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1.
Trials ; 21(1): 1028, 2020 Dec 22.
Article in English | MEDLINE | ID: mdl-33353566

ABSTRACT

BACKGROUND: Randomised controlled trials (RCTs) provide valuable information and inform the development of harm profiles of new treatments. Harms are typically assessed through the collection of adverse events (AEs). Despite AEs being routine outcomes collected in trials, analysis and reporting of AEs in journal articles are continually shown to be suboptimal. One key challenge is the large volume of AEs, which can make evaluation and communication problematic. Prominent practice is to report frequency tables of AEs by arm. Visual displays offer an effective solution to assess and communicate complex information; however, they are rarely used and there is a lack of practical guidance on what and how to visually display complex AE data. METHODS: In this article, we demonstrate the use of two plots identified to be beneficial for wide use in RCTs, since both can display multiple AEs and are suitable to display point estimates for binary, count, or time-to-event AE data: the volcano and dot plots. We compare and contrast the use of data visualisations against traditional frequency table reporting, using published AE information in two placebo-controlled trials, of remdesivir for COVID-19 and GDNF for Parkinson disease. We introduce statistical programmes for implementation in Stata. RESULTS/CASE STUDY: Visualisations of AEs in the COVID-19 trial communicated a risk profile for remdesivir which differed from the main message in the published authors' conclusion. In the Parkinson's disease trial of GDNF, the visualisation provided immediate communication of harm signals, which had otherwise been contained within lengthy descriptive text and tables. Asymmetry in the volcano plot helped flag extreme events that were less obvious from review of the frequency table and dot plot. The dot plot allowed a more comprehensive representation by means of a more detailed summary. CONCLUSIONS: Visualisations can better support investigators to assimilate large volumes of data and enable improved informal between-arm comparisons compared to tables. We endorse increased uptake for use in trial publications. Care in construction of visual displays needs to be taken as there can be potential to overemphasise treatment effects in some circumstances.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19 Drug Treatment , Data Display , Data Visualization , Drug-Related Side Effects and Adverse Reactions/diagnosis , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Parkinson Disease/drug therapy , Research Design/standards , Adenosine Monophosphate/adverse effects , Alanine/adverse effects , Antiparkinson Agents/adverse effects , Antiviral Agents/adverse effects , Computer Graphics , Data Accuracy , Data Analysis , Drug Monitoring/methods , Humans , Randomized Controlled Trials as Topic
2.
Gene Ther ; 24(4): 245-252, 2017 04.
Article in English | MEDLINE | ID: mdl-28276446

ABSTRACT

Injecting proteins into the central nervous system that stimulate neuronal growth can lead to beneficial effects in animal models of disease. In particular, glial cell line-derived neurotrophic factor (GDNF) has shown promise in animal and cell models of Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS). Here, systemic AAV9-GDNF was delivered via tail vein injections to young rats to determine whether this could be a safe and functional strategy to treat the SOD1G93A rat model of ALS and, therefore, translated to a therapy for ALS patients. We found that GDNF administration in this manner resulted in modest functional improvement, whereby grip strength was maintained for longer and the onset of forelimb paralysis was delayed compared to non-treated rats. This did not, however, translate into an extension in survival. In addition, ALS rats receiving GDNF exhibited slower weight gain, reduced activity levels and decreased working memory. Collectively, these results confirm that caution should be applied when applying growth factors such as GDNF systemically to multiple tissues.


Subject(s)
Amyotrophic Lateral Sclerosis/therapy , Central Nervous System/physiopathology , Glial Cell Line-Derived Neurotrophic Factor/therapeutic use , Motor Neurons/pathology , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/physiopathology , Animals , Central Nervous System/drug effects , Dependovirus/genetics , Disease Models, Animal , Genetic Therapy , Genetic Vectors/genetics , Genetic Vectors/therapeutic use , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Glial Cell Line-Derived Neurotrophic Factor/genetics , Hand Strength/physiology , Humans , Motor Neurons/metabolism , Rats , Spinal Cord/drug effects , Spinal Cord/physiopathology , Superoxide Dismutase/genetics
3.
Liver Transpl ; 22(4): 459-67, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26714616

