Perspectives in the management of Alzheimer's disease: Clinicalprofile of donepezil
S.L. Rogers
Bok Engelsk 1998
| Utgitt | 1998
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| Omfang | Side 29- 42
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| Opplysninger | Donepezil HCl is a piperidine-based reversible acetylcholinesterase(AChE) inhibitor, chemically distinct from other cholinesterase (ChE)inhibitors and rationally designed to treat the symptoms ofAlzheimer's disease (AD). It is highly selective for AChE in thecentral nervous system (CNS), with little or no affinity forbutyrylcholinesterase (BuChE). In preclinical studies in animals,donepezil produced increased CNS acetylcholine. The resultantenhancement of cholinergic activity gave rise to improved performanceby rats on tests of learning and memory, with no evidence of hepaticor renal toxicity. In subsequent phase I clinical evaluations inhealthy volunteers, donepezil demonstrated favorable pharmacokinetic,pharmacodynamic and safety profiles. Its long terminal dispositionhalf-life supported once-daily administration, with no requirementfor dose modification in the elderly or in patients with renal orhepatic impairment. A 14-week, phase II dose-finding study inpatients with mild to moderate AD (Clinical Dementia Rating [CDR], 1-2; MiniMental State Examination [MMSE], 10-26) showed that donepezilat a dose of 5 mg/day produced highly significant improvements incognition (as measured by the Alzheimer's Disease Assessment Scale,cognitive subscale [ADAS-cog]). Subsequently, two pivotal parallel-group, placebo-controlled phase III trials (of 15 and 30 weeks'duration) showed highly statistically significant improvements inADAS-cog, MMSE, Clinician's Interview-Based Impression of Change withcaregiver input (CIBIC plus) and CDR-SB (Sum of the Boxes) scores,compared with placebo, in mild to moderate AD patients treated witheither 5 or 10 mg/day donepezil. Adverse events in the phase II andIII trials were mild and transient and resolved with continueddonepezil administration. The donepezil clinical trials program hasshown that this drug is a clinically effective and well-toleratedonce-daily treatment for the symptoms of mild to moderate AD.
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