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Delineating pain and fear engrams in the prefrontal cortex
Ludínová, Kristýna ; Zitko, Jan (advisor) ; Herink, Josef (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Kristýna Ludínova Supervisor: PharmDr. Jan Zitko, Ph.D. External supervisors: Dr. Manfred Oswald, Prof. Dr. Rohini Kuner Title of diploma thesis: Delineating Pain and Fear Engrams in the Prefrontal Cortex Pain is a complex process associated with activation of various brain centres. According to evidence of imaging studies in humans and rodents the medial prefrontal cortex (mPFC) ranks amongst the brain area consistently activated during painful perception. The mPFC circuits underlies functionally-distinct processes, such as pain, emotional response, decision-making, attention amongst others. However, the precise contribution of mPFC in pain related function remains to be unknown. The aim of the study was to delineate how pain and fear are manifested at the cellular level within the regions of PFC. By employing activity dependent neuronal labelling we tested if cellular ensembles activated in pain and fear behaviours within the mPFC are distinct. We investigated a potential use of activity-dependent DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) expression in order to test for the functional role of PFC ensembles in pain and fear behaviour. Our...
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Molecular modeling study of potential mycobacterial enoyl-reductase inhibitors
Slovák, František ; Holas, Ondřej (advisor) ; Zitko, Jan (referee)
Charles University in Prague, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Diplomate: František Slovák Supervisor: PharmDr. Ondřej Holas, Ph.D. Title of Diploma Thesis: Molecular modeling study of potential mycobacterial enoyl ACP reductase inhibitors. Tuberculosis is a worldwide spread infectious disease. The biggest problem of our time are completely and multi resistant strains of Mycobacterium tuberculosis that do not respond to currently known drugs. The main reason for high resistance and drug resistance is a bacillus composition of its cell wall. It contains a high proportion of mycolic acids. The synthesis of mycolic acids takes several steps. The final step is a catalytic reduction by enzyme enoyl - ACP reductase ( InhA ). This work was focused on finding new potential substances that would be able to inhibit this enzyme. There were used methods of computing and molecular modeling to search these substances. Adjusting of crystallographic structures ran in the program Maestro and docking in the MOE program. Over the 30 000 thousand molecules from the ZND (Zinc Natural Derivates) were tested by molecular docking on 3 crystallographic structures of InhA enzyme. 8 of these molecules were selected from this amount because their...
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Alkylamino- Derivatives of Pyrazinamide as Potential Antituberculotic Drugs
Mlčoch, Michal ; Zitko, Jan (advisor) ; Musílek, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Michal Mlčoch Supervisor: Mgr. Jan Zitko, Ph.D. Title of candidate thesis: Alkylamino- derivatives of pyrazinamide as potential antituberculotic drugs This thesis is a result of intention to prepare potential effective derivatives from pyrazinamide (PZA) structure. These results contribute to enrichment of the research of new antituberculars (antiTBC) which has been carried out at the Dpt. of Pharmaceutical Chemistry and Drug Control at the Faculty of Pharmacy in Hradec Králové. The aim of the research to produce the new effective antituberculars is supported by the contemporary state of tuberculosis in the world. This state is closely described in this thesis. Despite of decreasing number of new cases in all six WHO regions, spreading of this infectious disease is not under the control. The main reason is a resistance formation of new mycobacterial strains which can cause hardly treatable cases. The prepared substances are PZA derivatives which represent one of the most important first line drugs for tuberculosis treatment. The latest research focused on mechanism of PZA showed new information which was included in this thesis. Furthermore, some...
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Derivatives of Pyrazinecarboxylic Acid as Potential Antituberculotics (Synthesis and Biological Evaluation)
Zitko, Jan ; Doležal, Martin (advisor) ; Vinšová, Jarmila (referee) ; Csöllei, Jozef (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department: Dpt. of Pharmaceutical Chemistry and Drug Control Candidate: Mgr. Jan Zitko Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Title of Doctoral Thesis: Derivatives of pyrazinecarboxylic acid as potential antituberculotics (synthesis and biological evaluation) This thesis deals with derivatives of pyrazine-2-carboxylic (POA) acid with potential antimycobacterial activity. In the theoretical part of the thesis there is a short description of tuberculosis (TB) disease, discussion of its epidemiology an associated risk factors of increasing resistance to fist-line antituberculars and the co-infection with HIV. Antituberculars used in clinical practice are described as well as the summary of new antituberculars under clinical trials is presented. Pyrazinamide (PZA) as one of the most important first-line antituberculars is in the focus of this thesis. Multiple up-to-date theories of PZA (POA) mechanism of action are described and discussed. Importantly, a summary of structural changes of PZA/POA attempted in the past to prepare new antituberculars is presented and the importance and relevance of individual structural changes is discussed. In the practical part of this thesis, 76 derivatives of PZA/POA were prepared, 68 of...
