Effects Of Pramipexole Research Articles

Examination of clinical effectiveness of Pramipexole for restless legs syndrome in hemodialysis patients

一般人口におけるレストレスレッグス症候群（restless legs syndrome：RLS）の有病率は，欧米で5～10％，日本で2～5％と報告されているのに対し，透析患者におけるRLSの出現頻度は4.8～32.2％と，明らかに高い有病率の報告がなされている．だが，本邦で透析患者を対象とした疫学調査は少数しか報告されていない．本邦では，プラミペキソール塩酸塩水和物（以下，プラミペキソール）が2010年1月特発性RLS治療薬として初めて認可された．そこで，われわれは血液透析患者103名（男性56名，女性47名）を対象に，RLS診断基準を用いて有病率を調査した．また，プラミペキソール投与の有効性についても検討した．有効性の判定には，国際レストレスレッグス症候群評価尺度（IRLS）とVisual Analogue Scale（VAS）を用いた．103名の透析患者のうち，RLSの4つの診断基準をすべて満たしたのは18名であった（有病率は17.5％）．この18名のうち，プラミペキソール服用に同意された患者は9名で，内服前後のIRLSスコアの平均値は投与前25±6.9点，1週間後18.3±9.1点，1か月後14.7±7.7点で，1か月後のIRLSスコア平均値は投与前と比較して有意に低下した．内服前後でのVASスコアの推移は，投与前68.8±12.2mm，1週間後36±19.7mm，1か月後28.3±24.5mmと1週間目から有意差をもって低下した．プラミペキソール服用により，IRLSスコア，VASスコアの改善が経時的に認められた．以上より，血液透析患者におけるRLSの有病率は高率であった．プラミペキソール投与により，RLSの症状改善が認められたことから，プラミペキソールは血液透析患者におけるRLS治療に有用であることが示唆された．

Effects of pramipexole on impulsive choice in male wistar rats.

Clinical reports, primarily with Parkinson's disease patients, note an association between the prescribed use of pramipexole (and other direct-acting dopamine agonist medications) and impulse control disorders, particularly pathological gambling. Two experiments examined the effects of acute pramipexole on rats' impulsive choices where impulsivity was defined as selecting a smaller-sooner over a larger-later food reward. In Experiment 1, pramipexole (0.1 to 0.3 mg/kg) significantly increased impulsive choices in a condition in which few impulsive choices were made during a stable baseline. In a control condition, in which impulsive choices predominated during baseline, pramipexole did not significantly change the same rats' choices. Experiment 2 explored a wider range of doses (0.01 to 0.3 mg/kg) using a choice procedure in which delays to the larger-later reinforcer delivery increased across trial blocks within each session. At the doses used in Experiment 1, pramipexole shifted choice toward indifference regardless of the operative delay. At lower doses of pramipexole (0.01 and 0.03 mg/kg), a trend toward more impulsive choice was observed at the 0.03 mg/kg dose. The difference in outcomes across experiments may be due to the more complex discriminations required in Experiment 2, that is, multiple discriminations between changing delays within each session.

Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Depression is common in patients with Parkinson's disease, but evidence on the efficacy of antidepressants in this population is lacking. Because depression in patients with Parkinson's disease might be related to dopaminergic dysfunction, we aimed to assess the efficacy of the dopamine agonist pramipexole for treatment of depressive symptoms in patients with Parkinson's disease. We did a 12-week randomised, double-blind, placebo-controlled (1:1 ratio) trial of pramipexole (0.125-1.0 mg three times per day) compared with placebo in patients with mild-to-moderate Parkinson's disease. Patients from 76 centres in 12 European countries and South Africa were included if they were on stable antiparkinsonian therapy without motor fluctuations and had depressive symptoms (15-item geriatric depression scale score > or =5 and unified Parkinson's disease rating scale [UPDRS] part 1 depression item score > or =2). Patients were randomly assigned by centre in blocks of four by use of a randomisation number generating system. Clinical monitors, the principal investigator, and patients were masked to treatment allocation. The primary endpoint was change in Beck depression inventory (BDI) score and all treated patients who had at least one post-baseline efficacy assessment were included in the primary analysis. We also did a pre-specified path analysis with regression models to assess the relation between BDI and UPDRS part 3 (motor score) changes. This trial is registered with ClinicalTrials.gov, number NCT00297778, and EudraCT, number 2005-003788-22. Between March, 2006, and February, 2008, we enrolled 323 patients. Of 296 patients randomly assigned to pramipexole or placebo, 287 were included in the primary analysis: 139 in the pramipexole group and 148 in the placebo group. BDI scores decreased by an adjusted mean 5.9 (SE 0.5) points in the pramipexole group and 4.0 (0.5) points in the placebo group (difference 1.9, 95% CI 0.5-3.4; p=0.01, ANCOVA). The UPDRS motor score decreased by an adjusted mean 4.4 (0.6) points in the pramipexole group and 2.2 (0.5) points in the placebo group (difference 2.2, 95% CI 0.7-3.7; p=0.003, ANCOVA). Path analysis showed the direct effect of pramipexole on depressive symptoms accounted for 80% of total treatment effect (p=0.04). Adverse events were reported in 105 of 144 patients in the pramipexole group and 101 of 152 in the placebo group. Adverse events in the pramipexole group were consistent with the known safety profile of the drug. Pramipexole improved depressive symptoms in patients with Parkinson's disease, mainly through a direct antidepressant effect. This effect should be considered in the clinical management of patients with Parkinson's disease.

The effects of pramipexole on prepulse inhibition and locomotor activity in C57BL/6J mice

Pramipexole (PRA) is a preferential D3R agonist that, in rats and humans, modifies prepulse inhibition (PPI) of the acoustic startle reflex, an operational measure of sensorimotor gating. The ability to use similar PPI measures across species, and the relative ease of genetic manipulations in mice, suggests that molecular studies of the D3R regulation of sensorimotor gating might be best pursued in mice. Here, we evaluate the effects of PRA on PPI and locomotion in C57BL/6J mice, the background strain for many gene knockout mouse models. Male C57BL/6J mice were tested for PPI and locomotor activity after injection of PRA. No significant effects of PRA on PPI were observed at any dose (0.1-10.0 mg/kg), but a significant reduction in startle magnitude was observed after 10 mg/kg PRA. In contrast, the D1/2 agonist, apomorphine (5 mg/kg) significantly reduced PPI in these mice. At doses of PRA that did not alter startle magnitude (0.3, 1, 3 mg/kg), significant decreases in the amount of locomotor and investigatory behavior were observed. Distinct from findings in rats and humans, it seems that either: (i) PRA does not activate D3Rs in C57BL/6J mice, or (ii) D3R agonists are not sufficient to alter PPI in this mouse strain.

Neuroprotective effect of the antiparkinsonian drug pramipexole against nigrostriatal dopaminergic degeneration in rotenone-treated mice

Pramipexole, an agonist for dopamine (DA) D2/D3-receptors, has been used to treat both early and advanced Parkinson's disease (PD). In this study, we examined the effect of pramipexole on DA neurons in a PD model of C57BL/6 mice, which were treated with rotenone (30 mg/kg, p.o.) daily for 28 days. Pramipexole (1 mg/kg, i.p.) was injected daily 30 min before each oral administration of rotenone. Chronic oral administration of rotenone caused a loss of DA neurons in the substantia nigra pars compacta (SNpc), motor deficits and the up-regulation of α-synuclein immunoreactivity in some surviving DA neurons. Pramipexole inhibited rotenone-induced DA neuronal death and motor deficits, and reduced immunoreactivity for α-synuclein. In addition, pramipexole inhibited the in vitro oligomerization of human wild-type α-synuclein by H 2O 2 plus cytochrome c. To examine the neuroprotective effect of pramipexole against oxidative stress, we used a DJ-1-knockdown SH-SY5Y cell line and electron spin resonance (ESR) spectrometry. Simultaneous treatment with H 2O 2 and pramipexole resulted in the significant protection of DJ-1-knockdown cells against cell death in a concentration-dependent manner. A high concentration of pramipexole directly scavenged hydroxyl radical ( OH) generated from H 2O 2 and Fe 2+. Furthermore, pramipexole increased Bcl-2 immunoreactivity in DA neurons in the SNpc. These results suggest that pramipexole may protect DA neurons against exposure to rotenone by chronic oral administration, and this effect is mediated by multiple functions including scavenging of OH and induction of Bcl-2 protein.

