Pergolide-induced circling in rats with 6-hydroxydopamine lesions in the nigrostriatal pathway

In rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal system we compared the behavioral effects of pergolide with those of L-dopa, bromocriptine, and lergotrile. In this animal model of parkinsonism, doses of 0.25 mg per kilogram pergolide (free base) induced vigorous circling for 24 hours. Pergolide was more potent than bromocriptine or lergotrile. Pretreatment with alpha-methylparatyrosine nearly abolished the effects of bromocriptine, markedly diminished the effects of lergotrile, and only partially diminished the effects of pergolide. These findings suggest that pergolide should be more effective than bromocriptine in the treatment of parkinsonism.     

Effects of pergolide on nocturia in Parkinson's disease: three female cases selected from over 400 patients

We started the subject screening from over 400 patients with Parkinson's disease using strict selection criteria to identify the patients with nocturia who would allow accurate and efficient evaluation of the pergolide effects. The subjects were confined to female patients to exclude patients with potential prostate hypertrophy. The patients treated with bromocriptine at 7.5-15 mg/day adjunctive to l-dopa were selected to replace bromocriptine with pergolide of the equivalent dosage approved in Japan. The nocturia was defined as having more than two episodes of urination during sleep per night on average. The subjects received the urinary sediment test before and during the study for screening urinary tract infection and the study was discontinued when urinary tract infection was found. As a result, we identified total 11 patients with nocturia and three of those completed the 12-week study of switching dopamine agonist from bromocriptine to pergolide. We observed a decrease in nocturia frequency in all three patients, a decrease in irritative urinary symptoms in two and an improvement of sleep QOL in two. The effect of pergolide on nocturia was independent of improvement of parkinsonian symptoms, suggesting a distinct mechanism from that of anti-parkinsonian effects. Our study also suggests that switching from bromocriptine to pergolide improves nocturia, thereby improving sleep status of patients with Parkinson's disease.     

The levodopa dose-sparing capacity of pergolide compared with that of bromocriptine in an open-label,crossover study

The levodopa dose-sparing capacity of pergolide and bromocriptine, along with the maximum ability to improve activity of daily living and motor scores, were compared in 33 patients with idiopathic Parkinson's disease (Hoehn-Yahr stage 2–4) in a 24-week, open-label, crossover study. Patients received one dopamine agonist for 12 weeks and then were crossed over to the other for 12 weeks (8 weeks, titration; 4 weeks, steady state in each period). The maximum doses allowed were pergolide 5 mg/day and bromocriptine 50 mg/day. As patients' clinical response to a dopamine agonist increased, the levodopa dose was decreased. Twenty-seven patients completed the study. No serious adverse events or clinically significant changes in vital signs or laboratory tests were observed. The mean doses of bromocriptine and pergolide at the end of titration were 21.7 ± 5.6 mg (bromocriptine data for the two groups combined) and 3.6 ± 1.1 mg (pergolide data for the two groups combined), respectively. The mean levodopa dose was reduced 83% with bromocriptine as the first agent and increased 28.0% with bromocriptine as the second agent The mean levodopa dose was reduced 31.4% with pergolide as the first agent and 15.5% with pergolide as the second agent Levodopa could not be discontinued in any of the patients. Statistically significant levodopa dose-sparing capacity and considerable clinical benefit were achieved with both agonists; however, the results were more favorable with pergolide.     

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.     

Pergolide mesylate treatment of cocaine withdrawal

Side effects occasionally limit the use of bromocriptine for cocaine withdrawal. The recently released medication pergolide shares some pharmacologic properties with bromocriptine but differs in potency and dopamine receptor subtype specificity. The authors tested pergolide in the treatment of 21 patients experiencing cocaine withdrawal. Sixteen patients reported rapid improvement in sleep and decreased cocaine craving. Side effects were limited primarily to gastrointestinal complaints.     

Parkinson''s disease: an open label trial of pergolide in patients failing bromocriptine therapy.

