Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?☑ Amantadine is effective drug in the treatment of Parkinson\'s disease (PD) that does not have a direct effect on the dopaminergic system. The oral formula is effective in reducing severity of dyskinesias and tremor for a long run. Intravenous amantadine was shown to have an immediate effect on dyskinesias.WHAT QUESTION DID THIS STUDY ADDRESS?☑ The aim of the study was to evaluate the long‐term effects of intravenous amantadine on patients with dyskinesias and patients who could not tolerate levodopa treatment.WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?☑ This study showed long‐term improvement in dyskinesia scores and stable immediate motor improvement in patients with and without dyskinesias that was preserved for at least 6 months from the beginning of treatment.HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?☑ Long‐term intravenous amantadine might be an effective treatment for ameliorating dyskinesias and improving motor symptoms of patients with PD.

 {#cts12684-sec-0002}

Levodopa is still considered the gold standard treatment for most of the motor symptoms in Parkinson\'s disease (PD). However, a large number of patients cannot be managed effectively by levodopa because of an insufficient response or adverse effects, mainly vomiting, vertigo, and orthostatic hypotension.[1](#cts12684-bib-0001){ref-type="ref"}, [2](#cts12684-bib-0002){ref-type="ref"} Moreover, almost 70% of patients who do respond to levodopa will acquire troublesome dyskinesias and response fluctuations within 5 years of treatment.[3](#cts12684-bib-0003){ref-type="ref"} One strategy to overcome levodopa‐induced dyskinesias is to reduce the dopaminergic medications at the expense of increased "off" periods. However, most patients prefer remaining in the "on" period with dyskinesias to becoming akinetic in the "off" period.[4](#cts12684-bib-0004){ref-type="ref"}, [5](#cts12684-bib-0005){ref-type="ref"}

One of the core pathogenetic mechanisms underlying dyskinesias in PD is over‐reactivity of the excitatory striatal output pathway due to an excessive glutaminergic influence of the corticostriatal projections to the striatum.[6](#cts12684-bib-0006){ref-type="ref"} Amantadine is a noncompetitive *N*‐methyl‐[d]{.smallcaps}‐aspartate receptor antagonist with dopaminergic properties. It is unique in its dual mode of action: it improves motor functions[7](#cts12684-bib-0007){ref-type="ref"}, [8](#cts12684-bib-0008){ref-type="ref"} while ameliorating dyskinesias. This is probably achieved by its reduction of the *N*‐methyl‐[d]{.smallcaps}‐aspartate sensitivity of the striatal medium spiny neurons to glutaminergic input[9](#cts12684-bib-0009){ref-type="ref"} and prevention of gamma‐Aminobutyric acid (GABA) release at the substantia nigra.[10](#cts12684-bib-0010){ref-type="ref"} Clinical trials showed a short‐term antidyskinetic effect of amantadine in patients with advanced PD.[11](#cts12684-bib-0011){ref-type="ref"}, [12](#cts12684-bib-0012){ref-type="ref"}, [13](#cts12684-bib-0013){ref-type="ref"}, [14](#cts12684-bib-0014){ref-type="ref"}

The aim of the present study was to investigate the long‐term effect of repeated intravenous infusions of amantadine in patients with PD with and without response fluctuations and dyskinesias. An open‐label design was used, with inclusion of patients with moderate disease who could not tolerate or had insufficient response to levodopa therapy and patients with advanced disease and levodopa‐induced dyskinesias.

Methods {#cts12684-sec-0003}
=======

Patients {#cts12684-sec-0004}
--------

Patients with PD were recruited from the Movement Disorder Unit of Rabin Medical Center. The study was approved by the local institutional ethics committee and the Israel Ministry of Health and was registered in the clinical trial registry of the National Institute of Health (NCT01190553). All patients had idiopathic PD according to the criteria of the United Kingdom Brain Bank with unilateral bradykinesia and/or rigidity and tremor. All patients signed an informed consent form. Patients underwent kidney function tests and electrocardiograms before enrolling. Those with abnormal kidney tests, cardiac arrhythmias, and known sensitivity to amantadine were excluded.

Experimental protocol {#cts12684-sec-0005}
---------------------

Patients arrived in the morning, before starting any antiparkinsonian treatment. A standard regimen of intravenous amantadine 200 mg in a 500 cc saline solution was administered over 3 hours. All patients were tested for response to treatment under the same conditions, in the same chair, by the same trained neurologist (A.K.). A total of six dosing visits were conducted. In the first visit, patients received daily amantadine infusions for three sequential days. This was followed by five once‐monthly visits in which patients received a single infusion of the same dose (200 mg in 500 cc saline). During the study, all patients were treated with oral amantadine between visits. Patients already being treated with oral amantadine did not take the drug on days of amantadine infusion.

