HPLC analýza potenciálních léčiv odvozených od aroylhydrazonu II

1. ABSTRAKT Vysokoúčinná kvapalinová chromatografia (HPLC) je v oblasti liečiv jednou z najčastejšie používanou analytickou technikou. Železo je dôležitým biogénnym prvkom, no napriek tomu jeho zvýšené množstvo v organizme pôsobí toxicky. Výskum vysoko selektívnych a účinných biokompatibilných chelátorov železa bol pôvodne inšpirovaný potrebou mobilizovať železo v tkanivách s chronickým preťažením železa. Avšak v posledných rokoch je pozornosť venovaná využitia chelátorov železa tiež pri liečbe bežných onemocnení. Salicylaldehyd isonicotinoyl hydrazon (SIH), biokompatibilný chelátor železa odvodený od aroylhydrazonu, je v dnešnej dobe predmetom aktívneho výskumu ako potenciálne liečivo. Okrem schopnosti viazať železo, vykazuje aj ďalšie zaujímavé farmakologické účinky: antioxidačný, antiproliferatívny, kardioprotektívny, antimalarický a antimikróbny. Táto práca sa zaoberá vypracovaním optimálnych chromatografických podmienok HPLC separácie SIH a jeho potenciálnych metabolitov (isoniazid, acetylisoniazid, salicylaldehyd) a následne využitia tejto separácie k štúdiu možnosti izolácie uvedených látok z moči králika pomocou SPE ako úpravy vzorku. Najlepšia chromatografická analýza bola dosiahnutá použitím kolóny od firmy Phenomenex (2504,6 mm I. D.) s náplňou Prodigy 5u ODS3 100A (5 μm). Mobilná fáza bola v...1. ABSTRACT High performance liquid chromatography (HPLC) is one of the most frequently used analytical techniques for the analysis of drugs. Although iron is a vital element, excessive amounts in the body are highly toxic. The search for highly selective and effective iron chelating agents has been mainly inspired by the need to mobilize iron from tissues that are chronically overloaded with iron. However, recent investigations focused on the possibility to use iron chelators for the treatment of many other pathologies. Salicylaldehyde isonicotinoyl hydrazone (SIH), a biocompatible iron chelator derived from aroylhydrazone, is under extensive investigation as a promising drug candidate. Besides ability to bind iron, it shows interesting pharmacological effects: antioxidative, antiproliferative, cardioprotective, antimalarical and antimicrobic. The aim of this study was to develop optimal HPLC conditions for the separation of SIH and its potential metabolites (isoniazide, acetylisoniazide, salicylaldehyde) and to apply the method to the study focused on the isolation of analytes from rabbit urine using SPE. The best chromatographic analysis was achieved on a HPLC column (Phenomenex 250 4.6 mm I. D.) packed with Prodigy 5u ODS3 100A (5 μm) as a stationary phase. The mobile phase was composed of methanol :...Katedra farmaceutické chemie a kontroly léčivDepartment of Pharmaceutical Chemistry and Drug ControlFaculty of Pharmacy in Hradec KrálovéFarmaceutická fakulta v Hradci Králov

HPLC analysis of drug candidates from the group of aroylhydrazones II.

1. ABSTRACT High performance liquid chromatography (HPLC) is one of the most frequently used analytical techniques for the analysis of drugs. Although iron is a vital element, excessive amounts in the body are highly toxic. The search for highly selective and effective iron chelating agents has been mainly inspired by the need to mobilize iron from tissues that are chronically overloaded with iron. However, recent investigations focused on the possibility to use iron chelators for the treatment of many other pathologies. Salicylaldehyde isonicotinoyl hydrazone (SIH), a biocompatible iron chelator derived from aroylhydrazone, is under extensive investigation as a promising drug candidate. Besides ability to bind iron, it shows interesting pharmacological effects: antioxidative, antiproliferative, cardioprotective, antimalarical and antimicrobic. The aim of this study was to develop optimal HPLC conditions for the separation of SIH and its potential metabolites (isoniazide, acetylisoniazide, salicylaldehyde) and to apply the method to the study focused on the isolation of analytes from rabbit urine using SPE. The best chromatographic analysis was achieved on a HPLC column (Phenomenex 250 4.6 mm I. D.) packed with Prodigy 5u ODS3 100A (5 μm) as a stationary phase. The mobile phase was composed of methanol :..

