Chemistry:Memantine

From HandWiki

Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease.[1][2][3] It is taken by mouth.[1][3]

Common side effects include headache, constipation, sleepiness, and dizziness.[1][2] Severe side effects may include blood clots, psychosis, and heart failure.[2] It is believed to work by acting on NMDA receptors, working as a pore blocker of these ion channels.[3][1]

Memantine was first discovered in 1963.[3][4][5] It was approved for medical use in Germany in 1989, in the European Union in 2002, and in the United States in 2003.[5][1][6] It is available as a generic medication.[2] In 2023, it was the 145th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[7][8]

Medical uses

Alzheimer's disease and dementia

Memantine is used to treat moderate-to-severe Alzheimer's disease, especially for people who are intolerant of or have a contraindication to AChE (acetylcholinesterase) inhibitors.[9][10] One guideline recommends memantine or an AChE inhibitor be considered in people in the early-to-mid stage of dementia.[11]

Memantine has been associated with a modest improvement;[12] with small positive effects on cognition, mood, behavior, and the ability to perform daily activities in moderate-to-severe Alzheimer's disease.[13][14] There does not appear to be any benefit in mild disease.[15]

Memantine when added to donepezil in those with moderate-to-severe dementia resulted in "limited improvements" in a 2017 review.[16] The UK National Institute for Clinical Excellence (NICE) issued guidance in 2018 recommending consideration of the combination of memantine with donepezil in those with moderate-to-severe dementia.[17]

Radiation therapy

Memantine has been recommended for use by professional organization consensus to prevent neurocognitive decline after whole brain radiotherapy.[18]

Adverse effects

Memantine is, in general, well tolerated.[12] Common adverse drug reactions (≥1% of people) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido.[12][19]

Like many other NMDA receptor antagonists, memantine behaves as a dissociative anesthetic at supratherapeutic doses.[20] Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability.[20] Additionally, memantine seems to lack effects such as euphoria or hallucinations.[21]

Memantine appears to be generally well tolerated by children with autism spectrum disorder.[22]

Pharmacology

Pharmacodynamics

Memantine is an uncompetitive NMDA receptor antagonist, with an IC50 binding affinity of ~500-1,000 nM (0.5-1 μM),[23] but displays higher potency at extrasynaptic NMDA receptors (IC50 = ~22 nM),[23] suggesting preferential inhibition of pathological glutamatergic signaling.

Memantine also exhibits activity at several other receptors:

  • Dopamine D2High receptor agonist (IC50 affinity = ~137-917 nM);[24] increases dopaminergic activity in the prefrontal cortex and striatum.[25][26] Memantine may inhibit the release of prolactin through D2 agonism, based on studies from isolated anterior pituitary cells.[24]
  • Alpha 7 nicotinic acetylcholine receptor antagonist (IC50 affinity = 340nM-5,000 nM or 0.34-5 μM).[27][28]
  • 5-HT3 receptor receptor antagonist (IC50 affinity = ~1,000 nM).[29][24]
  • Believed to block NMDA overactivation and restore cognitive dysfunction without significantly impairing normal synaptic transmission.
  • No meaningful acetylcholinesterase (AChE) inhibition.

Glutamatergic

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 ionotropic glutamate NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system.[30]

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors[31][32] with an IC50 binding affinity of ~500-1,000 nM (0.5-1 μM),[23] but displays higher potency at extrasynaptic NMDA receptors (~22 nM).[23]

Magnesium (Mg2+), the natural NMDA channel blocker, has an apparent dissociation constant (Ka/Ki) of roughly 2-3 mM (2,000,000-3,000,000 nM), making memantine ~1000x stronger at NMDA than Mg2+. By binding to the NMDA receptor with a higher affinity than Mg2+, 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 postsynaptic neuron.[33][34][35] 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 extrasynaptic NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's disease, although this has been suggested in animal models.[34]

Serotonergic

Memantine acts as a non-competitive antagonist of the serotonin 5-HT3 receptor, with a potency similar to that for the NMDA receptor.[29][36] Many 5-HT3 receptor antagonists function as antiemetics, however the clinical significance of this anti-serotonergic activity of memantine in Alzheimer's disease is unknown.

Cholinergic

Memantine acts as a non-competitive antagonist at the α7 nicotinic acetycholine receptor[28] (IC50 affinity = 340nM-5,000nM[37] or 0.34-5 μM). Several studies have observed that Memantine's antagonism at nAChRs is higher than both its affinity to NMDA and 5-HT3 receptors,[37][38] but this may be difficult to ascertain with accuracy due to rapid desensitization of nAChRs.

