Efficacy and safety of direct antiviral agents in a cohort of cirrhotic HCV/HIV-coinfected patients.

Background: New direct-acting antiviral agents (DAAs) have shown great efficacy and tolerability in clinical trials and real-life cohorts. However, data are scarce regarding efficacy and safety in cirrhotic HCV/HIV-coinfected patients. Methods: A multicentre prospective analysis was performed in 13 Spanish hospitals, including all cirrhotic HCV/HIV-coinfected patients starting DAA combinations from January to December 2015. Sustained virological response 12 weeks after treatment (SVR12) was analysed. Withdrawal due to toxicity and/or hepatic decompensation and change in liver stiffness measurement (LSM) after HCV treatment were evaluated. Results: Patients (n = 170) were mostly male (n = 125; 74.3%) with the following HCV genotype (Gt) distribution: Gt-1a, 68 (40%); Gt-1b, 21 (12.4%); Gt-4, 47 (27.6%); and Gt-3, 26 (15.3%). Baseline median LSM was 20.6 kPa (IQR 16.1-33.7) and log10 HCV-RNA 6.1 IU/mL (IQR 5.7-6.5). Most patients had a Child-Pugh class A score (n = 127; 74.7%) and 28 (16.5%) had prior hepatic decompensation. There were 89 (52.4%) pretreated patients with 40.4% (n = 36) of null responders. Preferred regimens were as follows: sofosbuvir/ledipasvir + ribavirin, 43 (25.3%) patients; sofosbuvir + simeprevir + ribavirin, 34 (20%); sofosbuvir/ledipasvir, 26 (15.3%) and sofosbuvir + daclatasvir + ribavirin, 25 (14.7%). Overall SVR12 was 92.9% (158/170), without differences between genotypes. Pretreated patients had lower SVR12 rates compared with naive (88.8% versus 97.5%; P = 0.026). Treatment failures were as follows: 7 (4.1%) relapses; 2 (1.2%) lost to follow-up; 1 (0.6%) toxicity-related discontinuation; 1 (0.6%) hepatic decompensation; and 1 (0.6%) viral breakthrough. On-treatment hepatic decompensation was recorded in four (2.4%) patients (encephalopathy and ascites, two each). Paired LSM in 33 patients showed a decrease of 5.6 kPa (95% CI 1.8-9.2; P = 0.004). Conclusions: In our cohort of cirrhotic HCV/HIV-coinfected patients, DAAs were highly safe and efficacious. Viral eradication was associated with a significant decrease in liver stiffness.

Efficacy and tolerability after 24 weeks of treatment with telaprevir, pegylated interferon and ribavirin in cirrhotic HIV-HCV coinfected subjects.

Efficacy and tolerability of telaprevir, pegylated interferon and ribavirin combination was assessed in 32 cirrhotic genotype 1 hepatitis C (HCV)-HIV coinfected patients. Undetectability of HCV-RNA was observed in 23/32 (71.9%) patients after 24 weeks. Treatment failure was observed in 9/32 subjects: four of them (45.5%) failed triple therapy due to virological rebound, while 5 patients (55.5%) experienced drug-related side effects driving to treatment interruption. These data suggest that telaprevir-containing triple therapy should be considered for treatment of genotype 1 HCV in HIV coinfected patients with liver cirrhosis, although a close vigilance is required because of potential drug-related side effects.

Vitamin E action on oxidative state, endothelial function and morphology in long-term myocardial preservation.

This study assesses the effects of a vitamin E analogue, Trolox, on the oxidative state, endothelial function and morphology in experimental heart transplantation. Heterotopic heart transplantation was carried out in pigs: untreated after 2 and 24 hours of ischemia and treated with Trolox after 24 hours of ischemia. Prolonged preservation of donor hearts was achieved with continuous perfusion and University of Wisconsin solution, in which acid-base balance and enzymes were determined during the procedure. In recipients, hemodynamic and biochemical parameters were determined at baseline and during reperfusion. Trolox diminished the pH of the preservation solution (p<0.01), the left ventricle of the transplanted heart recovered a systolic pressure equaling that of the 2h group and higher than that of the untreated 24h group (p<0.01), the antioxidant levels were not decreased and the glutathione reductase level was maintained throughout the first part of reperfusion. In this group also there was a direct correlation between the concentration of this enzyme and the antioxidant levels (p<0.001). Although the endothelin concentrations increased, the change was less marked in the Trolox group than in the untreated 24h group (p<0.01). Morphologically, mitochondria and myocardial vessels presented a normal structure in the Trolox group, and interstitial edema, inflammatory infiltrate and contraction bands were less prominent than in the untreated group. All these effects indicate that Trolox protected the transplanted heart, at least partially, against ischemia-reperfusion injury.

