Amantadine

Amantadine
Clinical data
Trade names Symmetrel
Synonyms 1-Adamantylamine
AHFS/Drugs.com Monograph
MedlinePlus a682064
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    administration    		 Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability 86–90%[1]
    Protein binding 67%[1]
    Metabolism Minimal (mostly to acetyl metabolites)[1]
    Elimination half-life 10–31 hours[1]
    Excretion Urine[1]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard 100.011.092 Edit this at Wikidata
    Chemical and physical data
    Formula C10H17N
    Molar mass 151.249 g/mol
    3D model (JSmol)
      (verify)

    Amantadine (trade name Symmetrel, by Endo Pharmaceuticals) is a medication that has U.S. Food and Drug Administration approval for use both as an antiviral and an antiparkinsonian medication. It is the organic compound 1-adamantylamine or 1-aminoadamantane, meaning it consists of an adamantane backbone that has an amino group substituted at one of the four methyne positions. Rimantadine is a closely related derivative of adamantane with similar biological properties.

    Apart from medical uses, this compound is useful as a building block in organic synthesis, allowing the insertion of an adamantyl group.

    According to the U.S. Centers for Disease Control and Prevention (CDC) 100% of seasonal H3N2 and 2009 pandemic flu samples tested showed resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza in the United States. Additionally, its effectiveness as an antiparkinsonian drug is undetermined, with a 2003 Cochrane Review concluding that there was insufficient evidence in support of or against its efficacy and safety.[2]

    Medical uses

    Parkinson's disease

    Amantadine is used to treat Parkinson's disease, as well as parkinsonism syndromes.[3] A 2003 Cochrane review concluded evidence was inadequate to support the use of amantadine for Parkinson's disease.[2]

    An extended release formulation is used to treat dyskinesia, a side effect of levodopa which is taken by people who have Parkinsons.[4]

    Influenza

    Amantadine is no longer recommended for treatment of influenza A infection. For the 2008/2009 flu season, the CDC found that 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes.[5] The CDC issued an alert to doctors to prescribe the neuraminidase inhibitors oseltamivir and zanamivir instead of amantadine and rimantadine for treatment of flu.[6][7] A 2014 Cochrane review did not find benefit for the prevention or treatment of influenza A.[8]

    Fatigue in multiple sclerosis

    Amantadine also seems to have moderate effects on multiple sclerosis (MS) related fatigue.[9]

    Adverse effects

    Amantadine has been associated with several central nervous system (CNS) side effects, likely due to amantadine's dopaminergic and adrenergic activity, and to a lesser extent, its activity as an anticholinergic. CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson's disease. The usefulness of amantadine as an anti-parkinsonian drug is somewhat limited by the need to screen patients for a history of seizures and psychiatric symptoms.

    Rare cases of severe skin rashes, such as Stevens-Johnson syndrome,[10] and of suicidal ideation have also been reported in patients treated with amantadine.[11][12]

    Livedo reticularis is a possible side effect of amantadine use for Parkinson's disease.[13]

    Mechanism of action

    Influenza

    The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated. The mechanism of amantadine's antiviral activity involves interference with the viral protein, M2, a proton channel.[14][15] After entry of the virus into cells via endocytosis, it is localized in acidic vacuoles; the M2 channel functions in transporting protons with the gradient from the vacuolar space into the interior of the virion. Acidification of the interior results in disassociation of ribonucleoproteins, and the initiation of viral replication. Amantadine and rimantadine function in a mechanistically identical fashion in entering the barrel of the tetrameric M2 channel, and blocking pore function (i.e., proton translocation). Resistance to the drug class is a consequence of mutations to the pore-lining residues of the channel, leading to the inability of the sterically bulky adamantane ring that both amantadine and rimantadine share, in entering in their usual way, into the channel.

    Influenza B strains possess a structurally distinct M2 channels with channel-facing side chains that fully obstruct the channel vis-a-vis binding of adamantine-class channel inhibitors, while still allowing proton flow and channel function to occur; this constriction in the channels is responsible for the ineffectiveness of this drug and rimantadine towards all circulating Influenza B strains.

