Acquired Immunodeficiency Syndrome (AIDS) is a disease caused by the Human Immunodeficiency Virus (HIV). Since its discovery in 1981, more than 25 million people died due to this disease. To date, an effective HIV-1 vaccine usable in prophylaxis or in the therapy of humans has not yet been identified. The failures and limited success of HIV vaccines have reinforced the role of chemotherapy and therefore research on the development of effective drugs. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) were the early agents introduced in the therapy and currently they are the most used, based on their concurrent high activity against the virus and low toxicity against human cells. In addition, the rapid development of virus resistance against these types of drugs, needs to find new molecules able to overcome this drawback. My thesis work started from the design of a small library of new molecules, with hybrid structures based on a template deriving from the natural product (+)-calanolide A and the synthetic molecule α-APA, both showing a potent and selective activity against reverse transcriptase. Docking calculation has allowed to select molecules having the best values of interaction energy with the viral enzyme. Chemical synthesis was carried out together with structural characterization by extensive spectroscopic analysis including NMR technique and mass spectrometry. In particular, the synthesis of the amide group present in the structure of some amino-pyrone compounds using the standard method, resulted in the expected N-acylation, but with a C-acyl byproduct. This result has suggested to look further into the study of N,C-acylation selectivity for the ambidentate amino-pyrone moiety, whose reactivity is poorly known. Regioselectivity was investigated under different conditions (organic bases, solvent, acylating agent), also for an enamino-ester taken as a model compound. Experimental procedures were optimized in order to synthesize selectively pure N- and C-acylated compounds. A preliminary enzymatic assay indicated a good activity in the early prepared compounds of the series, promising for the following in vitro tests on HIV infected cells of each molecule in the whole series. In addition, these compounds were tested against other common viruses for human infective pathologies. With the aim of identifying molecules with potential therapeutic applications, the antiviral activity must be related to cytostatic effect, in order to select the ones with a favored selectivity index. Unfortunately, the molecules showed paragonable values in antiviral and cytostatic effects, the latter one not easily predictable neither by the chemical structure, nor by a computational approach. If the drug design by molecular docking has failed in selecting a new scaffold for NNRTIs, the study has driven the interest towards new potential antitumoral molecules showing activity at sub-micromolar concentration against leukemic cell lines. Due to the structural similarity with recently studied antibacterial natural pyrones, the synthetic molecules showing the lowest values of cytotoxicity were investigated in the inhibition of bacterial strains. Some tested compounds have shown a good activity and selectivity against Gram(+) bacteria.

Made available in DSpace on 2016-04-25T16:45:06Z (GMT). No. of bitstreams: 1 JOSE ANIBAL FERREIRA DISSERTACAO DE MESTRADO 2008.pdf: 627590 bytes, checksum: 351f75774fae1e4a0decaf1df19d8b52 (MD5) Previous issue date: 2008-05-29 / This dissertation, carries out an exploratory research, in the scope of the companies of the sector druggist, in the adhesion of the outsourcing of information technology (IT), in that to be identified the procedures of evaluation and criteria of selection utilized for the choice of supplying companies of this kind of service. To empirical research contemplates two multinational and two national companies. Approach the information technology and evolution of the IT services outsourcing in the industry druggist. The methodology of research utilized was the multiple case study, what permitted to the researcher the deepening in aspects of the trial of selection and criteria of choice adopted companies for contracting services providers. To research was carried out on the basis of interviews with executives or managers of IT that act in the trial of selection in four companies that already possess IT outsourcing service contracts. The interviews were driven according to script, from the model of research. The end of the work, present results of the research applied in the four druggist companies to the procedures of evaluation and the synthesis of the service suppliers choice criteria of IT. The results reveal the immaturity of the companies interviewed in the contracting IT services. The majority of the companies researched considers, of general form, a rank of importance elevated for the procedures of evaluation and criterion of choice, but of practical interest do not do, or better, do not possess tools perform-them, what is going to conclude that exists an amateurism in the choice of the suppliers of IT services, what provides risks for the company. The application of the model proposed in this work will be able to help the companies it minimize risks in the outsourcing service acquisition of IT / Nesta dissertação, realiza-se uma pesquisa exploratória, no âmbito das empresas do setor farmacêutico, na adesão da terceirização de tecnologia da informação (TI), em que se pretende identificar os procedimentos de avaliação e critérios de seleção utilizados para a escolha de empresas fornecedoras deste tipo de serviço. A pesquisa empírica contempla duas empresas multinacionais e duas nacionais. Abordam-se, para tanto, a tecnologia da informação e sua evolução, a terceirização dos serviços de TI, e a indústria farmacêutica. A metodologia de pesquisa utilizada foi o estudo de casos múltiplos, o que permitiu ao pesquisador o aprofundamento em aspectos do processo de seleção e critérios de escolha adotados pelas empresas para a contratação dos prestadores de serviços. A pesquisa foi realizada com base em entrevistas, realizadas junto aos executivos ou gerentes de TI que atuam no processo de seleção em quatro empresas que já possuem contratos de serviços de terceirização de TI. As entrevistas foram conduzidas de acordo com o roteiro elaborado, a partir do modelo de pesquisa. Apresentam-se, ao final do trabalho, o resultado da pesquisa aplicada nas quatro empresas do setor farmacêutico relativos aos procedimentos de avaliação e a síntese dos critérios de escolha de fornecedores de serviços de TI. Os resultados revelam a imaturidade das empresas entrevistadas na contratação de serviços de TI. A maioria das empresas pesquisadas considera, de forma geral, um grau de importância elevado para os procedimentos de avaliação e critério de escolha, apresentados na pesquisa, mas do lado prático não fazem, ou melhor, não possuem ferramentas para executá-los, o que possibilita concluir que existe um amadorismo na escolha dos fornecedores de serviços de TI, o que proporciona riscos para a empresa, ao adquirir serviços que suportam o seu funcionamento. Acredita-se que a aplicação do modelo proposto neste trabalho poderá ajudar as empresas a minimizar riscos na aquisição de serviços de terceirização de TI