Antidepressant effects of pramipexole, a dopamine D 3/D 2 receptor agonist, and 7-OH-DPAT, a dopamine D 3 receptor agonist, in olfactory bulbectomized rats

Treatment with pramipexole, a dopamine D 3/D 2 receptor agonist, reduces depressive symptoms in patients suffering from Parkinson's disease. To test the putative antidepressant quality of pramipexole, its effects were assessed in one of the most attractive animal models of depression, the olfactory bulbectomized (OBX) rat. Two experiments studied the effects of pramipexole on bulbectomy-induced hyperactivity. In experiment I, pramipexole was tested at 0.3 and 1.0 mg/kg together with the reference dopamine D 3 receptor agonist 7-OH-DPAT (0.1 mg/kg) and the tri-cyclic antidepressant imipramine (10 mg/kg). In experiment II, pramipexole was tested at lower doses: 0.03 and 0.1 mg/kg, with the same reference compounds. All animals were tested in the open field on days one (acute), seven (sub-chronic) and fourteen (chronic) of administration, as well as one week after cessation of treatment. Pramipexole, in a U-shaped dose response, reduced bulbectomy-induced hyperactivity after (sub) chronic but not acute administration (like imipramine and 7-OH-DPAT). The highest dose of pramipexole (1.0 mg/kg) did not reduce OBX hyperactivity during treatment. However, one week after cessation of treatment, all pramipexole (including the 1.0 mg/kg dose), 7-OH-DPAT and imipramine groups showed a reduction in OBX-induced hyperactivity. Pramipexole and 7-OH-DPAT exert an antidepressant profile in the OBX-rat model in normalizing bulbectomy-induced hyperactivity during (sub) chronic treatment. Moreover, treatment with both these compounds induced long-lasting changes in the bulbectomized brain similar to established antidepressants, strongly predicting antidepressant activity in major depression.

Pramipexole effects on startle gating in rats and normal men

BackgroundDopamine D3 receptors regulate sensorimotor gating in rats, as evidenced by changes in prepulse inhibition (PPI) of startle after acute administration of D3 agonists and antagonists. In this study, we tested the effects of the D3-preferential agonist, pramipexole, on PPI in normal men and Sprague–Dawley rats.Materials and MethodsAcoustic startle and PPI were tested in clinically normal men, comparing the effects of placebo vs. 0.125 mg (n = 20) or placebo vs. 0.1875 mg (n = 20) pramipexole, in double blind, crossover designs. These measures were also tested in male Sprague–Dawley rats using a parallel design [vehicle vs. 0.1 mg/kg (n = 8), vehicle vs. 0.3 mg/kg (n = 8) or vehicle vs. 1.0 mg/kg pramipexole (n = 8)]. Autonomic and subjective measures of pramipexole effects and several personality instruments were also measured in humans.ResultsPramipexole increased drowsiness and significantly increased PPI at 120-ms intervals in humans; the latter effect was not moderated by baseline PPI or personality scale scores. In rats, pramipexole causes a dose-dependent reduction in long-interval (120 ms) PPI, while low doses actually increased short-interval (10–20 ms) PPI. Effects of pramipexole on PPI in rats were independent of baseline PPI and changes in startle magnitude.ConclusionThe preferential D3 agonist pramipexole modifies PPI in humans and rats. Unlike indirect DA agonists and mixed D2/D3 agonists, pramipexole increases long-interval PPI in humans, in a manner that is independent of baseline PPI and personality measures. These findings are consistent with preclinical evidence for differences in the D2- and D3-mediated regulation of sensorimotor gating.

