This thesis is a study of the synthesis of N-substituted di(2-thienylmethyl)acetamides.

This thesis is a study of 5-substituted-amino derivatives of 5-phenylhydantoin and anticonvulsant activity.

It has been shown in the case of a compound synthesized in this laboratory that substitution of the thienyl group for one of the phenyl groups in diphenyl hydantoin produces a compound with less toxicity and somewhat greater activity. It was considered of interest to carry out an analogous substitution in the series of 5-phenyl-5-alkoxymethylhydantions.

The project discussed in the paper consists of the substitution of another type of heterocycle, 2-tetrahydropyranyl, in position 5 of the hydantoin nucleus.

No description available.

The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders.

The anticonvulsant drug, Dilantin, in many cases must be taken by epileptic mothers to control seizures during pregnancy, but unfortunately, it has been characterized as a human teratogen. It has also been demonstrated that many of the teratogenic effects of Dilantin occur during postimplantation, but some studies implicate a detrimental role for Dilantin during the preimplantation stages of development. Some of the postimplantation effects include congenital malformations and the potential'loss of the fetus. Our lab has proposed that in preimplantation mouse embryos the drug may be altering the timing of expression of cell cycle regulatory proteins and therefore, we have begun to examine the expression of these proteins. Thus, it was the goal of this study to characterize and localize various cell cycle proteins at specific time points in normal in vivo preimplantation mouse embryos, as this will provide important baseline information for studies on how anticonvulsant drugs may alter cell cycle regulation in embryos.Western blotting has confirmed the presence of cyclin BI in G1 of the first cell cycle. Both cyclin E and CDK2 were not detected in GI or G2/M of the first cell cycle or GI of the second cell cycle.From the immunogold TEM experiments, the density of cyclin B1 staining was observed to be the highest at G1 of the first cell cycle and declined at S and G2/M. Cyclin B 1 was detected in all regions of the embryo including the microvilli, cortical cytoplasm, interior cytoplasm, and was observed to be associated with vesicles and some filaments. The gold particles at GI, S, and G2/N4 of the first cell cycle and G1 of the second cell cycle appear to be associated with filamentous and membraneous structures and not free in the cytoplasmic spaces. Cyclin B 1 expression was more concentrated around vesicles at G1 of the first cell cycle and in general, was more concentrated around vesicles than in microvilli and cortical cytoplasm, interior cytoplasm, or around filaments at each cell cycle stage tested. / Department of Biology

A great deal of research has been devoted in recent years to the search for new drugs for the treatment of epilepsy and related convulsive disorders. This emphasis is occasioned by the fact that no one drug is effective for all patients, and also by the fact that the toxicity of a drug varies considerably from one patient to another. Among the most effective drugs are certain members of the hydantoin and barbituric acid series. For some time there has been in progress in this laboratory an investigation of members of these two series in which a hetro atom attached directly to the hetrocyclic nucleus is introduced into the side chain at position five of these two series.

Objetivo: Identificar os medicamentos preferidos no Brasil para tratar o transtorno bipolar e a opinião dos psiquiatras brasileiros sobre a litioterapia. Métodos: Um questionário de múltipla escolha com 14 itens foi desenvolvido para estudar estas questões. Foram enviados 10.059 questionários para psiquiatras brasileiros. Resultados: 820 psiquiatras (8,6%) responderam aos questionários. Lítio foi a medicação de primeira escolha em todas as fases do transtorno. Antipsicóticos foram a segunda escolha no tratamento da mania, superando os anticonvulsivantes. Antidepressivos foram a segunda medicação mais utilizada nos episódios depressivos. Mais de 80% de psiquiatras acreditam que o lítio é um medicamento seguro e de fácil manejo. Características epidemiólogicas como região de origem, alto nível educacional, grande experiência clínica e interesses acadêmicos podem ter influenciado tais resultados. Conclusão: Lítio é o medicamento de primeira linha no tratamento do transtorno bipolar no Brasil, a despeito do que ocorre em outros países. Apesar deste panorama favorável, algumas dificuldades podem ser identificadas como a falta de conhecimento sobre o lítio por profissionais da área de saúde mental e pacientes. / Objective: Identify preferred drugs to treat bipolar disorder in Brazil and the impressions of Brazilian psychiatrits about lithium therapy. Methods: A 14 items multiple-choice questionnaire was developed to answer this issue. Questionnaires were posted to 10,059 Brazilian psychiatrists. Results: 820 psychiatrists (8.6%) have answered the questionnaires. Lithium was the preferred medication used in all phases of the disorder. Antipsychotics were second choice in treatment of mania, overcoming anticonvulsants. Antidepressants were the second more used medication for depressive episode. More than 80% of psychiatrists believe that lithium is a safe drug and there is no difficult to handle with. Epidemiological characteristics such region of origen, high degree, large clinical practice and academic interests may influenced those results. Conclusion: Lithium is the first line drug to treat bipolar disorder in Brazil, despite what occur in others countries. Although this favorable panel, some difficults can be identified as mental health professional and patients\' lack of information about lithium.