Antagonism of α7 nAChRs may contribute to initial worsening of cognitive function during early Memantine treatment. Nicotinic acetylcholine receptor, specifically α7 nAChR, upregulate quickly in response to antagonism, which could explain the possible cognitive-enhancing effects of Memantine.[39][40][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.[41]

Dopaminergic

Memantine has been shown to act as an agonist of dopamine D2High receptor with equal or slightly higher affinity than to NMDA receptors[24] (D2 IC50 affinity = ~137-917 nM).[24] In another study, Memantine was shown to increase dopaminergic activity in the prefrontal cortex and striatum of mice.[42]

At least one study questions the relevance of Memantine's D2 receptor action, suggesting low Ki binding affinity.[43]

Sigmaergic

Memantine acts as a weak agonist of the sigma σ1 receptor with low affinity (Ki = 2,600nM or 2.6 μM).[44] Due to this low affinity, therapeutic concentrations of memantine are most likely too low to have any sigmaergic effect as a typical therapeutic dose is 20 mg. The consequences of sigma activity would be unclear, as the role of sigma receptors in general is currently not very well understood. However, excessive doses of memantine taken for recreational purposes, which are many times greater than prescribed doses, may indeed activate this receptor.[45]

Other actions

Memantine does not appear to inhibit or induce several cytochrome P450 enzymes including CYP3A4/5, CYP1A2, CYP2D6, and CYP2C9.[3] It also does not inhibit CYP2A6 or CYP2E1.[46] However, it might have a small effect on CYP2B6.[3]

Pharmacokinetics

Absorption

The oral bioavailability of memantine is 100%.[3][46] Time to peak levels of memantine is 3 to 7 hours.[3][46] Food has no influence on the rate of absorption.[3][46] Memantine exposure is linear over a dose range of 10 to 40 mg.[3] Peak levels after a single 20 mg dose were found to be 24 to 29 μg/L (0.13–0.16 μmol/L or μM).[3] Steady-state levels of memantine with 20 mg/day are in the range of 0.5 to 1.0 μM.[46]

Distribution

Memantine has a relatively high volume of distribution (Vd) of 9 to 11 L/kg.[3][46] It easily crosses biological membranes, is widely distributed throughout the body, and crosses the blood–brain barrier into the central nervous system.[46] The drug is transported across the blood–brain barrier by the organic cation transporter novel 1 (OCTN1).[3] The plasma protein binding of memantine is 45% and is described as very low and not clinically significant.[3][46] Because of its low plasma protein binding, it is unlikely to interact with other highly protein-bound drugs such as warfarin or digoxin.[46]

Metabolism

Memantine does not undergo extensive metabolism.[46] It is negligibly metabolized by the cytochrome P450 enzymes.[3][46] As a result, it has a decreased potential for drug interactions.[46] Metabolites of memantine include memantine glucuronide, 6-hydroxymemantine, and 1-nitrosomemantine, all of which show minimal activity as NMDA receptor antagonists.[3][46]

Elimination

Memantine is eliminated primarily in urine, with 57 to 82% excreted in urine unchanged.[3][46] Its elimination half-life is 60 to 80 hours.[3][46] The renal clearance of memantine is dependent on urinary pH.[3][46] More alkaline urine slows the elimination of memantine, whereas more acidic urine accelerates its elimination.[3][46]

Chemistry

Memantine, also known as 3,5-dimethyl-1-aminoadamantane (DMAA), is an adamantane derivative and is closely structurally related to amantadine (1-aminoadamantane) and other adamantane derivatives.[3][47][48][49]

The synthesis of memantine has been described.[3]

History

Memantine was first synthesized, patented, and described by Eli Lilly and Company in 1963 as an anti-diabetic agent, but it was ineffective at lowering blood sugar.[3][4][5][50][51] By 1972, it was discovered to have central nervous system (CNS) activity, and was developed by Merz for treatment of neurological diseases, such as Parkinson's disease.[3][4] Memantine was first studied in the treatment of Alzheimer's disease in 1986.[5][6] The drug was first marketed for dementia in 1989 in Germany under the name Axura.[3][6][4]

It was not discovered to act as an NMDA receptor antagonist until 1989, after clinical trials had initiated.[3][4][52] Prior to this, it was theorized to directly and/or indirectly modulate the dopaminergic, noradrenergic, and serotonergic systems.[4][53][54][55] However, these actions were later realized to occur at 100-fold higher concentrations than those achieved therapeutically and hence are unlikely to be involved in its effects.[4][53][55]

In the United States, some CNS activities were discovered at Children's Hospital of Boston in 1990, and Children's licensed patents covering uses of memantine outside the field of ophthalmology to Neurobiological Technologies (NTI) in 1995.[56] In 1998, NTI amended its agreement with Children's to allow Merz to take over development.[57]

In 2000, Merz partnered with Forest to develop the drug for Alzheimer's disease in the United States under the brand name Namenda.[3][6] In 2000, Merz partnered with Suntory for the Japanese market and with Lundbeck for other markets including Europe;[58] the drug was originally marketed by Lundbeck under the name Ebixa.[6] Memantine was approved in the European Union in 2002 and in the United States in 2003.[3][5]

Sales of the drug reached $1.8 billion for 2014.[3][59] The cost of Namenda was $269 to $489 a month in 2012.[60]

In February 2014, as the July 2015 patent expiration for memantine neared, Actavis, which had acquired Forest, announced that it was launching an extended release (XR) form of memantine that could be taken once a day instead of twice a day as needed with the then-current "immediate release" (IR) version, and that it intended to stop selling the IR version in August 2014 and withdraw the marketing authorization. This is a tactic to thwart generic competition called product hopping. However the supply of the XR version ran short, so Actavis extended the deadline until the fall. In September 2014 the attorney general of New York, Eric Schneiderman, filed a lawsuit to compel Actavis to keep selling the IR version on the basis of antitrust law.[61][62]

