Made available in DSpace on 2016-03-15T19:31:17Z (GMT). No. of bitstreams: 1 Ramon Silva Leite.pdf: 1012552 bytes, checksum: b3d09d4e52a7267b02a8d3f6b152290c (MD5) Previous issue date: 2009-04-27 / Fundo Mackenzie de Pesquisa / The Vertical Collaborative Relationship has been a way encountered by companies to act cohesively and to get mutual benefits. Accordingly, this study aimed to examine the collaborative relationship and its impact on businesses performance, focusing on the footwear s industry array of production of Nova Serrana (MG) and its suppliers. In order to analyze it, a descriptive research was done about the transaction cost theory and also about the main conceptions and contributions about chain companies, productive arrangements and cooperation. Later this descriptive research, an extensive fieldwork was carried out, divided into two stages. The first one, based on an exploratory character, was composed of 24 interviews: 14 with footwear manufacturers and 10 with their main suppliers. This stage aimed to study the phenomenon in a greater depth, to gain familiarity with the analyzed object and to refine the patterns used in other studies addressed to the reality of the footwear s sector. The obtained data on this stage, concerned by the content analysis' methodology technique, revealed that: a) communication, adaptation, commitment, dependence and trust are important for collaborative relationship; b) small companies remain relations considered relations of market, contributing to higher transaction costs; and c) medium and major companies prefer higher collaborative relationships in order to reduce transaction costs, as well as costs of new products` development. The research s second stage, descriptive in nature, had four main objectives: 1st) to identify the predominant variables in the relationship between manufacturers and suppliers from both perspectives; 2nd) to validate and operationalize the keys identified as their connection s constructs; 3rd) to verify if some firms characteristics are associated to better performances, and 4th) to compare suppliers and manufacturers point of view about their relationship. This stage had two data collections. The first one involved 211 manufacturers, while the second involved a sample of 87 suppliers. The gathered data underwent several tests, including the Structural Equation Modeling and CHAID s (Chi-Square Automatic Interaction Detection) technique of segmentation. The results proved that: a) the major variables for the collaborative relationship differ from manufactures to suppliers for the sample of manufactures, communication and commitment influence the relationship significantly, while for the sample of suppliers trust and commitment were considered the most important; b) the patterns that composed the final model, right after some adjusts, reached acceptable values of validity and trustworthiness; c) footwear manufactures with certain characteristics, such as type of shoe produced and capacity, obtain better performance than its competitors; and d) there are significant divergences between manufactures and suppliers` views about relationship. Before the obtained results, it follows that there is a significant relation between collaboration and performance. Thus, the way companies deal with their partners leads them to better results. Moreover, the collaborative relationships benefits are greater for the suppliers. For manufacturers, it is interesting to develop collaborative relationships with their most important suppliers, while standard market relations may be more appropriate to the less strategic partners. Finally, it is suggested that future studies concern other variables and include larger samples. / Relacionamentos colaborativos verticais têm sido uma das formas encontradas pelas empresas para atuarem de maneira mais coesa, ao mesmo tempo em que procuram obter benefícios mútuos. Nesse sentido, este estudo procurou analisar o relacionamento colaborativo e suas repercussões no desempenho das empresas, tendo como foco as indústrias de calçados do arranjo produtivo de Nova Serrana (MG) e seus fornecedores. Para esse fim, foi feita uma revisão da literatura a respeito da teoria dos custos de transação, além dos principais conceitos e contribuições sobre redes de empresas, arranjos produtivos e cooperação. Após essa revisão, foi desenvolvido um extenso trabalho de campo, dividido em duas etapas. A primeira, de caráter exploratório, contou com 24 entrevistas, sendo 14 com fabricantes de calçados e 10 com os principais fornecedores desses fabricantes. Essa etapa buscou estudar o fenômeno com maior profundidade e obter familiaridade com o objeto de estudo, além de refinar as escalas utilizadas em outros estudos para a realidade do setor analisado. Os dados coletados nessa etapa, tratados pela técnica da análise de conteúdo, revelaram que: a) a comunicação, a adaptação, o comprometimento, a dependência e a confiança são importantes para o relacionamento colaborativo; b) as empresas menores mantêm relações consideradas de mercado, o que as leva a ter maiores custos de transação; e c) as empresas de médio e grande porte optaram por relacionamentos mais