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.

Comparative pharmacodynamic time-course of bemiparin and enoxaparin in healthy volunteers.

UNLABELLED: Low-molecular-weight heparins (LMWHs) are antithrombotic drugs that differ on biochemical and pharmacological properties. OBJECTIVE: This study was conducted to compare the pharmacodynamic time-course of two LMWHs, bemiparin and enoxaparin, at high prophylactic doses. METHODS: This was an open, randomized, single-blind, cross-over study to compare the pharmacodynamic time-course, safety and tolerability of two LMWHs, bemiparin 3500 IU and enoxaparin 4000 IU at subcutaneous single doses in 12 healthy male volunteers. Anti-Xa activity (main biomarker of heparin activity), anti-IIa activity, total and free tissue factor pathway inhibitor (TFPI), activated partial thromboplastin time (APTT), thrombin time (TT) and thromboplastin-thrombomodulin mediated time (Tp-TmT) were investigated. RESULTS: Bemiparin 3500 IU achieved more anti-Xa activity than enoxaparin 4000 IU, measured by the area under the curve (geometric mean AUC0t) (bemiparin 3.69 vs. enoxaparin 3.33 IU h/ml; p < 0.001). Maximum anti-Xa activity was reached at 3 hours and there were anti-Xa measurable levels up to 16 h after subcutaneous administration. Anti-Xa activity half-life was 5.44 hours for bemiparin and 4.71 hours for enoxaparin. Anti-IIa activity was above the limit of quantification (0.05 IU/ml) in only 2 volunteers after bemiparin and in 8 after enoxaparin. The "in-vivo" anti-Xa:IIa ratios were: bemiparin 37.9 (95% CI: 28.0 - 55.3, n = 2) and enoxaparin 16.3 (95% CI: 12.2 - 23.4, n = 8). Enoxaparin induced a higher release of total TFPI, but not on free TFPI, and a longer prolongation of APTT and TT (Emax) than bemiparin, with no differences between groups on Tp-TmT. Adverse events (one in each group) were mild and transient. CONCLUSION: Bemiparin 3500 IU showed more anti-Xa activity and higher anti-Xa: anti-IIa relationship than enoxaparin 4000 IU in healthy volunteers. Both treatments were well tolerated.

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.

Fármacos que pueden producir somnolencia excesiva / Drugs promoting excessive sleepiness

La somnolencia es un acontecimiento frecuente y fisiológico en ciertas circunstancias. La somnolencia excesiva durante el día se caracteriza por una sensación anormal de sueño con fuerte tendencia a dormirse en situaciones o momentos inapropiados, que debe diferenciarse de la fatiga. Entre las posibles causas de una somnolencia excesiva diurna está el consumo de fármacos. Hay dos posibilidades por las que los fármacos pueden considerarse como agentes etiológicos: a) a través de un mecanismo indirecto (compuestos que alteran la cantidad y la calidad del sueño y condicionan su fragmentación o deprivación) o b) por un efecto directo que propicia de forma mediada un aumento de la somnolencia diurna. Este favorecimiento de la somnolencia diurna debería identificarse como reacción adversa. Se describen los nuevos términos que la investigación de los mecanismos implicados en el control de la sucesión de sueño-vigilia está introduciendo en la farmacología de los fármacos productores de sueño: hipnóticos, promotores del sueño, intensificadores del sueño, modificadores de la biestabilidad y cronobióticos. Se identifican los factores farmacocinéticos que principalmente determinan la duración del efecto hipnótico tras administración única (volumen de distribución) y tras administración múltiple (eliminación) y se expone la importante variación interindividual en la frecuencia e intensidad con que los fármacos inducen una somnolencia excesiva. Por último, se completa la visión del posible impacto de los fármacos sobre el ciclo sueño-vigilia refiriendo los posibles efectos durante la noche de los fármacos tomados por la mañana, enfatizando la importancia de considerar el proceso como un todo continuo y no como compartimentos estancos (AU)

