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To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine. In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days. In a second phase, animals were treated with unloaded radiopaque beads or high dose VTB loaded beads (VERB100, 100 mg/mL). Tissue samples from embolized and non-embolized areas of the liver were evaluated at necropsy (30 and 90 days) for determination of VTB and metabolite levels and tissue pathology. Imaging was performed prior to sacrifice using multi-detector computed tomography (MDCT) and imaging findings correlated with pathological changes in the tissue and location of the radiopaque beads. The peak plasma levels of VTB (C max ) released from the various doses of VERB ranged between 6.19-17.3 ng/mL indicating a low systemic burst release. The plasma profile of VTB was consistent with a distribution phase up to 6 h after administration followed by elimination with a half-life of 20-23 h. The AUC of VTB and its major metabolite N-desmethyl vandetanib (NDM VTB) was approximately linear with the dose strength of VERB. VTB plasma levels were at or below limits of detection two weeks after administration. In liver samples, VTB and NDM VTB were present in treated sections at 30 days after administration at levels above the in vitro IC 50 for biological effectiveness. At 90 days both analytes were still present in treated liver but were near or below the limit of quantification in untreated liver sections, demonstrating sustained release from the VERB. Comparison of the reduction of the liver lobe size and associated tissue changes suggested a more effective embolization with VERB compared to the beads without drug. Hepatic intra-arterial administration of VERB results in a low systemic exposure and enables sustained delivery of VTB to target tissues following embolization. Changes in the liver tissue are consistent with an effective embolization and this study has demonstrated that VERB100 is well tolerated with no obvious systemic toxicity.

BACKGROUND AND OBJECTIVE: Remifentanil has a short duration of action and constant elimination, which allow administration of high doses, without prolonging recovery. Remifentanil has been compared to alfentanil, as part of a total intravenous anaesthetic technique, where remifentanil provided better anaesthetic conditions than alfentanil, without adverse effect on recovery. However, these results were obtained during anaesthesia involving neuromuscular blockade, which may mask both signs of insufficient anaesthesia and side-effects such as muscle rigidity. The aim of this study was to compare remifentanil with alfentanil for anaesthesia without neuromuscular blockade.METHODS: We performed a prospective, randomized, double-blind, four-centre study to compare remifentanil infusion 15 microg kg(-1) h(-1) and alfentanil infusion 60 microg kg(-1) h(-1), using a total intravenous technique for non-paralysed patients, and the laryngeal mask airway for airway management. We enrolled 192 patients, 18-65 yr of age with ASA I-II, undergoing minor surgery. The primary endpoint was the number of patients having pre-defined responses to surgical stimulation. A number of secondary criteria was evaluated to assess undesirable properties of the procedures.RESULTS: In the alfentanil group, 85% of patients responded to surgical stimulation, vs. 35% in the remifentanil group (P < 0.0001). No difference was found in recovery data, or in any other parameter than those related to insufficient anaesthesia.CONCLUSIONS: The remifentanil-based technique provided significantly better anaesthetic conditions than the alfentanil-based technique in the setting of this study, without causing any significant adverse effects.

AIMS: To compare the effects of ezetimibe plus orlistat or rimonabant on anthropometric and lipid parameters in nondiabetic statin-intolerant overweight/obese patients with dyslipidemia. METHODS AND RESULTS: Thirty participants received a hypocaloric diet and were randomized to open-label combination of ezetimibe (10 mg/day) with orlistat (120 mg, 3 times a day with meals; ezetimibe/orlistat [EO], n = 15) or rimonabant (20 mg/day; ezetimibe/rimonabant [ER], n = 15). Anthropometric and metabolic variables were assessed at baseline and 3 months posttreatment. Similar reductions in body weight, body mass index, and waist circumference were recorded in both groups (-8.3%, -8.6%, and -5.2% in the EO group and -7.3%, -7.2%, and -7.0% in the ER group, P < .01 vs baseline for all). Low-density lipoprotein cholesterol (LDL-C) levels decreased in both treatment groups, but this reduction tended to be more pronounced in the EO group (28.4% vs 15.3%, respectively; P < .01 vs baseline for both). Triglycerides tended to decrease more in the ER compared with the EO group (-20.4% vs -14.1%, P < .01 vs baseline for both). High-density lipoprotein cholesterol (HDL-C) levels tended to decrease in EO group, but remained unaltered with ER treatment. Apolipoprotein B levels were equally reduced in both treatment groups. CONCLUSION: For similar body weight reduction, the combination of ezetimibe with orlistat may be more efficient in LDL-C lowering, whereas the combination of ezetimibe with rimonabant may be more potent in terms of improving HDL-C and triglycerides. J Cardiovasc Pharmacol Ther

Summary Background S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. Patients and methods In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined. Results With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. Conclusions With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase I trials of S9788 infused over six hours precluded the further clinical development of S9788.

BACKGROUND AND PURPOSE: We aimed to assess the safety and efficacy of lubeluzole in patients with a clinical diagnosis of acute ( 70 at day 28, indicating no or mild disability, compared with 21 of 61 (34%) in the placebo group and 19 of 66 (29%) in the lubeluzole 20 mg/d group (P = NS). CONCLUSIONS: In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. Further clinical trials in a larger number of patients are ongoing to confirm efficacy.

