Central nervous system effects of the histamine‐3 receptor antagonist CEP‐26401, in comparison with modafinil and donepezil, after a single dose in a cross‐over study in healthy volunteers

Abstract

Aims:In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose-dependent disruption of sleep. In the current study, 3 lowdose levels of CEP-26401 were compared with modafinil and donepezil. Methods: In this double-blind, placebo-and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 μg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose.Results: The main endpoint between-errors of the spatial working memory-10-boxes task only improved for the 125 μg dose of CEP-26401 with a difference of 2.92 (confidence interval [CI] -1.21 to 7.05), 3.24 (CI -1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 μg dose of CEP-26401, −1.65 (CI -0.572 to 1.96) for modafinil and − 3.55 (CI -7.13 to 0.03) for donepezil. CEP-26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N-back, but a dose-related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP-26401 significantly changed several subjective visual analogue scales, which was strongest at 25 μg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone.Discussion: Of the doses tested, the 25 μg dose of CEP-26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP-26401 can have beneficial effects in clinical practice remains to be studied.

Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers

“…The outcome of the test is the average speed of the moving circle as a percentage of the maximum speed of the circle. In previous studies, CNS-stimulant compounds such as caffeine (60 mg), moda nil (200 mg), dexamphetamine (20 mg) and methylphenidate (average 20 mg) improved average adaptive tracking by approximately 1.6%, 34 1.8%, 29 4.2%, 15 and 2.2%, 30 respectively. For CNS-depressant compounds, such as benzodiazepines, an impairment of adaptive tracking has been demonstrated.…”

“…Volunteers were instructed to stand comfortably on a rm surface with their feet slightly apart and eyes closed for 2 minutes. In previous studies, CNS-stimulant compounds demonstrated reductions in body sway; for example, moda nil (200 mg), dexamphetamine (20 mg) and clinical doses (average 20 mg) of methylphenidate reduced body sway by approximately 35% 29 , 19.4% 15 and 36.8%, respectively. 30 Conversely, CNS-depressant compounds such as benzodiazepines are associated with increased body sway; for example, diazepam (10 mg) increased body sway by 119%.…”

“…TAK-653 increased SPV by 15.5 to 19.5 deg/s, which is larger than caffeine 60 mg (11.6 deg/s) 34 and dexamphetamine 20 mg (12.7 deg/s), 15 but smaller than moda nil 200 mg (24.6 deg/s). 29 Increases in smooth pursuit eye movements represented only roughly one-third of those induced by methylphenidate. 30 The increase in adaptive tracking of 1.6% with TAK-653 6 mg was comparable to moda nil (1.8%), 29 caffeine (1.6%), 34 and methylphenidate (2.2%), 30 but smaller than dexamphetamine (4.2%).…”

“…33 The parameter collected was saccadic peak velocity (SPV) in degrees/second (deg/s). Previous studies have demonstrated that CNS-stimulant compounds such as caffeine (60 mg), moda nil (200 mg) and dexamphetamine (20 mg) increased the average SPV by 11.6 deg/s, 34 24.6 deg/s, 29 and 12.7 deg/s, 15 respectively. CNS-depressant compounds such as benzodiazepines have been shown to decrease SPV.…”

“…From these measurements, three main factors, namely 'alertness', 'mood' and 'calmness', were calculated as described in previous publications. 34,43 Benzodiazepines have consistently shown reductions on VAS alertness, 44 whereas variable but consistent increases are observed with caffeine, 34 dexamphetamine, 15 moda nil, 29 and methylphenidate. 30 Psychedelic effects were measured using the Bowdle VAS as previously described.…”