A azatioprina (AZA) é um imunossupressor utilizado no tratamento de doenças autoimunes como lúpus eritematoso sistêmico, doença de Crohn, doença inflamatória intestinal e contra a rejeição em transplantes de órgãos sólidos. Após mais de 40 anos de uso a AZA continua exercendo um papel central nos regimes imunomoduladores, devido ao fato de combinar eficácia, segurança e baixo custo. Sabe-se que a atividade da tiopurina metiltransferase pode determinar, pelo menos em parte, a eficácia clínica da AZA. Esta enzima apresenta polimorfismo genético co-dominante e a distribuição dos alelos variantes é significativamente diferente entre as populações. A grande variabilidade farmacocinética no metabolismo AZA justifica a sua monitorização terapêutica. Neste trabalho otimizou-se uma metodologia para a quantificação dos metabólitos da AZA, 6-TGN e 6-MMP, por cromatografia líquida de alta eficiência (HPLC/UV-Vis), utilizando-se um detector de ultravioleta-visível em um único comprimento de onda, após a amostra passar por uma desproteinização ácida simples e ser aquecida para a conversão dos metabólitos em suas respectivas bases livres. Os valores destes metabólitos foram determinados em uma população de 124 pacientes transplantados renais. Para adequarmos o processo às legislações locais e internacionais, foram seguidas orientações da Anvisa, FDA e CLSI. A separação foi realizada em coluna de fase reversa, sendo a fase móvel A fosfato de potássio e a fase móvel B metanol. A detecção da 6-TGN e da 6-MMP foi realizada em 342 m (UV-Vis). O estudo da linearidade da 6-TGN variou entre 0,30 e 89,71 mol/L e da 6-MMP entre 0,30 e 93,86 mol/L. As recuperações, de 95,08 a 100,80% para 6-TGN e 95,38 a 105,06% para 6-MMP. Os CV da repetibilidade, de 0,04 a 5,06%, enquanto os CV da reprodutibilidade de 4,88 a 12,73% para 6-TGN e 6-MMP. Para ambos os metabólitos o LD e o LQ foram de 0,30 mol/L e 0,13 mol/L. Os eritrócitos lavados e as amostras tratadas, prontas para a injeção no HPLC, foram armazenadas abaixo de -5°C até a análise. Nesta temperatura estiveram estáveis durante 8 semanas e 1 dia, respectivamente. Os valores das concentrações de 6-TGN e 6-MMP encontrados nas amostras dos pacientes variaram entre não detectável a 1569 mol/8 x 108 RBC (mediana de 200,50) e não detectável a 113057 mol/8 x 108 RBC (mediana de 5166), respectivamente. As correlações entre os níveis de 6-TGN ou 6-MMP e as variáveis sexo, tempo pós-transplante, número de transplantes e dosagem de AZA (mg/kg) foram examinadas em diferentes grupos. O método proposto apresenta boa relação custo-benefício, é simples, preciso e rápido na determinação das concentrações intraeritrocitárias de 6-TGN e 6-MMP em pacientes sob terapia com AZA. O método validado permite que o laboratório forneça dados farmacocinéticos úteis e precisos para o ajuste do tratamento do paciente e pode ser facilmente adaptado para a análise rotineira destes metabólitos. Os resultados das amostras dos pacientes estão de acordo com os encontrados em outros estudos, atestando a utilidade dessa ferramenta analítica no acompanhamento dos pacientes / Azathioprine (AZA) is an immunosuppressant used in autoimmune pathologies like lupus erythematosus, Chrons disease, inflammatory bowel disease and against rejection in solid organs transplant. After more than 40 years of use, AZA continues exerting a central role in immunomodulatory regimens, due to the fact that it combines effectiveness, safety and low cost. It is well known that thiopurine methyltransferase activity may determine, at least in part, the clinical efficacy of AZA therapy. This enzyme exhibits codominant genetic polymorphism and the distribution of these variant alleles differs significantly among populations. The considerable pharmacokinetic variability in AZA metabolism justify the therapeutic drug monitoring of this drug. In this work a methodology was improved to quantify the metabolites of AZA, 6-TGN and 6-MMP, by high performance liquid chromatography (HPLC/UV-Vis) with an ultraviolet-visible detector, using a single wavelength reading, following a simple acid deproteinization and heating to convert the metabolites into their respective free bases. The values of these metabolites were determined in a population of 124 renal transplant recipients. To adequate the process to international and local legislation, Anvisa, FDA and CLSI guidelines were followed. Separation was achieved on a reversed-phase column; mobile phase A potassium phosphate and mobile phase B methanol. Detection of 6-TGN and 6-MMP was performed at 342 m (UV-Vis). Assay linearity for 6-TGN ranged from 0.30 to 89.71 mol/L and from 0.30 to 93.86 mol/L for 6-MMP. The recoveries were 95.08, 97.76 and 100.80% for 6-TGN and 104.79, 95.38 and 105.06% for 6-MMP. Repeatability CV were 3.50, 5.06, 1.09 and 0.04, 0.35, 1.58%, while reproducibility CV were 8.65, 7.18, 8.44 and 12.73, 6.40, 4.88% for 6-TGN and 6-MMP, respectively. LOQ and LOD of 6-TNG and 6-MMP were respectively 0.30 mol/L and 0.13 mol/L for both metabolites. The washed erythrocytes and the samples treated and ready for injection into the HPLC system were stored below -5 °C until analysis, at this temperature the samples were stable for 8 weeks and for 1 day, respectively. 