SUMMARY INTRODUCTION Healthcare associated infections (HAI) are the most frequent complication of hospitalized patients. The aim of this study was to describe the clinical and epidemiological characteristics of critically ill post-surgical patients with a diagnosis of healthcare associated infections, after a pattern of sedoanalgesia of at least 4 days. METHODS All patients over 18 years of age with a unit admission of more than 4 days were consecutively selected. The study population was the one affected by surgical pathology where sedation was based as analgesic the opioid remifentanil for at least 96 hours in continuous perfusion. Patients who died during admission to the unit and those with combined analgesia (peripheral or neuroaxial blocks) were excluded. Data analysis was performed using the statistical package Stata version 7.0. RESULTS The patients admitted to the Post-Surgical Critical Care Unit (PCU) during study were 1789 and the population eligible was comprised of 102 patients. 56.86% of patients suffered IACS. The most frequent IACS was pneumonia associated with mechanical ventilation (30.96 per 1000 days of mechanical ventilation), Pseudomonas aeruginosa being the most frequently isolated germ. The germs with the greatest involvement in multiple drug resistance (MDROs) were enterobacteria, mainly Klebsiella pneumoniae resistant to extended-spectrum beta-lactamases (ESBL). CONCLUSIONS Pneumonia associated with mechanical ventilation is the most prevalent HAI and Pseudomonas aeruginosa is the main etiological agent. The groups of antibiotics most frequently used were cephalosporin and aminoglycosides. It is necessary to implement the prevention strategies of the different HAI, since most of them are avoidable. RESUMO INTRODUCCIÓN Las infecciones asociadas a cuidados de salud (IACS) constituyen la complicación más frecuente de los pacientes hospitalizados. El objetivo de este estudio es describir las características clínicas y epidemiológicas de los pacientes críticos postquirúrgicos con diagnóstico de infección asociada a cuidados de salud, tras una pauta de sedoanalegia de al menos 4 días. MÉTODOS Se seleccionaron de manera consecutiva todos los pacientes mayores de 18 años con un ingreso en la Unidad de Reanimación Postquirúrgica (URP) superior a 4 días. La población de estudio fue aquella afectada por patología quirúrgica de cualquier origen donde la sedación se basó en cualquier hipnótico y como analgésico el opioide remifentanilo durante al menos 96 horas en perfusión continua. Se excluyeron los pacientes que fallecieron durante su ingreso en la unidad y aquellos pacientes con analgesia combinada (bloqueos periféricos o neuroaxiales). El análisis de los datos se realizó con paquete estadístico Stata versión 7.0. RESULTADOS El número de pacientes que ingresaron en la URP durante el periodo de estudio fueron de 1789. Tras aplicar los criterios de inclusión y exclusión, la población elegible quedó constituida por 102 pacientes. Un 56,86% de pacientes padecieron IACS. La IACS más frecuente fue la neumonía asociada a ventilación mecánica (30,96 por 1000 días de ventilación mecánica) siendo Pseudomona aeruginosa el germen más frecuentemente aislado. Los gérmenes con mayor implicación en las multirresistencias (MDROs) fueron las enterobacterias, principalmente Klebsiella pneumoniae resistente a betalactamasas de espectro extendido (BLEE). CONCLUSIONES La neumonía asociada a ventilación mecánica es la IACS más prevalente y Pseudomona aeruginosa es el principal agente etiológico. Los grupos de antibióticos más frecuentemente empleados fueron cefalosporinas y aminoglucósidos. Es necesario implementar las estrategias de prevención de las distintas IACS, ya que la mayoría de ellas son evitables.

Aims: Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme for nicotinamide adenine dinucleotide (NAD(+)) biosynthesis and recent evidence indicates its role in inflammatory processes. Here we investigated the potential effects of pharmacological Nampt inhibition with FK866 in a mouse myocardial ischemia/reperfusion model. In vivo and ex vivo mouse myocardial ischemia/reperfusion procedures were performed. Results: Treatment with FK866 reduced myocardial infarct size neutrophil infiltration and reactive oxygen species (ROS) generation within infarcted hearts in vivo in a mouse model of ischemia and reperfusion. The benefit of FK866 was not shown in the Langendorff model (ex vivo model of working heart without circulating leukocytes) suggesting a direct involvement of these cells in cardiac injury. Sera from FK866 treated mice showed reduced circulating levels of the neutrophil chemoattractant CXCL2 and impaired capacity to prime migration of these cells in vitro. The release of CXCL8 (human homolog of murine chemokine CXCL2) by human peripheral blood mononuclear cells (PBMCs) and Jurkat cells was also reduced by FK866 as well as by sirtuin (SIRT) inhibitors and SIRT6 silencing implying a pivotal role for this NAD(+) dependent deacetylase in the production of this chemokine. Innovation: The pharmacological inhibition of Nampt might represent an effective approach to reduce neutrophilic inflammation and oxidative stress mediated tissue damage in early phases of reperfusion after a myocardial infarction. Conclusions: Nampt inhibition appears as a new strategy to dampen CXCL2 induced neutrophil recruitment and thereby reduce neutrophil mediated tissue injury in mice. Antioxid. Redox Signal. 18 630 641.