A P-glicoproteína (P-gp) é uma transportadora transmembrana de múltiplos fármacos, produto do gene MDR1 (ABCB1). A P-gp contribui para a função de barreira de vários tecidos e órgãos, funcionando como uma bomba de efluxo para muitos substratos. Diminuição na expressão desta proteína é associada à sensibilidade a fármacos. Cães da linhagem dos Collies possuem uma alta incidência de uma mutação no gene MDR1, denominada nt230(del4). Animais homozigotos para a mutação apresentam a supressão total de uma P-gp funcional e um animal heterozigoto apresenta uma maior sensibilidade para substratos da P-gp, devido a uma diminuição na expressão da mesma. Alguns fármacos opioides, como a morfina e a metadona, foram identificados como substratos da P-gp. O tramadol é um dos analgésicos opioides mais utilizados em cães. No presente trabalho, a mutação MDR1 nt230(del4) foi analisada em vinte cães Collie, utilizando reação em cadeia de polimerase (PCR). A identificação foi realizada por eletroforese em gel de poliacrilamida de alta resolução, sendo o resultado confirmado por análise de sequênciamento de DNA. Como resultado, seis cães apresentaram normalidade nos dois alelos e 14 apresentaram heterozigose para a mutação. Estes animais foram submetidos à segunda fase do experimento, quando se administrou uma dose única de 100 mg de tramadol oral de liberação prolongada (SR), objetivando investigar o tramadol como sendo substrato da P-gp. Outro objetivo foi avaliar a farmacocinética deste tipo de formulação, pois ainda não foi estabelecida para cães. A análise farmacocinética do tramadol foi realizada utilizando cromatografia líquida de alta eficiência (CLAE) com detecção por espectrometria de massas para a determinação e quantificação de tramadol no soro canino. O analito e o padrão interno foram extraídos do soro por método líquido-líquido. A separação cromatográfica foi obtida a partir de uma coluna analítica C18, mantida a 30°C, sob condições isocráticas de uma fase móvel constituída por uma mistura de acetonitrila e ácido fórmico a 0,1% (80:20). A concentração de tramadol no soro foi maior do que o limite de quantificação (LOQ), em 17 cães. Os cães foram divididos em dois grupos, cães normais (MDR1 +/+) e heterozigotos (MDR1 +/-). Os cálculos farmacocinéticos para o tramadol oral SR obtiveram valores médios de concentração máxima no soro (Cmax) de 63,12 ng/mL ± 33,35 para o grupo normal e 58,00 ng/mL ± 27,29 para o grupo heterozigoto. Tmax (tempo de concentração plasmática maxima) foi de 4 h para ambos os grupos e t ½ (meia-vida) foram 2,85 h ± 1,61 e 2,81 ± 1,46 h para os cães normais e heterozigotos, respectivamente. A área sob a curva (AUC) média para o tramadol oral SR para o grupo normal e heterozigoto foram 350,20 ± 216,61 e 312,15 ± 155,43 ng.h/mL, respectivamente. A biodisponibilidade foi de 22% e 23% para os cães normais e heterozigotos, respectivamente. Não houve diferença estatística entre os grupos em todos os parâmetros farmacocinéticos. Os resultados sugerem que o tramadol não é um substrato da Pgp. A quantidade de dados farmacocinéticos do tramadol oral na formulação de liberação prolongada (SR) em cães é escassa, sendo necessários mais estudos farmacocinéticos e farmacodinâmicos para o tramadol oral de liberação prolongada em cães para estabelecer adequada dose e frequência de administração em cães. / The P-glycoprotein (P-gp) is a transmembrane multidrug transporter, product of the MDR1 (ABCB1) gene. P-gp contributes to the barrier function of several tissues and organs, acting as an efflux pump for many substrates. Decreased expression of this protein is associated with sensitivity to drugs. Collie dogs have a high incidence of a mutation in MDR1 gene, denominated MDR1 nt230 (del4). In homozygosis, this mutation results in the total absence of a functional P-gp and a heterozygote animal presents a greater sensibility to P-gp substrates, probably due to a decrease in the expression thereof. Some opioid drugs such as morphine and methadone were identified as P-gp substrates. Tramadol is one of the most commonly opioid used in dogs. In the present work MDR1nt230 (del4) mutation was analyzed in 20 healthy Collie dogs using allele-specific polymerase chain reaction (PCR) method. Thereby, 6 homozygous intact and 14 heterozygous mutated MDR1 genotypes can be differentiated by high resolution polyacrylamide gel electrophoresis, confirmed by DNA sequence analysis. These animals underwent the second phase of the experiment, when a single oral administration of 100 mg of sustained release (SR) tramadol was administrated to investigate the tramadol as P-gp substrate. In addition, another aim was evaluate