Progressive Deterioration Scale Research Articles

Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer’s disease

Objective:To evaluate the efficacy and safety of rapidly titrated rivastigmine administered twice (BID) or three times (TID) daily in patients with mild to moderate Alzheimer’s disease (AD).Methods:This was a 26...

3-Year Study of Donepezil Therapy in Alzheimer’s Disease: Effects of Early and Continuous Therapy

Delays in the diagnosis of Alzheimer’s disease, and, therefore, delays in treatment, may have a detrimental effect on a patient’s long-term well-being. This studyassessed the effects of postponing donepezil treatment for 1 year by comparing patients treated continuously for 3 years with those who received placebo for 1 year followed by open-label donepezil for 2 years. Patients (n = 286) with possible or probable Alzheimer’s disease (according to DSM-IV, NINCDS-ADRDA, and Mini-Mental State Examination criteria; see text) were randomized to receive donepezil (5 mg/day for 4 weeks, 10 mg/day thereafter) or placebo (delayed-start group) for 1 year. Of the 192 completers, 157 began a 2-year, open-label phase of donepezil treatment. Outcome measures were the Gottfries-Bråne-Steen scale, the Mini-Mental State Examination, the Global Deterioration Scale, the Progressive Deterioration Scale, the Neuropsychiatric Inventory, and safety (adverse events). Mixed regression analysis was used to compare changes between the groups over 3 years on the efficacy measures. There was a trend for patients receiving continuous therapy to have less global deterioration (Gottfries-Bråne-Steen scale) than those who had delayed treatment (p = 0.056). Small but statistically significant differences between the groups were observed for the secondary measures of cognitive function (Mini-Mental State Examination; p = 0.004) and cognitive and functional abilities (Global Deterioration Scale; p = 0.0231) in favor of continuous donepezil therapy. Over 90% of the patients in both cohorts experienced one treatment-emergent adverse event; most were considered mild or moderate. In conclusion, patients in whom the start of treatment is delayed may demonstrate slightly reduced benefits as compared with those seen in patients starting donepezil therapy early in the course of Alzheimer’s disease. These data support the long-term efficacy and safety of donepezil.

The Validation of a Caregiver Assessment of Dementia

The objective of this study was to refine and validate the Dementia Severity Scale (DSS), a newly developed assessment of dementia severity from a caregiver's perspective. The Dementia Severity Scale is designed to measure deficits in activities of daily living (ADL), behavioral disturbances, and the caregiver's perception of the patient's current cognitive abilities. Community dwelling caregiver/patient dyads were recruited from 12 clinical sites. Patients had a primary dementia diagnosis for at least one year. In this cross-sectional study, caregivers were administered the Dementia Severity Scale, the Quality of Life-Alzheimer's Disease (QOL-AD), the Progressive Deterioration Scale (PDS), and the Neuropsychiatric Inventory (NPI). Patients were administered the Mini-Mental State Examination (MMSE) and the QOL-AD. To evaluate test-retest reliability, 25% of caregivers were randomized to a second visit. One hundred eighty-three caregiver/patient dyads were recruited. Mean caregiver age was 67.5; mean patient age was 78.8; 93% of patients had probable Alzheimer disease. Eighty-eight (48.1%) patients were male. Exploratory factor analysis established 6 subscales (Activities of Daily Living [ADL], Instrumental ADL [IADL], Communication, Agitation, Memory, and Disorganized Thinking). Cronbach's alphas ranged from 0.82 to 0.90 for the 6 subscales. Test-retest reliability was good with intraclass correlation coefficients ranging from 0.79 to 0.89. DSS subscales were moderately-to-highly correlated with the QOL-AD, NPI, MMSE, and PDS. Subscales significantly discriminated among severity levels of dementia, identified by both physician ratings and MMSE scores. The Dementia Severity Scale demonstrated excellent psychometric properties and appears to be useful both in clinical practice and research endeavors. Further research is needed to establish the longitudinal sensitivity of the Dementia Severity Scale to the progression of dementia.

