Control is a concept that has received surprisingly little attention in the philosophy of action and ethics, given its prima facie ties to freedom, responsibility, intentionality and agency more generally. In this collection I take the first step towards an account of agential control: the kind of control that agents commonly exercise over actions, events, and even other agents. In the introduction I give a sketch of the complete thesis on control: characterising agential control as consisting primarily in the restriction or guidance of some process, and secondarily in the continuous monitoring of that same process. I go on to suggest that the primary aspect of control involves an agent’s having the ability to effectively intervene in the process that they are controlling. The collection itself consists of three journal style papers that, whilst not being focussed explicitly on control themselves, begin to fill out the sketch in my introduction: roughly, I think that control requires an ability to intervene (effectively, an ability to do otherwise), I think that ability should be understood as a kind of disposition to effectively intervene in a process should an agent try, and I think that to build a satisfactory conditional account of dispositions we need to appeal to the recently proposed contextualist account of dispositions from David Manley and Ryan Wasserman. The three papers aim to support each of these thoughts: The first paper, ‘The Anti-Akrasia Chip’, presents a counterexample to the well-known Fischer-Ravizza account of guidance control and suggests that what that account lacks is an emphasis on an agent’s being able to effectively intervene in their own behaviour; the second paper, ‘Getting Specific with Manley and Wasserman’, uses a novel counterexample to motivate a particular reading on Manley and Wasserman’s contextualist account of dispositions; and the final paper, ‘Relevant Abilities’, involves a defence of dispositional compatibilism by introducing the notion of a relevant ability: one grounded by the contextualist account of dispositions developed in the previous paper.

The objective of this research is to test the expensing of stock options as part of CEO compensation to earnings quality. Agency theory posits a conflict between the CEO's own self-interest and that of the owners who seek to maximize the long term value of their investment. To avoid this conflict compensation should align and bond these parties. Data was retrieved from Compustat, ExecuComp and Corporate Governance databases spanning the years of 2000 through 2009. The Dechow and Dichev (2002) earnings quality model using the change in working capital and error terms taken as the residuals was utilized. All hypotheses used earnings quality as a proxy for management choices and as the predictive power of accruals. The first hypothesis indicated granting of CEO stock options has a positive association to earnings quality. The second hypothesis tests the implementation of SFAS 123 (R) by expensing stock options and the association to earnings quality. The third and final hypothesis utilized the number of BOD members as to compare the association between expensing stock options as part of CEO compensation and earnings quality. Empirical support for all three hypotheses was found and consistent with expectations established by other research using earnings quality methodologies. Both the granting and expensing of stock options as part of CEO compensation has an association to earnings quality. There exists a stronger association between expensing stock options and earnings quality when firms have a larger number of BOD members. Support for agency theory was discovered because all three hypotheses were supported. This study was limited to U.S. firms that were publicly traded on major U.S. exchanges and only CEO compensation. Other executive compensation was not included. These limitations provide opportunities for future research. Knowledge was gained by exploring the earnings quality measures for evidence of bonding and alignment theory. This study extends the research in earnings quality by examining the relationship of granting and expensing of stock options as per SFAS 123 (R). It also contributes to the work in SFAS 123 (R) by testing four years before and after 2005, when implementation occurred.

O trabalho busca estudar os impactos dos custos tributários, incluídos os custos de conformidade à legislação, quanto às micro e pequenas empresas, mormente às produtoras de bebidas alcoólicas. As MPE desempenham um papel primordial ao desenvolvimento socioeconômico de um país, por representarem, dentre outras características, alta capacidade de absorção de mão-de-obra. Por essa razão, sua proteção e estímulo foram erigidos a princípio constitucional. Entretanto, as dificuldades enfrentadas pelos menores negócios, principalmente a elevada carga tributária e a complexidade legislativa, submetem-nos à alta taxa de mortalidade ou a manutenção das atividades de maneira informal. Para solucionar essa questão, foi editada a LC 123/06, no intuito de estabelecer regras facilitadoras nos diversos campos jurídicos, inclusive, na seara tributária, denominada \"Simples Nacional\". Referido diploma, apesar de ser um avanço quanto à desoneração tributária e a desburocratização da atividade, ainda apresenta problemas substanciais, não concretizando o tratamento diferenciado e favorecido previsto constitucionalmente às micro e pequenas empresas. A presente pesquisa se caracteriza por ser descritiva, de natureza teórica, cuja abordagem é qualitativa, utilizando-se, como procedimento, a pesquisa bibliográfica e documental. / The research aims to study the impacts of tax costs, including compliance costs, for micro and small enterprises, particularly for alcoholic beverage producers. Micro and small producers play a key role in the socioeconomic development of a country, since they represent, among other characteristics, a high capacity for labor absorption. For this reason, their protection and encouragement were erected in principle constitutional. However, the difficulties faced by the smaller businesses, especially the high tax burden and the legislative complexity, subject them to high mortality rates or the maintenance of activities in an informal way. In order to solve this issue, LC 123/06 was published, in order to establish facilitative rules in the various legal fields, including in the tax field, called \"Simples Nacional\". This diploma, despite being a step forward in tax relief and debureaucratization of the activity, still presents substantial problems, failing to materialize the differentiated and favored treatment constitutionally foreseen to micro and small companies. The present research is characterized by being descriptive, of a theoretical nature, whose approach is qualitative, using, as a procedure, bibliographical and documentary research.

