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Amantadine
Systematic (IUPAC) name
adamantan-1-amine
Identifiers
CAS number 768-94-5
ATC code N04BB01
PubChem 2130
DrugBank APRD00787
ChemSpider 2045
Chemical data
Formula C 10H17N 
Mol. mass 151.249 g/mol
SMILES eMolecules & PubChem
Synonyms 1-Adamantylamine
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
Therapeutic considerations
Pregnancy cat. C
Legal status
Routes oral
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Amantadine is the organic compound known formally as 1-aminoadamantane. The molecule consists of adamantane backbone that is substituted at one of the four methyne positions with an amino group. This compound 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 CDC, 100 percent of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes and it is no longer recommended to prescribe for treatment of the flu.

Contents

History

It 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[1][2][3][4] in adults. In 1969, the drug was also discovered by accident to help reduce symptoms of Parkinson's disease and drug-induced extrapyramidal syndromes.

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).

Off-label uses

Amantadine is frequently used to treat the characteristic fatigue often experienced by patients with multiple sclerosis.[5] Additionally, there have been anecdotal reports that low-dose amantadine has been successfully used to treat ADHD.[6] Amantadine has also been shown to relieve SSRI-induced sexual dysfunction.[7][8][9]

Misuse

In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.[10] 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.[10] Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine.

Resistance

For the the 2008/2009 flu season, the United States' Center for Disease Control [CDC] found that 100 percent of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to Adamantanes.[11]

The CDC issued an alert to doctors to prescribe the neuraminidase inhibitors Tamiflu and Relenza instead of Amantadine and Rimantadine for treatment of current circulating flu.[12][13]

Pharmacology

Preparation

Amantadine may be prepared by reacting adamantane with bromine or nitric acid to give the bromide or nitroester at the 1- position. Reaction of either compound with acetonitrile affords the acetamide, which is hydrolyzed to give 1-adamantylamine:[14]

Preparation of amantadine.png

Dosage and mechanism of action

A starting dose is often 100 mg once daily. Most influenza A 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 up to 400 mg.

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

  • The mechanism of Amantadine's antiviral activity involves interference with a viral protein, M2 (an ion channel),[15][16] which is required for the viral particle to become "uncoated" once taken inside a cell by endocytosis.

Possible side effects

Amantadine has been associated with several central nervous system 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 agent is somewhat limited by the need to screen patients for a history of seizures and psychiatric symptoms.

Rare cases of suicidal ideation in patients treated with amantadine have also been described.[18][19]

Another potential side effect is livedo reticularis, a dermatological reaction that results in skin mottling and purpurish mesh network of blood vessels.

References

  1. ^ David A. Hounshell and John Kenly Smith, "Science and Corporate Strategy: Du Pont R&D, 1902-1980", 1988, Cambridge University Press, p. 469. http://books.google.com/books?id=6ld0K9VNpmIC
  2. ^ "SALES OF FLU DRUG BY DU PONT UNIT A 'DISAPPOINTMENT'" (Last accessed May 19, 2008.) October 5, 1982, The New York Times.
  3. ^ Thomas H. Maugh. "Amantadine: An Alternative for Prevention of Influenza" Science. April 9, 1976. 192: 130-131. DOI: 10.1126/science.386515 Article (subscription required)
  4. ^ T.H. Maugh. "Panel urges wide use of antiviral drug" Science. November 30, 1979. 206: 1058-1060. DOI: 10.1126/science.192.4235.130 Article (subscription required)
  5. ^ Cohen RA, Fisher M. Amantadine treatment of fatigue associated with MS. Arch Neurol 1989;46:676–680
  6. ^ Hallowell, Edward M. and John J. Ratey, Delivered from Distraction: Getting the Most out of Life with Attention Deficit Disorder (2005), pp. 253-5.
  7. ^ Shrivastava RK, Shrivastava S, Overweg N, Schmitt M (February 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. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0271-0749&volume=15&issue=1&spage=83.  
  8. ^ Balogh S, Hendricks SE, Kang J (June 1992). "Treatment of fluoxetine-induced anorgasmia with amantadine". The Journal of clinical psychiatry 53 (6): 212–3. PMID 1607353.  
  9. ^ 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. PMID 9292832.  
  10. ^ 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.  
  11. ^ http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/weekly35.htm CDC weekly influenza report - week 35
  12. ^ "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.  
  13. ^ 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. (2007-07-15). "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. http://www.journals.uchicago.edu/doi/full/10.1086/518936. Retrieved 2008-05-19.  
  14. ^ I. K. Moiseev, R. I. Doroshenko and V. I. Ivanova (1976). "Synthesis of amantadine via the nitrate of 1-adamantanol". Pharmaceutical Chemistry Journal 10 (4): 450–451. doi:10.1007/BF00757832.  
  15. ^ Wang C, Takeuchi K, Pinto LH, Lamb RA (September 1993). "Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block". Journal of virology 67 (9): 5585–94. PMID 7688826. PMC 237962. http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=7688826.  
  16. ^ Jing X, Ma C, Ohigashi Y, et al. (August 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. PMID 18669647.  
  17. ^ Blanpied TA, Clarke RJ, Johnson JW (March 2005). "Amantadine inhibits NMDA receptors by accelerating channel closure during channel block". The Journal of neuroscience : the official journal of the Society for Neuroscience 25 (13): 3312–22. doi:10.1523/JNEUROSCI.4262-04.2005. PMID 15800186. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=15800186.  
  18. ^ Endo Pharmaceuticals (May 2003) (PDF). Symmetrel (Amantadine) Prescribing Information. http://www.symmetrel.com/PDF/symmetrel_pack_insert.pdf. Retrieved 2007-08-02.  
  19. ^ Cook et al., "Fatal overdose with amantadine". Can. J. Psychiatry (Nov 1986); 31(8), pp. 757-758.

See also








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