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CNS Drug Reviews 2003Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic... (Review)
Review
Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits Abeta production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.
Topics: Alzheimer Disease; Animals; Electrophysiology; Excitatory Amino Acid Antagonists; Humans; Memantine; Memory; Molecular Biology; Neuronal Plasticity; Neuropharmacology; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate
PubMed: 14530799
DOI: 10.1111/j.1527-3458.2003.tb00254.x -
Toxicology in Vitro : An International... Oct 2022Memantine is a non-competitive antagonist with a moderate affinity to the N-methyl-d-Aspartate (NMDA) receptor. The present study assessed memantine's neuroprotective...
Memantine is a non-competitive antagonist with a moderate affinity to the N-methyl-d-Aspartate (NMDA) receptor. The present study assessed memantine's neuroprotective activity using electrophysiology of ex-vivo hippocampal slices. Interestingly, a nicotinic component was necessary for memantine's neuroprotection (NP). Memantine demonstrated a bell-shaped dose-response curve of NP against NMDA. Memantine was neuroprotective at concentrations below 3 μM, but the NP declined at higher concentrations (>3 μM) when memantine inhibits the NMDA receptor. Additional evidence that memantine NP is mediated by an alternate mechanism independent of the inhibition of the NMDA receptor is supported by its ability to protect neurons when applied before or after the NMDA insult and in the presence of D(-)-2-Amino-5-phosphonopentanoic acid (APV), the standard NMDA receptor inhibitor. We found several similarities between the memantine NP mechanism and the neuroprotective nicotinic drug, the 4R cembranoid. Memantine's NP requires the release of acetylcholine, the activation of α4β2, and is independent of MEK/MAPK signaling. Both 4R and memantine require the activation of PI3K/AKT for NP against NMDA-mediated excitotoxicity, although at different concentrations. In conclusion, our studies show memantine is neuroprotective through a nicotinic pathway, similar to the nicotinic drug 4R. This information leads to a better understanding of memantine's mechanisms of action and explains its dose-dependent effectiveness in Alzheimer's and other neurological disorders.
Topics: Hippocampus; Memantine; N-Methylaspartate; Neuroprotection; Neuroprotective Agents; Nicotine; Phosphatidylinositol 3-Kinases; Receptors, N-Methyl-D-Aspartate
PubMed: 35944748
DOI: 10.1016/j.tiv.2022.105453 -
Annals of Internal Medicine Mar 2008The effectiveness of the 5 U.S. Food and Drug Administration-approved pharmacologic therapies for dementias in achieving clinically relevant improvements is unclear. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The effectiveness of the 5 U.S. Food and Drug Administration-approved pharmacologic therapies for dementias in achieving clinically relevant improvements is unclear.
PURPOSE
To review the evidence for the effectiveness of cholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and the neuropeptide-modifying agent memantine in achieving clinically relevant improvements, primarily in cognition, global function, behavior, and quality of life, for patients with dementia.
DATA SOURCES
Cochrane Central Register of Controlled Trials, MEDLINE, PREMEDLINE, EMBASE, Allied and Complementary Medicine Database, CINAHL, AgeLine, and PsycINFO from January 1986 through November 2006.
STUDY SELECTION
English-language randomized, controlled trials were included in the review if they evaluated pharmacologic agents for adults with a diagnosis of dementia, did not use a crossover design, and had a quality score of at least 3 on the Jadad scale.
DATA EXTRACTION
Data were extracted on study characteristics and outcomes, including adverse events. Effect sizes were calculated and data were combined when appropriate.
DATA SYNTHESIS
96 publications representing 59 unique studies were eligible for this review. Both cholinesterase inhibitors and memantine had consistent effects in the domains of cognition and global assessment, but summary estimates showed small effect sizes. Outcomes in the domains of behavior and quality of life were evaluated less frequently and showed less consistent effects. Most studies were of short duration (6 months), which limited their ability to detect delay in onset or progression of dementia. Three studies directly compared different cholinesterase inhibitors and found no differences in cognition and behavior.
LIMITATIONS
Limitations of available studies included short duration, inclusion of only patients with mild to moderate Alzheimer disease, poor reporting of adverse events, lack of clear definitions for statistical significance, limited evaluation of behavior and quality-of-life outcomes, and limited direct comparison of different treatments.
CONCLUSIONS
Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia.