Application of genetic algorithm for production scheduling of engineering company

This thesis is engaged in scheduling problem, his special types and methods of solving. Scheduling problem is a common operations research problem, which ranks among combinatorial problems. The aim of the scheduling problem is to assign certain activities and resources to individual time moments. Scheduling problem is NP-complete problem. Its computational complexity is thus so high, that there is currently no known algorithm that precisely solve its any instance in polynomial time. Is therefore used for its solution heuristics and metaheuristcs. In this thesis is described in detail metaheuristics of genetic algorithm. Application of genetic algorithm for production scheduling of specific engineering company is the main objective of this thesis

Application of genetic algorithm for production scheduling of engineering company

Tato práce se zabývá rozvrhovací úlohou, jejími speciálními typy a metodami jejího řešení. Rozvrhovací úloha je jedním ze základních problémů operačního výzkumu, řadí se mezi kombinatorické úlohy. Cílem rozvrhovací úlohy je přiřadit určité činnosti a zdroje jednotlivým časovým okamžikům. Rozvrhovací úloha patří do třídy NP-úplných úloh. Má tedy tak vysokou výpočetní náročnost, že v současné době není znám algoritmus, který by exaktně vyřešil její libovolnou instanci v polynomiálním čase. Proto se k jejímu řešení, hlavně rozsáhlejších úloh, využívá heuristických a metaheuristických metod. V této práci je podrobně popsána zejména metaheuristická metoda genetického algoritmu, jejíž aplikace na rozvrhování výroby konkrétní strojírenské firmy, je předmětem této práce.This thesis is engaged in scheduling problem, his special types and methods of solving. Scheduling problem is a common operations research problem, which ranks among combinatorial problems. The aim of the scheduling problem is to assign certain activities and resources to individual time moments. Scheduling problem is NP-complete problem. Its computational complexity is thus so high, that there is currently no known algorithm that precisely solve its any instance in polynomial time. Is therefore used for its solution heuristics and metaheuristcs. In this thesis is described in detail metaheuristics of genetic algorithm. Application of genetic algorithm for production scheduling of specific engineering company is the main objective of this thesis

Analytické hodnocení léčiv a potenciálních léčiv ze skupiny látek chelatujících železo

Univerzita Karlova v Praze, Farmaceutická fakulta v Hradci Králové Katedra Katedra farmaceutické chemie a kontroly léčiv Kandidát Mgr. Ján Stariat Školiteľ Prof. RNDr. Jiří Klimeš, CSc. Názov dizertačnej práce Analytické hodnotenie liečiv a potenciálnych liečiv zo skupiny látok chelatujúcich železo Vysokoúčinná kvapalinová chromatografia (HPLC) má v analýze liečiv dominantné postavenie, pretože patrí medzi robustné techniky, umožňujúce dosiahnutie účinnej separácie väčšiny analytov prítomných vo vzorku, a zároveň ich kvalitatívne aj kvantitatívne hodnotenie. Pokroky vo vývoji stacionárnych fáz a detekčných techník umožňujú výrazne skrátiť čas analýzy, a zároveň získať celé spektrum informácií o povahe analytov prítomných vo vzorkách aj vo veľmi nízkych koncentráciách. Nádorové ochorenia sa stále radia medzi významné príčiny smrti, z čoho vyplýva požiadavka na vývoj nových liečebných postupov. Stratégia založená na chelatácii železa vnútri nádorových buniek by mohla výraznou mierou prispieť k zlepšeniu prognózy u pacientov s tumormi rezistentnými voči štandardnej chemoterapii. Tento mechanizmus antiproliferativného pôsobenia je aktívne rozvíjaný u novej skupiny potenciálnych liečiv štruktúrne odvodených od thiosemikarbazonu, u ktorých bol cytostatický účinok pozorovaný in vitro aj in vivo Ďalší...Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Ján Stariat Supervisor Prof. RNDr. Jiří Klimeš, CSc. Title of Doctoral Thesis Analytical evaluation of drugs and drug candidates from the group of iron chelating agents High performance liquid chromatography (HPLC) ranks among the most important analytical techniques in the field of pharmaceutical analysis thanks to its robustness and the ability to separate and qualitatively and quantitatively analyse the compounds presented in various samples. The ongoing progress in the development of novel stationary phases and detection techniques allows rapid analysis and to get comprehensive characterization of the analytes presented in the complex samples even at very low concentrations. Cancer still remains a leading cause of death, thus the need for novel, efficient treatment strategies is of crucial importance. The mechanism based on iron chelation (Fe) inside the tumour cells represents one of the most promising strategy which could enhance the prognosis of patients suffering from cancer resistant to standard chemotherapy. Thiosemicarbazone iron chelators are currently under intensive development as novel anticancer drugs. Their strong antiproliferative...Department of Pharmaceutical Chemistry and Pharmaceutical AnalysisKatedra farmaceutické chemie a farmaceutické analýzyFaculty of Pharmacy in Hradec KrálovéFarmaceutická fakulta v Hradci Králov

HPLC analysis of drug candidates from the group of aroylhydrazones II.