Neuroprotective effects of pramipexole against tunicamycin-induced cell death in PC12 cells

1. Pramipexole (PPX), a dopamine D2 and D3 receptor agonist, exerts neuroprotective effects via both dopamine receptor-mediated and non-dopaminergic mechanisms. In the present study, we demonstrate that PPX reduces the toxicity of tunicamycin, a typical endoplasmic reticulum (ER) stressor, in PC12h cells, a subline of PC12 cells. 2. The PC12h cells were treated with 300 micromol / L PPX in the presence of 0.5 micromol / L tunicamycin for 24 h. The neuroprotective effects of PPX against tunicamycin-induced cell death were evaluated using 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, Hoechst 33258 staining and western blot analysis. 3. Tunicamycin (0.2, 0.3 and 0.5 microg / mL) dose-dependently decreased MTT activity and increased LDH release from PC12h cells. Treatment with 300 micromol / L PPX rescued the tunicamycin-induced decrease in cell viability. 4. Spiperone (10 micromol / L), a dopamine D2 and D4 receptor antagonist, had no effect on PPX neuroprotection against tunicamycin in these cells. Marker proteins of ER stress and apoptosis are known to be upregulated by tunicamycin, but we detected no significant effects of PPX on these factors. 5. In conclusion, we speculate that a combination of several mechanisms may be involved in PPX-induced neuroprotection.

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Association of the DRD2 and DRD3 polymorphisms with response to pramipexole in Parkinson’s disease patients

To evaluate the impact of the DRD2 TaqIA and DRD3 Ser9Gly polymorphisms on the efficacy of pramipexole in treating patients with Parkinson's disease (PD). Thirty patients with PD prospectively received pramipexole 0.25 mg three times daily for 2 months. Unified Parkinson Disease Rating Scale (UPDRS) assessments were conducted at baseline and 2 months after treatment initiation. Improvement by 20% or more in the total score on the UPDRS was considered to indicate responsiveness. The PCR-restriction fragment length polymorphism analysis was used to analyze the DRD2 Taq1A and DRD3 Ser9Gly genotype. The DRD2 Taq1A allele frequencies were A141.7 (A1) and 58.3% (A2), and the DRD3 Ser9Gly allele frequencies were 68.3 (Ser) and 31.7% (Gly). When the subjects were grouped by the DRD3 Ser9Gly polymorphism, the response rates for pramipexole treatment were significantly higher in the Ser/Ser group (60%) than in the group containing the Gly allele (13%). There was a significant association between the DRD3 Ser9Gly polymorphism and response rate to pramipexole in PD patients (P = 0.024). When the subjects were grouped by the DRD2 Taq1A polymorphism, there were no significant differences among the three Taq1A genotypes. DRD3 Ser9Gly polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with PD. A large-scale and multi-dose group study in patients with PD is necessary for evaluating the impact of the genetic polymorphisms of the dopamine receptor on the therapeutic effects of pramipexole.

Dopamine D2/3 receptor partial agonists failed to produce antidepressant‐like effects in the rat forced swim test

High efficacy, dopamine D3 receptor‐preferring agonists, such as pramipexole, produce antidepressant‐like effects in rodents that are mediated by either a combination of the D2 and D3 receptor subtypes or the D2 receptor alone. Little is known about the antidepressant‐like effects of D2/3 receptor partial agonists; therefore, this study investigated the antidepressant‐like activity of the D3‐preferring partial agonists, BP897, CJ998, and CJ1037, and the mixed action D2 partial agonist aripiprazole in rats. We hypothesized that a D3 partial agonist alone would not be sufficient to produce antidepressant‐like effects. These compounds were evaluated alone and as pretreatments to pramipexole in the rat forced swim test. These compounds produced little, if any, antidepressant‐like activity on their own; however, BP897 and aripiprazole antagonized the antidepressant‐like effects of pramipexole. These data suggest that partial agonist activity at the dopamine D3 and/or D2 receptors is not sufficient to produce antidepressant‐like activity and that partial agonists can block the actions of high efficacy agonists, consistent with receptor theory. Overall, these findings further demonstrate that activation of D2 and D3 receptors with high efficacy agonists is required to produce antidepressant‐like effects in rodents. This work was supported in part by USPHS grants DA020669 and T32 DA07268.

Effects of pramipexole on the duration of immobility during the forced swim test in normal and ACTH-treated rats

The dopamine D2/D3 receptor agonist pramipexole has clinically been proven to improve depression or treatment-resistant depression. However, the involvement of the dopamine receptor system on the effect of pramipexole on depression remains unclear. We examined the influence of pramipexole on the duration of immobility during the forced swim test in normal and adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which pramipexole acts in this model was explored specifically in relation to the site of action through the use of microinjections into the intramedial prefrontal cortex and nucleus accumbens. Pramipexole (0.3-1 mg/kg) significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by L-741,626, a D2 receptor antagonist, and nafadotride, a D3 receptor antagonist, in normal rats. Furthermore, infusions of pramipexole into the intranucleus accumbens, but not the medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Taken together, the results of these experiments suggested that pramipexole, administered into the intranucleus accumbens rather than the medial prefrontal cortex, exerted an antidepressant-like effect on ACTH-treated rats via the dopaminergic system. The immobility-decreasing effect of pramipexole may be mediated by dopamine D2 and D3 receptors.

