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Cabozantinib is an anti-cancer drug used mainly for the treatment of thyroid and renal cell carcinoma. It is classified as a low molecular weight selective tyrosine kinase inhibitor. Tyrosine kinases play a key role in signal transduction and regulation of many cellular processes such as growth, differentiation, and proliferation. The changes in the tyrosine kinase pathways are associated with the formation and progression of tumors where their growth is uncontrolled. Tyrosine kinase inhibitors act on tyrosine kinase receptors, thereby preventing the spread of cancer cells and slowing down the progression of cancer. Because cabozantinib, like other clinically used drugs, is metabolized by cytochromes P450, adverse drug interactions may occur that result in altered pharmacokinetics of the administered drugs and a consequent decrease in the efficacy of these drugs. In this diploma thesis, the effect of cabozantinib on the activity of the main enzymes of phase I biotransformation of xenobiotics, cytochromes P450, was investigated in vitro. The effect on the activity of both rat and human cytochrome P450 isoforms involved in xenobiotic metabolism was studied. CYP isoforms were predominantly incubated with cabozantinib at two concentrations; 10 µM and a concentration corresponding to the substrate...

Candidate: Daniela Mašková1 Supervisor: prof. RNDr. Jiří Vlček, CSc.1 Consultant: PharmDr. Zuzana Očovská1 Title of the master thesis: Analysis of drug-drug interactions in patients admitted to hospital (II.) 1 Department Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Drug-drug interactions (DDIs) are part of drug-related problems. Drug-related problems can be either potential (possibly leading to real problems for the patient) or manifest (the problem already impacts the patient). This study aims to identify potential DDIs in the medication history of patients acutely admitted to University Hospital Hradec Králové via the department of emergency medicine. The objectives are to determine the prevalence of hospital admissions with at least one potential DDI in the medication history and characterize the identified potential DDIs with respect to their mechanism, severity rating, level of documentation, and potential consequences. Another objectives was to identify medication classes involved in potential DDI. The design of this study is an observational cross-sectional study. The data were obtained from the previous study examining the drug-relatedness of 1252 hospital admissions. For the purpose of my master's thesis, a sample of 378 hospital admissions was...

Drug Information Centre service analysis IV. - drug interactions Author: Georg Michálek Supervisor: PharmDr. Kateřina Malá, Ph.D. Consultant: PharmDr. Petra Rozsívalová Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic Introduction: Drug information centre (DIC) of the Faculty of Pharmacy in Hradec Králové, Charles University, and University Hospital Hradec Králové was established in 1994. It provides drug information to healthcare professionals in the form of timely and accurate answers to drug-related enquiries, including drug interactions (DI). Aim: This study aimed to analyse enquiries related to DI processed by DIC from 2015 to 2020 and to solve three drug enquiries related to drug interactions. Methods: Quantitative and qualitative analysis of drug enquiries was carried out. Data was collected from individual enquiries related, but not limited to drug-drug, drug-herbal, and drug-disease interactions. The quantitative analysis based on descriptive statistical methods was performed on two levels: enquiry level and drug interaction level. On the enquiry level, ATC codes found in the enquiries were analysed and on the drug interaction level various parameters assigned to each DI were analysed, such as interacting components,...

IN ENGLISH LANGUAGE Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmacology and Toxicology Candidate: Mgr. Alžbeta Štefela Supervisor: Prof. PharmDr. Petr Pávek, PhD. Title of the doctoral thesis: Novel bile acid derivatives as promising therapeutic approach Bile acids (BAs) are amphipathic steroidal molecules that are traditionally known to facilitate intestinal digestion and absorption of lipids and fat-soluble substances. On top, the recent findings have revealed that they represent important signaling agents involved in the orchestration of lipid, glucose and energy metabolism and immune response. BAs exhibit these roles by activating intracellular nuclear receptors such as farnesoid X (FXR), pregnane X (PXR) vitamin D receptors. Furthermore, BAs act as endocrine signaling molecules and activate numerous biological cascades via a membrane G-protein-coupled receptor, termed TGR5. Therefore, the extensive modulation of BA scaffold underwent to identify compounds with specific targeting of above-mentioned receptors as a promising therapeutic approach for the treatment of various liver and metabolic disorders including cholestasis, biliary cirrhosis, nonalcoholic steatohepatitis or diabetes. The principal aim of this doctoral thesis was to investigate the structure...

