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The relationship between structure and activity of potential reactivators of acetylcholinesterase I.
Holas, Ondřej ; Opletalová, Veronika (advisor) ; Pohanka, Miroslav (referee)
The realtionship between structure and activity of potencial reactivators of acetylcholinesterase Organophosphorus compounds (OPC) are used as agricultural pesticides and in industry as fire retardants or plastificators. For military use there have been developed nerv agents (NA, e.g. tabun, sarin, somna, VX). The toxicity of these compounds is based upon phosphorylation or phosphonylation at the serine hydroxy group (Ser200) of the active site of the acetylcholinesterase. The current standard treatment consists of administration oxime reactivators in combination with anticholinergic drug (preferably atropin). Unfortunately, none from the currently used oximes is sufficiently effective against all types of the OPCs. The aim of this study is determination of the relationship between structure and activity of new reactivators against paraoxon inhibited AChE in vitro and comparison with currently available substances. For evaluation of reactivation activity has been chosen standard in vitro test using rat brain homogenate
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Nanofiltration
Heidrová, Hana ; Kučera, Radim (advisor) ; Holas, Ondřej (referee)
Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Nanofiltration Diploma thesis Candidate: Hana Heidrová Supervisor: doc. PharmDr. Radim Kučera, Ph.D. Consultant: PharmDr. Tomáš Holas, Ph.D. Nanofiltration is a pressure-driven membrane process which is characterized by using semipermeable membranes with approximately 1 nm pores. This method is used abundantly for the separation of substances with low molecular weight. It is used for example in the process of product isolation in pharmaceutical industry. This diploma thesis is focused on the description of the behaviour of three commercially produced nanofiltration membranes and also on testing of their potential use in the production of ergot alkaloids. The theoretical part is focused especially on the description of pressure-driven membrane processes, the use of nanofiltration in various areas and also on current and historical use of ergot alkaloids in therapy and on the description of their properties. The practical part is oriented particularly on examination of effect of various experimental parameters on the retention of selected ergot alkaloids (primarily of lysergic and isolysergic acid). The results are compared and critically analysed. Keywords: pressure-driven...
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Lipid based nanoparticles: drug delivery platform
Voldřichová, Lenka ; Holas, Ondřej (advisor) ; Svačinová, Petra (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of: Pharmaceutical Technology Supervisor: PharmDr. Ondřej Holas, Ph.D. Consultant: Mgr. Jana Kubačková Student: Lenka Voldřichová Title of thesis: Lipid based nanoparticles: drug delivery platform Lipic nanoparticles, as newly developed dosage forms, can overcome many drawbacks of conventional dosage forms. Their potential can be utilized in particular for prolonged, controlled and targeted release. They can also increase the bioavailability of drugs, especially those with poor solubility and also allow targeting, which causes increased accumulation of lipid nanoparticles in certain tissues compared to other tissues. nanoparticles suitable for drug encapsulation. The particles were prepared by the emulsion evaporation method. Their characterization was performed using a Zetasizer, which measured the particle size and the zeta potential. The properties of the formulations were evaluated in terms of nanoparticle size, polydispersity, zeta potential, and formulation properties. Differencial scanning calorimetry analysis was also performed on selected formulations. The selected final formulation was composed of 25 mg glycerol monostearate, 10 mg isopropyl myristate, 15 mg lecithin and Kolliphor P188 0,1% solution....
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Rheological behavior of branched polyesters
Martiška, Juraj ; Šnejdrová, Eva (advisor) ; Holas, Ondřej (referee)
CHARLES UNIVERSITY IN PRAGUE Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical technology Name: Juraj Martiska Title of diploma thesis: Rheological behavior of branched polyesters Supervisor: PharmDr. Eva Snejdrova, Ph.D. This thesis studies rheological and thermal properties of potencial polyester drug carrier composed of an equimolar proportion of D,L-lactic and glycolic acids, branched with tripentaerythritol at a concentration of 3%, and its analogs plasticized with methyl salicylate at different concentrations. The theoretical part deals with the characterization of polymers, their plasticizing and rotational rheometry. In the experimental part were prepared plasticized polyesters then were determined their glass transition temperatures using a DSC, and on rotational rheometer was tested their rheological behavior. According to the results of thermal analysis, methyl salicylate significantly lowers the glass transition temperature of the tested polyester and seems to be suitable plasticizer. The resulting data of rheological analyzes show that 3T plasticized polymer exhibits pseudoplastic behavior at 25řC and concentration of methyl salicylate 20% when the viscosity is highest. Viscosity of polymer systems significantly decreases with increasing temperature and concentration...
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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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Modulation of acetylcholinesterase activity using different organic compounds
Vavrošová, Petra ; Opletalová, Veronika (advisor) ; Holas, Ondřej (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Petra Vavrošová Supervisor: Assoc. Prof. RNDr. Veronika Opletalová, Ph.D. Title of thesis: Modulation of acetylcholinesterase activity using different organic compounds Acetylcholinesterase is a vital enzyme because of its ability to end a nerve impulse by decomposition of neurotransmitter acetylcholin. Inhibitors of cholinesterases have been used in many sectors, such as drugs, pesticides, or substances abused as biological weapons. Using chosen agents an existence of acetylcholinesterase inhibition was detected together with its rate and character. The detection was accomplished by the method of measuring the decrease of acetylcholinesterase activity. In this experiment some organic solvents, metal salts, and other agents like gelatine, tacrine or caffeine were used. Ellman's spectrophotometrical detection was used to determine the decrease of acetylcholinesterase activity. The data were evaluated by the graphical representation by Dixon and Boltzmann. In this experiment the acetylcholinesterase from electric eel was used. Results showed that many chosen agents have the ability to inhibit acetylcholinesterase and on the other hand many of them do not have this...
