研究所で電子化したコンテンツを使用している。

国立情報学研究所で電子化したコンテンツを使用している。

Before market authorization of new medicines, their efficacy and safety are evaluated using randomized controlled trials. While there is no doubt about the scientific value of randomized trials, they are usually conducted in selected populations with questionable generalizability to routine care.  In the digital data revolution era, with healthcare data growing at an unprecedented rate, drug monitoring in routine care is still highly under-utilized. Although many countries have access to data on prescription drugs at the individual level in ambulatory care, such data are often missing for hospitals. This is a growing problem considering the clear trend towards more new and expensive drugs administered in the hospital setting. The aim of this thesis was therefore to develop methods for extracting data on drug use from a hospital-based electronic health record system and further to build and evaluate models for real-time monitoring of effectiveness and safety of new drugs in routine care using data from electronic health records and regional and national health care registers. Using the developed techniques, we were able to demonstrate drug use and health service utilization for inflammatory bowel disease and to evaluate the comparative effectiveness and safety of antiarrhythmic drugs. With a rapidly evolving drug development, it is important to optimize the evaluation of effectiveness, safety and health economic value of new medicines in routine care. We believe that the models described in this thesis could contribute to fulfil this need.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Dronedarone is a new antiarrhythmic agent and amiodarone analogue developed to reduce the toxic effects related to amiodarone. Dronedarone was approved for the maintenance of the sinus rhythmic in adult patients with atrial fibrillation and to reduce the risk of hospitalization in these patients. It is commercially available as film-coated tablets. There are no official monographs in any pharmacopoeia or analytical methods described in the literature for the analysis of dronedarone in pharmaceutical dosage form or bulk form. In the present study, an analytical methodology was developed for the analysis of dronedarone in pharmaceutical dosage form and bulk form. The reversed-phase liquid chromatography method was performed using a Waters XBridge C18 column (250 mm × 4.6 mm). The mobile phase consisted of buffer solution pH 4.9 / acetonitrile (35:65, v/v), running at a flow rate of 1.0 mL/min, using photodiode array detector set at 289 nm. The chromatographic separation was obtained within 7.0 min and it was linear in the concentration range from 5.0 to 100.0 μg/mL (r = 0.9999). The spectrophotometric method was developed and validated and dronedarone was quantified at 289 nm, using methanol as diluent. The micellar electrokinetic method was also developed and validated, using nimesulide as internal standard. The analyses were performed on a fused-silica capillary (50 μm i.d.; effective length, 40 cm), using electrolyte solution consisted of 40 mm borate buffer and 50 mM SDS at pH 9.2, with detection by photodiode array detector set at 216 nm. The injection was performed using the hydrodynamic mode at 50 mbar for 7 s and a constant voltage of 28 kV was applied during analysis. The electrophoretic separation was obtained within 7.0 min and it was linear in the concentration range from 25 to 150 μg/mL (r = 0.9995). The procedures were validated evaluating parameters such as the specificity, linearity, precision, accuracy, limits of detection and quantitation and robustness, giving results within the acceptable range. The proposed methods were applied for the analysis of the pharmaceutical product, showing significant correlation between the results (p > 0.05). The spectrophotometric method was developed and validated using acetate buffer pH 4.5 as diluent and UV detection at 289 nm, which was applied to evaluate the dissolution test. The dissolution test was developed using 900 mL of acetate buffer pH 4.5 at 37°C, as dissolution medium, and paddle as apparatus at a stirring rate of 75 rpm. / A dronedarona é um novo agente antiarrítmico análogo à amiodarona, desenvolvido com o propósito de reduzir os efeitos adversos relacionados à amiodarona. Foi aprovado para a manutenção do ritmo cardíaco normal em pacientes com fibrilação atrial e, assim, reduzir os riscos de hospitalização. Comercialmente, encontra-se disponível na forma farmacêutica de comprimidos revestidos. Não há monografias descritas em farmacopeias ou métodos na literatura para análise de dronedarona em forma farmacêutica ou matéria-prima. No presente trabalho, foi desenvolvida metodologia para a avaliação de dronedarona em forma farmacêutica e matéria-prima. O método por cromatografia líquida em fase reversa foi realizado utilizando-se coluna Waters XBridge C18 (250 mm × 4,6 mm). A fase móvel foi composta por solução tampão pH 4,9 / acetonitrila (35:65, v/v) eluída no fluxo de 1,0 mL/min e detecção no ultravioleta em 289 nm. A separação cromatográfica foi obtida no tempo de 7,0 min, sendo linear na faixa de concentração de 5-100 μg/mL (r = 0,9999). Paralelamente, desenvolveu-se e validou-se método por espectrofotometria no ultravioleta em 289 nm utilizando metanol como diluente. Também foi desenvolvido e validado método por cromatografia eletrocinética micelar utilizando nimesulida como padrão interno. As análises foram realizadas em capilar de sílica fundida (comprimento efetivo de 40 cm e diâmetro de 50 μm), mantido a 30°C, utilizando solução eletrolítica composta de tampão borato 40 mM e SDS 50 mM, pH 9,2, com detecção no ultravioleta em 216 nm. A injeção foi realizada no modo hidrodinâmico a 50 mbar durante 7 s e voltagem constante de 28 kV foi aplicada durante as análises. A separação eletroforética foi obtida em 7,0 min, sendo linear na faixa de 25-150 μg/mL (r = 0,9995). Os procedimentos foram validados considerando-se os parâmetros especificidade, linearidade, precisão, exatidão, limite de detecção e quantificação e robustez, cujos resultados cumpriram os requisitos preconizados. Os métodos propostos foram aplicados na análise quantitativa de produtos farmacêuticos, demonstrando correlação significativa dos resultados (p > 0,05). Desenvolveu-se e validou-se método por espectrofotometria no UV utilizando tampão acetato pH 4,5 como diluente e detecção em 289 nm, o qual foi aplicado para avaliar a percentagem dissolvida dos comprimidos de dronedarona. O método de dissolução foi desenvolvido utilizando como meio 900 mL de tampão acetato pH 4,5 mantido a 37°C, aparato pá e rotação de 75 rpm.