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Dominika Bezděková Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: IN VITRO STUDY OF DRUG-DRUG INTERACTIONS OF HIV PROTEASE INHIBITOR DARUNAVIR ON EFFLUX ABC TRANSPORTERS Abstract: Darunavir is a drug used in the therapy of HIV belonging to the group of protease inhibitors. These protease inhibitors are used as a part of the combination antiretroviral therapy. For the increase of bioavailability, darunavir is always used in combination with ritonavir or cobicistat. As the CYP3A4 and ABCB1 (P-glycoprotein) transporter substrate, darunavir is a drug with a high potential to drug interactions. Considering the amount of adverse effects that can be caused by darunavir, it is necessary to know these drug interactions for the safety of therapy. Inhibition of the intestinal ABCB1 by the co-administrated drugs could also lead to the increased bioavailability of darunavir and to reduction of frequency of administration leading to a cheaper therapy. This thesis studies the drug-drug interactions of darunavir with in vitro methods using two cell lines - MDCKII and Caco-2 cells. The results from the transport of darunavir across the MDCKII cell monolayer indicates that darunavir is a ABCB1...

Candidate: Kateřina Kukrálová1 Supervisor: prof. RNDr. Jiří Vlček, CSc.1 Consultant: PharmDr. Zuzana Očovská1 1 Department Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Title of the master thesis: The analysis of drug-drug interactions in patients admitted to hospital (I.) The presence of potential drug-drug interactions (DDIs) is common in daily practice and only a small proportion of potential DDIs results in hospitalization of the patients. Nevertheless, DDIs represent a significant cause of hospital admissions. This study aims to identify DDIs in the medication history of the patients admitted to University Hospital Hradec Králové via the emergency department in August-November 2018. The objectives of this study are a) to determine the prevalence of potential DDIs; b) to categorize identified potential DDIs with respect to their mechanism, severity, risk rating, level of documentation and potential outcomes and c) to determine the prevalence of manifest DDIs. This study has a cross-sectional design. The following data were obtained retrospectively from electronic medical records: demographic data, medication history, past medical history, laboratory and clinical findings, and information about hospital admission. The identification of potential DDI was...

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...

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...

Univerzita Karlova 1. lékařská fakulta Studijní program: Biomedicína Studijní obor: Preventivní medicína MUDr. Karolína Hronová Polymorfismus genů účastnících se v metabolismu léčiv jako potenciální cíl prevence závažných komplikací léčby u novorozenců a dětí Polymorphism of drug metabolizing enzymes as a potential target of prevention of serious treatment complications in neonates and infants Disertační práce- ABSTRAKT V ANGLICKÉM JAZYCE Školitel: prof. MUDr. Ondřej Slanař, Ph.D. Konzultant: MUDr. Pavla Pokorná, PhD. Praha, 2018 Abstract Background and aims: The safety of analgosedative drugs includes drug interactions, adverse effects, withdrawal syndrome and drug dependence are factors that significantly affect morbidity and mortality. Its prevention is critical for quality improvement of care in paediatric patients. The aim of the thesis was to evaluate the prediction of efficacy and safety of analgosedative drugs sufentanil, midazolam, tramadol and valproic acid in neonates and children based on the occurrence of selected pharmacogenetic biomarkers. The incidence of drug interactions of phenobarbital with other analgosedative drugs has also been evaluated. Methodology: The thesis is based on two studies conducted on Intensive and Resuscitation Care Unit of the Clinic of Paediatric and Adolescent...