In December 2014, a judge granted New York State its request and issued an injunction, preventing Actavis from withdrawing the IR version until generic versions could launch. Actavis appealed and in May a panel of the Second Circuit Court of Appeals upheld the injunction, and in June Actavis asked that its case be heard by the full Second Circuit panel.[63][64] In August 2015, Actavis' request was denied.[65]

Society and culture

Recreational use

Recreational use of memantine at supratherapeutic doses has been reported.[66] It is a weak NMDA receptor antagonist and is reported to produce dissociative and phencyclidine (PCP)-like effects in animals and humans at sufficiently high doses.[66][67][68] Even therapeutic doses have been found to produce mild dissociative-like effects in clinical studies.[66] In any case, the very long duration of action of memantine (>40 hours) has likely limited its misuse potential.[66] Recreational use of the related drug amantadine has similarly been reported.[66]

A study examining self-reported use of memantine on the social network Reddit showed that the drug was used both recreationally and as a nootropic, but also that it was misused in various illnesses as self-medication without strong scientific basis.[69]

Brand names

As of August 2017, memantine is marketed under many brand names worldwide including Abixa, Adaxor, Admed, Akatinol, Alceba, Alios, Almenta, Alois, Alzant, Alzer, Alzia, Alzinex, Alzixa, Alzmenda, Alzmex, Axura, Biomentin, Carrier, Cogito, Cognomem, Conexine, Cordure, Dantex, Demantin, Demax, Dementa, Dementexa, Ebitex, Ebixa, Emantin, Emaxin, Esmirtal, Eutebrol, Evy, Ezemantis, Fentina, Korint, Lemix, Lindex, Lindex, Lucidex, Manotin, Mantine, Mantomed, Marbodin, Mardewel, Marixino, Maruxa, Maxiram, Melanda, Memabix, Memamed, Memando, Memantin, Memantina, Memantine, Mémantine, Memantinol, Memantyn, Memanvitae, Memanxa, Memanzaks, Memary, Memax, Memexa, Memigmin, Memikare, Memogen, Memolan, Memorel, Memorix, Memotec, Memox, Memxa, Mentikline, Mentium, Mentixa, Merandex, Merital, Mexia, Mimetix, Mirvedol, Modualz, Morysa, Namenda, Nemdatine, Nemdatine, Nemedan, Neumantine, Neuro-K, Neuroplus, Noojerone, Pertam, Polmatine, Prilben, Pronervon, Ravemantine, Talentum, Timantila, Tingreks, Tonibral, Tormoro, Valcoxia, Vilimen, Vivimex, Witgen, Xapimant, Ymana, Zalatine, Zemertinex, Zenmem, Zenmen, and Zimerz.[70]

It is marketed in some countries as a combination drug with donepezil (memantine/donepezil) under the brand names Namzaric, Neuroplus Dual, and Tonibral MD.[70]

Research

Psychiatric disorders

Memantine has been studied and used off-label in the treatment of a variety of psychiatric disorders.[71] These include depression, bipolar disorder, schizophrenia, obsessive–compulsive disorder (OCD), substance misuse, pervasive developmental disorders (PDDs), and binge eating disorder (BED).[71] A 2008 systematic review concluded that although it was promising for such uses, memantine could not be recommended for such indications due to inadequate data.[71]

Memantine does not appear to be effective in the treatment of unipolar major depression or bipolar depression on the basis of systematic reviews and meta-analyses, including a 2021 Cochrane review.[72][73][74][75][76] However, a 2022 systematic review and meta-analysis concluded that memantine was significantly effective in the treatment of depressive symptoms in various psychiatric disorders, although with a very small effect size (Hedges' g = -0.17).[77]

There are likewise limited data to support memantine in the treatment of schizophrenia based on systematic reviews and meta-analyses.[78][79] However, a 2019 systematic review and meta-analysis reported that memantine was effective in the treatment of the negative and cognitive symptoms of schizophrenia with medium to large effect sizes.[80]

Parkinson's disease

Memantine has been studied in the treatment of Parkinson's disease since the early 1970s.[5][4][81][82][83] Whereas the related drug amantadine is approved for the treatment of Parkinson's disease and has been since the early 1970s,[48] memantine is not approved for the treatment of Parkinson's disease as of 2024.[84] However, it has been said that memantine, along with amantadine, has been widely used as an antiparkinsonian agent since at least 1994.[81]

Although amantadine and memantine have fairly similar pharmacology, it has been said that memantine does not share the antidyskinetic effects of amantadine.[85][86] However, findings are conflicting, and some data suggest that memantine may also have antidyskinetic effects.[87][88][89] Similarly to amantadine and dopamine receptor agonists, memantine reverses haloperidol-induced catalepsy and monoamine depletion-induced sedation in animals.[85][90] Memantine has been found to reduce bradykinesia and resting tremor in people with Parkinson's disease.[85][86] Memantine and amantadine are said to have moderate anti-akinetic effects in the treatment of Parkinson's disease.[81][91] The doses of memantine used for Parkinson's disease are about 5- to 10-fold lower than those of amantadine, which has been attributed to greater potency of memantine.[81]

