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Pharmacokinetics of Intramuscularly Administered Thermoresponsive Polyacrylamides
Groborz, Ondřej
6 Pharmacokinetics of Intramuscularly Administered Thermoresponsive Polyacrylamides Author: Ondřej Groborz Supervisor: doc. Mgr. Martin Hrubý, Ph.D., DSc. Institute of Macromolecular Chemistry, Czech Academy of Sciences Advisers: Ing. Pavel Švec RNDr. Lenka Loukotová, PhD. Abstract Polymer solutions with lower critical solution temperature (LCST) undergo a phase separation when heated above their cloud point temperature (TCP). These thermoresponsive polymers have numerous promising medicinal applications, such as in situ depot-forming radiotherapy (brachytherapy), controlled drug-release, immuno-radiotherapy, injectable thermogelling for tissue engineering and cell culture and magnetic resonance imaging (MRI), among others. Yet, despite extensive research on medicinal applications of thermoresponsive polymers, their fate after their administration remains largely unknown. Thus, in our study, we synthesized and thoroughly characterized four different thermoresponsive polyacrylamides, namely poly(N-(2,2-difluoroethyl)acrylamide), poly(N- isopropylacrylamide), poly(N,N-diethylacrylamide) and poly(N-acryloylpyrrolidine) under physiologically relevant conditions. Subsequently, we determined their biodistribution kinetics in mice and proposed a data-based pharmacological model to describe their in vivo behaviour,...
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Geometric Semantic Genetic Programming
Končal, Ondřej ; Bidlo, Michal (referee) ; Sekanina, Lukáš (advisor)
This thesis examines a conversion of a solution produced by geometric semantic genetic programming (GSGP) to an instantion of cartesian genetic programming (CGP). GSGP has proven its quality to create complex mathematical models; however, the size of these models can get problematically large. CGP, on the other hand, is able to reduce the size of given models. This thesis combinated these methods to create a subtree CGP (SCGP). The SCGP uses an output of GSGP as an input and the evolution is performed using the CGP. Experiments performed on four pharmacokinetic tasks have shown that the SCGP is able to reduce the solution size in every case. Overfitting was detected in one out of four test problems.
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Pharmacokinetic modelling in Positron Emission Tomography
Čaňková, Lenka ; Jiřík, Radovan (referee) ; Mézl, Martin (advisor)
This bachelor thesis deals with pharmacokinetic compartmental modelling in positron emission tomography. It includes a description of the basic pharmacokinetic variables and models. Models for selected radiopharmaceuticals are theoretically developed. Simulations of different organs in the Simulink environment have been performed for the radiopharmaceutical 18F-FDG. A brain slice model for the radiopharmaceutical [11C]-PS13 was created. Estimation of constants and optimization of models based on real data was performed. Subsequently, graphs of radiopharmaceutical concentrations as a function of time were plotted and described.
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The effect of selected cannabinoids on quantitative EEG, behaviour, and their therapeutic potential
Uttl, Libor
Cannabinoids and especially CBD are these days a highly discussed topic with a huge overlap in the media space. Their ability to interact not only with cannabinoid receptors, but also with other pathways, in combination with a huge "hype", leads, despite the not very strong evidence of their effects in clinical practice, to the testing of cannabinoids in a broad spectrum of indications. Nowadays, we have more than 150 isolated cannabinoids, but the research is focused only on the main cannabinoids like for example THC, CBD, cannabigerol, cannabichromen or hexahydrocannabinol. For our research, we have chosen the two most well- known cannabinoids THC and CBD, and our key question was not only what is the role of these cannabinoids individually, but, also, how do they interact when administered together, how do they influence behaviour and how do they interact in dependence on the method of administration. All these questions were addressed within our rat experiments. Somewhat surprisingly, we did not observe the typical cannabinoid tetrad (decreased sensitivity to painful stimuli, hypothermia, catalepsy, and overall decrease in motor activity) after the THC administration, so we wondered what would happen if we used more potent and selective synthetic cannabinoids JWH- 073, JWH-210, instead of THC....
