A busca pelo entendimento da etiofisiopatogênese da esquizofrenia permanece desafiadora e tratamentos convencionais com medicações antipsicóticas que agem principalmente através da modulação da neurotransmissão dopaminérgica mostramse insuficientes, vistos os elevados índices de refratariedade e superrefratariedade nesta população. Estudos recentes apontam resultados promissores de moduladores do sistema glutamatérgico com ação em receptores NMDA, como o nitroprussiato de sódio (NPS), um doador de óxido nítrico, capaz de reduzir sintomas positivos, negativos e cognitivos do transtorno. O objetivo do presente estudo foi estudar os efeitos da administração repetida de NPS sobre a sintomatologia de pacientes com esquizofrenia. Recrutados 17 pacientes portadores de esquizofrenia acompanhados no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP, em idade entre 18-45 anos, submetidos ao protocolo experimental com delineamento cruzado, duplo-cego, randomizado e controlado por placebo. Cada participante recebeu oito infusões intravenosas, sendo destas, quatro de NPS (0,5 ?g/kg/min por 4 horas/sessão) e quatro de placebo, em intervalo de 15 dias entre as sessões. A avaliação dos sintomas positivos, negativos e cognitivos foi feita através dos seguintes instrumentos: Escala de Avaliação das Síndromes Positiva e Negativa para Esquizofrenia (PANSS), Escala de Avaliação Psiquiátrica Breve (BPRS), Escala de Impressão Clínica Geral - Esquizofrenia (CGI-SCH), Stroop Color Word Test (SCWT), N-back, Teste de Fluência Verbal (FAS). Para avaliação de efeitos colaterais das medicações foi usada a Escala de Avaliação de Efeitos Colaterais (UKU). A análise dos dados demográficos e clínicos da amostra foi realizada através de estatística descritiva. As análises estatísticas foram feitas com o programa Statistical Package for the Social Sciences versão 17.0. Para avaliar o efeito do NPS nos escores BPRS, PANSS, SCWT, N-back e FAS, os dados foram submetidos a análise de variância de medidas repetidas para modelos de estudo crossover. Análises independentes para sessões de nitroprussiato de sódio e placebo foram realizadas quando houve significância estatística, seguidas de teste t de Student, que também foi empregado para avaliações pareadas entre dados do ínicio e final das sessões. Para análise da CGI-SCH, foi utilizado o teste de Friedman para medidas não-paramétricas. O nível de significância adotado foi de p<0,05. A população amostral que completou o estudo foi de 14 indivíduos portadores de esquizofrenia crônica, refratária ou superrefratária, com bom nível de escolaridade, idade média de 32,94 anos e quase na totalidade usuários de clozapina. Foram realizadas 121 infusões. Observou-se diminuição estatisticamente significativa nos escores iniciais da BPRS, PANSS positiva e negativa e CGI-SCH, com manutenção da redução dos escores nos dias 15, 30 e 60 após término das sessões experimentais. Nas avaliações cognitivas, houve diferença significativa entre as sessões nos escores da SCWT e não houve diferença na análise da FAS e da Nback. Os resultados confirmaram achados anteriores de que o NPS, doador de NO, pode proporcionar melhora clínica significativa nos sintomas positivos e negativos daesquizofrenia, além de melhora parcial nos sintomas cognitivos. Além disso, o ensaio com administração repetida sugere que a droga é segura, não apresenta efeitos colaterais significativos na maioria dos casos e leva a uma melhora sustentada por até 60 dias nos sintomas da esquizofrenia / The knowledge about etiology of schizophrenia remains challenging and conventional treatments with antipsychotic medications that act mainly through the modulation of dopaminergic neurotransmission have proven insufficient, considering the high rates of treatment resistance in this population. Recent studies point to promising results of modulators of the glutamatergic system with action on NMDA receptors such as sodium nitroprusside (SNP), a nitric oxide donor, capable of reducing the positive, negative and cognitive symptoms of the disorder. The aim of the present study was to study the effects of repeated NPS administration on the symptomatology of patients with schizophrenia. A total of 17 schizophrenia patients were enrolled at the Ribeirão Preto Medical School University Hospital, aged 18-45 years took part in a double-blind, randomized, placebo-controlled, double-blind, experimental design. Each participant received eight intravenous infusions, four of SNP (0.5 ?g/kg/min for 4 hours/session) and four of placebo, with a 15-day interval between sessions. The Positive and Negative Syndromes Scale for Schizophrenia (PANSS), BPRS (Brief Psychiatric Rating Scale), Clinical Global Impression scale - Schizophrenia (CGI-SCH), in addition to the Stroop Color Word Test (SCWT), Nback, and the Verbal Fluency Test (FAS). The Side Effects Assessment Scale (UKU) was used to evaluate side effects. The analysis of the demographic and clinical data of the sample was performed through descriptive statistics. Statistical analyses were performed with the Statistical Package for Social Sciences. To evaluate the effect of SNP on BPRS, PANSS, SCWT, N-back and FAS scores, the data were subjected to repeated measures analysis of variance for crossover studies. Independent analyses for SNP and placebo sessions were performed when there were statistically significant differences between the conditions, followed by Student\'s t-test, which was also used for paired evaluations between data from the beginning and end of the sessions. For the analysis of CGI-SCH data, the Friedman test was used. The level of significance was set at p <0.05. The sample that completed the study consisted of 14 individuals with chronic, refractory or superrefractory schizophrenia, with a good level of education and mean age of 32.94 years . Almost all patients were in treatment with clozapine. A total of 121 infusions were performed. A statistically significant decrease was observed in the initial BPRS, PANSS positive and negative subscales, and CGI-SCH scores, which persisted on days 15, 30 and 60 after the end of the experimental sessions. In the cognitive assessments, there was a significant difference between the sessions in SCWT scores and no difference in respect to the FAS and N-back. The results confirmed earlier findings that SNP, an NO donor, can provide significant clinical improvement in the positive and negative symptoms of schizophrenia, as well as partial improvement in cognitive symptoms. In addition, the repeated administration trial suggests that the drug is safe, has no significant side effects in most cases and leads to sustained improvement for up to 60 days in the symptoms of schizophrenia