In certain circumstances sleepiness is a frequent and physiological event. Excessive daytime sleepiness is characterized by an abnormal sleep sensation with a strong tendency to fall asleep in inappropriate situations and time moments, which should be differentiated from fatigue. Among the possible causes of excessive daytime sleepiness there is drug consumption. There are two different possibilities to consider drugs as etiological agents: a)thought an indirect mechanism (compounds disrupting sleep quantity and quality resulting in sleep fragmentation or deprivation) or b) by a straight effect directly promoting an increase of daytime sleepiness. This promotion of daytime sleepiness should be identified as an adverse reaction. The new terms that research on the mechanisms which control the wake-sleep cycle is introducing in the pharmacology of drugs favouring sleep are described: hypnotics, sleep promoters, sleep enhancers, bi-stability modifiers and chronobiotics. The pharm acokinetic factors which mainly determine the duration of the hypnotic effects are identified, either after a single administration (volume of distribution) or after a repetitive administration (elimination) and the important interindividual variation in frequency and intensity of drug induced excessive sleepiness is explained. Lastly, the description of the potential drug impact on the wake-sleep cycle is completed by referring thee ventual effects that drug ingestion at morning time could induce during the night, highlighting the importance to consider the process as a continuum non-compartmental one (AU)

Quantifying drug-drug interactions in pharmaco-EEG.

A drug interaction refers to an event in which the usual pharmacological effect of a drug is modified by other factors, most frequently additional drugs. When two drugs are administered simultaneously, or within a short time of each other, an interaction can occur that may increase or decrease the intended magnitude or duration of the effect of one or both drugs. Drugs may interact on a pharmaceutical, pharmacokinetic or pharmacodynamic basis. Pharmacodynamic interactions arise when the alteration of the effects occurs at the site of action. This is a wide field where not only interactions between different drugs are considered but also drug and metabolites (midazolam/alpha-hydroxy-midazolam), enantiomers (ketamine), as well as phenomena such as tolerance (nordiazepam) and sensitization (diazepam). Pharmacodynamic interactions can result in antagonism or synergism and can originate at a receptor level (antagonism, partial agonism, down-regulation, up-regulation), at an intraneuronal level (transduction, uptake), or at an interneuronal level (physiological pathways). Alternatively, psychotropic drug interactions assessed through quantitative pharmaco-EEG can be viewed according to the broad underlying objective of the study: safety-oriented (ketoprofen/theophylline, lorazepam/diphenhydramine, granisetron/haloperidol), strictly pharmacologically-oriented (benzodiazepine receptors), or broadly neuro-physiologically-oriented (diazepam/buspirone). Methodological issues are stressed, particularly drug plasma concentrations, dose-response relationships and time-course of effects (fluoxetine/buspirone), and unsolved questions are addressed (yohimbine/caffeine, hydroxizyne/alcohol).

Pharmacokinetics of a new Autogel formulation of the somatostatin analogue lanreotide after a single subcutaneous dose in healthy volunteers.

The pharmacokinetics/tolerability of lanreotide Autogel have been evaluated. Healthy volunteers (n = 24) first received immediate-release lanreotide as a single subcutaneous (s.c.) injection. After two days, 40 or 60 mg lanreotide Autogel was injected subcutaneously. Blood was sampled at various intervals for 56 days. Systemic/local adverse events and changes in biological profile/vital signs were recorded. Lanreotide Autogel produced a prolonged-release pharmacokinetic profile: mean area under the serum concentration-time curve from time 0 to infinity (AUC) was 53.73 +/- 8.99 and 79.48 +/- 13.06 ng mL(-1) day for 40 and 60 mg, respectively, mean peak serum concentration (C(max)) was 4.38 +/- 2.91 and 5.71 +/- 3.52 ng mL(-1), respectively, median time to reach C (minimum-maximum) was 0.50 (0.083-18.0) and 0.38 (0.083-9.01) days, respectively, mean apparent elimination half-life was 21.63 +/- 9.42 and 22.01 +/- 9.87 days, respectively, and relative bioavailability was 0.93 +/- 0.12 and 0.82 +/- 0.15, respectively. Thus, lanreotide Autogel exhibited linear pharmacokinetics for the doses studied. Pharmacokinetic profiles were similar in both genders, apart from statistically significant differences in C(max) and C(max)/AUC. The Autogel formulation of lanreotide was well tolerated, with systemic adverse events being mild/moderate. Erythema and a painless subcutaneous induration were the most common local adverse events. Lanreotide Autogel provided a prolonged dosing interval and good tolerability for treating acromegaly and carcinoid syndrome.

