Acute response to cholinergic challenge predicts long‐term response to galantamine treatment in patients with Alzheimer's disease
British Journal of Clinical Pharmacology, vol. 88, pp. 2814–2829
Abstract
AIMS: Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response. METHODS: This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non-responders. RESULTS: A single dose of galantamine significantly reduced saccadic reaction time (-0.0099; 95% CI = -0.0195, -0.0003; P = .0430), absolute frontal EEG parameters in alpha (-14.9; 95% CI = -21.0, -8.3; P = .0002), beta (-12.6; 95% CI = -19.4, -5.3; P = .0019) and theta (-17.9; 95% CI = -25.0, -10.0; P = .0001) frequencies. Relative frontal (-1.669; 95% CI = -2.999, -0.339; P = .0156) and occipital (-1.856; 95% CI = -3.339, -0.372; P = .0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P = .0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (-20.4; 95% CI = -31.6, -7.47; P = .0046), beta (-15.7; 95% CI = -28.3, -0.93; P = .0390) and theta (-25.9; 95% CI = -38.4, -10.9; P = .0024) EEG parameters and of relative frontal theta power (-3.27%; 95% CI = -5.96, -0.58; P = .0187) on EEG significantly distinguished responders (n = 11) from non-responders (n = 32) after 6 months. CONCLUSIONS: This study demonstrates that acute PD effects after single dose of galantamine are correlated with long-term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.
Authors 15
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Anne Catrien Baakman Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Clinical Emergency Hospital Bucharest · Bucharest Emergency University Hospital
Affiliation as printed
Clinicii de neurologie a Spitalului Universitar de Urgenta Bucharest Romania
Clinicii de neurologie a Spitalului Universitar de Urgenta, Bucharest, Romania
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Lotte van Doeselaar Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Marieke de Kam Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Karen Broekhuizen Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Clinical Emergency Hospital Bucharest · Bucharest Emergency University Hospital
Affiliation as printed
Clinicii de neurologie a Spitalului Universitar de Urgenta Bucharest Romania
Clinicii de neurologie a Spitalului Universitar de Urgenta, Bucharest, Romania
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Laura Camps Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Amsterdam University Medical Centers
Affiliation as printed
Department of Clinical Pharmacology and Pharmacy Amsterdam UMC Amsterdam The Netherlands
Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, Amsterdam, The Netherlands
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Affiliation as printed
Department of Neurology Spaarne Gasthuis Haarlem The Netherlands
Department of Neurology, Spaarne Gasthuis, Haarlem, The Netherlands
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Affiliation as printed
Department of Neurology Spaarne Gasthuis Haarlem The Netherlands
Department of Neurology, Spaarne Gasthuis, Haarlem, The Netherlands
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Amsterdam University Medical Centers
Affiliation as printed
Alzheimer Center Amsterdam, Amsterdam UMC Amsterdam The Netherlands
Alzheimer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
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Amsterdam University Medical Centers
Affiliation as printed
Alzheimer Center Amsterdam, Amsterdam UMC Amsterdam The Netherlands
Alzheimer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
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Adam F. Cohen Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Joop van Gerven Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Geert Jan Groeneveld corresponding Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Leiden University Medical Center · Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Leiden University Medical Center Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
Leiden University Medical Center, Leiden, The Netherlands
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