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Applications of chiral and achiral chromatography in pharmacology and toxicology
Chytil, Lukáš ; Slanař, Ondřej (advisor) ; Bultas, Jan (referee) ; Coufal, Pavel (referee)
Development and validation of methods for analysis of several drugs or their metabolites are decribed in this thesis. The document is presented as a commentary to the original papers, which were published in peer reviewed journals. Discussion on the optimization of each method is presented and covers also method development and influence of preanalytical aspects. Additionally, examples of the application of the developed methods in clinical pharmacology and toxicology are shown. This dissertation consists of three parts: enantiomeric determination of tramadol and its metabolite, determination of some antihypertensive drugs, and qualitative analysis of benzodiazepines. Development of a method for chiral analysis of tramadol and its desmethylated metabolite O- desmethyltramadol (ODT) in human urine and plasma is described in the first part of the thesis. Tramadol is a centrally acting analgetic drug, which is used as racemate in clinical practise. Each enantiomer displays different binding properties for various receptors: (+)-tramadol preferentially inhibits serotonin reuptake while (-)-tramadol mainly inhibits noradrenalin reuptake. (+)-tramadol is considered 10-times more potent than (-)-tramadol. Major active metabolite (ODT), which is considered to be the main agent responsible for the...
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Correlation between benzodiazepines use and quality of life in regions of the Czech Republic
Brožková, Lenka ; Chomynová, Pavla (advisor) ; Šťastná, Lenka (referee)
The objective of this study is to explore and describe current use of benzodiazepines in the Czech Republic and to identify possible correlation with quality of life in particular regions. Benzodiazepines are widely prescribed for a variety of conditions: anxiety and insomnia in particular. Benzodiazepine addiction is often latent and therefore doesn't cause social segregation as psychoactive drugs and alcohol abuse. Environment in which people live significantly impacts our psychological state. The question is how significant the influence of quality of the environment on the general wellbeing is and how is it reflected on the use of benzodiazepines. These questions were answered by analysing results of the research carried on by National Monitoring Centre for Drugs and Addiction in 2016. The Centre conducted a survey with 3601 respondents in order to gain more understanding about use of benzodiazepines, excessive playing of video games and gambling in the Czech regions. Analysis of the responses reveals that medications used to treat insomnia and anxiety disorder (benzodiazepines included) are used mostly by people living in major cities. The lowest prevalence of benzodiazepine use is in small towns and villages. Benzodiazepines are still the most frequently prescribed group of medications used...
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Phytoextraction of Benzodiazepines from Water Solutions
Grasserová, Alena ; Smrček, Stanislav (advisor) ; Soudek, Petr (referee)
Abstract, key words The aim of this thesis was to perform a phytoextraction experiment with benzodiazepines chlordiazepoxide, diazepam, alprazolam and bromazepam on corn plant (Zea mays). After 14 days of growing of sterile cultivation, new medium (Murashige and Skoog) contaminated with benzodiazepine was added. The starting concentration of benzodiazepine was 10 mg · l-1. After every 24 hours, a sample of medium was collected. The actual concentration of benzodiazepine was measured on HPLC with UV detection. Extractable residues were also analysed to find out whether the benzodiazepine is being translocated to the upper parts of the plant. The same HPLC conditions were used for these samples. The greatest phytoextraction efficiency (the amount of drug extracted by 1 gram of biomass in 24 hours) was observed for chlordiazepoxide, followed by bromazepam, alprazolam and diazepam respectively. The extractable residues analysis confirmed the translocation to the upper parts of the plant for every of the benzodiazepines tested. That indicates a threat for the animals through the food chain contamination. Key words: phytoremediation, phytoextraction, benzodiazepines, extractable residuals, HPLC.
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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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Development of UHPLC-MS/MS screening method for the determination of benzodiazepines in urine samples
Havelková, Lucie ; Bosáková, Zuzana (advisor) ; Kozlík, Petr (referee)
The aim of this diploma thesis was the development of a screening method for analysis of 17 benzodiazepines in urine samples using ultra high-performance liquid chromatography with tandem mass spectrometric detection. The partial task was to optimize the conditions for the enzymatic hydrolysis of benzodiazepine glucuronides present in urine using design of experiments (DOE). The optimized chromatographic system consisted of a Zorbax Eclipse Plus Phenyl-Hexyl RRHD column (100 × 2.1 mm, 1.8 μm) and mobile phase consisting of water with 0.1 % acetic acid (component A) and acetonitrile with 0.1 % acetic acid (component B) in various ratios according to the gradient program. Flow rate was 0.2 ml/min, column temperature was 40 řC, and total analysis time was 12 min. Calibration curves for all analytes were measured under optimized conditions in methanol and urine. After optimal detection conditions for oxazepam-glucuronide were found, oxazepam glucuronide was hydrolysed using β-glucuronidase from the abalone to confirm the functionality of the enzyme within the pilot experiment. Optimization of enzymatic hydrolysis conditions via 27 experiments proposed by program Minitab 16 using the Box-Behnken design will be realized later.
