Made available in DSpace on 2017-07-10T18:01:55Z (GMT). No. of bitstreams: 1 Francielli De Bona Galvan.pdf: 2787047 bytes, checksum: dcf6ada2d9e9c708b2dadc574098b58b (MD5) Previous issue date: 2015-07-28 / Fundação Araucária / The removal of contaminants in aquatic environments must be performed by means of suitable treatment processes to ensure that water resources are not compromised because of this contamination. It is found that processes employing light have shown good results in the degradation of emergent contaminants. In this sense, this study aimed to determine the best photodegradation conditions of cephalexin antibiotic (CFX) in aqueous solution, using Advanced Oxidative Processes - AOP (UV, UV / H2O2, UV / H2O2 / TiO2 and UV / H2O2 / ZnO). In photocatalysis tests, the variables were organized in an experimental design to verify the influence of each variable in the degradation process, and the experimental results were evaluated using the statistical software Statistica®. It was observed from the analysis of the results that the best conditions for the degradations process were [H2O2] = 1000 mg L-1 and [TiO2] = 50 mg L-1 at pH 4 after two hours of irradiation. / A remoção de contaminantes nos ambientes aquáticos deve ser realizada por meio de processos de tratamento adequados, para garantir que os recursos hídricos não sejam comprometidos em virtude desta contaminação. Verifica-se que os processos que empregam luz têm apresentado bons resultados na degradação de poluentes emergentes. Neste sentido, o presente trabalho tem como objetivo determinar as melhores condições de fotodegradação do antibiótico cefalexina (CFX) em solução aquosa, empregando-se Processos Oxidativos Avançados - POA (UV, UV/H2O2, UV/H2O2/TiO2 e UV/H2O2/ZnO). Os experimentos foram acompanhados por espectrofotometria na região UV-VIS. Nos ensaios de fotocatálise, as variáveis foram organizadas em um planejamento experimental para verificar a influência de cada variável no processo de degradação, e os resultados experimentais foram avaliados empregando-se o software estatístico Statistica®. Observou-se pela análise dos resultados que as melhores condições para o processo de fotodegradação foram [H2O2] = 1000 mg L-1 e [TiO2] = 50 mg L-1 em pH 4.

