Lack of effects between rupatadine 10[thinsp]mg and placebo on actual driving performance of healthy volunteers

human psychopharmacologyHum. Psychopharmacol Clin Exp 2007; 22: 289–297.
Published online in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/hup.856 Lack of effects between rupatadine 10 mg and placeboon actual driving performance of healthy volunteers Eric Vuurman1*, Eef Theunissen2, Anita van Oers1, Cees van Leeuwen1 and Jelle Jolles1 1Brain and Behaviour Institute, Faculty of Medicine, Maastricht University, The Netherlands 2Brain and Behaviour Institute, Faculty of Psychology, Maastricht University, The Netherlands Rupatadine fumarate is a potent, selective, histamine H1-receptor antagonist and PAF inhibitor with demonstrated efficacy for the relief of allergic rhinitis. Rupatadine does not easily cross the blood–brain barrier and isbelieved to be non-sedating at therapeutic doses. Consequently, rupatadine should show no impairment on car driving.
Objective This study compared the acute effects of rupatadine, relative to placebo and hydroxyzine (as an active control), on healthy subjects’ driving performance.
Methods Twenty subjects received a single dose of rupatadine 10 mg, hydroxyzine 50 mg, or placebo in each period of this randomized, double-blind, three-way crossover study. Two hours postdosing, subjects operated a specially instrumentedvehicle in tests designed to measure their driving ability. Before and after the driving tests ratings of sedation were recorded.
Results There was no significant difference between rupatadine and placebo in the primary outcome variable: standard deviation of lateral position (SDLP); however, hydroxyzine treatment significantly increased SDLP ( p < 0.001 for bothcomparisons). Objective (Stanford sleepiness scale) and subjective sedation ratings (Visual Analogue Scales) showed similarresults: subjects reported negative effects after hydroxyzine but not after rupatadine.
Conclusion Rupatadine 10 mg is not sedating and does not impair driving performance. Copyright # 2007 John Wiley & key words — antihistamine; rupatadine; hydroxyzine; driving; safety of H1-antagonists are caused by their affinity for thecentral H1-receptors. The liposolubility of the older, Antihistamine therapy is the first choice in treatment 1st-generation H1-antagonists enables them to easily in many allergic conditions with H1 antihistamines cross the blood–brain barrier (Meltzer, 1990; Timmer- being one of the largest classes of drugs in use in the man, 2000). In the 1980’s newer, 2nd-generation H1- world. Besides mediating targeted peripheral func- antagonists have been developed which possess less tions, it however also affects the central nervous side effects such as the psychomotor impairment or system (CNS). The exact mechanism of action for sedation often found with the 1st-generation drugs histamine H1-receptor antagonists still remains un- (Rombaut and Hindmarch, 1994; Vuurman et al., known but the role of histamine as a neurotransmitter 2004). These 2nd-generation drugs penetrate poorly has been firmly established. Histaminergic pathways into the CNS and are therefore relatively non-sedating are prominent in the CNS and are related to mecha- (Bender et al., 2003; Timmerman, 2000). Also, in nisms that support alertness and vigilance (Nicholson, contrast to the 1st-generation antihistamines, the 1985; Qidwai et al., 2002). The sedative side effects newer drugs have little or no affinity for muscarinic,cholinergic, adrenergic, and serotonergic receptors(Sangalli, 1997). This also contributes to the relative * Correspondence to: Dr E. Vuurman, Brain & Behavior Institute, lack of other adverse CNS or peripheral effects Faculty of Medicine, Maastricht University, PO Box 616, 6200MD reported after use of the 2nd-generation drugs (Kay, Maastricht, The Netherlands. Tel.: þ31433881046.
E-mail: [email protected] 2000). Both the pharmacodynamics and side effects Copyright # 2007 John Wiley & Sons, Ltd.
