Investigation of the Long-Term Effects of Amantadine Use in Parkinson's Disease.
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SUBMITTER: Park S
PROVIDER: S-EPMC10236022 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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Investigation of the Long-Term Effects of Amantadine Use in Parkinson's Disease.
Park Sangmin S Shin Jung Hwan JH Jeon Seung Ho SH Lee Chan Young CY Kim Han-Joon HJ Jeon Beomseok B
Journal of movement disorders 20230524 2
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Project description:BackgroundNilotinib is US Food and Drug Administration-approved for leukemia, and this open-label study investigated the safety, tolerability, and potential clinical effects of nilotinib in medically optimized patients with Parkinson's disease.ObjectivesSafety and tolerability were the primary objectives, and clinical outcomes were exploratory.MethodsA total of 63 patients completed a 15-month phase 2, double-blind, placebo-controlled study and were rerandomized 1:1 into an open-label study of nilotinib 150 mg versus 300 mg for 12 months.ResultsNilotinib was safe and tolerated, and no adverse effects seemed to be related to the drug, and no differences in adverse events were observed between groups. Exploratory clinical outcomes showed that nilotinib 300 mg was remarkably stable from baseline to 27 months using partial and total Unified Parkinson's Disease Scale (UPDRS). Nilotinib 150 mg versus 300 mg, significantly declined using partial or the sum of UPDRS Parts I and II. There was no significant difference in nilotinib 150 mg versus 300 mg using UPDRS Part III (on levodopa) and total UPDRS Parts I to III. Subgroup analysis showed that late-start nilotinib 150 mg significantly worsened using the sum of UPDRS Parts II + III and total UPDRS Parts I to III compared with late-start nilotinib 300 mg. Quality of life using the Parkinson's Disease Questionnaire in nilotinib 150 mg significantly declined between 15 and 27 months compared with nilotinib 300 mg, and there was no change in cognition using the Montreal Cognitive Assessment between groups.ConclusionsThis study provides evidence that nilotinib is safe and tolerated in Parkinson's disease. The exploratory clinical data will inform an adequately powered larger study to evaluate the efficacy of nilotinib 300 mg in Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC8048914 | biostudies-literature
Project description:Parkinson's disease (PD) is a progressive neurodegenerative disease. Levodopa in combination with amantadine has a demonstrated efficacy in motility impairment. An extensive investigation of some enzymes described to be upregulated or downregulated in PD was made - adenylate kinase (AK), adenine phosphoribosyltransferase (APRT), ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), nucleoside-diphosphate kinase 3 (NDK3), purine nucleoside phosphorylase 1 (PNP1), and ecto-5'-nucleotidase (NT5E). Also, creatine kinase (CK) was included in the study because it is one of the main enzymes involved in the regulation of the nucleotide ratio in energy metabolism. To date, there is no proven link between amantadine treatment of PD and these enzymes. Because there are many AKs isoforms modified in PD, the AK was the first investigated. The molecular docking experiments allow the analysis of the selective binding of amantadine - unionized (with -NH2 group) and ionized form (with -NH3 + group) - to the AKs' isoforms implicated in PD. Using available X-ray 3D structures of human AKs in closed-conformation, it was demonstrated that there are notable differences between the interactions of the two forms of amantadine for the zebrafish AK1 (5XZ2), human AK2 (2C9Y), human AK5 (2BWJ), and AK from B.stearothermophilus. The cytosolic human AK1 and human AK2 mostly interact with ionized amantadine by AMP binding residues. The human AK5 interaction with ionized amantadine does not involve the residues from the catalytic site. Among other enzymes tested in the present study, APRT revealed the best results in respect of binding amantadine ionized form. The results offer a new perspective for further investigation of the connections between amantadine treatment of PD and some enzymes involved in purine metabolism.
