Memantine

Memantine
Clinical data
Trade names Originally, Axura, Ebixa, Namenda; many generic names worldwide[1]
AHFS/Drugs.com Monograph
MedlinePlus a604006
License data
Pregnancy
category
  • AU: B2
  • US: B (No risk in non-human studies)
Routes of
administration		 Oral
ATC code N06DX01 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability ~100%
Metabolism Hepatic (<10%)
Biological half-life 60–100 hours
Excretion Renal
Identifiers
CAS Number 19982-08-2 YesY
PubChem (CID) 4054
IUPHAR/BPS 4253
DrugBank DB01043 YesY
ChemSpider 3914 YesY
UNII W8O17SJF3T YesY
KEGG D08174 YesY
ChEMBL CHEMBL807 YesY
Chemical and physical data
Formula C12H21N
Molar mass 179.3 g/mol
3D model (Jmol) Interactive image
  (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 as a potential agent to treat diabetes; the NMDA activity was discovered in the 1980s.

Memantine is marketed under the brands Namenda among others. Memantine has been shown to have a modest effect in moderate-to-severe Alzheimer's disease[2] and in dementia with Lewy bodies.[3][4] Despite years of research, there is little evidence of effect on mild Alzheimer's disease.[5]

Medical use

Memantine is approved by the U.S. FDA and the European Medicines Agency for treatment of moderate-to-severe Alzheimer's disease,[6] 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.[7] 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[8] with only a small positive effect on cognition, mood, behavior, and the ability to perform daily activities in moderate to severe Alzheimer's disease.[9] There does not appear to be any benefit in mild disease.[5]

It has shown promising results in studies for treatment of obsessive compulsive disorder,[10][11] generalized anxiety disorder, as an augmentation therapy for anxiety disorders,[12] ADHD,[13] as well as to help slowing down or even reversing the tolerance development to opioids.[14]

Adverse effects

Memantine is, in general, well-tolerated.[9] 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.[8][15] It has been reported to induce reversible neurological impairment in multiple sclerosis patients, which led to the halt of an ongoing clinical trial.[16][17] 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,[18] and has substituted for phencyclidine in rodent and primate drug discrimination studies.[19] Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability.[18] Also memantine seems to lack most of the psychoactive effects recreational users are looking for, like euphoria, hallucinations etc.[20]

A recent study demonstrates therapeutically-relevant doses of memantine in the mouse can lead to disruption of cognitive flexibility.[21]

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.[22]

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.[23][24][25][26][27] 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.[28][29][30][31][24][25][32][33][34] The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. However, 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.[31]

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.[35] 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.[33][36][37] 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.[38]

Dopaminergic (D2 receptor)

Memantine acts as an agonist at the dopamine D2 receptor with equal or slightly higher affinity than to the NMDA receptors.[39]

Sigmaergic (σ1 receptor)

It acts as an agonist at the σ1 receptor with a low Ki of 2.6 µM.[40] 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 significant agonist effects, only exhibiting partial agonism or antagonism. Some of memantine's adverse effects arise through this route.

History

Memantine was first synthesized and patented by Eli Lilly and Company in 1968 as an anti-diabetic agent, but it was ineffective at lowering blood sugar. Later it was discovered to have CNS activity, and was developed by Merz for dementia in Germany; the NMDA activity was discovered after clinical trials had already begun. Memantine was first marketed for dementia in Germany in 1989 under the name Axura. In 2000 Merz partnered with Forest to develop the drug for Alzheimers in the U.S. under the name Namenda.[41]

In 2000 Merz partnered with Suntory for the Japanese market and with Lundbeck for other markets including Europe;[42] the drug was originally marketed by Lundbeck under the name Ebixa.[41] It is generic in many countries and is marketed under many brand names worldwide.[1]

Sales of the drug reached $1.8 billion for 2014.[43] The cost of Namenda is $269 to $489 a month.[44]

Research

Memantine is also being tested for neuropathic pain including Complex Regional Pain Syndrome,[45] nystagmus,[46] multiple sclerosis,[16] autism,[47] migraine,[48] schizophrenia,[49] and for protection of cognitive function during whole brain radiation.

