Digitized by Kansas Correctional Industries

In the development of new medicinal products, poor oral bioavailability, due to the low solubilities of many active pharmaceutical ingredients (APIs), is increasingly a barrier for treatments to be administered using tablet or capsule formulations and one of the main challenges facing the pharmaceutical industry. Non-crystalline phases such as the amorphous and nanostructured states can confer increased solubility to a drug, and therefore, have recently garnered a lot of interest from pharmaceutical researchers. However, little is known about local ordering in non-crystalline pharmaceuticals due to the lack of reliable experimental probes, hindering the clinical application of these compounds. The powerful tools of crystallography begin to lose their potency for structures on the nanoscale; conventional X-ray powder diffraction (XRPD) patterns become broad and featureless in these cases and are not useful for differentiating between different local molecular packing arrangements. In this thesis, we introduce the use of high energy X-rays coupled with total scattering pair distribution function (TSPDF) and fingerprinting analysis to investigate the local structures of non-crystalline pharmaceutical compounds. The high energy X-rays allow us to experimentally collect diffuse scattering intensities, which contain information about a sample's local ordering, in addition to the Bragg scattering available in conventional XRPD experiments, while the TSPDF allows us to view the intra- and inter-molecular correlations in real space. The goal of this study was to address some fundamental problems involving fingerprinting non-crystalline APIs using TSPDF in order to lay the groundwork for the proper use of the technique by the pharmaceutical community. We achieved this by developing the methodology as well as the exploring the scientific implications. On the methodology side, we introduced PDFGetX3, a new software program for calculating TSPDFs that simplifies the procedure and reduces user interaction. We also set a baseline for the minimum X-ray energy that is needed for fingerprinting analysis, which had implications on the type of X-ray diffractometers that can be used. On the science side, we investigated the local structures of nanocrystalline and amorphous materials as well mixtures containing crystalline and amorphous phases. First, we identified a non-crystalline sample of the mood-stabilizing drug carbamazepine as a nanocrystalline version of one of its polymorphs. Next, we found that amorphous forms created by spray drying and cryomilling a proprietary compound have the same local structure. Finally, we quantified the phase fractions of polymorphic and amorphous components in a sample of the antibiotic sulfamerazine that was recrystallizing from a cryomilling-induced amorphous state.

Foram desenvolvidas formulações de comprimidos do tipo matriz hidrofílica, contendo hidroxipropilmetil celulose, visando a liberação prolongada de rifampicina e isoniazida. Estudos de biodisponibilidade avaliaram a influência do pH do meio de dissolução da acidificação e alcalinização da matriz da modificação de porosidade e tortuosidade; das técnicas de preparação e da razão fármaco-agente formador da matriz. Os métodos de otimização e de estudos de correlação envolveram um plano experimental com quatro variáveis independentes e cinco níveis para cada uma. Para cada característica analisada foi construída uma equação, por regressão múltipla e a influência de cada variável independente foi analisada através de curvas isoresposta. / It was developed cellulose hidrophilic matrices, in order to provid a controlled release of isoniazid and rifampicin, anti-tuberculosis agents. The study of bioavailability brings to light the influence of the pH of the dissolution medium; of the acidification and alkalinization of the die; of the porosity and tortuosity of the production technic and of the drug-matrix raio. The optimization methods and correlational studies envolved an experimental plan with four independent variable and levels per variable. For each response variable, a multiple regression equation is established and the influence of each independent variable is identified by plotting combined and isoresponse curves.

