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Development of an LC-MS method for determination of new antimalarial drugs in biological matrices.
Klimeš, Jiří ; Kovaříková, Petra (advisor) ; Kučera, Radim (referee)
Artemisinin a representative of Endoperoxide class of drugs and its derivatives particularly artesunate are the most important class of antimalarial drugs used in clinical practice. They are recommended as the first-line treatment of malaria in combination with other longer-acting antimalarial drugs (lumefantrine, piperaquine). As the main skeleton of these compounds lacks UV visible or fluorescent chromophore, earlier methods of detection have used post-column on-line derivatisation or electrochemical detection in the reductive mode. However, these methods suffer from poor sensitivity and selectivity. Within this thesis the whole LC-MS method development for the analysis of artesunate and its major metabolite dihydroartemisin in biological samples from the very beginning was performed. It included tuning of ESI - triple quadrupole MS detector and optimization of chromatographic conditions, particularly mobile phase pH. Artesunate (ARST) and dihydroartemisin (DHA) were assayed in human plasma using artemisisnin as an internal standard. Different approaches of plasma sample treatment, (protein precipitation and liquid- liquid extraction) were optimized and compared. Pre-validation data for liquid-liquid extraction revealed LLOQ as 2.5 and 3.0 ng/ml for DHA and ARST, respectively using 400 μl of...
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Insulin like and other growth factors and tumors
Kučera, Radek ; Topolčan, Ondřej (advisor) ; Klimeš, Jiří (referee) ; Šafarčík, Kristian (referee)
Inzulinu podobné a jiné růstové faktory a nádory Insulin like and other growth factors and tumors Disertační práce Plzeň 2011 Mgr. Radek Kučera Summary The interaction between growth factors and cancer incidence and development has been discussed recently. First works suggesting possible connection between increased production of insulin like growth factors with an increased incidence of tumors came already from early 80s of the last century. The aim of my work was focused on evaluation of possible relation between insulin like growth factors or their binding proteins and tumors from different perspectives, to assess their significance and try to determine what role the IGFs and IGFBPs may play in the current tumor diagnostics. The work itself is divided into two parts, the theoretical and practical ones. In the theoretical part, I summarized the action of IGF in human body and also focused on previous findings on the role of IGF system in cancer diagnoses. In the practical part, divided into three subsections, I focused on investigation of relations in a large set of patients with different cancer diagnoses, in a group of women with breast cancer and, finally, I focused on changes of IGF1 levels during follow-up. Theoretical part Insulin-like growth factors (IGF) are peptides, that participate on growth...
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Determination of related compounds in final dosage forms based on cyclosporine by HPLC with chemiluminescent detection specific for nitrogen.
Mrůzek, Zbyněk ; Klimeš, Jiří (advisor) ; Kastner, Petr (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Pharmaceutical Chemistry and Drug Control Candidate: Zbyněk Mrůzek Supervisor: prof. RNDr. Jiří Klimeš. CSc Consultant thesis: Ing. Pavel Blatný. Ph.D. Title of thesis: Determination of related substances in the dosage forms based on cyclosporine by HPLC with nitrogen specific chemiluminescence detection. Development of an HPLC method with chemiluminescent detection specific for nitrogen for related substances determination in cyclosporine final dosage forms is described in this work. The method is capable to determine cyclosporine impurities originated from cyclosporine substance and relevant degradation products except isocyclosporines. The method utilizes the stationary phase Zorbax SB-C18, particle size 1.8 µm, 150x2.1 mm and gradient elution at flow rate 0.15 ml.min-1 at column temperature 100řC. Mobile phases are Acetone: TBME: water: TFA (30: 5.5: 64.5: 0.01) and Acetone: TBME: water: TFA (49: 5.5: 45.5: 0.01). The work includes the verification of method validability in terms of specificity, linearity, limit of quantittion, accuracy, precision and robustness. The method can be used for determination of cyclosporine impurities in final dosage forms in pharmacetical QC laboratories. Keywords: cyclosporine....
