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American Journal of Alzheimer's Disease... 2009In the severe stages of Alzheimer's disease, functional autonomy is lost, psychiatric and behavioral symptoms become increasingly troublesome, and cognitive deficits... (Review)
Review
In the severe stages of Alzheimer's disease, functional autonomy is lost, psychiatric and behavioral symptoms become increasingly troublesome, and cognitive deficits increase until most patients require complete care, usually in specialized nursing homes. Consequently,some health care professionals question the benefits of pharmacologic intervention during these later stages. Since primary care physicians are often first to see these patients, they have key roles in recognizing the benefits of treatment and initiating appropriate management and referral. Three prospective randomized clinical trials of donepezil in severe Alzheimer's disease have been conducted; these show donepezil treatment is associated with functional and cognitive benefits, although behavioral benefits were not consistently observed. Donepezil was well tolerated; side effects were transient, mild to moderately severe, and cholinergic in nature. Donepezil has strong data throughout the Alzheimer's disease spectrum and, therefore, represents a first-line monotherapy that can provide benefits to patients in all stages of Alzheimer's disease.
Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dopamine Agents; Humans; Indans; Memantine; Neuropsychological Tests; Piperidines; Primary Health Care; Randomized Controlled Trials as Topic; Severity of Illness Index
PubMed: 19246572
DOI: 10.1177/1533317509332094 -
Neurology India Sep 2004Memantine is a relatively new drug specially developed for use in moderate-to-severe dementia. It is an uncompetitive N-methyl-D-aspartate receptor antagonist and... (Review)
Review
Memantine is a relatively new drug specially developed for use in moderate-to-severe dementia. It is an uncompetitive N-methyl-D-aspartate receptor antagonist and reduces glutamatergic excitotoxicity. Though Alzheimer's disease (AD) is the commonest cause of dementia in the world, there is no "cure" available for the same. Cholinesterase inhibitors such as donepezil and rivastigmine have been shown to provide symptomatic relief in patients with AD but have no effect on disease progression or survival. Moreover, they are not helpful in more severe stages of dementia. Memantine has been shown to cause modest improvement in clinical symptoms in severe stages of AD and may retard the disease progression. Moreover, it has been shown to be useful in various forms of dementia including AD, vascular dementia and Wernicke-Korsakoff psychosis. It is also the first drug to cause complete disappearance of pendular nystagmus due to multiple sclerosis. The current review focuses on the pharmacological properties of memantine and examines the recent evidence in favor of memantine.
Topics: Alzheimer Disease; Cost-Benefit Analysis; Dementia; Dementia, Vascular; Excitatory Amino Acid Antagonists; Humans; Korsakoff Syndrome; Memantine; Nystagmus, Pathologic
PubMed: 15472417
DOI: No ID Found -
The Cochrane Database of Systematic... Nov 2022Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of... (Review)
Review
BACKGROUND
Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 12, 2014.
OBJECTIVES
To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adults treated with cranial irradiation.
SEARCH METHODS
For this review update we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and PsycInfo via Ovid to 12 September 2022.
SELECTION CRITERIA
We included randomised controlled (RCTs) trials that evaluated pharmacological or non-pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure.
DATA COLLECTION AND ANALYSIS
Two review authors (MK, JD) independently extracted data from selected studies and carried out a risk of bias assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled.
MAIN RESULTS
Eight studies met the inclusion criteria and were included in this updated review. Six were from the original version of the review, and two more were added when the search was updated. Nineteen further studies were assessed as part of this update but did not fulfil the inclusion criteria. Of the eight included studies, four studies investigated "prevention" of cognitive problems (during radiotherapy and follow-up) and four studies investigated "amelioration" (interventions to treat cognitive impairment as a late complication of radiotherapy). There were five pharmacological studies (two studies on prevention and three in amelioration) and three non-pharmacological studies (two on prevention and one in amelioration). Due to differences between studies in the interventions being evaluated, a meta-analysis was not possible. Studies in early radiotherapy treatment phase (five studies) Pharmacological studies in the "early radiotherapy treatment phase" were designed to prevent or ameliorate cognitive deficits and included drugs used in dementia (memantine) and fatigue (d-threo-methylphenidate hydrochloride). Non-pharmacological studies in the "early radiotherapy treatment phase" included a ketogenic diet and a two-week cognitive rehabilitation and problem-solving programme. In the memantine study, the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The d-threo-methylphenidate hydrochloride study found no statistically significant difference between arms, with few adverse events. The study of a calorie-restricted ketogenic diet found no effect, although a lower than expected calorie intake in the control group complicates interpretation of the results. The study investigating the utility of a rehabilitation program did not carry out a statistical comparison of cognitive performance between groups. Studies in delayed radiation or late effect phase (four studies) The "amelioration" pharmacological studies to treat cognitive complications of radiotherapy included drugs used in dementia (donepezil) or psychostimulants (methylphenidate and modafinil). Non-pharmacological measures included cognitive rehabilitation and problem solving (Goal Management Training). These studies included patients with cognitive problems at entry who had "stable" brain cancer. The donepezil study did not find an improvement in the primary cognitive outcome of overall cognitive performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. A study comparing methylphenidate with modafinil found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. Another study comparing two different doses of modafinil combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The Goal Management Training study suggested a benefit of the intervention, a behavioural intervention that combined mindfulness and strategy training, on executive function and processing speed. There were a number of limitations across studies and few were without high risks of bias.
