Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study).

OBJECTIVES: To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. PATIENTS AND METHODS: In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. RESULTS: In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. CONCLUSION: Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.

A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson's disease. The 053 Study Group.

OBJECTIVE: To compare the long-term efficacy and safety of ropinirole with bromocriptine over 3 years in patients with early PD with limited or no previous dopaminergic therapy. METHODS: In this prospective, double-blind, parallel-group study, 335 patients were randomized to 0.75 mg ropinirole or 1.25 mg bromocriptine titrated upward at weekly intervals--maximum permitted daily doses were 24 mg ropinirole, 40 mg bromocriptine. RESULTS: Approximately one third of patients in each group withdrew prematurely, mostly because of adverse experiences; 61/102 (60%) of ropinirole-treated and 59/112 (53%) of bromocriptine-treated patients completed the study on the dopamine agonist alone. Mean doses for all patients at completion were 12 mg (SD 6) ropinirole and 24 mg (SD 8) bromocriptine. Occurrence of adverse experiences in both groups was similar. Emergence of dyskinesias was low. Both treatments induced marked improvements in Unified Parkinson's Disease Rating Scale activities of daily living (ADL, Part II) and motor (Part III) scores over the first 12 weeks, which were maintained during the study. After 3 years, patients in the ropinirole group had a mean improvement in motor score of 31% compared with 22% in the bromocriptine group (p = 0.086) and a significantly better ADL score (treatment difference 1.46 points, p = 0.009) [corrected]. CONCLUSIONS: Both dopamine agonists are effective in the early treatment of a high proportion of PD patients; effectiveness persists for at least 3 years. Those who completed the study had a significantly better functional status on ropinirole than on bromocriptine.

The natural history of Parkinson's disease.

There are still insufficient data on the natural course of Parkinson's disease (PD) owing to lack of standardized longitudinal follow-up studies. Reported progression rates in early PD vary considerably by a factor of 2 to 3. Similarly, data from sequential [18F]dopa PET studies in PD patients have produced variable decline rates of PET indices ranging between 7 and 70% per decade. Risk factors for rapid progression include old age at onset, concomitant major depression, dementia, and akinetic-rigid symptom presentation. The introduction of levodopa into the routine treatment of PD patients had a dramatic impact on symptomatic control without affecting the underlying rate of disease progression. By contrast, monoamine oxidase (MAO) B inhibition by deprenyl monotherapy in early PD was shown to delay the need for levodopa by around 9 months. However, the neuroprotective action disappeared after 2 years of follow-up. Furthermore, deprenyl also failed to influence the subsequent development of levodopa-induced motor complications. Available studies on mortality in PD provide heterogeneous mortality rates, probably because of discrepancies between patient populations with respect to co-morbidity, disease stage at study entry, and diagnostic accuracy. However, the most recent follow-up from the DATATOP cohort suggests normal life expectancy in carefully selected patients without significant co-morbidity and with adequate treatment and expert follow-up.

Ropinirole in the treatment of early Parkinson's disease: a 6-month interim report of a 5-year levodopa-controlled study. 056 Study Group.

The efficacies of ropinirole and levodopa were compared after 6 months of treatment in a planned interim analysis of a 5-year, double-blind, randomized, multicenter study of patients with early Parkinson's disease requiring dopaminergic therapy. The percentage of improvement in the Unified Parkinson's Disease Rating Scale total motor examination score was significantly higher for levodopa (44%) than for ropinirole (32%). The proportion of "responders" (Unified Parkinson's Disease Rating Scale improvement of at least 30%) did not differ between groups (levodopa, 58%; ropinirole, 48%). There was no difference between the groups for improvement on the Clinical Global Impression scale in patients with Hoehn and Yahr stages I, I.5, or II, but a significantly higher proportion of patients with Hoehn and Yahr stages II.5 or III showed Clinical Global Impression score improvement with levodopa. Emergent adverse events occurred in 84% of patients in both treatment groups, the principal symptom in each group being nausea. The incidence of serious adverse events was low (8% for ropinirole, 9% for levodopa). The results suggest that ropinirole and levodopa are equally effective in less severe Parkinson's disease; in more advanced Parkinson's disease, levodopa is superior.

Ropinirole versus bromocriptine in the treatment of early Parkinson's disease: a 6-month interim report of a 3-year study. 053 Study Group.