[pt] Diante da importância terapêutica dos 1,2,3-triazóis e da versatilidade da reação de cicloadição 1,3-dipolar de Huisgen catalisada por cobre (reação CuAAC), o presente trabalho propõe a síntese de novos 1,2,3-triazóis-1,4-dissubstituídos abordando-se o conceito de hibridização molecular que associa ao núcleo triazólico outros grupos farmacofóricos privilegiados. Os compostos sintetizados foram divididos em duas séries e avaliados quanto ao potencial anticâncer, antileishmanial e distúrbios do sistema do nervoso central. Para obtenção da primeira série de triazóis utilizou-se como precursores aril azidas preparadas a partir de anilinas e éter propargílicos obtidos a partir de fenóis. A etapa chave da reação de CuAAC levou a obtenção dos 1,2,3-triazóis-1,4-dissubstituídos com rendimentos entre 50 e 85 porcento. Os compostos obtidos foram avaliados em diferentes linhagens celulares de glioblastoma (GBM, U87), incluindo linhagens celulares humanas altamente resistentes como a GBM02, GBM95, onde os compostos 2,2- (4,4-((1,3-phenilenebis(oxi))bis(methileno))bis(1H-1,2,3-triazol-4,1diyl))dibenzaldeído e (E)-4-metil-N-(2-(4-(fenoximetil)-1H-1,2,3triazolil)benzilideno)benzenosulfonohidrazida foram os mais ativos, com IC50 de 28,7 e 30,3 uM, respectivamente. Também foram avaliados nas linhagens de câncer de pulmão e próstata (A549, 22Rv1), entretanto, os compostos analisados não apresentaram atividade frente a estas linhagens celulares. Para a síntese da segunda série de compostos híbridos, tais quais os a-hidroxi-1,2,3-triazóis e benzocromenostriazóis, utilizou-se como materiais de partida aril azidas, preparadas através de ácidos aril borônicos e álcoois propargílicos, preparados a partir de benzaldeídos comerciais. A reação CuAAC na presença de metóxido de sódio levou a obtenção dos novos a-hidroxi-1,2,3-triazóis com rendimentos entre 35 e 75 porcento. A partir dos a-hidroxi-1,2,3-triazóis obtidos, realizou-se a reação de ativação C-H catalisada por paládio para obtenção benzocromenos-triazóis com rendimentos entre 35 e 40 porcento. Esses compostos foram avaliados como inibidores do transportador de glicina (Gly T1), transportadores relacionados a distúrbios neurológicos, e o composto (2-bromofenil)(1-(4-bromofenil)-1H-1,2,3-triazol-4-il)metanol apresentou 42porcento de inibição e IC50 de 13 uM, sendo este o melhor resultado de toda a série. Os compostos obtidos foram avaliados quanto a atividade antileishmanial (L. amazonenses), sendo que os compostos 2,2-(4,4-((1,3- phenilenebis(oxi))bis(methileno))bis(1H-1,2,3-triazol-4,1diyl)) dibenzaldeído e (E)-4-metil-N-(2-(4-(fenoximetil)-1H-1,2,3triazolil)benzilideno) benzenosulfonohidrazida apresentaram os melhores resultados, com IC50 de 8,85 e 8,81 uM, respectivamente. Todos os compostos sintetizados foram caracterizados por técnicas de espectroscopia de ressonância magnética nuclear (RMN), infravermelho (IV) e espectrometria de massas (CG-MS). / [en] In view of the therapeutic importance of 1,2,3-triazoles and the versatility of the copper-catalyzed Huisgen 1,3-dipolar cycloaddition (CuAAC), the present work proposes the synthesis of new compounds containing 1,2,3-triazoles-1,4-disubstituted derivatives by addressing the concept of molecular hybridization to obtain various triazole-containing compounds associated with other privileged pharmacophoric groups. The compounds synthesized were divided into two series and evaluated for their anticancer potential, as antileishmanial and central nervous system disorders. In order to the first series of triazoles, aryl azides were prepared from commercial anilines and propargylic ethers were obtained from commercial phenols. The key step of the CuAAC reaction afforded of 1,2,3-triazoles-1,4-disubstituted 50 - 85 percent in yields. All compounds were evaluated in different glioblastoma cell lines (GBM), including highly resistant human cell lines such as GBM02, GBM95, in which compounds 2,2-(4,4-((1,3 henylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))dibenzaldehyde and (E)-4-methyl-N-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)benzylidene)benzenesulfonohydrazide were the most active, with IC50 of 28.7 and 30.3 uM, respectively. The triazole derivatives were also evaluated for the lung and prostate cancer strains (A549, 22Rv1), however, the compounds analyzed did not show activity in these cell lines. For the synthesis