Thesis (doctoral)--University of Uppsala, 1980. / Includes bibliographical references (p. 41-50).

Pancreatic cancer (PC) is known to be highly resistant to chemotherapy. Transporters, which regulate the influx and efflux of substrates across the plasma membrane, may play a role in PC drug resistance. ABC transporters are a large family of transmembrane proteins with diverse physiological functions, several of which play major roles in cancer drug resistance. Given that 90% of PC express a mutant K-ras oncogene and that PC are highly hypoxic, I postulated that constitutive K-ras activation and/or hypoxia may correlate with ABC transporter expression, which in turn may promote drug resistance in PC. Using normal and PC cell lines either overexpressing mutant K-ras or subjected to hypoxic treatment, mRNA expression was profiled for 48 ABC transporters. My findings indicate that expression of mutant K-ras and hypoxic treatment, as well as long-term exposure to chemotherapy, may contribute to the development of drug resistance in PC cells in part by inducing the expression of ABC transporters. Similar to ABC transporters, I investigated whether amino acid transporters would mediate drug resistance in PC. The xc" amino acid transporter (xc") mediates cellular uptake of cystine for the biosynthesis of glutathione, a major detoxifying agent. Because the xc" has been regulates the growth of various cancer cell types, and x," is expressed in the pancreas, I postulated that the xc" may be involved in growth and drug resistance in PC. The xc" transporter is differentially expressed in normal pancreatic tissues and is overexpressed in PC in vivo. UsingPC cell lines, I found that cystine uptake via the N.: was required for growth and survival in response to oxidative stress, and that expression of the xc" correlated with gemcitabine resistance. Accordingly, inhibition of xc" expression via siRNA reduced PC cell proliferation and restored sensitivity to gemcitabine. I also identified the anti-inflammatory drug sulfasalazine as a mixed inhibitor of the x,-, which acts to inhibit cell proliferation via reducing xc" activity and not by reducing NFKB activity. My findings thus indicate that the xc" plays a role in PC growth in part by contributing to glutathione synthesis to promote PC cell proliferation, survival, and drug resistance.

Magister Pharmaceuticae - MPharm / The objective was to prepare new solid phases, i.e. co-crystal forms, of two sulfa antibiotic drugs (sulfamethoxazole and sulfasalazine) with trimethoprim and fourteen potential co-formers with GRAS status. Trimethoprim was chosen for its synergistic effects with both sulfa drugs and the other co-formers were selected in an attempt to improve the physicochemical properties of the antibiotics. A variety of co-crystallization techniques, including solvent assisted grinding, slow evaporation, slurry method and solidification of the melt were used to obtain these results. From these methods, three new solid phases were successfully isolated for the sulfamethoxazole antibiotic, viz. sulfamethoxazole-benzoic anhydride (SMZ-BAN) co-crystal by the slurry method, amorphous sulfamethoxazole-trimethoprim (SMZ-TMP) form by solidification of the melt and amorphous sulfamethoxazole-oxalic acid (SMZ-OA) by slow evaporation. For the sulfasalazine antibiotic, co-crystallization experimentation produced, sulfasalazine-trimethoprim salt (SSZ-TMPs) by slow evaporation, sulfasalazine-trimethoprim co-crystal (SSZ-TMP) by solvent assisted grinding and sulfasalazine-nicotinamide co-crystal (SSZ-NC) by solidification of the melt. Of these six compounds subjected to single crystal X-ray analysis, only one of their structures was elucidated i.e. the salt, SSZ-TMPs. Different techniques that were used to assess the thermal behaviour of the products included hot stage microscopy, differential scanning calorimetry and thermogravimetric analysis. FTIR provided information on the purity of the compounds and the suggested host-guest interaction sites. X-ray powder diffraction supported the determination of the new phase comparative to the parent compounds. Finally dissolution testing was carried out for successful candidates with encouraging recommendations for future work.

No description available.

