A avaliação da classe biofarmacêutica dos fármacos assume importância na política de medicamentos genéricos, já que as características de solubilidade e permeabilidade de um fármaco, conforme definidas pelo Sistema de Classificação Biofarmacêutica (SCB), constituem critério essencial para bioisenção na obtenção de registro de genéricos. O propósito do trabalho foi o de determinar a classe biofarmacêutica dos fármacos benzilato de anlodipino, fluconazol e cloridrato de fluoxetina, por meio da determinação de seus parâmetros de solubilidade e permeabilidade. Para o teste de solubilidade, foram desenvolvidos e validados métodos para a quantificação do benzilato de anlodipino, fluconazol e cloridrato de fluoxetina em água e nos tampões farmacopéicos pH 1,2; pH 4,5;pH 6,8 e 7,5. O estudo de solubilidade foi realizado pelo método shake flask num período de 72 horas de agitação a 37°C. A maior dose comercializada no mercado é de 10 mg, 200 mg e 20 mg respectivamente para o besilato de anlodipino, fluconazol e cloridrato de fluoxetina. Os valores de solubilidade para o besilato de anlodipino nos meios avaliados foram de 0,88 a 2,35 mg/mL enquanto intervalo da razão dose: solubilidade (D: S) foi de 4,24 mL a 11,36 mL. Para o fluconazol os valores de solubilidade foram: 8,22 a 14,4 mg/mL, e o intervalo da razão D: S foram de 13,38 mL a 24,33 mL. Já para o cloridrato de fluoxetina a solubilidade foi de 5,12 a 44,36 mg/mL, e o intervalo razão D: S foram de 0,45 a 3,91 mL. De acordo com o SCB, para classifacar um fármaco como de alta solubilidade a dose mais alta cormecializada do fármaco deve ser solúvel em 250 mL de meio aquoso na faixa de pH de 1 a 7,5 a 37º C e um fármaco é considerado como de alta permeabilidade quando a sua fração absorvida seja ≥ 90%. De acordo com esse critério, ambos os fármacos apresentam alta solubilidade. A avaliação da permeabilidade dos fármacos foi realizada por meio da determinação do fluxo de fármaco através de segmentos intestinais de ratos, isolados e contidos em câmaras de difusão vertical da plataforma manual para testes de permeabilidade. Os valores de permeabilidade aparente (Papp) obtidos nos experimentos indicam que o besilato de anlodipino e o fluconazol são fármacos de baixa permeabilidade, portanto, classe III e o cloridrato de fluoxetina alta permeabilidade, classe I. / The Biopharmaceutical Classification System (BCS) concept was established by Amidon and co-workers (1995) and BCS allows expectations regarding correlation between in vitro dissolution data and in vivo bioavailability data. According to the BCS, three major factors govern drug bioavailability: the drug aqueous solubility, the ability of the drug molecules to permeate biologic membranes and drug dissolution from the dosage form. Solubility criteria defined by the FDA to classify a drug as highly soluble requires the highest dose strength to be soluble in 250 mL of aqueous media over the pH range of 1-7.5 at 37°C and a drug is considered with high permeability when its fraction absorbed is ≥ 90%. The purpose of this study was to evaluate the solubility and permeability of amlodipine benzylate, fluconazole and fluoxetine hidrochoride in order to determine them BCS class. The solubility study was performed using the drug over a 72 hours period of agitation as the shake flask method at 37 °C. The results from solubility values are given in mg/mL and dose: solubility ratio is given in mL. The highest dose marketed is 10 mg, 200 mg and 20 mg, respectively for the amlodipine besylate, fluconazole and fluoxetine hydrochloride. The solubility values for the amlodipine besylate in the tested aqueous media range from 0.88 to 2.35 mg/mL, while dose solubility ratio (D: S) values range from 4.24 to 11.36 mL. The values for fluconazole solubility were 8.22 to 14.4 mg/mL, and the D: S was 13.38 to 24.33 mL. The fluoxetine hydrochloride solubility is range from 5.12 to 44.36 mg/mL, and the ratio D: S from 0.45 to 3.91 mL. According to BCS all the drugs have high solubility. The evaluation of the drugs permeability was performed by determining the drug flow through the rat intestinal segments, isolated and contained in vertical diffusion chambers platform for manual testing permeability. The apparent permeability values (Papp) obtained in the experiments indicate that the amlodipine besylate and fluconazole are low permeability drugs and fluoxetine hydrochloride high permeability. Considering Solubility and permeability assay, amlodipine besylate and fluconazole are Class III and fluoxetine hydrochloride is Class I.

