Made available in DSpace on 2016-04-25T20:21:15Z (GMT). No. of bitstreams: 1 Alexis Milonopoulos.pdf: 661841 bytes, checksum: 219e3a2790ffeae487d465869f4e13f4 (MD5) Previous issue date: 2014-09-15 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Based on a cartographic writing, Crack Machine shows the games of power and the struggling forces within the cracolandia field, pointing out not only the battles, the gears and specific arrangements placed on networks of strategic places, but also dislocations, sinuosity, transversals, tracks, ruts and thresholds that cross the whole cracolandia issue and question our politics. By showing the profusion of useless actions in that area this dissertation treats this matter reaching beyond the discussions about hygienization process and the real estate speculation, pointing out another dimension of the State and the politics and demonstrating a machine that lives off exclusion, speculation, immolation, safety and potentializing more and more lucrative businesses that go from wars against drugs to humanitarianism. In another movement, it exposes the matter of irrecoverable population management, extrapolating the cracolandia space and the discussion about crack cocaine and the control of the undesirable population through technologies that provide administration and risk management. It also shows how these ungovernable populations have been, also with the formation of a new drug market, the main effect of the austerity politics that have taken the globe, questioning our model of society and our political rationality related to the way power has struggled to manage populations since the appearance of the biopower. Taking a step forward from a strictly biopolitical analysis, rewriting the to make die and to let die in the mark of power technologies, pointing out how death became a normal governmental mechanism, inserted in a military-political project of war on drugs and being a privileged strategy that allows the creation of a tension between to make live, to make die and to let die / A partir de uma escritura cartográfica, Máquina Crack mostra jogos de poder e forças em luta no campo da cracolândia, evidenciando não só batalhas, engrenagens e arranjos específicos situados em redes de lugares estratégicos, mas também deslocamentos, sinuosidades, transversais, rastros, sulcos e limiares que atravessam todo a questão da cracolândia e que colocam a nossa política em questão. Ao mostrar a profusão de ações inócuas na área, trata esta questão indo além das discussões acerca de processos de higienização e do fenômeno da especulação imobiliária, evidenciando uma outra dimensão do Estado e da política e demonstrando toda uma máquina que vive da exclusão, da especulação, da imolação e da segurança e que cada vez mais potencializa lucrativos negócios que vão da guerra às drogas ao humanitarismo. Em um outro movimento, expõe a problemática da gestão de populações irrecuperáveis, extrapolando o espaço da cracolândia e a discussão em torno do crack e problematizando a questão da gestão estratégica de populações, mais precisamente da contenção e do controle de populações indesejáveis por meio de tecnologias que propiciam a administração e a gestão de riscos. Mostra também como estas populações ingovernáveis têm sido, juntamente com a formação de um novo mercado de drogas, o principal efeito das políticas de austeridade que tem tomado o globo, colocando em xeque nosso modelo de sociedade e nossa racionalidade política, relacionada ao modo com que o poder esforçou-se para gerir populações desde o aparecimento do biopoder. Dando um passo para além de uma análise estritamente biopolítica, reinscreve o fazer morrer e o deixar morrer no marco das tecnologias de poder, evidenciando como a morte tornou-se um mecanismo normal de governo, inserido-se em um projeto político-militar de guerra às drogas e sendo uma estratégia privilegiada que permite a criação de uma tensão singular entre fazer viver, fazer morrer e deixar morrer

