ArticleLiterature Review

Long term motor complications of levodopa: Clinical features, mechanisms, and management strategies

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Abstract

Levodopa is the most effective symptomatic treatment of Parkinson's disease. However, after an initial period of dramatic benefit, several limitations become apparent including, "dopa resistant" motor symptoms (postural abnormalities, freezing episodes, speech impairment), "dopa resistant" non-motor signs (autonomic dysfunction, mood and cognitive impairment, etc), and/or drug related side effects (especially psychosis, motor fluctuations, and dyskinesias). Motor complications include fluctuations, dyskinesias, and dystonias. They can be very disabling and difficult to treat. Therefore, strategies should ideally be developed to prevent them. Though mechanisms underlying motor complications are only partially understood, recent work has revealed the importance of pulsatile stimulation of postsynaptic dopamine receptors and the disease severity. As a result of intermittent stimulation there occurs a cascade of changes in cell signalling leading to upregulation of the N-methyl-D-aspartate subtype of gamma-aminobutryric acid-ergic neurones. Modified preparations of levodopa (controlled release preparations, liquid levodopa), catecholamine-o-methyltransferase inhibitors, dopamine agonists, amantidine, and various neurosurgical approaches have been used in the prevention and/or treatment of motor complications. Current management of motor complications is less than satisfactory. With better understanding of the pathogenetic mechanisms, it is hoped that future therapeutic strategies will provide a safer and targeted treatment.

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... Même si la Lévodopa reste la molécule la plus utilisée et la plus efficace pour la prise en charge de la maladie de Parkinson, celle-ci n'est pas exempte d'effets secondaires. D'une part, son efficacité décroit avec le temps, d'autre part de nouveaux symptômes moteurs (mouvements anormaux involontaires et contractions involontaires des muscles) et des complications peuvent apparaître comme des vomissements, une anorexie, une hypotension orthostatique (chute de la pression artérielle lors du passage de la position allongée à la position debout) [34]. Afin de soulager ces effets secondaires, des traitements alternatifs, actuellement en cours d'étude, agissent directement au niveau des récepteurs dopaminergiques via l'utilisation d'agonistes de la dopamine à longue demi-vie [35]. ...
... In vivo assays will be performed to evaluate GNL-loaded functional-652 ized NPs and their ability to cross the BBB and target neurons of interest. Indeed, Swastika 653 et al. recently demonstrated that suitably designed NLs would pass the BBB [30], of which 654 the tight junctions between endothelial cells greatly limit the cerebral passage of numer-655 ous compounds [33][34][35][36]. Therefore, the design and functionalization of new NL/GNLs fol-656 lowed by their formulation as nanoparticles would overcome this limitation and improve 657 the bioavailability of the active substances, through an increase in stealth and their ability 658 to target pathological sites, notably in order to modulate the pH and lysosomal activity. ...
... This hydrophilic nonionic surfactant and emulsifier is usually used at 1% (w/v) to stabilize aqueous formulations for parenteral administration. It is speculated that weak interactions control the formation of an adsorbed monolayer of polysorbate 80 onto the nanoparticle surface [34]. As a coating, polysorbate 80 presents some clinical advantages such as decreasing the drug dosage (therefore reducing the potential side effects) or increasing its viability. ...
Thesis
Cette thèse a porté sur le développement de nouveaux vecteurs thérapeutiques pour le traitement de la maladie de Parkinson. La maladie de Parkinson est une maladie neurodégénérative qui se caractérise notamment par la présence d’inclusions protéiques intracytoplasmiques appelées « corps de Lewy ». L'une des causes de la formation de ces « corps de Lewy », principalement composés d’α-synucléine, serait l’atteinte du système autophagie-lysosome, nécessaire à la dégradation des composants cellulaires. Le rétablissement des fonctions de l’autophagie constitue donc une cible thérapeutique intéressante pour lutter contre la maladie de Parkinson. Une approche interdisciplinaire a permis de travailler sur les diverses étapes de la recherche à visée thérapeutique, de la synthèse chimique de substances actives à leur nano-formulation, puis à l’évaluation biologique de ces nanovecteurs. Premièrement, les propriétés biologiques de restauration du pH lysosomal des nanoparticules de poly(acide lactique-co-glycolique) (PLGA) ont été étudiées. Cette première partie a permis de conclure que ces nanoparticules possédaient une activité neuroprotectrice, tout en améliorant la synucléinopathie et un rétablissement de la fonction lysosomale chez un modèle murin de la maladie de Parkinson. Deuxièmement, l’effet thérapeutique d’une substance active reconnue comme neuroprotectrice, le tréhalose, a été évalué in-vitro sur une lignée cellulaire (BE (2)-M17), notamment pour sa capacité d’activation de l’autophagie. Des dérivés nucléolipide-tréhalose (appelés GlycoNucléoLipides ou GNL) ont donc été développés et synthétisés avant leur encapsulation à l’intérieur de nanoparticules de PLGA. Ces GNL ont également montré leur capacité d’auto-assemblage pour former des nanoparticules solides lipidiques (appelées SLN) capables, comme leurs analogues de PLGA, de traverser les membranes cellulaires et d’induire une activation de l’autophagie.
... Long-term levodopa use is associated with complications such as motor fluctuations, dyskinesia and dystonia (Table 3). 25,28 Dyskinesia and motor fluctuations affect 40% of patients after 4-6 years of levodopa use. 29 Though more common in younger-onset PD, most patients taking levodopa will experience these complications. ...
... 29 Though more common in younger-onset PD, most patients taking levodopa will experience these complications. 24,28 There has been much debate about the early use of levodopa. In younger patients who will have the disease for many years and are more likely to develop longterm complications, there has been a trend to delay levodopa therapy as long as possible. ...
... Smaller, more frequent dosing may also help. 28 Changing to a controlled-release formulation could theoretically improve fluctuations; however, studies have shown no difference in symptoms compared to immediate-release preparations. 32 Adjunctive agents such as dopamine agonists, catechol-o-methyltransferase (COMT) inhibitors and monoamine oxidase-B (MAO-B) inhibitors have been shown to improve fluctuations. ...
Article
Parkinson’s disease is a chronic neurodegenerative disorder that mainly affects older people. It is predominately recognised as a movement disorder; however, the non‐motor symptoms are gaining increased recognition. Treating both motor and non‐motor symptoms can be challenging. Co‐morbidities, in particular dementia, polypharmacy and an increased susceptibility to adverse medication effects often necessitate a different approach to management compared to younger patients. In older people, the mainstay of treatment for motor symptoms is levodopa. However, long‐term side‐effects including motor fluctuations and dyskinesia can be severely disabling and may require the addition of adjunctive agents including dopamine agonists, catechol‐o‐methyltransferase inhibitors, monoamine oxidase‐B inhibitors and amantadine. Medications can significantly improve symptoms; however, optimal management of motor and non‐motor symptoms usually requires a multidisciplinary approach. In this article we present an evidence‐based review of Parkinson’s disease treatments and guidance to improve clinical management and outcomes in older people.
... Long-term use with L-DOPA in PD patients can evoke disabling involuntary uncontrolled chorea-like movements or dystonias, collectively termed L-DOPA-induced dyskinesias (LIDs) [167,168]. The mechanisms behind these LIDs remain to be fully elucidated, but aberrant glutamate signalling is implicated [169], and supported by the weak NMDA receptor antagonist amantadine being one of few drugs clinically used in the fight against LID [170]. ...
... The impact of synucleinopathies on olfaction have been recently highlighted by the deficits seen when AAV-α-synuclein is injected into the olfactory bulb [118]. This link is further supported by studies reporting olfactory impairment following the injection of PFFs into the sublaterodorsal tegmental nucleus, gut and olfactory bulb [168,175,176]. However, whether olfaction is affected in the striatally injected PFF model of PD is not yet known. ...
Article
Full-text available
Parkinson’s disease (PD) is a complex, multisystem disorder characterised by alpha synuclein pathology, degeneration of nigrostriatal dopaminergic neurons, multifactorial pathogenetic mechanisms and expression of a plethora of motor and non-motor symptoms. Animal models of PD have already been instructive in helping us unravel some of these aspects. However, much remains to be discovered, requiring continued interrogation by the research community. In contrast to the situation for many neurological disorders, PD benefits from of a wide range of available animal models (pharmacological, toxin, genetic and alpha-synuclein) but this makes selection of the optimal one for a given study difficult. This is especially so when a study demands a model that displays a specific combination of features. While many excellent reviews of animal models already exist, this review takes a different approach with the intention of more readily informing this decision-making process. We have considered each feature of PD in turn - aetiology, pathology, pathogenesis, motor dysfunctions and non-motor symptoms - highlighting those animal models that replicate each. By compiling easily accessible tables and figures, we aim to provide the reader with a simple, go-to resource for selecting the optimal animal model of PD to suit their research needs.
... [1][2][3][4] Various retrospective, communitybased, and young-onset PD studies indicate that the majority of patients with PD experience motor complications within 5-9 years of initial levodopa therapy. [5][6][7][8][9] More recent randomized studies of levodopa and other treatments of PD, however, have found that motor complications can emerge much earlier; one such study showed that 17% of patients experience these symptoms after only 9 months of treatment ( Table 1). [10][11][12] Motor complications profoundly affect patients; in a study of 173 consecutive patients with advanced PD of more than 6 years duration at a treatment center in the UK, fluctuating response to medication was ranked the most troublesome symptom. ...
Article
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In Parkinson’s disease (PD), OFF episodes continue to present a serious burden for patients, and their effective management remains a substantial unmet clinical need. Understanding of the pathophysiology of OFF episodes has advanced in recent years, providing valuable insights for improved treatments. OFF episodes generally appear 3–5 years after starting levodopa treatment, but can begin much earlier. They are characterized by motor symptoms (including tremor, rigidity, slowness, incoordination, and weakness) and are almost always associated with some non-motor symptoms (including psychological symptoms, pain, urinary problems, swallowing difficulties, and shortness of breath). In PD, higher doses of levodopa are associated with increased risk of motor and non-motor complications, which are notable limitations for longterm therapy. Their occurrence is associated with intermittent levodopa delivery and consequent fluctuating plasma levels. These issues can be offset using lower levodopa doses where possible, incremental dose increases, and combinations of levodopa with other pharmacological agents. OFF episodes in PD can be caused by gastroparesis and/or by Helicobacter pylori infection, which delays delivery of levodopa. These issues can be addressed using new formulations for continuous intrajejunal administration. In addition, pen injector, intranasal, and inhaled dosing systems have been studied and may provide relief via non-intestinal routes. Other approaches include deep-brain stimulation, which is effective but is restricted by costs and potential adverse events. This report presents the highlights of a satellite symposium held at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD™ 2019), Lisbon, Portugal, which discussed the nature of OFF episodes in PD, associated risk factors and the potential of current and future treatments to effectively manage them and increase ON time.
... Since its development in the late 1960s, levodopa (L-3,4-dihydroxyphenylalanine), as a direct precursor to DA, has remained the most efficacious symptomatic therapy for PD 5 . With prolonged treatment, however, the clinical response to levodopa progressively declines (i.e., wearing-off phenomenon) and leads to the occurrence of motor complications, including fluctuations, dyskinesia, and dystonia 6,7 . Hence, it is crucial to uncover levodopa-induced neural effects and functional brain reorganisation to provide new insights into optimising PD therapeutics. ...
Preprint
Full-text available
Levodopa has remained the mainstay of medical therapy for Parkinson's disease since its development in the 1980s. However, long-term medication use is associated with declining clinical efficacy and the emergence of motor complications. Unveiling the effects of levodopa on brain functional reorganisation at a relatively early treatment phase is therefore imperative to inform the optimisation of Parkinson's therapeutics. In this study, we comprehensively investigated levodopa's modulation on the resting-state functional connectivity in the cortico-basal ganglia-cerebellum system at regional and network levels, with dual cross-sectional and longitudinal designs. The data was extracted from the Parkinson's Progression Marker Initiative (PPMI) dataset. The cross-sectional patient groups comprised 17 Parkinson's patients on stable levodopa medication and 15 drug-naive patients, while the longitudinal set included 14 Parkinson's patients measured at both drug-naive and levodopa-medicated conditions. With nodes defined across cortical, basal ganglia, and cerebellar networks, we conducted univariate comparisons of the internodal connectivity strength between the medication conditions using nonparametric permutation. At the network level, we computed multivariate combinations of individual connections within and between the networks, followed by an assessment of their discriminative capabilities on patients' medication class using supervised machine learning. The univariate seed-based approach showed no statistically significant effect of levodopa in either dataset. However, the network connectivity pattern between basal ganglia and cerebellum displayed a robust classification power in the longitudinal dataset and a similar trend was observed in the cross-sectional. The role of cerebellum is often overlooked in previous functional integration investigations of Parkinson's disease and levodopa effects. Considering the recent evidence suggesting the bidirectional communications between cerebellum and basal ganglia networks, our study provides further insight into the importance of the inter-network functional connectivity in Parkinson's, as well as in the functional and plastic processes following levodopa medication.
