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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 -
Journal of Separation Science Feb 2011In this study, we investigated a simple, sensitive and reliable liquid chromatography-fluorescence detection method for the determination of memantine hydrochloride in...
In this study, we investigated a simple, sensitive and reliable liquid chromatography-fluorescence detection method for the determination of memantine hydrochloride in rat plasma which was based on derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl). For the first time, FMOC-Cl was introduced into derivatization of memantine hydrochloride in rat plasma. The amino groups of memantine hydrochloride and amantadine hydrochloride (internal standard) were trapped with FMOC-Cl to form memantine hydrochloride-FMOC-Cl and amantadine hydrochloride-FMOC-Cl compositions, which can be very compatible for LC-FLD. Precipitation of plasma proteins by acetonitrile was followed by vortex mixing and centrifugation. Chromatographic separation was performed on a C(18) column (DIAMONSIL 150 × 4.6 mm, id 5 μm) with a mobile phase consisting of acetonitrile and water at a flow rate of 1.0 mL/min. The retention times of memantine hydrochloride-FMOC-Cl and amantadine hydrochloride-FMOC-Cl compositions were 23.69 and 40.27 min, respectively. Optimal conditions for the derivatization of memantine hydrochloride were also described. The limit of quantification (LOQ) was 25 ng/mL for memantine hydrochloride in plasma, the linear range was 0.025-5.0 μg/mL in plasma with a correlation coefficient (r) of 0.9999. The relative standard deviations (RSDs) of intra-day and inter-day assays were 4.46-12.19 and 5.23-11.50%, respectively. The validated method was successfully applied to the determination of memantine hydrochloride in rat plasma samples.
Topics: Alzheimer Disease; Animals; Chromatography, High Pressure Liquid; Dopamine Agents; Fluorenes; Humans; Memantine; Rats; Rats, Wistar
PubMed: 21268245
DOI: 10.1002/jssc.201000579 -
Expert Opinion on Drug Safety Jan 2009Memantine is an uncompetitive antagonist of the N-methyl-D-aspartate glutamate receptor. It is now approved only for treatment of moderate-to-severe Alzheimer's disease... (Review)
Review
BACKGROUND
Memantine is an uncompetitive antagonist of the N-methyl-D-aspartate glutamate receptor. It is now approved only for treatment of moderate-to-severe Alzheimer's disease (AD). However, as a growing body of evidence indicates that disturbed glutamate neurotransmission may be central to the pathophysiology of such conditions as obesity, schizophrenia, depression, substance abuse, pain disorders and glaucoma, clinical trials have explored the role of memantine in these and other disorders.
OBJECTIVE
To provide a comprehensive review of the safety and efficacy of memantine across the range of clinical applications in which it has been studied.
METHODS
A search was done on Pubmed using keyword 'memantine' to identify clinical trials of memantine.
RESULTS/CONCLUSION
At present, clinical trial evidence supports the use of memantine in only moderate-to-severe AD. Preliminary studies suggest benefit in frontotemporal dementia, alcohol dependence, post-traumatic stress disorder, headache and obesity, but rigorous clinical trials are needed to confirm these results. Available data indicate that across a range of clinical applications, memantine is a safe and well-tolerated drug.
Topics: Anti-Obesity Agents; Cholinesterase Inhibitors; Clinical Trials as Topic; Humans; Memantine; Psychotropic Drugs; Receptors, N-Methyl-D-Aspartate; Substance-Related Disorders
PubMed: 19236221
DOI: 10.1517/14740330802528420 -
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 -
Journal of Attention Disorders Feb 2017To evaluate the efficacy and safety of memantine hydrochloride as an adjunct to stimulant pharmacotherapy for treating executive function deficits (EFDs) in adults with... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
To evaluate the efficacy and safety of memantine hydrochloride as an adjunct to stimulant pharmacotherapy for treating executive function deficits (EFDs) in adults with ADHD.
METHOD
This was a 12-week, double-blind, placebo-controlled, randomized clinical trial of memantine added to open-label treatment with stimulant medication. Because of the small sample size, we considered a standardized mean difference (equivalent to effect size) of ≥0.5 and odds ratios ≥2 as indicators of trend improvements.
RESULTS
Twelve participants received memantine and 14 received a placebo. Trend improvements favoring memantine were observed on Behavior Rating Inventory of Executive Functions-Adult Inhibition and Self-Monitor subscales when compared with Placebo. No significant changes were noted on the Cambridge Neuropsychological Test Automated Battery.
CONCLUSION
Among adults with ADHD and EFDs, adjunct treatment with memantine to osmotic release oral system-methylphenidate (OROS-MPH) was associated with improvements in selective areas of executive functioning, supporting the need for further research.