Made available in DSpace on 2016-04-26T14:54:57Z (GMT). No. of bitstreams: 1 Alexis Milonopoulos.pdf: 661841 bytes, checksum: 219e3a2790ffeae487d465869f4e13f4 (MD5) Previous issue date: 2014-09-15 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Based on a cartographic writing, Crack Machine shows the games of power and the struggling forces within the cracolandia field, pointing out not only the battles, the gears and specific arrangements placed on networks of strategic places, but also dislocations, sinuosity, transversals, tracks, ruts and thresholds that cross the whole cracolandia issue and question our politics. By showing the profusion of useless actions in that area this dissertation treats this matter reaching beyond the discussions about hygienization process and the real estate speculation, pointing out another dimension of the State and the politics and demonstrating a machine that lives off exclusion, speculation, immolation, safety and potentializing more and more lucrative businesses that go from wars against drugs to humanitarianism. In another movement, it exposes the matter of irrecoverable population management, extrapolating the cracolandia space and the discussion about crack cocaine and the control of the undesirable population through technologies that provide administration and risk management. It also shows how these ungovernable populations have been, also with the formation of a new drug market, the main effect of the austerity politics that have taken the globe, questioning our model of society and our political rationality related to the way power has struggled to manage populations since the appearance of the biopower. Taking a step forward from a strictly biopolitical analysis, rewriting the to make die and to let die in the mark of power technologies, pointing out how death became a normal governmental mechanism, inserted in a military-political project of war on drugs and being a privileged strategy that allows the creation of a tension between to make live, to make die and to let die / A partir de uma escritura cartográfica, Máquina Crack mostra jogos de poder e forças em luta no campo da cracolândia, evidenciando não só batalhas, engrenagens e arranjos específicos situados em redes de lugares estratégicos, mas também deslocamentos, sinuosidades, transversais, rastros, sulcos e limiares que atravessam todo a questão da cracolândia e que colocam a nossa política em questão. Ao mostrar a profusão de ações inócuas na área, trata esta questão indo além das discussões acerca de processos de higienização e do fenômeno da especulação imobiliária, evidenciando uma outra dimensão do Estado e da política e demonstrando toda uma máquina que vive da exclusão, da especulação, da imolação e da segurança e que cada vez mais potencializa lucrativos negócios que vão da guerra às drogas ao humanitarismo. Em um outro movimento, expõe a problemática da gestão de populações irrecuperáveis, extrapolando o espaço da cracolândia e a discussão em torno do crack e problematizando a questão da gestão estratégica de populações, mais precisamente da contenção e do controle de populações indesejáveis por meio de tecnologias que propiciam a administração e a gestão de riscos. Mostra também como estas populações ingovernáveis têm sido, juntamente com a formação de um novo mercado de drogas, o principal efeito das políticas de austeridade que tem tomado o globo, colocando em xeque nosso modelo de sociedade e nossa racionalidade política, relacionada ao modo com que o poder esforçou-se para gerir populações desde o aparecimento do biopoder. Dando um passo para além de uma análise estritamente biopolítica, reinscreve o fazer morrer e o deixar morrer no marco das tecnologias de poder, evidenciando como a morte tornou-se um mecanismo normal de governo, inserido-se em um projeto político-militar de guerra às drogas e sendo uma estratégia privilegiada que permite a criação de uma tensão singular entre fazer viver, fazer morrer e deixar morrer

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucia Šinaľová Supervisor: RNDr. Jakub Hofman, Ph.D. Title of diploma thesis: Testing of the cytotoxicity of potential drugs in the cell lines together with the measurement of their passage through the blood brain barrier by the PAMPA method This master thesis focuses on the prediction of tacrine derivatives permeability through blood- brain barrier and their cytotoxicity. We studied tacrine-benzothiazole and tacrine- thiaquinazoline derivates as potential drugs for treatment of Alzheimer's disease. The reason of testing new tacrine derivates was effort to find substances with same effect and lower toxicity, for which was the tacrine discarded from clinical practice. The probable permeability of the studied substances was determined in vitro by the PAMPA method. Based on the permeation coeficient values we have identified that tacrine-benzothiazole derivates A-D (Pe= 8,31- 16,9×10-6 cm/s) and tacrine-thiaquinazoline derivates 1, 3, 4 (Pe= 8,59-14,9×10-6 cm/s) were permeable through blood-brain barrier, tacrine-thiaquinazoline derivate 2 (Pe= 3,79×10-6 cm/s) had uncertain permeability and tacrine-thiaquinazoline derivate 5 (Pe= 2,0×10-6 cm/s) was not permeable. In the pre-clinical evaluation of...