profiles of the 2nd-generation H1-antagonists suggest investigated possible CNS effects of rupatadine doses that these drugs offer a safety advantage over the 1st- ranging between 10–80 mg. Using a battery of basic generation drugs, particularly for ambulant patients performance tests they found impairing effects of who drive automobiles or operate other potentionally rupatadine only at doses above 40 mg, suggesting a dangerous machinery. Although these newer-generation good balance between the clinical dose and that antihistamines were proven to be less sedative, most producing untoward side effects. In a more recent still show some level of CNS impairment, particularly study (Barbanoj et al., 2006) the combined effects of at supraclinical dose levels (Casale et al., 2003; rupatadine (10 and 20 mg) and alcohol (0.8 g/kg) on Holgate et al., 2003; Kay, 2000; Kay and Harris, 1999; cognitive performance were evaluated and compared Roberts and Gispert, 1999; Ridout and Hindmarch, to the effects of alcohol combined with hydroxyzine 2003; Rosenzweig and Patat, 1999; Simons, 1999; 25 mg and cetirizine 10 mg. The study showed that Theunissen et al., 2004; Verster et al., 2003). Reviews rupatadine 10 mg in combination with alcohol did not of the experimental studies which have examined the produce more cognitive and psychomotor impairment effects of H1-antagonists on performance measures than alcohol alone. In contrast, cetirizine and from driving simulators and on-road driving generally hydroxyzine did significantly increase the effect of have concluded that the 2nd-generation drugs pose little or no risk to safe driving (Ogden and Moskowitz, Although laboratory tests and driving simulators 2004; Verster and Volkerts, 2004), although individual have often proven to be reliable and consistent in adverse reactions cannot be ruled out.
measuring driving-related skills, their predictive More recently new drugs have been developed with validity is only about 33% (Verster, 2002). In this claims of being free of any sedative side effects, due to study the possible effects of rupatadine 10 mg on the fact that they are incapable of crossing the driving are investigated, employing a unique and blood–brain barrier. Amongst these new-generation sensitive method to test drug effects on driving in real antihistamines compounds are levocetirizine, fexofe- nadine, and desloratadine (Hindmarch et al., 2001;Ridout and Hindmarch, 2003). Although these newdrugs show little or no negative effects on psycho- motor performance or subjective rating of sedation, the claim that they are void of CNS effects cannotalways be held. In some cases an improvement of The study enrolled 22 evaluable subjects (11<, 11 ,) psychomotor performance has been found, pointing to through newspaper advertisements. Two subjects did possible slightly stimulating effects of these com- not complete the study: one moved to a different town pounds (Theunissen et al., 2006b; Vuurman et al., and one accepted job making participation impossible.
2004). This would imply that these compounds do Twenty subjects (10<, 10 ,) completed the study.
cross the blood–brain barrier or affect the CNS Mean subject age(SD) was 27.2(3.5) years (range, 22–35 years) with a mean weight(SD) of 69.7(10.6) kg Rupatadine (DCI) is a new chemical entity which (range, 52–92 kg) and a mean height(SD) of possesses a potent PAF antagonist and antihistamine 176.7(8.9) cm (range, 158–192 cm). Subjects were activity and has been selected from a series of required to have had a driver’s license for at least N-alkylpyridine derivatives, that has demonstrated a 3 years prior to the study and driving experience of at potent dual antihistamine and PAF antagonist activity least 7500 km per year. Subjects with a history or in animal an human models (Merlos et al., 1997).
symptoms of severe mental or physical disorders or Rupatadine is marketed in Spain in a 10 mg od tablet substance abuse were excluded from the study, as were formulation (Izquierdo et al., 2003), and has already subjects with active allergic rhinitis. Subjects were been registered in several European countries and screened by a medical history questionnaire and Brazil. Rupatadine is rapidly absorbed in humans physical examination, including a 12 lead ECG, blood when administered orally and extensively metabolized chemistry and haematology and urinary tests for drugs in the liver, mainly by CYP3A4. Rupatadine plasma of abuse. Additional exclusion criteria included half-life is 5.9 h. The efficacy of rupatadine for the excessive smoking (>10 cigarettes per day) or treatment of allergic rhinitis (both intermittent and consumption of caffeinated beverages (>5 cups/ persistent) and chronic idiopathic urticaria has been glasses per day); body weight more than 10% above well established in several controlled clinical studies the normal average for age, sex, and height; treat- (Stuebner et al., 2006). Another (Barbanoj et al., 2004) ment with central nervous system medications or Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 289–297.
medications with sedative effects; and known allergic operate a specially instrumented vehicle over a reactions to antihistamines. Women of childbearing distance of 100 km (61 miles) on a primary highway.
