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Evaluation of the cognitive, psychomotor and pharmacokinetic profiles of rupatadine, hydroxyzine and cetirizine, in combination with alcohol, in healthy volunteers.

INTRODUCTION: The Central Nervous System (CNS) impairment induced by moderate alcohol (ALC) ingestion may be enhanced if other drugs are taken simultaneously. Rupatadine (RUP) is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release in inflammatory reactions. OBJECTIVE: The main aim of the study was to assess the effects of ALC 0.8 g/Kg on RUP (10 mg and 20 mg) CNS effects. An evaluation of alcohol and RUP pharmacokinetics was also attained. METHODS: Eighteen healthy young volunteers of both sexes participated in a phase I, randomised, crossover, double-blind, placebo-controlled study. At 2-week intervals they received six treatments: (a) placebo (PLA), (b) ALC alone and ALC in combination with: (c) hydroxyzine 25 mg (HYD), (d) cetirizine 10 mg (CET), (e) RUP 10 mg or (f) RUP 20 mg. At baseline and several times thereafter, seven psychomotor performance tests (finger tapping, fine motoric skills, nystagmus, temporal estimation, critical-flicker-fusion frequency, 'd2' cancellation, simple reaction) and eleven subjective self-reports (drunkenness, sleepiness, alertness, clumsiness, anger, inattentiveness, efficiency, happiness, hostility, interest and extraversion) were carried out. Two-way (treatment, time) ANOVAs for repeated measures to each variable together with a multivariate non-parametric approach were applied. Plasma concentrations of alcohol, and of RUP and its metabolites, were quantified by validated immunofluorescence and LC/MS/MS methods, respectively. Plasma-time curves for all compounds were analysed by means of model-independent methods. RESULTS: The combination of alcohol with HYD, CET and RUP 20 mg produced more cognitive and psychomotor impairment as compared to alcohol alone, being the combination of alcohol and HYD the one which induced the greatest deterioration. The combination of alcohol and RUP 10 mg could not be differentiated from ALC alone. Subjective self-reports reflect effects on metacognition after the combination of alcohol with HYD and CET i.e. the increased objective impairment observed was not subjectively perceived by the subjects. No significant differences were obtained when comparing alcohol plasma concentrations assessed after the treatments evaluated. RUP showed a lineal kinetic relationship after 10 and 20 mg with a higher exposition to both metabolites assayed. CONCLUSIONS: Present results showed that single oral doses of rupatadine 10 mg in combination with alcohol do not produce more cognitive and psychomotor impairment than alcohol alone. Higher doses of rupatadine, in combination with alcohol, may induce cognitive and psychomotor deterioration as hydroxyzine and cetirizine at therapeutic doses.

Central and peripheral evaluation of rupatadine, a new antihistamine/platelet-activating factor antagonist, at different doses in healthy volunteers.

AIMS: To assess peripheral anti-H1 and central nervous system (CNS) activity of single increasing doses of rupatidine fumarate (RU), a new antihistamine/platelet-activating factor antagonist compound, in comparison with hydroxyzine and placebo. METHODS: Eighteen healthy young subjects of both sexes took part in a crossover, randomised, double-blind, placebo-controlled study. Treatments tested were: RU 10, 20, 40 and 80 mg and hydroxyzine 25 mg, as a positive standard. Before and several times after drug intake, peripheral anti-H1 activity was appraised by the skin reactivity to intradermal injection of histamine. CNS effects were also obtained by objective tests of psychomotor performance and subjective mood scales. RESULTS: All active treatments showed a significant reduction of the wheal and flare reaction in relation to placebo, RU displaying a potent dose-dependent inhibition pattern. The global nonparametric Friedman test to changes from placebo in 15 objective variables from psychomotor performance showed a significant impairment of similar magnitude after hydroxyzine 25 mg (p = 0.01) and RU 80 mg (p = 0.02), but this was slower in development and recovery after the latter. After RU 40 mg, a smaller impairment was also obtained (p = 0.04). Activity (p = 0.01) and drowsiness (p = 0.02) scales showed significant changes, the subjects feeling less active and more drowsy after all active treatments. CONCLUSION: RU presents a potent dose-dependent peripheral anti-H1 activity, displaying psychomotor impairment activity only at the highest dose (80 mg), while therapeutically relevant lower doses (10 and 20 mg) were similar to placebo.

