Application of the concept of continuous dopaminergic stimulation for the management of Parkinson's disease

Continuous dopaminergic stimulation（CDS）is a prominent therapeutic concept for the treatment of Parkinson＇s disease（PD）,which proposes that continuous brain dopamine-receptor stimulation,rather than intermittent doses of oral L-dopa,prevents or manages L-dopa-induced dyskinesias（LIDs）.In the normal situation,dopaminergic neurons in the substantia nigra pars compacta fire tonically to keep the dopamine receptor stimulation at a steady-state level.But when the dopaminergic pathway is impaired,the dopamine receptor stimulation becomes intermittent or pulsatile.This pulsatile stimulation causes a series of gene and protein changes in striatal neurons,leading to alterations in the firing patterns of basal ganglia neurons that result in LIDs.Studies in animal models and clinical trials of PD have shown that approaches providing CDS,currently including patches,extended-release formulations of L-dopa or dopamine agonists,continuous delivery of apomorphine and duodenal L-dopa infusion,are associated with a decreased risk of LIDs.In this review,we summarize both preclinical and clinical evidence for the five methods that may provide CDS in theory and compare the advantages and disadvantages of these methods.

Continuous Apomorphine Infusion in Patients with Advanced Parkinson’s Disease with Varying Degrees of Functional Impairment

Introduction: Continuous apomorphine infusion (CAI) is effective in improving complications in advanced Parkinson’s disease (APD). The effectiveness and tolerance of CAI in patients with APD with varying degrees of functional impairment was studied. Methods: In this comparative observational study, consecutive APD who started treatment with CAI were included. They were classified into two groups of functional impairment: A) moderate (Schwab and England (S & E) = 60% - 80% and Hoehn and Yahr (H & Y) = 2 - 3;Group (A), and (B) severe (S & E 3;Group B). Clinical follow-up was performed with concomitant medication and CAI adjustment at 3, 6 and 12 months. Clinical evaluation included a dyskinesia diary and AIMS, S & E, NPI, NMSS and HADS questionnaires. Results: Eighteen patients participated (A = 9 and B = 9) with EP diagnosed 7 (A) and 13 (B) years before. Their baseline dose of levodopa was 728 mg (A) and 925 mg (B), which did not change during follow-up. Dopamine agonists were progressively reduced in both groups. Progressive titration of CAI resulted in abandonment of apomorphine bolus administration. Both groups experienced improvements in all variables, higher in group A;motor fluctuations = 69% (A), 53% (B);AIMS = 82% (A), 71 (B);S & E = 32% (A), 18% (B);NMS = 62% (A), 19% (B);NPI = 75% (A), 50% (B);HADS (anxiety) = 26% (A), 21% (B);HADS (depression) = 52% (A), 31% (B). Adverse effects were generally mild and resolved without reducing CAI dose. There were no withdrawals. Conclusions: Patients with APD and moderate functional impairment treated with CAI may obtain greater functional, cognitive and emotional improvement than patients more severely affected.

Why do‘OFF’periods still occur during continuous drug delivery in Parkinson’s disease?

Continuous drug delivery(CDD)is used in moderately advanced and late-stage Parkinson’s disease(PD)to control motor and non-motor fluctuations(‘OFF’periods).Transdermal rotigotine is indicated for early fluctuations,while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD.All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD.A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of‘OFF’periods.However,data suggest that despite their efficacy in reducing the number and duration of‘OFF’periods,these strategies still do not prevent‘OFF’periods in the middle to late stages of PD,thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation.Why these emergent‘OFF’periods still occur is unknown.In this review,we analyse the potential reasons for their persistence.The contribution of drug-and device-related involvement,and the problems related to site-specific drug delivery are analysed.We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent‘OFF’periods unresponsive to dopaminergic therapy delivered via CDD.