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Acyclic nucleosides of 3-hydroxypyrazine-2-carboxamide bases
Chaloupecká, Ema ; Jindřich, Jindřich (advisor) ; Smrček, Stanislav (referee)
This thesis deals with the preparation of acyclic nucleosides and nucleoside phosphonates of compounds T-705 (6-fluoro-3-hydroxypyrazine-2-carboxamide) and T-1105 (3-hydroxypyrazine-2-carboxamide). Acyclic nucleoside phosphonates are substances that can terminate viral RNA or DNA replication, and some of them are used in the treatment of viral diseases. T-705 and T-1105 have shown activity against the influenza virus, and T-705 has already been approved for its treatment in Japan. Since both compounds mimic natural nucleobases in the body, their acyclic nucleosides and nucleoside phosphonates also have the potential to be biologically active. Methods for the synthesis of 3-fluoro-2-(phosphonomethoxy)propyl and 3-hydroxy-2-(phosphonomethoxy)propyl derivatives of T-705 and T-1105, their prodrugs containing lipophilic groups for the improvement of the pharmacokinetic properties and also their phosphonate diphosphates, suitable for the biological activity measurements, have been proposed. Some of these derivatives were subsequently prepared. Key words: acyclic nucleosides, acyclic nucleoside phosphonates, T-705, T-1105, favipiravir, antiviral activity, influenza
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Synthesis of Neuraminidase binders suitable for theranostics
Berenguer Albiñana, Carlos ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza viruses cause respiratory illnesses which can vary in severity depending on the strain of the virus, as well as the age and health condition of the host. Influenza remains a major threat to public health due to its nature prone to suffer mutations. As a result, vaccines have to be reformulated annually and new strains may cause sporadic global pandemics. Furthermore, the recent emergence of resistant strains of the virus against the current standard of care (oseltamivir and zanamivir) underlines the need of novel anti-influenza therapeutics. The aim of this dissertation work is to contribute to the discovery of new anti-influenza inhibitors either by rational drug-design and optimization of oseltamivir structure, or by developing screening assays suitable for the discovery of novel inhibitors of the enzymes neuraminidase or RNA-polymerase. Scheme 1. Overview of the strategy used for the development of new anti-influenza therapeutics. The dashed arrows indicate the inhibitors that were converted into probes and their corresponding target enzymes Two main modification points were explored for the improvement of oseltamivir properties (Scheme 1); modifications at carbon C-3 aimed to overcome oseltamivir resistance caused by common mutations like H274Y, meanwhile modifications at carbon C-5...
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Synthesis of peptidic inhibitors targeting PA-PB1 interface of influenza RNA polymerase
Palacková, Miroslava ; Machara, Aleš (advisor) ; Veselý, Jan (referee)
The submitted Thesis deals with preparation of a hexapeptides inhibiting protein-protein interaction of PA-PB1 subunits of influenza RNA polymerase. Crucial part of the Thesis represent modifications of particular small hexapeptide at its two "hot spots". It means at positions that significantly contribute to the binding of both subunits. These modifications resulted in preparation of two series of distinct hexapeptides. With regards to the fact that one designed hexapeptide contains unnatural and commercially unavailable amino acids this amino acid had to be prepared from simple building blocks. Apart from aforementioned work the Thesis also covers effort to prepared bicyclic peptide that contains sequences of peptidic inhibitor of protein-protein interactions and also cell-penetration peptide. Key words: synthesis, peptides, inhibitors, influenza, polymerase
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Development of high-throughput screening assay for the identification of inhibitors targeting influenza A polymerase
Karlukova, Elena ; Konvalinka, Jan (advisor) ; Obšil, Tomáš (referee)
Influenza virus A circulates in birds and mammals and causes severe infectious disease that affects from 3 to 5 million people each year. There are two classes of anti-influenza drugs currently available: neuraminidase and M2 channel inhibitors. However, increasing resistance against these two types of inhibitors along with the potential emergence of new viral strains and unpredictability of pandemic outbreaks emphasize an unmet need for new types of inhibitors. RNA-dependent influenza polymerase serves as a novel promising target for the development of anti-influenza medications. The aim of this master thesis is to develop in vitro high-throughput assays for screening of compounds targeting influenza RNA polymerase, particularly, its cap binding and endonuclease domains. For cap-binding domain the screening is based on DIANA (DNA-linked Inhibitor ANtibody Assay) method that was recently developed in our laboratory; for endonuclease domain, the method is based on AlphaScreen technology. For the purposes of the methods development, recombinant cap binding domain of PB2 subunit and N-terminal endonuclease domain of PA subunit of influenza polymerase were expressed with appropriate fusion tags and purified using affinity and gel permeation chromatography. The probes for the screening assays were...