<p>Breast cancers are the most common source of metastases to bone of which cancer-induced bone pain is a frequent pathological feature. Cancer-induced bone pain is a unique pain state with a multiplicity of determinants that remains to be well understood and managed. Current standard treatments are limited by dose-dependent side effects that can depress the quality of life of patients. Glutamate is a neurotransmitter and bone cell-signalling molecule that has been found to be released <em>via</em> the system x_C^-cystine/glutamate antiporter on cancer cells of types that frequently metastasize to bone, including breast cancers. This project examines the hypothesis that limiting glutamate release from cancer cells metastasized to bone will reduce bone tissue disruption and cancer-induced bone pain. A mouse model of cancer-induced bone pain was established with intrafemoral human breast cancer cells (MDA-MB-231), and behavioural measurements were taken for weight bearing and induced paw withdrawal thresholds. The system x_C^- inhibitors sulfasalazine and (S)-4-carboxyphenylglycine both attenuated glutamate release from cancer cells in a dose-dependent manner <em>in vitro</em>. Treatment with sulfasalazine induced a moderate delay in the onset of behavioural indicators of pain in mouse models, and treatment with (S)-4-carboxyphenylglycine had no apparent results. This data suggests that the limitation of extracellular glutamate released from cancers in bone with sulfasalazine may provide some alleviation of the often severe and intractable pain associated with bone metastases.</p> / Master of Science (MSc)

INTRODUÇÃO: A Artrite Reumatóide (AR) é caracterizada pelo aspecto inflamatório crônico articular e é a doença autoimune mais comum em todo o mundo. A categoria de medicamentos modificadores do curso da doença (MMCD) é dividido em dois grupos, sintéticos e biológicos. Há controversos estudos em relação a comparação entre estas alternativas, principalmente, devido ao elevado custo dos biológicos. O objetivo deste estudo foi realizar uma avaliação econômica do tratamento da AR, comparando a terapia combinada de MMCD sintéticos versus MMCD biológicos, utilizando de dados da literatura e de custo na perspectiva do SUS. MÉTODOS: Foi realizado uma revisão sistemática com metanálise das bases Medline e Embase os ensaios clínicos randomizados(ECR) que fizeram comparação direta entre o uso de MMCD sintéticos versus os MMCD biológicos. A remissão foi considerada para DAS28 < 2,6. Os itens que compõe o custo seguiram a diretrizes do Ministério da Saúde do Brasil e os valores foram recuperados da tabela do Sistema de Informação Ambulatorial do SUS, e do Sistema de Gerenciamento da Tabela de Procedimentos, Medicamentos e OPM do SUS, dados do ano 2016/2017. RESULTADOS: Foram incluídos 6 ECR. No seguimento de até 6 meses o RR=0,70 (IC95% 0,57 a 0,85) a favor dos biológicos. No seguimento entre 12 a 24 meses não houve diferença estatisticamente significante, RR=0,91 (IC95% 0,80 a 1,05). Um ano do tratamento com MMCDs combinado custa R$2445,60 e os Anti-TNF custa R$ 52.821,57. CONCLUSÃO: A remissão da atividade clínica da AR pode ser obtida pelo uso de DMARD sintéticos ou por Agentes Biológicos. Análise de custo-minimização mostrou que uma economia substancial a cada mês evitado de uso dos MMCD biológicos / INTRODUCTION: Rheumatoid arthritis (RA) is the most common autoimmune disease in the world, which leads to a chronic joint inflammation. There are two types of disease-modifying anti-rheumatic drugs (DMARD): synthetical and biological. The comparison between both drugs is controversial, mostly because of the high cost of the biological ones. The aim of this study was to develop an economic evaluation of RA treatments, comparing combined therapy with synthetic DMARD versus biological DMARD, based on literature review and cost analysis on SUS data. METHODS: Systematic review with meta-analysis of randomized clinical trials (RCT) was conducted on Medline and Embase database about direct comparisons of synthetic DMARD and biological DMARD. Remission was set for DAS28 < 2.6. Cost analysis was based on the guidelines of the Brazilian Ministry of Health and cost values were extracted from the SUS\'s Ambulatory Information System table, Management System of Procedures Table, and Medicine and OPM table, for 2016/2017. RESULTS: Six RCT were included. For six months follow-up, RR=0.70 (IC95% 0.57 to 0.85) in favour of biologicals. For 12-24 months follow-up, both DMARD were similar, RR=0.91 (IC95% 0.80 to 1.05). One-year treatment with DMARD costs R$2445,60 e Anti-TNF costs R$ 52.821,57. CONCLUSION: Remission of clinical activity of RA can be reached with synthetic or biologic DMARD. Minimizing-cost analysis showed a monthly expressive saving avoinding the biologic DMARD

