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Analysis of pramipexole dose-response relationships in Parkinson's disease.

ABSTRACT: Pramipexole (PPX), a non-ergot dopamine receptor agonist, is a first-line treatment for Parkinson's disease (PD). A critical dose level above which a better benefit-to-harm ratio exists has not been examined.Chinese PD patients (n=464) were retrospectively analyzed by PPX maintenance dose, PD stage, combined levodopa dose, and baseline tremor contribution. The sum score of Baseline Activities of Daily Living (part II) and Motor Examination (III) of the Unified Parkinson's Disease Rating Scale (UPDRS II+III) was used as a covariate for final score adjustment.Sustained-release (SR) and immediate-release (IR) PPX showed similar efficacy based on score changes at 18 weeks, with comparable tolerability. Approximately two-third of patients received PPX at ?1.5 mg/d, and one fourth of patients had ?20% tremor contribution to UPDRS II+III. After treatment, patients receiving PPX ?1.5 mg/d showed better improvement in UPDRS II+III scores (P=0.0025), with similar trends with the IR and SR formulations. Patients with ?20% tremor contribution showed better improvement in UPDRS II+III scores (P=0.0017). No differences were seen based on PD stage or combined levodopa dose. The overall proportions of adverse events (AEs) were similar. More patients discontinued because of intolerable side effects, and more investigator-defined drug-related AEs were recorded in the <1.5 mg/d subgroup.UPDRS II+III improvement was better with PPX ?1.5 than with <1.5 mg/d in Chinese PD patients after 18 weeks of treatment, with similar trends seen with IR and SR formulations. The frequency of AEs in PPX ?1.5 and <1.5 mg/d subgroups was similar.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5207331 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Analysis of pramipexole dose-response relationships in Parkinson's disease.

Wang Ying Y Sun Sheng-Gang SG Zhu Sui-Qiang SQ Liu Chun-Feng CF Liu Yi-Ming YM Di Qing Q Shang Hui-Fang HF Ren Yan Y Xiang Wei W Chen Sheng-Di SD

Drug design, development and therapy 20161223

<h4>Background</h4>Pramipexole (PPX), a non-ergot dopamine receptor agonist, is a first-line treatment for Parkinson's disease (PD). A critical dose level above which a better benefit-to-harm ratio exists has not been examined.<h4>Methods</h4>Chinese PD patients (n=464) were retrospectively analyzed by PPX maintenance dose, PD stage, combined levodopa dose, and baseline tremor contribution. The sum score of Baseline Activities of Daily Living (part II) and Motor Examination (III) of the Unified ...[more]

PMID: 28096656

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Project description:BackgroundIn models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD).MethodsBetween May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30-79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1·5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854.FindingsOf 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0·4 points, 95% CI -2·2 to 1·4, p=0·65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal (123)I-FP-CIT binding was -15·1% (SE 2·1) for early and -14·6% (2·0) for delayed pramipexole (difference -0·5 percentage points, 95% CI -5·4 to 4·4, p=0·84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug.InterpretationBy clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6-9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects.FundingBoehringer Ingelheim GmbH.

Project description:Pramipexole and ropinirole are dopamine agonists that are efficacious in treating motor disturbances of neuropathologies, e.g., Parkinson's disease and restless legs syndrome. A significant portion of treated patients develop impulsive/compulsive behaviors. Current treatment is dose reduction or switching to an alternative dopamine replacement, both of which can undermine the motor benefits. Needed is a preclinical model that can assist in identifying adjunct treatments to dopamine agonist therapy that reduce impulsive/compulsive behaviors without interfering with motor benefits of the dopamine agonist. Toward that objective, the current study implemented a rat model of Parkinson's disease to behaviorally profile chronically administered pramipexole. This was accomplished with male Sprague-Dawley rats wherein (i) 6-hydroxydopamine-induced lesions of the dorsolateral striatum produced Parkinson's disease-like akinesia, measured in the forelimbs, (ii) intracranial self-stimulation-mediated probability discounting indicated impulsivity/risk-taking, and (iii) two doses of pramipexole were continuously administered for 14-28days via osmotic minipumps to mirror the chronic, stable exposure achieved with extended release formulations. The atypical antidepressant, mirtazapine, is known to reduce behaviors associated with drug addiction in rats; thus, we demonstrated model utility here by determining the effects of mirtazapine on pramipexole-induced motor improvements versus probability discounting. We observed that forelimb akinesia subsequent to striatal lesions was attenuated by both pramipexole doses tested (0.3 and 1.2mg/kg/day) within 4h of pump implant dispensing 0.3mg/kg/day and 1h by 1.2mg/kg/day. By contrast, 12-14days of infusion with 0.3mg/kg/day did not alter discounting, but increases were obtained with 1.2mg/kg/day pramipexole, with 67% of 1.2mg/kg/day-treated rats meeting categorical criteria for 'high risk-taking'. Insertion of a second minipump delivering mirtazapine did not alter motor function during 14days of co-administration with pramipexole, but was sufficient to attenuate risk-taking. These outcomes revealed distinct probability discounting and anti-akinesia profiles for pramipexole, indicating that pharmacotherapy, (e.g., mirtazapine treatments), can be developed that reduce risk-taking while leaving motor benefits intact.

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Analysis of pramipexole dose-response relationships in Parkinson's disease.

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Analysis of pramipexole dose-response relationships in Parkinson's disease.

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