RESUMO
OBJECTIVE: The aim of this study was to compare the effects of concomitant administration of alcohol and bilastine versus alcohol alone on the central nervous system. METHODS: Twenty-four healthy young volunteers of both sexes participated in a randomized, double-blind, double-dummy, crossover, and positive-controlled and placebo-controlled clinical trials. At 1-week intervals, subjects received six different treatments: (i) placebo; (ii) alcohol 0.8 g/kg alone (ALC); (iii) ALC in combination with: bilastine 20 mg (B20 + A); (iv) bilastine 80 mg (B80 + A); (v) cetirizine 10 mg (CET + A); and (vi) hydroxyzine 25 mg (HYD + A). Psychomotor performance tests (fine motor, finger tapping, nystagmus, critical flicker-fusion frequency, temporal estimation, 'd2' cancellation, and simple reaction time) and subjective self-reports (drunkenness, drowsiness, mental slowness, clumsiness, anger, attentiveness, competence, happiness, hostility, interest, and extroversion) were carried out at baseline and multiple points thereafter. RESULTS: All active treatments induced a significant psychomotor impairment. The greatest and most lasting impairment was observed with HYD + A followed by B80 + A and CET + A. In contrast, objective measures showed less impairment with B20 + A and ALC, both with a similar magnitude. Self-reports showed a subjective perception of performance impairment in all active treatments. CONCLUSION: Concomitant administration of bilastine (at therapeutic dose) and alcohol does not produce greater central nervous system depressant effects than ACL alone.
Assuntos
Benzimidazóis/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Cetirizina/farmacologia , Etanol/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Hidroxizina/farmacologia , Piperidinas/farmacologia , Adolescente , Adulto , Afeto/efeitos dos fármacos , Consumo de Bebidas Alcoólicas , Benzimidazóis/efeitos adversos , Depressores do Sistema Nervoso Central/efeitos adversos , Cetirizina/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Etanol/efeitos adversos , Feminino , Antagonistas dos Receptores Histamínicos/efeitos adversos , Humanos , Hidroxizina/efeitos adversos , Masculino , Piperidinas/efeitos adversos , Desempenho Psicomotor/efeitos dos fármacos , Fatores Sexuais , Adulto JovemRESUMO
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.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Ciproeptadina/análogos & derivados , Antagonistas dos Receptores Histamínicos H1/farmacologia , Lorazepam/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Adulto , Estudos Cross-Over , Ciproeptadina/administração & dosagem , Ciproeptadina/farmacologia , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Humanos , Lorazepam/administração & dosagem , MasculinoRESUMO
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.
Assuntos
Afeto/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Dermatite de Contato/prevenção & controle , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Hidroxizina/administração & dosagem , Piperidinas/administração & dosagem , Desempenho Psicomotor/efeitos dos fármacos , Administração Oral , Adulto , Atenção/efeitos dos fármacos , Benzimidazóis/efeitos adversos , Estudos Cross-Over , Dermatite de Contato/etiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Histamina/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Hidroxizina/efeitos adversos , Injeções Intradérmicas , Testes Intradérmicos , Masculino , Percepção/efeitos dos fármacos , Piperidinas/efeitos adversos , Tempo de Reação/efeitos dos fármacos , Valores de Referência , Adulto JovemRESUMO
BACKGROUND: Ebastine is a long-acting, second-generation, selective histamine H1-receptor antagonist. A fast-dissolving tablet formulation of ebastine has been developed at 10- and 20-mg doses, with the intention of facilitating administration to patients experiencing problems with swallowing, including those confined to bed and elderly people, as well as those who may need to use ebastine when they do not have easy access to water to aid swallowing a tablet. OBJECTIVES: This study was conducted to assess the pharmacodynamic effects (ie, inhibition of wheal response to cutaneous histamine challenge, and subjective assessments of itching, flare, and pain) and tolerability of the fast-dissolving 20-mg ebastine tablet formulation compared with desloratadine 5-mg capsule and placebo. Acceptability and convenience of the fast-dissolving tablet were also evaluated. METHODS: This double-blind, double-dummy, randomized, placebo-controlled, 3-period crossover study was conducted at the Drug Research Centre, Department of Clinical Pharmacology, the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Healthy, nonatopic, white adults aged 18 to 40 years were randomly assigned to 1 of 6 study sequences: ABC, ACB, BAC, BCA, CBA, or CAB, where A was the ebastine fast-dissolving 20-mg tablet, B was the desloratadine 5-mg capsule, and C was placebo. All study drugs were given orally once daily (8-9 AM) on days 1 to 5 of each study period. Study periods were separated by a washout period of 7 to 10 days. Histamine skin-prick test (SPT) challenge was performed before study drug administration on day 1 of each period (baseline), and then every 20 minutes for 2 hours after administration and again after 24 hours. The final SPT was 24 hours after the day-5 dose was administered. The primary end point was inhibition o f the histamine response, defined as the percentage reduction from baseline wheal area 24 hours after 5 days of administration. Subjective symptoms (itching, flare, and pain) were assessed by subjects using visual analog scales every 20 minutes for 2 hours after administration on day 1. At study end, acceptability (taste, convenience, and overall preference) of the fast-dissolving tablet and capsule formulations were assessed using a questionnaire completed by subjects. Tolerability was assessed using physical examination, laboratory analysis, physician questioning, and spontaneous reporting. RESULTS: Thirty-six people were randomized (22 women, 14 men; mean [SD] age, 24.7 [4.1] years; mean [SD] weight, 63.2 [9.9] kg); 35 completed the study (1 subject was lost to follow-up after the second study period). Unadjusted mean (SD) wheal areas 24 hours after dose administration on day 5 were 72.9 (29.5), 115.0 (32.1), and 146.7 (32.2) mm(2), for ebastine, desloratadine, and placebo, respectively. Mean differences in reduction from baseline in wheal area were 29.0% for ebastine versus desloratadine and 43.7% for ebastine versus placebo (both, P < 0.001). Corresponding unadjusted mean (SD) wheal areas 24 hours after administration of the first dose on day 1 were 76.5 (22.5), 128.9 (24.0), and 140.5 (33.1) mm(2). Mean itching, flare, and pain ratings were not significantly different between study drugs. Results from the preference questionnaire indicated that the majority (80%) preferred the ebastine fast-dissolving tablet to the desloratadine capsule (and hypothetically also to tablets and oral solution, which were not tested in this study). Ninety-seven percent of subjects were of the opinion that compliance in the home setting would be facilitated by the fas-tdissolving tablet formulation. Fourteen adverse events (AEs) were reported in 9 (25%) volunteers; all AEs were of mild or moderate intensity. Five occurred with ebastine 20 mg (intermittent somnolence, back pain, pharyngolaryngeal pain, pyrexia, and oral pain [1 patient each]), 5 occurred with desloratadine 5 mg (asthenia [2 patients] and dry mouth, somnolence, and back pain [1 patient each]), and 4 occurred with placebo (diarrhea [2 patients] and somnolence and headache [1 patient each]). The relationship with the study drugs was considered unlikely in 6 cases and possible in the remaining 8 cases. An additional AE (back pain) occurred during a washout period. CONCLUSIONS: In this small study in healthy, nonatopic white subjects, inhibition of the response to histamine injection was significantly greater with the ebastine 20-mg fast-dissolving tablet compared with desloratadine 5-mg capsule and placebo after 1 and 5 days of administration. Most participants expressed an overall preference for the fast-dissolving tablet formulation over capsules. All study drugs were well tolerated.
Assuntos
Butirofenonas/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Histamina , Loratadina/análogos & derivados , Piperidinas/farmacologia , Testes Cutâneos , Adolescente , Adulto , Butirofenonas/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Loratadina/efeitos adversos , Loratadina/farmacologia , Masculino , Medição da Dor , Piperidinas/efeitos adversos , Prurido/induzido quimicamente , Prurido/prevenção & controle , Pele/patologiaRESUMO
BACKGROUND AND OBJECTIVE: Ebastine is a long-acting, second-generation selective histamine H(1) receptor antagonist. The pharmacodynamics of a new 10mg fast-dissolving tablet (FDT) oral lyophilisate tablet formulation of ebastine were compared with those of desloratadine and placebo following histamine skin intradermal test challenge. The acceptability of the FDT was also assessed. METHODS: This was a double-blind, double-dummy, placebo-controlled, randomised, crossover, three-period study in 36 healthy adults. The histamine skin intradermal test (0.05 mL of 100 microg/mL solution) was administered into volunteers' forearms, and wheal area was measured 15 minutes later. Ebastine 10 mg FDT, desloratadine 5mg capsule or placebo were given on days 1-5. On day 1, a skin intradermal test was performed at baseline, then every 20 minutes for 2 hours after administration and at 24 hours. The final skin intradermal test was on day 6, 24 hours after the last drug dose. Subjective symptoms (itching, heat and pain) were assessed on day 1 for 2 hours following the first drug dose. There was a washout period of 7-10 days between treatments. At study end, the acceptability of the new ebastine formulation was evaluated using a questionnaire. RESULTS: Ebastine 10mg inhibited the wheal response to histamine significantly more than desloratadine 5 mg or placebo 24 hours after 5 days' treatment (mean difference between treatments in wheal area reduction from baseline: 26.7%, p < 0.0001; 46.9%, p < 0.0001, respectively), and after 24 hours on day 1 (mean difference: 16.2%, p = 0.0082; 34.2%, p < 0.0001, respectively). The results with desloratadine were also significantly different from placebo on day 1 and after 5 days, but less than with ebastine after 5 days (difference, desloratadine vs placebo: 20.2%, p = 0.0001). No differences in itching, heat and pain were observed between the treatments. Most participants (70%) preferred the FDT, and all reported that it made adherence easier. CONCLUSION: Ebastine 10 mg FDT demonstrated significantly superior antihistamine activity compared with desloratadine and placebo.