Submitted by Natalia de Souza Gonçalves (natalia.goncalves@ufpe.br) on 2016-09-19T13:06:41Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Mestrado-André-Severino-da-Silva-FINAL-2016 digital ok.pdf: 968681 bytes, checksum: 7aa8797460dde7f9b350d87b19110eee (MD5) / Made available in DSpace on 2016-09-19T13:06:41Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Mestrado-André-Severino-da-Silva-FINAL-2016 digital ok.pdf: 968681 bytes, checksum: 7aa8797460dde7f9b350d87b19110eee (MD5) Previous issue date: 2016-02-23 / FACEPE / Compostos com núcleo pirimidínico têm grande potencial e importância farmacológica para a saúde humana, pois apresentam várias propriedades biológicas como atividade anti-inflamatória, antitumoral, bioherbicida, entre outras. Este trabalho busca analisar os efeitos genotóxicos dos compostos 4-Amino-2-(fenil)-6-(m-nitrofenil)-5-carbonitrila-pirimidina (5a), 4-Amino-2-(fenil)-6-(p-nitrofenil)-5-carbonitrila- pirimidina (5b) e 4-Amino-2-(fenil)-6-(p-anisil)-5-carbonitrila-pirimidina (5c), obtidos por síntese, por meio do teste SMART (Teste de Mutação e Recombinação Somática) e Ensaio Cometa em Drosophila melanogaster. Para o Ensaio Cometa, larvas de D. melanogaster da linhagem Oregon-R foram expostas por 24 horas aos compostos 5a, 5b e 5c, nas concentrações 0,39, 0,78, 1,56 e 3,12 mg/mL, e ao solvente (grupo controle negativo), além de um grupo controle positivo (Ciclofosfamida 1 mg/mL). Para a análise microscópica dos possíveis danos genéticos causados pelos compostos foram observadas as células da hemolinfa (hemócitos) de larvas. No processo metodológico do SMART, larvas de D. melanogaster foram expostas às concentrações 0,04, 0,09, 0,19, 0,39, 0,78, 1,56 e 3.12 mg/mL dos compostos 5a e 5b, além dos grupos controle negativo (tratado apenas com o solvente) e controle positivo (tratado com mitomicina 1mg/mL). Foi estabelecida uma curva de sobrevivência de acordo com o nascimento dos indivíduos adultos para verificar a citotoxicidade dos compostos. As manchas e pelos mutantes das asas dos indivíduos adultos tratados foram analisadas em microscópio óptico e comparados aos resultados do grupo controle negativo. Os resultados indicaram que não houve diferenças significativas entre os grupos tratados e os controles negativos, tanto para o teste SMART, quanto para o Ensaio Cometa. No teste SMART, as curvas de sobrevivência mostraram que os compostos 5a e 5b, não apresentaram toxicidade para os drosofilídeos testados. Podendo-se concluir, assim, que nas condições experimentais testadas em D. melanogaster os compostos não apresentaram atividade tóxica nem mutagênica, o que contribui para o uso dos compostos pirimidínicos aqui investigados na composição de novos fármacos para o tratamento da saúde humana. / Compounds of the core pyrimidine have great potential and pharmacological importance to human health and the environment and therefore exhibit different biological properties as anti-inflammatory, antitumor, bioherbicide among others. This work intent to analyze the genotoxic effects of the compounds 4-Amino-2-(phenyl)-6-(m-nitrophenyl)-5-carbonitrile-pyrimidine (5a) 4-Amino-2-(phenyl)-6-(p-nitrophenyl)-5-carbonitrile-pyrimidine (5b) and 4-Amino-2-(phenyl)-6-(p-anisyl)-5-carbonitrile-pyrimidine (5c) obtained by chemical synthesis using the SMART (Somatic Mutation and Recombination Test) and Comet Assay in Drosophila melanogaster. For SMART, D. melanogaster larvae were exposed to concentrations of 0.04, 0.09, 0.19, 0.39, 0.78, 1.56 and 3.12 mg/mL of the compounds 5a and 5b, and a negative control group treated only with the solvent. A survival curve was established in accordance with the birth of adults in order to check the cytotoxicity of the compounds. The spots and the mutants were analyzed by light microscopy and the results of the groups treated were compared to the negative control group. During the methodological process of the Comet Assay, larvae of D. melanogaster Oregon-R strain were exposed for 24 hours to the compounds 5a, 5b and 5c, at the concentrations 0.39, 0.78, 1.56 and 3.12 mg/mL, and to the solvent (the negative control group). To microscopic analysis of possible genetic damage caused by the compounds, were observed cells from the hemolymph (hemocytes) of larvae. The results indicated that in both tests there were no significant difference between the treated groups and the negative control. It leads us to conclude that the tested compounds showed neither toxic effect, nor mutagenic activity in D. melanogaster over the experimental conditions in D. melanogaster model.