As of 2022, a phase 3 clinical trial is studying the potential of memantine as disease-modifying treatment for Parkinson's disease that might slow progression of the disease.[92][93][94] It is specifically theorized to act by inhibiting cell-to-cell transmission of α-synuclein.[92][93]

Besides Parkinson's disease, memantine has been studied in the treatment of Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB).[95][96][97]

Apathy

Apathy is a disorder of diminished motivation characterized by diminished interest and activity.[98][99] Systematic reviews and meta-analyses published from 2016 to 2022 have found that memantine is not effective in the treatment of apathy in Alzheimer's disease and other dementias.[100][101][102] However, another 2022 review reported that it was effective.[103]

Long COVID

Memantine, along with amantadine, is being studied and used off-label in the treatment long COVID.[104][105]

Catatonia

Memantine, along with amantadine, has been reported to be effective in the treatment of catatonia in case reports and case series.[106][107][108]

Autism spectrum disorder

There is no evidence that memantine improves symptoms of autism spectrum disorder. A 2024 meta-analysis of NMDA antagonists (including memantine) found no benefit over placebo on core or associated symptoms and more adverse events,[109] while a 2022 review concluded the effect on core symptoms is uncertain.[110]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Memantine Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/memantine-hydrochloride.html. 
  2. ↑ 2.0 2.1 2.2 2.3 "Memantine hydrochloride". British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 303–304. ISBN 978-0-85711-338-2. OCLC 1050279948. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24 3.25 3.26 3.27 3.28 "Classics in Chemical Neuroscience: Memantine". ACS Chemical Neuroscience 8 (9): 1823–1829. September 2017. doi:10.1021/acschemneuro.7b00270. PMID 28737885. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Memantine and Alzheimer's disease". Diagnosis and Management in Dementia. Elsevier. 2020. pp. 511–527. doi:10.1016/b978-0-12-815854-8.00032-x. ISBN 978-0-12-815854-8. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Memantine in dementia: a review of the current evidence". Expert Opinion on Pharmacotherapy 12 (5): 787–800. April 2011. doi:10.1517/14656566.2011.558006. PMID 21385152. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Memantine hydrochloride". Nature Reviews. Drug Discovery 3 (2): 109–110. February 2004. doi:10.1038/nrd1311. PMID 15040575. 
  7. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  8. ↑ "Memantine Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Memantine. 
  9. ↑ "Alzheimer disease: progress or profit?". Nature Medicine 12 (7): 780–784. July 2006. doi:10.1038/nm0706-780. PMID 16829947. 
  10. ↑ NICE review of technology appraisal guidance 111 January 18, 2011 Alzheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
  11. ↑ "Medication appropriateness tool for co-morbid health conditions in dementia: consensus recommendations from a multidisciplinary expert panel". Internal Medicine Journal 46 (10): 1189–1197. October 2016. doi:10.1111/imj.13215. PMID 27527376. 
  12. ↑ 12.0 12.1 12.2 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  13. ↑ "Memantine for dementia". The Cochrane Database of Systematic Reviews 3 (3). March 2019. doi:10.1002/14651858.CD003154.pub6. PMID 30891742. 
  14. ↑ "A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease". Alzheimer Disease and Associated Disorders 21 (2): 136–143. 2007. doi:10.1097/WAD.0b013e318065c495. PMID 17545739. 
  15. ↑ "Lack of evidence for the efficacy of memantine in mild Alzheimer disease". Archives of Neurology 68 (8): 991–998. August 2011. doi:10.1001/archneurol.2011.69. PMID 21482915. 
  16. ↑ "Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: A meta-analysis". PLOS ONE 12 (8). 21 August 2017. doi:10.1371/journal.pone.0183586. PMID 28827830. Bibcode: 2017PLoSO..1283586C. 
  17. ↑ "Dementia: assessment, management and support for people living with dementia and their carers". 20 June 2018. https://www.nice.org.uk/guidance/ng97. 
  18. ↑ "Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline". Journal of Clinical Oncology 40 (5): 492–516. February 2022. doi:10.1200/JCO.21.02314. PMID 34932393. 
  19. ↑ British National Formulary (47th ed.). London: BMA and the Royal Pharmaceutical Society of Great Britain. 2004. ISBN 978-0-85369-584-4. 
  20. ↑ 20.0 20.1 "From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis 6 (7–8): 614–632. 2014. doi:10.1002/dta.1620. PMID 24678061. 