Ce mémoire de thèse est divisé en deux parties. La première est consacrée à l'étude de la superfluidité dans un gaz de fermions ultra-froids. En utilisant un gaz dégénéré de lithium 6 au voisinage d'une résonance de Feshbach nous avons obtenu un superfluide fermionique et étudié son évolution en fonction de l'énergie de liaison des paires. Afin de caractériser la transition BEC-BCS entre un condensat de Bose-Einstein de molécules et un état BCS de paires de Cooper faiblement liées, nous avons étudié l'expansion du nuage en absence ou en présence d'interactions. Nous avons ainsi extrait la distribution en impulsion du système et sondé son caractère hydrodynamique. La seconde partie concerne la conception et la réalisation d'un montage expérimental de seconde génération. Par rapport à l'ancien dispositif, ses principaux atouts sont un gain d'un ordre de grandeur sur le nombre d'atomes piégés, un bon accès optique, une grande stabilité et reproductibilité ainsi qu'un taux de répétition cinq fois supérieur. La nouvelle expérience a déjà permis d'atteindre le seuil de dégénérescence quantique du lithium 7 avec des performances très satisfaisantes et donne accès à la simulation de hamiltoniens de matière condensée avec des fermions ultra-froids.

In order to understand some of the superconducting mechanisms involving external electric fields at nanometric scales, a Lorentz-covariant extension of the phenomenological Ginzburg-Landau theory has been developed by analogy with the Higgs model of particle physics. Among the specific properties of this model, it has been shown that the phase diagram of some particular geometry submitted to crossed electric and magnetic fields in a stationary situation provides a criterion involving the applied electric field, which could discriminate between the usual Ginzburg-Landau theory and its covariant extension. A sub-microscopic device has been manufactured using microelectronics lithography techniques and was used to perform transport measurements at very low temperatures. However, the experimental measurements of the phase diagram do not reproduce the expectations based whether on the usual or the extended model, suggesting a screening of the electric field by some mechanism which is not accounted for by these phenomenological approaches. A microscopic approach has therefore been developed to extend the s-wave channel of the BCS theory in a relativistic framework, using the functional integral formalism of Finite Temperature Field Theory. In particular, the effective action related to the Ginzburg-Landau free energy was obtained up to second order in the fluctuations of the electromagnetic field and of the superconducting condensate density. This allowed for the identification of the electric and magnetic penetration lengths, inclusive of their dependences on temperature and the chemical potential, which fully explain the experimental results. Several analytic expressions have also been provided for the effective potential in the full range of temperatures between 0 K and the critical temperature, among which the Ginzburg-Landau potential was shown to reproduce this effective potential within the limited range of temperatures where it is expected to be valid.

This dissertation discusses the Landau-Zener (LZ) theory and its application in noisy environments and in many-body systems. The first project considers the effect of fast quantum noise on LZ transitions. There are two important time intervals separated by the characteristic LZ time. For each interval we derive and solve the evolution equation, and match the solutions at the boundaries to get a complete solution. Outside the LZ time interval, we derive the master equation, which differs from the classical equation by a quantum commutation term. Inside the LZ time interval, the mixed longitudinal-transverse noise correlation renormalizes the LZ gap and the system evolves according to the renormalized LZ gap. In the extreme quantum regime at zero temperature our theory gives a beautiful result which coincides with that of other authors. Our initial attempts to solve two experimental puzzles - an isotope effect and the quantized hysteresis curve of a single molecular magnet - are also discussed. The second project considers an ultracold dilute Fermi gas in a magnetic field sweeping across the broad Feshbach resonance. The broad resonance condition allows us to use the single mode approximation and to neglect the energy dispersion of the fermions. We then propose the Global Spin Model Hamiltonian, whose ground state we solve exactly, which yields the static limit properties of the BEC-BCS crossover. We also study the dynamics of the Global Spin Model by converting it to a LZ problem. The resulting molecular production from the initial fermions is described by a LZ-like formula with a strongly renormalized LZ gap that is independent of the initial fermion density. We predict that molecular production during a field-sweep strongly depends on the initial value of magnetic field. We predict that in the inverse process of molecular dissociation, immediately after the sweeping stops there appear Cooper pairs with parallel electronic spins and opposite momenta.