A 12-Month Study of the Efficacy of Rivastigmine in Patients with Advanced Moderate Alzheimer’s Disease

The efficacy of a centrally active cholinesterase inhibitor, rivastigmine tartrate (ENA 713), in patients with advanced moderate Alzheimer’s disease (AD) was evaluated in a 12-month placebo-controlled study. We aimed to investigate whether there was any evidence for the benefits of rivastigmine in patients with severe disease. These patients were compared with matched controls. In this study, 24 patients with advanced moderate AD received rivastigmine for 12 months. Another 20 patients received placebo. Mean daily doses of rivastigmine in the higher-dose group at 3, 6, 9, and 12 months were 6.1 ± 1.0, 8.3 ± 1.2, 8.9 ± 1.3, and 10.7 ± 1.6 mg/day, respectively. Cognitive abilities were assessed using the 11-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). Forty-five percent of placebo-treated patients declined by at least 4 points on the ADAS-cog. Conversely, only 18.3% of patients treated with rivastigmine declined by 4 or more points. Functional disabilities, as assessed using the Disability Assessment for Dementia Scale, remained significantly superior in rivastigmine-treated patients compared with placebo-treated patients. Patients benefited from high-dose rivastigmine treatment on all outcome measures, including the Mini-Mental State Examination, Progressive Deterioration Scale, as well as the Global Deterioration Scale. Patients receiving rivastigmine for 12 months significantly improved compared with placebo-treated patients (p < 0.001). By 52 weeks, patients originally treated with 6–12 mg/day rivastigmine had a significantly better cognitive function than patients originally treated with placebo. Long-term rivastigmine treatment appeared to be well tolerated in patients with advanced moderate AD and significantly benefits the cognitive and functional symptoms of AD.

Disease Stage in Alzheimer Disease and Treatment Effects of Rivastigmine

The efficacy and tolerability of the cholinesterase inhibitor rivastigmine in the treatment of Alzheimer disease (AD) have been demonstrated in several clinical trials, which included patients with a wide range of dementia severities. To investigate the association between severity of disease and treatment response, the combined data from three large randomized, placebo-controlled trials were analyzed. The pooled patient population was stratified into three cohorts showing moderately severe (Mini-Mental State Examination score [MMSE] < or = 15), moderate (MMSE 16-22), and mild (MMSE > or = 22) dementia. In each cohort, the effects of rivastigmine 6 to 12 mg/day versus placebo were evaluated using the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog) and the Progressive Deterioration Scale. Rivastigmine 6 to 12 mg/day maintained ADAS-cog scores at or above placebo levels in all cohorts, while cognitive deterioration with placebo was progressive and severity dependent. Activities of daily living showed statistically significant benefits with rivastigmine across all severity cohorts.

Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease.

Cholinesterase (ChE) inhibitors are primarily used in the treatment of mild to moderate Alzheimer's disease (AD), but may also be effective in more severe disease. To evaluate the dual ChE inhibitor, rivastigmine, in more severe dementia. We retrospectively analysed pooled data from three randomised, placebo-controlled, double-blind, 6-month trials, involving 2126 AD subjects. Subjects were selected according to baseline Mini-Mental State Examination (MMSE) score to identify subjects with more severe cognitive impairment (10-12 MMSE points). One-hundred-and-seventeen subjects were included who had been treated with rivastigmine 6-12 mg/day or placebo. The AD Assessment Scale-Cognitive Subscale (ADAS-Cog), the MMSE, a six-item subscore of the Progressive Deterioration Scale (PDS) and the BEHAVE-AD assessed efficacy. Tolerability was assessed by recording adverse events (AEs) and the relative risk (RR) of discontinuation. This group of subjects responded well to rivastigmine. After 6 months, the mean ADAS-Cog score declined by 6.3 points in the placebo group and increased by 0.2 points in the rivastigmine group (observed cases; p<0.001). Clinical benefits were also observed with the MMSE, the six-item PDS score and items of the BEHAVE-AD. Rivastigmine showed the same pattern of AEs as in other studies, but the RR of dropping out due to AEs was lower than in subjects with milder AD. Current treatment guidelines do not recommend treating individuals with severe AD with ChE inhibitors. However, this retrospective analysis suggests that rivastigmine 6-12 mg/day may benefit subjects with more severe disease, as well as subjects with mild to moderate impairment.

