ARICEPT - GENERIC

Bibliography and References. Review.
List of selected scientific articles (abstracts). Experimental and clinical data.

Brain Res. 2005 May 10;1043(1-2):236-41.
Neuroprotective effect of donepezil, a nicotinic acetylcholine-receptor activator, on cerebral infarction in rats.
Fujiki M, Kobayashi H, Uchida S, Inoue R, Ishii K.
Department of Neurosurgery, School of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Oita 879-5593, Japan.

This study evaluated the potential effect of donepezil, which is known as an acetylcholinesterase inhibitor used for treatment of Alzheimer's disease, against cerebral infarction induced by permanent left middle cerebral artery (MCA) occlusion. Donepezil was given orally in various regimens, prior to MCA occlusion in rats. Pretreatment with a single oral dose of donepezil (12 mg/kg), 2 h before ischemia, significantly attenuated cerebral infarction volume (165.5 +/- 105.3 vs. 377.1 +/- 48.5 mm(3); P < 0.05). These neuroprotective effects were prevented by coinjection with mecamylamine, a nicotinic acetylcholine-receptor (nAChR) antagonist, indicating that protection was mediated by nAChR activation.

Alzheimer's disease is common, incurable and disabling. It is expected to grow dramatically in prevalence over the next 50 years. At current, the standard of care for patients with mild and moderately severe Alzheimer's disease includes the use of acetylcholinesterase inhibitors. Donepezil (Aricept) is a highly selective acetylcholinesterase inhibitors with a pharmacokinetic profile allowing once-daily dosing. There is an extensive knowledge base derived from published clinical trials of donepezil in Alzheimer's disease, revealing consistent efficacy in cognition, global clinical ratings and daily function. Donepezil is also associated with additional meaningful outcomes such as reduced risk for, or delay to, nursing home placement. Despite a sense of limited efficacy of this drug class among prescribers, number needed-to-treat analyses suggest donepezil is highly effective at reducing the long-term adverse outcomes associated with Alzheimer's disease.

J Neurol Neurosurg Psychiatry. 2005 Mar;76(3):315-9.
Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease.
Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Koeppe RA, Meltzer CC, Constantine G, Davis JG, Mathis CA, Dekosky ST, Moore RY.
University of Pittsburgh, Liliane S Kaufmann Building, Suite 811, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA. nbohnen@pitt.edu.

OBJECTIVES: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer's disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy. METHODS: Cognitive and N-[(11)C]methyl-piperidin-4-yl propionate ([(11)C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy. RESULTS: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = -7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = -14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R(2) = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = -2.7; p<0.05). CONCLUSIONS: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Ann Pharmacother. 2005 Mar;39(3):563-6. Epub 2005 Feb 08.
Dramatic improvement in down syndrome-associated cognitive impairment with donepezil.
Kondoh T, Amamoto N, Doi T, Hamada H, Ogawa Y, Nakashima M, Sasaki H, Aikawa K, Tanaka T, Aoki M, Harada J, Moriuchi H.
Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.

OBJECTIVE: To report 2 cases of patients with Down syndrome and severe cognitive impairment who gained dramatic improvements in quality of life (QOL) upon donepezil treatment. CASE SUMMARIES: Case 1. A 38-year-old woman with Down syndrome, diagnosed with secondary progressive dementia when her mental state had deteriorated rapidly after graduation from junior high school, started donepezil treatment. The loading dose was 3 mg/day and was increased to 5 mg/day for maintenance. One month after the dose was increased, adverse effects such as soft stool and urinary incontinence appeared. These adverse effects disappeared when the dose was decreased again to 3 mg/day. Her QOL improved dramatically with this minimal dose. She recovered verbal and written communication skills that she had lost for the past 21 years. Case 2. A 22-year-old man with Down syndrome, who had been diagnosed as having severe mental retardation, was put on donepezil therapy. Both loading and maintenance doses were 3 mg/day. His QOL had also dramatically improved, with some recovery in verbal communication. Transient agitation/violence and transient muscle weakness appeared during the first few months of treatment. DISCUSSION: Patients with Down syndrome may be more sensitive to donepezil therapy than others and may benefit from this medicine, although they may also have adverse effects more frequently. CONCLUSIONS: Donepezil may be a useful medicine for some patients with Down syndrome with severe cognitive impairment or mental retardation if the adverse effects are manageable.

