Clinical Trials

Dyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias. Read More on PubMed

Several randomized placebo-controlled trials have consistently shown antidyskinetic effects of amantadine in levodopa treated patients with advanced Parkinson's disease (PD). However, all of these were of short duration and there have been claims that the effect of amantadine on levodopa induced dyskinesias (LID's) wear off after about 9 months of treatment. This randomized placebo-controlled parallel-group study was performed to assess the long-term antidyskinetic effect of amantadine in 32 PD patients, who after having been on stable amantadine therapy for LID over at least one year- were switched in a double blind manner to amantadine or placebo and followed for 3 weeks. Dyskinesia duration and intensity were assessed by UPDRS IV items 32 and 33 as well as by patient's diaries. The primary outcome was the score change of UPDRS IV items 32 + 33 between baseline and 3 weeks after treatment as well as the between treatment group comparison of the score change of UPDRS IV items 32 + 33. There was a significant increase of UPDRS IV items 32 + 33 in patients treated with placebo from 3.06 (95% CI, 2.1-4.03) at baseline to 4.28 (95% CI, 3.1-5.4) at three-week follow-up (P = 0.02) compared with no significant change between baseline 3.2 (95% CI, 2.1-4.4) to follow-up 3.6 (95% CI, 2.3-4.8) in patients staying on amantadine. These findings argue for long-term antidyskinetic efficacy of amantadine in PD patients with LID's. Read More on PubMed

Drug-induced dyskinesia is a common phenomenon in Parkinson's disease (PD) and is often socially as well as physically disabling for patients. The Movement Disorders Society commissioned a task force to assess available clinical rating scales, critique their clinimetric properties, and make recommendations regarding their clinical utility. A task force composed six clinical researchers who systematically searched the literature for scales measuring dyskinesia in PD, evaluated the scales' previous use, performance parameters, and quality of validation data (if available). A scale was designated "Recommended" if the scale has been used in clinical studies beyond the group that developed it, has been specifically used in PD reports, and if clinimetric studies have established that it is a valid, reliable, and sensitive. "Suggested" scales met two of the above criteria and those meeting one were "Listed." Based on the systematic review, eight rating scales for dyskinesia that have either been validated or used in PD were identified. These were the Abnormal Involuntary Movement Scale (AIMS), The Unified Parkinson's Disease Rating Scale (UPDRS) part IV, the Obeso Dyskinesia Rating Scale, the Rush Dyskinesia Rating Scale, the Clinical Dyskinesia Rating Scale (CDRS), the Lang-Fahn Activities of Daily Living Dyskinesia Scale, the Parkinson Disease Dyskinesia Scale (PDYS-26), and the Unified Dyskinesia Rating Scale (UDysRS). Based on this review, at present two of the reviewed dyskinesia scales (AIMS and the Rush Dyskinesia Rating Scale) fulfill criteria for Recommended for use in PD populations, albeit weakly so; all of the remaining met criteria to be Suggested. However, the two most recent scales (PDYS-26 and UDysRS) have excellent clinimetric properties and appear to provide a reliable and valid assessment tool of dyskinesia in PD. If they are used successfully beyond the groups that developed them, both have the potential to be re-ranked as Recommended. As further testing of these scales in PD is warranted, no new scales are needed until the available scales are fully tested clinimetrically. Read More on PubMed

Parkinson disease is a common neurodegenerative disease. The racial, sex, age, and geographic distributions of Parkinson disease in the US are unknown. Read More on PubMed

We developed and tested a rating scale aimed to capture the essential features of dyskinesia in Parkinson's disease (PD). Although several scales assess selected attributes of PD-dyskinesias, no comprehensive rating tool exists. Available rating scales were evaluated by the investigators and patient focus groups. Modifications were finalized into the Unified Dyskinesia Rating Scale (UDysRS). The UDysRS has four parts: I: Historical Disability (patient perceptions) of On-Dyskinesia impact (maximum 44 points); II: Historical Disability (patient perceptions) of Off-Dystonia impact (maximum 16 points); III: Objective Impairment (dyskinesia severity, anatomical distribution over seven body regions, and type (choreic or dystonic) based on four activities observed or video-recorded (28 points); IV: Objective Disability based on Part III activities (maximum 16 points). For clinimetric testing, 70 PD patients with all severities of dyskinesia were interviewed and videotaped. Twenty movement disorder experts rated the videotapes with the UDysRS. Internal consistency was examined with Cronbach's alpha. Inter- and intra-rater reliability was evaluated with generalized weighted and nonweighted Kappa coefficients, and intraclass correlation coefficients. Both subjective (Sections I and II) and objective (Sections III and IV) demonstrated high internal consistency (alpha: 0.915, 0.971). Interrater reliability for the objective sections was acceptable for all items and likewise for intrarater reliability except for right leg. Reliable factor structures were found for both subjective (six factors) and objective sections (five factors). The UDysRS is a clinimetrically sound rating scale for dyskinesia in PD, demonstrating acceptable levels of internal consistency and inter- and intra-rater reliability. Testing scale responsivity to treatment interventions is planned. Read More on PubMed

