L'étude par continuation des solutions périodiques et quasi-périodiques est appliquée à plusieurs modèles issus du violon. La continuation pour un modèle à un degré de liberté avec friction régularisée permet de montrer la préservation, par rapport à la friction de Coulomb, des bifurcations de cycle limite (une vitesse maximale et une force minimale permettant le mouvement de Helmholtz) et de propriétés globales de la branche de solution (croissance de l'amplitude avec la vitesse, décroissance de la fréquence avec la force normale). L'équilibrage harmonique est évalué sur la friction régularisée et a des propriétés de convergence intéressantes (erreur faible, monotone, à décroissance rapide). La continuation sur un modèle à deux modes donne accès aux solutions de registres supérieurs, dont la stabilité coïncide avec l'expérience. La valeur retenue pour l'inharmonicité peut modifier fortement le diagramme de bifurcation. Une nouvelle méthode de continuation des solutions quasi-périodiques est proposée. Elle associe l'EH étendu à deux pulsations avec la Méthode Asymptotique Numérique. Une attention particulière est portée à la rapidité des calculs, face à la croissance rapide de la taille des systèmes à inverser. Un modèle de friction prenant en compte la température au point de contact est reformulé à l'aide d'une dérivée fractionnaire. Nous proposons une méthode de continuation de solutions périodiques de systèmes contenant des dérivées ou intégrales fractionnaires. Nous établissons une condition suffisante pour que les cycles asymptotiques du cadre causal (Caputo) soient solutions du cadre que nous avons choisi. / The continuation of periodic and quasi-periodic solutions is performed on several models derived from the violin. The continuation for a one degree-of-freedom model with a regularized friction shows, compared with Coulomb friction, the persistence of limit cycle bifurcations (a maximum bow speed and a minimum normal force allowing Helmholtz motion) and of global properties of the solution branch (increase of amplitude with respect to the bow speed, decrease of frequency with respect to the normal force). The Harmonic Balance Method is assessed on this regularized friction system and shows interesting convergence properties (the error is low, monotone and rapidly decreasing). For two modes the continuation shows higher register solutions with a plausible stability. A stronger inharmonicity can greatly modify the bifurcation diagram. A new method is proposed for the continuation of quasi-periodic solutions. It couples a two-pulsations HBM with the Asymptotic Numerical Method. We have taken great care to deal efficiently with large systems of unknowns. A model of friction that takes into account temperature of the contact zone is reformulated with a fractional derivative. We then propose a method of continuation of periodic solutions for differential systems that contain fractional operators. Their definition is usually restricted to causal solutions, which prevents the existence of periodic solutions. Having chosen a specific definition of fractional operators to avoid this issue we establish a sufficient condition on asymptotically attractive cycles in the causal framework to be solutions of our framework.

The goal of thesis is to clarify the nature of the exchange rate and interest rate risk and the possibility to describe the management of these risks. It represents the individual tools used to ensure the exchange rate and interest rate risk and the specific examples explaining the principle of their functioning. The thesis is divided into three parts - the exchange rate hedging, interest rate hedging and risk management, or a summary of each procedure, a brief guide for managers of companies involved in the risk of fluctuations in exchange rates or interest rates touching. Case studies of specific examples shows the possibilities of treatment of exchange rate risk - the exporter trading currency pair EUR / CZK.