J Clin Psychiatry. 2005 Jan;66(1):107-10.
Beneficial effect of donepezil in the treatment of elderly patients with tardive movement disorders.
Bergman J, Dwolatzky T, Brettholz I, Lerner V.
Mental Health Center Tirat Carmel, Haifa, Israel.

BACKGROUND: Tardive dyskinesia and other delayed-onset abnormal involuntary movement disorders may occur as a result of the use of psychotropic drugs. A distinction is usually made between classic tardive dyskinesia (TD) (orobuccal-lingual-facial) and tardive dystonia, tardive tremor (TT), tardive akathisia, and other related syndromes. In spite of the development of atypical antipsychotics with fewer side effects, tardive movement disorders nevertheless continue to present a significant clinical and therapeutic challenge. Several reports have suggested that donepezil may be helpful in the treatment of TD. METHOD: A preliminary study was conducted of 7 patients (5 women and 2 men) enrolled over a period of 6 months who had been experiencing TT for a period of at least 1 year. The ages of the patients ranged from 64 to 79 years, and all patients were on stable antipsychotic therapy. Donepezil was added to their usual treatment for 8 weeks. The severity of patients' extrapyramidal symptoms was assessed using the tremor subscale of the Simpson-Angus Scale (SAS) and self-rated with a modification of the Clinical Global Impressions scale, the Subjective Clinical Improvement Impression scale. The clinical response was evaluated by comparing the rating scores at baseline prior to donepezil treatment and every 2 weeks thereafter. RESULTS: The addition of donepezil (up to 10 mg/day) was associated with a clinically significant improvement (from 37.5% to 63.6%) on the SAS tremor subscale following 4 weeks of therapy. Only 1 patient discontinued follow-up due to side effects. CONCLUSION: The results suggest that donepezil may be effective in the treatment of TT, and this finding should be evaluated further by a randomized controlled study.

Psychopharmacology (Berl). 2005 Jan 15.
Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model.
Van Dam D, Abramowski D, Staufenbiel M, De Deyn PP.
Laboratory of Neurochemistry and Behaviour, Born-Bunge Institute, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.

RATIONALE: APP23 mice are a promising model of Alzheimer's disease, expressing several histopathological, cognitive and behavioural hallmarks of the human condition. A valid animal model should respond to therapeutic interventions in an equivalent manner as human patients. OBJECTIVES: To further validate the APP23 model, we examined whether cognitive deficits could be antagonised by donepezil, rivastigmine, galantamine or memantine, which are approved drugs for symptomatic treatment of dementia. METHODS: Animals were tested at an age at which untreated APP23 mice display severe deficits in visual-spatial learning. Four-month-old APP23 mice and control littermates were administered donepezil (0.3 or 0.6 mg kg(-1)), rivastigmine (0.5 or 1.0 mg kg(-1)), galantamine (1.25 or 2.5 mg kg(-1)), memantine (2 or 10 mg kg(-1)) or saline through daily i.p. injections. After 1 week of treatment, acquisition phase commenced, with daily treatment continuing during cognitive testing. RESULTS: All cholinesterase inhibitors reduced cognitive deficits with the following optimal daily doses: galantamine 1.25 mg kg(-1), rivastigmine 0.5 mg kg(-1) and donepezil 0.3 mg kg(-1). Higher dosages often did not exert beneficial effects in accordance with inverted U-shaped dose-response curves described for cholinomimetics. Symptomatic efficacy of memantine on cognition was mild, with significant amelioration manifesting during probe trial. CONCLUSIONS: This is the first study to simultaneously evaluate the efficacy of therapeutically relevant doses of these four compounds in one particular learning and memory paradigm, being the Morris water maze. The fact that symptomatic intervention was able to diminish cognitive impairment, substantially adds to the validity of the APP23 model as a valuable tool to evaluate future therapeutic approaches.

