Levodopa: Past, Present, and Future
ABSTRACT 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.
- SourceAvailable from: Elisa Garbayo
[Show abstract] [Hide abstract]
- "At present, there is no cure for PD and treatments are merely symptomatic. Current therapy based on a dopamine replacement strategy consists mainly on the oral administration of the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but in long-term administration some secondary effects may appear (Ecker et al., 2009; Hauser, 2009). Novel drug and cell therapy approaches require extensive evaluation before routinely being used in humans (Poewe et al., 2012; Lindvall, 2013). "
ABSTRACT: Parkinson's disease (PD) is the second most frequent neurodegenerative disorder afflicting 2% of the population older than 65 years worldwide. Recently, brain organotypic slices have been used to model neurodegenerative disorders, including PD. They conserve brain three-dimensional architecture, synaptic connectivity and its microenvironment. This model has allowed researchers a simple and rapid method to observe cellular interactions and mechanisms. In the present study, we developed an organotypic PD model from rat brains that includes all the areas involved in the nigrostriatal pathway in a single slice preparation, without using neurotoxins to induce the dopaminergic lesion. The mechanical transection of the nigrostriatal pathway obtained during slice preparation induced PD-like histopathology. Progressive nigrostriatal degeneration was monitored combining innovative approaches, such as diffusion tensor magnetic resonance imaging (DT-RMI) to follow fiber degeneration and mass spectrometry to quantify striatal dopamine content, together with bright field and fluorescence microscopy imaging. A substantia nigra dopaminergic cell number decrease was observed by immunohistochemistry against rat tyrosine-hydroxylase (TH) reaching 80% after two days in culture associated with a 30% decrease of striatal TH-positive fiber density, a 15% loss of striatal dopamine content quantified by mass spectrometry and a 70% reduction of nigrostriatal fiber fractional anisotropy quantified by DT-RMI. In addition, a significant decline of medium spiny neuron density was observed from day 7 to 16. These sagittal organotypic slices could be used to study the early stage of PD, namely dopaminergic degeneration, and the late stage of the pathology with dopaminergic and GABAergic neuron loss. This novel model might improve the understanding of PD and may represent a promising tool to refine the evaluation of new therapeutic approaches.Neuroscience 10/2013; 256. DOI:10.1016/j.neuroscience.2013.10.021 · 3.33 Impact Factor
[Show abstract] [Hide abstract]
- "PD is currently treated primarily with various DA replacement pharmacological agents either as monotherapy or in combination with a dopamine decarboxylation inhibitor such as carbidopa or benserazide. This therapy is very effective for the first few years of the illness, but undesirable side effects may appear later (Ecker et al., 2009; Hauser, 2009). Interestingly, neuronal degeneration in this pathology is quite localized at first, so cell therapy has been explored as an alternative approach. "
ABSTRACT: Stem cell therapy is a promising treatment for neurological disorders such as cerebral ischemia, Parkinson's disease and Huntington's disease. In recent years, many clinical trials with various cell types have been performed often showing mixed results. Major problems with cell therapies are the limited cell availability and engraftment and the reduced integration of grafted cells into the host tissue. Stem cell-based therapies can provide a limitless source of cells but survival and differentiation remain a drawback. An improved understanding of the behaviour of stem cells and their interaction with the host tissue, upon implantation, is needed to maximize the therapeutic potential of stem cells in neurological disorders. Organotypic cultures made from brain slices from specific brain regions that can be kept in culture for several weeks after injecting molecules or cells represent a remarkable tool to address these issues. This model allows the researcher to monitor/assess the behaviour and responses of both the endogenous as well as the implanted cells and their interaction with the microenvironment leading to cell engraftment. Moreover, organotypic cultures could be useful to partially model the pathological state of a disease in the brain and to study graft-host interactions prior to testing such grafts for pre-clinical applications. Finally, they can be used to test the therapeutic potential of stem cells when combined with scaffolds, or other therapeutic enhancers, among other aspects, needed to develop novel successful therapeutic strategies or improve on existing ones.Experimental Neurology 07/2013; 248. DOI:10.1016/j.expneurol.2013.07.012 · 4.62 Impact Factor
- "Mavoglurant (AFQ056) is a noncompetitive antagonist at the metabotropic glutamate receptor 5 (mGluR5) and is currently under clinical development for the treatment of Parkinson disease–associated levodopa-induced dyskinesia (PD-LID). Levodopa has been used for many years as an effective treatment of Parkinson disease (PD) and still remains the gold standard of care (Hauser, 2009). However, its clinical use is hampered by the high incidence of dyskinesia, which affects approximately 40% of patients with PD after 4 to 6 years of treatment with levodopa (Ahlskog and Muenter, 2001). "
Conference Paper: Absorption and disposition of mavoglurant (AFQ056) in healthy volunteers[Show abstract] [Hide abstract]
ABSTRACT: Mavoglurant (AFQ056) is a selective mGluR5 antagonist under development for treatment of Parkinson`s disease-associated L-Dopa-induced dyskinesia and Fragile X syndrome. In the present work, the absorption and disposition of [14C]-radiolabeled mavoglurant were investigated in four healthy male volunteers after a single oral dose of 200 mg. Total radioactivity was determined in plasma, urine and feces. Mavoglurant was quantified in plasma by LC-MS/MS. Metabolite profiles were achieved in plasma and excreta by HPLC and radioactivity detection. The mavoglurant metabolite structures were elucidated by mass spectrometry, wet-chemical and enzymatic methods, NMR and comparison with reference compounds. For the metabolite profiling, the novel linked platecrane automated system was used, increasing significantly throughput. Sample analyses for this study were completed in a more efficient manner, as compared when using standard methods. Results: [14C]mavoglurant was absorbed with a Tmax of 2.6h and an oral bioavailability of ≥ 50% .The biotransformation of mavoglurant involved two main pathways: A) hydroxylation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6); B) hydroxylation of the phenyl ring leading to a hydroxylated metabolite (M3). The elimination of mavoglurant was fast and occurred predominantly by oxidative metabolism. The subjects were mainly exposed to mavoglurant and five metabolites (M6, M15, M18, M14, M30). Drug related material was excreted mostly in feces (58.6% of dose) and urine (36.7% of dose). After 7 days, the balance of excretion was almost complete (95.3% of dose).19th MDO and 12th European Regional International society for the study of xenobiotics Meeting;