L’atteinte de la fonction endothéliale représente une phase précoce de l’athérosclérose, un stade où les patients sont généralement asymptomatiques. Il existe donc un intérêt certain à détecter la dysfonction endothéliale. Nous avons développé une technique de mesure des variations de flot artériel au niveau des membres supérieurs, basée sur la spectroscopie proche infrarouge (NIRS). Cette approche permettrait d’étudier le niveau d’atteinte vasculaire et probablement de quantifier le degré de dysfonction endothéliale périphérique lors d’une hyperémie réactive. L'expérience a été exécutée sur deux cohortes de 13 et de 15 patients et a été comparée à la pléthysmographie par jauge de contrainte (SGP) qui est considérée comme une méthode de référence. Par la suite, nous avons caractérisé la réponse endothéliale par modélisation de la courbe hyperémique du flot artériel. Des études préliminaires avaient démontré que la réponse hyperémique adoptait majoritairement une forme bi-modale. Nous avons tenté de séparer les composantes endothéliales-dépendantes et endothéliales-indépendantes de l’hyperémie. La quantification des deux composantes de la réaction hyperémique permet de calculer un indice de la ‘santé’ du système endothélial local. Cet indice est nommé le ηfactor. Les résultats montrent une forte corrélation des mesures de flots entre la technique développée et la méthode de référence (r=0.91). Nous avons conclu que NIRS est une approche précise pour la mesure non-invasive du flot artériel. Nous avons obtenu une bonne répétabilité (ICC = 0.9313) pour le ηfactor indiquant sa robustesse. Cependant des études supplémentaires sont nécessaires pour valider la valeur de diagnostic du facteur défini. Mots clés: hyperémie réactive, réponse myogénique, oxyde nitrique, athérosclérose, spectroscopie proche infrarouge / Atherosclerotic diseases are mainly caused by coronary and peripheral blood vessel disorders. Endothelial dysfunction represents an early phase in these diseases, when patients are generally asymptomatic. We developed a technique, based on near infrared spectroscopy (NIRS), for measurement of arterial blood flow variations in limbs during reactive hyperemia. The technique allows the study of the level of vascular impairment and probably quantifying the level of endothelial dysfunction at peripheral arteries. The experiment was performed on two cohorts of 13 and 15 patients and was compared to strain gauge plethysmography (SGP) which is considered as gold standard. Afterward, we characterized endothelial reaction during reactive hyperemia through blood flow variations by modeling the hyperemic curve. Preliminary studies have shown that the hyperemic response generally adopts a bimodal form. The first peak was attributed to myogenic reaction that is endothelial independent and the second one to local endothelial cells reaction. The quantification of the two hyperemic response components makes it possible to calculate an index of ‘health’ for local endothelial cells, named ηfactor. The results showed a strong correlation (r = 0.91) of blood flow measurements between the developed method and the gold standard. We concluded that NIRS is a precise technique for non-invasive measurement of blood flow. Moreover, we found a high repeatability (ICC = 0.9313) of the ηfactor in repeated measurements indicating its robustness. Nonetheless, more studies are required to validate the diagnosis value of the defined factor. Key words: reactive hyperemia, myogenic response, endothelial dependent vasodilatation, nitric oxide, atherosclerosis, near infrared spectroscopy (NIRS)

Au cours du vieillissement, des modifications dans la compréhension du discours ont été rapportées, attribuées en partie aux changements cognitifs encourus lors du vieillissement. Néanmoins, diverses études suggèrent une réorganisation cérébrale lors du vieillissement. Cette étude a pour but d'évaluer l'influence de l'âge lors d'une tâche de compréhension du discours à l'aide de l'imagerie optique. Comme première hypothèse, il est attendu que les participants jeunes auront plus de bonnes réponses au niveau des micropropositions et des macropropositions et des performances équivalentes au niveau du modèle de situation. La deuxième hypothèse est que les réseaux neuronaux utilisés lors de la compréhension du discours subiront une réorganisation