potential were required to have a negative serum A licensed driving instructor, who could intervene if pregnancy test result at screening and to use an necessary by using duplicate controls, accompanied acceptable method of birth control before screening the subject during the test. The subject was instructed and during the study. Written informed consent was to attempt to maintain a constant speed of 95 km (58 obtained from all subjects prior to participation. This miles) per hour and a steady lateral position between study was conducted in accordance with Good the delineated boundaries of the right (slower) traffic Clinical Practice and the World Medical Association lane. The subject was allowed to deviate from this Declaration of Helsinki (1996) and subsequent procedure in order to pass slower vehicles. The revisions (Christie, 2000) and was approved by the vehicle’s speed and lateral position relative to the left Ethics Committee of Maastricht University.
lane delineation were continuously recorded, sampled,and stored on a computer system onboard. Offlineediting routines involved removal of all data segments that revealed signal loss, disturbance, or overtaking The study followed a single-center, randomized, manoeuvres. The remaining data were used to double-blind, placebo and active-controlled, three- calculate means and standard deviations for lateral way crossover design. Rupatadine (10 mg), hydroxy- position (SDLP) and speed (SDSP). A minimum of zine (50 mg), and placebo were administrated orally in 75% of ‘clean’ data was required for a reliable identical capsules once daily during treatment periods.
measurement. The primary measure was the SDLP, Treatment periods were separated by a washout period which measured the continuous road tracking error.
of at least 7 days. Tests were performed between SDLP is a very reliable characteristic of individual 2:00–4:30 h after dosing on each of the three test days.
driving performance: the test–retest reliability coeffi-cient for unmedicated young and middle-aged driversis r ¼ 0.85. It has also proven sensitive to many sedating agents, including alcohol in blood concen- Subjects were individually trained 1 or 2 weeks prior trations as low as 0.35 mg/mL [26,27]. The secondary to their first treatment to perform the driving tests and outcome variable was SDSP, giving an indication how familiarize them with the experimental procedure.
well subjects could maintain the designated speed.
They were required to adhere to specific procedures Details of the highway-driving test, including power prior to testing, including abstinence from alcohol or calculations have been described fully elsewhere other recreational drugs the day before testing and retiring for sleep a minimum of 8 h prior to test days.
On each test day subjects were collected from theirhomes in the morning and provided with a standardlight breakfast at the study center. Sleep quality was Car-following test. The car-following test (Ramae- measured upon arrival using the Groningen Sleep kers et al., 2002) involved the use of two vehicles Quality Scale (Mulder Hajonides et al., 1980) and driving behind each other on a secondary highway for subjects only continued with the testing procedures if approximately 25 min. The subject controlled the they reported good sleep quality (Groningen score following vehicle, while the investigator controlled <10) during the previous night. Additionally, subjects the leading car. Again, a licensed driving instructor were limited to one cup of tea or coffee with breakfast accompanied the subject in order to intervene when on test days, and habitual smokers had to refrain from necessary. During the test the investigator in the smoking for the duration of the testing (30 min before leading car initiated sinusoidal speed changes.
testing and until all tests were completed). Subjects Between these maneuvers, the investigator in the were monitored at each visit for adverse events. At the leading car randomly lit up the brake lights of his car end of each test day subjects were returned to their while the speed of the car remained constant. Subjects were instructed to maintain a 15–30 m distance to theleading car and to react as fast as possible to the brakelights by removing their foot from the accelerator pedal. Standard deviation of headway (SDHW) and Highway-driving test. During the highway-driving brake reaction time (BRT) were the primary outcome test (O’Hanlon et al., 1982), the subject’s task was to variables of this car-following test.
Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 289–297.
Subjective measures. Besides administering the driv- Standard Deviation Lateral Position (SDLP)
ing tests, the following rating scales were presented to Mean (± SEM)
- Stanford sleepiness scale. This is a well-known (Hoddes et al., 1972). The questionnaire indicates how ‘sleepy’ people are feeling and was presented twice on each test day: the first time prior to dosing to register a base-line value and once after perform-ing the driving test.
- Groningen Sleep Quality Scale (Mulder Hajonides et al., 1980). The quality of sleep at home the night Rupatadine
Hydroxyzine
before each trial day was assessed by means of this Drug Condition
questionnaire to ensure subjects were fit before they Mean (Æ SEM) standard deviation of lateral position (SDLP) scores for each treatment condition (rupatadine 10 mg, - Subjective rating of Sedation. Both the Subject as well as the Driving Instructor rated how ‘sedated’the subject was during the driving test. This wasdone by a 100 point VAS scale.