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Martin Huličiak Supervisor: PharmDr. Lukáš Červený, Ph.D Title of diploma thesis: Study of interactions of antiviral drugs with intestinal drug efflux ABC transporters P-gp, MRP2 and BCRP are efflux transporters, members of the family of ATP binding cassette (ABC) transporters. These transporters are located on the apical membrane of the intestinal epithelium, where they may limit absorption of orally administered drugs. Study of drug interactions with/on intestinal efflux transporters is necessary to provide safe and effective treatment. The Caco-2 cell line is FDA recommended in vitro model of intestinal barrier and it is used for bidirectional testing of substrates and inhibitors of ABC transporters in preclinical research. However, this methodology has several shortcomings, so the need of introduction of new experimental models is increasing and the ex vivo method based on human or rat intestine is a promising option. Precision-cut intestinal slices (PCIS) represent a mini-model of the organ and contain all types of cells of the tissue. We used both in vitro model using Caco-2 cell monolayers for drug transport study and in our lab established ex vivo method of PCIS for accumulation study...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Alice Mlčochová Supervisor: PharmDr. Martina Čečková, Ph.D. Title of diploma thesis: In vitro transport of abacavir across the monolayer of Caco-2 cells; interaction with etravirine and rilpivirine. Abacavir belongs among nucleoside reverse transciptase inhibitors (NRTIs) representing a basic component of combined antiretroviral therapy used in treatment of HIV-positive patients [1]. Etravirine and rilpivirine are newer non-nucleoside reverse transcriptase inhibitors (NNRTIs) combined in cART together with NRTI. ATP-dependent transporters, so called ABC transporters, are able to affect pharmacokinetic properties of drugs, thus they are important site of drug-drug interactions affecting absorption, distribution and excretion level. P-glycoprotein (Pgp, ABCB1) and BCRP (ABCG2) belong among the most clinically important ABC transporters able to cause drug-drug interactions. The aim of this thesis was to introduce and optimize the method for evaluation of drug absorption using monolayers of Caco-2human intestine cell lines, whose integrity was verified by evaluating TEER (transepithelial electrical resistance). This model was also used for abacavir transport studies. Significant...

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Bc. Michaela Jahodová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: In vitro and ex vivo study of drug-drug interactions of antiretrovirals on intestinal ATP-binding drug transporters The absorption of orally administered drugs takes place especially in the intestine, where it can affect by the activity of drug's ABC transporters located on the apical membrane of the intestinal epithelium. Study of drug interactions in intestinal ABC transporters is essential to ensure effective and safe pharmacotherapy. Testing of bi- directional transport on Caco-2 cells is generally the preferred method for in vitro evaluation of substrates and inhibitors of ABC transporters. Drawbacks of the Caco-2 model increase the need and necessity to introduce new models. A great potential is the involvement of ex vivo methodologies in the human or rat intestine. The aim of the work was to introduce an in vitro methodology using the Caco-2 cell monolayer and the ex vivo methodology of precision-cut rat intestinal slices. By the bi-directional transport method, we analyzed drug interactions of the model substrate P-gp and BCRP Rhodamine 123 (RHD123) and clinically-used tenofovir...

Drug interactions of drugs used in thyroid diseases Author: Veronika Teťáková1 Tutor: PharmDr. Josef Malý, Ph.D.1 1 Department of Social and Clinical Pharmacy, Charles University, Faculty of Pharmacy in Hradec Králové Introduction and objectives: Drug interactions are considered to be a significant aspect of pharmacotherapy that can lead to the potentiation of toxicity and side effects of drugs. However, their identification and adequate management of the use of drug combinations hampers a number of obstacles. The aim of this thesis was to summary information about the drug interactions of drugs used in thyroid diseases (levothyroxine, propylthiouracil, thiamazole) and to formulate articles describing the management of interactions in a clinical practice including information for the dispensation of these drugs. To compare the information presented in each database and to determine the degree of conformity between these sources. Methodology: Based on the use of numerous information sources (Micromedex, UpToDate, SPC, Stockley's Drug Interactions) lists of drug interactions of drugs used in thyroid disaeses were established. Information about these interactions were completed by findings from other sources (PubMed®, scientific reports, Google Scholar). The information presented in each of these...

