Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and pain (Escribano et al., 2003:203). Diclofenac, a classical NSAID, is considerably more effective as an analgesic, antipyretic and anti-inflammatory drug than other traditional NSAIDs, like indomethacin and naproxen (Grosser et al., 2011:986). However, the use of diclofenac is known for its many side effects, such as gastric disorders, while fluid and sodium retention are also commonly observed (Rossiter, 2012:391). Since topical diclofenac offers a more favourable safety profile, it is a valuable substitute for oral NSAID therapy in the treatment of osteoarthritis (Roth & Fuller, 2011:166). The benefits of topically applied NSAIDs, compared to oral administration and systemic delivery, include the easy cessation of treatment, should effects become troublesome (Brown et al., 2006:177), the avoidance of extensive, first-pass metabolism (Cleary, 1993:19; Kornick, 2003:953; Prausnitz & Langer, 2008:1261; Lionberger & Brennan, 2010:225), reduced systemic side effects (Colin Long, 2002:41), convenience of application and improved patient compliance (Cleary, 1993:19; Prausnitz & Langer, 2008:1261). An approach that is often applied in optimising the solubility and dissolution rate of poorly water soluble, weak electrolytes is to prepare a salt of the active pharmaceutical ingredient (API) (Minghetti et al., 2007:815; O’Connor & Corrigan, 2001:281-282). Diclofenac is frequently administered as a salt, due to the high partition coefficient and very low water solubility of this molecule (Fini et al., 1999:164). Formulating for efficacy (FFETM) is a software programme designed by JW Solutions to facilitate the formulation of cosmetic ingredients or solvents into a product that would optimally deliver active ingredients into the skin. The notion is built upon solubility, i.e. solubility of the active ingredient in the formulation and solubility of the formulation in the skin. This programme could also be employed to optimise amounts of predetermined ingredients, to propose formulations that would ensure optimal drug delivery, to calculate the skin delivery gap (SDG) and to demonstrate transdermal permeation of active ingredients and excipients (JW Solutions Software, 2013a). When the SDG is known, it mathematically indicates the optimal active ingredient and topical delivery vehicle to use (JW Solutions, 2013b). In this study, diclofenac sodium (DNa), diclofenac diethylamine (DDEA) and diclofenac N-(2- hydroxyethyl) pyrrolidine (DHEP) were each formulated in the following emulgels: * An emulgel optimised towards the stratum corneum (SC) (enhancing drug delivery into this layer and deeper tissues) (oily phase ~30%), * A more hydrophilic emulgel (oily phase ~15%), and * A more lipophilic emulgel (oily phase ~45%). Components of the oily phase and its respective amounts, as well as the SDG of formulations were determined by utilising the FFETM software of JW Solutions (2013a). The aqueous solubilities of DNa, DDEA and DHEP were determined and their respective values were 11.4 mg/ml, 8.0 mg/ml and 11.9 mg/ml, all indicative of effortless percutaneous delivery (Naik et al., 2000:319). Log D (octanol-buffer distribution coefficient) (pH 7.4) determinations for DNa, DDEA and DHEP were performed and their values established at 1.270 (DNa), 1.291 (DDEA) and 1.285 (DHEP). According to these values, diclofenac, when topically applied as a salt in a suitable vehicle, should permeate transdermally without the aid of radical intervention (Naik et al., 2000:319; Walters, 2007:1312). Membrane release studies were also carried out in order to determine the rate of API release from these new formulations. Results confirmed that diclofenac was indeed released from all nine of the formulated emulgels. The more hydrophilic DNa formulation released the highest average percentage of diclofenac (8.38%) after 6 hours. Subsequent transdermal diffusion studies were performed to determine the diclofenac concentration that permeated the skin. The more hydrophilic DNa emulgel showed the highest average percentage skin diffusion (0.09%) after 12 hours, as well as the highest average flux (1.42 ± 0.20 μg/cm2.h). The concentrations of diclofenac in the SC-epidermis (SCE) and epidermis-dermis (ED) were determined through tape stripping experiments. The more lipophilic DNa emulgel demonstrated the highest average concentration (0.27 μg/ml) in the ED, while the DNa emulgel that had been optimised towards the SC, had the highest concentration in the SCE (0.77 μg/ml). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and pain (Escribano et al., 2003:203). Diclofenac, a classical NSAID, is considerably more effective as an analgesic, antipyretic and anti-inflammatory drug than other traditional NSAIDs, like indomethacin and naproxen (Grosser et al., 2011:986). However, the use of diclofenac is known for its many side effects, such as gastric disorders, while fluid and sodium retention are also commonly observed (Rossiter, 2012:391). Since topical diclofenac offers a more favourable safety profile, it is a valuable substitute for oral NSAID therapy in the treatment of osteoarthritis (Roth & Fuller, 2011:166). The benefits of topically applied NSAIDs, compared to oral administration and systemic delivery, include the easy cessation of treatment, should effects become troublesome (Brown et al., 2006:177), the avoidance of extensive, first-pass metabolism (Cleary, 1993:19; Kornick, 2003:953; Prausnitz & Langer, 2008:1261; Lionberger & Brennan, 2010:225), reduced systemic side effects (Colin Long, 2002:41), convenience of application and improved patient compliance (Cleary, 1993:19; Prausnitz & Langer, 2008:1261). An approach that is often applied in optimising the solubility and dissolution rate of poorly water soluble, weak electrolytes is to prepare a salt of the active pharmaceutical ingredient (API) (Minghetti et al., 2007:815; O’Connor & Corrigan, 2001:281-282). Diclofenac is frequently administered as a salt, due to the high partition coefficient and very low water solubility of this molecule (Fini et al., 1999:164). Formulating for efficacy (FFETM) is a software programme designed by JW Solutions to facilitate the formulation of cosmetic ingredients or solvents into a product that would optimally deliver active ingredients into the skin. The notion is built upon solubility, i.e. solubility of the active ingredient in the formulation and solubility of the formulation in the skin. This programme could also be employed to optimise amounts of predetermined ingredients, to propose formulations that would ensure optimal drug delivery, to calculate the skin delivery gap (SDG) and to demonstrate transdermal permeation of active ingredients and excipients (JW Solutions Software, 2013a). When the SDG is known, it mathematically indicates the optimal active ingredient and topical delivery vehicle to use (JW Solutions, 2013b). In this study, diclofenac sodium (DNa), diclofenac diethylamine (DDEA) and diclofenac N-(2- hydroxyethyl) pyrrolidine (DHEP) were each formulated in the following emulgels: * An emulgel optimised towards the stratum corneum (SC) (enhancing drug delivery into this layer and deeper tissues) (oily phase ~30%), * A more hydrophilic emulgel (oily phase ~15%), and * A more lipophilic emulgel (oily phase ~45%). Components of the oily phase and its respective amounts, as well as the SDG of formulations were determined by utilising the FFETM software of JW Solutions (2013a). The aqueous solubilities of DNa, DDEA and DHEP were determined and their respective values were 11.4 mg/ml, 8.0 mg/ml and 11.9 mg/ml, all indicative of effortless percutaneous delivery (Naik et al., 2000:319). Log D (octanol-buffer distribution coefficient) (pH 7.4) determinations for DNa, DDEA and DHEP were performed and their values established at 1.270 (DNa), 1.291 (DDEA) and 1.285 (DHEP). According to these values, diclofenac, when topically applied as a salt in a suitable vehicle, should permeate transdermally without the aid of radical intervention (Naik et al., 2000:319; Walters, 2007:1312). Membrane release studies were also carried out in order to determine the rate of API release from these new formulations. Results confirmed that diclofenac was indeed released from all nine of the formulated emulgels. The more hydrophilic DNa formulation released the highest average percentage of diclofenac (8.38%) after 6 hours. Subsequent