O levantamento do número de medicamentos inovadores licenciados no Brasil pela agência reguladora de medicamentos durante quatro anos, entre 1998 e 2001, mostrou 154 medicamentos inovadores (fármacos com nova estrutura molecular). A maioria deles (57,1% do total) foi concentrada em quatro classes terapêuticas: quimioterapia sistêmica (39 produtos), analgesia e anestesia (20), aparelho cardiovascular (15) e hormônios e anti-hormônios (14). Medicamentos inovadores para uso crônico foram lançados com preços mais altos com relação às opções pré-existentes de sua mesma classe terapêutica. Quando comparados apenas a fármacos com estrutura química semelhante, o custo foi menor. O custo estimado de tratamento por um mês variou entre 14% do salário mínimo (R$ 27,90) até 580% (R$ 1.159,80), portanto quase seis vezes. O estudo mostrou que no Brasil os medicamentos inovadores não são acessíveis para as famílias de baixa renda. / During the four-year period of 1998-2001, the Brazilian government licensed 154 medicines with new molecular entities. Most of them (57,1%) belong to only four therapeutic classes: anti-infectives (39 products), anesthetics and analgesics (20), cardiovascular (15) and hormones and anti-hormones (14). New medicines for chronic term use were launched with prices higher than the pre-existing competitors of the same therapeutic class. When compared with drugs resembling similar molecular structure, the price was lower. When compared to the minimal monthly wage, the estimated cost of on month of treatment was between 14% (R$ 27,90) and 580% (1159,80), therefore almost six times more. The study showed that in Brasil medicines with new molecular entities are not affordable to families with low income.

O levantamento do número de medicamentos inovadores licenciados no Brasil pela agência reguladora de medicamentos durante quatro anos, entre 1998 e 2001, mostrou 154 medicamentos inovadores (fármacos com nova estrutura molecular). A maioria deles (57,1% do total) foi concentrada em quatro classes terapêuticas: quimioterapia sistêmica (39 produtos), analgesia e anestesia (20), aparelho cardiovascular (15) e hormônios e anti-hormônios (14). Medicamentos inovadores para uso crônico foram lançados com preços mais altos com relação às opções pré-existentes de sua mesma classe terapêutica. Quando comparados apenas a fármacos com estrutura química semelhante, o custo foi menor. O custo estimado de tratamento por um mês variou entre 14% do salário mínimo (R$ 27,90) até 580% (R$ 1.159,80), portanto quase seis vezes. O estudo mostrou que no Brasil os medicamentos inovadores não são acessíveis para as famílias de baixa renda. / During the four-year period of 1998-2001, the Brazilian government licensed 154 medicines with new molecular entities. Most of them (57,1%) belong to only four therapeutic classes: anti-infectives (39 products), anesthetics and analgesics (20), cardiovascular (15) and hormones and anti-hormones (14). New medicines for chronic term use were launched with prices higher than the pre-existing competitors of the same therapeutic class. When compared with drugs resembling similar molecular structure, the price was lower. When compared to the minimal monthly wage, the estimated cost of on month of treatment was between 14% (R$ 27,90) and 580% (1159,80), therefore almost six times more. The study showed that in Brasil medicines with new molecular entities are not affordable to families with low income.

Pharmaceuticals have benefitted countless lives. New therapies are being developed every day—many prove effective, but many do not. In order to ensure only safe and effective drugs enter the market, the United States' Food and Drug Administration (FDA) approves each treatment based on data garnered from clinical trials. Clinical trials take time, however, and investigational new drugs (INDs) can demonstrate signs of efficacy long before approval. These cases introduce a fundamental question: should the government limit patient access to a drug that has yet to be proven safe and effective? Or do patients have the right to freedom from governmental intervention in their medical decision-making? In this paper, the history of IND regulation will be explored, followed by an examination of the freedom to access from constitutional, ethical, and infrastructural perspectives. Changes to the current system will then be proposed.

Tuberculosis has for decades been the leading cause of death, worldwide, originating from merely one infectious matter i.e. the bacilli Mycobacterium tuberculosis (MTB). It is killing approximately 1.5 million people every year. The World Health Organization (WHO) estimates that 2 billion people might be infected by this specific bacterium, and that there emerges about 9 million new, active cases of TB each year. The aim with this thesis is to elucidate the possibilities and the difficulties with two new drugs against susceptible and resistant, latent and replicating strains of M. tuberculosis. A search for relevant articles on Pub Med, through the university library, was undertaken and approximately 35 articles were found. These articles were read; facts were sorted out and used for this paper. Figures were found through Creative Commons. The two new drugs discussed in this paper are TMC 207 and PA-824. They have two different mechanisms of action, and additionally and most importantly, that differ from the drugs used as first-line and second-line options. TMC 207 targets the mycobacterial ATP synthase. PA-824, a pro-drug, targets the cell wall synthesis and in addition causes respiratory poisoning, through the release of nitric oxide. The different mechanisms are vital in order to combat emerging resistance, due to various missense mutations in specific genes in the bacilli. The bactericidal activity of the drugs against mycobacteria is high, promising a successful cure for MDR (multi drug resistant)/XDR (extensively drug resistant) patients. The median survival is 4.1 years for MDR patients and 2.9 years for XDR patients, with currently available treatments. This is noticeably worse than some cancer prognoses. Perhaps with these drugs there is even a possibility of shortening the treatment time. The adverse events are mild to moderate, for both drugs. This is another additive advantage, since the toxicity of the drugs will be minimal and hopefully tolerable, and most importantly will bring about treatment commitment and the sought elimination of the disease. However, as with all new drugs the outcomes are still to be proven in real settings, the complex fields (in low- and middle income countries, with difficult TB cases), and with complicated cases (e.g. HIV co-morbidity) during a longer period of time. Reporting and evaluating the outcomes is crucial, since whatever is displayed from the drug consumption and the effects of it can lead to alterations in regimens, doses and treatment commitment.