  21. ↑ "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. April 2014. doi:10.1124/jpet.113.211185. PMID 24472725. 
  22. ↑ Clinical handbook of psychotropic drugs for children and adolescents (Tertiary source). Boston, MA: Hogrefe. 2019. pp. 366–369. ISBN 978-1-61676-550-7. OCLC 1063705924. 
  23. ↑ 23.0 23.1 23.2 23.3 "Key binding interactions for memantine in the NMDA receptor". ACS Chemical Neuroscience 4 (2): 255–260. February 2013. doi:10.1021/cn300180a. PMID 23421676. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 "Memantine agonist action at dopamine D2High receptors". Synapse 62 (2): 149–153. February 2008. doi:10.1002/syn.20472. PMID 18000814. 
  25. ↑ "Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat--a pharmacokinetic microdialysis study". European Journal of Pharmacology 262 (1–2): 21–26. September 1994. doi:10.1016/0014-2999(94)90023-x. PMID 7813574. 
  26. ↑ "Distinct effects of amantadine and memantine on dopaminergic transmission in the rat striatum". Neuroscience Letters 343 (3): 205–209. June 2003. doi:10.1016/S0304-3940(03)00398-7. PMID 12770697. 
  27. ↑ "Inhibition of human alpha 7 nicotinic acetylcholine receptors by open channel blockers of N-methyl-D-aspartate receptors". British Journal of Pharmacology 140 (7): 1313–1319. December 2003. doi:10.1038/sj.bjp.0705559. PMID 14645141. 
  28. ↑ 28.0 28.1 "Memantine has a nicotinic neuroprotective pathway in acute hippocampal slices after an NMDA insult". Toxicology in Vitro 84. October 2022. doi:10.1016/j.tiv.2022.105453. PMID 35944748. Bibcode: 2022ToxVi..8405453F. 
  29. ↑ 29.0 29.1 "Pharmacodynamics of memantine: an update". Current Neuropharmacology 6 (1): 55–78. March 2008. doi:10.2174/157015908783769671. PMID 19305788. 
  30. ↑ "The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease". International Journal of Geriatric Psychiatry 14 (1): 3–47. January 1999. doi:10.1002/(SICI)1099-1166(199901)14:1<3::AID-GPS897>3.0.CO;2-7. PMID 10029935. 
  31. ↑ "The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease". CNS Drug Reviews 9 (3): 275–308. 2003. doi:10.1111/j.1527-3458.2003.tb00254.x. PMID 14530799. 
  32. ↑ "Memantine: a review of its use in Alzheimer's disease". Drugs 66 (11): 1515–1534. 2006. doi:10.2165/00003495-200666110-00015. PMID 16906789. 
  33. ↑ "Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses". The Journal of Neuroscience 30 (33): 11246–11250. August 2010. doi:10.1523/JNEUROSCI.2488-10.2010. PMID 20720132. 
  34. ↑ 34.0 34.1 "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. November 2007. doi:10.1016/j.neuropharm.2007.07.013. PMID 17904591. 
  35. ↑ "Pathologically activated therapeutics for neuroprotection". Nature Reviews. Neuroscience 8 (10): 803–808. October 2007. doi:10.1038/nrn2229. PMID 17882256. 
  36. ↑ "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): 81–84. June 2001. doi:10.1016/S0304-3940(01)01872-9. PMID 11403963. 
  37. ↑ 37.0 37.1 37.2 "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons". The Journal of Pharmacology and Experimental Therapeutics 312 (3): 1195–1205. March 2005. doi:10.1124/jpet.104.077172. PMID 15522999. 
  38. ↑ "Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than n-methyl-D-aspartate receptors in rat hippocampal neurons". The Journal of Pharmacology and Experimental Therapeutics 312 (3): 1195–1205. March 2005. doi:10.1124/jpet.104.077172. PMID 15522999. 
  39. ↑ "Cognitive Enhancer Effects of Low Memantine Doses Are Facilitated by an Alpha7 Nicotinic Acetylcholine Receptor Agonist in Scopolamine-Induced Amnesia in Rats". Frontiers in Pharmacology 10: 73. 5 February 2019. doi:10.3389/fphar.2019.00073. PMID 30804787. 
  40. ↑ "Open-channel blockers at the human alpha4beta2 neuronal nicotinic acetylcholine receptor". Molecular Pharmacology 53 (3): 555–563. March 1998. doi:10.1124/mol.53.3.555. PMID 9495824. 
  41. ↑ "Neuronal nicotinic receptors: from structure to pathology". Progress in Neurobiology 74 (6): 363–396. December 2004. doi:10.1016/j.pneurobio.2004.09.006. PMID 15649582. 
  42. ↑ "Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat--a pharmacokinetic microdialysis study". European Journal of Pharmacology 262 (1–2): 21–26. September 1994. doi:10.1016/0014-2999(94)90023-x. PMID 7813574. 
  43. ↑ "Memantine Ki values". UNC. https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=Memantine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query. 
  44. ↑ "Involvement of the sigma 1 receptor in the modulation of dopaminergic transmission by amantadine". The European Journal of Neuroscience 19 (8): 2212–2220. April 2004. doi:10.1111/j.0953-816X.2004.03297.x. PMID 15090047. 
