From medications to surgery: advances in the treatment of motor complications in Parkinson’s disease

Abstract

Motor complications are responsible for the large burden of disability and poor quality of life in Parkinson’s disease (PD). The pulsatile nature of stimulation with oral dopaminergic therapies due to relatively short pharmacokinetic profiles and dysfunctional gastrointestinal absorption have been attributed to the development of PD motor complications. In this review, we will provide an overview of the pharmacologic and surgical therapies currently available and under investigation for the treatment of motor fluctuations and dyskinesia.

Motor and nonmotor symptoms in patients treated with 24-hour daily levodopa-carbidopa intestinal gel infusion: Analysis of the COmedication Study assessing Mono- and cOmbination therapy with levodopa-carbidopa inteStinal gel (COSMOS)

“…Oral levodopa has a short half-life and is poorly absorbed due to erratic gastric emptying, a problem that can become more paramount with age, leading to fluctuating levodopa levels in plasma [4][5][6]. Fluctuating levodopa concentrations cause pulsatile striatal dopamine receptor activation, which differs from typical continuous dopamine receptor activation under normal physiological circumstances [7,8].…”

Persistent Relief of Motor Symptoms in a Parkinsonian Mouse Model After Induction of LTD at Cortical Inputs to Indirect Pathway Striatal Neurons

“…In PD patients, DA replacement therapies induce persistent improvement in motor function, even after cessation of treatment, which is known as the long duration response (Hauser et al, 2009; Nagao and Patel, 2019) Our group and others have suggested that this persistent effect is mediated by DA modulation of corticostriatal synaptic strength (Anderson et al, 2014; Beeler et al, 2012). Therefore, we investigated the duration of motor improvement following oHFS/Quin treatment.…”

“…When DA is depleted in PD patients or animal models, DA replacement therapy takes a few days to reach maximal therapeutic effects, while cessation of treatment results in persistent relief of symptoms that lasts for days or even weeks. This important phenomenon in DA replacement therapy is known as the ‘long-duration response’ (LDR) (Hauser et al, 2009; Nagao and Patel, 2019). In these patients, the slow onset of therapeutic effects and the persistent motor improvement suggest that DA replacement promotes striatal synaptic plasticity, particularly at the principal excitatory inputs from motor cortex.…”

Real‐world considerations regarding the use of the combination of levodopa, carbidopa, and entacapone (Stalevo®) in Parkinson's disease

“…Controlled‐release levodopa is a theoretical response to this desideratum but, in practice, traditional approaches to the delivery of levodopa in a longer‐acting form have been associated with unpredictable absorption, substantial inter‐patient variability in pharmacokinetics, and no extension of levodopa half‐life. Recent innovations in this area have emphasized formulation technology designed to provide immediate and delayed release of levodopa and ancillary agents [4]. Some of these novel formulations have produced encouraging preliminary findings but none can be regarded as a conclusive breakthrough.…”