cérébrale lors du vieillissement. Trente-deux participants ont pris part à cette étude : 16 jeunes adultes et 16 adultes âgés. Alors que les participants étaient sous enregistrement en imagerie optique au niveau du cortex préfrontal (CPF), ils ont lu des courtes histoires chacune suivie d’une phrase et devaient décider si elle était en accord ou non avec la précédente histoire. Les résultats ne montrent aucune différence entre les groupes au niveau de l’exactitude des réponses, contrairement à la littérature. Le CPF a été davantage activé par les adultes âgés comparativement aux jeunes adultes témoignant d’une réorganisation cérébrale. / During aging, changes in discourse comprehension have been reported, attributed in part by cognitive changes that occur during aging. Moreover, various studies suggest a cerebral reorganization with aging. This study aims to evaluate the influence of aging on cerebral reorganization during discourse comprehension using near infrared spectroscopy (NIRS). The first hypothesis is that younger adults will have better accuracy on micropropositions and macropropositions, but will have equivalent performance for the situation model. The second hypothesis is that the neural networks used for discourse comprehension will be reorganized during aging. Thirty-two participants took part in this study: 16 young adults and 16 older adults. While undergoing NIRS recording on the prefrontal cortex (PFC), the participants read short stories each followed by a sentence deciding if it was in agreement or not with the previous story. Results didn’t show any differences for accuracy between the group, in opposition with the literature. The PFC was more activated by the older adults compared to the younger adults showing a cerebral reorganization.

Le vieillissement normal est associé à une réorganisation cérébrale qui peut être influencée par plusieurs facteurs. Des théories comme la réserve cognitive de Stern (2002) tentent d’expliquer les effets de ces différents facteurs. Certains, le niveau de scolarité par exemple, sont encore mal connus. Pourtant, le niveau de scolarité est connu pour avoir un impact sur les performances cognitives tout au long de la vie. Le but de ce mémoire est d’étudier les effets du niveau de scolarité sur l’oxygénation cérébrale de personnes âgées en santé lors d’une tâche d’évocation lexicale orthographique et sémantique. Chaque tâche est divisée selon un critère « plus productive » et « moins productive ». Les âgés faiblement scolarisés produisent moins de mots que les âgés fortement scolarisés. De plus, la différence de mots produits entre le critère plus productif et moins productif est plus grande pour la tâche sémantique que pour la tâche orthographique. Du point de vue hémodynamique, les deux groupes ont des activations semblables, contredisant le phénomène HAROLD. De plus, les participants peu scolarisés tendent à activer de façon plus importante l’hémisphère gauche, peu importe la tâche ou la condition. Par contre, les activations varient selon la tâche et la condition dans le cas du groupe fortement scolarisé. / Normal aging is associated with cerebral reorganisation which can be influenced by many factors. For example, the theory cognitive reserve (Stern, 2002) is trying to explain how those factors can have an impact on the reorganization. However, some factors, such as educational level, are known to have an impact on cognitive performance. The aim of this dissertation is to study the effect of educational level in cerebral oxygenation of healthy older adults during both phonologic and semantic verbal fluency tasks. Each task is divided into two criteria: more productive and less productive. Behavioural data showed that less educated elderly generate fewer words than more educated ones for both tasks. Moreover, the differences between the number of words for the more productive criterion and the less productive one are higher for the semantic than for the phonologic task. NIRS data showed that both groups activated prefrontal cortex, without difference between them. In addition, less educated participants tend to have bigger activations in the left hemisphere regardless of the task and the criterion. On the other hand, higher educated participants’ activations vary according to the task and the criterion unlike the HAROLD model’s predictions.