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The effect of selected cannabinoids on quantitative EEG, behaviour, and their therapeutic potential
Uttl, Libor ; Páleníček, Tomáš (advisor) ; Šlamberová, Romana (referee) ; Šustková, Magdaléna (referee)
Cannabinoids and especially CBD are these days a highly discussed topic with a huge overlap in the media space. Their ability to interact not only with cannabinoid receptors, but also with other pathways, in combination with a huge "hype", leads, despite the not very strong evidence of their effects in clinical practice, to the testing of cannabinoids in a broad spectrum of indications. Nowadays, we have more than 150 isolated cannabinoids, but the research is focused only on the main cannabinoids like for example THC, CBD, cannabigerol, cannabichromen or hexahydrocannabinol. For our research, we have chosen the two most well- known cannabinoids THC and CBD, and our key question was not only what is the role of these cannabinoids individually, but, also, how do they interact when administered together, how do they influence behaviour and how do they interact in dependence on the method of administration. All these questions were addressed within our rat experiments. Somewhat surprisingly, we did not observe the typical cannabinoid tetrad (decreased sensitivity to painful stimuli, hypothermia, catalepsy, and overall decrease in motor activity) after the THC administration, so we wondered what would happen if we used more potent and selective synthetic cannabinoids JWH- 073, JWH-210, instead of THC....
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Applied pharmacokinetics in preclinical research
Královičová, Jana ; Šíma, Martin (advisor) ; Večeřa, Rostislav (referee) ; Kmoníčková, Eva (referee) ; Paluch, Zoltán (referee)
Title: Applied pharmacokinetics in preclinical research Author: Mgr. Jana Královičová Abstract: This thesis addresses the topic of development and practical utilization of rat models in preclinical pharmacokinetic studies. An analysis dealing with the impact of intra- and inter- individual variability on the results of animal comparative studies showed that cross-over design brings more accurate conclusions in these experiments than the often-used parallel setting. Results obtained on the basis of a parallel design significantly differed in our investigation (AUClast ranged from 9.62 to 44.62 mg/ml.min.g). Furthermore, in 4 cases out of 15 pair comparisons of individual parallel groups, the confidence interval did not include the 100% value. That means that in more than a quarter of studies it would be misjudged that the compared drug formulations have different pharmacokinetic properties, though they are in fact the same product. The practical use of cross-over design is demonstrated in pharmacokinetic studies comparing the absorption of various formulations with abiraterone and cinacalcet. In a fasted state, a new, innovated formulation with abiraterone was better absorbed than the reference (AUClast of a reference 30.3 mg/ml.min.g, innovated formulation 81.0 mg/ml.min.g). Thiscorresponds to anticipations...
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Application of Mass Spectrometry for Analysis of Biologically Active and Clinically Significant Compounds.
Štícha, Martin ; Jelínek, Ivan (advisor) ; Smrček, Stanislav (referee) ; Tůma, Petr (referee)
- 8 - ABSTRACT (EN) The thesis is submitted as a commented set of reviewed publications documenting and depicting the possibilities of mass spectrometry in the field of chemical, biological and pharmaceutical research; namely for the purposes of structure elucidation of selected organometallic complexes, analyses of drugs and their metabolites, monitoring of important biological markers. In course of experimental work, the following objectives were studied and solved: Proposal and realization of micro-scale preparation of selected rhenium complexes with aromatic ligands, utilizing tetrabutyammonium tetrachlorooxorhenate as a starting material; preparation and structure characterization of oxorhenium(V) complexes with 1,2-dihydroxybenzene, 1,2,3-trihydroxybenzene, and 2,3- dihydroxynaphtalene as ligands by means of ESI/MS, APPI/MS and LDI-MS; ESI/MS and UV/Vis study of kinetic behavior of complexes arising from the reaction of tetrabutylamonnium tetrachlooxorhenate with pyrogallol and catechol as ligands. Special aim was devoted to the study of subsequent chemical transformation of primarily formed Re(V) complexes; structure characterization of selected ferrocene complexes with copper, gold and silver by means of ESI/MS. Proposal of methodology of structure characterization and quantification of the...