Sixty-three patients with Parkinson's disease who failed bromocriptine therapy for various reasons were treated in an open-label trial of pergolide. The data were evaluated in a retrospective manner. Forty-six percent had a good response and tolerated the pergolide. A comparison of the outcomes regarding response and toxicity revealed that bromocriptine and pergolide act differently in individual patients. A trial of pergolide in Parkinsonian patients failing bromocriptine therapy may be therapeutically useful.     

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.     

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.     

Conversion from dopamine agonists to pramipexole

Abstract.Background: Pramipexole is a nonergoline dopamine agonist with D2 and preferential D3 dopamine receptor activity. This selective activity may result in clinically different effects. Small clinical trials indicate that overnight switching from one agonist to another can be performed safely. Objective To determine safety and efficacy of overnight switching from dopamine agonists to pramipexole in patients with advanced Parkinsons disease (PD).Objective: To determine safety and efficacy of overnight switching from dopamine agonists to pramipexole in patients with advanced Parkinsons disease (PD).Methods: Patients with advanced PD and motor complications not optimally controlled by levodopa and a stable dose of bromocriptine, pergolide or ropinirole were converted to pramipexole overnight. Clinical assessments were performed just prior to conversion and after 2, 6 and 12 weeks of treatment, when an optimal dose of pramipexole was achieved.Results: Two hundred and seventeen patients were included in the trial. One hundred and twenty five were converted from pergolide to pramipexole, 58 from bromocriptine and 34 from ropinirole. After 12 weeks, the average dose of pramipexole was 2.8, 2.9 and 3.4 mg/d in patients converted from bromocriptine, pergolide, and ropinirole, respectively. UPDRS II, III and IV scores were reduced by 26–30 % in all patients (p < 0.0001). Mean levodopa dose was slightly reduced in all groups (p: NS). No serious or unexpected side effects were reported. The dose equivalences calculated from this trial were: bromocriptine: pramipexole 6.9:1, pergolide: pramipexole 0.9:1, ropinirole: pramipexole 1.5:1.Conclusion: Switching from bromocriptine, pergolide or ropinirole to pramipexole in an overnight schedule is safe. The observed clinical improvement may be related to a placebo effect, to the use of low doses of dopamine agonists or to a direct effect of pramipexole.     

Neuroleptic malignant-like syndrome after rapid switch from bromocriptine to pergolide

Neuroleptic malignant-like syndrome (NMLS) occurred after rapid switch from bromocriptine to pergolide in a Parkinsonian patient. Although the underlying mechanisms are as yet obscure, we hypothesize that differences in dopamine receptor affinities between bromocriptine and pergolide may be involved. Long-term treatment with bromocriptine may thus have induced plastic changes in intracellular signal processing in the nigrostriatal system, which resulted in reduced dopaminergic efficacy of pergolide. We recommend vigilant outpatient supervision during performance of rapid switchover from one dopamine agonist to another in advanced Parkinson's disease or in subjects with predisposing factors for onset of a neuroleptic malignant syndrome.     

Bromocriptine use and the risk of valvular heart disease

It has been reported that patients on pergolide and carbergoline have an increased risk of developing valvular heart disease. It is uncertain if bromocriptine, an ergot‐derived dopamine agonist (DA) with partial 5‐HT_2B activity, is associated with a similar risk. We assessed the frequency of valvular heart disease in Parkinson's disease (PD) patients on bromocriptine compared to pergolide and a control group of PD patients who had not been treated on any DA. Seventy‐two PD patients on bromocriptine, 21 patients on pergolide, and 47 control PD patients were recruited. Transthoracic echocardiographic studies were performed and reviewed by a blinded cardiologist. The risk for the bromocriptine group to develop any abnormal valvular regurgitation was 3.32 (adjusted OR, 95% CI: 1.11–9.92, P = 0.03) compared to controls, whereas the risk for the pergolide group was 3.66 (adjusted OR, 95% CI: 1.22–10.97, P = 0.02). When cumulative dose of bromocriptine was analyzed by quartiles, patients with a greater exposure to bromocriptine had significantly higher risk of developing both mild and moderate‐severe regurgitations (P for trend, 0.005 and 0.019, respectively). This study demonstrated that bromocriptine use was associated with an increased risk of developing valvular heart disease, which occurred in a cumulative dose‐dependent manner. © 2008 Movement Disorder Society     

