Influence of pharmacogenetics on the diversity of response to statins associated with adverse drug reactions.

Background: Statins are one of the most prescribed medications in developed countries as the treatment of choice for reducing cholesterol and preventing cardiovascular diseases. However, a large proportion of patients experience adverse drug reactions, especially myotoxicity. Among the factors that influence the diversity of response, pharmacogenetics emerges as a relevant factor of influence in inter-individual differences in response to statins and can be useful in the prevention of adverse drug effects. Content: A systematic review was performed of current knowledge of the influence of pharmacogenetics on the occurrence and prevention of statin-associated adverse reactions and clinical benefits of preemptive pharmacogenetics testing. Summary: Genetic variants SLCO1B1 (rs4149056) for all statins; ABCG2 (rs2231142) for rosuvastatin; or CYP2C9 (rs1799853 and rs1057910) for fluvastatin are associated with an increase in muscle-related adverse effects and poor treatment adherence. Besides, various inhibitors of these transporters and biotransformation enzymes increase the systemic exposure of statins, thereby favoring the occurrence of adverse drug reactions. Outlook: The clinical preemptive testing of this pharmacogenetic panel would largely prevent the incidence of adverse drug reactions. Standardized methods should be used for the identification of adverse effects and the performance and interpretation of genotyping test results. Standardization would allow to obtain more conclusive results about the association between SLCO1B1, ABCG and CYP2C9 variants and the occurrence of adverse drug reactions. As a result, more personalized recommendations could be established for each statin.

Determinación de linezolid en plasma mediante cromatografía líquida de alta resolución para la monitorización terapéutica en pacientes / Determination of linezolid in human plasma by high-performance liquid chromatography for therapeutic drug monitoring

Introducción. Linezolid es un antibiótico sintético de un nuevo grupo, las oxazolidinonas, con espectro de actividad para grampositivos. Está indicado en infecciones de piel y tejidos blandos e infecciones nosocomiales adquiridas en la comunidad así como infecciones causadas por Staphylococcus aureus y Enterococus meticilin y vancomicin-resistentes, respectivamente. El objetivo de este trabajo es desarrollar y evaluar un método de cromatografía líquida de alta resolución (HPLC) para la monitorización de niveles plasmáticos de linezolid en muestras de pacientes. Material y métodos. Se utilizó como fase móvil una mezcla de acetonitrilo y agua con flujo isocrático de 1mL y una columna corta C18. La detección se realizó en un detector ultravioleta/visible a 254nm. El tratamiento de la muestra fue por precipitación de proteínas con ácido tricloroacético y posterior inyección del sobrenadante. Resultados. El método fue lineal y validado para un intervalo de 0,25 a 20mg/L. La precisión intra e interensayo (CV) fue inferior al 1% y 1,6%, respectivamente. La exactitud osciló entre -4,3% y 0,4%. La recuperación media fue superior al 82%. No se encontraron interferencias con otros fármacos habitualmente utilizados en la terapia combinada con linezolid. Tampoco se detectaron interferencias endógenas de la propia matriz biológica. Conclusiones. El método descrito para cuantificar linezolid en muestras de plasma es sensible, reproducible, específico, rápido y requiere poca muestra, por lo que le hace adecuado para la monitorización terapéutica (AU)

Introduction. Linezolid is a synthetic antibiotic of the group of the oxazolidinones with Gram positive spectrum of activity. It is indicated in skin and soft tissue infections, community-acquired nosocomial infections and infections caused by methicillin-resistant and vancomycin-resistant Staphylococcus aureus and Enterococcus, respectively. The aim of this work is to develop and evaluate a high pressure (HPLC) method for the monitoring of plasma levels of linezolid in patients samples. Materials and methods. The mobile phase consisted of a mixture of acetonitrile and water with a flow rate of 1mL/min and a short C18 column. An ultraviolet/visible detector at 254nm was used to detect the peaks. Sample treatment consisted of precipitation of plasma proteins with trichloroacetic acid and then injection of the supernatant. Results. The method was linear and validated from 0,25 to 20mg/L. The within-day and between-day coefficient of variation (CV) was less 1% and 1,6%, respectively. The accuracy varied between −4,3% and 0,4%. The average recovery was greater than 82%. No interferences were found with other drugs habitually used in the therapy combined with linezolid. Endogenous interferences of the biological matrix were not detected. Conclusions. The method described to quantify linezolid in plasma samples is sensitive, reproducible, specific, rapid and needs very little sample, which makes it suitable for therapeutic drug monitoring (AU)

