Effect of butyrylcholinesterase genotype on the response to rivastigmine or donepezil in younger patients with Alzheimer's disease

A randomized double-blind trial evaluated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with Alzheimer's disease over a 2-year period. A retrospective analysis showed differential responses to cholinesterase inhibitors (ChE-Is) in patients younger than 75 years. This analysis investigated the effect of BuChE genotype on response to ChE-I therapy in these patients. In a retrospective analysis, patients younger than 75 who had consented to pharmacogenetic analysis were divided into groups according to BuChE genotype. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Changes on efficacy parameters were calculated for rivastigmine-treated and donepezil-treated patients in both groups. Of 114 (34.1%) patients younger than 75 who were successfully assessed for BuChE genotype, 76 (66.7%) were homozygous for wild-type BuChE, and 38 (33.3%) carried at least one BuChE K-variant allele. Wild-type BuChE carriers showed significantly greater responses to rivastigmine than to donepezil on the SIB, ADCS-ADL, GDS and NPI. No significant between-treatment differences in efficacy were observed in BuChE K-variant carriers, although adverse events were more frequent in rivastigmine-treated patients. In this retrospective analysis, Alzheimer's disease patients younger than 75 with wild-type BuChE exhibited differential efficacy to rivastigmine, while BuChE K-variant carriers experienced similar long-term treatment effects with both agents. These differences may reflect rivastigmine's ability to inhibit BuChE and AChE.     

Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant Lewy body pathology

BACKGROUND: A double-blind randomized trial evaluated the efficacy and tolerability of rivastigmine and donepezil in patients with Alzheimer's disease (AD) over 2 years. Baseline data indicated that some patients had symptoms suggestive of concomitant Lewy body disease. This retrospective analysis investigated whether AD patients with and without symptoms suggesting concomitant Lewy body pathology demonstrated different responses to therapy. METHODS: AD patients were divided by the presence/absence of symptoms suggestive of concomitant Lewy body disease. These were identified by a concomitant diagnosis of dementia with Lewy bodies and/or use of anti-parkinsonian medication at baseline. Baseline characteristics, demographics, changes on efficacy parameters and adverse event (AE) frequencies were calculated for rivastigmine- and donepezil-treated patients. Efficacy parameters were the Severe Impairment Battery (SIB), Mini-Mental State Examination (MMSE), Global Deterioration Scale (GDS), Neuropsychiatric Inventory (NPI) and AD Cooperative Study Activities of Daily Living scale (ADCS-ADL). Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT-LOCF) population. RESULTS: Both populations reached mean doses of rivastigmine and donepezil that were within therapeutic ranges. Nine hundred and ninety-four AD patients received study drug, of whom 49 (4.9%) had symptoms suggestive of concomitant Lewy body disease (25 rivastigmine, 24 donepezil). In this subpopulation, changes from baseline after 2 years of treatment with rivastigmine were significantly better than those seen with donepezil on the SIB, MMSE and ADCS-ADL (ANCOVA or Wilcoxon analyses, p < 0.05, ITT-LOCF). Statistical significance was not maintained in non-ITT-LOCF analyses, except for EP analyses on the SIB and ADCS-ADL (both p < 0.05). Rivastigmine also provided significantly better functioning than donepezil in patients without Lewy body pathology, as shown by a significant treatment difference at endpoint on the ADCS-ADL (p < 0.05, ITT-LOCF; not maintained in non-ITT-LOCF analyses). NPI changes from baseline did not differ significantly between treatment groups. AD patients with symptoms suggestive of concomitant Lewy body disease receiving rivastigmine or donepezil experienced fewer gastrointestinal side effects, leading to fewer discontinuations due to AEs, compared with patients without Lewy body pathology. CONCLUSION: In this retrospective analysis, AD patients who had symptoms suggestive of concomitant Lewy body disease appeared to show greater treatment responses to rivastigmine than to donepezil, and experienced fewer adverse events under either drug, compared with patients without Lewy body pathology.     

Effect of age on response to rivastigmine or donepezil in patients with Alzheimer's disease

ABSTRACT

Background: Younger Alzheimer's disease (AD) patients appear to differ genetically and neuropathologically from older AD patients, and may experience a more aggressive disease course compared with older patients. A randomised trial investigated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with AD over a 2-year period. This retrospective analysis investigated whether younger and older patients showed differential tolerability and efficacy responses to cholinesterase inhibitor treatment.