Introdução: A esquizofrenia é um dos principais transtornos mentais e promove distúrbios comportamentais e cognitivos. Apesar do grande impacto social, pouco se conhece sobre a patofisiologia e etiologia da esquizofrenia. Pacientes com desordens psicóticas têm aumentado risco de desenvolver epilepsia, e pacientes com epilepsia do lobo temporal tem alta frequência de psicoses. A utilização de modelos experimentais animais de esquizofrenia e epilepsia pode ajudar a entender a neurobiologia dessas doenças e ter papel importante no desenvolvimento de novas estratégias terapêuticas. As interações complexas das crises epilépticas e quadros psicóticos tem sido aos poucos desvendadas. O óxido nítrico (NO) é um importante modulador da neurotransmissão e doadores de NO como o nitroprussiato de sódio (NPS) tem efeitos promissores em pacientes com esquizofrenia. Em modelos animais de epilepsia, NO pode ter efeito pró ou anticonvulsivante, sugerindo que o uso de NPS em pacientes com epilepsia e psicose pode não ser tão simples. Objetivos: Desenvolver um modelo animal de epilepsia e psicose comórbida, e compará-lo do ponto de vista comportamental e neuropatológico com modelos animais puros de epilepsia e esquizofrenia. Além disso, verificar a possível modulação desencadeada pelo tratamento com NPS nos modelos citados. Metodologia: Ratos Wistar machos (260-300g) foram divididos em grupos controle (SAL+SAL), epilepsia puro (PILO+SAL), esquizofrenia (SAL+QUET), epilepsia e psicose comórbida (PILO+QUET) e suas versões tratadas com NPS (SAL+SAL+NPS, PILO+SAL+NPS, SAL+QUET+NPS e PILO+QUET+NPS). Esses animais foram avaliados em diferentes aspectos comportamentais (campo aberto, teste de inibição pré- pulso, memória de reconhecimento de objeto e memória de trabalho), e filmados ao longo de 71 dias para o monitoramento de crises epilépticas espontâneas recorrentes. Também foram avaliadas a perda neuronal e a expressão de nNOS em diferentes regiões cerebrais. Resultados: NPS reduziu a frequência de crises nos animais com epilepsia e psicose comórbida quando comparados a animais não tratados. NPS também teve efeito ansiolítico no modelo animal de epilepsia com e sem psicose, e diminuiu os correlatos comportamentais de sintomas positivos dos animais no modelo de psicose e no de epilepsia + psicose, além de reverter o prejuízo no filtro sensório motor nos animais que receberam pilocarpina e quetamina. No reconhecimento de objeto o modelo de epilepsia e epilepsia+psicose o tratamento com NPS não interferiu no desempenho de memória de curto prazo, porém NPS melhorou a memória de longo prazo no modelo de psicose. NPS preservou regiões como o córtex entorrinal e subiculum nos animais epilépticos, mas a camada granular e córtex pré-límbico revelaram perda significativa nos animais controles. Alta expressão de nNOS em diferentes regiões cerebrais foram visualizadas nos animais com epilepsia, com destaque para aqueles que receberam tratamento com NPS. Conclusão: O tratamento com NPS foi efetivo na amenização de sintomas correlatos comportamentais de psicose no modelo puro de esquizofrenia e no comórbido VIII com epilepsia. Além disso, não exacerbou crises e contribuiu para diminuição delas nos animais do modelo de epilepsia e psicose, que apresentou grandes similaridades com o que é encontrado em casos clínicos. Nossos resultados sugerem que o uso do NPS pode ter resultados na melhoria dos sintomas da psicose interictal humana, assim como já observado para a esquizofrenia. / Introdution: Schizophrenia is a major mental disorder that affects 1% of young adults and has a great impact on quality of life, behavior, and cognition. Despite the high social burden, little is known about the pathophysiology and etiology of schizophrenia. Patients with psychotic disorders have increased risk of developing epilepsy, and patients with temporal lobe epilepsy have a high frequency of psychoses. The use of experimental animal models of epilepsy and schizophrenia may help to better understand the neurobiology of these diseases and play an important role in the development of potential new therapeutic strategies. The complex interactions of seizures and psychotic symptoms are being unveiled. Nitric oxide (NO) is an important modulator of neurotransmission and NO donors such as sodium nitroprusside (SNP) have shown promising effects in schizophrenic patients. In animal models of epilepsy, NO may exert pro- or anticonvulsant effects, suggesting that the use of SNP in patients with epilepsy and psychosis may not be so straightforward. Objectives: To develop an animal model of epilepsy and comorbid psychosis, and compare it from the behavioral and neuropathological point of view with pure animal models of epilepsy and schizophrenia. It was hoped, to verify the possible modulation triggered by the treatment with SNP. Metodology: Males Wistar rats weighing 260-300g were divided in controls group (SAL+SAL), pure epilepsy (PILO+SAL), schizophrenia (SAL+QUET), comorbid psychosis (PILO+KET) and their versions treated with SNP (SAL+SAL+SNP, PILO+SAL+SNP, SAL+KET+SNP and PILO+KET+SNP). These animals were evaluated in a variety of behavioral tests (open field, prepulse inhibition startle reflex, object recognition and working memory), and were filmed over 71 days to monitor spontaneous recurrent seizures. We also evaluated neuronal loss and nNOS expression in different brain regions. Results: SNP reduced seizure frequency in animals with epilepsy and psychosis when compared to those not treated with SNP. SNP