transdermal diffusion studies were performed to determine the diclofenac concentration that permeated the skin. The more hydrophilic DNa emulgel showed the highest average percentage skin diffusion (0.09%) after 12 hours, as well as the highest average flux (1.42 ± 0.20 μg/cm2.h). The concentrations of diclofenac in the SC-epidermis (SCE) and epidermis-dermis (ED) were determined through tape stripping experiments. The more lipophilic DNa emulgel demonstrated the highest average concentration (0.27 μg/ml) in the ED, while the DNa emulgel that had been optimised towards the SC, had the highest concentration in the SCE (0.77 μg/ml). / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Made available in DSpace on 2014-06-11T19:30:54Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-07-13Bitstream added on 2014-06-13T20:01:03Z : No. of bitstreams: 1 broggiocosta_st_dr_sjrp.pdf: 4201433 bytes, checksum: 2214bf546b6f30fd6a4412a471fab1f8 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Os Mastoparanos são peptídeos curtos e catiônicos extraídos do veneno de vespas. Estes peptídeos dependem de sua seqüência primária, composição, hidrofobicidade, ângulo polar, anfipaticidade e amidação do C-terminal para apresentar diferentes atividades biológicas. A conformação em hélice anfipática parece ser fundamental para interação destes peptídeos com a bicamada membranar. Neste trabalho buscamos as correlações destas características com as atividades antimicrobianas e hemolíticas apresentadas por três mastoparanos conhecidos, usando simulações por dinâmica molecular em misturas de TFE-água. Misturas de TFE-água apresentam um caráter hidrofóbico e hidrofílico assim como o ambiente membranar. Um dos peptídeos estudados é o Eumenine Mastoparano-AF (EMP-AF), no qual constatamos que a desamidação do C-terminal acarretou na desestruturação da conformação helicoidal e na perda da anfipaticidade nesta região, devido à atração eletrostática entre a carga negativa do grupo carboxila e os grupos catiônicos das cadeias laterais de alguns resíduos. Por esse fato a atividade hemolítica é perdida. Outro peptídeo investigado é o Paulista-MPI, para o qual propomos como estrutura estável uma hélice-.. anfipática. Para este caso, também exploramos as razões da existência de atividade antimicrobiana e ausência da atividade hemolítica. O outro peptídeo estudado foi o Anoplin com e sem o grupo amida do C-terminal. O Anoplin natural, Anoplin-NH2 é um peptídeo antimicrobiano. Novamente esta atividade pode ser associada com sua estrutura helicoidal anfipática que se apresenta estável por fatores como o equilíbrio eletrostático entre os grupos carregados das cadeias laterais; pela predominância dos grupos apolares das moléculas de TFE na região dos átomos eletronegativos da cadeia principal; e pela solvatação da cadeia lateral... / Mastoparans is a class of peptides extracted from wasp venom, named after their first recognized biological action, the degranulation of mast cells. They are short and cationic peptides that depending on their primary sequence, degree of charge and amidation of Cterminal present different biological activities. Fundamental for their interactions with biological membranes seems to be an amphipatic helix conformation. In this work we search for correlations among these characteristics and the antimicrobial and hemolytic activities of three known mastoparans, using molecular dynamics simulation in TFEwater mixtures. TFE-water media shows both hydrophobic and hydrophilic character and in this way mimics a membrane-like environment. The peptides studied are the Eumenine Mastoparan (EMP-AF), for which the desamidation of the C-terminal leads to the lost of the helix conformation and amphipaticity at this region, due to the electrostatic attraction among the negative charge of carboxylate group and the cationic groups of the lateral chain of some residues. Consequently the hemolytic activity is lost. Another peptide studied is Paulista-MPI, for which an amphipatic ..-helix is proposed as a stable structure. We rationalize also the reasons for its antimicrobial activities and the absence of hemolytic activity. The last peptide studied is Anoplin, the C-terminal amidated wild type and its carboxylated analog. The former type, Anoplin-NH2, is an antimicrobial and nonhemolytic peptide. Again this can be associated to the amphipatic helical structure, that we show is maintained by factors as the electrostatic equilibrium between charged groups, predominance of apolar groups of TFE molecules around the electronegative atoms of the main chain and solvation of lateral side chains. Deamidation of C-terminal, rendering Anoplin-OH, abolishes its antimicrobial activity due to the unfolding of the helix terminal... (Complete abstract, click electronic address below