Dysmenorrhoea, defined as cramping pain in the lower abdomen occurring during menstruation, is known to affect up to 90% of women of childbearing age to varying degrees. The underlying causes of this condition are believed to be due to a number of factors, but are mainly attributed to increased myometrial activity, increased prostaglandin production and hormonal influences. Although there are pharmaceutical treatments available, they mainly concentrate on symptomatic relief, with the main treatment being the use of non-steroidal anti-inflammatory drugs (NSAIDs) to directly relieve the pain. Other treatments include the use of the combined oral contraceptives which are believed to influence myometrial contractility via regulation of hormonal activity. However due to the gastric and contraceptive side effects of these treatments respectively, other alternative treatments are becoming increasingly popular. One such treatment is the use of Bak foong pills (BFP), a traditional Chinese medicine used in China for the treatment of various gynaecological disorders including primary dysmenorrhoea. The aims of the current project were therefore to highlight the major beneficial effects of BFP and attempt to elucidate its major mechanisms of action in treating dysmenorrhoea. / The study demonstrated that BFP's anti-dysmenorrhoeal properties were due to a combination of hormonal, myometrial relaxant and analgesic effects. Treatment of mice with BFP caused an estrogen-like effects as demonstrated with increased cystic fibrosis transmembrane conductance regulator (CFTR) mRNA expression. Furthermore, serum estrogen and progesterone levels were also elevated in BFP treated rats. BFP was also able to significantly reduce myometrial contractions, indicating that BFP's anti-dysmenorrhoeal effect may be aided by reduced contractility of the myometrium following treatment. The uterine relaxation caused by BFP was not dependant on increases in nitric oxide or cAMP, but appeared to affect calcium mobilization. Investigation of the analgesic effect of BFP, assessed using a visceral pain model in mice showed that following sub-chronic (72 hour) treatment with BFP, there was a significant reduction in pain response, demonstrating that BFP had direct analgesic effect. (Abstract shortened by UMI.) / Rowlands Dewi Kenneth. / "July 2005." / Adviser: Hsiao Chang Chan. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3533. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 148-165). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

Orientador: Maria Palmira Daflon Gremião / Banca: Raul Cesar Evangelista / Banca: Leila Aparecida Chiavacci / Banca: Célio Lopes Silva / Banca: Marco Vinícius Chaud / Resumo: A zidovudina (AZT) é um fármaco amplamente usado no tratamento da síndrome da imunodeficiência adquirida. O AZT apresenta baixa biodisponibilidade oral pois sofre rápido e extenso metabolismo de primeira passagem hepática, além de curto t1/2. Sendo assim, altas e freqüentes doses são requeridas para se manter concentrações plasmáticas efetivas e, dessa maneira, apresenta graves efeitos colaterais, dose-dependentes, que limitam o seu uso em determinados tipos de pacientes. As nanopartículas são eficientes sistemas poliméricos que contribuem para a redução da toxicidade de fármacos, pois são capazes de liberá-los de maneira prolongada, proporcionando maior tempo de contato do fármaco com o plasma e tecidos. A via de administração intranasal é uma rota interessante, quando se deseja evitar o metabolismo de primeira passagem e, também, pode oferecer um ótimo perfil de absorção para nanopartículas. Neste trabalho, estudouse a incorporação de AZT em nanopartículas de PLA e de blendas de PLA-PEG com diferentes razões molares. A caracterização físico-química demonstrou que a presença do PEG influenciou a forma, o diâmetro médio, a eficiência de encapsulação, assim como o potencial de superfície das partículas. O diâmetro médio e a eficiência de encapsulação das nanopartículas aumentaram com o aumento crescente da razão molar de PEG na blenda. A forma geral e a apresentação das partículas variaram em função da concentração de PEG, sendo que os melhores resultados foram obtidos com as menores razões molares deste na blenda. Os experimentos de liberação in vitro mostraram que a liberação do AZT a partir das nanopartículas foi mais lenta em relação ao AZT em solução. A presença do PEG nas nanopartículas alterou o perfil de liberação do AZT, tornando...(Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Zidovudine (AZT) is a drug widely used in the treatment of acquired immunodeficiency syndrome. AZT shows low bioavailability because it suffers fast and extensive by pass hepatic metabolism, besides of low t1/2. High and frequent doses are requested to achieve effective plasmatic concentrations, and thus, it shows serious and dosedependents side effects that limit its use in certain kind of patients. Nanoparticles are efficient polymeric systems that contributes to reduce the drug toxicity, because maintain prolonged drug release, making longer the contact between drug and plasma/tissues. The intranasal way is a very interesting route to avoid the by pass metabolism, and also offers a great absorption profile to nanoparticles. In the present work, the AZT encapsulation in PLA e PLA-PEG blends nanoparticles was studied. The physico-chemical characterization showed that the presence of PEG influences the nanoparticles shape, mean diameter, encapsulation efficiency and superficial charge. The mean diameter and encapsulation efficiency increase with increasing PEG proportion in the blend. The nanoparticles shape varied in function of PEG concentration, the better results being obtained with the lowest PEG concentration. In vitro experiments showed that AZT release from nanoparticles was slower than that of AZT solution. The presence of PEG in nanoparticles altered the AZT release profile, making it faster than that from PLA nanoparticles. The ex vivo phagocytosis experiments demonstrated that PLA-PEG blends nanoparticles were more efficient in avoiding the activation of phagocytic cells. The intranasal bioavailability in rats shows that blend PLA-PEG nanoparticles demonstrated longer plasmatic circulating times than that those make of PLA alone. These results demonstrate that PLA and PLA-PEG blends nanoparticles can be used as an efficient intranasal drug delivery system. / Doutor