Assuntos
Butirofenonas/administração & dosagem , Butirofenonas/uso terapêutico , Dermatite de Contato/prevenção & controle , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Histamina , Loratadina/análogos & derivados , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Adulto , Butirofenonas/efeitos adversos , Química Farmacêutica , Dermatite de Contato/patologia , Método Duplo-Cego , Feminino , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Humanos , Loratadina/administração & dosagem , Loratadina/efeitos adversos , Loratadina/uso terapêutico , Masculino , Medição da Dor , Aceitação pelo Paciente de Cuidados de Saúde , Piperidinas/efeitos adversos , Pele/patologia , Comprimidos , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the peripheral antihistaminic activity of bilastine, rupatadine and desloratadine in inhibiting the histamine-induced wheal and flare (W&F) response. RESEARCH DESIGN AND METHODS: Twenty-four healthy volunteers aged 18-40 years participated in this crossover, randomized, double-blind, placebo-controlled clinical study. Subjects received single doses of bilastine 20 mg, desloratadine 5 mg, rupatadine 10 mg and placebo. W&F responses induced by intradermal injection of histamine 5 µg were evaluated before treatment (basal value) and at 0.5, 1, 2, 4, 6, 9, 12 and 24 hours after treatment. Fifteen minutes after histamine injection, W&F surface areas (cm2) were quantified using the Visitrak System. Itching sensation was evaluated using a 100 mm visual analog scale. EudraCT number: 2015-000790-13. MAIN OUTCOME MEASURES: The primary outcome measure was the percentage reduction in W&F areas after each active treatment compared with corresponding basal values. RESULTS: Bilastine induced the greatest inhibition in wheal area and was significantly superior to desloratadine and rupatadine from 1 to 12 hours (both p < .001). Rupatadine and desloratadine were better than placebo without differences between them. Maximum wheal inhibition occurred at 6 hours (bilastine 83%, desloratadine 38%, rupatadine 37%). Onset of action was 1 hour for bilastine and 4 hours for desloratadine and rupatadine. Bilastine was significantly superior to desloratadine and rupatadine for flare inhibition from 1-24 hours (both p < .001) with an onset of action at 30 minutes. Bilastine was significantly better than desloratadine (2-12 hours; at least p < .05) and rupatadine (2-9 hours; at least p < .01) for reducing itching sensation. Neither desloratadine nor rupatadine significantly reduced itching compared to placebo. All active treatments were well tolerated. CONCLUSIONS: Bilastine 20 mg induced significantly greater inhibition of the W&F response compared with desloratadine 5 mg and rupatadine 10 mg throughout the 24 hour study period, and had the fastest onset of action. Only bilastine significantly reduced itching sensation versus placebo.