[Ischemia-reperfusion injury during experimental heart transplantation. Evaluation of trimetazidine's cytoprotective effect]. / Daño por isquemia-reperfusión durante el trasplante cardíaco experimental. Evaluación del papel citoprotector de la trimetazidina.

INTRODUCTION AND OBJECTIVES: The objectives of this study were to analyze the ischemia-reperfusion injury due to free radicals that occurs during heart transplantation and to determine the potential cytoprotective effect of trimetazidine. MATERIAL AND METHOD: A total of 21 orthotopic heart transplantations were performed in pigs. We divided the experimental animals into 2 groups: in group A (n=11),standard myocardial protection was used; in group B (n=10), trimetazidine was added to the cardioplegic solution used to protect the donor heart and to the solution administered to the recipient prior to release of the aortic clamp (trimetazidine, 10(-5) mol/L), and recipients were pretreated with trimetazidine, 2.5 mg/kg. Blood samples were taken from the recipients coronary sinus at three times: at baseline, during ischemia, and during reperfusion. We measured the levels of malondialdehyde, a marker of lipid peroxidation, and of several antioxidants: glutathione peroxidase, glutathione reductase, superoxide dismutase, alpha-tocopherol, and retinol. The total antioxidant status was also determined. RESULTS: Malondialdehyde production and enzymatic antioxidant activity rose during ischemia and reperfusion, while the retinol level decreased. The increases in malondialdehyde level and glutathione peroxidase activity that occurred between baseline and reperfusion were significantly higher in group A. CONCLUSIONS. The degree of lipid peroxidation and the level of activity of intracellular antioxidant mechanisms increased progressively throughout transplantation. Trimetazidine had a cytoprotective effect. It ameliorated free radical-induced reperfusion injury and modified the response pattern of several defense mechanisms.

Daño por isquemia-reperfusión durante el trasplante cardíaco experimental. Evaluación del papel citoprotector de la trimetazidina / Ischemia-reperfusion injury during experimental heart transplantation. Evaluation of trimetazidine’s cytoprotective effect

Introducción y objetivos. El objetivo de este trabajo fueanalizar el daño por isquemia-reperfusión mediado por radicales libres que se produce durante el trasplante cardíaco y eva-luar el posible efecto citoprotector de la trimetazidina (TMZ). Material y método. Se realizaron 21 trasplantes cardíacos ortotópicos en cerdos. Dividimos los experimentos en 2 grupos: A (n = 11), en el que se realizó una protección miocárdica estándar, y B (n = 10), en el que se administró TMZ en la cardioplejía empleada para parar el corazón donante (TMZ, 10–5 mol/l), como pretratamiento intravenosodel receptor (TMZ, 2,5 mg/kg) y como parte de la cardio-plejía infundida en el receptor antes de despinzar la aorta(TMZ, 10–5 mol/l). Se tomaron muestras de sangre del senocoronario del receptor en 3 momentos: basal, isquemia y reperfusión. Se determinó la concentración de malonildial-dehído como marcador de peroxidación lipídica y de variosantioxidantes: glutatión peroxidasa, glutatión reductasa,superóxido dismutasa, α-tocoferol, retinol y estado de antioxidantes totales. Resultados. Durante la isquemia-reperfusión aumentóla producción de malonildialdehído y la actividad de losantioxidantes enzimáticos, mientras que el retinol disminuyó. El incremento de malonildialdehído y de la actividad de la glutatión peroxidasa entre el momento basal y la reperfusión fue significativamente mayor en el grupo A. Conclusiones. Durante el trasplante se incrementó progresivamente el nivel de peroxidación lipídica y se activaronlos sistemas antioxidantes intracelulares. La TMZ ejerció un efecto citoprotector y limitó el daño por isquemia-reperfusión generado por los radicales libres, además de modificar el patrón de reacción de parte de los sistemas de defensa