Foram desenvolvidas formulações de comprimidos do tipo matriz hidrofílica, contendo hidroxipropilmetil celulose, visando a liberação prolongada de rifampicina e isoniazida. Estudos de biodisponibilidade avaliaram a influência do pH do meio de dissolução da acidificação e alcalinização da matriz da modificação de porosidade e tortuosidade; das técnicas de preparação e da razão fármaco-agente formador da matriz. Os métodos de otimização e de estudos de correlação envolveram um plano experimental com quatro variáveis independentes e cinco níveis para cada uma. Para cada característica analisada foi construída uma equação, por regressão múltipla e a influência de cada variável independente foi analisada através de curvas isoresposta. / It was developed cellulose hidrophilic matrices, in order to provid a controlled release of isoniazid and rifampicin, anti-tuberculosis agents. The study of bioavailability brings to light the influence of the pH of the dissolution medium; of the acidification and alkalinization of the die; of the porosity and tortuosity of the production technic and of the drug-matrix raio. The optimization methods and correlational studies envolved an experimental plan with four independent variable and levels per variable. For each response variable, a multiple regression equation is established and the influence of each independent variable is identified by plotting combined and isoresponse curves.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Allergic drug reactions account for 6.5% of hospital admissions, prolonged hospitalization 15.1% of patients and are severe in 6.7% of patients. There are difficulties in understanding the immune mechanisms, diagnosis and treatment of patients. Therefore, such reactions are considered a Public Health problem. The objective of this study was to describe the cases of patients with suspected allergic hypersensitivity to drugs and to evaluate the response of individuals to skin tests. A total of 63 patients were included in the study. The experimental design was a cross-sectional observational study from June 2008 to October 2011. We applied a questionnaire to investigate the clinical and laboratory informations. Eight patients received other diagnosis and three died due to other reasons, so that 52 patients completed the study. Most patients were men (56.36%), non atopic, with a median age of 52 year. The drugs most commonly implicated were NSAIDs and the oral administration was the most commonly route used. It was documented 69 suspected reactions; most of them were considered as delayed hipersensitivity. Maculopapular rash and erythema multiforme were the most frequent manifestations. According to the severity of the reactions, most was considered moderate (72.46%). The patch test was performed in 22 patients for investigation of delayed reaction. Seven cases were positive (31.81%), DRESS (rash with eosinophilia and systemic symptoms) caused by captopril (+), contact eczema by rifamycin (+ +), lichenoid eruption by captopril (+), maculopapular rash + ampicillin and cephalexin to angioedema (+), two cases of fotoeczema one by captopril and another by AAS, both with positive results (+) and one case of Stevens-Johnson syndrome caused by phenytoin (++). For immediate hypersensitivity, 3 in 10 patients have shown positive results for prick test with AAS diluted to 1/1000. It was possible to confirm the liability of the drug reactions in 19 (27.53%), which demonstrated the importance of application of skin tests in the clinical investigation of allergic drug reactions. As for causality, 26 reactions were considered possible, 20 defined, 13 probable, 9 and a conditional reaction was considered not related to drugs. Given its importance, the performance of skin tests with these patients has opened perspectives on the possibility to incorporate this service in routine outpatient Dermatology HUWC. / As reaÃÃes alÃrgicas medicamentosas sÃo responsÃveis por 6,5% das admissÃes hospitalares, prolongam a hospitalizaÃÃo de 15,1% dos pacientes e sÃo graves em 6,7% dos pacientes. Hà dificuldades quanto à compreensÃo dos mecanismos imunolÃgicos, diagnÃstico e tratamento dos pacientes. Portanto, tais reaÃÃes sÃo consideradas um problema de saÃde pÃblica. O objetivo deste trabalho foi descrever os casos de pacientes com suspeita de hipersensibilidade alÃrgica a fÃrmacos e avaliar a resposta desses indivÃduos aos testes cutÃneos. Um total de 63 pacientes foram incluÃdos no trabalho, cujo delineamento experimental foi de um estudo observacional descritivo transversal realizado entre junho de 2008 e outubro de 2011. Utilizou-se um questionÃrio para investigaÃÃo das informaÃÃes clÃnico-laboratoriais. Oito pacientes receberam outro diagnÃstico e trÃs foram a Ãbito por outros motivos, de forma que 52 pacientes completaram o estudo. A maioria dos pacientes era homem (56,36%), nÃo atÃpicos, com mediana de idade de 52 anos. Os fÃrmacos mais implicados foram os AINES (anti-inflamatÃrios nÃo esteroidais) e a via oral foi a mais utilizada. Foram documentadas 69 reaÃÃes suspeitas, a maioria do tipo tardia. Exantema maculopapuloso e eritema multiforme foram as manifestaÃÃes mais freqÃentes entre as reaÃÃes tardias. Quanto à gravidade, a maioria foi considerada moderada (72,46%). O teste de contato foi realizado em 22 pacientes para investigaÃÃo de reaÃÃo tardia. Em sete casos, houve resultado positivo (31,81%), ou seja, DRESS (Rash com eosinofilia e sintomas sistÃmicos) causado por captopril (+), eczema de contato por rifamicina (++), erupÃÃo liquenÃide por captopril (+), exantema maculopapuloso + angiodema para cefalexina e ampicilina (+), dois casos de fotoeczema, um por captopril e outro por Ãcido acetilsalicÃlico (AAS), ambos com resultado (+) e um caso de sÃndrome de Steven-Johnson por fenitoÃna (++). Foram realizados dez testes de puntura e em trÃs pacientes houve positividade para AAS diluÃdo a 1/1000. Foi possÃvel confirmar a imputabilidade do fÃrmaco em 19 reaÃÃes (27,53%), o que demonstra a importÃncia da aplicaÃÃo dos testes cutÃneos na investigaÃÃo clÃnica das reaÃÃes alÃrgicas a medicamentos. Quando à causalidade, 26 reaÃÃes foram consideradas possÃveis, 20 definidas, 13 provÃveis, 9 condicionais e uma reaÃÃo foi considerada nÃo relacionada com fÃrmacos. Dada a sua importÃncia, a realizaÃÃo dos testes cutÃneos com esses pacientes abriu perspectivas sobre a possibilidade incorporar esse serviÃo na rotina do ambulatÃrio de Dermatologia do HUWC.

