Galantamine Abstracts 1

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Optimal dosing of galantamine in patients with mild or moderate Alzheimer's disease: post Hoc analysis of a randomized, double-blind, placebo-controlled trial.
            (Aronson et al., 2009) Download
BACKGROUND: Galantamine (hydrobromide), a reversible acetylcholinesterase inhibitor and allosteric nicotinic receptor modulator, slows cognitive and functional decline in mild to moderate dementia of the Alzheimer's type. Although several drugs are indicated for mild to moderate Alzheimer's disease (AD), no published study has separately analysed mild and moderate AD subgroups to assess the effect of dosage. OBJECTIVE: To compare the efficacy and safety of galantamine 16 and 24 mg/day in patient subgroups with mild or moderate AD. METHODS: This post hoc analysis (n = 838) of a 5-month, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of galantamine 16 and 24 mg/day in a subgroup of patients with mild AD (Mini-Mental State Examination [MMSE] >18) and a subgroup with moderate AD (MMSE 10-18). Efficacy outcomes included the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) score and treatment response (ADAS-cog maintenance [>or=0-point improvement], improvement >or=4 points and improvement >or=7 points). RESULTS: Mean ADAS-cog scores of patients with mild AD demonstrated significant improvement from baseline with galantamine 16 and 24 mg/day (p < 0.001 for both), whereas cognitive function did not change significantly for placebo recipients (p = 0.559). Patients with moderate AD improved with galantamine 24 mg/day (p = 0.009) but not with 16 mg/day (p = 0.768); a decline occurred with placebo (p < 0.001). A greater proportion of patients treated with galantamine 16 mg/day (76% and 52% for mild and moderate AD, respectively) or 24 mg/day (69% and 61%, respectively) demonstrated a treatment response (i.e. ADAS-cog was maintained or improved) relative to placebo (55% and 28%, respectively; p < 0.05). Patients with moderate AD trended toward greater response with the 24 mg/day dosage than with the 16 mg/day dosage. Galantamine was well tolerated. Adverse events were comparable for all study groups with mild or moderate AD. CONCLUSION: This post hoc analysis suggests that galantamine 16 mg/day is the optimal dosage for patients with mild AD, as similar efficacy is observed with the 24 mg/day dose. However, patients with moderate AD appear to gain additional benefit from galantamine 24 mg/day.

Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease.
            (Hager et al., 2014) Download
BACKGROUND: Currently available treatments for Alzheimer's disease (AD) can produce mild improvements in cognitive function, behavior, and activities of daily living in patients, but their influence on long-term survival is not well established. This study was designed to assess patient survival and drug efficacy following a 2-year galantamine treatment in patients with mild to moderately severe AD. METHODS: In this multicenter, double-blind study, patients were randomized 1:1 to receive galantamine or placebo. One primary end point was safety; mortality was assessed. An independent Data Safety Monitoring Board monitored mortality for the total deaths reaching prespecified numbers, using a time-to-event method and a Cox-regression model. The primary efficacy end point was cognitive change from baseline to month 24, as measured by the Mini-Mental State Examination (MMSE) score, analyzed using intent-to-treat analysis with the 'last observation carried forward' approach, in an analysis of covariance model. RESULTS: In all, 1,024 galantamine- and 1,021 placebo-treated patients received study drug, with mean age ~73 years, and mean (standard deviation [SD]) baseline MMSE score of 19 (4.08). A total of 32% of patients (661/2,045) completed the study, 27% (554/2,045) withdrew, and 41% (830/2,045) did not complete the study and were discontinued due to a Data Safety Monitoring Board-recommended early study termination. The mortality rate was significantly lower in the galantamine group versus placebo (hazard ratio [HR] =0.58; 95% confidence interval [CI]: 0.37; 0.89) (P=0.011). Cognitive impairment, based on the mean (SD) change in MMSE scores from baseline to month 24, significantly worsened in the placebo (-2.14 [4.34]) compared with the galantamine group (-1.41 [4.05]) (P<0.001). Functional impairment, based on mean (SD) change in the Disability Assessment in Dementia score (secondary end point), at month 24 significantly worsened in the placebo (-10.81 [18.27]) versus the galantamine group (-8.16 [17.25]) (P=0.002). Incidences of treatment-emergent adverse events were 54.0% for the galantamine and 48.6% for the placebo group. CONCLUSION: Long-term treatment with galantamine significantly reduced mortality and the decline in cognition and daily living activities, in mild to moderate AD patients. IDENTIFICATION: This study is registered at ClinicalTrials.gov (NCT00679627).

Galantamine for Alzheimer's disease and mild cognitive impairment.
            (Loy and Schneider, 2006) Download
BACKGROUND: Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. OBJECTIVES: To assess the clinical effects of galantamine in patients with mild cognitive impairment (MCI), 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 April 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 and from http://www.clinicalstudyresults.org/. 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 MCI or 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 versus probable Alzheimer's disease. MAIN RESULTS: Ten trials with a total 6805 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 = 8 studies), at all dosing levels except for 8 mg/d . Confidence intervals for the ORs overlapped across the dose range of 16 mg to 36 mg per day, with point estimates of 1.6 - 1.8 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 = 8), with greater effect over six months compared to three months. Confidence intervals again overlapped. Point estimate of effect was lower for 8 mg/d but similar for 16 mg to 36 mg per day. For example, treatment effect for 24 mg/d over six months was 3.1 point 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 seven recruiting patients with probable AD. Galantamine's adverse effects appeared similar to those of other cholinesterase inhibitors and to be dose related. Prolong release / once daily formulation of galantamine at 16 - 24mg/d was found to have similar efficacy and side-effect profile as the equivalent twice-daily regime. Data from the two MCI trials suggest marginal clinical benefit, but a yet unexplained excess in death rate. AUTHORS' 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 three to six months' duration. Although there was not a statistically significant dose-response effect, doses above 8 mg/d were, for the most part, consistently statistically significant. Galantamine's safety profile in AD 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 four 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. Galantamine use in MCI is not recommended due to its association with an excess death rate.

