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Current Opinion in Pharmacology Feb 2015The clinical benefits of the glutamate receptor antagonists memantine and ketamine have helped sustain optimism that glutamate receptors represent viable targets for... (Comparative Study)
Comparative Study Review
The clinical benefits of the glutamate receptor antagonists memantine and ketamine have helped sustain optimism that glutamate receptors represent viable targets for development of therapeutic drugs. Both memantine and ketamine antagonize N-methyl-D-aspartate receptors (NMDARs), a glutamate receptor subfamily, by blocking the receptor-associated ion channel. Although many of the basic characteristics of NMDAR inhibition by memantine and ketamine appear similar, their effects on humans and to a lesser extent on rodents are strongly divergent. Some recent research suggests that preferential inhibition by memantine and ketamine of distinct NMDAR subpopulations may contribute to the drugs' differential clinical effects. Here we review studies that shed light on possible explanations for differences between the effects of memantine and ketamine.
Topics: Animals; Drug Design; Excitatory Amino Acid Antagonists; Humans; Ketamine; Memantine; Molecular Targeted Therapy; Receptors, N-Methyl-D-Aspartate
PubMed: 25462293
DOI: 10.1016/j.coph.2014.11.006 -
Medicine Apr 2024Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial.
OBJECTIVE
The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis.
METHODS
We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results.
RESULTS
All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs.
CONCLUSION
ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.
Topics: Humans; Alzheimer Disease; Donepezil; Galantamine; Memantine; Molecular Docking Simulation; Cholinesterase Inhibitors; Rivastigmine
PubMed: 38640313
DOI: 10.1097/MD.0000000000037799 -
PloS One 2015We performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer's disease (AD). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer's disease (AD).
METHODS
The meta-analysis included randomized controlled trials of memantine monotherapy for AD, omitting those in which patients were also administered a cholinesterase inhibitor. Cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects were compared between memantine monotherapy and placebo groups. The primary outcomes were cognitive function and behavioral disturbances; the others were secondary outcomes.
RESULTS
Nine studies including 2433 patients that met the study's inclusion criteria were identified. Memantine monotherapy significantly improved cognitive function [standardized mean difference (SMD)=-0.27, 95% confidence interval (CI)=-0.39 to -0.14, p=0.0001], behavioral disturbances (SMD=-0.12, 95% CI=-0.22 to -0.01, p=0.03), activities of daily living (SMD=-0.09, 95% CI=-0.19 to -0.00, p=0.05), global function assessment (SMD=-0.18, 95% CI=-0.27 to -0.09, p=0.0001), and stage of dementia (SMD=-0.23, 95% CI=-0.33 to -0.12, p=0.0001) scores. Memantine was superior to placebo in terms of discontinuation because of inefficacy [risk ratio (RR)=0.36, 95% CI=0.17¬ to 0.74, p=0.006, number needed to harm (NNH)=non significant]. Moreover, memantine was associated with less agitation compared with placebo (RR=0.68, 95% CI=0.49 to 0.94, p=0.02, NNH=non significant). There were no significant differences in the rate of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups.
CONCLUSIONS
Memantine monotherapy improved cognition, behavior, activities of daily living, global function, and stage of dementia and was well-tolerated by AD patients. However, the effect size in terms of efficacy outcomes was small and thus there is limited evidence of clinical benefit.
Topics: Activities of Daily Living; Alzheimer Disease; Humans; Memantine; Publication Bias; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 25860130
DOI: 10.1371/journal.pone.0123289 -
Bioengineered Mar 2022Oxaliplatin is an effective chemotherapeutic agent for the treatment of malignant tumors. However, severe oxaliplatin-induced neurotoxicity has been well documented....
