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| Systematic (IUPAC) name | |
|---|---|
| 3,5-dimethyltricyclo[3.3.1.13,7]decan-1amine or |
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| Clinical data | |
| Trade names | Namenda |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a604006 |
| Licence data | EMA:Link, US FDA:link |
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Pregnancy
category |
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Legal status
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Routes of
administration |
Oral |
| Pharmacokinetic data | |
| Bioavailability | ~100% |
| Metabolism | Hepatic (<10%) |
| Half-life | 60–100 hours |
| Excretion | Renal |
| Identifiers | |
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CAS Registry Number
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19982-08-2 Y |
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ATC code
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N06DX01 |
| PubChem | CID 4054 |
| DrugBank | DB01043 Y |
| ChemSpider | 3914 Y |
| UNII | W8O17SJF3T Y |
| KEGG | D08174 Y |
| ChEMBL | CHEMBL807 Y |
| Chemical data | |
| Formula | C12H21N |
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Molecular mass
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179.3 g/mol |
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SMILES
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InChI
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| Y (what is this?) (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 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[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]
Contents
- 1 Medical use
- 2 Adverse effects
- 3 Biochemistry
- 4 Pharmacology
- 4.1 Glutamatergic (NMDA receptor)
- 4.2 Serotonergic (5-HT3 receptor)
- 4.3 Cholinergic (nicotinic acetylcholine receptor)
- 4.4 Dopaminergic (D2 receptor)
- 5 Availability
- 6 History
- 7 Research
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
Medical use
Memantine is approved by the U.S. F.D.A 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]
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][9] It has been reported to induce reversible neurological impairment in multiple sclerosis patients, which led to the halt of an ongoing clinical trial.[10][11] 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,[12] and has substituted for phencyclidine in rodent and primate drug discrimination studies.[13] Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability.[12]
A recent study demonstrates therapeutically-relevant doses of memantine in the mouse can lead to disruption of cognitive flexibility.[14]
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.[15]
Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.[16][17][18][19][20] 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.[21][22][23][24][17][18][25][26][27] 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.[24]
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.[28] 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.[26][29][30] 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.[31]
Dopaminergic (D2 receptor)
Memantine acts as an agonist at the dopamine D2 receptor.[32]
Availability
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.
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. [33] The cost of Namenda is $269 to $489 a month.[34]
Research
Memantine is also being tested for fibromyalgia,[35] generalized anxiety disorder, epilepsy, opioid dependence, systemic lupus erythematosus, depression, bipolar disorder,[36] obsessive compulsive disorder, Tourette Syndrome, problem gambling, attention-deficit hyperactivity disorder (ADHD),[37] glaucoma, tinnitus, neuropathic pain including Complex Regional Pain Syndrome,[38] pervasive developmental disorders, HIV associated dementia,[39] nystagmus,[40] multiple sclerosis,[10] autism,[41] migraine,[42] amyotrophic lateral sclerosis,[43] Down syndrome[44] and for protection of cognitive function during whole brain radiation.
See also
- Neramexane
- Nitromemantine
- NMDA receptor antagonist
References
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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. Cite uses deprecated parameter
|coauthors=(help) - ^ Mount C, Downton C (July 2006). "Alzheimer disease: progress or profit?". Nat Med. 12 (7): 780–4. doi:10.1038/nm0706-780. PMID 16829947.
- ^ NICE technology appraisal January 18, 2011 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
- ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
- ^ 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.
- ^ Joint Formulary Committee (2004). British National Formulary (47th ed.). London: BMA and the Royal Pharmaceutical Society of Great Britain. ISBN 0-85369-584-9.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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).
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b 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.
- ^ 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.
- ^ 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.
- ^ Lipton SA (October 2007). "Pathologically activated therapeutics for neuroprotection". Nature Reviews Neuroscience 8 (10): 803–8. doi:10.1038/nrn2229. PMID 17882256.
- ^ Rammes G, Rupprecht R, Ferrari U, Zieglgänsberger W, Parsons CG (June 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". Neurosci Lett. 306 (1–2): 81–4. doi:10.1016/S0304-3940(01)01872-9. PMID 11403963.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Drugs.com Namenda Sales Data. February 2014.
- ^ ConsumerReportsHealth. Evaluating Prescription Drugs Used to Treat: Alzheimer’s Disease. Comparing Effectiveness, Safety, and Price. Updated in May 2012.
- ^ Efficacy of memantine in the treatment of fibromyalgia: a double-blind randomised controlled trial with 6-month follow-up. [1]
- ^ http://www.psycheducation.org/depression/meds/memantine.htm
- ^ Open-Label Pilot Study of Namenda in Adult Subjects With ADHD and ADHD NOS [2]
- ^ Dan Ziegler. "New drugs to prevent or treat diabetic polyneuropathy" (PDF). Retrieved 2008-01-07. [dead link]
- ^ Schifitto G, Navia BA, Yiannoutsos CT et al. (September 2007). "Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study". AIDS 21 (14): 1877–86. doi:10.1097/QAD.0b013e32813384e8. PMID 17721095. CS1 maint: Explicit use of et al. (link)
- ^ 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.
- ^ Aman, Michael (Interviewee) (2010-07-29). Drug Used in Alzheimer's Tested In Kids With Autism. Ohio: Ohio State University Medical Center.