Dans cette étude, nous avons développé un composé dérivé du NADPH, nommé Nanoshutter (NS). NS a été conçu pour inhiber l'activité catalytique de la NOS, c'est à dire la synthèse de NO, en occupant la place du NADPH dans le domaine réductase du NOS. La voie de synthèse de NO chez les mammifère correspond à l'oxydation de la L-arginine catalysée par la NOS, qui se produit dans son domaine oxygénase. Basée sur des données de modélisation moléculaire, la structure de NS est composée deux sous-unités: (i) le motif nucléotidique de reconnaissance du NADPH a été retenu, permettant au composé NS un ciblage approprié du site de liaison au NADPH de la NOS, (ii) le motif nicotinamide de NADPH a été remplacé par un groupe stilbène lié à un groupement terminal accepteur d'électrons. De plus, ce fragment est caractérisé par une très bonne section efficace d'absorption à deux photons (130 GM à 840 nm). NS1, le composé prototype de la famille NS, contient un groupe terminal NO2 en tant que groupe accepteur d'électrons. La valeur de Kd (~ 4,2 µM) a été estimée dans des expériences de titrage sous excitation un- ou deux-photons, et suggère une bonne affinité de liaison de NS1 à la NOS. De façon inattendue, NS1 présente une bonne sélectivité, en terme de rendement quantique de fluorescence, pour les isoformes de NOS par rapport à d'autres protéines qui contiennent ou non un site de liaison NADPH. En outre, il a été montré que NS1 inhibait de façon compétitive NOS par rapport au NADPH. Dans les expériences d'imagerie de fluorescence réalisées sur des cellules endothéliales (HUVEC), NS1 a démontré une internalisation rapide et efficace, avec un signal de fluorescence mis en évidence principalement dans la région périnucléaire, accompagné d’un signal plus sporadique à la membrane plasmique. Cette observation est en parfait accord avec la colocalisation de NS1 et eNOS mesurée par immunomarquage, démontrant ainsi que NS1 cible eNOS dans les cellules endothéliales. La vasoconstriction NO-dépendante attendue dans les anneaux aortiques isolés de souris a été montrée, mais uniquement en présence de catalase qui convertit H2O2 en H2O et O2. En revanche, en l'absence de catalase, la vasorelaxation a plutôt été observée. Ce résultat indique que la NOS n’est très certainement pas l’unique cible de NS1 dans le système endothélial, et que d’autres cibles en rapport avec la modulation de ROS (Reactive Oxygen Species) sont impliquées. En accord avec ce résultat, NS1 provoque une réponse biphasique de la production de ROS dans les cellules HUVEC : Une phase d'augmentation est observée aux faibles concentrations de NS1 (en dessous de 2 µM), suivie d'une diminution (inhibition de ROS) pour des concentrations de NS1 plus élevées. En outre, NS1 inhibe la production de O2- dans les macrophages de souris et les productions de H2O2 et de O2- survenant dans des conditions de découplage de nNOS in vitro. Des explications possibles pour interpréter ces données sont: NS1 probablement inhibe la production de ROS, soit produites au niveau de la NADPH oxydase ou (et) au cours du découplage de la NOS. L'origine de la phase d’augmentation reste plus difficile à interpréter, mais pourrait correspondre au ciblage de la glucose-6-phosphate deshydrogénase. Enfin, NS1 exerce un effet anti -angiogénique sur les cellules endothéliales et empêche la prolifération de cellules du mélanome. En conclusion, NS1 rempli l'objectif principal de cibler et inhiber la NOS en ciblant plus particulièrement le domaine réductase - il est aussi caractérisé par des propriétés d’absorption et de fluorescence à deux photons intéressantes permettant des applications in vitro et in vivo. L’ensemble de ces caractéristiques présentent un profil intéressant pour de futures applications d’imagerie en temps réel et non-invasive, avec également un fort potentiel pour des applications cliniques liées aux maladies NO-dépendantes. / In this study, we introduced a NADPH derivative named as Nanoshutter (NS). NS was designed to inhibit the catalytic activity of NOS, i.e. synthesis of NO, by occupying the NADPH site in the reductase domain of NOS. In mammals, NO participates in extensive physiological/pathological processes in the cardiovascular, nervous and immune systems. The pathway of mammal NO synthesis is the oxidation of L-arginine catalyzed by NOS, which occurs in its oxygenase domain. The catalysis requires three co-substrates (L-arginine, NADPH, and O2) and five cofactors groups (FAD, FMN, calmodulin, BH4 and heme). Guided by molecular modeling, the structure of NS contains two conjugated subunits: (i) the nucleotide recognition motif of NADPH was retained in NS, allowing a proper targeting to the NADPH binding site of NOS- (ii) the nicotinamide moiety of NADPH is replaced by a stilbene moiety linked with a terminal electron acceptor group, preventing electron flow from the reductase to the oxygenase domain of NOS. Furthermore, this moiety is characterized by a large two-photon absorption cross-section (130 at 840 nm). NS1, the first compound of the NS family, contains a NO2 terminal group as an electron acceptor group. NS1 displayed distinct fluorescence properties in its free and NOS-bound states. The Kd value (around 4.2 µM) was estimated in titration experiments performed under one- or two-photon excitation