Valvular heart disease in Parkinson's disease vs. controls: An echocardiographic study.

Restrictive valvulopathy has been reported in association with dopamine agonist therapy in parkinsonian patients. The majority of reports have been related to pergolide, but anecdotal cases following treatment with bromocriptine or cabergoline have also been presented. It is presently unclear whether the potential induction of restrictive cardiac valvulopathy is a class effect of all dopamine agonists or if there is a differential risk between ergot and nonergot compounds. In this study, the frequency of a valvular regurgitation as assessed by routine transthoracic echocardiography was compared between 75 patients with Parkinson's disease (PD) treated with pergolide (n = 29), cabergoline (n = 13), pramipexole or ropinirole (n = 33), and 49 age-matched nonparkinsonian controls. The exposure to pergolide and cabergoline was associated with higher frequencies of valvular regurgitation grades 2 and 3 (31% and 47%) compared with age-matched controls (13%), while there was no increase of valvular regurgitation grades 2 and 3 in patients treated with nonergot compounds (10%). Evidence for restrictive valvulopathy was found in one patient treated with pergolide and cabergoline each. While this study shows similarly increased frequencies of valvular regurgitation in patients treated with the ergot agonists pergolide and cabergoline in comparison to both normal controls and patients treated with nonergot agonists, evidence for restrictive valvulopathy was only found in two cases. These results highlight the need for further prospective studies of the prevalence and underlying mechanisms of cardiac valvulopathy in PD patients treated with different dopamine agonists.     

Dopaminagonisten als Antidepressiva

Results of preclinical and clinical studies implicate that, in addition to serotonin and norepinephrin, dopaminergic mechanisms play a role in the pathogenesis and treatment of depression. Newer antidepressants such as bupropion, sertraline, and venlafaxine act as partial inhibitors of presynaptic dopamine reuptake. Experimental studies show that dopaminergic effects contribute to the development of anxiety, depression, and anhedonia. These studies revealed, among the new nonergot dopamine agonists, anxiolytic properties for ropinirole and anxiolytic, antidepressive, and antianhedonic effects of pramipexole which seem to relate to its specific action on D(2) and D(3) receptors in the mesolimbic system and prefrontal cortex. In addition, affective disorders may be associated with impairments of neuronal plasticity, and pramipexole seems to exert neurotrophic properties. Controlled and open studies in depressed patients with Parkinson's disease show therapeutic effects of dopamine agonists on motor deficits, anhedonia, and depression. Various dopamine agonists have been tested in open studies in patients with depression and may add to the spectrum of treatment options in mood disorders. Recently published placebo-controlled trials in small patient groups implicate that pramipexole is effective as additional treatment to mood stabilizers in I and II bipolar depression.     

Cardiac valve regurgitation with pergolide compared with nonergot agonists in Parkinson disease

BACKGROUND: Although most studies have suggested an increased risk of valvulopathy (primarily regurgitation) with pergolide mesylate use, one study suggested that this problem may also occur with use of the non-ergot-derived dopamine agonists pramipexole dihydrochloride and ropinirole hydrochloride. OBJECTIVE: To determine if cardiac valve regurgitation occurs more commonly in patients with Parkinson disease (PD) treated with pergolide than in those treated with nonergot agonists at a comparable dose. DESIGN: A case-control study of echocardiographic findings of valve function in patients receiving dopamine agonists for PD. SETTING: University-based referral center. Patients Thirty-six patients with idiopathic PD taking pergolide were compared with a matched control group of patients taking nonergot agonists with regard to the frequency and severity of cardiac valve regurgitation. Main Outcome Measure Valve scores (1 indicates trace; 2, mild; 3, moderate; and 4, severe) for the pergolide group were compared with those for the nonergot agonist control group. RESULTS: The mean +/- SD valve regurgitation scores in the matched pergolide group compared with the nonergot group were as follows: aortic, 0.83 +/- 1.23 vs 0.19 +/- 0.53 (P = .01); mitral, 1.42 +/- 1.0 vs 0.39 +/- 0.65 (P<.001); and tricuspid, 1.43 +/- 1.0 vs 0.19 +/- 0.53 (P<.001). Lifetime exposure to a dopamine agonist was not statistically different between the pergolide and nonergot agonist groups (P = .18). CONCLUSIONS: These data strengthen the conclusion that pergolide contributes to cardiac valve regurgitation when used in the long term as a treatment for PD. There appears to be low risk of cardiac valve regurgitation when using non-ergot-derived dopamine agonists.     

Reversible Glückspielsucht unter Pramipexol

In the recent past, pathological gambling has been increasingly reported to be related with dopamine agonist application in patients with Parkinson's disease. We present the case of a female patient whose gambling behavior occurred shortly after reaching the final dose of a combined levodopa and pramipexole therapy and resolved completely after stopping pramipexole. Pathological gambling seems to be a rare and serious but reversible adverse reaction to treatment with dopamine agonists of which clinicians should be aware in patients with Parkinson's disease.     

Cardiac and noncardiac fibrotic reactions caused by ergot‐and nonergot‐derived dopamine agonists

There is growing evidence that the ergot‐derived dopamine agonists cabergoline and pergolide can cause fibrotic cardiac valvulopathy. Data on other fibrotic reactions and nonergot‐derived dopamine agonists are sparse. Aim of this study was to investigate whether there are signals that dopamine agonists are related to cardiac and other fibrotic reactions. We identified all reports of fibrotic reactions at the heart, lung, and retroperitoneal space associated with dopamine agonists within the US Adverse Event Reporting System database. Disproportionality analyses were used to calculate adjusted reporting odds ratios (RORs). For ergot‐derived dopamine agonists (bromocriptine, cabergoline, pergolide), the RORs of all reactions under study were increased, whereas no such increases were observed for nonergot‐derived drugs (apomorphine, pramipexole, ropinirole, rotigotine). Fibrotic reactions due to ergot‐derived dopamine agonists may not be limited to heart valves. For nonergot‐derived dopamine agonists, no drug safety signals were evident. © 2008 Movement Disorder Society     

Pramipexole--a new dopamine agonist for the treatment of Parkinson's disease

Although L-DOPA is the current 'gold standard' for treatment of Parkinson's disease, its effectiveness fades rapidly and its use results in serious motor fluctuations (on-off, wearing off, freezing, involuntary movements) for most patients with Parkinson's disease. Pramipexole is an aminothiazole dopamine agonist with selective actions at dopamine receptors belonging to the D2 subfamily, where it possesses full activity similar to dopamine itself. Pramipexole's preferential affinity for the D3 receptor subtype could contribute to efficacy in the treatment of both the motor and psychiatric symptoms of Parkinson's disease. Both in vitro and in vivo studies in animals suggest that pramipexole possesses numerous neuroprotective properties, including dopamine autoreceptor agonist properties, antioxidant properties, ability to block the mitochondrial permeability transition pore and the ability to stimulate the release of trophic factors. Clinical studies have demonstrated that pramipexole has excellent pharmacokinetic properties and that it is an effective monotherapy in treating early Parkinson's disease and an effective adjunctive therapy with L-DOPA in treating late Parkinson's disease. In addition, pramipexole has demonstrated efficacy in a clinical trial for the treatment of major depression. In the early disease studies, pramipexole was able to retard the need for L-DOPA treatment for several years. Thus, a new 'L-DOPA-sparing' paradigm for treating Parkinson's disease may now be possible, whereby patients are initially treated with pramipexole and L-DOPA is added only as necessary.     

Anhedonia, depression, and motor functioning in Parkinson's disease during treatment with pramipexole

Anhedonia, a core symptom of depression, correlates with motor alterations in major depressive disorder and has been assumed to be frequent in depressed patients with Parkinson's disease (PD). In the present study, the authors assessed for the first time frequency of anhedonia in patients with idiopathic Parkinson's disease (N = 657) and the relationship of anhedonia and parkinsonian motor deficits during treatment with pramipexole. Mild depression was present in 47% of the patients and moderate to severe depression in 22%. Anhedonic individuals included 45.7% of all patients and 79.7% of depressed Parkinson's disease patients. Anhedonic Parkinson's disease patients had greater motor deficits, restrictions in activities of daily living, and depression compared to nonanhedonic patients. Frequency of anhedonia and depression was significantly reduced during treatment with pramipexole. Future studies should further investigate antianhedonic efficacy of dopamine agonists including pramipexole in depressed patients with Parkinson's disease.     

Pramipexole, a nonergot dopamine agonist, is effective against rest tremor in intermediate to advanced Parkinson's disease.

We evaluated the efficacy of the nonergot dopamine receptor agonist pramipexole in 16 patients with advanced Parkinson's disease and marked rest tremor during an "on" period. The patients were drawn from a larger placebo-controlled, double-blind, randomized trial, which was not originally designed to investigate the effect of pramipexole on tremor. Eleven patients received pramipexole. The first effects were seen with a pramipexole dose of 0.75 mg/d with a reduction of the tremor item A of Unified Parkinson's Disease Rating Scale (UPDRS III, "on" state) by 25% and of rigidity and akinesia by 22%. Under the highest dose, 4.5 mg/d, the tremor score was improved by 61% over baseline (p < 0.0056, Wilcoxon signed rank) and the sum of rigidity and akinesia items by 66% (p < 0.0038, Wilcoxon signed rank). Five patients received placebo and did not improve. Based on this sample of patients, the nonergot dopamine receptor agonist pramipexole appears to have a potent anti-rest tremor action while being effective against akinesia and rigidity.     

Dopamine agonists in Parkinson's disease

Dopamine agonists are established as effective drugs for the symptomatic treatment of Parkinson's disease (PD) throughout its course. As monotherapy, they produce effective control of motor symptoms and combine this with a low risk for motor complications. As an adjunct to levodopa, they improve motor control and limit the need for levodopa in those patients in whom this may be considered relevant. The non-ergot dopamine agonists in particular have a good safety profile, although as with other agonists, sedation, and cognitive and behavioral problems may be limiting in some patients. Pramipexole has shown benefit in improving depressive symptoms in PD. Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Thus, dopamine agonists contribute to several dimensions of the management of PD and have become an integral part of the disease treatment algorithm.     

Pramipexole-induced antecollis in Parkinson's disease

We report a case of antecollis, or dropped head with Parkinson's disease (PD) induced by pramipexole, a nonergot dopamine agonist. An 80-year-old woman presented with progressively severe neck flexion, which developed within a few weeks of taking pramipexole at 3 mg/day. She had a disturbed gait and complained of difficulty in daily activity because of restricted visual field and severe stooped posture. Surface EMG showed disproportionate tonus of the neck muscles but needle EMG of the neck muscles was normal. Withdrawal of pramipexole resulted in immediate improvement; the patient could keep the head in natural position and walk normally. Pramipexole-induced antecollis may be serious, but is a reversible dystonia in patients with PD. Clinicians should be aware of such complication.     

Pleuropulmonary fibrosis after long-term treatment with the dopamine agonist pergolide for Parkinson Disease

Dopamine agonists are increasingly used in the treatment of Parkinson disease, but they may cause serious adverse effects. In December 1983, symptoms of Parkinson disease developed in a 55-year-old man with no history of pulmonary disease, smoking, or asbestos exposure. He began treatment with dopamine agonists bromocriptine mesylate (in 1984) and pergolide mesylate (in 1989). In late 2000, pulmonary symptoms developed. Chest radiographs and computed tomographic findings showed a mass in the right upper lobe and effusion. A biopsy specimen showed pleural and parenchymal fibrosis. This syndrome resolved after cessation of pergolide therapy and a switch to pramipexole dihydrochloride. This case draws attention to the association of long-term ergot dopamine agonist therapy with pleuropulmonary fibrosis, which can develop as late as 11 years after the initiation of therapy. We also review evidence that the risk of this complication is substantially lower with the newer nonergot dopamine agonists.     

Comparing dopamine agonists in Parkinson's disease

Dopamine agonists are effective in the management of both advanced and early-stage Parkinson's disease. Unfortunately, randomized head-to-head comparative studies between the many different dopamine agonists now available are sparse. Indirect comparisons of dopamine agonists show that ergot derivatives, such as pergolide and cabergoline, are as effective as non-ergot derivatives, such as ropinirole and pramipexole, in ameliorating Parkinson's disease symptoms in patients in early or advanced stages of the condition. As far as safety and tolerability are concerned, no significant differences between dopamine agonists are found. However, some specific adverse events, such as somnolence and sleep attacks, seem less frequent in monotherapy studies with pergolide than in those with the non-ergot dopamine agonists; however, because of the lack of direct-comparison studies this cannot be proved conclusively. Randomized, controlled comparative studies between dopamine agonists are necessary to verify any possible differences in their effectiveness and tolerability in the treatment of Parkinson's disease.     

Pramipexole versus sertraline in the treatment of depression in Parkinson’s disease

In addition to treating the motor symptoms of Parkinson's disease, the dopamine agonist pramipexole has shown an antidepressant effect. The trials, however, included patients with motor complications, raising the question of whether the antidepressant benefit represented only a treatment-related motor improvement. To address this issue, we have conducted a 14-week randomized trial comparing pramipexole with an established antidepressant in patients without motor complications. At seven Italian centers, 67 Parkinsonian outpatients with major depression but no history of motor fluctuations and/or dyskinesia received open-label pramipexole (at 1.5 to 4.5 mg/day) or sertraline (at 50 mg/day). In both groups, the Hamilton Depression Rating Scale (HAM-D) score decreased throughout 12 weeks of treatment, but in the pramipexole group the proportion of patients who recovered, as defined by a final HAM-D score 相似文献   

Changing dopamine agonist treatment in Parkinson's disease: experiences with switching to pramipexole

1202 patients suffering from Parkinson's disease switched from other dopamine agonists to pramipexole under open conditions either abruptly or in an overlapping, gradual manner. Mostly insufficient effectiveness motivated the switch. The investigators gave equal preference to either an abrupt or an overlapping switch to pramipexole in this observational study. There was a tendency in favour of the overlapping switch procedure in those patients who were on a relatively higher dose of a dopamine agonist before the switch. The switch was performed because the investigators expected the effect of pramipexole on tremor, motor functions and depression/anhedonia to be better compared with previous dopamine agonists. The main reasons for switching to pramipexole (anti-tremor effect, anti-depressive/anti-anhedonic effect) as given by the physicians at baseline came up to expectations. The switch to pramipexole mostly yielded further improvements irrespective of the mode of switching.     

Compulsive eating and weight gain related to dopamine agonist use.

Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinson's disease (PD). These have included gambling, hypersexuality, hobbyism, and other repetitive, purposeless behaviors ("punding"). In this report, we describe 7 patients in whom compulsive eating developed in the context of pramipexole use. All of the affected patients had significant, undesired weight gain; 4 had other comorbid compulsive behaviors. In the 5 patients who lowered the dose of pramipexole or discontinued dopamine agonist treatment, the behavior remitted and no further weight gain occurred. Physicians should be aware that compulsive eating resulting in significant weight gain may occur in PD as a side-effect of dopamine agonist medications such as pramipexole. Given the known risks of the associated weight gain and obesity, further investigation is warranted.     

The use of pramipexole in Parkinson's disease: are its actions D(3) mediated?

Pramipexole is a non-ergot dopamine agonist recently approved for the treatment of early and advanced Parkinson's disease (PD). It has preferential affinity for the D(3) dopamine receptor, compared to previous dopamine agonists that have higher affinity for D(2) dopamine receptors. The ultimate question is whether its efficacy is linked to its action at the D(3) dopamine site or due to its binding to D(2) dopamine receptors. There is no direct experimental evidence available to answer this question. Based on a review of the pharmacological literature, it is likely that the motor benefits of pramipexole in PD patients are due to D(2) stimulation, whereas its putative effects on mood and apathy may be related to its D(3) agonist properties.     

How to succeed in using dopamine agonists in Parkinson's disease

Dopamine receptor agonists are assuming increased importance in the treatment of both early and advanced symptoms of Parkinson's disease (PD). However, tolerability of these drugs can be a problem. Identifying patients who are at increased risk of adverse effects is central to using dopamine agonists in PD. The newer agonists, pramipexole and ropinirole, are generally adequate without levodopa for early symptoms and carry the hope for a more acceptable profile of long-term side-effects. In the patient with advanced disease, all four dopamine agonists significantly augment the response to levodopa, which reduces the problems of motor fluctuations and drug related dyskinesia. Understanding the common pitfalls when prescribing these drugs will facilitate their safety and efficacy.     

Pramipexole extended release in Parkinson's disease

Pramipexole extended release (ER) is a new once-daily formulation of pramipexole, a nonergot dopamine agonist, which is available in five dosage strengths: 0.26 (0.375) mg, 0.52 (0.75) mg, 1.05 (1.5) mg, 2.1 (3) mg and 3.15 (4.5) mg (all doses are expressed in terms of pramipexole base and the corresponding dose strengths of pramipexole salt are given in brackets). Pramipexole ER is currently approved as monotherapy in early Parkinson's disease (PD), as well as an adjunct therapy to levodopa in advanced PD. Compared with the immediate release (IR) formulation, the ER formulation offers several advantages, including the potential for improved compliance owing to its simple once-daily dosing regimen and steadier plasma levels over 24 h. Double-blind, randomized, placebo and active comparator controlled trials in early, as well as advanced PD, established the superiority of both pramipexole ER and IR over placebo. The overnight switch from pramipexole IR three times a day to ER once-daily in early PD has been shown to be successful in more than 80% of patients. Pramipexole ER is well tolerated, with a similar adverse event profile to pramipexole IR. The aim of this article is to provide a short review of the most relevant pharmacological and clinical data on pramipexole ER.     

Ergoline and non-ergoline derivatives in the treatment of Parkinson's disease

There are a large variety of dopamine agonists available. Especially de novo patients are treated with dopamine agonists to avoid dyskinesia. Dopamine agonists can be subdivided into ergoline and non-ergoline derivatives. This distinction raises the question whether there are differences in the effects to treat symptoms, not only in the side effects between the individual dopamine agonists but also between these two groups. Pergolide is now considered a second line drug because of its particularly high tendency towards valvular heart disease. Some authors claim that all ergoline-derivatives may cause this problem, while own results do not necessarily support this view. We recommend performing echocardiography on those patients being treated with an ergot-derivative. New data support the view that all dopaminergic drugs may cause somnolence and that there is no preference for non-ergots. It may be that the number of gamblers is slightly higher among patients treated with pramipexole than in others. Dopamine agonists with a high affinity to D3 receptors have a good anti-anhedonic potency. In cell culture all dopamine agonists studied so far show neuroprotective properties in cell culture. The introduction of a slow-release formulation for ropinirole and the rotigotine and lisuride patches have opened new ways of continuous dopamine receptor stimulation. Taken together, dopamine agonists show individual properties and there are differences between ergot and non-ergot derivatives.     

Pramipexole in the treatment of advanced Parkinson's disease

Pramipexole is a novel nonergoline dopamine agonist with a preference for the dopamine D₃ receptor subtype. Its efficacy and safety in the treatment of advanced Parkinson's disease has been investigated in several clinical studies. This review provides a summary of the data currently available, particularly in reference to the recent results of the European clinical phase III study and the potential tremorlytic activity of pramipexole. Interim analysis of the open-label European clinical phase III study has provided evidence of long-term efficacy and safety of pramipexole. In another study pramipexole has been shown to be significantly superior to placebo with an improvement in tremor score by 48% (vs. 13% in the placebo group). In addition to its likely usefulness in the treatment of rest tremor in Parkinson's disease, data suggest that pramipexole is of interest due to its reported low frequency of cardiovascular and gastrointestinal side-effects. However, studies comparing pramipexole with other antiparkinsonian agents would be useful to further define its benefits in the treatment of tremor-dominant Parkinson's disease and to further document its favourable adverse event profile.