Oxaliplatin is an effective chemotherapeutic agent for the treatment of malignant tumors. However, severe oxaliplatin-induced neurotoxicity has been well documented. Memantine is a drug for the management of Alzheimer's Disease (AD) due to its promising neuroprotective properties. We hypothesize that Memantine possesses a beneficial role against chemotherapy-induced neuronal damages. In this study, we established an oxaliplatin-induced neurotoxicity assay model in human SHSY-5Y neuronal cells and investigated the protective effect of Memantine. We showed that Memantine treatment ameliorated oxaliplatin-elevated intracellular production of reactive oxygen species (ROS), lipid product malondialdehyde (MDA), and NOX-2 expression. Memantine alleviated impairment of the mitochondrial membrane potential and ATP production by oxaliplatin. As a result, Memantine showed a protective role against oxaliplatin-induced cytotoxicity. Moreover, the terminal deoxynucleotidyl Transferase-mediated dUTP nick end labeling (TUNEL) apoptosis assay revealed that Memantine protected oxaliplatin-induced apoptosis through mitigating the ratio of Bax/Bcl-2 and Caspase-3 cleavage. We concluded Memantine ameliorated the neurotoxicity of oxaliplatin in a mitochondrial-dependent pathway.
Topics: Apoptosis; Humans; Memantine; Membrane Potential, Mitochondrial; Mitochondria; Oxaliplatin; Oxidative Stress; Reactive Oxygen Species
PubMed: 35235756
DOI: 10.1080/21655979.2022.2026553 -
Journal of Affective Disorders Jun 2016Acetylcholinesterase inhibitors (AceI) and memantine might prove useful in bipolar disorder (BD) given their neuroprotective and pro-cognitive effects, as highlighted by... (Meta-Analysis)
Meta-Analysis Review
Acetylcholinesterase inhibitors and memantine in bipolar disorder: A systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions.
BACKGROUND
Acetylcholinesterase inhibitors (AceI) and memantine might prove useful in bipolar disorder (BD) given their neuroprotective and pro-cognitive effects, as highlighted by several case reports. We aimed to systematically review the efficacy and safety of AceI and memantine across multiple outcome dimensions in BD.
METHODS
Systematic PubMed and SCOPUS search until 04/17/2015 without language restrictions. Included were randomized controlled trials (RCTs), open label studies and case series of AceI or memantine in BD patients reporting quantitative data on depression, mania, psychotic symptoms, global functioning, or cognitive performance. We summarized results using a best-evidence based synthesis.
RESULTS
Out of 214 hits, 12 studies (RCTs=5, other designs=7, total n=422) were included. Donepezil (studies=5; treated=102 vs. placebo=21): there was strong evidence for no effect on mania and psychotic symptoms; low evidence indicating no effect on depression. Galantamine (studies=3; treated=21 vs. controls=20) (placebo=10, healthy subjects=10): there was strong evidence for no effect on mania; moderate evidence for no effect on depression; low evidence for no effect on global functioning. Memantine (studies=4; treated=152 vs. placebo=88): there was conflicting evidence regarding efficacy for mania, depression and global functioning.
LIMITATIONS
Paucity of RCTs; small sample size studies; heterogeneous design, outcome and patient characteristics.
CONCLUSION
There is limited but converging evidence of no effect of AceI in BD, and conflicting evidence about memantine in BD. Too few studies of mostly medium/low quality and lacking sufficient numbers of patients in specific mood states, especially mania, contributed data, focusing solely on short-term/medium-term treatment, necessitating additional high-quality research to yield more definite results.
Topics: Adult; Bipolar Disorder; Case-Control Studies; Cholinesterase Inhibitors; Clinical Trials as Topic; Depression; Depressive Disorder; Donepezil; Evidence-Based Medicine; Excitatory Amino Acid Antagonists; Female; Galantamine; Humans; Indans; Male; Memantine; Middle Aged; Piperidines; Psychotic Disorders; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 27010579
DOI: 10.1016/j.jad.2016.03.034 -
Molecular Neurodegeneration Jul 2023Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant... (Review)
Review
Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a "gatekeeper" role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke.
Topics: Animals; Receptors, N-Methyl-D-Aspartate; Alzheimer Disease; Ischemic Stroke; Memantine; Stroke
PubMed: 37400870
DOI: 10.1186/s13024-023-00636-1 -
Drug Design, Development and Therapy 2016Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the -methyl-D-aspartate... (Review)
Review
Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the -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.
Topics: Adolescent; Adult; Alzheimer Disease; Biological Availability; Cholinesterase Inhibitors; Cognition; Delayed-Action Preparations; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Male; Memantine; Middle Aged; Nootropic Agents; Piperidines; Severity of Illness Index; Young Adult
PubMed: 27757016
DOI: 10.2147/DDDT.S86463 -
Turkish Journal of Medical Sciences Jun 2022Cancer cells express higher levels of N-methyl-d-aspartate (NMDA) receptor. In this study, we aimed to use memantine as a potential blocker to inhibit the action of the...