of the second series of hybrid compounds such as a-hydroxy-1,2,3-triazoles and benzochromenes-triazoles, aryl azides were prepared from aryl boronic acids and the propargylic alcohols from commercial benzaldehydes. The CuAAC reaction in the presence of sodium methoxide provided the novel a-hydroxy-1,2,3-triazoles in 35 and 75 percents yields. The a-hydroxy-1,2,3-triazoles, were aplied palladium-catalyzed intermolecular (C-O) cyclization reaction and provided benzocromenes-triazoles in 35-40 percent yields. These compounds were evaluated as inhibitors of glycine transporter (Gly T1), which are related to neurological disorders. Therefore, compound (2-bromophenyl) (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methanol showed the best result with 42 percent of inhibition and IC50 of 13 uM. All compounds were avaluated for antileishmanial activity (L. amazonenses), compounds 2,2-(4,4-((1,3-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))dibenzaldehyde and (E)-4-methyl-N-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)benzylidene)benzenesulfonohydrazide presented the best results, with IC50 de 8,85 e 8,81 uM, respectively. All the compounds synthesized were characterized by nuclear magnetic resonance (NMR), infrared (FTIR) spectroscopy and mass spectrometry (GC-MS) techniques.

La fraîcheur est un paramètre clé de la qualité du poisson. Les méthodes actuelles appliquées en routine pour déterminer la fraîcheur du poisson ne sont pas applicables à toutes les espèces et reflètent davantage un début d'altération du produit. Ainsi, la recherche d'indicateurs précoces de fraîcheur du poisson représente encore un défi majeur et d'actualité dans l'industrie de la pêche. Le but de ces travaux de thèse était de démontrer que les fonctions et l'intégrité mitochondriales étaient susceptibles de constituer des indicateurs précoces de la fraîcheur de filets de poisson. En effet, la mitochondrie est la "centrale" énergétique de la cellule eucaryote et joue un rôle clef dans les mécanismes de mort cellulaire tels que l'apoptose et la nécrose. Les fonctions et l'intégrité mitochondriales de cellules musculaires de filets de poisson ont été étudiées à différents temps de conservation post mortem à 4°C. Le modèle d'étude était la daurade royale (Sparus aurata) (lignée cellulaire de fibroblastes (SAF-1) et muscles de poisson). Dans un premier temps, la structure des mitochondries de poisson a été étudiée par microscopie électronique à transmission. De nombreuses dégradations de la structure des mitochondries ont été observées dans les filets à partir de 72 heures (J3) de conservation à 4°C. Ces altérations se sont accentuées à J4 et J6. La fonctionnalité des mitochondries a ensuite été évaluée selon deux approches : la respiration mitochondriale (oxygraphie) et le potentiel membranaire mitochondrial (ΔΨₘ) estimé avec la sonde fluorescente Rhodamine 123. A partir de 96 heures de conservation à 4°C (J4), ces deux paramètres ont été significativement impactés témoignant d'une altération des fonctions et de l'intégrité mitochondriales.Ces résultats sont ainsi en corrélation avec l'altération structurale observée par microscopie. En parallèle, une méthode d'évaluation du potentiel membranaire a été développée avec un fluorimètre à microvolume à partir d'un modèle bactérien puis de mitochondries isolées. Ces travaux de thèse ont démontré que l'étude des fonctionnalités mitochondriales constitue un marqueur fiable et précoce de la fraîcheur des filets de poisson. Des connaissances supplémentaires sur les mécanismes cellulaires post mortem ont également été apportées. Ces résultats constituent ainsi le point de départ pour le développement d'un kit d'évaluation de la fraîcheur et ouvrent la voie pour la recherche de marqueurs de fraîcheur et de congélation/décongélation basés sur les fonctionnalités et intégrité mitochondriales. / Freshness is a key parameter of fish quality. Current routine techniques to determine fish freshness are not applicable to all species and reflect a late stage of alteration. Thus, research on early indicators of fish freshness still represents a major and topical challenge in fishing industry. This PhD research project aimed to demonstrate that mitochondrial functions and integrity constitute early indicators of fish fillet freshness. Mitochondria are the powerhouse of the cell and play a central