... People with Parkinson's disease generally use pain relievers such as AP. Long-term use of L-dopa and AP can have a toxic effect on the body, so it is important to control their concentration in the body [66]. This sensor is made from a C 60 -functionalized CNT composite with a sensor manufacturing method similar to [50,51]. ...
Article
Full-text available
Carbon nanomaterials have attracted researchers in pharmaceutical applications due to their outstanding properties and flexible dimensional structures. Carbon nanomaterials (CNMs) have electrical properties, high thermal surface area, and high cellular internalization, making them suitable for drug and gene delivery, antioxidants, bioimaging, biosensing, and tissue engineering applications. There are various types of carbon nanomaterials including graphene, carbon nanotubes, fullerenes, nanodiamond, quantum dots and many more that have interesting applications in the future. The functionalization of the carbon nanomaterial surface could modify its chemical and physical properties, as well as improve drug loading capacity, biocompatibility, suppress immune response and have the ability to direct drug delivery to the targeted site. Carbon nanomaterials could also be fabricated into composites with proteins and drugs to reduce toxicity and increase effectiveness in the pharmaceutical field. Thus, carbon nanomaterials are very effective for applications in pharmaceutical or biomedical systems. This review will demonstrate the extraordinary properties of nanocarbon materials that can be used in pharmaceutical applications.
... This diminished effect of a levodopa dose has been termed an OFF episode, and these fluctuate with benefit (or ON) of subsequent doses [4]. OFF episodes appear within 1-2 years in some patients, by 5 years in 50 % of patients, and in most patients beyond 9 years [5,6]. OFF episodes continue to be present despite daily adjunctive medications and increasing dose and frequency of levodopa [7][8][9][10][11][12][13][14]. ...
Article
Full-text available
We discuss a shift in the treatment paradigm for OFF episode management in patients with Parkinson’s disease, based on clinical experience in the United States (US). Three “on-demand” treatments are currently available in the US as follows: subcutaneous apomorphine, levodopa inhalation powder, and sublingual apomorphine. We empirically propose that “on-demand” treatments can be utilized as a complementary treatment when OFF episodes emerge and can be utilized when needed rather than reserving these treatments only until other treatment approaches (adjustment of baseline treatment and/or addition of adjunctive treatment with “ON-extenders”) have failed. Current treatment approaches combine “ON-extenders” with increasing levodopa dosing and/or frequency to treat OFF episodes. Yet, OFF episodes often persist, with a substantial amount of daily OFF time. OFF episode treatment is hindered by variable gastrointestinal (GI) absorption of oral levodopa, reflecting GI dysmotility and protein competition. Novel “on-demand” treatments bypass the gut and can improve OFF symptoms more rapidly and reliably than oral levodopa. With the emergence of novel “on-demand” treatments, we conclude that a shift in treatment paradigm to the earlier, complementary use of these medications be considered.
... However, levodopa therapy efficacy decreases with time. Moreover, it is problematic in chronic settings due to treatment-induced dyskinesia and other levodopa-induced motor symptoms such as postural abnormalities and speech impairments [11]. Moreover, levodopa treatment involves non-motor side effects such as nausea, depression, insomnia, and gambling addiction [12]. ...
Article
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Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D2 (D2R) has been shown to be involved in central nervous system diseases. While different D2R-targeting drugs have been approved by the FDA, they all suffer from major drawbacks due to promiscuous receptor activity leading to adverse effects. Increasing the number of potential D2R-targeting drug candidates bears the possibility of discovering molecules with less severe side-effect profiles. In dire need of novel D2R ligands for drug development, combined in silico/in vitro approaches have been shown to be efficient strategies. In this study, in silico pharmacophore models were generated utilizing both ligand- and structure-based approaches. Subsequently, different databases were screened for novel D2R ligands. Selected virtual hits were investigated in vitro, quantifying their binding affinity towards D2R. This workflow successfully identified six novel D2R ligands exerting micro- to nanomolar (most active compound KI = 4.1 nM) activities. Thus, the four pharmacophore models showed prospective true-positive hit rates in between 4.5% and 12%. The developed workflow and identified ligands could aid in developing novel drug candidates for D2R-associated pathologies.
... When the patient missed the daily dose, no worsening of symptoms can be detected. This is because levodopa is still available in the presynaptic sites but, as the disease progress, the symptoms getting worse due to extensive destruction of the neurons and the patient will suffer from symptoms longer time before the next dose comes 27 Dopamine agonists are also advised to be given to Parkinson disease. As they stimulate the dopamine action in the brain. ...
... The standard drug levodopa (LD) is the only approved symptomatic treatment for PD but shows several problems: "dopa-resistant" motor symptoms (postural abnormalities, freezing episodes, and speech impairment) and non-motor symptoms, such as autonomic dysfunction, mood and cognitive impairment, and/or drug-related side effects (especially psychosis, motor fluctuations, and dyskinesias) [50,51]. It would be useful to identify a treatment that could complement LD, allowing for the reduction of the LD dose while preventing the various motor and nonmotor symptoms that sometimes accompany this reduction. ...
Article
Full-text available
Parkinson’s disease (PD), a progressive neurodegenerative disorder, affects dopaminergic neurons. Oxidative stress and gut damage play critical roles in PD pathogenesis. Inhibition of oxidative stress and gut damage can prevent neuronal death and delay PD progression. The objective of this study was to evaluate the therapeutic effect of embelin or the combination with levodopa (LD) in a rotenone-induced PD mouse model. At the end of experimentation, the mice were sacrificed and the midbrain was used to evaluate various biochemical parameters, such as nitric oxide, peroxynitrite, urea, and lipid peroxidation. In the substantia nigra (midbrain), tyrosine hydroxylase (TH) expression was examined by immunohistochemistry, and Nurr1 expression was evaluated by western blotting. Gut histopathology was evaluated on tissue sections stained with hematoxylin and eosin. In silico molecular docking studies of embelin and α-synuclein (α-syn) fibrils were also performed. Embelin alone or in combination with LD ameliorated oxidative stress and gut damage. TH and Nurr1 protein levels were also significantly restored. Docking studies confirmed the affinity of embelin toward α-syn. Taken together, embelin could be a promising drug for the treatment of PD, especially when combined with LD.
... Levodopa is the standard of care drug most commonly prescribed to patients with PD (Jankovic and Stacy 2007). However, the clinical symptoms are not fully controlled and resolved with Levadopa and/or other drugs (Thanvi and Lo 2004;Toth et al. 2008;Redenšek et al. 2019). Thus, novel therapeutic approaches should be advanced. ...
Article
Full-text available
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurodegeneration and deposition of alpha-synuclein. Mechanisms associated with PD etiology include oxidative stress, apoptosis, autophagy, and abnormalities in neurotransmission, to name a few. Drugs used to treat PD have shown significant limitations in their efficacy. Therefore, recent focus has been placed on the potential of active plant ingredients as alternative, complementary, and efficient treatments. Berberine is an isoquinoline alkaloid that has shown promise as a pharmacological treatment in PD, given its ability to modulate several molecular pathway associated with the disease. Here, we review contemporary knowledge supporting the need to further characterize berberine as a potential treatment for PD.
... Lack of dopamine causes motor system malfunctions such as bradykinesia, rigidity, tremor, gait disorders and postural instability with the consequent high risk of fall [2]. A temporary inhibition of symptoms occurs after taking levodopa (L-DOPA), which is currently the most effective symptomatic treatment [3,4]. ...
Article
Full-text available
The synthetic indices are widely used to describe balance and stability during gait. Some of these are employed to describe the gait features in Parkinson’s disease (PD). However, the results are sometimes inconsistent, and the same indices are rarely used to compare the individuals affected by PD before and after levodopa intake (OFF and ON condition, respectively). Our aim was to investigate which synthetic measure among Harmonic Ratio, Jerk Ratio, Golden Ratio and Trunk Displacement Index is representative of gait stability and harmony, and which of these are more sensitive to the variations between OFF and ON condition. We found that all indices, except the Jerk Ratio, significantly improve after levodopa. Only the improvement of the Trunk Displacement Index showed a direct correlation with the motor improvement measured through the clinical scale UPDRS-III (Unified Parkinson’s Disease Rating Scale–part III). In conclusion, we suggest that the synthetic indices can be useful to detect motor changes induced by, but not all of them clearly correlate with the clinical changes achieved with the levodopa administration. In our analysis, only the Trunk Displacement Index was able to show a clear relationship with the PD clinical motor improvement.
... The absence of dopamine produces several disorders, including motor and cognitive disabilities for PD patients. There is no definite cure for PD, and existing pharmacological treatments cause several side effects [1,2]. As a complementary therapy for reducing the complications of PD and improving the quality of life, technological-based interventions and aiding devices are recommended. ...
Article
Full-text available
Parkinson's Disease (PD) is a neurodegenerative disorder that causes movement and behavioral problems. Pharmacological advancements for preventing disease progression have limited success for many PD patients; therefore, supportive care is necessary. The advancement of the digital world and the revolution of computerized applications pave the way for a better understanding of PD and inventing technological apparatus for helping PD patients to provide them a more normal life. In this review, the most recent technological advancements regarding the rehabilitation, monitoring, and early prognosis of PD are presented. Furthermore, the possible neurological mechanisms responsible for the positive effects of technological-based interventions are discussed.
... Also, from the literature survey, the percentage of PD diagnostic error is identified [16]. A prolonged levodopa medication in a misdiagnosed patient can create problems worse than PD [17]. Despite clinical trials, diagnosis of motor symptoms with a wide number of new and diverse techniques have the potential to early diagnostic landscape [18,19]. ...
Article
Full-text available
This paper investigates the objective and quantitative benefits of using wireless Inertial Measurement Unit (IMU) sensors in combination with Internet of Things (IoT) for measuring the resting tremor severity in Parkinson’s disease (PD) subjects to aid monitoring and prognostic purposes. Detection of tremor episodes in PD subjects using automated devices will be helpful in the early diagnosis of the disease. Thus, profound research has been reported in the development of various sensors to analyze PD tremors. However, majority of these devices are designed to be used in controlled lab environment, limiting the diagnosis in daily living conditions. In this research, a wearable glove with IMU sensor and wireless device is designed to collect the tremor intensity and disseminate the data 24/7 (Note: 10 days observation period) to the clinician with the help of IoT medium. This will assist the clinician in providing Unified Parkinson’s Disease score scale (MDS-UPDRS) score recommended by the Movement Disorder Society. 30 PD subjects from SRM Medical College Hospital and Research Centre, who were diagnosed with stage-1 PD as per MDS-UPDRS score, were investigated to find the resting tremor frequency. In this study majority of them has been diagnosed to have resting tremor in the frequency range of 4–6 Hz. The Bland Altman’s analysis for proportional bias and linear regression analysis was performed. The viability of continuous monitoring was comprehended by comparing the MDS-UPDRS score obtained using wearable IMU sensor and MDS-UPDRS score given by Clinician.
... Levodopa (L-DOPA), a precursor of dopamine (DA), is used as a symptom-relieving treatment for Parkinson's disease (PD) (Poewe et al., 2010). The usage of L-DOPA for PD is still debated due to its side effects with long-term treatment (Thanvi and Lo, 2004;Fahn, 2005;Lipski et al., 2011). Several researchers suggested that L-DOPA might be harmful to SNc cells by a mechanism that probably involves oxidative stress (Pardo et al., 1995;Carvey et al., 1997;Takashima et al., 1999). ...
Article
Full-text available
Parkinson's disease (PD) is caused by the progressive loss of dopaminergic cells in substantia nigra pars compacta (SNc). The root cause of this cell loss in PD is still not decisively elucidated. A recent line of thinking has traced the cause of PD neurodegeneration to metabolic deficiency. Levodopa (L-DOPA), a precursor of dopamine, used as a symptom-relieving treatment for PD, leads to positive and negative outcomes. Several researchers inferred that L-DOPA might be harmful to SNc cells due to oxidative stress. The role of L-DOPA in the course of the PD pathogenesis is still debatable. We hypothesize that energy deficiency can lead to L-DOPA-induced toxicity in two ways: by promoting dopamine-induced oxidative stress and by exacerbating excitotoxicity in SNc. We present a systems-level computational model of SNc-striatum, which will help us understand the mechanism behind neurodegeneration postulated above and provide insights into developing disease-modifying therapeutics. It was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During L-DOPA therapy, it was observed that higher L-DOPA dosage results in increased loss of terminals in SNc. It was also observed that co-administration of L-DOPA and glutathione (antioxidant) evades L-DOPA-induced toxicity in SNc neurons. Our proposed model of the SNc-striatum system is the first of its kind, where SNc neurons were modeled at a biophysical level, and striatal neurons were modeled at a spiking level. We show that our proposed model was able to capture L-DOPA-induced toxicity in SNc, caused by energy deficiency.
... For example, levodopa is a common medicine that is also the most effective treatment for Parkinson's disease (Jankovic and Stacy 2007). However, it has been documented that consumption of levodopa results in various complications (Thanvi and Lo 2004;Toth et al. 2008). ...