L’étude du cerveau humain est un domaine en plein essor et les techniques non-invasives de l’étudier sont très prometteuses. Afin de l’étudier de manière non-invasive, notre laboratoire utilise principalement l’imagerie par résonance magnétique fonctionnelle (IRMf) et l’imagerie optique diffuse (IOD) continue pour mesurer et localiser l’activité cérébrale induite par une tâche visuelle, cognitive ou motrice. Le signal de ces deux techniques repose, entre autres, sur les concentrations d’hémoglobine cérébrale à cause du couplage qui existe entre l’activité neuronale et le flux sanguin local dans le cerveau. Pour être en mesure de comparer les deux signaux (et éventuellement calibrer le signal d’IRMf par l’IOD), où chaque signal est relatif à son propre niveau de base physiologique inconnu, une nouvelle technique ayant la capacité de mesurer le niveau de base physiologique est nécessaire. Cette nouvelle technique est l’IOD résolue temporellement qui permet d’estimer les concentrations d’hémoglobine cérébrale. Ce nouveau système permet donc de quantifier le niveau de base physiologique en termes de concentrations d’hémoglobine cérébrale absolue. L’objectif général de ma maîtrise était de développer un tel système afin de l’utiliser dans une large étude portant sur la condition cardiovasculaire, le vieillissement, la neuroimagerie ainsi que les performances cognitives. Il a fallu tout d’abord construire le système, le caractériser puis valider les résultats avant de pouvoir l’utiliser sur les sujets de recherche. La validation s’est premièrement réalisée sur des fantômes homogènes ainsi qu’hétérogènes (deux couches) qui ont été développés. La validation des concentrations d’hémoglobine cérébrale a été réalisée via une tâche cognitive et appuyée par les tests sanguins des sujets de recherche. Finalement, on présente les résultats obtenus dans une large étude employant le système d’IOD résolue temporellement en se concentrant sur les différences reliées au vieillissement. / Our understanding of the functional organization of the human brain has been greatly influenced by the development of new medical imaging techniques. Pr. Hoge’s research has focused on the use of functional magnetic resonance imaging (fMRI) and continuous diffuse optical imaging (DOI) for non-invasive localization and quantification of brain activity associated with behavioral stimuli or tasks (e.g. cognitive, motor or visual). The respective signals of both techniques are based on cerebral haemoglobin concentrations because of the coupling that exists between neuronal activity and cerebral blood flow. Relating BOLD fMRI signals with those acquired using DOI has been complicated by the fact that fMRI yields fractional change values, while the majority of DOI methods have provided absolute changes from an unknown baseline. To address this, we adopted a newer technique known as time-resolved DOI, which allows absolute quantification of cerebral haemoglobin concentrations. Time-resolved DOI thus has the capacity to quantify the subject’s resting hemoglobin concentrations in absolute micromolar units. The main objective of my masters’ project was to implement and optimize a time-resolved DOI system for use in a large study exploring the links between cardiovascular fitness, aging, neuroimaging markers, and cognitive performance. In this thesis we describe the fabrication of the system, followed by its characterisation and validation using solid optical phantoms (homogeneous and heterogeneous) developed for this purpose. Haemoglobin concentrations obtained non-invasively with the system are validated against blood draws, while the sensitivity to variations in concentration are assessed during a cognitive task. Finally, we present the results of a large study in which the time-resolved DOI system was used to characterize age-related vascular changes in the brain.

