3 research outputs found
Evaluation of critical parameters in the hollow-fibre system for tuberculosis: A case study of moxifloxacin
AimsThe hollowâfibre system for tuberculosis (HFSâTB) is a preclinical model qualified by the European Medicines Agency to underpin the antiâTB drug development process. It can mimic in vivo pharmacokinetic (PK)âpharmacodynamic (PD) attributes of selected antimicrobials, which could feed into in silico models to inform the design of clinical trials. However, historical data and published protocols are insufficient and omit key information to allow experiments to be reproducible. Therefore, in this work, we aim to optimize and standardize various HFSâTB operational procedures.MethodsFirst, we characterized bacterial growth dynamics with different types of hollowâfibre cartridges, Mycobacterium tuberculosis strains and media. Second, we mimicked a moxifloxacin PK profile within hollowâfibre cartridges, in order to check drugâfibres compatibility. Lastly, we mimicked the moxifloxacin total plasma PK profile in human after once daily oral dose of 400âmg to assess PKâPD after different sampling methods, strains, cartridge size and bacterial adaptation periods before drug infusion into the system.ResultsWe found that final bacterial load inside the HFSâTB was contingent on the studied variables. Besides, we demonstrated that drugâfibres compatibility tests are critical preliminary HFSâTB assays, which need to be properly reported. Lastly, we uncovered that the sampling method and bacterial adaptation period before drug infusion significantly impact actual experimental conclusions.ConclusionOur data contribute to the necessary standardization of HFSâTB experiments, draw attention to multiple aspects of this preclinical model that should be considered when reporting novel results and warn about critical parameters in the HFSâTB currently overlooked
Implementasi Algoritma Winnowing Untuk Mendeteksi Kemiripan Pada Dokuken Teks
Plagiarism is one of the main problems which the academic world must cope with recently. Many student papers and assignments had been found containing lines or sentences directly copied or sourced without sufficient acknowledgments to their original authors. Based on this fact, this research is conducted by developing software capable of detecting similarity between text documents, using âWinnowing algorithmâ which is a document fingerprinting algorithm. The goal of this research is to measure its effectiveness in comparing test documents and reporting their similarity by percentage
Model-based analysis of bactericidal activity and a new dosing strategy for optimised-dose rifampicin
Background Higher doses of rifampicin for tuberculosis have been shown to improve early bactericidal activity (EBA) and at the same time increase the intolerability due to high exposure at the beginning of treatment. To support dose optimisation of rifampicin, this study investigated new and innovative staggered dosing of rifampicin using clinical trial simulations to minimise tolerability problems and still achieve good efficacy. Methods Rifampicin population pharmacokinetics and time-to-positivity models were applied to data from patients receiving 14 days of daily 10â50 mg/kg rifampicin to characterise the exposure-response relationship. Furthermore, clinical trial simulations of rifampicin exposure were performed following four different staggered dosing scenarios. The simulated exposure after 35 mg/kg was used as a relative comparison for efficacy. Tolerability was derived from a previous model-based analysis relating exposure at day 7 and the probability of having adverse events. Results The linear relationship between rifampicin exposure and bacterial killing rate in sputum indicated that the maximum rifampicin EBA was not reached at doses up to 50 mg/kg. Clinical trial simulations of a staggered dosing strategy starting the treatment at a lower dose (20 mg/kg) for 7 days followed by a higher dose (40 mg/kg) predicted a lower initial exposure with lower probability of tolerability problems and better EBA compared with a regimen of 35Â mg/kg daily. Conclusions Staggered dosing of 20 mg/kg for 7 days followed by 40 mg/kg is predicted to reduce tolerability while maintaining exposure levels associated with better efficacy