Amantadine

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Amantadine
Systematic (IUPAC) name
adamantan-1-amine
Clinical data
Trade namesSymmetrel
AHFS/Drugs.commonograph
MedlinePlusa682064
Pregnancy cat.C
Legal status-only (US)
Routesoral
Pharmacokinetic data
Bioavailabilitywell absorbed
Protein bindingapprox 67%
Metabolismnegligible
Half-life10–14 hours, in renal impairment up to 7–10 days
Excretionrenal
Identifiers
CAS number768-94-5 YesY
ATC codeN04BB01
PubChemCID 2130
DrugBankDB00915
ChemSpider2045 YesY
UNIIBF4C9Z1J53 YesY
KEGGD07441 YesY
ChEBICHEBI:2618 YesY
ChEMBLCHEMBL660 YesY
Synonyms1-Adamantylamine
Chemical data
FormulaC10H17N 
Mol. mass151.249 g/mol
 YesY (what is this?)  (verify)
 
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Amantadine
Systematic (IUPAC) name
adamantan-1-amine
Clinical data
Trade namesSymmetrel
AHFS/Drugs.commonograph
MedlinePlusa682064
Pregnancy cat.C
Legal status-only (US)
Routesoral
Pharmacokinetic data
Bioavailabilitywell absorbed
Protein bindingapprox 67%
Metabolismnegligible
Half-life10–14 hours, in renal impairment up to 7–10 days
Excretionrenal
Identifiers
CAS number768-94-5 YesY
ATC codeN04BB01
PubChemCID 2130
DrugBankDB00915
ChemSpider2045 YesY
UNIIBF4C9Z1J53 YesY
KEGGD07441 YesY
ChEBICHEBI:2618 YesY
ChEMBLCHEMBL660 YesY
Synonyms1-Adamantylamine
Chemical data
FormulaC10H17N 
Mol. mass151.249 g/mol
 YesY (what is this?)  (verify)

Amantadine (trade name Symmetrel, by Endo Pharmaceuticals) is a drug that has US 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, 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 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 or against its efficacy and safety.[1]

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[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[edit]

Parkinson's disease[edit]

Amantadine is a weak antagonist of the NMDA type glutamate receptor, increases dopamine release, and blocks dopamine reuptake. 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).

Despite a 2003 Cochrane review of the scientific literature concluding that there is inadequate evidence to support the use of amantadine for Parkinson's, the drug continues to be prescribed for this indication.[1]

Influenza[edit]

Amantadine is no longer recommended for treatment of influenza A 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[edit]

Amantadine is frequently used to treat the chronic fatigue often experienced by patients with multiple sclerosis.[9] Additionally, there have been anecdotal reports[10] and a small number of pilot studies[11][12] that show low-dose amantadine as a potential treatment for ADHD. Limited data has shown that amantadine may help to relieve SSRI-induced sexual dysfunction.[13][14][15]

Some open-label uncontrolled studies have found it to possess value as an adjunct to antidepressant therapy.[16]

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[17] and suicidal ideation in patients treated with amantadine have also been reported.[18][19]

Livedo reticularis is a possible side effect of amantadine use for Parkinson's disease.[20]

Physical and chemical properties[edit]

Synthesis[edit]

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:[21][22][23]

Preparation of amantadine.png

Dosage and mechanism of action[edit]

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.

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

Research in brain injury[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.[28]

Veterinary misuse[edit]

In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.[29] 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.[29] 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.

See also[edit]

References[edit]

  1. ^ a b Crosby, Niall J; Deane, Katherine; Clarke, Carl E (2003). "Amantadine in Parkinson's disease". In Clarke, Carl E. 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. Archived from the original on 3 May 2008. 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. doi:10.1001/archneur.1989.00520420096030. 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. ^ Mohammadi, MR; Kazemi MR, Zia E, Rezazadeh SA, Tabrizi M, Akhondzadeh S (November 2010). "Amantadine versus methylphenidate in children and adolescents with attention deficit/hyperactivity disorder: a randomized, double-blind trial". Human Psychopharmacology: Clinical and Experimental 25: 560–6. doi:10.1002/hup.1154. PMID 21312290. Retrieved 7 April 2013. 
  12. ^ Donfrancesco, Renato; Calderoni, D; Vitiello, B (2007). "Open-Label Amantadine in Children with Attention-Deficit/Hyperactivity Disorder". Journal of Child and Adolescent Psychopharmacology 17 (5): 657–663. doi:10.1089/cap.2006.0128. PMID 17979585. Retrieved 7 April 2013. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ Stryjer, R; Strous RD, Shaked G, Bar F, Feldman B, Kotler M, Polak L, Rosenzcwaig S, Weizman A (2003). "Amantadine as augmentation therapy in the management of treatment-resistant depression.". International Journal of Psychopharmacology 18 (2): 93–96. PMID 12598820. 
  17. ^ K C Singhal & S Z Rahman, Stevens Johnson Syndrome induced by Amantadine, Rational Drug Bulletin, 2002, Vol. 12, No. 1: 6
  18. ^ Endo Pharmaceuticals (May 2003). Symmetrel (Amantadine) Prescribing Information (PDF). Retrieved 2007-08-02. 
  19. ^ Cook, PE; Dermer, SW; McGurk, T (1986). "Fatal overdose with amantadine". Canadian Journal of Psychiatry 31 (8): 757–8. PMID 3791133. 
  20. ^ 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. 
  21. ^ Moiseev, I. K.; Doroshenko, R. I.; Ivanova, V. I. (1976). "Synthesis of amantadine via the nitrate of 1-adamantanol". Pharmaceutical Chemistry Journal 10 (4): 450. doi:10.1007/BF00757832.  edit
  22. ^ 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. 
  23. ^ J.C. Watts, P. Marvin, U.S. Patent 3,310,469 (1967).
  24. ^ 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. 
  25. ^ 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. 
  26. ^ 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.
  27. ^ 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. 
  28. ^ 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.  edit
  29. ^ a b Sipress, Alan (2005-06-18). "Bird Flu Drug Rendered Useless". Washington Post. pp. A01. Retrieved 2007-08-02.