O remifentanil é um opióide potente comparável ao fentanil, mas, possui rápida eliminação plasmática e por isso necessariamente deve ser adiministrado por infusão contínua. A administração transdérmica pode liberar fármacos de forma prolongada, contínua e controlada. Características que facilitariam a administração do remifentanil, contornariam sua limitação farmacocinética e ampliariam os casos em que este fármacos seria útil. Lipossomas deformáveis são formados por fosfolipídios e por tensoativo que normalmente é um surfactante de cadeia simples que aumenta a flexibilidade da bicamada lipídica da membrana e torna os lipossomas deformáveis. Os lipossomas deformáveis são capazes de disponibilizar, de forma expressiva, várias substâncias transdermicamente incluindo macromoléculas e podem ser um eficiente sistema de liberação controlada de remifentanil. O presente estudo desenvolve diferentes dispersões de lipossomas deformáveis de remifentanil e caracteriza essas dispersões quanto a tamanho de diâmetro dos lipossomas, eficiência de encapsulação dos lipossomas, elasticidade da membrana, permeação e retenção cutânea in vitro. As dispersões de lipossomas deformáveis preparadas foram compostas por remifentanil, fosfatidilcolina de soja, tensoativo tween 80 ou tween 20 e etanol a 10% ou a 20% e foram preparadas por dois métodos: sonicação e hidratação de filme e sonicação. O tamanho e a distribuição de tamanho foram obtidos por espalhamento dinâmico de luz, a eficiência de encapsulação por diálise, a elasticidade por filtração, seguido de determinação do tamanho. Células de difusão de Franz e pele de orelha de porco foram usadas para estudar a permeação e a retenção cutânea in vitro. Os lipossomas deformáveis preparados apresentaram pequeno diâmetro (40 a 71 nm) quando comparado a outros na literatura e seus tamanhos foram dependentes da formulação. Todos os lipossomas deformáveis preparados apresentaram boa elasticidade e permeação dependente da eficiência de encapsulação e do tamanho de diâmetro. A solução hidroetanólica com remifentanil e a mistura física dos excipientes com remifentanil não apresentaram permeação e retenção. A eficiência de encapsulação dos lipossomas deformáveis é coerente com outros resultados na literatura e foi dependente da formulação e do método de preparação. A avaliação da permeação de dispersões de lipossomas deformáveis com remifentanil não encapsulado foi feita para se obter informações sobre os mecanismos de ação pelos quais estes lipossomas agem. Verificou-se que o transporte de substâncias encapsuladas nos lipossomas foi o mecanismo de maior importância / Remifentanil is a potent opioid comparable to fentanyl. Remifentanil has rapid systemic elimination and, therefore, it necessarily has to be administered by continuous parenteral infusion. Transdermal delivery can provide extended, continuous and controlled delivery of drug. Characteristics that could make the remifentanil administration easier, could resolve its phamacocinetcs limitation and could enlarge the cases that this drug would be useful. Deformable liposomes consist of phospholipid and surfactant that is often a single chain surfactant that increases the membrane lipid bilayer flexibility and makes the liposome deformable. Deformable liposomes are able to expressively improve skin delivery of many drugs, including macromolecules and could be an efficient controlled delivery system of remifentanil. The aim of this study has been to develop different deformable liposomes dispersions of remifentanil and to characterize those dispersions by liposome diameter size, liposome entrapment efficiency, membrane elasticity and in vitro skin permeation and deposition. The deformable liposomes consisted of remifentanil, soybean phosphatidylcholine, surfactant tween 80 or tween 20, and ethanol at 10% or 20%. They have been prepared by two methods: sonication or conventional mechanical dispersion and sonication. The size was determined by light scattering, the entrapment efficiency by dialysis, the membrane elasticity by filtration and size determination. Franz diffusion cells and ear porcine skin wore used to evaluate the in vitro skin permeation and the skin deposition. The deformable liposomes showed small size (40 a 71 nm) compared with others from literature and their sizes wore dependent of the formulation. All deformable liposomes showed good membrane elasticity and showed permeation that was dependent of the formulation and diameter size. The remifentanil hidroetanolic solution and the excipients physical mixture with remifentanil did not have any permeation and retention. The deformable liposomes entrapment efficiency has been coherent with others literature results and also was dependent of the formulation and preparation method. The permeation of deformable liposomes dispersions wore evaluated to get information about the deformable liposome action mechanisms. The transport of encapsulated substances on liposome was the action mechanism of major importance.