conditions, suggesting an effective binding of NS1 to NOS with a good affinity. Surprisingly, in terms of fluorescence quantum yield, NS1 displayed a good selectivity to the NOS isoforms over other proteins which contain or not a NADPH binding site. Furthermore, NS1 was shown to competitively inhibit nNOS in a dose-dependent manner. In fluorescence imaging experiments with endothelial cells (HUVEC), NS1 displayed a rapid and efficient internalization, with highlighted fluorescence signal at the perinucleus region and sporadic signal at the plasma membrane. This observation was in accordance with the colocalization imaging between NS1 and eNOS as shown by immunostaining, showing that NS1 actually targets eNOS in endothelial cells. The expected NO-dependent vasoconstriction in isolated mouse aortic rings was only evidenced in the presence of catalase, which converts H2O2 into H2O and O2. By contrast, in the absence of catalase, a contradictory vasorelaxation was observed. This result indicates that NS1 may target more than NOS in endothelium system, which is (are) likely related to Reactive Oxygen Species (ROS) production. Accordingly, NS1 led to a biphasic response of ROS production in HUVEC cells: An increasing phase occurred at low NS1 concentration (below 2 µM) and followed by a decreasing phase (ROS inhibition) at higher NS1 concentrations. Furthermore, NS1 was shown to inhibit O2- production in mouse macrophages and H2O2 and O2- production in uncoupled nNOS in vitro. Altogether, the possible but not exclusive explanations for current data are: in addition to its inhibition effect on NO production, NS1 probably also inhibits the ROS production either produced by NADPH Oxidase or by electron leakage from uncoupled NOS, or a combination of both. The origin of the increasing phase remains more elusive but could correspond to the targeting of glucose-6-phosphate-dehydrogenase (G6PD). Additionally, NS1 displayed anti-angiogenesis effect on endothelial cells and prevented proliferation of melanoma. In conclusion, NS1 fulfilled the goal as a new NOS inhibitor targeting the reductase domain and displayed a unique two-photon property in vitro and in vivo, these features may provide a promising future for non-invasive real-time imaging, and to potential clinical applications in the NO-dependent diseases.

Dans cette thèse, nous étudions le problème de réduction de la dimension dans le cadre du modèle de régression suivant Y=g(B X,e), où X est un vecteur de dimension p, Y appartient à R, la fonction g est inconnue et le bruit e est indépendant de X. Nous nous intéressons à l'estimation de la matrice B, de taille dxp où d est plus petit que p, (dont la connaissance permet d'obtenir de bonnes vitesses de convergence pour l'estimation de g). Ce problème est traité en utilisant deux approches distinctes. La première, appelée régression inverse nécessite la condition de linéarité sur X. La seconde, appelée semi-paramétrique ne requiert pas une telle condition mais seulement que X possède une densité lisse. Dans le cadre de la régression inverse, nous étudions deux familles de méthodes respectivement basées sur E[X f(Y)] et E[XX^T f(Y)]. Pour chacune de ces familles, nous obtenons les conditions sur f permettant une estimation exhaustive de B, aussi nous calculons la fonction f optimale par minimisation de la variance asymptotique. Dans le cadre de l'approche semi-paramétrique, nous proposons une méthode permettant l'estimation du gradient de la fonction de régression. Sous des hypothèses semi-paramétriques classiques, nous montrons la normalité asymptotique de notre estimateur et l'exhaustivité de l'estimation de B. Quel que soit l'approche considérée, une question fondamentale est soulevée : comment choisir la dimension de B ? Pour cela, nous proposons une méthode d'estimation du rang d'une matrice par test d'hypothèse bootstrap. / In this thesis, we study the problem of dimension reduction through the following regression model Y=g(BX,e), where X is a p dimensional vector, Y belongs to R, the function g is unknown and the noise e is independent of X. We are interested in the estimation of the matrix B, with dimension d times p where d is smaller than p (whose knowledge provides good convergence rates for the estimation of g). This problem is processed according to two different approaches. The first one, called the inverse regression, needs the linearity condition on X. The second one, called semiparametric, do not require such an assumption but only that X has a smooth density. In the context of inverse regression, we focus on two families of methods respectively based on E[X f(Y)] and E[XX^T f(Y)]. For both families, we provide conditions on f that allow an exhaustive estimation of B, and also we compute the better function f by minimizing the asymptotic variance. In the semiparametric context, we give a method for the estimation of the gradient of the regression function. Under some classical semiparametric assumptions, we show the root n consistency of our estimator, the exhaustivity of the estimation and the convergence in the processes space. Within each point, an important question is raised : how to choose the dimension of B ? For this we propose a method that estimates of the rank of a matrix by bootstrap hypothesis testing.

