A double-blind study of bromocriptine and L-dopa in de novo Parkinson's disease. Short-term results. Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study. 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. The sydney multicentre study of Parkinson's disease: progression and mortality at 10 years. Pramipexole in patients with early Parkinson's disease. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Chronic effects of dopaminergic replacement on cognitive function in Parkinson's disease: a two-year follow-up study of previously untreated patients. Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study. Alpha-dihydroergocryptine in the treatment of de novo parkinsonian patients: results of a multicentre, randomized, double-blind, placebo-controlled study. Dihydroergocryptine in the treatment of Parkinson's disease: a six months' double-blind clinical trial. Ropinirole for the treatment of early Parkinson's disease. The Ropinirole Study Group. Efficacy of piribedil as early combination to levodopa in patients with stable Parkinson's disease: a 6-month, randomized, placebo-controlled study. 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. Long term bromocriptine treatment in de novo parkinsonian patients. A placebo-controlled evaluation of ropinirole, a novel D2 agonist, as sole dopaminergic therapy in Parkinson's disease. Long-term double masked trial of early treatment with L-dopa plus bromocriptine versus L-dopa alone in Parkinson's disease. Interim results. 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. 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. The long-acting dopamine receptor agonist cabergoline in early Parkinson's disease: final results of a 5-year, double-blind, levodopa-controlled study. Trial of subtherapeutic pergolide in de novo Parkinson's disease. The effect of deprenyl and levodopa on the progression of Parkinson's disease. CQA 206-291: a novel dopamine agonist in the treatment of Parkinson's disease. Pergolide monotherapy in the treatment of early PD: a randomized, controlled study. Pergolide Monotherapy Study Group. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. The Pramipexole Study Group. Does combined levodopa and bromocriptine therapy in Parkinson's disease prevent late motor complications?
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. 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 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 report on a 10 year follow up of patients with idiopathic Parkinson's disease, particularly with respect to mortality and the effect of early treatment with bromocriptine.
                The patients are from the 149 new patients recruited for a double blind, randomised study of low dose levodopa-carbidopa versus low dose bromocriptine. Patients were examined neurologically at least yearly. Neuropsychological examinations were performed at 0, 3, 5, and 10 years. Mortality and cause of death in these patients were compared with the Australian population using standardised mortality ratios (SMRs). Mortality and disease progression were compared by sex and treatment group. Predictors of death within 10 years, nursing home admission, and progression in Columbia score of >/=20 points were examined by logistic regression analysis.
                Thirteen patients were excluded as having atypical Parkinsonism and six were lost to follow up. All available patients have been followed up for 10 years. Fifty patients (38%) were dead by 10 years and 63 by the last follow up. The SMR was 1.58 for all patients (p<0. 001). There was no significant difference in SMRs between the sexes. The mean duration of disease until death was 9.1 years. Parkinson's disease was thought to have contributed substantially to the death of 30 patients. The most common cause of death was pneumonia. Women progressed at a similar rate to men until 8 years, when the severity of their disease as measured by Hoehn and Yahr stage became greater (p<0.05). Older age of onset correlated with increased risk of death but the SMR was increased even in those aged <70 years (SMR 1.80, p=0.03). Early use of bromocriptine did not reduce mortality or slow progression of disease. One quarter of all patients had been admitted to nursing homes by 10 years. Only four patients were still employed.
                Mortality in Parkinson's disease remains increased despite low dose levodopa-carbidopa therapy and no additional benefit was gained from early use of bromocriptine. Duration of disease was similar to that in the era before levodopa. We evaluated the efficacy, safety, tolerability, and pharmacokinetics of pramipexole, a novel dopamine D2 receptor agonist, in early Parkinson's disease (PD). The study design was a parallel, placebo-controlled trial using an ascending dose of 4.5 mg/day pramipexole maximum. All subjects received selegiline (10 mg/day) but were not treated with levodopa. Of the 55 subjects who received at least one dose of the study medication, all but one, in the placebo group, completed the trial, which was 9 weeks in duration. The primary efficacy endpoints were changes in scores from baseline to final measurement on the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II and III. The pramipexole group had a significantly greater improvement (p = 0.002) than the placebo group on UPDRS Part II (Activities of Daily Living). The change in score from baseline to final measurement on UPDRS Part III (Motor Examination) was not significantly different (p = 0.10) between the pramipexole and placebo groups, although the trend favoured the pramipexole group. All subjects in both the pramipexole and the placebo groups experienced one or more episodes of asymptomatic orthostatic hypotension; there was no significant difference between the pramipexole and the placebo groups in the number of subjects experiencing symptomatic orthostatic hypotension. The adverse events profile of pramipexole was similar, in general, to that of other dopamine receptor agonists. Plasma pramipexole levels increased linearly with dose. Pramipexole appears to be promising agent in the treatment of early PD. 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. The cognitive effects of dopaminergic treatment in Parkinson's disease (PD) are still controversial.
