Amantadine
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Amantadine
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| Systematic (IUPAC) name | |
| adamantan-1-amine | |
| Identifiers | |
| CAS number | |
| ATC code | N04 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | C10H17N |
| Mol. mass | 151.249 g/mol |
| 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 |
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.
Contents |
[edit] 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:[1]
[edit] Dosage
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.
[edit] Uses
[edit] Approved
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[2][3][4][5] 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).
[edit] Off-label uses
Amantadine is frequently used to treat the characteristic fatigue often experienced by patients with multiple sclerosis.[6] Additionally, there have been anecdotal reports that low-dose amantadine has been successfully used to treat ADHD.[7] Amantadine has also been shown to relieve SSRI-induced sexual dysfunction.[8][9][10]
[edit] 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 thus limited by the need to screen patients for a history of seizures and psychiatric symptoms. In Parkinson's patients who show such symptoms, the risks of amantadine may well outweigh the benefits. Vomiting has been recorded in pigeons fed amantadine.
Cases of suicidal ideation in patients treated with amantadine have been described,[11] although this psychiatric adverse event is relatively rare. Nevertheless, clinical surveillance of suicidal ideation in patients on amantadine is warranted at the clinician's discretion, as amantadine has been implicated as the major fatal (biologically toxic) factor in completed patient suicides.[12]
Another potential side effect is livedo reticularis, a dermatological reaction that results in skin mottling and purpurish mesh network of blood vessels.
[edit] Mechanism of action
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),[13] 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[14] as well as an anticholinergic.
[edit] Misuse
In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.[15] 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.[15] Avian flu (H5N1) strains in China and southeast Asia are resistant to amantadine, but strains circulating elsewhere 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.
[edit] Declining effectiveness
Early in the 2005/2006 flu season, the United States' Center for Disease Control [CDC] found rates of amantadine resistance to be much higher than in previous seasons. Looking at samples from 26 states yielded the following findings:
A total of 193 (92.3%) of 209 influenza A(H3N2) and 2 (25%) of 8 influenza A(H1N1) viruses analyzed contained point mutations resulting in a serine-to-asparagine change at amino acid 31 (S31N) of the M2 protein that conferred amantadine resistance.[16]
A resistance rate of 92% for the major flu strain was called "alarmingly high". The CDC issued an alert to doctors not to prescribe amantadine any more for the season.[17] Among some Asian countries, A/H3N2 and A/H1N1 resistance has reached 100%.[18]
[edit] References
- ^ 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:.
- ^ 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
- ^ "SALES OF FLU DRUG BY DU PONT UNIT A 'DISAPPOINTMENT'" (Last accessed May 19, 2008.) October 5, 1982, The New York Times.
- ^ 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)
- ^ 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)
- ^ Cohen RA, Fisher M. Amantadine treatment of fatigue associated with MS. Arch Neurol 1989;46:676–680
- ^ Hallowell, Edward M. and John J. Ratey, Delivered from Distraction: Getting the Most out of Life with Attention Deficit Disorder (2005), pp. 253-5.
- ^ 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. PMID 7714234. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0271-0749&volume=15&issue=1&spage=83.
- ^ 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.
- ^ 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.
- ^ Endo Pharmaceuticals (May 2003) (PDF). Symmetrel (Amantadine) Prescribing Information. http://www.symmetrel.com/PDF/symmetrel_pack_insert.pdf. Retrieved on 2007-08-02.
- ^ Cook et al., "Fatal overdose with amantadine". Can. J. Psychiatry (Nov 1986); 31(8), pp. 757-758.
- ^ 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.
- ^ 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:. PMID 15800186. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=15800186.
- ^ 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 on 2007-08-02.
- ^ Bright, R A; Shay, D K; Shu, B;Cox, N J;Klimov, A I (2006-02-22). "Adamantane Resistance Among Influenza A Viruses Isolated Early During the 2005-2006 Influenza Season in the United States". Journal of the American Medical Association 295 (8): 891–894. doi:. BL Shelfmark 4689.000000. ISSN 0098-7484. OCLC 194229372. PMID 16456087. http://jama.ama-assn.org/cgi/content/full/295.8.joc60020v1. Retrieved on 2008-05-20.
- ^ "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 on 2008-05-20.
- ^ 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:. http://www.journals.uchicago.edu/doi/full/10.1086/518936. Retrieved on 2008-05-19.
[edit] See also
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