The Effects of Donepezil in Alzheimer’s Disease – Results from a Multinational Trial&lt;sup&gt;1&lt;/sup&gt;

Burns, Alistair; Rossor, Martin N.; Hecker, Jane; Gauthier, Serge; Petit, H; Möller, Hans‐Jürgen; Rogers, Sherise C.; Friedhoff, Lawrence

doi:10.1159/000017126

Cited by 550 publications

(427 citation statements)

References 22 publications

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“…Both are current therapies for Alzheimer's disease and have been shown to improve cognitive ability in Alzheimer's disease patients (Burns et al, 1999;Winblad et al, 2001Winblad et al, , 2006Peskind et al, 2006;Takeda et al, 2006). In the present study, both of these compounds also increased the distance moved in response to the acoustic stimulus in a similar manner to rolipram.…”

Section: Discussionsupporting

confidence: 67%

Non-Associative Learning in Larval Zebrafish

Best¹,

Berghmans²,

Hunt³

et al. 2007

Neuropsychopharmacol

216

150

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Habituation, where a response is reduced when exposed to a continuous stimulus is one of the simplest forms of non-associative learning and has been shown in a number of organisms from sea slugs to rodents. However, very little has been reported in the zebrafish, a model that is gaining popularity for high-throughput compound screens. Furthermore, since most of the studies involving learning and memory in zebrafish have been conducted in adults, we sought to determine if zebrafish larvae could display non-associative learning and whether it could be modulated by compounds identified in previous rodent studies. We demonstrated that zebrafish larvae (7 days post fertilization) exhibit iterative reduction in a startle response to a series of acoustic stimuli. Furthermore, this reduction satisfied criteria for habituation: spontaneous recovery, more rapid reductions in startle to shorter intertrial intervals and dishabituation. We then investigated the pathways mediating this behavior using established compounds in learning and memory. Administration of rolipram (PDE4 inhibitor), donepezil (acetylcholinesterase inhibitor), and memantine (N-methyl-D-aspartic acid (NMDA) receptor antagonist) all increased the acoustic startle response and decreased habituation in the larvae, similar to previous rodent studies. Further studies demonstrated that NMDA blocked the memantine response and the effect of donepezil was blocked by mecamylamine but not atropine suggesting that the donepezil response was mediated by nicotinic rather than muscarinic receptors. Zebrafish larvae possess numerous advantages for medium to high-throughput screening; the model described herein therefore offers the potential to screen for additional compounds for further study on cognition function.

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Section: Discussionsupporting

confidence: 67%

Non-Associative Learning in Larval Zebrafish

Best¹,

Berghmans²,

Hunt³

et al. 2007

Neuropsychopharmacol

216

150

View full text Add to dashboard Cite

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“…Neurophysiologic studies suggest that both donepezil and galantamine treatment may reduce rapid eye movement (REM) latency, 56,57 leading to decreased slow-wave sleep. 58 In clinical trials 53,59 with donepezil, insomnia was observed 2-to 3-fold more frequently in patients treated with donepezil than placebo. Direct studies of REM latency and density have provided evidence supporting the targeted activity of rivastigmine in the brain.…”

Section: Central and Peripheral Nervous System Adverse Eventsmentioning

confidence: 99%

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Grossberg

2003

Current Therapeutic Research

304

156

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Background: Cholinesterase (ChE) inhibitors currently used in the treatment of Alzheimer's disease (AD) are the acetylcholinesterase (AChE)-selective inhibitors, donepezil and galantamine, and the dual AChE and butyrylcholinesterase (BuChE) inhibitor, rivastigmine. In addition to differences in selectivity for AChE and BuChE, ChE inhibitors also differ in pharmacokinetic and pharmacodynamic properties, and these differences could significantly impact on safety, tolerability, and efficacy.Objective: The aim of this article was to provide an overview of the ChE inhibitors widely used in AD, focusing on key pharmacologic differences among agents and how these may translate into important differences in safety, tolerability, and efficacy in clinical practice.Methods: Using published literature collected over time by the author, a review was conducted, focusing on the pharmacology and clinical data of donepezil, galantamine, and rivastigmine.

