Does combined levodopa and bromocriptine therapy in Parkinson's disease prevent late motor complications? Comparison of lisuride and bromocriptine in the treatment of advanced Parkinson's disease. [Bromocriptin in the treatment of progressive stages of Parkinson's disease (author's transl)]. Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. International Pramipexole-Bromocriptine Study Group. A double-blind study of bromocriptine and L-dopa in de novo Parkinson's disease. Short-term results. 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. Bromocriptine versus placebo in levodopa treated patients with Parkinson's disease. Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial. Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.
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 Twenty patients with advanced idiopathic Parkinson's disease were studied, all having a deteriorating response to levodopa and suffering from daily fluctuations in disability. A double-blind randomized cross-over study was conducted. Basic levodopa and anticholinergic treatment was continued unchanged in all patients. The dose increment period of 4-8 weeks was followed by a 4 week treatment period on a fixed optimal dose. In both treatment groups the mean optimal daily dose of lisuride was 1.3 mg (range 0.2-2.4 mg) and that of bromocriptine about 15 mg (range 3.75-30.0), without any significant differences between the treatment groups. The addition of lisuride or bromocriptine to levodopa treatment resulted in a significant and equal further improvement of parkinsonian disability. The therapeutic profiles of both lisuride and bromocriptine were similar. There was significantly more improvement in tremor than in other parkinsonian symptoms. Both lisuride and bromocriptine elicited a significant improvement in fluctuations of disability. No significant differences between the treatments were observed. The occurrence of clinical side effects seemed to be similar with both treatment regimens. In advanced parkinsonian patients the therapeutic efficacy of lisuride seems to be equal to that of bromocriptine as far as parkinsonian disability and fluctuations in disability are concerned. Forty patients with severe Parkinson's disease (23 men, 17 women) who had been treated for six years with L-dopa-decarboxylase inhibitor, were part of a placebo-controlled double-blind trial to test the effectiveness of bromocriptin. In all patients the effectiveness of L-dopa had been decreasing, 34 patients had L-dopa-induced dyskinesias, 35 "on-off" symptoms. Bromocriptin dosage was gradually increased to a total dose of 30 - 40 mg daily. This led to a 25% reduction in L-dopa requirements. The symptoms of Parkinson's disease were favourably influenced, with rigor, tremor and also walking disturbances responding better than bradykinesia of the hands. At the same time, there was a marked prolongation of the periods of good mobility ("on" time) from 7 to 10.8 hours without influence on other "on-off" symptoms such as paradoxical akinesia. Two patients had to be excluded from the trial because the treatment caused side effects (orthostatic hypotension, exogenous psychotic symptoms). Other side effects, such as nausea and mild forms of collapse, could be controlled by drugs. Pramipexole is a new, selective, nonergoline dopamine agonist that acts on D2 and preferentially on D3 dopamine receptors. Phase II and III clinical trials have shown this drug to be useful in treating both early and advanced Parkinson's disease (PD) patients. A double-blind, randomized, multicenter study was performed to compare the safety, tolerance, and efficacy of pramipexole versus placebo in patients with advanced PD with motor fluctuations. A bromocriptine treatment group was included to enable comparisons between bromocriptine and placebo groups, but the study was not powered to show statistical differences between the active treatment groups. The study included 247 patients with "wearing off." Patients were Hoehn and Yahr stages II to IV during "on" times. The trial included three phases: dose escalation, 6 months' maintenance, and dose reduction. The primary end points were the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. Up to 4.5 mg per day of pramipexole and 30 mg per day of bromocriptine were used. The results of the study showed that the UPDRS part II improved by 26.7% for pramipexole (p = 0.0002) and 14% for bromocriptine (p = 0.02) versus 4.8% for placebo. The UPDRS part III showed improvements of 34% for pramipexole (p = 0.0006) and 23.8% for bromocriptine (p = 0.01) versus 5.7% for placebo. There were no major differences in safety data. In the active treatment groups there were more reports of dyskinesia and nausea compared with placebo. In regard to comparison of the Global Clinical Assessment of Efficacy between active treatment groups, there was a trend to significance (p = 0.056) in favor of pramipexole. We conclude that pramipexole-treated patients with advanced PD improved significantly more than placebo for both primary end points. The first phase of a longitudinal multicenter study comparing bromocriptine and L-dopa (as Sinemet) as de novo therapy for Parkinson's disease using a double-blind randomized design has recently been completed. Over a period of 5.5 months, bromocriptine and L-dopa were equipotent in reducing functional and neurological disability. These observations complement and extend earlier studies and suggest a role for bromocriptine as de novo therapy of Parkinson's disease. 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. Twenty patients with idiopathic parkinsonism who had been on optimal levodopa therapy for at least 3 months prior to the investigation and where effect of the treatment was decreasing or side effects were increasing, were treated with bromocriptine in a double-blind crossover trial during a 12 + 12 weeks period. Reduction in disability scores was found significant. Hyperkinesia was more frequent in the bromocriptine period than in the placebo period, but reduction of dose in six patients for this reason was not followed by deterioration. Both hyperkinesia and other side effects disappeared after dose reduction. Doses were 2.5 mg-40 mg. Bromocriptine seems a valuable supplement to previous therapy in these patients. 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. 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.
Based on a qualitative review of the available data we conclude that in the treatment of early Parkinson's disease, bromocriptine may be beneficial in delaying motor complications and dyskinesias with comparable effects on impairment and disability in those patients that tolerate the drug.