Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Ropinirole in the treatment of levodopa-induced motor fluctuations in patients with Parkinson's disease. A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related fluctuations. Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.
To evaluate the efficacy of ropinirole 24-hour prolonged release (ropinirole 24-hour) as an adjunct to levodopa in patients with Parkinson disease (PD) and motor fluctuations.
                In a double-blind, placebo-controlled, 24-week study, 393 subjects with PD were randomized to ropinirole 24-hour (n = 202) or placebo (n = 191). The primary outcome measure was reduction in hours of daily "off" time.
                At week 24, the mean dose of ropinirole 24-hour was 18.8 mg/day with a mean reduction in daily levodopa of 278 mg. There was a mean reduction in daily "off" time of 2.1 hours in the ropinirole 24-hour group and 0.3 hours with placebo. Secondary outcome measures including change in hours and percent of daily "on" time and "on" time without troublesome dyskinesia, Unified PD Rating Scale motor and activities of daily living subscales, Beck Depression Inventory-II, PDQ-39 subscales of mobility, activities of daily living, emotional well-being, stigma and communication, and PD Sleep Scale were significantly improved at week 24 with ropinirole 24-hour. The most common adverse events (AE) with ropinirole 24-hour were dyskinesia, nausea, dizziness, somnolence, hallucinations, and orthostatic hypotension and AEs led to study withdrawal in 5% of both the active and placebo groups.
                Ropinirole 24-hour was effective and well tolerated as adjunct therapy in patients with Parkinson disease (PD) not optimally controlled with levodopa. Ropinirole 24-hour demonstrated an improvement in both motor and non-motor PD symptoms, while permitting a reduction in adjunctive levodopa dose. Forty-six patients with Parkinson's disease experiencing motor fluctuations and not optimally controlled on levodopa received as adjunct therapy a new nonergoline dopamine agonist, ropinirole, in a 3-month randomized placebo-controlled trial. Ropinirole significantly reduced the duration of off periods as assessed by self-scoring diary cards. There were more nonserious dopaminergic adverse events in the ropinirole group. More patients withdrew because of adverse events or insufficient therapeutic effect in the placebo group. Ropinirole has beneficial adjuvant effects in parkinsonian patients with moderate motor disability and motor fluctuations. To evaluate the nonergot dopamine agonist ropinirole as an adjunct to L-dopa in a randomized, double-blind trial in PD patients with motor fluctuations.
                L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset.
                Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial.
                A significantly greater number of ropinirole patients were able to achieve a 20% or greater reduction in both L-dopa dose and in percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa dose was reduced significantly with ropinirole treatment (242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7% versus 5.1%; p = 0.039). There was no difference in the percent of patients who withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on placebo).
                Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for PD patients with motor fluctuations. There is debate about whether the initial treatment for patients with Parkinson's disease should be levodopa or a dopamine agonist.
                In this prospective, randomized, double-blind study, we compared the safety and efficacy of the dopamine D2-receptor agonist ropinirole with that of levodopa over a period of five years in 268 patients with early Parkinson's disease. If symptoms were not adequately controlled by the assigned study medication, patients could receive supplementary levodopa, administered in an open-label fashion. The primary outcome measure was the occurrence of dyskinesia.
                Eighty-five of the 179 patients in the ropinirole group (47 percent) and 45 of the 89 patients in the levodopa group (51 percent) completed all five years of the study. In the ropinirole group 29 of the 85 patients (34 percent) received no levodopa supplementation. The analysis of the time to dyskinesia showed a significant difference in favor of ropinirole (hazard ratio for remaining free of dyskinesia, 2.82; 95 percent confidence interval, 1.78 to 4.44; P<0.001). At five years, the cumulative incidence of dyskinesia (excluding the three patients who had dyskinesia at base line), regardless of levodopa supplementation, was 20 percent (36 of 177 patients) in the ropinirole group and 45 percent (40 of 88 patients) in the levodopa group. There was no significant difference between the two groups in the mean change in scores for activities of daily living among those who completed the study. Adverse events led to the early withdrawal from the study of 48 of 179 patients in the ropinirole group (27 percent) and 29 of 89 patients in the levodopa group (33 percent). The mean (+/-SD) daily doses given by the end of the study were 16.5+/-6.6 mg of ropinirole (plus 427+/-221 mg of levodopa in patients who received supplementation) and 753+/-398 mg of levodopa (including supplements).
