Continuous Dopaminergic Stimulation as a Treatment for Parkinson's Disease: Current Status and Future Opportunities

Olanow, C. Warren; Calabresi, Paolo; Obeso, José A.

doi:10.1002/mds.28215

Cited by 55 publications

(54 citation statements)

References 133 publications

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“…These observations led to the hypothesis that continuous delivery of levodopa might restore dopamine to the brain in a more physiological manner and reduce the risk of motor complications. This concept has been supported by numerous animal studies [6,7], and by a double-blind study in PD patients showing that continuous intrajejunal infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) was associated with significantly reduced motor fluctuations compared to optimized oral levodopa [10]. However, continuous intestinal levodopa fusion is associated with potentially serious side effects related to the surgical procedure and the need for a persistent indwelling jejunal catheter [10,11].…”

Section: Introductionmentioning

confidence: 98%

“…Increasing evidence indicates that motor complications are related to the non-physiologic restoration of brain dopamine with intermittent doses of standard oral levodopa [6,7]. Under normal conditions, striatal dopamine concentrations are maintained at a relatively continuous level [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Under normal conditions, striatal dopamine concentrations are maintained at a relatively continuous level [8,9]. However, in the dopamine-depleted state, intermittent levodopa doses result in marked fluctuations in striatal dopamine leading to molecular and neurophysiologic changes and ultimately to motor complications [6,7]. These observations led to the hypothesis that continuous delivery of levodopa might restore dopamine to the brain in a more physiological manner and reduce the risk of motor complications.…”

Section: Introductionmentioning

confidence: 99%

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Continuous Subcutaneous Levodopa Delivery for Parkinson’s Disease: A Randomized Study

Olanow

Espay

Stocchi

et al. 2021

JPD

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Background: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson’s disease (PD) experiencing motor fluctuations Objective: Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. Methods: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour ‘waking-day’ infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). Results: A total of 38 patients were randomized and 33 (87% ) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[– 3.3, – 0.7] hours (p = 0.003). ON time with no/mild dyskinesia was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[– 1.8, – 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (– 2.8[– 4.6, – 0.9] hours; p = 0.004) than in the 14-hour group (– 1.3[– 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. Conclusion: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Continuous Subcutaneous Levodopa Delivery for Parkinson’s Disease: A Randomized Study

Olanow

Espay

Stocchi

et al. 2021

JPD

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“…This in turn causes molecular changes in striatal neurons, neurophysiologic changes in pallidal output neurons, and the development of motor fluctuations and dyskinesias. 21,22 These observations suggest that pharmacodynamic factors can contribute to the development of OFF periods as they do to the development of dyskinesias. Indeed, extending the half-life of levodopa with the addition of a COMT inhibitor to provide more continuous levels prevents or reverses motor fluctuations in a rodent model of PD.…”

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confidence: 94%

On‐Demand Therapy for OFF Episodes in Parkinson's Disease

et al. 2021

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A BS TRACT: Levodopa is the most effective therapy for Parkinson's disease; however, chronic treatment is associated with the development of OFF episodes, in which there is a return of parkinsonian features following a dose of levodopa and prior to the onset of benefit from the subsequent dose. OFF episodes can be a major source of disability for PD patients and frequently result in depression, apathy and an unwillingness to participate in social activities. Most currently available medical and surgical therapies are designed to reduce total daily OFF time but do not provide a rapid and reliable "on-demand" therapy for individual OFF episodes. Indeed, responses to individual doses of levodopa during an acute OFF episode are unreliable, frequently leading to partial-ON, delayed-ON, or no-ON responses even at different times in the same patient. There are now 3 therapies that are available for the on-demand treatment of OFF episodes; subcutaneous injection of apomorphine, sublingual apomorphine film, and inhaled levodopa. The first has not enjoyed widespread use in the PD community, whereas the latter 2 therapies have only recently been approved. This review will consider the currently available on-demand therapies and their potential advantages and disadvantages.

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“…Parkinson's disease (PD) is characterized by the loss of dopamine neurons, leading to motor and nonmotor dysfunction [1]. PD patients reached 5 million in the USA, affecting 1% of above 60-year-old population [2].…”

Section: Introductionmentioning

confidence: 99%

Lee Silverman Voice Treatment to Improve Speech in Parkinson’s Disease: A Systemic Review and Meta-Analysis

Huang

Kong

et al. 2021

Parkinson's Disease

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Background. Speech changes occur in the early stages of Parkinson’s disease (PD) and cause communication difficulties, leading to social isolation. Lee Silverman voice treatment (LSVT) is a speech therapy approach designed to improve patients’ language and voice capabilities. Objective. The effectiveness of the LSVT was compared with that of other speech interventions or no treatment to evaluate PD patients with dysarthria. Design. Systematic review with meta-analysis of randomized trials. Data Sources: PubMed, Embase, Cochrane Library, CNKI, and SinoMed library were searched from inception to December 2021 related to PD and LSVT. Method. Abstracts were screened and reviewed against the eligibility criteria (intervention group participants were PD assessed based on LSVT (LSVT Loud) and randomized control). Result. Ten randomized controlled trials were identified on speech symptoms in patients with PD. Compared with the respiratory therapy (RET) exercise, or no training group, a significant improvement was detected in the sound press level (SPL) after immediate treatment during the reading of vowel and rainbow passages and an increase in semitone standard deviation (STSD). Furthermore, the LSVT training significantly increased the participants’ scores on unified Parkinson’s disease rating scale (UPDRS-III) and speech intelligibility. Conclusion. This meta-analysis demonstrated the efficacy of LSVT in increasing vocal loudness and functional communication among individuals with PD. However, most studies included participants with mild-moderate PD. Thus, additional randomized controlled trials (RCTs) with large sample sizes are needed to validate the efficacy of LSVT in patients with different progressions of PD, including severe PD.

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Continuous Dopaminergic Stimulation as a Treatment for Parkinson's Disease: Current Status and Future Opportunities

Cited by 55 publications

References 133 publications

Continuous Subcutaneous Levodopa Delivery for Parkinson’s Disease: A Randomized Study

Continuous Subcutaneous Levodopa Delivery for Parkinson’s Disease: A Randomized Study

On‐Demand Therapy for OFF Episodes in Parkinson's Disease

Lee Silverman Voice Treatment to Improve Speech in Parkinson’s Disease: A Systemic Review and Meta-Analysis

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