This work is focused on improvement of particle formation and separation processes in drinking water. These include the comparison of the dynamics of different coagulation reagents (aluminum sulphate and ferric sulphate) to find the optimal dose of coagulant. During centrifugation test is important to find such a setting centrifuge where we get the best results. In this work we studied the influence of the total mineralization at the optimum dose of coagulant.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Trypanosoma evansi is a pathogenic trypanosomatid with world distribution, which may cause big economic losses and affect almost all mammalian species. One of the most affected species is horses, which may develop a disease known as Mal das cadeiras. There are several clinical signs and pathologies resulting from this parasite infection. The acute phase is characterized by intermittent fever, subcutaneous edema, progressive anemia, blindness, lethargy and hemostatic abnormalities. In the chronic phase, animals exhibit cachexia, edema, incoordination and paralysis. The most common treatment for this infection is the use of drugs; however, these drugs have a moderate efficacy, and they may present toxicity, especially to kidney and liver. Thus, it is important to study new therapies for the treatment of the disease caused by T. evansi. The aim of this study was to investigate the anti-trypanosomal effect of the treatment with 3‟deoxyadenosine (cordycepin - adenosine analogue) combined with deoxycoformycin (pentostatin - inhibitor of the adenosine deaminase (ADA) enzyme and deoxyadenosine analogue) in mice experimentally infected with T. evansi. Furthermore, we also verified the influence of the therapy in the hematologic, biochemical and ADA activity parameters, makers of cell viability and toxicity, oxidative stress and histopathology analyses. These analyses were divided into three experiments. The first one showed that the combination of cordycepin (2mgkg-1) and pentostatin (2mgkg-1) was 100% effective in the T. evansi-infected groups; however, the treatment increased significantly the liver enzyme levels, which were accompanied by histological lesions in the liver and kidneys. The second experiment showed a reduction in the levels of plasma total protein in healthy mice and treated with 1mg/kg cordycepin or 1mg/kg pentostatin. The animals treated with pentostatin alone or associated with cordycepin showed an ADA activity significantly reduced. The third experiment showed that the combination of cordycepin (2.0 mg kg-1) and pentostatin (0.2, 0.5, 1.0, 2.0 mg kg-1) is effective in the clearance of T. evansi, although at higher concentrations (cordycepin 2mg kg-1 and pentostatin 2mg kg-1), toxicity was observed. Therefore, the dose cordycepin 2.0 mg kg-1 in combination with pentostatin 0.2 mg kg-1 was recommended as a therapeutic option. This combination showed to be 100% effective in the experimentally infected animals and presented no toxicity to the animals. / Trypanosoma evansi é um tripanossomatídeo patogênico de distribuição mundial, causador de grandes prejuízos econômicos, podendo afetar várias espécies de mamíferos, principalmente equinos, espécie na qual produz uma doença conhecida como Mal das cadeiras . Muitos são os sinais clínicos e as patologias decorrentes da infecção por este parasito. A fase aguda da doença é caracterizada pelo surgimento de febre intermitente, edema subcutâneo, anemia progressiva, cegueira, letargia e alterações hemostáticas. Na fase crônica os animais apresentam caquexia, edema, incoordenação motora e paralisia de membros posteriores. O tratamento para essa infecção é medicamentoso, no entanto, os produtos químicos disponíveis possuem eficácia moderada e toxicidade, especialmente para os rins e fígado. Assim, é importante a pesquisa de terapias alternativas para o tratamento da doença causada pelo T. evansi. O objetivo deste estudo foi investigar a susceptibilidade do T. evansi à 3′-deoxiadenosina (cordicepina - análogo da adenosina) associada a deoxicoformicina (pentostatina - inibidor da adenosina deaminase (ADA) e análogo da desoxiadenosina) em camundongos infectados experimentalmente e verificar a influência desta terapia nos parâmetros hematológicos, bioquímicos, de atividade da ADA, marcadores de viabilidade e toxicidade celular e de estresse oxidativo e análise histopatológica. Essas análises foram divididas em três experimentos. O primeiro experimento demonstrou que a combinação de cordicepina (2 mg kg−1) e pentostatina (2 mg kg−1) foi 100% efetiva na cura dos animais infectados, mas esse tratamento ocasionou um aumento significativo nos níveis de enzimas hepáticas e produziu lesões histológicas no fígado e rins. O segundo experimento demonstrou uma reducão nos níveis de proteínas plasmáticas totais nos roedores sadios e tratados com 1mg/kg de cordicepina ou 1mg/kg de pentostatina, tendo os animais pertencentes aos grupos tratados com pentostatina isolada ou associada a cordicepina, uma diminuição da atividade da ADA. O terceiro experimento mostrou que as combinações de cordicepina (2,0 mg kg-1) e pentostatina (0,2; 0,5; 1,0; 2,0 mg kg1) foram eficazes na cura de animais infectados, mas na dose mais alta (cordicepina 2mg kg-1 e pentostatina 2mg kg-1), foi observado toxicidade elevada. A dose de cordicepina 2.0 mg kg-1 associada a pentostatina 0.2 mg kg-1 foi recomendada como opção terapêutica, com 100% de cura dos animais infectados experimentalmente sem apresentar toxicidade aos mesmos.