role in cell death mecanisms such as apoptosis and necrosis. Mitochondrial function and integrity in fish filet muscle cells were studied at different times of storage post mortem at 4°C. The species studied as a model was the gilthead seabream (Sparus aurata) (gilthead seabream fibroblast cell line (SAF-1) and fish fillets). Firstly, the structure of fish mitochondria was studied by transmission electron microscopy. Numerous mitochondrial structural alterations have been observed in fish fillet from 72 hours (D3) of storage at 4°C. These alterations were more pronounced at D4 and D6. Then, mitochondrial functionality was assessed with two approaches: mitochondrial respiration (oxygraphy) and mitochondrial membrane potential (ΔΨₘ) estimated with the fluorescent probe Rh123. From 96 hours of storage at 4°C (D4), these two parameters were significantly disrupted demonstrating the alteration of mitochondrial function and integrity. The results are in correlation with the mitochondrial structural alterations described by microscopy. In parallel, a method of mitochondrial membrane potential evaluation has been developed with a micro-volume fluorimeter, first using bacteria and then isolated mitochondria. This work demonstrated that the mitochondrial functionality study constitutes a reliable and early fish filet freshness indicator. Additional knowledge on cell mechanisms in post mortem condition has been brought. These results constitute the starting point for the development of a fish freshness assay kit and pave the way to research on others freshness and freeze-thawing indicators based on mitochondrial integrity and functionality.

O desenvolvimento da Medicina Nuclear, aliado à evolução dos equipamentos de diagnóstico e terapia, necessita, cada vez mais, da disponibilidade comercial de radioisótopos. Nesse contexto, o IPEN tem buscado atender e abastecer o mercado nacional. Um dos investimentos nesta área foi a aquisição de um ciclotron de 30 MeV, modelo Cyclone-30, que permitiu a produção dos radioisótopos tais como, o 18F, 67Ga, 201Tl e o 123I, sendo este último o foco do presente trabalho. Através de dados de produções rotineiras de 123I via irradiação com prótons em alvo gasoso de Xenônio com enriquecimento superior a 99,8% em 124Xe, foi realizado um estudo para identificar os fatores relevantes que influenciam diretamente o rendimento de obtenção de 123I com altíssimo grau de pureza. Embora a metodologia seja bem conhecida, quando se trata de produção comercial há uma escassez de dados sobre os parâmetros operacionais utilizados. Os parâmetros avaliados foram: pressão do gás 124Xe, intensidade de corrente de feixe de prótons, tempo de irradiação, temperatura de operação do sistema durante a irradiação, tempo de espera para formação de 123I, tempo de aquecimento do porta-alvo para recuperação do 123I formado, temperatura de aquecimento da solução de lavagem e influência do revestimento interno da câmara de irradiação com Ni. Com os resultados obtidos, foi possível alterar as condições operacionais nas produções rotineiras, conduzindo a um aumento de eficiência do processo em torno de 30%. / The development of diagnosis equipment and therapy procedures in nuclear medicine depends on the availability of commercial radioisotopes. IPEN is the most important institution that provides radioisotopes for national market. In order to achieve this function, IPEN had invested in the acquisition of a 30 MeV Cyclone-30 cyclotron to produce mainly 18F, 67Ga, 201Tl and 123I. The 123I production is the aim of the present work. With the 123I routine production data obtained by proton irradiation of Xe targets with an enrichment greater than 99.8%, it was possible to identify the important parameters that have direct influence on the production yield of high purity degree 123I. Even though the methodology for the commercial production of 123I, there are an scarcity of operational parameters data for this task. In this work the evaluated parameters were: 124Xe pressure, proton beam quality, irradiation time, operational temperature of the irradiation system under irradiation, waiting time to obtain 123I, temperature of washing solution and the impact of the internal Ni coating in the target. With the obtained results it was possible to modify the operational conditions for routine production and increasing the efficiency in about 30%.