OBJETIVO: Comparar a eficácia e a tolerabilidade dos fármacos antiepiléticos (FAE) no tratamento em monoterapia de pacientes com epilepsia focal ou generalizada. MÉTODOS: Uma revisão sistemática foi realizada por meio da busca nas bases de dados eletrônicas Pubmed, Scopus, Web of Science e Cochrane Register of Controlled Trials. Foram incluídos os ensaios clínicos controlados com pacientes com epilepsia, em tratamento com FAE, via oral, em monoterapia, e que avaliaram o número de pacientes que atingiram a remissão das crises epilépticas, que interromperam o tratamento devido à ineficácia terapêutica ou à ocorrência de reações adversas (RAM) intoleráveis. Meta-análises de comparação de múltiplos tratamentos foram realizadas por meio do modelo bayesiano de efeitos randômicos que permitiu o cálculo do Odds Ratio meta-analítico para os FAE estudados. Também foi realizado um ranqueamento da probabilidade de cada FAE ser a melhor opção em eficácia e tolerabilidade. RESULTADOS E CONCLUSÕES: A busca identificou 18874 publicações, no entanto apenas 71 estudos foram selecionados, compreendendo 17555 pacientes com epilepsia. Vinte e nove estudos apresentaram os desfechos de eficácia no tratamento de crises focais, 19 em crises generalizadas e 58 apresentaram dados de tolerabilidade. Nesses estudos, 15 FAE foram avaliados. No tratamento das crises focais, os FAE de nova geração levetiracetam (LEV), lamotrigina (LTG), oxcarbazepina, sultiame e topiramato (TPM) demonstraram possuir eficácia equivalente à carbamazepina (CBZ), clobazam e valproato (VPA). No entanto, a CBZ apresentou o pior perfil de tolerabilidade devido à grande probabilidade do paciente abandonar o tratamento devido à RAM intoleráveis. Quanto ao tratamento das crises generalizadas, a LTG, LEV e TPM são tão eficazes quanto o VPA para o tratamento de crises generalizadas tônico-clônicas, tônicas e clônicas. O VPA e a etosuximida constituem as melhores opções para o tratamento de crises de ausências, enquanto que a LTG mostrou-se menos eficaz. Para o tratamento de crises mioclônicas e espasmos infantis mais ensaios clínicos randomizados são necessários para fornecer boas evidências que possam guiar a decisão clínica dos profissionais de saúde. Dentre os FAE com perfil de eficácia adequado, a LTG destacou-se pela menor probabilidade de manifestar RAM intoleráveis. / OBJECTIVE: To compare the efficacy and tolerability of the antiepileptic drugs (AED) in monotherapy of patients with focal or generalized epilepsy. METHODS: A systematic review was in the Medline/Pubmed, Scopus, Web of Science and Cochrane Register of Controlled Trials databases. We included randomized clinical trials of patients with epilepsy treated with oral monotherapy AED, which evaluated number of patients becoming seizure free at the maintenance treatment period; number of patients which withdrawals from the study because of therapeutic inefficacy and number of patients which withdrawals from the study because of intolerable adverse reaction. Network meta-analyses were performed using Bayesian random effects model. We also carried out a ranking of the probability of each AED be the best option in the efficacy and tolerability outcomes. Sensitivity analyses were conducted in order to check the robustness of the results. RESULTS AND CONCLUSIONS: The research identified 18,874 publications, but only 71 studies were selected, comprising 17555 patients with epilepsy.Twenty-nine trials showed the efficacy outcomes in the treatment of focal seizures, 19 in generalized seizures and 58 showed tolerability data. In the treatment of focal seizures, levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine, sultiame and topiramate (TPM) have demonstrated equivalent efficacy to carbamazepine (CBZ), clobazam and valproate (VPA). LTG, LEV and TPM are as effective as the VPA for the treatment of generalized tonic-clonic, tonic and clonic seizures. VPA and ethosuximide are the best options for the treatment of absence seizures, whereas LTG was less effective. For the treatment of myoclonic seizures and infantile spasms, more randomized clinical trials are needed to provide good evidence to guide the clinical decision of health professionals. Among the AED with adequate efficacy profile, LTG stands out as the AED with the best tolerability profile, suggesting it may be the best option for the treatment of patients with epilepsy.