During development, higher organisms grow from a single fertilized egg cell to the adult animal. The many processes that lead to the eventual shape of the developed organism are subsumed as morphogenesis, which notably involves the growth of tissues by repeated rounds of cell division. Whereas coordinated tissue growth is a prerequisite for animal development, excessive cell division in adult animals is the key ingredient to cancer. In this thesis, we investigate the collective organization of cells by cell division and cell death. The multicellular dynamics of growing tissues is influenced by mechanical conditions and can give rise to cell rearrangements and movements. We develop a continuum description of tissue dynamics, which describes the stress distribution and the cell flow field on large scales. Cell division and apoptosis introduce stress sources that, in general, are anisotropic. By combining cell number balance with dynamic equations for the stress source, we show that the tissue effectively behaves as a viscoelastic fluid with a relaxation time set by the rates of division and apoptosis. If the tissue is confined in a fixed volume, it reaches a homeostatic state in which division and apoptosis balance. In this state, cells undergo a diffusive random motion driven by the stochasticity of division and apoptosis. We calculate the effective diffusion coefficient as a function of the tissue parameters and compare our results concerning both diffusion and viscosity to simulations of multicellular systems. Introducing a second material component that accounts for the extracellular fluid, we show that a finite permeability of the tissue gives rise to additional mechanical effects. In the limit of long times, the mechanical response of the tissue to external perturbations is confined to a region of which the size depends on the ratio of tissue viscosity and cell-fluid friction. The two-component description furthermore allows to clearly distinguish the different contributions to the isotropic part of the mechanical stress, i.e., the fluid pressure and the stress exerted by cells. Last but not least, we study the propagation of an interface between two different cell populations within a tissue driven by differences in the mechanical control of the rates of cell division and apoptosis. Combining simple analytical limits and numerical simulations, we distinguish two different modes of propagation of the more proliferative population: a diffusive regime in which relative fluxes dominate the expansion, and a propulsive regime in which the proliferation gives rise to dominating convective flows. / Die Entwicklung höherer Organismen beginnt mit einer einzelnen befruchteten Eizelle und endet beim erwachsenen Tier. Die vielen Prozesse, die zur endgültigen Form des entwickelten Organismus führen, werden als Morphogenese zusammengefasst; diese umfasst insbesondere das Wachstum von Geweben durch wiederholte Zellteilungszyklen. Während koordiniertes Gewebewachstum eine Voraussetzung normaler Entwicklung ist, führt übermäßige, unkontrollierte Zellteilung letztlich zu Krebs. In dieser Arbeit untersuchen wir den Einfluss von Zellteilung und Zelltod auf die Organisation von Zellen in Geweben. Die Dynamik wachsender Gewebe wird durch mechanische Bedingungen beeinflusst, die u.a.~Anlass zu Zellbewegungen sein können. Wir entwickeln eine Kontinuumsbeschreibung der Gewebedynamik, die die mechanischen Spannungen und das Zellströmungsfeld auf großen Skalen beschreibt. Zellteilung und Apoptose wirken als Spannungsquellen, die in der Regel anisotrop sind. Indem wir die Erhaltungsgleichung für die Zellanzahldichte mit dynamischen Gleichungen für die Spannungsquellen kombinieren, zeigen wir, dass sich das Gewebe effektiv wie eine viskoelastische Flüssigkeit verhält, deren Relaxationszeit von Zellteilungs- und Apoptose-Raten abhängt. Wenn das Gewebe in einem gegebenen Volumen eingeschlossen ist, erreicht es einen homöostatischen Zustand, in dem Zellteilung und der Apoptose im Gleichgewicht sind. In diesem Zustand unterliegen die Zellen einer diffusiven Bewegung aufgrund der Stochastizität von Zellteilung und Apoptose. Wir berechnen den effektiven Diffusionskoeffizienten als Funktion der Gewebeparameter und vergleichen unsere Ergebnisse sowohl hinsichtlich der Diffusion und als auch der Viskosität mit numerischen Simulationen solcher vielzelliger Systeme. Die Berücksichtigung der extrazellulären Flüssigkeit als einer zweiten Materialkomponente erlaubt uns zu zeigen, dass eine endliche Permeabilität des Gewebes zusätzliche mechanische Effekte bedingt. Auf langer Zeitskalen bleibt die mechanische Reaktion des Gewebes auf externe Störungen auf einen Bereich beschränkt, dessen Größe vom Verhältnis der Gewebeviskosität zum Permeabilitätskoeffizienten abhängt. Die Zweikomponenten-Beschreibung erlaubt darüber hinaus eine klare Unterscheidung der verschiedenen Beiträge zum isotropen Teil der mechanischen Spannung, d.h., des hydrodynamischen und des von Zellen ausgeübten Drucks. Zuletzt untersuchen wir die Dynamik einer Grenzfläche zwischen zwei verschiedenen Zellpopulationen innerhalb eines Gewebes, die durch Unterschiede in der mechanischen Kontrolle der effektiven Zellteilungsraten angetrieben wird. Mithilfe der Kombination einfacher analytischer Grenzfälle und numerischer Simulationen zeigen wir, dass zwei unterschiedliche Ausbreitungsmodi unterschieden werden können: ein diffusives Regime, in dem relative Flüsse die Expansion der stärker wachsenden Zellpopulation dominieren, sowie ein Regime, in dem die Grenzfläche durch konvektive Strömungen angetrieben wird. / Les organismes supérieurs se développent à partir d\'une seule cellule fécondée jusqu\'à l\'animal adulte. Les nombreux processus qui conduisent à la forme finale de l\'organisme sont connus sous le nom de morphogenèse, qui comprend notamment la croissance des tissus par des cycles répétés de division cellulaire. Alors que la croissance coordonnée des tissus est une condition nécessaire au développement des animaux, la division cellulaire excessive chez les animaux adultes est l\'ingrédient clé du cancer. Dans cette thèse, nous étudions l\'organisation