the pharmacokinetics of sustained release formulation, which has not been established for dogs. Pharmacokinetic analysis of tramadol was evaluated using high performance liquid chromatography (HPLC) with tandem mass spectrometry for determination and quantification of tramadol in canine serum. The analyte and internal standard (IS) were extracted from serum using liquid-liquid method. Chromatographic separation was achieved on a C18 analytical column, kept at 30°C, under isocratic conditions of a mobile phase consisted by a mixture of acetonitrile and water contained 0,1% formic acid (80:20). Serum tramadol concentration was greater than the limit of quantification (LOQ) in 17 dogs. The dogs were divided into two groups, normal dogs (MDR1 +/+) and heterozygous (MDR1 +/-) according to the MDR1 genotype. The median values of maximum serum concentration (Cmax) were 63.13 ng/mL ± 33.35 for the normal group and 58.01 ng/mL ± 27.29 for the heterozygous group. Tmax (time to maximum serum concentration) was 4 h for both groups and t ½ (half-life) were 2,85h ± 1,61 e 2,81h ± 1,46 for normal and heterozygous dogs, respectively. The mean area-under-the-curve (AUC) values for the sustained release tramadol compounds for the normal and heterozygous group were 350,20 ±216,61 and 312,15 ± 155,43 ng.h/mL, respectively. The bioavailability was 22% and 23% for normal and heterozygous dogs respectively. There was no statistic difference between groups in all pharmacokinetics parameters. The findings suggest that tramadol is not a P-gp substrate. The amount of pharmacokinetics data of SR formulation of tramadol in dogs is sparse. Therefore, more studies of oral SR tramadol in dogs are needed to establish appropriate dose and frequency of administration in dogs.

Submitted by MARCIA ROVADOSCHI (marciar@unifra.br) on 2018-08-20T12:23:08Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_CayaneGenroSantos.pdf: 3426105 bytes, checksum: 7a9b15fe21608009c9d6ca592e708bf4 (MD5) / Made available in DSpace on 2018-08-20T12:23:08Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_CayaneGenroSantos.pdf: 3426105 bytes, checksum: 7a9b15fe21608009c9d6ca592e708bf4 (MD5) Previous issue date: 2017-03-20 / Polymers are part of our life and have many applications in different branches of industry. In pharmaceutics they are widely used in systems for the modified release of drugs. Polymer blends appear as an alternative to the use of individual polymers and have been utilized to produce nanocarriers. In the present study a polymeric material was developed to respond to a specific aim of the pharmaceutical industry, which is the sustained release of drugs. For this purpose, for the first time, a polymeric blend of poly(methyl methacrylate) - polyl(ethylenoglycol) (PMMA-PEG) was developed for the production of nanocapsules and the appication for the sustained delivery of a model-pharmaceutical, in this case, simvastatin. Tests were also performed for the characterization and stability of this nanostructure. Further, the cyto and genotoxicity of the nanocapsules in mononuclear cells of peripheral blood was evaluated, and an intermediate product was developed (nanocapsules of powdered simvastatin) to be used later by the pharmaceutical industry. The polymer blend of PMM-PEG was obtained with a high yield, 94 ± 3.7%. The infrared spectrum shows the typical bands at 3349 cm-1 and 2922 cm-1 corresponding to the vibration of the lengthening of -O-H and -C-H bonds. Characteristic bands at 1731 and 1102 cm-1 were attributed to -C=O and -C-O-C lengthening. In the 1H-RMN spectrum the sign of methylenic protons was observed at 3.68 ppm (-CH2OCH2-) of PEG and the peak at 3.61 ppm of the protons of cluster -OCH3 of PMMA. The molecular weight determined by GPC was 101.581 Da and the polydispersion index was 5.342. Analyses of DSC suggested that the mixture is a molecularly well dispersed system, and the curves of TGA indicated two weight losses in relation to both polymers. The nanocapsules produced by the polymeric blend presented a particle size and polydispersion index of 198.2 ± 1.4 nm and 0.08 ± 0.01 for the white nanocapsules and 194.4 ± 1.7 nm and 0.07 ± 0.00 for the nanocapsules with simvastatin. The zeta potential value was -11.22 ± 3,01 mV for the nanocapsule with simvastatin and -9.19 ± 0.26 mV for the white nanocapsules, and efficiency of simvastatin encapsulation was high, 98.64 ± 0.00%. The condition of refrigerated storage (± 4 ºC) was what best ensured the preservation of the physicochemical characteristics of the suspensions over 90 days. The cyto and genotoxicity tests indicated that the samples tested were not toxic and, therefore, are