Understanding the nature and outcome of childhood wheezing

<h3>Introduction</h3> Clinical depression is usually treated in primary care with psychological therapies and antidepressant medication. However, when patients do not respond to at least two or more antidepressants within a depressive episode, they are considered to have treatment resistant depression (TRD). Previous small randomised controlled trials suggested that pramipexole, a dopamine D2/3 receptor agonist, may be effective for treating patients with unipolar and bipolar depression as it is known to influence motivational drive and reward processing. PAX-D will compare the effects of pramipexole vs placebo when added to current antidepressant medication for people with TRD. Additionally, PAX-D will investigate the mechanistic effect of pramipexole on reward sensitivity using a probabilistic decision-making task. <h3>Methods and analysis</h3> PAX-D will assess effectiveness in the short- term (during the first 12 weeks) and in the longer-term (48 weeks) in patients with TRD from the UK. The primary outcome will be change in self-reported depressive symptoms from baseline to week 12 post-randomisation measured using the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16). Performance on the decision-making task will be measured at week 0, week 2 and week 12. Secondary outcomes include anhedonia, anxiety and health economic measures including quality of life, capability, well-being and costs. PAX-D will also assess the adverse effects of pramipexole including impulse control difficulties. <h3>Discussion</h3> Pramipexole is a promising augmentation agent for TRD and may be a useful addition to existing treatment regimes. PAX-D will assess its effectiveness and test for a potential mechanism of action in patients with TRD. <h3>Trial registration number</h3> ISRCTN84666271

Dopamine and cognitive functioning in de novo subjects with Parkinson's disease: Effects of pramipexole and pergolide on working memory

Very few studies have investigated the relationship between dopaminergic therapy and working memory (WM) functioning in Parkinson's disease (PD) patients. The aim of the present study was to explore the effects of pharmacological treatment with pergolide (a D 1 + D 2 receptor agonist) and pramipexole (a D 2 + D 3 receptor agonist) on performance in visual–spatial, visual-object, and verbal WM tasks in PD patients. Participants included 19 “de novo” PD patients and 13 healthy controls (HC). The experimental task consisted of an n-back paradigm with verbal, visual-object, or visual–spatial stimuli. PD patients performed the task twice: after 18–24 h of therapy wash-out and after administration of pergolide (nine patients) or pramipexole (ten patients). HCs performed the task only once, without drug administration. Depending on how they performed in the “Off” and “On” therapy conditions, the nine PD patients each were classified into groups of low performers (i.e., performance on the n-back paradigm was below the median value of the experimental sample) and high performers (i.e., performance was above the median value). One PD patient was excluded from the analysis because his performance pattern clearly revealed that he was an outlier. In the low performer PD patients, administration of both pergolide and pramipexole improved accuracy on all WM tasks. No effect of the drugs was found in the high performer patients. The results of the present study show that stimulation of dopaminergic receptors improves high-level WM processes in PD patients, possibly by modulating activity in frontal–striatal circuits.

Beneficial effect of pramipexole for motor function and depression in Parkinson&amp;rsquo;s disease

We examined whether pramipexole (PPX) can influence depressive scale in normal and mild depressive parkinsonian patients. In an open study of PPX as an add-on to L-dopa therapy or single administration, 36 nondemented outpatients with Parkinson's disease (PD) were entered first. All were in the stage II or III of Hoehn and Yahr scale (H&Y). PPX were started at 0.125 mg/day and daily doses were increased to 1.5 mg/day. At 3 months after PPX treatment, patients were re-evaluated. Hamilton Depression Rating Scale (HAM-D), Unified Parkinson's Disease Rating Scale III, H&Y stage, and freezing of gait questionnaire were compared in patients before and after PPX treatment. These scores were significantly improved after PPX administration. There were no correlations between HAM-D and those motor functions. We suggest that PPX treatment has antidepressant effects in depressive PD patients and also ameliorates HAM-D score in nondepressive PD patients in addition to motor function.