collective des cellules par division et mort cellulaire. La dynamique multicellulaire des tissus en croissance est influencée par des conditions mécaniques et peut donner lieu à des réarrangements ainsi qu\'à des mouvements cellulaires. Nous élaborons une description continue de la dynamique des tissus qui décrit la distribution des contraintes et le champ d\'écoulement des cellules sur de grandes échelles. La division cellulaire et l\'apoptose introduisent des sources de contraintes qui, en général, sont anisotropes. En combinant l\'équation de conservation du nombre de cellules avec des équations dynamiques des sources de contraintes, nous montrons que le tissu se comporte de manière effective comme un fluide viscoélastique avec un temps de relaxation fixé par les taux de division et d\'apoptose. Si le tissu est confiné dans un volume donné, il atteint un état homéostatique dans lequel division et apoptose s\'équilibrent. Dans cet état, les cellules subissent un mouvement diffusif aléatoire dû à la stochasticité de la division et de l\'apoptose. Nous calculons le coefficient de diffusion effectif en fonction des paramètres du tissu et comparons nos résultats concernant à la fois la diffusion et la viscosité à des simulations numériques de tels systèmes multicellulaires. En introduisant un deuxième composant qui représente le liquide extracellulaire, nous montrons qu\'une perméabilité finie du tissu donne lieu à des effets mécaniques supplémentaires. Dans la limite des temps longs, la réponse mécanique du tissu à des perturbations extérieures est confinée à une région dont la taille dépend du rapport entre la viscosité tissulaire et le coefficient de frottement entre les cellules et le liquide extracellulaire. La description à deux composants permet en outre de distinguer clairement les différentes contributions à la partie isotrope de la contrainte mécanique, c\'est-à-dire la pression du fluide et la contrainte exercée par les cellules. Finalement, nous étudions la propagation d\'une interface entre deux populations de cellules différentes, due à des différences dans le contrôle mécanique des taux de division et de mort cellulaire. En combinant de simples limites analytiques et des simulations numériques, nous distinguons deux modes de propagation différents de la population cellulaire la plus proliférante : un régime diffusif dans lequel les flux relatifs dominent l\'expansion, et un régime de propulsion dans lequel la prolifération domine et entraine des flux convectifs.

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Orientador: Marcos Antônio Correa / Resumo: A busca por ativos naturais que apresentem mais de uma função em uma única formulação é pautada em um novo conceito de praticidade e economia, estando em acordo com a visão crítica do consumidor moderno. Neste contexto, a presença dos compostos fenólicos em plantas tem sido estudada por estes apresentarem diversas atividades farmacológicas e cosméticas. Os ácidos hidroxibenzoicos fazem parte desse grupo de compostos orgânicos, sendo o ácido gálico um de seus representantes, conhecido principalmente por sua atividade antioxidante. Um grande número de formulações tópicas contendo antioxidantes tem sido lançado nos últimos anos. O objetivo deste trabalho foi estudar a eficácia do ácido gálico para uso cosmético. Para escolha dos solventes utilizados no estudo levou-se em consideração o desenvolvimento sustentável da pesquisa, ou seja a utilização de solventes verdes. Para a avaliação da atividade antioxidante foram utilizados dois métodos diferentes o DPPH e o ABTS. Também foi realizada a avaliação das atividades despigmentantes, antimicrobiana, citotóxica, bem como estudos da formulação desenvolvida, como: estabilidade, liberação, permeação e retenção, através de experimentos in vitro. Os resultados demonstram que o ácido gálico é um potente antioxidante, suas ações despigmentante e antimicrobiana também foram comprovadas. Pelos estudos de citotoxidade in vitro pode-se constatar que a porcentagem de ácido gálico utilizada na emulsão desenvolvida é segura. A validação da metodol... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The search for natural assets that present more than one function in a single formulation is based on a new concept of practicality and economy, being in agreement with the critical view of the modern consumer. In this context, the presence of phenolic compounds in plants has been studied because they present several pharmacological and cosmetic activities. Hydroxybenzoic acids are part of this group of organic compounds, and gallic acid is one of its representatives, known mainly for its antioxidant activity. A large number of topical formulations containing antioxidants have been launched in recent years. The objective of this work was to study the efficacy of gallic acid for cosmetic use. To choose the solvents used in the study took into consideration the sustainable development of the research, ie the use of green solvents. For the evaluation of the antioxidant activity, two different methods were used: DPPH and ABTS. The evaluation of depigmenting activities, antimicrobial, cytotoxic, as well as studies of the developed formulation, such as: stability, release, permeation and retention, were carried out through in vitro experiments. The results demonstrate that gallic acid is a potent antioxidant, its depigmenting and antimicrobial actions have also been proven. By in vitro cytotoxicity studies it can be verified that the percentage of gallic acid used in the developed emulsion is safe. The validation of the methodology by HPLC ensured all parameters necessary for the s... (Complete abstract click electronic access below) / Mestre