We compared the efficacy and safety of ropinirole with that of bromocriptine after 6 months of treatment in a planned interim analysis of a 3-year, double-blind, randomized, multicenter study of 335 patients with early Parkinson's disease requiring dopaminergic therapy. Patients, treated with or without selegiline, received either ropinirole or bromocriptine. The mean Unified Parkinson's Disease Rating Scale (UPDRS) total motor examination scores (Part III) at baseline were similar in the four strata. Overall, and in the non-selegiline subgroup, the percentage improvement in the UPDRS total motor examination score was significantly higher for ropinirole than for bromocriptine, as was the proportion of "responders." In the selegiline subgroup, however, there was no significant difference between treatments. Similarly, in the non-selegiline subgroup, there was a significantly higher proportion of "improvers" on the Clinical Global Impression scale with ropinirole than with bromocriptine, whereas in the selegiline subgroup, there was no significant difference. Emergent adverse events occurred in 80% of patients in both treatment groups, the principal symptom in each group being nausea. The incidence of serious adverse events was low (3% for ropinirole, 6.6% for bromocriptine). The data indicate that (a) in the absence of selegiline, ropinirole is effective and superior to bromocriptine; and (b) selegiline does not affect the response in patients treated with ropinirole, but enhances the effects of bromocriptine.

The natural history of Parkinson's disease.

A large body of evidence indicates that the progression of Parkinson's disease (PD) may be fast in the preclinical stage as well as during the first years of the disease, with a subsequent slowing down of the disease process. As has been shown in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination scores declined at a rate of 8 to 9% per year in untreated patients. A subgroup of levodopa-naive DATATOP patients ("survivors") showed a much slower rate of progression, in the order of 3% per year, suggesting a more benign disease course. A number of clinical factors that may govern the rate of motor decline, such as age at onset, disease duration, gender, and clinical phenotype (akinetic-rigid versus tremulous) have been proposed; however, none of them is proven. In contrast, dopaminergic substitution undoubtedly has had a major impact on the natural history of PD, resulting in a reduction of the mortality ratio from about 3.0 to 1.5. This benefit has been noted particularly in patients in whom levodopa therapy was started early. The positive impact of levodopa is largely derived from its symptomatic action; its influence on the disease process itself remains controversial.

Clinical aspects of motor fluctuations in Parkinson's disease.

Fluctuations in motor response eventually affect most patients with Parkinson's disease who have been exposed to chronic, intermittent levodopa administration for longer than 5 years. Response oscillations are often related to the timing of levodopa doses (predictable "wearing-off"), but random "on-off" effects also occur in one subgroup of patients. The underlying pathophysiology of each type of effect may be different. Treatment also differs: Patients with complex refractory oscillations may benefit from continuous dopaminergic stimulation with enteral infusions of levodopa or subcutaneous infusions of apomorphine. Three major types of abnormal drug-induced involuntary movements (interdose and biphasic dyskinesias and "off-period" dystonia) accompany these response oscillations in most patients, making fluctuating Parkinson's disease symptoms the most challenging problem in antiparkinsonian therapy. The underlying mechanisms for motor fluctuations have only been partially explained, and preventive treatment strategies have yet to be defined in properly designed prospective long-term studies.

Effects of treatment with trihexyphenidyl on cognitive function in early Parkinson's disease.

13 patients with PD of recent onset underwent a series of neuropsychological tests for frontal lobe associated functions (Sternberg paradigm, WCST, CVLT) before and during treatment with Artane. Test results at baseline were not significantly different from those of an age-matched control group (n = 13). Retesting after a mean of 2 weeks' treatment with trihexyphenidyl revealed only slight impairment in CVLT while performance on the other tests remained unchanged.

Dystonia in Parkinson's disease: clinical and pharmacological features.

We studied the features of dystonia in 9 patients with untreated idiopathic Parkinson's disease and in 56 patients on sustained treatment with L-dopa. Dystonia was seen as an initial symptom in patients with both early- and late-onset Parkinson's disease and included action dystonia of the limbs and cranial dystonia. Although the coexistence of parkinsonism and dystonia suggests a common pathophysiology, antiparkinsonian drugs did not consistently influence dystonic spasms. L-dopa-induced dystonia was seen as an off-period, biphasic, or peak-dose phenomenon. Each type showed a distinctive pattern of localization of dystonic spasms, possibly reflecting neurochemical aspects of basal ganglia somatotopy. Neuropharmacological studies performed in 12 patients suggest that off-period dystonia is genuinely induced by L-dopa and best relieved by antiparkinsonian agents.