safe for biomedical application. The release of the drug from the nanocapsules was more sustained than its free form and the presence of PEG in the polymer blend of PMMA-PEG modified the release mechanism and increased the quantity of simvastatin released compared to the nanocapsules produced only with PMMA. Forty-five per cent release of simvastatin was observed in 24 hours, from the nanocapsules produced by the PMMA-PEG blend, and 34% from the capsules produced only with PMMA., while the non-encapsulated simvastatin was fully released in 17 hours. Finally, the suspensoins were efficiently dried by spray-drying, and resulted in an intermediate product with a yield of 66.83% and presented adequate physicochemical characteristics. Thus, we can conclude that the polymer blend was obtained successfully through a simple, efficient process, and served to develop a nanocarrier of drug.s The nanocapsules produced by the polymer blend promoted a sustained release of the drug, indicating that these nanocapsules are good candidates for use as drug carriers. / Os polímeros fazem parte da nossa vida e têm inúmeras aplicações em diversos setores industriais. Na área farmacêutica, são amplamente empregados em sistemas de liberação modificada de fármacos. As blendas poliméricas surgem como uma alternativa ao uso de polímeros individuais e têm sido utilizadas para produção de nanocarreadores. Neste trabalho, desenvolveu-se um material polimérico para atender a um fim específico da indústria farmacêutica, que é a liberação sustentada de fármacos. Para isso, produziu-se pela primeira vez, uma blenda polimérica de poli(metil metacrilato) (PMMA)-poli(etilenoglicol) (PEG) para a produção de nanocápsulas e aplicação na entrega sustentada de um fármaco-modelo, nesse caso, a sinvastatina. Realizaram-se testes de caracterização e estabilidade dessa nanoestrutura. Avaliou-se a cito e genotoxicidade das nanocápsulas em células mononucleares de sangue periférico e desenvolveu-se um produto intermediário (nanocápsulas de sinvastatina em pó) para ser usado posteriormente pela indústria farmacêutica. A blenda polimérica de PMMA-PEG foi obtida com alto rendimento, 94 ± 3,7%. O espectro de infra-vermelho mostra as bandas típicas em 3349 cm-1 e 2922 cm-1 correspondente à vibração de alongamento das ligações -O-H e -C-H. Bandas características em 1731 e 1102 cm-1 foram atribuídas ao alongamento -C=O e -C-O-C-. No espectro de 1H-RMN foi observado o sinal de prótons metilênicos em 3,68 ppm (-CH2OCH2-) do PEG e o pico em 3,61 ppm dos prótons do grupamento -OCH3 do PMMA. O peso molecular determinado por GPC foi 101.581 Da e índice de polidispersão foi 5,342. Análises de DSC sugeriram que a mistura é um sistema molecularmente bem disperso e as curvas de TGA indicaram duas perdas de peso em relação a ambos os polímeros. As nanocápsulas produzidas pela blenda polimérica apresentaram tamanho de partícula e índice de polidispersão de 198,2 ± 1,4 nm e 0,08 ± 0,01 para as nanocápsulas brancas e de 194,4 ± 1,7 nm e 0,07 ± 0,00 para as nanocápsulas com sinvastatina. O valor de potencial zeta foi -11,22 ± 3,01 mV para as nanocápsulas com sinvastatina e de -9,19 ± 0,26 mV para as nanocápsulas brancas e a eficiência de encapsulação da sinvastatina foi elevada, 98,64 ± 0,00%. A condição de armazenamento sob refrigeração (± 4 ºC) foi a que melhor garantiu a preservação das características físico-químicas das suspensões ao longo de 90 dias. Os ensaios de cito e genotoxicidade indicaram que as amostras testadas não foram tóxicas e, portanto, são seguras para aplicação biomédica. A liberação do fármaco das nanocápsulas foi mais sustentada do que a sua forma livre e a presença do PEG na blenda polimérica de PMMA-PEG modificou o mecanismo de liberação e aumentou a quantidade de sinvastatina liberada quando comparada com nanocápsulas produzidas apenas com o PMMA. Observou-se 45% de liberação, em 24 horas, da sinvastatina das nanocápsulas produzidas pela blenda de PMMA-PEG e 34% das nanocápsulas produzidas apenas com PMMA, enquanto a sinvastatina não encapsulada foi liberada totalmente em 17 horas. Por fim, a secagem das suspensões por spray-drying foi eficiente e resultou em um produto intermediário cujo rendimento foi de 66,83% e apresentou características físico-químicas adequadas. Assim, podemos concluir que a blenda polimérica foi obtida com sucesso através de um processo simples e eficiente e serviu para o desenvolvimento de um nanocarreador de fármacos. As nanocápsulas produzidas pela blenda polimérica promoveram uma liberação sustentada do fármaco indicando que estas nanocápsulas são bons candidatos para uso como transportadores de fármacos.