L'exploitation des ressources non conventionnelles de roches mères telles que les schistes gazeux contribue de plus en plus au mix énergétique mondial en raison de la raréfaction des ressources conventionnelles. L'exploitabilité de ces réservoirs repose principalement sur la qualité, la teneur et le type de matière organique qu'ils contiennent. En effet, il est admis que plus de la moitié des hydrocarbures présents dans les schistes sont adsorbés dans la matière organique solide, appelée kérogène, dont la structure est microporeuse et amorphe, et qui représente à la fois la source et le réservoir d'hydrocarbures. Le kérogène se trouve sous forme dispersée dans la matière minérale et représente environ 5% de la masse totale de la roche. La compréhension des propriétés de transport des fluides à l'échelle des micropores, en particulier leur dépendance aux conditions thermodynamiques et aux propriétés structurelles du matériau, revêt une importance cruciale pour l'optimisation de la récupération de ces ressources. De ce point de vue, l'objectif principal de cette thèse vise à bien documenter les propriétés de transport des hydrocarbures à travers les kérogènes et améliorer leur description théorique. Pour ce faire, nous avons fait le choix d'étudier les propriétés de transport des fluides à travers ces matériaux en utilisant une approche numérique basée sur des simulations moléculaires de type dynamique moléculaire et Monte Carlo, conduites sur des modèles moléculaires de kérogène mature et sur un système modèle simplifié. Ceci nous a permis d’explorer les mécanismes de transport à une échelle où l'observation expérimentale est difficile, voire impossible, et également de nous situer dans des conditions thermodynamiques supercritiques (haute pression, haute température) caractéristiques des réservoirs de gaz de schiste. La première partie de ce travail a consisté à étudier les propriétés de transport et d'adsorption des fluides purs dans des structures de kérogène mature reconstruites par simulations moléculaires. Ensuite, la dépendance des propriétés de transport aux variations des conditions thermodynamiques (température à gradient de pression fixe) ainsi qu'à la distribution de tailles de pores a été étudiée. Concernant le deuxième objectif, afin de mieux comprendre et modéliser la diffusion des fluides à l'échelle d'une constriction microporeuse entre deux pores, nous avons étudié un système modèle constitué d'une seule fente microporeuse formée dans un solide mono-couche. L'étude a consisté à simuler la diffusion de transport d'un fluide à travers la constriction en variant les paramètres géométriques (rapport d’aspect entre la largeur du pore et la taille des molécules diffusantes) et thermodynamiques (température, chargement en fluide). Ces résultats de simulations ont été comparés aux prédictions d'un modèle théorique, fondé sur la théorie cinétique des gaz et la mécanique statistique classique, qui prend en compte l'effet de la température sur la porosité accessible ainsi que l'effet du chargement en fluide à l'entrée du seuil de pore. Un bon accord a été observé entre les valeurs simulées des coefficients de diffusion et les prédictions du modèle proposé. Ce système a ainsi contribué à la compréhension des phénomènes de tamisage moléculaire survenant lors du franchissement d'une constriction microporeuse, inhérents au transport de fluides dans les matériaux microporeux tels que le kérogène. / The share of unconventional resources in the global energy mix is expected to rise because of the shortage of conventional fossil resources. The major part of these unconventional resources are found in source rocks such as gas shales. The profitability of shale reservoirs strongly depends on the quality, type and content of organic matter contained in the rock. Indeed, it is admitted that more than half of the hydrocarbons stored in the shale are adsorbed in the solid organic matter, the so-called kerogen. The latter exhibits a microporous amorphous structure, and acts as both the source and the reservoir of hydrocarbons. Kerogen is finely dispersed in the mineral matrix and represents about 5% of the total mass of the rock. The understanding of the transport of fluids at the microporous scale is of crucial importance for optimizing the recovery of these resources. More specifically, how the structural properties of the microporous material and thermodynamic conditions influence its transport properties is an open question. In this regard, the main objective of this thesis is to document the transport properties of hydrocarbons through kerogens and to improve their theoretical description. To do so, we opted for a numerical approach based on molecular simulations of molecular dynamics and Monte Carlo codes performed on molecular models of mature kerogen, as well as simplified model systems. We thus explored transport mechanisms at the molecular scale, at which experimental observations are difficult, if not impossible. Supercritical thermodynamic conditions (high pressure, high temperature) were considered, which are characteristic of shale gas reservoirs. The first part of this work has consisted in studying the transport and adsorption properties of pure fluids in mature kerogen structures reconstructed by molecular simulations. We studied the dependence of the transport properties on the variations of the thermodynamic conditions (pressure gradient at a fixed temperature) as well as the influence of the pore size distribution. In order to better understand and describe the diffusion of fluids at the scale of a microporous constriction between two pores, the second objective of this thesis focused on a model system, which consisted of a single-layer solid with a slit aperture of controllable width. We simulated the diffusional transport of simple fluids through the constriction for various geometrical parameters (aspect ratio between the width of the pore and the size of the diffusing molecules) and thermodynamic conditions (temperature, fluid loading). These simulations results have been compared to the predictions of a theoretical model, based on the kinetic theory and classical statistical mechanics, which accounts for the effect of temperature on the accessible porosity and the effect of fluid loading at the entrance of the pore. A good agreement was observed between the simulated values of the diffusion coefficients and the predictions of the proposed model. The investigation of this simplified system helped in understanding the molecular sieving phenomena inherent to the transport of fluids in microporous materials such as kerogen.