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The pharmacokinetics of isoflavonoides
Ungerová, Lucie ; Pourová, Jana (advisor) ; Mladěnka, Přemysl (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Ungerová Supervisor: PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: The pharmakokinetics of isoflavonoids The aim of this diploma thesis is to summarize currently available informations about the pharmacokinetics of the polyfenolic compounds from a large group of flavonoids, isoflavonoids. Isoflavonoids are coumpounds found in many plant families, but especially in some members of Fabaceae family. One of the main well-known sources are soy beans containing the most famous isoflavones - genistein and daidzein, their pharmakokinetics is the main theme of this diploma thesis. Since isoflavonoids are mainly contained in the diet, their oral administration is very relevant. Isoflanonoids in the human diet occurs predominantly in the form of glykosides and therefore, after ingestion, they have to be deglycosylated by β- glucosidase enzyme family to aglycones. After that they are able to pass through the intestine into the systemic circulation and they are available for action. This is already happening in the oral cavity and the absorption occurs in the small intestine. The intestinal bacterial microflora composition is also very important for pharmacokinetics, for example I can mention...
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Evaluation of rationality and risks of pharmacotherapyin older patients in long-term care facilities
Lukačišinová, Anna ; Fialová, Daniela (advisor) ; Alušík, Štefan (referee) ; Paluch, Zoltán (referee)
Objectives Main objectives of this doctoral thesis were to review available information on pharmacological properties of benzodiazepines and their age-related changes; to evaluate the prevalence of benzodiazepine use in older patients residing in long term care facilities; to investigate the association between use of benzodiazepines and occurrence of falls in acutely hospitalized older patients; and to describe utilization of benzodiazepines in the Czech Republic. Methods A narrative review of literature focused on pharmacokinetics, pharmacodynamics, adverse effects and association of benzodiazepines with falls in older population was conducted. The evaluation of benzodiazepine use in long term care facilities was analysed in a retrospective cross-sectional study using data from the EC 7th Framework Program SHELTER project (Service and Health in the Elderly in Long Term Care). A prospective cohort study data of acutely hospitalized patients in Australia were used to evaluate association between benzodiazepines and falls. To describe utilization of benzodiazepines in the Czech Republic, data from the State Institute for Drug Control and from databases of General Health Insurance Fund were used. This dissertation thesis is a summary of published articles from above stated works and analyses. Results...
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Study on the role of pharmacokinetic mechanisms of drug resistance in new anticancer drugs with focus on solid tumors
Vagiannis, Dimitrios ; Hofman, Jakub (advisor) ; Souček, Pavel (referee) ; Zendulka, Ondřej (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Dimitrios Vagiannis Supervisor RNDr. Jakub Hofman, Ph.D. Title of Doctoral Thesis Study on the role of pharmacokinetic mechanisms of drug resistance in new anticancer drugs with focus on solid tumors Cancer chemotherapy is an important tool for the cure of cancer. Although the development of new anticancer drugs has been rapidly progressing, the phenomenon of multidrug resistance (MDR) continues to be a key issue leading to therapy failure in oncological patients. MDR is based on pharmacodynamic as well as pharmacokinetic mechanisms. Pharmacokinetic MDR includes drug efflux transporters and biotransformation enzymes that decrease the amount of (active form of) a drug in tumors. While the MDR role of transporters has been well understood, the participation of drug metabolizing enzymes is still unclear. This thesis investigates the role of cytochromes P450 (CYPs) in cytostatic resistance. Furthermore, it focuses on the modulation of pharmacokinetic MDR using pharmacokinetic drug-drug interactions of new targeted antitumor drugs. Finally, it aims to confirm the in vitro findings in ex vivo patient-derived tumor explants. In our latest publication, we demonstrate the significant role of...
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