To reduce the influence of dopamine‐containing drugs, oral dopaminergic medications were administered after motor symptoms were evaluated. Disease severity was assessed at each visit before and after treatment using the motor part (part III) of the Unified Parkinson\'s Disease Rating Scale (UPDRS).[15](#cts12684-bib-0015){ref-type="ref"} The severity of levodopa‐induced dyskinesias was assessed with the Abnormal Involuntary Movement Scale (AIMS),[16](#cts12684-bib-0016){ref-type="ref"} at each visit before amantadine infusion (from 8 [am]{.smallcaps} to 9 [am]{.smallcaps}) and 30 minutes after its completion (from 11 [am]{.smallcaps} to 12 [pm]{.smallcaps}).

Statistical analysis {#cts12684-sec-0006}
--------------------

Statistical analysis was performed using the SPSS version 19 (Chicago, IL). Demographic data were analyzed by *t*‐test (age) or Wilcoxon test (motor scores). Paired *t*‐test for independent samples was used to compare motor scores and dyskinesia scores before and after infusion of amantadine at each visit and between the first and final visits.

Results {#cts12684-sec-0007}
=======

Twelve patients were enrolled in the study, six with dyskinesias, and six without dyskinesias and motor fluctuations. In the group with dyskinesias, mean age was 74.0 ± 3.3 years and mean disease duration 13.3 ± 4.9 years. The initial mean UPDRS motor score was 35.7 ± 12.4 (range 21--57), and the initial mean AIMS score was 6.33 ± 2.7 (range 2--10). In the group without dyskinesias, mean age was 68.3 ± 7.6 years, mean disease duration was 5.7 ± 2.5 years, and the initial mean UPDRS motor score was 31.5 ± 11.9 (range 13--48).

Four of the six patients without dyskinesias could not tolerate levodopa, and the other two had minor response to the drug in low doses but could not tolerate any increase of dosage. All patients with dyskinesias were receiving levodopa treatment, of whom four had been treated with oral amantadine for at least 1 year prior to the study. Two patients without dyskinesias were receiving treatment with levodopa and one was also receiving oral amantadine. The drug regimen in the patients in both groups being treated with oral amantadine had not been changed for at least 6 months before their entry to the study.

Five patients with dyskinesias completed all study visits; the remaining patient dropped out after four visits owing to a hip fracture following a fall. Of the patients without dyskinesias, three completed all study visits and three dropped out because of a lack of response: two patients after three visits and one patient after four visits.

Analysis of the response to repeated intravenous amantadine treatment showed that in the patients with moderate disease without dyskinesias (**Table** [1](#cts12684-tbl-0001){ref-type="table"}), amantadine infusion had a significant acute effect on the UPDRS motor score after visits 1, 2, 3, and 5, with a trend for improvement after visits 4 and 6. The change in mean motor score from onset of treatment (before the first infusion; 31.5 ± 11.9) to after 6 months of treatment (following the last infusion; 25.3 ± 16.7) was not statistically significant (*P *= 0.3). In the advanced‐disease group with dyskinesias (**Table** [2](#cts12684-tbl-0002){ref-type="table"}), there was a trend for improvement of the UPDRS score from before to after each visit. A significant difference in mean UPDRS motor score was recorded at all visits except the first. The change in mean UPDRS motor score from onset of treatment (35.7 ± 12.4) to after 6 months of treatment (24.8 ± 11.6) was not statistically significant (*P *= 0.6). An acute improvement in mean AIMS dyskinesia score was noted after visit 1 (from 6.3 ± 2.7 before the visit to 2.17 ± 2 after; *P *= 0.001) and visit 2 (from 4.3 ± 1.5 to 1.8 ± 2.2; *P *= 0.02). In addition, there was a trend for improvement of the AIMS score after visit 6 (from 3.8 ± 2.2 to 1.6 ± 1.3; *P *= 0.06). Comparison of the AIMS dyskinesia scores between the first visit (6.3 ± 2.7) and the last (1.6 ± 1.3) yielded a statistically significant difference (*P *= 0.014).