ABSTRACT

Moderate macrovesicular steatosis (>30%), which is present in almost 50% of livers considered for transplantation, increases the risk of primary graft dysfunction. Our previously published data showed that glial cell line-derived neurotrophic factor (GDNF) is protective against high-fat diet (HFD)-induced hepatic steatosis in mice. Hence, we hypothesized that perfusion of steatotic livers with GDNF may reduce liver fat content before transplantation. Livers from 8 weeks of regular diet (RD) and of HFD-fed mice were perfused ex vivo for 4 hours with either vehicle, GDNF, or a previously described defatting cocktail. The liver's residual fat was quantified colorimetrically using a triglyceride (TG) assay kit and by Oil Red O (ORO) and Nile red/Hoechst staining. Liver tissue injury was assessed by using a lactate dehydrogenase (LDH) activity assay. In vitro induction of lipolysis in HepG2 cells was assessed by measuring glycerol and free fatty acid release. ORO staining showed significantly more steatosis in livers from HFD-fed mice compared with RD-fed mice (P < 0.001). HFD livers perfused with GDNF had significantly less steatosis than those not perfused (P = 0.001) or perfused with vehicle (P < 0.05). GDNF is equally effective in steatotic liver defatting compared to the defatting cocktail; however, GDNF induces less liver damage than the defatting cocktail. These observations were consistent with data obtained from assessment of liver TG content. Assessment of liver injury revealed significant hepatocyte injury in livers perfused with the control defatting cocktail but no evidence of injury in livers perfused with either GDNF or vehicle. In vitro, GDNF reduced TG accumulation in HepG2 cells and stimulated increased TG lipolysis. In conclusion, GDNF can decrease mice liver fat content to an acceptable range and could be a potential defatting agent before liver transplantation.


Subject(s)
Fatty Liver/therapy , Glial Cell Line-Derived Neurotrophic Factor/therapeutic use , Liver Transplantation/methods , Primary Graft Dysfunction/prevention & control , Triglycerides/metabolism , Animals , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/metabolism , Colorimetry , Diet, High-Fat/adverse effects , Disease Models, Animal , Fatty Liver/etiology , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Graft Survival/drug effects , Hep G2 Cells , Hepatocytes/metabolism , Humans , Lipolysis/drug effects , Male , Mice , Mice, Inbred C57BL , Perfusion , Rats , Triglycerides/analysis
4.
Neurotoxicology ; 52: 46-56, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26535469

ABSTRACT

Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000µg/month). No cerebellar toxicity was observed at lower doses (450 and 900µg/month) in the same study, or at similar or higher doses (up to 10,000µg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.


Subject(s)
Cerebellum/drug effects , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Animals , Cerebellum/pathology , Cerebellum/physiopathology , Dose-Response Relationship, Drug , Glial Cell Line-Derived Neurotrophic Factor/administration & dosage , Humans , Infusions, Intraventricular , Microinjections , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/adverse effects , Putamen/drug effects
5.
Curr Pain Headache Rep ; 15(3): 185-92, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21327569

ABSTRACT

A treatment for neuropathic pain is an important unmet medical need because this pain often is refractory to many medical interventions. An important element in the development of neuropathic pain is a dysfunction in the activity of peripheral nerves. Because neurotrophic factors affect nerve development and maintenance, modulating the activity of these factors can alter neuronal pathophysiology and produce a disease-modifying effect. Blocking the activity of nerve growth factor or enhancing the activity of either glial-derived neurotrophic factor or artemin has shown potential for normalizing neuronal activity and attenuating signs of neuropathic pain in animal models and clinical studies. This article discusses the role of these factors in neuropathic pain and the implications for the development of novel therapeutics.


Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Neuralgia/metabolism , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Glial Cell Line-Derived Neurotrophic Factor/antagonists & inhibitors , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Humans , Intercellular Signaling Peptides and Proteins/adverse effects , Nerve Growth Factor/adverse effects , Nerve Growth Factor/antagonists & inhibitors , Nerve Growth Factor/metabolism , Nerve Growth Factors/adverse effects , Nerve Growth Factors/antagonists & inhibitors , Nerve Growth Factors/metabolism , Neuralgia/drug therapy , Neuralgia/etiology
6.
Folia Histochem Cytobiol ; 48(3): 434-41, 2010 Sep 30.
Article in English | MEDLINE | ID: mdl-21071351