In this work, I designed and synthesized two different classes of compounds capable of binding to the YTH domain of the YTHDF1-3 proteins. The first class of inhibitors includes ebselen analogs, an organoselenium compound that emerged as the top hit from a high-throughput screening of an in-house compound library; the second class is derived from a computational study. The YTHDF1-3 reader proteins are a class of three highly conserved paralogs that selectively recognize and bind the m6A modification on mRNA. They represent an emerging target in cancer research because m6A regulates several critical biological functions, triggering a cascade of events or directly modulating almost every aspect of tumorigenesis and cancer progression. The interest in targeting these proteins is a growing and recent cutting-edge focus. At the beginning of this thesis, no inhibitors capable of interfering with the m6A recognition process of the YTHDF1-3 proteins were described. Ebselen is a covalent drug capable of forming a selenium-sulfur bond with the cysteine residue located near the YTH domain of the YTHDF1-3 proteins, thereby interfering with the m6A binding process. This work investigated the role of the covalent warhead, which can be either a selenium or a sulfur atom. Furthermore, supported by covalent docking calculations, several analogs were designed and synthesized by modifying the molecular structure of ebselen to improve potency, selectivity, and physicochemical properties. The analogs were purified, fully characterized (NMR spectroscopy, MS spectrometry) and were then tested in an homogeneous time-resolved fluorescence (HTRF) assay to assess their affinity for the target, resulting in low single digit micromolar IC50. In addition, selected compounds were co-crystallized with the YTH domain of the YTHDF1 protein to further demonstrate the covalent binding mechanism of action and to study the effects of the binding on protein conformation. The second hit compound studied in this thesis (m6A71) is able to non-covalently bind the YTH domain of the YTHDF1 protein. The molecular structure of this hit was analyzed to determine the pharmacophore and several analogs were synthesized. In addition, docking calculations were performed to aid in the design of selected analogs and to initiate the lead optimization. The obtained analogs were then evaluated in an HTRF assay and other orthogonal biochemical assays (e.g. RNA electrophoretic mobility shift assay - REMSA), providing valuable insight into the molecular structural features required for the target interactions, that could be further explored and optimized.