Sabe-se que diversas regiões do cérebro humano trabalham em sincronia, mesmo anatomicamente separadas, sugerindo conexões funcionais e estruturais. Dessa forma, nosso cérebro pode ser considerado uma rede que pode ser estudada para diferenças entre indivíduos e entre tarefas, em que os nodos podem ser diferentes regiões e as arestas podem ser medidas de conectividade funcional entre séries temporais de um sinal de ressonância magnética de cada região. Neste estudo, propomos analisar como conectividade funcional e parâmetros de rede cerebral se relacionam com desempenho intelectual e um estado de atenção sustentada. Foram adquiridas imagens de ressonância magnética de 30 indivíduos saudáveis jovens em estado de repouso e de atenção sustentada, a partir delas foram calculadas as conexões funcionais entre 90 regiões cerebrais usando o coeficiente de correlação entre pares de series temporais. Destes sujeitos foram estimados sete índices de inteligência a partir da aplicação do teste WAIS-III. As matrizes de conectividade evidenciariam um comportamento de rede complexa de mundo pequeno para limiares entre 0,2 e 0,5. Não foram encontradas associações entre parâmetros globais das redes ponderadas em estado de repouso e os índices de inteligência. Conectividade funcional e alguns parâmetros de rede locais evidenciaram correlações com pontuações de inteligência, principalmente nas regiões frontal, pré-central, parietal e occipital, giro fusiforme e supramarginal e caudado. Embora o p-valor não-corrigido seja bem pequeno e/ou haja simetria entre hemisférios em alguns resultados, ao ser considerado o efeito de múltiplas comparações para análise inteira não foram encontradas associações estatisticamente significativas, por isso as análises foram corrigidas para cada região (p-valor corrigido pelo FDR<0,05). Ainda assim, possivelmente um aumento do número de sujeitos levaria a resultados mais conclusivos. Não foram encontrados resultados que confirmassem a hipótese de que, para indivíduos normais, haveria uma maior anti-correlação de redes extrínsecas e intrínsecas como um todo para o estado de atenção focada em relação ao estado de repouso. Entretanto, durante o estado de atenção sustentada, foram encontradas algumas diferenças estatisticamente significantes nas conexões locais dentro das redes positivas e negativas à tarefa, evidenciadas por um aumento na magnitude das correlações positivas ou negativas durante a atenção sustentada, além de uma tendência de anti-correlação em conexões entre regiões positivas e negativas à tarefa. / It\'s known that some regions of the human brain work synchronously, even if they are anatomically separated, suggesting functional and structural connections. In this way, our brain can be considered a network that can be studied for individual or task differences and in which nodes can be the different regions and edges can be the measurements of functional connectivity between blood oxygen level-dependent signal time series from each region. In this study, we aim to analyze how functional connectivity and brain network parameters relate to intellectual performance and to sustained attention state. Resonance Magnetic images were acquired in 30 healthy young volunteers in resting and attentional state. The functional connections between 90 brain regions were computed from them using correlation coefficient between pairs of temporal series. Seven intelligence indices were estimated from these subjects through WAIS-III test application and associations between functional connectivity values or brain network parameters were sought. Connectivity matrices evidenced a small-world complex network behavior for thresholds between 0.2 and 0.5. No associations between global parameters using weighted networks were found. Functional connectivity and network parameters have evidenced some correlations with intelligence scores, mainly in frontal, pre-central, parietal, occipital regions, fusiform and supramarginal gyrus and caudate nucleus. Even that the uncorrected p-value was small and/or there was symmetry between hemispheres in several results, statistical significant associations were not found considering multiple comparisons correction for the entire analysis, therefore the analysis were corrected for each region (FDR corrected p-value <0.05). Even, increasing the number of subjects possibly would get more conclusive results. Results corroborant to the initial hypothesis of greater anti-correlation between default mode network and task-positive regions were not found for the sustained attention state. However, during sustained attention state, some statistically significant differences in local connections within task-positive and negative regions were found, evidenced by the increase of the strength of positive and negative correlations, besides of a trend of anti-correlation in connections between task-positive and negative regions.