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative disorder marked by cell death in the Substantia nigra (SN). Docosahexaenoic acid (DHA) is the major polyunsaturated fatty acid (PUFA) in the phospholipid fraction of the brain and is required for normal cellular function. Glial cell line derived neurotrophic factor (GDNF) and neurturin (NTN) are very potent trophic factors for PD. The aim of the study was to evaluate the neuroprotective effects of GDNF and NTN by investigating their immunostaining levels after administration of DHA in a model of PD. For this reason we hypothesized that DHA administration of PD might alter GDNF, NTN expression in SN. MPTP neurotoxin that induces dopaminergic neurodegeneration was used to create the experimental Parkinsonism model. Rats were divided into; control, DHA-treated (DHA), MPTP-induced (MPTP), MPTP-induced+DHA-treated (MPTP+DHA) groups. Dopaminergic neuron numbers were clearly decreased in MPTP, but showed an increase in MPTP+DHA group. As a result of this, DHA administration protected dopaminergic neurons as shown by tyrosine hydroxylase immunohistochemistry. In the MPTP+DHA group, GDNF, NTN immunoreactions in dopaminergic neurons were higher than that of the MPTP group. In conclusion, the characterization of GDNF and NTN will certainly help elucidate the mechanism of DHA action, and lead to better strategies for the use of DHA to treat neurodegenerative diseases.


Subject(s)
Docosahexaenoic Acids/pharmacology , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Neurturin/metabolism , Parkinson Disease, Secondary/pathology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Disease Models, Animal , Dopamine/metabolism , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Glial Cell Line-Derived Neurotrophic Factor/pharmacology , Immunohistochemistry , Male , Nerve Degeneration/chemically induced , Nerve Degeneration/pathology , Neurons/drug effects , Neuroprotective Agents/pharmacology , Neurotoxins , Neurturin/adverse effects , Neurturin/pharmacology , Random Allocation , Rats , Rats, Wistar , Substantia Nigra/cytology , Substantia Nigra/metabolism , Substantia Nigra/pathology , Tyrosine 3-Monooxygenase/immunology , Tyrosine 3-Monooxygenase/metabolism
7.
Neuroscience ; 171(1): 344-50, 2010 Nov 24.
Article in English | MEDLINE | ID: mdl-20736053

ABSTRACT

Sensitization to mechanical stimuli is important in most pain syndromes. We evaluated the populations of nociceptors mediating mechanical hyperalgesia and those mediating mu-opioid receptor (MOR) and delta-opioid receptor (DOR) agonist-induced inhibition of hyperalgesia, in the rat. We found that: (1) intradermal injection of both the endogenous ligand for the Ret receptor, glia-derived growth factor (GDNF), and the ligand for the tropomyosin receptor kinase A (TrkA) receptor, nerve growth factor (NGF)-which are present on distinct populations of nociceptors-both produce mechanical hyperalgesia; (2) DOR agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC) but not MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) inhibit GDNF-induced hyperalgesia; (3) both DAMGO and SNC inhibit NGF hyperalgesia, even in rats pretreated with isolectin B4 (IB4)-saporin, a toxin that destroys IB4-binding neurons; (4) co-administration of low doses of DAMGO and SNC produce enhanced analgesia, and; (5) repeated administration of DAMGO produces cross-tolerance to the analgesic effect of SNC. These findings demonstrate that, most nociceptors have a role in mechanical hyperalgesia, only the DOR agonist inhibits GDNF hyperalgesia, and MOR and DOR are co-localized on a functionally important population of TrkA-positive nociceptors.


Subject(s)
Hyperalgesia/pathology , Nociceptors/metabolism , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Analgesics, Opioid/pharmacology , Analgesics, Opioid/therapeutic use , Animals , Cholera Toxin/metabolism , Cysteine/adverse effects , Cysteine/analogs & derivatives , Disease Models, Animal , Drug Synergism , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/therapeutic use , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Horseradish Peroxidase/metabolism , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Male , Pain Threshold/drug effects , Pain Threshold/physiology , Rats , Rats, Sprague-Dawley , S-Nitrosothiols/adverse effects , Vasodilator Agents/adverse effects
8.
Pharm Res ; 26(10): 2227-36, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19609743