O desenvolvimento da Medicina Nuclear, aliado à evolução dos equipamentos de diagnóstico e terapia, necessita, cada vez mais, da disponibilidade comercial de radioisótopos. Nesse contexto, o IPEN tem buscado atender e abastecer o mercado nacional. Um dos investimentos nesta área foi a aquisição de um ciclotron de 30 MeV, modelo Cyclone-30, que permitiu a produção dos radioisótopos tais como, o 18F, 67Ga, 201Tl e o 123I, sendo este último o foco do presente trabalho. Através de dados de produções rotineiras de 123I via irradiação com prótons em alvo gasoso de Xenônio com enriquecimento superior a 99,8% em 124Xe, foi realizado um estudo para identificar os fatores relevantes que influenciam diretamente o rendimento de obtenção de 123I com altíssimo grau de pureza. Embora a metodologia seja bem conhecida, quando se trata de produção comercial há uma escassez de dados sobre os parâmetros operacionais utilizados. Os parâmetros avaliados foram: pressão do gás 124Xe, intensidade de corrente de feixe de prótons, tempo de irradiação, temperatura de operação do sistema durante a irradiação, tempo de espera para formação de 123I, tempo de aquecimento do porta-alvo para recuperação do 123I formado, temperatura de aquecimento da solução de lavagem e influência do revestimento interno da câmara de irradiação com Ni. Com os resultados obtidos, foi possível alterar as condições operacionais nas produções rotineiras, conduzindo a um aumento de eficiência do processo em torno de 30%. / The development of diagnosis equipment and therapy procedures in nuclear medicine depends on the availability of commercial radioisotopes. IPEN is the most important institution that provides radioisotopes for national market. In order to achieve this function, IPEN had invested in the acquisition of a 30 MeV Cyclone-30 cyclotron to produce mainly 18F, 67Ga, 201Tl and 123I. The 123I production is the aim of the present work. With the 123I routine production data obtained by proton irradiation of Xe targets with an enrichment greater than 99.8%, it was possible to identify the important parameters that have direct influence on the production yield of high purity degree 123I. Even though the methodology for the commercial production of 123I, there are an scarcity of operational parameters data for this task. In this work the evaluated parameters were: 124Xe pressure, proton beam quality, irradiation time, operational temperature of the irradiation system under irradiation, waiting time to obtain 123I, temperature of washing solution and the impact of the internal Ni coating in the target. With the obtained results it was possible to modify the operational conditions for routine production and increasing the efficiency in about 30%.