Le procédé d'agglomération humide trouve des applications dans des secteurs industriels d'importance (e.g. agroalimentaire, pharmaceutique, génie civil, etc.) et s'appuie encore fortement sur le savoir-faire des opérateurs. Ce travail porte sur l'étude des contributions des apports hydriques et mécaniques à l'agglomération humide d'une poudre réactive (transformation de la semoule de blé en grains de couscous). Une approche découplée des apports d'eau et d'énergie mécanique est proposée. L'apport d'eau est étudié par la modélisation de l'influence des paramètres formulation et procédé de l'atomisation liquide sur la taille des gouttes pulvérisées. Les apports d'énergie mécanique sont étudiés à l'aide d'un équipement modèle de malaxage. La répartition des contraintes verticales dans le milieu granulaire à l'état statique est identifiée via une "cartographie 2D des isocontraintes". Le comportement de la poudre au malaxage est étudié au cours du déplacement de la pale dans le malaxeur modèle, par l'analyse des champs de vitesses des particules (obtenus par vélocimétrie par images de particules), et par la mesure des contraintes verticales au niveau de la pale. Une étude de la sthénique et de la cinématique des écoulements granulaires permet d'identifier des longueurs caractéristiques impliquées dans le comportement du milieu granulaire à l'état statique et sous sollicitation mécanique. L'étude couplée des apports hydriques et mécaniques est réalisée par suivi des dynamiques d'agglomération humide dans un malaxeur à pale. Elles sont décrites par des mesures en continu de la consommation énergétique et des mesures in situ des spectres d'absorption proche infra-rouge. / The wet agglomeration process presents large applications in different industrial fields (e.g. food, pharmaceutics, civil engineering, etc.) and is still mainly based on technical know-how and empiricism of operators. This thesis work investigates the contributions of water and mechanical energy inputs to the wet agglomeration of a reactive powder, in the particular case of the transformation of durum wheat semolina in couscous grains. A uncoupled approach of both water and mechanical energy inputs is carried out. The water addition is studied through a modelisation of the influence of operating and formulation parameters of the liquid atomization process on the droplet size. Mechanical energy inputs are studied using a model experimental mixing equipment. Vertical stress distribution in the granular bed in static conditions is identified thanks to the establishment of a "2D iso-stress cartography". The granular medium behaviour under mechanical solicitation is studied during the blade motion in the model mixing equipment thanks to the analysis of granular flows and velocity fields (obtained by particle image velocimetry) and to vertical stress measurements directly on the blade. A sthenic and kinematic study of granular flows allows to identify characteristic lengths involved in the granular medium behaviour under mechanical solicitation. The coupled study of water and mechanical inputs is conducted by following in-line the wet agglomeration dynamics in a pilot mixing device using energetical consumption measurements as well as in situ acquiring of near infrared absorption spectra.

Chernozem became the crucial soil for the beginnings of soil science through the work of Dokuchaev from 1883. Since then the genesis of chernozems in Central Europe has raised many questions among soil scientists, botanists and paleo-environmentalists. While in Eastern Europe chernozems have been described as zonal soils, that are typical for continental steppe and forest-steppe areas, there are areas in Central Europe which are predisposed by their climatic characteristics to the presence of woodlands. The goal of this dissertation is to enrich the discussion about the genesis of chernozems by restoring the environmental conditions that were prevalent during the formation of chernozem soils in Central Europe. Chernozems are usually developed on loess with a very thick and dark organic surface which passes directly to a calcareous horizon. The organic matter underwent a polymerization in dependence on climate contrasts. However, in Central Europe, the climatic characteristics of the areas of chernozems are a bit different. These chernozems are supposed to have been formed under the climatic conditions that dominated Central Europe during the Late Glacial and the Early Holocene. The climatic nuances may contribute to the explanation of the differences in distribution of chernozems ("drier") and...

