Amantadine

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Amantadine
Amantadine.svg
Amantadine ball-and-stick model.png
Systematic (IUPAC) name
Adamantan-1-amine
Clinical data
Trade names Symmetrel
AHFS/Drugs.com Monograph
MedlinePlus a682064
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 86–90%[1]
Protein binding 67%[1]
Metabolism Minimal (mostly to acetyl metabolites)[1]
Biological half-life 10–31 hours[1]
Excretion Urine[1]
Identifiers
CAS Number 768-94-5 YesY
ATC code N04BB01 (WHO)
PubChem CID 2130
IUPHAR/BPS 4128
DrugBank DB00915 YesY
ChemSpider 2045 YesY
UNII BF4C9Z1J53 YesY
KEGG D07441 YesY
ChEBI CHEBI:2618 YesY
ChEMBL CHEMBL660 YesY
Synonyms 1-Adamantylamine
Chemical data
Formula C10H17N
Molar mass 151.249 g/mol
  (verify)

Amantadine (trade name Symmetrel, by Endo Pharmaceuticals) is a drug that has U.S. Food and Drug Administration approval for use both as an antiviral and an antiparkinsonian drug. 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 have shown 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[edit]

Parkinson's disease[edit]

Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.[3] This makes it a weak therapy for Parkinson's disease. Although, as an antiparkinsonian, it can be used as monotherapy, or together with L-DOPA to treat L-DOPA-related motor fluctuations (i.e., shortening of L-DOPA duration of clinical effect, probably related to progressive neuronal loss) and L-DOPA-related dyskinesias (choreiform movements associated with long-term L-DOPA use, probably related to chronic pulsatile stimulation of dopamine receptors).

A 2003 Cochrane review of the scientific literature concluded evidence was inadequate to support the use of amantadine for Parkinson's disease.[2]

Influenza[edit]

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.[4] The CDC issued an alert to doctors to prescribe the neuraminidase inhibitors oseltamivir and zanamivir instead of amantadine and rimantadine for treatment of flu.[5][6] A 2014 Cochrane review did not find benefit for the prevention or treatment of influenza A.[7]

Fatigue in multiple sclerosis[edit]

Amantadine also seems to have moderate effects on multiple sclerosis (MS) related fatigue.[8]

Adverse effects[edit]

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,[9] and of suicidal ideation have also been reported in patients treated with amantadine.[10][11]

Livedo reticularis is a possible side effect of amantadine use for Parkinson's disease.[12]

Mechanism of action[edit]

Influenza[edit]

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.[13][14] 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 to interior of the virion. Acidification of the interior results in disassociation of ribonucleoproteins, and the onset 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 share in entering in their usual way, into the channel.[citation needed]

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[edit]

Amantadine appears to act through several pharmacological mechanisms, but no dominant mechanism of action has been identified. It is a dopaminergic, noradrenergic and serotonergic substance, blocks NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels.[citation needed] Amantadine probably does not inhibit MAO enzyme.[15] Moreover, the mechanism of its antiparkinsonian effect is poorly understood.[citation needed] 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[16][17] 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.[18] 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.[18]

History[edit]

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[19][20][21][22] in adults. In 1969, the drug was also discovered by accident to help reduce symptoms of Parkinson's disease, drug-induced extrapyramidal syndromes, and akathisia.

Research[edit]

In a 2012 study, 184 patients with severe traumatic brain injury were treated with amantadine or placebo for four weeks. In this study, the drug accelerated functional brain recovery during treatment. However, the placebo group had improved just as much as the amantadine group at six weeks — two weeks after the drug administration ended.[23]

Veterinary misuse[edit]

In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.[24] 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.[24] 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 the scarcer and costlier oseltamivir and zanamivir, which work by a different mechanism and are less likely to trigger resistance.

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.[25]

See also[edit]

References[edit]

  1. ^ a b c d e "SYMMETREL® (amantadine hydrochloride)" (PDF). TGA eBusiness Services. NOVARTIS Pharmaceuticals Australia Pty Limited. 29 June 2011. Retrieved 24 February 2014. 
  2. ^ a b 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. ^ Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. p. 3962. ISBN 978-3-85200-181-4. 
  4. ^ CDC weekly influenza report - week 35, cdc.gov
  5. ^ "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 3 May 2008. Retrieved 2008-05-20. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ Braley, TJ; Chervin, RD (Aug 2010). "Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment.". Sleep. 33 (8): 1061–7. PMC 2910465free to read. PMID 20815187. 
  9. ^ Singhal, KC; Rahman, SZ (2002). "Stevens Johnson Syndrome Induced by Amantadine". Rational Drug Bulletin. 12 (1): 6. 
  10. ^ "Symmetrel (Amantadine) Prescribing Information" (PDF). Endo Pharmaceuticals. May 2003. Retrieved 2007-08-02. 
  11. ^ Cook, PE; Dermer, SW; McGurk, T (1986). "Fatal overdose with amantadine". Canadian Journal of Psychiatry. 31 (8): 757–8. PMID 3791133. 
  12. ^ 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 1796527free to read. PMID 5580722. 
  13. ^ 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 237962free to read. PMID 7688826. 
  14. ^ 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 2492755free to read. PMID 18669647. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. 
  18. ^ a b 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. 
  19. ^ Hounshell, David A.; Kenly Smith, John (1988). Science and Corporate Strategy: Du Pont R&D, 1902-1980. Cambridge University Press. p. 469. 
  20. ^ "Sales of flu drug by du Pont unit a 'disappointment'". The New York Times. Wilmington, Delaware. October 5, 1982. Retrieved May 19, 2008. 
  21. ^ Maugh, T. (1979). "Panel urges wide use of antiviral drug". Science. 206 (4422): 1058–60. doi:10.1126/science.386515. PMID 386515. 
  22. ^ 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. 
  23. ^ Giacino, J. T.; Whyte, J.; Bagiella, E.; Kalmar, K.; Childs, N.; Khademi, A.; Eifert, B.; Long, D.; Katz, D. I.; Cho, S.; Yablon, S. A.; Luther, M.; Hammond, F. M.; Nordenbo, A.; Novak, P.; Mercer, W.; Maurer-Karattup, P.; Sherer, M. (2012). "Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury". New England Journal of Medicine. 366 (9): 819–826. doi:10.1056/NEJMoa1102609. PMID 22375973. 
  24. ^ a b Sipress, Alan (2005-06-18). "Bird Flu Drug Rendered Useless". Washington Post. pp. A01. Retrieved 2007-08-02. 
  25. ^ "Enforcement Report - Week of September 23, 2015". FDA.gov. US Food and Drug Administration, US Department of Health & Human Services.