Novel antiepileptic drug levetiracetam decreases dyskinesia elicited by L-dopa and ropinirole in the MPTP-lesioned marmoset.

Long-term dopamine replacement therapy of Parkinson's disease leads to the occurrence of dyskinesias. Altered firing patterns of neurons of the internal globus pallidus, involving a pathological synchronization/desynchronization process, may contribute significantly to the genesis of dyskinesia. Levetiracetam, an antiepileptic drug that counteracts neuronal (hyper)synchronization in animal models of epilepsy, was assessed in the MPTP-lesioned marmoset model of Parkinson's disease, after coadministration with (1) levodopa (L-dopa) or (2) ropinirole/L-dopa combination. Oral administration of levetiracetam (13-60 mg/kg) in combination with either L-dopa (12 mg/kg) alone or L-dopa (8 mg/kg)/ropinirole (1.25 mg/kg) treatments was associated with significantly less dyskinesia, in comparison to L-dopa monotherapy during the first hour after administration. Thus, new nondopaminergic treatment strategies targeting normalization of abnormal firing patterns in basal ganglia structures may prove useful as an adjunct to reduce dyskinesia induced by dopamine replacement therapy without affecting its antiparkinsonian action.     

Long-term,open-label,safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease

Long-term safety of once-daily ropinirole extended/prolonged release (ropinirole XL/PR) was evaluated in subjects with early and advanced Parkinson's disease (PD) in this study, 101468/248. Subjects (n = 419) who completed one of three prior studies evaluating ropinirole XL/PR for the treatment of PD were enrolled in this open-label, multicenter, extension study, and were to be followed for up to 73 months. Ropinirole XL/PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/d). Levodopa (L-dopa) and other nondopamine agonist PD medications were permitted. Safety outcomes that were investigated included frequency of adverse events (AEs). Subjects’ preference regarding once daily versus three times daily study medication regimens was also investigated in a subset of the study population. The median duration of ropinirole XL/PR exposure was 1275 d. Most subjects (87%) reported at least one AE, with the most common (≥ 10%) AEs being, back pain (14%), hallucinations (13%), somnolence (11%) and peripheral edema (11%). Twenty-five percent of subjects discontinued the study prematurely due to an AE during the treatment period. Long-term treatment with ropinirole XL/PR was not associated with any new or unexpected safety concerns in patients with early and advanced PD, and a majority of subjects preferred the once-daily dosing regimen.     

Switch from oral pramipexole or ropinirole to rotigotine transdermal system in advanced Parkinson’s disease: an open-label study

Objective: Investigate safety, feasibility and efficacy of switching therapy in patients with advanced-stage Parkinson’s disease (PD) inadequately controlled with pramipexole (≤ 3.5 mg/day) or ropinirole (≤ 14 mg/day) to rotigotine transdermal system (≤ 14 mg/24 h; dose adjustments ≤ 16 mg/24 h permitted).

Methods: PD0009 (ClinicalTrials.gov: NCT01711866) was an open-label study in patients with advanced-stage PD receiving levodopa, and experiencing sleep disturbance or early-morning motor impairment. Pramipexole/ropinirole was switched to equivalent dose rotigotine overnight or in two stages. During the 4-week treatment period rotigotine dose adjustments were permitted (up to 16 mg/24 h). Primary variable: Clinical Global Impressions (CGI) item 4: side effects (assessing safety) at end of treatment.

Results: 79/87 (91%) patients completed the study; 2 (2%) withdrew due to adverse events (AEs). Most (84; 97%) had CGI item 4 score < 3 indicating switch did not interfere with functioning; three experienced drug-related AEs interfering with functioning (score = 3). 62% patients improved on Patient Global Impression of Change, assessing effectiveness. AEs occurring ≥ 5%: application site pruritus (10%), application site erythema (7%), dizziness (7%), dyskinesia (7%), erythema (6%), pruritus (6%). Unified Parkinson’s Disease Rating Scale II and III, Parkinson’s Disease Sleep Scale-2 and Pittsburgh Sleep Quality Index were unchanged. Numerical improvements in ‘off’ time, awakenings and nocturias were observed.

Conclusions: Switch from pramipexole or ropinirole to rotigotine (up to 14 mg/24 h) was feasible and possibly associated with some benefit.     

Ropinirole: Current status of the studies

Abstract. Ropinirole is a modern, non-ergoline dopamine agonist which has been shown to be effective as monotherapy as well as combination therapy against idiopathic Parkinsons disease. In addition to improving bradykinesia, rigor and tremor, it will ameliorate the abilities of daily living as well as depressive mood. The long-term complications of L-dopa are diminished and the existing complications are reduced. A neuroprotective effect is under discussion. In addition to Parkinsons disease, ropinirole is also used successfully in the treatment of restless legs syndrome.     

Adverse drug reactions to dopamine agonists: A comparative study in the french pharmacovigilance database

Pharmacodynamical differences between dopamine agonists (DAs) suggest differences in their adverse drug reactions (ADRs) profile. In this study, frequencies of ADR to DAs or levodopa reports in the French Pharmacovigilance Database were explored. Reports occurring between January 1, 1984 and December 31, 2008 were selected (2,189 for DAs and 1,315 for levodopa). The numbers of ADRs by system organ class were compared using ropinirole as a reference. Diurnal somnolence was less frequently reported with all DAs when compared with ropinirole (P < 0.001). Impulse control disorders (ICDs) were more frequently reported with pramipexole (P < 0.001). Significant difference was found among DAs in the frequency of confusion or disorientation (P < 0.001), nausea and vomiting (P < 0.05), or edemas (P < 0.001). No difference among DAs was observed in the frequency of hallucination or arterial hypotension ADR reports (P = 0.3 and P = 0.1). Pleural effusions were more frequently reported with pergolide or bromocriptine (P < 0.001). Somnolence or ICD reports were less frequent with levodopa, whereas confusion was more frequently reported. In summary, our data show significant differences in the kind of ADRs reported for each DA. © 2010 Movement Disorder Society.     