1. ABSTRACT High performance liquid chromatography (HPLC) is one of the most frequently used analytical techniques for the analysis of drugs. Although iron is a vital element, excessive amounts in the body are highly toxic. The search for highly selective and effective iron chelating agents has been mainly inspired by the need to mobilize iron from tissues that are chronically overloaded with iron. However, recent investigations focused on the possibility to use iron chelators for the treatment of many other pathologies. Salicylaldehyde isonicotinoyl hydrazone (SIH), a biocompatible iron chelator derived from aroylhydrazone, is under extensive investigation as a promising drug candidate. Besides ability to bind iron, it shows interesting pharmacological effects: antioxidative, antiproliferative, cardioprotective, antimalarical and antimicrobic. The aim of this study was to develop optimal HPLC conditions for the separation of SIH and its potential metabolites (isoniazide, acetylisoniazide, salicylaldehyde) and to apply the method to the study focused on the isolation of analytes from rabbit urine using SPE. The best chromatographic analysis was achieved on a HPLC column (Phenomenex 250 4.6 mm I. D.) packed with Prodigy 5u ODS3 100A (5 μm) as a stationary phase. The mobile phase was composed of methanol :..

Analytical Evaluation of Drugs and Drug Candidates from the Group of Iron Chelating Agents

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Department of Pharmaceutical Chemistry and Drug Control Candidate Mgr. Ján Stariat Supervisor Prof. RNDr. Jiří Klimeš, CSc. Title of Doctoral Thesis Analytical evaluation of drugs and drug candidates from the group of iron chelating agents High performance liquid chromatography (HPLC) ranks among the most important analytical techniques in the field of pharmaceutical analysis thanks to its robustness and the ability to separate and qualitatively and quantitatively analyse the compounds presented in various samples. The ongoing progress in the development of novel stationary phases and detection techniques allows rapid analysis and to get comprehensive characterization of the analytes presented in the complex samples even at very low concentrations. Cancer still remains a leading cause of death, thus the need for novel, efficient treatment strategies is of crucial importance. The mechanism based on iron chelation (Fe) inside the tumour cells represents one of the most promising strategy which could enhance the prognosis of patients suffering from cancer resistant to standard chemotherapy. Thiosemicarbazone iron chelators are currently under intensive development as novel anticancer drugs. Their strong antiproliferative..

Optimizing production in an engineering company

Tato práce se zabývá rozvrhovací úlohou, jejími speciálními typy a metodami jejího řešení. Rozvrhovací úloha je jedním ze základních problémů operačního výzkumu, řadí se mezi kombinatorické úlohy. Cílem rozvrhovací úlohy je přiřadit určité činnosti a zdroje jednotlivým časovým okamžikům. Rozvrhovací úloha patří do třídy NP-úplných úloh. Má tedy tak vysokou výpočetní náročnost, že v současné době není znám algoritmus, který by exaktně vyřešil její libovolnou instanci v polynomiálním čase. Proto se k jejímu řešení, hlavně rozsáhlejších úloh, využívá heuristických a metaheuristických metod. I přesto se pokusím, navrhnou exaktní model a aplikovat ho na optimalizaci výroby konkrétní strojírenské firmy.This thesis is engaged in scheduling problem, his special types and methods of solving. Scheduling problem is a common operations research problem, which ranks among combinatorial problems. The aim of the scheduling problem is to assign certain activities and resources to individual time moments. Scheduling problem is NP-complete problem. Its computational complexity is thus so high, that there is currently no known algorithm that precisely solve its any instance in polynomial time. Is therefore used for its solution heuristics and metaheuristics. Even though I try, suggest the exact model and apply it to optimize the production of concrete engineering company

HPLC methods for determination of two novel thiosemicarbazone anti-cancer drugs (N4mT and Dp44mT) in plasma and their application to in vitro plasma stability of these agents

The aim of this study was to develop and validate HPLC methods for the determination in plasma of two novel thiosemicarbazone anti-tumour drugs developed in our laboratories (Dp44mT and N4mT). The appropriate separations were achieved using a HS F5 HPLC column with the mobile phase composed of a mixture of either acetate buffer/EDTA or EDTA and acetonitrile (62:38 and 50:50, v/v, respectively). The plasma samples were pretreated with SPE (phenyl and C18, respectively). Furthermore, these methods were successfully applied to in vitro plasma stability experiments. The investigation has clearly shown that both thiosemicarbazones are markedly more stable in plasma than their aroylhydrazone forerunners.7 page(s