Faculty of Arts School of Humanities 9709128f enzo@hixnet.co.za / This research report undertook an original exploration into the workings of addiction. The theoretical insights of discursive psychology were applied to the study of opiate addiction and were used to analyse the manner in which using and non-using informants were able to constitute addiction through discourse. By comparing the discursive accounts of self-defined recovered, recovering and currently addicted users, the report highlighted how ways of speaking about substances and their use may be implicated in the maintenance and cessation of addiction. The transcripts of four focus groups, consisting of a total number of 15 informants, were qualitatively analysed using a thematic method that focused on the informants’ strategic use of discourse. The analysis revealed important differences between using and non-using informants in terms of the self employed discursive practices that they used in constructing their experience of addiction. Differences included variations in the attribution of agency to either the opiate or the informant and the degree to which opiate use was presented as cause for concern or not. These and other differences were explored in detail together with their potential implications, functions and apparent effects on the users’ capacity to maintain abstinence as opposed to continuing to use.

Digitized by Kansas Correctional Industries

Pleasure Consuming Medicine investigates the significance of the classification of drugs for conceptions of personhood in the context of consumer citizenship. It examines how drug discourses operate politically to sustain particular notions of personhood and organise bodies. As the normative conception of social life shifts to a discourse of consumer agency and active citizenship, it is argued, drugs come to describe the moral boundaries of a freedom configured around personal consumption. The thesis tracks the parallel rise of two discourses of drug mis/use from the 1970s - a discourse of 'drug abuse' and a discourse of 'patient compliance' - illustrating how these discourses bind personal agency to medical authority through a vocabulary of self-administration. It describes how illicit drugs are constructed as a sign and instance of excessive conformity to consumer culture, and how this excess is opportunistically scooped off and spectacularised to stage an intense but superficial battle between the amoral market and the moral state. Pleasure Consuming Medicine uses a theoretical frame developed from queer theory, corporeal feminism, governmentality studies and cultural studies to explore the political character of drug regimes, tracing some of the ramifications for sex, race, class, and citizenship. Then it turns to the field of gay men's HIV education to conceive some alternative and provisional vocabularies of safety. The thesis develops an argument on the exercise of power in consumer society, with the aim of contributing to cultural and critical understandings of consumption, embodiment, sex, health, and citizenship.