  45. ↑ "Pharms - Memantine (also Namenda): Erowid Exp: Main Index". https://erowid.org/experiences/subs/exp_Pharms_Memantine.shtml. 
  46. ↑ 46.00 46.01 46.02 46.03 46.04 46.05 46.06 46.07 46.08 46.09 46.10 46.11 46.12 46.13 46.14 46.15 46.16 Cite error: Invalid <ref> tag; no text was provided for refs named Schmitt_2007
  47. ↑ "Nascent pharmacological advancement in adamantane derivatives". Archiv der Pharmazie 357 (3). March 2024. doi:10.1002/ardp.202300595. PMID 38128028. 
  48. ↑ 48.0 48.1 "Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials". Journal of Neural Transmission 128 (2): 127–169. February 2021. doi:10.1007/s00702-021-02306-2. PMID 33624170. 
  49. ↑ "Actoprotector and Adaptogen Properties of Adamantane Derivatives (A Review)". Pharmaceutical Chemistry Journal 35 (5): 235–238. May 2001. doi:10.1023/A:1011905302667. 
  50. ↑ "The Adamantyl Group in Medicinal Agents. I. Hypoglycemic N-Arylsulfonyl-N'-adamantylureas". Journal of Medicinal Chemistry 6 (6): 760–763. November 1963. doi:10.1021/jm00342a029. PMID 14184942. 
  51. ↑ The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. 2014. p. 432. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA432. Retrieved 2024-09-12. 
  52. ↑ "Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels". European Journal of Pharmacology 166 (3): 591–592. August 1989. doi:10.1016/0014-2999(89)90385-3. PMID 2553441. 
  53. ↑ 53.0 53.1 "Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist--a review of preclinical data". Neuropharmacology 38 (6): 735–767. June 1999. doi:10.1016/s0028-3908(99)00019-2. PMID 10465680. 
  54. ↑ "[Pharmacodynamics and pharmacokinetics of memantine]" (in de). Arzneimittel-Forschung 33 (8): 1122–1134. 1983. OCLC 115684407. PMID 6357202. 
  55. ↑ 55.0 55.1 "Studies on the mechanism of action of the antiparkinsonian drugs memantine and amantadine: no evidence for direct dopaminomimetic or antimuscarinic properties". Archives Internationales de Pharmacodynamie et de Thérapie 320: 21–42. 1992. PMID 1284458. 
  56. ↑ "Form 10-KSB For the fiscal year ended June 30, 1996". SEC Edgar. 30 September 1996. https://www.sec.gov/Archives/edgar/data/918112/0000950005-96-000781.txt.  NTI-Children's license is included in the filing.
  57. ↑ "Cash is king, focus is queen". Silicon Valley Business Journal. 9 January 2000. http://www.bizjournals.com/sanjose/stories/2000/01/10/smallb1.html. 
  58. ↑ "Lundbeck signs memantine licensing agreement for Merz+Co". The Pharma Letter. 15 August 2000. http://www.thepharmaletter.com/article/lundbeck-signs-memantine-licensing-agreement-for-merz-co. 
  59. ↑ "Namenda Sales Data". Drugs.com. February 2014. https://www.drugs.com/stats/namenda. 
  60. ↑ "Evaluating Prescription Drugs Used to Treat: Alzheimer's Disease. Comparing Effectiveness, Safety, and Price.". Consumer Reports Health. May 2012. http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/AlzheimersFINAL.pdf. 
  61. ↑ "Forest Laboratories' Namenda Is Focus of Lawsuit". The New York Times. 15 September 2014. https://www.nytimes.com/2014/09/16/business/new-york-files-antitrust-suit-against-maker-of-alzheimers-drug.html. 
  62. ↑ "Drug Product Life-Cycle Management as Anticompetitive Behavior: The Case of Memantine". Journal of Managed Care & Specialty Pharmacy 22 (4): 339–344. April 2016. doi:10.18553/jmcp.2016.22.4.339. PMID 27023687. 
  63. ↑ "Actavis Confirms Appeals Court Ruling Requiring Continued Distribution of Namenda IR". Actavis. 22 May 2015. https://www.allergan.com/news/news/thomson-reuters/actavis-confirms-appeals-court-ruling-requiring-co. 
  64. ↑ "Actavis, Others Plotted To Delay Generic Namenda, Suit Says". Law360. 9 June 2015. https://www.law360.com/articles/665234/actavis-others-plotted-to-delay-generic-namenda-suit-says. 
  65. ↑ "Second Circuit Denies Petition for Actavis Rehearing | David Kleban". Patterson Belknap Webb & Tyler LLP. 12 August 2015. https://www.pbwt.com/david-kleban/antitrust-update-blog-2/second-circuit-denies-petition-for-actavis-rehearing/. 
  66. ↑ 66.0 66.1 66.2 66.3 66.4 "From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis 6 (7–8): 614–632. 2014. doi:10.1002/dta.1620. PMID 24678061. 
  67. ↑ "Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans". Neuropharmacology 142: 89–115. November 2018. doi:10.1016/j.neuropharm.2018.01.049. PMID 29427652. 
  68. ↑ "Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine". Behavioural Pharmacology 9 (3): 231–243. May 1998. OCLC 121220269. PMID 9832937. 
