Stress assessment based on EEG univariate features and functional connectivity measures.

The biological response to stress originates in the brain but involves different biochemical and physiological effects. Many common clinical methods to assess stress are based on the presence of specific hormones and on features extracted from different signals, including electrocardiogram, blood pressure, skin temperature, or galvanic skin response. The aim of this paper was to assess stress using EEG-based variables obtained from univariate analysis and functional connectivity evaluation. Two different stressors, the Stroop test and sleep deprivation, were applied to 30 volunteers to find common EEG patterns related to stress effects. Results showed a decrease of the high alpha power (11 to 12 Hz), an increase in the high beta band (23 to 36 Hz, considered a busy brain indicator), and a decrease in the approximate entropy. Moreover, connectivity showed that the high beta coherence and the interhemispheric nonlinear couplings, measured by the cross mutual information function, increased significantly for both stressors, suggesting that useful stress indexes may be obtained from EEG-based features.

A bioavailability/bioequivalence and pharmacokinetic study of two oral doses of torasemide (5 and 10 mg): prolonged-release versus the conventional formulation.

1. The main objective of the present study was to compare the bioavailability/bioequivalence of a new prolonged-release (PR) formulation of torasemide with an immediate-release (IR) formulation. In addition, we assessed the pharmacokinetics of both formulations, as well as the urine pharmacodynamics. 2. Two doses (5 and 10 mg) of PR torasemide were compared with the same doses of IR torasemide in a single-blind, single-dose, two-treatment, two-period, cross-over, sequence-randomized clinical trial in 20 healthy volunteers (two groups; n = 10 in each group). Torasemide plasma concentrations were measured by high-pressure liquid chromatography-electrospray ionization mass spectrometry. Torasemide urine concentrations, the diuretic effect of torasemide, urine electrolytes and urine density were also determined. 3. Plasma bioequivalence parameters, based on logged values, were as follows: (i) in the 5 mg group, the area under the plasma drug concentration-time curve from t = 0 to last measurable drug concentration at time t (AUC(0-t)) tablet ratio was 1.03 (90% confidence interval (CI) 0.91-1.17) and C(max) was 0.82 (90% CI: 0.68-0.98); and (ii) in the 10 mg group, the AUC(0-t) was 1.07 (90% CI 0.99-1.14) and C(max) was 0.68 (90% CI 0.60-0.78). The PR formulation showed a significantly prolonged t(max) compared with the IR formulation. The amount of torasemide recovered in the urine 24 h after administration was higher with the PR formulation for both doses. The natriuretic rate versus torasemide excretion rate for the PR and IR formulations were successfully regressed to a sigmoid E(max) model. Pharmacodynamic urine evaluations were similar with both formulations, although urine volume and urine electrolyte excretion were lower for the PR formulation in the first hour after administration. However, the PR formulation showed higher natriuretic efficiency. No significant adverse events were reported. 4. In conclusion, both formulations of torasemide showed similar systemic exposure (AUC). However, the PR formulation had a lower rate of absorption (lower C(max) and prolonged t(max)). The PR formulation had urinary excretion rates that were associated with a higher natriuretic efficiency and more constant diuresis.

Comparison of repeated-dose pharmacokinetics of prolonged-release and immediate-release torasemide formulations in healthy young volunteers.

The major aim of the study was to compare the pharmacokinetic profile of repeated-dose administration of a prolonged-release (PR) formulation of torasemide with that of an immediate-release (IR) dosage. Sixteen volunteers received one daily dose, on four consecutive days, of 10 mg of torasemide-PR or torasemide-IR in a single-blind, two-treatment, two-period, repeated-dose, cross-over, sequence-randomized clinical trial. Blood samples were collected at various time points on day 1 (single-dose) and on day 4 (repeated-dose) and torasemide concentrations were analysed by LC/MS/MS. Diuretic effect and urine electrolytes were measured. Urinary urgency was subjectively assessed by visual analogue scales. Safety and tolerability were also determined. Based on logged values, bioequivalence parameters, were: on day 1, ratio = 1.07 (90% CI 1.02-1.1), C(max) ratio = 0.69 (90% CI 0.67-0.73); and on day 4, ratio = 1.02 (90% CI 0.98-1.05), C(max) ratio = 0.62 (90% CI 0.55-0.70). PR had longer t(max) than IR and showed significantly lower fluctuations of plasma concentrations. Urine evaluations were similar with both formulations, although PR showed a lower urine volume in the first hours post-administration. Episodes of acute urinary urgency occurred later and were subjectively less intensive with PR. No significant adverse events were reported.

Different acute tolerance development to EEG, psychomotor performance and subjective assessment effects after two intermittent oral doses of alprazolam in healthy volunteers.

BACKGROUND/AIMS: Benzodiazepines (BZDs) are the most effective of the psychotropic drugs in the treatment of anxiety disorders. Tolerance has been reported for the majority of BZDs after chronic administration. However, little attention has been paid to the possibility that tolerance might be present after the intermittent oral administration of BZDs. The objectives of the present study were to assess tolerance development after the administration of two intermittent single oral doses of alprazolam given 15 days apart in healthy volunteers, and to compare the results obtained using measures from different domains: neurophysiological, psychomotor and subjective. METHODS: Twenty-four healthy volunteers received 2 mg of alprazolam orally on two experimental days, 15 days apart. Plasma concentrations and pharmacodynamics (PD) were assessed before drug intake and at different times in the following 24 h. PD was assessed through EEG (relative alpha and relative beta-1 activities), cancellation task (total and correct number of responses) and visual analogue scales (activity and drowsiness). RESULTS: No differences were observed in the PKs of alprazolam between occasions. A proteresis was present in both administrations for impairments of psychomotor performance and relative beta-1 activity, whereas it was present only after the second administration for subjective assessments and relative alpha activity. The proteresis on the second occasion was higher than on the first one. CONCLUSIONS: The administration of two single oral doses of alprazolam, 2 weeks apart in healthy volunteers, yielded the same PKs on both occasions, but significant changes were observed in the PD profile. Acute tolerance was observed after the second administration. Two patterns of acute tolerance development were obtained: (1) impairments of psychomotor performance and relative beta-1 activity, and (2) subjective assessments and relative alpha activity.