As Boas Práticas de Fabricação de Medicamentos (BPFM) enfatizam que a indústria farmacêutica deve dirigir seus esforços no sentido de compreender a variação do processo, incluindo as fontes, o grau de variação e o impacto dessa variação nas características de qualidade do produto. O processo de fabricação de medicamentos tem apresentado significativas mudanças, em especial no que se refere à introdução de tecnologias analíticas que permitem o controle do processo em tempo real. A abordagem baseada na análise de risco e no novo Sistema de Qualidade Farmacêutica constitui ponto central das BPFM para o século XXI. Os órgãos regulatórios têm exigido da indústria farmacêutica sua adesão na melhoria contínua relativa ao desempenho de seus processos e, por consequência, na qualidade do produto. O objetivo do presente trabalho foi o desenvolvimento e validação de método analítico empregando espectroscopia no infravermelho próximo, assim como a avaliação do processo de fabricação de comprimidos de Captopril 25 mg, empregando abordagem racional-científica. Com referência à avaliação do processo, foram adotadas as seguintes ferramentas: análise de modos e efeitos de falhas (FMEA); gráficos de controle; índices de capacidade e análise de variância (ANOVA). A espectroscopia por infravermelho próximo (NIR) foi selecionada por apresentar maior rapidez na obtenção dos resultados, maior simplicidade na preparação das amostras, multiplicidade das análises a partir de uma única leitura e por apresentar característica não invasiva. Os resultados comprovaram a adequação dessa tecnologia na avaliação quantitativa do Captopril nas etapas de mistura de pós e de compressão. Os desvios padrão relativos na determinação da uniformidade de Captopril na mistura de pós e nos comprimidos empregando método no NIR foram, respectivamente 3,15 e 0,18%. No que se refere à avaliação da estabilidade e da capacidade do processo, as ferramentas adotadas permitiram a compreensão das fontes de variabilidade, assim como a determinação de seu grau, nas diferentes etapas do processo. Os índices de capacidade (CpK) relativos à uniformidade de Captopril (% p/v) na mistura de pós, ao peso médio do comprimido, à uniformidade de conteúdo e à % (p/v) dissolvida de Captopril, no ensaio de dissolução, foram 0,70, 1,94, 1,80 e 2,19, respectivamente. / The Good Manufacturing Practices (GMP) for Medicinal Products point out that the pharmaceutical industry must direct efforts to understand the variation of the processes, including the sources, the level of variation and the variation impact on the process in characteristics of the product. The manufacturing process has shown meaningful changes, especially in the introduction of new analytical technologies that allow the process control in real time. The approach based on risk analyses and on the new Pharmaceutical Quality System is a central key for the GMP for the XXI century. The Regulatory Agencies have demanded the pharmaceutical industry to adhere the continuous improvement related to the performance of its processes and, consequently, the product quality. Thus, the present paper aimed the development and validation of the analytical method employing NIR spectroscopy as the assessment of manufacturing process of Captopril 25 mg tablets, using rational scientific approach. Regarding the process assessment, the following tools were adopted: analysis of failure modes and effects analysis (FMEA), control charts, capability indexes, as well as analysis of variance (ANOVA). The near-infrared spectroscopy was selected due to its greater speed in getting the results, simplicity in sample preparation, and multiplicity of analysis from a single reading and provide non-invasive feature. The results confirmed the suitability of this technology in quantitative assessment of Captopril on the steps of mixing powders and compression. The relative standard deviations for the determination of Captopril uniformity in the post mixtures and in the tablets employing NIR were 3,15 e 0,18%, respectively. In reference to the stability assessment and process capacity, the tools adopted permitted the understanding of the sources of variability, as well as the determination of their level in different phases of the process. The capacity indexes relating to Captopril uniformity (% p/v) in the powder mixture, the average weight of the tablet, the content uniformity and the % (p/v) dissolved Captopril, in the dissolution assay were 0,70, 1,94, 1,80 and 2,19, respectively.

L’objectif de cette thèse est de démontrer le potentiel de la spectroscopie proche infrarouge multipoints pour suivre en ligne des milieux diffusants et absorbants dont les propriétés physique et chimique varient au cours du temps. Des travaux ont tout d’abord porté sur l’étude d’un milieu où seule la diffusion varie au cours du temps. Le suivi de la réaction de précipitation de la silice a été choisi pour illustrer un tel milieu. Dans un premier temps, des spectres en transmission collimatée ont été mesurés sur des échantillons prélevés au cours du procédé. Grâce à l’application de la loi de Beer-Lambert, il a été possible d'obtenir les coefficients de diffusion de chaque échantillon et ainsi retrouver les différentes étapes de la réaction. Une analyse en composante principale de ces coefficients a montré la présence de deux régimes de diffusion dans le milieu réactionnel. Dans