Para os ingredientes farmacêuticos ativos (APIs) que exibem baixa solubilidade e/ou estabilidade e/ou perfis de dissolução, dentre outros problemas capazes de afetar a sua eficácia terapêutica, as abordagens da Engenharia de Cristais têm se destacado nas últimas décadas como uma solução satisfatória. No estado sólido, os APIs podem apresentar polimorfos, sais, solvatos, co-cristais, amorfos e combinações dos mesmos. Associadas a cada estado sólido estão propriedades físicas e químicas, que podem ou não variar em relação ao API de referência. Neste contexto, este projeto de pesquisa visou o planejamento racional, síntese e caracterização de novas formas sólidas do pró-fármaco 5-fluorocitosina (5-FC) e do fármaco antineoplásico 5-fluorouracila (5-FU), ambos exibindo problemas fisicoquimicos que dificultam sua aplicação em formas de dosagem sólidas. Apesar de ser usado como fungicida, recentemente o 5-FC se tornou um dos pró-fármacos mais utilizados na terapia antineoplásica por meio de terapia dirigida por gene-enzima-pró-fármaco, uma vez que na presença da enzima citosina-desaminase o 5-FC é convertido em 5-FU dentro das células cancerosas. Para esta finalidade, coformadores adequados foram pre-selecionados a partir de análises estatísticas, realizadas utilizando o banco de dados estruturais da Cambridge, com base na competição entre sintons. Na sequencia, protocolos de cristalização foram desenvolvidos de acordo com duas técnicas: evaporação a partir de solvente e mecanoquímica, em particular a moagem com gota-solvente (SDG). Nove estruturas foram obtidas com 5-FC. Todas foram analisadas por microscopia óptica de luz polarizada e por difração de raios X por monocristal. Seis foram caracterizadas como co-cristais e três como sais. Sais farmacêuticos são preferidos nas formulações porque melhoram consideravelmente a solubilidade dos APIs. Co-cristais farmacêuticos têm sido cada vez mais explorados porque promovem igualmente melhorias nas propriedades físico-químicas dos APIs sem alterar a natureza dos mesmos. Os sais de 5-FC foram obtidos com os ácidos fumárico, oxálico e maleico e os cocristais com os ácidos adípico, tereftálico, málico, succínico e benzóico. Além disso, obteve-se um co-cristal multi-API, de 5-FC e 5-FU. Estes resultados, obtidos por meio do desenho racional de novas formas sólidas, concordaram bem com a regra de três, implementada para variações nos valores pKa (pKabase - pKaácido). Esta regra permite estimar a formação sais/co-cristais durante o processo de cristalização. Os sais de 5-FC foram analisados estrutural e termicamente. Os cocristais de 5-FC foram estruturalmente avaliados. O co-cristal multi-API também foi sintetizado por mecanoquímica, como parte dos esforços direcionados à aplicação dos princípios da Química Verde para a produção em larga escala de fármacos. Os resultados obtidos nesta tese oferecem um API como forte candidato a coformador, a saber a 5-FC, e introduz um co-cristal multi-API como potencial candidato para a terapia antineoplásica. / For active pharmaceutical ingredients (APIs) exhibiting low solubility and/or stability and/or dissolution profiles, among other problems capable of affecting their therapeutic efficacy, Crystal Engineering approaches have been highlighted in recent decades as a satisfactory solution. In the solid state, APIs may exhibit polymorphs, salts, solvates, hydrates, cocrystals, amorphous and combinations of them. Associated to each solid form are physical and chemical properties which may or not vary in relation to the reference API. In this context, this research project aimed to rationally design, synthesize and characterize new solid forms of the prodrug 5-fluorocytosine (5-FC) and the antineoplastic drug 5-fluorouracil (5-FU), by considering that both exhibit physicochemical issues that difficult their application in solid dosage forms. Although used as a fungicide, 5-FC has become one of the most used prodrugs for cancer treatment by gene-directed enzyme prodrug therapy, as in the presence of the enzyme cytosine deaminase, 5-FC is converted into 5-FU inside cancer cells. For this purpose, suitable coformers were pre-selected from statistical analyses performed on the Cambridge Structural Database, based on the synthon competition approach. Briefly, crystallization protocols were designed following two techniques: slow evaporation from solution and mechanochemistry, in particular the solvent-drop grinding (SDG). Nine structures were obtained with 5-FC. All were analyzed by polarized light optical microscopy and by single-crystal X-ray crystallography. Six were characterized as cocrystals and three as salts. Pharmaceutical salts are preferred in formulations because they considerably improve the solubility/stability of APIs. Cocrystals have been increasingly explored because they promote improvements in the physicochemical properties of the API while not altering the API´s nature. 5-FC salts were obtained with fumaric, oxalic, and maleic acids, and 5-FC cocrystals with adipic, terephthalic, malic, succinic, and benzoic acids. In addition, a multi-API cocrystal of 5-FC and 5-FU was obtained. These results, derived from the rational design of new solid forms, agreed well with the rule of three, implemented to variations in pKa values (pKabase - pKaácido). This rule allows for estimation of the salts/cocrystals formation during the crystallization process. The 5-FC salts were structurally and thermally analyzed. The 5-FC´s cocrystals were structurally evaluated. The multi-API co-crystal was also synthesized by SDG as part of the ongoing efforts toward Green Chemistry application for drug scale-up production. The results obtained in this thesis offer a strong API candidate to be used as a coformer, namely the 5-FC, and introduce a multi-API co-crystal as a potential candidate for anticancer therapy.