Article
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Long-term exposure to organophosphates might result in neurodegenerative diseases, comprising Parkinson’s disease. Malathion is an organophosphate pesticide with high neurotoxicity. Oxidative stress, apoptosis, and α-synuclein accumulation are important underlying mechanisms in Parkinson’s disease. According to studies, crocin, an active constituent of saffron, has anti-apoptotic, anti-inflammatory, and antioxidant properties. Thus, the effect of crocin on malathion-induced striatal biochemical deficits in rats was investigated in this study. Six groups of male Wistar rats were used: 1. control (normal saline); 2. malathion (100 mg/kg/day, i.p.); 3. crocin (10 mg/kg/day, i.p.) + malathion; 4. levodopa (10 mg/kg/day, i.p.) + malathion; 5. crocin (40 mg/kg/day, i.p.); and 6. polyethylene glycol (PEG) (vehicle of levodopa) groups. The drugs were administered for 28 days. The amounts of Bcl-2, Bax, and caspases 3, 8, and 9 proteins in the striatum were measured by western blotting. Also, the amounts of protein and mRNA level of the α-synuclein in striatum tissue were measured by western blotting and RT-qPCR methods. Malathion induced apoptosis by increasing the amount of Bax/Bcl2 ratio and caspases 3 and 9 proteins in rat striatum tissue. It also increased the protein and mRNA level of α-synuclein in striatal tissue. Co-administration of crocin or levodopa with malathion inhibited the toxic effects of malathion on striatal tissue. Crocin ameliorates the neurotoxic effect of malathion by its anti-apoptotic activity and regulating the expression of proteins involved in Parkinson’s disease pathogenesis. As a result, crocin has the potential to be used as a treatment for malathion-induced neurotoxicity.
... 4,5 Motor fluctuations can affect approximately 50% of patients within the first five years of initiating levodopa therapy and as early as one to two years . [6][7][8][9] The symptoms of wearing off generally present as predictable motor fluctuations and can even occur within a few hours after each dose of levodopa. ...
Article
Objective To provide a review of opicapone as a treatment for end-of-dose wearing off associated with long-term levodopa therapy in patients with Parkinson’s disease (PD). Data Sources PubMed, Web of Science, and Google Scholar were searched for relevant literature using the following terms: management, treatment, opicapone, BIA 9-1067, entacapone, and tolcapone. Current guidelines and the manufacturer’s package inserts were also reviewed. Study Selection/Data Extraction Recent literature and published studies of opicapone in the management of wearing off. Data Synthesis Long-term use of levodopa is associated with known complications of motor fluctuations and dyskinesia. The addition of a drug with fewer daily administrations may reduce the complexity of the current medication regimen, improve adherence, and reduce the risk of adverse events in older people with PD. The Food and Drug Administration (FDA) approved a new catechol- O -methyltransferase (COMT) inhibitor opicapone in combination with levodopa/carbidopa to treat wearing off in PD patients on April 24, 2020. Conclusion Opicapone offers patients with PD a once-daily option with a favorable side effect profile, increased exposure to levodopa, and reduction in “off” time. It may be an appropriate second line option in patients who are intolerant or do not respond with entacapone.
... Thus, along with the well-known Chronic Dopaminergic Dysregulation Syndrome (CDDS), it is of crucial importance to consider that with the advancing age of patients several collateral symptoms (e.g. cardiovascular, intestinal and urinary), in addition to pharmaco toxic psychosis and cognitive disorders, may represent an additional dilemma associated with L-dopa therapy (Thanvi & Lo, 2004). The main objective of this theoretical-scholarly paper is to promote a rapid and updated review of some of the most discussed concepts related to PD Deep Brain Stimulation (DBS), with a special emphasis on current neuropsychological input. ...
Article
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Cuadernos de Neuropsicología / Panamerican Journal of Neuropsychology (ISSN: 0718-4123) Parkinson's disease (PD) is a chronic-degenerative condition associated with the loss of dopaminergic innervation in the striatum. The functional neurosurgical intervention in PD aims, primarily, to restore neurological functions, promoting quality of life. Deep Brain Stimulation (DBS) therapy, in essence, consists of implanting electrodes in specific and predetermined brain targets, mainly in the Subthalamic Nucleus (STN) and the Globus Pallidus interna (GPi). Using a telemetric device with a specific software program, it is possible to select which zones of contact will be active, in addition to the configuration of a variety of electrical parameters, so as to minimize motor and non-motor symptoms. Neuropsychological aspects and a list of basic concepts such as election criteria for DBS; possible surgical complications; device settings; multidisciplinarity; combined therapies; ethical aspects, and future challenges will be succinctly addressed in this theoretical rapid-review article.
... Dopamine replacement therapy is the gold standard frontline treatment, with remarkable efficacy in reducing symptoms and restoring motor control. Unfortunately, over time, decreased therapeutic efficacy, combined with the development of uncontrolled movements or dyskinesia, along with psychiatric side effects limit this treatment strategy (Barbeau, 1976;Lane, 2019;Marsden, 1994;Mosharov et al., 2015;Thanvi and Lo, 2004). Alternative pharmacological approaches that target cholinergic or adenosine receptor systems do not relieve symptoms to the same degree. ...
Preprint
In Parkinson's disease (PD) patients, dopamine replacement therapy requires days to reach maximal effects, and the return of symptoms without treatment is similarly delayed. We previously postulated that these phenomena are mediated by plasticity of coritcostriatal synapses. As dopamine depletion is expected to promote aberrant potentiation of the cortical inputs onto indirect pathway neurons, we reasoned that induction of LTD here could reduce motor deficits in a PD model. Optogenetic cortical stimulation combined with a D2 receptor agonist, quinpirole, induces robust optical LTD (oLTD) in brain slices from 6-OHDA lesioned mice. When lesioned mice were subjected to corticostriatal oLTD treatment over 5 days, motor performance was improved for >3 weeks. Consistent with LTD induction, oLTD-treated mice had reduced VGLUT1 expression in striatum and greater excitability of D2 neurons. These findings suggest that reversing aberrant corticostriatal synaptic plasticity in the indirect pathway may lead to persistent relief of PD motor symptoms.
... For example, levodopa is a common medicine that is also the most effective treatment for Parkinson's disease (Jankovic and Stacy 2007). However, it has been documented that consumption of levodopa results in various complications (Thanvi and Lo 2004;Toth et al. 2008). ...
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Background Long-term exposure to organophosphates might result in neurodegenerative diseases, comprising Parkinson's disease. Malathion is an organophosphate pesticide with high neurotoxicity. Oxidative stress, apoptosis, and α-synuclein accumulation are important underlying mechanisms in Parkinson’s disease. According to studies, crocin, an active constituent of saffron, has anti-apoptotic, anti-inflammatory, and anti-oxidant properties. Thus, the effect of crocin on malathion-induced Parkinson-like disease in rats was investigated in this study. Materials and methods6 groups of male Wistar rats were used: 1. Control (normal saline), 2. Malathion (100 mg/kg/day, i.p), 3. Crocin (10 mg/kg/day, i.p) + malathion, 4. Levodopa (10 mg/kg/day, i.p) +malathion, 5. Crocin (40 mg/kg/day, i.p), and 6. Polyethylene glycol (PEG) (vehicle of levodopa) groups. The drugs were administered for 28 days. The amounts of Bcl-2, Bax, caspases 3, 8, 9 proteins in the striatum were measured by western blotting. Also, the amounts of protein and mRNA level of the α-synuclein in striatum tissue were measured by western blotting and RT-qPCR methods.ResultsMalathion induced apoptosis by increasing the amount of Bax/Bcl2 ratio, caspase 3 and 9 proteins in rat striatum tissue. It also increased the protein and mRNA level of α-synuclein in striatal tissue. Co-administration of crocin or levodopa with malathion inhibited the toxic effects of malathion on striatal tissue. Conclusion Crocin ameliorates the neurotoxic effect of malathion by its anti-apoptotic activity and regulating the expression of proteins involved in Parkinson's disease pathogenesis. As a result, crocin has the potential to be used as a treatment for malathion-induced neurotoxicity.
... Levodopamine (L-Dopa) remains the most sought-after drug to ameliorate the symptoms of PD to date (Poewe et al. 2010). As a result of its persistence in the treatment of the disorder, L-Dopa remains a benison after more than 50 years of its discovery and is hitherto used in the primary treatment of symptomatic PD, hence, acting as the first-line medicament in the course of PD treatment (Rao et al. 2006;Thanvi et al. 2004). Despite its high response rates and being a highly prescribed drug for the treatment of PD, the subject of its responsiveness remains a prominent issue in the field of medicine. ...
... Levodopamine (L-Dopa) remains the most sought-after drug to ameliorate the symptoms of PD to date (Poewe et al. 2010). As a result of its persistence in the treatment of the disorder, L-Dopa remains a benison after more than 50 years of its discovery and is hitherto used in the primary treatment of symptomatic PD, hence, acting as the first-line medicament in the course of PD treatment (Rao et al. 2006;Thanvi et al. 2004). Despite its high response rates and being a highly prescribed drug for the treatment of PD, the subject of its responsiveness remains a prominent issue in the field of medicine. ...
Article
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects a sizable fraction of the population and degrades the quality of life. Levodopamine (L-Dopa) is the first-line treatment drug for PD and remains ubiquitously used. However, the drug response prediction of L-Dopa is still an exigent task and there is an unresolved absence of any substantial biomarkers for a robust prediction of L-Dopa response for a robust prediction of L-Dopa response in Parkinson’s disease. The present study intends to develop a robust prediction model to predict the L-Dopa drug response in PD using machine learning approaches. This work intended to utilize the MJFF Levodopa Response Study data of Parkinson’s subjects with conclusive pre-clinical and clinical assessments for resolving the significantly impending task of drug response prediction. The problem was identified as a classification task which employed four different supervised machine learning classification algorithms for data analysis and predictive learning. The underlying task of predictive classification of drug response classified the responders as “good” and “bad,” based on comprehensive analysis on the selected feature space which identified the participants with an improvement in the symptoms as “good” responders and the ones with degraded or no improvement in the symptoms as “bad” responders. The decision tree’s (classification and regression tree) classification accuracy was 88.89% (area under receiver operating characteristics curve 0.9) for predicting levodopamine response. The presence or absence of the symptoms along with Unified Parkinson’s Disease Rating Scale (UPDRS) scores and Hoehn and Yahr scale (H and Y) scores were recognized as the most distinguishing feature subset. The research stipulates the required preliminary evidence to the adaptive advancement of decision trees as an illuminating technique that can facilitate the prediction of the drug treatment response for Parkinson’s disorder, however, an extended effort is necessary to provide efficient predictive performance.
... Nowadays, Parkinson's disease is mostly treated by LD [2,3]. As the traditional-orally administered-LD therapy progresses, the therapeutic window (on time) becomes narrow, and the blood level becomes unpredictable [4]. This leads to side effects, called LD-related motor complications (LRMCs) [5,6], resulting in the so-called on-off phenomenon [7,8], which could be managed by the efficient control of drug release. ...
Article
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Background: The drug release of antiparkinsonian drugs is an important issue during the formulation process because proper release kinetics can help to reduce the off periods of Parkinson’s disease. A 2-factor, 3-level (3^2) full-factorial design was conducted to evaluate statistically the influence of the hydrophobicity of mesoporous silica on drug release. Methods: Hydrophobization was evaluated by different methods, such as contact angle measurement, infrared spectroscopy and charge titration. After loading the drug (levodopa methyl ester hydrochloride, melevodopa hydrochloride, LDME) into the mesopores, drug content, particle size, specific surface area and homogeneity of the products were also analyzed. The amorphous state of LDME was verified by X-ray diffractometry and differential scanning calorimetry. Results: Drug release was characterized by a model-independent method using the so-called initial release rate parameter, as detailed in the article. The adaptability of this method was verified; the model fitted closely to the actual release results according to the similarity factor, independently of the release kinetics. Conclusions: The API was successfully loaded into the silica, resulting in a reduced surface area. The release studies indicated that the release rate significantly decreased (p < 0.05) with increasing hydrophobicity. The products with controlled release can reduce the off period frequency.
... With insidious onset and slow progression, PD patients need long-term management. Considering the complications associated with anti-Parkinson drugs, they will not choose to start early if PD symptoms did not interfere with their daily lives (Thanvi and Lo, 2004). Therefore, clinicians and researchers are eagerly seeking more strategies to increase the efficacy and reduce the side effects of anti-Parkinson drugs. ...
