Orientador: Jose Pedrazzoli Junior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-12T03:40:36Z (GMT). No. of bitstreams: 1 Morita_MilenaRodrigues_M.pdf: 4296553 bytes, checksum: 165726f88ad105c8817c9cc33149c67a (MD5) Previous issue date: 2008 / Resumo: Objetivo: Desenvolver e validar um método analítico para quantificação de levocetirizina em plasma humano. Além disso, a biodisponibilidade relativa de uma formulação contendo 5 mg de dicloridrato de levocetirizina (formulação teste e formulação referência produzida por Farmalab Indústrias Químicas e Farmacêuticas Ltda.) foi avaliada em trinta e seis voluntários sadios de ambos os sexos. Método: O plano de estudo utilizado foi aberto, randomizado, cruzado com um intervalo de washout de 7 dias. As amostras de plasma foram obtidas por um período de 48 horas. As concentrações plasmáticas de levocetirizina foram analisadas por cromatografia líquida de alta eficiência acoplada à espectrometria de massas (HPLC-MS/MS), com modo de ionização electrospray positivo usando um monitoramento de reação simples (SRM). O método analítico foi validado considerando os seguintes parâmetros: especificidade, linearidade, precisão, exatidão, recuperação e estabilidades de acordo com a RE n°899/03 (ANVISA). Das curvas de concentração plasmática versus o tempo para levocetirizina, os seguintes parâmetros farmacocinéticos foram obtidos: ASC0-48h, ASC0-inf e Cmax. Resultados: A curva de calibração foi linear de 0,5 a 500,0 ng/mL. O método obteve uma corrida cromatográfica de 2,0 minutos usando uma coluna POLARIS C18 (3 µm, 50 mm x 2,0 mm). A precisão inter-corrida dos controles de qualidade foi 4,76% (CQB 1,5 ng/mL), 7,14% (CQM 200,0 ng/mL) e 3,78% (CQA 400,0 ng/mL). A exatidão inter-corrida dos controles de qualidade acima mencionados foi de 98,00%, 99.63% e 97,84%, respectivamente. A razão das médias geométricas dos dois medicamentos (teste e referência) e o intervalo de confiança (IC) foram respectivamente: 101,11% (90% IC= 97,42% - 104,93%) para ASC0-48h, 101,17% (90% IC= 97,49% - 104,99%) para ASC0-inf, 99,43% (90% IC= 94,29% - 104,86%) para Cmax. Conclusão: O método analítico mostrou-se preciso, exato e rápido para quantificação de levocetirizina em plasma humano. Desde que os IC 90% para ASC0-48h, ASC0-inf e Cmax apresentaram-se dentro do intervalo de 80-125% proposto pela ANVISA, foi concluído que a formulação teste Levocetirizina 5 mg é bioequivalente a formulação Zyxem® fabricada pelo laboratório Farmalab Indústrias Químicas e Farmacêuticas Ltda. / Abstract: Objective: To develop and validate an analytical method for levocetirizina quantification in human plasma. Moreover, it was evaluated the relative bioavailability of a levocetirizine dichloridrate 5 mg tablet formulation (test formulation vs reference formulation from Farmalab Ltda.) in 36 healthy volunteers of both sexes. Methods: The study was conducted using an open, randomized, two-period crossover design with 7 days washout period between doses. Plasma samples were obtained over a 48 h period. Plasma levocetirizine concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) with positive ion electrospray ionization using single reaction monitoring (SRM). The analytical method was validated considering specificity, linearity, precision, accuracy, recovery and stabilities parameters according to RE n°899/03 (ANVISA). From the levocetirizine plasma concentration vs time curves, the following pharmacokinetic parameters were obtained: AUC0-48h, AUC0-inf e Cmax. Results: The calibration curve was linear over de range from 0,5 to 500,0 ng/mL. The method chromatographic run was 2,0 minutes using a POLARIS C18 column (3 µm, 50 mm x 2,0 mm). The between-run precision of quality controls was 4,76% (CQB 1,5 ng/mL), 7,14% (CQM 200,0 ng/mL) e 3,78% (CQA 400,0 ng/mL). The between-run accuracy for the above mentioned quality controls was 98,00%, 99.63% e 97,84% respectively.The limit of quantification was 0.5 ng/mL. The geometric mean ratio of both formulations (test and reference) and respective 90% confidence interval (CI) were: 101,11% (90% CI= 97,42% - 104,93%) for AUC0-48h, 101,17% (90% CI= 97,49% - 104,99%) for AUC0-inf, 99,43% (90% CI= 94,29% - 104,86%) for Cmax. Conclusion: The analytical method has proven to be precise, accurate and fast to levocetirizina quantification in human plasma. Since the 90% CI for AUC0-48h, AUC0-inf and Cmax ratios were within the 80-125% interval proposed by the ANVISA, it was concluded that levocetirizine formulation elaborated by Eurofarma Laboratórios Ltda. is bioquivalent to Zyxem® formulation. / Mestrado / Mestre em Farmacologia