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Evolution of host specificity in avian influenza
Divín, Daniel ; Vinkler, Michal (advisor) ; Horníková, Lenka (referee)
Avian influenza is a dangerous viral disease, which threats animals and people's health and nowadays evokes great concerns linked with pandemic threat. Veterinary procedures tries to limit spreading of infection by eradication of all birds nearby the outbreak place of the disease to limit as much economic damage as possible. However, there is obvious considerable variability in susceptibility, course and transmission of the disease in different species. In model species (Anas platyrhynchos f. domestica a Gallus gallus f. domestica), we can see a big difference in course of the disease linked with different equipment of immunity genes. There is fragmented information about other species. The main aim is therefore to summarize knowledge about avian influenza, it's origin, evolution, diversity, spreading in environment and susceptibility of different species to this disease.
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Opinions of the adult population about mandatory and optional vaccination in the Czech Republic
NEDBALOVÁ, Martina
For my bachelor thesis, I have chosen the topic of Adult Population Opinions on Mandatory and Optional Vaccination in the Czech Republic. The thesis is divided into theoretical and practical part. In the theoretical part I deal with the history of vaccination, basic concepts related to vaccination, composition of vaccines, and distribution of vaccines. A separate chapter is vaccination under the National Immunization Program, i.e. all mandatory, regular vaccinations. Out of the optional vaccinations we take a closer look at vaccination against flu and vaccination against cervical cancer, which are vaccinations around which there are many unanswered questions. The last chapters deals with the side effects of vaccination and negative attitudes of people towards vaccination, where I quote mainly the views of doctors who are against vaccination. The theoretical part is followed by the practical part for which I've set three goals. The primary objective is to find out what is the opinion on compulsory and optional vaccinations in the Czech Republic in the adult population. I also try to find out whether there are people in the population who do not agree with the vaccination. The final objective is to find out what are the vaccination rates for optional vaccines. Part of the thesis is quantitative research based on the questioning method. The questionnaire is based on research assumptions and has been published on the Internet. In one month, 366 respondents answered the questionnaire. The results are presented in form of graphs. My bachelor thesis can help you to better understand the issues concerning vaccination, to deepen the knowledge and, last but not least, to reflect on and build your own opinion on this controversial topic.