Primary CNS lymphoma presenting as a choreic movement disorder followed by segmental dystonia.

Clinical presentation of primary CNS lymphoma with an extrapyramidal movement disorder has not been recorded. A 66-year-old woman presented with chorea involving her left arm and subsequently developed right-sided segmental dystonia with prominent hemifacial dystonic spasms, milder torticollis and dystonia of the right arm. Investigations revealed primary CNS lymphoma with extensive involvement of the right-sided basal ganglia as well as lesions confined to the head of the left caudate nucleus and the corpus callosum. Chorea of her left arm subsided with progressing disease while remission of right-sided segmental dystonia was observed following radiotherapy of the brain. This patient's findings and a review of the literature suggest a possible relation between cranio-cervical dystonia and pathology affecting the head of the caudate nucleus.

Clinical and pharmacokinetic observations with Madopar HBS in hospitalized patients with Parkinson's disease and motor fluctuations.

The efficacy of a novel oral sustained-release preparation of L-dopa (Madopar HBS) was compared to that of previous standard L-dopa treatment in 10 patients with idiopathic Parkinson's disease and severe fluctuations in motor performance in an open inpatient trial. Clinical assessment included evaluation of self-scoring 'on-off' diaries kept by the patients throughout the study. It revealed a reduction of end-of-dose deterioration and, to a lesser degree, of random 'on-off' swings in 6 cases. Doses of Madopar HBS required for an optimal response averaged the 1.6-fold of previous conventional L-dopa. Plasma levels of L-dopa were more stable with Madopar HBS compared to standard L-dopa treatment in 4 of 5 patients.

Low-dose L-dopa therapy in Parkinson's disease: a 6-year follow-up study.

Thirty-five patients with early mild Parkinson's disease were treated from the outset with small doses of L-dopa (mean dose, 396 to 454 mg daily) and a peripheral decarboxylase inhibitor, for a mean of 6 years. Overall mortality ratio was 1.2:1, worse for women than for men. After 6 years of treatment, only one-third of patients were better, and drug-related complications were common (peak-dose dyskinesias in 54% of patients, off-period dystonia 20%, wearing-off effects 52%, on-off oscillations 6%, visual hallucinations and toxic confusional states 17%). We found no evidence that long-term results were markedly improved with low-dose regimens.

Inhibition of L-[18F]fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography.

The brain uptake of L-[18F]fluorodopa was measured by positron emission tomography in a healthy male volunteer both under fasting conditions and during intravenous amino acid loading. A significant reduction of tracer uptake into the brain was demonstrated with amino acid loading. This finding represents the first direct evidence for competition between L-dopa and other amino acids for uptake across the blood-brain barrier obtained in vivo in a human subject. It underlines the possible importance of interference by dietary amino acids with the therapeutic actions of L-dopa in Parkinson's disease.

Treatment of motor fluctuations in Parkinson's disease with an oral sustained-release preparation of L-dopa: clinical and pharmacokinetic observations.

Ten patients with idiopathic Parkinson's disease and severe motor-fluctuations participated in an open inpatient trial comparing the efficacy of standard L-Dopa/benserazide (Madopar) treatment with that of an oral sustained-release preparation (Madopar HBS) combined with the standard drug. Clinical assessments of the patients' parkinsonian disabilities were performed daily by one of the investigators and subjects kept self-scoring "on-off" diaries throughout the trial. Plasma concentrations of L-Dopa were followed during both types of therapy in five cases using standard high performance liquid chromatography technique. Sustained-release L-Dopa treatment led to a reduction in end-of-dose deterioration and on-off swings in six patients and doses needed averaged 1.6-fold of previous standard L-Dopa. Drug-induced dyskinesias decreased in one case with sustained-release therapy, remained unchanged in three, and increased in six cases when compared with conventional L-Dopa. Plasma levels of L-Dopa were more stable with the sustained-release preparation in four of five patients. During subsequent outpatient follow-ups of up to 4 months, three of the six responders in this study continued to obtain benefit from the trial drug. It is concluded that oral sustained-release L-Dopa treatment can reduce response-fluctuations in patients with Parkinson's disease.