The objective of the proposed research is to realize a 10-Gb/sec serial data link over band-limited channels, such as backplanes, multi-mode fiber, and copper-based cables that were originally designed for data rates less than 1Gb/sec. This is achieved using electrical equalization implemented in an integrated circuit (IC). To successfully compensate for various band-limited channels at the targeted data rate with a single equalizer IC, a reconfigurable equalizer topology is proposed. In order to realize the proposed goal, various channels are characterized of their forward transmission frequency response. Based on the measured channel data, system simulations are performed to identify the required specifications for IC implementation. This provides information such as optimal number of taps, fractionally-spaced tap delay, and tap coefficients for the proposed IC. With the obtained system requirements, IC building blocks are designed and fabricated in a 0.18- and #956;m CMOS technology. The fully-integrated reconfigurable CMOS equalizer provides a single-chip solution for compensating various band-limited channels. This enables 10-Gb/sec serial data transmission achieving signal integrity beyond their designed specifications.

Background: It is argued that most of the new product do not fail in the end but it fails in the beginning of the innovation. Managing front end of NPD, is the most important and difficult challenges facing the innovation managers. Effectively promoting front end activities can contribute directly to the success of the new product. So, integrating market-based partners (suppliers and customers) in the front-end phase enhances the quantity and quality of ideas. Problem discussion: Authors have suggested the involvement of market-based partners as early as possible in the NPD process will reduce the fuzziness in front end phase. The collaboration process with market-based partners implies that combining the idiosyncratic resources in unique ways, firms would relish greater innovation success. But this process of integration or collaboration with market-based partners are not that easy as it entails different appropriation and coordination concerns. Majority of the literature is concentrated on integrating market-based partners in the back-end activities of NPD, leaving a bit of void in the front-end phase of NPD. Method: The methodological choice of this thesis follows an exploratory study to seek new insights into an existing subject. The thesis is a following a deductive approach and is qualitative in the research choice. Purpose: To provide insights on integrating market-based partners in the front-end phase of new product development where the information is scattered around. This thesis identifies a structure that facilitates the integration of market-based partners in the fuzzy front end of NPD to mitigate the appropriation concerns and challenges.

Made available in DSpace on 2015-04-14T13:55:02Z (GMT). No. of bitstreams: 1 419772.pdf: 577605 bytes, checksum: 2e838d9686c1eb2d03dec4db04d1e570 (MD5) Previous issue date: 2009-11-30 / Com o surgimento da comunica??o em n?vel global, os seres humanos encontramse ligados como nunca antes na hist?ria da humanidade. Em meio ao que convencionamos denominar de Globaliza??o, a racionalidade humana recebe novos desafios que se perfilaram com o desenrolar hist?rico. Frente a estes novos desafios, os antigos paradigmas da racionalidade ocidental, bem como nossa organiza??o social tentam configurar-se com sa?das que respeitem as conquistas anteriores tais como a condena??o da escravid?o e os direitos humanos e, ao