                To evaluate, in previously untreated patients with PD, whether chronic dopaminergic stimulation produces significant cognitive changes; whether they are sustained beyond the period of a few months; and whether the cognitive status of two motor-comparable groups is differently affected by levodopa and pergolide.
                Parallel, randomized open study with blind neuropsychologic evaluation of 20 consecutive de novo patients with PD before and 3, 6, 12, 18, and 24 months after monotherapy with levodopa (n = 10) or pergolide (n = 10; 6-month monotherapy; pergolide + levodopa thereafter).
                Both treatments were associated with a significant improvement in motor scores and in tests assessing learning and long-term verbal and visual memory, visuospatial abilities, and various frontal tasks. While improvement in motor scores persisted, improvement in activities of daily living and in semantic fluency, Luria's rhythm and motor and long-term memory tests was not sustained at the 24-month examination. Further, performance on attentional, short-term memory, and the Stroop tests did not change over the course of the study.
                Both treatments were associated with incomplete but long-lasting (18 mos) improvement in many cognitive tasks which declined thereafter, suggesting that dopaminergic replacement is not enough to compensate for all cognitive deficits of PD. 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. A multicentre, randomized, double-blind, placebo-controlled, parallel group study was carried out in 123 patients suffering from never treated (de novo) idiopathic Parkinson's disease (PD). The aim of the study was to confirm the efficiency and safety of alpha-dihydroergocryptine (alpha-DHEC) given as monotherapy in the symptomatic treatment of PD. The total score of the Unified Parkinson's Disease Rating Scale (UPDRS) was identified as the efficacy target variable.
                Sixty-two patients (32 males, 30 females, mean age +/- SD 64 +/- 10) were randomized to alpha-dihydroergocryptine and 61 (30 males, 31 females, mean age 63.8 +/- 9.1) to placebo. According to the experimental design, a 18-month double-blind phase vs placebo was followed. Two interim analyses were planned both at the 3rd and 12th month of treatment, in order to avoid continuation on placebo, if clear differences between groups were found (stopping criterium: nominal significance level equal to 0.022 in the analysis of the target variable). Analysis of variance was performed both on the per protocol (PP) and intent-to-treat (ITT) sample.
                The results on the first interim analysis showed significant differences between treatment groups of the UPDRS total score both in the ITT (115 patients, alpha-DHEC: No. 56; placebo: No. 59; P=0.019) and PP (96 patients, alpha-DHEC: No. 46; placebo: No. 50; P=0.001) sample, why the trial was stopped. At the time of stopping the trial, 73 patients (alpha-DHEC: No. 37; placebo: No. 36) had reached the 6-month observation visit; the analysis carried out on this subset of patients confirmed the efficacy of alpha-dihydroergocryptine in early PD and the correctness of the decision to stop. The incidence of adverse drug reactions (ADR) did not differ between alpha-dihydroergocryptine and placebo recipients, gastrointestinal complaints being the most frequent.