A dipirona sódica em associação com o cloridrato de papaverina é usada como medicamento analgésico e antiespasmódico. O objetivo desta pesquisa foi o desenvolvimento e validação de métodos analíticos para a determinação de dipirona sódica e cloridrato de papaverina em preparações farmacêuticas. A solução oral contendo dipirona sódica isolada e a solução oral contendo a associação de dipirona sódica e cloridrato de papaverina foram determinadas por cromatografia líquida de alta eficiência, com as condições padronizadas: Coluna cromatográfica: Supelcosil C18 - LCPH (250 mm X 4,6 mm, 5µm) Supelco e pré coluna C -18 (20 X 4,6 mm, 5µm) Supelco, fase móvel: água: acetonitrila: metanol (70: 20: 10) trietilamina 0,3% e pH: 3,0 ajustado com ácido ortofosfórico, vazão de 0,7 mL/min e detecção no UV a 254 nm. Para a solução injetável contendo cloridrato de papaverina foi padronizado e validado o método por cromatografia líquida de alta eficiência, empregando coluna cromatográfica Merck LiChrospher® 100 RP - 18 (125 X 4,6 mm, 5µm), fase móvel: água : acetonitrila : metanol ( 70 : 20 : 10 ) trietilamina 0,3% e pH: 3,0 ajustado com ácido ortofosfórico, vazão: 1,0 mL/min e detecção no UV a 254 nm. Para a determinação simultânea de dipirona sódica e cloridrato de papaverina em solução oral, foi desenvolvida uma nova metodologia utilizando espectrofotometria na região do ultravioleta (UV) e calibração multivariada. Neste sistema, utilizou-se a faixa de leitura: 210 a 300 nm (passo 0,5 nm) e metanol como solvente. A calibração foi feita com 25 soluções nas concentrações de 15,0 a 35,0 µg/mL para a dipirona sódica e de 0,5 a 1,5 µg/mL para o cloridrato de papaverina. As curvas de calibração foram lineares. Os excipientes das amostras não interferiram nas metodologias. Foram apresentados adequados resultados de desvio padrão e média de recuperação. Os métodos propostos mostraram especificidade, precisão e exatidão para a determinação de dipirona sódica e cloridrato de papaverina em formulações farmacêuticas. / Dipyrone sodium and papaverine hydrochloride are used as an analgesic and antispasmodic drugs. The objective of this study was to develop and validate analytical methods for determination of dipyrone sodium and papaverine hydrochloride in pharmaceutical preparations. The commercial formulations with dipyrone hydrochloride alone and its combination with papaverine hydrochloride were analysed by liquid chromatography. A Supelcosil C18 - LCPH column (250 X 4.6 mm, 5µm) Supelco and a mobile phase constituted by water: acetonitrile: methanol (70:20:10), with 0.3% of triethylamine and pH adjusted to 3.0 with phosphoric acid were used. The flow rate was 0.7 mL/min and UV detection at 254 nm. The injection formulation with papaverine hydrochloride was analysed by a high performance liquid chromatographic method. The method was standardized and validated using a Merck LiChrospher® 100 RP 18 column (125 X 4.6 mm, 5µm) and a mobile phase constituted of water: acetonitrile: methanol (70:20:10), with 0.3% of triethylamine and pH adjusted to 3.0 with phosphoric acid. The flow rate was 1.0 mL/min and UV detection at 254 nm. The same oral solution with the combination of dipyrone sodium and papaverine hydrochloride was also quantified by UV spectrophotometry using multivariate calibration, in the range of 210 to 300 nm. The calibration set was constructed with twenty-five solutions in the concentration ranges from 15.0 to 35.0 µg mL-1 for dipyrone sodium and 0.5 to 1.5 µg mL-1 for papaverine hydrochloride in methanol. The results show that the methods presented good relative standard deviation and good recovery values. The obtained data indicates specificity, precision and accuracy of the proposed methods for the simultaneous determination of dipyrone sodium and papaverine hydrochloride in pharmaceutical formulations.