[pt] O foco deste estudo está na avaliação da indústria farmacêutica brasileira sob o ponto de vista de suas operações de logística e as relações entre as empresas que compõem sua cadeia de distribuição. Os objetivos principais desta dissertação são entender a dinâmica do setor farmacêutico nacional, desde a consolidação de suas operações em nível mundial e seus reflexos no Brasil, até as atuais tendências gerenciais no sentido de otimizar processos produtivos. A partir deste cenário competitivo estudar-se-ão técnicas modernas de gestão da cadeia de distribuição que visam um desempenho superior, possibilitando vantagens aos seus participantes. Em particular serão abordadas técnicas de reposição automática de estoques e o seu atual estágio de aplicação na indústria farmacêutica brasileira. Busca-se compreender, além disso, como as operações logísticas podem trazer benefícios a uma atividade sensível à saúde da população, bem como de que forma as empresas brasileiras estão se preparando para adotar novos sistemas de gestão de cadeias de suprimentos se é que elas estão. / [en] The focus of this study is to evaluate the Brazilian pharmaceutical industry under the perspective of its logistics operations, and the relations between the companies that work together in a distribution chain. The main goal of this dissertation is to understand the dynamics of the domestic pharmaceutical sector, since the consolidation of its global operations and their consequences in Brazil. To reach this objective there will be analyzed the most recent managerial tendencies towards the optimization of the manufacturing processes from raw materials to finished goods. In this competitive scenario there will be studied the new techniques of supply chain management that aim a superior performance. In particular, there will be reviewed systems of inventory automatic replenishment and its present stage of development in Brazilian pharmaceutical industry. Finally, we will try to understand how logistics operations can benefit such a sensitive activity to people s health, as well as how Brazilian companies are getting ready to adopt new systems of supply chain management - if they are.

A biodisponibilidade é uma característica decisiva para a eficácia dos medicamentos, podendo sua intensidade ser estimada através da cedência "in vitro". Vários fatores são capazes de influenciá-la, entre eles a composição quali e quantitativa dos adjuvantes, assim como as características da substância ativa e da forma farmacêutica. A hidroclorotiazida é um diurético de amplo emprego, que apresenta problemas de biodisponibilidade e bioequivalência devido a sua baixa hidrossolubilidade. Através de planejamento fatorial 2 3 foram preparadas formulações de cápsulas de gelatina dura contendo 50 mg de hidroclorotiazida. Foi analisada a influência dos fatores material de enchimento (lactose e celulose microcristalina), reguladores de fluxo (dióxido de silício altamente disperso e estearato de magnésio) e hidrofilizante (polissorbato 80) sobre as características de qualidade dos complexos farmacêuticos e das cápsulas. O regulador de fluxo ou a interação entre este e o material de enchimento foram os fatores determinantes nas características de fluxo dos complexos farmacêuticos, analisadas através do ângulo de repouso e do índice de compressibilidade. A cedência "in vitro" das cápsulas, determinada com auxílio de aparelho de célula de fluxo e parametrizada pela eficiência de dissolução, foi influenciada preponderantemente pelo regulador de fluxo. Foram comparados os perfis de cedência "in vitro" entre as cápsulas e comprimido do mercado. O comportamento intermediário demonstrado pelo comprimido indica a necessidade de avaliação comparativa entre medicamentos contendo hidroclorotiazida a fim de assegurar sua bioequivalência. / The bioavailability is a decisive characteristic to drugs efficacy that can be predict by different "in vitro" dissolution methods. The bioavailability has been shown to be dependent on factors such as the drug, the dosage forms, type and quality of adjuvants. Hydrochlorothiazide is a widely used diuretic. Due to its limited aqueous solubility, this drug has potencial bioavailability problems. Eight differents hydrochlorothiazide hard gelatin capsules, containing 50 mg of the drug, were prepared according to a 2 3 factorial design. The influence of fillers (lactose or microcrystaline cellulose), glidants (magnesium stearate or coloidal silicon dioxide) and surfactant (polysorbate 80) on the pharmaceutical characteristics of powder mixtures and capsules were evaluated. The powder mixtures flow characteristics were evaluated through repose angle and compressibility index. It was determined that the glidant and its interaction with filler influenced this characteristic. The "in vitro" release of hydrochlorothiazide from capsules was carried out by a open flow-though dissolution method. The dissolution efficiency was the selected parameter to express the drug release. The glidant was the determinant factor. The dissolution profile of these capsules and marketed tablets was compared. The results evidenced the importance of comparative evaluation of hydrochlorothiazide dosage forms to assure their bioequivalence.

