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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.
- Source :
-
British journal of clinical pharmacology [Br J Clin Pharmacol] 2019 May; Vol. 85 (5), pp. 970-985. Date of Electronic Publication: 2019 Mar 14. - Publication Year :
- 2019
-
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 low-dose levels of CEP-26401 were compared with modafinil and donepezil.<br />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.<br />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.<br />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.<br /> (© 2019 The British Pharmacological Society.)
- Subjects :
- Adolescent
Adult
Brain physiology
Cognition drug effects
Cognition physiology
Cognitive Dysfunction drug therapy
Cohort Studies
Cross-Over Studies
Donepezil administration & dosage
Donepezil pharmacokinetics
Dose-Response Relationship, Drug
Double-Blind Method
Female
Healthy Volunteers
Histamine Antagonists pharmacokinetics
Humans
Male
Memory drug effects
Memory physiology
Middle Aged
Modafinil administration & dosage
Modafinil pharmacokinetics
Pyridazines pharmacokinetics
Pyrrolidines pharmacokinetics
Reaction Time drug effects
Reaction Time physiology
Receptors, Histamine H3 metabolism
Sleep drug effects
Sleep physiology
Young Adult
Brain drug effects
Histamine Antagonists administration & dosage
Pyridazines administration & dosage
Pyrrolidines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2125
- Volume :
- 85
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- British journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 30710391
- Full Text :
- https://doi.org/10.1111/bcp.13885