Peptide identification using tandem mass spectrometry depends on matching the observed spectrum with the theoretical spectrum. The raw data from tandem mass spectrometry, however, is often not optimal because it may contain noise or measurement errors. Denoising this data can improve alignment between observed and theoretical spectra and reduce the number of peaks. The method used by Lewis et. al (2018) uses a combined constant and moving threshold to denoise spectra. We compare the effects of using the standard preprocessing methods baseline removal, wavelet smoothing, and binning on spectra with Lewis et. al’s threshold method. We consider individual methods and combinations, using measures of distance from Lewis et. al's scoring function for comparison. Our findings showed that no single method provided better results than Lewis et. al's, but combining techniques with that of Lewis et. al's reduced the distance measurements and size of the data set for many peptides.

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Identifying a peptide on the basis of a scan from a mass spectrometer is an important yet highly challenging problem. To identify peptides, we present a Bayesian approach which uses prior information about the average relative abundances of bond cleavages and the prior probability of any particular amino acid sequence. The scoring function proposed is composed of two overall distance measures, which measure how close an observed spectrum is to a theoretical scan for a peptide. Our use of our scoring function, which approximates a likelihood, has connections to the generalization presented by Bissiri and co-workers of the Bayesian framework. A Markov chain Monte Carlo algorithm is employed to simulate candidate choices from the posterior distribution of the peptide sequence. The true peptide is estimated as the peptide with the largest posterior density.

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The field-programmable gate array (FPGA) is a dynamically reconfigurable digital logic chip used to implement custom hardware. The large densities of modern FPGAs and the capability of the on-thely reconfiguration has made the FPGA a viable alternative to fixed logic hardware chips such as the ASIC. In high-performance computing, FPGAs are used as co-processors to speed up computationally intensive processes or as autonomous systems that realize a complete hardware application. However, due to the limited capacity of FPGA logic resources, denser FPGAs must be purchased if more logic resources are required to realize all the functions of a complex application. Alternatively, partial reconfiguration (PR) can be used to swap, on demand, idle components of the application with active components. This research uses PR to swap components to improve the performance of the application given the limited logic resources available with smaller but economical FPGAs. The swap is called ”resource sharing PR”. In a pipelined design of multiple hardware modules (pipeline stages), resource sharing PR is a technique that uses PR to improve the performance of pipeline bottlenecks. This is done by reconfiguring other pipeline stages, typically those that are idle waiting for data from a bottleneck, into an additional parallel bottleneck module. The target pipeline of this research is a two-stage “slow-toast” pipeline where the flow of data traversing the pipeline transitions from a relatively slow, bottleneck stage to a fast stage. A two stage pipeline that combines FPGA-based hardware implementations of well-known Bioinformatics search algorithms, the X! Tandem algorithm and the Smith-Waterman algorithm, is implemented for this research; the implemented pipeline demonstrates that characteristics of these algorithm. The experimental results show that, in a database of unknown peptide spectra, when matching spectra with 388 peaks or greater, performing resource sharing PR to instantiate a parallel X! Tandem module is worth the cost for PR. In addition, from timings gathered during experiments, a general formula was derived for determining the value of performing PR upon a fast module.

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