6-TGN and 6-MMP patient analysis values ranged from non detectable to 1569 mol/8 x 108 RBC (median of 200.50) and non detectable to 113057 mol/8 x 108 RBC (median of 5166), respectively. The correlations between 6-TGN or 6-MMP levels and variables sex, time post-transplant, number of transplants and AZA dosage (mg/kg) were examined in different groups. The proposed HPLC method has a good cost-benefit ratio, is straightforward, precise, accurate and fast at the determining 6-TGN and 6-MMP concentrations in red blood cells of patients under AZA therapy. The validated method is good enough to enable the laboratory to routinely provide useful and accurate pharmacokinetic data in time to adjust patient regimens. It can be easily adopted for routine analysis of these drug metabolites. The results of patient samples are in agreement with others studies, thus certifying the usefulness of this analytical tool in monitoring of patients

No topo do sistema de nappes Andrelândia, borda sul do cráton do São Francisco, ocorrem nappes formadas predominantemente por rochas metasedimentares com metabásicas e metaultramáficas subordinadas, que registram metamorfismo de fácies granulito de alta pressão no Ediacarano. São as nappes Três Pontas - Varginha, Pouso Alto e as klippen Aiuruoca e Carvalhos. Na Klippe Carvalhos predominam paragnaisses a rutilo, cianita, granada e ortoclásio pertítico, que estão colocados sobre micaxistos em fácies anfibolito da Nappe Liberdade. A assembléia mineral dos paragnaisses sugere uma progressão metamórfica saindo do campo de estabilidade da estaurolita (inclusa em granada), passando pela quebra de muscovita (ausente nos litotipos com menor retrogressão) e chegando na quebra parcial de biotita com geração de granada + ortoclásio + fundido. Durante a retrogressão essas reações foram novamente cruzadas em sentido contrário, sendo que a granada foi parcialmente a totalmente consumida por intercrescimentos vermiformes e/ou esqueletais de biotita + quartzo. Na porção leste da klippe e nas proximidades de zonas de cisalhamento é comum a ocorência de silimanita + biotita substituindo parcialmente granada e substituições diretas de cianita por silimanita. Rochas metabásicas, boudinadas dentro dos paragnaisses, apresentam paragênese reliquiar de granada + clinopiroxênio + quartzo ± plagioclásio. Nessas rochas a retrogressão está registrada em coronas de intercrescimentos de hornblenda + plagioclásio que substituem parcial a totalmente a granada. Localmente essas coronas são seguidas por uma fina e descontínua corona de minerais opacos granulares, possivelmente ilmenita. Na hidratação os cristais de clinopiroxênio, ricos em microexsoluções de quartzo e/ou feldspato, foram parcial a totalmente substituídos por hornblenda. E em locais com retrogressão mais intensa, próximos a zonas de cisalhamento, ocorre ortopiroxênio associado a clinopiroxênio. Em sua porção sudoeste, a klippe está em contato com gnaisses Paleoproterozóicos conhecidos como Migmatitos Alagoa. As rochas básicas intercaladas nesses gnaisses, em geral, registram metamorfismo de fácies anfibolito. Porém próximo ao contato com a klippe, ocorre um corpo com composição granítica e ortopiroxênio ígneo (charnockito), que apresenta coronas de granada + clinopiroxênio + quartzo + plagioclásio entre os cristais de ortopiroxênio e plagioclásio, evidenciando um metamorfismo progressivo chegando ao fácies granulito de alta pressão. Essas coronas podem estar relacionadas a superimposição do metamorfismo de alta pressão, sofrido pelas rochas da klippe no Ediacarano, no embasamento mais antigo. O pico metamórfico calculado para os paragnaisses da klippe através do termômetro de Zr em rutilo e do barômetro GASP é de 850 ºC e 16 Kbar. Esses dados corroboram com os cálculos termométricos realizados através da reintegração de feldspatos ternários (plagioclásio antipertítico) que chegam a temperaturas de 870 ± 50ºC. Em rochas metabásicas os resultados dos cálculos termobarométricos são 850ºC e 15 ± 2 Kbar. Datações U-Pb (ID-TIMS) de monazita colocam o pico metamórfico em 618 ± 2.2Ma. E datações K-Ar em anfibolio de 582.9 ± 14.8 Ma não são coerentes com resfriamento, em uma trajetória de exumação rápida, evidenciada pela preservação das paragêneses de pico metamórfico. Os metasedimentos presentes na Klippe Carvalhos apresentam composição variada, desde metasedimentos pelíticos com altas razões A/CNK até metasedimentos imaturos, ricos em feldspato, como metagraywackes e metarcósios. Apesar do alto grau metamórfico, os metasedimentos presentes na klippe apresentam padrões de ETR muito semelhantes aos de rochas sedimentares pós-arqueanas. Os granada-biotita-plagioclásio