Amantadine


Amantadine
Amantadine
Systematic (IUPAC) name
adamantan-1-amine
Clinical data
Trade names Symmetrel
AHFS/Drugs.com monograph
MedlinePlus a682064
Pregnancy cat. C
Legal status -only (US)
Routes oral
Pharmacokinetic data
Bioavailability well absorbed
Protein binding approx 67%
Metabolism negligible
Half-life 10-14 hours, in renal impairment up to 7-10 days
Excretion renal
Identifiers
CAS number 768-94-5 YesY
ATC code N04BB01
PubChem CID 2130
DrugBank APRD00787
ChemSpider 2045 YesY
UNII BF4C9Z1J53 YesY
KEGG D07441 YesY
ChEBI CHEBI:2618 YesY
ChEMBL CHEMBL660 YesY
Synonyms 1-Adamantylamine
Chemical data
Formula C10H17N 
Mol. mass 151.249 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Amantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an antiparkinsonian drug. Rimantadine is a closely related derivative of adamantane with similar biological properties.

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

According to the US Centers for Disease Control and Prevention, 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. Additionally, its effectiveness as an antiparkinsonian drug is controversial, with a 2003 Cochrane Review concluding that it was ineffective for this purpose.[1]

Contents

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[2][3][4][5] 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.

Indications

Parkinson

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).

Contrary to its continued use, a 2003 Cochrane review of the scientific literature concluded that there is inadequate evidence to support the use of amantadine for Parkinson's.[1]

Influenza

Amantadine is no longer recommended for treatment of influenza B infection.

For the 2008/2009 flu season, the United States' Centers for Disease Control and Prevention (CDC) found that 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes.[6] The CDC issued an alert to doctors to prescribe the neuraminidase inhibitors oseltamivir and zanamivir instead of amantadine and rimantadine for treatment of current circulating flu.[7][8]

Off-label uses

Amantadine is frequently used to treat the chronic fatigue often experienced by patients with multiple sclerosis.[9] Additionally, there have been anecdotal reports that low-dose amantadine has been successfully used to treat ADHD.[10] Limited data has shown that amantadine may help to relieve SSRI-induced sexual dysfunction.[11][12][13]

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[14] and suicidal ideation in patients treated with amantadine have also been reported.[15][16]

Livedo reticularis is a possible side effect of amantadine use for Parkinson's disease.[17]

Physical and chemical properties

Synthesis

Amantadine may be prepared by reacting adamantane with bromine or nitric acid to give the bromide or nitroester at position one. Reaction of either compound with acetonitrile affords the acetamide, which is hydrolyzed to give 1-adamantylamine:[18][19][20]

Preparation of amantadine.png

Dosage and mechanism of action

A starting dose is often 100 mg once daily. All influenza B strains, many influenza A strains (and virtually all H1N1 "swine flu" strains) are resistant to amantadine, so a failure at this dose is likely due to resistance and not underdosing. For its anti-Parkinsonian effects, a starting dose of 300 mg once daily is normal, but can be increased to a limit of about 400 mg.

The mechanisms for amantadine's antiviral and antiparkinsonian effects appear to be unrelated.

  • The mechanism of Amantadine's antiviral activity involves interference with a viral protein, M2 (an ion channel),[21][22] which is required for the viral particle to become "uncoated" once taken inside a cell by endocytosis.

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 monoaminoxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels.[citation needed]

Veterinary misuse

In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.[25] 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.[25] 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.