A prática da reutilização de produtos médico-hospitalares de uso único vem sendo aplicada desde meados da década de setenta. A principal razão que tem contribuído para disseminação desta conduta pelas instituições hospitalares radicadas tanto nos países em desenvolvimento como naqueles considerados ricos, tem sido a aparente economia de custos. Apesar dos riscos relacionados com a prática da reutilização, como reações pirogênicas, danos ocasionados por bactérias consideradas patogênicas em pacientes imunologicamente comprometidos, danos na integridade fisica dos produtos, assim como aumento do período de permanência dos pacientes no hospital, têm despertado o interesse em avaliar aspectos fisicos e biológicos dos produtos médico-hospitalares reutilizados. Baseando-se nestas considerações foram aplicados desafios com esporos de Bacillus Subtilis varo niger ATCC 9372 e endotoxina bacteriana E. coli 055:B5. Os produtos desafiados foram cateteres intravenosos, torneira três vias e tubos de traqueostomia. A possível presença microbiana foi investigada após contaminação intencional dos esporos de B. Subtillis (107 ufc/unid.) com submissão das unidades contaminadas à limpeza e posterior esterilização, utilizando óxido de etileno/CFC na proporção 12:88. Os ciclos de reprocessamentos simulados de produtos médico-hospitalares consistiram de contaminação de cada unidade teste com carga microbiana, lavagem com detergente enzimático, secagem e esterilização. Ao término de cada ciclo de reprocessamento foram separadas unidades representativas para avaliação por contagem microbiana (pour plate), testes de esterilidade por inoculação direta e indireta, citotoxidade por cultura de células e microscopia eletrônica de varredura. A eficiência da esterilidade foi avaliada tanto por contagem microbiana como pelos testes de esterilidade, que resultaram em níveis microbianos de 103 ufc/unid. e detecção de contaminação até o 6° ciclo de reprocessamento nos cateteres intravenosos, tubos de traqueostomia e torneiras três vias. A segurança dos reprocessamentos dos produtos médico-hospitalares foi avaliada pela cultura de células de fibroblastos de camundongo (NCTC clone 929), as quais não apresentaram toxicidade. Entretanto, os resultados obtidos durante microscopia eletrônica de varredura comprovaram presença de carga microbiana após 10° ciclo de reprocessamento, assim como danos na superficie polimérica. Durante desafio com endotoxina bacteriana, que consistiu em contaminar as unidades com 200 UE, secagem e exposição ao ciclo de esterilização com óxido de etileno/CFC (12:88), verificou-se que após ciclos de reprocessamentos simulados, totalizando dez ciclos, foi possível detectar valores de recuperação de endotoxina em torno de 100%. Os cateteres-guia que foram adquiridos em instituição hospitalar após quatro reutilizações, apresentaram níveis de contaminação de 105 ufc/unid., assim como presença de bactérias consideradas patogênicas em pacientes comprometidos imunologicamente, já a detecção de endotoxina bacteriana nestes cateteres não foi considerada significativa. Logo, as avaliações aplicadas nas unidades submetidas aos ciclos de reprocessamentos simulados, assim como nos cateteres-guia reprocessados e reutilizados quatro vezes, refletiram a realidade de algumas instituições no âmbito nacional e internacional que praticam a reutilização de produtos médico-hospitalares de uso-único. Os resultados obtidos vêm enfatizar objeções quanto à prática da reutilização, considerando que a ausência de segurança pode ocasionar em danos ao paciente. / The practices of reutilization of single use hospital medical devices came into practice since mid seventies. The main reason that has contributed for dissemination of this practice by institutional hospitals in underdeveloped as well as those considered as rich countries has been the appellant economy of costs. Despite well known risks related with the practice of reutilization, such as pyrogenic reactions, damages caused by bacteria\'s considered pathogenic in patients immunologically compromised, damages to the physical integrity of the materials, as well as prolonged permanence of the patient in the hospital, has raised interests in the evaluation of physical and biological aspects of the reused medical device. Based on these considerations, challenges had been applied with spores of Bacillus Subtilis varo niger 9372 ATCC and bacterial endotoxin E. coli 055:B5. The selected materials includes, intravenous catheters, three-way stopcocks and traqueostomy tubes. The possible presence of bacteria was investigated after intentional contamination with spores of B. Subtillis (107 cfu/unit) followed by submission of the inoculated units to the cleaning process and posterior