Os cuidados com a pele abrangem gama de ações: cuidados com a exposição solar, alimentação balanceada, não tabagismo e alcoolismo e aplicação de produtos cosméticos, dentre outras. Sabe-se que subtâncias antioxidantes, endógenas e exógenas, auxiliam na manutenção do aspecto saudável e jovial da pele. A rutina, flavonoide pertencente à classe dos flavonóis, apresenta intensa atividade antioxidante, sendo empregada na indústria alimentícia, na prevenção ou tratamento da insuficiência venosa ou linfática e na prevenção aos danos causados pela radiação ultravioleta, por exemplo. Porém, a rutina possui taxa reduzida de permeação cutânea. O presente trabalho destinou-se a incorporar a rutina em etossomas, avaliando a segurança in vitro e in vivo, e a eficácia in vitro e ex vivo. As vesículas foram analisadas quanto ao tamanho de partícula, potencial zeta, taxa de encapsulação da rutina, atividade antirradicalar e potencial de irritação in vitro. As formulações foram avaliadas quanto ao valor de pH, características organolépticas, atividade antioxidante in vitro e ex vivo e permeação cutânea ex vivo. Os etossomas, com e sem rutina, foram obtidos por meio técnica de dispersão mecânica seguida de nova hidratação de filme, com partículas em dimensão nanométrica (369,5 e 247,0 nm, respectivamente). O potencial zeta para os etossomas sem rutina correspondeu à -39,3, enquanto que para aqueles com rutina foi -19,6. A rutina associada ao sistema etossomal foi igual a 80,1%. A rutina nas vesículas etossomais foi capaz de manter o potencial antirradicalar do flavonoide, verificado em ensaio in vitro. Os etossomas com rutina demonstraram-se seguros por meio dos ensaios in vitro e in vivo, sendo aplicados em ensaio posterior de permeação cutânea ex vivo, em voluntários. Foi observada taxa de permeação cutânea superior da rutina em etossomas em comparação com a rutina livre, assim, etossomas contendo rutina tornam-se um possível ingrediente ativo para adição em dermocosméticos destinados para uso contra o envelhecimento precoce. / Skin care covers a range of actions: limited sun exposure, a balanced diet, non smoking and non-alcoholism, and application of cosmetics. It is known that antioxidants, both endogenous and exogenous substances, assist in maintaining a healthy and youthful appearance of the skin. Rutin, a flavonoid belonging to the class of flavonols, has intense antioxidant activity and it is used in the food industry, in the prevention or treatment of venous or lymphatic insufficiency, and to prevent the damage caused by UV radiation. However, rutin has low skin permeation rate. This study was designed to incorporate rutin in ethosomes, evaluating their safety in vitro and in vivo, and efficacy in vitro and ex vivo, in order to assess the improvement of the skin permeation of the flavonoid. The ethosomes with and without rutin were obtained by a mechanical dispersion technique followed by a new lipid film hydration. The ethosomes were analyzed for particle size, zeta potential, encapsulation rate of rutin, antiradical activity and in vitro irritation potential. The formulations were evaluated for pH, organoleptic characteristics, antioxidant activity in vitro and ex vivo and ex vivo skin permeation. The association of rutin with ethosomal vesicles was able to mantain the antiradical potential of flavonoid. The ethosomes with rutin have shown to be safe through in vitro and in vivo safety assays, being applied in subsequent ex vivo tests to evaluate the skin permeation of rutin in human volunteers. A higher skin permeation rate was observed for rutin in ethosomes compared to the free rutin, thus rutin loaded ethosomes have potential as a compound in dermocosmetic formulations for premature aging.