    Parkinson's disease

    Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.[16] Amantadine probably does not inhibit MAO enzyme.[17] Moreover, the mechanism of its antiparkinsonian effect is poorly understood[18]. The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist[19][20] as well as an anticholinergic, specifically a nicotinic alpha-7 antagonist like the similar pharmaceutical memantine.

    In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the σ1 receptor (Ki = 7.44 µM and 2.60 µM, respectively), and that activation of the σ1 receptor is involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations.[21] These findings may also extend to the other adamantanes such as adapromine, rimantadine, and bromantane, and could explain the psychostimulant-like effects of this family of compounds.[21]

    History

    Amantadine was approved by the U.S. Food and Drug Administration in October 1966 as a prophylactic agent against Asian influenza, and eventually received approval for the treatment of influenzavirus A[22][23][24][25] in adults. In 1969, the drug was also discovered by accident upon trying to help reduce symptoms of Parkinson's disease, drug-induced extrapyramidal syndromes, and akathisia.

    In 2017, the U.S. Food and Drug Administration approved the use of amantadine in an extended release formulation developed by Adamas Pharma for the treatment of dyskinesia, an adverse effect of levodopa, that people with Parkinson's experience.[26]

    Veterinary misuse

    In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.[27] In Western countries and according to international livestock regulations, amantadine is approved only for use in humans. Chickens in China have received an estimated 2.6 billion doses of amantadine.[27] Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine, although strains circulating elsewhere still seem to be sensitive. If amantadine-resistant strains of the virus spread, the drugs of choice in an avian flu outbreak will probably be restricted to neuraminidase inhibitors oseltamivir and zanamivir which block the action of viral neuraminidase enzyme on the surface of influenza virus particles.[28] However, there is an increasing incidence of oseltamivir resistance in circulating influenza strains (e.g.: H1N1), highlighting the serious need for the development of new anti-influenza therapies.[29]

    On September 23, 2015, the US Food and Drug Administration announced the recall of Dingo Chip Twists "Chicken in the Middle" dog treats because the product has the potential to be contaminated with amantadine.[30]

