Amantadine

Dr. Robert Schwab reported the first group of patients with PD who improved with their symptoms with Amantadine. When at the University of Iowa from 1968 to 1971, He did several clinical trials using amantadine for the treatment of symptoms of parkinson patients. The drug was well tolerated in cognitively intact patients and did give a mild to moderate clinical symptomatic benefit. The average dose was 200mg (100mg two times a day) and it was also the highest dose given in those clinical trials. A lower dose was needed in patients with renal failure since it was mostly excreted by the kidneys. It was also noted that more advanced patients, ones especially with cognitive impairment, were likely to have disturbing dreams, confusion, and/or hallucinations. It seemed to lose its detectable antiparkinson effect after six months in many of the patients. Its pharmacological action at the time was thought to be due to increasing the synthesis of dopamine from l-dopa in the presynaptic neuron and/or increasing the release of the dopamine from the presynaptic neuron. L-dopa became widely available in the early 70's and since l-dopa had such a robust benefit clinically, the use of amantadine rapidly decreased, primarily because it lacked a sustained robust clinical benefit. Yet some patients remained on it for many years.

Over the last several years amantadine has been noted to be able clinically to reduce dyskinesias, mostly peak dyskinesias. Several articles have documented this benefit and have also noted that there was no significant worsening in the other parkinson's
symptoms, especially tremor, akinesia, and rigidity. It has been known that amantadine has an antagonist effect (blocking effect) on the NMDA (N-methyl-D-aspartate) receptor (a type of glutamate receptor), which is downstream (past the presynaptic dopamine nigralstriatal neuron). It is thought that the mechanism or mechanisms for motor fluctuations and dyskinesias are downstream from the degenerating nigralstriatal dopamine system. It is also thought that the glutamatergic system or projections are involved and there is a subtype of receptors in this system known as NMDA subtypes that when blocked in the rat model, reverse l-dopa-induces dyskinesias. This reduction of dyskinesias in animals and in IPD patients has been attributed to the knowledge that amantadine is an NMDA-receptor antagonist. It is the NMDA receptor that is present downstream that is acted upon by the excitatory glutamate, which has predominance because of the dopamine deficit.

There is also a theoretical consideration for the use of amantadine as a nueroprotective agent. It is thought that amantadine may protect nerve cells from abnormal unphysiological excitotoxic effects of excessive glutamatergic receptor stimulation or hyperactivity. This excessive activity is out of balance since the dopaminergic system is deficient. The excess glutamate stimulation increases the calcium influx into the neuron and hence brings about glutamate excitotoxicity. The excess unphysiological high calcium influx into the neuron may cause neuron death that is excelerated and/or the neuron becomes dysfunctional and then dies (apoptosis).

A number of well studied parkinson patient groups have supported the use of amantadine to reduce dyskinesias (Rajput and Verhagen). Potential side effects of amantadine are anxiety, irritability, vivid dreams, hallucinations (usually visual), delusions, and confusion. Because this can occur and is especially seen in cognitively impaired patients, the drug should be started at 100mg a day for one week and then increased by 100mg every seven days until the dose is up to 100mg three times a day. Edema of the feet and ankles associated with a "chicken wire discoloration" (livedo reticularis) can also be seen and is considered a benign side effect, unless the edema becomes a problem.