Eslicarbazepine acetate (ESL) is a new-generation voltage-gated sodium channel blocker, which has been demonstrated to be effective and well tolerated in the treatment of epilepsy. The primary objective of this study was to investigate the effect of ESL on the pharmacokinetics of digoxin. This study was a randomized, double-blind, placebo-controlled, two-way crossover study of 12 healthy subjects (six men and six women). The study included two 8-day treatment periods with a washout of >or=10 days. In each period, subjects received either ESL 1200 mg once-daily or placebo, concomitantly with a loading oral dose of digoxin 0.5 mg on days 1 and 2, followed by a once-daily maintenance dose of 0.25 mg on days 3-8. Maximum serum digoxin plasma concentrations (C(max)) were reached (t(max)) at 0.5-2.0 h post-dose (median = 1.0 h) and at 0.5-4.0 h post-dose (median = 1.0 h) with Reference (digoxin plus placebo) and Test (digoxin plus ESL) treatments, respectively. The Test/Reference digoxin geometric mean ratios and 90% confidence intervals (90% CI) were 0.96 and 0.90-1.03 for the area under the plasma concentration-time curve over the dosing interval (AUC(0-24)) and 0.85 and 0.68-1.07 for C(max). The 90% CI was within the bioequivalence range (0.80-1.25) for AUC(0-24), thus demonstrating bioequivalence. The 90% CI was outside the 0.80-1.25 range for digoxin C(max), but it appeared to be caused by a higher variability in digoxin C(max) following co-administration of digoxin with placebo than with ESL. Co-administration of ESL and digoxin was well tolerated. Concomitant administration of ESL has no clinically relevant effect in the systemic exposure to digoxin.
Objective
To investigate whether reactive hyperemia measured by peripheral arterial tonometry correlates with markers of endothelial dysfunction and may be used to identify sepsis in critical illness.
Methods
A prospective study was performed using a cohort of critically ill patients. Endothelial dysfunction was assessed on admission by quantifying reactive hyperemia-peripheral arterial tonometry and plasma levels of endothelin-1, soluble E-selectin, endocan and syndecan-1. Septic patients were compared to patients without evidence of infection.
Results
Fifty-eight septic patients were compared to 28 controls. The natural logarithm of reactive hyperemia-peripheral arterial tonometry was negatively correlated with cardiovascular comorbidities, disease severity and plasma levels of soluble E-selectin (p = 0.024) and syndecan-1 (p < 0.001). The natural logarithm of reactive hyperemia-peripheral arterial tonometry was lower in septic patients than in controls (0.53 ± 0.48 versus 0.69 ± 0.42, respectively). When adjusted for age, the multivariable model predicted that each 0.1-unit decrease in natural logarithm of reactive hyperemia-peripheral arterial tonometry increased the odds for infection by 14.6%. m.
Conclusion
Reactive hyperemia-peripheral arterial tonometry is closely related to soluble E-selectin and syndecan-1, suggesting an association between endothelial activation, glycocalyx degradation and vascular reactivity. Reactive hyperemia-peripheral arterial tonometry appears to be compromised in critically ill patients, especially those with sepsis.
Predictions of mortality may help in the selection of patients who benefit from intensive care. Endothelial dysfunction is partially responsible for many of the organic dysfunctions in critical illness. Reactive hyperaemia is a vascular response of the endothelium that can be measured by peripheral arterial tonometry (RH-PAT). We aimed to assess if reactive hyperaemia is affected by critical illness and if it correlates with outcomes. Prospective study with a cohort of consecutive patients admitted to an Intensive Care Unit. RH-PAT was accessed on admission and on the 7th day after admission. Early and late survivors were compared to non-survivors. The effect of RH-PAT variation on late mortality was studied by a logistic regression model. The association between RH-PAT and severity scores and biomarkers of organic dysfunction was investigated by multivariate analysis. 86 patients were enrolled. Mean ln(RHI) on admission was 0.580 and was significantly lower in patients with higher severity scores (p < 0.01) and early non-survivors (0.388; p = 0.027). The model for prediction of early-mortality estimated that each 0.1 decrease in ln(RHI) increased the odds for mortality by 13%. In 39 patients, a 2nd RH-PAT measurement was performed on the 7th day. The variation of ln(RHI) was significantly different between non-survivors and survivors (− 24.2% vs. 63.9%, p = 0.026). Ln(RHI) was significantly lower in patients with renal and cardiovascular dysfunction (p < 0.01). RH-PAT is correlated with disease severity and seems to be an independent marker of early mortality, cardiovascular and renal dysfunctions. RH-PAT variation predicts late mortality. There appears to be an RH-PAT impairment in the acute phase of severe diseases that may be reversible and associated with better outcomes.
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