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Evaluation of rationality and risks of pharmacotherapy in 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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Phytoextraction of benzodiazepines
Rychlovská, Kristýna ; Smrček, Stanislav (advisor) ; Soudek, Petr (referee)
The aim of this study was to carry out experiments with maize (Zea mays) for the purpose of finding out the efficiency of phytoextraction of chosen pharmaceuticals from the nutrient solution. The plants were cultivated for three weeks in a sterile environment. Then was added a nutrient solution enriched with chosen benzodiazepines - diazepam, flunitrazepam, nitrazepam and bromazepam - in concentration 5-10 mg/L. The samples from each plant were taken every day (24 hours) and then were analyzed with HPLC/UV. The efficiency of phytoextraction was evaluated in two ways. The first one as an percentage of a decrease of the concentration of the pharmaceuticals in the solution with time, the second one as an amount of phytoextracted pharmaceutical in milligrames per gram of the plant matter. From the standpoint of the decrease of the concentration was as the most efficient measured the phytoextraction of nitrazepam (74,7 %), less efficient diazepam and bromazepam (55,2 %, respectively 53,9 %) and the least efficient flunitrazepam (38,0 %). When converted to the mass of the plant matter the most efficient was found the phytoextraction of bromazepam (0,08 mg of drug to 1 gram of plant matter), lower efficiency by bromazepam and diazepam (both 0,02 mg) and the lowest again by flunitrazepam (0,01 mg). key...
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Phytoextraction of Bromazepam
Konečná, Markéta ; Smrček, Stanislav (advisor) ; Petrová, Šárka (referee)
The aim of this bachelor thesis was to determine the possibility of phytoextraction of benzodiazepine bromazepam as a widely used drug with anxiolytic effects. Benzodiazepines are compounds with high biological activity and together with their metabolites are excreted into urine. These substances then get into municipal wastewater treatment plant, whereas efficiency of removal in wastewater treatment plants is not high and compounds enter into surface water. Afterwards, the entire ecosystem including food chains is contaminated. A long-term exposure to trace concentrations can have a great effect on aquatic and terrestrial organisms. Maize (Zea mays) was used to study the phytoextraction. The Murashige and Skoog medium was enriched by 10 mg · L-1 bromazepam and samples of medium were taken at 24 hour intervals. After that, samples were analysed in reverse phase at 233 nm by HPLC/UV. Time dependence of bromazepam concentrations in medium was evaluated, which showed decrease of ca. 40 % during 168 hours of cultivation. Ability of corn cultivar to extract bromazepam from aqueous solutions was clearly demonstrated. The amount of extracted bromazepam corresponds to 0.03 milligrams per 1 gram of plant fresh weight. Although the tested concentrations of the xenobiotic used are substantially higher than the actual...
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Drugs and possibility of their elimination in sewage waters
Křivánková, Zuzana ; Repková, Martina (referee) ; Vávrová, Milada (advisor)
This bachelor thesis deals with issue of increasing consumption of pharmaceuticals and its influence on the environment. In the Czech Republic the pharmaceuticals from the benzodiazepine group are still widely prescribed and used by patients. There was tracked four representatives of this group alprazolam, bromazepam, diazepam and oxazepam which are indicated for therapy of insomnia, psychiatric diseases but also like a general anesthetics or antiepileptics. Presence of this pharmaceuticals is being repeatedly confirmed in wastewaters and surface waters troughout the whole Europe and other developed countries even though their negative effects for the water ecosystem are known. The target od this thesis is to optimalizethe methods for determination of choosen pharmaceuticals in watewaters in Brno and surrounded area. There was also evaluatedthe hazard level for water ecosystem related to the presence of pharmaceuticals in target matrices which were the wastewaters from wastewater treatment plants in towns Brno – Modřice and from two another towns in south Moravia. Concentrations of the pharmaceuticals were tracked in the influents and effluents. The analytes were isolated from the matrices by solid-phase extraction (SPE) and quantificated by ultra-high performance liquid chromatography (UHPLC) with detection by the diode array (DAD).
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Applications of chiral and achiral chromatography in pharmacology and toxicology
Chytil, Lukáš ; Slanař, Ondřej (advisor) ; Bultas, Jan (referee) ; Coufal, Pavel (referee)
Development and validation of methods for analysis of several drugs or their metabolites are decribed in this thesis. The document is presented as a commentary to the original papers, which were published in peer reviewed journals. Discussion on the optimization of each method is presented and covers also method development and influence of preanalytical aspects. Additionally, examples of the application of the developed methods in clinical pharmacology and toxicology are shown. This dissertation consists of three parts: enantiomeric determination of tramadol and its metabolite, determination of some antihypertensive drugs, and qualitative analysis of benzodiazepines. Development of a method for chiral analysis of tramadol and its desmethylated metabolite O- desmethyltramadol (ODT) in human urine and plasma is described in the first part of the thesis. Tramadol is a centrally acting analgetic drug, which is used as racemate in clinical practise. Each enantiomer displays different binding properties for various receptors: (+)-tramadol preferentially inhibits serotonin reuptake while (-)-tramadol mainly inhibits noradrenalin reuptake. (+)-tramadol is considered 10-times more potent than (-)-tramadol. Major active metabolite (ODT), which is considered to be the main agent responsible for the...
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