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==Research==
==Research==
Memantine is also being tested for [[neuropathy|neuropathic pain including Complex Regional Pain Syndrome]],<ref name="zeigler2">{{cite web |url=http://www.medforum.nl/idm/IDM1332001LA.pdf |title=New drugs to prevent or treat diabetic polyneuropathy|author=Dan Ziegler |accessdate=2008-01-07 |format= pdf|work=}} {{Dead link|date=September 2010|bot=H3llBot}}</ref> [[pathologic nystagmus|nystagmus]],<ref>{{cite journal|author=Corbett J |title=Memantine/Gabapentin for the treatment of congenital nystagmus|journal=Curr Neurol Neurosci Rep |volume=7 |issue=5 |pages=395–6 |date=September 2007|pmid=17764629 |doi=10.1007/s11910-007-0061-z }}</ref> [[multiple sclerosis]],<ref name="pmid19092106">{{cite journal |author=Villoslada P, Arrondo G, Sepulcre J, Alegre M, Artieda J|title=Memantine induces reversible neurologic impairment in patients with MS |journal=Neurology|volume= 72|issue= 19|pages= 1630–3|date=December 2008 |pmid=19092106|doi=10.1212/01.wnl.0000342388.73185.80 |url=}}</ref> [[autism]],<ref name="osumc">{{cite video |people=Aman, Michael (Interviewee) | date=2010-07-29 | url=http://www.youtube.com/watch?v=UZ2Rpm7syKY | title=Drug Used in Alzheimer's Tested In Kids With Autism | location=Ohio |publisher=Ohio State University Medical Center}}</ref> [[migraine]],<ref>{{cite journal|last=Borghol|first=Amne|author2=Kirkwood A |author3=Hawawini F |title=Memantine for the Treatment of Migraine|journal=US Pharm|date=May 2010|volume=35|issue=5|pages=28–35|url=http://www.uspharmacist.com/content/c/20753/}}</ref> and for protection of cognitive function during whole brain radiation.
Memantine is also being tested for [[neuropathy|neuropathic pain including Complex Regional Pain Syndrome]],<ref name="zeigler2">{{cite web|url=http://www.medforum.nl/idm/IDM1332001LA.pdf |title=New drugs to prevent or treat diabetic polyneuropathy |author=Dan Ziegler |accessdate=2008-01-07 |format=pdf |work= |deadurl=yes |archiveurl=https://web.archive.org/20050525221801/http://www.medforum.nl:80/idm/IDM1332001LA.pdf |archivedate=25 May 2005 }}</ref> [[pathologic nystagmus|nystagmus]],<ref>{{cite journal|author=Corbett J |title=Memantine/Gabapentin for the treatment of congenital nystagmus|journal=Curr Neurol Neurosci Rep |volume=7 |issue=5 |pages=395–6 |date=September 2007|pmid=17764629 |doi=10.1007/s11910-007-0061-z }}</ref> [[multiple sclerosis]],<ref name="pmid19092106">{{cite journal |author=Villoslada P, Arrondo G, Sepulcre J, Alegre M, Artieda J|title=Memantine induces reversible neurologic impairment in patients with MS |journal=Neurology|volume= 72|issue= 19|pages= 1630–3|date=December 2008 |pmid=19092106|doi=10.1212/01.wnl.0000342388.73185.80 |url=}}</ref> [[autism]],<ref name="osumc">{{cite video |people=Aman, Michael (Interviewee) | date=2010-07-29 | url=http://www.youtube.com/watch?v=UZ2Rpm7syKY | title=Drug Used in Alzheimer's Tested In Kids With Autism | location=Ohio |publisher=Ohio State University Medical Center}}</ref> [[migraine]],<ref>{{cite journal|last=Borghol|first=Amne|author2=Kirkwood A |author3=Hawawini F |title=Memantine for the Treatment of Migraine|journal=US Pharm|date=May 2010|volume=35|issue=5|pages=28–35|url=http://www.uspharmacist.com/content/c/20753/}}</ref> and for protection of cognitive function during whole brain radiation.


