Concomitant Use Of Memantine Research Articles

Influence of CYP2D6, CYP3A5, ABCB1, APOE polymorphisms and nongenetic factors on donepezil treatment in patients with Alzheimer's disease and vascular dementia.

PurposeThis study aims to evaluate the influence of genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and APOE genes and nongenetic factors on steady-state plasma concentrations (Cpss) of donepezil and therapeutic outcomes in Thai patients with Alzheimer’s disease (AD) and vascular dementia (VAD).Patients and methodsEighty-five dementia patients who received donepezil for at least six months were recruited. CYP2D6, CYP3A5, ABCB1, and APOE polymorphisms were genotyped. Cpss of donepezil was measured. Association of genetic and non-genetic factors with Cpss and clinical outcomes of donepezil (cognitive function as measured by the Thai Mental State Examination score; TMSE) were determined by using univariate and multivariate analysis.ResultsBoth univariate and multiple linear regression analysis indicated that only CYP2D6*10 allele was associated with higher Cpss (p-value =0.029 and B =0.478, p-value =0.032, respectively) that might influence the clinical outcomes of donepezil. ie, TMSE (p-value =0.010 and B =4.527, p-value =0.001) and ΔTMSE (p-value =0.023 and B =4.107, p-value =0.002), especially in patients with AD. Interestingly, concomitant use of memantine was found to be associated with increased Cpss of donepezil (p-value =0.007 and B =0.511, p-value =0.014). Whereas, co-medication with antidepressant drugs attenuated clinical responses in patients with AD (TMSE: B =−2.719, p-value =0.013 and ΔTMSE: B =−2.348, p-value =0.028). Age was a significant predictor of donepezil response in VAD patients. No significant association of CYP3A5*3, ABCB1 3435C>T or ABCB1 1236C>T, and APOE ε4 genotypes with Cpss or clinical outcomes of donepezil was found in this study.ConclusionOur results suggests that CYP2D6*10 strongly influences Cpss and there is a trend toward better outcomes of donepezil in patients with AD. Nongenetic factors including concomitant drugs treatment might alter Cpss of donepezil or clinical outcomes.

Effect of concomitant use of memantine on mortality and efficacy outcomes of galantamine-treated patients with Alzheimer's disease: post-hoc analysis of a randomized placebo-controlled study.

BackgroundA large, prospective, 2-year, randomized study in patients with mild-to-moderate Alzheimer’s disease or mixed dementia demonstrated reductions in mortality and cognitive/functional decline in galantamine-treated patients. A post-hoc analysis was conducted to study the effect of (the presence or absence of) concomitant memantine use on treatment outcome.MethodsRandomized patients (N = 2045) were divided into subgroups based on memantine use. Analyses included demographic and clinical characteristics (age, nursing home placement, Mini-Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD) scores) and mortality endpoints.ResultsOverall, 496 (24.3 %) patients were memantine users and were older (mean (SD), 74.0 (8.76) vs 72.8 (8.76), p = 0.008), with lower MMSE scores (18.2 (4.16) vs 19.2 (4.02), p < 0.0001) and DAD scores (58.0 (23.49) vs 62.5 (20.52), p < 0.0001) than nonusers. Mortality rates (per 100 patient-years) in memantine nonusers (n = 1549) were lower for galantamine (1.39) vs placebo-treated patients (4.15). In memantine users, mortality rates were similar for placebo-treated (4.49) and galantamine-treated patients (5.57). In memantine nonusers at 24 months, the decline in MMSE scores (effect size (95 % CI) 0.25 (0.14; 0.36)) and DAD scores (0.17 (0.06; 0.28)) from baseline was lower in galantamine patients vs placebo patients. The absence of these benefits in memantine users could not be explained by baseline age, MMSE, or DAD scores.ConclusionThis post-hoc analysis shows that the beneficial effects of galantamine at 2 years post treatment were not observed in patients who had been placed on background memantine. The reasons for memantine treatment and the possibility of interaction between memantine and galantamine merit further investigation.Trial registrationClinicalTrials.gov NCT00679627. Registered 15 May 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0214-x) contains supplementary material, which is available to authorized users.

Evaluating high-dose rivastigmine patch in severe Alzheimer's disease: analyses with concomitant memantine usage as a factor.