Nous utilisons un gaz fermionique de lithium-6 en tant que système modèle pour étudier l'effet de la superfluidité. Les deux cas limites de la superfluidité sont la formation d'un condensat de Bose-Einstein (BEC) et la supraconductivité, décrite par la théorie de Bardeen, Cooper et Schrieffer (BCS). Dans un gaz de lithium-6 on peut explorer toute la transition entre ces deux limites, la transition BEC-BCS, grâce à une résonance de Feshbach. Nous étudions le comportement de la distribution d'impulsions du gaz dans la zone de cette transition et la comparons avec des modèles théoriques. L'expansion hydrodynamique, caractéristique d'un gaz superfluide, est aussi étudiée. Nous observons un changement brusque de la forme du gaz en expansion à proximité de la transition vers la phase superfluide. Nous avons aussi localisé des résonances de Feshbach hétéronucléaires entre Li-6 et Li-7. Au cours d'une reconstruction du montage vers une expérience de deuxième génération, un nouveau système laser, basé sur des diodes laser à haute puissance, a été developpé. Des améliorations dans notre enceinte à vide, y compris une reconstruction complète du ralentisseur Zeeman, ont augmenté le flux d'atomes, permettant de diminuer le temps de répétition de l'expérience. La géometrie des pièges magnétiques a été modifiée afin d'augmenter le nombre d'atomes piégés.

ABSTRACT This thesis contains solution of issue Effect of season to condition Holstein cattle breed in period from December 2013 to December 2014 in BONAGRO, a. s. in Šlapanice city in herd about 80 dairy cows in the first stage of lactation. Experiments were made periodically on the first week of month, overall twelve times per a year. Whole thesis is based on subjective evaluation of body condition of cows. I statistically demonstrated effect of season to condition of cows. I also showed that season affected feed factions. I subdued these factions to special sieve analysis (Penn State Separator). Furthermore, I found statistically conclusive effect of season to residual amount of washed excrements, which I subdued to primary analysis. Feed and excrement analysis place together with evaluation of body condition. At the same time, I measured temperature inside the stable and compared it with temperature in surroundings of Šlapanice. In the end, I made an analysis of milk in university laboratory, which were compared with results of control of heredity, regularly made on the farm. All results are shown in this thesis and are complemented by graphs, tables, analysis and photos.

No description available.

Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2016-08-30T12:40:36Z No. of bitstreams: 1 PDF - Ana Paula Barbosa Felisberto.pdf: 15150593 bytes, checksum: 91492d03c403e10e2661ddddfff9d3fe (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2016-08-31T18:13:01Z (GMT) No. of bitstreams: 1 PDF - Ana Paula Barbosa Felisberto.pdf: 15150593 bytes, checksum: 91492d03c403e10e2661ddddfff9d3fe (MD5) / Made available in DSpace on 2016-08-31T18:13:01Z (GMT). No. of bitstreams: 1 PDF - Ana Paula Barbosa Felisberto.pdf: 15150593 bytes, checksum: 91492d03c403e10e2661ddddfff9d3fe (MD5) Previous issue date: 2015-08-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Most active pharmaceutical ingredients are made largely for being administered orally. A major challenge for medicinal products development containing Active Pharmaceutical Ingredients (APIs) with low solubility, especially Class II according to Biopharmaceutical Classification System - BCS, is to add technology to the development process in order to increase the bioavailability of these APIs and at the same time ensure their stability. Thus, the objective was to develop analytical methods to characterize lyophilized solid dispersions of ibuprofen obtained by using carboxymethylcellulose (CMC), hydroxymethylpropylcellulose (HPMC) and polyethylene glycol (PEG) 6000, comparing them in terms of thermal stability. The dispersions were characterized correlating the data obtained by the following techniques: Differential Scanning Calorimetry (DSC), Differential Scanning Calorimetry Coupled to a Photovisual System (DSC-photovisual), Thermogravimetry Analysis (TG) and Vibrational Absorption using Fourier Transform Infrared Spectroscopy (FTIR) to investigate possible physical and/or chemical interaction between the ibuprofen and its excipients. For thermal stability evaluation, the products were subjected to dynamic thermogravimetric analysis, by applying Osawa kinetic model, and to isothermal analysis by Arrhenius model at temperatures of 125, 130, 135, 140 and 145 °C, showing zero order kinetics reaction for the drug in the two models applied. According to the data obtained from the thermal analysis for the characterization and stability, the lyophilized solid dispersions containing PEG as a dispersing agent were more stable. The DSC and FTIR data showed the absence of physical and chemical interaction between the formulation components. / A maioria dos insumos farmacêuticos ativos é viabilizada em grande parte para serem administrados por via oral. Um dos grandes desafios para o desenvolvimento de medicamentos contendo Insumos Farmacêuticos Ativos (IFAs) com baixa solubilidade, em especial os de Classe II relacionados no Sistema de Classificação Biofarmacêutica – SCB, é agregar tecnologias ao processo de desenvolvimento no sentido de aumentar a biodisponibilidade destes IFAs ao mesmo tempo que possa garantir a estabilidade dos mesmos. Assim, objetivou-se desenvolver metodologias analíticas para caracterizar dispersões sólidas liofilizadas de ibuprofeno obtidas com carboximetilcelulose (CMC), hidroximetilpropilcelulose (HPMC) e polietilenoglicol (PEG) 6000, comparando-as em termos de estabilidade térmica. As dispersões foram caracterizadas correlacionando-se os dados obtidos pelas técnicas de calorimetria exploratória diferencial (DSC), calorimetria exploratória diferencial acoplada ao sistema fotovisual (DSC-fotovisual), termogravimetria (TG) e espectroscopia vibracional de absorção na região do infravermelho com transformada de Fourier (FTIR), a fim de investigar possíveis interações físicas e/ou químicas entre o ibuprofeno e seus excipientes. Para avaliação da estabilidade térmica, os produtos foram submetidos à análise termogravimétrica dinâmica, aplicando-se o modelo cinético de Osawa, e isotérmica pelo modelo de Arrhenius nas temperaturas de 125, 130, 135, 140 e 145 °C, apresentando cinética de reação de ordem zero para o fármaco nos dois modelos aplicados. De acordo com os dados obtidos a partir da análise térmica para caracterização e estabilidade, as dispersões sólidas liofilizadas contendo PEG como agente dispersante mostraram-se mais estáveis. Nos dados de DSC e FTIR mostraram a ausência de interação física e química entre os componentes da formulação.