A atividade do óxido nítrico na Química e Biologia não é completamente conhecida. Centenas de artigos são publicados por ano, somente sobre este assunto. Muito mais estudos necessitam ser feitos nesta área. Cientistas no campo da Biologia que queiram estudar como o óxido nítrico se comporta em diferentes sistemas necessitam de algum tipo de composto modelo que libera NO, para auxiliá-los em seus estudos farmacocinéticos. O óxido nítrico (NO) é tão importante que há um grande desejo da sociedade cientifica em obter compostos que possibilitem liberá-lo. Ele apresenta aplicações diversificadas. Investigando a cinética de liberação de NO, poderemos saber como o mesmo pode ser aplicado nas mais diversas atividades, tais como: controlar a relaxação cardiovascular, pressão sanguínea ou mesmo o desenvolvimento do câncer. Neste trabalho sintetizamos e caracterizamos cis-[RuCl(NO)(bpy)2](PF6)2 e trans-[RuCl(NO)(bpy)2](PF6)2. Os valores obtidos para o complexo cis-[RuCl(NO)(bpy)2](PF6)2 por voltametria cíclica foram: E1/2= 0,21 V vs Fe ;UV-vis(298nm,332nm); FTIR:νNO= 1930 cm-1 ; para o complexo trans-[RuCl(NO)(bpy)2](PF6)2 a voltametria cíclica apresentou E1/2= 0,19 V vs Fe ;UV-vis (298nm,312nm); FTIR:νNO= 1921 cm-1. O desenvolvimento de sistemas de liberação de NO a partir de complexos nitrosilos de rutênio podem ser discutidos com particular referencia ao produto de necessidade médica. Uma compreensão apropriada das propriedades da molécula doadora de NO, em um sistema de liberação de fármaco, é essencial antes do uso de interesse na terapia clinica. Foram estudadas as propriedades físico-quimicas dos compostos cis / trans-[RuCl(NO)(bpy)2](PF6)2 em emulsão água / óleo (A/O) e avaliadas as taxas de liberação de NO encapsulado na fase aquosa interna da emulsão. O perfil de liberação de NO pelos complexos cis / trans-[RuCl(NO)(bpy)2](PF6)2 também foi estudada utilizando-se membrana de acetato de celulose, cujos resultados mostram um comportamento não linear com taxa de 4,53x10-4 mol/cm2 para a espécie cis-[RuCl(bpy)2NO]2+ e 3,33x10-4 mol/cm2 para a espécie trans-[RuCl(bpy)2NO]2+. A permeação transdérmica e a acumulação dos complexos cis /trans-[RuCl(bpy)2NO]2+ sobre a pele foi também estudada utilizando-se pele da orelha de porco. Os dados obtidos por espectro de absorção UV-visível exibiram aumentos da concentração acumulada dos complexos sobre a pele quando os mesmos foram formulados em emulsão na forma livre, para ambos os isômeros. Tais resultados mostraram que os complexos ficaram acumulados principalmente na epiderme. Também foram observados espectros UV-visível, utilizando-se acoplado um sensor seletivo para NO, que demonstraram que é possível liberar NO a partir dos complexos cis / trans-[RuCl(NO)(bpy)2](PF6)2 através da eletro-redução em meio aquoso ou em emulsão A/O, quando um potencial de 0,00 V vs Ag/AgCl foi aplicado. Estes resultados nos sugerem que o sistema de complexos de rutênio nitrosil veiculados em emulsão A/O poderia ser utilizado com sucesso no desenvolvimento de um sistema de liberação prolongada de NO / Nitric oxide activity in chemistry and biology is not yet fully discovered. There are more than 5,000 papers alone on this subject each year. A lot more work needs to be done in this area. For people in biology who want to study how nitric oxide works in different systems, they need some kind of model compound to release nitric oxide to help them do their pharmacokinetic studies. Nitric oxide (NO) is very important, there is a great need in the scientific society to have a compound that can release it. There are many applications. By investigating the nitric oxide releasing kinetics, we will know if it can be applied to any of these activities such as controlling cardiovascular relaxation, blood pressure or cancer growth. We have synthesized and characterized cis-[RuCl(NO)(bpy)2](PF6)2 and trans-[RuCl(NO)(bpy)2](PF6)2. We found that cis-[RuCl(NO)(bpy)2](PF6)2 show by cyclic voltammetry E1/2= 0,21 V vs Fe ;UV-vis(298nm,332nm); FTIR:νNO= 1930 cm-1 and trans-[RuCl(NO)(bpy)2](PF6)2 show by cyclic voltammetry E1/2= 0,19 V vs Fe ;UV-vis(298nm,312nm); FTIR:νNO= 1921 cm-1. The development of delivery systems for nitric oxide release from nitrosyl ruthenium complexes could be discussed with particular reference to the products of unmet medical needs. A proper understanding of the properties of the NO donor molecule in a drug delivery system is essential before an appropriate use in clinical therapy. We have studied the physical and chemical properties of cis/trans-[RuCl(bpy)2NO](PF6)2 in a water/oil emulsion (W/O) and evaluate release rates of nitric oxide encapsulated in internal aqueous phase. The cis/trans-[RuCl(bpy)2NO]2+ release was also studied with a cellulose membrane, which show non-linear behavior with rate of 4,53x10-4 mol/cm2 for cis-[RuCl(bpy)2NO]2+ and 3,33x10-4 mol/cm2 for trans-[RuCl(bpy)2NO]2+. The transdermal permeation and skin accumulation of is/trans-[RuCl(bpy)2NO]2+ on the percutaneous penetration was also studied through pig skin. Data showed that UV-vis absorber exhibited increases in skin accumulation when is formulated in emulsions in free form for both isomers. Those results showed that the complexes were mainly accumulated on epidermis. We also found by UV-visible and using a NO sensor that the cis/trans-[RuCl(bpy)2NO]2+ can release NO by electro-reduction in aqueous solution or in W/O emulsion when a potential of 0.0 V vs Ag/AgCl was applied. Those results suggest us that a W/O emulsion system bearing nitrosyl ruthenium complex could successfully be used in the development of long acting nitric oxide release system.