  69. ↑ "Memantine misuse and social networks: A content analysis of Internet self-reports". Pharmacoepidemiology and Drug Safety 29 (9): 1189–1193. September 2020. doi:10.1002/pds.5070. PMID 32602152. 
  70. ↑ 70.0 70.1 "International brands for memantine". Drugs.com. https://www.drugs.com/international/memantine.html. 
  71. ↑ 71.0 71.1 71.2 "A systematic review of off-label uses of memantine for psychiatric disorders". Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (6): 1362–1374. August 2008. doi:10.1016/j.pnpbp.2008.01.008. PMID 18262702. 
  72. ↑ "Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder". The Cochrane Database of Systematic Reviews 9 (9). September 2021. doi:10.1002/14651858.CD011612.pub3. PMID 34510411. 
  73. ↑ "Efficacy of off-label augmentation in unipolar depression: A systematic review of the evidence". European Neuropsychopharmacology 27 (5): 423–441. May 2017. doi:10.1016/j.euroneuro.2017.03.003. PMID 28318897. 
  74. ↑ "A Meta-Analysis of Memantine for Depression". Journal of Alzheimer's Disease 57 (1): 113–121. 2017. doi:10.3233/JAD-161251. PMID 28222534. 
  75. ↑ "Acetylcholinesterase inhibitors and memantine in bipolar disorder: A systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions". Journal of Affective Disorders 197: 268–280. June 2016. doi:10.1016/j.jad.2016.03.034. PMID 27010579. https://kclpure.kcl.ac.uk/portal/en/publications/701407e1-19a7-41c7-95c0-294f8da2fdac. 
  76. ↑ "Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials". Journal of Psychiatric Research 143: 230–238. November 2021. doi:10.1016/j.jpsychires.2021.09.018. PMID 34509090. 
  77. ↑ "The efficacy and tolerability of memantine for depressive symptoms in major mental diseases: A systematic review and updated meta-analysis of double-blind randomized controlled trials". Journal of Affective Disorders 306: 182–189. June 2022. doi:10.1016/j.jad.2022.03.047. PMID 35331821. 
  78. ↑ "Memantine as an Augmentation Treatment for Schizophrenia: Limitations of Meta-Analysis for Evidence-Based Evaluation of Research". The Journal of Clinical Psychiatry 78 (9): e1307–e1309. 2017. doi:10.4088/JCP.17f11998. PMID 29178686. 
  79. ↑ "Anti-Dementia Drugs for Psychopathology and Cognitive Impairment in Schizophrenia: A Systematic Review and Meta-Analysis". The International Journal of Neuropsychopharmacology 21 (8): 748–757. August 2018. doi:10.1093/ijnp/pyy045. PMID 29762677. 
  80. ↑ "Adjunctive memantine for major mental disorders: A systematic review and meta-analysis of randomized double-blind controlled trials". Schizophrenia Research 209: 12–21. July 2019. doi:10.1016/j.schres.2019.05.019. PMID 31164254. 
  81. ↑ 81.0 81.1 81.2 81.3 "Glutamatergic drugs in Parkinson's disease". Life Sciences 55 (25–26): 2067–2075. January 1994. doi:10.1016/0024-3205(94)00387-4. PMID 7997066. 
  82. ↑ "[Effects of intravenous administration of memantine in parkinsonian patients (author's transl)]" (in German). Arzneimittel-Forschung 27 (7): 1487–1489. July 1977. PMID 332193. 
  83. ↑ "[Effects of oral memantine administration on Parkinson symptoms. Results of a placebo-controlled multicenter study]" (in de). Deutsche Medizinische Wochenschrift 109 (25): 987–990. June 1984. doi:10.1055/s-2008-1069311. PMID 6734455. 
  84. ↑ "Memantine - Children's Medical Center Corporation/Merz Pharma". 5 November 2023. https://adisinsight.springer.com/drugs/800006923. 
  85. ↑ 85.0 85.1 85.2 "N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer's disease, vascular dementia and Parkinson's disease". Current Alzheimer Research 9 (6): 746–758. July 2012. doi:10.2174/156720512801322564. PMID 21875407. 
  86. ↑ 86.0 86.1 "Effect of memantine (NMDA antagonist) on Parkinson's disease: a double-blind crossover randomized study". Clinical Neuropharmacology 22 (5): 273–276. 1999. PMID 10516877. 
  87. ↑ "Non-Dopaminergic Treatments for Motor Control in Parkinson's Disease: An Update". CNS Drugs 34 (10): 1025–1044. October 2020. doi:10.1007/s40263-020-00754-0. PMID 32785890. 
  88. ↑ "Chapter 3 - Amantadine and antiglutamatergic drugs in the management of Parkinson's disease". Parkinson's Disease: Current and Future Therapeutics and Clinical Trials. Cambridge medicine. Cambridge University Press. 2016. p. 16. ISBN 978-1-107-05386-1. https://books.google.com/books?id=hGOSCwAAQBAJ&pg=PA16. Retrieved 12 September 2024. 
  89. ↑ "Unexpected improvement in levodopa-induced dyskinesia and on-off phenomena after introduction of memantine for treatment of Parkinson's disease dementia". Journal of the American Geriatrics Society 61 (1): 170–172. January 2013. doi:10.1111/jgs.12058. PMID 23311565. 