gnaisses da klippe, possíveis metarenitos imaturos, apresentam uma composição química aparentemente sem perda considerável de líquidos silicáticos gerados por fusão parcial. Isso provavelmente é resultado de baixas taxas de fusão parcial (<10%), que não permitem a conexão e extração dos líquidos. Essas baixas taxas de fusão parcial provelmente estão relacionadas às pequenas quantidades de muscovita nessas composições. Portanto, os granada-biotita-plagioclásio gnaisses provavelmente não foram composições férteis para geração magmas. Provavelmente os metapelitos foram as principais fontes de magma dentro da klippe, devido a quantidade elevada de muscovita nessas composições, que permitem uma geração considerável de líquidos através da quebra de muscovita, em temperaturas inferiores a 850ºC. / At the top of Andrelândia Nappes System, southern border of São Francisco craton, occur nappes formed dominantly by metasedimentary rocks with subordinated metabasics and metaultramafics which record metamorphism of high pressure granulite facies in the Ediacaran. These nappes are Três Pontas - Varginha, Pouso Alto and Klippen Airuoca and Carvalhos. In Carvalhos Klippe are predominant rutile, kyanite, garnet and pertitic orthoclase bearing paragneisses, which are placed over micaschists in amphibolite facies of Liberdade Nappe. The mineral assemblage of paragneisses suggests a metamorphic progression starting from stability field of estaurolite (as inclusion inside garnet), passing by muscovite breakdown (absent in lithotypes with less retrogresion) and reaching parcial breakdown of biotite, forming garnet + orthoclase + melt. During retrogression these reactions were crossed again in the opposite way, with granet being partially to totally consumed by vermiforms and/or eskeletals intergrowths of biotite + quartz. In the eastern portion of the Klippe and near shear zones are very common the substitution of garnet by sillimanite + biotite or kyanite by sillimanite. Metabasic rocks, boudinated inside paragneisses, exhibit relicts of garnet + clinopyroxene + quartz ± plagioclase. In these rocks retrogression is recorded in intergrowth coronas of hornblende + plagioclase which substitute garnet partially to totally. Locally these coronas followed by a thin and descontinuous corona formed by granular opaque minerals, probably ilmenite. During hidratation reactions, clinopyroxene crystals, rich in microexsolutions of quartz and/or feldspar, were partial to totally replaced by hornblende. Where retrogression were more intense, nearby shear zones, occur orthopyroxene associated with clinopyroxene. In its southwestern portion is in contact with Paleoproterozoic gneisses known as Alagoa Migmatites. The basic rocks, intercalated with these gneisses, usually record amphibolite facies metamorphism. However, close to the contact with klippe, occur a body with granitic composition and igneous orthopyroxene (charnockite), which presents coronas of garnet + clinopyroxene + quartz + plagioclase, between orthopyroxene and plagioclase crystals, showing a progressive metamorphism reaching high pressure granulite facies. These coronas can be related to a superimposed metamorphism of high pressure in the older embasement. The metamorphic peak calculated for the paragneisses of klippe using Zr-inrutile thermometer and the GASP barometer is 850ºC and 16Kbar. These data are compatible with thermometric calculations done by ternary feldspar reintegration (antiperthitic plagioclase), which reachs temperatures of 870±50ºC. In metabasic rocks, the results of themobarometric calculations are 850ºC and 15±2Kbar. U-Pb dating (ID-TIMS) of monazite put the metamorphic peak in 618±2.2Ma and K-Ar dating in amphibole of 582.9±14.8Ma are not coherent with cooling in a fast exhumation pathway, showed by preservation of metamorphic peak paragneisses. The metasediments present in Carvalhos Klippe show variated composition, including pelitic metasediments with high A/CNK ratios and imature metasediments, rich in feldspar, like metagraywackes and metarkoses. In spite of high metamorphic grade, the metasediments present in the klippe show ETR patterns very similar to the post-archean rocks. The garnet-biotite-plagioclase gneisses of Klippe, probably imature metarenites, show a chemical composition aparently without considerable loss of silicatic melts, formed by partial melt. This probably results from low partial melt rates (<10%), which dont allow the conection and extraction of the liquids. The low partial melt rates are probably related to small amounts of muscovite in these compositions. Therefore, the garnet-biotiteplagioclase gneisses probably were not fertile compositions to form magmas. Probably the metapelites were the main sources of magma inside the klippe, due to high amounts of muscovite in these compositions, which allow a considerable generation of liquids through the muscovite breakdown, in temperatures below 850ºC.