ACTION, a 24-week, prospective, randomized, parallel-group, double-blind study in patients with severe Alzheimer's disease (AD), demonstrated significant efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on the Severe Impairment Battery (SIB) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Overall, 61% of the study population received at least 1 dose of concomitant memantine, regardless of dose or duration. This retrospective analysis investigated the effects of concomitant memantine on the efficacy, safety and tolerability of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch. Patients were stratified according to whether or not they received at least one dose of concomitant memantine during the double-blind phase. Changes from baseline on the SIB and ADCS-ADL-SIV were compared using analysis of covariance (ANCOVA) with treatment, pooled center, memantine usage and treatment-by-memantine as factors, and baseline as a covariate. Safety and tolerability were assessed. Memantine-treated patients were younger than those not receiving memantine (mean 75.9 and 78.8 years, respectively), with a lower screening Mini-Mental State Examination (8.6 and 9.2, respectively). ANCOVA confirmed there was no significant interaction (p>0.1) between study treatment and memantine use on the SIB or ADCS-ADL-SIV. The incidence of adverse events was: 71.4%, 13.3 mg/24 h patch with memantine; 79.7%, 13.3 mg/24 h patch alone; 74.7%, 4.6 mg/24 h patch with memantine; and 71.1%, 4.6 mg/24 h patch alone. These data suggest benefit of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch, regardless of concomitant memantine use. The incidence of adverse events with highdose patch was similar in memantine-treated patients and those not receiving memantine.

Evaluation of an 8-item Severe Impairment Battery (SIB-8) vs. the full SIB in moderate to severe Alzheimer's disease patients participating in a donepezil study

The Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the SIB - the SIB-8 - which takes about 3 min to administer, may represent a more convenient tool for use in clinical practice. The current analyses further explored the SIB-8 scale with respect to its validity and sensitivity. A post hoc analysis was performed using data from a 24-week trial of donepezil 23 mg/day and 10 mg/day in > 1400 patients with moderate to severe AD [baseline Mini-Mental State Examination (MMSE) score 0-20]. Treatment effects on cognition (patterns of score change) were assessed using the full SIB and SIB-8 in the total study population and subgroups based on concomitant memantine use and baseline MMSE. Internal consistency/agreement and correlations between the SIB and SIB-8 and other clinical end points were evaluated. Assessment of score changes from baseline to week 24 with donepezil (23 or 10 mg/day) demonstrated comparable patterns of change when using the SIB-8 and the full SIB, despite inherent differences in the total score ranges for the two scales. Internal consistency/agreement between the full SIB and SIB-8 was good (Cronbach's alphas: 0.77-0.95). SIB-8 scores reliably correlated with SIB total scores (r = 0.859, baseline; r = 0.900, week 24; p < 0.0001), as well as MMSE scores (r = 0.7163, baseline; r = 0.7963, week 24; p < 0.0001). Scores on both SIB scales were moderately associated with functional measures at baseline and week 24. In this post hoc analysis, similar treatment effects were measured by the full SIB and the SIB-8. Very good internal consistency/agreement and strong correlations between the SIB and the more rapid and convenient SIB-8 indicate that the SIB-8 may be a useful and efficient clinical proxy for the full SIB in evaluating treatment response in patients with advanced AD.

High-dose 13.3 mg/24 h rivastigmine patch efficacy and safety in mild-to-moderate Alzheimer's disease with and without concomitant memantine use

High-dose 13.3 mg/24 h rivastigmine patch efficacy and safety in mild-to-moderate Alzheimer's disease with and without concomitant memantine use

Efficacy and safety of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer's disease with and without concomitant memantine use

Efficacy and safety of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer's disease with and without concomitant memantine use

The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer's disease to nursing homes: cost-effectiveness analysis in France.