J Mol Neurosci. 2004;24(1):85-91.
Donepezil-induced improvement in delayed matching accuracy by young and old rhesus monkeys.
Buccafusco JJ, Terry AV.
Alzheimer's Research Center, Medical College of Georgia, Augusta, GA 30912, USA. jbuccafu@mcg.edu

Donepezil (Aricept), a long-acting cholinesterase inhibitor, is widely used in the treatment of Alzheimer's disease to improve cognition and memory. Many drugs within the class of cognition-enhancing agents, both currently approved medications and those under development, have clinical indications narrowly relegated to Alzheimer's disease. The purpose of this study was to determine whether the efficacy attributed to donepezil in its ability to improve delayed matching accuracy by monkeys was independent of age. Male and female rhesus monkeys (n = 17) ranging from 9to 29 yr of age were administered donepezil (10, 25, 50, and 100 microg/kg, im) during 4 discrete test days. Donepezil treatment improved average task accuracy, but intersubject variability prohibited statistical significance. When animals were considered individually, the most effective dose of donepezil was associated with a highly significant increase in group task performance that was consistent with enhanced recall during testing. The variability associated with the dose-response analysis was attributable primarily to subject age, such that older monkeys required higher doses of donepezil. Yet at doses that were effective in all subjects, there was no relationship between age and the improvement in task accuracy. Likewise, there was no association between baseline task proficiency and improvement in task accuracy. Copyright 2004 Humana Press Inc.

Pharmacology. 2004 Sep;72(1):1-5.
Noncognitive symptoms and long-term treatment expectations for Alzheimer disease.
Blesa R.
Neurology Department, Hospital Sta Creu i Sant Pau, Barcelona, Spain. rblesa@hsp.santpau.es

Alzheimer disease (AD) is characterized by both cognitive and noncognitive symptoms that can lead to functional impairment, increased caregiver burden, and institutionalization. Pharmacologic therapies traditionally used to treat cognitive symptoms of AD may prevent and/or control many noncognitive symptoms as well. The acetylcholinesterase inhibitors (AChEIs) galantamine, rivastigmine, and donepezil have been shown to maintain or improve function for at least 1 year. They also have been shown to improve or delay the onset of neuropsychiatric and behavioral symptoms. These noncognitive benefits can impact greatly the lives of patients with AD as well as the persons who care for them.

Int J Geriatr Psychiatry. 2004 Jul;19(7):624-33.
Donepezil for the symptomatic treatment of patients with mild to moderate Alzheimer's disease: a meta-analysis of individual patient data from randomised controlled trials.
Whitehead A, Perdomo C, Pratt RD, Birks J, Wilcock GK, Evans JG.
The University of Reading, Medical and Pharmaceutical Statistics Research Unit, Reading, UK. P.A.Whitehead@reading.ac.uk

BACKGROUND: The objective was to evaluate the efficacy and tolerability of donepezil (5 and 10 mg/day) compared with placebo in alleviating manifestations of mild to moderate Alzheimer's disease (AD). METHOD: A systematic review of individual patient data from Phase II and III double-blind, randomised, placebo-controlled studies of up to 24 weeks and completed by 20 December 1999. The main outcome measures were the ADAS-cog, the CIBIC-plus, and reports of adverse events. RESULTS: A total of 2376 patients from ten trials were randomised to either donepezil 5 mg/day (n = 821), 10 mg/day (n = 662) or placebo (n = 893). Cognitive performance was better in patients receiving donepezil than in patients receiving placebo. At 12 weeks the differences in ADAS-cog scores were 5 mg/day-placebo: - 2.1 [95% confidence interval (CI), - 2.6 to - 1.6; p < 0.001], 10 mg/day-placebo: - 2.5 ( - 3.1 to - 2.0; p < 0.001). The corresponding results at 24 weeks were - 2.0 ( - 2.7 to - 1.3; p < 0.001) and - 3.1 ( - 3.9 to - 2.4; p < 0.001). The difference between the 5 and 10 mg/day doses was significant at 24 weeks (p = 0.005). The odds ratios (OR) of improvement on the CIBIC-plus at 12 weeks were: 5 mg/day-placebo 1.8 (1.5 to 2.1; p < 0.001), 10 mg/day-placebo 1.9 (1.5 to 2.4; p < 0.001). The corresponding values at 24 weeks were 1.9 (1.5 to 2.4; p = 0.001) and 2.1 (1.6 to 2.8; p < 0.001). Donepezil was well tolerated; adverse events were cholinergic in nature and generally of mild severity and brief in duration. CONCLUSION: Donepezil (5 and 10 mg/day) provides meaningful benefits in alleviating deficits in cognitive and clinician-rated global function in AD patients relative to placebo. Increased improvements in cognition were indicated for the higher dose. Copyright 2004 John Wiley & Sons, Ltd.