Methods: For the current analysis, patients were divided according to age at baseline: those aged < 75 years and those aged ≥ 75 years. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the AD Cooperative Study Activities of Daily Living scale (ADCS‐ADL). Changes in efficacy parameters and adverse event frequencies were calculated for rivastigmine and donepezil-treated patients in both age groups. Exploratory analyses were also conducted on SIB, ADCS‐ADL and NPI in patients who consented to pharmacogenetic testing at baseline. Genotyping of the apolipoprotein E (APOE) ε4 allele and the BuChE K-variant was conducted using the TaqMan assay. Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT‐LOCF) population.

Results: Of the 994 patients who received the study drug, 362 (36.4%) were younger than 75 years and 632 (63.6%) were aged 75 years or over. Rivastigmine provided significant benefits in younger patients compared with donepezil on the NPI‐10, NPI‐12, NPI‐D, GDS and ADCS‐ADL (all p < 0.05, ITT‐LOCF). With the exception of the NPI‐D in favour of donepezil (?p < 0.05, ITT‐LOCF), no significant treatment differences were observed in older patients. Younger patients with two wild-type BuChE alleles had a significantly greater response to rivastigmine than donepezil on the ADCS‐ADL (?p < 0.01, ITT‐LOCF) and SIB (?p < 0.05, ITT‐LOCF). The most common adverse events were nausea and vomiting and these were more frequent in rivastigmine-treated patients.

Conclusion: In this sub group analysis, patients younger than 75 years of age showed greater treatment responses to rivastigmine than donepezil. Analysis of response by BuChE genotype suggests that this differential effect may be due to the inhibition of BuChE, in addition to AChE, by rivastigmine.     

Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period

OBJECTIVES: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period. METHODS: Patients were randomly assigned to rivastigmine 3-12 mg/day or donepezil 5-10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs. RESULTS: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT-LOCF population. However, this was not maintained in the non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment. CONCLUSIONS: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.     

Effects of switching from an AChE inhibitor to a dual AChE-BuChE inhibitor in patients with Alzheimer's disease

OBJECTIVE: Cholinesterase (ChE) inhibitors are the only medications approved for the treatment of Alzheimer's disease (AD). The features of ChE inhibitors differ considerably. In addition to acetylcholinesterase (AChE) inhibition, rivastigmine also inhibits butrylcholinesterase (BuChE), providing dual AChE and BuChE inhibition. An observational study was performed to determine the response in routine clinical practice to switching AD patients to rivastigmine from a selective AChE inhibitor when that treatment no longer delivered a satisfactory clinical response. RESEARCH DESIGN AND METHODS: A prospective, multicentre, 3-month observational trial in patients with mild to moderately severe AD (adjusted Mini Mental State Examination [MMSE] score 10-26) deteriorating (at least 2 adjusted MMSE points in last 6 months) on selective AChE inhibitor treatment. Adjusted MMSE, activities of daily living (ADL) and instrumental activities of daily living (IADL), the Zarit caregiver burden and global function (short Clinical Global Impression of Change, CGIC) scores were noted before the switch and 3 months after the switch. RESULTS: 225 patients entered the study. The switches made were from donepezil to rivastigmine in (D-R) in 188 patients, galantamine to rivastigmine (G-R) in 33 patients and donepezil to galantamine (D-G) in four patients. Ten patients discontinued due to adverse events and eight for other reasons. More than half of the switches were within 36 hours of a patient's first treatment visit. In the D-R and G-R groups, 67.7% and 66.7% of patients responded (CGIC score < or = 4), respectively. In non-responders, worsening (CGIC score 5-7) was mild in approximately 80% or more of patients. Adjusted MMSE improved after the switch from both donepezil and galantamine to rivastigmine (+0.69 +/- 3.2, p = 0.008 and +0.6 +/- 1.6, p = 0.05, respectively). Mean ADL, IADL, and Zarit scores remained stable. The proportion of patients on concomitant antipsychotic therapy diminished by 30.5% and benzodiazepines were discontinued in all patients, except one. CONCLUSIONS: AD patients deteriorating on selective AChE inhibitor treatment can benefit from switching to a dual AChE-BuChE inhibitor, such as rivastigmine, in terms of stabilization of disease, improvement in cognitive function and reduction in the burden of concomitant psychoactive treatment. The switch was well tolerated. Confirmation of these results is required in a controlled study.     