also showed anxiolytic effects in the animal model of epilepsy with or without psychosis, decreased behavioral correlates of positive symptoms in the animal model of epilepsy + psychosis, and prevented sensorimotor gating deficits in epilepsy + psychosis IX model, The object recognition test showed that in epilepsy and epilepsy + psychosis models the treatment with SNP did not interfere with short-term memory performance, but SNP improved long-term memory in the psychosis model. SNP preserved brain regions like entorhinal cortex and subiculum in epileptic animals, but the granular layer and prelimbic cortex revealed significant loss in controls animals. High expression of NOS in same brain regions was observed in the animal model of epilepsy, especially in the animals receiving SNP. Conclusion: Treatment with SNP was effective in ameliorating symptoms of behavioral correlates of psychosis in the pure model of schizophrenia and the model comorbid with epilepsy. Moreover, SNP did not exacerbate seizures and reduced seizure frequency in the animal model of epilepsy + psychosis, which showed striking similarities to clinical cases. Our results suggest that the use of SNP could ameliorate symptoms of human interictal psychosis, such as those observed in schizophrenia.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Organotellurium compounds have been reported as antioxidants in several models of oxidative stress, especially in the brain. This study investigated the effect of telluroacetylenes a-d on pharmacological assays in vitro. A second objective of this study was to investigate the antioxidant action of compound b against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain. In in vitro experiments, lipid peroxidation (LP) and protein carbonyl (PC) levels and δ-aminolevulinate dehydratase (δ-ALA-D) activity were carried out in rat brain homogenate. The mechanisms involved in the antioxidant effect of telluroacetylenes a-d were studied. The glutathione peroxidase (GPx)-like activity, glutathione S-transferase (GST)-like activity and the protection against Fe2+ autooxidation were determined. Furthermore, the scavenger effect of 2,2 -diphenyl-1-picrylhydrazyl (DPPH ) and 2,2 -azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS +) radicals and hydrogen peroxide (H2O2) were investigated. In in vivo experiments, mice received SNP (0.335 μmol per site) intra cerebroventricular (i.c.v.) thirty minutes after oral administration of telluroacetylene b (10 mg/kg). After 1 h, animals were euthanized. The levels of LP and δ- ALA-D, GPx, GST, catalase (CAT) and glutathione reductase (GR) activities were carried out in mouse brain homogenate. Telluroacetylenes a-d, at low μM range, reduced LP and PC levels in rat brain homogenate. Telluroacetylenes a-d showed effect of scavenging DPPH and ABTS + radicals and H2O2. However the compounds had no GPx-like and GST-like activities or protected against Fe2+ autooxidation, discarding that these mechanisms are involved in the antioxidant effect of telluroacetylenes a-d. δ-ALA-D activity was inhibited by telluroacetylenes a-d, at high μM range, in rat brain homogenate. In the in vivo experiments, brains of mice treated with SNP showed an increase in LP and the reduction in δ-ALA-D, GR and GST activities. Telluroacetylene b protected against the oxidative stress caused by SNP in brain of mice. Moreover, telluroacetylene b incresead per se GPx activity in brains of mice. The results support an antioxidant effect of telluroacetylenes a-d in vitro. Telluroacetylene b protected against oxidative damage caused by SNP in mouse brain, suggesting an antioxidant effect of this compound in vivo. / Compostos orgânicos de telúrio apresentam propriedades antioxidantes em muitos modelos de estresse oxidativo, principalmente no cérebro. Este estudo investigou o efeito de compostos teluroacetilenos a-d em testes farmacológicos in vitro. Um segundo objetivo deste trabalho foi investigar a ação antioxidante do composto b contra o dano oxidativo induzido por nitroprussiato de sódio (SNP) em cérebro de camundongos. Nos experimentos in vitro, os níveis de peroxidação lipídica (PL) e proteína carbonilada (PC) e a atividade da δ-aminolevulinato desidratase (δ-ALA-D) foram determinados em homogeneizado de cérebro de rato. Para estudar o mecanismo pelo qual os teluroacetilenos apresentaram efeito antioxidante, verificou-se o efeito mimético destes compostos na atividade das enzimas glutationa peroxidase (GPx) e glutationa S-transferase (GST) e o efeito protetor na auto-oxidação do Fe2+. Além disso, estudou-se o efeito dos teluroacetilenos a-d como scavenger dos radicais 2,2 -difenil-1-picril-hidrazil (DPPH ) e 2,2 -azino-bis(3-etilbenzotiazolina-6-ácido sulfônico) (ABTS +) e o efeito scavenger de peróxido de hidrogênio (H2O2). Nos experimentos in vivo, camundongos receberam SNP (0,335 μmol per site) intracerebroventricular (i.c.v.) trinta minutos após a administração oral de teluroacetileno b (10 mg/kg). Após uma hora, os animais foram submetidos à eutanásia e foram determinados os níveis de PL e as atividades das enzimas δ-ALA-D, GPx, GST, catalase (CAT) e glutationa redutase (GR) no cérebro de camundongos. Os teluroacetilenos a-d, em baixas concentrações, reduziram os níveis de PL e PC no homogeneizado de cérebro de rato. Os teluroacetilenos a-d apresentaram efeito scavenger de radicais DPPH e ABTS +, bem como efeito scavenger de H2O2. Entretanto, os compostos não apresentaram efeito mimético da atividade das enzimas GPx e GST, nem efeito protetor contra a auto-oxidação do Fe2+, descartando que estes mecanismos estariam envolvidos na ação antioxidante dos teluroacetilenos a-d. A atividade da δ-ALA-D foi inibida pelos teluroacetilenos a-d em homogeneizado de cérebro de ratos somente em concentrações maiores do que as necessárias para o efeito antioxidante. Nos experimentos in vivo, os cérebros dos camundongos tratados com SNP apresentaram um aumento nos níveis de PL e inibição na atividade das enzimas δ-ALA-D, GR e GST. O teluroacetileno b protegeu contra o estresse oxidativo causado pelo SNP em cérebro de camundongos. Ainda, o teluroacetileno b aumentou per se a atividade da GPx em cérebro de camundongos. Estes resultados comprovam o efeito antioxidante dos teluroacetilenos a-d in vitro. Além disso, o teluroacetileno b protegeu contra o dano oxidativo causado pelo SNP em cérebro de camundongos, demonstrando o efeito antioxidante deste composto in vivo.

