|
|
The influence of polyphenolic compounds and their metabolites on platelet activation
Applová, Lenka ; Mladěnka, Přemysl (advisor) ; Bultas, Jan (referee) ; Šimůnek, Tomáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Applová Lenka, MSc. Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of Doctoral Thesis: The influence of polyphenolic compounds and their metabolites on platelet activation Blood aggregation is a very difficult and complex process, in which platelets play crucial role. On the other hand, their activation is excessive and therefore undesirable under pathophysiological conditions. Cardiovascular diseases are the most common cause of mortality in developed countries and unfortunately, despite significant advances in treatment, the Czech Republic remains in mortality from these diseases behind most Western European countries. Epidemiological studies suggest, that higher intake of (iso)flavonoids is associated with reduced cardiovascular mortality. It is also worth mentioning, that the Czech Republic is among European countries with the lowest content of flavonoids in diet. The aim of this doctoral thesis was to find out, if polyphenolic compounds, especially (iso)flavonoids and/or their metabolites, are able to influence platelet aggregation and thus indirectly to support epidemiological findings, i.e. whether there may be a link between these substances and possible positive...
|
|
|
Ultrasonographic evaluation of cardiovascular abnormalities in patients with Fabry disease
Paleček, Tomáš ; Bultas, Jan (advisor) ; Pudil, Radek (referee) ; Kittnar, Otomar (referee)
Fabry disease is an X-linked glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. This leads to progressive intracellular accumulation of neutral glycosphingolipids, mainly globotriaosylceramide. Besides various extracardiac disease-related abnormalities, cardiovascular involvement represents a typical manifestation of Fabry disease. The primary underlying mechanism relies on pathological substrate accumulation in cardiomyocytes, conduction system cells, valvular fibroblasts, endothelial cells and vascular smooth muscle cells. The development of cardiac and vascular hypertrophy represents a characteristic cardiovascular feature of Fabry disease. The aim of our studies was to describe in detail cardiovascular abnormalities in patients with Fabry disease using ultrasonography, which currently represents basic noninvasive imaging modality in cardiology. We focused on structural and functional abnormalities of ventricles, valvular apparatus and their relationship to vascular involvement expressed on common carotid arteries. We also compared the diagnostic accuracy of the two novel echocardiographic methods used for the left ventricular diastolic function assessment. The possible existence of circulating proliferative factor, which might be associated with...
|
|
|
Familiar hyperlipoproteinemias and other risk factors of cardiovascular diseases in men with erectile dysfunction
Prusíková, Martina ; Češka, Richard (advisor) ; Bultas, Jan (referee) ; Rosolová, Hana (referee)
Background: The relationship between erectile dysfunction and risk factors of atherosclerosis has been confirmed by a number of previous investigations. There are also plausible pathophysiological mechanisms explaining the observed association. One of the tested hypotheses in our work was the assumption that risk factors of atherosclerosis would be more prevalent in men with erectile dysfunction than in controls selected from the representative sample of the Czech population. Our work did not confirm this hypothesis. Most likely explanation can be greater representation of younger-middle aged men in our group than in the Czech post-Monica study in which the age distribution was equal. On the other hand authors of the Czech post-Monica study admit worse compliance in younger participants of their survey. Nevertheless, the risk factors of atherosclerosis occur very frequently in males with erectile dysfunction. Results: In our group mean cardiovascular risk calculated according to the SCORE chart was 3.39% (±3,39). In the Czech post-MONICA study conducted between 2007 and 2008 the mean SCORE risk reached 2.47%. There was a trend, though not statistically significant, towards direct relationship between the severity of ED and the SCORE CVD risk. Asymptomatic atherosclerosis was detected in 56.25% of our study...
