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Neurology. Clinical Practice Jun 2021Once-daily extended-released memantine with donepezil (hereafter memantine/donepezil) may improve medication adherence but has a 60-fold higher cost compared with...
BACKGROUND
Once-daily extended-released memantine with donepezil (hereafter memantine/donepezil) may improve medication adherence but has a 60-fold higher cost compared with combined generic components. Little is known about factors associated with prescribing memantine/donepezil. We examined the association between pharmaceutical industry payments to physicians and prescribing memantine/donepezil in Medicare.
METHODS
A cross-sectional study was conducted. Using 2015-2016 Centers for Medicare and Medicaid Services Open Payments and Part D prescription databases, we identified unique physicians who prescribed ≥11 memantine/donepezil prescriptions from 2015 to 2016. Outcome variable was the number of memantine/donepezil prescriptions written per physician per year. The key independent variable was physician receipt of industry payments defined in 2 models: (1) number of payments and (2) amount of payment ($100 units) for memantine/donepezil received per physician per year. Multivariable Poisson regression was used, adjusting for potential confounders.
RESULTS
Among 4,895 unique eligible physicians in 2015-2016, the median number of memantine/donepezil prescriptions per physician per year was 19.5 (25th percentile 13, 75th percentile 32). Physicians received between 0 and 75 payments per year (median 1, 25th percentile 0, 75th percentile 2.5) for memantine/donepezil, totaling an average of $92 per year (median $10.5, 25th percentile $0, 75th percentile $33.20). Every 1 additional payment received was associated with a 2% increase in new memantine/donepezil prescriptions prescribed per physician per year (rate ratio [RR] 1.02, 95% confidence interval [CI] 1.02-1.02). Every $100 increase in payment for memantine/donepezil was associated with a 0.3% increase in new memantine/donepezil prescriptions prescribed per physician per pear (RR 1.003, 95% CI 1.002-1.004).
CONCLUSIONS
Receipt of industry payments for memantine/donepezil was independently associated with increased likelihood of physician prescribing memantine/donepezil in Medicare.
PubMed: 34484885
DOI: 10.1212/CPJ.0000000000000870 -
Journal of Personalized Medicine May 2022Donepezil and memantine are the most common drugs used for Alzheimer's disease. Their low effectiveness could partly be explained by genetic factors. Thus, we aim to...
Donepezil and memantine are the most common drugs used for Alzheimer's disease. Their low effectiveness could partly be explained by genetic factors. Thus, we aim to identify Single Nucleotide Polymorphisms (SNPs) associated with pharmacokinetics, pharmacodynamics, and the safety of donepezil and memantine. For this regard, 25 volunteers enrolled in a bioequivalence clinical trial were genotyped for 67 SNPs in 21 genes with a ThermoFisher QuantStudio 12K Flex OpenArray. The statistical strategy included a univariate analysis that analyzed the association of these SNPs with pharmacokinetic parameters or the development of adverse drug reactions (ADRs) followed by a Bonferroni-corrected multivariate regression. Statistical analyses were performed with SPSS software v.21 and R commander (version v3.6.3). In the univariate analysis, fourteen and sixteen SNPs showed a significant association with memantine's and donepezil's pharmacokinetic parameters, respectively. Rs20417 () was associated with the development of at least one ADR. However, none of these associations reached the significance threshold in the Bonferroni-corrected multivariate analysis. In conclusion, we did not observe any significant association of the SNPs analyzed with memantine and donepezil pharmacokinetics or ADRs. Current evidence on memantine and donepezil pharmacogenetics does not justify their inclusion in pharmacogenetic guidelines.
PubMed: 35629210
DOI: 10.3390/jpm12050788 -
The Cochrane Database of Systematic... Feb 2021Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of... (Review)
Review
BACKGROUND
Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment.
OBJECTIVES
To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes.
SEARCH METHODS
We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources.
SELECTION CRITERIA
We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods.
MAIN RESULTS
We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias. Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty). Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty). We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review.
AUTHORS' CONCLUSIONS
This review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well-designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers.
Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Humans; Memantine; Parkinson Disease; Quality of Life; Rivastigmine
PubMed: 35608903
DOI: 10.1002/14651858.CD009081.pub2 -
CNS Neuroscience & Therapeutics Oct 2018Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 45 million people worldwide. Patients with severe AD require help with daily activities and... (Review)
Review
BACKGROUND
Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 45 million people worldwide. Patients with severe AD require help with daily activities and show severe memory impairment. Currently, donepezil is one of two drugs approved by FDA and Health Canada for the treatment of severe AD (MMSE score <10). It is prescribed as 5 or 10 mg/d and an FDA-approved 23-mg/d dose.
METHOD
This review will discuss risks and benefits of donepezil at these doses in severe AD. Articles were identified using PubMed using the MeSH terms "donepezil" AND "Alzheimer Disease" AND "severe." Three double-blind, placebo-controlled, randomized studies, one post hoc analysis, and one subgroup analysis were selected.
RESULTS
Donepezil was found to benefit patients in cognition and global functioning. The most consistent improvement was in severe impairment battery (SIB) scores. However, more patients treated with high dosage of donepezil discontinued their treatment due to various adverse events (AEs).
CONCLUSION
Clinicians must weigh benefits against adverse events when determining the course of therapy, as recommendations for cholinesterase inhibitors in advanced AD remain unclear and vary with different guidelines.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; PubMed
PubMed: 30058285
DOI: 10.1111/cns.13035 -
Neurotherapeutics : the Journal of the... Oct 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1 mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.
Topics: Humans; Mice; Animals; Amyotrophic Lateral Sclerosis; Donepezil; Nebivolol; Phosphatidylinositol 3-Kinases; HeLa Cells; Quality of Life; Spinal Cord; Disease Progression; Disease Models, Animal; Mice, Transgenic; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 37782409
DOI: 10.1007/s13311-023-01444-7 -
PloS One 2023Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug...
A causal inference study: The impact of the combined administration of Donepezil and Memantine on decreasing hospital and emergency department visits of Alzheimer's disease patients.
Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimer's disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimer's Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.
Topics: Humans; Alzheimer Disease; Donepezil; Memantine; Hospitals; Emergency Service, Hospital
PubMed: 37708117
DOI: 10.1371/journal.pone.0291362 -
Drug Design, Development and Therapy 2022Chronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess...
PURPOSE
Chronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess antioxidant and anti-inflammatory properties believed to be contributory factors in reversing cognitive decline. 6-Methoxyflavone (6-MOF), a flavonoid occurring naturally in medicinal plants, has been reported to instigate neuroprotection by reversing cisplatin-induced hyperalgesia and allodynia. Consequently, this study was designed to investigate 6-MOF activity in models of chronic ethanol-induced cognitive impairment along with neurochemical correlates.
METHODS
Mice were given ethanol orally (2.0 g/kg daily) for 24 days plus either saline, 6-MOF (25-75mg/kg) or donepezil (4mg/kg) and then ethanol was withdrawn for the next 6 days. Animals were subsequently assessed for their cognitive performance in several models on days 1, 12, and 24, during abstinence (Day-26) and on the 7th day of the washout period. Following behavioral assessment, post-mortem dopamine, noradrenaline and vitamin C concentrations were quantified in the frontal cortex, hippocampus and striatum, using HPLC with UV detection.
RESULTS
Chronic ethanol treatment suppressed locomotor activity and impaired cognitive tasks, which included novel object recognition, performance in the Morris water maze as well as the Y-maze, socialization and nest-building behavior throughout the protocol and during withdrawal. These behavioral deficits were at least partially restored by the co-administration of 6-MOF or donepezil with ethanol as were ethanol-induced deficits in frontal cortical and hippocampal dopamine plus noradrenaline, together with striatal dopamine. 6-MOF co-administration with ethanol also modestly restored striatal vitamin C levels.
CONCLUSION
It is postulated that, apart from donepezil, 6-MOF may be useful not only in the treatment of ethanol withdrawal severity but also in the management of chronic ethanol withdrawal induced cognitive impairment.
Topics: Animals; Ascorbic Acid; Cognitive Dysfunction; Donepezil; Dopamine; Ethanol; Flavones; Hippocampus; Maze Learning; Mice; Norepinephrine
PubMed: 35665194
DOI: 10.2147/DDDT.S360677 -
Alzheimer's Research & Therapy Jun 2023Donepezil is an approved therapy for the treatment of Alzheimer's disease (AD). Results across clinical trials have been inconsistent, which may be explained by... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Donepezil is an approved therapy for the treatment of Alzheimer's disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to donepezil differs in mild cognitive impaired (MCI) individuals demonstrating different magnetic resonance imaging (MRI) subtypes.
