Update on the use of memantine in Alzheimer&amp;rsquo;s disease

Marum, Rob J. van

doi:10.2147/ndt.s4048

Cited by 101 publications

(72 citation statements)

References 56 publications

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“…Memantine is a noncompetitive NMDA receptor antagonist and has been shown to have mild clinically relevant effects in moderate-to-severe AD (35). Riluzole inhibits the release of glutamate and also blocks some of the postsynaptic effects of glutamate (36).…”

Section: Discussionmentioning

confidence: 99%

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Kong¹,

Chang²,

Takahashi³

et al. 2014

J. Clin. Invest.

125

136

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Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box-binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Kong¹,

Chang²,

Takahashi³

et al. 2014

J. Clin. Invest.

125

136

View full text Add to dashboard Cite

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“…The C max at steady state of memantine ER in plasma was 127.1 ± 21.1 ng/mL which is approximately 3 to 4 times the C max reported for memantine 20 mg (22 to 46 ng/mL). 16,18 However, there was no direct relationship between the increased C max in the memantine ER study and increased adverse events. 16 …”

Section: Pharmacokinetic Profile Of Memantine Ir Vs Memantine Ermentioning

confidence: 94%

Critical appraisal and role of memantine extended-release in the management of Alzheimer’s disease

Singh¹,

Grossberg²

2011

DNND

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Alzheimer's disease (AD) is a progressive, degenerative brain disease. Currently available US FDA-approved pharmacological management options for AD are cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate receptor antagonist (memantine). These treatment options may provide symptomatic benefits. Medication adherence is one of the many problems faced by the caregivers of patients with dementia. The currently available FDA-approved memantine immediate-release (IR) has been found safe and efficacious at a dose of 10 mg twice daily (20 mg/day) both as monotherapy and in combination with cholinesterase inhibitors in moderate to severe dementia. Memantine extended-release (ER) 28 mg, a new once-daily form at a higher dose, has also been found to be safe and well tolerated in 2 studies: one in 24 healthy volunteers which showed relatively minor fluctuation in plasma levels of memantine during the steady-state dosing interval and second, a multinational multi-center study, comparing memantine ER 28 mg and placebo in patients with moderate to severe AD stable on concurrent cholinesterase inhibitor (ChEI). In this study, memantine ER was found to be an efficacious drug with a good safety and tolerability profile. Both memantine IR 20 mg and memantine ER 28 mg are now FDA-approved for the treatment of moderate to severe AD, either alone, or in combination with a ChEI. Both are efficacious, safe, and well tolerated. Medication adherence with the ER preparation should improve because of once-daily dosing. There is a possibility of superior efficacy of the higher dose memantine ER (28 mg) over the currently approved dosage of memantine IR (20 mg). However, further randomized, controlled, double-blind comparator studies of memantine ER 28 mg vs memantine IR 20 mg and/or 30 mg in single and/or divided doses are required to assess the possible benefits of memantine ER over memantine IR.

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“…Long-term studies show good tolerability of memantine with an acceptable side-effect profile [41]. It must be concluded that memantine is a relatively safe drug with few side effects and neglectable risk of drug-drug interactions, but adverse drug reactions (ADRs) of memantine (Stop using memantine serious side effects: cough, chest tightness, fever, trouble breathing; chest pain, fast heart rate; confusion, hallucinations; sudden numbness or weakness, especially on one side of the body; lack of coordination; fainting or seizure (convulsions); urinating less than usual or not at) are found in clinical trials in mild to severe dementia [42]. The effectiveness and side effects of memantine might be determined by the hepatic clearance of caffeine or various drugs.…”

Section: Long-term Effects Of Combined Treatment With Memantine and Dmentioning

confidence: 99%

Long-Term Effects Of Combined Treatment With Memantine And Donepezil On Alzheimer's Disease Patients: 72-Week Study

Wake¹,

Araki²,

Miyaoka³

et al. 2018

Neuropsychiatry

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Objective: In this study, we evaluated the long-term effects of memantine on cognitive function, BPSD, and the care burden in patients with moderate to severe Alzheimer's disease (AD) for 72 weeks. Further, we examined the association between the long-term effects of memantine and brain blood flow using near-infrared spectroscopy (NIRS). Methods:We evaluated the effects of memantine administration from baseline using the Clinical Global Impression -Improvement scale (CGI-I) , Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI), and NIRS on two groups; a combined donepezil and memantine administration group (combination group, n=19), and donepezil only administration group (control group, n=18) were assessed at weeks 0, 4, 12, 24, 48 and 72.Results: A significant difference was found between the combination group and the control group in the scores of CGI-I after 4 weeks, CDT after 24 weeks, and NPI and J-ZBI after 12 weeks. A significant correlation was observed between the irritability subscore of NPI and total score of J-ZBI. In the NIRS measurements, there was no significant interaction in total value of OxyHb integral from of all channels at the 72nd week, although oxyhemoglobin suppression was observed in CH5, CH7, and CH8 at 12th and 24th week. Conclusions:In this study, long-term administration of memantine to AD patients improved clinical symptoms overall, cognitive function, and BPSD, thereby reducing the burden of caregivers and inhibited transiently the reduction of cerebral blood flow in the prefrontal area.

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Update on the use of memantine in Alzheimer’s disease

Cited by 101 publications

References 56 publications

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Critical appraisal and role of memantine extended-release in the management of Alzheimer’s disease

Long-Term Effects Of Combined Treatment With Memantine And Donepezil On Alzheimer's Disease Patients: 72-Week Study

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Update on the use of memantine in Alzheimer&rsquo;s disease

Cited by 101 publications

References 56 publications

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection

Critical appraisal and role of memantine extended-release in the management of Alzheimer&rsquo;s disease

Long-Term Effects Of Combined Treatment With Memantine And Donepezil On Alzheimer's Disease Patients: 72-Week Study

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Product

Resources

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Update on the use of memantine in Alzheimer’s disease

Critical appraisal and role of memantine extended-release in the management of Alzheimer’s disease