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

Translational Neurodegeneration 2022年第1期11卷 280-293页

作者： Silvia Rota Daniele Urso Daniel J.van Wamelen Valentina Leta Iro Boura Per Odin Alberto J.Espay Peter Jenner K.Ray Chaudhuri Department of Basic and Clinical Neurosciences Institute of PsychiatryPsychology and NeuroscienceKing’s College LondonLondonUK Parkinson’s Foundation Centre of Excellence King’s College HospitalLondonUK Department of Neuroimaging Institute of PsychiatryPsychology and NeuroscienceKing’s College LondonLondonUK Centre for Neurodegenerative Diseases and the Aging Brain Department of Clinical Research in NeurologyUniversity of Bari‘Aldo Moro“Pia Fondazione Cardinale G.Panico”73039 TricaseItaly Donders Institute for Brain Cognition and BehaviourDepartment of NeurologyRadboud University Medical CentreNijmegenThe Netherlands School of Medicine University of CreteCreteGreece Department of Neurology University Hospital of HeraklionCreteGreece Division of Neurology Department of Clinical Sciences LundLund UniversityLundSweden University of Cincinnati Gardner Neuroscience Institute Gardner Family Center for Parkinson’s Disease and Movement DisordersDepartment of NeurologyUniversity of CincinnatiCincinnatiOHUSA Institute of Pharmaceutical Sciences Faculty of Life Science and MedicineKing’s College LondonLondonUK.

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.

关键词： ‘OFF’periods continuous drug delivery continuous dopaminergic stimulation Rotigotine patch Subcutaneous apomorphine infusion Levodopa-carbidopa intestinal gel

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