Arch Phys Med Rehabil. 2004 Jul;85(7):1050-5.
Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury.
Zhang L, Plotkin RC, Wang G, Sandel ME, Lee S.
Department of Rehabilitation Medicine, University of Texas Health Science Center, San Antonio, TX, USA. neurorehab@yahoo.com

OBJECTIVE: To examine effects of donepezil on short-term memory and sustained attention in postacute patients with traumatic brain injury (TBI). DESIGN: A 24-week, randomized, placebo-controlled, double-blind crossover trial. SETTING: Outpatient clinics in 2 teaching hospitals. PARTICIPANTS: Eighteen postacute TBI patients with cognitive impairment. INTERVENTION: Patients were randomly assigned to group A or group B. Patients in group A received donepezil for the first 10 weeks and then a placebo for another 10 weeks. The 2 treatment phases were separated by a washout period of 4 weeks. Patients in group B received the preparations in the opposite order. MAIN OUTCOME MEASURES: Short-term memory and sustained attention were assessed by 2 indexes (Auditory Immediate Index [AII], Visual Immediate Index [VII]) of the Wechsler Memory Scale-III and the Paced Auditory Serial Addition Test (PASAT), at baseline, week 10, and week 24 of the trial. RESULTS: Intragroup comparison of different phases of the trial in both groups showed that donepezil significantly increased the testing scores of the AII and VII, as well as PASAT scores, compared with baseline. There was no significant change in the testing scores between assessment at baseline and the end of the placebo phase in group B. Intergroup comparison at the 10-week assessment showed significantly improved testing scores in group A with donepezil over group B with the placebo. The improved testing scores with donepezil in group A were sustained after the washout period and placebo phase, suggesting a carry-over effect of the medication. CONCLUSIONS: Donepezil increased neuropsychologic testing scores in short-term memory and sustained attention in postacute TBI patients. Cholinergic augmentation may be a viable approach to restore memory and attention after TBI.

CNS Spectr. 2004 Jul;9(7 Suppl 5):24-8.
Understanding the latest advances in pharmacologic interventions for Alzheimer's disease.
van Dyck CH.
Alzheimer's Disease Research Unit, Yale University School of Medicine, 1 Church Street, New Haven, CT 06510, USA. christopher.vandyck@yale.edu

Alzheimer's disease (AD) is a complex medical condition involving abnormalities in multiple biological and environmental domains. Current knowledge suggests that simultaneous intervention in these domains may be the most effective way to help AD patients and their families. Treatments for AD are centered on the inhibition of enzymes responsible for the degradation of acetylcholine--a neurotransmitter that is reduced in AD patients. Four cholinesterase inhibitors have been approved by the United States Food and Drug Administration, three of which are routinely used for the symptomatic treatment of mild-to-moderate AD. Strategies will be reviewed with regard to cognitive, functional, and behavioral domains. Providing a different treatment option for patients with AD, memantine is a low-to-moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that has been approved for the treatment of moderate-to-severe AD. The clinical efficacy and tolerability of memantine monotherapy and combination therapy in patients with AD will be presented. Finally, the role of nonpharmacologic intervention will be discussed.

Int J Neuropsychopharmacol. 2004 Sep;7(3):351-69. Epub 2004 Jul 01.
Evidence-based pharmacotherapy of Alzheimer's disease.
Evans JG, Wilcock G, Birks J.
Cochrane Dementia and Cognitive Improvement Group, University of Oxford, UK.