Desarrollo y validación de un método para la determinación de darunavir en plasma mediante LC-MS/MS / Development and assessment of a method for the determination of darunavir in plasma by LC-MS/MS

Introducción. Darunavir es uno de los fármacos inhibidores de la proteasa de última generación utilizado para el tratamiento de la inmunodeficiencia adquirida por VIH debido a su destacada eficacia terapéutica y su mejor tolerancia, entre otras peculiaridades. Varios estudios demuestran una correlación entre la dosis y el efecto de darunavir, aunque todavía no se ha establecido un intervalo terapéutico para las concentraciones del fármaco. Estos factores junto con una elevada variabilidad farmacocinética interindividual además de interacciones farmacológicas con otros fármacos, refuerzan la idea de la importancia de disponer de un método sensible para la monitorización de sus concentraciones plasmáticas en pacientes tratados. Objetivos. Validación técnica de un método para la determinación de las concentraciones plasmáticas de darunavir mediante LC/MS/MS. Materiales y métodos. El proceso de validación se desarrolló según el procedimiento descrito en la guía ICH Topic Q 2B Validation of Analytical Procedures: Methodology (CPMP/ICH/281/95). El darunavir se extrae del plasma mediante una precipitación de proteínas. La separación cromatográfica se consiguió utilizando una columna X-BridgeTM C18 3,5μm 2,1 × 100mm (Waters®) con un programa de elución en gradiente de acetonitrilo y tampón. Para la detección de los analitos, se utilizó un espectrómetro de masas de triple cuadrupolo Quattro micro con electroespray en modo de ionización positivo. Resultados. Linealidad (0,1-10μg/mL): y=18,85×-150,4 r2: 0,997. Precisión: CV intraensayo: 1,07-4,62%. CV interensayo: 2,72-4,70%. Exactitud: intra-ensayo: 1-9%; inter-ensayo: 2-7%; LD: 0,05μg/mL; LQ: 0,15μg/mL. Conclusiones. Este método desarrollado basado en LC/MS/MS, posee una adecuada sensibilidad y reproducibilidad para la determinación de darunavir en plasma de pacientes tratados (AU)

Introduction. Darunavir is a latest generation of protease inhibitors (PI) drugs used as a treatment of HIV infection owing to its improved efficacy and its better tolerance among other characteristics. Several studies have demonstrated a correlation between the dose and the effect of darunavir, although a therapeutic range for the drug concentrations has not yet been established. These factors, besides the high inter-individual variability and the adverse effects resulting from drug interactions, reinforce the need for having a sensitive method for monitoring its plasma concentrations in treated patients. Objective. Technical validation of a new method for darunavir plasma concentration monitoring by LC/MS/MS. Materials and methods. The method validation procedure was based on the recommendations published in the guidelines ICH Topic Q 2B Validation of Analytical Procedures: Methodology (CPMP/ICH/281/95). Darunavir was extracted from plasma samples by a protein precipitation procedure. The chromatographic separation was achieved with a gradient program (acetonitrile/buffer) on an X-BridgeTM C18 3.5μm 2.1×100mm (Waters®). Analytes quantification is performed by electrospray ionization in positive mode, a Quattro Micro triple quadrupole mass spectrometer. Results. Linearity (0.1-10μg/mL): y=18.85×-150.4 r2: 0.997. Precision: Intra-assay CV: 1.07-4.62%. Inter-assay CV: 2.72-4.70%. Accuracy: Intra-assay: 1-9%. Inter-assay: 2-7%. LOD: 0.05μg/mL, LLOQ: 0.15μg/mL. Conclusion. The developed method based on LC/MS/MS has an adequate sensibility and reproducibility for the determination of plasma concentrations of darunavir in treated patients (AU)

Recommendations for management of Chagas disease in organ and hematopoietic tissue transplantation programs in nonendemic areas.

The substantial immigration into Spain from endemic areas of Chagas disease such as Latin America has increased the number of potential donors of organs and tissues. In addition, an increasing number of patients with advanced Chagas heart disease may eventually be eligible to receive a heart transplant, a universally accepted therapeutic strategy for the advanced stages of this disease. Therefore, it is necessary to establish protocols for disease management. This document is intended to establish the guidelines to be followed when a potential donor or a tissue or organ recipient is potentially affected by Chagas disease and summarizes the action criteria against the possibility of Chagas disease transmission through the donation of organs, tissues, or hematopoietic stem cells and aims to help professionals working in this field. A single registry of transplants in Trypanosoma cruzi infected donors and/or recipients will provide and disseminate experience in this area, which has shown a low recorded incidence to date.