Desde 1964, o Brasil tem lançado programas de políticas públicas para melhorar o acesso da população aos medicamentos considerados essenciais. Em 1999, com a criação da Agência Nacional de Vigilância Sanitária e a introdução dos medicamentos genéricos no mercado brasileiro, o Brasil passou a ter três classes de medicamentos disponíveis no mercado farmacêutico: referência, similar e genérico. O objetivo deste estudo foi avaliar a bioequivalência e intercambialidade entre dois antipsicóticos (referência e similar) utilizados pelo Instituto de Psiquiatria do Hospital das Clínicas da Universidade de São Paulo, contendo 2 mg de risperidona. Foi desenvolvido e validado um método analítico que emprega a cromatografia líquida de alta eficiência acoplada à espectrometria de massas para a determinação da risperidona (RSP) e seu principal metabólito a 9-hidroxirisperidona (9OH-RSP) em plasma. Para se avaliar a bioequivalência entre os medicamentos foram recrutados 22 voluntários sadios, os quais participaram do estudo clínico conduzido de forma cruzada e aleatória. As coletas sanguíneas para o ensaio de bioequivalência foram realizadas em tubos heparinizados (5 mL) e os tempos de coleta foram 0 (antes da medicação); 0,25; 0,5; 1; 1,5; 3; 5; 8; 12; 24; 48; 72; 96 e 120 horas após a administração da medicação. A determinação da bioequivalência entre os dois medicamentos deu-se através da comparação dos parâmetros farmacocinéticos: concentração plasmática máxima (Cmax), tempo para atingir a concentração plasmática máxima (Tmax) e área sobre a curva de decaimento plasmático (ASCT). Os resultados obtidos foram submetidos à análise de variância (ANOVA) e foi adotado o intervalo de confiança de 90% (IC 90%). Os valores médios para Cmax, Tmax e ASCT para RSP para os medicamentos referência e teste foram 16,02 ng/mL; 1,5 h e 348,94 ng.h/mL e 12,65 ng/mL; 1,5 h e 286,03 ng.h/mL, respectivamente. Já os valores médios para Cmax, Tmax e ASCT para 9OH-RSP para os medicamentos referência e teste foram 21,00 ng/mL; 5,0 h e 821,40 ng.h/mL e 17,85 ng/mL; 5,0 h e 632,92 ng.h/mL. Os valores de IC 90% para Cmax e ASCT para RSP para os medicamentos referência e teste foram 74 a 82% e 76 a 85%, respectivamente, e os valores de IC 90% para os mesmos parâmetros para 9OH-RSP foram 83 a 87% e 75 a 78%, respectivamente. Os resultados demonstraram diferenças significativas entre os medicamentos testados, o que permite concluir que os mesmos não são bioequivalentes e, portanto, não podem ser intercambiáveis / Brazil has launched programmes of public policies aiming to improve essential medicines access for the population since 1964. It was created in 1999 the National Agency for Sanitary Vigilance, which introduced the generic medicines in the Brazilian market, which already had the reference and the pharmaceutical equivalent ones. The objective of this study was to evaluate the bioequivalence and interchangeability between two antipsychotics (reference and pharmaceutical equivalent) used by the Institute of Psychiatry, Hospital of the Universidade de São Paulo, containing 2 mg of risperidone. It was developed and validated a high-performance liquid chromatography coupled to mass spectrometry method for the determination in plasma of risperidone (RSP) and its main metabolite, 9- hydroxy-risperidone (9OH-RSP). To assess bioequivalence between the medicines it was recruited 22 healthy volunteers, which took part in a clinical cross and random studies. The blood collections were performed on heparinizades tubes (5 ml) and runtimes collections were 0 (before medication); 0.25; 0.5; 1; 1.5; 3; 5; 8; 12; 24; 48; 72; 96 and 120 hours after the administration of medication. The determination of bioequivalence between the two drugs was achieved by a comparison of the following pharmacokinetic parameters: plasma concentration (Cmax), time to achieve Cmax (Tmax), and area under the plasma concentration-time curve (AUCT). Results were subjected to analysis of variance (ANOVA), adopting a confidence interval CI 90%. The average values for Cmax, Tmax and AUCT for RSP were 16.02 ng/ml, 1.5 h and 348.94 ng.h/ml for reference medicines and 12.65 ng/ml, 1.5 h and 286.03 ng.h/ml for testing ones. The average values for Cmax, Tmax and AUCT for 9OH-RSP were 21.00 ng/ml, 5.0 h and 821.40 ng.h/ml for reference medicines and 17.85 ng/ml, 5.0 h and 632.92 ng.h/ml for testing ones. CI 90% for Cmax and AUC (RSP) were 74-82% and 76-85%, respectively. The CI 90% for the same parameters for 9OH-RSP was 83-87% for reference medicines and 75-78% for testing ones. There was significant difference between the products tested, thus one can conclude they are not bioequivalents, therefore cannot be interchanged