|
|
|
Frequency of selected genetic polymorphisms of cytochrome P450 in the Czech population and the influence of CYP2C9 genotype on the hypolipidemic effect of fluvastatin
Buzková, Helena ; Perlík, František (advisor) ; Bultas, Jan (referee) ; Mičuda, Stanislav (referee)
55 Abstract Frequency of selected genetic polymorphisms of cytochrome P450 in the Czech population and the influence of CYP2C9 genotype on the hypolipidemic effect of fluvastatin Introduction: One of the main factors of genetically determined variability in response of humans to administered drugs are differences in catalytic activity of metabolizing enzymes, which are caused mainly by genetic polymorphisms in cytochrom P450 family enzymes. This thesis consists of two parts and it is presented as a commentary to the original papers. The first aim was to investigate the frequency of functionally important variant alleles of three main isoenzymes of cytochrome P450 gene: CYP2D6, CYP2C9, CYP2C19, throughout the Czech population, predict the prevalence of poor metabolizer phenotypes, and then to compare the results to the data from other populations. Secondly, we analysed the correlation between the CYP2C9 genotype and cholesterol-lowering effect of fluvastatin in human hypercholesterolemic patients. Methods: Genotypes were determined by PCR-RFLP. The presence of alleles CYP2D6*1, *6, *5, *4, *3, and gene duplication was analysed in 233 healthy volunteers, CYP2C9*1, *2 and*3 in 254 subjects and CYP2C19*1, *2 and *2 in 218 subjects. Eighty seven patients on fluvastatin therapy, and 48 patients on monotherapy...
|
|
|
Cardiac tolerance to oxygen deprivation: the effects of inhalational and intravenous anesthetics
Říha, Hynek ; Pirk, Jan (advisor) ; Bultas, Jan (referee) ; Geršl, Vladimír (referee)
Background: Surgical procedures are invariably accompanied by the use of inhalational and intravenous anesthetics. Both groups have strong influence on cardiovascular system by the interaction with myocardial oxygen supply/demand ratio and cardiomyocyte functions at the level of cell membranes, ion channels and regulatory enzymes. Aims: 1. To examine the effects of different isoflurane concentrations on the left ventricular (LV) dimensions and systolic function in the rat. 2. To examine the effects of isoflurane-induced myocardial preconditioning (APC) on the cardiac tolerance to ischemia- reperfusion (I-R) injury. 3. To compare the influence of anesthesia, based on ketamine- dexmedetomidine (KET-DEX), on the release of biochemical markers of myocardial injury and the early postoperative course with the anesthesia, based on sevoflurane-sufentanil (SEVO), in the patients undergoing coronary artery bypass grafting (CABG). Methods: 1. We carried out transthoracic echocardiographic examination in the rats immobilized by 1.5-3% concentration of isoflurane. 2. After inducing APC by isoflurane (0.5 and 1 MAC), we evaluated ventricular arrhythmias during regional ischemia (45 min), induced by the occlusion of the left anterior descending artery, and subsequent reperfusion (60 min), using the model of...
|
|
|
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...
|
|
|
The influence of polyphenolic compounds and their metabolites on platelet activation
Applová, Lenka ; Mladěnka, Přemysl (advisor) ; Bultas, Jan (referee) ; Šimůnek, Tomáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Applová Lenka, MSc. Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of Doctoral Thesis: The influence of polyphenolic compounds and their metabolites on platelet activation Blood aggregation is a very difficult and complex process, in which platelets play crucial role. On the other hand, their activation is excessive and therefore undesirable under pathophysiological conditions. Cardiovascular diseases are the most common cause of mortality in developed countries and unfortunately, despite significant advances in treatment, the Czech Republic remains in mortality from these diseases behind most Western European countries. Epidemiological studies suggest, that higher intake of (iso)flavonoids is associated with reduced cardiovascular mortality. It is also worth mentioning, that the Czech Republic is among European countries with the lowest content of flavonoids in diet. The aim of this doctoral thesis was to find out, if polyphenolic compounds, especially (iso)flavonoids and/or their metabolites, are able to influence platelet aggregation and thus indirectly to support epidemiological findings, i.e. whether there may be a link between these substances and possible positive...