Les essais cliniques de phase I en cancérologie permettent d’identifier la dose optimale (DO), définie comme la dose maximale tolérée (DMT). Les approches conventionnelles de recherche de dose reposent uniquement sur les événements de toxicité observés au cours du premier cycle de traitement. Le développement des thérapies moléculaires ciblées (TMC), habituellement administrées sur de longues périodes, a remis en question cet objectif. Considérer uniquement le premier cycle de traitement n’est pas suffisant. De plus, comme l'activité n'augmente pas nécessairement de façon monotone avec la dose, la toxicité et l'activité doivent être prises en compte pour identifier la DO. Récemment, les biomarqueurs continus sont de plus en plus utilisés pour mesurer l'activité.L’objectif de cette thèse était de proposer et d'évaluer des designs adaptatifs pour identifier la DO. Nous avons développé deux designs de recherche de dose, basés sur une modélisation conjointe des mesures longitudinales de l'activité des biomarqueurs et de la première toxicité dose-limitante (DLT), avec un effet aléatoire partagé. En utilisant des propriétés de distribution normales asymétriques, l'estimation reposait sur la vraisemblance sans approximation ce qui est une propriété importante dans le cas de petits échantillons qui sont souvent disponibles dans ces essais. La DMT est associée à un certain risque cumulé de DLT sur un nombre prédéfini de cycles de traitement. La DO a été définie comme la dose la moins toxique parmi les doses actives, sous la contrainte de ne pas dépasser la DMT. Le second design étendait cette approche pour les cas d’une relation dose-activité qui pouvait atteindre un plateau. Un modèle à changement de pente a été implémenté. Nous avons évalué les performances des designs avec des études de simulations en étudiant plusieurs scénarios et divers degrés d'erreur de spécification des modèles.Finalement, nous avons effectué une analyse de 27 études des TMCs de phase I, en tant que monothérapie. Les études ont été réalisées par l'Institut National du Cancer. L'objectif principal était d'estimer le risque par cycle et l’incidence cumulative de la toxicité sévère, jusqu’à six cycles. Les analyses ont été effectuées séparément pour différents sous-groupes de doses, ainsi que pour les toxicités hématologiques et non-hématologiques. / Conventional dose-finding approaches in oncology of phase I clinical trials aim to identify the optimal dose (OD) defined as the maximum tolerated dose (MTD), based on the toxicity events observed during the first treatment cycle. The constant development of molecularly targeted agents (MTAs), usually administered in chronic schedules, has challenged this objective. Not only, the outcomes after the first cycle are of importance, but also activity does not necessarily increase monotonically with dose. Therefore, both toxicity and activity should be considered for the identification of the OD. Lately, continuous biomarkers are used more and more to monitor activity. The aim of this thesis was to propose and evaluate adaptive designs for the identification of the OD. We developed two dose-finding designs, based on a joint modeling of longitudinal continuous biomarker activity measurements and time to first dose limiting toxicity (DLT), with a shared random effect, using skewed normal distribution properties. Estimation relied on likelihood that did not require approximation, an important property in the context of small sample sizes, typical of phase I/II trials. We addressed the important case of missing at random data that stem from unacceptable toxicity, lack of activity and rapid deterioration of phase I patients. The MTD was associated to some cumulative risk of DLT over a predefined number of treatment cycles. The OD was defined as the lowest dose within a range of active doses, under the constraint of not exceeding the MTD. The second design extended this approach for cases of a dose-activity relationship that could reach a plateau. A change point model was implemented. The performance of the approaches was evaluated through simulation studies, investigating a wide range of scenarios and various degrees of data misspecification. As a last part, we performed an analysis of 27 phase I studies of MTAs, as monotherapy, conducted by the National Cancer Institut. The primary focus was to estimate the per-cycle risk and the cumulative incidence function of severe toxicity, over up to six cycles. Analyses were performed separately for different dose subgroups, as well as for hematologic and non-hematologic toxicities.