                The results indicate that alpha-dihydroergocryptine is safe and effective in improving symptoms of de novo parkinsonian patients. The short-term efficacy of dihydro-alpha-ergocryptine (DEK), a hydrogenate ergot derivative with dopamine (DA) agonist properties was evaluated in 20 L-dopa (LD) stable responder parkinsonian patients by a 6-month double-blind randomized, placebo-controlled study. A motor improvement was found only in DEK-treated patients at mean daily doses of approximately 40 mg, ranging from 15 to 60 mg. The side effects never required the withdrawal of the drug or changes in its schedule. The authors demonstrate the efficacy and the good tolerability of DEK as a new DA agonist drug that can be added to LD in the treatment of parkinsonian patients. A prospective, randomized, placebo-controlled, double-blind, parallel-group, 6-month study assessed the efficacy and safety of ropinirole, a nonergoline D2-dopamine agonist, in patients with early Parkinson's disease (n = 241; Hoehn & Yahr stages I to III) with limited or no prior dopaminergic therapy. Patients (mean age, 62.8 years), stratified by concomitant use of selegiline, were randomized to ropinirole (n = 116) or placebo (n = 125). The starting dose of ropinirole was 0.25 mg tid with titration to at least 1.5 mg tid (maximum dose, 8 mg tid). Primary efficacy endpoint was the percentage improvement in Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Ropinirole-treated patients had a significantly greater percentage improvement in UPDRS motor score than patients who received placebo (+24% vs -3%; p < 0.001). Ropinirole was well tolerated and patient withdrawals were infrequent. Most adverse experiences were related to peripheral dopaminergic activity. Ropinirole monotherapy is an effective and well-tolerated therapeutic option for treatment of early Parkinson's disease. Piribedil is a non-ergot D2/D3 agonist with a significant antagonist action on alpha2A and alpha2C adrenergic receptor subtypes. This double-blind placebo-controlled study was undertaken to confirm the efficacy of 150 mg/day piribedil po in improving motor symptoms of idiopathic Parkinson's disease (PD) in nonfluctuating patients insufficiently controlled by a stable daily dose of levodopa (L-dopa). Efficacy was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) III score as primary criterion over 4 months. A second comparison was planned at 6 months, after possible adjustment of L-dopa. At 4 months, the rate of response, defined as a 30% decrease from baseline on UPDRS III score, was significantly greater with piribedil compared with placebo (56.4% vs. 37.7%; P = 0.040). At 6 months, the better efficacy of piribedil was maintained (61.8% of responders vs. 39.6% on placebo; P = 0.020). The difference between groups on UPDRS III change from baseline reached statistical significance only at 6 months: -10.0 points in the piribedil group vs. -6.7 points in the placebo group (P = 0.037). Secondary end-points were not significantly different. The most frequently reported adverse events were gastrointestinal symptoms (27 of 61 patients in the piribedil group vs. 13 of 54 patients in the placebo group). In conclusion, a 6-month oral administration of 150 mg/day piribedil in combination with L-dopa is well tolerated, except for minor gastrointestinal symptoms at the beginning of the treatment and significantly improves motor symptoms compared with placebo in PD nonfluctuating patients.
                Copyright 2003 Movement Disorder Society 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. nan The efficacy and safety of ropinirole, a novel nonergot dopamine D2-like receptor agonist, was assessed as monotherapy for the treatment of patients with early-stage Parkinson's disease. In this double-blind, multicenter trial, patients were randomly allocated in a ratio of 2:1 to receive, over a 12-week period, either ropinirole or placebo. Clinical status was assessed using the Unified Parkinson's Disease Rating Scale (UP-DRS), Clinician's Global Evaluation (CGE), and a finger-tapping score. In all, 41 patients received ropinirole and 22 received placebo. The end-point analysis, on an intention-to-treat basis, revealed a significant difference (p = 0.018) in improvement in UP-DRS motor score from baseline between treatment groups (ropinirole, 43.4%; and placebo, 21.0%). Other parameters, including the number of responders and improvement in CGE, showed similar results. Three patients in the ropinirole group and one patient in the placebo group discontinued the study because of adverse events. There was no significant difference between the treatment groups in the overall incidence of adverse events. Although the dopaminergic side effects were reported significantly more frequently in the ropinirole group than in the placebo group (dizziness, p = 0.0326; nausea, p = 0.001; and somnolence, p = 0.005), none necessitated study withdrawal. There was no evidence of any chronic effect of the study medication on vital signs. In conclusion, ropinirole is a safe and well-tolerated drug and, as monotherapy, provided significant therapeutic benefit compared with placebo to patients in the early stages of Parkinson's disease. The quality and duration of control in two groups of parkinsonian patients under treatment with an L-dopa-based drug alone or L-dopa-based drug which has been partially substituted with bromocriptine are being compared over a 5-year period using a double-blind placebo-controlled study design. The aim is to establish whether early addition of bromocriptine will minimise late L-dopa complications. Results are presented after 1 year. Of 31 patients randomised, 13 were treated with combined L-dopa/bromocriptine and 14 with L-dopa/placebo. 4 patients were withdrawn for various reasons. In both groups any dose adjustments were aimed at maintaining the pre-entry clinical condition. In the group receiving bromocriptine combination therapy, progressive reduction of L-dopa was possible without deterioration of the patients' condition. In patients receiving L-dopa alone, the dose of L-dopa at 12 months was almost similar to that recorded on entry to the study. The total number of patients reporting adverse events in the L-dopa/bromocriptine combination and L-dopa alone groups were 8 and 7, respectively. At the present interim stage of the study it is not possible to compare the incidence of L-dopa long-term complications in either group. 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 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. Cabergoline is an ergoline derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabergoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson's disease.