colaborativos como mecanismo para reduzir custos de transação, bem como os custos de desenvolvimento de novos produtos. Já a segunda etapa da pesquisa, de caráter descritivo, teve quatro objetivos principais: 1˚) identificar as variáveis preponderantes no relacionamento, sob o ponto de vista dos fabricantes e fornecedores; 2˚) validar e operacionalizar os construtos identificados como principais no relacionamento; 3˚) averiguar se determinadas características das empresas estão associadas a melhores desempenhos; e 4˚) comparar a visão de fabricantes e fornecedores sobre o relacionamento. Essa etapa contou com duas coletas de dados. A primeira envolveu 211 fabricantes, enquanto a segunda contou com uma amostra de 87 fornecedores. Os dados coletados passaram por diversas análises, dentre elas a Modelagem de Equações Estruturais e a técnica de segmentação CHAID (Chi-Square Automatic Interaction Detection). Os resultados demonstraram que: a) as variáveis preponderantes para o relacionamento colaborativo são diferentes para fabricantes e fornecedores - para a amostra de fabricantes a comunicação e o comprometimento influenciam de forma mais significativa o relacionamento, já para a amostra de fornecedores a confiança e o comprometimento foram preponderantes; b) as escalas que compuserem o modelo final, após alguns ajustes, atingiram valores aceitáveis de validade e confiabilidade; c) fabricantes de calçados com determinadas características, tais como tipo de calçado produzido e porte, obtêm desempenhos superiores aos de seus pares; e d) há divergências significativas entre as visões de fabricantes e fornecedores sobre o relacionamento. Diante dos resultados obtidos, conclui-se que há uma relação significativa entre colaboração e desempenho. Assim, a forma como as empresas lidam com seus parceiros leva-as a ter desempenhos melhores. Além disso, os benefícios do relacionamento colaborativo são maiores para os fornecedores. Já para os fabricantes é interessante que desenvolvam relacionamentos colaborativos com seus fornecedores mais importantes, enquanto que para parceiros menos estratégicos relações do tipo mercado podem ser mais adequadas. Por fim, sugere-se que futuros estudos incluam outras variáveis no modelo, além de contemplar amostras maiores.

Photosensitizing effects of xenobiotics are of increasing concern in public health since modern lifestyle often associates sunlight exposure with the presence of chemical substances in the skin. An important number of chemicals like perfumes, sunscreen components, or therapeutic agents have been reported as photosensitizers. In this context, a considerable effort has been made to design a model system for photosafety assessment. Indeed, screening for phototoxicity is necessary at the early phase of drug discovery process, even before introducing drugs and chemicals into clinical therapy, to prevent undesired photoreactions in humans. In the case of new pharmaceuticals, their phototoxic potential has to be tested when they absorb in the regions corresponding to the solar spectrum, that is, for wavelengths >290 nm. So, there is an obvious need for a screening strategy based on in vitro experiments. The goal of the present thesis was the photochemical study of different photoactive drugs to investigate the key molecular aspects responsible for their photosensitivity side effects. In a first stage, rosuvastatin was considered in chapter 3 as representative compound of the statin family. This lipid-lowering drug, also known as “superstatin”, contains a 2-vinylbiphenyl-like moiety and has been previously described to decompose under solar irradiation, yielding stable dihydrophenanthrene analogues. During photophysical characterization of rosuvastatin, only a long-lived transient at ca. 550 nm was observed and assigned to the primary photocyclization intermediate. Thus, the absence of detectable triplet-triplet absorption and the low yield of fluorescence ruled out the role of the parent drug as an efficient sensitizer. In this context, the attention was placed on the rosuvastatin main photoproduct (ppRSV). Indeed, the photobehavior of this dihydrophenanthrene-like compound presented the essential components needed for an efficient biomolecule photosensitizer i.e. (i) a high intersystem crossing quantum yield (ΦISC =0.8), (ii) a triplet excited state energy of ca. 67 kcal mol−1 , and (iii) a quantum yield of singlet oxygen formation (Φ∆) of 0.3. Furthermore, laser flash photolysis studies revealed a triplet-triplet energy transfer from the triplet excited state of ppRSV to thymidine, leading to the formation of cyclobutane thymidine dimers, an important type of DNA lesion. Finally, tryptophan was used as a probe to investigate the Type I and/or Type II character of ppRSV-mediated oxidation. In this way, both an electron transfer process giving rise to the tryptophanyl radical and a singlet oxygen mediated oxidation were observed. On the basis of the obtained results, rosuvastatin, through its major photoproduct ppRSV, should be considered as a potential sensitizer. Then, itraconazole (ITZ), a broad-spectrum antifungal agent, was chosen as main character of chapter 4. Its photochemical properties