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“…Adverse effects on sleep have been noted in patients receiving conventional AChE inhibitors (8,46). In a study assessing the efficacy and tolerability of galantamine in patients switched from previous donepezil treatment, PSQI scores were significantly improved within 6 weeks of commencing galantamine therapy (43).…”

Section: Benefits Of Galantamine On Sleep Qualitymentioning

confidence: 99%

Galantamine — a Novel Cholinergic Drug with a Unique Dual Mode of Action for the Treatment of Patients with Alzheimer's Disease

2002

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Galantamine hydrobromide is a tertiary alkaloid drug that has been developed and approved in a number of countries including the USA and several countries in Europe as a treatment for mild-to-moderate Alzheimer's disease (AD). Galantamine has a unique, dual mode of action. It is a reversible, competitive inhibitor of acetylcholinesterase (AChE), and is the only drug actively marketed for the treatment of AD with proven activity as an allosteric modulator of nicotinic acetylcholine receptors (nAChRs). This latter activity is thought to be particularly important since decreases in the expression and activity of nAChRs make a large contribution to the reduction in central cholinergic neurotransmission in patients with AD. Galantamine exhibits favorable pharmacokinetic characteristics including predictable linear elimination kinetics at the recommended maintenance doses (16 and 24 mg/day), a relatively short half-life (approximately 7 h) and high bioavailability. It is extensively metabolized in numerous pathways, mainly in the liver via cytochrome P450 enzymes CYP2D6 and CYP3A4, and has a low potential for clinically significant drug-drug interactions. During four large randomized, double-blind, placebocontrolled trials of up to 6 months duration, galantamine 16 and 24 mg/day significantly benefited cognitive and global function, ability to perform activities of daily living (ADL) and behavior, relative to placebo and baseline, for up to 6 months. Caregiver burden (time spent by caregivers supervising patients or assisting them with ADL), and caregiver distress (related to patients' behavioral symptoms) were also reduced. Cognitive and functional abilities were preserved at or near baseline for at least 12 months in patients who re- 159CNS Drug Reviews Vol. 8, No.2, pp. 159-176 © 2002 Neva Press, Branford, Connecticut Address correspondence and reprint requests to: Sean Lilienfeld, MBBCh, FCP(SA), MMed(Neuro), Janssen Pharmaceutica Inc, Janssen Research Foundation, Div of Janssen Pharmaceutica Ltd, 1125 Trenton Harbourton Road, Titusville NJ 08560. Tel.: +1 (609) 730-3414; Fax: +1 (609) 730-2441; E-mail: slilien1@janus.jnj.com ceived galantamine 24 mg/day for 12 months in a long-term US study. These benefits were maximized by early and continued galantamine treatment and, again, were associated with significant reductions in caregiver burden. Trials of the efficacy of galantamine in dementia related to cerebrovascular disease have also yielded positive results. There are no safety concerns associated with the use of galantamine. The incidence of adverse events, particularly cholinergically mediated events affecting the gastrointestinal system, is generally low and can be minimized using the recommended slow dose-escalation scheme. Galantamine may, therefore, help to reduce the overall burden and cost involved in caring for dementia patients. Taking all evidence into account, galantamine has the potential to become a first-line therapy for dementia.

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The Effects of Donepezil in Alzheimer’s Disease – Results from a Multinational Trial<sup>1</sup>

Abstract: ABCFax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com

Cited by 550 publications

References 22 publications

Non-Associative Learning in Larval Zebrafish

Non-Associative Learning in Larval Zebrafish

Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease:

Galantamine — a Novel Cholinergic Drug with a Unique Dual Mode of Action for the Treatment of Patients with Alzheimer's Disease

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