Os extratos obtidos a partir da própolis vermelha brasileira (PVB) têm sido investigados devido às suas amplas atividades biológicas. Recentemente, em nosso grupo de pesquisa, demonstramos a viabilidade da incorporação de um extrato n-hexânico de PVB em nanoemulsões de uso tópico, bem como sua permeação/retenção em pele de orelha suína. No presente estudo, avaliamos as propriedades físico-químicas e reológicas de hidrogéis contendo essas nanoemulsões visando a obtenção de um produto semissólido adequado para aplicação tópica. Em uma primeira fase, foram preparadas nanoemulsões compostas de núcleo oleoso contendo extrato n–hexânico de PVB, miristato de isopropila, lecitina de ovo (NE) e DOTAP (NE/DT), e fase externa aquosa. O polímero gelificante hidroxietilcelulose foi incorporado às formulações após a sua obtenção por emulsificação espontânea (H-NE e H-NE/DT). As formulações apresentaram-se monodispersas com diâmetro médio na faixa de 200-300 nm, confirmado por microscopia eletrônica de transmissão. H-NE apresentou um potencial zeta negativo (-38mV), enquanto o mesmo parâmetro para H-NE/DT foi positivo (+36mV), devido à presença do lipídeo catiônico DOTAP na formulação. O teor de benzofenonas totais, determinado por cromatografia líquida de alta eficiência (CLAE), foi de cerca de 85 mg/g de extrato. Esses parâmetros mantiveram-se constantes durante 90 dias de armazenamento a 4C. As formulações H/NE e H-NE/DT apresentaram um comportamento não-Newtoniano pseudoplástico. Estudos de permeação/retenção das benzofenonas através da pele de orelha suína foram realizados utilizando células de difusão do tipo Franz. A maior retenção das benzofenonas na pele (18,11 μg/cm² após 8h) foi observada para a formulação H-NE/DT, demonstrando o efeito do lipídeo catiônico DOTAP nesse parâmetro. Em uma última etapa, investigou-se a capacidade das formulações de conferirem proteção à pele de orelha suína frente ao dano oxidativo gerado pela sua exposição à luz UVA/UVB. A proteção da pele de orelha suína foi evidenciada pelas técnicas de TBARS, carbonilação de proteínas e grupamentos tióis totais. Os resultados obtidos sugerem que os Hidrogéis contendo extrato de PVB apresentam propriedades físico-químicas e reológicas adequadas para serem utilizadas topicamente para a prevenção do dano oxidativo causado pela exposição à luz UVA/UVB. / Brazilian red propolis (BRP) extracts have been investigated due to their extensive biological activities. Recently, in our research group, we demonstrated the feasibility of incorporating an n-hexane extract of BRP into topical nanoemulsions, as well as the permeation/retention of these compounds in porcine ear skin. In the present study, we evaluated the physicochemical and rheological properties of hydrogels containing these nanoemulsions in order to obtain a semi-solid product suitable for topical application. In a first step, nanoemulsions composed of an oil nucleus containing BRP n-hexane extract, isopropyl myristate, egg lecithin (NE) and DOTAP (NE/DT), and an aqueous external phase were prepared. The hydroxyethylcellulose gelling polymer was incorporated into the formulations after being obtained by spontaneous emulsification (H-NE and H-NE/DT). The formulations were monodisperse exhibiting a mean diameter in the 200-300 nm range, confirmed by transmission electron microscopy. H-NE presented a negative zeta potential (-38mV), while H-NE/DT showed a positive value (+ 36mV) due to the presence of the cationic lipid DOTAP in the formulation. The total benzophenone content, determined by high performance liquid chromatography (HPLC), was about 85 mg/g extract. These parameters were maintained constant for 90 days of storage at 4°C. The formulations H/NE and H-NE/DT presented a non-Newtonian pseudoplastic behavior. Permeation/retention studies of benzophenones through porcine ear skin were performed using Franz type diffusion cells. The highest retention of benzophenones in the skin (18.11 μg/cm² after 8h) was observed for the H-NE/DT formulation, demonstrating the effect of the DOTAP cationic lipid on this parameter. In a last step, the ability of the formulations to confer protection of porcine ear skin against oxidative damage, generated by its exposure to UVA/UVB light, was investigated. The protection was evidenced by the TBARS, carbonylation of proteins, and total thiol groups techniques. The results obtained suggest that the hydrogels containing BRP have adequate physicochemical and rheological properties to be used topically for the prevention of oxidative damage caused by exposure to UVA/UVB light.