Topics: Activities of Daily Living; Affect; Cholinesterase Inhibitors; Cognition; Dementia; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Humans; Indans; Memantine; Phenylcarbamates; Piperidines; Quality of Life; Rivastigmine; Tacrine
PubMed: 18316756
DOI: 10.7326/0003-4819-148-5-200803040-00009 -
Dementia and Geriatric Cognitive... 2018Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly used in the management of dementia. In routine clinical practice, dementia is often monitored via the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly used in the management of dementia. In routine clinical practice, dementia is often monitored via the Mini-Mental State Examination (MMSE). We conducted a systematic review and meta-analysis of the effects of these drugs on MMSE scores.
SUMMARY
Eighty trials were identified. Pooled effect estimates were in favour of both AChEIs and memantine at 6 months. Meta-regression indicated that dementia subtype was a moderator of AChEI treatment effect, with the effect of treatment versus control twice as high for patients with Parkinson disease dementia/ dementia with Lewy bodies (2.11 MMSE points at 6 months) as for patients with Alzheimer disease/vascular dementia (0.91 MMSE points at 6 months). Key Messages: AChEIs demonstrate a modest effect versus control on MMSE scores which is moderated by dementia subtype. For memantine the effect is smaller.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cognition; Dementia, Vascular; Dopamine Agents; Humans; Memantine; Treatment Outcome
PubMed: 29734182
DOI: 10.1159/000486546 -
Aggressive Behavior May 2022Rates of childhood trauma are high amongst violent offenders who frequently recidivate. Few clinical options are available to treat excessive and recurring violent...
Rates of childhood trauma are high amongst violent offenders who frequently recidivate. Few clinical options are available to treat excessive and recurring violent aggression associated with childhood trauma. Those that do exist are largely ineffective and often replete with side effects. One promising pharmacological target is the glutamate binding N-methyl- d-aspartate receptor (NMDAR). Clinically available NMDAR antagonists have proven successful in mitigating violent and aggressive behavior associated with a host of psychiatric diseases and have both immediate and long-term effects on nervous system function and behavior. This study examined the impact of three NMDAR antagonists on long-lasting aggression brought on by early-life stress: MK-801, memantine, and ketamine. We find that social isolation early in adolescence followed by acute traumatic stress in the form of noncontingent foot shock (FS) late in adolescence works in tandem to promote long-lasting excessive aggression in mice when measured 1 week later. Systemic injections of MK-801 and memantine 30 min before FS suppressed the long-lasting attack behavior induced by our early life stress induction protocol. Systemic injections of ketamine, on the other hand, significantly enhanced the long-lasting attack behavior when injected before FS. These findings indicate that MK-801, memantine, and ketamine have distinct and opposing effects on early life stress-induced aggression, suggesting these drugs may be mechanistically distinct. This study identifies memantine as a promising pharmacological treatment for aggressive behavior associated with early life stress and demonstrates the need for greater care when using glutamate receptor antagonists to treat aggression.
Topics: Adverse Childhood Experiences; Aggression; Animals; Dizocilpine Maleate; Humans; Ketamine; Memantine; Mice; Receptors, N-Methyl-D-Aspartate
PubMed: 35122262
DOI: 10.1002/ab.22022 -
Basic & Clinical Pharmacology &... Feb 2016Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral,...
Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation.
Topics: Administration, Cutaneous; Administration, Intravenous; Administration, Oral; Alzheimer Disease; Animals; Area Under Curve; Biological Availability; Disease Models, Animal; Dose-Response Relationship, Drug; Half-Life; Memantine; Nootropic Agents; Rats; Transdermal Patch
PubMed: 26310825
DOI: 10.1111/bcpt.12479 -
British Journal of Clinical Pharmacology Apr 2012
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Drug Design; Excitatory Amino Acid Antagonists; Galantamine; Humans; Memantine; Plaque, Amyloid
PubMed: 22409497
DOI: 10.1111/j.1365-2125.2012.04217.x -
Drug Discovery Today Apr 2015For many chronic diseases, translational success using the animal model paradigm has reached an impasse. Using Alzheimer's disease as an example, this review employs a... (Review)
Review
For many chronic diseases, translational success using the animal model paradigm has reached an impasse. Using Alzheimer's disease as an example, this review employs a networks-based method to assess repeatability of outcomes across species, by intervention and mechanism. Over 75% of animal studies reported an improved outcome. Strain background was a significant potential confounder. Five percent of interventions had been tested across animals and humans, or examined across three or more animal models. Positive outcomes across species emerged for donepezil, memantine and exercise. Repeatable positive outcomes in animals were identified for the amyloid hypothesis and three additional mechanisms. This approach supports in silico reduction of positive outcomes bias in animal studies.
Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Data Mining; Databases, Factual; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Exercise Therapy; Humans; Indans; Memantine; Piperidines; Species Specificity; Systems Biology; Systems Integration; Translational Research, Biomedical
PubMed: 25448761
DOI: 10.1016/j.drudis.2014.10.015 -
Clinical Interventions in Aging 2015The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied... (Review)
Review
The use of multi drug regimens among the elderly population has increased tremendously over the last decade although the benefits of medications are always accompanied by potential harm, even when prescribed at recommended doses. The elderly populations are particularly at an increased risk of adverse drug reactions considering comorbidity, poly-therapy, physiological changes affecting the pharmacokinetics and pharmacodynamics of many drugs and, in some cases, poor compliance due to cognitive impairment and/or depression. In this setting, drug-drug interaction may represent a serious and even life-threatening clinical condition. Moreover, the inability to distinguish drug-induced symptoms from a definitive medical diagnosis often results in addition of yet another drug to treat the symptoms, which in turn increases drug-drug interactions. Cognitive enhancers, including acetylcholinesterase inhibitors and memantine, are the most widely prescribed agents for Alzheimer's disease (AD) patients. Behavioral and psychological symptoms of dementia, including psychotic symptoms and behavioral disorders, represent noncognitive disturbances frequently observed in AD patients. Antipsychotic drugs are at high risk of adverse events, even at modest doses, and may interfere with the progression of cognitive impairment and interact with several drugs including anti-arrhythmics and acetylcholinesterase inhibitors. Other medications often used in AD patients are represented by anxiolytic, like benzodiazepine, or antidepressant agents. These agents also might interfere with other concomitant drugs through both pharmacokinetic and pharmacodynamic mechanisms. In this review we focus on the most frequent drug-drug interactions, potentially harmful, in AD patients with behavioral symptoms considering both physiological and pathological changes in AD patients, and potential pharmacodynamic/pharmacokinetic drug interaction mechanisms.
Topics: Aged; Alzheimer Disease; Anti-Arrhythmia Agents; Antidepressive Agents; Antipsychotic Agents; Benzodiazepines; Cholinesterase Inhibitors; Drug Interactions; Excitatory Amino Acid Antagonists; Humans; Memantine
PubMed: 26392756
DOI: 10.2147/CIA.S87466 -
The American Journal of Managed Care Nov 2011Every 69 seconds, a person in the United States develops Alzheimer's disease (AD). By 2050, this rate is expected to double. Total direct costs of AD and dementia (AD/D)... (Review)
Review
Every 69 seconds, a person in the United States develops Alzheimer's disease (AD). By 2050, this rate is expected to double. Total direct costs of AD and dementia (AD/D) are estimated at $183 billion, and are expected to increase to $1.1 trillion by 2050. In 2010, unpaid care was valued at an estimated $202 billion. Caregivers of patients with AD are usually family members, and provide up to 70 hours of care per week. By delaying institutionalization of an AD patient, a savings of $2029 per month in direct healthcare costs could be realized; therefore, caregiver support is a significant factor in controlling costs. It is important for those with AD/D to have prescription plans that optimize access to AD/D therapies. Among older adults who previously did not have prescription coverage, 80% are now enrolled in Medicare Part D. Three preferred AD/D agents (donepezil, extended release galantamine hydrochloride, and memantine hydrochloride) have been identified by an expert panel. It is important, given the clinical course of AD, especially with progression to moderate-to-severe disease, that physicians continue to have access to preferred medications as demonstrated through evidence-based clinical evaluations. Many Medicare Part D beneficiaries are subject to a gap in prescription coverage known as the "donut hole," including 64% of patients with AD. Because of the increased out-of-pocket expenditures associated with this coverage gap, some patients stop taking their medication completely or reduce medication use. It is critical to avoid lapses in maintenance therapy, as functional and cognitive abilities cannot be regained. Numerous clinical trials have demonstrated the pharmacoeconomic benefits of appropriate and preferred AD therapies; greater therapeutic availability may lead to better adherence and therefore improved outcomes.
Topics: Age Factors; Aging; Alzheimer Disease; Cholinesterase Inhibitors; Disease Progression; Donepezil; Galantamine; Health Care Costs; Health Expenditures; Humans; Indans; Medicare; Medicare Part D; Memantine; Piperidines; Psychometrics; United States
PubMed: 22214393
DOI: No ID Found