The D1/D5 Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson’s Disease: A Feasibility Study (original) (raw)
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Dopamine D1 Agonists: First Potential Treatment for Late-Stage Parkinson’s Disease
Biomolecules
Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson’s disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D1/5 dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Caregiver assessment was the primary efficacy measure because caregivers were with patients throughout the study, and standard clinical metrics inadequately gauge efficacy in LsPD. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2–3). Clinicians and caregivers completed the clinical impression o...
Dopamine D1 agonist effects in late-stage Parkinson’s disease
BackgroundCurrent pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson’s disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients.ObjectiveExplore if a D1/5 dopamine agonist will have efficacy in LsPD that will be detected most sensitively by caregivers in a phase I study.MethodsA double-blind controlled phase Ia/b study compared the D1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Throughout the study, caregivers were with the patients. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2 and 3). Clinicians and caregivers completed clinical impression of change questionnaires, and caregivers participated in a...
Parkinson's disease severity and use of dopaminergic medications
Parkinsonism & Related Disorders, 2015
Background-The effects of dopaminergic therapy in Parkinson's disease (PD) can vary depending on the class of medication selected. Objective-The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD. Methods-A non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life. Results-The outcomes measured at the beginning of the study showed lower disease burden for participants on initial DA monotherapy compared to those taking combined LD and DA therapy after controlling for age, education, taking cogmeds and amantadine. Conclusion-This observation suggests that clinicians treating early PD patients favor combined LD and DA therapy in patients with more disabling features over DA monotherapy. As such, studies of PD progression in treated PD patients may be affected by the class of symptomatic dopaminergic therapy.
Clinical Drug Investigation, 2018
Background and Objectives There is an unmet medical need for additional treatment options for Parkinson's disease. This was a Phase I, double-blind clinical trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of the novel dopamine D1 receptor partial agonist, PF-06669571, in subjects with idiopathic Parkinson's disease on a stable dose of L-DOPA. Methods Subjects received PF-06669571 (or matching placebo) titrated from 1 mg to 3 mg over 7 days. The primary pharmacodynamic endpoint was the change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III total motor score at the pharmacodynamic time of maximum change from baseline on day 7. Results Twenty subjects were randomized and 19 completed the study. Maximum plasma concentrations (C max) of PF-06669571 were reached 3.35 and 3.19 h post-dose on day 1 and day 7. Geometric mean C max and area under the plasma concentration-time profile from time 0 to 24 h post-dose on day 7 were 92.51 ng/mL and 1626 ngÁh/mL, respectively. The primary pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement; however, the criteria were met in a sensitivity analysis excluding data from a L-DOPA outlier (L-DOPA dose of 2550 mg/d). The most common adverse events (AEs) were nausea (experienced by 2 subjects each in the PF-06669571 and placebo groups). There were no permanent discontinuations or dose reductions due to AEs. Discussion Multiple daily doses of PF-06669571 were safe and well tolerated with no notable safety concerns. The pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement. Clinicaltrials.gov identifier NCT02565628.
A reassessment of risks and benefits of dopamine agonists in Parkinson's disease
The Lancet Neurology, 2009
Neurologists have several choices of drugs that have been shown to be eff ective for the treatment of the symptoms of Parkinson's disease. Among the fi rst options are the dopamine agonists, which are commonly used both as an early monotherapy and as an adjunct therapy to levodopa. However, before starting any treatment, the overall benefi t-torisk ratio to individual patients must be considered. For the dopamine agonists, the available evidence on their symptomatic effi cacy, eff ect on long-term levodopa-related motor complications, putative eff ect on progression of disease, and adverse event profi le must be taken into account. Recently, the ocurrence of adverse events such as leg oedema, daytime somnolence, impulse control disorders, and fi brosis have increasingly been recognised. The risks of these potentially serious adverse events must therefore be taken into account and treatment decisions should be based on considerations of risks versus benefi ts for individual patients.
Lancet, 2014
Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease. In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, num...
Earlier dopaminergic treatment in Parkinson's disease is not associated with improved outcomes
Movement Disorders Clinical Practice, 2019
Background Background: The appropriate timing of dopaminergic treatment initiation in Parkinson's disease (PD) remains a matter of debate. The primary objective of this study was to determine whether earlier initiation of treatment was associated with less worsening of total UPDRS scores over 48 months. Methods Methods: We performed a secondary analysis of data from the CALM-PD (Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease) trial to examine the associations between years since diagnosis and 48-month changes in total and component UPDRS scores, Parkinson's Disease Quality of Life Scale (PDQUALIF) score, and the EuroQol-5D visual analogue scale (VAS) score. Results Results: There were no associations between years since PD diagnosis and 48-month changes in total UPDRS, component UPDRS scores, PDQUALIF score, or EuroQol-5D VAS score. Conclusion Conclusion: Earlier treatment was not associated with improved long-term outcomes in this secondary analysis. Prospective studies are required to determine the appropriate timing of initiation of dopaminergic treatment to inform clinical practice.
Selective D-1 dopamine receptor agonist treatment of parkinson's disease
Journal of Neural Transmission, 1987
Preclinical evidence suggests that the D-1 dopamine receptor contributes to the generation of behaviors used as models for human extrapyramidal disorders. To evaluate the potential of D-1 receptor stimulation in neurologic disease, SKF 38393, a selective D-1 dopamine receptor agonist, was administered to seven patients with idiopathic Parkinson's disease in a double-blind, placebo controlled study. SKF 38393 was found to be rapidly absorbed when administered orally, and to occur in micromolar concentrations in spinal fluid. No change in scores of parkinsonian severity were noted when SKF 38393 was administered alone, or when the drug was combined with intravenous levodopa. The results support the view that the pathophysiology of Parkinson's disease may relate exclusively to the D-2 subclass of dopamine receptors.
Treatment of Parkinson's disease should begin with a dopamine agonist
Movement Disorders, 2000
The occurrence of side effects with long-term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinson's disease. Several strategies can be used, such as monotherapy or "early" or "late" combination with levodopa. Results of recent well-performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa-induced late motor side effects.