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.
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.
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.