A furosemida é um fármaco de ação diurética e amplamente utilizado em tratamentos de doenças renais, cardíacas e pulmonares. Sua absorção é problemática e de alta variabilidade inter e intraindividual. Este fármaco tem sido classificado como pertencente às classes II (baixa solubilidade e alta permeabilidade) ou IV (baixa permeabilidade e baixa solubilidade) do Sistema de Classificação de Biofarmacêutica (SCB). Em estudos anteriores da equipe de pesquisa, SPRICIGO e colaboradores (2008) e SILVA (2014) desenvolveram complexos de furosemida com hidroxipropil-&#946;-ciclodextrina que permitiram a otimização da solubilidade deste fármaco. Entretanto, dados sobre a sua permeabilidade intestinal, quando complexado, não foram determinados. Somando-se a isto, a literatura apresenta informações distintas em relação a este parâmetro, o que corrobora a importância de se avaliar a permeabilidade deste fármaco. Diversas técnicas têm sido empregadas para a avaliação da permeabilidade intestinal dos fármacos. No presente trabalho empregou-se o modelo de perfusão in situ de passagem tripla, cuja técnica possibilita avaliar a permeabilidade em três segmentos diferentes em um mesmo animal e ainda, apresenta características interessantes, pois trata-se de um método que proporciona, durante todo o experimento, condições mais próximas daquelas encontradas durante o processo in vivo de absorção de fármacos no intestino tais como: suprimento sanguíneo, inervação intacta, preservação das proteínas transportadoras de membranas e presença da camada de muco. O presente trabalho foi dividido nas seguintes etapas: (i) obtenção da furosemida complexada com hidroxipropil-&#946;-ciclodextrina, (ii) caracterização dos fármacos utilizando técnicas de análises térmicas, (iii) estudo de perfusão in situ de passagem tripla nos três segmentos intestinais (duodeno, jejuno e íleo) de ratos machos Wistar na ausência e na presença de inibidores da glicoproteína P e de enzimas metabolizadoras CYP3A4 com posterior análise estatística do impacto da ciclodextrina e inibidores na permeabilidade da furosemida e; (iv) análise histológica das microvilosidades intestinais após o ensaio de perfusão in situ nos três segmentos intestinais. Os valores encontrados em cada segmento para furosemida complexada foram: 8,58 ± 0,002 x 10-5 cm.s-1; 9,15 ± 0,003 x10-5 cm.s-1 e; 8,06 ± 0,002 x 10-5 cm.s-1, respectivamente para duodeno, jejuno e íleo enquanto que para furosemida pura encontraram-se os seguintes: 3,42 ± 0,08 x 10-5 cm.s-1 para duodeno; 3,87 ± 0,11 x 10-5 cm.s-1 para jejuno e 3,08 ± 0,001 x 10-5 cm.s-1 para íleo. Assim sendo, os valores obtidos para a permeabilidade da furosemida complexada foram significativamente superiores (p < 0,05) aos da furosemida pura, sugerindo que, a ciclodextrina pode ter influência no mecanismo de transporte da furosemida, que é via passiva paracelular. Quanto aos mecanismos envolvidos na permeabilidade da furosemida através dos enterócitos, pode-se sugerir que observou-se pouca influência dos inibidores da glicoproteína P (P-gp) e da enzima CYP3A4, sugerindo que não há uma participação importante destes mecanismos em sua absorção intestinal. / Furosemide, which is a diuretic drug, is widely used in heart, kidney and pulmonary disease treatments. The absorption is problematic with high variability inter and intra individuals. This drug has been classified as belonging to class II (low solubility and high permeability) or IV (low permeability and low solubility) of the Biopharmaceutical Classification System (BCS). In previous studies of the research team, Spricigo and colleagues (2008) and Silva (2014) developed complex of furosemide with hydroxypropyl-&#946;-cyclodextrin which allowed the optimization of the solubility of this drug. However, datas concerning it\'s intestinal permeability, when complexed, have not been determined. Addicted to this, the literature shows many information regarding to this parameter, which confirms the importance of the evaluation of the permeability of this drug. Some techniques have been employed in order to evaluate the intestinal permeability of drugs. In the present work, a triple single-pass intestinal perfusion technique was used for three different segments. This technique enables the evaluation of the permeability of different segments in the same animal and also has interesting features such as: it provides during all the experiment conditions closer to those found in in vivo process of a drug absorption in the gut; blood supply; intact innervations; preservation of membrane transporter proteins and presence of mucus layer. This study was divided into the following steps: (i) obtaining furosemide complexed with hydroxypropyl-&#946;-cyclodextrin, (ii) characterization of drugs using techniques of thermal analysis, (iii) perfusion study in situ triple passage in three segments (duodenum, jejunum and ileum) from male Wistar rats in the absence and presence of inhibitors of P-glycoprotein and metabolizing enzymes CYP3A4 and subsequential statistical analysis of the impact of the cyclodextrin and the inhibitors in the permeability of furosemide and (iv) histological analysis of intestinal microvilli after in situ perfusion assay in three segments. The values found in each segment for complexed furosemide were: 8,58 ± 0,002 x 10-5 cm.s-1; 9,15 ± 0,003 x 10-5 cm.s-1; 8,06 ± 0,002 x 10-5 cm.s-1, respectively for duodenum, jejunum and ileum while for pure furosemide, the values were: 3,42 ± 0,08 x 10-5 cm.s-1 to duodenum; 3,87 ± 0,11 x 10-5 cm.s-1 to jejunum and 3,08 ± 0,001 x 10-5 cm.s-1 to ileum. Thus, the values obtained for the permeability of the complexed furosemide were significantly higher (p < 0,05) than those found for pure furosemide, suggesting that the cyclodextrin might have an influence on the transport mechanism of furosemide, which is passive paracellular route. About the mechanisms involved in the permeability of furosemide through the enterocytes, it can be suggested that there was little effect of P-glycoprotein (P-gp) inhibitors and CYP3A4 enzyme, suggesting that there is an important role of these mechanisms in the furosemide intestinal absorption.