                This study was a double-blind, multicentre trial that compared cabergoline and levodopa as initial therapy for Parkinson's disease. A total of 419 levodopa-, DA- and selegiline-naive patients with newly diagnosed Parkinson's disease were randomised to receive either cabergoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1-5, the cabergoline group was receiving cabergoline at average daily doses ranging from 2.8-2.9 mg, with added levodopa at mean daily doses ranging from 322 mg at year 1 to 431 mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784 mg. Thus, patients in the cabergoline group received <50% levodopa than patients in the levodopa group.
                Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabergoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabergoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabergoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabergoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabergoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson's Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician- and patient- rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabergoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabergoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). Cabergoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabergoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabergoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly.
                This study showed that, compared with levodopa, initial therapy with cabergoline in patients with Parkinson's disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema. The effect of pergolide 25 mug twice daily on levodopa initiation was assessed in a randomized, placebo-controlled, parallel group, double-blind multicenter trial in 106 untreated early Parkinson's disease patients. The primary endpoint of mean time until levodopa was 520 days (95% confidence interval [CI], 422-618 days) for pergolide versus 434 days (95% CI, 358-609 days) for placebo. However, this increase of 86 days for pergolide was not statistically significant. The wash-in effect of pergolide was significant at 6 weeks (change in mean Unified Parkinson's Disease Rating Scale [UPDRS] 2 and 3 was -0.1 [95% CI, -1.4 to 1.3] for pergolide vs. 2.2 [95% CI, 1.1-3.3] for placebo). At termination, the change from baseline in mean UPDRS 2 and 3 score was 11.4 (95% CI, 8.8-14) for pergolide and 14.6 (95% CI, 12-17.2) for placebo (P=0.08). There was no significant change in UPDRS 2 and 3 for the 83 patients achieving the planned 4-week washout at termination (pergolide 1.2 [95% CI, -0.8 to 3.2] vs. placebo 0.0 [95% CI, -1.6 to 1.6]. Adverse events were infrequent and occurred equally for pergolide and placebo. The study shows no evidence of a neuroprotective effect but indicates a mild symptomatic benefit from pergolide at a dose normally considered subtherapeutic. We have performed a 14-month, prospective, randomized, double-blind, placebo-controlled study to evaluate the effect of deprenyl and levodopa/carbidopa (Sinemet) on the progression of signs and symptoms in patients with mild Parkinson's disease (PD). One hundred one untreated PD patients were randomly assigned to one of the following four treatment groups: Group I, deprenyl + Sinemet; Group II, placebo-deprenyl + Sinemet; Group III, deprenyl + bromocriptine; and Group IV, placebo-deprenyl + bromocriptine. The final visit was performed at 14 months, i.e., 2 months after withdrawal of deprenyl or its placebo and 7 days after withdrawal of Sinemet or bromocriptine. Deterioration in Unified Parkinson's Disease Rating Score (UPDRS) between untreated baseline and final visits was used as an index of disease progression. Placebo-treated patients deteriorated by 5.8 +/- 1.4 points, while deprenyl-treated patients deteriorated by 0.4 +/- 1.3 points (p < 0.001). This effect was sufficiently powerful that a significant deprenyl effect could be detected in the subgroup of 41 patients randomized to Sinemet (p < 0.01) as well as in the 23 patients who completed a 14-day washout of Sinemet or bromocriptine (p < 0.05). No difference in the extent of deterioration was detected in patients randomized to Sinemet versus bromocriptine. This study demonstrates that deprenyl attenuates deterioration in UPDRS score in patients