Tem sido reportado que os danos UV induzidos são devidos principalmente pela geração de EROs. Assim, compostos capazes de inibir a ação e a formação destas EROs, serão capazes de proteger a pele dos danos UV induzidos. Devido suas propriedades, a própolis pode ser aplicada como antioxidante tópico para prevenir e/ou tratar os danos UV induzidos. Desta forma, o objetivo deste trabalho foi avaliar o conteúdo de flavonóides e polifenóis e a atividade antioxidante, em diferentes sistemas ?in vitro?, dos extratos fluido e seco de própolis brasileira verde. Em adição, formulações tópicas adicionadas com extrato fluido de própolis verde foram desenvolvidas e sua estabilidade física e funcional foi avaliada. Foram também avaliadas a capacidade de liberação, permeação e retenção dos compostos antioxidantes destas formulações. O conteúdo de flavonóides e polifenóis encontrado para ambos extratos foi de 2,29 mg/g e 18 mg/g, respectivamente. Foi observado que o extrato de própolis verde apresentou a mesma quantidade de polifenóis que outros extratos de própolis já estudados, entretanto apresentou menor quantidade de flavonóides. Este extrato demonstrou ainda, atividade antioxidante de forma dose dependente contra diferentes radicais, tais como DPPH?, superóxido (O2-), hidroxila (OH?), peroxila (LOO?) e alkoxila (LO?). E ainda, as formulações desenvolvidas foram estáveis fisicamente e funcionalmente. A F 01 foi capaz de liberar seus compostos antioxidantes mais eficazmente que as outras formulações desenvolvidas. Entretanto, somente a F 03 reteve seus compostos antioxidantes na epiderme viável. Estes resultados dão boas perspectivas para aplicar o extrato de própolis verde topicamente para prevenir e/ou tratar os danos UV induzidos na pele. Em adição, pode ser sugerido que F 03 pode ser aplicada topicamente para prevenir e/ou tratar o estresse oxidativo UV induzido na pele com probabilidade de sucesso. / It has been reported that UV- induced damage is due mainly to the generation of ROS. Then, compounds able to inhibit the action and the formation of these ROS, will be able to protect the skin from UV-induced damage. Due to their properties, propolis can be applied as topical antioxidants to prevent and/or treat UV-induced damages. Thus, the purpose of this work was to evaluate the polyphenol and flavonoid contents and the antioxidant activity, in different ?in vitro? systems, of the Brazilian green propolis fluid and dry extracts. In addition, topical formulations added with green propolis fluid extract were developed and their physicalchemical and functional stabilities were assessed. It was also evaluated the release, permeation and skin retention capacity of the antioxidant compounds from these formulations. The flavonoid and polyphenols contents found for both extracts were 2.29 mg/g and 18 mg/g, respectively. It was observed that green propolis extract showed the same amount of polyphenols as other propolis extracts which has already been studied, however showed lower amounts of flavonoids. This extract also showed antioxidant activity in a dose dependent manner against different radicals, such as DPPH?, superoxide (O2-), hydroxyl (OH?), alkoxyl (LO?) and peroxyl radicals. Furthermore, the formulations developed were physically and functionally stable. F 01 was able to release its antioxidant compounds in more efficient way than the other developed formulations. However, only F 03 retained its antioxidant compounds on viable epidermis. These results give good perspectives to apply green propolis extract topically in order to prevent and/or treat UV-damaged skin. In addition, it may be suggested that F 03 could be topically applied to prevent and/or treat UV- induced oxidative stress on skin with probability of success.

ABSTRACT Recent global interests in developing hydrogen economy generate substantial research and development for hydrogen production worldwide. Pd membranes are especially suited for high temperature hydrogen separation and membrane reactor applications. Alloying Pd with Ag not only suppresses hydrogen embrittlement, but also increases the permeability of the alloy membrane. The main objective of this work was to carry out fundamental studies to understand the properties of the porous stainless steel (PSS), morphologies of Pd and Ag deposits on PSS, and the structural changes of the membrane layer upon heat treatment. Both coating and diffusion and co-plating techniques were employed in the study. The Pd-Ag membranes that had sandwiched Ag layers suffered from very low selectivity due to the voids formed because of high diffusion rate of Ag. Alloy membranes with high selectivity can be prepared by applying intermediate annealing after each Ag deposition. On the other hand, the homogeneity of the alloy depended very much on the thickness of the deposited layers and annealing temperature and time. A stable co-plating bath was developed to co-plate Pd and Ag simultaneously. Pd-Ag membranes were prepared from co-plating bath using ultrasound to accelerate the plating rate.