by Ma Chin Kwan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 129-131). / Chapter Chapter 1. --- Introduction --- p.1 / Chapter Chapter 2. --- Theory --- p.4 / Chapter Chapter 3. --- The Retention Mechanism of Cyano-Bonded Stationary Phase for Some Basic Drugs in Polar Eluents / Chapter 3.1 --- Introduction --- p.18 / Chapter 3.2 --- Experimental / Chapter 3.2.1 --- Reagents --- p.20 / Chapter 3.2.2 --- Equipment --- p.21 / Chapter 3.2.3 --- Standard Preparation --- p.21 / Chapter 3.2.4 --- Procedures --- p.22 / Chapter 3.3 --- Results and Discussion / Chapter 3.3.1 --- Acetonitrile-Perchloric Acid Systems --- p.29 / Chapter 3.3.2 --- Acetonitrile-Perchlorate Salts Eluent Systems --- p.42 / Chapter 3.3.3 --- Retention and Acetonitrile Composition --- p.49 / Chapter 3.4 --- Conclusion --- p.54 / Chapter 3.5 --- References --- p.55 / Chapter Chapter 4. --- Detector Response / Chapter 4.1 --- Introduction --- p.56 / Chapter 4.2 --- Experimental / Chapter 4.2.1 --- Reagents and Equipment --- p.57 / Chapter 4.3 --- Results and Discussion / Chapter 4.3.1 --- "The Relationship between Peak Area, Peak Height, and Detector Response" --- p.58 / Chapter 4.3.2 --- Detector Response and Eluent Strength --- p.60 / Chapter 4.3.3 --- Detector Response and Flow Rate --- p.74 / Chapter 4.4 --- Conclusion --- p.77 / Chapter 4.5 --- References --- p.78 / Chapter Chapter 5. --- Determination of Benzhexol Hydrochloride and Ethambutol Hydrochloride tablets by HPLC / Chapter 5.1 --- Introduction --- p.79 / Chapter 5.2 --- Experimental / Chapter 5.2.1 --- Reagents --- p.84 / Chapter 5.2.2 --- Equipment --- p.85 / Chapter 5.2.3 --- Samples --- p.86 / Chapter 5.2.4 --- Preparation of Reagents and Standards --- p.88 / Chapter 5.2.5 --- Sample Preparation and Determination --- p.89 / Chapter 5.3 --- Results and Discussion / Chapter 5.3.1 --- Sample Treatment and Extraction of Active Ingredient(s) --- p.91 / Chapter 5.3.2 --- Explanation of Chromatograms --- p.92 / Chapter 5.3.3 --- Choice of Experimental Conditions --- p.96 / Chapter 5.3.4 --- Linear Dynamic Response --- p.102 / Chapter 5.3.5 --- Sensitivity --- p.102 / Chapter 5.3.6 --- Analysis Results --- p.103 / Chapter 5.3.7 --- Comparison of Results from the Methods --- p.106 / Chapter 5.3.8 --- Precision and Accuracy --- p.113 / Chapter 5.3.9 --- Effect of Methanol Content on the Chromatographic Behaviour in Analysing Benzhexol Hcl --- p.117 / Chapter 5.3.10 --- Discussion on the Pharmacopoeial Assay of Benzhexol HC1 Tablets --- p.120 / Chapter 5.3.11 --- Discussion on the Various Factors Influencing the Pharmacopoeial Assay of Ethambutol HC1 Tablets --- p.123 / Chapter 5.4 --- Conclusion --- p.128 / Chapter 5.5 --- References --- p.129 / Appendix --- p.132

by Chan, Kim Hung. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 76-89). / Abstract also in Chinese. / Chapter 1. --- INTRODUCION --- p.1 / Chapter 1.1 --- amino acid analysis by high performance liquid chromatography --- p.1 / Chapter 1.1.1 --- History and Development --- p.1 / Chapter 1.1.2 --- Separation mechanism --- p.2 / Chapter 1.1.3 --- Derivatization --- p.4 / Chapter 1.1.4 --- Dqproteinization --- p.8 / Chapter 1.1.5 --- Ion-exchange or Reversed-phase HPLC --- p.9 / Chapter 1.2 --- amino acid pattern in cancer patient --- p.11 / Chapter 1.2.1 --- Cancer cachexia --- p.11 / Chapter 1.2.2 --- Causes of cancer cachexia --- p.11 / Chapter 1.2.3 --- Cytokines --- p.12 / Chapter 1.2.4 --- Metabolic Alteration in cancer cachexia --- p.13 / Chapter 1.2.5 --- Amino Acid Studies --- p.14 / Chapter 1.3 --- methodology chosen --- p.19 / Chapter 1.4 --- patient sample chosen --- p.21 / Chapter 2. --- OBJECTIVES --- p.22 / Chapter 3. --- MATERIALS AND METHOD --- p.23 / Chapter 3.1 --- apparatus --- p.23 / Chapter 3.1.1 --- HPLC System --- p.23 / Chapter 3.1.2 --- Column --- p.23 / Chapter 3.1.3 --- Detector --- p.23 / Chapter 3.1.4 --- ChemStation --- p.24 / Chapter 3.2 --- reagents --- p.24 / Chapter 3.2.1 --- Reagent and Chemical source --- p.24 / Chapter 