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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 α and relative β-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 β-1 activity, whereas it was present only after the second administration for subjective assessments and relative α 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 β-1 activity, and (2) subjective assessments and relative α activity. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The time course of the pupillary light reflex (PLR) is determined by the successive activation of parasympathetic and sympathetic innervations of the iris, latency and amplitude reflecting parasympathetic activity and recovery time showing mainly sympathetic activity. Objective: To determine the effects of tobacco cigarette smoking on the PLR in smokers after an abstinence period of at least 12 h. Methods: Ten smokers (mean 15.7 cigarettes/day) and 10 non-smokers participated in a randomised, non-intervention controlled, cross-over study that included a parallel control group. Smokers underwent two sessions with a time interval between 3 and 8 days; two recordings were taken at each session, separated by 20 min: session 1, without smoking, and session 2, smoking 3 cigarettes within a 30-min period. Non-smokers underwent one session; two recordings were taken separated by 20 min. At each recording, in both groups, PLR was elicited with four light flashes of increasing luminance. Results: The relationship between PLR parameters and light intensity was linear in each subject. The slope of the regression line for relative amplitude increase versus intensity was significantly flatter in abstinent smokers than in non-smokers (p = 0.033); the slope returned significantly after smoking (p = 0.043). No other significant effects were obtained. Conclusions: Kinetic parameters of PLR provide a sensitive pharmacological test to detect cholinergic neurotransmission manipulation effects, as they seem to detect changes in moderate smokers after 12 h of abstinence, and their reversal on return to smoking. These results suggest an enhancement in the suppression of the parasympathetic oculomotor reflex arc rather than a facilitation of the sympathetic drive to the iris. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]