Récemment avec les nouvelles possibilités d'études expérimentales de noyaux exotiques riches en proton, un regain d'intérêt s'est porté sur la problématique des corrélations d'appariement proton-neutron. Ce travail a pour but l'étude des corrélations au delà du champ moyen et en particulier du pairing proton-neutron isoscalaire et isovecteur pour différents isotopes de Germanium N ~ Z. Nous avons d'abord traité l'approche BCS classique avec l'approximation Lipkin-Nogami (LN) de projection sur le bon nombre de particules en utilisant une interaction résiduelle de type contact. Ensuite dans une approche appelée Higher Tamm-Dancoff Approximation (HTDA) les corrélations proton-neutron ont été traitées en conservant explicitement le nombre de particules. Dans les deux cas, nous avons développé les codes numériques correspondants pour traiter les couplages proton-neutron. Les résultats des applications numériques pour quelques noyaux sont discutés et comparés dans les deux approches BCS(LN) et HTDA avec pairing isoscalaire et isovecteur. Nous avons montré que les deux approches donnent une description semblable des corrélations du fondamental mais que la méthode HTDA est plus efficace dans le régime de faible pairing. Nous avons mis en évidence le rôle crucial de la conservation du nombre de particules pour la description des corrélations d'appariement proton-neutron. La prise en compte du pairing T = 0 génère une énergie de liaison supplémentaire pour les noyaux N = Z contribuant au terme d'énergie de Wigner.