un second temps, une sonde de mesures multipoints, a été immergée dans un réacteur de fabrication. Des spectres ont été mesurés à des angles de 30°, 90°, 150°, 170° et 180° par rapport à la source, tout au long de la précipitation. Une analyse univariée, aux différents angles, a montré des différences et des similitudes entre les positions, en lien avec les interactions lumière matière. Puis une analyse multivariée multi tableaux ACCPS (Analyses en Composantes Communes et Poids Spécifiques) a été appliquée. Elle permet de combiner les informations issues des différents angles et de montrer les informations communes et spécifiques. Cela a permis de valider l’utilisation de la mesure multipoints pour le contrôle du procédé. Grâce à l’analyse des scores globaux, différents types de diffusion et la spécificité de certains angles dans la détection de modifications physiques, ont été identifiés. L’analyse des loadings individuels, a confirmé les différentes étapes réactionnelles identifiées et a révélé des phénomènes relatifs à la diffusion de la lumière comme l’allongement du trajet optique. La même démarche, analyses en laboratoire puis en ligne, a été appliquée à un milieu où la diffusion et l’absorption varient. Le suivi des produits issus des procédés pour l’amélioration de l’extraction du pétrole a été choisi pour illustrer un tel milieu. Dans un premier temps, des microémulsions (eau, huile et tensio-actif) ont été fabriquées de sorte à ce que les propriétés chimiques et physiques soient différentes. Puis chaque phase a été analysée séparément. Une analyse en composantes principales a permis de caractériser les systèmes grâce à l’identification des phases. Elle a également montré que les différences entre elles étaient liées, à la fois à l’absorption et à la diffusion. Pour séparer ces deux phénomènes, une résolution multivariée de courbes par régression alternée a été appliquée. Cela a permis d’expliquer plus en détail les différences entre les phases et d’obtenir des suivis semi-quantitatifs. Enfin dans la dernière partie, les mêmes échantillons ont été analysés en circulation avec une sonde multipoints. Une ACCPS a de nouveau été appliquée et a montré que des phénomènes de diffusion différents avaient lieu entre les classes. De plus elle a mis en lumière une hétérogénéité dans la composition des phases, qui ne pouvait pas être détectée avec des mesures en statique. / The aim of this thesis is to demonstrate the potential of multipoint near infrared spectroscopy to monitor online scattering and absorbing environments, where physical and chemical properties change over time. The work was first based on the study of an environment where scattering was the only parameter varying over time. Monitoring of the silica precipitation reaction has been chosen to illustrate that environment. First of all, spectra in collimated transmittance mode were acquired from samples collected during the process. Thanks to the Beer-Lambert law, scattering coefficients of each sample were obtained and from them the different steps of the reaction were found. A principal component analysis of those coefficients showed the existence of two scattering modes into the reaction environment. In the second phase, a multipoint probe was submerged in an industrial reactor. Spectra were measured during the precipitation with angle of 30°, 90°, 150°, 170° and 180° to the source. A univariate analyse at those different angles showed differences and similarities between the positions, linked to the interaction of light and matter. Then, a multiblock and multivariate analysis, CCSWA (Common Component and Specific Weight Analysis), was applied. It allows the combination of information from different angles and also shows common and specific information, in order to validate the use of multipoint measurement to monitor the process. Thanks to the analysis of global scores, different kind of scattering and the specificity of some angle, in the detection of physical modifications were identified. The analysis of individual loadings confirmed the identification of the different steps of reaction and has revealed some phenomena related to light scattering, such as the extension of the optical path. The same approach, analysis in the laboratory then online, was applied on an environment where scattering and absorption vary. Monitoring of products from the process to improve oil extraction, has been chosen to illustrate that environment. First of all, micro emulsions (water, oil and surfactant) were made so that physical and chemical properties would be different between samples. Then, each phase was analysed separately. A principal component analysis was used to characterize the system by phase identification. It also showed the differences between the phases were linked, both to absorption and scattering. In order to separate those two phenomena, a multivariate resolution by alternate regression has been applied. It has permitted to explain in more details the differences between the phases and to obtain semi-quantitative monitoring. Finally, in the last part, the same samples were analysed in circulation with a multipoint probe. A CCSWA has been applied again and showed that different scattering phenomenon occurred between the categories. Moreover, it highlighted a heterogeneity in the phases' composition that couldn’t be detected in static measurement.