The costs associated with the care of Alzheimer’s disease patients are very high, particularly those associated with nursing home placement. The combination of a cholinesterase inhibitor (ChEI) and memantine has been shown to significantly delay admission to nursing homes as compared to treatment with a ChEI alone. The objective of this cost-effectiveness analysis was to evaluate the economic impact of the concomitant use of memantine and ChEI compared to ChEI alone. Markov modelling was used in order to simulate transitions over time among three discrete health states (non-institutionalised, institutionalised and deceased). Transition probabilities were obtained from observational studies and French national statistics, utilities from a previous US survey and costs from French national statistics. The analysis was conducted from societal and healthcare system perspectives. Mean time to nursing home admission was 4.57 years for ChEIs alone and 5.54 years for combination therapy, corresponding to 0.98 additional years, corresponding to a gain in quality adjusted life years (QALYs) of 0.25. From a healthcare system perspective, overall costs were €98,609 for ChEIs alone and €90,268 for combination therapy, representing cost savings of €8,341. From a societal perspective, overall costs were €122,039 and €118,721, respectively, representing cost savings of €3,318. Deterministic and probabilistic (Monte Carlo simulations) sensitivity analyses indicated that combination therapy would be the dominant strategy in most scenarios. In conclusion, combination therapy with memantine and a ChEI is a cost-saving alternative compared to ChEI alone as it is associated with lower cost and increased QALYs from both a societal and a healthcare perspective.

Efficacy, safety and tolerability of a higher-dose 13.3 mg/24 h rivastigmine patch in people with severe Alzheimer's disease with and without concomitant memantine use

symptoms in peoplewithmemory loss. The purpose of this studywas to determine if lavender can be an effective tool tomanage sleep disruption in patients residing in a memory care assisted living facility.Methods: Twenty-two residents from memory care units in the Deer Crest assisted living facility (Red Wing, MN) were enrolled in this blinded, randomized-controlled cross-over trial of lavender oil versus placebo oil. Participants were monitored with actigraphs for 3 weeks and acclimated to study procedures in the first week. Participants were randomized to receive either lavender or placebo (almond) oil in week 2 and switched to the other oil during week 3.While dressing for participant’s bedtime, resident assistants applied lotion (for acclimation week) or essential oil to the participant’s neck, upper back, and spine over a period of one minute. A diffuser containing the corresponding treatment was also turned on for 20 minutes. Total minutes of sleep were calculated after sleep periods were manually defined using data from sleep logs. A linear-mixed effects model was conducted on data from four, 24 hr weekday epochs adjusting for patient-level clustering, patient-specific time trend, sequence of oil application, and overall time trend across all subjects.Results: The average participant was 85.7 yr, 29% male, with a Montreal Cognitive Assessment score of 7.0. As expected, there was considerable variation in sleeping patterns across subjects. The total minutes of sleep per night with placebo oil was 408 minutes (sd1⁄486). This significantly increased (p1⁄4.01) by 41 minutes (95% CI: 44.7, 38.35) during the week they received lavender. There was not a significant effect of time or the order in which oils were applied. Conclusions: The use of lavender shows promise as a non-pharmacologic alternative for management of sleep disturbance in people with memory loss.

High‐Dose Donepezil (23 mg/day) for the Treatment of Moderate and Severe Alzheimer's Disease: Drug Profile and Clinical Guidelines

To provide healthcare professionals with a comprehensive assessment of donepezil 23 mg and its role in treating Alzheimer's disease (AD), the Donepezil 23 mg Expert Working Group (EWG) convened in June 2011 to critically evaluate the clinical trial database for this higher dose formulation and the members' clinical experience with its use. Discussions were based on a large, 6-month, phase 3 clinical trial in patients with moderate to severe AD that compared continuing donepezil 10 mg/day versus switching to 23 mg/day. In this trial, donepezil 23 mg/day demonstrated significantly greater cognitive benefits (mean change in Severe Impairment Battery score, 2.11 points; P < 0.001). Prespecified analyses showed that benefits were significant irrespective of concomitant memantine use. The EWG considered integrating these new data into clinical practice approaches. Dementia severity, tolerability of the 10 mg dose, and need for additional therapy were key selection criteria, as was monitoring of gastrointestinal side effects, as consideration of titration strategies is an important aspect of implementation. The EWG concluded that donepezil 23 mg is an efficacious therapy for moderate to severe AD, with or without concomitant memantine, extending the treatment opportunities available to manage moderate to severe AD dementia. EWG guidelines offer assistance to clinicians in choosing and implementing treatment options.