  90. ↑ "Are NMDA antagonistic properties relevant for antiparkinsonian-like activity in rats?--case of amantadine and memantine". Journal of Neural Transmission. Parkinson's Disease and Dementia Section 7 (3): 155–166. October 1994. doi:10.1007/BF02253435. PMID 7710668. 
  91. ↑ "Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson's disease". Journal of Neural Transmission. Parkinson's Disease and Dementia Section 4 (4): 277–282. 1992. doi:10.1007/BF02260076. PMID 1388698. 
  92. ↑ 92.0 92.1 "Therapeutics in the Pipeline Targeting α-Synuclein for Parkinson's Disease". Pharmacological Reviews 74 (1): 207–237. January 2022. doi:10.1124/pharmrev.120.000133. PMID 35017177. 
  93. ↑ 93.0 93.1 "Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2022 Update". Journal of Parkinson's Disease 12 (4): 1073–1082. 2022. doi:10.3233/JPD-229002. PMID 35527571. 
  94. ↑ Clinical trial number NCT03858270 for "Inhibition of α-synuclein Cell-cell Transmission by NMDAR Blocker, Memantine" at ClinicalTrials.gov
  95. ↑ "Treatment of dementia with Lewy bodies and Parkinson's disease dementia". Drugs & Aging 28 (10): 769–777. October 2011. doi:10.2165/11594110-000000000-00000. PMID 21970305. 
  96. ↑ "Current Treatment Options for Alzheimer's Disease and Parkinson's Disease Dementia". Current Neuropharmacology 14 (4): 326–338. 2016. doi:10.2174/1570159x14666151208112754. PMID 26644155. 
  97. ↑ "Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis". Journal of Neurology, Neurosurgery, and Psychiatry 86 (2): 135–143. February 2015. doi:10.1136/jnnp-2014-307659. PMID 24828899. 
  98. ↑ "Disorders of diminished motivation". The Journal of Head Trauma Rehabilitation 20 (4): 377–388. 2005. doi:10.1097/00001199-200507000-00009. PMID 16030444. 
  99. ↑ "The role of dopamine in the pathophysiology and treatment of apathy". Motivation - Theory, Neurobiology and Applications. Progress in Brain Research. 229. 2016. pp. 389–426. doi:10.1016/bs.pbr.2016.05.007. ISBN 978-0-444-63701-7. 
  100. ↑ "Pharmacological Therapy for Apathy in Alzheimer's Disease: A Systematic Review and Meta-Analysis". The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques 44 (3): 267–275. May 2017. doi:10.1017/cjn.2016.426. PMID 28148339. 
  101. ↑ "Apathy in Dementia: Systematic Review of Recent Evidence on Pharmacological Treatments". Current Psychiatry Reports 18 (11): 103. November 2016. doi:10.1007/s11920-016-0737-7. PMID 27726067. 
  102. ↑ "Methylphenidate and Other Pharmacologic Treatments for Apathy in Alzheimer's Disease". The Journal of Clinical Psychiatry 83 (1). February 2022. doi:10.4088/JCP.22f14398. PMID 35120284. 
  103. ↑ "Pharmacological Management of Apathy in Dementia". CNS Drugs 36 (2): 143–165. February 2022. doi:10.1007/s40263-021-00883-0. PMID 35006557. 
  104. ↑ "Aminoadamantanes: from treatment of Parkinson's and Alzheimer's disease to symptom amelioration of long COVID-19 syndrome?". Expert Review of Clinical Pharmacology 16 (2): 101–107. February 2023. doi:10.1080/17512433.2023.2176301. PMID 36726198. 
  105. ↑ "Evaluation and treatment approaches for neurological post-acute sequelae of COVID-19: A consensus statement and scoping review from the global COVID-19 neuro research coalition". Journal of the Neurological Sciences 454. November 2023. doi:10.1016/j.jns.2023.120827. PMID 37856998. 
  106. ↑ "Alternative treatment strategies for catatonia: A systematic review". General Hospital Psychiatry 48: 1–19. September 2017. doi:10.1016/j.genhosppsych.2017.06.011. PMID 28917389. 
  107. ↑ "Memantine and catatonia: a case report and literature review". Journal of Psychiatric Practice 17 (4): 292–299. July 2011. doi:10.1097/01.pra.0000400268.60537.5e. PMID 21775832. 
  108. ↑ "Can Memantine Improve Catatonia and Co-occurring Cognitive Dysfunction? A Case Report and Brief Literature Review". Psychosomatics 61 (6): 759–763. 2020. doi:10.1016/j.psym.2020.05.026. PMID 32665151. 
  109. ↑ "NMDA antagonist agents for the treatment of symptoms in autism spectrum disorder: a systematic review and meta-analysis". Frontiers in Pharmacology 15. 2024-07-23. doi:10.3389/fphar.2024.1395867. PMID 39108755. 
  110. ↑ "Memantine for autism spectrum disorder". The Cochrane Database of Systematic Reviews 8 (8). August 2022. doi:10.1002/14651858.CD013845.pub2. PMID 36006807. 

Further reading

  • "The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism". Current Alzheimer Research 2 (2): 155–165. April 2005. doi:10.2174/1567205053585846. PMID 15974913. 



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