See also

References

  1. 1 2 Drugs.com International brand names for memantine Page accessed April 6, 2016
  2. ↑ 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. PMID 12672860.
  3. ↑ 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.
  4. ↑ 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.
  5. 1 2 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.
  6. ↑ Mount C, Downton C (July 2006). "Alzheimer disease: progress or profit?". Nat Med. 12 (7): 780–4. doi:10.1038/nm0706-780. PMID 16829947.
  7. ↑ NICE technology appraisal January 18, 2011 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
  8. 1 2 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  9. 1 2 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.
  10. ↑ Haghighi M, Jahangard L, Mohammad-Beigi H, Bajoghli H, Hafezian H, Rahimi A, Afshar H, Holsboer-Trachsler E, Brand S (2013). "In a double-blind, randomized and placebo-controlled trial, adjuvant memantine improved symptoms in inpatients suffering from refractory obsessive-compulsive disorders (OCD)". Psychopharmacology. 228 (4): 633–40. doi:10.1007/s00213-013-3067-z. PMID 23525525.
  11. ↑ Stewart SE, Jenike EA, Hezel DM, Stack DE, Dodman NH, Shuster L, Jenike MA (2010). "A single-blinded case-control study of memantine in severe obsessive-compulsive disorder". Journal of Clinical Psychopharmacology. 30 (1): 34–9. doi:10.1097/JCP.0b013e3181c856de. PMID 20075645.
  12. ↑ Schwartz, Thomas L.; Siddiqui, Umar A.; Raza, Shafi (2012). "Memantine as an Augmentation Therapy for Anxiety Disorders". Case Reports in Psychiatry. 2012: 1–3. doi:10.1155/2012/749796.
  13. ↑ Hosenbocus S, Chahal R (2013). "Memantine: a review of possible uses in child and adolescent psychiatry". Journal of the Canadian Academy of Child and Adolescent Psychiatry. 22 (2): 166–71. PMC 3647634Freely accessible. PMID 23667364.
  14. ↑ Bisaga A, Comer SD, Ward AS, Popik P, Kleber HD, Fischman MW (2001). "The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans". Psychopharmacology. 157 (1): 1–10. doi:10.1007/s002130100739. PMID 11512037.
  15. ↑ Joint Formulary Committee (2004). British National Formulary (47th ed.). London: BMA and the Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9.
  16. 1 2 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.
  17. ↑ 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.
  18. 1 2 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 (7–8): 614–32. doi:10.1002/dta.1620. PMID 24678061.
  19. ↑ Parsons, C.G.; Danysz, W.; Quack, G. (1999). "Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data". Neuropharmacology. 38 (6): 735–67. doi:10.1016/S0028-3908(99)00019-2. PMID 10465680.
  20. ↑ Swedberg MD, Ellgren M, Raboisson P (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): 155–64. doi:10.1124/jpet.113.211185. PMID 24472725.
  21. ↑ Saab BJ, Luca RM, Yuen WB, Saab AM, Roder JC (2011). "Memantine affects cognitive flexibility in the Morris water maze". Journal of Alzheimer's Disease. 27 (3): 477–82. doi:10.3233/JAD-2011-110650. PMID 21860092.
  22. ↑ 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.
  23. ↑ 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 (3): 589–590. doi:10.1016/0014-2999(89)90384-1. PMID 2680528.
  24. 1 2 Chen HS, 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.
  25. 1 2 Chen HS, 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. doi:10.1113/jphysiol.1997.sp021909. PMC 1159335Freely accessible. PMID 9061638.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ Xia P, Chen HS, 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 2932667Freely accessible. PMID 20720132.
  29. ↑ 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.
  30. ↑ 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.
  31. 1 2 Parsons CG, Stöffler A, Danysz W (November 2007). "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. 53 (6): 699–723. doi:10.1016/j.neuropharm.2007.07.013. PMID 17904591.
  32. ↑ 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.
  33. 1 2 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.
  34. ↑ Lipton SA (October 2007). "Pathologically activated therapeutics for neuroprotection". Nature Reviews Neuroscience. 8 (10): 803–8. doi:10.1038/nrn2229. PMID 17882256.
  35. ↑ Rammes G, Rupprecht R, Ferrari U, Zieglgänsberger W, Parsons CG (2001). "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". Neuroscience Letters. 306 (1–2): 81–4. doi:10.1016/S0304-3940(01)01872-9. PMID 11403963.
  36. ↑ Buisson B, Bertrand D (1 March 1998). "Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor". Mol Pharmacol. 53 (3): 555–63. PMID 9495824.
  37. ↑ Aracava Y, Pereira EF, Maelicke A, Albuquerque EX (March 2005). "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons". J Pharmacol Exp Ther. 312 (3): 1195–205. doi:10.1124/jpet.104.077172. PMID 15522999.
  38. ↑ Gotti C, Clementi F (December 2004). "Neuronal nicotinic receptors: from structure to pathology". Prog Neurobiol. 74 (6): 363–96. doi:10.1016/j.pneurobio.2004.09.006. PMID 15649582.
  39. ↑ 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.
  40. ↑ Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E (Apr 2004). "Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine". Eur J Neurosci. 19 (8): 2212–20. doi:10.1111/j.0953-816X.2004.03297.x. PMID 15090047.
  41. 1 2 Witt A, Macdonald N, Kirkpatrick P. Memantine hydrochloride. Nat Rev Drug Discov. 2004 Feb;3(2):109-10. PMID 15040575
  42. ↑ Staff, the Pharma Letter. August 15, 2000 Lundbeck signs memantine licensing agreement for Merz+Co
  43. ↑ Drugs.com Namenda Sales Data. February 2014.
  44. ↑ ConsumerReportsHealth. Evaluating Prescription Drugs Used to Treat: Alzheimer’s Disease. Comparing Effectiveness, Safety, and Price. Updated in May 2012.
  45. ↑ Dan Ziegler. "New drugs to prevent or treat diabetic polyneuropathy" (PDF). Archived from the original (pdf) on 25 May 2005. Retrieved 2008-01-07.
  46. ↑ 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.
  47. ↑ Aman, Michael (Interviewee) (2010-07-29). Drug Used in Alzheimer's Tested In Kids With Autism. Ohio: Ohio State University Medical Center.
  48. ↑ Borghol, Amne; Kirkwood A; Hawawini F (May 2010). "Memantine for the Treatment of Migraine". US Pharm. 35 (5): 28–35.
  49. ↑ Clinical trial number NCT00757978 for "Memantine as Adjunctive Therapy for Schizophrenia Negative Symptoms" at ClinicalTrials.gov

Further reading

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