The Parkinson's-Reversing Breakthrough

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Pergolide, an ergoline-derived dopamine agonist, was approved in the United States in 1989. Like bromocriptine, pergolide has high affinity for the D2 receptor and mild a2-adrenergic activity, but it does not have 5-HT activity. In addition, pergolide has significant D3 activity and mild D1-agonist activity (Table 1) (1). Pergolide is available in three tablet sizes, 0.05 mg, 0.25 mg, and 1.0 mg, and is usually titrated to an effective dosage or an initial maximum dosage of 3 mg/d in three divided doses over the course of six to eight weeks (Table 3) (15). If clinical benefit is seen at 3 mg/d, this dosage may be increased if needed to a maximum of 6 to 8 mg/d. This agent is rapidly absorbed from the gut and reaches a peak plasma concentration in one to three hours. Although the duration of action is typically four to eight hours, the half-life ranges from 15 to 42 hours with a mean of 27 hours. Pergolide is highly protein bound, and greater than 50% of the drug is excreted through the kidney (1). Side effects of pergolide are similar to bromocriptine, and include retroperitoneal fibro-sis, erythromelalgia, somnolence, orthostatic hypotension, and hallucinations. These side effects are 2% to 12% higher with pergolide than with placebo (Table 2) (15,23).

Pergolide has been demonstrated to be effective in both early and advanced PD (24, 25). A de novo PD study, Pergolide versus L-Dopa Monotherapy and Positron Emission Tomography trial (PELMOPET) with randomization to levodopa or pergolide and concurrent positron emission tomography (PET) scanning was completed. In this double-blind study, 294 subjects were randomized to pergolide (n = 148) or levodopa (n = 146) and treated without levodopa rescue for 36 months (4). Seventy-seven subjects (52%) receiving pergolide compared to 90 subjects (61.6%) treated with levodopa completed the study. The mean dosage of pergolide was 3.23 mg/d, whereas subjects receiving levodopa averaged 504 mg/d. Although differences were noted in change from baseline UPDRS motor score (13.4 ± 8.8 pergolide vs. 18.1 ± 10.1 lev-odopa), dyskinesia was three times more frequent in the levodopa group. In addition, 88 subjects were followed by 18F-Dopa PET scans. There was a decrease in uptake in the putamen of 7.9% in the pergolide group and 14.5% in the levodopa group, but these were nonsignificant differences (P = 0.288).

Olanow et al. reported a 24-week, double-blind trial of 377 PD subjects with motor fluctuations randomized to pergolide (n = 189) or placebo (n = 187). Significant improvements were seen in UPDRS motor scores and off time, and levodopa dosages were reduced by approximately 25% in the pergolide group (26).

A database review, comparing efficacy in adjunct therapy trials of pergolide and bromocriptine, found that pergolide was superior to bromocriptine in regards to motor function and ADLs (19). In addition, more subjects recorded a marked or moderate improvement with pergolide than with bromocriptine. However, no significant differences in motor fluctuations, dyskinesia, levodopa dose reduction, dropouts, or adverse events were found.

Cardiopulmonary fibrosis has been reported in patients on long-term pergolide therapy. One patient with no previous underlying pulmonary disease was reported to develop pulmonary symptoms 16 years after the start of bromocriptine and 11 years after starting pergolide. Chest radiograph and CT defined a mass in the right upper lobe, and a biopsy revealed pleural and parenchymal fibrosis. The patient improved after a change from pergolide to pramipexole (27). A subsequent chart review compared 55 patients taking pergolide to 63 control patients (28). Echocardiograms revealed aortic regurgitation in 45% of the pergolide group compared to 21% in the control group (P = 0.006). In the pergolide group, other diseases affected the tricuspid (11%) and mitral (13%) valves, and the aortic valve involvement was judged to be moderate to severe in 13% of subjects. There was also some suggestion of a dosage effect with higher daily doses of pergolide, possibly associated with moderate to severe aortic regurgitation (P = 0.05).

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