3.2.2 --- Mobile phase --- p.24 / Chapter 3.2.3 --- Derivatization Reagent --- p.25 / Chapter 3.2.4 --- Standard preparation --- p.26 / Chapter 3.2.5 --- Internal standard --- p.28 / Chapter 3.3 --- sample preparation --- p.28 / Chapter 3.4 --- chromatographic conditions --- p.29 / Chapter 3.4.1 --- Column Temperature --- p.29 / Chapter 3.4.2 --- Injector Program --- p.29 / Chapter 3.4.3 --- Time Table for gradient elution and flow program --- p.32 / Chapter 3.5.1 --- OP A and sample Ratio and Volume --- p.32 / Chapter 3.5.2 --- Derivatization Concentration --- p.33 / Chapter 3.5.3 --- Derivatization time --- p.33 / Chapter 3 6 --- analytical performance --- p.34 / Chapter 3.6.1 --- Linearity testing --- p.34 / Chapter 3.6.2 --- Recovery studies --- p.34 / Chapter 3.6.3 --- Precision --- p.34 / Chapter 3.6.4 --- Sample storage --- p.35 / Chapter 3.7 --- clinical sample studies --- p.35 / Chapter 3.8 --- statistical analysis --- p.36 / Chapter 4 --- RESULT --- p.37 / Chapter 4.1 --- chromatographic separation --- p.37 / Chapter 4.2 --- optimization --- p.40 / Chapter 4.2.1 --- OPA and sample Ratio and Volume --- p.40 / Chapter 4.2.2 --- Derivatization time --- p.43 / Chapter 4.2.3 --- OPA Concentration --- p.43 / Chapter 4.3 --- analytical performance --- p.46 / Chapter 4.3.1 --- Linearity --- p.46 / Chapter 4.3.2 --- Recovery studies --- p.46 / Chapter 4.3.3 --- Precision Studies --- p.50 / Chapter 4.3.4 --- Sample storage studies --- p.53 / Chapter 4.4 --- clinical sample study --- p.55 / Chapter 5. --- DISCUSSION --- p.64 / Chapter 5.1 --- analytical --- p.64 / Chapter 5.2 --- clinical --- p.71 / Chapter 5.2.1 --- Normal controls --- p.71 / Chapter 5.2.2 --- Colorectal Cancer --- p.71 / Chapter 5.2.3 --- Lung Cancer --- p.72 / Chapter 5.2.4 --- Nasopharyngeal Cancer --- p.73 / Chapter 5.2.5 --- Summary --- p.74 / Chapter 6. --- CONCLUSION --- p.75 / Chapter 7. --- REFERENCES --- p.75

Quantum phase transitions (QPT) on the border of magnetism have provided a fertile hunting ground for the discovery of new states of matter, for example; the marginal Fermi Liquid and non Fermi Liquid states as well high T$_C$ cuprate and magnetically mediated superconductivity. In this thesis I present work on three materials in which it may be possible to tune the system through a magnetic QPT with the application of hydrostatic pressure. Although the details of the underlying physics are different in each of the materials, they are linked by the possibility of finding new states on the border of magnetism. Applying hydrostatic pressure, we have suppressed the ferromagnetic (FM) transition in metallic Fe$_2$P to very low temperature and to a potential QPT. Counter-intuitive broadening of the magnetic hysteresis leading up to the FM-AFM QPT may well be a crucial clue as to the nature of the model needed to understand this phase transition. A sharp increase in the quasi-particle scattering cross-section as well as the residual resistivity accompany a departure from the quadratic temperature dependence of the resistivity. This possible deviation from Fermi liquid behaviour is stable over a significant range of temperature. The unexplained upturn in the resistivity of CeGe that accompanies the AFM transition was studied under pressure. Pressure increased the residual resistivity as well as decreasing the relative size of the upturn, but had a moderate effect on the Neel temperature. The insensitivity of the N$\acute e$el temperature to pressure has been compared to its relative sensitivity to applied feld. The existence of the upturn and its evolution with pressure and applied feld can reasonably be argued to be due to the details of the electron band structure in the system. By applying pressure we have drastically reduced the resistivity of the insulating antiferromagnet NiPS$_3$. Concurrent work on FePS$_3$ has shown metallisation under pressure. It seems reasonable to speculate that NiPS$_3$ may also metallise at higher pressure. The energy gap is narrowed in both materials as pressure is increased. Magnetisation measurements have revealed a low temperature upturn indicating some possible ferromagnetic component or proximity to another magnetic state. A peak in the magnetisation is also seen at 45K in zero-feld cooled measurements. Both of these features point to a system with a complex magnetic ground state.

The study of matter at extreme conditions has been of great importance for modern society. A correct understanding of materials and environments subject to high pressures and temperatures enabled the development of car and jet engines, manufacture of goods, energy production and space travels among other human milestones. Discoveries in magnetism, geology, chemistry, and crystallography have been reported in literature as well, illustrating relevant contributions of this research area. Science at extreme conditions constantly requires to innovate instruments and characterisation methods. Sophisticated proficiencies are needed to explore and reproduce conditions of interest for this field. Since the 1990s, high pressure instruments for neutron scattering have boosted the study of compressed matter. The design and subsequent improvement of the Paris-Edinburgh (PE) press and toroidal anvils successfully impacted this area, currently being the most extensively used instrument for high pressure neutron scattering, commonly used for pressures of the order of 10 GPa. Recent incorporation of toroidal anvils made of Zirconia Toughened Alumina (ZTA) has opened new experimental possibilities. Neutron transparency and mechanical resistance are key properties of this ceramic material. At this point it is essential to understand ZTA anvils design and working conditions in order to increase experimental capabilities and access new frontiers in compressed matter. Computer-based modelling technique Finite Element Analysis (FEA) has been a recent ally for instrumentation design and optimisation. Phenomena such as mechanical stress, deformations, and thermal distributions can be modelled in an object, gathering information regarding its mechanical stability, behaviour and failure. Although this method is popular in industrial and engineering design and applications, it has not been widely employed in high pressure research due to scarce information in material properties under extreme conditions, as well as in innovative ceramics and metallic alloys introduced in these types of scientific devices.

No description available.

Thesis. 1976. Sc.D.--Massachusetts Institute of Technology. Dept. of Aeronautics and Astronautics. / Microfiche copy available in Archives and Barker. / Vita. / Includes bibliographical references. / Sc.D.

La convection dans le manteau terrestre est la principale force motrice du mouvement des plaques tectoniques. Alors que les parties inférieures du manteau supérieur se déforment de manière ductile, les plaques tectoniques sont rhéologiquement plus rigides que l'asthénosphère sous-jacente. Pour comprendre le couplage entre la convection profonde et les plaques tectoniques à la surface de la Terre, il est essentiel de comprendre les mécanismes de déformation visqueuse et frictionnelle du manteau lithosphérique. Mais à ce jour, la rhéologie du manteau supérieur juste au-dessous de la discontinuité de Mohorovicic est encore mal comprise. De plus, les premiers stades de la déformation viscoplastique à des températures intermédiaires (600-1000 ° C) pertinentes pour le manteau lithosphérique, ne sont ni bien documentés ni quantifiés. Dans le passé, la plupart des expériences de déformation étaient effectuées à des températures très élevées (> 1200 ° C). Pour fournir des valeurs mécaniques précises pour le manteau lithosphérique, nous avons besoin de données mécaniques mais aussi de la caractérisation de la microstructure associée pour comprendre la physique des mécanismes en jeu lors de la déformation permanente des roches riches en olivine. Dans cette thèse, nous avons réalisé des expériences de déformation en compression axiale à l'aide d'une presse Paterson (Géosciences Montpellier, Université de Montpellier, France) à haute pression et température (300 MPa, 1000-12000 ° C) et en torsion (‘rotary shear frictional testing machine’ au laboratoire de mécanique des roches, université de Durham, Royaume-Uni) à pression et température ambiantes. Les échantillons ont été caractérisés par microscopie électronique à balayage, diffraction d’ d'électrons rétrodiffusés et microscopie électronique en transmission. Après un chapitre d'introduction où l'état de l'art est détaillé et un chapitre consacré aux méthodes expérimentales et analytiques utilisées dans les projets scientifiques, la thèse s'organise en trois chapitres, chacun correspondant à trois articles scientifiques: le premier est publié (1) Évolution de la contrainte et des microstructures associées au fluage transitoire de l'olivine à 1000-1200 °C (Phys. Earth Planet. Int., doi: 10.1016/ j.pepi.2018.03.002. (https: //hal.archives- ouvertes.fr/hal-01746122) et les deux autres sont en préparation, (2) Densité de disclinaisons dans l'olivine polycristalline déformée expérimentalement à 1000 ° C et 1200 ° C (3) Déformation par cisaillement de l'olivine nano- et micro-cristalline. Le