Effects of the South American psychoactive beverage ayahuasca on regional brain electrical activity in humans: a functional neuroimaging study using low-resolution electromagnetic tomography.

Ayahuasca, a South American psychotropic plant tea obtained from Banisteriopsis caapi and Psychotria viridis, combines monoamine oxidase-inhibiting beta-carboline alkaloids with N,N-dimethyltryptamine (DMT), a psychedelic agent showing 5-HT(2A) agonist activity. In a clinical research setting, ayahuasca has demonstrated a combined stimulatory and psychedelic effect profile, as measured by subjective effect self-assessment instruments and dose-dependent changes in spontaneous brain electrical activity, which parallel the time course of subjective effects. In the present study, the spatial distribution of ayahuasca-induced changes in brain electrical activity was investigated by means of low-resolution electromagnetic tomography (LORETA). Electroencephalography recordings were obtained from 18 volunteers after the administration of a dose of encapsulated freeze-dried ayahuasca containing 0.85 mg DMT/kg body weight and placebo. The intracerebral power density distribution was computed with LORETA from spectrally analyzed data, and subjective effects were measured by means of the Hallucinogen Rating Scale (HRS). Statistically significant differences compared to placebo were observed for LORETA power 60 and 90 min after dosing, together with increases in all six scales of the HRS. Ayahuasca decreased power density in the alpha-2, delta, theta and beta-1 frequency bands. Power decreases in the delta, alpha-2 and beta-1 bands were found predominantly over the temporo-parieto-occipital junction, whereas theta power was reduced in the temporomedial cortex and in frontomedial regions. The present results suggest the involvement of unimodal and heteromodal association cortex and limbic structures in the psychological effects elicited by ayahuasca.

Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers.

AIMS: Ayahuasca is a traditional South American psychoactive beverage used in Amazonian shamanism, and in the religious ceremonies of Brazilian-based syncretic religious groups with followers in the US and several European countries. This tea contains measurable amounts of the psychotropic indole N,N-dimethyltryptamine (DMT), and beta-carboline alkaloids with MAO-inhibiting properties. In a previous report we described a profile of stimulant and psychedelic effects for ayahuasca as measured by subjective report self-assessment instruments. In the present study the cerebral bioavailability and time-course of effects of ayahuasca were assessed in humans by means of topographic quantitative-electroencephalography (q-EEG), a noninvasive method measuring drug-induced variations in brain electrical activity. METHODS: Two doses (one low and one high) of encapsulated freeze-dried ayahuasca, equivalent to 0.6 and 0.85 mg DMT kg(-1) body weight, were administered to 18 healthy volunteers with previous experience in psychedelic drug use in a double-blind crossover placebo-controlled clinical trial. Nineteen-lead recordings were undertaken from baseline to 8 h after administration. Subjective effects were measured by means of the Hallucinogen Rating Scale (HRS). RESULTS: Ayahuasca induced a pattern of psychoactive effects which resulted in significant dose-dependent increases in all subscales of the HRS, and in significant and dose-dependent modifications of brain electrical activity. Absolute power decreased in all frequency bands, most prominently in the theta band. Mean absolute power decreases (95% CI) at a representative lead (P3) 90 min after the high dose were -20.20+/-15.23 microV2 and -2.70+/-2.21 microV2 for total power and theta power, respectively. Relative power decreased in the delta (-1.20+/-1.31% after 120 min at P3) and theta (-3.30+/-2.59% after 120 min at P3) bands, and increased in the beta band, most prominently in the faster beta-3 (1.00+/-0.88% after 90 min at P3) and beta-4 (0.30+/-0.24% after 90 min at P3) subbands. Finally, an increase was also seen for the centroid of the total activity and its deviation. EEG modifications began as early as 15-30 min, reached a peak between 45 and 120 min and decreased thereafter to return to baseline levels at 4-6 h after administration. CONCLUSIONS: The central effects of ayahuasca could be objectively measured by means of q-EEG, showing a time pattern which closely paralleled that of previously reported subjective effects. The modifications seen for the individual q-EEG variables were in line with those previously described for other serotonergic psychedelics and share some features with the profile of effects shown by pro-serotonergic and pro-dopaminergic drugs. The q-EEG profile supports the role of 5-HT2 and dopamine D2-receptor agonism in mediating the effects of ayahuasca on the central nervous system.