Made available in DSpace on 2015-05-14T12:59:54Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 7265191 bytes, checksum: 432cedb6fda0226806b02fd0634dfff5 (MD5) Previous issue date: 2013-08-12 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The poisonous plants to livestock research has been restricted only the identification of poison species, epidemiology and clinical signs. But the active principle of toxic plants are little known and its knowledge its very important to develop preventive methods to poisoning which are responsible by countless cattle deaths. This work aimed the contribution to knowledge of active principle these plants, Crotalaria vitellina Ker Gawl (Fabaceae) e Ipomoea philomega (Vell.) House (Convolvulaceae). This work aimed the contribution to knowledge of active principle these plants, Crotalaria and Ipomoea were submitted to phytochemical study for the isolation of its chemical constituents by cromatographic methods followed by its identification through spectroscopic techniques such as Infrared (IR), one and two-dimentional Nuclear Magnetic Resonance (NMR) of 1H and 13C, and Mass Spectrometry (MS) besides literature data. The phytochemical study of C. vitellina resulted on the isolation of the pyrrolizidine alkaloid (type otonecine) named crotavitelin (Cv-1), and were obtained from the crude extract of its fruits, described by first time in the literature. This substance was subjected to acute toxicological evaluation according to OECD Guide 423 (Guideline for Testing of Chemicals), in mice (males and females) orally exposed to 50 and 300 mg/Kg doses and showed a low toxicity on the parameters evaluated. However, histopatologic studies should be performed to investigate the possible toxic effects in celular and tissue levels. Ipomoea philomega was submitted also to phytochemical studies and were isolated eight compounds from the dicloromethane phase of the ethanolic crude extract of the leaves: lanosterol (Ip-1), caffeic acid (Ip-2), ethyl p-coumarate (Ip-3), lupeol (Ip-4), ethyl caffeate (Ip-5), umbelliferone (Ip-6), scopoletin (Ip-7), and the 1,2-benzopirone (Ip-8), has been described for first time in I. philomega. / A pesquisa sobre plantas tóxicas para animais têm-se limitado principalmente à identificação das espécies, bem como à sua epidemiologia, patologia e sinais clínicos. Sendo, no entanto, pouco conhecidos os seus princípios ativos, cujo conhecimento é de grande importância no desenvolvimento de métodos preventivos da intoxicação, responsáveis por inúmeras mortes de animais e, consequentemente, perdas econômicas. Visando contribuir para o conhecimento dos princípios ativos dessas plantas, as espécies Crotalaria vitellina Ker Gawl (Fabaceae) e Ipomoea philomega (Vell.) House (Convolvulaceae) foram submetidas a um estudo fitoquímico para isolamento de seus constituintes químicos por métodos cromatográficos, seguidos de identificação através de métodos espectroscópicos tais como Infravermelho (IV), Ressonância Magnética Nuclear (RMN) de 1H e 13C uni e bi-dimensionais e Espectroscopia de Massas (EM) juntamente com a comparação com dados da literatura. O estudo fitoquimico do extrato etanólico bruto dos frutos e folhas de C. vitellina resultou no isolamento de um alcalóide pirrolizidínico do tipo otonecina, descrito pela primeira vez na literatura, nomeado crotavitelina (Cv-1). Essa substância foi submetida avaliação da toxicidade pré-clínica aguda, de acordo com o Guia da OECD-423 (Guideline for Testing of Chemicals), em camundongos (machos e fêmeas) nas doses de 50 e 300 mg/Kg e apresentou baixa toxicidade nos parâmetros avaliados. Entretanto, estudos histopatológicos, especialmente em nível de tecido hepático, devem ser realizados para a investigação de possíveis efeitos tóxicos em nível celular e tecidual. Ipomoea philomega, Convolvulaceae, igualmente submetida a estudo fitoquímico do extrato etanólico bruto das suas folhas possibilitou o isolamento de oito substâncias da fase diclorometano: lanosterol (Ip-1), ácido cafeico (Ip-2), p-cumarato de etila (Ip-3), lupeol (Ip-4), cafeato de etila (Ip-5), umbeliferona (Ip-6), escopoletina (Ip-7) e a 1,2- benzopirona (Ip-8), descritas pela primeira vez para I. philomega.

Les scandales sanitaires ayant émaillé le médicament ont mis la sécurité d’utilisation au cœur des préoccupations des acteurs de santé. Tout au long de son cycle de vie, le médicament est susceptible d’exposition à des conditions de stress pouvant conduire à sa dégradation et potentiellement, à la modification du rapport bénéfice/risque. Ce problème est d’autant plus marqué en milieu hospitalier où les médicaments en post – AMM sont manipulés pour des besoins spécifiques des patients. Quid de la maîtrise des modifications de leurs microenvironnements ? Etendre son espace de connaissances est admis comme étant le meilleur moyen pour circonscrire ces phénomènes. Dans le cadre de ce projet doctoral, une stratégie d’étude du cycle de vie des médicaments en post – AMM a été mise en place afin de renforcer leur sécurité d’utilisation. Compte tenu de la place prépondérante des formes solides dans l’arsenal thérapeutique, le ticagrelor, un récent antiagrégant plaquettaire (AAP) présenté sous forme de comprimés, a été choisi pour cette étude. La première étape a consisté à l’utilisation des conditions de stress pour évaluer sa stabilité intrinsèque et l’élucidation structurale des produits de dégradations grâce au couplage LC-HR-MSn donnant accès aux compositions élémentaires. Les voies de dégradation ont été proposées et la sécurité des produits a été évaluée grâce à l’approche in silico. Par ailleurs, compte tenu de l’utilisation des AAP en association, dans la seconde partie de ce travail, l’extension de l’espace de connaissances du ticagrelor a permis d’envisager une stratégie de préformulation avec l’aspirine à l’état solide en utilisant des techniques complémentaires comme la LC-HR-MSn, la DSC, la DRX ou l’ATG. La formation d’un simple eutectique a été observée avec le mélange des deux principes actifs. Nous avons démontré que la dégradation du ticagrelor est liée à la décomposition de l’aspirine, modulée par les conditions environnementales. Le modèle d’étude du ticagrelor ouvre clairement des perspectives sur la maîtrise de la sécurité en l’élargissant à d’autres médicaments et pourra contribuer à leur recyclage approprié. / Tragedies caused by the misuse of pharmaceuticals have put the drug safety at the core of the concerns of healthcare providers. Throughout its life cycle, a drug may be subjected to environmental stresses, which can lead to its degradation. Thorough understanding about the susceptibility of a drug to degrade is an essential step to avoid it. This problem is in particular relevant in a hospital setting, where commercial drugs are usually applied to specific cases without a clear understanding of its limitations. As part of this PhD project, a life cycle study strategy for a commercial drug has been implemented in order to increase its safety in use. Given the prominence of solid forms in the therapeutic arsenal, ticagrelor, a recent antiplatelet agent (APA) in tablet form, was chosen for this study. The first step was devoted to the evaluation of the intrinsic stability and the structural elucidation of the degradation products making use of LC-HR-MSn, providing access to the elemental composition. Degradation pathways have been proposed and the safety of the products has been evaluated via an in silico toxicological approach. Furthermore because antiplatelet agents are often used in combination therapy, in the second part, a preformulation strategy with aspirin in the solid state has been studied using the complementary techniques LC-HR-MSn, DSC, PXRD, and TGA. The mixture of the two active pharmaceutical ingredients gave rise to a simple eutectic. We have demonstrated that the degradation of ticagrelor in these mixtures is closely related to the stability of aspirin, which is modulated by environmental conditions. The ticagrelor study provides a model for the safety management of other drugs and can contribute to their appropriate recycling.