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Pyrazinamide derivatives as potential antimicrobial compounds
Čečetková, Martina ; Zitko, Jan (advisor) ; Kučerová, Marta (referee)
Charles University, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical analysis Candidate: Martina Čečetková Supervisor: PharmDr. Jan Zitko, Ph.D. Title of Diploma Thesis: Pyrazinamide derivatives as potential antimicrobial compounds Even in 21st century, tuberculosis still remains a serious and global health threat. Tuberculosis is one of the 10 most common causes of death, the most burdened are developing countries, but this disease infects up to 1/3 of population worldwide. Due to ineffective treatment of tuberculosis in developing countries, the prevalence of tuberculosis which does not respond to standard treatment is increasing. It is necessary to develop new drugs effective against multidrug-resistant tuberculosis and prevent further spread of the disease. The design of final structures is based on previously synthesized molecule 6- chloro-N-(4-(4-fluorophenyl)thiazol-2-yl)pyrazine-2-carboxamide, which structure comes from first line antitubercular pyrazinamide (PZA) and 4-arylthiazol-2-amine scaffold with formerly identified antimycobacterial activity. This starting compound exhibits high activity against M. tuberculosis described by MIC = 0,78 µg/mL and low cytotoxicity. The object of study was to determine effect of substitution...
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Synthesis and in vitro testing of tacrine-troloxic derivatives as potential inhibitors of acetylcholinesterase
Ondřejíček, Aleš ; Doležal, Martin (advisor) ; Zitko, Jan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Aleš Ondřejíček Supervisor: prof. PharmDr. Martin Doležal, Ph.D. Supervisor specialist: PharmDr. Jan Korábečný, Ph.D. Title of Diploma thesis: Synthesis and in vitro testing of tacrine-trolox derivatives as potential inhibitors of acetylcholinesterase Alzheimer's disease (AD) is a complex neurodegenerative disorder, which involves gradual loss of episodic memory and impairment of cognitive functions. Characteristic histopathological hallmarks of AD are neuritic plaques and neurofibrillary tangles present in brain tissue as well as deterioration of cholinergic neurotransmission. Currently there are only two classes of drugs used for the treatment of AD. The first group represents inhibitors of acetylcholinesterase (AChEI), whereas the second only memantin, NMDA receptor antagonist. The aim of the thesis was to synthesize three series of tacrine - trolox derivatives. In particular derivatives of trolox with tacrine, 7-methoxytacrine and 6- chlorotacrine, which were connected by various linkers. To determine the therapeutical potential of new compounds Ellman method was used and results were compared with tacrine, 7-methoxytacrine and 6-chlorotacrine as standards. The...
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Compounds combining pyrazinamide and 4-aminobenzoic acid fragments as potential antituberculars
Žecová, Jana ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical chemistry and Pharmaceutical analysis Author: Jana Žecová Supervisor: PharmDr. Jan Zitko, Ph.D. Title of diploma thesis: Compounds combining pyrazinamide and 4-aminobenzoic acid fragments as potential antituberculars Tuberculosis is a severe infectious disease, which has been afflicting the human world population for centuries. It's figuring in the scale of the deadliest diseases as well as the occurring of strains resistant to therapy requires a serious approach to this problem and the research of new therapeutic means. Among the actual antituberculars figure two compounds, PZA and PAS. Pyrazinamide is a first line drug, and its derivatives are subject of the research in the Department of Pharmaceutical chemistry and Pharmaceutical analysis. Structurally similar to 4-aminobenzoic acid, PAS is a second line antitubercular, which is again actual in the therapy of resistant form of TBC. This diploma thesis treats about possibilities of the use of compounds combining fragments of PZA and 4-aminobenzoic acid as potential antituberculars. Furthermore, this thesis evaluates the influence of PAS fragment in the derivatives prepared with this antimycobacterial purpose. The theoretical part describes the actual state of...
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Conditions for convergence of the restarted and augmented GMRES method
Nádhera, David ; Zítko, Jan (advisor) ; Strakoš, Zdeněk (referee)
The GMRES method is one of the most useful methods for solving a system of linear algebraic equations with nonsymmetric matrix. So on, many bounds for the residual norm have been derived, that can give us information about the convergence or possible stagnation of the method. A generalization of the GMRES method is the augmented GMRES method. In this paper we will analyze the implementation of augmented GMRES method proposed by Morgan. In these consequences we will be interested in how precise harmonic Ritz vectors approximate the eigenvectors belonging to the smallest in magnitude eigenvalues. We generalize some previous results concerning the convergence of restarted GMRES method for the case of augmented GMRES method. This is the rst contribution of the work. Another main point will be numerical testing and comparing of the bounds for restarted and augmented GMRES and an attempt to state a criterion, when it is suitable to stop the improvement of augmenting vectors, i. e. apply the augmented GMRES method without additional computations.
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Transformace Sylvestrovy matice a výpočet největšího společného dělitele dvou polynomů
Eckstein, Jiří ; Zítko, Jan (advisor) ; Tůma, Miroslav (referee)
In this thesis we study the computation of the greatest common divisor of two polynomials. Firstly, properties of Sylvester matrices are considered as well as their role in computation. We then note, that this approach can be naturally generalized for several polynomials. In the penultimate section, Bézout matrices are studied as an analogy to the Sylvester ones, providing necessary comparison. Extension for more than polynomials is presented here as well. Algorithms corresponding to the individual approaches are presented as well. Finally, the algorithms are implemented in MATLAB and are compared in numerical experiments. Powered by TCPDF (www.tcpdf.org)
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