Differential cognitive effects of ebastine and (+)‐chlorpheniramine in healthy subjects: Correlation between cognitive impairment and plasma drug concentration

Abstract

Aims 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 signi®cantly prolonged (e.g. ratios of after/before dosing: placebo (0.998t0.113) vs (+)-chlorpheniramine 2 mg (1.103t0.083; P<0.05) or (+)-chlorpheniramine 6 mg (1.170t0.139; P<0.001) in a 7 ms visual discrimination time task) and the accuracy was signi®cantly decreased (e.g. ratios: placebo (1.038t0.158) vs (+)-chlorpheniramine 2 mg (0.792t0.202; P<0.01) or (+)-chlorpheniramine 6 mg (0.837t0.222; 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; 1.014t0.067 and accuracy ratio; 0.990t0.146) in a 7 ms task). Subjective sleepiness was also not affected by ebastine but (+)-chlorpheniramine signi®cantly 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 signi®cantly correlated with plasma (+)-chlorpheniramine concentration.

Neuroimaging of histamine H1‐receptor occupancy in human brain by positron emission tomography (PET): A comparative study of ebastine, a second‐generation antihistamine, and (+)‐chlorpheniramine, a classical antihistamine

“…Our previous studies demonstrated that several second-generation antihistamines such as epinastine, terfenadine, azelastine, mequitazine and astemizole occupy 10±30% of brain H 1 -receptors [3]. We recently demonstrated that ebastine does not impair cognitive functions nor induce sleepiness in healthy normal subjects [15]. Those studies together with our present study lead to a recognition of the nonsedative characteristic of ebastine due to lower brain H 1 -receptor occupancy.…”

“…Our previous study revealed that impairment of cognitive performance and sleepiness occurred following (+)-chlorpheniramine 2 mg [15]. Our present and previous studies demonstrate that cognitive function and brain H 1 -receptor occupancy by (+)-chlorpheniramine are signi®cantly correlated with the plasma concentration of (+)-chlorpheniramine.…”

“…Recently, using attention-demanding cognitive tasks, we demonstrated that ebastine did not cause signi®cant sedation [15]. In that study, comparing the effects of ebastine and (+)-chlorpheniramine on cognitive performance, we also revealed that the cognitive functions were not affected by the increase of plasma concentration of carebastine, but were impaired by that of (+)-chlorpheniramine concentration.…”

“…and of (+)-chlorpheniramine was measured by a liquid chromatography-mass spectrometry (LC-MS) at Dainippon Pharmaceutical Co., Ltd, as described previously [15].…”

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

“…The therapeutic plasma concentrations of chlorpheniramine typically range from 12.5 to 30 nM (Tagawa et al, 2001;Tagawa et al, 2002), The toxic plasma concentrations of chlorpheniramine has been shown to be 500 nM in the case report, which is ~10 times greater than the mean peak plasma level measured after a single therapeutic dose (Baselt and Cravey, 1995). Blood concentrations reported in two overdose fatalities were 1.25 and 2.75 μM (Reed, 1981;Baselt and Cravey, 1995).…”