Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. Amantadine and a fixed combination of levodopa and carbidopa in the treatment of Parkinson's disease. The effect of amantadine on levodopa-induced dyskinesias in Parkinson's disease: a double-blind, placebo-controlled study. A double-blind, placebo-controlled trial of amantadine for the treatment of fatigue in patients with the post-polio syndrome. Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Long-term evaluation of amantadine and levodopa combination in parkinsonism by double-blind corssover analyses. Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease. Double blind study using amantadine hydrochloride in the therapy of Parkinson's disease. Amantadine therapy for fatigue in multiple sclerosis.
To determine the effects of the N-methyl-D-aspartate (NMDA) antagonist amantadine on levodopa-associated dyskinesias and motor fluctuations in Parkinson's disease (PD).
                NMDA receptor blockade can ameliorate levodopa-induced dyskinesias in primates and PD patients. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was recently found to possess NMDA antagonistic properties.
                Eighteen patients with advanced PD participated in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week treatment arm, parkinsonian and dyskinesia scores were obtained during a steady-state intravenous levodopa infusion. Motor fluctuations and dyskinesias were also documented with patient-kept diaries and Unified Parkinson's Disease Rating Scale (UPDRS) interviews.
                In the 14 patients completing this trial, amantadine reduced dyskinesia severity by 60% (p = 0.001) compared to placebo, without altering the antiparkinsonian effect of levodopa. Motor fluctuations occurring with patients' regular oral levodopa regimen also improved according to UPDRS and patient-kept diaries.
                These findings suggest that amantadine given as adjuvant to levodopa can markedly improve motor response complications and support the view that hyperfunction of NMDA receptors contributes to the pathogenesis of levodopa-associated motor complications. Forty-two patients with Parkinson's disease were given amantadine HC1 (Symmetrel) and placebo in an 18 week double-blind cross-over study to determine if amantadine provided additional benefit when combined with levodopa and carbidopa (Sinemet). Analysis of our results showed that amantadine effected a 92% improvement over baseline in symptom scores and a 95% improvement over baseline in activity impairment scores, compared with corresponding values of 4% and 18% for placebo. The difference between amantadine and placebo was statistically significant. Except for one case of mild livedo reticularis and two of blurred vision in the amantadine group, side effects were generally similar for amantadine and placebo in type and frequency. This study provides new evidence of the importance of combinations of antiparkinson drugs to achieve maximum therapeutic benefit. We performed a double-blind, placebo-controlled, crossover study to assess the effect of amantadine versus placebo on levodopa-induced dyskinesias in Parkinson's disease. We found a 24% reduction in the total dyskinesia score after amantadine administration (p = 0.004). This improvement was achieved without any influence on the severity of "on" period parkinsonism. The results confirm that amantadine reduces levodopa dyskinesias and support the hypothesis that dyskinesias can be reduced by blockade of excitatory pathways in the basal ganglia. Because amantadine has been shown to reduce fatigue in patients with multiple sclerosis, we performed a double-blind, placebo-controlled study to assess its efficacy in the disabling symptom of post-polio fatigue. Twenty-three patients completed six weeks of therapy. Fatigue was measured by the patients using visual analogue scales (twice per day) and numerical fatigue severity scales (once per week) and by overall impression (at end of therapy). Formal neuropsychological testing and serum drug levels were performed to assess compliance. On all measures, no significant difference was found between treatment and placebo groups. Fifty-four percent of patients given amantadine and 43% given placebo reported a decrease in fatigue; however, the visual analogue scales and fatigue severity scales failed to reflect any improvement. Several patients in the treatment group elected to continue amantadine therapy after the study was completed. Our findings suggest that amantadine is not significantly better than placebo in reducing the sensation of fatigue in post-polio syndrome, and that the measures we employed were insensitive to capture the subjective response experienced by a few patients. To examine the acute effects of the NMDA receptor antagonist amantadine on motor and cognitive function in Huntington's disease (HD).