BACKGROUND
Cancer cells express higher levels of N-methyl-d-aspartate (NMDA) receptor. In this study, we aimed to use memantine as a potential blocker to inhibit the action of the NMDA receptor in cancer cells in vivo in order to investigate the potential chemopreventive effect of memantine in 4T1 tumor-bearing mice.
METHODS
To determine the potential chemopreventive effect of the compound, mice weights, tumor volumes, spleen IL-6, and tumor DNA methylation levels were investigated. A total of 26 Balb/c female mice were allocated into three groups. G1 (n = 6): tumor control group, G2 (n = 10): low dose (5mg/kg) memantine group, G3: high dose (10 mg/kg) memantine group (n = 10). G1 was inoculated with 4T1 cells without any memantine treatment. G2 and G3 were pretreated with 5 and 10 mg/kg memantine daily intraperitoneal (ip) injection (weekend off) for 10 days, respectively. Both G2 and G3 were subdivided into two groups as G2a (n = 4) and G3a (n = 4): tumor free groups and G2b (n = 6) and G3b (n = 6) tumor bearing groups.
RESULTS
Our results revealed that G3: high dose (10 mg/kg) memantine group, significantly (p = 0.0248) reduced the tumor volumes. We found that spleen IL-6 levels were significantly higher in memantine pretreated tumor free group p = 0.0204 ) We also found that high dose memantine treated tumor free group (G3a) has significantly lower genome-wide DNA methylation levels when compared to tumor control group (G1) p = 0.0012.
DISCUSSION
To the best of our knowledge, it is the first study that highlights a potential chemopreventive effect of memantine in vivo in the mouse 4T1 breast tumor model. But further investigations should be carried out to explore the chemopreventive mechanism of action for memantine in cancer.
Topics: Animals; Female; Mice; Memantine; Interleukin-6; Mice, Inbred BALB C; Disease Models, Animal; Injections, Intraperitoneal
PubMed: 36326318
DOI: 10.55730/1300-0144.5381 -
BMC Neurology Oct 2013Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae... (Review)
Review
Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction.
Topics: Antineoplastic Agents; Central Nervous System Stimulants; Cholinesterase Inhibitors; Clinical Trials as Topic; Cognition Disorders; Donepezil; Humans; Indans; Memantine; Neoplasms; Piperidines
PubMed: 24156319
DOI: 10.1186/1471-2377-13-153 -
Schizophrenia Research Aug 2014The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were... (Review)
Review
The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia projects were designed to facilitate the development of new drugs for the treatment of cognitive impairments in people with schizophrenia. The MATRICS project identified three drug mechanisms of particular interest: dopaminergic, cholinergic, and glutamatergic. As a group, while people with schizophrenia have moderate cognitive impairment, it is the best predictor of long-term outcome. Unfortunately, there are no approved medications for cognitive impairment in this population. Hence, the development of new pharmacological approaches is critical for reducing illness-related disability. The combination of an acetylcholinesterase inhibitor (AChEI) and memantine is more effective than either medication alone to improve cognition in Alzheimer's dementia. Galantamine is not only an AChEI, but also a positive allosteric modulator of the α4β2 and α7 nicotinic receptors. Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathophysiology of cognitive symptoms in schizophrenia and hence memantine may positively impact cognition. Memantine decreases the tonic NMDA current and galantamine enhances the action potential mediated by a postsynaptic NMDA current. This results in an increased signal transmission; therefore, a greater signal-to-noise ratio occurs with the combination than memantine alone. Galantamine improves the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA)-mediated signaling which could be neuroprotective and may improve memory coding. The combination of galantamine and memantine may be particularly effective in schizophrenia in order to increase the selective cognition enhancement produced by either medication alone. In the future, multitarget-directed ligands may play a role in the treatment of complex diseases like schizophrenia.
Topics: Animals; Cognition Disorders; Drug Therapy, Combination; Galantamine; Humans; Memantine; Nootropic Agents; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 24878431
DOI: 10.1016/j.schres.2014.04.037