Stanford sleepiness scale (STANFORD) and Driving - Subjective rating of Driving Quality (DQ). Both the Quality rating by the subject (DQ-S).
Subject as well as the Driving Instructor rated thequality of the subject’s driving. This was done by a100-point VAS scale.
Standard deviation of lateral position (SDLP) Figure 1 shows the mean SDLP (ÆSEM) for each of Statistical analysis. Sample size was based upon a the three treatment conditions. The means of the power calculation of the primary outcome variable in rupatadine and placebo conditions were comparable the driving test, SDLP. With a sample size of 20 (18.64 and 18.81 cm, respectively) and the SDLP in subjects, an a level of 0.05 (two-tailed), differences the hydroxyzine condition was much higher than the of 0.65 standardized units were detectable with a other two (23.35 cm). The higher SDLP indicated power of 85% (O’Hanlon and Ramaekers, 1995). Data worse driving. ANOVA showed a significant overall analysis was performed employing the GLM routines from the SPSS statistical program series (Version 13, sequent paired comparisons showed significant inc- Norusis, 2004) on Windows-XP microcomputer. Effi- rease in SDLP after hydroxyzine treatment compared cacy variables were analyzed with an analysis of variance model (ANOVA) for crossover designs with terms for treatment, phase, and subject effects. Pair- 1,36 ¼ 25.57; p < 0.001). There was no difference in SDLP between the rupatadine and wise comparisons were performed using the least square means from the model. The active control of period was found, indicating a lack of learning or group (hydroxyzine) was included for reference pur- habituation to the driving test procedure.
poses. Since the study was oriented towards safety, asignificance level of a ¼ 0.05 was used in all statistical The mean (ÆSEM) scores of the secondary outcome variable on the highway-driving test, SDSP are shown in Figure 2. Twenty evaluable data sets were availablefor the analysis. Subjects were instructed to maintain a steady speed at all times and the deviation from Due to a technical error the data of subject #17 are the mean speed was comparable for the rupatadine incomplete for the hydroxyzine condition. The follow- and placebo conditions. In the hydroxyzine condi- ing analyses were therefore based on a dataset of tion subjects showed a larger variation in speed 19 subjects in stead of the full 20 subjects: car- difference during the test. Overall ANOVA showed following test (BRT and SDHW; Subjective scales: this to be highly significant (F2,36 ¼ 17.04; p < 0.001).
Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 289–297.
Standard Deviation Speed (SDSP)
ment on SDHW (F2,35 ¼ 0.67; p < 0.517). Pairwise Mean (± SEM)
comparisons showed no differences between means of either rupatadine and hydroxyzine (F1,35 ¼ 0.97; p < 0.333), hydroxyzine and placebo (F1,35 ¼ 0.01; p < 0.986), or rupatadine and placebo (F1,35 ¼ 1.04; p < 0.315). A small positive, but significant effect was found for period (F2,35 ¼ 3.84; p ¼ 0.031), [ km/hr ] 1.8
indicating a slight learning effect over the study.
Rupatadine
Hydroxyzine
treatment conditions. A higher score implied that Drug Condition
subjects were slower to respond to the brake signal Mean (Æ SEM) standard deviation of speed (SDSP) presented. The mean BRT was slightly lower for the scores for each treatment condition (rupatadine 10 mg, placebo, rupatadine condition compared to both placebo and hydroxyzine. ANOVA did not show an overalltreatment effect (F2,35 ¼ 1.59; p < 0.218) and pairwise Subsequent pairwise comparisons showed that after comparisons did not show an effect between either treatment with hydroxyzine, subjects significantly rupatadine and hydroxyzine (F1,35 ¼ 2.41; p < 0.130), varied in speed more compared to both rupatadine hydroxyzine and placebo (F1,35 ¼ 0.01; p < 0.957), or (F1,36 ¼ 21.75; p < 0.001) as well as placebo (F1,36 ¼ 28.87; p < 0.001) conditions. Scores in the p < 0.135). There was no effect of period on this rupatadine group were not different from scores in the variable, indicating subjects did not improve or placebo group (F1,36 ¼ 0.50; p ¼ 0.482). There was no effect of period on this variable, indicating subjectsdid not improve or degrade in time over the study.
