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Memantine



Memantine
Systematic (IUPAC) name
1-amino-3,5-dimethyl-adamantane
Identifiers
CAS number 19982-08-2
ATC code N06DX01
PubChem 4054
DrugBank APRD00221
Chemical data
Formula C12H21N 
Mol. mass 179.3 g/mol
Pharmacokinetic data
Bioavailability ~100%
Metabolism Hepatic (<10%)
Half life 60–100 hours
Excretion Renal
Therapeutic considerations
Licence data

EU US

Pregnancy cat.

B2 (Au), B (U.S.)

Legal status

S4 (Au), POM (UK), ℞-only (U.S.)

Routes Oral

Memantine is the first in a novel class of Alzheimer's disease medications acting on the glutamatergic system. 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 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 , Ebixa® by Lundbeck and Memox® by Unipharm.

Additional recommended knowledge

Contents

Pharmacology

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.[1]

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.[2][3] 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 and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the physiological function of the receptor as it can still be activated by the relatively high concentrations of glutamate released following depolarization of the presynaptic neuron.[4][5] This unique molecular mechanism of action of memantine was first discovered by the laboratory of Stuart A. Lipton, MD, PhD, then at Harvard Medical School and now at the Burnham Institute for Medical Research in La Jolla, California.[6][7][8][9][10] Whether the interaction of memantine with NMDA receptors plays a role in the symptomatic improvement the drug produces in Alzheimer's disease is a matter of speculation. 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.[5]

Serotonergic (5-HT3 receptor)

Memantine acts as an uncompetitive antagonist at the 5HT3 receptor, with a potency similar to that for the NMDA receptor.[11] The clinical significance of this serotonergic activity in the treatment of Alzheimer's disease is unknown.

Cholinergic (Nicotinic acetylcholine receptor)

Memantine acts as an uncompetitive antagonist at different neuronal nicotinic neuronal receptors (nAChRs) at potencies possibly similar to the NMDA receptor, but this is difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in these experiments.[12][13][9] 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.[14]

Clinical use

Indications

Although memantine is approved for treatment of moderate to severe Alzheimer's Disease[15] its usage has been recommended against by the UK's National Institute for Clinical Excellence,[16] on the grounds that its high cost outweighs the benefits of treatment in most patients.

Memantine has been associated with a moderate decrease in clinical deterioration in Alzheimer's disease.[17] 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.[18]

Memantine is also being tested for Opioid dependence, systemic lupus erythematosus, depression, obsessive compulsive disorder, glaucoma, tinnitus, neuropathic pain, and pervasive developmental disorders.

Adverse drug reactions

Memantine is generally well-tolerated.[18] 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.[19][17]

See also

References

  1. ^ Cacabelos R, Takeda M, Winblad B. The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease puku. Int J Geriatr Psychiatry 1999;14(1):3-47. PMID 10029935
  2. ^ Rogawski, MA; Wenk GL (2003). "The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease". CNS Drug Rev 9 (3): 275-308. PMID 14530799.
  3. ^ Robinson, DM; Keating GM (2006). "Memantine: a review of its use in Alzheimer's disease". Drugs 66 (11): 1515-1534. PMID 16906789. Retrieved on 2007-01-17.
  4. ^ Rogawski, MA (2000). "Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents--toward an understanding of their favorable tolerability". Amino Acids 19 (1): 133-149. PMID 11026482.
  5. ^ a b Parsons CG, Stoffler A, Danysz W. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse.Neuropharmacology 2007;53:699-723. PMID 17904591
  6. ^ Chen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, Lipton SA. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci 1992;12:4427-4436. PMID 1432103
  7. ^ Chen HS, Lipton SA. Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism. J Physiol 1997;499 (Pt 1):27-46. PMID 9061638
  8. ^ Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 2006;5:160-170. PMID 16424917
  9. ^ a b Chen HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 2006;97:1611-1626. PMID 16805772
  10. ^ Lipton SA. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 2007;8:803-808. PMID 17882256
  11. ^ Rammes G, Rupprecht R, Ferrari U, Zieglgansberger W, Parsons CG. The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 2001;306(1-2):81-4. PMID 11403963
  12. ^ Buisson B, Bertrand D. Open-channel blockers at the human α4β2 neuronal nicotinic acetylcholine receptor. Mol Pharmacol 1998;53:555–63. PMID 9495824
  13. ^ Aracava Y, Pereira EF, Maelicke A, Albuquerque EX. Memantine blocks α7* nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther 2005;312:1195–205. PMID 15522999
  14. ^ Gotti C, Clementi F. Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 2004;74:363–96. PMID 15649582
  15. ^ Mount C, Downton C. Alzheimer's Disease: Progress or Profit?. Nature Medicine 2006 (12) 3: 1280-1284. PMID 16829947
  16. ^ NICE technology appraisal guidance 111 Donepezil, galantamine, rivastigmine (review) and memantine for the treatment of Alzheimer’s disease
  17. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  18. ^ a b Areosa SA, Sherriff F, McShane R. Memantine for dementia. Cochrane Database Syst Rev 2005;(3):CD003154. PMID 16034889
  19. ^ Joint Formulary Committee. British National Formulary. 47th ed. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain; 2004. ISBN 0-85369-584-9
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Memantine". A list of authors is available in Wikipedia.
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