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

Anne C. Baakman, Rob Zuiker, Joop M. A. van Gerven, Nicholas Gross, Ronghua Yang, Michael Fetell, Ari Gershon, Yossi Gilgun-Sherki, Edward Hellriegel, Ofer Spiegelstein

Research output: Contribution to journalArticleAcademicpeer-review

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. 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.
Original languageEnglish
Pages (from-to)970-985
JournalBritish Journal of Clinical Pharmacology
Volume85
Issue number5
DOIs
Publication statusPublished - 1 May 2019

Cite this

Baakman, Anne C. ; Zuiker, Rob ; van Gerven, Joop M. A. ; Gross, Nicholas ; Yang, Ronghua ; Fetell, Michael ; Gershon, Ari ; Gilgun-Sherki, Yossi ; Hellriegel, Edward ; Spiegelstein, Ofer. / 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. In: British Journal of Clinical Pharmacology. 2019 ; Vol. 85, No. 5. pp. 970-985.
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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. 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.",
author = "Baakman, {Anne C.} and Rob Zuiker and {van Gerven}, {Joop M. A.} and Nicholas Gross and Ronghua Yang and Michael Fetell and Ari Gershon and Yossi Gilgun-Sherki and Edward Hellriegel and Ofer Spiegelstein",
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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. / Baakman, Anne C.; Zuiker, Rob; van Gerven, Joop M. A.; Gross, Nicholas; Yang, Ronghua; Fetell, Michael; Gershon, Ari; Gilgun-Sherki, Yossi; Hellriegel, Edward; Spiegelstein, Ofer.

In: British Journal of Clinical Pharmacology, Vol. 85, No. 5, 01.05.2019, p. 970-985.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - 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

AU - Baakman, Anne C.

AU - Zuiker, Rob

AU - van Gerven, Joop M. A.

AU - Gross, Nicholas

AU - Yang, Ronghua

AU - Fetell, Michael

AU - Gershon, Ari

AU - Gilgun-Sherki, Yossi

AU - Hellriegel, Edward

AU - Spiegelstein, Ofer

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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. 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.

AB - 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. 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30710391

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