O desenvolvimento de fitoterápicos coloca em evidência a interligação de conhecimentos botânicos, fotoquímicos, farmacológicos e tecnológicos visando obter medicamentos com eficiência terapêutica e viabilidade industrial. Desse modo, com base em pesquisas anteriores realizadas com a Achyrocline satureioldes (Lam.) DC. Compositae, as quais relatam, entre outras, atividades antiviral e antiinflamatória tópica, foi desenvolvida forma farmacêutica plástica contendo extrato concentrado deste vegetal. Foram desenvolvidas e adaptadas metodologias de avaliação da qualidade que fossem viáveis tanto pare a matéria-prima vegetal quanto para os produtos intermediários e final. Para a análise qualitativa a cromatografia em papel preencheu estes pré-requisitos. A determinação quantitativa foi efetuada através do doseamento de queratina por cromatografia em papel associada a espectrofotometria no ultravioleta (CP/UV) e do doseamento de flavonóides totais. A inviabilidade técnica de incorporação às bases monoestearato de glicerina e hidrofílica, do macerado hidroalcoélico a 7,5% (m/V) das sumidades floridas, conduziu a sua concentração e posterior tratamento com polissorbato 80. A incorporação do extrato concentrado tratado causou alterações nas características das bases verificadas através do índice de óleo, espalhabilidade e comportamento reológico. Para a avaliação da liodisponibilidade de constituintes do extrato, foi desenvolvido dispositivo de liberação multicompartimental, dotado de membrana sintética, que propiciou resultados reprodutíveis, demonstrando sue adequabilidade em ensaios comparativos. Estudo preliminar de estabilidade da pomada monoestearato de glicerina, efetuado pelo método da degradação térmica acelerada, detectou alterações nas suas características reológicas sem comprometimento do perfil cromatográfico, da concentração de queratina e da liodisponibilidade. / The development of phytotherapeutic frugs involves ethnopharmacological, botanical, phytochemical, pharmacological and technological knowledges. It aims the obtaintion of a therapeutical efficient and industrial viable product. Based on prior researchs performed with Achyrocline satureioides (Lam.) DC., Compositae, which confirm its antiviral and antiinflammatory properties, it was developed a plastic phasmaceutical dosage form containing a concentrated extract of this plant. The methods for the quality evaluation were choosen in order to improve its viability in the analysis of both plant raw material so as of intermediary and final products. For the qualitative analyisis, paper chromatography fulfilled these purpouses. The quantitative determinations of quercetinthrougt paper chromatography associated to ultraviolet spectrophotometry so as the total flavonoids assay showed to be applicable in this study. The technical problematic incorporation of an hydroalcoholic macerate at 7,5 % (w/v) of the floral summits to the glyceryl monostearate and hydrophilic bases led to its concentration and subsequent treatment with polysorbate 80. The incorporation of the treated extract caused alteration in the oil index, spreading and rheological behavior of the ointment bases. For the "in vitro" release sudies a multicompartimental device with two chambers separated by a synthetic membrane was developed. The results showed reproducibility and adequacy in comparatives assays.Preliminary studey of the stability under accelerated thermal conditions detected alteration in the rheological bahavior, without modification of the chromatographic profile, of the concentration of quercetin and of the lyoavailability of the glyceryl monostearate ointment.

[pt] O propósito deste estudo é analisar o advento dos genéricos e verificar seu impacto nas estratégias competitivas implementadas por empresas da indústria farmacêutica brasileira. Este trabalho adota como base o estudo de Michael Porter sobre tipologias, identificando as estratégias relevantes e os grupamentos existentes nesse segmento industrial, buscando também relacionar o posicionamento estratégico assumido pelos laboratórios ao desempenho observado. O método de análise constitui-se do levantamento de uma base de dados obtida a partir de relatórios de consultorias especializadas, da identificação de indicadores estratégicos e de desempenho, bem como da implementação de procedimentos estatísticos. Busca-se ainda relacionar os posicionamentos e desempenhos identificados entre os anos de 1999 e 2002 aos resultados obtidos no estudo envolvendo o período imediatamente anterior ao advento dos genéricos, isto é, ao período compreendido entre os anos de 1995 e 1998, permitindo-se assim a elaboração de uma análise longitudinal da indústria. Os resultados obtidos sugerem um forte deslocamento no sentido de adoção de custos como arma estratégica, bem como demonstram uma perda de foco estratégico por parte dos laboratórios voltados à diferenciação. Por fim, o estudo também identifica indícios de queda na rentabilidade total da indústria. / [en] The aim of this study is to analyze the launching of generic drugs and verify their impact on competitive strategies implemented by Brazilian pharmaceutical companies during the period of 1999 to 2002. This research is based on Michael Porter´s studies on strategic typologies, identifying the relevant strategies and the existing groups in this industrial sector. The study also relates the strategic positioning of the pharmaceutical companies to the achieved performance. The methodology adopted is based on the analysis of collected database from reports of specialized consulting companies, the survey of strategy and performance indicators, as well as the implementation of statistical procedures. Furthermore, the relation of positioning and performance identified in this study to the results obtained in a previous one involving the pharmaceutical industry during the period immediately before the generic drugs launching, that is, the period between the years 1995 and 1998, is also investigated, thus allowing a longitudinal analysis of the Brazilian pharmaceutical industry. The results suggest a movement to adoption of cost as strategy, as well as demonstrate a loss of strategic focus of the pharmaceutical companies that are oriented to differentiation. Finally, the study also identifies a reduction yield trend of the pharmaceutical industry.