O objetivo da presente pesquisa consiste numa tradução e comentários dos três primeiros capítulos do primeiro tratado do Liber de Philosophia Prima sive Scientia Divina Livro referente à Primeira Filosofia ou Ciência Divina -, de Avicena, que trata do estabelecimento da Metafísica como ciência filosófica a partir da delimitação de seu objeto formal e de sua conveniente denominação. / The objective of this research entails translation and commentaries of three first chapters of first treaty of Liber de Philosophia Prima sive Scientia Divina Book on First Philosophy or Divine Science -, of Avicenne, which is about the establishment of Metaphysic as philosophic science from delimitation of its subject matter and its convenient denomination.

Made available in DSpace on 2014-06-12T18:27:29Z (GMT). No. of bitstreams: 2 arquivo1000_1.pdf: 571217 bytes, checksum: 93a758c7adac1d3cf14e47e2bb42147d (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2010 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Nasrollah Nejad, Abbas; Simis, Aron. The Aluffi algebra of an ideal. 2010. Tese (Doutorado). Programa de Pós-Graduação em Matemática, Universidade Federal de Pernambuco, Recife, 2010.

Submitted by Biblioteca da Faculdade de Farmácia (bff@ndc.uff.br) on 2017-03-27T17:09:17Z No. of bitstreams: 1 Abdalla, Marcela Campos Esqueff [Dissertação, 2015].pdf: 6309451 bytes, checksum: 904cac016c0d6d4e36749aa917ce03f5 (MD5) / Made available in DSpace on 2017-03-27T17:09:17Z (GMT). No. of bitstreams: 1 Abdalla, Marcela Campos Esqueff [Dissertação, 2015].pdf: 6309451 bytes, checksum: 904cac016c0d6d4e36749aa917ce03f5 (MD5) / No Brasil, o consumo de medicamentos é favorecido pela multiplicidade de produtos lançados no mercado, pela publicidade que os cerca e pelo simbolismo que o medicamento pode assumir no contexto da saúde. A propaganda é a divulgação do medicamento promovida pela indústria, com foco na marca, utilizando diversas estratégias e cujo retorno é garantido, uma vez que vários estudos apontam que a propaganda consegue alterar o padrão de prescrição dos médicos. Logo, considerando o possível impacto sobre as práticas terapêuticas, seria esperado que o material de propaganda de medicamentos apresentasse informações importantes e confiáveis sobre o produto anunciado. Porém, nem sempre é isto que se observa. No caso de medicamentos, essa prática é fiscalizada e regulamentada pela Agência Nacional de Vigilância Sanitária (ANVISA) que, em 2002, firmou um convênio com várias instituições federais de ensino superior, ampliando a avaliação das propagandas de medicamentos, através do Projeto Monitora - finalizado em 2009. O Projeto expôs em suas considerações finais a grande quantidade de informações irregulares detectadas pelas instituições de ensino. Cinco anos após a finalização do projeto, será analisada a conformidade sanitária das peças publicitárias anunciadas pelas indústrias farmacêuticas. Objetivo: avaliar a conformidade das peças publicitárias divulgadas pela indústria farmacêutica em relação à legislação sanitária (Resolução da Diretoria Colegiada nº 96/08) Metodologia: coleta de peças publicitárias distribuídas em revistas técnicas, hospitais e consultórios médicos localizados no município de Niterói-RJ e análise através do confronto com a legislação sanitária e banco de dados da ANVISA. Resultados e discussão: nenhuma peça publicitária cumpre a legislação sanitária na íntegra. As principais não conformidades detectadas foram nos seguintes itens: legibilidade de informações obrigatórias (29%), frases de alerta (63%), denominação da substância ativa (51%), indicação (14%), contraindicações (20,5%), cuidados e advertências (38,5%), reações adversas (45,5%), interações medicamentosas (23,7%), posologia (24,4%) e destaque de contraindicação e interação medicamentosa (64%). A maioria das indústrias aplica estratégias que dificultam o acesso a informações de restrição de uso do medicamento prejudicando seu uso racional. Conclusão: é evidente a necessidade de um novo modelo fiscalizador e regulador mais rígido que priorize, acima de todos os interesses particulares, um interesse maior, que é o da sociedade. Esta deve ser protegida da propaganda enganosa e abusiva, promovendo o uso racional do medicamento / In Brazil, the consumption of medicines is favored by the multiplicity of products on the market, by advertising that surrounds them and the symbolism that the medicine can take in the context of health. Advertising is the dissemination of the medicine promoted by the industry, with emphasis on brand, using various