Early combination of bromocriptine and levodopa in Parkinson's disease: a prospective randomized study of two parallel groups over a total follow-up period of 44 months including an initial 8-month double-blind stage. Does combined levodopa and bromocriptine therapy in Parkinson's disease prevent late motor complications? Five-year follow-up of early lisuride and levodopa combination therapy versus levodopa monotherapy in de novo Parkinson's disease. The French Lisuride Study Group. Selegiline slows the progression of the symptoms of Parkinson disease. Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study. Does selegiline modify the progression of early Parkinson's disease? Results from a five-year study. The Norwegian-Danish Study Group. Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study. Efficacy of a physical therapy program in patients with Parkinson's disease: a randomized controlled trial. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial.
To determine if the combination of levodopa (LD) plus bromocriptine (Br) in the early stages of Parkinson's disease (PD) permits reduction of LD dosage and consequently results in fewer motor fluctuations and dyskinesias, a double-blind, multicenter prospective study in 50 PD patients who had responded favorably to LD while under treatment with that drug for < or = 6 months was undertaken. Patients were randomized into two parallel groups (LD alone and LD plus Br). During the first placebo-controlled stage of the study lasting 8 months, association of a fixed dose of Br (15 mg/day) in the LD regimen did not allow a significant reduction in the daily LD dose. Still, in patients on combined LD plus Br, there was a tendency toward smaller daily requirements of LD as compared with those on LD alone, and the difference in LD dose between the two groups was significantly different (515.4 +/- 240 vs. 725.6 +/- 230 mg/day; p < 0.01) after 44 months of continuous treatment in the 40 patients still enrolled in the open-label stage. At that point in time, the mean dose of Br had been increased by 9.2 mg in the combined treatment group, and the mean dose of LD was 40.7% lower than in the group receiving LD alone. On subsequent evaluations, the number of patients with dyskinesias or describing wearing-off fluctuations severe enough to require changes in treatment was lower than in the group under combined therapy, the differences being significant after 20 and 44 months, respectively (36.8 vs. 9.5 and 47.3 vs. 14.2%). Our results support early combined LD-Br therapy in PD, but no conclusions can be drawn as to whether this dopamine agonist exerts a preventive effect on the late side effects of LD or has another mechanism of action. Levodopa-carbidopa (LD) in low dosages adequately controls symptoms in most patients with Parkinson's disease and delays the appearance of fluctuations and dyskinesias. It has been suggested that early combination therapy with bromocriptine and levodopa delays or prevents the onset of late treatment complication associated with LD monotherapy in Parkinson's disease. We have conducted this study to assess the possible benefit of combined therapy compared with levodopa monotherapy. Seventy-eight previously untreated patients with Parkinson's disease were recruited over a period of 54 months and randomly allocated to either a levodopa-carbidopa (LD) Group or a levodopa-carbidopa in combination with low-dose bromocriptine (LD-Br) Group. The appearance of motor complications determined the end point of the study. We gradually increased the doses of bromocriptine (2.5-15 mg/d) or levodopa (125-500 mg/d) until the maximum "on" time was reached. In six patients, the doses of levodopa had to be increased up to the optimal dose (625-1000 mg/day). In the last evaluation the on-time and parkinsonian disability were similar in both treatment groups. We did not find statistically significant differences in the frequency of motor complications when comparing the two groups of treatment. Our study suggests that early combination of levodopa and bromocriptine does not confer any clinical benefit over levodopa alone in treating early Parkinson's disease, nor will it influence the evolution of the disease.Copyright Lippincott-Raven Publishers The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.
                Copyright 2000 S. Karger AG, Basel To study the long-term effects of selegiline in monotherapy and in combination with levodopa in the early phase of Parkinson disease (PD).
                One hundred fifty-seven de novo PD patients were randomized in a double-blind, placebo-controlled study of 7 years' duration. In the monotherapy part, selegiline significantly delayed the initiation of levodopa therapy vs placebo. The authors now report the results from the combination part of the study, in which 140 patients received selegiline or placebo in addition to individually tailored levodopa therapy.