Selective inhibitors of butyrylcholinesterase: a valid alternative for therapy of Alzheimer's disease?

The brain of mammals contains two major forms of cholinesterases (ChEs): acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally and in their kinetics. Butyrylcholine is not a physiological substrate in mammalian brains which makes the function of BuChE difficult to interpret. In human brains, BuChE is found in neurons and glial cells as well as in neuritic plaques and tangles in patients with Alzheimer's disease (AD).While AChE activity decreases progressively in the brain of patients with AD, BuChE activity shows some increase. In order to study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor. We found that extracellular acetylcholine levels increased 15-fold from 5 nmol/L to 75 nmol/L concentrations, with little cholinergic adverse effect in the animal. Based on these data, we postulated that two pools of ChEs may be present in the brain: one mainly neuronal and AChE dependent; and one mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of acetylcholine concentration in the brain and can be separated with selective inhibitors. The recent development of highly selective BuChE inhibitors will allow us to test these new agents in patients with AD in order to find out whether or not they represent an advantage for the treatment of patients with AD as compared with selective (donepezil) or relatively non-selective (rivastigmine, galantamine) ChE inhibitors presently in use. The association between a BuChE-K variant and AD has not been confirmed in several studies. In conclusion, additional experimental and clinical work is necessary in order to elucidate the role of BuChE in normal brain function and in the brains of patients with AD. In the future, it may be possible that selective BuChE inhibitors will have a role in treatment of patients with advanced AD.     

Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period

ABSTRACT

Objectives: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period.

Methods: Patients were randomly assigned to rivastigmine 3–12?mg/day or donepezil 5–10?mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs.

Results: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT–LOCF population. However, this was not maintained in the non-ITT–LOCF populations. In secondary sub-group analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment.

Conclusions: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.     

Effects of switching from an AChE inhibitor to a dual AChE-BuChE inhibitor in patients with Alzheimer's disease

ABSTRACT

Objective: Cholinesterase (ChE) inhibitors are the only medications approved for the treatment of Alzheimer's disease (AD). The features of ChE inhibitors differ considerably. In addition to acetylcholinesterase (AChE) inhibition, rivastigmine also inhibits butyrylcholinesterase (BuChE), providing dual AChE and BuChE inhibition. An observational study was performed to determine the response in routine clinical practice to switching AD patients to rivastigmine from a selective AChE inhibitor when that treatment no longer delivered a satisfactory clinical response.

Research design and methods: A prospective, multicentre, 3‐month observational trial in patients with mild to moderately severe AD (adjusted Mini Mental State Examination [MMSE] score 10–26) deteriorating (at least 2 adjusted MMSE points in last 6 months) on selective AChE inhibitor treatment. Adjusted MMSE, activities of daily living (ADL) and instrumental activities of daily living (IADL), the Zarit caregiver burden and global function (short Clinical Global Impression of Change, CGIC) scores were noted before the switch and 3 months after the switch.

Results: 225 patients entered the study. The switches made were from donepezil to rivastigmine (D‐R) in 188 patients, galantamine to rivastigmine (G‐R) in 33 patients and donepezil to galantamine (D‐G) in four patients. Ten patients discontinued due to adverse events and eight for other reasons. More than half of the switches were within 36 hours of a patient's first treatment visit. In the D‐R and G‐R groups, 67.7% and 66.7% of patients responded (CGIC score ≤ 4), respectively. In non-responders, worsening (CGIC score 5–7) was mild in approximately 80% or more of patients. Adjusted MMSE improved after the switch from both donepezil and galantamine to rivastigmine (+0.69 ± 3.2, p = 0.008 and +0.6 ± 1.6, p = 0.05, respectively). Mean ADL, IADL and Zarit scores remained stable. The proportion of patients on concomitant antipsychotic therapy diminished by 30.5% and benzodiazepines were discontinued in all patients, except one.