Orientadores: Lucia Regina Durrant, Alexandre Nunes Ponezi / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-20T15:30:45Z (GMT). No. of bitstreams: 1 Santos_IvanJoseSantana_M.pdf: 1134875 bytes, checksum: 88af103bdbd26ade9ec5e063cbd582c5 (MD5) Previous issue date: 2012 / Resumo: 17a-etinilestradiol (EE2), carbamazepina (CBZ) e ibuprofeno (IBU) são substâncias farmacêuticas muito utilizadas em todo o mundo e vêm sendo frequentemente detectadas em estações de tratamento de efluentes e em águas naturais em vários países, inclusive no Brasil. A grande preocupação da presença destes fármacos em quantidades residuais na água potável e nos ambientes aquáticos são os potenciais efeitos adversos para a saúde humana e animal. O objetivo principal deste trabalho foi avaliar o potencial de fungos ligninolíticos e bactérias para degradar esses três compostos, individualmente. Linhagens de bactérias e fungos ligninolíticos foram crescidas em meio mineral com os fármacos, na presença ou ausência de glicose. Primeiramente, foi realizada uma seleção com o objetivo de escolher linhagens bacterianas e fúngicas com maior capacidade de degradação dessas drogas, avaliando a necessidade da presença de glicose para que a degradação ocorresse. As linhagens que apresentaram maior capacidade de degradar tais compostos foram selecionadas e, em seguida, foram realizados ensaios com o intuito de se otimizar o período de incubação, visando-se uma maior porcentagem de degradação no menor período de incubação possível. Posteriormente, foram realizadas análises de atividade das enzimas lacase, lignina peroxidase (LiP) e manganês peroxidase (MnP) produzidas pelos fungos selecionados e foi avaliada a participação dessas na degradação dos fármacos. A atuação das enzimas do Citocromo P450 na degradação dos fármacos foi avaliada por meio da adição de piperonil butóxido (PB), o qual inibe esse complexo enzimático. A toxicidade dos fármacos e seus metabólitos para a bactéria Vibrio fischeri também foram avaliadas. A quantificação dos fármacos em todas as amostras foi realizada por meio de cromatografia líquida de alta eficiência. EE2 foi totalmente degradado por todos os fungos avaliados, sem a necessidade de glicose no meio de cultivo; no entanto, nenhuma das bactérias estudadas foi capaz de degradá-lo significativamente. Pleurotus ostreatus (Jacq.) P. Kumm linhagem P1 foi selecionado para os ensaios subsequentes. Após 6 dias, foi encontrada atividade de MnP igual a 5122,11 U.L-1. A lacase teve como atividade 307,69 U.L-1, valor encontrado após 4 dias de incubação. Não foi detectada atividade da enzima LiP em nenhum dos tempos analisados. Apesar da detecção de atividade dessas enzimas, elas não foram capazes de degradar o EE2 na ausência do micélio fúngico. Nos ensaios de toxicidade foi encontrada uma CE50 igual a 76% para o EE2 e os metabólitos não apresentaram toxicidade. Trametes sp. linhagem BNI foi a selecionado para degradar CBZ, sendo a glicose necessária para o processo de biodegradação. Após 28 dias de incubação, houve 42% de degradação de CBZ. A atividade máxima de lacase foi de 1740,17 U.L-1, sendo encontrada após 21 dias de incubação. LiP teve como atividade máxima 663,08 U.L-1, valor encontrado após 14 dias de incubação. Não foi detectada atividade da enzima MnP em nenhum dos tempos analisados. Não houve a degradação de CBZ utilizando apenas o caldo enzimático. A presença de PB inibiu totalmente a degradação de CBZ. CBZ e seus metabólitos não apresentaram toxicidade. Nenhuma das bactérias foi capaz de degradar CBZ. IBU foi totalmente degradado por todos os fungos avaliados sem a necessidade de glicose no meio de cultivo, sendo Trametes sp. linhagem BNI selecionado para os ensaios posteriores. Após 2 dias de incubação, BNI foi capaz de degradar totalmente IBU. Lacase foi a única enzima que teve atividade detectada nesse ensaio, sendo a atividade máxima detectada igual a 478,18 U.L-1, no sexto dia de incubação. Não foi detectada degradação de IBU utilizando apenas o caldo enzimático e a presença de PB no meio não inibiu a degradação deste fármaco. Nos ensaios de toxicidade foi encontrada uma CE50 igual a 86% para o IBU e os metabólitos não apresentaram toxicidade. Staphylococcus arlettae e Bacillus megaterium foram capazes de degradar significativamente IBU na presença de glicose. B. megaterium foi selecionado para os ensaios subsequentes. Após 3 dias, essa linhagem foi capaz de degradar todo IBU disponível no meio. Nos ensaios de toxicidade para os metabólitos do processo de biodegradação por B. megaterium, o IBU apresentou uma CE50 inicial igual a 47% e os metabólitos não apresentaram toxicidade. Esses resultados comprovam que fungos ligninolíticos e bactérias são capazes de degradar fármacos encontrados em matrizes ambientais, sendo plausível a utilização destes micro-organismos, ou suas enzimas, em sistemas de tratamento de água e esgoto / Abstract: 17a-ethinylestradiol (EE2), carbamazepine (CBZ) and ibuprofen (IBU) are pharmaceutical drugs used worldwide and have been frequently detected in wastewater treatment plants and in natural waters in several countries, including Brazil. The major concern about the occurrence of these drugs in trace amounts in drinking water and aquatic environments are the potential adverse effects on human and animal health. The main objective of this study was to assess the potential of ligninolytic fungi and bacteria to degrade these 3 compounds individually. Bacteria