                Compared with placebo, selegiline slowed the progression of disease disability as measured by the Unified Parkinson Disease Rating Scale (UPDRS) total score (p = 0.003) or by motor (p = 0.002) and Activities of Daily Living (p = 0.0002) subscores. After 5 years in combination therapy, the mean difference in the UPDRS total score was nearly 10 points, with patients receiving placebo having 35% higher scores. Simultaneously, patients receiving placebo needed progressively higher doses of levodopa than patients receiving selegiline; after 5 years, the mean dosage of levodopa was 19% higher with placebo than with selegiline (p = 0.0002). Considering the entire (monotherapy and combination therapy) 7-year study time, there was a trend for selegiline to delay the start of wearing-off fluctuations (hazard ratio 0.55, p = 0.08). In both phases of the study, selegiline was safe and well tolerated.
                The results of this long-term study confirm earlier findings indicating that selegiline delays the progression of the signs and symptoms of Parkinson disease. Long-term levodopa treatment in Parkinson's disease is typically associated with "motor side effects" consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p = 0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p = 0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with > 50% substitution by bromocriptine exhibited half the risk observed in those with < 30% (p = 0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p = 0.046). In conclusion, partial substitution of levodopa by bromocriptine (> 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control. The objective of this study was to examine the effect of long-term treatment with selegiline on the progression of Parkinson's disease (PD). One hundred and sixty-three patients with early PD were treated with levodopa and benserazide, combined with selegiline or placebo in a five-year randomized, placebo-controlled, double-blind, parallel group study followed by a one-month wash-out of selegiline or placebo. The main outcome measures were assessments of the severity of parkinsonism, levodopa requirements and the development of end-of-dose motor fluctuations over time and after wash-out at the end of the study period. Results indicated that patients treated with the combination of selegiline and levodopa developed markedly less severe parkinsonism and required lower doses of levodopa during the five-year study period than patients treated with levodopa and placebo. There was no trend towards worsening during wash-out among patients previously treated with selegiline. The results cannot easily be explained by a symptomatic effect of selegiline.
                Copyright Lippincott Williams & Wilkins 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. To investigate the effects of a physical therapy (PT) program in groups of people with Parkinson's disease (PD).
                Randomized controlled trial with a crossover design.
                Two outpatient rehabilitation clinics in Boston and Amsterdam, respectively.
                Sixty-eight subjects diagnosed with typical, idiopathic PD, Hoehn and Yahr stage II or III, and stable medication use.
                Group A received PT and medication therapy (MT) for the first 6 weeks, followed by MT only for the second 6 weeks. Group B received only MT for the first 6 weeks and PT and MT for the second 6 weeks.
                The Sickness Impact Profile (SIP-68), the mobility portion of the SIP-68, the Unified Parkinson's Disease Rating Scale (UPDRS), and comfortable walking speed (CWS) at baseline, 6-week, 12-week, and 3-month follow-up.
                At 6 weeks, differences between groups were significant for the SIP mobility ( P =.015; effect size [ES]=.55), for CWS ( P =.012; ES=.49), for the activities of daily living (ADL) section of the UPDRS ( P =.014; ES=.45), and for the total UPDRS ( P =.007; ES=.56). The total SIP and the mentation and motor sections of the UPDRS did not differ significantly between groups. Significant differences were found at 3 months compared with baseline for CWS, the UPDRS ADL, and total scores.
                People with PD derive benefits in the short term from PT group treatment, in addition to their MT, for quality of life related to mobility, CWS, and ADLs; long-term benefits were found in CWS, UPDRS ADL, and total scores but varied between groups. 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.
This systematic review revealed no evidence to support the use of early BR/LD combination therapy as a strategy to prevent or delay the onset of motor complications in the treatment of PD.