Absorption of drug substances across the intestinal epithelium is a complex and dynamic process. Counter transport proteins are responsible for the efflux of specific drug molecules after they have been absorbed. One of the key counter transport efflux proteins, which is of importance in this study, is P–glycoprotein. The efflux pump P–glycoprotein plays a major role in altering the pharmacokinetics of a wide variety of drugs limiting their absorption and therefore also bioavailability. Many flavonoids have been shown to interact with P–glycoprotein mediated efflux in vitro studies. Numerous in vitro methods have been used to study drug absorption across the intestinal membranes, but it is often not possible to use only one in vitro model to accurately predict permeability characteristics. The purpose of this study was to determine the effect of four selected hydroxy– and methoxy– flavonoids on the in vitro transport of Rhodamine 123, a known P–gp substrate, across excised rat and pig intestinal tissue using the Sweetana–Grass diffusion apparatus. The results were further used to determine if the two different animal tissue models corresponded with regard to the flavonoids' effects on P–glycoprotein related efflux. Two control groups were included in the experimental design. In the negative control group, the transport of Rhodamine 123 was tested alone and no modulator was added. In the positive control group, the transport of Rhodamine 123 was determined in the presence of Verapamil, which is a known P–glycoprotein inhibitor. The experiments with the flavonoids Morin, Galangin, 6–Methoxyflavone and 7–Methoxyflavone were done in triplicate to determine repeatability of the results. The transport of Rhodamine 123 was evaluated in both the apical to basolateral (absorptive) and basolateral to apical (secretory) directions. The relative transport of Rhodamine 123, the apparent permeability coefficient (P app) values and flux (J) values in both directions as well as the efflux ratio (ER) and net flux (J net) were calculated. The concentration Rhodamine 123 present in the acceptor chamber was determined by means of a validated HPLC method. Statistical analysis was used to compare the results of the test groups with the control groups in order to indicate significant differences. It has been found that Morin, Galangin and 6–Methoxyflavone have a significant inhibitory effect on the Rhodamine 123 efflux (probably P–glycoprotein related) in both the rat and pig intestinal tissue models with p–values smaller than 0.05. On the other hand, 7–Methoxyflavone showed a significant effect on the efflux of Rhodamine 123 in the pig intestinal tissue model (p < 0.05) but not in the rat intestinal tissue model (p > 0.05). These flavonoids may increase the bioavailability of drugs that are substrates for P–glycoprotein and thereby cause clinically significant pharmacokinetic interactions, however, this should be confirmed with in vivo studies. On the other hand, these flavonoids may be used for drug absorption enhancement when applied under controlled circumstances. With regard to the different animal tissue models used it can be concluded that data obtained from the rat intestinal tissue model cannot be compared and extrapolated to data obtained from the pig intestinal tissue model. It is recommended that the in vitro results be correlated to in vivo findings to identify the most suitable model. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Absorption of drug substances across the intestinal epithelium is a complex and dynamic process. Counter transport proteins are responsible for the efflux of specific drug molecules after they have been absorbed. One of the key counter transport efflux proteins, which is of importance in this study, is P–glycoprotein. The efflux pump P–glycoprotein plays a major role in altering the pharmacokinetics of a wide variety of drugs limiting their absorption and therefore also bioavailability. Many flavonoids have been shown to interact with P–glycoprotein mediated efflux in vitro studies. Numerous in vitro methods have been used to study drug absorption across the intestinal membranes, but it is often not possible to use only one in vitro model to accurately predict permeability characteristics. The purpose of this study was to determine the effect of four selected hydroxy– and methoxy– flavonoids on the in vitro transport of Rhodamine 123, a known P–gp substrate, across excised rat and pig intestinal tissue using the Sweetana–Grass diffusion apparatus. The results were further used to determine if the two different animal tissue models corresponded with regard to the flavonoids' effects on P–glycoprotein related efflux. Two control groups were included in the experimental design. In the negative control group, the transport of Rhodamine 123 was tested alone and no modulator was added. In the positive control group, the transport of Rhodamine 123 was determined in the presence of Verapamil, which is a known P–glycoprotein inhibitor. The experiments with the flavonoids Morin, Galangin, 6–Methoxyflavone and 7–Methoxyflavone were done in triplicate to determine repeatability of the results. The transport of Rhodamine 123 was evaluated in both the apical to basolateral (absorptive) and basolateral to apical (secretory) directions. The relative transport of Rhodamine 123, the apparent