                Early Parkinson's disease can be managed successfully for up to five years with a reduced risk of dyskinesia by initiating treatment with ropinirole alone and supplementing it with levodopa if necessary. The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear.
                To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes.
                Multicenter, parallel-group, double-blind, randomized controlled trial.
                Academic movement disorders clinics at 22 sites in the United States and Canada.
                Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001.
                Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability.
                Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events.
                Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups.
                Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles. Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa. The long-term effectiveness of three different initial drug regimes in patients with early, mild PD was evaluated by the PD Research Group of the United Kingdom (PDRGUK). In 1995, the selegiline arm of the trial was terminated following an interim analysis.
                This was an open, randomized trial. Between 1985 and 1990, 782 patients with de-novo PD were recruited and randomized to one of three treatment arms: levodopa plus dopa decarboxylase inhibitor; levodopa plus decarboxylase inhibitor and selegiline; or bromocriptine. The main endpoints were mortality, disability, and adverse events. Intention-to-treat analysis was used.
                There was no significant difference in mortality between the bromocriptine and the levodopa arms (hazard ratio 1.15 [95% CI 0.90, 1.47]). Patients initially randomized to bromocriptine had slightly worse disability scores throughout follow-up. This difference was significant during the first years. Patients in the bromocriptine arm returned to pretreatment disability levels one year earlier than those in the levodopa arm. Patients randomized to bromocriptine had a significantly lower incidence of dyskinesias than those randomized to levodopa (rate ratio 0.73 [95% CI 0.57, 0.93]). However, this difference was not significant when only moderate to severe dyskinesias were considered. Patients in the bromocriptine arm had slightly lower rates of dystonias and on-off fluctuations, but moderate and severe forms were equally frequent in both arms.
                Starting treatment with the dopamine agonist bromocriptine does not reduce mortality in PD. A slightly lower incidence of motor complications is achieved at the expense of significantly worse disability scores throughout the first years of therapy. To establish, in a double blind manner, the antiparkinsonian effects of repeated dosing with entacapone, a peripheral COMT inhibitor.
                A one month, cross over study was conducted. During the two four-week treatment periods, entacapone (200 mg) or placebo was given with each levodopa dose four to 10 times daily. Motor responses were repeatedly quantified using the motor part of UPDRS. Plasma levodopa and its metabolites were measured.
                Entacapone prolonged the availability of levodopa in the plasma and thus to the brain by decreasing its peripheral O-methylation and slowing its elimination rate, without affecting the maximum plasma levodopa concentration or the time to maximum concentration. Corresponding with the pharmacokinetic findings, entacapone prolonged the duration of motor response to an individual levodopa/DDC inhibitor dose by 34 minutes (24%, P = 0.001) and dyskinesiae by 39 minutes (37%, P = 0.002) compared with placebo, without affecting their magnitude or starting time. Entacapone treatment resulted in a reduction of 16% in the mean total daily levodopa dose due to dyskinesiae. Also, according to the home diaries, the mean daily "on" time increased by 2.1 hours compared with placebo, despite the lowered mean levodopa intake.
                The efficacy of repeated entacapone dosing as an adjuvant to levodopa/DDC inhibitor treatment for Parkinson's disease with levodopa related fluctuations is verified. Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.
                (c) 2005 Movement Disorder Society.
Ropinirole therapy can reduce levodopa dose but at the expense of increased dyskinetic adverse events. No clear effect on off time reduction was found but this may have been due to the under-powering of the single evaluable trial. Inadequate data on motor impairments and disability was collected to assess these outcomes. These conclusions apply to short and medium term treatment, up to 26 weeks. Further longer term trials are required, with measurements of effectiveness, and also studies to compare the newer with the older dopamine agonists.