METHODS
From the Hippocampus Study double-blind, randomized clinical trial, we included 173 MCI individuals (donepezil = 83; placebo = 90) with structural MRI data, at baseline and at clinical follow-up assessments (6-12-month). Efficacy outcomes were the annualized percentage change (APC) in hippocampal, ventricular, and total grey matter volumes, as well as in the AD cortical thickness signature. Participants were classified into MRI subtypes as typical AD, limbic-predominant, hippocampal-sparing, or minimal atrophy at baseline. We primarily applied a subtyping approach based on continuous scale of two subtyping dimensions. We also used the conventional categorical subtyping approach for comparison.
RESULTS
Donepezil-treated MCI individuals showed slower atrophy rates compared to the placebo group, but only if they belonged to the minimal atrophy or hippocampal-sparing subtypes. Importantly, only the continuous subtyping approach, but not the conventional categorical approach, captured this differential response.
CONCLUSIONS
Our data suggest that individuals with MCI, with hippocampal-sparing or minimal atrophy subtype, may have improved benefit from donepezil, as compared with MCI individuals with typical or limbic-predominant patterns of atrophy. The newly proposed continuous subtyping approach may have advantages compared to the conventional categorical approach. Future research is warranted to demonstrate the potential of subtype stratification for disease prognosis and response to treatment.
TRIAL REGISTRATION
ClinicalTrial.gov NCT00403520. Submission Date: November 21, 2006.
Topics: Humans; Donepezil; Cognitive Dysfunction; Magnetic Resonance Imaging; Alzheimer Disease; Atrophy
PubMed: 37353809
DOI: 10.1186/s13195-023-01253-2 -
Alzheimer's Research & Therapy Aug 2023There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have...
BACKGROUND
There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population.
OBJECTIVE
To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic.
METHODS
Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019.
RESULTS
Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval [CI] 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020.
CONCLUSIONS
The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.
Topics: Humans; Male; Female; Alzheimer Disease; Donepezil; Rivastigmine; Memantine; Cholinesterase Inhibitors; Retrospective Studies; Pandemics; Prevalence; Piperidines; Phenylcarbamates; Indans; COVID-19; Galantamine
PubMed: 37537656
DOI: 10.1186/s13195-023-01271-0 -
Biosensors Aug 2022Fast and reliable determination of enzyme inhibitors are of great importance in environmental monitoring and biomedicine because of the high biological activity and...
Fast and reliable determination of enzyme inhibitors are of great importance in environmental monitoring and biomedicine because of the high biological activity and toxicity of such species and the necessity of their reliable assessment in many media. In this work, a flow-through biosensor has been developed and produced by 3D printing from poly(lactic acid). Acetylcholinesterase from an electric eel was immobilized on the inner walls of the reactor cell. The concentration of thiocholine formed in enzymatic hydrolysis of the substrate was monitored amperometrically with a screen-printed carbon electrode modified with carbon black particles, pillar[5]arene, electropolymerized Methylene blue and thionine. In the presence of thiocholine, the cathodic current at -0.25 V decreased because of an alternative chemical reaction of the macrocycle. The conditions of enzyme immobilization and signal measurements were optimized and the performance of the biosensor was assessed in the determination of reversible (donepezil, berberine) and irreversible (carbofuran) inhibitors. In the optimal conditions, the flow-through biosensor made it possible to determine 1.0 nM-1.0 μM donepezil, 1.0 μM-1.0 mM berberine and 10 nM to 0.1 μM carbofuran. The AChE biosensor was tested on spiked samples of artificial urine for drugs and peanuts for carbofuran. Possible interference of the sample components was eliminated by dilution of the samples with phosphate buffer. Easy mounting, low cost of replaceable parts of the cell and satisfactory analytical and metrological characteristics made the biosensor a promising future application as a point-of-care or point-of-demand device outside of a chemical laboratory.
Topics: Acetylcholinesterase; Berberine; Biosensing Techniques; Carbofuran; Carbon; Donepezil; Electrodes; Enzymes, Immobilized; Methylene Blue; Phosphates; Soot; Thiocholine
PubMed: 36140061
DOI: 10.3390/bios12090676