The Parkinson's-Reversing Breakthrough

Treatment for Parkinsons

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Pramipexole was approved in the United States in 1997 and is a synthetic, nonergot dopamine agonist. Like the ergot-derived dopamine agonists, this agent is active at the D2, D3, and D4 receptors. Pramipexole also has affinity for a- and P-adrenoreceptors, acetylcholine receptors, and 5-HT receptors (Table 1). The drug is available in 0.125, 0.25, 0.5, 1.0, and 1.5 mg tablets, and the usual dosage is 3.0 mg/d in three divided doses titrated over five weeks (Table 3) (15). This drug reaches peak plasma levels within one to three hours and has an elimination half-life of 8 to 12 hours. The agent is excreted mostly unchanged in the urine and less than 20% is protein bound. Pivotal trials with pramipexole report that nausea, vomiting, somnolence, and orthostatic hypotension were 0% to 13% higher than in subjects randomized to placebo (Table 2) (2,29-32).

Pramipexole has been studied in de novo and advanced PD populations. Three large trials evaluated the effectiveness of pramipexole as monotherapy in early PD (2,29-32). A large dose-ranging trial (n = 264) conducted by the Parkinson Study Group found most patients tolerated dosages of 6 mg/d or less of pramipexole. In this 10-week study, 98% (placebo), 81% (1.5 mg/d), 92% (3.0 mg/d), 78% (4.5 mg/d), and 67% (6.0mg/d) of subjects tolerated the drug (29). A 20% benefit in UPDRS motor scores was seen in all active treatment groups, and it was determined that the optimum dosage range was 1.5 to 4.5 mg/d. In a 6-month study, 335 subjects were randomized to pramipexole (n = 164) or placebo (n = 171). Investigators reported a greater than 20% improvement in the UPDRS ADL and motor scores in the active treatment group (30). Side effects in these investigations included nausea, somnolence, dizziness, and hallucinations.

The Parkinson Study Group reported data comparing pramipexole to levodopa in early PD in the Comparison of the Agonist Pramipexole versus Levodopa on Motor Complications in Parkinson's Disease (CALM-PD) trial (2,31,32). In this trial, 301 subjects were randomized to pramipexole or levodopa and were followed for four years. At the conclusion of the trial, 52% of pramipexole and 74% of levodopa subjects reached the primary endpoint of motor complications. Furthermore, dyskinesia occurred in 25% on pramipexole and 54% on levodopa, and wearing off occurred in 47% of the pramipexole group and 67% of the levodopa group. However, UPDRS assessments found significant improvements (~4 points) in subjects receiving levodopa (31). Eighty-two subjects in the CALM-PD cohort also underwent single photon emission computed tomography (SPECT) imaging with P-CIT to assess striatal uptake of this dopamine transporter (2). Comparisons between the pramipexole group (n=42) and the levodopa group (n = 40) found significant differences ranging from 6.4% to 9.5% in transporter uptake at 22, 34, and 46 months, suggesting less functional decline with pramipexole. Supplemental levodopa was allowed in the CALM-PD study, whereas it was not allowed in the PELMOPET study, comparing pergolide to levodopa. The dosages of pramipexole averaged 2.78 mg/d with 48% of subjects receiving a mean levodopa supplement of 264 mg/d, whereas 36% of the levodopa-treated subjects required levodopa supplementation with a mean dosage of 509 mg/d.

Two randomized clinical trials of pramipexole in levodopa-treated patients demonstrated significant benefit in off time (31% and 15%), ADLs (22% and 27%), motor function (25% and 35%), and levodopa dosage reduction (27%) (30,33). The mean dosage of pramipexole was 3.36 mg/d, and side effects included dyskinesia, orthostatic hypotension, dizziness, insomnia, hallucinations, nausea, confusion, and headache (30, 33) (Table 2).

Since pramipexole has come to market, unexpected sleep episodes and increased impulsivity such as pathological gambling have been reported, and although seen with other dopamine agents, are most often associated with this agent (34-39).

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