Introduction and objectives. The objectives of thisstudy were to analyze the ischemia-reperfusion injury dueto free radicals that occurs during heart transplantationand to determine the potential cytoprotective effect of trimetazidine. Material and method. A total of 21 orthotopic heart transplantations were performed in pigs. We divided the experimental animals into 2 groups: in group A (n=11),standard myocardial protection was used; in group B(n=10), trimetazidine was added to the cardioplegic solution used to protect the donor heart and to the solution administered to the recipient prior to release of the aortic clamp (trimetazidine, 10–5mol/L), and recipients were pretreated with trimetazidine, 2.5 mg/kg. Blood samples weretaken from the recipient’s coronary sinus at three times: at baseline, during ischemia, and during reperfusion. We measured the levels of malondialdehyde, a marker of lipid peroxidation, and of several antioxidants: glutathione peroxidase, glutathione reductase, superoxide dismutase, α-tocopherol, and retinol. The total antioxidant status wasalso determined. Results. Malondialdehyde production and enzymaticanti oxidant activity rose during ischemia and reperfusion, while the retinol level decreased. The increases in malondialdehyde level and glutathione peroxidase activity that occurred between baseline and reperfusion were significantly higher in group A. Conclusions. The degree of lipid peroxidation and the level of activity of intracellular antioxidant mechanisms increased progressively throughout transplantation. Trimetazidine had a cytoprotective effect. It ameliorated free radical-induced reperfusion injury and modified the response pattern of several defense mechanisms

La antibioterapia en monodosis: una opción de mejora en las neumonías adquiridas en la comunidad / Single-dosse antibiotic therapy: an option for improvement in community-acquired pneumonias

Introducción: El tratamiento de las neumonías adquiridas en la comunidad (NAC) con antibióticos en monoterapia y monodosis (MM) ha demostrado la misma efectividad clínica que las pautas clásicas de antibioterapia fraccionada, a la vez que disminuye la estancia hospitalaria. Esto hace que la MM constituya una opción de mejora. Objetivo: Comprobar sí las características del tratamiento de las NAC con MM eran exportables a un hospital diferente de aquellos en los que se habían descrito inicialmente. Material y método. Estudio de intervención para la mejora de la calidad, en el período de enero a mayo de 1999. Tipo de muestreo: consecutivo. Datos recogidos: edad, sexo, puntuación APACHE II e índice de Charlson para comorbilidades, tiempo de estancia, mortalidad a 30 días, reingresos en los 10 días siguientes del alta hospitalaria, tiempos de enfermería en preparar y suministrar el tratamiento. En la etapa I se compararon las pautas de MM con levofloxacino o ceftriaxona frente a la pauta clásica de cefotaxima cada 6 h acompañada de un macrólido cada 12 h. En la etapa II se compararon entre sí las pautas de MM: levofloxacino frente a ceftriaxona. Durante todo el estudio se aplicaron guías de práctica clínica comunes a todos los pacientes con NAC. En la etapa III, según los resultados obtenidos y a las evidencias bibliográficas, el grupo de expertos seleccionó la pauta definitiva. Resultados: En la etapa I el tiempo medio ñ desviación estándar (DE) de estancia de las NAC tratadas con MM fue de 151 ñ 80,6 h frente a 204 ñ 110,4 horas en el tratamiento clásico, siendo la diferencia estadísticamente significativa y clínicamente relevante. No se detectaron diferencias en la mortalidad y reingresos; el tiempo de enfermería fue de 4 min/paciente/día en la MM frente a 16 minutos en el tratamiento clásico. En la segunda etapa no se detectaron diferencias entre los dos tipos de MM empleadas; si bien no se alcanzó el tamaño adecuado de la muestra. El grupo de expertos seleccionó la MM con levofloxacino por permitir un tratamiento secuencia¡ sin cambio de fármaco y porque su biodisponibilidad oral próxima al cien por cien permite iniciar el tratamiento oral rápidamente. Comentario: Nuestros resultados ponen de manifiesto que la MM supone una opción de mejora en nuestro hospital, dado que al disminuir los tiempos de estancia por paciente junto con un ahorro en el tiempo de enfermería mejora la utilización de las camas sin incrementar los riesgos para el paciente (AU)