|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||B2 (AU) B (US)|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Mol. mass||179.3 g/mol|
|(what is this?)|
Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system by blocking NMDA receptors. It was first synthesized by Eli Lilly and Company in 1968. Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm. Memantine has been shown to have a modest effect in moderate-to-severe Alzheimer's disease and in dementia with Lewy bodies. Despite years of research, there is little evidence of effect on mild Alzheimer's disease.
- 1 Medical use
- 2 Adverse effects
- 3 Biochemistry
- 4 Pharmacology
- 5 Availability
- 6 History
- 7 Research
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
Memantine is approved by the U.S. F.D.A and the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease, and has now received a limited recommendation by the UK's National Institute for Health and Care Excellence for patients who fail other treatment options. Within the new guidance memantine is recommended as an option for managing Alzheimer’s disease for people with: moderate Alzheimer’s disease who are intolerant of or have a contraindication to AChE (acetylcholinesterase) inhibitors or those with severe Alzheimer’s disease.
Memantine has been associated with a moderate decrease in clinical deterioration with only a small positive effect on cognition, mood, behavior, and the ability to perform daily activities in moderate to severe Alzheimer's disease. There does not appear to be any benefit in mild disease.
Memantine is, in general, well-tolerated. Common adverse drug reactions (≥1% of patients) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido. It has been reported to induce reversible neurological impairment in multiple sclerosis patients, which led to the halt of an ongoing clinical trial. Though exceedingly rare, extrapyramidal side effects (such as dystonic reactions, etc.) may occur, in particular, in the younger population.
Like many other NMDA antagonists, memantine behaves as a dissociative anesthetic at supratherapeutic doses, and has substituted for phencyclidine in rodent and primate drug discrimination studies. Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability.
A recent study demonstrates therapeutically-relevant doses of memantine in the mouse can lead to disruption of cognitive flexibility.
The drug belongs to a class of drugs called NMDA receptor antagonists, which reduce certain types of brain activity by binding to NMDA receptors on brain cells and blocking the activity of the neurotransmitter glutamate. At normal levels, glutamate aids in memory and learning, but if levels are too high, glutamate appears to overstimulate nerve cells, killing them through excitotoxicity.
Glutamatergic (NMDA receptor)
A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology 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.
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, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the presynaptic neuron. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. Moreover, there is no evidence as yet that the ability of memantine to protect against NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's, although this has been suggested in animal models.
Serotonergic (5-HT3 receptor)
Memantine acts as a non-competitive antagonist at the 5-HT3 receptor, with a potency similar to that for the NMDA receptor. The clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown.
Cholinergic (nicotinic acetylcholine receptor)
Memantine acts as a non-competitive antagonist at different neuronal nicotinic acetylcholine receptors (nAChRs) at potencies possibly similar to the NMDA and 5-HT3 receptors, but this is difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in these experiments. It can be noted that memantine is an antagonist at alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment. It has been shown that the number of nicotinic receptors in the brain are reduced in Alzheimer's disease, even in the absence of a general decrease in the number of neurons, and nicotinic receptor agonists are viewed as interesting targets for anti-Alzheimer drugs. Consequently, this may also suggest that administration of nicotine itself may act against the effects of Alzheimer's disease. In fact a recent small double blind placebo controlled randomized trial published in the Journal Neurology demonstrated a significant benefit from use of 15 mg nicotine patches in non-smoking elderly patients with mild cognitive impairment. The small sample sizes suggest that the effect size is substantial due to the limited statistical power inherent in a small N trial. (see : http://www.ncbi.nlm.nih.gov/pubmed/22232050)
Dopaminergic (D2 receptor)
The hydrochloride (Memantine HCl) is white water soluble powder available as capsule-shaped film-coated tablets or oral solution. The tablets are available as 5 mg, 10 mg or 20 mg of memantine hydrochloride. The oral solution contains 2 mg of memantine hydrochloride per ml.
Memantine was first synthesized and patented by Eli Lilly and Company in 1968 (as cited in the Merck Index), and then developed by Merz in collaboration with Neurobiological Technologies, Inc. and Children's Hospital, Boston/Harvard Medical School, and then licensed to Forest for the U.S. and Lundbeck for selected European and international markets.
Sales of the drug reached $1.8 billion for 2010.
Memantine is also being tested for generalized anxiety disorder, epilepsy, opioid dependence, systemic lupus erythematosus, depression, bipolar disorder, obsessive compulsive disorder, Tourette Syndrome, problem gambling, attention-deficit hyperactivity disorder (ADHD), glaucoma, tinnitus, neuropathic pain including Complex Regional Pain Syndrome, pervasive developmental disorders, HIV associated dementia, nystagmus, multiple sclerosis, autism, migraine, amyotrophic lateral sclerosis, Down syndrome and for protection of cognitive function during whole brain radiation.
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