Dementia is an acquired global impairment of cognitive capacities. Approximately 5% of people aged over 65 yr are affected by dementia, and some 70% of cases are thought to be due primarily to Alzheimer's disease. Descriptions of the clinical manifestations of Alzheimer's disease have been increasingly refined in the last decade but there is no diagnostic test for what remains fundamentally a pathologically defined condition. At the present time interventions for Alzheimer's disease are limited to those that modify the manifestations of the disease, and foremost amongst the candidates available are the cholinesterase inhibitors. The rationale for the use of cholinergic drugs for Alzheimer's disease lies in enhancing the secretion of, or prolonging the half-life of, acetylcholine in the brain. Several potential compounds have been tested, but short half-lives and a high incidence of cholinergic and other adverse effects have eliminated most. Only three are widely licensed for use, donepezil, galantamine and rivastigmine. Their efficacy is relatively modest. These drugs have been tested in 32 randomized, placebo-controlled trials. The trials assess cognitive function primarily, and in addition they may assess global function, activities of daily living, quality of life and behavioural disturbance typically over 3 or 6 months. The performance of each drug is summarized in a Cochrane review, a systematic review carried out according to strict guidelines. There was a significant benefit in favour of treatment compared with placebo for cognition and activities of daily living, but withdrawals due to adverse events were significantly higher for treatment than placebo for all three drugs. There is little evidence from direct comparisons between the three drugs. There are several economic analyses of the cost-effectiveness of these drugs, but the findings cannot be considered robust owing to inadequate data. A range of other pharmacological treatments have been tested, including selegiline, piracetam, vitamin E, Ginkgo biloba, anti-inflammatory drugs and hormone replacement therapy, but, so far, Cochrane reviews have not established the efficacy of these interventions for Alzheimer's disease. A Cochrane review of memantine shows benefits on cognitive and global function of the same order of magnitude as seen for the cholinesterase inhibitors. Memantine has been licensed in Europe for treatment of patients with moderately severe to severe Alzheimer's disease.

Geriatrics. 2004 Jun;59(6):22-7.
NMDA receptor antagonists. A new therapeutic approach for Alzheimer's disease.
Farlow MR.
Department of Neurology, Indiana University School of Medicine, Indianapolis, USA.

Research into Alzheimer's disease (AD) pathology has identified several underlying disease processes that are potential targets for drug discovery and development. One strategy targets glutamatergic neurotransmission mediated by the N-methyl-D-aspartate (NMDA) receptor. Therapeutic intervention with high-affinity NMDA receptor antagonists, such as phencyclidine (PCP) and MK-801, is not practical due to adverse side effects; however, a low-moderate affinity, uncompetitive and strongly voltage-dependent NMDA receptor antagonist, memantine (NamendaTM), is well tolerated and recently has been approved by the U.S. Food and Drug Administration for the treatment of moderate to severe AD. Clinical results support NMDA receptor antagonism as a viable therapeutic strategy for AD and suggest that this novel pharmacologic approach, either alone or in combination with other drugs, is likely to significantly impact the current AD treatment paradigm.

Lancet. 2004 Jun 26;363(9427):2105-15.
Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial.
Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P; AD2000 Collaborative Group.
Trials Unit, University of Birmingham, Birmingham, UK.

BACKGROUND: Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? METHODS: 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. FINDINGS: Cognition averaged 0.8 MMSE (mini-mental state examination) points better (95% CI 0.5-1.2; p<0.0001) and functionality 1.0 BADLS points better (0.5-1.6; p<0.0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0.4) or progression of disability (58% vs 59% at 3 years; p=0.4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0.97 (95% CI 0.72-1.30; p=0.8); the relative risk of progression of disability or entering institutional care was 0.96 (95% CI 0.74-1.24; p=0.7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil. INTERPRETATION: Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease.

Am J Alzheimers Dis Other Demen. 2004 May-Jun;19(3):153-60.
Ganstigmine and donepezil improve neurodegeneration in AD11 antinerve growth factor transgenic mice.
Capsoni S, Giannotta S, Stebel M, Garcia AA, De Rosa R, Villetti G, Imbimbo BP, Pietra C, Cattaneo A.
Lay Line Genomics S.p.A., Rome, Italy.