POTENTIAL LONG‐TERM EFFECTS OF RIVASTIGMINE ON DISEASE PROGRESSION MAY BE LINKED TO DRUG EFFECTS ON VASCULAR CHANGES IN ALZHEIMER BRAINS

SUMMARYAlzheimer's disease patients with hypertension or other vascular risk factors have been shown to receive greater symptomatic benefits than patients with strictly Alzheimer's disease following short‐term treatment with rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase. We evaluated the long‐term efficacy of rivastigmine in Alzheimer's disease patients with or without hypertension. Subjects in a 26‐week placebo‐controlled trial of rivastigmine entered an open‐label extension study for 104 weeks. Efficacy measures included the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS‐cog), Progressive Deterioration Scale (PDS) and Global Deterioration Scale (GDS). Subjects were stratified by the presence or absence of hypertension at baseline. At 104 weeks, there was a trend for hypertensive patients from the original rivastigmine 6–12 mg/day group (early starters), who received rivastigmine for the full 104 weeks) to have better ADAS‐cog scores than the original placebo group (late starters), who received open‐label rivastigmine for the last 78 weeks only). Significant treatment differences were observed in the hypertensive subgroup on the PDS and GDS. In non‐hypertensive patients, changes from baseline at week 104 were similar in ‘early’ and ‘late’ starters of rivastigmine treatment. The additional apparent benefits on disease progression detected in patients with hypertension and Alzheimer's disease may be linked to drug effects on cerebrovascular factors. These findings may have an important influence on the way cholinesterase inhibitors are prescribed.

RIVASTIGMINE IN PATIENTS WITH ALZHEIMER'S DISEASE AND CONCURRENT HYPERTENSION

SUMMARYRivastigmine has demonstrated significant benefits in patients with mild to moderate Alzheimer's disease (AD). We aimed to confirm whether rivastigmine was effective in patients with or without concurrent vascular risk factors (VRF), as previously suggested. We chose to stratify the 725 patients involved in an international dose‐ranging study according to the presence of arterial hypertension (a marker of VRF) at baseline. Efficacy in each subgroup was assessed using the ADAS‐cog, a measure of cognitive performance, the Progressive Deterioration Scale (PDS) and the Clinician's Interview‐Based Impression of Change (CIBIC) with caregiver input. Patients receiving rivastigmine 6–12 mg/day showed better outcomes on the ADAS‐cog than those receiving placebo, in both the hypertensive and non‐hypertensive subgroups. Hypertensive patients receiving rivastigmine 6–12 mg/day also showed improvement over those receiving 1–4 mg/day (p=0.023). Rivastigmine 6–12 mg/day also provided better outcomes than placebo on the PDS in the hypertensive (p=0.031) and non‐hypertensive (p=0.035) subgroups. All patients receiving rivastigmine 6–12 mg/day had superior CIBIC‐plus scores than those receiving placebo. There was a trend for lower incidences of nausea and vomiting in rivastigmine‐treated patients with hypertension than in those without hypertension. No cardiac adverse events or drug‐drug interactions were reported. Our data support the hypothesis that rivastigmine provides benefits to patients with or without hypertension, and contribute to the evidence that particular benefits may be observed in those with vascular risk factors.