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The issue of vaccination of workers in social services against the flu with a focus on homes for the elderly
OLIVOVÁ, Vladimíra
The diploma thesis deals with issues of vaccination of workers in social services against seasonal influenza in homes for the elderly. Furthermore, this diploma thesis deals with possible ethical dilemmas in connection with cancellation of mandatory vaccination against seasonal influenza as a result of the change of legislation in 2010. The thesis is divided into a theoretical and a practical part. The theoretical part summarizes the basic information concerning seasonal influenza, its impact and prevention, and also provides an overview of long stay services focused on homes for the elderly. In the theoretical part there are also described the basic aspects relating to ensuring the quality of the service provided. Results of the quantitative research carried out in six homes for the elderly are presented and evaluated in the practical part of the thesis. The main goal of the diploma thesis is to map trends concerning the immunization coverage of workers in social services against seasonal influenza, opinions of these workers, their attitudes towards and motivation for such vaccination. Survey research shows that the cancellation of mandatory vaccination against seasonal influenza had a negative impact on immunization coverage of the workers in social services and that in the past the most common reason for vaccination was the duty laid down by law. Moreover, it follows from the results of the research that currently the main reason for refusal of vaccination lies in distrust in efficiency of vaccination. The research has also shown the importance of practising physicians' recommendations for vaccination and their irreplaceable part in provision of information about influenza. The secondary aim of the thesis was to discover how the workers in homes for the elderly perceive the impact of sickness rate of workers in social services caused by seasonal influenza on functioning of the organisation and on the quality of the services provided. As the research has shown, the workers do not believe that incapacity for work due to influenza has an impact on the functioning and quality of the services provided. Another secondary aim of this thesis was to obtain an overview of possible motivation of the workers in homes for the elderly for increase in immunization coverage against seasonal influenza. It follows from the results of the research in question that the strongest motivation for the workers would be represented by reintroduction of mandatory vaccination. The third secondary aim of the thesis was to identify possible ethical dilemmas with respect to change in duty of vaccination against seasonal influenza. These dilemmas are defined in the conclusion of the practical part of the thesis. The results may be utilized as resource materials for motivation of both the senior employees and other employees of the homes for the elderly for vaccination against seasonal influenza with respect to protection of their clients.
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The Spanish Flu Pandemic 1918/19 with particular reference to the Bohemian Lands and Central European relations
Salfellner, Harald ; Hlaváčková, Ludmila (advisor) ; Fialová, Ludmila (referee) ; Pock, Lumír (referee)
Charles University First Medical Faculty Study programme: History of Medicine Summary of dissertation The Spanish Flu Pandemic 1918/19 with particular reference to the Bohemian Lands and Central European relations Dr. med. univ. Harald Salfellner Prague, 2017 Summary Towards the end of the First World War, in 1918 and 1919, humanity faced a previously unparalleled flu pandemic; within a few months, more people had been killed than in all the battles of the 1914-18 war put together. The precise number of victims is unknown but is today generally reckoned at between 20 and 50 million. The whole world was affected by the Spanish flu, with the exception of a few remote islands, and Europe, already bled to death by industrialised warfare, was particularly hard hit. In summer 1918, the pandemic reached Bohemia in an early, relatively benign wave. A few weeks later, thousands were struck down in Prague in a second and far more deadly phase of the illness. In October 1918, as the First Czechoslovakian Republic arose from the ashes of the multiethnic Austrian state, and the masses celebrated in the cities, thousands of feverish patients were coughing behind drawn curtains, and facing an uncertain fate. In the USA, the flu pandemic - the greatest health disaster of the 20th century - has been the subject of many...
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Infectious complications in chronic renal failure
Kielberger, Lukáš ; Eiselt, Jaromír (advisor) ; Dusilová Sulková, Sylvie (referee) ; Matoušovic, Karel (referee)
INFECTIOUS COMPLICATIONS IN CHRONIC RENAL FAILURE Infections represent a serious problem in chronic kidney disease (cohort and they are) associated with signifficant morbidity and mortality. The thesis originated in the nephrology division of the Department of Internal Medicine I., Charles University Teaching Hospital and Medical Faculty in Pilsen, an institution with a long standing research activity in the field. In the theoretical part of this work, a general summary of infectious complications in chronic kidney disease population is presented. The other part of this work presents results of our research dealing with pharmacoeconomical aspects of cytomegalovirus infection and finally our results in the field of influenza vaccination. The Aim of the first presented work was to evaluate the cost impact of four different strategies for prevention of cytomegalovirus infection after renal transplantation. We provide post hoc analysis of 2 randomized studies performed in our department and calculating direct CMV-related expenses using valacyclovir prophylaxis, ganciclovir prophylaxis, preemptive vlaganciclovir treatment and deferred therapy. To simulate ihe impact of varying prices of prharmacotherapy or diagnostic procedures, a sensitivity analysis was performed. With respect to our results, valacyclovir...
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