Comparison of pergolide and bromocriptine therapy in parkinsonism

Twenty-four parkinsonian patients compared pergolide and bromocriptine therapy in a randomized double-blind, two-period crossover study. Both drugs were adjusted to an optimal balance between benefits and side effects. The mean daily dose and dose range for pergolide and bromocriptine were 3.3 mg (0.7 to 7.2) and 42.7 mg (5.8 to 87.5), respectively. Adjunctive medications, which for most patients included levodopa (plus carbidopa), were not altered during the study. A similar spectrum of clinical effects was found with both drugs and with lisuride, which was used to treat 13 of the patients in a previous study. Despite neurochemical differences in the antiparkinsonian ergots, their clinical utility is quite similar. We draw attention to hepatotoxicity and pleural reactions that may occur rarely with these drugs.     

Chronic agonist therapy for Parkinson's disease: a 5-year study of bromocriptine and pergolide

We used pergolide to treat 10 patients with idiopathic Parkinson's disease who had first responded to, and then failed, bromocriptine therapy. At the end of 5 years, patients had improved when compared with study entry. Peak efficacy, equal with both drugs, was seen at 12 months. After a mean treatment of 29 months, bromocriptine was no longer effective, but pergolide was still beneficial.     

Synergistic effects of D1 and D2 dopamine agonists on turning behaviour in rats

In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, a specific D1 dopamine receptor agonist, SKF 38393A, at a dose that does not itself produce turning, significantly increased the contralateral rotation observed following a low dose of the specific D2 agonist LY 171555. Doses of SKF 38393A or the D2 agonist bromocriptine, which would themselves not induce turning, in combination produced a high rate of turning. These results suggest a synergistic interaction between D1 and D2 dopamine receptors in this system.     

Differential effects of three dopamine receptor agonists in MPTP-treated monkeys

Summary The behavioral effects of cabergoline, pergolide and bromocriptine were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity, as evidenced by irritability, excitability and aggressiveness. All three drugs improved the parkinsonism in a dose-dependent fashion following a single injection. Among the three dopamine (DA) receptor agonists used, the antiparkinsonian effect of pergolide was the strongest and had an immediate effect, while cabergoline showed the longest duration of the antiparkinsonian effect and was least potent in inducing hyperactivity.     

Effects of pergolide and bromocriptine on male rat sexual behavior

Summary Intact adult male rats were treated with bromocriptine 0–20 mg/kg and pergolide 0–3.2 mg/kg. Two hours after the injection of the respective drug the male rat was presented with a receptive female and various components of the sexual behavior were recorded. Pergolide produced a dose-dependent decrease in the number of intromissions preceding ejaculation and a shortening of the ejaculation latency. The only effect observed after the injection of bromocriptine was an increase in the post-ejaculatory interval at high doses.     

Cross-sensitization between the motor activating effects of bromocriptine and caffeine: role of adenosine A(2A) receptors

The acute motor response to caffeine was studied in rats repeatedly treated with vehicle or the dopamine D(2) agonist bromocriptine either in a novel cage or in the home cage. Rats receiving bromocriptine (5 mg/kg i.p.) in a novel cage were sensitized to the motor stimulating effects of bromocriptine itself and showed cross-sensitization to the acute administration of low (10 mg/kg s.c. ) but not high (25 mg/kg s.c.) doses of caffeine, no matter if the novel cage was identical or different from the test cage. In contrast, caffeine (10 mg/kg i.p.) administered to rats which had received bromocriptine (5 mg/kg i.p.) in the home cage and which showed no sign of a sensitized response to bromocriptine, failed to show an increased locomotor and stereotyped response as compared to vehicle pretreated rats. Similarly to caffeine, the selective adenosine A(2A) antagonist SCH 58261 (3 mg/kg i.p.) showed an increased motor response in bromocriptine sensitized rats. The sensitized response to caffeine or SCH 58261 did not appear to be due to an higher basal motor activity of bromocriptine sensitized rats since acute administration of vehicle induced a similar motor response in bromocriptine and vehicle pretreated rats. Dopamine D(2) and adenosine A(2A) receptors are colocalized in striatal efferent neurons where they control in an opposite direction motor behavior. The results of the present study showed that changes in the sensitivity of D(2) receptors influenced the sensitivity of the adenosine antagonist caffeine through an action on A(2A) receptors. D(2) and A(2A) receptors, therefore, not only acutely interact in the mediation of motor behavior but long-term modification of the D(2) receptors, such as sensitization, affected the response of adenosine A(2A) receptors.     

