|
| |
|
|
Biotransformation, disposition and toxicological detection of psychedelic phenylalkylamine drugs of abused
Rohanová, Miroslava ; Balíková, Marie (advisor) ; Martásek, Pavel (referee) ; Květina, Jaroslav (referee)
Background: New synthetic drugs known for their psychotropic effects (stimulating, psychedelic and enthactogenic) are drugs of abuse causing number of health and social issues. Together with their consumption the cases of intoxication have increased and therefore the requirements for the differential diagnosis and appropriate therapy have arisen. The aim of the submitted work has been to investigate the disposition and biotransformation profiles of selected synthetic phenylalkylamine derivatives using experimental rats and thus to obtain useful data that might be the base for laboratory diagnostics and appropriate therapy of drug abuse and/or intoxications. These studies have been focused on 2C-B (4-bromo-2,5-dimethoxyphenylethylamine) and PMMA (4-methoxymethamphetamine). (...) Drug concentration levels in blood serum or plasma have been low in relation to much higher tissue concentrations which exceeded multiple times blood concentrations. Proven accumulation abilities of both drugs in lungs and delayed but efficient incorporation with persistence in brain tissue are important pharmacokinetic properties that may explain the delayed onsets and prolonged psychotropic potential. PMMA forms the active psychotropic metabolite PMA that has been, in significant concentrations, present in the brain and together...
|
|
|
Molecular Pathology of Rett Syndrome
Záhoráková, Daniela ; Martásek, Pavel (advisor) ; Kubala Havrdová, Eva (referee) ; Mazura, Ivan (referee)
Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder affecting almost exclusively girls. It belongs to autistic spectrum disorders and it is characterized especially by psychomotor regression, loss of acquired speech, microcephaly, repetitive stereotypic hand movements, and seizures. Most of RTT cases are caused by de novo mutations in the gene for the methyl-CpG-binding protein 2 (MECP2) and familial cases are extremely rare. The MECP2 gene product plays an important role in chromatin remodeling, regulation of gene expression and is also involved in RNA splicing. Some atypical RTT cases are caused by mutations in other genes, such as CDKL5, FOXG1 or NTNG1. In this paper we give an overview of RTT, its clinical aspects, molecular basis, diagnostic criteria, medical management and DNA diagnosis.
|
|
|
The role of transmembrane domains in the structure and function of P2X receptors
Jindřichová, Marie ; Zemková, Hana (advisor) ; Langmeier, Miloš (referee) ; Martásek, Pavel (referee)
Purinergic P2X receptors represent a novel structural type of ligand-gated ion channels activated by extracellular ATP. So far, seven P2X receptor subunits have been found in excitable as well as non-excitable tissues. In the past ten years, the number of studies on P2X receptors has dramatically increased as investigators have begun to determine the physiological roles played by extracellular ATP and specific P2X receptor subtypes. It is already known that purinergic signaling is a key mechanism in pain sensation, brain injury, and immune processes. Little is known about their structure, mechanism of channel opening, localization and termination of ATP action by ectonucleotidases. Detailed knowledge about these events and the structure of purinergic receptor proteins evoke hope that new drugs will be developed that could prevent chronic pain and would be effective in protection against many diseases. The aim of this work is to summarize recent investigations and describe our contribution to elucidating the structure of P2X receptors. We examined the structure of transmembrane domains of the P2X4 receptor subtype, the main purinergic receptor-channel in the central nervous system, the mechanism of channel opening and closing and its sensitivity to agonists and allosteric modulator ivermectin. To...
|
|
|
Genetic and Ethiopatogenetic Aspects of the Restless Legs Syndrome
Kemlink, David ; Nevšímalová, Soňa (advisor) ; Martásek, Pavel (referee) ; Seeman, Pavel (referee)
The restless legs syndrome (RLS) is a sensomotor disoder characterized by urge to move lower extremities and this urge is usualy associated with unpleasnat sensations. The symtoms of RLS are alleviated with movement and, on the contrary, worsen during rest. The urge presents circadian rhytmicity peaking in the evening and the first half of night. The diagnosis of RLS is set according to patients' history fulfilling the essential criteria. The prevalence of RLS is quite high in western countries about 11%, women being affected twice as often as men. The disease has two forms, secondary and idiopathic. In the idiopathic RLS, positive family history is observed at about 50% of cases. There are already 3 genetic susceptibility loci on chromosomes 12, 14 and 9 published to be linked with RLS (RLS1, RLS2 a RLS3). Furhter 2 new loci were identified on chromosomes 17 and 4 insofar unpublished study. The current opinion suggests a complex model of inheritance in RLS. The aim of this project was to compare clinical and laboratory parameters in sporadic to familiar RLS and in families affected by RLS to confirm linkage previously detected loci, and eventually discover new susceptibility loci. The RLS patients were appart clinical evaluation examined with a set of hematological and biochemical tests, incuding...
|
|
|
Metabotropic glutamate receptors: mechanism of activation
Hlaváčková, Veronika ; Blahoš, Jaroslav (advisor) ; Vyklický, Ladislav (referee) ; Martásek, Pavel (referee) ; Konvalinka, Jan (referee)
Any living organism receives constantly many signals that have to be evaluated and weighted to respond in an appropriate way. To perform all functions needed for precise control of homeostasis and for communication with the surrounding environment, signals coming from the outside are recognized and transferred into modulation of intracellular signaling cascades. These mediate response to the extracellular stimulus as well as intercellular communication. Cell communication is mediated by several types of receptors, located either intracellularly (including nuclear receptors) that modulate gene transcription and receptors localized on plasma membrane. Cell membrane receptors are transmembrane proteins that are divided into three superfamilies according to their structure and principles of signal transduction. These are ion channel-linked receptors, enzyme-linked receptors and G-protein-coupled receptors (GPCRs). GPCRs comprise the biggest family of membrane receptors and are one of the largest gene families in general. They are encoded by about 1% of genes in mammals. Many of them bind sensory ligands (rhodopsin, taste and olfactory receptors), but others also recognize ions, amino acids, nucleotides, peptides and large glycoproteins (1). They play a crucial role in such distant physiological functions as...
|
|
| |
|
| |
|
| |
|
| |
guest ::