AUTHORS' CONCLUSIONS
In this update, limited additional evidence was found for the treatment or amelioration of cognitive deficits in adults treated with cranial irradiation. As concluded in the original review, there is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil, methylphenidate and modafinil may have a role in treating cognitive deficits in adults with brain tumours who have been treated with cranial irradiation; patient withdrawal affected the statistical power of these studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher certainty of evidence. There is evidence from only a single small study to support non-pharmacological interventions in the amelioration of cognitive deficits. Further research is required.
Topics: Adult; Humans; Modafinil; Donepezil; Memantine; Quality of Life; Cognitive Dysfunction; Cranial Irradiation; Cognition; Methylphenidate; Brain Neoplasms; Fatigue; Dementia
PubMed: 36427235
DOI: 10.1002/14651858.CD011335.pub3 -
International Journal of Molecular... Aug 2022Since 1906, when Dr. Alois Alzheimer first described in a patient "a peculiar severe disease process of the cerebral cortex", people suffering from this pathology have... (Review)
Review
Since 1906, when Dr. Alois Alzheimer first described in a patient "a peculiar severe disease process of the cerebral cortex", people suffering from this pathology have been waiting for a breakthrough therapy. Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder and the most common form of dementia in the elderly with a long presymptomatic phase. Worldwide, approximately 50 million people are living with dementia, with AD comprising 60-70% of cases. Pathologically, AD is characterized by the deposition of amyloid β-peptide (Aβ) in the neuropil (neuritic plaques) and blood vessels (amyloid angiopathy), and by the accumulation of hyperphosphorylated tau in neurons (neurofibrillary tangles) in the brain, with associated loss of synapses and neurons, together with glial activation, and neuroinflammation, resulting in cognitive deficits and eventually dementia. The current competitive landscape in AD consists of symptomatic treatments, of which there are currently six approved medications: three AChEIs (donepezil, rivastigmine, and galantamine), one NMDA-R antagonist (memantine), one combination therapy (memantine/donepezil), and GV-971 (sodium oligomannate, a mixture of oligosaccharides derived from algae) only approved in China. Improvements to the approved therapies, such as easier routes of administration and reduced dosing frequencies, along with the developments of new strategies and combined treatments are expected to occur within the next decade and will positively impact the way the disease is managed. Recently, Aducanumab, the first disease-modifying therapy (DMT) has been approved for AD, and several DMTs are in advanced stages of clinical development or regulatory review. Small molecules, mAbs, or multimodal strategies showing promise in animal studies have not confirmed that promise in the clinic (where small to moderate changes in clinical efficacy have been observed), and therefore, there is a significant unmet need for a better understanding of the AD pathogenesis and the exploration of alternative etiologies and therapeutic effective disease-modifying therapies strategies for AD. Therefore, a critical review of the disease-modifying therapy pipeline for Alzheimer's disease is needed.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Donepezil; Humans; Memantine; Patient-Centered Care; Polypharmacology
PubMed: 36012569
DOI: 10.3390/ijms23169305 -
IUBMB Life Apr 2018Increased transendothelial permeability and subsequent blood-brain barrier damage play a key role in the pathological progression of human brain ischemia and secondary...
