Levodopa: Past, Present, and Future
Departments of Neurology, Molecular Pharmacology, and Physiology, University of South Florida, Tampa, FL 33606, USA. European Neurology
(Impact Factor: 1.36).
10/2008; 62(1):1-8. DOI: 10.1159/000215875
Levodopa has been the mainstay of treatment for Parkinson's disease (PD) for more than 40 years. During this time, researchers have strived to optimize levodopa formulations to minimize side effects, enhance central nervous system (CNS) bioavailability, and achieve stable therapeutic plasma levels. Current strategies include concomitant treatment with inhibitors of dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) to prolong the peripheral levodopa half-life and increase CNS bioavailability. Levodopa combined with DDC inhibition is the current standard method of delivering levodopa for symptomatic treatment of PD. Recent research suggests that continuous dopaminergic stimulation that more closely approximates physiological stimulation may delay or prevent the development of motor fluctuations ('wearing off') and dyskinesias. Strategies currently being used to achieve more continuous dopaminergic stimulation include the combination of an oral levodopa/DDC inhibitor with a COMT inhibitor and the enteral infusion of a levodopa gel formulation. Attempts are underway to develop oral and transdermal very long-acting levodopa preparations.
Available from: Peter Valkovic
- "(Aarsland et al 2003). Dopamine replacement with levodopa was first shown to reduce clinical symptoms of PD in the 1960s (Yahr et al 1969) and since then has remained the mainstay in the treatment of PD (Hauser 2009; Olanow et al 2004). While the majority of PD patients initially respond positively to conventional dopaminergic medication, during the disease progression and chronic L-dopa treatment, disabling mainly motor complications, including " OFF " periods (state of poor mobility and stiffness), " ON-OFF " phenomenon (unpredictable swing from mobility to immobility) and L-dopa-induced dyskinesias occur in most PD patients especially in advanced stages (Ahlskog & Muenter 2001). "
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ABSTRACT: OBJECTIVES: Levodopa is the gold standard of Parkinson’s disease (PD) treatment, but
is often associated with disabling motor complications in patients with advanced PD.
Levodopa/carbidopa intestinal gel (LCIG) infusion has been proved be beneficial on motor
complications in the short-term as well as in long-term follow-up. Therefore is becoming
an established therapeutic option for advanced PD patients with motor fluctuating
symptoms unresponsive to conventional treatment. The aim of our study was to evaluate
the impact of LCIG treatment to motor fluctuations.
METHODS: The assessments (performed at baseline and at a follow-up visit after PEG/J procedure
using UPDRS IV, MDS-UPDRS scales) were realised in 21 patients with advanced
stages of PD to analyse the LCIG efficacy in motor complications.
RESULTS: LCIG has demonstrated efficacy in reducing motor complications in advanced
PD patients. A notable reduction of “OFF“ time (p<0.0001) and “ON“ time with dyskinesias
(p=0.007) was observed in treated patients. Simultaneously, improvement of the
functional severity of dyskinesias was achieved (p=0.02). The significant improvement of
motor scores (UPDRS part III) in LCIG patients was estimated as well.
CONCLUSON: LCIG has demonstrated efficacy in reducing levodopa-associated motor
complications in patients with advanced PD as well as improvement of motor functions
evaluated by using UPDRS scores. LCIG is a useful treatment alternative recommended for
patients with motor fluctuations and dyskinesias inadequately responding to traditional
Available from: M. Sardina
- "zambongroup.com. therapy becomes less effective and motor complications , including dyskinesia and fluctuations, eventually develop . About 40% of patients will experience motor fluctuations and dyskinesia after 4–6 years of levodopa therapy . "
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ABSTRACT: Abstract: Background: Safinamide is a novel α-aminoamide with dopaminergic and non-dopaminergic properties developed as adjunctive therapy for patients with PD. Results from a 24-month double-blind controlled study suggested that as add-on to levodopa (and other PD medications) the benefits of safinamide on dyskinesia may be related to severity of dyskinesia at baseline.Objective: This post-hoc analysis further characterized the effects of safinamide on dyskinesia in mid- to late-stage PD patients.Methods: Patients were stratified by the presence or absence of dyskinesia at baseline, and by whether or not the dose of levodopa had been changed during the 24-month treatment period. Differences between safinamide and placebo were evaluated using the Wilcoxon rank-sum test.Results: For the overall treated population (with or without baseline dyskinesia), safinamide 100 mg/day significantly improved the dyskinesia rating scale score, compared with placebo, in the subgroup of patients with no change in levodopa dose (p = 0.0488). For patients with baseline dyskinesia, improvements over placebo were also significant (p = 0.0153) in patients with or without changes in levodopa dose, and nearly significant (p = 0.0546) in patients with no change in levodopa dose, suggesting that these improvements were not due to levodopa dose reductions.Conclusions: While no statistically significant difference in mean DRS scores was seen between safinamide and placebo in the original study population, the present post-hoc analysis helps to provide a meaningful interpretation of the long-term effects of safinamide on dyskinesia. These results may be related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, and are unlikely due to reduced dopaminergic stimulation.
- "Although the major metabolic pathway of levodopa is catalyzed by the aromatic l-amino acid decarboxylase (AADC), COMT enzyme expressed in extracerebral tissues is also significantly involved in the peripheral metabolism of levodopa (Hauser, 2009; Gárdián and Vécsei, 2010; Salat and Tolosa, 2013). Consequently, oral levodopa therapy has been improved using a combination of levodopa/AADC inhibitor plus a COMT inhibitor; this triple combination prolongs the half-life time of levodopa, increases its cerebral bioavailability and reduces its peripheral side effects (Kaakkola, 2000; Hauser, 2009; Olanow et al., 2009; Contin and Martinelli, 2010). However, the COMT inhibitors currently marketed (tolcapone and entacapone) exhibit important drawbacks that limit their clinical success (Keating and Lyseng-Williamson, 2005; Bonifácio et al., 2007; Lees, 2008) and, therefore, opicapone is emerging as a safer, more potent and longer-acting COMT inhibitor (Kiss et al., 2010; Almeida et al., 2013). "
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ABSTRACT: Opicapone is a novel potent, reversible and purely peripheral third generation catechol-O-methyltransferase inhibitor, currently under clinical trials as an adjunct to levodopa therapy for Parkinson's disease. To support additional non-clinical pharmacokinetic studies, a novel high-performance liquid chromatographic method coupled to a diode array detector (HPLC-DAD) to quantify opicapone and its active metabolite (BIA 9-1079) in rat plasma and tissues (liver and kidney) is herein reported. The analytes were extracted from rat samples through a deproteinization followed by liquid-liquid extraction. Chromatographic separation was achieved in less than 10 min on a reversed-phase C18 column, applying a gradient elution program with 0.05 M monosodium phosphate solution (pH 2.45 ± 0.05) and acetonitrile. Calibration curves were linear (r(2) ≥ 0.994) within the ranges of 0.04-6.0 µg/mL for both analytes in plasma, 0.04-4.0 µg/mL for opicapone in liver and kidney homogenates, and 0.07-4.0 µg/mL and 0.06-4.0 µg/mL for BIA 9-1079 in liver and kidney homogenates, respectively. The overall intra- and inter-day accuracy ranged from -12.68% to 7.70% and the imprecision values did not exceed 11.95%. This new HPLC-DAD assay was also successfully applied to quantify opicapone and BIA 9-1079 in a preliminary pharmacokinetic study. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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