Conclusions: AD patients deteriorating on selective AChE inhibitor treatment can benefit from switching to a dual AChE-BuChE inhibitor, such as rivastigmine, in terms of stabilization of disease, improvement in cognitive function and reduction in the burden of concomitant psychoactive treatment. The switch was well tolerated. Confirmation of these results is required in a controlled study.     

Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer's disease

Donepezil and rivastigmine are acetylcholinesterase (AChE) inhibitors used to improve cholinergic neurotransmission and cognitive function in Alzheimer's disease (AD). This study examined direct effects of these drugs on AChE activity in the frontal, temporal, and parietal cortices in AD. Six AD patients were scanned with positron emission tomography before and after 3 months of treatment with donepezil (10 mg/day), and five AD patients were scanned before and after 3 to 5 months of treatment with rivastigmine (9 mg/day). Healthy unmedicated controls were imaged twice to evaluate the reproducibility of the method. A specific AChE tracer, [methyl-11C]N-methyl-piperidyl-4-acetate, and a 3D positron emission tomography system with MRI coregistration were used for imaging. Treatment with donepezil reduced the AChE activity (k3 values) in the AD brain by 39% in the frontal (p < 0.001, Bonferroni corrected), 29% in the temporal (p = 0.02, corrected) and 28% in the parietal cortex (p = 0.05, corrected). The corresponding levels of inhibition for rivastigmine were 37% (p = 0.003, corrected), 28% (p = 0.03, uncorrected) and 28% (p = 0.05, corrected). When the treatment groups were combined, the level of AChE inhibition was significantly greater in the frontal cortex compared to the temporal cortex (p = 0.03, corrected). The test-retest analysis with healthy subjects indicated good reproducibility for the method, with a nonsignificant 0% to 7% intrasubject variability between scans. The present study provides first evidence for the effect of rivastigmine on cortical AChE activity. Our results indicate that the pooled effects of donepezil and rivastigmine on brain AChE are greater in the frontal cortex compared to the temporal cortex in AD. This regional difference is probably related to the prominent temporoparietal reduction of AChE in AD. We hypothesize that the clinical improvement in behavioral and attentional symptoms of AD due to AChE inhibitors is associated with the frontal AChE inhibition.     

Cost-effectiveness of memantine in moderate-to-severe Alzheimer's disease patients receiving donepezil*

ABSTRACT

Objective: The efficacy and safety of memantine in patients with moderate-to-severe Alzheimer's disease (AD) receiving stable doses of donepezil were recently demonstrated in a phase III trial. The cost-effectiveness of such therapy is unknown.

Research design and methods: A microsimulation model was developed to depict AD progression over time and associated clinical and economic outcomes. AD progression was measured in terms of decline in cognitive function, as assessed by the Severe Impairment Battery (SIB). At model entry, patients were assumed to have moderate-to-severe AD, to be on stable doses of donepezil, and to begin combination therapy with memantine, or continue to receive donepezil alone; duration of therapy was assumed to be 1 year. Drug efficacy was based on data from a phase III trial. Key assumptions of the model included: (1) efficacy of study drugs would extend to 1 year; (2) measures of cognitive function could be mapped to one another, as well as to global measures of disease severity; and (3) following therapy discontinuation, cognitive function would revert immediately to natural history levels. Cost-effectiveness was assessed in terms of cost (2005 US$) per quality-adjusted life-year (QALY) gained over a lifetime (3% discount rate).

Results: SIB scores were estimated to improve by 3.3 over 1 year from therapy with memantine plus donepezil (vs. donepezil alone). While pharmacotherapy costs were estimated to increase by $1250 during the year of memantine treatment, costs of formal and informal services were estimated to decrease by $1240 over this period and by $1493 (discounted present value) over a lifetime. Findings were sensitive to the assumed SIB score at therapy initiation; cost-effectiveness was better for patients with higher initial SIB scores (i.e., less severe disease).

Conclusion: In patients with moderate-to-severe AD already receiving donepezil, treatment with memantine results in improved clinical outcomes and reduced total costs of care.     

Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors

Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.     