Article
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Objective: This systematic review and meta-analysis aimed to assess the effects of the combination of acupuncture-related therapies with conventional medication compared with conventional medication in patients with Parkinson's disease (PD). Methods: A literature search within eight databases [including Medline, Embase, the Cochrane Library, PubMed, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), VIP, and Wanfang Database] was performed covering a time frame from their inception to August 2020. Randomized controlled trials (RCTs) comparing acupuncture-related therapies combined with conventional medication vs. conventional medication in patients with PD were eligible. Two authors independently assessed the risk of bias. Assessments were performed with the total and subscales scores of the Unified Parkinson's Disease Rating Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), the dosage of Madopar, Mini-Mental State Examination (MMSE), and 17-item Hamilton Depression Scale (HAMD). Data were analyzed by adopting the Cochrane Collaboration's RevMan 5.4 (Review Man, Copenhagen, Denmark); and mean effect sizes and 95% confidence intervals were estimated. Tests for heterogeneity were used to assess differences in treatment effects across different types of acupuncture used. Results: Sixty-six trials met the inclusion criteria, of which 61 trials provided data for the meta-analysis. We defined high-quality articles as those with a low risk of bias in four or more domains; and only 10 (15.15%) articles were of high quality. Compared with the controls, acupuncture-related therapies with conventional medication achieved a benefit in the primary outcomes of UPDRS (motor subscore: −3.90, −4.33 to −3.49, P < 0.01; total score: −7.37 points, −8.91 to −5.82, P < 0.001; activities of daily living subscore: −3.96, −4.96 to −2.95, P < 0.01). For the subgroup difference test among the effects of different acupuncture methods, significant differences existed in outcomes with the UPDRS-III, UPDRS-I, UPDRS-IV, and PDQ-39 scores and Madopar dosage, while non-significant differences existed with the UPDRS-total, UPDRS-II, HAMD, and MMSE scores. Conclusions: Acupuncture-related therapies combined with conventional medication may benefit individuals with PD. Our review findings should be considered with caution because of the methodological weaknesses in the included trials. Future, large randomized trials of acupuncture-related therapies for PD with high methodological quality are warranted. Systematic Review Registration: Identifier CRD42021228110.
... It controls the PD associated symptoms and is applied in almost every phase of the disease progression yet, largely augments the risk of dyskinesia or involuntary movements (Jankovic and Aguilar, 2008). Besides, the constant usage of the drug for four to five years reduces its effectiveness to combat PD symptoms, making the development of a novel drug essential (Thanvi and Lo, 2004). Therefore, targeting proinflammatory mediators may affect the progression of PD, for which the repurposing anti-inflammatory drugs might be a promising solution. ...
Article
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Parkinson’s disease (PD) is the result of dopaminergic (DA) neuronal death in the substantianigra pars compacta (SNc). Current treatments for PD such as L-dopa are limited in effectiveness and fail to address the cause.Targeted anti-inflammatory therapies, particularly directed at nuclear factor kappa B (NF‐κB) activity in alleviating degeneration of DA-neurons is of evolving interest. In the present study, we hypothesised that dexmedetomidine (DEX), an alpha-2 receptor adrenergic agonist, suppress the inflammatory responses associated with PD and restores dopaminergic levels by alleviating substantia nigral degeneration. Male mice (C57Bl/10, 8–11 months old and of 34–40 g of weight) were divided into: the control, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and MPTP+dexmedetomidine (MPTP+DEX) (n=26 each group). Dex restored dopamine levels in SNpc of MPTP-induced PD mice model. Results of immunohisto staining revealed that Dex treatment post-MPTP induction restored TH-positive cells, with only 12.37 % increase (##p< 0.01 vs MPTP) on the third day and a steep 55% increase (###p < 0.001 vs MPTP) following the seventh day of Dex treatment. Moreover, the expressions of proinflammatory markers regulated by NF-κB were diminished in Dex+MPTP group. In addition, cylinder test revealed that Dex treatment improved asymmetric limb usage pattern in MPTP induced mice over the course of 7 days. Hence, in this study, we provided insight on the effect of Dex in the inhibition of NF-κB1 regulated proinflammatory mediators to improve dopamine levels and reduce SNpc dopaminergic neuronal degeneration.
... Motor fluctuations consist of periods when symptoms improve as a result of the beneficial effect of a dose of carbidopa/levodopa ("ON") and periods when symptoms reappear or worsen ("OFF" episodes) [10]. Motor fluctuations have been reported in 50% of patients with PD after 5 years of initiating carbidopa/levodopa and in 70% of patients beyond 9 years of treatment [11,12]. The duration of "OFF" episodes that patients experience varies, but ~65% of individuals reported spending at least 2 hours of their day in "OFF" and >20% reported 4 A c c e p t e d M a n u s c r i p t hours or more of "OFF" time per day in a survey conducted by the Michael J. Fox Foundation for Parkinson's Research [13]. ...
Article
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Aims Within 5 years of initiating carbidopa/levodopa, ∼50% of patients with Parkinson’s disease (PD) experience “OFF” episodes; little is known about the cost burden. We investigated the association of “OFF” episodes with patient characteristics, healthcare resource utilization (HCRU), and healthcare costs. Methods Analyses used neurologist-provided data from the US-specific 2017 and 2019 Adelphi Real World Disease Specific Programme for PD, including duration of “OFF” episodes and HCRU for 10–12 consecutive patients. Patients were grouped by presence/absence of “OFF” episodes and by average hours of daily “OFF” time. Between-group differences were assessed for demographics, personal circumstances, and clinical characteristics. Regression analyses modeled the relationship of “OFF” episodes with HCRU and costs. Results Of 1309 patients, 41% experienced “OFF” episodes, 25% of whom were “OFF” ≥4 hours/day. Patients having “OFF” episodes had more severe PD, were diagnosed for longer, and were younger than those without “OFF” (P < 0.0001). “OFF” episodes were associated with a greater number of prescribed PD drugs (P < 0.0001). Patients without “OFF” episodes were more likely to have full-time employment and less likely to be retired or unemployed because of PD (P < 0.001). Patients with and without “OFF” episodes had different living situations (P < 0.001): patients experiencing “OFF” were less likely to live alone and more likely to live in a nursing home and have a professional caregiver (P < 0.001). In the past 12 months, the number of hospitalizations, intensive care admissions, and emergency room visits; nights hospitalized; costs of consultations and hospitalizations; and total direct costs were all higher for patients experiencing “OFF” episodes (P < 0.05). Conclusion Patients with PD and “OFF” episodes had higher HCRU and costs than those without “OFF,” suggesting that “OFF” episodes contribute to the economic burden of PD. Further research is warranted to examine the extent that current PD treatments and treatment patterns impact HCRU and costs.
... Levodopa efficacy is enhanced when used in combination with caribidopa, a decarboxylation inhibitor that prevents the breakdown and metabolism of levodopa in the peripheral blood [603]. Long-term use of levodopa is associated with motor fluctuations and involuntary movements (dyskinesia) [604]. Dopamine receptor activation is another therapeutic strategy. ...
Article
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Since 2015, 170 small molecules, 60 antibody-based entities, 12 peptides, and 15 gene- or cell-therapies have been approved by FDA for diverse disease indications. Recent advancement in medicine is facilitated by identification of new targets and mechanisms of actions, advancement in discovery and development platforms, and the emergence of novel technologies. Early disease detection, precision intervention, and personalized treatments have revolutionized patient care in the last decade. In this review, we provide a comprehensive overview of current and emerging therapeutic modalities developed in the recent years. We focus on nine diseases in three major therapeutics areas, diabetes, autoimmune, and neurological disorders. The pathogenesis of each disease at physiological and molecular levels is discussed and recently approved drugs as well as drugs in the clinic are presented.
... Motor fluctuations consist of periods when symptoms improve as a result of the beneficial effect of a carbidopa/levodopa dose ("ON") and periods when symptoms reemerge or worsen ("OFF" episodes) [25]. Motor fluctuations have been reported to occur in 38 to 50% of patients with PD within 2 years of initiating carbidopa/levodopa [26][27][28][29] and in nearly 100% of patients after 10 years of carbidopa/levodopa treatment [30]. In a survey conducted by the Michael J. Fox Foundation for Parkinson's Research,~65% of respondents reported spending at least 2 h of their day in "OFF" time and > 20% reported 4 h or more of "OFF" time [31]. ...
Article
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Background Many patients with Parkinson’s disease (PD) who receive carbidopa/levodopa experience symptom reemergence or worsening, or “OFF” episodes. This study assessed the association of “OFF” episodes with health-related quality of life (HRQoL). Methods US-specific data from the 2017 and 2019 Adelphi Real World Disease Specific Programme for PD, a real-world cross-sectional survey, were used. Neurologists provided data for 10–12 consecutive patients with PD who completed the 39-item Parkinson’s Disease Questionnaire (PDQ-39) and the EuroQol 5-Dimension (EQ-5D). Data were grouped by patients who experienced “OFF” episodes versus those who did not and by average hours of daily “OFF” time. Differences between patient groups were assessed for demographics and clinical characteristics; regression analyses were used to model the relationship between HRQoL and “OFF” episodes with age, sex, body mass index, current PD stage on the Hoehn and Yahr scale, and number of concomitant conditions related and unrelated to mobility as covariates. Results Data from 722 patients were analyzed. Overall, 321 patients (44%) had “OFF” episodes (mean of 2.9 h of daily “OFF” time). Patients who experienced “OFF” episodes were less likely to work full-time and more likely to live with family members other than their spouse/partner or reside in a long-term care facility than those without “OFF” episodes. The presence of “OFF” episodes, regardless of the average hours of daily “OFF” time, was significantly associated with high scores (reflecting poor HRQoL) on most PDQ-39 dimensions and the summary index and low scores (reflecting poor health status) on the EQ-5D health utility index, visual analog scale (VAS), and all dimensions. Furthermore, increased average hours of daily “OFF” time was significantly correlated with higher scores for all PDQ-39 dimensions and the summary index, as well as with the EQ-5D health utility index and VAS scores. Patients with “OFF” episodes experienced reduced HRQoL even after correcting for potentially confounding variables. Conclusions This study demonstrated that the occurrence of “OFF” episodes in patients with PD is associated with reduced HRQoL and that the impact on HRQoL increased incrementally with increasing average hours of daily “OFF” time.
... Levodopa (L-DOPA), a precursor of DA, is used as a symptom-relieving treatment for PD 125 . The usage of L-DOPA for PD is still debated due to its side-effects with long-term treatment [126][127][128] . Several researchers suggested that L-DOPA might be harmful to SNc cells by a mechanism that probably involves oxidative stress [129][130][131] . ...
Article
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Parkinson’s disease (PD) is the second most prominent neurodegenerative disease around the world. Although it is known that PD is caused by the loss of dopaminergic cells in substantia nigra pars compacta (SNc), the decisive cause of this inexorable cell loss is not clearly elucidated. We hypothesize that “Energy deficiency at a sub-cellular/cellular/systems level can be a common underlying cause for SNc cell loss in PD.” Here, we propose a comprehensive computational model of SNc cell, which helps us to understand the pathophysiology of neurodegeneration at the subcellular level in PD. The aim of the study is to see how deficits in the supply of energy substrates (glucose and oxygen) lead to a deficit in adenosine triphosphate (ATP). The study also aims to show that deficits in ATP are the common factor underlying the molecular-level pathological changes, including alpha-synuclein aggregation, reactive oxygen species formation, calcium elevation, and dopamine dysfunction. The model suggests that hypoglycemia plays a more crucial role in leading to ATP deficits than hypoxia. We believe that the proposed model provides an integrated modeling framework to understand the neurodegenerative processes underlying PD.
... The use of L-dopa in the treatment of PD is considered a "gold standard" and L-dopa preparations have been successfully used as pharmacotherapy in PD since the 1960s (Fahn, 2015). Unfortunately, the L-dopa clinical outcome is weakened by motor and nonmotor side effects, including neurotoxic effects (Gesi et al., 2001), subsequent to long-term treatment (Thanvi et al., 2004). In recent years, more and more studies indicate that they may cause enhanced ROS generation. ...
Article
Parkinson’s disease (PD) is the second most common cause of neurodegeneration. Over the last two decades, various hypotheses have been proposed to explain the etiology of PD. Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration. Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients. DNA oxidation may produce various lesions in the course of PD. Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine. The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD. SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E. PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein. Over 100 mutations have been found among the 12 exons of PRKN. PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases. More than 50 PD-promoting mutations have been found in PINK1. Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases. Around 20 mutations have been found in DJ1 among PD patients thus far. Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD. Treatment of PD patients, especially in the advanced stages of the disease, is very difficult. The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa. The next step is the introduction of advanced therapies, such as deep brain stimulation. Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress. Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.
... PD has commonly been treated with the dopamine precursor levodopa, which is absorbed by the gastrointestinal tract and accesses the brain to induce elevated striatal dopamine levels (Koller and Rueda, 1998). However, after prolonged treatment with levodopa, the development of dopa-resistant motor symptoms and non-motor symptoms has been observed alongside levodopa-related side effects (Thanvi and Lo, 2004). Once levodopa turns ineffective or induces therapy-related motor complications, a set of other drugs can be prescribed such as dopamine agonists, catechol-o-methyl-transferase inhibitors, monoamine oxidase type B-inhibitors, and non-dopaminergic agents (Jankovic and Aguilar, 2008;Poewe et al., 2017). ...