The effect of pramipexole on mood and motivational symptoms in parkinson's disease: A meta-analysis of placebo-controlled studies

Background: Mood and motivational symptoms have been reported in up to 35% and 51%, respectively, of patients with Parkinson's disease (PD). Preliminary evidence indicates that pramipexole may have a positive effect on these symptoms. Objective: This analysis was conducted to evaluate the effects of pramipexole on mood and motivational symptoms in patients with PD. Methods: Data for the meta-analysis were extracted from all randomized, double-blind, placebo-controlled trials of pramipexole in the manufacturer's database that included part I of the Unified Parkinson's Disease Rating Scale (UPDRS) as an outcome measure. Only patients with baseline scores >0 (range, 0–4) on item 3 (mood) and item 4 (motivation) were included. Separate analyses were performed for mood and motivational symptoms. The outcome of interest was improvement in scores, with no improvement including both unchanged and increased scores. Odds ratios (ORs), 95% CIs, and Cochran-Mantel-Haenszel tests were calculated to compare rates of improvement and no improvement, stratified by trial. Results: Fourteen randomized, double-blind, placebo-controlled trials of pramipexole were identified, all employing the severity of motor symptoms of PD as a primary outcome. Seven of these trials (N = 1296) employed part I of the UPDRS as a secondary outcome measure and were included in the meta-analysis; no other measure of mood or motivational symptoms was used in any of the 14 studies. Six of the 7 studies included patients with motor fluctuations due to levodo-pa treatment, and the remaining study included patients who did not yet require levodopa. Six studies were published in peer-reviewed journals, and all 7 were included in the New Drug Application for pramipexole. The published study reports were usually limited to motor symptoms; only 1 reported on mood and motivation. However, for the purpose of this meta-analysis, the authors had access to data that were not reported in the original publications. In the pooled data set, 480 patients (59.8% male; mean age, 63.3 years) had a baseline score >0 on item 3 (mood). These mood symptoms improved in 64.7% of patients treated with pramipexole and 43.4% of those receiving placebo (OR weighted by trial = 2.41; P < 0.001). Five hundred seventy patients (64.9% male; mean age, 64.1 years) had a baseline score >0 on item 4 (motivation). These motivational symptoms improved in 63.2% of patients treated with pramipexole and 45.0% of those receiving placebo (OR weighted by trial = 2.06; P < 0.001). Conclusions: This meta-analysis of 7 randomized controlled trials suggests that pramipexole had a beneficial effect on mood and motivational symptoms in PD patients who did not have major depressive disorder. The clinical value of pramipexole in the treatment of depressive and apathetic syndromes requires further investigation.

Effect of pramipexole on RLS symptoms and sleep: A randomized, double-blind, placebo-controlled trial

Background Patients with Restless Legs Syndrome (RLS) often seek treatment because of sleep problems related to nocturnal symptoms. Our goal was to test the ability of pramipexole to improve sleep in RLS patients and to reconfirm its efficacy for primary RLS symptoms. Methods Adults with moderate or severe RLS were randomized to receive placebo or pramipexole (flexibly titrated from 0.25 to 0.75 mg), 2–3 h before bedtime for 12 weeks. The co-primary outcome measures were change in Medical Outcomes Study (MOS) sleep disturbance score and International RLS Study Group Rating Scale (IRLS) score at 12 weeks. Results The intent-to-treat population included 357 patients: 178 received pramipexole and 179 received placebo. At 12 weeks, the adjusted mean change from baseline was greater for pramipexole (vs. placebo) for IRLS score (−13.4 ± 0.7 vs. −9.6 ± 0.7) and MOS sleep disturbance score (−25.3 ± 1.5 vs. −16.8 ± 1.5) ( p ⩽ 0.0001; ANCOVA). Responder rates (clinical and patient global impression and IRLS) were also significantly higher in the pramipexole group. RLS-QOL score was improved over placebo at Week 12 ( p < 0.01) as were MOS sleep adequacy ( p = 0.0008) and quantity ( p = 0.08) scores. Nine percent of patients in each group withdrew because of adverse events. Conclusions Pramipexole is effective and well-tolerated for RLS and related sleep disturbance.