Made available in DSpace on 2014-12-17T15:42:05Z (GMT). No. of bitstreams: 1 AnaCON_DISSERT.pdf: 2560306 bytes, checksum: 01b4c26da4748508add3442c02e1b43b (MD5) Previous issue date: 2013-02-04 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / In this work, the quantitative analysis of glucose, triglycerides and cholesterol (total and HDL) in both rat and human blood plasma was performed without any kind of pretreatment of samples, by using near infrared spectroscopy (NIR) combined with multivariate methods. For this purpose, different techniques and algorithms used to pre-process data, to select variables and to build multivariate regression models were compared between each other, such as partial least squares regression (PLS), non linear regression by artificial neural networks, interval partial least squares regression (iPLS), genetic algorithm (GA), successive projections algorithm (SPA), amongst others. Related to the determinations of rat blood plasma samples, the variables selection algorithms showed satisfactory results both for the correlation coefficients (R?) and for the values of root mean square error of prediction (RMSEP) for the three analytes, especially for triglycerides and cholesterol-HDL. The RMSEP values for glucose, triglycerides and cholesterol-HDL obtained through the best PLS model were 6.08, 16.07 e 2.03 mg dL-1, respectively. In the other case, for the determinations in human blood plasma, the predictions obtained by the PLS models provided unsatisfactory results with non linear tendency and presence of bias. Then, the ANN regression was applied as an alternative to PLS, considering its ability of modeling data from non linear systems. The root mean square error of monitoring (RMSEM) for glucose, triglycerides and total cholesterol, for the best ANN models, were 13.20, 10.31 e 12.35 mg dL-1, respectively. Statistical tests (F and t) suggest that NIR spectroscopy combined with multivariate regression methods (PLS and ANN) are capable to quantify the analytes (glucose, triglycerides and cholesterol) even when they are present in highly complex biological fluids, such as blood plasma / No presente trabalho, a an?lise quantitativa de glicose, triglicer?deos e colesterol (total e HDL) em plasma sangu?neo de ratos e humanos foi realizada sem necessidade de pr?tratamentos de amostras, atrav?s do uso da espectroscopia no infravermelho pr?ximo (NIR), aliada a m?todos multivariados. Para tanto, foram comparadas diferentes t?cnicas e algoritmos utilizados para pr?-processamentos de dados, sele??o de vari?veis e regress?es multivariadas, tais como a regress?o por m?nimos quadrados parciais (PLSR), regress?o n?o linear via redes neurais artificiais (ANN), regress?o por m?nimos quadrados parciais por intervalos (iPLS), algoritmo gen?tico (GA), algoritmo das proje??es sucessivas (SPA), entre outros. Para as determina??es em sangue de ratos, os algoritmos de sele??o de vari?veis apresentaram resultados satisfat?rios tanto em rela??o aos coeficientes de correla??o (R?) quanto para os valores de erro quadr?tico m?dio de previs?o (RMSEP) para os tr?s analitos, especialmente para triglicer?deos e colesterol-HDL. Os valores de RMSEP para glicose, triglicer?deos e colesterol-HDL atrav?s do melhor modelo PLS foram de 6,08, 16,07 e 2,03 mg dL-1, respectivamente. Para as determina??es em sangue de humanos, as previs?es atrav?s de modelos PLS apresentaram resultados insatisfat?rios, com comportamento n?o linear e presen?a de bias. A regress?o ANN foi investigada como uma alternativa ao PLS, por sua habilidade de modelar sistemas n?o lineares. O erro quadr?tico m?dio de monitoramento (RMSEM) para glicose, triglicer?deos e colesterol total, para os melhores modelos ANN, foram de 13,20, 10,31 e 12,35 mg dL-1, respectivamente. Testes estat?sticos (F e t) sugerem que a espectroscopia NIR aliada a m?todos de regress?o multivariados (PLS e ANN) possuem capacidade de quantificar os analitos (glicose, triglicer?deos e colesterol) mesmo quando os mesmos est?o presentes em fluidos biol?gicos altamente complexos, como o plasma sangu?neo