Introdução: A esquizofrenia é um dos principais transtornos mentais e promove distúrbios comportamentais e cognitivos. Apesar do grande impacto social, pouco se conhece sobre a patofisiologia e etiologia da esquizofrenia. Pacientes com desordens psicóticas têm aumentado risco de desenvolver epilepsia, e pacientes com epilepsia do lobo temporal tem alta frequência de psicoses. A utilização de modelos experimentais animais de esquizofrenia e epilepsia pode ajudar a entender a neurobiologia dessas doenças e ter papel importante no desenvolvimento de novas estratégias terapêuticas. As interações complexas das crises epilépticas e quadros psicóticos tem sido aos poucos desvendadas. O óxido nítrico (NO) é um importante modulador da neurotransmissão e doadores de NO como o nitroprussiato de sódio (NPS) tem efeitos promissores em pacientes com esquizofrenia. Em modelos animais de epilepsia, NO pode ter efeito pró ou anticonvulsivante, sugerindo que o uso de NPS em pacientes com epilepsia e psicose pode não ser tão simples. Objetivos: Desenvolver um modelo animal de epilepsia e psicose comórbida, e compará-lo do ponto de vista comportamental e neuropatológico com modelos animais puros de epilepsia e esquizofrenia. Além disso, verificar a possível modulação desencadeada pelo tratamento com NPS nos modelos citados. Metodologia: Ratos Wistar machos (260-300g) foram divididos em grupos controle (SAL+SAL), epilepsia puro (PILO+SAL), esquizofrenia (SAL+QUET), epilepsia e psicose comórbida (PILO+QUET) e suas versões tratadas com NPS (SAL+SAL+NPS, PILO+SAL+NPS, SAL+QUET+NPS e PILO+QUET+NPS). Esses animais foram avaliados em diferentes aspectos comportamentais (campo aberto, teste de inibição pré- pulso, memória de reconhecimento de objeto e memória de trabalho), e filmados ao longo de 71 dias para o monitoramento de crises epilépticas espontâneas recorrentes. Também foram avaliadas a perda neuronal e a expressão de nNOS em diferentes regiões cerebrais. Resultados: NPS reduziu a frequência de crises nos animais com epilepsia e psicose comórbida quando comparados a animais não tratados. NPS também teve efeito ansiolítico no modelo animal de epilepsia com e sem psicose, e diminuiu os correlatos comportamentais de sintomas positivos dos animais no modelo de psicose e no de epilepsia + psicose, além de reverter o prejuízo no filtro sensório motor nos animais que receberam pilocarpina e quetamina. No reconhecimento de objeto o modelo de epilepsia e epilepsia+psicose o tratamento com NPS não interferiu no desempenho de memória de curto prazo, porém NPS melhorou a memória de longo prazo no modelo de psicose. NPS preservou regiões como o córtex entorrinal e subiculum nos animais epilépticos, mas a camada granular e córtex pré-límbico revelaram perda significativa nos animais controles. Alta expressão de nNOS em diferentes regiões cerebrais foram visualizadas nos animais com epilepsia, com destaque para aqueles que receberam tratamento com NPS. Conclusão: O tratamento com NPS foi efetivo na amenização de sintomas correlatos comportamentais de psicose no modelo puro de esquizofrenia e no comórbido VIII com epilepsia. Além disso, não exacerbou crises e contribuiu para diminuição delas nos animais do modelo de epilepsia e psicose, que apresentou grandes similaridades com o que é encontrado em casos clínicos. Nossos resultados sugerem que o uso do NPS pode ter resultados na melhoria dos sintomas da psicose interictal humana, assim como já observado para a esquizofrenia. / Introdution: Schizophrenia is a major mental disorder that affects 1% of young adults and has a great impact on quality of life, behavior, and cognition. Despite the high social burden, little is known about the pathophysiology and etiology of schizophrenia. Patients with psychotic disorders have increased risk of developing epilepsy, and patients with temporal lobe epilepsy have a high frequency of psychoses. The use of experimental animal models of epilepsy and schizophrenia may help to better understand the neurobiology of these diseases and play an important role in the development of potential new therapeutic strategies. The complex interactions of seizures and psychotic symptoms are being unveiled. Nitric oxide (NO) is an important modulator of neurotransmission and NO donors such as sodium nitroprusside (SNP) have shown promising effects in schizophrenic patients. In animal models of epilepsy, NO may exert pro- or anticonvulsant effects, suggesting that the use of SNP in patients with epilepsy and psychosis may not be so straightforward. Objectives: To develop an animal model of epilepsy and comorbid psychosis, and compare it from the behavioral and neuropathological point of view with pure animal models of epilepsy and schizophrenia. It was hoped, to verify the possible modulation triggered by the treatment with SNP. Metodology: Males Wistar rats weighing 260-300g were divided in controls group (SAL+SAL), pure epilepsy (PILO+SAL), schizophrenia (SAL+QUET), comorbid psychosis (PILO+KET) and their versions treated with SNP (SAL+SAL+SNP, PILO+SAL+SNP, SAL+KET+SNP and PILO+KET+SNP). These animals were evaluated in a variety of behavioral tests (open field, prepulse inhibition startle reflex, object recognition and working memory), and were filmed over 71 days to monitor spontaneous recurrent seizures. We also evaluated neuronal loss and nNOS expression in different brain regions. Results: SNP reduced seizure frequency in animals with epilepsy and psychosis when compared to those not treated with SNP. SNP also showed anxiolytic effects in the animal model of epilepsy with or without psychosis, decreased behavioral correlates of positive symptoms in the animal model of epilepsy + psychosis, and prevented sensorimotor gating deficits in epilepsy + psychosis IX