Manuel-José Barbanoj

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.

Ocular Reduction in EEG Signals Based on Adaptive Filtering, Regression and Blind Source Separation

Quantitative electroencephalographic (EEG) analysis is very useful for diagnosing dysfunctional neural states and for evaluating drug effects on the brain, among others. However, the bidirectional contamination between electrooculographic (EOG) and cerebral activities can mislead and induce wrong conclusions from EEG recordings. Different methods for ocular reduction have been developed but only few studies have shown an objective evaluation of their performance. For this purpose, the following approaches were evaluated with simulated data: regression analysis, adaptive filtering, and blind source separation (BSS). In the first two, filtered versions were also taken into account by filtering EOG references in order to reduce the cancellation of cerebral high frequency components in EEG data. Performance of these methods was quantitatively evaluated by level of similarity, agreement and errors in spectral variables both between sources and corrected EEG recordings. Topographic distributions showed that errors were located at anterior sites and especially in frontopolar and lateral–frontal regions. In addition, these errors were higher in theta and especially delta band. In general, filtered versions of time-domain regression and of adaptive filtering with RLS algorithm provided a very effective ocular reduction. However, BSS based on second order statistics showed the highest similarity indexes and the lowest errors in spectral variables.

Comparison of peripheral and central effects of single and repeated oral dose administrations of bilastine, a new H1 antihistamine: a dose-range study in healthy volunteers with hydroxyzine and placebo as control treatments.

Peripheral anti-H1 and central nervous system (CNS) activities after single (day 1) and repeated (day 7) administrations of increasing doses of bilastine (BIL) were assessed in 20 healthy volunteers throughout a crossover, randomized, double-blind, placebo (PLA)-controlled study. Repeated doses of BIL 20, 40, or 80 mg and hydroxyzine 25 mg (HYD) as positive standard were administered on 7 consecutive days. Before and at several time points after drug intake, skin reactivity to the intradermal injection of histamine, objective tests of psychomotor performance, and subjective mood scales were evaluated. All active treatments led to a significant and similar reduction in the wheal reaction in relation to PLA after both the single (P < 0.001) and repeated administrations (P < 0.001). No delay was observed in the onset of its peripheral activity after the first dose of BIL as compared with HYD. No tolerance or sensitization was seen when comparing acute and repetitive assessments. Central nervous system effects showed that HYD induced the greatest psychomotor impairment (P < 0.05). Repeated HYD intake showed a lower number of significant alterations in comparison to acute administration. Bilastine 80 mg also showed some impairment (P < 0.05). Subjectively, the only active treatment that could not be differentiated from PLA was BIL 20 mg. Hydroxyzine 25 mg showed the greatest differentiation (P < 0.01). A clear dissociation between peripheral anti-H1 and CNS activity was found after BIL treatment. Significant and sustained peripheral H1-blocking effects were observed after both single and repeated administrations of the therapeutic dose of 20 mg BIL. The 40-mg dose of BIL produced subjective report of sedation, whereas unwanted objective CNS side effects were observed only with the 80-mg dose.

Repeated co-administration of caffeine and bromocriptine prevents tolerance to the effects of caffeine in the turning behavior animal model

The present study examined the effects of repeated co-administrations of caffeine and bromocriptine for 9 consecutive days on contralateral turning in unilateral nigrostriatal 6-hydroxydopamine denervated rats. In agreement with previous data, our results showed that on the first administration, both caffeine and bromocriptine injected plus saline produced a significant increase in contralateral rotational behavior as compared to saline-saline injections. However, with repeated administrations, tolerance was observed to caffeine, but not to bromocriptine. The combination of different doses of bromocriptine (0.1, 0.2, 0.4 and 0.8 mg/kg) with caffeine (40 mg/kg) significantly enhanced the effects of either drug injected with saline on rotational behavior, and no tolerance was observed with repeated treatment. The continuous co-administration of both substances was necessary to maintain elevated levels of rotational behavior, since withdrawing one or the other drug led to decreased contralateral turning. These results demonstrate that when caffeine is administered repeatedly in combination with bromocriptine, tolerance to its psychostimulant effects is not observed, suggesting that caffeine could be used as an adjunctive therapeutic agent with dopamine agonists for the treatment of Parkinsons disease.

Methylxanthines Reverse the Adipsic and Aphagic Syndrome Induced by Bilateral 6-Hydroxydopamine Lesions of the Nigrostriatal Pathway in Rats

This study investigated whether methylxanthines (caffeine and theophylline) would restore food and water intake in rats made aphagic and adipsic by bilateral 6-hydroxydopamine lesions of the nigrostriatal bundle, and these results were compared with the effects of d-amphetamine, the dopamine D(1) agonist SKF 38393, and the D(2/3) agonist quinpirole. In a separate experiment, we investigated whether the selective D(1) antagonist, SCH 23390, or the selective D(2) antagonist, sulpiride, would prevent the caffeine-induced restoration of food and water intake in bilaterally 6-hydroxydopamine denervated rats. The results showed that caffeine, theophylline, and quinpirole significantly reversed the aphagia and adipsia observed in lesioned animals. SKF 38393 had no significant effects on water intake, while it significantly restored food intake at the highest dose used. In contrast, d-amphetamine had no significant effects on food or water intake. Results from the second experiment showed that sulpiride attenuated the caffeine-induced restoration of food and water intake in lesioned rats to a greater extent than did SCH 23390. These data suggest that methylxanthines may mediate their effects on food and water intake in bilateral 6-hydroxydopamine-lesioned rats through an action at the dopaminergic system.

Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study

AIM The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. METHODS Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. RESULTS Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. CONCLUSION Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations.

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 µg/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.

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.

Sex differences in sleep after a single oral morning dose of olanzapine in healthy volunteers

Polysomnography abnormalities are frequent in schizophrenia and have been correlated with clinical variables. Because women with schizophrenia present a general better clinical outcome than men, we aimed to determine whether sex differences in antipsychotic‐induced effects on sleep could contribute to this difference.

Waking and Sleep Electroencephalogram Variables as Human Sleep Homeostatic Process Biomarkers after Drug Administration

Background/Aims: The correlation between theta activity during wakefulness and slow-wave activity (SWA) during sleep observed after sleep deprivation suggests such patterns can be used as electroencephalogram (EEG) biomarkers of the sleep homeostasis process. Since these EEG components would be very useful objective measures to assess CNS drug effects, we investigated whether the relationship between sleep homeostatic EEG biomarkers could be reproduced after an experimental pharmacological intervention. Methods: Seventeen healthy volunteers took part in a phase I randomized, double-blind, crossover design study. To increase sleep propensity, all participants received a single morning oral dose of olanzapine (5 mg) and placebo. Quantitative EEG analysis was done by power spectra calculations: theta activity (3.5–7.5 Hz) during wakefulness and SWA (0.5–4.0 Hz) during sleep. The relationship between the 2 EEG parameters was assessed by correlating the rise rate (percent/hour) of theta activity in wakefulness and the increase (percent) of SWA in the first non-REM sleep episode. Results: Following olanzapine administration we observed increases in theta activity during wakefulness, and increases in total sleep time, sleep efficiency and slow-wave sleep time during sleep. However, a weak and unreliable correlation was observed between the increases in theta activity and changes in sleep SWA. Conclusions: From these results, we cannot affirm that these waking and sleep EEG variables behave as biomarkers of human sleep homeostasis after drug administration. It is possible that these EEG biomarkers reflect different physiological mechanisms if they are assessed during drug CNS effects.