INTRODUÇÃO: A Artrite Reumatóide (AR) é caracterizada pelo aspecto inflamatório crônico articular e é a doença autoimune mais comum em todo o mundo. A categoria de medicamentos modificadores do curso da doença (MMCD) é dividido em dois grupos, sintéticos e biológicos. Há controversos estudos em relação a comparação entre estas alternativas, principalmente, devido ao elevado custo dos biológicos. O objetivo deste estudo foi realizar uma avaliação econômica do tratamento da AR, comparando a terapia combinada de MMCD sintéticos versus MMCD biológicos, utilizando de dados da literatura e de custo na perspectiva do SUS. MÉTODOS: Foi realizado uma revisão sistemática com metanálise das bases Medline e Embase os ensaios clínicos randomizados(ECR) que fizeram comparação direta entre o uso de MMCD sintéticos versus os MMCD biológicos. A remissão foi considerada para DAS28 < 2,6. Os itens que compõe o custo seguiram a diretrizes do Ministério da Saúde do Brasil e os valores foram recuperados da tabela do Sistema de Informação Ambulatorial do SUS, e do Sistema de Gerenciamento da Tabela de Procedimentos, Medicamentos e OPM do SUS, dados do ano 2016/2017. RESULTADOS: Foram incluídos 6 ECR. No seguimento de até 6 meses o RR=0,70 (IC95% 0,57 a 0,85) a favor dos biológicos. No seguimento entre 12 a 24 meses não houve diferença estatisticamente significante, RR=0,91 (IC95% 0,80 a 1,05). Um ano do tratamento com MMCDs combinado custa R$2445,60 e os Anti-TNF custa R$ 52.821,57. CONCLUSÃO: A remissão da atividade clínica da AR pode ser obtida pelo uso de DMARD sintéticos ou por Agentes Biológicos. Análise de custo-minimização mostrou que uma economia substancial a cada mês evitado de uso dos MMCD biológicos / INTRODUCTION: Rheumatoid arthritis (RA) is the most common autoimmune disease in the world, which leads to a chronic joint inflammation. There are two types of disease-modifying anti-rheumatic drugs (DMARD): synthetical and biological. The comparison between both drugs is controversial, mostly because of the high cost of the biological ones. The aim of this study was to develop an economic evaluation of RA treatments, comparing combined therapy with synthetic DMARD versus biological DMARD, based on literature review and cost analysis on SUS data. METHODS: Systematic review with meta-analysis of randomized clinical trials (RCT) was conducted on Medline and Embase database about direct comparisons of synthetic DMARD and biological DMARD. Remission was set for DAS28 < 2.6. Cost analysis was based on the guidelines of the Brazilian Ministry of Health and cost values were extracted from the SUS\'s Ambulatory Information System table, Management System of Procedures Table, and Medicine and OPM table, for 2016/2017. RESULTS: Six RCT were included. For six months follow-up, RR=0.70 (IC95% 0.57 to 0.85) in favour of biologicals. For 12-24 months follow-up, both DMARD were similar, RR=0.91 (IC95% 0.80 to 1.05). One-year treatment with DMARD costs R$2445,60 e Anti-TNF costs R$ 52.821,57. CONCLUSION: Remission of clinical activity of RA can be reached with synthetic or biologic DMARD. Minimizing-cost analysis showed a monthly expressive saving avoinding the biologic DMARD