| S-EPMC8915579 | biostudies-literature
Project description:The aim was to compare the short and long-term effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait dysfunction and other cardinal symptoms of Parkinson's disease (PD). Two groups of patients were studied. The first group (short-term DBS, n = 8) included patients recently implanted with STN DBS (mean time since DBS 15.8 months, mean age 58.8 years, PD duration 13 years); the second group (long-term DBS, n = 10) included patients with at least 5 years of DBS therapy (mean time since DBS 67.6 months, mean age 61.7 years, PD duration 17.1 years). Both groups were examined using the Unified Parkinson's Disease Rating Scale (UPDRS) and Gait and Balance scale (GABS) during four stimulation/medication states (ON/OFF; OFF/OFF; OFF/ON; ON/ON). Data were analyzed using repeated measures ANOVA with time since implantation (years) between groups and medication or DBS effect (ON, OFF) within groups. In the short-term DBS group, stimulation improved all UPDRS subscores similar to dopaminergic medications. In particular, average gait improvement was over 40% (p = 0.01), as measured by the UPDRS item 29 and GABS II. In the long-term DBS group, stimulation consistently improved all clinical subscores with the exception of gait and postural instability. In these patients, the effect of levodopa on gait was partially preserved. Short-term improvement of gait abnormalities appears to significantly decline after 5 years of STN DBS in PD patients, while effectiveness for other symptoms remains stable. Progressive non-dopaminergic (non-DBS responsive) mechanisms or deleterious effects of high frequency STN stimulation on gait function may play a role.
| S-EPMC8531078 | biostudies-literature
Project description:BackgroundComputerized cognitive training may be promising to improve cognitive impairment in Parkinson's disease and has even been suggested to delay cognitive decline. However, evidence to date is limited. The aim of this study was to assess the durability of eight-week cognitive training effects at up to two years follow-up.MethodsOne hundred and thirty-six (1 3 6) individuals with Parkinson's disease, subjective cognitive complaints but without severe cognitive impairment (Montreal Cognitive Assessment ≥ 22) participated in this double-blind RCT. Participants underwent an eight-week home-based intervention of either adaptive, computerized cognitive training with BrainGymmer (n = 68) or an active control (n = 68). They underwent extensive neuropsychological assessment, psychiatric questionnaires and motor symptom assessment at baseline and one and two years after the intervention. We used mixed-model analyses to assess changes in cognitive function at follow-up and performed Fisher's exact tests to assess conversion of cognitive status.ResultsThere were no group differences on any neuropsychological assessment outcome at one- and two-year follow-up. Groups were equally likely to show conversion of cognitive status at follow-up. A considerable amount of assessments was missed (1y: n = 27; 2y: n = 33), most notably due to COVID-19 regulations.ConclusionsEight-week cognitive training did not affect long-term cognitive function in Parkinson's disease. Future studies may focus on one cognitive subgroup to enhance reliability of study results. Intervention improvements are needed to work towards effective, lasting treatment options.
| S-EPMC10724826 | biostudies-literature
Project description:BackgroundSpinal cord stimulation (SCS) exerts neuroprotective effects in animal models of Parkinson's disease (PD). Conventional stimulation techniques entail limited stimulation time and restricted movement of animals, warranting the need for optimizing the SCS regimen to address the progressive nature of the disease and to improve its clinical translation to PD patients.ObjectiveRecognizing the limitations of conventional stimulation, we now investigated the effects of continuous SCS in freely moving parkinsonian rats.MethodsWe developed a small device that could deliver continuous SCS. At the start of the experiment, thirty female Sprague-Dawley rats received the dopamine (DA)-depleting neurotoxin, 6-hydroxydopamine, into the right striatum. The SCS device was fixed below the shoulder area of the back of the animal, and a line from this device was passed under the skin to an electrode that was then implanted epidurally over the dorsal column. The rats were divided into three groups: control, 8-h stimulation, and 24-h stimulation, and behaviorally tested then euthanized for immunohistochemical analysis.ResultsThe 8- and 24-h stimulation groups displayed significant behavioral improvement compared to the control group. Both SCS-stimulated groups exhibited significantly preserved tyrosine hydroxylase (TH)-positive fibers and neurons in the striatum and substantia nigra pars compacta (SNc), respectively, compared to the control group. Notably, the 24-h stimulation group showed significantly pronounced preservation of the striatal TH-positive fibers compared to the 8-h stimulation group. Moreover, the 24-h group demonstrated significantly reduced number of microglia in the striatum and SNc and increased laminin-positive area of the cerebral cortex compared to the control group.ConclusionsThis study demonstrated the behavioral and histological benefits of continuous SCS in a time-dependent manner in freely moving PD animals, possibly mediated by anti-inflammatory and angiogenic mechanisms.