strategies and whose return is guaranteed, since several studies show that advertising can change the prescription. Therefore, considering the possible impact on the therapeutic practices, it would be expected that the medicine advertising material presented important and reliable information about the advertised product. However, it is not always that which is observed. For medicinal products, this practice is supervised and regulated by Agência Nacional de Vigilância Sanitária (ANVISA), which in 2002 signed an agreement with several federal institutions of higher education, extending the evaluation of drug advertisements, through the Monitoring Project - finalized in 2009. The project exposed in his final considerations the large amount of irregular information detected by the institutions. Five years after the completion of the project, it will be analyzed the health compliance of advertising announced by pharmaceutical companies. Objective: to evaluate the conformity of advertisements released by the pharmaceutical industry in relation to the health legislation (Resolução da Diretoria Colegiada nº 96/08) Methodology: collection of advertisements distributed in technical journals, hospitals and medical offices located in Niterói-RJ and analysis through the confrontation with the health legislation and ANVISA´s database. Results and discussion: any advertising piece meets the health legislation. The main non-conformities were detected in the following items: readability required information (29%), warning phrases (63%), name of the active substance (51%), indication (14%), contraindication (20.5%), cautions and warnings (38.5%) adverse reactions (45.5%), drug interactions (23.7%), posology (24.4%) and highlight of contraindication and drug interaction (64%). Most industries apply strategies that hinder access to restricted information of use of medication impairing their rational use. Conclusion: clearly the need for a new model and more rigid regulatory legislation that prioritizes above all particular interests, a larger interest, which is the interest of society. This must be protected from false and abusive advertising, promoting the rational use of medicines

I alla tider har man byggt modeller över saker som skall byggas för att på så sätt åskådliggöra det som skall skapas. Dessa modeller hjälper till att förstå och formulera problem och lösningar, hur sammanhangen är och vilka beståndsdelar som skall ingå. Beroende på vilken typ av produkt som skall konstrueras, kommer olika modeller att få olika betydelse. En utvecklare har ofta en inre bild, en mental modell, av vilken typ av system som skall utformas. Denna bild kan vara detaljerad eller bara en avlägsen idé. Med hjälp av olika typer av modeller kan en utvecklingsgrupp visualisera, specificera, konstruera och dokumentera strukturen och beteendet för den tänkta produkten. Genom att använda ett standardiserat modelleringsspråk, som till exempel Unified Modelling Language, UML, kan samtliga medlemmar i en utvecklingsgrupp meddela sina beslut på ett tydligt sätt. En process för programvaruutveckling är Rational Unified Process, RUP. Denna process är ett väldefinierat sätt för att tilldela och hantera de olika arbetsuppgifter och ansvar som förekommer i en utvecklingsorganisation. Målet för denna process är att, inom givna tidsramar och budget, producera högkvalitativ programvara som uppfyller slutanvändarens behov. RUP kan anpassas för att tillgodose varje enskilt företags speciella behov. Vår undersökning visar på vilket sätt RUP används inom olika företag som bedriver någon form av systemutveckling. Den visar även om dessa företag använder utvecklingsprocessen på det sätt som det rekommenderas i teorin eller om de istället utvecklar en egen utvecklingsprocess, med RUP som utgångspunkt. Undersökningen visar även varför företag väljer just denna process. För att komma fram till svaren på detta har det genomförts en litteraturstudie samt att olika företag har intervjuats. Intervjuerna har utförts genom att en elektronisk enkät har skickats till ett antal företag. De resultat som framkommit genom ovan nämnda undersökning, visar att de företag som idag använder utvecklingsprocessen RUP tycks vara nöjda. Orsaken till detta är framförallt att de olika företagen oftast vill ha en fast grund att utgå ifrån där de sedan kan utveckla processen efter sina egna önskemål och behov. De kan även välja att arbeta med processen på det sätt som rekommenderas i teorin, där RUP fungerar som en databas med råd och riktlinjer som kan användas under ett projektarbetes gång.