    See also

    References

    1. 1 2 3 4 5 "SYMMETREL® (amantadine hydrochloride)" (PDF). TGA eBusiness Services. NOVARTIS Pharmaceuticals Australia Pty Limited. 29 June 2011. Retrieved 24 February 2014.
    2. 1 2 Crosby, Niall J; Deane, Katherine; Clarke, Carl E (2003). Clarke, Carl E, ed. "Amantadine in Parkinson's disease". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD003468.
    3. ↑ "Amantadine – FDA prescribing information,". Drugs.com. Retrieved 2017-08-28.
    4. ↑ "Amantadine extended release capsules" (PDF). FDA. August 2017. For label updates, see FDA index page for NDA 208944
    5. ↑ CDC weekly influenza report – week 35, cdc.gov
    6. ↑ "CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season". CDC Health Alert. Centers for Disease Control and Prevention. 2006-01-14. Archived from the original on 2008-05-03. Retrieved 2008-05-20.
    7. ↑ Deyde, Varough M.; Xu, Xiyan; Bright, Rick A.; Shaw, Michael; Smith, Catherine B.; Zhang, Ye; Shu, Yuelong; Gubareva, Larisa V.; Cox, Nancy J.; Klimov, Alexander I. (2007). "Surveillance of Resistance to Adamantanes among Influenza A(H3N2) and A(H1N1) Viruses Isolated Worldwide". Journal of Infectious Diseases. 196 (2): 249–257. doi:10.1086/518936. PMID 17570112.
    8. ↑ Alves Galvão, MG; Rocha Crispino Santos, MA; Alves da Cunha, AJ (21 November 2014). "Amantadine and rimantadine for influenza A in children and the elderly". The Cochrane Database of Systematic Reviews. 11: CD002745. doi:10.1002/14651858.CD002745.pub4. PMID 25415374.
    9. ↑ Braley, TJ; Chervin, RD (Aug 2010). "Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment". Sleep. 33 (8): 1061–7. PMC 2910465. PMID 20815187.
    10. ↑ Singhal, KC; Rahman, SZ (2002). "Stevens Johnson Syndrome Induced by Amantadine". Rational Drug Bulletin. 12 (1): 6.
    11. ↑ "Symmetrel (Amantadine) Prescribing Information" (PDF). Endo Pharmaceuticals. May 2003. Retrieved 2007-08-02.
    12. ↑ Cook, PE; Dermer, SW; McGurk, T (1986). "Fatal overdose with amantadine". Canadian Journal of Psychiatry. 31 (8): 757–8. PMID 3791133.
    13. ↑ Vollum, DI; Parkes, JD; Doyle, D (June 1971). "Livedo reticularis during amantadine treatment". Br Med J. 2 (5762): 627–8. doi:10.1136/bmj.2.5762.627. PMC 1796527. PMID 5580722.
    14. ↑ Wang C, Takeuchi K, Pinto LH, Lamb RA (1993). "Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block". Journal of Virology. 67 (9): 5585–94. PMC 237962. PMID 7688826.
    15. ↑ Jing X, Ma C, Ohigashi Y, et al. (2008). "Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel". Proc. Natl. Acad. Sci. U.S.A. 105 (31): 10967–72. doi:10.1073/pnas.0804958105. PMC 2492755. PMID 18669647.
    16. ↑ Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. p. 3962. ISBN 978-3-85200-181-4.
    17. ↑ Strömberg, U.; Svensson, T. H. (November 1971). "Further Studies on the Mode of Action of Amantadine". wiley.com. Acta Pharmacologica et Toxicologica, Nordic Pharmacological Society. 30 (3–4): 161–171. doi:10.1111/j.1600-0773.1971.tb00646.x.
    18. ↑ https://www.ncbi.nlm.nih.gov/mesh/68000547
    19. ↑ Kornhuber, J; Bormann, J; Hübers, M; Rusche, K; Riederer, P (1991). "Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study". Eur. J. Pharmacol. Mol. Pharmacol. Sect. 206: 297–300. doi:10.1016/0922-4106(91)90113-v.
    20. ↑ Blanpied, TA; Clarke, RJ; Johnson, JW (2005). "Amantadine inhibits NMDA receptors by accelerating channel closure during channel block". Journal of Neuroscience. 25 (13): 3312–22. doi:10.1523/JNEUROSCI.4262-04.2005. PMID 15800186.
    21. 1 2 Peeters, Magali; Romieu, Pascal; Maurice, Tangui; Su, Tsung-Ping; Maloteaux, Jean-Marie; Hermans, Emmanuel (2004). "Involvement of the sigma1 receptor in the modulation of dopaminergic transmission by amantadine". European Journal of Neuroscience. 19 (8): 2212–2220. doi:10.1111/j.0953-816X.2004.03297.x. ISSN 0953-816X. PMID 15090047.
    22. ↑ Hounshell, David A.; Kenly Smith, John (1988). Science and Corporate Strategy: Du Pont R&D, 1902–1980. Cambridge University Press. p. 469.
    23. ↑ "Sales of flu drug by du Pont unit a 'disappointment'". The New York Times. Wilmington, Delaware. October 5, 1982. Retrieved May 19, 2008.
    24. ↑ Maugh, T. (1979). "Panel urges wide use of antiviral drug". Science. 206 (4422): 1058–60. doi:10.1126/science.386515. PMID 386515.
    25. ↑ Maugh, T. H. (1976). "Amantadine: an Alternative for Prevention of Influenza". Science. 192 (4235): 130–1. doi:10.1126/science.192.4235.130. PMID 17792438.
    26. ↑ Bastings, Eric. "NDA 208944 Approval Letter" (PDF).
    27. 1 2 Sipress, Alan (2005-06-18). "Bird Flu Drug Rendered Useless". Washington Post. pp. A01. Retrieved 2007-08-02.
    28. ↑ Kumar (April 2018). "The emerging influenza virus threat: status and new prospects for its therapy and control". Archives of Virology (4): 831–844. doi:10.1007/s00705-018-3708-y.
    29. ↑ Aoki (2007). "Influenza virus susceptibility and resistance to oseltamivir". PMID 17944268.
    30. ↑ "Enforcement Report – Week of September 23, 2015". FDA.gov. US Food and Drug Administration, US Department of Health & Human Services.

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