The Stanford sleepiness scale was administered twice on each of the three treatment days: the first time The SDHW provides information on how ‘well’ predosing as a baseline value and the second time after subject keep an equal distance to the car in front of concluding the Driving tests. Figure 5 shows them. Figure 3 shows the means (ÆSEM) for all treat- differences in Mean Compound Scores, a higher ment conditions. The mean values for all conditions score indicating an increase in subjective sleepiness.
were similar and ANOVA revealed no effect of Treat- Mean scores for the hydroxyzine treatment condition Break Reaction Time (BRT)
Standard Deviation Headway
Mean (± SEM)
Mean (± SEM)
illisec ] 450
Rupatadine
Hydroxyzine
Rupatadine
Hydroxyzine
Drug Condition
Drug Condition
Mean (Æ SEM) brake reaction time (BRT) scores for Mean (Æ SEM) standard deviation of headway (SDHW) each treatment condition (rupatadine 10 mg, placebo, hydroxyzine scores for each treatment condition (rupatadine 10 mg, placebo, Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 289–297.
Stanford Sleepiness Scale
Driving Quality
Mean difference from baseline (± SEM)
Mean (± SEM)
VAS score [ % ] 45
Rupatadine
Hydroxyzine
Subject Instructor
Subject Instructor
Subject Instructor
Drug Condition
Rupatadine Placebo
Hydroxizine
Mean (Æ SEM) difference scores on the Stanford scale Mean (Æ SEM) rating of Driving Quality for each for each treatment condition (rupatadine 10 mg, placebo, hydroxy- treatment condition (rupatadine 10 mg, placebo, hydroxyzine 50 mg; N ¼ 20 for instructor rated sedation and N ¼ 19 for subject were about twice as high compared to both the rupa- The mean scores for DQ-I resembled those for tadine and placebo treatment condition, and a signi- DQ-S. Again the score is lowest in the hydroxyzine ficant overall effect for treatment was found (F2,35 ¼ group; although the absolute differences are smaller, 12.89; p < 0.001). Pairwise comparisons showed that like the standard error. An overall treatment effect is both the mean differences between rupatadine and found (F2,36 ¼ 4.72; p < 0.015); with the hydroxyzine hydroxyzine as well as placebo and hydroxyzine were group rating worse compared to rupatadine (F1,36 ¼ significantly different (F1,35 ¼ 18.63; p < 0.001 and 5.75; p < 0.022) and placebo (F1,36 ¼ 8.20; p < 0.007).
F1,35 ¼ 20.48; p < 0.001, respectively). The small No difference was found between the rupatadine and difference between the placebo and rupatadine groups placebo groups (F1,36 ¼ 0.22; p < 0.644). No effect for was not significant (F1,35 ¼ 0.04; p < 0.840). No effect eriod was found for the DQ-S and DQ-I variables.
of period was found on this variable.
Perceived Sedation was recorded by presenting the subject and the instructor with a VAS rating scaledirectly after completing the Driving Test. Figure 7 Driving Quality scale (subject and instructor) shows the means of the Instructor rated Sedation Both the instructor as well as the subject rated how (SED-I) and Subject rated Sedation (SED-S), indi- well the subject had performed in the driving test and cating how much they judged the subject to be sedated.
rated this as the DQ on a Visual Analogue Scalerunning from 0–100. The higher the score the better Sedation Rating
Mean (± SEM)
Mean Subject rated Driving Quality (DQ-S) and Instructor rated Driving Quality (DQ-I) are shown in Figure 6 .The best mean score for DQ-S was seen in the rupatadine treatment condition, with a slightly lower rating for the placebo treatment condition. The scores in the hydroxyzine were almost 33% lower compared to the rupatadine group, indicating a large VAS score [ % ] 15
difference in rating. ANOVA showed a highly signi- ficant effect of treatment (F2,35 ¼ 23.73; p < 0.001) with likewise significant effect for differences between rupatadine and hydroxyzine (F1,35 ¼ 42.20; Subject Instructor
Subject Instructor
Subject Instructor
p < 0.001) and the difference between placebo and Rupatadine Placebo Hydroxizine
hydroxyzine (F1,35 ¼ 28.44; p < 0.001). Mean scores Mean (Æ SEM) rating of sedation for each treatment of the rupatadine group did not differ from placebo condition (rupatadine 10 mg, placebo, hydroxyzine 50 mg; N ¼ 20 for instructor rated sedation and N ¼ 19 for subject sedated rating) Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 289–297.