and ligninolytic fungi strains were grown on mineral medium with these drugs and with or without glucose. A selection was carried out to choose bacterial and fungal strains with capacity to degrade these drugs and if an addition of a carbon source (glucose) was needed for degradation. Strains with greater capacity to degrade these compounds were selected and assays were performed in order to optimize the incubation time to obtain the highest degradation rate in the shortest incubation time. Subsequently, the enzymatic activities of laccase, lignin peroxidase (LiP) and manganese peroxidase (MnP) produced by the selected fungi was assessed. Also, the action of these enzymes in the degradation of the drugs was evaluated. The involvement of cytochrome P450 enzymes in degradation of the pharmaceutical drugs was evaluated by the addition of piperonyl butoxide (PB), which inhibits this enzyme complex. The toxicity of the drugs and metabolites to Vibrio fischeri were also evaluated. The quantification of the drugs was performed by high performance liquid chromatography. EE2 was completely degraded by all fungi without glucose in the medium, however none of the studied bacteria was capable to degrade it significantly. Pleurotus ostreatus (Jacq.) P. Kumm strain P1 was selected for subsequent tests. The maximum enzyme activity produced by P1 was 5122.11 UL-1 for MnP after 6 days and 307.69 UL-1 for lacase after 4 days, while LiP activity was not detected. Although the detection of the enzymes activity, they were not able to degrade EE2 without the fungal mycelia. Toxicity studies showed the half maximal effective concentration (EC50) value equal to 76% to EE2 prior to fungal treatment, after this no toxicity was observed. Trametes sp. strain BNI was selected to degrade CBZ, and glucose was shown to be necessary for the biodegradation process. After 28 days of incubation, 42% of CBZ was degraded. The maximum laccase activity was 1740.17 UL-1, after 21 days of incubation. LiP maximum activity was 663.08 UL-1, found after 14 days of incubation, while MnP activity was not detected. There was no CBZ degradation using only the enzymatic supernatant. The addition of PB completely inhibited the degradation of CBZ. CBZ and its metabolites did not show toxicity. IBU was completely degraded by all fungi without glucose in the medium, and Trametes sp. strain BNI was selected for further analyses. 17a-ethinylestradiol (EE2), carbamazepine (CBZ) and ibuprofen (IBU) are pharmaceutical drugs used worldwide and have been frequently detected in wastewater treatment plants and in natural waters in several countries, including Brazil. The major concern about the occurrence of these drugs in trace amounts in drinking water and aquatic environments are the potential adverse effects on human and animal health. The main objective of this study was to assess the potential of ligninolytic fungi and bacteria to degrade these 3 compounds individually. Bacteria and ligninolytic fungi strains were grown on mineral medium with these drugs and with or without glucose. A selection was carried out to choose bacterial and fungal strains with capacity to degrade these drugs and if an addition of a carbon source (glucose) was needed for degradation. Strains with greater capacity to degrade these compounds were selected and assays were performed in order to optimize the incubation time to obtain the highest degradation rate in the shortest incubation time. Subsequently, the enzymatic activities of laccase, lignin peroxidase (LiP) and manganese peroxidase (MnP) produced by the selected fungi was assessed. Also, the action of these enzymes in the degradation of the drugs was evaluated. The involvement of cytochrome P450 enzymes in degradation of the pharmaceutical drugs was evaluated by the addition of piperonyl butoxide (PB), which inhibits this enzyme complex. The toxicity of the drugs and metabolites to Vibrio fischeri were also evaluated. The quantification of the drugs was performed by high performance liquid chromatography. EE2 was completely degraded by all fungi without glucose in the medium, however none of the studied bacteria was capable to degrade it significantly. Pleurotus ostreatus (Jacq.) P. Kumm strain P1 was selected for subsequent tests. The maximum enzyme activity produced by P1 was 5122.11 UL-1 for MnP after 6 days and 307.69 UL-1 for lacase after 4 days, while LiP activity was not detected. Although the detection of the enzymes activity, they were not able to degrade EE2 without the fungal mycelia. Toxicity studies showed the half maximal effective concentration (EC50) value equal to 76% to EE2 prior to fungal treatment, after this no toxicity was observed. Trametes sp. strain BNI was selected to degrade CBZ, and glucose was shown to be necessary for the biodegradation process. After 28 days of incubation, 42% of CBZ was degraded. The maximum laccase activity was 1740.17 UL-1, after 21 days of incubation. LiP maximum activity was 663.08 UL-1, found after 14 days of incubation, while MnP activity was not detected. There was no CBZ degradation using only the enzymatic supernatant. The addition of PB completely inhibited the degradation of CBZ. CBZ and its metabolites did not show toxicity. IBU was completely degraded by all fungi without glucose in the medium, and Trametes sp. strain BNI was selected for further analyses / Mestrado / Ciência de Alimentos / Mestre em Ciência de Alimentos

