RESUMEN

Objetivos: Implantar un programa de optimización del uso de antimicrobianos (PROA) para intervenir en el uso de antimicrobianos. Analizar el impacto de las intervenciones mediante indicadores basados en el consumo.Métodos: Fase 1. Creación equipo PROA: nombramiento; asesoramiento externo; formación; desarrollo programa informático. Fase 2. Análisis indicadores de consumo: estudio retrospectivo de intervención cuasi-experimental con evaluación pre-post: se evaluaron los indicadores del uso de antimicrobianos basados en el consumo en fase no-intervención y en fase intervención. El programa PROA consistió en un modelo de intervención no restrictivo.Resultados: Se formó e implantó el equipo PROA como órgano estructural y organizativo para la consulta, intervención y vigilancia del uso de antimicrobianos. Durante la fase intervención se realizaron 134 recomendaciones: terapia secuencial (12,69%), cambio de antimicrobiano/desescalada terapéutica (31,34%), suspensión de tratamiento antimicrobiano (55,97%); el grado de aceptación fue del 67,16%. Se analizaron 13 indicadores. En 11 de ellos se observó mejoría: consumo global antibacterianos (-2,26%), consumo global antifúngicos sistémicos (-40,60%), consumo carbapenémicos (-22,63%), consumo fluoroquinolonas (-16,52%), ratio macrólidos i.v./fluoroquinolonas respiratorias i.v. (17,49%), ratio metronidazol/carbapenémicos + piperacilina-tazobactam (15,82%), consumo fosfomicina (69,21%), ratio agentes anti-SASM/agentes anti-SARM (45,14%), ratio amoxicilina-clavulánico/piperacilina-tazobactam (24,38%), diversificación betalactámicos antipseudomónicos (7,61%), ratio fluconazol/equinocandinas (8,74%). Los indicadores en los que se obtuvo resultado negativo fueron: terapia secuencial (-8,89%), ratio amoxicilina/amoxicilina-clavulánico (-4,03%). ... (AU)

Objectives: Implementation of a program for optimizing the use of antibiotics (PROA) to manage the use of antimicrobials. Analyse the impact through indicators based on consumption.Methods: Phase 1. Creation of PROA: appointment; external advice; training; software development. Phase 2. Consumption indicators analysis: interventional, quasi-experimental, retrospective study with pre-post evaluation: indicators based on consumption were evaluated in non-intervention phase and in intervention phase. PROA consisted of a non-restrictive intervention model.Results: PROA was formed and implemented as a structural and managing body for the advice, intervention and monitoring of the use of antimicrobials. During the intervention phase, 134 recommendations related to sequential therapy IV/PO (12.69%), change of antimicrobial/de-escalation (31.34%), discontinuation of antimicrobial treatment (55.97%) were made; the degree of acceptance was 67.16%. 13 indicators based on consumption were analysed. 11 of them led to an improvement: antibacterials global consumption (-2.26%), systemic antifungals global consumption (-40.60%), carbapenems consumption (-22.63%), fluoroquinolones consumption (-16.52%), macrolide IV/ respiratory fluoroquinolones IV ratio (17.49%), metronidazole/carbapenem + piperacillin-tazobactam ratio (15.82%), fosfomycin consumption (69.21%), anti-MSSA agents/anti-MRSA agents ratio (45.14%), amoxicillin-clavulanic/piperacillin-tazobactam ratio (24.38%), diversification antipseudomonic beta-lactam (7.61%), fluconazole/echinocandins ratio (8.74%). Indicators with negative result were: sequential therapy IV/PO (-8.89%), amoxicillin/amoxicillin-clavulanic ratio (-4.03%). ... (AU)

Asunto(s)

RESUMEN

Refractoriness to the pharmacological treatment of cancer is dependent on the expression levels of genes involved in mechanisms of chemoresistance and on the existence of genetic variants that may affect their function. Thus, changes in genes encoding solute carriers may account for considerable inter-individual variability in drug uptake and the lack of sensitivity to the substrates of these transporters. Moreover, changes in proteins involved in drug export can affect their subcellular localization and transport ability and hence may also modify the bioavailability of antitumor agents. Regarding pro-drug activation or drug inactivation, genetic variants are responsible for changes in the activity of drug-metabolizing enzymes, which affect drug clearance and may determine the lack of response to anticancer chemotherapy. The presence of genetic variants may also decrease the sensitivity to pharmacological agents acting through molecular targets or signaling pathways. Recent investigations suggest that changes in genes involved in DNA repair may affect the response to platinum-based drugs. Since most anticancer agents activate cell death pathways, the evasion of apoptosis plays an important role in chemoresistance. Several genetic variants affecting death-receptor pathways, the mitochondrial pathway, downstream caspases and their natural modulators, and the p53 pathway, whose elements are mutated in more than half of tumors, and survival pathways, have been reported. The present review summarizes the available data regarding the role of genetic variants in the different mechanisms of chemoresistance and discusses their potential impact in clinical practice and in the development of tools to predict and overcome chemoresistance.

Asunto(s)

RESUMEN

When considered together, enterohepatic tumours, i.e., those affecting the liver, the biliary tree and gallbladder and the intestine, constitute the first cause of death due to cancer. Although in many cases surgery and radiotherapy are efficacious, these therapeutic strategies cannot always be implemented. Moreover, even when the removal of tumours is possible, pre- and post-operative pharmacological adjuvant regimens are often needed. However, one important limitation to the use of cytostatic drugs to treat enterohepatic tumours is that they generally exhibit marked refractivity to currently available pharmacological approaches. In addition, most of them increase their chemoresistance during treatment. In view of the high refractivity of these tumours to anti-cancer drugs and the existence of undesirable side effects, both of which are drawbacks in the available chemotherapy, several novel therapeutic approaches have been devised. The purpose of the present review is to offer some insight into the different types of strategies that have already been evaluated and incorporated into clinical practice, such as therapies based on the use of molecular targets, as well as into the approaches that are still under experimental development, such as the chemosensitization of cancer cells, genetic manipulation of tumour or host cells, and cell-specific enhancement of intracellular concentrations of the active agent by efficient targeting of pro-drugs or by using inhibitors of efflux pumps.

Asunto(s)

RESUMEN

Using cytokeratin-7-positive trophoblast cells (hTr) isolated from human term placentas and the choriocarcinoma cell lines (hCC) BeWo, Jeg-3 and JAr, the expression of genes involved in the hepatobiliary excretion of cholephilic compounds was investigated by RT-PCR/sequencing followed by measurement of the absolute abundance of mRNA by real-time RT-PCR. Although mRNA of BSEP was detectable and its expression confirmed by Western blotting, its very low expression (higher in hTr than in whole placenta and hCC) did not permit its detection by immunohistochemistry. In hTr, the expression was high for OATP-B/2B1, OATP-8/1B3, MRP1, MRP3, BCRP, FIC1, RARalpha, FXR and SHP, low for OSTalpha, MRP2, MRP4, MRP8, MDR1, CAR and SXR, very low for OATP-A/1A2 and MDR3, and not detectable for OATP-C/1B1, HNF1alpha and HNF4. Expression patterns in hCC mimicked those in hTr, although some important cell line-specific differences were found. The functionality of transporters expressed in hCC was confirmed by their ability to take up and export estradiol 17beta-d-glucuronide in a self-inhibitable and temperature-sensitive manner. In conclusion, several transporters, export pumps, and nuclear receptors involved in the liver excretory function may play a similar role in the placenta, whose specific aspects can be studied by selectively using BeWo, Jeg-3 or JAr cells.

Asunto(s)