Article
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Parkinson’s disease (PD) has been modeled in several animal species using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product 1-methyl-4-phenylpyridinium (MPP+). MPP+ selectively kills dopaminergic neurons in pars compacta of the substantia nigra, inducing parkinsonian symptoms in animals. Typically, neurotoxicity models of PD in zebrafish assess acute drug effects on locomotion. In the present study, we examined the lasting effects of MPP+ exposure and drug treatment in zebrafish larvae. Larvae were incubated in 500 μM MPP+, from 1 to 5 days post fertilization (dpf), followed by 24 h drug-free acclimation. At 6 dpf, the behavior was analyzed for locomotion, thigmotaxis, and sleep. Next, in separate assays we assessed the drug effects of brain injected glial cell-derived neurotrophic factor (GDNF) and 4-phenylbutyrate (PBA), co-incubated with MPP+. We show that MPP+ exposure consistently reduces swim distance, movement frequency, and cumulative time of movement; thus mimicking a parkinsonian phenotype of reduced movement. In contrast, MPP+ exposed larvae demonstrate reduced anxiety-like behavior and exhibit a sleep phenotype inconsistent with human PD: the larvae display longer sleep bouts, less sleep fragmentation, and more sleep. Previously reported rescuing effects of PBA were not replicated in this study. Moreover, whereas GDNF attenuated the sleep phenotype induced by MPP+, PBA augmented it. The current data suggest that MPP+ exposure generates a multifaceted phenotype in zebrafish and highlights that analyzing a narrow window of data can reveal effects that may be inconsistent with longer multi-parameter approaches. It further indicates that the model generally captures motor symptoms more faithfully than non-motor symptoms.
... Currently, the most common treatment for PD is levodopa, which effectively improves clinical symptoms. However, several motor complications of levodopa are challenging to treat [3,4]. Levodopa does not enable the recovery of losses in dopaminergic neurons and does not delay or protect against progression of the disease; thus, the development of new adjuvant therapies is crucial. ...
Article
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The prevalence and incidence of Parkinson’s disease (PD), an age-related neurodegenerative disease, are higher among elderly people. Independent of etiology, dysfunction and loss of dopaminergic neurons are common pathophysiological changes in PD patients with impaired motor and non-motor function. Currently, preventive or therapeutic treatment for combating PD is limited. The ghrelin axis and ghrelin receptor have been implicated in the preservation of dopaminergic neurons and have potential implications in PD treatment. Teaghrelin, a compound originating from Chin-Shin Oolong tea, exhibits ghrelin agonist activity. In this study, the neuroprotective potential of teaghrelin against PD was explored in a cell model in which human neuroblastoma SH-SY5Y cells were treated with the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). Upon MPP+ exposure, SH-SY5Y cells exhibited decreased mitochondrial complex I activity and apoptotic cell death. Teaghrelin activated AMP-activated protein kinase (AMPK)/sirtuin 1(SIRT1)/peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α) and extracellular signal–regulated kinases 1 and 2 (ERK1/2) pathways to antagonize MPP+-induced cell death. Herein, we propose that teaghrelin is a potential candidate for the therapeutic treatment of PD.
... Levodopa has therefore been combined with carbidopa, which inhibits this peripheral conversion and deactivation of levodopa by AADC, increasing the quantity of levodopa transported to the brain for conversion into dopamine [11]. During the natural course of PD, pharmacologic management becomes less effective with progression of motor complications, specifically motor fluctuations [11][12][13][14][15]. In addition, levodopa is commonly used in conjunction with a COMT in order to prevent the degradation of levodopa and increase dopamine concentration in the brain. ...
Article
While CDD directly to the CSF can provide a constant delivery of the dopaminergic drug resulting in a more stable treatment effect without the limitations of traditional oral therapy without peripheral effects, it is still young and longitudinal data is lacking. These experimental therapies show promise and further investigation into their efficacy and safety could extend the frontiers for management of PD.
Article
Silybin has a neuroprotective effect in different models of neurodegenerative diseases as the MPTP‐induced parkinsonian model. However, silybin has poor water solubility, decreasing its efficacy when administered orally. Therefore, the search for possible vehicles or transport systems is relevant. Among the options are the drug delivery systems (DDS). In this work, we evaluated if the use of specific solvents (water or oil) or DDS [carboxymethylated silica nanoparticles (SiO2_SIL) or starch (CMS‐SIL)] would preserve the neuroprotective effect of silybin when administered orally in a Parkinson's model induced with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). C57BL/6J male mice were exposed to MPTP (30 mg/kg i.p) and, 30 minutes after, were treated with 100 mg/kg of silybin in oil or water as solvents or coupled to silica nanoparticles or carboxymethyl starch for five consecutive days. After the last administration of MPTP and silybin, striatal dopamine levels were determined on day seven. Our results showed that silybin in water as the non‐vehicle control had no protective effect in the MPTP model. Silybin in oil preserved 57 % dopamine levels in contrast to 72 % with SiO2_SIL and 50.7 % with CSM‐SIL. In conclusion, we demonstrated that silybin was effectively coupled to carboxymethylated silica nanoparticles and carboxymethylated starch‐based DDS without losing its neuroprotective effects. This work describes the preparation and characterization of carboxymethylated silica nanoparticles or carboxymethylated starch conjugated to silybin, a poorly soluble molecule with neuroprotective effects. Both silybin conjugated nanocarriers showed an improved neuroprotective effect when administered orally in a C57BL/6J male mice Parkinson's model induced with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) in comparison to other silybin delivery systems.
Article
Since the 1960s, levodopa (LDA) has been the standard drug for treating of Parkinson's disease. In this study, a novel benzothiadiazole-based conjugated microporous polymer-coated graphene heterostructure (CMP-rGO) was synthesized and used to construct a sensitive photoelectrochemical (PEC) sensor capable of detecting LDA. Under optimal experimental conditions, the intensity of the photocurrent produced by the sensor was linear from 0.005 to 40 μM, and the limit of detection of the sensor was 0.0027 μM. The sensor showed good repeatability, stability, and selectivity for LDA detection. Finally, the constructed sensor was used to detect LDA in levodopa tablets, human serum samples, and urine samples and satisfactory results were obtained. Therefore, the PEC sensor provides a novel platform for the detection of LDA in real samples and broadens the applications of conjugated microporous polymers in PEC sensing.
Article
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Parkinson’s disease (PD) is primarily idiopathic and a highly heterogenous neurodegenerative disease with patients experiencing a wide array of motor and non-motor symptoms. A major challenge for understanding susceptibility to PD is to determine the genetic and environmental factors that influence the mechanisms underlying the variations in disease-associated traits. The pathological hallmark of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compacta region of the brain and post-mortem Lewy pathology, which leads to the loss of projecting axons innervating the striatum and to impaired motor and cognitive functions. While the cause of PD is still largely unknown, genome-wide association studies provide evidence that numerous polymorphic variants in various genes contribute to sporadic PD, and 10 to 15% of all cases are linked to some form of hereditary mutations, either autosomal dominant or recessive. Among the most common mutations observed in PD patients are in the genes LRRK2, SNCA, GBA1, PINK1, PRKN, and PARK7/DJ-1. In this review, we cover these PD-related mutations, the use of induced pluripotent stem cells as a disease in a dish model, and genetic animal models to better understand the diversity in the pathogenesis and long-term outcomes seen in PD patients.
Article
Levodopa (L-dopa) is an effective medication for Parkinson's disease. However, excess intake from overdose or the intake of natural sources of L-dopa can be dangerous, causing, for example, tardive dyskinesia. Therefore, in medicated individuals, it is important to monitor the levels of L-dopa in the body. In this paper, we report a simple, wearable, noninvasive, and portable metal−organic framework (MOF)-based electrochemical sensor with integrated enzymes for monitoring the concentration of levodopa in sweat, which can be used as a proxy for L-dopa levels in the body. Zeolitic imidazolate framework/graphene oxide (ZIF-8/GO) composites were prepared by the in-situ growth of ZIF-8 nanoparticles on the surface of GO, and, subsequently, tyrosinase was loaded onto the composite to yield the sensor. Integration with a wireless electronic circuit enabled communication between the sensor and a smartphone application for continuous analysis. The sensor was found to have a wide linear response range from 1 to 95 µM, a low limit of detection of 0.45 µM, satisfactory reproducibility, and excellent selectivity. In addition, the sensor showed high sensitivity and good stability as a result of the anchoring of the enzyme. Thus, the sensor shows promise for continuous, noninvasive point-of-care drug monitoring and management.
Article
Aim: To compare efficacy of apomorphine sublingual film (APL) and levodopa inhalation powder (CVT-301) for ‘on-demand’ treatment of Parkinson's disease ‘OFF’ episodes. Patients & methods: Patient-level data from an APL pivotal study were re-weighted to match average baseline characteristics from a CVT-301 study (SPAN-PD). Placebo-adjusted treatments were compared at week 12. Results: Improvements in predose Unified Parkinson's Disease Rating Scale Part III scores were significantly larger for APL versus CVT-301 at 60 min postdose (least squares mean difference-in-difference: -8.82; p = 0.002); difference at 30 min favored APL but was not statistically significant (-4.46; p = 0.103). Total daily ‘OFF’ time reductions were significantly larger for APL versus CVT-301 (-1.31 h; p = 0.013). Conclusion: Results suggest APL treatment may lead to improved efficacy versus CVT-301.
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Background: “On-demand” treatments approved in the United States (US) for “OFF” episodes in Parkinson’s disease (PD) include apomorphine hydrochloride injection (SC-APO), apomorphine sublingual film (APL), and levodopa inhalation powder (CVT-301). APL received US approval in 2020, and its cost-effectiveness has not been compared with SC-APO and CVT-301. Objective: To develop a cost-effectiveness analysis model comparing APL versus SC-APO and CVT-301 for treatment of patients with PD experiencing “OFF” episodes from a US payer perspective. Methods: The model estimated total costs and effectiveness for each comparator arm, informed from the treatments’ pivotal studies or literature, over a 10-year horizon. Total and incremental patient costs (in 2020 US dollars), total time spent without “OFF” episode symptoms, and quality-adjusted life years (QALY) gained were summarized and compared. Incremental cost-effectiveness ratios for APL versus SC-APO and CVT-301 were estimated and expressed as incremental patient costs per patient QALY gained and incremental cost per “OFF” hour avoided. Scenario analyses varying inputs and including caregiver costs were also conducted. Results: In the base case, APL had the lowest total “on-demand” treatment costs ($42,095) compared with SC-APO ($276,320; difference: –$234,225) and CVT-301 ($69,577; difference: –$27,482) over the 10-year horizon. APL was also associated with the highest utility, with incremental QALYs of 0.019 versus SC-APO and 0.235 versus CVT-301. APL was dominant over CVT-301 in terms of incremental cost per “OFF” hour, and dominant over both CVT-301 and SC-APO in terms of incremental cost per QALY gained. In all scenario analyses, APL was dominant against both SC-APO and CVT-301, confirming the robustness of the base-case results. Discussion: APL was dominant compared with both comparator arms, being less costly and more effective on average than SC-APO and CVT-301 in terms of QALYs. For SC-APO, cost-effectiveness of APL was driven by lower “on-demand” treatment costs and adverse event–related disutilities. For CVT-301, cost-effectiveness of APL was driven by lower “on-demand” treatment costs and substantially higher efficacy. Conclusions: From a US payer perspective, APL represents a cost-effective option compared with SC-APO and CVT-301 for treatment of “OFF” episodes in patients with PD.
Article
L-dopa is a chiral drug that has been extensively used for the treatment of Parkinson’s disease. The concentration of L-dopa plays a vital role in the treatment, and this work emphasizes on designing a versatile platform for the quantitative and selective detection of L-dopa using reduced graphene quantum dot (rGQD). The platform is efficient in three different sensing methods, viz. fluorescence turn-on, filter paper-based sensing, and electronic measurements. The rGQD undergoes a dramatic fluorescence turn-on in the presence of L-dopa in aqueous media and artificial urine with a detection limit as low as 1.307 µM and 1.217 µM respectively. Experimental evidence revealed that the fluorescence enhancement is attributed to aggregation-induced emission mechanism. The system is also applicable for visual detection of L-dopa using filter paper strips treated with rGQD and develops bright fluorescence under ultra-violet irradiation. Apart from this, electrical sensors for L-dopa were also developed by preparing rGQD treated poly-vinyl alcohol films, and the increase in the current conduction with varying concentrations of L-dopa was observed. The films produce 2.5 order higher current conduction at 300 μM of L-dopa with a detection limit of about 13.136 µM. At the final stage, we have designed flexible electronic devices using these materials that develop 1.3 order higher current for L-dopa. The devices exhibit excellent air stability under varied relative humidity conditions as well as high bending stability for potential practical applications.