premier projet du chapitre III a montré que le durcissement mécanique observé ne peut pas provenir d'une simple augmentation de la densité de dislocations (e.g., la forêt) et que d'autres mécanismes doivent être mis en œuvre pour compenser les limites de glissements des dislocations. Dans le chapitre IV, les densités de dislocation géométriquement nécessaires (GND, défauts de translation) et les disclinaisons (défauts de rotation) sont quantifiées sur une série de roches déformées à différentes températures, déformations finies et niveaux de contrainte, mais aucune corrélation n'a été identifiée entre la densité de disclinaisons, et la contrainte, la déformation finie, ou la densité de GND. Le rôle des disclinaisons serait donc limité à la migration aux joints de grains, ce qui peut être suffisant pour débloquer les dislocations dans l'agrégat d'olivine polycristalline. Au chapitre V, les expériences de torsion ont confirmé l'effet négligeable de la taille du grain (olivine de 0,7 à 70 µm) sur la diminution drastique du coefficient de frottement, mais la caractérisation des échantillons n’a pas permis d'élucider le mécanisme principal de déformation. Cette thèse a permis de mieux caractériser la transition fragile-ductile d'une roche de type dunite à grains fins soumise à une déformation permanente aux températures du manteau sommitale. / Convection in Earth’s mantle is the major driving force behind the movement of tectonic plates. While the lower parts of the upper mantle deform in a ductile way, the plates themselves are rheologically more rigid than the asthenosphere beneath. To understand how convection yields tectonic plates, it is vital to quantify the viscous and frictional strength of the lithospheric mantle. Yet to date, the rheology of the uppermost mantle just below the Mohorovicic discontinuity is still poorly understood. Furthermore, the early stages of visco-plastic deformation at intermediate temperatures (600 – 1000 °C) relevant of the lithospheric mantle are not well documented or quantified. In the past, most deformation experiments were performed at high temperatures (> 1200 °C). To provide accurate mechanical values for the lithospheric mantle, we need mechanical data but also a characterization of the associated microstructure to understand the deformation mechanisms at play during permanent deformation of olivine-rich rocks. In this thesis, I have performed deformation experiments in axial compression using a Paterson press (at Géosciences Montpellier, University of Montpellier, France) at high pressure and temperature (300 MPa, 1000 -12000 °C) and in torsion using a low to high velocity rotary shear frictional testing machine (Rock Mechanics Laboratory, Durham University, UK) at room pressure and temperatures. The recovered samples were characterized using scanning electron microscopy, electron backscatter diffraction and transmission electron microscopy. After an introduction chapter where the state-of-the-art is detailed, and a chapter focusing on experimental and analytical methods used during scientific projects, the thesis is organized as three subsequent chapters, each of them corresponding to three scientific articles: one is published (1) Stress evolution and associated microstructure during transient creep of olivine at 1000-1200 °C (Phys. Earth Planet. Int., doi: 10.1016/j.pepi.2018.03.002.); and the two others are in preparation, (2) Disclination density in polycrystalline olivine experimentally deformed at 1000 °C and 1200 °C; and (3) Shear deformation of nano- and micro-crystalline olivine at seismic slip rates. Chapter III has shown that the observed mechanical hardening can not come from a simple increase in dislocation density (e.g., entanglement) and that other mechanisms must be at play to compensate for the limitations of dislocation slip. For the first time, in chapter IV the densities of geometrically necessary dislocations (GND, translational defects) and disclinations (rotational defects) are quantified on a series of rocks deformed at different temperatures, finite strains and stress levels. No correlation has been identified between disclination density and stress, strain or GND. The role of the disclinations will therefore be limited to migration at grain boundaries, which may be sufficient to unblock dislocations in the polycrystalline olivine aggregate. In chapter V, torsion experiments confirmed the negligible effect of grain size (olivine from 0.07 to 70 μm) on the drastic decrease of the coefficient of friction, but the characterization of the samples did permit to shed light on the main mechanism of deformation. Thanks to an experimental approach and up-to-date material characterization, this thesis permitted better characterization of the brittle-ductile transition of a fine-grained dunite-type rock subjected to permanent deformation at uppermost mantle temperatures.