Increased transendothelial permeability and subsequent blood-brain barrier damage play a key role in the pathological progression of human brain ischemia and secondary reperfusion. Memantine is a licensed drug providing clinically relevant efficacy in patients with Alzheimer's disease. However, little information is known regarding its effects on brain endothelial permeability. In this study, we investigated the effects of memantine on endothelial permeability and the underlying mechanisms in an ischemia-reperfusion (I/R) injury model in primary human brain microvascular endothelial cells. First, we found that memantine treatment prevented I/R-induced expression of tumor necrosis factor-α and interleukin-1β at both the mRNA and the protein levels. Additionally, our results indicate that memantine treatment significantly reduced endothelial monolayer permeability after I/R by increasing the expression of tight junction protein occludin and the adherens junction protein VE-cadherin. In addition, we found that memantine reduced the expression and activity of matrix metalloproteinase (MMP)-2 but not MMP-9 after I/R. Memantine also elevated the expression of tissue inhibitors of metalloproteinase-2. Mechanistically, we found that memantine increased the expression of the transcriptional factor Krueppel-like factor 2 (KFL2) through activating extracellular signal regulated kinase (ERK5). In conclusion, our results identified a novel function of memantine in maintaining brain vascular barrier function and suggested that memantine might be a potential therapeutic agent for the treatment of stroke. © 2018 IUBMB Life, 70(4):336-343, 2018.
Topics: Brain; Cell Proliferation; Cells, Cultured; Endothelium, Vascular; Excitatory Amino Acid Antagonists; Humans; Memantine; Protective Agents; Reperfusion Injury
PubMed: 29542225
DOI: 10.1002/iub.1729 -
Canadian Family Physician Medecin de... Feb 2006
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Canada; Cholinesterase Inhibitors; Dopamine Agents; Humans; Memantine; Resource Allocation
PubMed: 16529383
DOI: No ID Found -
The Cochrane Database of Systematic... Jan 2009Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). There is an understanding that an increase in L-glutamate contributes to... (Review)
Review
BACKGROUND
Alzheimer's dementia (AD) is the most common form of dementia in people with Down Syndrome (DS). There is an understanding that an increase in L-glutamate contributes to the pathogenesis of cerebral ischemias and AD. Memantine acts as an antagonist of N-methyl-D-aspartate (NMDA) type receptors, which is thought to reduce abnormal activation of glutamate neurotransmission. It binds with a low affinity to the NMDA receptor and so should not prevent learning and the formation of memory. Memantine can improve cognitive function and slow the decline of AD in the general population over time, and is the subject of this review. It is important to note that people with DS tend to present with AD at a much younger age than the normal population as well as having subtle differences in physiology (e.g. metabolism and heart rate) and may therefore have different requirements from the general population.
OBJECTIVES
To determine the effectiveness and safety of memantine for people with DS who develop AD.
SEARCH STRATEGY
CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, BIOSIS, SCI, SSCI and the NRR were searched up to October 2008. We contacted the manufacturers of memantine, as well as experts in the field, to ask about reports of unpublished or ongoing trials.
SELECTION CRITERIA
Randomised controlled trials of participants with DS and AD in which treatment with memantine was administered compared with a placebo group.
DATA COLLECTION AND ANALYSIS
No study was identified which met the inclusion criteria for this review.
MAIN RESULTS
No study was identified which met inclusion criteria for this review, however there is an on-going randomised controlled study being conducted in the UK and data are expected in 2009.
AUTHORS' CONCLUSIONS
As there are no included trials, recommendations cannot be made about memantine for AD in DS. Well-designed, adequately powered studies are required.
Topics: Alzheimer Disease; Down Syndrome; Humans; Memantine; Receptors, N-Methyl-D-Aspartate
PubMed: 19160343
DOI: 10.1002/14651858.CD007657 -
BMJ Open Jul 2022Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally... (Randomized Controlled Trial)
Randomized Controlled Trial
Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease.
INTRODUCTION
Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2-3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine.
METHODS AND ANALYSIS
Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments.
ETHICS AND DISSEMINATION
MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants.
TRIAL REGISTRATION NUMBERS
European Clinical Trials Registry (2019-000099-41); NCT04302870.
Topics: Amyotrophic Lateral Sclerosis; Double-Blind Method; Humans; Memantine; Motor Neuron Disease; Neurodegenerative Diseases; Riluzole; Trazodone; Treatment Outcome
PubMed: 35798516
DOI: 10.1136/bmjopen-2022-064173 -
TheScientificWorldJournal 2013Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage.
OBJECTIVES
This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD.
METHOD
Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007-2012.
RESULTS AND CONCLUSION
Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of "adequacy and representativeness." Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24-52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Donepezil; Female; Humans; Indans; Male; Memantine; Piperidines; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 24288512
DOI: 10.1155/2013/925702 -
Journal of Alzheimer's Disease : JAD 2018Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.
Topics: Alzheimer Disease; Animals; Humans; Memantine; Neuroprotective Agents
PubMed: 29254093
DOI: 10.3233/JAD-170672