###### 

Changes in UPDRS scores for individual visits in patients without dyskinesias

  Pt. no./sex                                        Continuous treatment                 UPDRS motor score before and after amantadine infusion                                                                                                                                        
  -------------------------------------------------- ------------------------------------ -------------------------------------------------------- ------------ ------------ ------------ ------------ ------------ ------------- ------------ ----------- -------------- ------------- -----
  1/F                                                Levodopa, ropinorole                 32                                                       16           23           14           34           28           32            25           35          25             27            20
  2/M                                                Levodopa, oral amantadine            40                                                       39           35           27           48           36           47            45           39          33             52            44
  3/M                                                Rasagiline                           29                                                       11           35           21           27           21           30            15           23          11             28            12
  4/M                                                                                     48                                                       27           40           32           41           30           49            30           ---         ---            ---           ---
  5/F                                                                                     13                                                       8            25           13           30           14           ---           ---          ---         ---            ---           ---
  6/F                                                Pramipexol, ropinorole, rasagiline   27                                                       22           21           13           29           17           ---           ---          ---         ---            ---           ---
  Mean score                                         31.5 ± 11.9                          20.5 ± 11.4                                              29.8 ± 7.8   20.0 ± 8.0   34.8 ± 8.1   24.3 ± 8.4   39.5 ± 9.9   28.7 ± 12.5   32.3 ± 8.3   23 ± 11.1   35.6 ± 14.41   25.3 ± 16.7   
  *P* value[a](#cts12684-note-0002){ref-type="fn"}   0.023                                0.0001                                                   0.001        0.068        0.034        0.068                                                                                         

UPDRS, Unified Parkinson\'s Disease Rating Scale.

Change from before to after treatment.

John Wiley & Sons, Ltd

###### 

Changes in UPDRS scores for individual visits in patients with dyskinesias

  Pt. no./sex                                        Continuous treatment                              UPDRS motor score before and after amantadine infusion                                                                                                                                             
  -------------------------------------------------- ------------------------------------------------- -------------------------------------------------------- ------------- ----------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- -----
  1/M                                                Levodopa, pramipexole                             35                                                       22            33          25            34            35            39            26            39            27            41            24
  2/M                                                Levodopa, amantadine, ropinorole                  21                                                       10            22          14            30            28            18            16            24            17            28            15
  3/M                                                Levodopa, amantadine, rasagiline COMT inhibitor   37                                                       24            33          22            32            28            31            23            37            31            39            31
  4/F                                                Levodopa                                          57                                                       44            57          46            57            53            53            43            50            45            53            41
  5/M                                                Levodopa, amantadine                              26                                                       10            25          8             21            11            21            6             23            11            21            13
  6/M                                                Levodopa, amantadine, ropinorole                  38                                                       52            51          49            38            35            46            37            ---           ---           ---           ---
  Mean score                                         35.7 ± 12.5                                       27.0 ± 17.5                                              36.8 ± 14.1   27.3 ± 17   35.3 ± 12.0   30.0 ± 14.8   36.3 ± 11.9   25.2 ± 13.5   34.6 ± 11.3   26.2 ± 13.2   36.4 ± 12.4   24.8 ± 11.6   
  *P* value[a](#cts12684-note-0004){ref-type="fn"}   0.117                                             0.005                                                    0.042         0.0001      0.005         0.002                                                                                             

UPDRS, Unified Parkinson\'s Disease Rating Scale.

Change from before to after treatment.

John Wiley & Sons, Ltd

There were no major amantadine‐related side effects during the study. Two serious adverse events unrelated to amantadine were recorded (fall with right hip fracture and elective total knee replacement).

Discussion {#cts12684-sec-0008}
==========

The rationale for continuous repeated intravenous amantadine treatment in patients with PD is based on findings of an improvement in motor function and amelioration of dyskinesias in long‐term studies of oral amantadine and short‐term studies of intravenous amantadine. The present pilot study sought to determine the effectiveness of boosts of intravenous amantadine.

Our results indicate that repeated intravenous infusions over 6 months significantly reduce levodopa‐induced dyskinesias, with no loss of the benefit of levodopa. The drop in dyskinesia scores ranged from 25% to 33% by the end of the trial. However, there was no continuous reduction in dyskinesia scores and no long‐term improvement of parkinsonian symptoms. A trend for improvement of the UPDRS motor scores was noted between visits, probably owing to the weak dopaminergic effect of amantadine, which could not surpass the ceiling effect of levodopa.

