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Amantadine Information Summary

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A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for testing in the Neuroprotection Clinical Trial.

AMANTADINE

Amantadine is an uncompetitive, low affinity, NMDA receptor antagonist - a substance that reduces the physiological response of another chemical substance. The drug is well absorbed after oral administration, and is primarily eliminated renally.

Amantadine is well-tolerated in PD patients and has been used for over 30 years. The most frequent side effects reported are nausea, dizziness and insomnia. Amantadine can also cause dry mouth, urinary retention and blurred vision, and confusion. Orthostasis and peripheral edema can also occur. Livedo reticular is a common side effect and occurs more in men and than in women.

Scientific Rationale

  • Uncompetitive, low affinity, NMDA receptor antagonist
  • Antagonizes the effects of pathologic glutamate concentrations, not physiologic- therefore fewer adverse events than with MK801

Kornhuber, Eur J Pharmac Molec Pharmac Sect 1991;206:297-300
Chen, J Neurosci 1992; 12:4427-4436

Animal Model Data

RODENT: Gerbils received 40 mg/kg MPTP for 4 days. On the fifth day, animals were treated with 15 mg/kg of deprenyl, amantadine or the combination and were sacrificed either 1, 2, or 5 hours later. Brain concentrations of serotonin and dopamine metabolites were analyzed using HPLC. Whereas animals who received only MPTP experienced a 25-31% reduction in both dopaminergic and serotonergic metabolites, both deprenyl and amantadine caused accumulation of DA and 5-HT. There was some evidence of synergy of the two compounds.

PRIMATE: only studied for symptomatic effects

Kornhuber, Eur J Pharmac Molec Pharmac Sect 1991;206:297-300 0
Chen, J Neurosci 1992; 12:4427-4436

Pharmacokinetics(including BBB penetration)

Amantadine transverses the BBB after oral administration. In a study of post-mortem brain tissue from 21 patients who had received amantadine, brain concentrations were found to range from 48.2 - 386 mcM whereas CSF concentrations were much lower (<17 mcM). This suggests an accumulation in the tissue.

The drug is well absorbed after oral administration, and is primarily eliminated renally. It has a plasma t ½ of 16 hours in patients with normal renal function. In older individuals, the t ½ can increase to 45 h. The dose must be adjusted in renal dysfunction.

Kornhuber, Neuropharmacol 1995;34:713-721
Aoki, Clin Pharmacokin 1988;14:35-51

Safety/Tolerability in Humans

Amantadine is well-tolerated in patients with PD and has been used for over 30 years. The most frequent adverse effects reported are (5-10% of patients) nausea, dizziness and insomnia. Amantadine can also cause anticholinergic side effects such as dry mouth, urinary retention, blurred vision, and confusion. Orthostasis and peripheral edema can also occur. Livedo reticularis is a common side effect and occurs more in men than in women

MD consult, 2002

Drug Interaction Potential

No known pharmacokinetic drug interactions of clinical importance. May have synergistic effect with deprenyl

Aoki, Clin Pharmacokin 1988;14:35-51

Clinical Trial/Epidemiological Evidence in Human PD

Amatadine has short term symptomatic benefits in PD. It is commonly used at doses of 200mg to 300mg day divided twice daily or three times daily respectively. Withdrawal symptoms are common

Survival was studied in 836 PD patients who had been treated by a single center over a 23 year period. Five independent predictors of improved survival were identified by multivariate analysis: high 10 y survival, amantadine use, absence of dementia, PD vs. other causes of parkinsonism and low Hoehn & Yahr; at presentation. The mean duration of treatment with amantadine was 37 months. The improved survival may be due to symptomatic effects (the difference was about 4 months) but may be evidence of neuroprotection.

Timberlake. Ann Neuro 1978; 3: 119-128.
Uitti RJ, Neurology 1996; 46: 1551-1556

Last updated February 09, 2005