ABSTRACT

PURPOSE: Glial-derived neurotrophic factor (GDNF) is a potential therapy for stroke, Parkinson's disease, or drug addiction. However, GDNF does not cross the blood-brain barrier (BBB). GDNF is re-engineered as a fusion protein with a chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR), which acts as a molecular Trojan horse to deliver the GDNF across the BBB. The pharmacokinetics (PK), toxicology, and safety pharmacology of the HIRMAb-GDNF fusion protein were investigated in Rhesus monkeys. METHODS: The fusion protein was administered as an intravenous injection at doses up to 50 mg/kg over a 60 h period to 56 Rhesus monkeys. The plasma concentration of the HIRMAb-GDNF fusion protein was measured with a 2-site sandwich ELISA. RESULTS: No adverse events were observed in a 2-week terminal toxicology study, and no neuropathologic changes were observed. The PK analysis showed a linear relationship between plasma AUC and dose, a large systemic volume of distribution, as well as high clearance rates of 8-10 mL/kg/min. CONCLUSIONS: A no-observable-adverse-effect level is established in the Rhesus monkey for the acute administration of the HIRMAb-GDNF fusion protein. The fusion protein targeting the insulin receptor has a PK profile similar to a classical small molecule.


Subject(s)
Antibodies, Monoclonal/pharmacokinetics , Blood-Brain Barrier/metabolism , Drug Delivery Systems/methods , Glial Cell Line-Derived Neurotrophic Factor/pharmacokinetics , Recombinant Fusion Proteins/pharmacokinetics , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Blood-Brain Barrier/drug effects , Dose-Response Relationship, Drug , Female , Glial Cell Line-Derived Neurotrophic Factor/administration & dosage , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Macaca mulatta , Male , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects
9.
J Control Release ; 135(2): 119-26, 2009 Apr 17.
Article in English | MEDLINE | ID: mdl-19154763

ABSTRACT

Glial cell line-derived neurotrophic factor (GDNF) has shown promise in the treatment of neurodegenerative disorders of basal ganglia origin such us Parkinson's disease (PD). In this study, we investigated the neurorestorative effect of controlled GDNF delivery using biodegradable microspheres in an animal model with partial dopaminergic lesion. Microspheres were loaded with N-glycosylated recombinant GDNF and prepared using the Total Recirculation One-Machine System (TROMS). GDNF-loaded microparticles were unilaterally injected into the rat striatum by stereotaxic surgery two weeks after a unilateral partial 6-OHDA nigrostriatal lesion. Animals were tested for amphetamine-induced rotational asymmetry at different times and were sacrificed two months after microsphere implantation for immunohistochemical analysis. The putative presence of serum IgG antibodies against rat glycosylated GDNF was analyzed for addressing safety issues. The results demonstrated that GDNF-loaded microspheres, improved the rotational behavior induced by amphetamine of the GDNF-treated animals together with an increase in the density of TH positive fibers at the striatal level. The developed GDNF-loaded microparticles proved to be suitable to release biologically active GDNF over up to 5 weeks in vivo. Furthermore, none of the animals developed antibodies against GDNF demonstrating the safety of glycosylated GDNF use.


Subject(s)
Brain/metabolism , Drug Delivery Systems , Glial Cell Line-Derived Neurotrophic Factor/administration & dosage , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Microspheres , Parkinson Disease/therapy , Animals , Cell Differentiation/drug effects , Corpus Striatum/drug effects , Disease Models, Animal , Drug Carriers/chemistry , Female , Fluorescent Antibody Technique, Indirect , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Glial Cell Line-Derived Neurotrophic Factor/genetics , Glial Cell Line-Derived Neurotrophic Factor/ultrastructure , Glycosylation , Immunohistochemistry , Kinetics , Lactic Acid/chemistry , Models, Neurological , PC12 Cells , Particle Size , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Rats , Rats, Sprague-Dawley , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism
10.
Expert Opin Ther Targets ; 12(4): 437-47, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18348680