The results for SED-I showed an overall treatment but and questionnaires support the findings of the driving SED-S did not (F2,36 ¼ 12.56; p < 0.001 and F2,36 ¼ tests. Rupatadine showed no effect on driving perfor- 0.25; p < 0.782, respectively). Paired comparisons mance related scales in contrast with the sedating only showed effects on SED-I, with hydroxyzine rated effect of hydroxyzine on both the Stanford sleepiness more sedative compared to both rupatadine as well as scale and the rating of DQ. An interesting finding was Placebo (F1,36 ¼ 17.40; p < 0.001 and F1,36 ¼ 20.19; the large difference in rating of sedation between the instructor and the subject in the hydroxyzinecondition. The instructor clearly rated the sedationto be much worse than the subject. Judging from the performance data the subjects underrated their A total of 16 adverse effects (AE) were reported for all sedation in the hydroxyzine condition.
22 subjects that enrolled in the study. Most frequently The effects of other 2nd-generation antihistamines ‘tiredness’ (5 reports) and ‘drowsiness/sleepiness’ have also been investigated in studies that utilized (4 reports). Adverse events were reported after hydroxy- similar driving and psychomotor performance test zine (7 reports), rupatadine (3 reports), placebo (3 reports), and prior to dosing (1 report). Most reports Ramaekers, 1995). Overall, the results of these studies of AE were expected and did not pose any serious demonstrated that driving and psychomotor perform- safety hazard to the subjects’ health. All AE’s were resolved within 24 h after onset. In seven experimental 2nd-generation antihistamines and possibly among procedures the actual driving was terminated for such 2nd-generation agents as loratadine and cetir- safety reasons. This meant that the Driving Instructor izine as well. Previous studies (Theunissen et al., observed that the subject was getting too sedated or 2006a; Vermeeren and O’Hanlon, 1998; Vuurman sleepy to continue safely and terminated the test. In et al., 2004; Vuurman et al., 1994; Theunissen et al., two cases this was after treatment with rupatadine and 2006a) show that treatment with the recommended in five cases after hydroxyzine. This is commonly seen therapeutic dose of 2nd-generation antihistamines in this test and has been documented in over 60 studies such as mizolastine ebastine, desloratatadine, mequi- with other drugs affecting psychomotor behavior, tazine, or fexofenadine results in mean SDLP values especially after the subject has been driving over comparable with placebo. However, sedation or 40 min and vigilance effects become predominant somnolence are also reported in trials with new (O’Hanlon and Ramaekers, 1995). In all cases enough antihistamines such as levocetirizine (Bachert et al., data from the driving tests were available (>75%) to 2004). Driving studies with the recommended therapeutic dose of cetirizine are less straightforwardand show either moderate impairment (Ramaekerset al., 1992) or lack of impairment (Volkerts and van Laar, 1995). However, most antihistamines affect Findings from the highway-driving test confirm the driving performance when given at twice the absence of drug-induced impairment in subjects who recommended therapeutic dose. The effect seems to received rupatadine, with almost identical SDLP be beneficial with fexofenadine; (Vermeeren and scores as placebo treated subjects. In contrast, the O’Hanlon, 1998) in contrast, cetirizine and loratadine SDLP score in the hydroxyzine condition was cause a less favorable sedative effect. The differential significantly higher (4.54 cm) and relevant, having an impairing effect comparable to a Blood Alcohol 2nd-generation antihistamines may have different concentration of 0.9% (Brookhuis, 1998). The results mechanisms of action. As for the compound under of the car-following test were less conclusive. In the investigation in this study, Barbanoj et al. (2004) hydroxyzine condition the BRT was not slower showed a dose dependent relation of higher doses of compared to the placebo condition. Also no effect rupatadine with reported sedation, although psycho- for hydroxyzine was found on the SDHW. No motor impairment on the used tests is only seen after a straightforward explanation for this finding can be 80 mg dose of rupatadine. This does however support given. In previous studies with the same test the the notion that rupatadine has some CNS effects at positive control condition did show effects (Ramae- higher doses too. The effects are however only kers et al., 2002; Vuurman et al., 2004). Nonetheless apparent at doses well above those administered there was also no impairment in the rupatadine clinically, giving the drug a large margin of safety. One treatment condition. Results of the subjective scales noteworthy finding was the large difference between Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 289–297.
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