mesmo tempo, criem solu??es para graves problemas como os de cunho ambiental e da satisfa??o das necessidades sejam elas econ?micas ou morais da comunidade globalizada. Para tanto, baseado no ideal Kantiano de uma Paz Perp?tua onde os povos, al?m de adotarem um modelo republicano, ainda viveriam em harmonia com as demais republicas, Otrified H?ffe, prop?em a forma??o de uma Republica Mundial ?nica. Respeitando a diversidade e os Estados nacionais j? existentes, garanta o cumprimento de normas ambientais e dos direitos humanos. Tal rep?blica remonta sua legitima??o frente a uma nova forma de teoriza??o sobre o estado, que n?o busca mais suas especifica??es apenas no conflito ou apenas na coopera??o, mas em uma nova forma de fundamenta??o: a troca. H?ffe n?o mais embasa a legitima??o sob pontos de vistas que se polarizam entre um altru?smo ou um ego?smo, mas em trocas rec?procas que garantam determinados objetivos. Tal mudan?a ? acompanhada pela proposta de uma mudan?a no paradigma racional, que agora visa uma comunica??o ?tica. Onde um sistema ou a burocracia estatal deve manter-se afastada de um mundo da vida, de cada sujeito, proporcionando de forma ?tica a conviv?ncia de todos os seres humanos. Em sua teoria de agir comunicativo, Habermas apresenta tal prot?tipo, relegando uma importante contribui??o para filosofia. No presente trabalho, ap?s uma apresenta??o detalhada de ambas as propostas, ser? proposta um debate entre as id?ias de ambos os autores, a fim de proporcionar uma nova vis?o sobre a possibilidade da cria??o de uma Rep?blica Mundial Subsidi?ria, de tal forma que a import?ncia de tal discuss?o se apresenta no mesmo grau da inova??o para uma Rep?blica Mundial Subsidi?ria, que, por sua vez, se efetivada, tocar? na vida cotidiana de cada um dos sujeitos do mundo.

Made available in DSpace on 2015-04-14T13:55:05Z (GMT). No. of bitstreams: 1 381798.pdf: 779651 bytes, checksum: 633bf7bb2a84c779b838c5ebff04fec5 (MD5) Previous issue date: 2006-08-29 / A tese, Paz e Rep?blica Mundial: de Kant a H?ffe, como o pr?prio t?tulo j? denuncia, est? centrada no estudo do modelo kantiano de paz mundial e que serve de base para o projeto de uma Rep?blica Mundial, elaborado pelo fil?sofo alem?o contempor?neo Otfried H?ffe. Na concep??o kantiana, a paz perp?tua repousa no campo do direito e ?, conseq?entemente, uma miss?o jur?dica. Os homens t?m o dever de abandonar o estado de natureza e ingressar num estado civil marcado pelo direito e capaz de garantir a paz e a seguran?a entre eles. Uma vez ingresso no estado civil, Kant reclama dos Estados uma constitui??o republicana por compreend?-la como a que melhor atende ao preceito de se alcan?ar a paz entre os homens. Assim, a primeira parte do trabalho tem como escopo analisar a teoria contratualista kantiana, os argumentos apresentados na defesa de um Estado republicano e na sua representa??o para uma efetiva e eficaz promo??o da paz. Sustentamos que os princ?pios republicanos, que hodiernamente podem ser traduzidos como democr?ticos, permanecem defens?veis. De forma an?loga aos indiv?duos, Kant tamb?m exige que os Estados regulem suas a??es pelo direito e sugere a uni?o dos mesmos em torno de uma federa??o de Estados livres. Defendemos, no entanto, que essa federa??o corresponde a um suced?neo negativo e, como tal, tem um car?ter provis?rio que deve ser suplantado com a gradativa implanta??o de um Estado Mundial. Essa tese encontra respaldo nos pr?prios argumentos kantianos, que procuraremos demonstrar na segunda parte do trabalho. Kant d? margem para o entendimento de que os Estados, segundo a raz?o, tamb?m devem consentir em se submeter ?s leis p?blicas coativas e materializar a id?ia positiva de uma rep?blica mundial. A partir do entendimento acima referido, analisaremos, na terceira parte do trabalho, a proposta de um Estado Mundial elaborado por Otfried H?ffe. Para dar forma ao preceito kantiano de paz mundial, H?ffe defende que os Estados tamb?m devem se submeter a uma organiza??o internacional, com poder de coa??o, e sugere a cria??o de uma Rep?blica Mundial, que, na nossa vis?o, al?m de ser condizente com a racionalidade kantiana, tamb?m ? defens?vel e apropriada para enfrentar problemas do mundo contempor?neo.