model, The object recognition test showed that in epilepsy and epilepsy + psychosis models the treatment with SNP did not interfere with short-term memory performance, but SNP improved long-term memory in the psychosis model. SNP preserved brain regions like entorhinal cortex and subiculum in epileptic animals, but the granular layer and prelimbic cortex revealed significant loss in controls animals. High expression of NOS in same brain regions was observed in the animal model of epilepsy, especially in the animals receiving SNP. Conclusion: Treatment with SNP was effective in ameliorating symptoms of behavioral correlates of psychosis in the pure model of schizophrenia and the model comorbid with epilepsy. Moreover, SNP did not exacerbate seizures and reduced seizure frequency in the animal model of epilepsy + psychosis, which showed striking similarities to clinical cases. Our results suggest that the use of SNP could ameliorate symptoms of human interictal psychosis, such as those observed in schizophrenia.

The synergistic effect of nitric oxide toward dephosphorylation reactions involving phosphate esters was the subject of investigation in this research. Sodium nitroprusside under UV irradiations at 254nm, 365nm and white light was utilized as nitric oxide donor in solutions. The effects of cobalt trimethylenediamine and nitroprusside towards dephosphorylation of nitrophenylphosphate and pyrophosphate which were modeled as organophosphate ester substrates were also investigated. The activated substrate models showed more rate enhancement than the unactivated models in all cases. The direct interaction of nitric oxide with the phosphorus centre is presumed to be the reason for enhanced hydrolysis. This study demonstrates the possible role of nitric oxide in decontamination reactions of poorly biodegradable phosphate esters in the biosphere. / Chemistry / M. Sc. (Chemistry)

Apesar dos numerosos estudos enfocando a compreensão da esquizofrenia, sua etiologia permanece desconhecida. Atualmente, as medicações antipsicóticas disponíveis são baseadas principalmente na hipótese dopaminérgica, porém, apresentam eficácia parcial no tratamento dos sintomas. Diante disso, outros sistemas neurais têm sido investigados e, nesse contexto, a hipótese glutamatérgica conquistou grande importância. Essa hipótese postula a presença de uma hipoatividade do receptor glutamatérgico N-metil-D-aspartato na esquizofrenia e, consequentemente, de uma desregulação na neurotransmissão do óxido nítrico. Um ensaio clínico recente com a administração de nitroprussiato de sódio, um doador de óxido nítrico, mostrou resultados significativos na melhora da sintomatologia de pacientes esquizofrênicos, entretanto, nenhum estudo de neuroimagem investigou quais são os efeitos dessa droga no sistema nervoso central. No crescente campo de estudo da neuroimagem funcional as redes neurais foram descobertas, sendo a default mode network uma das mais estudadas na esquizofrenia. Os recentes estudos de neuroimagem funcional têm evidenciado alterações do funcionamento dessa rede neural nos pacientes portadores da doença, evidenciando assim, a importância da default mode network na compreensão da esquizofrenia. Nesse caminho, o presente estudo investigou os efeitos agudos da administração de nitroprussiato de sódio na conectividade funcional da rede default mode network através da ressonância magnética funcional mediada pelo contraste BOLD (blood oxygen level dependent) em pacientes portadores de esquizofrenia e em voluntários saudáveis. Os pacientes portadores de esquizofrenia foram divididos em dois grupos de acordo com a medicação antipsicótica em uso: grupo sem clozapina (n=13) e grupo com clozapina (n=13). Os voluntários saudáveis também foram divididos em grupo controle (n=14) e grupo controle com tarefa de escuta passiva (n=5). Todos os pacientes portadores de esquizofrenia e o grupo controle foram submetidos a um protocolo de infusão de nitroprussiato de sódio com aquisição simultânea de imagens funcionais. Nossos resultados mostraram um aumento da conectividade funcional da default mode network com a infusão da medicação nos pacientes portadores de esquizofrenia, especialmente no hemisfério direito, enquanto esse mesmo padrão não foi encontrado nos controles saudáveis. Além disso, o aumento na conectividade se mostrou distinto entres os grupos de pacientes avaliados, sendo mais precoce e amplo no grupo de pacientes que não estava em uso do antipsicótico clozapina. Observamos também que o efeito modulatório da droga ocorreu sobre regiões da default mode network já estudadas e fortemente implicadas na fisiopatogenia da esquizofrenia. Assim, nossa investigação neurofuncional contribuiu para a compreensão dos efeitos terapêuticos do nitroprussiato de sódio na sintomatologia de pacientes portadores de esquizofrenia. Nossos achados também reforçam a importância do nitroprussiato de sódio como uma nova ferramenta farmacológica adjuvante no tratamento da esquizofrenia / Despite numerous studies focusing on the understanding of schizophrenia, its etiology remains unknown. Currently, available antipsychotic medications are mainly based on dopamine hypothesis, however, they exhibit partial efficacy in the treatment of the symptoms. Therefore, other neural systems have been investigated and, in this context, the glutamatergic hypothesis gained great importance. This hypothesis postulates the presence of a hypoactivity of the N-methyl-D-aspartate glutamate receptor in schizophrenia and, consequently, a deregulation of nitric oxide neurotransmission. A recent clinical trial with the administration of sodium nitroprusside, a nitric oxide donor, showed significant results in improving the symptoms of schizophrenic patients, however, no neuroimaging study investigated what are the effects of this drug on the central nervous system. The neural networks were discovered from the growing field of functional neuroimaging study and the default mode network is one of the most studied in schizophrenia. The recent functional neuroimaging studies have shown alterations in the functioning of this neural network in patients with the disease, highlighting the importance of the default mode network in the understanding of schizophrenia. In this way, the present study investigated the acute effects of sodium nitroprusside administration in the functional connectivity of the default mode network using blood oxygen level dependent (BOLD) functional magnetic resonance imaging in patients with schizophrenia and healthy volunteers. Schizophrenic patients are divided into two groups according to antipsychotic medication used: group treated without clozapine (n = 13) and group treated with clozapine (n = 13). Healthy volunteers were also divided into control group (n = 14) and control group with passive listening task (n = 5). All schizophrenic patients and healthy volunteers were subjected to a sodium nitroprusside infusion protocol simultaneously to acquisition of functional images. Our results showed increased default mode network functional connectivity with the drug infusion in patients with schizophrenia, mainly in the right hemisphere, while this same pattern was not found in healthy controls. In addition, the increase in connectivity was distinct between groups of patients because it was earlier and more extensive in the group of patients that was not in use of clozapine antipsychotic. We also note that the drug modulatory effect occurred on default mode network regions already studied and strongly implicated in the schizophrenia pathogenesis. Thus, our neurofunctional research contributed to the understanding of the sodium nitroprusside therapeutic effects on the schizophrenia symptoms. Our findings also underline the importance of sodium nitroprusside as a new adjuvant pharmacological tool in the treatment of schizophrenia

High blood pressure, also called hypertension is one of the most common worldwide diseases afflicting humans and is a major risk factor for stroke, myocardial infarction, vascular disease, and chronic kidney disease. If blood pressure is controlled and oscillations in the hemodynamic variables are reduced, patients experience fewer complications after surgery. In clinical practice, this is usually achieved using manual drug delivery. Given that different patients have different sensitivity and reaction time to drugs, determining manually the right drug infusion rates may be difficult. This is a problem where automatic drug delivery can provide a solution, especially if it is designed to adapt to variations in the patient’s conditions. This research work presents an investigation into the development of abnormal blood pressure (hypertension) controllers for postoperative patients. Control of the drugs infusion rates is used to simultaneously regulate the hemodynamic variables such as the Mean Arterial Pressure (MAP) and the Cardiac Output (CO) at the desired level. The implementation of optimal control system is very essential to improve the quality of patient care and also to reduce the workload of healthcare staff and costs. Many researchers have conducted studies earlier on modelling and/or control of abnormal blood pressure for postoperative patients. However, there are still many concerns about smooth transition of blood pressure without any side effect. The blood pressure is classified in two categories: high blood pressure (Hypertension) and low blood pressure (Hypotension). The hypertension often occurred after cardiac surgery, and the hypotension occurred during cardiac surgery. To achieve the optimal control solution for these abnormal blood pressures, many methods are proposed, one of the common methods is infusing the drug related to blood pressure to maintain it at the desired level. There are several kinds of vasodilating drugs such as Sodium Nitroprusside (SNP), Dopamine (DPM), Nitro-glycerine (NTG), and so on, which can be used to treat postoperative patients, also used for hypertensive emergencies to keep the blood pressure at safety level. A comparative performance of two types of algorithms has been presented in chapter four. These include the Internal Model Control (IMC), and Proportional-Integral-Derivative (PID) controller. The resulting controllers are implemented, tested and verified for three sensitivity patient response. SNP is used for all three patients’ situation in order to reduce the pressure smoothly and maintain it at the desire level. A Genetic Algorithms (GAs) optimization technique has been implemented to optimise the controllers’ parameters. A set of experiments are presented to demonstrate the merits and capabilities of the control algorithms. The simulation results in chapter four have demonstrated that the performance criteria are satisfied with the IMC, and PID controllers. On the other hand, the settling time for the PID control of all three patients’ response is shorter than the settling time with IMC controller. Using multiple interacting drugs to control both the MAP and CO of patients with different sensitivity to drugs is a challenging task. A Multivariable Model Reference Adaptive Control (MMRAC) algorithm is developed using a two-input, two-output patient model. Because of the difference in patient’s sensitivity to the drug, and in order to cover the wide ranges of patients, Model Reference Adaptive Control (MRAC) has been implemented to obtain the optimal infusion rates of DPM and SNP. This is developed in chapters five and six. Computer simulations were carried out to investigate the performance of this controller. The results show that the proposed adaptive scheme is robust with respect to disturbances and variations in model parameters, the simulation results have demonstrated that this algorithm cannot cover the wide range of patient’s sensitivity to drugs, due to that shortcoming, a PID controller using a Neural Network that tunes the controller parameters was designed and implemented. The parameters of the PID controller were optimised offline using Matlab genetic algorithm. The proposed Neuro-PID controller has been tested and validated to demonstrate its merits and capabilities compared to the existing approaches to cover wide range of patients.