A hipóxia mantida de curta duração (HM) está associada a alterações cardiorrespiratórias e ao desencadeamento de processo inflamatório em humanos e modelos experimentais. Ademais, há evidências de que a HM pode alterar a transmissão sináptica na região do Núcleo do Trato Solitários (NTS). No presente estudo, utilizamos a minociclina, um inibidor da ativação microglial e antiinflamatório, para avaliar a influência da inflamação desencadeada pela HM sobre a neurotransmissão glutamatérgica nos neurônios do NTS que enviam projeções para a região ventrolateral da medula (NTS-VLM). A hipótese geral do nosso estudo foi a seguinte: a HM induz processo inflamatório no tronco encefálico, o qual contribui para o aumento da neurotransmissão glutamatérgica em neurônios NTS-VLM, colaborando para a elevação da pressão arterial média (PAM) observada nestes ratos. Embora tenhamos observado aumento da pressão arterial média em ambos os grupos de ratos tratados com veículo (solução salina + água destilada, ip) ou minociclina [(30mg/Kg ip por 3 dias) submetidos a 24h de HM (FiO2 0.1) em relação aos seus respectivos grupos controle (FiO2 0,28), o aumento da MAP foi menor nos ratos previamente tratados com minociclina. Os registros eletrofisiológicos utilizando a técnica de whole cell patch-clamp mostraram que a HM não produziu alterações nas propriedades ativas e passivas dos neurônios NTS-VLM. No entanto, os neurônios de ratos submetidos a HM apresentaram aumento nas correntes glutamatérgicas espontâneas e evocadas pelo estímulo do trato solitário. Esse grupo de animais também apresentou aumento no número de microgliais na região do NTS. As alterações mencionadas foram atenuadas pelo tratamento prévio com minociclina. Concluímos que a inflamação induzida pela HM contribui para o aumento da neurotransmissão glutamatérgica nos neurônios NTS-VLM o qual poderia estar relacionado com a hipertensão arterial observada nestes ratos. / Short-term Sustained hypoxia (SH) is associated with cardiorespiratory changes and inflammatory process in humans and experimental models. There is also evidence that SH can change the synaptic transmission in the nucleus tractus solitarius (NTS) region. Here we use the minocycline, an anti-inflammatory and microglial inhibitor, to evaluate the role of inflammation triggered by SH on the excitatory neurotransmission in the NTS neurons sending projections to the ventrolateral medulla (NTS-VLM). We hypothesized that SH induces brainstem inflammatory process, which may contribute to increase in excitatory neurotransmission and excitability of the NTS-VLM neurons, collaborating to the high blood pressure observed on these rats. Although we have observed increased MAP in both groups of rats treated with vehicle (saline + distilled water, i.p) or minociclina [(30mg/Kg i.p for 3 days) submitted to 24h of SH (FiO2 0.1) in relation to their respective control groups (FiO2 0.28), the MAP increase was lower in rats treated with minociclina. The whole cell patch-clamp recordings showed that SH produced no changes in active properties of NTS neurons. However, neurons of rats submitted SH presented an increase in the glutamatergic neurotransmission and the number of microglial at the NTS region. These increases were prevented in the groups previously treated with minociclina. We conclude that inflammation induced by SH contributes to the increased excitatory neurotransmission in NTS-VLM neurons that could be associated to high blood pressure observed in these rats.

