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Design and synthesis of a potential orexin receptor OX2R modulator with the use of in silico methods
Kárová, Barbora ; Doležal, Rafael (advisor) ; Kolář, Karel (referee)
Orexinergic nervous system is a complex of neurons playing a significant role in managing sleep cycle and food intake. Orexin neurons situated in the lateral hypothalamus produce orexin neuropeptides A and B, which interact with two orexin receptors in a broad range of neurons in the brain. A reduced production of these neuropeptides due to the loss of orexin neurons is the cause of a specific and rare disease narcolepsy, which is currently incurable. A significant milestone in terms of drug research and development against narcolepsy is a study of Takashi Nagaraha's scientific group (2015), which was the first one to synthesize a non-peptidic agonist of the orexin 2 receptor (OX2R) that has inspired further design of new drug candidates with an increased chance to reach the clinical practice. This Bachelor Thesis is focused on the design and organic synthesis of a novel OX2R agonist with a 2-deoxystreptamine substructure and follows the Nagahara's study using rational and computer-aided drug design. The theoretical part is dedicated to the literature review of this issue, the practical part focuses on the design of 11 ligands using in silico and medicinal chemistry methods. The organic synthesis was then proposed, based on a retrosynthetic analysis, for the final candidate with the optimal...
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Application of modern analytical methods in clinical research
Vernerová, Andrea ; Kujovská Krčmová, Lenka (advisor) ; Doležal, Rafael (referee) ; Malíř, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Analytical Chemistry Doctoral Degree Program Bioanalytical Methods Candidate Mgr. Andrea Vernerová Supervisor Assoc. Prof. RNDr. Lenka Kujovská Krčmová, Ph.D. Advisor MUDr. Ondřej Sobotka, Ph.D. Title of Doctoral Thesis Application of modern analytical methods in clinical research The dissertation thesis, composed as a compilation of five publications, is dealing with the development, optimization and validation of chromatographic methods and extraction procedures for the determination of early activation of the immune system biomarkers (neopterin, kynurenine, and tryptophan) in saliva and gingival crevicular fluid in oncological patients and patients with periodontal diseases. Furthermore, the potential of the use of Clark's sensor to determine the correct function of platelets by measuring mitochondrial respiration and its application in clinical research is under investigation. This work was based on cooperation with several clinical departments of the University Hospital Hradec Králové and Olomouc, and Oroboros Instruments (Innsbruck, Austria). The theoretical part of the thesis is focused on detail description of the individual analytes, their clinical significance, used biological matrices and their...
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Application of modern analytical methods in clinical research
Vernerová, Andrea ; Kujovská Krčmová, Lenka (advisor) ; Doležal, Rafael (referee) ; Malíř, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Training Workplace Department of Analytical Chemistry Doctoral Degree Program Bioanalytical Methods Candidate Mgr. Andrea Vernerová Supervisor Assoc. Prof. RNDr. Lenka Kujovská Krčmová, Ph.D. Advisor MUDr. Ondřej Sobotka, Ph.D. Title of Doctoral Thesis Application of modern analytical methods in clinical research The dissertation thesis, composed as a compilation of five publications, is dealing with the development, optimization and validation of chromatographic methods and extraction procedures for the determination of early activation of the immune system biomarkers (neopterin, kynurenine, and tryptophan) in saliva and gingival crevicular fluid in oncological patients and patients with periodontal diseases. Furthermore, the potential of the use of Clark's sensor to determine the correct function of platelets by measuring mitochondrial respiration and its application in clinical research is under investigation. This work was based on cooperation with several clinical departments of the University Hospital Hradec Králové and Olomouc, and Oroboros Instruments (Innsbruck, Austria). The theoretical part of the thesis is focused on detail description of the individual analytes, their clinical significance, used biological matrices and their...