Early treatment benefits of ropinirole prolonged release in Parkinson's disease patients with motor fluctuations

We performed a retrospective analysis of the Efficacy And Safety Evaluation in Parkinson's Disease (EASE‐PD) Adjunct Study, assessing the minimum time to symptom improvement after initiation of ropinirole prolonged release (2–24 mg/day) versus placebo in patients with moderate‐to‐advanced PD not optimally controlled with levodopa. Ropinirole prolonged release was superior to placebo at Week 2 for change from baseline in “off” time (adjusted mean treatment difference [AMTD] – 0.7 hours; 95% confidence interval [CI], –1.1, –0.2; P = 0.0029), and “on” time without troublesome dyskinesia (0.4 hours; 95%CI, 0.01, 0.88; P = 0.0444). At Week 4, improvements were seen in change from baseline in Unified Parkinson's Disease Rating Scale total motor score (AMTD, –3.1; 95%CI, –4.4, –1.8; P < 0.0001), activities of daily living score (AMTD, –1.1; 95%CI, –1.7, –0.5; P = 0.0004), and the cardinal symptoms of PD compared with placebo. These analyses indicate that once‐daily, adjunctive ropinirole prolonged release can offer PD symptom control 2 weeks after treatment initiation. © 2010 Movement Disorder Society     

Effect of Ropinirole on Sleep Outcomes in Patients with Restless Legs Syndrome: Meta-Analysis of Pooled Individual Patient Data from Randomized Controlled Trials

Study Objective. To compare the effects of ropinirole with those of placebo on sleep, as evaluated by specific domains of the Medical Outcomes Study (MOS) sleep scale, as well as the Clinical Global Impression-Improvement (CGI-I) scale, in patients with restless legs syndrome (RLS). Design. Meta-analysis of six randomized, double-blind, placebo-controlled, parallel-group trials conducted in the United States and Europe. Patients. A total of 1679 patients aged 18–79 years with primary moderate-to-severe RLS who received ropinirole (835 patients) or placebo (844 patients). Measurements and Main Results. A systematic review of MEDLINE (January 1980-January 2007) and clinical trial registers was performed to identify placebo-controlled trials of ropinirole that used the 12-item MOS sleep scale to assess sleep in patients with RLS. Individual patient data from both published and nonpublished trials were pooled for meta-analysis. In the eligible studies, immediate-release ropinirole 0.25-6 mg or placebo had been given for at least 12 weeks. In addition, sleep scale summary scores for the domains of sleep quantity, adequacy, disturbance, and daytime somnolence had to have been assessed at baseline and at 12 weeks. Our meta-analysis found that at baseline study patients slept an average of 5.8 hours/night. At the end of 12 weeks, ropinirole-treated patients slept a mean of 2.5 hours/week more and had a 21% greater improvement from baseline in sleep adequacy scores compared with patients receiving placebo. Ropinirole-treated patients also had 14% less sleep disturbance and 8% less daytime somnolence than patients receiving placebo. Clinicians rated 63% of ropinirole-treated patients and 47% of patients receiving placebo as responders based on the CGI-I scale. Mixed effects analysis of covariance was used to estimate treatment effect adjusting for study center as a random effect, as well as the following fixed effects known to affect sleep: baseline sleep characteristics, age, sex, and chronic medical conditions. All differences were statistically significant (p<0.05), even after adjusting for multiple comparisons. Conclusion. Pooled data from six similarly designed clinical trials provide evidence that ropinirole improves sleep quantity and adequacy, and lessens sleep disturbance and daytime somnolence in patients with primary RLS.     

Parkinson's disease treatment may cause impulse–control disorder via dopamine D3 receptors

In treating Parkinson's disease with dopaminergic agonists, such as pramipexole, ropinirole, pergolide, rotigotine, apomorphine, or bromocriptine, it has been observed that a significant number of patients develop impulse–control disorders, such as compulsive shopping, pathological gambling, or hypersexuality. Because the dopamine agonists have high affinities for the dopamine D2 and D3 receptors, the drug dissociation constants of these drugs at the functional high‐affinity states of these receptors, namely D2High and D3High, were compared. The data show that, compared to the other dopamine agonist drugs, pramipexole has a relatively high selectivity for the dopamine D3 receptor, as compared to D2, suggesting that the D3 receptor may be a primary target for pramipexole. There is a trend showing that the proportion of impulse–control disorders is related to the selectivity for D3 receptors over D2 receptors, with pramipexole having the highest association with, or frequency of, impulse–control disorders. While the number of studies are limited, the proportion of patients with impulse–control disorder in Parkinson patients treated with an add‐on agonist were 32% for pramipexole, 25% for ropinirole, 16% for pergolide, 22% for rotigotine, 10% for apomorphine, and 6.8% for bromocriptine. Clinically, temporary replacement of pramipexole by bromocriptine may provide relief or reversal of the impulsive behavior associated with selective D3 stimulation by either pramipexole or ropinirole, while maintaining D2 stimulation needed for the anti‐Parkinson action. Synapse, 69:183–189, 2015 . © 2015 Wiley Periodicals, Inc.