| S-EPMC7309445 | biostudies-literature
Project description:BackgroundDyskinesias are some of the major motor complications that impair quality of life for patients with Parkinson's disease. The purpose of the present study was to investigate the efficacy of amantadine in Parkinson's disease patients suffering from dyskinesias.MethodsIn this multi-center, double-blind, randomized, placebo-controlled, cross-over trial, 36 patients with Parkinson's disease and dyskinesias were randomized, and 62 interventions, which included amantadine (300 mg/day) or placebo treatment for 27 days, were analyzed. At 15 days after washout, the treatments were crossed over. The primary outcome measure was the changes in the Rush Dyskinesia Rating Scale (RDRS) during each treatment period. The secondary outcome measures were changes in the Unified Parkinson's Disease Rating Scale part IVa (UPDRS-IVa, dyskinesias), part IVb (motor fluctuations), and part III (motor function).ResultsRDRS improved in 64% and 16% of patients treated with amantadine or placebo, respectively, with significant differences between treatments. The adjusted odds-ratio for improvement by amantadine was 6.7 (95% confidence interval, 1.4 to 31.5). UPDRS-IVa was improved to a significantly greater degree in amantadine-treated patients [mean (SD) of 1.83 (1.56)] compared with placebo-treated patients [0.03 (1.51)]. However, there were no significant effects on UPDRS-IVb or III scores.ConclusionsResults from the present study demonstrated that amantadine exhibited efficacious effects against dyskinesias in 60-70% of patients.Trial registrationUMIN Clinical Trial Registry UMIN000000780.
| S-EPMC3013111 | biostudies-literature
Project description:Background and purposeCognitive rehabilitation has demonstrated efficacy in producing short-term cognitive and brain changes in patients with Parkinson's disease (PD). To date, no study has assessed the long-term effects of cognitive rehabilitation using neuroimaging techniques in PD. The aim was to assess the longitudinal effects of a 3-month cognitive rehabilitation programme evaluating the cognitive, behavioural and neuroimaging changes after 18 months.MethodsFifteen patients with PD underwent a cognitive, behavioural and neuroimaging assessment at pre-treatment (T0 ), post-treatment (T1 ) and after 18 months (T2 ). This study examined the long-term effects (from T0 to T2 ) and the maintenance of the changes (from T1 to T2 ). T1-weighted, diffusion-weighted, functional magnetic resonance imaging during both a resting-state and a memory paradigm were acquired. Voxel-based morphometry and tract-based spatial statistics were used for grey and white matter analyses. A region-of-interest-to-region-of-interest approach was used for resting-state functional connectivity (FC) and a model-based approach was used for brain activation during the memory paradigm.ResultsPatients with PD showed increased cognitive performance, decreased functional disability, increased brain FC and activation at T2 compared with T0 (P < 0.05, FDR). Moreover, patients showed maintenance of the improvements in cognition and functionality, and maintenance of the increased brain FC and activation at T2 compared with T1 . However, significant grey matter reduction and alterations of white matter integrity were found at T2 (P < 0.05, FWE).ConclusionsFindings suggest that the improved cognitive performance and increased brain FC and activation after cognitive rehabilitation were significantly maintained after 18 months in patients with PD, despite the structural brain changes, consistent with a progression of neurodegenerative processes.
