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A series of 2-alkyl-3-arylpyrido[2,3-d]pyrimidones were synthesized for testing as potential antiepileptic drugs. The goal was to achieve better neurological activity and/or lower toxicity than displayed by a series of 2-alkyl-3-aryl-4(3H)-quinazolinones prepared previously in our research group. From the pharmacological testing data of these target compounds, we have found that the additional nitrogen at the C-8 position of the quinazolinone framework increased the anticonvulsant activity. However, the neurological toxicity increased as well. The anticonvulsant and neurotoxic activity seen in the variuos 2-alkyl side chains and 3-aryl substituents incorporated into these new pyridopyrimidones was consistent with the activity observed with the same substituents on the 4(3H)-quinazolinones. The 3-aryl group consists of various ortho-substituted phenyl rings, while the 2-alkyl chain consists of a 2-(2-aryl-2-oxo)ethyl or 2-arylethenyl group. / Master of Science

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Antiepileptic drug utilization Author: Kateřina Stuchlíková Supervisor: PharmDr. Eva Zimčíková, Ph.D. Department of Social and Clinical Pharmacy Faculty of Pharmacy in Hradec Králové, Charles University, Czech Republic Introduction: Antiepileptics (AEDs) are drugs that prevent the development of epileptic seizures. Objective: The objective of this diploma thesis was to evaluate the utilization of AEDs in the Czech Republic in the period from 01. 01. 2004 to 31. 12. 2018 using data from the State Institute for Drug Control (SIDC). Methods: Retrospective analysis of drug utilization data. Data on the utilization of antiepileptic drugs were received from the SIDC database and included all AEDs that were distributed to medical facilities during the reporting period. The relative comparative unit DID was calculated - the number of defined daily doses per 1000 inhabitants per day. The data on the number of residents were obtained from the Czech Statistical Office. Results: Consumption of antiepileptics has increasing trend. During the period it increased from 7.43 DID to 15.87 DID. Especially in the group of new antiepileptics an increase was observed, where 1.15 DID raised to 10.59 DID, while in the classical antiepileptic group this value decreased from 6.28 DID to 5.28 DID. The most frequently used...

A number of immune abnormalities have been found in epileptic patients treated with antiepileptic drugs (AED). The alterations seen range from mild suppression of immunoglobulins to severly impaired humoral and cellular immunities. There is evidence for both drug effects and genetic or acquired factors as contributors to these abnormalities. In order to examine the basis for immune abnormalities in patients with epilepsy, a number of experimental designs were employed: clinical studies, in vitro studies, and use of an animal model. Peripheral blood mononuclear cells (PBMC) isolated from epileptic patients currently receiving AED were found to have a reduced OKT4+/0KT8+ ratio. A reduced natural killer (NK) cell activity was found which may be due to a low proportion of Leu 11+ cells. A reduced NK cell activity was also found in healthy siblings of the patients, indicating a possible genetic basis for the level of this activity. Antibody-dependent cell-mediated cytotoxicity {ADCC), mitogenic responses, and total rosette-forming cells of PBMC isolated from patieots were found to be normal. The AED phenytoin has been associated with a variety of immune function alterations and lymphoma. In this study, phenytoin was found to depress basal and augmented NK cell activity of human cells in a dose-dependent manner in vitro. This depression was reversible following short-term exposure and at levels considered therapeutic. Phenytoin also depressed ADCC, thus one mechanism by which phenytoin alters immune function is by its depression of cell -mediated cytotoxicity. In contrast to results obtained with phenytoin, the AED carbamazepine did not significantly alter NK cell activity, but the diluent propylene glycol depressed activity. NFS mice given phenytoin produced lower specific antibody titers following antigen challenge. Body weights, specific organ weights for thymus, spleen, and liver, and blood cell counts were normal in these mice. The protocol was well tolerated by the animals at phenytoin dosages ranging from therapeutic to neurotoxic. Susceptibility to murine hepatitis virus was found to be increased in mice given a high dose of phenytoin. This animal model should allow investigations into toxic dose levels and mechanisms by which phenytoin and other AED alter immune function.

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The study herein described represents a continuation of the work on 5-(2-thienyl)-5-substituted hydantoins which has been in progress in the laboratories of the North Texas State College for the past several years. It has for its purpose the study of the effect of lengthening the carbon chain connecting a cyclohexyl radical to 5-(2-thienyl)hydantoin in the 5- position.

Side effects of seizure medications in individuals with intellectual disabilities (ID) may affect speech and language development for this population. Research information about these effects may be useful for speech-language pathologist practitioners, since they will most likely work in environments that involve assessing and treating individuals with ID. In this meta-analysis, a total of 19 articles were reviewed to examine the side effects of AEDs in individuals with ID and seizure disorders. Side effects from AEDs were found; however, research regarding how AEDs and seizure disorders affected speech and language development was not available. Based on the findings, participants on AEDs regimens experienced a variety of side effects that included behavioral side effects, adverse cognitive side effects, and non-behavioral side effects. However, information regarding AEDs side effects and speech and language development was nonexistent. Based on the findings, further research in this is much needed for practicing speech-language pathologists in this topic. / text

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Chaloupková Supervisor: Prof. MUDr. Radomír Hrdina, CSc. Title of diploma thesis: Treatment of epilepsy Epilepsy is a serious chronic disease affecting all ages which can be characterized by recurrent epileptic attacks. It affects about 1,3-4 % of the population and endangers the patient's life at every incoming attack. Long-term treatment must be preceded by thorough diagnosis and classification of the disease, which can be very difficult. The aim of the treatment is to prevent recurrent epileptic attacks, or at least mitigate them while minimizing the side effects of the treatment and reducing the negative impact on the quality of life. When choosing a suitable drug for an adult, the doctor usually decides individually depending on the type of epileptic attack. In children, the choice of the treatment often depends on the diagnosed type of syndrome, which appears more in the lower age category than in adult patients. The doctor should follow expert standards of the treatment of epilepsy, and also their own most recent experience and knowledge gained during the course of lifelong learning. The therapy begins with monotherapy, and only when not successful, it is necessary to...