Resume - Supplementary Protection Certificates for Medicinal Products Nowadays, the pharmaceutical industry plays an important role in the world's economy and the pharmaceutical research has a decisive impact on the continuing improvement in public health. The system of patent law is of cardinal significance to the industry because it confers monopolies, for a limited period of time, on using innovations and provides a crucial incentive for basic research activities. Innovative companies require the guaranteed period of market exclusivity afforded by patents in order to sustain drug prices, recoup research and development expenditures and finance the development of new products. Although the availability of a patent protection for chemical and pharmaceutical products has, from a historical perspective, only been reaffirmed in the near past, it has been widely accepted as a global standard mainly through the provisions of the WTO's TRIPS agreement. On the other hand, despite the existence of various international treaties harmonising patent laws, patents have to date in their effects remained strictly limited to individual jurisdictions. Closely bound to the patent system itself are the means of the so-called off-patent protection - supplementary protection certificates and the others, for example market...

Approved for public release, distribution unlimited / Approved for public release; distribution unlimited. / Healthcare costs throughout the United States are on the rise, drawing increased scrutiny from government officials and Congress. The cost of pharmacy operations and pharmaceuticals is growing at a rate that is alarmingly higher than that of the total cost of military healthcare itself. Recent congressional legislation has essentially given the Department of Defense the ultimatum to cut costs for beneficiaries wherever possible, or risk having benefits arbitrarily cut by Congress. In the face of this possibility, cutting costs through better business practices must be explored, particularly within the area of pharmacy operations. This project explores the potential cost savings that can be realized by implementing Lean Six Sigma (LSS) methodology in the pharmacy operations of the DoD Medical Treatment Facilities (MTF). This research proves that implementing Lean Six Sigma methodology will improve military pharmacy operations, often at little cost, while realizing significant savings and increased customer satisfaction.

This thesis focuses on the research of RTDI policies (research, technology, development and innovation), and the main theme of this thesis is to link the three variables together: RTDI policy-making process, the contents of RTDI policies, the appropriateness of RTDI policies on configuration of the national, the sectoral and the technological innovation systems. We assume the policy-making process of RTDI policies would shape the contents of the RTDI policies. Once the contents of RTDI policies are implemented, the RTDI policies would influence, whether appropriate or inappropriate, on configuration of the three innovation systems. We define the configuration of the three innovation systems as national, sectoral and technological innovation system (NSTIS). We use the Taiwanese biotechnology and related sectoral policies as the empirical examples. Biotechnology in Taiwan configures with three sectors, i.e. pharmaceuticals, agriculture and medical device. Between 2000 and 2008, the Taiwanese government intensively promoted many policies in order to support the development of biotechnology and related sectors. Among the various policies, we choose the National Science and Technology Programs and the regulation policies (in terms of Law of Pharmaceutical Affairs and the Agro-pesticides Management Act) as our two empirical cases and set up the in-depth discussion for the policy-making process of the two policies.On the basis of the empirical cases of Taiwan, we explore the influence of the RTDI policy-making process on the contents of RTDI policies which further shapes the development of the NSTIS.

Pharmaceutical preparations of quinine (injection solutions), sulfanilamide, aminophenazone, barbital (tablets), caffeine, phenobarbital (dragee), and theophylline (suppositories) about seventy years old were analyzed using RP-HPLC. Samples were quantified by HPLC-UV and UV-spectrophotometry. Products of degradation were identified using HPLC-UV and HPLC-MS. Conditions of separation were optimized. The samples of quinine injection solutions consist of 92% or 87% of declared quinine content. Quinotoxine has been identified as the product of quinine degradation. The quantification of theophylline in suppositories and caffeine in dragee did not show any degradation after more than 67 years from their manufacturing. Decrase of potent amount (decrase about 8-22 %) were found in drugs containing sulfanilamide, barbital, phenobarbital and aminophenazone. Products of degradation of these pharmaceuticals were not found.

Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI) and the active ingredient in Prozac®, is found in the environment and disrupts feeding and metabolism in exposed fish. The objective of this research was to investigate the mechanisms involved in the feeding and metabolism disruption in the model goldfish (Carassius auratus). Two short-term waterborne fluoxetine exposures (7- and 14-days) were performed using two environmentally relevant doses of fluoxetine (0.5 and 1 μg/L) and metabolic effects at the level of the brain, liver, serum and bile in goldfish were investigated. Abundances of mRNA transcripts coding for six feeding neuropeptides were examined to determine which may be involved in the initial neural changes associated with decreased appetite in goldfish. The 7-day fluoxetine exposure at 1 μg/L caused corticotropin-releasing factor (CRF) mRNA levels to increase by 2-fold in female hypothalamus and telencephalon, indicating that CRF may be one of the first of the feeding neuropeptides to be altered. Six hepatic miRNAs were also evaluated in the goldfish liver that were previously associated with fluoxetine exposure in zebrafish (Danio rerio). Following the 7-day exposure at 1 μg/L, miR-22b, miR-140, miR-210, miR-301a and miR-457b levels increased in the female goldfish liver by 4-6 fold. The 14-day fluoxetine exposure at 1 μg/L caused 2-fold increases in miR-210, miR-301a, miR-457b and let-7d in male goldfish liver. These miRNAs were associated with the down-regulation of anabolic metabolic pathways in zebrafish, indicating a conservation of miRNA and fluoxetine effect between fish species. Serum and bile metabolite profiles of fluoxetine exposed goldfish were evaluated using ultra performance liquid chromatography coupled to quadrupole time of flight mass spectrometry. Following the 14-day exposure at 1 μg/L, the bile metabolite profiles of male goldfish were significantly different from controls as detected by cluster analysis and fluoxetine was tentatively identified in the serum. No other discriminant metabolites were identified as of yet. The data presented suggest that fluoxetine causes metabolic disruption in goldfish at multiple organ levels. Because of the widespread detection of fluoxetine and other emerging SSRIs in the aquatic environment, future research is required to firmly establish this pharmaceutical class as a metabolic and endocrine disrupting chemical.

This project is at the controversial intersection of medicine patent protection and access to medicines at the international level. Advocates for medicine access argue that medicine patent protection may allow prices to become elevated, thereby frustrating medicine access. But advocates for medicine patent protection argue that the patent system incentivized the research and development to make the product possible in the first place. While this ideological debate is valuable, this doctoral project acknowledges the patent system’s existence and seeks to produce research to advance medicine access pragmatically within this context, especially in developing countries and especially for drugs appearing on the World Health Organization’s Model List of Essential Medicines (MLEM). In cooperation with the World Intellectual Property Organization, this project commenced with a legal study to assess the patent status of the entire MLEM (375 medicines) in 137 developing countries. Gathering these patent data and verifying them with global pharmaceutical suppliers was this project’s principal data collection. The patent data were further linked to development indicators of the countries implicated by our study and to economic data detailing medicine procurements made by those working with assistance from international organizations. Building upon the techniques refined during the MLEM study, three supplementary patent studies were performed to investigate very specific questions regarding medicine patenting and medicine access. With these patent data collected, we investigated companies’ medicine patent filing behaviours internationally. Various policy approaches to accelerating access at the international level were compared, including those that disregard patent protection and those are based on cooperation between medicine suppliers. Of the approaches considered, the cooperative approaches appeared to be the most efficient, especially voluntary licensing practices (i.e., originator companies license generic manufacturers to supply the product to developing countries in exchange for royalties). We find that while patents may detour generic competition at times, we also find they may serve as springboards for collaborative endeavours and global medicine access campaigns, like the one for HIV drugs. This thesis concludes by arguing that improved international medicine patent transparency by pharmaceutical suppliers is one of the most powerful ways to foster such collaborations to improve medicine access.

This thesis deals with global governance and its changing structures reflected in the challenges to the functioning of post-war intergovernmental institutions. The main aim of the thesis is to find out whether the World Trade Organization is effective enough in dealing with emerging global issues, which is tested on the case study of the adoption of the TRIPS agreement with special focus on pharmaceuticals. In the first chapter, it provides a theoretical framework of the global governance theory and the means for evaluating the effectiveness of international institutions in global governance through input and output legitimacy. The second chapter deals with the role of the World Trade organization in global governance and evaluating its performance. The third chapter evaluates the role of the World Trade Organization in protection of intellectual property rights with focus on pharmaceuticals. The methods used in the thesis include analysis, synthesis, deduction while the research is supported with quantitative data, tables and case study.

No description available.