Article
Background: Levodopa is the most-commonly used therapy for Parkinson's Disease (PD). Imaging findings show increased cerebral blood flow (CBF) response to levodopa, but the artery morphological change is less studied. Purpose: To investigate the effect of levodopa on cerebral arteries and CBF. Study type: Prospective. Population: 57 PD patients (56 ± 10 years, 26 males) and 17 age-matched healthy controls (AMC, 57 ± 9 years, 9 males) were scanned at baseline (OFF). Patients were rescanned 50 minutes after taking levodopa (ON). Field strength and sequence: 3 T; Simultaneous noncontrast angiography intraplaque imaging (SNAP) based on turbo field echo; Pseudo-continuous arterial spin labeling (PCASL) based on echo-planner imaging. Assessment: The Unified Parkinson's Disease Rating Scale (UPDRS-III) was used to assess the disease severity. Length and radius of arteries were measured from SNAP images. CBF was calculated from PCASL images globally and regionally. Statistical tests: Mann Whitney U tests were conducted in comparing PD vs. AMC. Wilcoxon matched-pairs signed rank tests were used in comparing OFF vs. ON, and the more-affected vs. the less-affected hemisphere in PD. Linear regressions were performed to test the correlations of neuroimaging findings with behavioral changes. Significance threshold was P < 0.05 with Bonferroni correction. Results: PD patients were identified with significantly lower CBF (PD OFF Mean = 40.15 ± 5.99, AMC Mean = 43.48 ± 6.21 mL/100 g/min) and shortened total artery length (PD OFF Mean = 5851.07 ± 1393.45, AMC Mean = 7479.16 ± 1335.93 mm). Levodopa elevated CBF of PD brains (PD ON Mean = 41.48 ± 6.32 mL/100 g/min) and expanded radius of proximal arteries. Artery radius change significantly correlated with CBF change in corresponding territories (r = 0.559 for Internal Carotid Arteries, r = 0.448 for Basilar Artery, and r = 0.464 for Middle Cerebral Artery M1). Global CBF significantly related to UPDRS-III (r = -0.391) post-levodopa. Data conclusion: Levodopa can increase CBF by dilating proximal arteries. Level of evidence: 1 TECHNICAL EFFICACY STAGE: 4.
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Our understanding of the progression and mechanism underlying the onset of Parkinson's disease (PD) has grown enormously in the past few decades. There is growing evidence suggesting that poly (ADP-ribose) polymerase 1 (PARP-1) hyperactivation is involved in various neurodegenerative disorders, including PD, and that poly (ADP-ribose) (PAR)-dependent cell death is responsible for neuronal loss. In this review, we discuss the contribution of PARP-1 and PAR in the pathological process of PD. We describe the potential pathways regulated by the enzyme, review clinically relevant PARP-1 inhibitors as potential disease-modifying therapeutics for PD, and outline important factors that need to be considered for repurposing PARP-1 inhibitors for use in PD.
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Introduction The clinical symptoms and nutritional status of patients with Parkinson's disease (PwP) are interrelated, and the clinical outcomes in malnourished patients are often poor. Only a few studies have reviewed the prevalence of malnutrition and nutrition-related risk factors in PwP. Objective To explore the prevalence of malnutrition/ malnutrition risk among PwP, and estimate nutrition-related risk factors. Methods PubMed, EMBASE, and Cochrane Library were systematically searched. Literatures published between 1 January 1995 and 1 November 2020, subjects were patients with idiopathic PD underwent Mini Nutritional Assessment (MNA) were included. Result Sixteen articles, including 1650 PwP from 13 countries/regions, were included in the meta-analysis. The prevalence of malnutrition and malnutrition risk were 8.8% (Confidence interval [CI] 95%, 5.3%–12.2%) and 35.3% (CI 95%, 29.0%–41.7%), and the prevalence of nutritional disorders was 42.3% (CI 95%, 33.7%–51%). The prevalence of malnutrition in developing countries was higher than that in the developed countries. Meta-analysis reveals there were significant differences in the course of the disease (0.88 years; 95% CI, 0.26–1.50), levodopa equivalent daily dose (LEDD; 60.77 mg/day; 95% CI, 2.7–118.8), Hoehn and Yahr (H&Y) staging (0.323; CI 95%, 0.164–0.482), and unified Parkinson's disease rating scale (UPDRS) scores (total: 13.66, CI 95%: 10.57–16.75 and part III: 5.52, CI 95%: 3.79–7.25) between normal and nutritional disorder groups. Conclusions Malnutrition/malnutrition risk prevalence in PwP are high. The duration of the disease, LEDD, H&Y staging, and UPDRS score (part III and total) may be nutrition-related risk factors in PwP.
Thesis
Die tiefe Hirnstimulation ist eine etablierte und hocheffiziente operative Behandlungsmethode für Patienten mit idiopathischem Parkinson- Syndrom (IPS). Als Zielgebiet dient in den meisten Fällen der Nucleus subthalamicus. Die Indikationen zur Implantation einer tiefen Hirnstimulation (THS) sind medikamentös nicht behandelbare motorische Fluktuationen und Dyskinesien oder ein medikamentös nicht kontrollierbarer Tremor. Bislang erfolgt eine kontinuierliche Stimulation. Little et al. konnten jedoch bereits in ihrer 2013 veröffentlichen Studie zeigen, dass eine adaptive Stimulation, gemessen am UPDRS, um 27 % effektiver war und entsprechend die Stimulationszeit um 56 % gesenkt werden konnte. Voraussetzung für die Anwendbarkeit einer adaptiven Stimulation im klinischen Alltag ist der Nachweis eines oder mehrerer Physiomarker, welche als Rückkopplungssignal für den Stimulationsbeginn dienen. Diese Marker müssen verlässlich mit dem Auftreten und der Ausprägung der Bewegungsstörungen korrelieren. Die Systeme müssen die Signale auslesen und entsprechend darauf reagieren können, damit ein sogenanntes Closed- loop- Verfahren entstehen kann. Bei diesen Markern handelt es sich um sogenannte lokale Feldpotenzialaktivitäten, das heißt niederfrequente Potentialänderungen von Zellen in subkortikalen Arealen des Gehirns, welche über Elektroden der THS abgeleitet werden können. Der Stimulator Activa PC+S (Medtronic) ermöglicht es erstmalig Aufzeichnungen von LFP- Daten, außerhalb eines experimentellen Laboraufbaus, mittels dauerhaft implantiertem Gerät vorzunehmen und damit auch Langzeitanalysen durchzuführen. Erkenntnisse vergangener Studien ergaben, dass die synchronisierte, pathologisch gesteigerte oszillatorische Aktivität im Beta-Frequenzband (13- 35 Hz) eine bedeutende Rolle im Bezug auf die Pathophysiologie des IPS spielt und als krankheitsspezifische Aktivität gilt. Es konnte bereits belegt werden, dass die Verbesserung der motorischen Symptome (Bradykinese und Rigor) mit dem Ausmaß der Suppression der Betaband- Aktivität korreliert. Die Betabandaktivität als lokale Feldpotentialaktivität kann als Physiomarker einer adaptiven Stimulation dienen. Unser Hauptaugenmerk galt daher der Analyse der Betabandaktivität oder anderer Frequenzbereiche während des Schlafes um hier die THS bedarfsgerecht einzusetzen. Hierfür wurden nächtliche subkortikale LFP- Aufzeichnungen parallel zur Schlaf- Polysomnographie durchgeführt. Zudem erfolgte in der vorliegenden Arbeit sowohl in unserem Vorversuch als auch in unserem Hauptversuch die Anwendung des UPDRS Teil III zur Erfassung der motorischen Symptome, sowie die Durchführung von Fragebögen zur Erfassung der nicht- motorischen Symptome, insbesondere des Schlafes vor und nach Implantation der tiefen Hirnstimulation. Wir konnten belegen, dass es nach Implantation der THS zu einer Erhöhung der Schlafeffizienz und zu einer Erhöhung des Anteils der Schlafstadien II und III und damit einhergehend zu einer Steigerung der Schlafqualität kommt. Übereinstimmend mit anderen Studien konnten wir zeigen, dass sich die Motorik unter Stimulation deutlich verbessert. Im Vorversuch reduzierte sich der mittlere präoperative MDS- UPDRS III im MedsOFF verglichen mit dem mittleren postoperativ MDS- UPDRS III im MedsOFF/StimON um 37 %. In der PC+S- Studie imponierte eine Reduktion um 67%. Zudem zeigte sich eine Reduktion der nicht- motorischen Symptome durch die THS, insbesondere in der Kategorie Schlaf. Die Ergebnisse der vorliegenden Arbeit ergaben außerdem, dass die Betabandaktivität im Schlafstadium II und vor allem im Schlafstadium III am geringsten ist. Im Schlafstadium I und REM ist die Betabandaktivität höher als im Schlafstadium II und III. Hierbei war entscheidend, dass die Patienten eine klar abgrenzbare Betabandaktivität im Wachstadium aufwiesen und die Elektrodenkontakte im dorsolateralen Kerngebiet des STN lokalisiert waren. Gegenläufig dazu verhält sich die Deltaaktivität. Sie ist im Schlafstadium II und besonders im Stadium III am höchsten. Stadium I ist mit durchschnittlich um 7,3 % niedriger als im Wachstadium. Am geringsten ist sie jedoch im REM-Schlafstadium. Indem wir mit der Betabandaktivität und Deltaaktivität in den einzelnen Schlafstadien einen stabilen und reproduzierbaren Physiomarker finden konnten, sind wir unserem Ziel der adaptiven THS ein Stück näher gekommen.
Article
Levodopa has been a standard drug for treating Parkinson's disease since the 1960s, but it has caused many side effects such as wearing-off, motor fluctuation, and dystonia. In this work, we developed glutathione-conjugated carbon quantum dots (GSH-CQDs) as a novel fluorescent sensor for sensitive and selective detection of levodopa. The GSH-CQDs were prepared by EDC/NHS coupling reaction of glutathione (GSH) with amine-functionalized CQDs (N-CQDs) synthesized using meta-phenylenediamine and ethylenediamine. The synthesized GSH-CQDs emitted bright green fluorescence with a high quantum yield (QY) of 22.42 ± 6.88%. However, upon the addition of levodopa to GSH-CQDs under alkaline conditions, the fluorescence of GSH-CQDs was quenched. Since levodopa is converted to dopaquinone in an alkaline environment, it is presumed that thiol groups of GHS-CQDs form covalent bonds with dopaquinone, causing fluorescence quenching through photoinduced electron transfer. Therefore, as the concentration of levodopa increased, the fluorescence intensity of GSH-CQDs was gradually decreased. Under optimal conditions, a linear response was observed in the range of 0.05–1 μM, and limit of detection (LOD) was determined to be 0.057 μM. The GSH-CQDs exhibited high specificity to levodopa over other non-target biological substances, quinone derivatives, and Parkinson’s medications. Furthermore, the capability of this GSH-CQDs sensor for monitoring levodopa in human serum were validated with excellent precision and recovery rates of 100.20 to 103.33%.
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Background The US Food and Drug Administration approved in 2015 the use of deep brain stimulation for Parkinson disease after “four years duration and with recent onset of motor complications”. The aim of this study was to identify neurosurgeons’ attitudes and perspectives around the use of deep brain stimulation for Parkinson disease earlier in the disease course. Methods An anonymous survey examining attitudes and perceptions towards deep brain stimulation practice and timing in Parkinson disease was developed by the study team and distributed by the American Society for Stereotactic and Functional Neurosurgeons to its members. Results from 32 subjects with answers to at least 50% of the survey were included. Data were analyzed with descriptive statistics and chi-square test. Results Motor fluctuations, dyskinesia, quality of life impairment, and medically refractory tremor were the most important reasons to proceed with deep brain stimulation, which was overall considered more useful after the onset of motor symptoms. Unresponsiveness to levodopa, cognitive impairment, and unclear diagnosis were important reasons not to consider deep brain stimulation. Earlier surgery was considered to be less risky compared to later in the disease progression. Ten out of 25 neurosurgeons reported considering deep brain stimulation as a therapeutic option after a minimum disease duration of three to four years. Conclusions We conclude that neurosurgeons support the use of earlier deep brain stimulation, but not preceding motor complications. Further research surrounding the benefits and adverse effects of earlier deep brain stimulation is needed to guide practice and better inform potential candidates.
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Apomorphine is an on-demand treatment of "OFF" episodes in patients with Parkinson's disease (PD). A joint parent-metabolite population pharmacokinetic (PK) model characterized apomorphine and apomorphine-sulfate following administration of apomorphine sublingual film (APL) and two formulations of subcutaneous apomorphine. Overall, 2485 samples from 87 healthy subjects and 71 patients with PD and "OFF" episodes were analyzed using nonlinear mixed-effects modeling. Apomorphine PK was adequately described by a two-compartment model with first-order transit absorption via both routes of administration and first-order metabolism to apomorphine-sulfate with one-compartment disposition and first-order elimination. Bioavailability of apomorphine sublingual film was ~ 18% relative to subcutaneous apomorphine. Among covariates tested, only body weight had a large effect on apomorphine exposure (maximum plasma concentration and area under the concentration-time curve [AUC0-∞ ]), with greater weight resulting in lower exposure. Model-predicted apomorphine exposure was similar between apomorphine sublingual film 30 mg and subcutaneous apomorphine 5 mg (median AUC0-24 , 66.7 ng•h/mL, geometric mean ratio of 0.99; 90% confidence interval [CI], 0.96-1.03) and was comparable between apomorphine sublingual film 35 mg and subcutaneous apomorphine 6 mg (median AUC0-24 , 75.4 and 80.0 ng•h/mL, respectively; geometric mean ratio of 0.94; 90% CI, 0.90-0.97) administered every 2 h for a maximum of 5 doses per day. In a typical patient with PD, predicted apomorphine exposure increased with increasing doses of apomorphine sublingual film; however, the increase was less than dose proportional. Similar apomorphine exposure was predicted in patients with mild renal impairment versus normal renal function. PK properties of apomorphine sublingual film support its administration for a wide range of patients with PD and "OFF" episodes, regardless of demographic and clinical characteristics.
