Amantadine

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.

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.

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.