== See also ==
== See also ==

Revision as of 20:46, 9 January 2016

Memantine
Clinical data
Trade namesNamenda
AHFS/Drugs.comMonograph
MedlinePlusa604006
License data
Pregnancy
category
  • AU: B2
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability~100%
MetabolismHepatic (<10%)
Elimination half-life60–100 hours
ExcretionRenal
Identifiers
  • 3,5-dimethyltricyclo[3.3.1.13,7]decan-1amine
    or
    3,5-dimethyladamantan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.217.937 Edit this at Wikidata
Chemical and physical data
FormulaC12H21N
Molar mass179.3 g/mol g·mol−1
3D model (JSmol)
  • NC12CC3(CC(C1)(CC(C2)C3)C)C
  • InChI=1S/C12H21N/c1-10-3-9-4-11(2,6-10)8-12(13,5-9)7-10/h9H,3-8,13H2,1-2H3 checkY
  • Key:BUGYDGFZZOZRHP-UHFFFAOYSA-N checkY
  (verify)

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 among others. Memantine has been shown to have a modest effect in moderate-to-severe Alzheimer's disease[1] and in dementia with Lewy bodies.[2][3] Despite years of research, there is little evidence of effect on mild Alzheimer's disease.[4]

Medical use

Memantine is approved by the U.S. FDA and the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease,[5] 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.[6] 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[7] with only a small positive effect on cognition, mood, behavior, and the ability to perform daily activities in moderate to severe Alzheimer's disease.[8] There does not appear to be any benefit in mild disease.[4]

It has shown promising results in studies for treatment of generalized anxiety disorder,[9] ADHD[10] as well as to help slowing down or even reversing the tolerance development to opioids[9] and, while not yet widely known, it actually gets prescribed off-label for these conditions.

Adverse effects

Memantine is, in general, well-tolerated.[8] 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.[7][11] It has been reported to induce reversible neurological impairment in multiple sclerosis patients, which led to the halt of an ongoing clinical trial.[12][13] Though exceedingly rare, extrapyramidal side effects (such as dystonic reactions, etc.) may occur, in particular, in the younger population.[citation needed]

Like many other NMDA antagonists, memantine behaves as a dissociative anesthetic at supratherapeutic doses,[14] and has substituted for phencyclidine in rodent and primate drug discrimination studies.[15] Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability.[14] Also memantine seems to lack most of the psychoactive effects recreational users are looking for, like euphoria, hallucinations etc.[16]

A recent study demonstrates therapeutically-relevant doses of memantine in the mouse can lead to disruption of cognitive flexibility.[17]

Biochemistry

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.

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.[18]

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.[19][20][21][22][23] 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.[24][25][26][27][20][21][28][29][30] 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.[27]

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.[31] 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.[29][32][33] 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.[34]

Dopaminergic (D2 receptor)

Memantine acts as an agonist at the dopamine D2 receptor with equal or slightly higher affinity than to the NMDA receptors.[35]

Sigmaergic (σ1 receptor)

It acts as an agonist at the σ1 receptor with a low Ki of 2.6µM.[36] The consequences of this activity are unclear (as the role of sigma receptors in general is not yet that well understood) and memantine is probably too weak at the sigma binding site to exhibit either significant effects or adverse effects through this route.

Availability

The hydrochloride (Memantine HCl) is a white, water-soluble powder available as capsule-shaped, film-coated tablets or oral solution.

Memantine is marketed under the brands Axura, Akatinol, Namenda, Ebixa, Abixa, and Mimetix,

History

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 2014.[37] The cost of Namenda is $269 to $489 a month.[38]

Research

Memantine is also being tested for neuropathic pain including Complex Regional Pain Syndrome,[39] nystagmus,[40] multiple sclerosis,[12] autism,[41] migraine,[42] and for protection of cognitive function during whole brain radiation.