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Introduction : Levodopa is the most effective drug in the treatment of Parkinson’s disease, but its chronic treatment is linked to the occurrence of motor complications with fluctuations of motor performance and dyskinesia. Unpredictable OFF episodes can be severe and disabling and current rescue medications cannot always be used safely. A rescue therapy characterized by a rapid and predictable ON response and the safety profile of levodopa will represent a major advantage for patients affected from unresponsive OFF episodes. Areas covered : CVT-301 is new inhaled formulation of LD recently developed as a self-administered treatment for OFF periods. Herein, the pharmacodynamic and pharmacokinetic properties, efficacy, and safety of CVT-301 are reviewed. Expert opinion : CVT 301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma level variability. It should be noted that the delivery device used has been described as relatively simple to use, but the few steps required to prepare and self-administer the dose can challenging for PD patients during their OFF state. Additionally, resolution of an OFF episode requires the administration of two capsules of CVT-301, which further complicates the use of the device.
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For determination of levodopa (L‐DOPA) and paracetamol (PAR), selective, effective and sensitive electrochemical sensor based on 3,5‐diamino‐1,2,4‐triazole (35DT) on glassy carbon (GC) electrode was reported. The DPV method was used to obtain the oxidation peak current of L‐DOPA which increased linearly with its concentration at the range of 1–99 μM and 99–480 μM. The linear relationship between the concentration of PAR and its peak current was obtained in the range of 0.3‐55μM and 55‐475μM. The limit of detection values for PAR and L‐DOPA were found to be 0.1 and 0.25 μM, respectively. Satisfactory results were obtained in pharmaceutical samples.
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Fifty four patients with idiopathic Parkinson's disease receiving levodopa therapy were studied. Thirty three of these patients displayed peak-dose dyskinesia. Neither the duration of Parkinson's disease nor the duration of levodopa therapy discriminated between patients with and patients without peak-dose dyskinesia. Consequently, these criteria could not determine whether the first appearance of peak-dose dyskinesia depends on the duration of Parkinson's disease--a factor that is related to the severity of the disease--or on the duration of levodopa therapy. A subgroup of nineteen patients with unilateral or unequivocally asymmetrical peak-dose dyskinesia was examined 12 hours after withdrawal of levodopa. A levodopa testdose provoked unilateral or unilateral preponderant peak-dose dyskinesia which always involved the most severely affected side and which also happened to be the side of onset of the disease. This demonstrates that the severity of Parkinson's disease is the main risk factor for peak-dose dyskinesia.
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Fourteen Parkinsonian patients with fluctuations in therapeutic response to levodopa completed a double-blind, crossover trial of controlled-release levodopa/carbidopa (Sinemet CR4) vs standard Sinemet 25/100 (STD). Significant increases in mean interdose interval and per cent of the waking day spent "on", as well as reductions in the number of daily medication doses and number of "off" episodes were noted. In the double-blind part of the study, relative to open treatment with STD, ten patients rated themselves as improved while taking CR4, whereas only three considered themselves improved with STD. Difficulties using CR4 included an increased "lag-time" to the onset of antiparkinson effect, a tendency to produce increasingly severe dyskinesia late in the day, and a somewhat lessened predictability of motor response. Nonetheless, since the overall level of motor function through the day was equal to or better than that attained with STD, but with fewer medication administrations, Sinemet CR4 should prove a useful antiparkinsonian agent.
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There is debate about whether the initial treatment for patients with Parkinson's disease should be levodopa or a dopamine agonist. In this prospective, randomized, double-blind study, we compared the safety and efficacy of the dopamine D2-receptor agonist ropinirole with that of levodopa over a period of five years in 268 patients with early Parkinson's disease. If symptoms were not adequately controlled by the assigned study medication, patients could receive supplementary levodopa, administered in an open-label fashion. The primary outcome measure was the occurrence of dyskinesia. Eighty-five of the 179 patients in the ropinirole group (47 percent) and 45 of the 89 patients in the levodopa group (51 percent) completed all five years of the study. In the ropinirole group 29 of the 85 patients (34 percent) received no levodopa supplementation. The analysis of the time to dyskinesia showed a significant difference in favor of ropinirole (hazard ratio for remaining free of dyskinesia, 2.82; 95 percent confidence interval, 1.78 to 4.44; P<0.001). At five years, the cumulative incidence of dyskinesia (excluding the three patients who had dyskinesia at base line), regardless of levodopa supplementation, was 20 percent (36 of 177 patients) in the ropinirole group and 45 percent (40 of 88 patients) in the levodopa group. There was no significant difference between the two groups in the mean change in scores for activities of daily living among those who completed the study. Adverse events led to the early withdrawal from the study of 48 of 179 patients in the ropinirole group (27 percent) and 29 of 89 patients in the levodopa group (33 percent). The mean (+/-SD) daily doses given by the end of the study were 16.5+/-6.6 mg of ropinirole (plus 427+/-221 mg of levodopa in patients who received supplementation) and 753+/-398 mg of levodopa (including supplements). Early Parkinson's disease can be managed successfully for up to five years with a reduced risk of dyskinesia by initiating treatment with ropinirole alone and supplementing it with levodopa if necessary.
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Motor complications are a major source of disability for patients with advanced Parkinson's disease. Surgical therapies provide benefit to some, but these treatments are expensive and associated with adverse effects. Current research indicates that motor complications are associated with abnormal, intermittent, pulsatile stimulation of denervated dopamine receptors using short acting dopaminergic agents such as levodopa. Retrospective studies suggest that the use of longer-acting more continuous dopaminergic therapies can improve both motor fluctuations and dyskinesia. We performed a prospective, long-term (4-year) trial comparing patients randomized to receive subcutaneous infusion of the dopamine agonist lisuride versus conventional therapy with oral levodopa and dopamine agonists. We demonstrate that patients receiving lisuride infusions experienced a significant reduction in both motor fluctuations and dyskinesia compared with patients receiving standard dopaminergic therapies. Benefits persisted for the 4-year duration of the study. Mean Unified Parkinson's Disease Rating Scale scores in "ON" and "OFF" states did not significantly change between baseline and 4 years for patients in the lisuride group, but deteriorated in patients in the levodopa group. This study indicates that continuous lisuride infusion can be beneficial for patients with advanced Parkinson's disease and reverse established motor fluctuations and dyskinesia.
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Background Increased neuronal activity in the subthalamic nucleus and the pars interna of the globus pallidus is thought to account for motor dysfunction in patients with Parkinson's disease. Although creating lesions in these structures improves motor function in monkeys with induced parkinsonism and patients with Parkinson's disease, such lesions are associated with neurologic deficits, particularly when they are created bilaterally. Deep-brain stimulation simulates the effects of a lesion without destroying brain tissue. Methods We performed a prospective, double-blind, crossover study in patients with advanced Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus or pars interna of the globus pallidus and who then underwent bilateral high-frequency deep-brain stimulation. We compared scores on the motor portion of the Unified Parkinson's Disease Rating Scale when the stimulation was randomly assigned to be turned on or off. We performed unblinded evaluations of motor function preoperatively and one, three, and six months postoperatively. Results Electrodes were implanted bilaterally in 96 patients in the subthalamic-nucleus group and 38 patients in the globus-pallidus group. Three months after the procedures were performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score (as compared with no stimulation) of 49 percent, and stimulation of the pars interna of the globus pallidus with a median improvement of 37 percent (P<0.001 for both comparisons). Between the preoperative and six-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 percent to 74 percent (P<0.001) with subthalamic stimulation and from 28 percent to 64 percent (P<0.001) with pallidal stimulation. Adverse events included intracranial hemorrhage in seven patients and infection necessitating removal of the leads in two. Conclusions Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus is associated with significant improvement in motor function in patients with Parkinson's disease whose condition cannot be further improved with medical therapy.
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THE depletion by reserpine of storage in the body of 5-hydroxytryptamine (`Serotonin') and of the catechol amines is now well established1-3. In reserpinized animals the peripheral part of the adrenergic system does not function owing to lack of the transmitter2. This is presumably true also of the central part of the adrenergic system. However, it remains to be proved to what extent the central action of reserpine may be attributed to changes in brain catechol amines and/or 5-hydroxytryptamine.
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The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson’s disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson’s disease were randomized into two groups for treatment with L-dopa alone or L-dopa &plus; lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson’s Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4&percnt;) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa &plus; lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.
Article
The aim of this study was to ascertain whether the stage of Parkinson’s disease (PD) (according to the Hoehn and Yahr staging system) would affect the length of time between the introduction of levodopa therapy and appearance of levodopa-associated motor complications. Forty patients with clinically definite PD were studied. In all, clinical and therapeutic data were collected from the time of diagnosis to the time of levodopa-associated motor complications (i.e. dyskinesia, motor fluctuations). In 17 patients, levodopa could be started in Hoehn and Yahr stage I (H&Y-I; 16.2 months after the onset of PD), whilst in 13 patients levodopa could be started in H&Y-II (19.6 months after the onset of the disease) and in 10 in H&Y-III (45.1 months after the onset of PD). Cox proportional hazard regression model shows that the PD patients in whom the initial levodopa treatment was introduced at stage III develop both dyskinesias and motor fluctuations significantly earlier than the patients whose levodopa started in stage I and II of PD. The median interval to develop dyskinesias was 66, 72 and 24 months for patients in whom levodopa was introduced in stage I, II and III, respectively. These values were 64, 55 and 14 months for motor fluctuations. These findings add to the clinical arguments that favour an essential role of severity of PD at levodopa initiation as a risk factor for the development of levodopa-associated motor complications.
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Bei der Behandlung des idiopathischen Parkinson-Syndroms stellen die L-Dopa-induzierten motorischen Spätkomplikationen wie Wirkungsfluktuationen (wearing-off, End-of-dose-Akinese) und Dyskinesien ernste Komplikationen dar. Diese prospektive offene Studie zeigt, dass eine Add-on-Therapie mit Entacapon Wearing-off-Phänomene und die End-of-dose-Akinese signifikant verringert. Die Therapie ist gut verträglich und einfach durchführbar. The treatment of idiopathic Parkinson's disease becomes rather difficult if levodopa-induced late complications such as motor fluctuations or dyskinesias occur. This prospective and open study shows that an add-on therapy with entacapone can significantly lower wearing-off and end-of-dose akinesia. This treatment is well tolerated and easy to perform.
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The distribution of noradrenaline und dopamine (3-hydroxytyramine) in human adult and newborn brains has been investigated. The greatest amounts of noradrenaline were found in the hypothalamus, the central gray matter of the mesencephalon, the reticular formation and in the area postrema. The highest amount of dopamine was found in the neostriatum.
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We report observations on the treatment of 66 patients with presumed dopa-responsive dystonia (DRD). Forty-seven of these patients had hereditary disease; 19 had disease of sporadic occurrence. Initial diagnostic confusion with "cerebral palsy" or "spastic diplegia" existed in 16 patients. Several patients benefited from anticholinergic medications and a few from carbamazepine. Levodopa was the most effective treatment in all cases. In the majority, there was an excellent response, with continued long-term clinical stability on levodopa therapy for as long as 10 to 22 years. Four men with sporadic disease and 1 woman with a sister affected with adolescent-onset parkinsonism had similar initial treatment response, but developed "wearing-off" and a less satisfactory response to levodopa within the first few years of treatment. This indicates that some patients with clinical syndromes suggestive of DRD may not have an excellent prognosis on long-term levodopa treatment and may represent misclassified cases of childhood-onset parkinsonism.
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We examined the ability of L-DOPA to induce dyskinesias in MPTP-treated and normal squirrel monkeys to establish whether the underlying neuropathology associated with parkinsonism is an absolute requirement or merely promotes the development of drug-induced dyskinesias. Administration of L-DOPA (5-40 mg/kg p.o., following a 60 min pretreatment with carbidopa 2.5-20 mg/kg p.o.) induced a range of dopamine-mediated behaviours including locomotor activity, stereotyped scratching, and climbing in both lesioned and nonlesioned animals. However, the dose-response curves showed a marked (three- to fourfold) shift to the left in lesioned animals, indicating behavioural supersensitivity. In contrast, L-DOPA-induced dyskinesias were only observed in MPTP-treated monkeys. Doses required for induction of dyskinesias were lower than those required to induce climbing. These findings provide further evidence that nigrostriatal damage is essential for the genesis of L-DOPA-induced dyskinesias.
