Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid.

OBJECTIVES: To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. METHODS: The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. RESULTS: We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. CONCLUSIONS: In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.

Cocaine degradation using a rotating biological disc reactor: Techno-economic and environmental analysis using experimental data.

A bacterial mixed culture that utilizes cocaine as the sole carbon and energy sources was isolated and used in a Rotary Disc Reactor as an alternative method for the final disposal of seized cocaine. This study aimed to compare the performances of cocaine incineration (oven) and biodegradation (Rotary Disc Reactor), considering economic and environmental aspects. There was a 99.4% cocaine removal efficiency when bacterial C1T consortium was grown in a Rotary Disc Reactor for 42 h. The economic analysis allowed determining the high potential of the biotechnological cocaine degradation to be evaluated at higher scales. Indeed, the unit disposition price of the biotechnological degradation pathway was 58% higher than the calculated value for the incineration process considering an initial cocaine concentration of 30 g/L. Moreover, the economic sensitivity analysis demonstrated a price reduction of 20% in the unit disposition price of the biotechnological degradation using a rotary disc reactor. Further, cocaine degradation using a rotary disc reactor system presented a better environmental performance than the incineration process considering atmospheric and toxicological impact categories because of the low release of hazardous materials to the atmosphere.

Bioequivalencia de dos formulaciones de Metformina, tabletas de 850 mg, en voluntarios sanos colombianos / Bioequivalence of two metformin formulations: 850 mg tablets in healthy colombian volunteers

Introducción: la metformina es un antihiperglicemiante útil en el manejo de la diabetes mellitus tipo II, del que se encuentran en el mercado colombiano tanto el producto innovador como diferentes formulaciones genéricas. Para garantizar la seguridad y eficacia de estas últimas, es necesario demostrar su bioequivalencia con respecto al producto innovador.Objetivo: determinar si el producto Dimefor®/Metformina MK es bioequivalente con el producto Glucophage? (referencia) cuando se administran en dosis iguales a un grupo de voluntarios sanos.Método: el estudio se realizó sobre veinticuatro voluntarios que cumplieron con los requisitos de inclusión y decidieron participar espontáneamente después de ser informados sobre su función en el estudio. Se utilizó un diseño aleatorio cruzado, en dos períodos, dos secuencias y doble ciego. Se administró una dosis única de 850 mg de cada producto y se tomaron muestras de sangre por un período de 24 horas. La cuantificación de la metformina se realizó por HPLC (High Performance Liquid Chromatography). Para la determinación estadística de bioequivalencia se utilizó la prueba de Schuirmann.Resultados: los dos productos fueron bioequivalentes con intervalos de confianza contenidos entre 80.0 por ciento y 125.0 por ciento para ln ABC0-8 (84.6 por ciento-100.0 por ciento), ln Cmax (89.1 por ciento-109.0 por ciento) e ln ABC0-Tmax (83.4 por ciento-101.4 por ciento) y entre 80.0 por ciento y 120.0 por ciento para Tmax (85.1 por ciento y 109.8 por ciento).

INTRODUCTION: Metformin is an orally active antidiabetic agent used to treat type II diabetes; it is found in the Colombian market in both the innovator brand and the generic formulations. The latter have to prove some biopharmaceutical quality outcomes to guarantee interchangeable proprieties. OBJECTIVE: To determine whether the drug Dimefor®/Metformina MK is bioequivalent to the reference product Glucophage®, when the products are administrated, at the same dose, to a group of healthy volunteers. METHOD: The study was made with 24 healthy volunteers who met the inclusion criteria and spontaneously decided to participate after being thoroughly informed. We used a two-sequence threeperiod randomized, crossed and double-blind study. The volunteers took an 850 mg dose of each medicine; then, blood samples were taken throughout 24 hours and the metformin quantification in plasma was determined by High Performance Liquid Chromatography with UV detection (HPLC/UV). For statistical analysis, Schuirmann's test was used. RESULTS: The study showed that both preparations are bioequivalent; confidence intervals for ln AUC0-∞, ln Cmax, ln AUC0-Tmax and Tmax were [84.6-100.0%], [89.1-109.0%], [83.4­01.4%] and [85.1-109.8% ], respectively.