See also

References

  1. ^ Reisberg, B; Doody, R; Stöffler, A; Schmitt, F; Ferris, S; Möbius, HJ; Study Group, Memantine (2003). "Memantine in moderater-to-severe Alzheimer's disease". New Engl. J. Med. 348 (14): 1333–41. doi:10.1056/nejmoa013128.
  2. ^ Aarsland, D; Ballard, C; Walker, Z; Bostrom, F; Alves, G; Kossakowski, K; Leroi, I; Pozo-Rodriguez, F; Minthon, L; Londos, E (July 2009). "Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial". Lancet neurology. 8 (7): 613–8. doi:10.1016/S1474-4422(09)70146-2. PMID 19520613.
  3. ^ Johansson, C; Ballard, C; Hansson, O; Palmqvist, S; Minthon, L; Aarsland, D; Londos, E (February 2011). "Efficacy of memantine in PDD and DLB: an extension study including washout and open-label treatment". International journal of geriatric psychiatry. 26 (2): 206–13. doi:10.1002/gps.2516. PMID 20665553.
  4. ^ a b Schneider, LS; Dagerman, KS; Higgins, JP; McShane, R (August 2011). "Lack of evidence for the efficacy of memantine in mild Alzheimer disease". Archives of neurology. 68 (8): 991–8. doi:10.1001/archneurol.2011.69. PMID 21482915.
  5. ^ Mount C, Downton C (July 2006). "Alzheimer disease: progress or profit?". Nat Med. 12 (7): 780–4. doi:10.1038/nm0706-780. PMID 16829947.
  6. ^ NICE technology appraisal January 18, 2011 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
  7. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  8. ^ a b Areosa SA, Sherriff F, McShane R (2005). Areosa Sastre, Almudena (ed.). "Memantine for dementia". Cochrane Database Syst Rev (3): CD003154. doi:10.1002/14651858.CD003154.pub4. PMID 16034889.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b Bisaga, A.; Comer, S. D.; Ward, A. S.; Popik, P.; Kleber, H. D.; Fischman, M. W. (1 August 2001). "The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans". Psychopharmacology. 157 (1): 1–10. doi:10.1007/s002130100739. ISSN 0033-3158. PMID 11512037.
  10. ^ Hosenbocus, Sheik; Chahal, Raj (1 May 2013). "Memantine: A Review of Possible Uses in Child and Adolescent Psychiatry". Journal of the Canadian Academy of Child and Adolescent Psychiatry. 22 (2): 166–171. ISSN 1719-8429. PMC 3647634. PMID 23667364.
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  12. ^ a b Villoslada P, Arrondo G, Sepulcre J, Alegre M, Artieda J (December 2008). "Memantine induces reversible neurologic impairment in patients with MS". Neurology. 72 (19): 1630–3. doi:10.1212/01.wnl.0000342388.73185.80. PMID 19092106.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Green AJ (February 2009). "Understanding pseudo. The symptoms are real, the cause is unclear". Neurology. 72 (19): 1626–7. doi:10.1212/01.wnl.0000345879.39454.68. PMID 19246422.
  14. ^ a b Morris, H.; Wallach, J. (2014). "From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis. 6: 614–632. doi:10.1002/dta.1620. PMID 24678061. {{cite journal}}: Cite has empty unknown parameter: |1= (help)
  15. ^ Parsons, C.; Danysz, W. (1999). "Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data" (PDF). Neuropharmacology. 38: 735–767. doi:10.1016/s0028-3908(99)00019-2.
  16. ^ Swedberg, Michael D. B.; Ellgren, Maria; Raboisson, Patrick (1 April 2014). "mGluR5 antagonist-induced psychoactive properties: MTEP drug discrimination, a pharmacologically selective non-NMDA effect with apparent lack of reinforcing properties". The Journal of Pharmacology and Experimental Therapeutics. 349 (1): 155–164. doi:10.1124/jpet.113.211185. ISSN 1521-0103. PMID 24472725.
  17. ^ Bechara J. Saab, Ruxandra M. Luca, Wing B. Yuen, Adam M. P. Saab, John C. Roder "Memantine Affects Cognitive Flexibility in the Morris Water Maze", Journal of Alzheimer's Disease Volume 27 Issue 3 (December 2011).