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Polymeric stabilizers maintaining the supersaturation solubility of itraconazole nanocrystals after dissolution process
Kubačková, Jana ; Holas, Ondřej (advisor) ; Paraskevopoulos, Georgios (referee)
Title of thesis: Polymeric stabilizers maintaining the saturation solubility of itraconazole nanocrystals after dissolution process Author: Jana Kubačková Department: Pharmaceutical Technology Supervisor: PharmDr. Ondřej Holas, Ph.D. Specialized supervisor: Assoc. Prof. Leena Peltonen, Ph.D. The increase of bioavailability of poorly water soluble drugs is still an issue. One of the techniques improving aqueous drug substance solubility, and consequently enhancing bioavailability, is formation of nanoparticles. However, the bioavailability is determined by the concentration of the dissolved drug achieved at the time of absorption. This fact emphasizes the importance of the maintenance of the high solubility until the absorption area is reached. Sufficiently stabilised nanocrystalline drugs offer a solution to this problem. In this thesis, the solid nanoparticle formations of an antifungal agent itraconazole (ITZ) are presented. Wet milling was employed to create the nanosuspension stabilised by binary mixture of stabilisers or by a single stabiliser. An aggregation inhibitor Poloxamer 407 (F127) in the combination with a polymeric precipitation inhibitor hydroxypropyl methylcellulose (HPMC) or polyvinyl pyrrolidone (PVP) at different ratios, or a single precipitation inhibitor, were utilised. The...
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Synthesis of pyrazino[2,3-b]pyrazines - azaphthalocyanine precursors
Šebl, René ; Zimčík, Petr (advisor) ; Holas, Ondřej (referee)
CHARLES UNIVERSITY IN PRAGUE FACULTY OF PHARMACY IN HRADEC KRÁLOVÉ DEPARTMENT OF PHARMACEUTICAL CHEMISTRY AND DRUG CONTROL Name: René Šebl Supervisor: Doc. PharmDr. Petr Zimčík,Ph.D Title of the thesis: Synthesis of pyrazino[2,3-b]pyrazines - azaphthalocyanine precursors The topic of my thesis was synthesis of azaphtalocyanines containing pyrazinopyrazine units. These molecules have been published only in few publication till now. Since these molecules are extended by one pyrazine nucleuson each unit, their extended conjugation leads to an increased absorption in the higher regions of the absorption spectrum. In the first step, I focused on the synthesis of precursors for subsequent cyclotetramerization. Starting compound for the preparation of various precursors was 6,7- dichloropyrazino [2,3-b] pyrazine-2,3-dicarbonitrile. It underwent nucleophilic substitution leading to products substituted with various substiuents attached via heteroatoms such as oxygen or nitrogen. Another option is the condensation of 5,6-diaminopyrazine-2,3- dicarbonitrile with appropriate diketon. This attempt did not lead to the successful preparation of the precursor. The precursors were subsequently cyclotetramerized to corresponding macrocycles. We succeeded only with one precursor...
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Preparation of biodegradable nanoparticles for hydrophilic macromolecular drugs delivery
Szanyiová, Alexandra ; Holas, Ondřej (advisor) ; Dittrich, Milan (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Consultant: PharmDr. Ondřej Holas, PhD. Student: Alexandra Szanyiová Title of thesis: Preparation of biodegradable nanoparticles for hydrophilic macromolecular drugs delivery This study investigates the formulation of nanoparticles containing hydrophilic macromolecular components (e.g. proteins). Selected material was PLGA based compounds synthesized at Department of Pharmaceutical Technology. As model compounds were used Rhodamine B, FITC labelled dextran and FITC labelled albumin. Selected methods of nanoparticles formulation were double-emulsion technique and nanoprecipitation. Prepared nanoparticles were purified by three cycles of centrifugation and encapsulation efficacy and recovery yield was measured. Effect of different polymers and stabilizers was followed. More specifically, the principal objective was to explore the differences between size, zeta potential and efficacy of encapsulation. Changes in these characteristics were brought about by the chosen polymers, stabilizers, encapsulated compound, length of centrifugation period. Prepared nanoparticles had size ranging between 150-474 nm and zeta potential approximately 30 mV. Even though the main goal of the study was to...
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Pyrazine derivatives as potential drugs V.
Horová, Anna ; Marek, Jan (advisor) ; Holas, Ondřej (referee)
Charles University in Prague, Pharmaceutical Faculty in Hradec Králové Department: Department of Pharmaceutical Chemistry and Drug Control Diplomate: Anna Horová Supervisor: PharmDr. Jan Marek, Ph.D. Title of Diploma Thesis: Pyrazine derivatives as potential drugs V. TBC is a specific world-wide infectious disease, compounded by increased migrations of people, the spread of HIV and the growth of MDR-TB, including extremely resistant strains. Precisely for the growth of MDR-TB resistant mycobacteria the work is focused on the preparation and development of other possible antituberculosis drugs (Pyrazine derivatives). Research into new medications lays emphasis on altering the effects of enzymes important for the vitality of mycobacteria. As part of my diploma thesis, pyrazine derivative modifications of clinical pyrazinamide medications were prepared. PZA is an important part of the short-term TBC treatment, having a sterile effect and the ability to work in an acidic environment and has a significant synergy with rifampicin. The small PZA molecule is a precursor to the pyrazine acid activated by pyrazinamide or nicotinamide. Hydrolysis of PZA in mycobacterial cells create Pyrazinecarboxylic acid (POA). In the experimental part, we have examined the variation molecules pyrazinamide and preparing the...
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