Lack of Effects of Pramipexole on REM Sleep Behavior Disorder in Parkinson Disease

REM sleep behavior disorder (RBD) is a common manifestation of Parkinson disease (PD) which is characterized by dream-enacting behaviors, unpleasant dreams, and loss of muscle atonia during REM sleep. Dopaminergic mechanisms are thought to play a role in RBD pathogenesis. To further asses such a role, we have evaluated the effect of pramipexole, a dopamine receptor agonist, on RBD features in PD patients. University hospital sleep disorder center. Eleven PD patients with untreated RBD. interventions: Not applicable. In a prospective study, 11 consecutive PD patients with untreated RBD on levodopa monotherapy were placed on pramipexole to further ameliorate their parkinsonism. The effects on RBD were evaluated before and 3 months after stable pramipexole therapy through patient and bed partner interviews and blind assessment of video-polysomnographic measures. Pramipexole improved parkinsonism in all patients. Patients and bed partners reported no significant changes in frequency and severity of the abnormal RBD related motor and vocal sleep behaviors or the frequency of unpleasant dreams. Video-polysomnography analyses showed no differences in RBD related sleep measures including tonic submental electromyographic activity, phasic submental electromyographic activity, percentage of REM sleep time spent with abnormal behaviors, and severity of the abnormal behaviors detected on the videotapes. In PD, pramipexole improved parkinsonism but did not modify RBD related symptoms and objective video-polysomnographic abnormalities. This observation suggests that in PD, dopamine mechanisms do not play a central role in the pathogenesis of RBD.

Defining the Boundaries of the Response of Sleep Leg Movements to a Single Dose of Dopamine Agonist

To define which leg movements (LM) associated with restless legs syndrome (RLS) respond to dopamine-agonist treatment and verify if they fall within current diagnostic criteria for periodic LM during sleep (PLMS). Single-blind placebo-controlled study. Sleep laboratory. 43 consecutive untreated patients with idiopathic restless legs syndrome. Patients underwent clinical and neurophysiological evaluation, hematological screening, and 2 consecutive full-night polysomnographic studies. Before the second polysomnographic study, all patients were randomized to receive 0.25 mg of pramipexole or placebo. LM parameters such as duration, amplitude, interval, and periodicity were analyzed. Compared to placebo, pramipexole significantly (P < 0.01) reduced PLMS while increasing sleep efficiency. Specifically we observed a significant (P < 0.01) reduction in LM ranging 2-4 s in duration and with intermovement interval of 6-46 s and a significant decrease in the periodicity of motor events. No effect of pramipexole was observed on isolated LM. These results support a heterogeneous basis for LM in RLS patients; while isolated LM do not respond to pramipexole treatment, most, but not all, PLMS classified by means of the current criteria do. Further studies with different pramipexole doses or dopamine agonists with different receptor-binding preference are warranted to better define the borders of dopamine response of PLMS.

S.01.03 Dopamine partial agonists – do they live up to their expectations?

Pramipexole (SND 919) is a dopamine D2 autoreceptor agonist which is structurally related to talipexole (B-HT 920), a potential antipsychotic agent. The aim of this study was to investigate the effects of pramipexole on the extracellular concentration of dopamine in vivo. Dopamine and its metabolites, 3,4-dihydrophenylacetic acid and homovanillic acid, were measured in the anterior striatum of freely moving rats by microdialysis and high-performance liquid chromatography with electrochemical detection. Pramipexole (30 and 100 μg/kg) caused long-lasting decreases in the extracellular concentrations of dopamine and its metabolites. Talipexole (30 μg/kg) produced similar effects. Sulpiride (5 mg/kg), a selective dopamine D2 antagonist, caused a transient increase in the concentration of dopamine and long-lasting increases in the concentrations of its metabolites; it also reversed the effects of pramipexole. SCH-23390 (100 μg/kg), a selective dopamine D1 receptor antagonist, caused a transient increase in the concentration of dopamine but did not affect the concentrations of the metabolites. SCH-23390 failed to reverse the effects of pramipexole. These results indicate that pramipexole reduces the extracellular concentrations of dopamine and its metabolites in vivo through a reversible interaction with the dopamine D2 receptor.