***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Galantamine improved symptoms in  Alzheimer 's disease ( AD ) patients after 5 to 6 months of treatment . To examine long-term outcomes , this study assessed if continuing of galantamine treatment beyond 12 months delayed further cognitive deterioration . It consisted of two phases : an open label ( OL ) phase ( 12 months ) , followed by a double blind , r and omized , placebo controlled withdrawal phase ( up to 24 months ) . Subjects with mild to moderate AD were included in the study and titrated up to 16 mg/day of galantamine . Subjects were eligible to enter the double blind phase if a cognitive decline of < 4 points on AD Assessment Scale-cognitive subscale (ADAS-cog)/11  was recorded at the end of the OL phase . The differences between galantamine and placebo in time to dropout were estimated using the Cox proportional hazard model . 47.4 % of galantamine and 31.7 % of placebo subjects completed the double blind phase . Placebo subjects were more likely to discontinue prematurely  than galantamine subjects for any reason ( hazard ratio [ HR ] 1.76 , 95 % confidence interval [ CI ] 1.10 - 2.81 , p = 0.02 ) , or lack of efficacy ( HR 1.80 , 95 % CI 1.02 - 3.18 , p = 0.04 ) ; no statistically significant difference was seen for a change in ADAS-cog ≥ 4 between treatment groups ( HR 1.66 , 95 % CI 0.78 - 3.54 , p = 0.19 ) . Subjects who responded to 12 months of galantamine treatment benefited from continued drug therapy for up to 36 months . Galantamine was effective in delaying time to cognitive deterioration in subjects with mild to moderate AD . Treatment was generally safe and well tolerated To evaluate the impact of galantamine treatment on the function , caregiver time , and re source used in the treatment of patients with mild to moderate Alzheimer 's disease ( AD ) , costs and outcomes were evaluated during a 52-week prospect i ve , r and omized , double-blind , community-controlled trial of galantamine .  Patients received either galantamine treatment ( n=72 ) or no treatment ( n=66 ) . The analysis was performed from a societal perspective . Galantamine treatment reduced time spent caring for the patients and maintained improved functional capacity , whereas , when no treatments were given , a great increase in caregiver time and progressive functional deteriorations were observed . Saved caregiver time was equivalent to 113 working days per year . After 52 weeks , mean total annual costs per patient were 14,735,000 Korea Won ( KRW ) ( USD 12,315 ) for patients with galantamine treatment and 25,325,000 KRW ( USD 21,166 ) for patients without treatment . Adjusted annual cost saving  of galantamine treatment was 6,428,000 KRW ( USD 5,372 ) when compared to no treatment ( p=0.0089 ) . Galantamine had a beneficial effect not only to slow functional decline in patients with mild to moderate AD , but also to save a substantial amount of costs , closely related to reduction in caregiver burden and decrease in caregiver time The 24‐week , prospect i ve , r and omized , double‐blind ACTION study investigated the efficacy , safety , and tolerability of 13.3 versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer 's disease ( AD ) CONTEXT Memantine is a low- to moderate-affinity , uncompetitive N-methyl-D-aspartate receptor antagonist . Controlled trials have demonstrated the safety and efficacy of memantine monotherapy for patients with moderate to severe Alzheimer disease ( AD ) but no controlled trials of memantine in patients receiving a cholinesterase inhibitor have been performed . OBJECTIVE To compare the efficacy and safety of memantine vs placebo in patients with moderate to severe AD already receiving stable treatment with donepezil . DESIGN , SETTING , AND PARTICIPANTS A r and omized , double-blind , placebo-controlled clinical trial of 404 patients with moderate to severe AD and Mini-Mental State Examination scores of 5 to 14 , who received stable doses of donepezil , conducted at 37 US sites between June 11 , 2001 , and June 3 , 2002 . A total of 322 patients ( 80 % ) completed the trial . INTERVENTIONS Participants were r and omized to receive memantine ( starting dose 5 mg/d , increased to 20 mg/d , n = 203 ) or placebo ( n = 201 ) for 24 weeks . MAIN OUTCOME MEASURES Change from baseline on the Severe Impairment Battery ( SIB ) , a measure of cognition , and on a modified 19-item AD Cooperative Study -Activities of Daily Living Inventory ( ADCS-ADL19 ) . Secondary outcomes included a Clinician 's Interview-Based Impression of Change Plus Caregiver Input ( CIBIC-Plus ) , the Neuropsychiatric Inventory , and the Behavioral Rating Scale for Geriatric Patients ( BGP Care Dependency Subscale ) . RESULTS The change in total mean ( SE ) scores favored memantine vs placebo treatment for SIB ( possible score range , 0 - 100 ) , 0.9 ( 0.67 ) vs -2.5 ( 0.69 ) , respectively ( P<.001 ) ; ADCS-ADL19 ( possible score range , 0 - 54 ) , -2.0 ( 0.50 ) vs -3.4 ( 0.51 ) , respectively ( P = .03 ) ; and the CIBIC-Plus ( possible score range , 1 - 7 ) , 4.41 ( 0.074 ) vs 4.66 ( 0.075 ) , respectively ( P = .03 ) . All other secondary measures showed significant benefits of memantine treatment . Treatment discontinuations because of adverse events for memantine vs placebo were 15 ( 7.4 % ) vs 25 ( 12.4 % ) , respectively . CONCLUSIONS In patients with moderate to severe AD receiving stable doses of donepezil , memantine result ed in significantly better outcomes than placebo on measures of cognition , activities of daily living , global outcome , and behavior and was well tolerated . These results , together with previous studies , suggest that memantine represents a new approach for the treatment of patients with moderate to severe AD BACKGROUND This study is an extension of a 28-week , r and omized , double-blind , placebo-controlled study of memantine in 252 patients with moderate to severe Alzheimer disease . OBJECTIVE To evaluate long-term memantine treatment in moderate to severe Alzheimer disease . DESIGN , SETTING , AND PATIENTS Open-label , 24-week extension trial . Raters remained blind to the patients ' initial