We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD. Read More on PubMed

This paper reviews the epidemiology, pathophysiology, clinical features and rationale for managing dyskinesias associated with Parkinson's disease. These are a common clinical problem occurring in up to 90% of patients and more frequently affect those with early-onset. Dyskinesias have a negative impact on quality of life and are an important cause of disability. Their precise etiology is still poorly understood, although it is recognized that dopaminergic pre-synaptic and post-synaptic mechanisms are involved together with extra-dopaminergic factors. The phenomenology of dyskinesias encompasses a variable mixture of two prevalent features: dystonia and chorea. We have studied their time course following a single acute levodopa challenge and have found that dystonia occurs throughout the duration of the on period, whereas choreiform movements occur only at the peak of therapeutic dopaminergic motor responses. This allows a schematic relationship to be drawn between a short duration motor response and the occurrence of dystonia and chorea. There is currently no satisfactory treatment for dyskinesias. Managing the therapeutic window does not provide an adequate solution due to the appearance of a dyskinesia threshold dose that narrows the therapeutic margin. High frequency stimulation of the subthalamic nucleus probably has some specific anti-dyskinetic action, but is limited by the small number of patients who are candidates for this treatment. Research efforts are currently focused on the development of specific anti-dyskinetic medications. Their availability will certainly change the current clinical practice and will widen again the therapeutic window of dopaminergic medications that has now become too narrow. Read More on PubMed

Levodopa is the most effective agent to alleviate motor dysfunction in Parkinson's disease but its long-term use is associated with the development of dyskinesias. Although the pathogenic processes behind the development of levodopa-induced dyskinesias are still being elucidated, it appears that chronic administration of this short-lived agent results in nonphysiologic pulsatile stimulation of striatal neurons and abnormal firing patterns in the basal ganglia. Dyskinesias have been associated with decreased quality of life, and a number of methodologies to evaluate severity of dyskinesias are now available. Strategies to avoid, reduce, or eliminate dyskinesias include providing more continuous dopaminergic stimulation, administering an antidyskinetic agent, and surgery. Several new compounds that may provide an antidyskinetic effect are also under investigation. Read More on PubMed

The abuse potential of methylphenidate has been related to the drug's capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-a-day osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediate-release methylphenidate. Read More on PubMed

We evaluated the effects of amantadine on levodopa-induced dyskinesia (LID) in eighteen consecutive Parkinson's disease (PD) patients in a randomized, double-blind, placebo-controlled study. The primary outcomes were the Clinical Dyskinesia Rating Scale (CDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS) part IVa score changes. The secondary outcomes were the UPDRS II and III score changes. Amantadine did not change the CDRS score for hyperkinesia or dystonia, but decreased the duration of LID and its influence on daily activities (p=0.04) and the UPDRS II score (p=0.01) more than placebo. These findings show that amantadine reduces the duration of LID and improves motor disability in PD. Read More on PubMed

Recent short-term studies suggested that amantadine (Ama) might ameliorate dyskinesia in patients with Parkinson's disease. A double-blind study programmed over 12 months was designed to assess the duration of the antidyskinetic effect of amantadine on levodopa induced dyskinesia. Read More on PubMed

In the USA, the stimulant drug methylphenidate (MPH) is used to treat a large number (2 million or more per year) of children with Attention Deficit Hyperactivity Disorder (ADHD). Although the US FDA approved MPH in the 1960s, the pharmacokinetic (PK) properties of serum concentrations of MPH in children with ADHD were not described until the 1980s, and then in only a few cases. Recently, information from drug development programs have increased our knowledge about the serum PK and some pharmacodynamic (PD) characteristics of MPH in ADHD children, and studies based on positron emission tomograpy (PET) in adult volunteers have provided new knowledge about the PK properties of MPH at the primary site of action in the brain. We will review these two topics and use this new information to evaluate the mechanisms of action of MPH. Read More on PubMed