Assuntos
Benzimidazóis/farmacologia , Ciproeptadina/análogos & derivados , Antagonistas dos Receptores Histamínicos/farmacologia , Loratadina/análogos & derivados , Piperidinas/farmacologia , Pele/efeitos dos fármacos , Adulto , Estudos Cross-Over , Ciproeptadina/farmacologia , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Histamina/farmacologia , Humanos , Injeções Intradérmicas , Loratadina/farmacologia , MasculinoRESUMO
The bioequivalence of two capsule formulations containing 400 mg gabapentin (CAS 60142-96-3) was assessed in 24 healthy volunteers in an open, randomised, crossover, 2 periods x 2 sequences, with a minimum washout period of 7 days, single-dose study. Plasma samples were obtained at fixed time points, over 48 h (baseline (pre-dose), +0.5 h, +1 h, +1.5, +2, +2.5, +3, +3.5, +4, +8, +5, +6, +8, +10, +12, +24, +36 and +48 h after administration) and gabapentin concentrations were determined by means of an HPLC-MS method (LLOQ 50.2 ng/mL). Pharmacokinetic parameters used for bioequivalence assessment (AUCtlast, AUCinf and Cmax) were determined from the gabapentin concentration data using non-compartmental analysis. The results showed that all 90 % confidence intervals (obtained by ANOVA) were all within the predefined ranges: 93.87-111.87 % for Cmax 94.04-108.21 % for AUCtlast and 94.23-108.29 % for AUCinf. Consequently, this bioequivalence study was well designed in order to conclude that the test formulation and reference formulation were bioequivalent in terms of rate and extent of absorption.
Assuntos
Aminas/farmacocinética , Anticonvulsivantes/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácido gama-Aminobutírico/farmacocinética , Adolescente , Adulto , Aminas/administração & dosagem , Anticonvulsivantes/administração & dosagem , Área Sob a Curva , Cápsulas , Química Farmacêutica , Estudos Cross-Over , Ácidos Cicloexanocarboxílicos/administração & dosagem , Feminino , Gabapentina , Humanos , Masculino , Equivalência Terapêutica , Ácido gama-Aminobutírico/administração & dosagemRESUMO
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.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Cetirizina/farmacologia , Cognição/efeitos dos fármacos , Etanol/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Hidroxizina/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Análise de Variância , Cetirizina/sangue , Cetirizina/farmacocinética , Estudos Cross-Over , Ciproeptadina/análogos & derivados , Ciproeptadina/sangue , Ciproeptadina/farmacocinética , Ciproeptadina/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Antagonistas dos Receptores Histamínicos H1/sangue , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Humanos , Hidroxizina/sangue , Hidroxizina/farmacocinética , Masculino , Fatores de TempoRESUMO
This investigation aimed to provide evidence on the lack of pharmacokinetic interaction of paroxetine (20 mg/d) and alprazolam (1 mg/d) in combined therapy. In addition, the central effects of both drugs when administered alone and in combination were assessed to rule out any relevant synergistic depressant central effect. Twenty-five healthy young adult volunteers participated in a double-blind, double-dummy, placebo-controlled, repeated dose (15 days), 4-period crossover study. Each subject received each of 4 treatment sequences (ie, paroxetine-alprazolam placebo, alprazolam-paroxetine placebo, paroxetine-alprazolam, and paroxetine placebo-alprazolam placebo) in randomized order. The ratios for area under the curve within a dosing interval and maximum plasma concentration of the paroxetine plus alprazolam sequence to single agent paroxetine were 1.07 (90% confidence interval = 0.99 to 1.16) and 1.05 (90% confidence interval = 0.97 to 1.13), respectively, with no statistically significant differences between the 2 treatments. Similarly, for alprazolam, ratios for the combined to the single treatment sequence were 0.99 (90% confidence interval = 0.93 to 1.05) and 1.00 (90% confidence interval = 0.94 to 1.07) for area under the curve within a dosing interval and maximum plasma concentration, respectively, showing no evidence for interaction. Comparative pharmacodynamics on the combination was assessed using 6 Psychomotor Performance Tests and 5 Visual Analogue Scales focused on mood variables. Alprazolam and paroxetine plus alprazolam induced similar and significant performance impairment and sedation after both single and repeated dose administration, being less evident on day 15. After dosing, paroxetine plus alprazolam showed a lower recovery pattern than alprazolam alone, especially on day 15. No treatment sequence showed cumulative effects after repeated dose administration. Psychomotor Performance Tests and Visual Analogue Scales data suggested lack of pharmacodynamic interactions. Accordingly, study results showed no evidence for pharmacologic interactions between paroxetine and alprazolam at steady state. The most commonly reported adverse event was drowsiness, with a higher incidence under both single and combined alprazolam treatments.
Assuntos
Alprazolam/sangue , Alprazolam/farmacologia , Paroxetina/sangue , Paroxetina/farmacologia , Adulto , Alprazolam/administração & dosagem , Alprazolam/farmacocinética , Análise de Variância , Área Sob a Curva , Distribuição de Qui-Quadrado , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas/fisiologia , Feminino , Humanos , Masculino , Análise Multivariada , Paroxetina/administração & dosagem , Paroxetina/farmacocinética , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologiaRESUMO
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.