- ^ Borghol, Amne; Kirkwood A; Hawawini F (May 2010). "Memantine for the Treatment of Migraine". US Pharm 35 (5): 28–35.
- ^ Wang, R.; Zhang, D. (2005). "Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model". European Journal of Neuroscience 22 (9): 2376–2380. doi:10.1111/j.1460-9568.2005.04431.x. PMID 16262676. edit
- ^ Costa, ACS; Boada R; Hutaff-Lee C; Schrader A; Weitzenkamp D; Benke TA; Goldson EJ (July 17, 2012). "Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial". Translational Psychiatry 2 (e141). doi:10.1038/tp.2012.66.
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.
External links
- Namenda website
- About Namentda drugs
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UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
- 1. 認知症の治療 treatment of dementia
- 2. レビー小体型認知症の予後および治療 prognosis and treatment of dementia with lewy bodies
- 3. 予後良好な患者における脳転移の治療 treatment of brain metastases in favorable prognosis patients
- 4. 脳血管性認知症の治療および予防 treatment and prevention of vascular dementia
- 5. 認知症治療におけるコリンエステラーゼ阻害剤 cholinesterase inhibitors in the treatment of dementia
English Journal
- The basal forebrain cholinergic system in aging and dementia. Rescuing cholinergic neurons from neurotoxic amyloid-β42 with memantine.
- Nyakas C, Granic I, Halmy LG, Banerjee P, Luiten PG.SourceNeuropsychopharmacological Research Group of Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary; Department of Molecular Neurobiology, University of Groningen, Groningen, The Netherlands.
- Behavioural brain research.Behav Brain Res.2011 Aug 10;221(2):594-603. Epub 2010 May 27.
- The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in the pathogenesis of Alzheimer's disease (AD). The evidence pointing to cholinergic impairments come from studies that report a decline in the activity of choli
- PMID 20553766
- Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome.
- Lockrow J, Boger H, Bimonte-Nelson H, Granholm AC.SourceDepartment of Neuroscience, Center on Aging, Medical University of South Carolina, 173 Ashley Avenue, Ste 410D, Charleston, SC 29425, USA.
- Behavioural brain research.Behav Brain Res.2011 Aug 10;221(2):610-22. Epub 2010 Apr 2.
- Memantine is a partial NMDA receptor antagonist that has been shown to improve learning and memory in several animal models, and is approved for the treatment of Alzheimer's disease (AD). Chronic treatments using memantine in animal models of Alzheimer's disease show disease-modifying effects and su
- PMID 20363261
Japanese Journal
- 新規NMDA受容体拮抗剤であるメマンチン塩酸塩の中等度から高度アルツハイマー型認知症に対する第3相試験--有効性および安全性の検討
- 中村 祐,本間 昭,北村 伸 [他]
- 老年精神医学雑誌 22(4), 464-473, 2011-04
- NAID 40018785832
- 新規NMDA受容体拮抗剤であるメマンチン塩酸塩の中等度から高度アルツハイマー型認知症に対する後期第2相試験--有効性・安全性および推奨用量の検討
- 北村 伸,本間 昭,中村 祐 [他]
- 老年精神医学雑誌 22(4), 453-463, 2011-04
- NAID 40018785831
Related Links
- Before taking this medicine You should not use memantine if you are allergic to it. To make sure memantine is safe for you, tell your doctor if you have: epilepsy or other seizure disorder; liver disease; kidney disease; urination ...
- Memantine is an oral N-methyl-D-aspartate glutamate receptor antagonist used in the therapy of Alzheimer disease and dementia. Memantine is associated with a minimal rate of serum enzyme elevations during therapy and has only ...
- Easy-to-read patient leaflet for Memantine Tablets. Includes indications, proper use, special instructions, precautions, and possible side effects. ... Drugs.com provides accurate and independent information on more than ...
Related Pictures
★リンクテーブル★
| リンク元 | 「メマンチン」 |
| 拡張検索 | 「memantine hydrochloride」 |
「メマンチン」
- NMDA受容体拮抗薬。
- NMDA受容体は大脳皮質や海馬に高密度に存在し、記憶に関係する長期増強や発達か蘇生においてちゅうしんてきにな役割を担う。ADではシナプス間隙のグルタミン酸濃度が持続的に上昇し、シナプティックノイズが上昇し、記憶を形成する神経伝達シグナルが隠されるため、記憶・学習機能が障害される。まｔあ、AβがNMDA受容体のグルタミン酸認識部位に結合して細胞内にCa2+が過剰に流入して神経細胞が障害されるとも言われている。(週刊 医学会新聞 2011/5/23)
- 中等症から重症の認知症に用いられる。
- 5mgから開始して、2週間かけて5mgずつ増量し、20mgまで増量して維持量とする。
- 重度の腎機能障害(Ccr 30ml/min)の場合には、維持量は10mgとする。
- 相互作用注意：ドパミン作動薬(レボドパ)、ヒドロクロロチアジド、腎尿細管分泌(カチオン輸送系)により排泄される薬剤(シメチジン)、尿アルカリ化を起こす薬剤(アセタゾミド)、アマンタジン、デキストロメトルファン