20 patients (12 men and 8 women, mean age 65 years) affected by severe Parkinson's disease (PD) with peak-dose and/or diphasic dyskinesias or painful dyskinesia were treated with amantadine (300 mg/day) as adjunctive therapy to current levodopa, carbidopa and dopaminoagonist. UPDRS (Unified Parkinson's disease rating scale), dyskinesias rating scale (DRS) and IGA (investigator global assessment) scale were used to evaluate the severity of PD symptoms during follow-up. After 15 days with amantadine treatment all patients improved with an average 38% reduction in dyskinesias (p<0.001). After 2-8 months. amantadine was withdrawn in all patients. After amantadine withdrawal, 2 patients experienced severe hyperthermia (39 degrees C and 40 degrees C). No difference was found between end of treatment dyskinesia scores and final withdrawal scores (p<0.5). In the two patients with hyperthemia amantadine was reintroduced; after four days hyperthermia subsided and amantadine was finally tapered over 15 days without further adverse reactions. Read More on PubMed

We investigated the prevalence of dyskinesias and motor fluctuations, and the factors determining their occurrence, in a community-based population of patients with Parkinson's disease. Among 124 patients with Parkinson's disease, 87 (70%) had received a levodopa preparation. Among these 87 patients, 28% were experiencing treatment-induced dyskinesias and 40% response fluctuations. The prevalence of motor fluctuations was best predicted by disease duration and dose of levodopa, whereas dyskinesias could be best predicted by duration of treatment. Patients with a shorter time from symptom onset to initiation of levodopa and younger patients had developed motor complications earlier, and patients who had started treatment with a dopamine agonist had developed these treatment complications later. Although a satisfactory response to medication was associated with higher rates of motor complications, poor or moderate response was associated with lower quality of life in patients with a disease duration of /=10 years. We conclude that motor fluctuations are most strongly related to disease duration and dose of levodopa, and dyskinesias to duration of levodopa treatment. However, poorer quality of life associated with inadequate dosage of levodopa may be the price for a low rate of motor complications in patients with Parkinson's disease. Read More on PubMed

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. Read More on PubMed

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. Read More on PubMed

In a recent acute study, amantadine was found to have antidyskinetic effect against levodopa-induced motor complications in patients with Parkinson disease. The longevity of this effect was not addressed but is of interest in light of the controversy in the literature regarding the duration of amantadine's well-established antiparkinsonian action. Read More on PubMed

The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. Read More on PubMed

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). Read More on PubMed

Amantadine is a drug with diverse uses ranging from prevention of influenza A illness to the treatment of patients with Parkinson's disease. It is available only in oral formulations from which it is well absorbed and widely distributed, little drug being present in the circulation. Apparent volume of distribution is inversely related to dose over the therapeutic range and accounts in part for a noteworthy logarithmic increase in plasma concentration as a function of dose. Elimination is primarily by renal clearance by both glomerular filtration and tubular secretion. Amantadine accumulates in patients with renal dysfunction. Hence, doses must be reduced in such patients to avoid toxicity. Interactions with other drugs appear uncommon. Relationships have been demonstrated between amantadine therapeutic effects and plasma concentrations in different study cohorts, but not in individual patients. Dose schedules have been suggested for individuals in whom amantadine kinetics are different from healthy subjects. However, these schedules are controversial in their choice of target concentrations and in being untested as to predictive value. Read More on PubMed

The relative toxicities of amantadine and rimantadine were compared in a double-blind, placebo-controlled study involving healthy adults. In separate studies, drugs were administered at a dosage of 200 mg/day (52 volunteers) or 300 mg/day (196 volunteers) for 4.5 days. Both drugs were well tolerated at the lower dosage. At 300 mg/day amantadine recipients had a greater frequency and severity of central nervous system (nervousness, lightheadedness, difficulty concentrating) and sleep (insomnia, fatigue) complaints compared with rimantadine or placebo recipients. Amantadine recipients also performed less well on an objective test measuring sustained attention and problem-solving ability. Both amantadine and rimantadine recipients reported adverse gastrointestinal symptoms more often than placebo recipients. Because of better tolerance at higher dosage, rimantadine offers more promise than amantadine for treatment of influenza A virus infections. Read More on PubMed

In a four-week double-blind trial of 62 patients with Parkinsonism 29 were treated withamantadine and 33 with a placebo. Modest but statistically significant improvement was observed in the first group, optimum benefit occurring after the first two weeks. Patients' reactions to the drug were favourable in 79%, and side effects were insignificant. Though amantadine appears to be a useful additive drug in the treatment of Parkinsonism, its value as a single treatment is as yet undetermined. Read More on PubMed