Higher-Dose (23 mg/day) Donepezil Formulation for the Treatment of Patients with Moderate-to-Severe Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly. An estimated 5.4 million people in the United States have AD, and its prevalence is expected to increase rapidly in the coming years. Few US Food and Drug Administration (FDA)-approved treatment options for AD are currently available. Donepezil is 1 of only 2 therapies approved in the United States for the treatment of moderate–to–severe AD. In 2010, the FDA approved a higher daily dose of donepezil (23 mg/day) for the treatment of AD in the moderate–to–severe stages based on positive results from a large, global, phase 3 clinical trial that compared switching to donepezil 23 mg/day with continuing treatment with donepezil 10 mg/day. In that trial, no benefit was seen in the co–primary endpoint of global functioning; however, donepezil 23 mg/day provided a small but significant improvement in the cognitive endpoint compared with donepezil 10 mg/day. A subgroup analysis subsequently showed that the cognitive benefits were significant irrespective of concomitant memantine use. Adverse events were mainly gastrointestinal related and were more prevalent in patients receiving the donepezil 23-mg/day dose during the first month of therapy, but were relatively infrequent thereafter. These data indicate that once–daily donepezil 23 mg may be an effective treatment option for patients with moderate–to–severe AD with or without concomitant memantine. This article reviews the rationale for using higher–dose donepezil, the clinical data supporting its use, and some of the practical implications that should be considered by practicing physicians when using donepezil 23 mg/day for patients with AD.

Efficacy and Safety of Donepezil 23 mg versus Donepezil 10 mg for Moderate-to-Severe Alzheimer’s Disease: A Subgroup Analysis in Patients Already Taking or Not Taking Concomitant Memantine

Background/Aims: A large multicenter trial of donepezil 23 mg/day versus donepezil 10 mg/day for moderate-to-severe Alzheimer’s disease allowed patients taking concomitant memantine. We evaluated the efficacy/safety of donepezil 23 and 10 mg/day in this trial, with respect to concomitant memantine use. Methods: Prespecified analysis of data from a 24-week, randomized, double-blind trial. Patients were randomized to donepezil doses (23 vs. 10 mg/day) and stratified by concomitant memantine use (yes or no). Efficacy and safety were assessed for each donepezil dose in subgroups taking or not taking concomitant memantine. Results: At week 24, donepezil 23 mg/day provided significant cognitive benefits over 10 mg/day (p < 0.01) on the Severe Impairment Battery, with or without concomitant memantine (ANCOVA adjusted for baseline score, country and treatment). The higher dose showed no benefit on the global function, Mini-Mental State Examination or activities of daily living measures in either memantine subgroup. Rates of treatment-emergent adverse events (AEs) were higher for donepezil 23 mg/day with memantine (80.7%) than 23 mg/day without memantine (69.7%) or 10 mg/day with/without memantine (66.7/62.0%); across all treatment groups, most events were mild/moderate in severity. Individual rates of serious AEs were low (<1.0%), regardless of concomitant memantine use. Conclusion: In this population, concomitant memantine use did not alter the response profile of donepezil 23 vs. 10 mg/day. Donepezil 23 mg was generally safe and well tolerated among patients receiving donepezil alone and among patients receiving a combination of donepezil and memantine therapy.

Economic Evaluation of the Impact of Memantine on Time to Nursing Home Admission in the Treatment of Alzheimer Disease

An observational study showed that combining memantine with a cholinesterase inhibitor (ChEI) treatment significantly delayed admission to nursing homes in patients with Alzheimer disease (AD). Our study aimed to evaluate the economic impact of the concomitant use of memantine and a ChEI, compared with a ChEI alone, in a Canadian population of patients with AD. A cost-utility analysis using a Markov model during a 7-year time horizon was performed according to a societal and Canadian health care system perspective. The Markov model includes the following states: noninstitutionalized, institutionalized, and deceased. The model includes transition probabilities for institutionalization and death, adjusted with mortality rates specific to AD. Utilities associated with institutionalization and noninstitutionalization were included. For the health care system perspective, costs of medication as well as costs of care provided in the community and in nursing homes were considered. For the societal perspective, costs of direct care and supervision provided by caregivers were added. From both perspectives, the concomitant use of a ChEI and memantine is a dominant strategy, compared with the use of a ChEI alone. On a per patient basis, there was a gain of 0.26 quality-adjusted life years with the treatment including memantine and cost decreases of Can$21 391 and Can$30 512, respectively, for the societal and health care system perspective. This economic evaluation indicates that institutionalization is the largest cost component in AD management and that the use of memantine, combined with a ChEI, to treat AD is a cost-effective alternative, compared with the use of a ChEI alone.

Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease

Background:Patients using cholinesterase inhibitors (ChEIs) have a delay in nursing home (NH) admission compared with those who were not using the medication. There are no long-term studies of the effects...