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 H₃R antagonist CEP‐26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20μg), and a dose‐dependent disruption of sleep. In the current study, three low dose levels of CEP‐26401 were compared with modafinil and donepezil.

Methods

In this double‐blind, placebo‐ and positive‐controlled, randomized, partial six‐way cross‐over study, 40 healthy subjects received single doses of placebo, CEP‐26401 (5, 25, or 125 μg) or modafinil 200mg or donepezil 10mg. Pharmacokinetic and pharmacodynamic measurements were performed pre‐dose and at designated time points post‐dose.

Results

The main endpoint between‐errors of the SWM‐10‐boxes task only improved for the 125 μg dose of CEP‐26401 with a difference of 2.92 (CI ‐1.21 – 7.05), 3.24 (CI ‐1.57 – 8.04) and 7.45 (CI 2.72 – 12.19) for respectively the 5, 25 and 125 μg dose of CEP‐2640, ‐1.65 (CI ‐.572 – 1.96) for modafinil and ‐3.55 (CI ‐7.13 – 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 VAS 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.

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