This research investigates the key characteristics of design leaders in the context of New Product Development (NPD) at the Fuzzy Front End (FFE) or early stage of this process. It particularly focuses on how design leaders communicate design to non-designers. It is often observed that designers struggle to communicate design to non-designers. Previous research has identified design leaders as competent design communicators. However, the definition and key characteristics of design leaders remain unclear. By reviewing the literature on leadership studies, design leadership and project leadership, it is evident that no single universal definition of leadership exists. The most common definition is that leaders apply their knowledge and skills to conduct activities and use their traits to influence other people’s actions. Leadership requires different characteristics for different tasks. To understand the characteristics of design leaders, triangulated research was employed at a real-life NPD project involving young designers and non-designers at early stages of NPD as part of the first study. All participants (N=32) were directly observed, interviewed in semi-structured interviews and administered with assistive questionnaires to compare design and non-design participants’ leadership and communication styles. The second study was in-depth, focusing on UK design leaders (N=11) through semi-structured interviews and based on deficiencies in leadership and communicating design, identified from the first study and the literature review. Comparative studies indicate that designers and design leaders vary their attitudes towards non-designers, motivation and communication style. This study highlights the key characteristics of design leaders: an epiphany by experiencing the entire NPD process, interest in the benefits of NPD stakeholders, a good understanding of design competency, reflectively flexible working attitude and strong, active listening. Thus, a conceptual model was formulated and evaluated, able to guide designers who wish to become design leaders and help to enhance design communication and relationships with non-designers.

Ces travaux de recherche ont consisté à mettre au point un nouveau prototype compact et miniaturisé d'instrument de mesure basée sur la technique de Fluorescence par Faisceau d'Electrons (FFE). Cet instrument est un canon à électrons destiné à la caractérisation d'écoulements hypersoniques à basses densités en vol à bord de démonstrateurs de rentrée atmosphérique. Les paramètres à mesurer sont les températures de rotation (TR), de vibration (TV) et les densités d'espèces telles que N2 et NO pour une rentrée atmosphérique terrestre et N2, CO, CO2 pour une rentrée atmosphérique martienne. La première partie de cette étude a été consacrée à la conception du prototype de canon à électrons destiné à des mesures embarquées. Nous avons ainsi choisi les différents composants avec des spécifications techniques compatibles avec un cahier des charges typique d'un instrument spatial. Les tests de qualification et de stabilité du faisceau d'électrons ont été réalisés en caisson à vide dans un gaz statique, ce qui a permis une première validation du fonctionnement du canon à électrons de 20 keV avec un courant de faisceau de 1 mA se propageant sur une distance de 30 cm avec peu de dispersion pour des pressions inférieures au millibar. Le prototype a été testé sur différents gaz et mélanges afin de mettre au point un modèle de dispersion. Deux campagnes de mesures en soufflerie aérodynamique (CNRS MARHy et ONERA F4) ont permis de valider le bon fonctionnement du prototype sous vide et/ ou en conditions d'écoulement libre et en présence d'une onde de choc. Une analyse spectroscopique a permis de valider les codes de simulation et d'inversion de spectres et d'identifier la majeure partie des systèmes vibrationnels et rotationnels issus des transitions électroniques, vibrationnelles et rotationnelles de N2, CO et CO2 et des espèces ionisées associées.

Ce document synthétise mes actions de recherches dans la métrologie optique pour l'hypersonique à haute enthalpie rencontré lors d'une rentrée atmosphérique. Je présente en début de ce document la problématique de la rentrée atmosphérique dont la maîtrise est primordiale pour le retour sur Terre d'un vol habité ou d'une sonde de retour d'échantillons. Je décris ensuite les moyens de mesures servant à caractériser le gaz en écoulement autour d'un véhicule de rentrée en test dans une soufflerie ou en vol de démonstration. En particulier les moyens d'optique linéaire que sont la fluorescence induite par faisceau d'électrons (FFE) ou par laser, la spectroscopie d'absorption ou d'émission et le LIDAR à diffusion Rayleigh.