  18. ^ Cacabelos R, Takeda M, Winblad B (January 1999). "The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease". Int J Geriatr Psychiatry. 14 (1): 3–47. doi:10.1002/(SICI)1099-1166(199901)14:1<3::AID-GPS897>3.0.CO;2-7. PMID 10029935.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Kornhuber J, Bormann J, Retz W, Hübers M, Riederer P (1989). "Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex". Eur.J.Pharmacol. 166: 589–590. doi:10.1016/0014-2999(89)90384-1. PMID 2680528.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ a b Chen HSV, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, Lipton SA (1 November 1992). "Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity". J. Neurosci. 12 (11): 4427–36. PMID 1432103.{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "Chen1992" was defined multiple times with different content (see the help page).
  21. ^ a b Chen HSV, Lipton SA (15 February 1997). "Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism". J. Physiol. (Lond.). 499 (Pt 1): 27–46. PMC 1159335. PMID 9061638. Cite error: The named reference "Chen1997" was defined multiple times with different content (see the help page).
  22. ^ 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. doi:10.1111/j.1527-3458.2003.tb00254.x. PMID 14530799.
  23. ^ Robinson, DM; Keating GM (2006). "Memantine: a review of its use in Alzheimer's disease". Drugs. 66 (11): 1515–34. doi:10.2165/00003495-200666110-00015. PMID 16906789.
  24. ^ Xia P, Chen HSV, Zhang D, Lipton SA (2010). "Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses". J. Neurosci. 30 (33): 11246–11250. doi:10.1523/JNEUROSCI.2488-10.2010. PMC 2932667. PMID 20720132.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Kornhuber J, Weller M (1997). "Psychotogenicity and NMDA receptor antagonism: implications for neuroprotective pharmacotherapy". Biol. Psychiatry. 41 (2): 135–144. doi:10.1016/S0006-3223(96)00047-9. PMID 9018383.
  26. ^ 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): 133–49. doi:10.1007/s007260070042. PMID 11026482.
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  28. ^ Lipton SA (February 2006). "Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond". Nature Reviews Drug Discovery. 5 (2): 160–70. doi:10.1038/nrd1958. PMID 16424917.
  29. ^ a b Chen HS, Lipton SA (June 2006). "The chemical biology of clinically tolerated NMDA receptor antagonists". J Neurochem. 97 (6): 1611–26. doi:10.1111/j.1471-4159.2006.03991.x. PMID 16805772.
  30. ^ Lipton SA (October 2007). "Pathologically activated therapeutics for neuroprotection". Nature Reviews Neuroscience. 8 (10): 803–8. doi:10.1038/nrn2229. PMID 17882256.
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  35. ^ Seeman P, Caruso C, Lasaga M (February 2008). "Memantine agonist action at dopamine D2High receptors". Synapse. 62 (2): 149–53. doi:10.1002/syn.20472. PMID 18000814.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  36. ^ Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E. (April 2004). "Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine". Eur J Neurosci. 19: 2212–20. doi:10.1111/j.0953-816X.2004.03297.x. PMID 15090047.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  37. ^ Drugs.com Namenda Sales Data. February 2014.
  38. ^ ConsumerReportsHealth. Evaluating Prescription Drugs Used to Treat: Alzheimer’s Disease. Comparing Effectiveness, Safety, and Price. Updated in May 2012.
  39. ^ Dan Ziegler. "New drugs to prevent or treat diabetic polyneuropathy" (PDF). Archived from the original (pdf) on 25 May 2005. Retrieved 7 January 2008. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  40. ^ Corbett J (September 2007). "Memantine/Gabapentin for the treatment of congenital nystagmus". Curr Neurol Neurosci Rep. 7 (5): 395–6. doi:10.1007/s11910-007-0061-z. PMID 17764629.
  41. ^ Aman, Michael (Interviewee) (29 July 2010). Drug Used in Alzheimer's Tested In Kids With Autism. Ohio: Ohio State University Medical Center.
  42. ^ Borghol, Amne; Kirkwood A; Hawawini F (May 2010). "Memantine for the Treatment of Migraine". US Pharm. 35 (5): 28–35.

Further reading

  • Lipton SA (2005). "The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism". Current Alzheimer research. 2 (2): 155–65. doi:10.2174/1567205053585846. PMID 15974913.

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