This study examines whether preliminary estimates of real growth of GDP and the major user side components in the Swedish quarterly national accounts are unbiased forecasts of revised estimates, and whether available information from the process of reconciling GDP from the production and user side is used efficiently to minimise revisions. Regression analysis is performed to find that preliminary GDP growth estimates are rational forecasts of revised estimates. The results are mixed for the user side components. Preliminary estimates of growth of investments and exports are rational forecasts whereas revisions of growth of government spending could be minimised by more efficiently using information about preliminary estimate values. Moreover, information about the statistical discrepancy between the GDP growth estimates from the production and user side could be used to minimise revisions of growth of consumer spending and imports, but these conclusions are sensitive to the period of volatile economic development 2008-2010.

Rational drug design is a powerful method in which new and innovative therapeutics can be designed based on knowledge of the biological target aiming to provide more efficacious and responsible therapeutics. Understanding aspects of the targeted biological agent is important to optimize drug design and preemptively design to slow or avoid drug resistance. Chagas disease, an endemic disease for South and Central America and Mexico is caused by Trypanosoma cruzi, a protozoan parasite known to consist of six separate genetic clusters or DTUs (discrete typing units). Chagas disease therapeutics are problematic and a call for new therapeutics is widespread. Many researchers are working to use rational drug design for developing Chagas drugs and one potential target that receives a lot of attention is the T. cruzi trans-sialidase protein. Trans-sialidase is a nuclear gene that has been shown to be associated with virulence. In T. cruzi, trans-sialidase (TcTS) codes for a protein that catalyzes the transfer of sialic acid from a mammalian host coating the parasitic surface membrane to avoid immuno-detection. Variance in disease pathology depends somewhat on T. cruzi DTU, as well, there is considerable genetic variation within DTUs. However, the role of TcTS in pathology variance among and within DTU’s is not well understood despite numerous studies of TcTS. These previous studies include determining the crystalline structure of TcTS as well as the TS protein structure in other trypanosomes where the enzyme is often inactive. However, no study has examined the role of natural selection in genetic variation in TcTS. In order to understand the role of natural selection in TcTS DNA sequence and protein variation, we sequenced 540 bp of the TcTS gene from 48 insect vectors. Because all 48 sequences had multiple polymorphic bases, we examined cloned sequences from two of the insect vectors. The data are analyzed to understand the role of natural selection in shaping genetic variation in TcTS and interpreted in light of the possible role of TcTS as a drug target.

Business leaders are increasingly responsible for the societal and environmental impacts of their actions. Yet conceptual views on responsible leadership differ in their definitions and theoretical foundations. This study attempts to reconcile these diverse views and uncover the phenomenon from a business leader's point of view. Based on rational egoism theory, this article proposes a formal mathematical model of responsible leadership that considers different types of incentives for stakeholder engagement. The analyses reveal that monetary and instrumental incentives are neither sufficient nor necessary for business leaders to consider societal and environmental stakeholder needs. Non-monetary and non-instrumental incentives, such as leaders' values and authenticity, as well as their planning horizons, counterbalance pure monetary and instrumental orientations. The model in this article complements the growing body of research on responsible leadership by reconciling its various conceptual views and providing a foundation for future theory development and testing.

The rational emotive psychology movement has contributed significantly to the development of training approaches to explore the behavioral characteristics and emotional dynamics of full and healthy living. In response, this study was initiated to assess the effects of rational behavior training (RBT) upon emotionally disturbed adolescents in an alternative special education program.

M.A. / Please refer to full text to view abstract