Apesar dos numerosos estudos enfocando a compreensão da esquizofrenia, sua etiologia permanece desconhecida. Atualmente, as medicações antipsicóticas disponíveis são baseadas principalmente na hipótese dopaminérgica, porém, apresentam eficácia parcial no tratamento dos sintomas. Diante disso, outros sistemas neurais têm sido investigados e, nesse contexto, a hipótese glutamatérgica conquistou grande importância. Essa hipótese postula a presença de uma hipoatividade do receptor glutamatérgico N-metil-D-aspartato na esquizofrenia e, consequentemente, de uma desregulação na neurotransmissão do óxido nítrico. Um ensaio clínico recente com a administração de nitroprussiato de sódio, um doador de óxido nítrico, mostrou resultados significativos na melhora da sintomatologia de pacientes esquizofrênicos, entretanto, nenhum estudo de neuroimagem investigou quais são os efeitos dessa droga no sistema nervoso central. No crescente campo de estudo da neuroimagem funcional as redes neurais foram descobertas, sendo a default mode network uma das mais estudadas na esquizofrenia. Os recentes estudos de neuroimagem funcional têm evidenciado alterações do funcionamento dessa rede neural nos pacientes portadores da doença, evidenciando assim, a importância da default mode network na compreensão da esquizofrenia. Nesse caminho, o presente estudo investigou os efeitos agudos da administração de nitroprussiato de sódio na conectividade funcional da rede default mode network através da ressonância magnética funcional mediada pelo contraste BOLD (blood oxygen level dependent) em pacientes portadores de esquizofrenia e em voluntários saudáveis. Os pacientes portadores de esquizofrenia foram divididos em dois grupos de acordo com a medicação antipsicótica em uso: grupo sem clozapina (n=13) e grupo com clozapina (n=13). Os voluntários saudáveis também foram divididos em grupo controle (n=14) e grupo controle com tarefa de escuta passiva (n=5). Todos os pacientes portadores de esquizofrenia e o grupo controle foram submetidos a um protocolo de infusão de nitroprussiato de sódio com aquisição simultânea de imagens funcionais. Nossos resultados mostraram um aumento da conectividade funcional da default mode network com a infusão da medicação nos pacientes portadores de esquizofrenia, especialmente no hemisfério direito, enquanto esse mesmo padrão não foi encontrado nos controles saudáveis. Além disso, o aumento na conectividade se mostrou distinto entres os grupos de pacientes avaliados, sendo mais precoce e amplo no grupo de pacientes que não estava em uso do antipsicótico clozapina. Observamos também que o efeito modulatório da droga ocorreu sobre regiões da default mode network já estudadas e fortemente implicadas na fisiopatogenia da esquizofrenia. Assim, nossa investigação neurofuncional contribuiu para a compreensão dos efeitos terapêuticos do nitroprussiato de sódio na sintomatologia de pacientes portadores de esquizofrenia. Nossos achados também reforçam a importância do nitroprussiato de sódio como uma nova ferramenta farmacológica adjuvante no tratamento da esquizofrenia / Despite numerous studies focusing on the understanding of schizophrenia, its etiology remains unknown. Currently, available antipsychotic medications are mainly based on dopamine hypothesis, however, they exhibit partial efficacy in the treatment of the symptoms. Therefore, other neural systems have been investigated and, in this context, the glutamatergic hypothesis gained great importance. This hypothesis postulates the presence of a hypoactivity of the N-methyl-D-aspartate glutamate receptor in schizophrenia and, consequently, a deregulation of nitric oxide neurotransmission. A recent clinical trial with the administration of sodium nitroprusside, a nitric oxide donor, showed significant results in improving the symptoms of schizophrenic patients, however, no neuroimaging study investigated what are the effects of this drug on the central nervous system. The neural networks were discovered from the growing field of functional neuroimaging study and the default mode network is one of the most studied in schizophrenia. The recent functional neuroimaging studies have shown alterations in the functioning of this neural network in patients with the disease, highlighting the importance of the default mode network in the understanding of schizophrenia. In this way, the present study investigated the acute effects of sodium nitroprusside administration in the functional connectivity of the default mode network using blood oxygen level dependent (BOLD) functional magnetic resonance imaging in patients with schizophrenia and healthy volunteers. Schizophrenic patients are divided into two groups according to antipsychotic medication used: group treated without clozapine (n = 13) and group treated with clozapine (n = 13). Healthy volunteers were also divided into control group (n = 14) and control group with passive listening task (n = 5). All schizophrenic patients and healthy volunteers were subjected to a sodium nitroprusside infusion protocol simultaneously to acquisition of functional images. Our results showed increased default mode network functional connectivity with the drug infusion in patients with schizophrenia, mainly in the right hemisphere, while this same pattern was not found in healthy controls. In addition, the increase in connectivity was distinct between groups of patients because it was earlier and more extensive in the group of patients that was not in use of clozapine antipsychotic. We also note that the drug modulatory effect occurred on default mode network regions already studied and strongly implicated in the schizophrenia pathogenesis. Thus, our neurofunctional research contributed to the understanding of the sodium nitroprusside therapeutic effects on the schizophrenia symptoms. Our findings also underline the importance of sodium nitroprusside as a new adjuvant pharmacological tool in the treatment of schizophrenia