Valvular heart disease in Parkinson's disease treated with ergot derivative dopamine agonists.

Valvular heart disease, associated with ergot derivative dopamine agonists, has been reported in patients with Parkinson's disease (PD). There are few comparative studies on the frequency, severity, and dose dependency of valvular disease associated with ergot derivatives. We analyzed these factors in 58 PD patients who were taking ergot derivatives (22 were taking bromocriptine and 36 were taking pergolide) and compared them with 20 age-matched controls based on the two-dimensional echocardiographic findings. Aortic, mitral, and tricuspid valvular thicknesses, as well as tenting areas and tenting distance of the mitral valve were measured. We also assessed the correlation between the cumulative or daily doses of ergot derivatives and each valvular parameter. There was no significant increase in the frequency of valvulopathy in the PD patients taking bromocriptine or pergolide. We identified a positive correlation between the daily dose of pergolide and the tenting area of the mitral valve (r = 0.385; P = 0.020). However, other valvular parameters were not found to correlate with the age, disease duration, treatment duration, or dosage of medication. Our study failed to uncover definitive harmful effects of ergot derivative dopamine agonists on cardiac valves; this is considering the relatively lower daily doses than other reported cases. To establish a dosage dependency with valvulopathy, a more detailed study with higher doses of ergot derivatives for longer duration of treatment may be needed.     

Progressive supranuclear palsy: clinical features and response to treatment in 16 patients

Among 415 patients with parkinsonism, 16 (3.9%) had findings of progressive supranuclear palsy (PSP). This report reviews the clinical features and response to drug therapy in those 16 patients. Anticholinergic drugs failed to benefit any of the 5 patients treated, while presynaptic dopaminergic drugs (Sinemet or amantadine) were beneficial in only 5 of 22 patient trials. Alternatively, dopamine agonists (bromocriptine and pergolide) caused improvement in 9 of 14 patient trials despite the fact that all but 1 of these patients had previously failed to respond to presynaptic dopaminergic drugs. Dopamine agonists such as bromocriptine and pergolide may be useful in some patients with PSP.     

Anti-fibrillogenic and fibril-destabilizing activities of anti-Parkinsonian agents for alpha-synuclein fibrils in vitro

The aggregation of alpha-synuclein (alphaS) in the brain has been implicated as a critical step in the development of Lewy body diseases (LBD) and multiple system atrophy (MSA). Among the antioxidant strategies proposed, increasing evidence points to the possibility of achieving neuroprotection by dopamine agonists, as well as monoamine oxidase B inhibitors. We showed previously that the anti-Parkinsonian agents dose-dependently inhibited beta-amyloid fibrils (fAbeta)(1-40) and fAbeta(1-42) formation as well as destabilized preformed fAbetas. Using fluorescence spectroscopy with thioflavin S, electron microscopy, and atomic force microscopy, we examined the effects of anti-Parkinsonian agents, selegiline, dopamine, pergolide, bromocriptine, and trihexyphenidyl on the formation of alphaS fibrils (falphaS) and on preformed falphaS. All molecules except for trihexyphenidyl, dose-dependently inhibited the formation of falphaS. Moreover, these molecules dose-dependently destabilized preformed falphaS. The overall activity of the molecules examined was in the order of: selegiline = dopamine > pergolide > bromocriptine. These agents and other compounds related structurally could be key molecules for the development of therapeutics for LBD and MSA.