Ganstigmine (CHF2819) is an acetylcholinesterase inhibitor that increases acetylcholine in rat hippocampus and ameliorates scopolamine-induced amnesia. In this article, we examined whether and how ganstigmine might prevent or rescue the neurodegenerative phenotype in AD11 antinerve growth factor (anti-NGF) mice, a transgenic model for Alzheimer's disease. The effects of ganstigmine were compared with those obtained after administration of donepezil. Results demonstrate that intraperitoneal and oral administration of ganstigmine and donepezil can reverse the cholinergic and behavioral deficit in AD11 mice but not the amyloid and phosphotau accumulation, uncovering different mechanisms leading to neurodegeneration in AD11 mice.

Brain Inj. 2004 Aug;18(8):739-50.
The effects of Donepezil on traumatic brain injury acute rehabilitation outcomes.
Walker W, Seel R, Gibellato M, Lew H, Cornis-Pop M, Jena T, Silver T.
Defense and Veterans Brain Injury Center, McGuire Veterans Administration Medical Center, Richmond, VA 23249, USA.

PRIMARY OBJECTIVE: To evaluate the effects of administering Donepezil during inpatient rehabilitation for individuals with TBI. RESEARCH DESIGN: Retrospective, age and injury severity matched, mixed between-within subjects analysis. METHODS AND PROCEDURES: Thirty-six patients with moderate-to-severe TBI admitted to acute rehabilitation within 90 days of injury. Main outcome measures included FIM cognitive total scores and rehabilitation lengths of stay. INTERVENTION: Initiation of Donepezil administration beginning at 5 mg daily. Dose titration and continuation based on perceived clinical response. MAIN OUTCOMES AND RESULTS: No differences in cognitive improvement were observed between the Donepezil treatment group and the matched control group. Sub-set analyses suggested that administration of Donepezil early in the rehabilitation stay was significantly related to higher rates of cognitive improvement. CONCLUSIONS: Preliminary evidence suggests that Donepezil administration early in the rehabilitation stay may have advantageous treatment effects. A prospective, randomized, placebo-controlled clinical trial with standard timing, dosage and treatment duration is recommended to further evaluate treatment efficacy.

Rev Neurol. 2004 May 16-31;38(10):938-43.
[Donepezil therapy in patients with vascular and post-traumatic cognitive impairment: some clinical observations]
[Article in Spanish]
Olazaran-Rodriguez J, Cruz-Orduna I, Jimenez-Martin I.
Consulta de Neurologia, CEP Hermanos Sangro, Area 1 Atencion Especializada del INSALUD, Madrid, Spain. javier@mariawolff.es

INTRODUCTION: Donepezil is a procholinergic drug that slows down cognitive and functional impairment in patients with Alzheimer's disease. Little research has been carried out to study its effect in other types of neurobehavioural disorders. AIMS: The purpose of this study was to describe the response to donepezil therapy in patients with neurobehavioural disorders due to vascular and post-traumatic causes. CASE REPORTS: Donepezil was administered to four patients with mild cognitive impairment due to vascular causes, to two patients with vascular dementia and to two patients with post-traumatic dementia. Following an average time of four months, the effects exerted on the cognitive, functional and behavioural areas were evaluated. One patient did not tolerate the drug and another suffered an episode of congestive heart failure that gave rise to a moderate neurobehavioural exacerbation. Two patients underwent a moderate improvement, three patients showed a slight improvement and no changes were observed in one patient. In general, memory, attention, depression, apathy and psychotic traits tended to improve. Aggressiveness/irritability tended to get worse. The functional repercussions of these changes were negligible or inexistent. CONCLUSIONS: Treatment with donepezil improved cognition and conduct in patients with neurobehavioural disorders due to vascular or post-traumatic causes. These results will have to be confirmed and expanded by means of controlled studies, and research must continue into the characteristics of responding patients and the relevance of their responses.

Neurosci Lett. 2004 May 6;361(1-3):56-9.
Comparative effects of huperzine A, donepezil and rivastigmine on cortical acetylcholine level and acetylcholinesterase activity in rats.
Liang YQ, Tang XC.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.