An Economic Evaluation of Donepezil in Mild to Moderate Alzheimer’s Disease: Results of a 1-Year, Double-Blind, Randomized Trial

The costs and consequences of donepezil versus placebo treatment in patients with mild to moderate Alzheimer’s disease (AD) were evaluated as part of a 1-year prospective, double-blind, randomized, multinational clinical trial. Patients received either donepezil (n = 142; 5 mg/day for 28 days followed by 10 mg/day according to the clinician’s judgement) or placebo (n = 144). Unit costs were assessed in 1999 Swedish kronas (SEK) and converted to US dollars (USD). Donepezil-treated patients gained functional benefits relative to placebo on the Progressive Deterioration Scale (p = 0.042) and Instrumental Activities of Daily Living scale (p = 0.025) at week 52. Caregivers of donepezil-treated patients spent an average of 400 h less annually providing care than caregivers of placebo-treated patients. Mean annual healthcare costs were SEK 137,752 (USD 16,438) per patient for the donepezil group and SEK 135,314 (USD 16,147) in the placebo group. With the average annual cost of donepezil at SEK 10,723 (USD 1,280) per patient, the SEK 2,438 (USD 291) cost difference represented a 77% cost offset. When caregiver time and healthcare costs were included, mean annual costs were SEK 209,244 (USD 24,969) per patient in the donepezil group and SEK 218,434 (USD 26,066) in the placebo group, a total saving associated with donepezil treatment of SEK 9,190 (USD 1,097) per patient [95% CI of SEK –43,959 (USD –5,246), SEK 25,581 (USD 3,053); p = 0.6]. The positive effects on the efficacy outcome measures combined with no additional costs from a societal perspective indicate that donepezil is a cost-effective treatment, representing an improved strategy for the management of patients with AD.

Impact of Alzheimer's disease and rivastigmine treatment on activities of daily living over the course of mild to moderately severe disease

Objectives: To investigate the relationship between activities of daily living (ADL) impairment and Alzheimer's disease (AD) severity in mild to moderately severe AD patients receiving the cholinesterase (ChE) inhibitor rivastigmine. Methods: ADLs were evaluated using the Progressive Deterioration Scale (PDS). Disease severity was assessed with the Global Deterioration Scale (GDS). Patients were participants in one of three double-blind, placebo-controlled trials with rivastigmine. Results: Baseline PDS scores differed significantly ( P<.001) by disease severity. At Week 26, PDS declines from baseline for placebo patients were significantly different at all disease stages. Specific ADL affected were disease stage-dependent. Rivastigmine treatment (6–12 mg/day) resulted in total PDS scores being significantly improved compared with placebo at all disease stages, although the effect on individual items differed by severity. Conclusions: ADL impairment differs across the stages of AD. Greater impairment in total ADL scores is observed with increasing severity of illness. However, the stage of illness determines the type of ADLs lost. Treatment response to rivastigmine occurs with mild, moderate and moderately severe AD, with the largest effect in patients with advancing severity of disease.

Rivastigmine for alzheimer's disease: Canadian interpretation of intermediate outcome measures and cost implications

Background: Clinical studies have shown that patients with Alzheimer's disease (AD) who are treated with rivastigmine have statistically significantly better scores on 5 scales used to assess AD than control patients receiving placebo. However, the clinical meaning and cost implications of these differences are not clear. Objective: The purpose of this study was to assess the clinical meaning and cost implications of statistically significant results obtained in clinical trials of rivastigmine for the treatment of AD. Potential cost implications for the health care system, caregivers, and society are considered. Methods: Data on clinical effects of rivastigmine were obtained from published North American and European clinical studies of patients with mild to moderately severe AD receiving rivastigmine 6 to 12 mg/d (n = 828) or placebo (n = 647). Differences in scores on the Alzheimer's Disease Assessment Scale-Cognitive Function, Clinician's Interview-Based Impression of Change with both clinical and caregiver information considered, Progressive Deterioration Scale, Mini-Mental State Examination (MMSE), and Global Deterioration Scale were assessed. A convenience panel of 9 Canadian specialists experienced in the treatment of AD provided their opinions on the clinical importance of the trial results. Chart review was performed to identify specific behaviors that improved, and cost implications of improvements were assessed. Results: The panel determined that statistically significant differences in scores on all scales except the MMSE were likely associated with functional or cognitive differences that were clinically relevant for patients, reflecting stabilization that would have beneficial consequences for caregivers and health care resource use. Subsequent chart review showed that improvement on specific scale items confirmed the physician panel's opinion. Analysis of possible cost implications to society indicated that medication expenditures would be offset largely by delays in the need for paid home care and institutionalization, positive effects on caregiver health, and less time lost from work for the caregiver. Conclusions: From the perspective of a Canadian specialist panel, rivastigmine treatment for AD produces clinically relevant effects for patients that are beneficial to caregivers. These effects suggest decreased use of caregiver resources and delays in the need for institutionalization, both of which reduce societal costs.