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Real world data and health-economics aspects of treatment of respiratory diseases in the Czech Republic
Valena, Tomáš ; Klimeš, Jiří (advisor) ; Vlček, Jiří (referee)
CharlesUniversityinPrague Faculty of Pharmacy in Hradec Králové Department of Social and Clinical Pharmacy Candidate Mgr. TomášValena Supervisor PharmDr. Jiří Klimeš,Ph.D.,MBA Title of RigorosumThesis Real world data and health-economicaspectsoftreatment of respiratory diseasesinthe CzechRepublic The aim of this PharmD thesis was to present comprehensive commentary on author`s publications focusingonthe healtheconomicsaspectsandreal worlddatainthe areaof healthtechnologiesinthe CzechRepublic,specificallyforrespiratorydiseases. The Health Technology Assessment (HTA) is a multidisciplinary evaluation process that assess information on medical, social, economic (cost-effectiveness and budget impact) and ethical aspects relatedtothe use of ahealthtechnologythroughoutitslifespan.Healtheconomicsandevidencefrom real worldare an integral partof HTA. Research focuses on the importance and application of data collection and adaptation of health economic analyses in conditions of local clinical practice in the treatment of respiratory diseases, namely chronic obstructive pulmonary disease (COPD) and severe asthma. This data could be subsequentlyusedasatool for value demonstrationformanagedentryof the drugwhere there isan uncertaintyfromregulatororpayer,whetheronthe side of outcomesorcosts of intervention. The...
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The budget impact and cost-effectiveness thresholds in the context of other criteria in reimbursement decision making of medicinal products
Duong, Thuy Linh ; Klimeš, Jiří (advisor) ; Kostřiba, Jan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Social and Clinical Pharmacy Author: Duong Thuy Linh Supervisor: PharmDr. Jiří Klimeš, PhD., MBA Title of Thesis: The budget impact and cost-effectiveness thresholds in the context of other criteria in reimbursement decision making of medicinal products KEY WORDS: cost-effectiveness analysis, Willingness to pay threshold, medicines, MCDA - multi- criteria decision analysis OBJECTIVES: The aim of this study was to provide a structured overview of selected criteria that are / may be key to adopt new innovative technology in the reimbursement system, based on a retrospective analysis of selected decisions of the State Institute for Drug Control. It was investigated the relationship between the individual criteria (and scoring results) coming from the multi-criteria analysis and the value of ICER and BIA, for these medicinal products entering the reimbursed system. METHODS: Retrospective analysis of selected legally closed, published and publicly available administrative proceedings of the State Institute for Drug Control in the period January 2020 - May 2021. A total of 20 administrative proceedings were selected for the final analysis, of which 12 medicinal products that were selected, entered the permanent reimbursement and the...
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Optimization of Semiempirical Quantum Mechanical Methods for in Silico Drug Design
Kříž, Kristian ; Řezáč, Jan (advisor) ; Klimeš, Jiří (referee) ; Kolář, Michal (referee)
Optimization of Semiempirical Quantum Mechanical Methods for in Silico Drug Design Doctoral thesis Kristian Kříž The subject of this thesis is the optimization of semiempirical quantum mechanical methods (SQM) for their use in in silico drug design. The thesis covers two topics - COSMO2 solvation model optimization part and PLF547, PLA15 dataset development part. The first part is devoted to the optimization of COSMO solvation model by addition of a nonpolar term and reparametrization of the model for SQM methods PM6 and PM7. We have shown that the accuracy of the resulting "COSMO2" optimized model improved on all the tested datasets and we have compared it to other selected SQM solvation models. The method has also been tested on the protein ligand complexes as a part of a scoring function, where it provides better preditction of binding affinity of drug candidates for their target protein. The second part of the thesis describes the construction of datasets for noncovalent interactions aimed speicificly to represent an environment of an enyzme active site complexed with a ligand with reliable benchmark values of interaction energies in vacuum and solvent (water). The developed PLF547 and PLA15 datasets are suitable for testing and development of methods for the use in drug design. We have...
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