A combined neurophysiological and behavioural study into the stimulating effects of fexofenadine on performance
ABSTRACT Antihistamines are known for their sedative effects. However, some studies suggested mild stimulant effects in the case of fexofenadine. The goals of this study are to examine whether fexofenadine possesses stimulating properties and to determine whether such stimulating effects are related to workload. Sixteen healthy volunteers received a single dose of 180 and 360 mg fexofenadine and placebo on separate test days. Drug effects were assessed using a divided attention task (DAT), continuous performance task (CPT) and motor choice reaction time test (MCRT). Sensitivity of the tasks was increased by manipulating the workload during task performance. Event Related brain Potentials (ERPs) were measured in the DAT and CPT to study the underlying neurophysiological processes. An interaction effect of Treatment and Workload was found on tracking performance in the DAT and on movement time in the MCRT. Performance on the DAT was less affected by increments in workload after fexofenadine as compared to placebo. P1 and P3 latency were affected by Treatment x Workload and Treatment respectively and indicated faster attentional and information processing latencies following fexofenadine treatment. Treatment did not influence performance in the CPT task or in the ERPs measured during this task. The MCRT demonstrated faster movement times following fexofenadine treatment. These results suggest that although the neurophysiological data indicate central nervous system (CNS) activation after fexofenadine treatment, the magnitude of the centrally activating effects is too small to produce relevant performance improvement at the behavioural level.
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ABSTRACT: RATIONALE: P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates. OBJECTIVES: The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans. METHODS: An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone. RESULTS: The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus. CONCLUSION: It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.Psychopharmacology 04/2013; DOI:10.1007/s00213-013-3075-z · 3.99 Impact Factor
Journal of clinical psychopharmacology 04/2013; 33(2):276-9. DOI:10.1097/JCP.0b013e31828052ac · 3.76 Impact Factor
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ABSTRACT: It is well known that the sedative properties of antihistamines can differ considerably between individual drugs. Several factors have been suggested to determine the presence, absence, and/or magnitude of sedation by antihistamines. Research has suggested that the sedative effects caused by central H1 blockade partly depend on the availability of histamine competing for the same receptor and that this competition is affected by a mechanism related to sleep. Consequently, the present study was designed to compare the effects of evening and morning doses of the first-generation antihistamine hydroxyzine on cognition. It was expected that the sedative effect of hydroxyzine would be apparent in the evening after an evening dose but would be smaller in the morning after a morning dose owing to the greater release of histamine shortly after awakening. Eighteen participants (9 females) participated in a placebo-controlled, randomized, double-blind 3-way crossover design. Performance was assessed using several psychomotor tests: that is, divided attention task, critical tracking task, stop signal task, the attention network test, and the experimental attention switch task. Results demonstrated that evening doses of hydroxyzine impaired performance on the divided attention and the attention network test. Impairment after morning doses was generally larger in magnitude and affected performance measures in all tasks. It is concluded that hydroxyzine-induced impairment at tmax is more prominent after morning doses compared with evening doses and that the present study could not present direct evidence to substantiate the hypothesis that histamine availability inversely affects the magnitude of antihistamine impairment.Journal of clinical psychopharmacology 06/2011; 31(3):294-301. DOI:10.1097/JCP.0b013e318218943c · 3.76 Impact Factor