As Boas Práticas de Fabricação de Medicamentos (BPFM) enfatizam que a indústria farmacêutica deve dirigir seus esforços no sentido de compreender a variação do processo, incluindo as fontes, o grau de variação e o impacto dessa variação nas características de qualidade do produto. O processo de fabricação de medicamentos tem apresentado significativas mudanças, em especial no que se refere à introdução de tecnologias analíticas que permitem o controle do processo em tempo real. A abordagem baseada na análise de risco e no novo Sistema de Qualidade Farmacêutica constitui ponto central das BPFM para o século XXI. Os órgãos regulatórios têm exigido da indústria farmacêutica sua adesão na melhoria contínua relativa ao desempenho de seus processos e, por consequência, na qualidade do produto. O objetivo do presente trabalho foi o desenvolvimento e validação de método analítico empregando espectroscopia no infravermelho próximo, assim como a avaliação do processo de fabricação de comprimidos de Captopril 25 mg, empregando abordagem racional-científica. Com referência à avaliação do processo, foram adotadas as seguintes ferramentas: análise de modos e efeitos de falhas (FMEA); gráficos de controle; índices de capacidade e análise de variância (ANOVA). A espectroscopia por infravermelho próximo (NIR) foi selecionada por apresentar maior rapidez na obtenção dos resultados, maior simplicidade na preparação das amostras, multiplicidade das análises a partir de uma única leitura e por apresentar característica não invasiva. Os resultados comprovaram a adequação dessa tecnologia na avaliação quantitativa do Captopril nas etapas de mistura de pós e de compressão. Os desvios padrão relativos na determinação da uniformidade de Captopril na mistura de pós e nos comprimidos empregando método no NIR foram, respectivamente 3,15 e 0,18%. No que se refere à avaliação da estabilidade e da capacidade do processo, as ferramentas adotadas permitiram a compreensão das fontes de variabilidade, assim como a determinação de seu grau, nas diferentes etapas do processo. Os índices de capacidade (CpK) relativos à uniformidade de Captopril (% p/v) na mistura de pós, ao peso médio do comprimido, à uniformidade de conteúdo e à % (p/v) dissolvida de Captopril, no ensaio de dissolução, foram 0,70, 1,94, 1,80 e 2,19, respectivamente. / The Good Manufacturing Practices (GMP) for Medicinal Products point out that the pharmaceutical industry must direct efforts to understand the variation of the processes, including the sources, the level of variation and the variation impact on the process in characteristics of the product. The manufacturing process has shown meaningful changes, especially in the introduction of new analytical technologies that allow the process control in real time. The approach based on risk analyses and on the new Pharmaceutical Quality System is a central key for the GMP for the XXI century. The Regulatory Agencies have demanded the pharmaceutical industry to adhere the continuous improvement related to the performance of its processes and, consequently, the product quality. Thus, the present paper aimed the development and validation of the analytical method employing NIR spectroscopy as the assessment of manufacturing process of Captopril 25 mg tablets, using rational scientific approach. Regarding the process assessment, the following tools were adopted: analysis of failure modes and effects analysis (FMEA), control charts, capability indexes, as well as analysis of variance (ANOVA). The near-infrared spectroscopy was selected due to its greater speed in getting the results, simplicity in sample preparation, and multiplicity of analysis from a single reading and provide non-invasive feature. The results confirmed the suitability of this technology in quantitative assessment of Captopril on the steps of mixing powders and compression. The relative standard deviations for the determination of Captopril uniformity in the post mixtures and in the tablets employing NIR were 3,15 e 0,18%, respectively. In reference to the stability assessment and process capacity, the tools adopted permitted the understanding of the sources of variability, as well as the determination of their level in different phases of the process. The capacity indexes relating to Captopril uniformity (% p/v) in the powder mixture, the average weight of the tablet, the content uniformity and the % (p/v) dissolved Captopril, in the dissolution assay were 0,70, 1,94, 1,80 and 2,19, respectively.