Review of outcome measurement instruments in Alzheimer's disease drug trials: psychometric properties of functional and quality of life scales.

The psychometric properties of functional and quality of life outcome measures that were used for the purpose of showing changes in antidementia drug trials for Alzheimer's disease are described and critiqued. The seven functional scales reviewed for reliability, validity, and responsiveness to change included the Geriatric Evaluation by Relative's Rating Instrument, the Physical Self-Maintenance Scale, the Instrumental Activities of Daily Living, the Blessed Dementia Scale, Part 1 and its revised version, the Interview for Deterioration in Daily Living with Dementia, the Unified Activities of Daily Living, and the Dependence Scale. The Progressive Deterioration Scale and Quality of Life Assessment were classified as quality of life scales. The majority of the scales were found to exhibit serious limitations, such as incomplete reliability and validity assessment for the intended uses. The most pervasive problem was a lack of data on responsiveness to change. It is recommended that further research be conducted to develop new tools or enhance existing measures for the assessment of both quality of life and functional ability.

Rivastigmine for Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. One of the most successful therapeutic strategies for Alzheimer's disease has been the use of acetylcholinesterase inhibitors to enhance surviving cholinergic neurotransmission by inhibiting breakdown of released acetylcholine. The first generation acetylcholinesterase inhibitors, such as tacrine, revealed major limitations to use including hepatotoxicity. Several second generation acetylcholinesterase inhibitors have now been introduced, including rivastigmine, which are believed to have superior proprieties. The mode of action and metabolism of rivastigmine suggest that it is unlikely to interact significantly with other medications. This is of particular relevance in elderly AD patients, the majority of whom are likely to be receiving concomitant medication. Large multi-centre trials have been completed in the USA, Canada, Europe and South Africa. Rivastigmine has received EU approval for use in all member states. It has approval in 30 countries but not the US. It is currently under review by the Food and Drug Administration, who requested additional analyses in 1998. To determine the clinical efficacy and safety of rivastigmine for patients with dementia of the Alzheimer's type. The Cochrane Controlled Trials Register, the Dementia Group Register of Clinical Trials, other electronic databases and other sources of reports were searched using the terms ENA 713, EXELON, and rivastigmine in addition to the terms for controlled trials in dementia (see the Group's search strategy for full details). All unconfounded, double-blind, randomised trials in which treatment with rivastigmine was administered for more than one day and compared to placebo for patients with dementia of the Alzheimer's type. Data were extracted by the reviewer (JSB) and entered into an appropriate meta-analysis. The data extracted were cross-checked by the second reviewer (VI). For each outcome measure, data were sought on every patient randomised. To allow an intention-to-treat analysis, the data were sought irrespective of compliance, whether or not the patient was subsequently deemed ineligible, or otherwise excluded from treatment or follow-up. If these data were not available, an analysis of data on patients who completed treatment was conducted. There are seven included trials. There are no published reports for two large phase III trials, B304 and B351, although they were completed more than 3 years ago. These are part of the Novartis ADENA programme and comprise 1379 (49%) out of 2803 phase III patients. It is unclear how missing data are replaced in ITT analyses, as reports from the ADENA programme provide no description of the use of this method. This has a profound effect on the results: if the method is substantially the same as LOCF, the benefits of treatment inferred from the analyses described in the publications as ITT, may be exaggerated. The meta-analysis reveals benefits on cognitive function as measured by ADAS-Cog test scores for the higher dose of rivastigmine compared to placebo at 26 weeks and for the lower dose. An additional analysis of ADAS-Cog dichotomised into those showing less than 4 points improvement and those showing 4 or more points improvement at 26 weeks shows benefit for cognitive function for the higher dose of rivastigmine compared to placebo and not for the lower dose. Global clinical state, dichotomised, counting those showing no change or decline, against those showing improvement shows benefit due to lower dose rivastigmine compared to placebo at 26 weeks and not for the higher dose. One trial reported results at 18 weeks and there are no significant differences between higher dose rivastigmine and placebo. One trial reported results at 13 weeks, and there are no significant differences between the 4 or 6 mg/d rivastigmine group and p

