Differential cognitive effects of ebastine and (+)-chlorpheniramine in healthy subjects: correlation between cognitive impairment and plasma drug concentration.
OBJECTIVE
It has been widely recognized that classical antihistamines induce sedation as an adverse effect, while second-generation antihistamines have few if any sedative effects. In order to evaluate the sedative properties of ebastine, a second-generation antihistamine, its effect on cognitive performance in healthy subjects was compared with placebo and (+)-chlorpheniramine.


METHODS
Twelve healthy male subjects were instructed to perform six types of attention-demanding cognitive tasks, and objective measurements of reaction times and accuracy was made before and after drug administration. Their sleepiness levels were also monitored. Test drugs were ebastine 10 mg, placebo and two doses of (+)-chlorpheniramine 2 mg and 6 mg, as positive controls. Plasma drug concentrations at the end of the study were analysed.


RESULTS
After treatments with (+)-chlorpheniramine, the reaction times of the tasks were significantly prolonged (e.g. ratios of after/before dosing: placebo (0.998 +/- 0.113) vs (+)-chlorpheniramine 2 mg (1.103 +/- 0.083; P<0.05) or (+)-chlorpheniramine 6 mg (1.170 +/- 0.139; P<0.001) in a 7 ms visual discrimination time task) and the accuracy was significantly decreased (e.g. ratios: placebo (1.038 +/- 0.158) vs (+)-chlorpheniramine 2 mg (0.792 +/- 0.202; P<0.01) or (+)-chlorpheniramine 6 mg (0.837 +/- 0.222; P<0.05) in a 7 ms task). On the other hand, performance was not affected by ebastine or placebo treatment (e.g. ebastine 10 mg (reaction time ratio; 1.014 +/- 0.067 and accuracy ratio; 0.990 +/- 0.146) in a 7 ms task). Subjective sleepiness was also not affected by ebastine but (+)-chlorpheniramine significantly increased sedation. With respect to the relationship between plasma drug concentrations and task performance, the latter deteriorated with an increase in plasma (+)-chlorpheniramine concentration (e.g. r=0.439 (P=0.007) in a 5 ms and r = 0.352 (P=0.039) in a 7 ms task), but it did not correlate with the plasma concentration of carebastine, an active metabolite of ebastine.


CONCLUSIONS
Ebastine 10 mg did not cause any cognitive impairment or subjective sleepiness. On the other hand, (+)-chlorpheniramine impaired cognitive function and induced sleepiness even at 2 mg, the recommended dose in over-the-counter medication. In addition, impaired CNS performance was significantly correlated with plasma (+)-chlorpheniramine concentration.
Tagawa
Masaaki
M
Department of Pharmacology, Tohoku University School of Medicine, Cyclotron and Radioisotope Center, Tohoku University, Japan.
Kano
Michiko
M
Okamura
Nobuyuki
N
Higuchi
Makoto
M
Matsuda
Michiaki
M
Mizuki
Yasuyuki
Y
Arai
Hiroyuki
H
Fujii
Toshihiko
T
Komemushi
Sadao
S
Itoh
Masatoshi
M
Sasaki
Hidetada
H
Watanabe
Takehiko
T
Yanai
Kazuhiko
K
D000284:Administration, Oral; D000328:Adult; D002090:Butyrophenones / Q000009:adverse effects* / Q000097:blood; D002744:Chlorpheniramine / Q000009:adverse effects* / Q000097:blood; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000009:adverse effects* / Q000097:blood; D006801:Humans; D008297:Male; D010880:Piperidines / Q000009:adverse effects* / Q000097:blood; D011930:Reaction Time / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D013237:Stereoisomerism; D014796:Visual Perception / Q000187:drug effects
D002090:Butyrophenones; D006634:Histamine H1 Antagonists; D010880:Piperidines; D002744:Chlorpheniramine; C058249:ebastine