Apesar da existência de uma quimioterapia, a tuberculose (TB) ainda permanece como uma das principais causas de mortalidade no mundo, especialmente nos países em desenvolvimento, em grande parte devido à epidemia da AIDS. Geralmente, a atual terapia da TB é eficiente, no entanto, ela implica em um longo tratamento com efeitos colaterais não desejáveis e consequentemente com pouca adesão. Tem sido relatada uma crescente incidência de cepas de Mycobacterium tuberculosis resistentes a múltiplos fármacos, sendo que uma das maiores razões para isso é a terapia ineficaz, provavelmente devido à carência na adesão. Portanto, a busca por novos fármacos e com o desenvolvimento de uma terapia eficiente para a TB, que aumente a adesão do paciente e reduza o surgimento de cepas resistentes á múltiplos fármacos é muito importante. A microencapsulação pode ser usada de forma segura para a liberação sistêmica de fármacos e também para direcionar a ação para o sítio de infecção. Dessa forma, um análogo sintético de neolignana (ASN) que apresentou destacada aitividade in vitro contra o M. tuberculosis foi encapsulado em micropartículas de co-polímeros do ácido lático e glicólico (PLGA) para a liberação sustentada deste composto. Tipos diferentes de micropartículas de PLGA contendo este fármaco foram desenvolvidas pela técnica de evaporação de solvente e posteriormente, elas foram avaliadas. A formulação contendo o ASN que exibiu a melhor eficiência de encapsulação e também demonstrou uma liberação sustentada foi verificada em um modelo de camundongo infectado com TB. O tratamento com as formulações de micropartículas resultou em uma depuração dos bacilos comparado aos controles. Além disso, os resultados da análise de cortes histológicos sugerem que estas formulações não induzem a nenhuma hepatotoxicidade. Estes resultados demonstraram a possibilidade de se usar formulações de micropartículas contendo o ASN para a obtenção de resultados efetivos em modelos murinos de TB, e indicaram o potencial do ASN como um novo fármaco antimicobacteriano. / Despite the existence of chemotherapy, tuberculosis (TB) still remains a leading cause of mortality of worldwide, especially in the developing countries, in part due to the AIDS epidemic. Current therapy of TB is generally effective, however, it involves a long course of treatment with unwanted side effects and consequently with poor compliance. An increasing incidence of multiple-drug-resistant strains of Mycobacterium tuberculosis (MDR-TB) has been related and one of the major reasons for this is inefficient therapy, probably due to lack of compliance. Thus, it is very important to search for new drugs with a development of an effective therapy for TB that improves patient compliance and reduces the emergency of MDR-TB. Microencapsulation technology can be used to safely deliver drugs systemically and target drugs to the site of infection. In this way, a synthetic analogue of a neolignan (SAN) that had a remarkable in vitro activity against M. tuberculosis was entrapped in poly (D,L-lactide-co-glycolide) (PLGA) microparticles for sustained delivery of this compound. Different types of PLGA microparticles containing this drug were developed by the solvent evaporation technique and then they were evaluated. A microparticle formulation containing the SAN that exhibited the best entrapment efficiency and also showed a sustained release was assessed in an infect mouse model of TB. Treatment with the microparticles formulation resulted in a clereance of bacilli compared to the controls. Besides that, results suggest that these formulations do not induce any hepatotoxicity on a histopathology basis. These results demonstrated the ability to use microparticles formulations containing SAN to achieve effective results in a murine TB model and indicate the potencial of SAN as a novel antimycobacterial drug.

A bas nombre de Reynolds, le concept de voilure battante apparaît comme une alternative auxconcepts conventionnels de voilure fixe et voilure tournante. Dans le cadre d’une applicationpratique (micro-drones ou MAVs), l’évaluation de l’adaptabilité d’un tel mode de sustentationrequiert la compréhension fine des principaux mécanismes aérodynamiques mis en jeu et de leurimpact sur les efforts résultants. Ces derniers se caractérisent par une instationnarité forte et descomportements complexes.Les travaux de cette thèse se concentrent sur l'étude du mouvement de vol battu à bas Reynolds (del'ordre de 1000), dans une configuration de vol stationnaire. Le modèle est constitué d’une ailerectangulaire à profil symétrique animé d’un mouvement couplé de battement et de tangage. Cemode de sustentation se caractérise par la génération à proximité de l'aile de structurestourbillonnaires plus ou moins persistantes influant fortement les efforts appliqués à l’aile.L'objectif consiste à analyser l'évolution des mécanismes instationnaires et des efforts en résultant.L'étude porte en particulier sur une analyse approfondie d'un cas de référence, comparé ensuite àd'autre résultats lors d'une étude paramétrique portant sur l’influences de l'allongement d'une part, etde la cinématique du mouvement d'autre part.Les moyens d’investigations adoptés pour mener cette étude sont à la fois numériques etexpérimentaux, L’analyse repose d’une part sur une approche numérique DNS utilisant unetechnique de maillage « chimère », et d’autre part sur des mesures en bassin de type PIV 3D-3Crésolues en temps. La mesure directe des efforts instationnaires de faible niveau étant difficilementenvisageable, une part importante du travail a consisté à adapter une méthode d’évaluation desefforts par bilan de quantité de mouvement à partir des champs de vitesse PIV résolus en temps. Lespoints durs de cette approche, en particulier l’évaluation de la pression à partir des champs devitesse, font l’objet d’une attention particulière. / A low Reynolds number, flapping wings appears as an alternative to conventional concepts of fixed wings and rotary wings aircrafts. In the context of a practical application (micro air vehicles, MAVs), assessing the suitability of such mode of lift generation requires a detailed understanding of the key aerodynamic mechanisms involved and their impact on resulting forces. These are characterized by a strong unsteadiness and complex behaviors.This work focuses on the study of flapping flight at low Reynolds (around 1 000), in a hover configuration. The model consists of a rectangular wing with a symmetrical profile in a flapping motion. This mode is characterized by the generation of vortex structures more or less persistent that strongly influence the forces applied to the wing.The objective is to analyze the evolution of unsteady mechanisms and resulting forces. The study focuses in particular on a thorough analysis of e reference case, then compared to other results in a parametric study on the influence of aspect-ratio on the one hand, and on the kinematic of movement on the other.The means of investigation adopted for this study are both numerical and experimental. The analysis is based in part on a numerical approach using a DNS meshing technique “chimera”, and on experimental approach with 3C-3D TR-PIV measures. Direct measurement of unsteady low forces being difficult to consider, an important part of the work was to adapt a method for evaluating loads by applying momentum equation using PIV velocity fields. The bottleneck of this approach which is the evaluation of the pressure from the velocity fields is subject to special attention.