sterilization using ethylene oxide at 12:88. The simulated reprocessing cycles of the medical device had consisted of contamination of each test unit with predetermined microbial load, washing with enzymatic detergent, drying and sterilization. At the end of each reprocessing cycle, representative sarnples had been segregated to evaluate microbial count (pour plate), terility test through direct and indirect inoculation, cytotoxicity test through cell culture and scanning electron microscopy. The efficiency of the sterility was evaluated through microbial count, as for the sterility tests, that had resulted in microbial count of 103 cfu/unit and detection of contamination until the 6th cycle of reprocessing in the intravenous catheters, three-way stopcocks and traqueostomy tubes. The safety of these reprocessed medical devices was evaluated by mouse fibroblasts cell culture (NCTC clone 929), which didn\'t presented significant toxicity. However, the results obtained by scanning electron microscopy proved the presence of microbial load after 10th reprocessing cycle, as well as damages to the polymeric surface. During challenge with bacterial endotoxin, that consisted of contaminating the units with 200 EU, drying and submission to sterilization cycles with ethylene oxide/cfe (12:88), it was verified that after ten simulated reprocessing cycles, it was possible to recover around 100% of endotoxin. The catheter guide that were acquired from institutional hospital after four times reuse, had presented levels of contamination of 105 cfu/unit, as well as presenee of bacteria considered pathogenic in patients immunologically compromised, on the other hand the detention of bacterial endotoxin in these catheters was not considered significant. The evaluations studies condueted with the units submitted to the simulated reprocessing cycles, as well as the catheter guide reprocessed and reused four times, had reflected the reality of some national and foreign hospitais which reutilize single use medical device. The results obtained lead us to raise objections to the reusing practice, considering the absence of adequate patients safety.

A associação entre os fármacos delapril (DEL) e manidipino (MAN) apresenta um efeito anti-hipertensivo sinérgico de longa duração, sendo considerada uma importante alternativa no tratamento e controle da hipertensão arterial. O presente trabalho faz referência à utilização de diversas técnicas instrumentais para avaliar a qualidade de DEL e MAN na forma farmacêutica e matérias-primas. Neste sentido, amostras de matérias-primas dos fármacos provenientes de diferentes fornecedores foram analisadas utilizando a calorimetria diferencial exploratória, termogravimetria, difração de raios X, espectrofotometria no infravermelho, espectroscopia Raman e microscopia eletrônica de varredura. Os resultados permitiram observar inconsistências entre as amostras de DEL, provavelmente devido à presença de uma impureza em uma das substâncias, demonstrando a importância da pesquisa e controle dos insumos farmacêuticos, bem como de programas de qualificação de fornecedores. Além disso, metodologias analíticas por espectrofotometria derivada, cromatografia líquida com detecção no ultravioleta (CL-UV) e CL acoplada à espectrometria de massas (EM) foram desenvolvidas objetivando a determinação de DEL e MAN nos comprimidos. Os procedimentos foram validados, cumprindo com os requisitos internacionalmente aceitos para especificidade, linearidade, precisão, exatidão, robustez e limites de detecção e quantificação, além de demonstrarem diferença não significativa (p > 0,05) entre si na quantificação simultânea dos fármacos. A estabilidade dos fármacos nas condições alcalina e fotolítica (para o DEL e MAN, respecivamente) também foi investigada. Através dos métodos por CL-UV e CL-EM pode-se propor a identidade dos principais produtos de degradação formados, os quais não apresentaram evidências de citotoxicidade em estudo utilizando células mononucleares humanas. Além disso, os estudos de cinéticas de degradação indicaram que o DEL segue uma cinética de primeira ordem (R2 = 0,9991) enquanto o MAN segue uma reação de ordem zero (R2 = 0,9867). De forma adicional, foi desenvolvido e validado um método de dissolução para avaliação de comprimidos contendo DEL e MAN. O uso de tampão citrato pH 3,2 como meio de dissolução e dispositivo pá a 75 rpm demonstrou resultados satisfatórios para a avaliação da liberação simultânea dos fármacos do produto farmacêutico, bem como capacidade de simular o comportamento in vivo do MAN a partir de dados da literatura. Desse modo, estabeleceram-se procedimentos analíticos que podem ser aplicados para aprimorar o controle da qualidade dos medicamentos a serem