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Determination of oxidative stress biomarkers by HPLC
Váňová, Nela ; Jun, Daniel (advisor) ; Doležal, Rafael (referee) ; Hroch, Miloš (referee)
and keywords Although reactive oxygen and nitrogen species have a fundamental role in physiological processes occurring in living organisms, their overproduction induced by endogenous and/or exogenous sources may lead to serious imbalance in redox homeostasis, damage to intracellular components and thus, dramatically alter their function or even trigger cell death. Oxidative stress is believed to be very important mechanism of toxicity of xenobiotics, including drugs, and may be responsible for the development of their unwanted side effects. Considering a very low number of studies evaluating oxidative stress after the treatment with oxime reactivators of acetylcholinesterase (AChE) in vivo and in vitro, the relationship between their toxicity and generation of specific biomarkers of oxidative damage is not still fully understood. In order to monitor antioxidant/prooxidant properties of drugs, high performance liquid chromatography method coupled with tandem mass spectrometry (LC-MS/MS) for simultaneous determination of two biomarkers of oxidative stress, malondialdehyde (MDA) and 3-nitrotyrosine (3-NT), in biological matrices was developed. Validation of this LC-MS/MS method demonstrated the acceptable appreciable selectivity, accuracy, intra- and interday precission, and recovery of sample...
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A theological view of healing in Christianity and selected spiritual streams of the 20th century
Doležal, Rafael ; Bouma, David (advisor) ; Ventura, Václav (referee)
DOLEŽAL Rafael: A theological view of healing in Christianity and selected spiritual streams of the 20th century, Praha: Teologická fakulta Univerzity Karlovy, 2012. The subject of the diploma thesis consists in study of healing, which is seen from a position of fundamental theology. Attention is paid especially to those claiming to be classified as miraculous ones. A theologically seized recovery is then compared with the concept of healing in selected spiritual streams of the 20th century, belonging to the group New Age. This diploma thesis analyzes the characteristics of miraculous healing, and examines their significance for religion. Keywords: fundamental theology, miracle, healing, New Age, holistic health
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Usage of HPLC and UHPLC-MS/MS techniques for clinical research
Kučerová, Kateřina ; Matysová, Ludmila (advisor) ; Doležal, Rafael (referee) ; Kučera, Radim (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Analytical Chemistry Candidate: Mgr. Kateřina Kučerová Supervisor: assoc. prof. PharmDr. Ludmila Matysová, Ph.D. Consultant: assoc. prof. RNDr. Lenka Kujovská Krčmová, Ph.D. Title of Dissertation Thesis: Usage of HPLC and UHPLC - MS/MS techniques for clinical research The dissertation thesis is dealing with the extraction techniques and with development, optimization and validation of chromatographic methods for the determination of omeprazol which is drug from the group of proton pump inhibitors, and retinol as a new potential biomarker of kidney damage. The theoretical part of the thesis is focused on detailed description of the individual analytes, their clinical significance, options of determination and the matrix in which the target analytes were determined. Furthermore, the preparation of the sample before the analysis is discussed and validation recommendations related to chromatographic methods used in both pharmaceutical analysis and bioanalysis are also mentioned. In the experimental part the development, optimization and validation of UHPLC methods and their subsequent use are described in detail. The pharmaceutical-analytical part of the work describes the determination of omeprazole in new suspension preparations,...
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Usage of HPLC and UHPLC-MS/MS techniques for clinical research
Matoušová, Kateřina ; Matysová, Ludmila (advisor) ; Doležal, Rafael (referee) ; Kučera, Radim (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Analytical Chemistry Candidate: Mgr. Kateřina Kučerová Supervisor: assoc. prof. PharmDr. Ludmila Matysová, Ph.D. Consultant: assoc. prof. RNDr. Lenka Kujovská Krčmová, Ph.D. Title of Dissertation Thesis: Usage of HPLC and UHPLC - MS/MS techniques for clinical research The dissertation thesis is dealing with the extraction techniques and with development, optimization and validation of chromatographic methods for the determination of omeprazol which is drug from the group of proton pump inhibitors, and retinol as a new potential biomarker of kidney damage. The theoretical part of the thesis is focused on detailed description of the individual analytes, their clinical significance, options of determination and the matrix in which the target analytes were determined. Furthermore, the preparation of the sample before the analysis is discussed and validation recommendations related to chromatographic methods used in both pharmaceutical analysis and bioanalysis are also mentioned. In the experimental part the development, optimization and validation of UHPLC methods and their subsequent use are described in detail. The pharmaceutical-analytical part of the work describes the determination of omeprazole in new suspension preparations,...
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