Doctor of Philosophy / Department of Civil Engineering / Asadollah Esmaeily / Over the past 30 years, FRP composites (carbon, glass, or aramid fibers) have arisen as a method of retrofitting existing reinforced concrete structures to bring them up to current code standards of confinement and ductility. The development of stress-strain models for FRP confined concrete began with the adaptation of steel confinement models then progressed to models specifically developed based on test results from FRP confined specimens. State of the art stress-strain models for FRP confined concrete models may now be validated against a wide variety of published experimental results. Recent publications show researchers branching out and looking at other aspects of FRP confined concrete behavior, including the impact of sustained service loads on long term and ultimate behavior. An experimental program which examines the effects of sustained service loading on the ultimate axial performance of FRP confined concrete is presented. The program's purpose is to determine whether or not a material model developed without the presence of a sustained load accurately predicts the ultimate stress-strain response of FRP confined concrete previously subjected to a sustained service load. Equipment and procedures were developed to model the critical events in a building life cycle: construction, sustained service loading, minor critical events, rehabilitation, and ultimate performance. Varying the order of these events produces a simulated life cycle allowing analysis of the impact of strain history on ultimate performance. The results of the experimental program indicate that the presence of a sustained service load changes the expected failure mode from FRP rupture to FRP de-lamination and the stress-strain response of a specimen is approximately 10% below published models when sustained service loads are included in the life cycle. A comprehensive modeling process is proposed for modeling significant events in a structure's life cycle. Impacts on earthquake engineering and reliability studies are addressed and future research suggested. This research shows that life cycle modeling can improve the design and rehabilitation of structures so that they meet safety requirements in future seismic events.

We propose making an empirical application of the temporal view of stakeholder management theory by applying it in the particular context of the Canadian wind industry. The temporal view builds on insights from the resource-based view (RBV), institutional theory, and stakeholder salience theory. We argue that both early stage competitive advantage and late stage sustained competitive advantage could be dependent on the use of salient stakeholders as a special network of resources. We contribute to the literature in various ways. First we determine an empirical list of five salient stakeholders specific to the wind industry. Second, we show that, at early stages, the moderating effects of firm size and market conditions determines stakeholder support or rejection. Lastly, we show that, at late stages, the sustainability equation must take into account the introduction of new salient stakeholders. Also, we make practical recommendations for industry players and policy makers. We reached theory refinement by adopting an exploratory qualitative methodology based on interviews with seven cases of large and small wind firms operating in different electricity market types and provinces across Canada.