Topics: Administration, Oral; Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Delayed-Action Preparations; Double-Blind Method; Drug Therapy, Combination; Executive Function; Female; Humans; Male; Memantine; Methylphenidate; Middle Aged; Osmosis; Pilot Projects; Treatment Outcome; Young Adult
PubMed: 24970718
DOI: 10.1177/1087054714538656 -
Expert Opinion on Pharmacotherapy Feb 2007Memantine is the first and only medication that has been approved by European, US and Canadian regulatory agencies for the treatment of moderate-to-severe Alzheimer's... (Review)
Review
Memantine is the first and only medication that has been approved by European, US and Canadian regulatory agencies for the treatment of moderate-to-severe Alzheimer's disease (AD). It is an NMDA receptor antagonist that works to prevent excitotoxicity and cell death, which are mediated by the excessive influx of calcium during a sustained release of glutamate. Preclinical studies of memantine reveal that it has the potential to improve memory and learning processes after impairment has occurred, as well as to prevent further neuronal damage. Although memantine has been considered for the treatment of earlier AD, it has not yet been approved for this. Randomized controlled trials of memantine in the treatment of mild-to-moderate AD have demonstrated small treatment effects in measures of cognition, global assessment and behavior favoring the use of memantine. However, the differences between treatment groups were not consistently significant. Two ongoing long-term trials are further investigating the efficacy of memantine in the treatment of mild-to-moderate AD.
Topics: Aged; Alzheimer Disease; Calcium; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Humans; Memantine; Receptors, N-Methyl-D-Aspartate
PubMed: 17257090
DOI: 10.1517/14656566.8.2.203 -
Nature Chemical Biology Nov 2023
Topics: Humans; Memantine; HEK293 Cells; Receptors, N-Methyl-D-Aspartate
PubMed: 37798356
DOI: 10.1038/s41589-023-01423-1 -
Journal of Analytical Toxicology May 2007Postmortem fluid and tissue concentrations of memantine (Namenda), a drug recently approved for the treatment of Alzheimer's Disease by the FDA, are reported in a...
Postmortem fluid and tissue concentrations of memantine (Namenda), a drug recently approved for the treatment of Alzheimer's Disease by the FDA, are reported in a suspicious death. In addition, memantine concentrations considered to be incidental findings in three other cases are included to aid in the interpretation in future toxicological investigations. Memantine was extracted from biological samples by a standard liquid-liquid basic drug method followed by analysis utilizing a gas chromatograph-mass spectrometer operated in SIM mode. Blood concentrations ranged from 0.03 to 1.8 mg/L, and the liver concentration was 6.1 mg/kg.
Topics: Alzheimer Disease; Cause of Death; Drug Overdose; Excitatory Amino Acid Antagonists; Forensic Toxicology; Gas Chromatography-Mass Spectrometry; Humans; Liver; Male; Memantine; Middle Aged; Vitreous Body
PubMed: 17555649
DOI: 10.1093/jat/31.4.233 -
Drugs of Today (Barcelona, Spain : 1998) Apr 2016Donepezil (and other cholinesterase inhibitors [ChEIs]) and memantine are the mainstays of treatment in Alzheimer's dementia, addressing respectively, the cholinergic... (Review)
Review
Donepezil (and other cholinesterase inhibitors [ChEIs]) and memantine are the mainstays of treatment in Alzheimer's dementia, addressing respectively, the cholinergic and glutamatergic dysregulation which underlies or results from its pathophysiology. To alleviate the pill burden and swallowing difficulties associated with the condition, a fixed drug combination of extended-release memantine and donepezil was developed. This combination was shown to be both bioequivalent to the components administered separately and could be administered sprinkled over soft food. The mode of action, pharmacokinetics, clinical efficacy and safety and tolerability of the combination are discussed together with the wider, often conflicting trial literature of combination versus monotherapy with memantine and ChEIs, their meta-analyses and treatment guidelines.
Topics: Alzheimer Disease; Donepezil; Drug Therapy, Combination; Humans; Indans; Memantine; Piperidines; Practice Guidelines as Topic
PubMed: 27252988
DOI: 10.1358/dot.2016.52.4.2479357 -
Expert Opinion on Pharmacotherapy Oct 2018Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide and carries an immense societal burden. Unfortunately, no curative or disease-modifying... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide and carries an immense societal burden. Unfortunately, no curative or disease-modifying treatment has yet been discovered. The currently approved medications are symptomatic. They include two classes: the cholinesterase inhibitors, such as donepezil, and the NMDA receptor antagonist memantine. Most evidence has shown that combining both classes is superior to monotherapy but may complicate the treatment regimen for patients and families. Namzaric®, a fixed dose combination of donepezil and memantine extended-release (ER) (FDC memantine ER/donepezil), was recently approved by the U.S. Food and Drug Administration (FDA) for patients with moderate to severe AD and warrants further consideration as a clinically useful and advantageous pharmacotherapy in AD. Areas covered: This review discusses the pharmacological properties, efficacy, and safety/tolerability data of this FDC memantine ER/donepezil as well as its benefits and disadvantages for patients and families. A literature search using PubMed was conducted using Namzaric, donepezil, memantine, AD, and medication adherence as keywords. Expert opinion: Aside from its cost, FDC memantine ER/donepezil improves adherence to medication and reduces caregiver burden. It allows patients to benefit from combination therapy as the disease progresses, especially in those with dysphagia, poor adherence and limited caregiver support.
Topics: Alzheimer Disease; Antiparkinson Agents; Cholinesterase Inhibitors; Donepezil; Drug Therapy, Combination; Humans; Memantine
PubMed: 30244611
DOI: 10.1080/14656566.2018.1519022