Rivastigmine for Alzheimer's Disease: Improvement Versus Reduced Worsening.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in later life. It is manifested by gradual and progressive decline in cognitive function and ability to perform activities of daily living (ADL) and the development of behavioral disturbances. Progressive reduction in functional ability reduces independence and quality of life and adversely affects caregivers and society. Therefore, benefit from any AD therapy may be obtained not only from improved function but also from stabilization or reduced worsening of function. METHOD: This retrospective study of pooled data from 3 randomized, placebo-controlled trials (N = 2126) compared the incidence of different levels of worsening between 2 rivastigmine treatment groups and a placebo group at week 26 for cognition, using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog); global functioning, using the Clinicians' Interview-Based Impression of Change-Plus (CIBIC-Plus); and ADL, using the Progressive Deterioration Scale (PDS). Categories of worsening analyzed for each scale were as follows: ADAS-Cog: any decline, >/= 4-point decline, >/= 7-point decline; CIBIC-Plus: stabilized/worsened (rating = 4, 5, 6, or 7), any worsening (rating = 5, 6, or 7); PDS: any worsening, >/= 10% worsening. RESULTS: Patients treated with rivastigmine, 6-12 mg/day, showed significantly less decline in cognition, global functioning, and ADL for all categories of worsening examined compared with patients who received placebo. The reduction in decline compared with placebo was greater in the group receiving 6-12 mg/day of rivastigmine compared with the treatment group receiving 1-4 mg/day of rivastigmine. CONCLUSION: Rivastigmine reduces the amount of worsening observed in cognition, global functioning, and ADL in a 6-month trial period.

How useful are cholinesterase inhibitors in the treatment of Alzheimer's disease? A number needed to treat analysis.

To report on a Numbers Needed to Treat (NNT) analysis of the literature identified through a systematic review of trials of cholinesterase inhibitors in Alzheimer's Disease. Search of Medline (1966-1998), EMBASE (1994-1999) and Psychlit (1974-1998) using the keywords cholinesterase and placebo dementia. Double-blind, randomised, placebo-controlled trials. People with Alzheimer's Disease. Drug trials of acetylcholinesterase inhibitors (ChIs). Main outcome measuresAlzheimer's Disease Assessment Scale (Cognitive subscale), Clinician's Interview Based Impression of Change Plus, Mini Mental State Examination, Progressive Deterioration Scale. Small numbers of patients (in most cases between 3 and 7) need to be treated with appropriate dosages of ChIs to ameliorate the clinical symptoms, or postpone deterioration in one of them. These small NNTs suggest that, despite their expense, the cholinesterase inhibitors have a valuable place in the current clinical management of AD.

Acetylcholinesterase inhibitors in Alzheimer's disease.

Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. Traditionally thought of as an untreatable degenerative condition, recent advances in drug therapy have challenged this view. The disease is characterised by an insidious decline in cognitive and non-cognitive function. Classically, short and long-term memory is impaired while language skills, concentration and attention are often affected. This results in impaired ability to learn and retain new skills as well as the loss of existing ones. Non-cognitive function is the global term used to describe problems such as depression, agitation, personality changes, delusions and hallucinations. These factors have a significant impact on patient behaviour and a very real impact on the quality of life for both patients and caregivers. Diagnosis of AD is clinically based, and using the NINCDS-ADRDA criteria (Table 1) [1], a diagnosis of probable or possible AD can be made. Definitive diagnosis relies on pathological confirmation, which in the majority of cases is rarely completed. With the development of AD specific treatments, definition of AD from other types of dementia is very important. Table 1 NINCDS-ADRDA Criteria for clinical diagnosis of Alzheimer’s disease. Pathogenesis The pathogenesis of AD has not yet been elucidated. It is widely accepted that a combination of genetic susceptibility factors and environmental triggers are responsible for late onset sporadic AD, the most common form of the disease. An understanding of the disease mechanism remains elusive, and is the key to developing a disease modifying agent. Currently, it is proposed that beta amyloid protein, abnormal tau protein or possibly both play key factors in the development of disease. It has been widely postulated that oxidative damage and a slow inflammatory process are two possible mechanisms involved. As yet, no product with proven disease modifying properties is available, and current treatments offer symptomatic benefit only. The development of acetylcholinesterase (AChe) inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD [2] and the resultant cholinergic deficit contributes to the cognitive impairment of these patients [3]. Although many believe this ‘cholinergic hypothesis’ to be important, others feel it represents a less significant component of the disease process [4]. Many other neurotransmitters are affected in AD, and the relative importance of each in relation to clinical findings has not been fully elucidated. Initial work focused on the use of acetylcholine precursors, using a similar rationale to dopamine therapy in Parkinson’s disease. A series of small trials using precursors such as choline and phosphatidylcholine showed no reliable improvement in cognitive function, with only 10 out of 43 trials reporting any positive effect [5]. There has been renewed interest in muscarinic agonists drugs, which when first introduced, had major problems with adverse cholinergic effects. Better understanding of the molecular pathology of muscarinic receptors and their subtypes has led to the development of more specific agonists. Drugs such as xanomeline, milameline, and civimeline have reached clinical trials, and the improvements seen in cognitive function are reviewed by Avery et al. [6]. There are also claims that these drugs have disease modifying properties, with effects on APP processing and tau phosphorylation. Muscarinic agonists remain in trial, but have yet to fulfil their potential in AD treatment. The only group of drugs currently licensed for AD treatment is the AChe inhibitors, which act through inhibition of the enzyme acetylcholinesterase (AChe), responsible for the breakdown of ACh in the neural synapse. A meta-analysis of the early AChe inhibitor treatments was encouraging [7] and these proceeded to larger placebo controlled double-blind trials.

Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer’s disease: review and current status

Alzheimer’s disease is, in part, characterised by the loss of neurones in the basal forebrain cholinergic cells that project to the cerebral cortex and hippocampus. These impairments have correlated with the memory loss noted in dementia of the Alzheimer’s type. This ‘cholinergic hypothesis’ has led to the rational design of drugs to enhance or stimulate acetylcholine-mediated neurotransmission. Early acetylcholinesterase inhibitors, such as tacrine and physostigmine, are poorly tolerated and have a short duration of action. Rivastigmine is a centrally-selective acetylcholinesterase inhibitor with a relatively long duration of action and is a ‘pseudo-irreversible’ cholinesterase inhibitor due to slow dissociation of a carbamoyl derivative from the esteratic site of acetylcholinesterase. Preclinical studies confirmed the central selectivity of the drug and its distribution into the cerebrospinal fluid (CSF). Early studies demonstrated that rivastigmine improved cognition and was relatively well-tolerated at moderate doses. Clinical investigations of rivastigmine administered at doses of 6 - 12 mg/day significantly improved cognition, as measured by the ADAS-Cog score, and activities of daily living, as measured by the Progressive Deterioration Scale. Significant global improvements were also noted as measured by the Clinician’s Interview Based Impression of Change that required the use of caregiver information. The most frequent adverse effects noted in clinical trials were consistent with peripheral cholinergic stimulation and included nausea, vomiting, abdominal pain, dizziness and diarrhoea. These effects were dose-related and minimised by slow dose-escalation upon initiation of therapy. Rivastigmine undergoes minimal metabolism by the cytochrome P450 system. As a result, it has few drug interactions. The drug is currently marketed widely in over 60 countries worldwide. In the United States, the drug received ‘approvable’ status subsequent to the NDA filing, and should be available later this year.

Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial.

Objectives: To assess the effects of rivastigmine on the core domains of Alzheimer's disease.Design: Prospective, randomised, multicentre, double blind, placebo controlled, parallel group trial. Patients received either placebo, 1-4 mg/day...

Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials. Dementia Trialists' Collaboration.

To determine the effects of cholinesterase inhibition with tacrine hydrochloride for the symptoms of Alzheimer disease in terms of cognitive performance, clinical global impression, behavior, and functional autonomy. The Cochrane Dementia Group registry of trials. Unconfounded, randomized, double-blind, placebo-controlled trials in which tacrine had been given for more than 1 day and that were completed before January 1, 1996. Two reviewers independently selected trials for inclusion and individual patient data were sought. Data were analyzed from 12 trials that included 1984 patients with Alzheimer disease. At 12 weeks, cognitive performance, as measured by the Mini-Mental State Examination (score range, 0-30), was better in patients receiving tacrine than in patients receiving placebo by 0.62 points (95% confidence interval [CI], 0.23-1.00; P=.002). Compared with similar untreated patients who would be expected to deteriorate by 0.50 to 1.00 points on the Mini-Mental State Examination during 12 weeks, the progress of patients receiving tacrine would be expected to range between an improvement of 0.12 and a deterioration of 0.38 points. The odds ratio for improvement on the Clinical Global Impression of Change scale (range, 1-7) for patients receiving tacrine compared with those receiving placebo was 1.58 (95% CI, 1.18-2.11; P=.002). The behavioral noncognitive subscale of the Alzheimer's Disease Assessment Scale (range, 0-50) showed a difference in favor of tacrine of 0.58 points (95% CI, 0.17-1.00; P= .006). Improvement on the Progressive Deterioration Scale, largely an index of functional activities, was not significant (0.75; 95% CI, -0.43 to 1.93; P=.21). Age, severity of dementia, and exposure to tacrine prior to randomization had no clear influence on the treatment effect. There was a nonsignificant trend toward increasing effect with increasing dose for cognitive function and the Clinical Global Impression of Change. For patients without prior exposure to tacrine, the odds of patients' withdrawing during the study while they were receiving tacrine compared with placebo was 3.63 (95% CI, 2.80- 4.71; P<.001). Eleven (95% CI, 7-31) patients would need to be treated to achieve any improvement on the Clinical Global Impression scale, and 42 (95% CI, 23-125) to achieve a moderate or marked improvement. One patient would be expected to withdraw for every 4 (95% CI, 3-5) patients treated. Cholinesterase inhibition with tacrine appears to reduce deterioration in cognitive performance during the first 3 months and increase the odds of global clinical improvement. Effects observed on measures of behavioral disturbance were of questionable clinical significance, and functional autonomy was not significantly affected. The clinical relevance of the benefits of cholinesterase inhibition remains controversial, and long-term trials with clinically relevant end points are required.

Quality of life in Alzheimer's disease.

We reviewed and independently ranked the measurement properties of quality of life (QL) instruments currently used in anti-dementia drug trials for Alzheimer's disease. Of 36 read reports, 5 measured and 4 mentioned QL. Eight instruments, labelled QL measures, included questionnaires measuring function, self-rating instruments measuring the caregivers' impression of the impact of sickness and deterioration of memory, and observational rating scales measuring function. The most thoroughly tested QL measure was the Progressive Deterioration Scale. The instruments with the most promising measurement properties were the Progressive Deterioration Scale and the Italian Quality of Life Scale. Most instruments now used to assess QL in antidementia drug trials have not been adequately validated in patients with Alzheimer's disease. Effort should be directed both to conceptual and practical development in the assessment of QL in dementia.