References

  1. ^ 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. 
  2. ^ David A. Hounshell and John Kenly Smith, "Science and Corporate Strategy: Du Pont R&D, 1902-1980", 1988, Cambridge University Press, p. 469.
  3. ^ "Sales of flu drug by du Pont unit a 'disappointment'" (Last accessed May 19, 2008.) October 5, 1982, The New York Times.
  4. ^ Maugh, T. (1979). "Panel urges wide use of antiviral drug". Science 206 (4422): 1058–60. doi:10.1126/science.386515. PMID 386515. 
  5. ^ 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. 
  6. ^ CDC weekly influenza report - week 35, cdc.gov
  7. ^ "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. http://www.cdc.gov/flu/han011406.htm. Retrieved 2008-05-20. 
  8. ^ 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. 
  9. ^ Cohen, RA; Fisher, M (1989). "Amantadine treatment of fatigue associated with multiple sclerosis". Archives of neurology 46 (6): 676–80. PMID 2730380. 
  10. ^ Hallowell, Edward M. and John J. Ratey, Delivered from Distraction: Getting the Most out of Life with Attention Deficit Disorder (2005), pp. 253-5 ISBN 0-345-44230-X
  11. ^ Shrivastava RK, Shrivastava S, Overweg N, Schmitt M (1995). "Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors". Journal of clinical psychopharmacology 15 (1): 83–4. doi:10.1097/00004714-199502000-00014. PMID 7714234. 
  12. ^ Balogh S, Hendricks SE, Kang J (1992). "Treatment of fluoxetine-induced anorgasmia with amantadine". The Journal of clinical psychiatry 53 (6): 212–3. PMID 1607353. 
  13. ^ Keller Ashton A, Hamer R, Rosen RC (1997). "Serotonin reuptake inhibitor-induced sexual dysfunction and its treatment: a large-scale retrospective study of 596 psychiatric outpatients". Journal of sex & marital therapy 23 (3): 165–75. doi:10.1080/00926239708403922. PMID 9292832. 
  14. ^ K C Singhal & S Z Rahman, Stevens Johnson Syndrome induced by Amantadine, Rational Drug Bulletin, 2002, Vol. 12, No. 1: 6
  15. ^ Endo Pharmaceuticals (May 2003) (PDF). Symmetrel (Amantadine) Prescribing Information. http://www.symmetrel.com/PDF/symmetrel_pack_insert.pdf. Retrieved 2007-08-02. 
  16. ^ Cook, PE; Dermer, SW; McGurk, T (1986). "Fatal overdose with amantadine". Canadian Journal of Psychiatry 31 (8): 757–8. PMID 3791133. 
  17. ^ Vollum DI, Parkes JD, Doyle D (June 1971). Livedo reticularis during amantadine treatment. 2. pp. 627–8. PMC 1796527. PMID 5580722. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1796527. 
  18. ^ Moiseev, I. K.; Doroshenko, R. I.; Ivanova, V. I. (1976). "Synthesis of amantadine via the nitrate of 1-adamantanol". Pharmaceutical Chemistry Journal 10: 450. doi:10.1007/BF00757832.  edit
  19. ^ H. Stetter, J. Mayer, M. Schwarz, K. Wulf (1960). "Über Verbindungen mit Urotropin-Struktur, XVI. Beiträge zur Chemie der Adamantyl-(1)-Derivate". Chem. Ber. 93: 226. doi:10.1002/cber.19600930133. 
  20. ^ J.C. Watts, P. Marvin, U.S. Patent 3,310,469 (1967).
  21. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=237962. 
  22. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2492755. 
  23. ^ 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.
  24. ^ 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. 
  25. ^ a b Sipress, Alan (2005-06-18). "Bird Flu Drug Rendered Useless". Washington Post. pp. A01. http://www.washingtonpost.com/wp-dyn/content/article/2005/06/17/AR2005061701214.html. Retrieved 2007-08-02. 

See also


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Look at other dictionaries:

  • Amantadine — Général Nom IUPAC tricyclo[3.3.1.13,7]décan 1 amine No …   Wikipédia en Français

  • Amantadine — Strukturformel Allgemeines Freiname Amantadin Andere Namen …   Deutsch Wikipedia

  • amantadine — noun Etymology: International Scientific Vocabulary amantad (alteration of adamantane, C10H16) + amine Date: 1964 a drug used especially as the hydrochloride C10H17N•HCl to prevent infection (as by an influenza virus) by interfering with virus …   New Collegiate Dictionary

  • amantadine — (ah man tah den) An antiviral compound used to prevent type A influenza infections …   Dictionary of microbiology

  • amantadine — Used as an antiviral agent (especially against influenza virus). Produces some symptomatic relief in Parkinsonism …   Dictionary of molecular biology

  • amantadine — /euh man teuh deen /, n. Pharm. a water soluble crystalline substance, C10H17NHCl, used as an antiviral and antiparkinsonian drug. [1960 65; coinage appar. based on the chemical name 1 aminoadamantane; see AMINO , ADAMANTANE] * * * …   Universalium

  • amantadine — noun A polycyclic amine, 1 aminoadamantane, that is an antiviral drug used in the treatment of Parkinsons disease …   Wiktionary

  • amantadine — aman·ta·dine ə mant ə .dēn n a drug administered orally esp. in the form of its hydrochloride C10H17N·HCl to prevent infection (as by the virus causing influenza A) by interfering with virus penetration into host cells and in the treatment of… …   Medical dictionary

  • amantadine — aman·ta·dine …   English syllables

  • amantadine — n. an antiviral drug that increases the activity of dopamine in the brain and is used mainly to treat Parkinson s disease. Common side effects include nervousness, loss of muscular coordination, and insomnia. Trade names: Symmetrel …   The new mediacal dictionary


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