds with capability to insert themself between nucleic acids base pairs. This phenomenon is accompanied by structural or functional disruption of said nucleic acid. Some of these compounds are used as therapeutics for cancer, bacterial or parasital infection or are used as antivirotics. This work summarizes different mechanisms which are responsible for antiviral effects of three significant classes of intercalating agents, acridine derivates, quinolines and quinolones. Except for intercalation into nucleic acids, these compounds are also capable of alkalization of cellular organels, inhibition of some viral enzymes (helicase, integrase) and immunomodulation. These abilities enables them to disrupt viral life cycle.
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Impact of plant alkaloids on viral infection
Šnejdarová, Aneta ; Horníková, Lenka (advisor) ; Váňová, Jana (referee)
Plant products have been used to treat various diseases since ancient times thanks to the many active substances they contain. One such group of substances are alkaloids. Alkaloids are biologically active substances which, in addition to antimicrobial, anti-inflammatory, antioxidant and many other properties, also possess antiviral properties. As a result, they can help treat viral infections, which are still a major medical problem today. Alkaloids affect all steps of virus replication, both viral components but especially cellular processes, without which a successful progress of viral cycle is not possible. In connection with the treatment of viral infections, the tropane, troponol, purine and isoquinoline alkaloids have been best investigated, which are also the subject of this work. The tropane alkaloid atropine acts mainly on enveloped viruses due to its ability to change the properties of biological membranes. Purine alkaloid caffeine, thanks to its ability to inhibit the cellular enzyme phosphodiestrase, causes an increase in intracellular cAMP levels and it has an impact on viral replication. Its antioxidant and immunomodulatory properties are also beneficial for the treatment. The anti-inflammatory effects of the tropane alkaloid colchicine stem from its ability to inhibit the dynamics of...
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