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Galantamine for Alzheimer's disease.

BACKGROUND
Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor.


OBJECTIVES
To assess the clinical effects of galantamine in patients with probable or possible Alzheimer's disease (AD), and potential moderators of effect.


SEARCH STRATEGY
The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, last updated on 25 August 2005 using the terms galanthamin*, galantamin* and Reminyl. Published reviews were inspected for further sources. Additional information was collected from unpublished clinical research reports for galantamine obtained from Janssen.


SELECTION CRITERIA
Trials selected were randomised, double-blind, parallel-group comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in subjects with AD.


DATA COLLECTION AND ANALYSIS
Data were extracted independently by the reviewers and pooled where appropriate and possible. Outcomes of interest include the clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Assessment Scale-cognitive sub scale (ADAS-cog), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). Potential moderating variables of treatment effect assessed included trial duration, dose, and diagnosis of possible vs. probable Alzheimer's disease.


MAIN RESULTS
Seven trials with a total 3777 subjects were included in the analysis. Treatment with galantamine led to a significantly greater proportion of subjects with improved or unchanged global rating scale rating (k=7), at all dosing levels except for 8mg/d . Confidence intervals for the ORs overlapped across the dose range of 16mg to 36mg per day, with point estimates of 1.6-2.1 when analysed with the intention-to-treat sample. Treatment with galantamine also led to significantly greater reduction in ADAS-cog score at all dosing levels (k=7), with greater effect over 6 months compared to 3 months. Confidence intervals again overlapped. Point estimate of effect was lower for 8mg/d but similar for 16mg to 36mg per day. For example, treatment effect for 24mg/d over 6 months was 3.1point reduction in ADAS-cog (95%CI 2.6-3.7, k=4, ITT).ADCS-ADL, DAD and NPI were reported only in a small proportion of trials: all showed significant treatment effect in some individual trials at least. Confidence interval of treatment effect for the one trial recruiting patients with possible AD overlapped with the other six recruiting patients with probable AD. Galantamine's adverse effects appeared similar to those of other cholinesterase inhibitors and to be dose related.


REVIEWERS' CONCLUSIONS
Subjects in these trials were similar to those seen in earlier anti dementia AD trials, consisting primarily of mildly to moderately impaired outpatients. Galantamine's effect on more severely impaired subjects has not yet been assessed.Nevertheless, this review shows consistent positive effects for galantamine for trials of 3 to 6 months duration. Although there was not a statistically significant dose-response effect, doses above 8mg/d were, for the most part, consistently statistically significant. Galantamine's safety profile is similar to that of other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over a 4 week period, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably most preferable initially. Longer term use of galantamine has not been assessed in a controlled fashion.