|
|
|
The influence of polyphenolic compounds and their metabolites on platelet activation
Applová, Lenka ; Mladěnka, Přemysl (advisor) ; Bultas, Jan (referee) ; Šimůnek, Tomáš (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Applová Lenka, MSc. Supervisor: Assoc. Prof. Přemysl Mladěnka, PharmD., Ph.D. Title of Doctoral Thesis: The influence of polyphenolic compounds and their metabolites on platelet activation Blood aggregation is a very difficult and complex process, in which platelets play crucial role. On the other hand, their activation is excessive and therefore undesirable under pathophysiological conditions. Cardiovascular diseases are the most common cause of mortality in developed countries and unfortunately, despite significant advances in treatment, the Czech Republic remains in mortality from these diseases behind most Western European countries. Epidemiological studies suggest, that higher intake of (iso)flavonoids is associated with reduced cardiovascular mortality. It is also worth mentioning, that the Czech Republic is among European countries with the lowest content of flavonoids in diet. The aim of this doctoral thesis was to find out, if polyphenolic compounds, especially (iso)flavonoids and/or their metabolites, are able to influence platelet aggregation and thus indirectly to support epidemiological findings, i.e. whether there may be a link between these substances and possible positive...
|
|
|
Frequency of selected genetic polymorphisms of cytochrome P450 in the Czech population and the influence of CYP2C9 genotype on the hypolipidemic effect of fluvastatin
Buzková, Helena ; Perlík, František (advisor) ; Bultas, Jan (referee) ; Mičuda, Stanislav (referee)
55 Abstract Frequency of selected genetic polymorphisms of cytochrome P450 in the Czech population and the influence of CYP2C9 genotype on the hypolipidemic effect of fluvastatin Introduction: One of the main factors of genetically determined variability in response of humans to administered drugs are differences in catalytic activity of metabolizing enzymes, which are caused mainly by genetic polymorphisms in cytochrom P450 family enzymes. This thesis consists of two parts and it is presented as a commentary to the original papers. The first aim was to investigate the frequency of functionally important variant alleles of three main isoenzymes of cytochrome P450 gene: CYP2D6, CYP2C9, CYP2C19, throughout the Czech population, predict the prevalence of poor metabolizer phenotypes, and then to compare the results to the data from other populations. Secondly, we analysed the correlation between the CYP2C9 genotype and cholesterol-lowering effect of fluvastatin in human hypercholesterolemic patients. Methods: Genotypes were determined by PCR-RFLP. The presence of alleles CYP2D6*1, *6, *5, *4, *3, and gene duplication was analysed in 233 healthy volunteers, CYP2C9*1, *2 and*3 in 254 subjects and CYP2C19*1, *2 and *2 in 218 subjects. Eighty seven patients on fluvastatin therapy, and 48 patients on monotherapy...
|
|
|
Familiar hyperlipoproteinemias and other risk factors of cardiovascular diseases in men with erectile dysfunction
Prusíková, Martina ; Češka, Richard (advisor) ; Bultas, Jan (referee) ; Rosolová, Hana (referee)
Background: The relationship between erectile dysfunction and risk factors of atherosclerosis has been confirmed by a number of previous investigations. There are also plausible pathophysiological mechanisms explaining the observed association. One of the tested hypotheses in our work was the assumption that risk factors of atherosclerosis would be more prevalent in men with erectile dysfunction than in controls selected from the representative sample of the Czech population. Our work did not confirm this hypothesis. Most likely explanation can be greater representation of younger-middle aged men in our group than in the Czech post-Monica study in which the age distribution was equal. On the other hand authors of the Czech post-Monica study admit worse compliance in younger participants of their survey. Nevertheless, the risk factors of atherosclerosis occur very frequently in males with erectile dysfunction. Results: In our group mean cardiovascular risk calculated according to the SCORE chart was 3.39% (±3,39). In the Czech post-MONICA study conducted between 2007 and 2008 the mean SCORE risk reached 2.47%. There was a trend, though not statistically significant, towards direct relationship between the severity of ED and the SCORE CVD risk. Asymptomatic atherosclerosis was detected in 56.25% of our study...
|
guest ::