Publikace Soubor kazuistik z farmakologie přibližuje použití léčiv v reálné klinické praxi a interaktivní formou představuje některé z nežádoucích účinků či nevhodných kombinací léčiv. Vychází z reálných případů publikovaných v domácích a zahraničních odborných periodicích a je určen především studentům Všeobecného lékařství. The collection of prepared cases is based on the real cases published in the scientific journals and is intended for the students of General medicine. The aim of this study material is to give insight to the use of drugs in the clinical practice and to introduce some of the adverse reactions and unsuitable drug combinations in this attractive and interactive form. The reports are classified into three subgroups with regard to the relation of their content to the medical subspecialities.

Heart rate changes mediate the embryotoxic effect of antiarrhythmic drugs in the chick embryo A significant increase in cardiovascular medication use during pregnancy has occurred in recent years but only limited evidence on its safety profile is available. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. We tested metoprolol, carvedilol, or ivabradine for embryotoxicity and their acute effect on chick embryonic model. We used video microscopy and ultrasound biomicroscopy. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared to controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, 53%, respectively (controls 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of -adrenergic receptors showed a downward tendency during embryonic development but a negative chronotropic effect of tested drugs was increasingly pronounced with embryonic maturity. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death....

Drug interactions of cardiovascular drugs and their analysis in the patients of community pharmacy II. Author: Lenka Skořepová1 Tutor: PharmDr. Josef Malý, Ph.D.1 1 Department of Social and Clinical Pharmacy, Charles university in Prague, Faculty of Pharmacy in Hradec Králové Introduction: Drug interactions are a major cause of toxicity, side effects of drugs and increase the risk of harm to the patient. The pharmacist has an indispensable role in the process of minimizing risks and resolving of drug interactions. Objectives: The aim of the thesis was to carry out a research focused on drug interactions of selected groups of cardiovascular drugs and to describe their management in clinical practice, which could be used during dispensing medicine. Then was evaluated occurrence of these drug interactions in pharmacotherapy of community pharmacy patients. Methods: With the help of selected databases were described individual drug interactions of ACEI and created their management in clinical practice. Sample of patients of community pharmacy was screened for drug interactions. The data were processed by retrospective analysis. For 12 patients with drug interactions were processed case reports and tested solution of drug interactions with using of described management of drug interactions during the...

Interaction of drugs used in gynecology and urology and their management Author: Kupka Vojtěch Tutor: PharmDr. Martin Doseděl Ph.D., Department of Social and Clinical Pharmacy, Charles University in Prague, Faculty of Pharmacy in Hradec Králové Introduction: Drug interactions represent a serious health problem and they cause adverse drug effects and toxicity of drugs. Objectives: The goal of the thesis was to create an overview of possible drug interactions with drugs used in gynecological and urological practice. Methodology: From a theroretical introduction was selected registred drugs to 1 st January 2015 by State Institute for Drug Controle. Information about drug interactions were collected and collated from databases Vademecum Infopharm and Micromedex. From database Micromedex, the drug interactions were selected with quality of documentation "excellent" or "good". Pubmed database (www.pubmed.gov) with entering key words "basic drug", "drug interaction" and "interactive drug" was applied to create a current information. To complement the information was also gathered from magazines Practical Pharmacy and Clinical Pharmacology and Pharmacy. In case of not finding relevant information was drawn from the summary information of medicine (SPC). Results: The results were categorized into a research...

Drug interactions of cardiovascular drugs and their analysis in the patients of community pharmacy Author: Zuzana Vávrová1 Tutor: PharmDr. Josef Malý, Ph.D.1 1 Department of Social and Clinical Pharmacy, Charles University in Prague, Faculty of Pharmacy in Hradec Králové Introduction: Drug interactions represent a serious health problem and they cause many hospitalizations. Although their identification and documentation received a considerable attention, they remain unrecognized for many patients. Objectives: The goal of the thesis was to analyze serious drug interactions between cardiovascular drugs, to describe their management in clinical practice, which is useful during dispensation, and to evaluate occurrence of these drug interaction in a community pharmacy. Methodology: The information was gained from several databases and compared, and afterwards management of major drug interactions of betablockers and calcium channel blockers was created. Patients of a community pharmacy were screened for these drug interactions. The data were processed by frequency analysis. Results: In the theoretical part, 94 drug interactions were analysed. The total number of patients who received betablockers or calcium channel blockers in the community pharmacy was 525. Serious drug interactions described in this...