The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer's disease.
            (Nordstrom et al., 2013) Download
AIMS: Cholinesterase inhibitors (ChEIs) are used for symptomatic treatment of Alzheimer's disease. These drugs have vagotonic and anti-inflammatory properties that could be of interest also with respect to cardiovascular disease. This study evaluated the use of ChEIs and the later risk of myocardial infarction and death. METHODS AND RESULTS: The cohort consisted of 7073 subjects (mean age 79 years) from the Swedish Dementia Registry with the diagnoses of Alzheimer's dementia or Alzheimer's mixed dementia since 2007. Cholinesterase inhibitor use was linked to diagnosed myocardial infarctions (MIs) and death using national registers. During a mean follow-up period of 503 (range 0-2009) days, 831 subjects in the cohort suffered MI or died. After adjustment for confounders, subjects who used ChEIs had a 34% lower risk for this composite endpoint during the follow-up than those who did not [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.56-0.78]. Cholinesterase inhibitor use was also associated with a lower risk of death (HR: 0.64, 95% CI: 0.54-0.76) and MI (HR: 0.62, 95% CI: 0.40-0.95) when analysed separately. Subjects taking the highest recommended ChEI doses (donepezil 10 mg, rivastigmine >6 mg, galantamine 24 mg) had the lowest risk of MI (HR: 0.35, 95% CI: 0.19-0.64), or death (HR: 0.54, 95% CI: 0.43-0.67) compared with those who had never used ChEIs. CONCLUSION: Cholinesterase inhibitor use was associated with a reduced risk of MI and death in a nationwide cohort of subjects diagnosed with Alzheimer's dementia. These associations were stronger with increasing ChEI dose.

The Effects of Galantamine Hydrobromide Treatment on Dehydroepiandrosterone Sulfate and Cortisol Levels in Patients with Chronic Fatigue Syndrome
            (Turan et al., 2009) Download
OBJECTIVE: Mental fatigue, cognitive disorders, and sleep disturbances seen in chronic fatigue syndrome (CFS) may be attributed to cholinergic deficit. A functional deficiency of cholinergic neurotransmission may cause the hypothalamic-pituitary-adrenal axis hypoactivity seen in CFS. Therefore, we investigated the alterations in stress hormones such as cortisol and dehydroepiandrosterone sulfate (DHEAS) in CFS patients before and after 4-week administration of galantamine hydrobromide, a selective acetylcholinesterase inhibitor, and aimed to investigate whether there are any relationships between the probable hormonal changes and cholinergic treatment. METHODS: Basal levels of cortisol and DHEAS were measured in 29 untreated CFS patients who were diagnosed according to Centers for Disease Control (CDC) criteria and in 20 healthy controls. In the patient group, four weeks after 8 mg/d galantamine hydrobromide treatment, cortisol and DHEAS levels were measured again. After the treatment 22 patients who stayed in study were divided into two subgroups as responders and nonresponders according to the reduction in their Newcastle Research Group ME/CFS Score Card (NRG) scores. RESULTS: Important findings of this study are lower pre-and post-treatment cortisol levels and in all CFS patients compared to controls (F=4.129, p=0.049; F=4.803, p=0.035, respectively); higher basal DHEAS values and higher DHEAS/cortisol molar ratios which were normalized following four weeks' treatment with 8 mg/d galantamine hydrobromide in the treatment-respondent group (F=5.382, p=0.029; F=5.722, p=0.025, respectively). CONCLUSION: The findings of the decrease in basal DHEAS levels and DHEAS/cortisol molar ratios normalizing with galantamine treatment may give some support to the cholinergic deficit hypothesis in CFS.

 

 


References

Aronson, S, et al. (2009), ‘Optimal dosing of galantamine in patients with mild or moderate Alzheimer’s disease: post Hoc analysis of a randomized, double-blind, placebo-controlled trial.’, Drugs Aging, 26 (3), 231-39. PubMedID: 19358618
Hager, K, et al. (2014), ‘Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease.’, Neuropsychiatr Dis Treat, 10 391-401. PubMedID: 24591834
Loy, C and L Schneider (2006), ‘Galantamine for Alzheimer’s disease and mild cognitive impairment.’, Cochrane Database Syst Rev, (1), CD001747. PubMedID: 16437436
Nordstrom, P, et al. (2013), ‘The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer’s disease.’, Eur Heart J, 34 (33), 2585-91. PubMedID: 23735859
Turan, T., et al. (2009), ‘The Effects of Galantamine Hydrobromide Treatment on Dehydroepiandrosterone Sulfate and Cortisol Levels in Patients with Chronic Fatigue Syndrome’, Psychiatry Investig, 6 (3), 204-10. PubMedID: 20046396