with early PD. These findings are not readily explained by the drug's symptomatic effects and are consistent with the hypothesis that deprenyl has a neuroprotective effect. The antiparkinsonian efficacy and tolerability of CQA 206-291, a novel ergoline derivative with potent dopamine agonist properties, were studied during 2 months of treatment in 72 parkinsonian patients. In 36 de novo patients (patients who have not previously been treated with levodopa or dopamine agonists), CQA 206-291 was studied in an open design, while in 36 levodopa-treated patients, CQA 206-291 was studied in a randomized, double-blind, parallel-group, placebo-controlled design. CQA 206-291 induced in both groups a significant antiparkinsonian effect with an effective dose range of 5-30 mg/day. The spectrum of adverse events was similar to what is commonly observed with dopamine agonists. Further studies are required to assess the putative therapeutic advantages of CQA 206-291 when compared to other antiparkinsonian drugs. To determine whether pergolide monotherapy provides symptomatic relief in early PD.
                Early treatment with dopamine agonists may reduce the risk of motor fluctuations, which are most likely linked to levodopa therapy. Pergolide, a D1-D2 dopamine agonist, has been studied as "add on" therapy in PD, but no controlled clinical trial studying the efficacy of pergolide monotherapy is available.
                The efficacy and tolerability of pergolide were evaluated in a multicenter, double-blind, randomized, parallel-group, 3-month trial versus placebo. Patients with a diagnosis of idiopathic PD, a modified Hoehn & Yahr score of 1 to 3, and a score greater than 14 points on the Unified Parkinson's Disease Rating Scale (UPDRS) part III at baseline were enrolled in the study (pergolide, n = 53; placebo, n = 52).
                Patient characteristics at study entry were comparable in the two study groups. The pergolide group showed a significantly greater percent of responders (defined as a -30% decrease in UPDRS part III score at end point) compared with placebo (57% versus 17%; p < 0.001). Pergolide-treated patients experienced a significantly greater improvement than placebo-treated patients (p < 0.001) in UPDRS (overall, part II, and part III) score, Schwab & England score, and Clinical Global Impression improvement score. By the study end the mean dose of pergolide was 2.06 mg/day. Six patients in the pergolide group versus two patients in the placebo group discontinued the study because of treatment emergent side effects.
                This study suggests that pergolide monotherapy may be an efficacious and well-tolerated first-line treatment in patients with early-stage PD. A total of 335 patients with early Parkinson's disease (PD) were enrolled in a multicenter, randomized, double-blind trial designed to assess the efficacy and safety of pramipexole. Entry was restricted to patients with idiopathic PD who were not receiving levodopa. Pramipexole was administered according to an ascending dose schedule up to 4.5 mg/d. During the 7-week dose-escalation phase, each subject was titrated to his or her maximally tolerated dose of study medication. This was followed by a 24-week period of maintenance therapy. The mean daily dose during the maintenance period was 3.8 mg. Pramipexole significantly reduced the severity of PD symptoms and signs compared with placebo, as measured by decreases in parts II (Activities of Daily Living) and III (Motor Examination) of the Unified Parkinson's Disease Rating Scale at week 24 compared with baseline (p < or = 0.0001). Differences between the active drug and placebo groups emerged at week 3 (1.5 mg/d) in the ascending-dose interval and persisted throughout the maintenance phase (p < or = 0.0001). The majority of patients completed the study (pramipexole 83%, placebo 80%). In the assessment of adverse events, nausea, insomnia, constipation, somnolence, and visual hallucinations occurred more frequently in the pramipexole treatment group compared with placebo patients. No clinically significant changes were noted in blood pressure or pulse rate. Overall, these results indicate that pramipexole is safe and effective in the treatment of early PD. 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
This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa.