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.     

Pergolide in the treatment of patients with early and advanced Parkinson's disease

Introduced on the market in 1989, pergolide, a D1/D2 dopamine receptor agonist, is still widely prescribed for the treatment of patients with early and advanced Parkinson's disease (PD). Initially, pergolide was introduced as an adjunct therapy to levodopa treatment in patients exhibiting fluctuating motor responses and dyskinesias. Results of recent randomized controlled clinical trials in de novo patients with PD show that pergolide is able to improve parkinsonian symptoms when used as monotherapy. Moreover, preliminary results of a long-term monotherapy study in early PD suggest that pergolide is as effective as levodopa, and that a significant delay in the time of the onset of levodopa-induced motor complications can be obtained. A number of randomized studies have shown that pergolide is more effective than bromocriptine as adjunct therapy to levodopa in patients with advanced PD; the greater benefit found with pergolide could be ascribed to its action on both D1 and D2 dopamine receptors. However, controlled comparative studies with new dopamine agonists, such as ropinirole, cabergoline, and pramipexole, have not been performed yet. Interestingly, few open studies in patients with complicated PD have shown that high doses of pergolide (> 6 mg/d) are able to improve motor fluctuations and dyskinesias through a dramatic reduction of levodopa dosage. The side-effect profile of pergolide is similar to that of other dopamine agonists, and complications such as sleep attack and serosal fibrosis have been rarely reported.     

A review of the efficacy of the dopamine agonists pergolide and bromocriptine in the treatment of Parkinson's disease

This review summarizes those studies, completed over the last 15 years, which compare the clinical benefit of the two most commonly used dopamine agonists, pergolide and bromocriptine. In these studies, both drugs were evaluated as adjunctive therapy to levodopa for the treatment of Parkinson's disease (PD). Ten studies are analyzed and the affect of pergolide and bromocriptine on PD compared. Although variation in study design and disease rating scales prevents the opportunity for a true meta-analysis, this review analyses the outcome of each individual study to assess the benefit of pergolide over bromocriptine. Pergolide improves patients' activities-of-daily-living and their clinical PD symptoms over bromocriptine. Additionally, a large percentage of patients who do not respond to bromocriptine, or whose PD symptoms worsened, improved on pergolide. Furthermore, patients who are adequately treated with bromocriptine experienced additional improvement with pergolide therapy. In summary, pergolide provided benefits to PD patients over bromocriptine in nine studies and was equivalent in the tenth. The benefits associated with pergolide may be partly due to the action of pergolide on dopamine D₁ and D₂ receptors (bromocriptine is associated with the D₂ agonism). In conclusion, in the majority of completed studies to date, pergolide provided greater improvement to the clinical signs and symptoms of PD than bromocriptine.     

Isolated pulmonary hypertension and pergolide

Pergolide, an ergot-derived dopamine agonist prescribed since the late 1980's mainly in Parkinson's disease and restless leg syndrome has recognized fibrosis side effects, affecting the pleural, pericardial and retroperitoneal systems. Pergolide-induced valvulopathies were first reported in 2002. We present here the history of a patient developing an isolated pulmonary hypertension related to the intake of pergolide. The dyspnea related to the pulmonary hypertension as well as the echocardiographic abnormalities improved after treatment replacement. Valvulopathies and pulmonary hypertension were previously described under appetite-suppressant drugs after years of clinical use, in a similar way.     

Treatment of juvenile Parkinson disease and the recurrent emergence of pathologic gambling.

OBJECTIVE: To describe the recurrent emergence of pathologic gambling (PG) during the sequential treatment of a patient with Juvenile Parkinson disease (PD) with different dopamine agonists. METHOD: Single case report. RESULTS: A patient with Juvenile PD developed PG soon after beginning treatment with pergolide, a mixed D1/D2 dopamine agonist that is also supposed to exhibit D3 activity. This behavior remitted upon the discontinuation of the drug. A subsequent therapeutic trial with pramipexole, a dopamine agonist with preferential D3 dopamine receptor activity, resulted in the recurrence of PG. Remarkably, previous treatment with levodopa was not associated with this side effect. CONCLUSIONS: These findings seem to confirm previous suggestions that dopaminergic hyperactivity plays an important role in the pathogenesis of PG. They further indicate that patients with PD may develop PG as a side effect of more than one dopamine agonist. There is still no consensus regarding the best strategy to deal with this potentially disturbing phenomenon.     

Pergolide-induced pleural effusion in a patient with juvenile parkinsonism]

A male patient with juvenile parkinsonism having been treated with pergolide developed pleural effusion. Treatment of pergolide started when the patient was 49. And the symptom appeared 11 years later. The patient had no history of heart disease, chronic cough, or lung tuberculosis. His medications included pergolide 1,000 micrograms/day for the past 7 years. Pergolide had been used since 1990 at the maximum dosage of 2,250 micrograms/day. Chest radiogram showed pleural effusion in the right lung. Parenchymal changes and thickened pleura were observed in the left lung. CT scan of the chest showed encapsulated pleural effusion and atelectasis in the mid and lower zones of the right lung. Interstitial fibrosis and pleural thickening were observed in the left lung. Pleuropulmonary changes are rare adverse effects of pergolide treatment, although they were described in other dopamine agonists such as bromocriptine. The author recommends that patients with parkinsonism who receive pergolide treatment should be regularly monitored for the development of pleuropulmonary complications.     

Dopamine agonists

Dopamine agonists provide an effective means of treating early, middle, and late stages of Parkinson's disease. This article outlines the advantages and disadvantages of dopamine agonists as compared with levodopa therapy. The features and costs of the four Food and Drug Administration-approved agonists (bromocriptine, pergolide, pramipexole, and ropinirole) and apomorphine, another agonist presently under investigation, are discussed.     

Dopamine agonist‐induced antecollis in Parkinson's disease

Few cases of dopamine agonist‐induced antecollis in Parkinson's disease (PD) have been reported. Literature review of 16 PD patients including our 3 cases with dopamine agonist‐induced antecollis showed predominance of (1) Japanese, (2) women, and (3) Hoehn‐Yahr stage of ≥3. We experienced three Japanese PD patients who subacutely exhibited antecollis following increased dopamine agonist dose that improved just after withdrawal of the agonist. One patient developed antecollis during increasing pramipexole dose in combination with cabergoline. Antecollis in another patient appeared during increasing pramipexole dose; it worsened after substituting pergolide for pramipexole, but improved after withdrawal of pergolide. Our cases indicate that there is no specific dopamine agonist causing antecollis, and it is possibly caused by a number of single dopamine agonists or a combination of them. Dopamine agonist‐induced antecollis should be considered when encountering antecollis in PD patients being treated with dopamine agonists and withdrawal of the agonist can improve symptoms. © 2009 Movement Disorder Society     

Disinhibitory abnormal behavior induced by treatment of Parkinson disease

The treatment of Parkinson disease has considerably progressed in the last 20 years. However, such treatments results in the adverse event of disinhibitory abnormal behavior, which includes impulse control disorders, punding, and dopamine dysregulation syndrome. Pathological gambling is the most extensively studied among such abnormal behaviors. It has been associated with the use of dopamine agonists and its prevalence increases according to the does of the drugs. The maximum dose of the ergot dopamine agonist pergolide is 1.25 mg/day in Japan, which is a quarter of that used in Western countries. The maximum dose of the non-ergot dopamine agonist, pramipexole is 4.5 mg/day in Japan, which is the same as in Western countries. Pramipexole was launched in 2004 in Japan, and since then cases of pathological gambling associated with dopamine agonists used has been increasing. Because of the excellent health-care system in Japan, patients can easily acquire expensive dopamine agonists. Although the prevalence of these abnormal behaviors has not been studied in Japan, it could be highly proportionate to the amount of dopamine agonists. Disinhibitory abnormal behavior is also induced by deep brain stimulation of the subthalamic nucleus. This technology was approved in 2000 in Japan. The mechanisms by which these behaviors are induced are different between dopamine replacement therapy and deep brain stimulation. Parkinson disease patients and their caregivers occasionally believe the disinhibitory abnormal behavior as arising from the original personality of the patient rather than as an adverse event of treatment. Neurologists should be aware of the occurrence of disinhibitory abnormal behavior in the clinical practice.     

Lergotrile in the treatment of parkinsonism

Lergotrile mesylate, a direct-acting dopamine agonist, was administered for up to 10 months to 25 patients with Parkinson disease. Of six patients not receiving levodopa concurrently, five showed definite improvement in parkinsonian signs and symptoms. These results are the first clear indication that lergotrile is efficacious, independently of any interaction with levodopa, in the treatment of Parkinson disease. The drug was also effective in relieving some complications of long-term levodopa therapy. Lergotrile was more effective in alleviating on-off problems than in reversing loss of levodopa efficacy. Side effects of lergotrile included exacerbation of hallucinations, dyskinesias, hypotension, and alterations in liver function tests.     

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.     

Double-blind trial of pergolide for Parkinson's disease

Pergolide mesylate, a dopamine agonist, was studied as adjunctive therapy in a 6-month double-blind trial in 20 patients with Parkinson's disease who were achieving less than optimal response from Sinemet. As pergolide or placebo was administered in increasing dosage, Sinemet was reduced if side effects developed. Both the pergolide and placebo groups improved significantly (p less than 0.05). The pergolide group improved 30% at the end of 24 weeks, and the placebo group 23%. There was no significant difference between drug and placebo groups, possibly due to a fortuitous support group and the side effects that may have burdened the pergolide group. Nevertheless, pergolide had a definite antiparkinsonian effect.     

Initial treatment of early Parkinson’s disease: A review of recent, randomized controlled trials

Many studies have shown dopamine agonists to significantly improve parkinsonian symptoms compared with placebo in early Parkinson’s disease (PD), but how do agonists compare with the standard treatment of levodopa? Recently, three large, multicenter, randomized controlled studies directly comparing a dopamine agonist with levodopa as initial therapy in early PD have been published. These studies suggest that although both agents effectively ameliorate parkinsonian symptoms, levodopa was superior to dopamine agonists as measured by improvement in Unified Parkinson’s Disease Rating Scale (UPDRS) scores. However, levodopa was more frequently associated with dopaminergic motor complications, and the dopamine agonists were more commonly associated with adverse events. Until further studies clearly demonstrate the beneficial effects of one therapeutic strategy over another, the decision to initiate treatment in early PD with either an agonist or levodopa will be based on the favorable motor complication profile of agonists versus the more potent antiparkinsonian effects and the favorable side-effect profile of levodopa.     

Treatment of Parkinson's disease should begin with a dopamine agonist.

The occurrence of side effects with long-term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinson's disease. Several strategies can be used, such as monotherapy or "early" or "late" combination with levodopa. Results of recent well-performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa-induced late motor side effects.     

Diagnosis, assessment and management of delusional jealousy in Parkinson’s disease with and without dementia

Patients with Parkinson’s disease (PD) may present delusional jealousy (DJ). In a previous cross-sectional prevalence study we identified 15 cognitively preserved and five demented PD patients with DJ. The current study aimed at evaluating their clinical (motor and non-motor) characteristics and the pharmacological treatments associated with DJ, and its subsequent pharmacological management. Patients were assessed by neurologists and psychiatrists using the Hoehn and Yahr scale, the Unified Parkinson’s Disease Rating Scale, the Brief Psychiatric Rating Scale, the Beck Depression Inventory, the Hamilton Anxiety Scale and the Neuropsychiatric Inventory. Efficacy of DJ management was evaluated in follow-up visits. All patients were in therapy with dopamine agonists. A subgroup of five cognitively preserved patients developed DJ after a short period of treatment of therapy with dopamine agonists, while other patients developed DJ after a longer period of dopaminergic treatment. Psychiatric comorbidities were common in cognitively preserved and in demented patients. The pharmacological management included the interruption of dopamine agonists in two patients and the reduction of dopamine agonist dose plus the use of antipsychotics in other patients. These clinical data suggest that the management of medicated PD patients should include investigation for the presence of DJ and the evaluation of clinical characteristics potentially relevant to the prevention or the early recognition of delusions.     

Pergolide in late-stage Parkinson disease

Twenty-six patients with late-stage Parkinson disease were given 0.4 to 15 mg of pergolide mesylate daily in addition to, or as replacement for, levodopa or bromocriptine therapy. Despite treatment with individually determined optimum doses of levodopa, bromocriptine, and anticholinergics, they had shown response failure or fluctuating response. Forty percent (11 patients) were unable to tolerate pergolide. Nausea and vomiting, somnolence, and psychiatric disturbances were the most frequent side effects. Eleven of the remaining patients improved on pergolide, 2 were unchanged, and 2 were slightly worse. Among the patients who benefited, pergolide improved dose-related response fluctuations more than non-dose-related fluctuations, with a reduction in number and duration of “off” periods and improvement in quality of sleep and early morning akinesia but little change in freezing episodes. Despite treatment failure in many cases, pergolide is at present the best available drug for specific latestage management problems.     

Pathologic gambling in patients with restless legs syndrome treated with dopaminergic agonists

Pathologic gambling is an impulse control disorder previously reported to complicate dopamine agonist therapy in patients with Parkinson disease. It has not been described in association with dopamine agonist therapy of other conditions. We report three patients treated in our sleep disorders center who developed pathologic gambling while receiving treatment with dopamine agonists for restless legs syndrome.     

Apomorphine: a rapid rescue agent for the management of motor fluctuations in advanced Parkinson disease

Parkinson disease is one of the most common neurodegenerative diseases in the United States, and the number of late stage patients is rising. In advance-stage disease, fluctuations in motor function, variability in response to dopaminergic therapy, and dyskinesias related to increasing doses of dopamine agonists and levodopa, present a variety of challenges to a managing physician. Traditional methods of treatment have concentrated on therapies to anticipate or prevent states of poor motor function. With the approval of apomorphine as a rapid-acting, subcutaneous injectable anti-Parkinson disease therapy, these off periods may now be treated with apomorphine as a "rescue" medication when they occur. This article reviews the pharmacology of apomorphine, the clinical data that support its use and suggest dosing and methods for initiating therapy in this challenging population of patients with Parkinson disease.     

Predictors of impaired daytime sleep and wakefulness in patients with Parkinson disease treated with older (ergot) vs newer (nonergot) dopamine agonists

BACKGROUND: Patients with Parkinson disease (PD) treated with the nonergot dopamine agonists pramipexole dihydrochloride and ropinirole hydrochloride have been reported to have sleep attacks without warning. OBJECTIVE: To perform a systematic evaluation of excessive daytime sleepiness using standard polysomnographic techniques. DESIGN: Two overnight studies and daytime sleep tests were performed on a prospective sample. Pathologic daytime sleep latency was indexed by a mean Multiple Sleep Latency Test score of no greater than 5 minutes or a mean Maintenance of Wakefulness Test latency of no greater than 20 minutes. PATIENTS AND SETTING: Eighty nondemented, independent PD patients treated with dopamine agonists at the Toronto Western Hospital Sleep Research Unit, Toronto, Ontario. RESULTS: Patients treated with pramipexole dihydrochloride (n = 29), ropinirole (n = 28), or bromocriptine mesylate or pergolide mesylate (n = 23) did not differ with respect to mean Multiple Sleep Latency Test scores (overall, 12.1 minutes [SD, 5.1 minutes], F(2,77) = 0.11; P =.90) or mean Maintenance of Wakefulness Test latencies (overall, 26.7 minutes [SD, 5.4 minutes]; F(2,77) = 1.1; P =.29). Fifteen patients (18.8%) exhibited pathologic daytime sleep latencies. The main risk factor associated with pathologic daytime sleep latency was high levodopa dosage equivalents (>867.5 mg; odds ratio, 4.2; 95% confidence interval, 1.3-13.7). Subjective accounts of daytime sleep and wakefulness, as indexed by scores on the Epworth Sleepiness Scale, were not related to impaired daytime sleepiness or wakefulness (chi(2)(1) [n = 80], 0.13; P =.72). CONCLUSIONS: Total dopaminergic drug dose rather than the specific dopamine agonist used is the best predictor of daytime sleepiness in PD patients receiving dopamine agonist therapy. Physicians concerned with daytime hypersomnolence in PD patients treated with dopamine agonists and receiving high levodopa dosage equivalents should consider polysomnographic monitoring for impaired daytime sleep latency.     

Comparative effects of repeated administration of dopamine agonists on circling behavior in rats

Summary. A paucity of studies are available concerning the comparative therapeutic effectiveness of presently available dopamine agonist agents in the control of Parkinson symptoms. To provide a basis for resolving this issue, we measured the circling response in unilaterally nigrotomized (6-OHDA) rats following the administration of ropinirole, pramipexole, pergolide, bromocriptine, and cabergoline. Cabergoline, and to a lesser extent pergolide, produced the most vigorous and longest lasting circling response. This response was sustained with administration of these agents over a nine day period. Bromocriptine, pramipexole and ropinirole were all less effective. These results suggest that dopamine agonists whose effect is primarily on D1 and D2 receptors are more effective than those whose actions do not include D1 activation. Received February 8, 2000; accepted March 8, 2000