comercializados, bem como contribuir para garantir a segurança e eficácia no uso terapêutico. / The association of delapril (DEL) and manidipine (MAN) has a synergic antihypertensive effect and may be regarded as an important alternative to arterial hypertension treatment. The present study refers to use of some instrumental techniques to assess the quality of DEL and MAN in pharmaceutical formulation and raw materials. In this context, samples of the drugs raw materials, obtained from different suppliers, were evaluated using differential scanning calorimetry, thermogravimety, X-ray powder diffraction, infrared spectroscopy, Raman spectroscopy and scanning electron microscopy. Inconsistent results were observed between DEL samples, probably due to an impurity presence in some substance, demonstrating the importance of research and control of pharmaceutical ingredients, as well as the quality programs of pharmaceuticals suppliers. In addition, a derivative spectrophotometric, liquid chromatography (LC) and LC coupled to mass spectrometry (MS) methods were developed for simultaneous analysis of DEL and MAN in commercial tablets. The procedures were validated and the results were in accordance with internationally accepted requirements by specificity, linearity, precision, accuracy, robustness and detection and quantitation limits. Therefore, the methods were successfully applied for the simultaneous quantitative analysis of DEL and MAN in the tablet dosage form, showing non-significant difference (p > 0.05). The drugs stability in alkaline and photolytic conditions (for DEL and MAN, respectively) was also investigated. The main degradation products formed were analyzed by LC-UV and LC-ESI-MS methods and its identity could be suggested, without isolation or purification processes. Additionally, the degradation kinetic of both drugs and the cytotoxicity of the degraded samples were also studied. No evidence of cytotoxicity in human mononuclear cells was observed for drugs degraded samples. Furthermore, the present study also conducted the development and validation of a dissolution method for DEL and MAN combination tablets. The use of citrate buffer pH 3.2 as dissolution medium in combination with paddle at rotation of 75 rpm, resulted in an appropriate dissolution profile of both drugs, allowing the simultaneous quality control of DEL and MAN in combination tablets, as well as the ability to simulate the in vivo behavior of MAN from literature data. Then, the established procedures can be applied to improve the quality control of the products that will be marketed, as well as to contribute for assure the safety and therapeutic efficacy of the drugs.

Objetivos: os objetivos gerais deste trabalho foram desenvolver, validar e comparar métodos analíticos para caracterização e determinação quantitativa de vildagliptina (VLG) na forma farmacêutica comprimidos, assim como determinar a cinética de degradação do fármaco em condição de estresse. Métodos: método indicativo de estabilidade por cromatografia líquida de alta eficiência com detecção ultravioleta (CLAE-UV) foi desenvolvido e validado, conforme as normas da International Conference on Harmonisation (ICH). A cinética de degradação do fármaco foi determinada frente à hidrólise alcalina. A possível estrutura do produto de degradação majoritário, formado sob condições básicas, oxidativas e térmicas foi proposta de acordo com análises realizadas por espectrometria de massas (EM). Foi desenvolvido e validado, também, método por espectrofotometria ultravioleta derivada para quantificação do fármaco na forma farmacêutica. Resultados e Conclusões: o método de CLAE indicativo de estabilidade desenvolvido e validado demonstrou ser adequado para a quantificação da substância ativa na forma farmacêutica sem sofrer a interferência dos excipientes presentes na formulação e também na presença dos produtos de degradação. Os principais fatores extrínsecos que promoveram a degradação do fármaco foram: oxidação, hidrólise alcalina e temperatura. Determinou-se a cinética de degradação, sob condições alcalinas, como sendo de primeira ordem indicando, assim, que o processo de degradação é dependente da concentração de fármaco. O método por espectrofotometria UV derivada também se mostrou adequado para a quantificação de vildagliptina nos comprimidos. A comparação entre os métodos desenvolvidos não mostrou diferença estatística significativa demonstrando que ambos os métodos podem ser utilizados para determinação de vildagliptina no controle de qualidade dos comprimidos. / Objectives: the aim of the present work was to develop, validate and compare analytical methods to characterization and quantitative determination of vildagliptin (VLG) in tablet dosage form, as well as to determinate the degradation kinetics of the drug in a stress condition. Methods: stability-indicating method for the analysis of VLG by high performance liquid chromatography (HPLC) with ultraviolet detection was developed and validated according to the International Conference on Harmonisation (ICH) guidelines. The degradation kinetics of the drug under the alkaline hydrolysis was determined. The possible molecular structure of the major degradation product obtained under the stress studies by alkaline hydrolysis, oxidation and thermal degradation was predicted by mass spectrometry (MS) Results and Conclusions: The developed stability-indicating method was adequate to determine the active substance in the formulation even in the presence of the excipient ingredients in the formulation and, also, in the presence of the degradation products. The main extrinsic factors which promoted the drug degradation were: oxidation, alkaline hydrolysis and thermal degradation. The degradation kinetics was determined, under alkaline conditions, as first order showing that the process is dependent on the drug concentration. The derivative spectrophotometric method also was adequate to the quantification of vildagliptin in tablets. There was no statistical significant difference between the methods demonstrating that both methods can be used for the determination of vildagliptin in quality control of pharmaceutical tablets.

Orientador: Edvaldo Assunção / Resumo: Neste trabalho são propostos resultados para a estabilidade de sistemas lineares sujeitos a parâmetros variantes no tempo (do inglês, Linear Parameter Varying - LPV) e incertezas paramétricas. De início, apresenta-se um método para o projeto de um controlador robusto e gain scheduled via desigualdades matriciais lineares (do inglês, Linear Matrix Inequalitities - LMIs), com base na teoria de estabilidade segundo Lyapunov, com parâmetro variante no tempo e empregando a realimentação derivativa. Propõe-se um método para projetar o controlador gain scheduled usando realimentação derivativa, considerando também incertezas paramétricas. Esta nova formulação foi obtida utilizando o Lema de Finsler, o que permitiu determinar o ganho do controlador sem a necessidade de inverter uma matriz literal. Condições menos conservadoras foram projetadas para um controlador gain scheduled considerando a realimentação dos estados do sistemas. Simulações computacionais com exemplos numéricos mostram que os teoremas propostos neste trabalho são menos conservadores do que os existentes na literatura. A metodologia apresentada foi implementada no sistema de suspensão ativa. / Abstract: In this work, results for the stability of linear parameter-varying (LPV) systems and parametric uncertainties are poposed. At first, a method for desining a gain scheduled and robust controller is described via linear matrix inequalities (Linear Matrix Inequalitities - LMIs), based on the stability theory of Lyapunov, with time-variant parameters and using state derivative feedback. A method to design a gain scheduling controller using state derivative feedback and also considering parametric uncertains is proposed. This new formulation was manipulated using the Finsler’s Lemma, and allowed to determine the control law without having to invert a symbolic matrix. Less conservative conditions were designed for a gain scheduled controller considering system state feedback. Computational simulations with numerical examples show that the theorems proposed in this work are less conservative than those in the literature. The presented methodology was implemented in the active suspension system. / Doutor

Several existing pricing models of financial derivatives as well as the effects of volatility risk are analyzed. A new option pricing model is proposed which assumes that stock price follows a diffusion process with square-root stochastic volatility. The volatility itself is mean-reverting and driven by both diffusion and compound Poisson process. These assumptions better reflect the randomness and the jumps that are readily apparent when the historical volatility data of any risky asset is graphed. The European option price is modeled by a homogeneous linear second-order partial differential equation with variable coefficients. The case of underlying assets that pay continuous dividends is considered and implemented in the model, which gives the capability of extending the results to American options. An American option price model is derived and given by a non-homogeneous linear second order partial integro-differential equation. Using Fourier and Laplace transforms an exact closed-form solution for the price formula for European call/put options is obtained.