were investigated in connection with its reported skin photosensitivity disorders. Steady state photolysis, fluorescence and phosphorescence experiments were performed to understand ITZ photoreactivity in biological media. The drug is unstable under UVB irradiation, suffering a primary dehalogenation of the 2,4-dichlorophenyl moiety that occurs mainly at the ortho-position. In poorly H-donating solvents, as acetonitrile, the major photoproduct arises from intramolecular attack of the initially generated aryl radical to the triazole ring. In addition, reduced compounds resulting from homolytic cleavage of the C-Cl bond in ortho or para positions and subsequent Habstraction from the medium are obtained to a lesser extent. In good H-donating solvents, such as ethanol, the main photoproducts are formed by reductive dehalogenation. Furthermore, irradiation of a model dyad containing a tryptophan unit and the reactive 2,4-dichlorophenyl moiety of itraconazole leads to formation of a new covalent link between these two substructures revealing that homolysis of the C-Cl bond of ITZ can result in alkylation of reactive amino acid residues of proteins, leading to formation of covalent photoadducts. Therefore, it has been established that the key process in the photosensitization by itraconazole is cleavage of the carbon-halogen bond, which leads to aryl radicals and chlorine atoms. These highly reactive species might be responsible for extensive free radical-mediated biological damage, including lipid peroxidation or photobinding to proteins. In chapter 5, photobehavior of imatinib (IMT) was addressed. This is a promising tyrosine kinase inhibitor used in the treatment of some types of human cancer, which constitutes a successful example of rational drug design based on the optimization of the chemical structure to reach an improved pharmacological activity. Cutaneous reactions, such as increased photosensitivity or pseudoporphyria, are among the most common nonhematological IMT side effects; however, the molecular bases of these clinical observations have not been unveiled yet. Thus, to gain insight into the IMT photosensitizing properties, its photobehavior was studied together with that of its potentially photoactive anilino-pyrimidine and pyridyl-pyrimidine fragments. In this context, steady-state and time resolved fluorescence, as well as laser flash photolysis experiments were run, and the DNA photosensitization potential was investigated by means of single strand breaks detection using agarose gel electrophoresis. The obtained results revealed that the drug itself and its anilino-pyrimidine fragment are not DNA-photosensitizers. By contrast, the pyridyl-pyrimidine substructure displayed a marked photogenotoxic potential, which was associated with the generation of a long-lived triplet excited state. Interestingly, this reactive species was efficiently quenched by benzanilide, another molecular fragment of IMT. Clearly, integration of the photoactive pyridyl-pyrimidine moiety in a more complex structure strongly modifies its photobehavior, which in this case is fortunate as it leads to an improved toxicological profile. Thus, on the bases of the experimental results, direct in vivo photosensitization by IMT seems unlikely. Instead, the reported photosensitivity disorders could be related to indirect processes, such as the previously suggested impairment of melanogenesis or the accumulation of endogenous porphyrins. Finally, a possible source of errors in the TEMPO/EPR method for singlet oxygen detection was analyzed. For many biological and biomedical studies, it is essential to detect the production of 1O2 and to quantify its production yield. Among the available methods, detection of the characteristic 1270 nm phosphorescence of singlet oxygen by time-resolved near infrared (TRNIR) emission constitutes the most direct and unambiguous approach. An alternative indirect method is electron paramagnetic resonance (EPR) in combination with trapping. This is based on the detection of the TEMPO free radical formed after oxidation of TEMP (2,2,6,6- tetramethylpiperidine) by singlet oxygen. Although the TEMPO/EPR method has been largely employed, it can produce misleading data. This was demonstrated by the present study, where the quantum yields of singlet oxygen formation obtained by TRNIR emission and by the TEMPO/EPR method were compared for a set of well-known photosensitizers. The results revealed that the TEMPO/EPR method leads to significant overestimation of singlet oxygen yield when the singlet or triplet excited state of the photosensitizers were efficiently quenched by TEMP, acting as electron donor. In such case, generation of the TEMP+• radical cation, followed by deprotonation and reaction with molecular oxygen gives rise to a EPR detectable TEMPO signal that is not associated with singlet oxygen production. This knowledge is essential for an appropriate and error-free application of the TEMPO/EPR method in chemical, biological and medical studies. / Nardi, G. (2014). MECHANISTIC STUDIES ON THE PHOTOTOXICITY OF ROSUVASTATIN, ITRACONAZOLE AND IMATINIB [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/48535 / TESIS