Actuellement, une voie de développement de formulations médicamenteuses novatrices passe par la vectorisation de principes actifs connus dans des nanoparticules. Des matériaux hybrides sont ainsi formés, possédant de nouvelles propriétés liées au nano-confinement. Les travaux ici menés s’appuient sur la sensibilité de la Résonance Magnétique Nucléaire (RMN) du solide aux phénomènes prenant place aux échelles moléculaires, pour effectuer une analyse structurelle et dynamique de deux vecteurs. Le premier, hydrophile, est une matrice nanoporeuse de silice sol-gel, dans laquelle sont confinés des complexes de nitroprussiate de sodium isolés. À partir de mesures de relaxation de spin et d’anisotropie de déplacement chimique, différents régimes de dynamique moléculaire sont mis en évidence. Ils sont modulés par la présence de molécules de solvant résiduelles (H2O). Des gammes de température et d’hydratation sont identifiées, pour lesquelles le complexe reste associé malgré un état ‘‘pseudo-liquide’’. Dans la condition limite d’absence d’eau, la restriction du mouvement des complexes confinés est élucidée en caractérisant les interactions dipolaires hôtes / invités. Le second système allie la double vectorisation de la curcumine hydrophobe dans des nanoparticules de lipides solides encapsulées dans une matrice de silice (SBA-15). Une stratégie d’étude conjointe par RMN du solide et par calorimétrie différentielle à balayage (DSC) est mise en place. Les résultats montrent que d’autres facteurs que la compartimentalisation (polymorphisme, dynamique moléculaire des composés hôtes) doivent également être pris en compte pour la compréhension des propriétés de ces matériaux très hétérogènes. Malgré le recours à une instrumentation RMN de dernière génération (spectromètre 1GHz, sonde MAS 1.3mm), la présence de principe actif est observée uniquement dans les compartiments de tensioactif. Ces résultats permettent d’émettre de nouvelles hypothèses sur la distribution du principe actif, tout en montrant les limites de l’approche RMN basée uniquement sur l’étude des noyaux 1H. / Nowadays, a way of developing novel medicinal compounds focuses on confinement of known active molecules inside nanoparticles. Therefore, hybrid materials emerge, exhibiting new properties related to nano-confinement. This work relies on the sensibility of solid-state Nuclear Magnetic Resonance (SS-NMR) towards molecular scale phenomena in order to perform structural and dynamical analysis of two delivery systems. They are modulated by the influence of residual solvent molecules (H2O). Temperature and hydration ranges are identified, for which the complex stays associated, although it is in a liquid-like state. Toward the limit of water absence, movement restrictions of the confined complexes are elucidated by characterizing dipolar host / guest interactions. The second system combines a double vectorization of hydrophobic curcumin molecules inside solid lipid nanoparticles, encapsulated inside a silica matrix (SBA-15). A joint SS-NMR and Differential Scanning Calorimetry (DSC) characterization strategy is put in place. The results show that other factors than compartmentalization (polymorphism, molecular dynamics of host compounds) should also be taken into account to understand the properties of these very heterogeneous materials. Despite resorting to the latest NMR instrumentation (1GHz spectrometer, 1.3mm MAS probehead), presence of the active ingredient is only detected inside the surfactant compartment. These results allow making new assumptions for the distribution of curcumin inside the material while showing the limits of an NMR approach relying solely on the study of 1H nuclei.

The synergistic effect of nitric oxide toward dephosphorylation reactions involving phosphate esters was the subject of investigation in this research. Sodium nitroprusside under UV irradiations at 254nm, 365nm and white light was utilized as nitric oxide donor in solutions. The effects of cobalt trimethylenediamine and nitroprusside towards dephosphorylation of nitrophenylphosphate and pyrophosphate which were modeled as organophosphate ester substrates were also investigated. The activated substrate models showed more rate enhancement than the unactivated models in all cases. The direct interaction of nitric oxide with the phosphorus centre is presumed to be the reason for enhanced hydrolysis. This study demonstrates the possible role of nitric oxide in decontamination reactions of poorly biodegradable phosphate esters in the biosphere. / Chemistry / M. Sc. (Chemistry)