permeability coefficient (P app) values and flux (J) values in both directions as well as the efflux ratio (ER) and net flux (J net) were calculated. The concentration Rhodamine 123 present in the acceptor chamber was determined by means of a validated HPLC method. Statistical analysis was used to compare the results of the test groups with the control groups in order to indicate significant differences. It has been found that Morin, Galangin and 6–Methoxyflavone have a significant inhibitory effect on the Rhodamine 123 efflux (probably P–glycoprotein related) in both the rat and pig intestinal tissue models with p–values smaller than 0.05. On the other hand, 7–Methoxyflavone showed a significant effect on the efflux of Rhodamine 123 in the pig intestinal tissue model (p < 0.05) but not in the rat intestinal tissue model (p > 0.05). These flavonoids may increase the bioavailability of drugs that are substrates for P–glycoprotein and thereby cause clinically significant pharmacokinetic interactions, however, this should be confirmed with in vivo studies. On the other hand, these flavonoids may be used for drug absorption enhancement when applied under controlled circumstances. With regard to the different animal tissue models used it can be concluded that data obtained from the rat intestinal tissue model cannot be compared and extrapolated to data obtained from the pig intestinal tissue model. It is recommended that the in vitro results be correlated to in vivo findings to identify the most suitable model. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

[pt] A importância terapêutica dos compostos contendo 1,2,3-triazóis deve-se ao seu espectro de atuação farmacológica, entre as quais podemos destacar a ação anticâncer, antiviral, antibacteriana, antifúngica, anticonvulsivante entre outras. A facilidade sintética de obtenção de 1,2,3- triazóis por meio da reação de cicloadição 1,3 –dipolar catalisada por cobre (CuAAc), também denominada click chemistry, bem como a reação de cicloadição térmica 1,3-dipolar, torna este grupo bastante atraente como um grupo farmacofórico. O presente trabalho tem como objetivo geral o planejamento, síntese e avaliação de fenil(1-fenil-1H-1,2,3-triazóis-4-il)metanol, também denominados hidróxi-1,2,3-triazóis, visando analisar suas ações farmacológicas frente a leishmaniose. Duas estratégias foram desenvolvidas para a obtenção destes compostos: (i) reação de cicloadição 1,3-dipolar catalisada por cobre (CuAAC) entre 1-fenil-3-(trimetilsilil)prop-2-in-1-óis e aril azidas substituídas previamente preparadas levando assim a obtenção dos fenil(1-fenil-1H-1,2,3-triazóis-4-il)metanol com rendimentos entre 20 e 30 por cento. As aril azidas foram preparadas à partir das anilinas em 60 a 85 por cento de rendimentos e os 1-fenil-3-(trimetilsilil)prop-2-in-1-óis foram preparados à partir da adição de etiniltrimetilsilano aos benzaldeídos comerciais (ii) reação de cicloadição térmica entre aril azidas e (E)-3-(dimetilamino)-1-fenilprop-2-en-1-ona - previamente preparadas à partir de 4-bromoacetofenonas, em rendimentos de 40-50 por cento, seguida de redução dos fenil(1-fenil-1H-1,2,3-triazóis-4-il)metanona com rendimentos variando entre 35-50 por cento levando assim a obtenção dos fenil(1-fenil-1H-1,2,3-triazóis-4-il)metanóis com rendimentos entre 20 e 30 por cento. Os compostos sintetizados foram caracterizados por técnicas de espectroscopia de ressonância magnética nuclear (RMN), infravermelho (IV) e espectrometria de massas (CG-MS). / [en] The therapeutic importance of compounds containing 1,2,3-triazoles is due to their spectrum of pharmacological activity, among which we can highlight the anticancer, antiviral, antibacterial, antifungal, anticonvulsant action, among others. The synthetic facility to obtain 1,2,3-triazoles through the 1,3-dipolar copper-catalyzed cycloaddition reaction (CuAAc), also called click chemistry, as well as the 1,3-dipolar thermal cycloaddition reaction, makes this group quite attractive as a pharmacophoric group. The present work has a general objective the planning, synthesis and evaluation of phenyl (1-phenyl-1H-1,2,3-triazoles-4-yl) methanol, also called hydroxy-1,2,3-triazoles, aiming to analyze their pharmacological actions against leishmaniasis. Two strategies were developed to obtain these compounds: (i) 1,3-dipolar copper-catalyzed cycloaddition reaction (CuAAC) between 1-phenyl-3- (trimethylsilyl) prop-2-in-1-ois and aryl azides substituted previously prepared thus leading to obtaining phenyl (1-phenyl-1H-1,2,3-triazoles-4-yl) methanol with yields between 20 and 30 percent. Aryl azides (50a-i) were prepared from anilines in 60 to 85 percent yields and 1-phenyl-3- (trimethylsilyl) prop-2-in-1-ois were prepared from the addition of ethinyltrimethylsilane to commercial benzaldehydes (ii) thermal cycloaddition reaction between aryl azides and (E) -3- (dimethylamino) -1-phenylprop- 2-en-1-one - previously prepared from 4-bromoacetophenones, in yields of 40-50 percent, followed by reduction of phenyl (1-phenyl-1H-1,2,3-triazoles-4- il) methanone with yields varying between 35-50 percent thus leading to the obtaining of phenyl (1-phenyl-1H-1,2,3-triazoles-4-yl) methanols with yields between 20 and 30 percent. The synthesized compounds were characterized by nuclear magnetic resonance (NMR), infrared (IR) and mass spectrometry (CG-MS) techniques.