Article
The management of fluctuations in motor function complicating advanced Parkinson's disease with continuously administered dopaminomimetics was studied in 12 patients. In response to 7 to 12 days of round-the-clock intravenous infusions of levodopa, fluctuations in motor performance gradually diminished, ultimately by more than 40%. The beneficial effect persisted for about 6 days after withdrawal of continuous parenteral treatment and resumption of standard oral therapy. Clinical improvement was associated with changes in several pharmacological indices: Acute dose-response studies of intravenous levodopa showed a shift of the curve to the right in the immediate postinfusion phase compared to preinfusion studies; the therapeutic index improved significantly as patients demonstrated about 76% increased beneficial antiparkinsonian response with an equal degree of toxic dyskinetic effects; and the duration of action of levodopa was prolonged by 30%. These results suggest that changes in central dopaminergic mechanisms contributing to motor complications in advanced Parkinson's disease can be modified by procedures that provide continuous dopamine replacement. Presumably these modifications underlie the gradual amelioration of motor fluctuations over several days of round-the-clock therapy. Results of the present study also suggest potential deleterious effects of chronic intermittent oral treatment in the development of motor complications and thus support the role of long-term, continuous administration of dopaminomimetics.
Article
The relationship between severity of dopa-induced parkinsonian symptoms and the latency and severity of dopa-induced dyskinesias was studied in monkeys exposed to the toxin MPTP. Levodopa and D-2 receptor agonist-induced dyskinesias appeared early, between 2 and 12 days after initiation of dopa therapy in severely parkinsonian animals. In these animals, it was difficult to find a dose of L-dopa which had beneficial effects clinically and no dyskinesia-producing effects. These animals were all found to have massive (greater than or equal to 95%) striatal dopamine loss. A monkey with mild parkinsonian symptoms never developed dyskinesias similar to those produced in the severely affected animals. Stereotypies could be induced in this animal with excessively high doses of L-dopa or the dopamine D-2 receptor agonist, LY-171555. These movements were controlled by reducing the drug dose. This animal had less severe striatal dopamine loss (less than 80%) than the former group of monkeys. These results suggest that dopa dyskinesias in parkinsonian monkeys may be related to the extent of damage sustained by the nigrostriatal system.
Article
Several controlled-release carbidopa/levodopa preparations have been formulated to achieve a more stable and extended antiparkinsonian action. The most effective is Sinemet CR (Sinemet CR4), with an erodible polymer matrix that retards release of levodopa. In 19 parkinsonians with prominent dose-by-dose fluctuations, double-blind crossover trials comparing 8-week regimens of standard carbidopa/levodopa (25/100) to Sinemet CR (50/200) showed comparable clinical outcomes, with mean daily dosing for optimal control reduced from 10.2 to 5.4 (although mean daily levodopa dosage increased from 1,340 to 1,781 mg/day). Most patients improved on the Sinemet CR regimen in hours "on" and in ratings of clinical state and disability. With pharmacokinetic studies correlated to clinical ratings, plasma levodopa was less variable during Sinemet CR treatment, and clinical responses showed greater uniformity. Compared to standard Sinemet 25/100, time to peak levodopa concentration (2.3 versus 1.1 hrs), onset of maximal clinical improvement (2.2 versus 1.1 hrs), and other indices were significantly delayed with Sinemet CR. Levodopa bioavailability and clearance were similar between formulations. Although onset of clinical response is slower, the Sinemet CR formulation lessens peak-dose and "wearing-off" responses occurring with conventional carbidopa/levodopa and offers substantial improvement for some parkinsonians.
Article
The contribution of the peripheral and central pharmacokinetic mechanisms of levodopa to the pathogenesis of the motor fluctuations that complicate its long-term administration was studied in 28 parkinsonian patients. The rate of levodopa clearance from the general circulation, its plasma half-life, and apparent volume of distribution were indistinguishable between patients with the on-off or the wearing-off phenomenon and those with a stable response to levodopa or those who had not been previously treated with levodopa. Peripheral pharmacokinetic factors are thus unlikely to account for the development of these response fluctuations. Conversely, the efficacy half-time of levodopa differed markedly among the four response groups studied and may provide a quantitative index of central mechanisms that favor the development of the wearing-off and on-off phenomena. Although symptom duration was the best predictor of the severity of untreated parkinsonism, levodopa dose correlated best with response half-time. The wearing-off phenomenon may primarily reflect the loss of buffering capacity caused by degeneration of the dopamine neurons, while the development of the on-off phenomenon appears to require additional postsynaptic changes, possibly at the receptor level.
Article
The incidence of L dopa induced dyskinesias in 20 Guamanian patients with parkinsonism dementia (PD) was compared with that found in 14 Guamanians with amyotrophic lateral sclerosis (ALS), who were matched for dose and duration of drug exposure. While 55% of the PD patients developed abnormal involuntary meovements during the first 6 mth of treatment, none of the ALS patients manifested this complication. In PD patients no definite correlation could be documented between pretreatment parkinsonian severity or degree of response to L dopa and the appearance of dyskinesias. The results suggest that lesions of the type which produce Parkinson disease increase the susceptibility to L dopa induced dyskinesias, but that apparently denervation supersensitivity alone does not account for this phenomenon.
Article
An analysis of 51 patients with Parkinsonism who have developed L-dopa induced dyskinesias is presented. The cause has not been proven, although various hypotheses are discussed. One third of the total number of patients treated developed dyskinesia. These patients tend to respond better to L-dopa than the other group. There is a tendency for the older patient or the patient with long-standing disease to develop dyskinesias. There appears to be no way of predicting which patients will develop dyskinesia by analysis of the symptoms or the aetiology of the Parkinsonism syndrome. The unilateral characteristic of the dyskinesia in patients with hemi-Parkinsonism and patients with unilateral thalamotomies suggests that structural abnormalities are critical in determining the presence and localization of dyskinesias. This is supported by non-occurrence of similarly treated patients without Parkinsonism.
Article
Levodopa-induced dyskinesia of the limbs in thirteen cases of Parkinsonism, which was choreic, ballistic or dystonic in type, was alleviated almost completely by stereotaxic surgery using a microelectrode technique for the ventralis oralis anterior and posterior nuclei of the thalamus, but much less by the ventralis intermedius nucleus. Control of levodopa-induced dyskinesias by thalamic lesions in the course of routine treatment of Parkinsonism is discussed.
Article
Ventroposterolateral pallidotomy was used in the surgical treatment of 259 patients suffering from intractable Parkinson's disease. Pallidotomy was equally effective against tremor, rigor, bradykinesia, and the L-dopa-induced dyskinesias. The effect of surgery seemed to be long-lasting, and side effects were rare. The author believes that the beneficial effect of pallidotomy is based on interruption of striopallidal and pallidosubthalamic pathways.
Article
Four patients with Parkinson's disease, optimally treated with levodopa/carbidopa (LD/CD) tablets but experiencing severe motor fluctuations, underwent an open trial of a levodopa/carbidopa/ascorbic acid solution (LCAS) orally at timed intervals. LCAS reduced bradykinesia, decreased dysfunctional dyskinesia, and increased functional "on" time when compared with previous LD/CD tablet therapy. Oral LCAS allowed better titration of levodopa dosage and offered a more predictable response than LD/CD tablets. Preparation and oral consumption of LCAS was easy and inexpensive. LCAS may be a practical alternative for patients whose motor fluctuations fail to respond to optimal therapy with LD/CD tablets.
Article
Motor response fluctuations and dyskinesias compromise long-term levodopa therapy in Parkinson's disease. Variations in plasma levodopa levels contribute to adverse reactions associated with chronic therapy. Therefore, sustained-release levodopa preparations may be associated with less motor fluctuations and a better outcome. We conducted a large, 5-year, multicenter study to address this hypothesis. Six hundred and eighteen nonfluctuating patients with Parkinson's disease never exposed to levodopa therapy were randomized to (Sinemet CR 50/200) sustained-release or immediate-release (Sinemet 25/100) carbidopa/levodopa preparations in 35 centers worldwide. Dosage titration occurred over the 5 years of evaluations to maintain an optimal response. The primary endpoint, the 'event', was the presence of motor fluctuations, as defined by 20% 'off' time or 10% 'on' time with dyskinesias as recorded in the patient diary, or greater than or equal to a 50% positive response on the physician fluctuations questionnaire. Clinical rating scales, Nottingham Health Profile (NHP) and adverse reactions were also recorded. During the 5 years of the study, both treatment groups responded extremely well to therapy. The incidence of all patients reaching the 'event' was low, approximately 20% by diary criteria and 16% by questionnaire definition, and there was no significant difference between the two treatment groups. Activities of daily living scores in the Unified Parkinson Disease Rating Scale (UPDRS) consistently favored the Sinemet CR treatment group and a number of the NHP scales also favored the CR group. Based upon the frequency of adverse experiences, and the overall low incidence of withdrawals, the two treatment groups demonstrated very similar safety profiles. The most common drug-related effect was nausea; seen in 20% of patients. Other drug-related effects were dizziness, insomnia, abdominal pain, dyskinesia, headache and depression. Drug-related withdrawals were less than 10% of all patients, primarily due to nervous/psychiatric complaints. During a 5-year treatment period, control of parkinsonian symptoms was maintained by both immediate-release and sustained-release carbidopa/levodopa. Both treatment regimens were associated with a low incidence of motor fluctuations and dyskinesias. There was a statistically significant difference (p < 0.05) in activities of daily living as measured by the UPDRS in favor of Sinemet CR.
Article
Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson’s disease. No other drug matches its ability to suppress parkinsonian symptoms, especially in patients with advanced disease. But over time, initial benefits begin to wane, not so much because of a decline in efficacy against core symptoms, but rather because of a rise in adverse effects. Most common are the motor response complications that appear within a few years of treatment initiation and ultimately affect most parkinsonian patients. These progressively disabling complications include response fluctuations and abnormal involuntary movements. Current evidence indicates that ‘wearing-off’ fluctuations, typically the first motor complication to become clinically evident, initially reflect the loss of buffering normally provided by striatal dopaminergic terminals. Thus, with increasing degeneration of the nigrostriatal system, swings in plasma levodopa concentrations associated with standard dosage regimens produce nonphysiological fluctuations in intrasynaptic dopamine. As a result of long term discontinuous stimulation, secondary changes occur at sites downstream from the dopamine system and now appear to underlie the progressive worsening of ‘wearing-off’ phenomena as well as the eventual appearance of other response complications. Chronic intermittent stimulation of normally tonically active dopaminergic receptors activates specific signalling cascades in striatal dopaminoceptive medium spiny neurons, and this evidently results in long term potentiation of the synaptic efficacy of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype on these GABAergic efferents. As a consequence of their increasing sensitivity to excitation by cortical glutamatergic projections, it would, however, appear that medium spiny neuron function changes to favour the appearance of response fluctuations of the ‘on-off’ type and peak dose dyskinesias. The inability of standard levodopa treatment to restore striatal dopaminergic function in a more physiological manner clearly contributes to the appearance of motor complications. Continuous dopaminergic replacement not only reverses these complications in parkinsonian patients but also prevents their development in animal models of Parkinson’s disease. Thus, pharmaceutical approaches that provide relatively continuous dopamine receptor stimulation might confer both prophylactic and palliative benefit to parkinsonian patients. Several such strategies are currently under development, and include various methods to prolong the duration of action of levodopa as well as the use of transdermally administered or very long acting dopamine agonists.
Article
The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.
Article
Increasing laboratory and clinical evidence indicates that pulsatile stimulation of dopamine receptors contributes to the development of levodopa-related motor complications in PD. In keeping with this concept, clinical trials have demonstrated that initiating therapy with a long-acting dopamine agonist reduces the risk of inducing motor complications in comparison to levodopa. However, the introduction of levodopa is associated with the development of motor complications even in the presence of a long-acting dopamine agonist in both PD patients or MPTP treated monkeys. Administration of levodopa with a catechol-O-methyl transferase (COMT) inhibitor increases its plasma half-life, smoothes out peaks and troughs, and delivers levodopa to the brain in a more continuous fashion. We hypothesize that the risk of developing motor complications in PD patients when levodopa is introduced can be reduced if the levodopa is coupled with a COMT inhibitor so as to provide more continuous dopaminergic stimulation of dopamine receptors. A proposed algorithm for the treatment of the early PD patient is to initiate therapy with a dopamine agonist, and supplement with levodopa coupled with a COMT inhibitor when the dopamine agonist cannot provide satisfactory clinical benefits.
Article
To estimate the need for and the costs of carotid Doppler and carotid endarterectomy after stroke or TIA in non-selected hospitalized patients. During 25 months hospitalized patients with stroke or TIA, in whom carotid endarterectomy could be relevant, were examined with carotid Doppler. If a significant stenosis was found, they were further evaluated for surgery. Based on our results, the requirement for future carotid endarterectomy and Doppler screening was estimated, and the costs of the procedures calculated. Among 1351 patients 703 were screened with carotid Doppler. Forty-five had severe (70-99%) stenosis of the relevant carotid artery. Only 3 were operated on. The future costs of screening were estimated under different assumptions. Carotid endarterectomy is expensive due to the large number of patients screened with carotid Doppler per operated patient. A careful clinical selection of patients for screening is necessary.
Article
To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.