Comparison of biodisponibility between test-formulation and reference-formulation of propafenone (Ritmonorm®) in phenotipically selected healthy volunteers of both sexes

Orientador: Gilberto de NucciTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: O cloridrato de propafenona é um fármaco antiarrítmico da classe 1C, que exerce efeito estabilizador de membrana na célula miocárdica. Possui propriedades bloqueadoras de canais de sódio nas fibras ventriculares e de Purkinje, além de leve ação betabloqueadora, cerca de 1/50 da potência do propranolol, e fraca atividade bloqueadora de canais de cálcio. É metabolizada primariamente no fígado pelo citocromo P-450 2D6, mas a ocorrência de hepatoxicidade é rara, sendo reportado na literatura científica até o ano de 2013, apenas 8 casos clínicos. O presente trabalho teve como objetivo comparar a biodisponibilidade de duas formulações pelo método de cromatografia líquida de alta eficiência acoplada a espectrometria de massas em tandem (LC-MS/MS): formulação referência (Ritmonorm® ¿ propafenona comprimido 300 mg ¿ Abbott Laboratórios do Brasil Ltda.) e formulação teste (propafenona comprimido 300 mg ¿ Biolab Sanus Farmacêutica Ltda.), em voluntários sadios de ambos os sexos, selecionados fenotipicamente com base na atividade para a enzima CYP2D6. A debrisoquina 2.5 mg foi utilizada para a fenotipagem de voluntários, quantificando-se na urina as concentrações de 4-hidroxidebrisoquina, que corresponde à debrisoquina biotransformada primariamente pela CYP2D6, e debrisoquina excretada de forma inalterada, após 5 horas da administração do medicamento. Os metabolizadores extensivos para a debrisoquina foram selecionados para participar da avaliação de bioequivalência entre formulações de propafenona, princípio ativo este que também é primariamente metabolizado pela CYP2D6. Os resultados das etapas clínicas e analíticas mostraram que as duas formulações foram consideradas bioequivalentes para velocidade e extensão de absorção, além de serem seguras e bem toleradas. Dois métodos analíticos foram desenvolvidos e validados, com seletividade satisfatória e com tempos de corrida curtosAbstract: Propafenone hydrochloride is a 1C class of antiarrhythmic drug, which exerts a membrane stabilizing effect on the myocardial cell. It has sodium channel blocking properties in the ventricular and Purkinje fibers, as well as a weak beta blocker action, about 1/50 of the potency of propranolol, and a calcium channel blocker. Propafenone is metabolized primarily in the liver by cytochrome P-450 2D6, but occurrence of hepatotoxicity is rare with only 8 clinical cases reported in the scientific literature until 2013. The objective of the present study was to compare the bioavailability of two formulations by high performance liquid chromatography coupled to tandem mass spectrometry method: reference formulation (Ritmonorm® - propafenone tablet 300 mg - Abbott Laboratories do Brasil Ltda.) and test formulation (300 mg Biolab Sanus Pharmaceuticals Ltda.), in healthy volunteers of both sexes, phenotypically selected based on activity for CYP2D6 enzyme. Debrisoquine 2.5 mg was administered for phenotyping purpose by quantifying urine concentrations of 4hydroxydebisoquine, which corresponds to the biotransformed debrisoquine primarily by CYP2D6, and debrisoquine excreted unaltered, after 5 hours of administration of drug. Extensive metabolizers of debrisoquine were selected to participate in the bioequivalence study between propafenone formulations, which is also primarily metabolized by CYP2D6. The results of the clinical and analytical stages showed that the two formulations were considered bioequivalent for speed and extent of absorption, being also safe and well tolerated. Two analytical methods were developed and validated, with satisfactory selectivity and presenting short run timesDoutoradoFarmacologiaDoutor em Farmacologia01-P-3371/2017CAPE

Adverse Effects and Choice between the Injectable Agents Amikacin and Capreomycin in Multidrug-Resistant Tuberculosis

Background: The prolonged use of injectable agents in an MDR-TB regimen is recommended by the WHO despite association with ototoxicity and nephrotoxicity.Objective: We undertook this study to look at the relative adverse effects of capreomycin and amikacin.Methods: We reviewed the case notes of 100 consecutive patients treated at 4 MDR-TB treatment centres in the UK.Results: The median total duration of treatment with an injectable agent was 178 (IQR 109-192, n=73) days for those with MDR-TB, 179 (104-192, n=12) days for those with MDR-TB plus fluoroquinolone resistance and 558 (324-735, n=8) days for those with XDR-TB. Injectable use was longer for those started with capreomycin at 183 (IQR 123-197) days compared to 119 (IQR 83-177) days with amikacin (p=0.002). Excluding XDR-TB, 51 (51/85, 60%) patients were treated with an injectable for over 6 months and 12 (12/85, 14%) for over 8 months. 40 % of all patients discontinued the injectable due to hearing loss. 55% of patients experienced ototoxicity: 5 times (hazard ratio (HR) 5.2, CI 1.2-22.6, p=0.03) more likely in those started on amikacin compared to treatment with capreomycin only. Amikacin was associated with less hypokalemia than capreomycin (Odds ratios: 0.28 (0.11-0.72)), with 5 (5/37, 14%) patients stopping capreomycin due to recurrent electrolyte loss. There was no difference in the number experiencing a creatinine rise of > 1.5 times baseline.Conclusion: Hearing loss is frequent in this cohort, though significantly lower in those starting capreomycin which should be given greater consideration as a first line agent

The effect of low dose rate irradiation on the tensile properties and microstructure of austenitic stainless steel.

To assess the effects of long-term, low-dose-rate neutron exposure on mechanical strength and ductility, tensile properties were measured on 12% and 20% cold-worked Type 316 stainless steel. Samples were prepared from reactor core components retrieved from the EBR-II reactor following final shutdown. Sample locations were chosen to cover a dose range of 1-56 dpa at temperatures from 371-440 C and dose rates from 0.5-5.8 x10{sup -7} dpa/s. These dose rates are approximately an order of magnitude lower than those of typical EBR-II test sample locations. The tensile tests for the 12% CW material were performed at 380 C and 430 C while those for the 20% CW samples were performed at 370 C. In each case, the tensile test temperature approximately matched the irradiation temperature. To help understand the tensile properties, microstructural samples with similar irradiation history were also examined. The strength and loss of work hardening increase the fastest as a function of irradiation dose for the 12% CW material irradiated at lower temperature. The decrease in ductility with increasing dose occurs more rapidly for the 12% CW material irradiated at lower temperature and the 20% cold-worked material. Post-tensile test fractography indicates that at higher dose, the 20% CW samples begin a shift in fracture mode from purely ductile to mainly small facets and slip bands, suggesting a transition toward channel fracture. The fracture for all of the 12% cold-worked samples was ductile. For both the 12% and 20% CW materials, the yield strength increases correlate with changes in void and loop density and size