The cholinesterase inhibitors huperzine A, donepezil and rivastigmine were compared for their effects on extracellular acetylcholine concentration and acetylcholinesterase activity in the rat cortex. After i.p. injection, huperzine A (0.25-0.75 micromol/kg), donepezil (2-6 micromol/kg) and rivastigmine (0.75-1.5 micromol/kg) dose-dependently elevated the concentration of acetylcholine. The duration of huperzine A was longest. The time courses of cortical acetylcholinesterase inhibition with middle doses of these agents mirrored the increases of acetylcholine at the same doses. However, acetylcholinesterase inhibition was disproportionately greater after middle dose of rivastigmine than doses of huperzine A and donepezil that increased acetylcholine to a similar extent. Muscle fasciculation appeared only after donepezil with a dose-dependent incidence and intensity. In molar terms, huperzine A was 8- and 2-fold more potent than donepezil and rivastigmine, respectively, in increasing cortical acetylcholine levels, with a longer-lasting effect.

Aging Clin Exp Res. 2004 Feb;16(1):60-7.
Donepezil use in US nursing homes.
Pedone C, Lapane KL, Mor V, Bernabei R.
Centro di Medicina dell'Invecchiamento, Universita Cattolica del Sacro Cuore, Roma, Italy. claudio_pedone@rm.unicatt.it

BACKGROUND AND AIMS: Donepezil is effective in slowing the progression of Alzheimer's disease (AD). No data are available on the patterns of donepezil use among nursing home residents. We estimate the prevalence of the use of donepezil and the frequency of its initiation, and describe the demographic and clinical characteristics of residents taking this drug. METHODS: We used data from the Minimum Data Set (N=174659). We compared users and non-users of donepezil with respect to demographic, clinical and functional variables. We estimated the 6-month incidence of donepezil use. All analyses were stratified by the admission status of the residents (newly admitted/long-stay). RESULTS: Among those meeting the manufacturer's indication for donepezil (mild to moderate AD), the prevalence of use was 30% among newly admitted, and 19% among long-stay residents. About 3% of residents not meeting the manufacturer's indication for donepezil were taking it. The proportion of people with AD still taking donepezil after six months was 44.8% among newly admitted, and 59.5% among long-stay residents. Donepezil use was associated with cognitive impairment, behavioral problems and the use of psychotropic drugs including anti-psychotics and anti-depressants. In people without a diagnosis of AD, there seems to be an association between behavioral problems and use of donepezil. CONCLUSIONS: Donepezil is frequently used in the nursing home setting for the management of AD. Off-label use of donepezil is also relatively frequent. This may reflect an empirical perception of effectiveness on outcomes different from cognitive impairment, such as behavioral problems, although evidence is lacking.

Dement Geriatr Cogn Disord. 2004;18(1):37-43. Epub 2004 Apr 06.
Donepezil for Alzheimer's disease in clinical practice--The DONALD Study. A multicenter 24-week clinical trial in Germany.
Froelich L, Gertz HJ, Heun R, Heuser I, Jendroska K, Kornhuber J, Kurz A, Mueller-Thomsen T, Ries F, Waechtler C, Metz M, Goebel C.
Division of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, University of Heidelberg, Heidelberg, Germany. froelich@zi-mannheim.de

This multicenter open-label clinical trial was designed to investigate the safety and efficacy of donepezil, a selective acetylcholinesterase inhibitor, in the treatment of Alzheimer's disease (AD) in routine clinical practice in Germany. A total of 237 patients with mild-to-moderate AD were treated with donepezil for 24 weeks, 186 completed the study according to the protocol. In the completer group, mean MMSE score for efficacy showed an improvement from baseline of +1.6 points at week 12 (95% CI +1.1 to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7). In more than 80% of the patients, global tolerability was rated to be very good or good. There were only insignificant effects on ECG parameters. This study confirms the results obtained in previous double-blind trials, which showed that donepezil is effective and well tolerated in patients with mild-to-moderately severe AD. Copyright 2004 S. Karger AG, Basel.