在各大藥廠明星藥品專利到期、新藥開發數量銳減的當下，全球首例植物新藥MediGene Veregen™ 的核准上市為製藥產業帶來新的希望，雖然製藥價值鏈與商品化模式已為人所熟知，但針對植物新藥特殊性所架構之商品化模式還是一個全新的議題，為了架構一個適合台灣中小型藥廠的植物新藥開發模式，本研究嘗試以技術層面為根基，從法規面、產品面與產業面深入探討MediGene Veregen™ 關鍵的成功因素，從中獲取值得台灣藥廠參考的經驗，同時考量台灣植物新藥開發的大環境限制因素，包括法規與健保，給予台灣藥廠一些植物新藥商品化策略建議。 本研究之架構以實務觀點出發，首先整理參考文獻以探討植物新藥包含的範圍與藥品開發流程，幫助藥廠了解植物新藥商品化需要具備的條件與資訊；接著針對台灣與美國在植物新藥方面審查上市之法規、流程與審核成果進行研究，結果顯示目前台灣有兩種植物新藥審查系統「中藥新藥」與「植物抽取新藥」，對廠商而言並不如美國單一系統來得便利；再者藉由探討植物新藥的價值鏈結構、法規結構、產品結構與產業結構，試圖架構植物新藥商品化模式；接下來以兩家新藥開發廠商為例進行實際個案研究，一家為成功推出植物新藥商品的德國藥廠MediGene AG，一家為台灣藥廠中天生技/合一生技，主要藉由分析MediGene Veregen™ 商品化過程的關鍵成功因素，比較中天生技/合一生技WH-1商品化模式的異同，探討是否有足以借鏡與改進之處。最後，歸納整理上述的研究做出結論，並且對於台灣藥廠提出策略建議，希望能對於台灣新藥開發公司有實質上的幫助。 / While the star drug patents of each big pharmaceutical company are expired one after another and the quantity of their newly developed drugs sharply declines in these years, MediGene Veregen™, the first botanical new drug in the world, enters the market and therefore brings a new hope for the pharmaceutical industry. Although the value chain and the commercialization model of pharmaceutical industry have been known and researched a lot, the specific construction of commercialization model for botanical drugs is still a brand new subject. In older to construct the model that is suitable for Taiwanese middle and small pharmaceutical companies for the process from development to commercialization of botanical new drugs, this research, based on the technical analysis, attempts to discuss the key success factors of MediGene Veregen™ through analyzing the aspects of the laws, regulations, industry and product itself. With the case study about the environmental limited factors of new drug development in Taiwan, including the laws and regulations as well as the health insurance, this research tries to offer Taiwan pharmaceutical companies some strategic suggestions for the development and commercialization of botanical new drugs. The structure of this research is based on the practical viewpoints. First, we reorganize the reference in order to define the scope of botanical new drugs and the processes of drug development. It can help pharmaceutical companies understand the conditions and information needed for botanical new drug commercialization. Then, our studies focus on the laws and regulations in Taiwan and the United States, as well as the application processes and approvals for botanical new drugs. The results show that there are two evaluation systems in Taiwan for botanical new drug applications. For those pharmaceutical companies, the dual system is not as convenient as the sole evaluation system in the States. Furthermore; based on the discussion on the structure of the value chain, laws, regulations, product and industry, this paper makes an attempt to construct a better commercialization model of botanical new drugs. Next, two pharmaceutical companies are chosen as case study in this paper. One is a German pharmaceutical company, MediGene AG, which launched the first botanical new drug. The other is a Taiwan pharmaceutical company, MicroBio Co., Ltd/Oneness Bio-Tech Co., Ltd. By analyzing the key success factors in the commercialization process of MediGene Veregen™ and comparing its commercialization model with MicroBio Co., Ltd/Oneness Bio-Tech Co. WH-1, we try to get any valuable idea and insight. Finally, our conclusion and strategic suggestions may have solid help for Taiwan botanical new drug pharmaceutical companies.