                Chorea in HD and in the levodopa-induced dyskinesias of PD may be clinically indistinguishable. In PD, hyperphosphorylation of NMDA receptors expressed on striatal medium spiny neurons contributes to peak-dose dyskinesias, and drugs that block these receptors can diminish chorea severity. Because these spiny neurons are the primary target of the neurodegenerative process in HD, sensitization of NMDA receptors on residual striatal neurons might also participate in the generation of motor dysfunction in HD.
                To evaluate this possibility, 24 patients with HD entered a double-blind placebo-controlled crossover study of amantadine with two 2-week arms.
                Chorea scores were lower with amantadine (usually 400 mg/d) than placebo, with a median reduction in extremity chorea at rest of 36% (p = 0.04) for all 22 evaluable patients and of 56% in the 10 individuals with the highest plasma drug levels. Improvement correlated with plasma amantadine concentrations (p = 0.01) but not CAG repeat length. Parkinsonian rating scores did not worsen and there was no consistent change in cognitive measures. Adverse event profile was benign.
                Results suggest that NMDA receptor supersensitivity may contribute to the clinical expression of choreiform dyskinesias in HD and that selective antagonists at that site can safely confer palliative benefit. Twenty-three patients with Parkinson's disease participated in long-term, double-blind evaluations of the effectiveness and side effects of amantadine in combination with levodopa therapy. Sixteen patients completed the year-long study, which consisted of randomized crossover of amantadine and placebo before levodopa was begun and again after 5 and 11 months of continuous levodopa therapy. Initially, 16 of 23 patients (70 percent) had a favorable response to amantadine during the first crossover period. After 1 year of levodopa, at least eight of 16 patients (50 percent) responded favorably to amantadine compared with placebo. Some of the amantadine responders previously had been nonresponders, and vice versa. The response to amantadine was quantitatively similar in the responders even after the patients had been receiving levodopa therapy. Amantadine should be tried as a therapeutic agent in addition to levodopa for parkinsonism if more beneficial effect is desired, even if amantadine was previously ineffective in the same patient. L-Dopa-induced dyskinesias constitute a challenge to the management of advanced Parkinson's disease. According to recent reports, treatment with the NMDA receptor antagonist amantadine may significantly diminish L-dopa-induced dyskinesias. In the present study, the effect of amantadine on L-dopa-induced dykinesias was assessed in a 5-week, double-blind crossover trial. Dyskinesia severity as assessed following oral L-dopa challenges and by self-scoring dyskinesia diaries were reduced approximately 50% after amantadine treatment compared with baseline or placebo phases. Similarly, dyskinesia assessments on the Unified Parkinson's Disease Rating Scale, part IV (items 32 and 33) also revealed significant improvement after treatment with amantadine. The magnitude of the L-dopa motor response to oral challenges was not different after amantadine or placebo treatment, and there was no significant reduction of daily off-time when patients received active treatment. These results confirm previous observations concerning the antidyskinetic potential of amantadine. nan We carried out a double blind control study of fatigue in 32 patients with multiple sclerosis, comparing amantadine hydrochloride 100 mg twice a day and placebo. On amantadine 31% had marked improvement; 15.6% moderate improvement; 15.6% mild improvement; and 36.5% unchanged. On placebo, none noted marked improvement; one claimed moderate improvement on either amantadine or placebo. 18.7% reported mild improvement on placebo; and most of them had similar or more response to amantadine. No patient selected placebo over amantadine at the end of the trial. Overall improvement was seen in 62.5% of patients on amantadine and 21.8% on placebo. Additional experience up to two years suggests continued benefit but common and important side-effects.
A considerable amount of evidence on the effectiveness of amantadine has accrued from non-controlled trials, often in patients with Parkinsonian conditions other than idiopathic Parkinson's disease. However, rigorous analysis of the six randomised controlled trials of amantadine reveals insufficient evidence of its efficacy and safety in the treatment of idiopathic Parkinson's disease.