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      A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease

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          Abstract

          Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.

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          Most cited references 67

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          Fixed-dose combinations improve medication compliance: a meta-analysis.

          Compliance with treatment is a sine qua non for successful treatment of chronic conditions like hypertension. Fixed-dose combinations are designed to simplify the medication regimen and potentially improve compliance. However the data on comparison of fixed-dose combination with free-drug regimen to improve patient's medication compliance is limited. We conducted a MEDLINE search of studies using the words fixed-dose combinations, compliance and/or adherence. The inclusion criteria were studies which involved fixed-dose combination versus free-drug components of the regimen given separately. Only studies which reported patient's compliance were included. Of the 68 studies on fixed-dose combinations, only 9 studies fulfilled the inclusion criteria. Two studies were in patients with tuberculosis, 4 in the hypertensive population, 1 in patients with human immunodeficiency virus (HIV) disease and 2 in the diabetic population. A total of 11,925 patients on fixed-dose combination were compared against 8317 patients on free-drug component regimen. Fixed-dose combination resulted in a 26% decrease in the risk of non-compliance compared with free-drug component regimen (pooled relative risk [RR] 0.74; 95% confidence interval [CI], 0.69-0.80; P <.0001). There was no evidence of heterogeneity in this analysis (chi(2)=14.49, df=8; P=.07). A subgroup analysis of the 4 studies on hypertension showed that fixed-dose combination (pooled RR 0.76; 95% CI, 0.71-0.81; P <.0001) decreased the risk of medication non-compliance by 24% compared with free-drug combination regimen. Fixed-dose combination decreases the risk of medication non-compliance and should be considered in patients with chronic conditions like hypertension for improving medication compliance which can translate into better clinical outcomes.
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            Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine--searching for the connections.

            β-amyloid (Aβ) is widely accepted to be one of the major pathomechanisms underlying Alzheimer's disease (AD), although there is presently lively debate regarding the relative roles of particular species/forms of this peptide. Most recent evidence indicates that soluble oligomers rather than plaques are the major cause of synaptic dysfunction and ultimately neurodegeneration. Soluble oligomeric Aβ has been shown to interact with several proteins, for example glutamatergic receptors of the NMDA type and proteins responsible for maintaining glutamate homeostasis such as uptake and release. As NMDA receptors are critically involved in neuronal plasticity including learning and memory, we felt that it would be valuable to provide an up to date review of the evidence connecting Aβ to these receptors and related neuronal plasticity. Strong support for the clinical relevance of such interactions is provided by the NMDA receptor antagonist memantine. This substance is the only NMDA receptor antagonist used clinically in the treatment of AD and therefore offers an excellent tool to facilitate translational extrapolations from in vitro studies through in vivo animal experiments to its ultimate clinical utility. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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              Assessing the impact of neuropsychiatric symptoms in Alzheimer's disease: the Neuropsychiatric Inventory Caregiver Distress Scale.

              To develop an adjunct scale to the Neuropsychiatric Inventory (NPI) for assessing the impact of neuropsychiatric symptoms in Alzheimer's disease (AD) patients on caregiver distress. Cross-sectional descriptive and correlational study. University out-patient memory disorders clinics. Eighty-five AD subjects and their caregivers (54 spouses, 31 children). The NPI and NPI Caregiver Distress Scale (NPI-D) were used to assess neuropsychiatric symptoms in AD patients and related caregiver distress, respectively. Criterion validity of the NPI-D was examined (N = 69) by comparison with an abridged version of the Relatives' Stress Scale (RSS'), a general measure of caregiver stress, using item clusters that had previously been correlated to behavioral disturbances in demented patients. Test-retest (n = 20) and inter-rater reliability (n = 16) of the NPI-D were also assessed. Test-retest and interrater reliability of the NPI-D were both adequate. Overall, caregiver NPI-D distress ratings were correlated significantly with the RSS' (r = .60, P < .001). RSS' ratings correlated strongly with NPI scores (r = .64, P < .001), even after controlling for degree of cognitive impairment based on the Mini-Mental State Exam (MMSE) score (r = .61). MMSE scores showed a moderate correlation to RSS' ratings (-.30, P = .02), but this association was markedly attenuated when controlling for the degree of neuropsychiatric disturbance based on the NPI score (r = -. 14). NPI-D ratings for 9 of 10 NPI symptom domains correlated most strongly with either NPI symptom severity or total (frequency x severity) scores. Agitation, dysphoria, irritability, delusions, and apathy were the symptoms most often reported to be severely distressing to caregivers. The NPI-D provides a reliable and valid measure of subjective caregiver distress in relation to neuropsychiatric symptoms measured by the NPI. Neuropsychiatric alterations are more strongly associated than cognitive symptoms to caregiver distress. The NPI-D may be useful in both clinical and research settings for assessing the contribution to caregiver distress of neuropsychiatric symptoms in AD patients.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                03 October 2016
                : 10
                : 3267-3279
                Affiliations
                Department of Psychiatry, St Louis University School of Medicine, St Louis, MO, USA
                Author notes
                Correspondence: George T Grossberg, Department of Psychiatry, St Louis University School of Medicine, 1438 South Grand St Louis, MO 63104, USA, Tel +1 314 977 4829, Fax +1 314 977 4878, Email grossbgt@ 123456slu.edu
                Article
                dddt-10-3267
                10.2147/DDDT.S86463
                5055113
                © 2016 Deardorff and Grossberg. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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