Molecular structure of memantine
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Memantine

Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system. Memantine was developed by Merz and licensed to Forest for the U.S. and Lundbeck for selected European and international markets. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest and Ebixa by Lundbeck. more...

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Pharmacology

NMDA receptor

A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is involved in the aetiology of Alzheimer's disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system. (Cacabelos et al., 1999)

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions which forms the basis of neuronal excitotoxicity. The low-affinity of memantine, however, preserves the physiological function of the receptor as it can still be activated by the relatively high concentrations of glutamate released following depolarisation of the presynaptic neuron.

5-HT3

Memantine acts as an uncompetitive antagonist at the 5HT3 receptor, with a potency similar to that for the NMDA receptor. (Rammes et al., 2001) The clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown.

Clinical use

Indications

Memantine is indicated for the treatment of the symptoms of moderate to severe Alzheimer's disease. (Joint Formulary Committee, 2004; Rossi, 2006)

Memantine has been associated with a moderate decrease in clinical deterioration in Alzheimer's disease. (Rossi, 2006) A systematic review of randomised controlled trials found that memantine has a small positive effect on cognition, mood, behaviour, and the ability to perform daily activities in moderate to severe Alzheimer's disease, but an unknown effect in mild to moderate disease. (Areosa et al., 2005)

Memantine is also being tested for depression, glaucoma, and neuropathic pain.

Adverse drug reactions

Memantine is generally well-tolerated. (Areosa et al., 2005) Common adverse drug reactions (ADRs) include: confusion, dizziness, drowsiness, headache, insomnia, agitation, and hallucinations. (Rossi, 2006) Less common ADRs include: vomiting, anxiety, hypertonia, cystitis, and increased libido. (Joint Formulary Committee, 2004)

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Memantine for treatment of Alzheimer's disease
From American Family Physician, 9/1/04 by Caroline Wellbery

Memantine was recently approved by the U.S. Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. It is the first drug in a new class called N-methyl-aspartate (NMDA) receptor antagonist. Tariot and colleagues assessed the clinical efficacy, safety, and tolerability of memantine in patients on a stable regimen of donepezil therapy.

In this double-blinded, multicenter trial, 203 participants with moderate to severe Alzheimer's disease were randomized to receive treatment with memantine for 24 weeks, following a one- or two-week single-blinded lead-in period, and 201 received placebo. All patients had been taking a stable dosage of donepezil for at least six months at entry and were required to continue this baseline drug for the duration of the trial.

Outcome measures included cognition, function, and global performance, as measured by the Severe Impairment Battery (SIB) and a modified AD Cooperative Study--Activities of Daily Living Inventory (ADCS--ADL). Secondary outcome measures included performance on additional rating scales: the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), the Neuropsychiatric Inventory (NPI), and the Behavioral Rating Scale for Geriatric Patients (BGP).

Significantly more patients completed the memantine arm of the study than the placebo arm. There was a statistically significant improvement in patients taking memantine in both primary outcomes. The mean CIBIC-Plus score was significantly better in the memantine group, and 55 per-cent of the patients taking memantine were rated as improved or unchanged compared with 45 percent of the placebo group. There were fewer behavioral disturbances and psychiatric symptoms, as measured by the NPI score, in the patients taking memantine. In addition, the BGP dependency subscale was significantly improved with memantine use. More participants in the placebo group discontinued therapy because of adverse effects. The adverse effect most often associated with discontinuation was confusion.

The authors conclude that the efficacy of memantine is significantly better than that of placebo in the treatment of moderate to severe Alzheimer's disease in patients taking stable dosages of donepezil, as measured by cognitive function, activities of daily living, behavior, and clinical global status.

Tariot PN, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil. A randomized controlled trial. JAMA January 21, 2004;291:317-24.

EDITOR'S NOTE: Memantine can be an expensive option. A recent review found that memantine, in dosages of 20 mg per day, had beneficial effects on cognition and function but not on clinical impression of change when compared with placebo. (1) The clinical impression of change is considered an essential adjunct to basic cognitive and functional scales. However, because most of the health care costs of Alzheimer's disease relate to advanced disease, memantine may be cost-effective even if the absolute clinical benefits are small. (2)--C.W.

REFERENCES

(1.) Areosa Sastre A, Sherriff F. Memantine for dementia. Cochrane Database Syst Rev 2004;3:CD003154.

(2.) Wilcock GK. Memantine for the treatment of dementia. Lancet Neurol 2003;2:503-5.

COPYRIGHT 2004 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group

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