A study comparing the inhibitory effects of single and repeated oral doses of ebastine and fexofenadine against histamine-induced skin reactivity.

OBJECTIVE: The aim of this double-blind, randomized, crossover, placebo-controlled clinical trial was to compare the inhibition of the histamine-induced skin reaction induced by ebastine 20 mg with respect to that induced by fexofenadine 120 mg or placebo. METHODS: Eighteen volunteers (10 males, 8 females) received the three treatments once daily for 5 days, with a mean 7-day washout period between treatments. Intradermal tests, using 0.05 ml from a solution containing 100 microg/ml of histamine, were performed at baseline and at 1, 1.5, 2, 3, 10 and 24 h after a single dose and repeated 5-day dose, and in addition after 34, 48, 58 and 72 h after repeated 5-day dose. RESULTS: After 24 h of acute administration, ebastine 20 mg was significantly more effective than fexofenadine 120 mg in reducing the wheal and flare induced by histamine challenge (p<0.001). Although fexofenadine 120 mg had the shortest onset of action (1.5 vs. 3 h in ebastine 20 mg), the duration of its antihistamine effect was the shortest (24 vs. 58 h in ebastine 20 mg) and wheal reduction after 24 h was not significantly different from placebo. The overall effect after single and repeated 5-day dose, expressed as the AUC of reduction of wheal and flare area (%/h), showed the following order of magnitude: ebastine 20 mg>fexofenadine 120 mg>placebo. No significant differences in the incidence of adverse events were found between the three treatments. CONCLUSIONS: The present results clearly show a superior and long-acting effect of ebastine 20 mg compared with fexofenadine 120 mg on the skin response to histamine 24 h after dosing.

Basics of PK-PD using QEEG: acute/repetitive administration, interactions. Focus on anxiolytics with different neurochemical mechanisms as examples.

Utilizing computer-assisted quantitative analysis of the electroencephalogram (EEG) in combination with certain statistical procedures and under specific design conditions, it is possible to objectively evaluate the functional bioavailability of psychotropic substances in the target organ: the human brain. Specifically, one may determine whether a drug is active in the central nervous system (CNS) compared with placebo in humans, the dose effect (including nonmonotonic drug effects along the continuum range of concentrations) and the time effect (including time-dependent pharmacodynamic phenomena as tolerance and sensitization), as well as its activity in relation to the formulation and route of application. Methodological aspects are introduced, discussing the usefulness of evaluating different treatments, doses, time points, states, target variables, electrodes and even different groups. Several issues are raised in relation to acute vs. repetitive administration, particularly those dealing with statistical comparisons when making conclusions about acute, repetitive or superimposed effects, and in relation to human psychotropic interactions, such as mechanistic drug-drug interaction descriptions, drug metabolites and enantiomers, as well as the importance of acquiring drug plasma concentrations, elapse of time and topographic distributions to accurately identify its occurrence. PK-PD modeling is introduced as a tool to enlarge the scope of inferences that can be derived when using pharmaco-EEG. The examples presented in order to develop the arguments are mainly focused on anxiolytic compounds belonging to the different neurochemical groups, benzodiazepines and azaspirones. Questions that have yet to been resolved are also addressed.

Clinical pharmacokinetics of dexketoprofen.