A harsh, cold, and icy environment is of no surprise to the conditions of a winter climate, where the wide use of de-icing salts on roads and highways allows for the initiation of chloride-induced corrosion of the reinforcement of concrete structures; a reduced service life, loss of structural integrity, visible damages, and ultimately structural failure are among the many unwanted effects of rebar corrosion. Chloride ingress into concrete has been extensively studied for the last four decades; however, most of the relevant research to date does not take into account the effects of sustained loading on chloride transport properties. Therefore, the objectives of this study were to investigate the influence of sustained compressive and tensile stresses on chloride ingress into concrete, and ultimately to understand what the effect of sustained stress is on chloride penetration depth, on chloride concentration by % weight of concrete, and on apparent diffusion coefficients by comparing results to those of unloaded control specimens. To achieve these objectives, six post-tensioned and four non-reinforced control concrete beams were constructed with different water-to-cement (w/c) ratios and completely submerged in a 4-5% de-icing salt (NaCl) solution for 12 weeks, allowing chloride transfer to be completely governed by continuous diffusion. The effects of supplementary cementing material on chloride ingress are also studied. Concrete beams were post-tensioned to induce variable sustained compressive and tensile stresses along the beam. After 12 weeks of exposure, beams were fractured at specific locations and sprayed with a 0.1N silver nitrate (AgNO3) solution to determine average penetration depths; chloride concentration profiles were obtained from potentiometric titration of grinded powder samples. Apparent chloride diffusion coefficients were then obtained from the results of spraying AgNO3 and titration, the latter by non-linear regression curve-fitting to Fick’s second law of diffusion. A good agreement between results from both methods reveals that the use of AgNO3 in field is acceptable in predicting the rate of chloride ingress in concrete sustaining stress. The chloride diffusivity for each profile, relative to that of the unstressed section, was related to the compressive and tensile stresses in the concrete section. The experimental results indicate the dependence of chloride ingress and concentration on the type and level of sustained stress. An analysis of the results to study the effects of the w/c ratio using colourimetric (silver nitrate spray) and potentiometric titration methods was also completed.

Orientador: Francisco Benedito Teixeira Pessine / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-24T11:11:00Z (GMT). No. of bitstreams: 1 Barboza_AnaClaudiaRuedaNery_D.pdf: 6657696 bytes, checksum: 97ec0acb030267fe87c6983093726afb (MD5) Previous issue date: 2013 / Resumo: O objetivo foi deste trabalho foi obter, caracterizar e avaliar suspensões aquosas de micropartículas poliméricas bioadesivas para liberação sustentada do antisséptico digluconato de clorexidina (CHG), trabalhando somente em meio aquoso e com substâncias reconhecidamente biocompatíveis e de baixa toxicidade, para potencial aplicação na cavidade bucal. As micropartículas foram obtidas por complexação dos polieletrólitos quitosana e alginato de sódio, com auxílio de íons cálcio, e da clorexidina. O método de obtenção desenvolvido permitiu obter suspensões com distribuição de diâmetros de partículas adequada e boa estabilidade. Através de delineamento experimental fatorial, avaliou-se o efeito dos principais componentes da suspensão sobre o diâmetro médio das micropartículas e sobre a incorporação de CHG. A liberação de CHG em meio simulador da cavidade oral (saliva artificial) ocorreu de forma gradual e por longos períodos, indicando existência de interação entre o ativo, de natureza catiônica, e as terminações aniônicas do biopolímero alginato. A cinética de liberação de sistemas onde tais interações ocorrem é complexa e sua compreensão envolve diversos fenômenos físico-químicos, que se procurou identificar e discutir. Realizou-se, de forma simplificada, a modelagem da cinética de liberação através do modelo matemático semiempírico de Peppas-Korsmeyer, o que também indicou a combinação de diferentes fenômenos influenciadores da liberação. Testes preliminares de eficácia antimicrobiana indicaram que a clorexidina do sistema de liberação sustentada manteve sua eficácia sobre os microrganismos padrão avaliados em comparação com a clorexidina livre / Abstract: The objective of this project was to obtain, characterize and evaluate aqueous suspensions of bioadhesive polymeric microparticles for sustained release of the antiseptic chlorhexidine digluconate (CHG), working in aqueous media and with substances recognized as biocompatible and of low toxicity, for potential application to the oral cavity. Microparticles were obtained by complexation of the polyelectrolytes chitosan and sodium alginate, with pre-gelation by calcium ions, and CHG. The method of obtention developed resulted in suspensions with adequate particle size distribution and good stability. Through factorial experimental design, the effect of main suspension components on the median particle diameter and CHG incorporation was evaluated. Chlorhexidine release in oral cavity simulating media (artificial saliva) occurred gradually and for extended periods, indicating the presence of interactions between the cationic active substance, and the anionic moieties of the alginate biopolymer. The release kinetics where those interactions occur is somewhat complex and its understanding involves various physicochemical phenomena that we tried to identify and discuss. Simplified modeling of the release kinetics through the Peppas-Korsmeyer semi-empirical mathematical model was done, also indicating the combination of various release-influencing phenomena. Preliminary microbiological tests indicated that sustained-release CHG kept its efficacy against standard microorganisms evaluated in comparison to free CHG / Doutorado / Físico-Química / Doutora em Ciências