These results are in agreement with previous studies of amantadine in PD. These studies focused mainly on long‐term oral treatment or short‐term intravenous infusions. The first double‐blind randomized study of oral amantadine, conducted in 14 patients, documented significant improvement of dyskinesias after 3 weeks.[17](#cts12684-bib-0017){ref-type="ref"} Since then, others have shown both acute and long‐term antidyskinetic effects in \> 50% of patients with advanced disease. As in the former study, oral amantadine was used.[18](#cts12684-bib-0018){ref-type="ref"}, [19](#cts12684-bib-0019){ref-type="ref"} In 17 patients who were re‐examined after 1 year of treatment with oral amantadine, the beneficial antidyskinetic effect remained nearly to the magnitude of the acute effect.[20](#cts12684-bib-0020){ref-type="ref"} Acute intravenous amantadine also reduced dyskinesias by nearly 50%[13](#cts12684-bib-0013){ref-type="ref"}; this effect lasted for at least 5 hours.

In our study, plasma levels of amantadine were not evaluated, but we assumed that peak levels are gained rapidly following intravenous administration and that they remain high for several days, adding to the levels achieved by the regular oral treatment. One reason for this could point to the different pharmacokinetics of oral and intravenous amantadine, as shown in an animal study by Siao *et al*.[21](#cts12684-bib-0021){ref-type="ref"} In the patients with moderate disease without dyskinesias, an acute improvement in motor symptoms was noted immediately after amantadine infusion. However, it did not last for many days, as indicated by the lack of improvement in UPDRS motor scores compared with the previous visit. Indeed, not only there was no long‐term improvement in UPDRS scores after 6 months of treatment, the final mean score was only slightly and nonsignificantly higher than the initial score, most probably as a consequence of the rapid disease progression in two of the patients.

Oral amantadine is commonly used in the treatment of early PD, especially in patients reluctant to initiate treatment with levodopa. Data on the duration of its beneficial effect are limited. A few nonrandomized studies showed significant improvement in motor scores,[22](#cts12684-bib-0022){ref-type="ref"}, [23](#cts12684-bib-0023){ref-type="ref"} but thus far, studies of the long‐term effect of intravenous amantadine in non‐levodopa‐treated patients with early disease are lacking. Parenteral amantadine is commonly used in patients undergoing major abdominal surgeries who are unable to consume medications.[24](#cts12684-bib-0024){ref-type="ref"}, [25](#cts12684-bib-0025){ref-type="ref"} Another advantage of intravenous amantadine is its potential to acutely improve freezing symptoms.[14](#cts12684-bib-0014){ref-type="ref"}, [23](#cts12684-bib-0023){ref-type="ref"} Therefore, in our study, the patients with dyskinesias apparently reached their steady state, which would explain the lack of significant change in UPDRS scores after the third visit.

This study was limited by its open‐label design and the large variability in patient background characteristics. Furthermore, the sample was too small for us to draw conclusions regarding the use of this mode of treatment in patients who are unable to tolerate levodopa. Another drawback of the study is that 1 of the 6 patients without dyskinesias and 4 of 6 patients with dyskinesias had been treated with oral amantadine before enrollment to the study. This fact may have had a possible influence on the reaction to intravenous amantadine infusion. The small number of amantadine‐naïve patients makes it difficult to fully evaluate the effect of intravenous infusions. The small sample size may also explain the lack of statistically significant results in UPDRS and dyskinesia scores.

In conclusion, our preliminary results may point to a beneficial effect of intravenous amantadine in patients who are unresponsive to conventional antiparkinsonian medications and for treatment of response fluctuations and dyskinesias. Further studies with larger samples are warranted to investigate the long‐term effects of intravenous amantadine on dopaminergic and nondopaminergic (freezing gait and falls) symptoms in PD.

Funding {#cts12684-sec-0009}
=======

No funding was received for this work.

Conflicts of Interest {#cts12684-sec-0010}
=====================

I.S. serves on the editorial board of the Journal of Neurological Sciences, Journal of NeuroVirology, and Medicine Neurology (Hebrew). He is a consultant and member of the Data Safety Monitoring Board for Actelion and Genentech/Roche. He received honoraria from Teva Pharmaceutical Industries Ltd. All other authors declared no competing interests for this work.

Author Contributions {#cts12684-sec-0011}
====================

A.K., I.S., and R.D. wrote the manuscript. I.S., T.T., and R.D. designed the research. A.K. and R.D. performed the research. T.T. analyzed the data.