Efficacy,safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study

ABSTRACT

Objective: The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD).

Methods: VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50–85 years were randomized to rivastigmine capsules (3–12?mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects.

Trial registration: NCT00099216.

Results: 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p?≤?0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (≥?75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine–placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance.

Conclusion: Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology.     

Acetylcholinesterase inhibitors and sleep architecture in patients with Alzheimer's disease

BACKGROUND AND OBJECTIVE: Studies suggest that some acetylcholinesterase inhibitors (AChEIs) increase rapid eye movement (REM) sleep and nightmares in patients with Alzheimer's disease (AD) but few have studied their effect on other sleep parameters. The objective of this study was to examine differences in sleep architecture in AD patients taking different AChEIs. METHODS: 76 participants (51 men, 25 women) [mean age = 78.2 years; SD = 7.7] with mild to moderate AD underwent medication history screening as well as polysomnography to determine the percentage of each sleep stage. Participants were divided into groups based on AChEI used: donepezil (n = 41), galantamine (n = 15), rivastigmine (n = 8) or no AChEI (n = 12). General univariate linear model analyses were performed. RESULTS: AChEI therapy had a significant effect on the percentage of stage 1 (p = 0.01) and stage 2 (p = 0.03) sleep. Patients in the donepezil group had a significantly lower percentage of stage 1 sleep than patients in the galantamine group (mean = 17.3%, SD = 11.7 vs 29.2%, SD = 15.0, respectively; p = 0.01), but there was no significant difference between the donepezil group and the rivastigmine (mean = 25.0%, SD = 12.3) or no AChEI groups (mean = 27.6%, SD = 17.7) in this respect. No significant differences in percentage of stage 1 between other groups were seen. Patients in the donepezil group also had a significantly higher percentage of stage 2 sleep than patients in the no AChEI group (mean = 63.6%, SD = 14.4 vs 51.4%, SD = 16.9, respectively; p = 0.04), but there was no significant difference between the donepezil group and either the galantamine group (mean = 56.5%, SD = 8.7) or the rivastigmine group (mean = 59.9%, SD = 8.4). There were no significant differences between groups in terms of percentage REM sleep or other sleep parameters. CONCLUSION: Subgroups of AD patients (classified according to AChEI treatment) in this study differed with respect to the amount of stage 1 and stage 2 sleep experienced, with the donepezil-treated group having the lowest percentage of stage 1 sleep and the highest percentage of stage 2 sleep. There was no significant difference in the amount of REM sleep between the groups. Our data suggest that sleep architecture may be affected by the use of donepezil in patients with AD. Although not elicited in this study because of the small sample size, there may be a class effect of AChEIs on sleep architecture. Double-blind, placebo-controlled studies are needed to better understand causality and the effect of each AChEI on sleep architecture in patients with AD.     

Efficacy and safety of rivastigmine in patients with Alzheimer's disease who failed to benefit from treatment with donepezil

BACKGROUND: Selective acetylcholinesterase (AChE) and dual acetyl- and butyrylcholinesterase inhibitors constitute the only approved agents for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is a specific, reversible inhibitor of AChE, while rivastigmine is a slowly reversible (pseudoirreversible) dual cholinesterase (ChE) inhibitor, with brain-regional specificity for the cerebral cortex and hippocampus. According to the European Marketing Authorisations, the clinical benefit of ChE inhibitors should be reassessed on a regular basis and discontinuation should be considered when evidence of a therapeutic effect is no longer present. However, substantial differences in the pharmacological and pharmacokinetic profiles of the available ChE inhibitors suggest that it may be desirable to switch between ChE inhibitors if patients fail to show efficacy, deteriorate or are unable to tolerate their initially prescribed medication. DESIGN: This open-label, six-month study evaluated the efficacy and safety of rivastigmine in 382 AD patients who had previously failed to benefit from treatment with donepezil (80% due to lack of efficacy, 11% due to tolerability problems, 9% both reasons). RESULTS: At the end of the study, 56.2% of patients were responders to rivastigmine, as assessed using a global function scale (the Clinicians' Global Impression of Change). Cognitive performance (measured by the Mini-Mental State Examination) and the ability to perform activities of daily living (measured by the Instrumental Activities of Daily Living scale) were improved/stabilised in 48.9% and 57.0% of patients, respectively. Rivastigmine was generally well tolerated, the most common adverse events being nausea and vomiting, consistent with reports from previous clinical studies. The occurrence of side-effects or lack of efficacy with donepezil treatment was not a predictor of similar problems when treated with rivastigmine. CONCLUSION: Rivastigmine treatment appears to be beneficial in AD patients who have previously failed to benefit from, or were unable to tolerate treatment with, donepezil.     

Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors

SUMMARY

Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD.

Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that

approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine.

In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.     

Functional,cognitive and behavioral effects of donepezil in patients with moderate Alzheimer's disease

OBJECTIVE: To investigate the efficacy and safety of donepezil in a subgroup of patients with Alzheimer's disease (AD) of moderate severity from a previous trial. METHODS: Two hundred and seven patients with moderate AD (standardized Mini-Mental State Examination [sMMSE] score 10-17) were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patents received either donepezil, 5 mg/day for the first 28 days and 10 mg/day thereafter according to the clinician's judgement (n = 102), or placebo (n = 105). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC-plus) at week 24 using a last observation carried forward (LOCF) analysis. RESULTS: Baseline patient demographics were similar between treatment groups. Mean age was 74.3 years (range 48-92). Least-squares (LS) mean sMMSE scores at baseline were 13.6 +/- 0.3 for the donepezil group and 13.9 +/- 0.3 for the placebo group. LS mean CIBIC-plus scores for donepezil-treated patients were improved from, or close to, baseline severity at all visits, and were significantly different from placebo at weeks 8, 12, 18, and 24 (week 24 LOCF mean difference = 0.53, p = 0.0003). LS mean change from baseline scores on the sMMSE and Severe Impairment Battery (SIB) for the donepezil group improved throughout the study, and were significantly different from placebo at each visit for the sMMSE (week 24 LOCF mean difference = 2.06, p = 0.0002) and from week 8 for the SIB (week 24 LOCF mean difference = -4.44, p = 0.0026). LS mean change scores on the Disability Assessment for Dementia remained at or above baseline levels throughout the study for the donepezil group, while the placebo group showed a steady decline; treatment differences were significant at each visit (week 24 LOCF mean difference = -9.25, p < 0.0001). LS mean change scores on the Neuropsychiatric Inventory 12-item total improved throughout the study for the donepezil group and were significantly different from placebo at weeks 4 and 24 (week 24 LOCF mean difference = 5.92, p = 0.0022). Eighty-one per cent of donepezil-treated and 89% of placebo-treated patients completed the trial, with 9% and 5%, respectively, discontinuing due to adverse events (AEs). Eighty-two per cent of donepezil-treated and 80% of placebo-treated patients experienced AEs, the majority of which were rated mild in severity and, in general, were similar between treatment groups. CONCLUSION: The significant treatment responses observed with donepezil in these patients reinforce the findings from earlier studies that show donepezil to have important benefits, compared wih placebo, across functional, cognitive, and behavioral symptoms, with good tolerability, in patients with AD of moderate severity.     

Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro

This study was designed to compare the in vitro inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of donepezil and some other cholinesterase (ChE) inhibitors which have been developed for the treatment of Alzheimer's disease. The carbamate derivatives physostigmine and rivastigmine needed preincubation to exhibit appropriate anti-ChE activity. The maximum ChE inhibition by physostigmine developed within 30-60 min, while the inhibitory effect of rivastigmine on AChE and BuChE activities reached its peak after 48 and 6 h, respectively. The order of inhibitory potency (IC50) towards AChE activity under optimal assay conditions for each ChE inhibitor was: physostigmine (0.67 nM) > rivastigmine (4.3 nM) > donepezil (6.7 nM) > TAK-147 (12 nM) > tacrine (77 nM) > ipidacrine (270 nM). The benzylpiperidine derivatives donepezil and TAK-147 showed high selectivity for AChE over BuChE. The carbamate derivatives showed moderate selectivity, while the 4-aminopyridine derivatives tacrine and ipidacrine showed no selectivity. The inhibitory potency of these ChE inhibitors towards AChE activity may illustrate their potential in vivo activity.