[pt] Este estudo tem por objetivo testar as tipologias estratégicas de Porter, Mintzberg e Miles & Snow nas indústrias farmacêuticas que operam no Brasil, destacando o trade-off clássico, poder explanatório versus parcimonialidade na capacidade descritiva destas tipologias. Para isso, foi feita uma revisão bibliográfica compreendendo estratégias, ambiente e desempenho, e utilizada uma base de dados com informações sobre as cinqüenta maiores indústrias farmacêuticas em operação no Brasil, selecionadas pelo critério de faturamento. Desta base de dados foram extraídas dez variáveis estratégicas e sete variáveis de desempenho. Estas variáveis foram avaliadas estatisticamente empregando-se entre outras análises, a análise de cluster e MANOVA, de forma a permitir a identificação de grupos estratégicos de acordo com as tipologias em estudo. Por fim, o desempenho médio dos grupos estratégicos formados foi comparado com os resultados esperados pelos respectivos modelos teóricos. Constatou-se que as três tipologias testadas exibem capacidades descritivas distintas, sendo que a de Porter demonstrou maior aderência às indústrias farmacêuticas em operação no Brasil. A parcimonialidade venceu o poder explanatório neste mercado em profunda transformação. / [en] This study’s objective is to test of Porter’s, Mintzberg’s and Miles & Snow’s strategic typologies in the pharmaceutical industries that operate in Brazil, detaching the explanatory capability versus parsimony classic trade-off in its capacity to describe these typologies. A bibliographical revision was made including strategies, environment and performance, using a database with information about the largest fifty pharmaceutical industries operating in Brazil based on invoicing criteria. Ten strategic variables and seven performance variables had been extracted from this database. These variables had been evaluated using statistical procedures as cluster analysis and MANOVA, in order to allow the identification of strategic groups according to the typologies being studied. Finally, the strategic groups average performances were compared to the respective theoretical models expected results. The three tested typologies showed distinct descriptive capabilities. Porter’s typology demonstrated greater tack to the pharmaceutical industries operating in Brazil. The parsimony won the explanatory capability in this market in deep transformation.

[pt] O propósito desse estudo é analisar as estratégias competitivas implementadas por empresas da indústria farmacêutica brasileira. Este trabalho adota como base o estudo de Chrisman sobre tipologias, identificando as estratégias relevantes e os grupos existentes nessa indústria, relacionando o posicionamento estratégico adotado pelos laboratórios com seu desempenho no setor. Além disso, a pesquisa busca analisar impactos do advento dos genéricos nessa indústria. O método de análise utilizado constituí- se do levantamento de uma base de dados obtida a partir de relatórios de consultorias especializadas, da identificação de variáveis estratégicas e de desempenho e da implementação de procedimentos estatísticos. Os posicionamentos e desempenhos identificados entre os anos de 1999 e 2002 sugerem a adoção de redução de custos como arma estratégica, ao contrário do que acontecia antes no mercado, onde havia um foco maior em diferenciação. O estudo também sugere que os grandes laboratórios ainda conseguem obter um desempenho superior baseados em suas marcas reconhecidas e grande escala de operação, enquanto os laboratórios nacionais, de menor porte, estão investindo cada vez mais no segmento de medicamentos genéricos. / [en] The aim of this study is to analyze the competitive strategies implemented by Brazilian pharmaceutical companies. This research is based on Chrisman s studies on strategic typologies, identifying the relevant strategies and the existing groups in this industrial sector. The study also relates the strategic positioning of the pharmaceutical companies to the achieved performance and analyzes the impact of the generic drugs launching in the sector. The methodology adopted is based on the analysis of collected database from reports of specialized consulting companies, the survey of strategy and performance indicators, as well as the implementation of statistical procedures. The relation of positioning and performance identified in the period between the years 1999 and 2002 suggests a movement to adoption of cost strategy, against the differentiation oriented focus of the industrial sector before the generic drugs launching. The results also suggest that the great companies are still able to have a superior performance due to their well known marks and operation scale, while smaller companies tend to invest in the generic drugs segment.

Mestre -- Escola Nacional de Saude Publica, Rio de Janeiro, 2001.