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Amantadine

Clinical data
Trade names	Symmetrel
Other names	1-Adamantylamine
AHFS/Drugs.com	Monograph
MedlinePlus	a682064
Pregnancy category	C
Routes of administration	oral
ATC code	N04BB01 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	well absorbed
Protein binding	approx 67%
Metabolism	negligible
Elimination half-life	10-14 hours, in renal impairment up to 7-10 days
Excretion	renal
Identifiers
IUPAC name adamantan-1-amine
CAS Number	768-94-5
PubChem CID	2130
DrugBank	DB00915
ChemSpider	2045
UNII	BF4C9Z1J53
KEGG	D07441
ChEBI	CHEBI:2618
ChEMBL	ChEMBL660
CompTox Dashboard (EPA)	DTXSID8022117
ECHA InfoCard	100.011.092
Chemical and physical data
Formula	C10H17N
Molar mass	151.249 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES NC13CC2CC(CC(C1)C2)C3
InChI InChI=1S/C10H17N/c11-10-4-7-1-8(5-10)3-9(2-7)6-10/h7-9H,1-6,11H2 Key:DKNWSYNQZKUICI-UHFFFAOYSA-N
(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.

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 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.

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. 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.

Off-label uses

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

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 and suicidal ideation in patients treated with amantadine have also been reported.

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

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:

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), which is required for the viral particle to become "uncoated" once taken inside a cell by endocytosis.

• The mechanism of its antiparkinsonian effect is poorly understood. 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 as well as an anticholinergic.

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.

Veterinary misuse

In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza. 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. 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. ^ 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. Retrieved 2008-05-20.
8. Deyde, Varough M. (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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). "Symmetrel (Amantadine) Prescribing Information" (PDF). Retrieved 2007-08-02. {{cite journal}}: Cite journal requires |journal= (help)
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 (1971). "Livedo reticularis during amantadine treatment". 2 (5762): 627–8. PMC 1796527. PMID 5580722. {{cite journal}}: Cite journal requires |journal= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
18. Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1007/BF00757832, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1007/BF00757832 instead.
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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
25. ^ Sipress, Alan (2005-06-18). "Bird Flu Drug Rendered Useless". Washington Post. pp. A01. Retrieved 2007-08-02.

See also

• Rimantadine
• Tromantadine

• Antiparkinsonian agents
• Amines
• Anti-influenza agents
• NMDA receptor antagonists
• Antivirals
• Adamantanes