Dexketoprofen trometamol is a water-soluble salt of the dextrorotatory enantiomer of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen. Racemic ketoprofen is used as an analgesic and an anti-inflammatory agent, and is one of the most potent in vitro inhibitors of prostaglandin synthesis. This effect is due to the (S)-(+)-enantiomer (dexketoprofen), while the (R)-(-)-enantiomer is devoid of such activity. The racemic ketoprofen exhibits little stereoselectivity in its pharmacokinetics. Relative bioavailability of oral dexketoprofen (12.5 and 25mg, respectively) is similar to that of oral racemic ketoprofen (25 and 50mg, respectively), as measured in all cases by the area under the concentration-time curve values for (S)-(+)-ketoprofen. Dexketoprofen trometamol, given as a tablet, is rapidly absorbed, with a time to maximum plasma concentration (tmax) of between 0.25 and 0.75 hours, whereas the tmax for the (S)-(+)-enantiomer after the racemic drug, administered as tablets or capsules prepared with the free acid, is between 0.5 and 3 hours. The drug does not accumulate significantly when administered as 25mg of free acid 3 times daily. The profile of absorption is changed when dexketoprofen is ingested with food, reducing both the rate of absorption (tmax) and the maximal plasma concentration. Dexketoprofen is strongly bound to plasma proteins, particularly albumin. The disposition of ketoprofen in synovial fluid does not appear to be stereoselective. Dexketoprofen trometamol is not involved in the accumulation of xenobiotics in fat tissues. It is eliminated following extensive biotransformation to inactive glucuroconjugated metabolites. No (R)-(-)-ketoprofen is found in the urine after administration of dexketoprofen, confirming the absence of bioinversion of the (S)-(+)-enantiomer in humans. Conjugates are excreted in urine, and virtually no drug is eliminated unchanged. The analgesic efficacy of the oral pure (S)-(+)-enantiomer is roughly similar to that observed after double dosages of the racemic compound. At doses above 7mg, dexketoprofen was significantly superior to placebo in patients with moderate to severe pain. A dose-response relationship between 12.5 and 25mg could be seen in the time-effects curves, the superiority of the 25mg dose being more a result of an extended duration of action than of an increase in peak analgesic effect. A plateau in the analgesic activity of dexketoprofen trometamol at the 25mg dose is suggested. The time to onset of pain relief appeared to be shorter in patients treated with dexketoprofen trometamol. The drug was well tolerated.

Pharmacokinetics of dexketoprofen trometamol in healthy volunteers after single and repeated oral doses.

The pharmacokinetics of dexketoprofen trometamol were evaluated in two studies using healthy volunteers. In the first study, the relative bioavailability of a single oral capsule of dexketoprofen free acid 25 mg or dexketoprofen trometamol 25 mg (given as 37 mg of the trometamol salt) was compared to ketoprofen 50 mg in 18 healthy volunteers. In the second study, the pharmacokinetics and tolerability of oral dexketoprofen trometamol in tablet form were evaluated after either a single 25 mg dose (24 volunteers) or a repeated dose of 25 mg twice daily for 7 days (12 volunteers). The absorption of dexketoprofen from dexketoprofen trometamol capsules was bioequivalent to that of ketoprofen. On the other hand, the extent of absorption of dexketoprofen free acid was significantly lower than that for ketoprofen. Dexketoprofen trometamol showed the most rapid absorption rate, with highest Cmax and shortest t(max) values, whereas dexketoprofen free acid had the slowest absorption rate, and ketoprofen had an intermediate absorption rate. After repeated-dose administration of dexketoprofen trometamol, the pharmacokinetic parameters were similar to those obtained after single doses, indicating that no drug accumulation occurred. Dexketoprofen trometamol was well tolerated, with no clinically relevant adverse events reported.

Evaluation of psychotropic drug consumption related to psychological distress in the elderly: hospitalized vs. nonhospitalized.

The use of psychotropic drugs in general has become more extended in the past 20 years. The elderly, particularly geriatric inpatients, are the group with the highest consumption. The aim of the present study was to evaluate in two groups of elderly, hospitalized patients (H) vs. nonhospitalized subjects (nH), psychotropic drug consumption related to psychological distress. This was carried out in a total 238 subjects aged above 65 years (112 geriatric inpatients and 126 interviewed in social welfare centers). Sociodemographic, clinical and pharmacological data, general health and psychological distress were evaluated. The latter was assessed by means of the Symptom Distress Checklist (SCL-90) which included 9 subscales. 23% of the subjects received psychotropic drugs (P), of which 84% were benzodiazepines, 10% antidepressants and 1.5% antipsychotics. After evaluating the SCL-90 subscales, it was noted that anxiety, depression and obsessiveness/compulsiveness scored higher in P subjects than in those not receiving psychotropic drugs (nP). When treated nH and H were analyzed separately, it was observed that the former scored higher in anxiety and depression, while the latter showed higher scores in anxiety and obsessiveness/compulsiveness. Considered globally, the H group compared to nH showed higher scores in depression. Although evaluating psychotropic drug utilization in geriatric patients is complex due to the large number of influencing factors, SCL-90 has proved to be useful for assessing the qualitative aspects of this drug consumption in the elderly.