Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements.

Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL = 3.68 + 0.22 · (residual diuresis/100) and V = 33.00 · (weight/73)(2.07), where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (fu ) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the ƒ uT >MIC), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the ƒ uT >MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population.

Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach.

Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the α,ß-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 ± 0.01 µM in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N'-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 µM and inhibited the migration and invasion of human breast carcinoma cells at 0.4 µM. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties.

Recomendaciones metodológicas de las agencias reguladoras / Methodological recommendations of the Regulatory Agencies

Las autoridades sanitarias, mediante las agencias de medicamentos, determinan la idoneidad de los nuevos tratamientos para su uso en la población general en términos de beneficio y riesgo, y regulan su comercialización y condiciones de utilización según criterios estrictos de calidad, seguridad y eficacia. Para aplicar el principio de transparencia, las agencias hacen públicos los requisitos que después se exigirán, en forma de documentos guía, fácilmente disponibles en internet. Todas estas guías incorporan de uno u otro modo unas recomendaciones básicas: a) metodología adecuada al objetivo y especificada en detalle a priori; b) trazabilidad; c) comprobación de la adecuación de los métodos usados; d) justificación de cualquier desviación del plan inicial, y e) demostración de la robustez de los resultados en distintos escenarios. Las directrices reguladoras difieren de otras referencias metodológicas en un énfasis sobre los aspectos prácticos del diseño y la conducción de los estudios, los principios metodológicos aceptables y los sistemas de control de calidad de la investigación. Si bien estas exigencias pueden no ser de aplicación estricta a algunos tipos de investigación, las guías están fácilmente disponibles y son una buena referencia a considerar para la autoría, revisión y edición de ensayos clínicos. El objetivo de este artículo es revisar algunas de estas directrices que pueden ser de especial utilidad (AU)

The suitability of new drugs for use in the general population in terms of risk and benefit is assessed by the health authorities through their drug agencies. These agencies regulate the entry of drugs on the market and their conditions for use according to strict criteria of quality, safety and efficacy. To preserve the principle of transparency, the requirements are previously published as guidelines, which are freely available on the Internet. All these guidelines have the following basic recommendations in common: (a) appropriate methodology for the objective, defined in detail a priori, (b) traceability, (c) verification of the appropriateness of the methodology applied, (d) justification of any deviation from the initial plan and (e) demonstration of the robustness of the results in distinct scenarios. Regulatory guidelines differ from other methodological references in their emphasis on the practical issues of the design and performance of studies, accepted methodological principles, and systems to ensure quality assurance in research. Although these requirements might not be universally applied to all types of research, the guidelines are freely available and are a good reference for the authorship, review and publication of clinical trials. The present article aims to review some of the guidelines that could be especially useful (AU)

Comentario. El papel de las agencias reguladoras en la evaluación de la seguridad de los medicamentos: a propósito de los inhibidores selectivos de la recaptación de serotonina / Comment. The role of regulatory agencies in the evaluation of drug safety: speaking about of selective serotonin receptore inhibitors

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[Methodological recommendations of the Regulatory Agencies]. / Recomendaciones metodológicas de las agencias reguladoras.

The suitability of new drugs for use in the general population in terms of risk and benefit is assessed by the health authorities through their drug agencies. These agencies regulate the entry of drugs on the market and their conditions for use according to strict criteria of quality, safety and efficacy. To preserve the principle of transparency, the requirements are previously published as guidelines, which are freely available on the Internet. All these guidelines have the following basic recommendations in common: (a) appropriate methodology for the objective, defined in detail a priori, (b) traceability, (c) verification of the appropriateness of the methodology applied, (d) justification of any deviation from the initial plan and (e) demonstration of the robustness of the results in distinct scenarios. Regulatory guidelines differ from other methodological references in their emphasis on the practical issues of the design and performance of studies, accepted methodological principles, and systems to ensure quality assurance in research. Although these requirements might not be universally applied to all types of research, the guidelines are freely available and are a good reference for the authorship, review and publication of clinical trials. The present article aims to review some of the guidelines that could be especially useful.