study treatment . Patients ( n = 175 ) were enrolled from the previous double-blind study in an outpatient setting . INTERVENTION Twenty mg of memantine was given daily . MAIN OUTCOME MEASURES Efficacy assessment s from the double-blind study were continued and safety parameters were monitored . RESULTS Patients who switched to memantine treatment from their previous placebo therapy experienced a significant benefit in all main efficacy assessment s ( functional , global , and cognitive ) relative to their mean rate of decline with placebo treatment during the double-blind period ( P<.05 ) . The completion rate for the extension phase of the study was high ( 78 % ) and the favorable adverse event profile for memantine therapy was similar to that seen in the double-blind study . CONCLUSION These results extend previous findings that demonstrated the efficacy and safety of memantine in the treatment of patients with moderate to severe Alzheimer disease BACKGROUND Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer 's disease . METHODS In a double-blind study , we evaluated subjects with the amnestic subtype of mild cognitive impairment . Subjects were r and omly assigned to receive 2000 IU of vitamin E daily , 10 mg of donepezil daily , or placebo for three years . The primary outcome was clinical ly possible or probable Alzheimer 's disease ; secondary outcomes were cognition and function . RESULTS A total of 769 subjects were enrolled , and possible or probable Alzheimer 's disease developed in 212 . The overall rate of progression from mild cognitive impairment to Alzheimer 's disease was 16 percent per year . As compared with the placebo group , there were no significant differences in the probability of progression to Alzheimer 's disease in the vitamin E group ( hazard ratio , 1.02 ; 95 percent confidence interval , 0.74 to 1.41 ; P=0.91 ) or the donepezil group ( hazard ratio , 0.80 ; 95 percent confidence interval , 0.57 to 1.13 ; P=0.42 ) during the three years of treatment . Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group , the donepezil group had a reduced likelihood of progression to Alzheimer 's disease during the first 12 months of the study ( P=0.04 ) , a finding supported by the secondary outcome measures . Among carriers of one or more apolipoprotein E epsilon4 alleles , the benefit of donepezil was evident throughout the three-year follow-up . There were no significant differences in the rate of progression to Alzheimer 's disease between the vitamin E and placebo groups at any point , either among all patients or among apolipoprotein E epsilon4 carriers . CONCLUSIONS Vitamin E had no benefit in patients with mild  cognitive impairment . Although donepezil therapy was associated with a lower rate of progression to Alzheimer 's disease during the first 12 months of treatment , the rate of progression to Alzheimer 's disease after three years was not lower among patients treated with donepezil than among those given placebo BACKGROUND Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease ( AD ) . Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment ( 5 and 10 mg/d ) significantly improves cognition and global function . OBJECTIVE To investigate the long-term benefits of donepezil treatment in patients with AD . DESIGN Multicenter , open-label , 144-week extension of 2 US phase 3 , double-blind , placebo-controlled clinical trials : a 15-week study ( 12 weeks of treatment followed by a 3-week placebo washout ) and a 30-week study ( 24 weeks of treatment followed by a 6-week placebo washout ) . INTERVENTIONS All patients ( N = 763 ) initially received donepezil , 5 mg/d , for 6 weeks , after which an increase to 10 mg/d was encouraged . MEASURES Primary efficacy measures were the Alzheimer 's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes . RESULTS After the shorter 3-week placebo washout , donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment . Benefits on Alzheimer 's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment . In contrast , donepezil-associated benefits were lost after the 6-week placebo washout , and scores decreased below original baseline values for all patient groups . Although scores improved relative to the new open-label study baseline scores after drug use was restarted , patients remained below original baseline values . The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient ; 17 % of patient discontinuations were associated with adverse events . CONCLUSIONS Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks ( 2.8 years ) , and sustained treatment may confer some advantages Background Treatment of Alzheimer ’s disease with acetylcholinesterase inhibitors can result in symptomatic benefits , but patients often show variable responses . The objective of this post hoc analysis was to investigate relationships between easily identifiable baseline characteristics/demographics and cognitive response in patients treated with either donepezil 23 mg/d or 10 mg/d and to identify factors potentially influencing response . Methods A post hoc analysis was conducted using data from a large , 24-week , r and omized , double-blind , international study enrolling patients with moderate to severe Alzheimer ’s disease ( baseline Mini-Mental State Examination [ MMSE ] , 0 - 20 ) ( NCT 00478205 ) .  Cognitive changes in subgroups of patients based on selected baseline and demographic characteristics were compared using the least squares mean changes in Severe Impairment Battery scores at Week 24 . Univariate and multivariate analyses were also performed . Results Donepezil 23 mg/d provided statistically significant incremental cognitive benefits over donepezil 10 mg/d irrespective of baseline functional severity , measured by scores on the Alzheimer ’s Disease Cooperative Study -Activities of Daily Living-severe version ( P < 0.05 ) . When patients were categorized by baseline cognitive severity ( MMSE score ) , significant benefits of donepezil 23 mg/d 
    Output:
    
IMPLICATION S Only drugs that affect cholinergic function have shown consistent , but modest , clinical effects , even in late-phase trials .