ABSTRACT

BACKGROUND: The search for therapeutic agents that might alter the disease course in Parkinson's disease (PD) is ongoing. One area of particular interest involves neurotrophic factors (NTFs), with those of the glial cell line-derived neurotrophic factor (GDNF) family showing greatest promise. The safety and efficacy of these therapies has recently come into question. Furthermore, many of the key questions pertaining to such therapies, such as the optimal method of delivery, timing of treatment and selection of patients most likely to benefit, remain unanswered. OBJECTIVE: In this review we sought to evaluate the therapeutic potential of NTFs in the treatment of PD. We appraised the evidence provided by both in vitro and in vivo work before proceeding to a critical assessment of the relevant clinical trial data. METHODS: Relevant literature was identified using a PubMed search of articles published up to October 2007. Search terms included: 'Parkinson's disease', 'Neurotrophic factors', 'BDNF' (Brain-derived neurotrophic factor), 'GDNF' and 'Neurturin'. Original articles were reviewed, and relevant citations from these articles were also appraised. CONCLUSION: NTF therapy has potential in the treatment of nigrostriatal dysfunction in PD but numerous methodological and safety issues will need to be addressed before this approach can be widely adopted. Furthermore PD is now recognized as being more than a pure motor disorder, and one in which neuronal loss is not just confined to the dopaminergic nigrostriatal system. Non-motor symptomatology in PD is unlikely to benefit from therapies that target only the nigrostriatal system, and this must inform our thinking as to the maximal achievable benefit that NTFs are ever likely to provide.


Subject(s)
Antiparkinson Agents/pharmacology , Nerve Growth Factors/pharmacology , Parkinson Disease/drug therapy , Animals , Antiparkinson Agents/adverse effects , Antiparkinson Agents/therapeutic use , Clinical Trials as Topic , Disease Models, Animal , Drug Delivery Systems , Drug Evaluation, Preclinical , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Glial Cell Line-Derived Neurotrophic Factor/pharmacology , Glial Cell Line-Derived Neurotrophic Factor/therapeutic use , Humans , Nerve Growth Factors/adverse effects , Nerve Growth Factors/therapeutic use
12.
Neurosurg Focus ; 20(5): E1, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16711657

ABSTRACT

OBJECT: Glial cell line-derived neurotrophic factor (GDNF) infused unilaterally into the putamen for 6 months was previously shown to improve motor functions and quality of life measures significantly in 10 patients with Parkinson disease (PD) in a Phase I trial. In this study the authors report the safety and efficacy of continuous treatment for 1 year or more. After the trial was halted by the sponsor, the patients were monitored for an additional year to evaluate the effects of drug withdrawal. METHODS: During the extended study, patients received unilateral intraputaminal infusion of 30 mg/day GDNF at a basal infusion rate supplemented with pulsed boluses every 6 hours at a convection-enhanced delivery rate to increase tissue penetration of the protein. When the study was stopped, the delivery system was reprogrammed to deliver sterile saline at the basal infusion rate of 2 ml/hour. The Unified PD Rating Scale (UPDRS) total scores after 1 year of therapy were improved by 42 and 38%, respectively, in the "off" and "on" states. Motor UPDRS scores were also improved: 45 and 39% in the off and on conditions, respectively. Benefits from treatment were lost by 9 to 12 months after GDNF infusion was halted. At that time, the patients had returned to their baseline UPDRS scores and required higher levels of conventional antiparkinsonian drugs to treat symptoms. After 11 months of treatment, the delivery system had to be removed in one patient because of the risk of infection. In seven patients antibodies to GDNF developed, with no evidence of clinical sequelae. There was also no evidence of GDNF-induced cerebellar toxicity, as evaluated using magnetic resonance imaging analysis and clinical testing. CONCLUSIONS: Unilateral administration of GDNF results in significant, sustained bilateral benefits. These improvements are lost within 9 months after drug withdrawal. Safety concerns with GDNF therapy can be closely monitored and managed.


Subject(s)
Glial Cell Line-Derived Neurotrophic Factor/administration & dosage , Parkinson Disease/drug therapy , Putamen/drug effects , Aged , Antiparkinson Agents/therapeutic use , Clinical Trials, Phase I as Topic , Drug Administration Schedule , Female , Glial Cell Line-Derived Neurotrophic Factor/adverse effects , Glial Cell Line-Derived Neurotrophic Factor/therapeutic use , Humans , Levodopa/therapeutic use , Male , Middle Aged , Movement/drug effects , Parkinson Disease/physiopathology , Severity of Illness Index , Treatment Outcome
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