| S-EPMC5765471 | biostudies-literature
Project description:ObjectivesDeep brain stimulation (DBS) of the subthalamic nucleus (STN) has been reported to have a positive effect on sleep-wake disturbance in Parkinson's disease (PD). We aimed to investigate the long-term effects of STN DBS on sleep in patients with PD.MethodsSixty-one patients with PD who had undergone bilateral STN DBS were followed for 3 years with assessments including the Parkinson's disease sleep scale (PDSS), Epworth sleepiness scale (ESS), total sleep hours per day, Unified PD Rating Scale part I-III, Hoehn & Yahr stage, levodopa equivalent dose, quality of life measure, and depression scale measured preoperatively and at 6 months after postoperatively, and annually thereafter.ResultsAmong the 61 patients at baseline, 46 patients completed the last follow-up assessment. The total PDSS score significantly improved after STN DBS from baseline up to 3 years after STN DBS (79.0±30, 100.0±23.3, 98.8±23.0, 97.1±29.6, and 93.3±28.0 at baseline, 6, 12, 24, and 36 months, respectively, p = 0.006 for the change over time). Among the eight PDSS domains, the domains for overall quality of a night's sleep, sleep onset and maintenance insomnia, and nocturnal motor symptoms showed significant improvement after STN DBS (p = 0.036, 0.029, and < 0.001, respectively, for the change over time). The total sleep hours per day were increased, but the total ESS score did not show significant change after STN DBS (p = 0.001 and 0.055, respectively, for the change over time). Changes in the total PDSS were associated with changes in the depression and motivation items in the Unified PD Rating Scale part I, depression scale, and quality of life measure, but those variables at baseline were not predictive of changes in the total PDSS after STN DBS.ConclusionIn the largest systematic long-term follow-up study, the improvement in subjective sleep quality after bilateral STN DBS was sustained in PD patients. Improved nocturnal sleep and nocturnal motor symptoms were correlated with an improved mood and quality of life. However, STN DBS did not reduce excessive daytime sleepiness despite reductions in antiparkinsonian medications.
| S-EPMC6711522 | biostudies-literature
Project description:IntroductionGocovri (amantadine) extended release capsules are approved for treatment of dyskinesia and as a levodopa adjunct for OFF episodes in patients with Parkinson's disease (PD). We report treatment-related effects on non-motor symptoms (NMS) assessed as secondary outcomes in two trials using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I.MethodsEASE LID and EASE LID 3 enrolled levodopa-treated patients with PD and ≥ 1 h/day ON time with troublesome dyskinesia. Patients were randomized to Gocovri (274 mg) or placebo taken daily at bedtime. Treatment differences from baseline to week 12 in MDS-UPDRS Part I were evaluated for the pooled population (N = 196) from both trials. Correlation analyses of NMS (MDS-UPDRS Part I) with dyskinesia using Unified Dyskinesia Rating Scale (UDysRS) scores were performed.ResultsFor changes in the MDS-UPDRS Part I items, the treatment difference favored Gocovri in daytime sleepiness (P = 0.006) and depression (P = 0.049) scores, but favored placebo in cognitive impairment (P = 0.038), and hallucinations and psychosis (P < 0.001) scores. The treatment difference for the changes in total Part I score was -0.8, favoring Gocovri (P = 0.22). At baseline, MDS-UPDRS Part I modestly correlated with UDysRS score (r +0.25, P < 0.001), and improvement in NMS correlated with improvement in dyskinesia at week 12 for Gocovri (r +0.39, P < 0.001) but not placebo (r +0.12, P = 0.29). The most commonly reported adverse events for Gocovri were hallucination (21%); dizziness, dry mouth, and peripheral edema (16% each); and constipation, falls, and orthostatic hypotension (13% each).ConclusionThis post hoc analysis shows potential benefit with Gocovri treatment for the NMS of daytime sleepiness and depression in dyskinetic PD patients. Overall, improvement in NMS scores correlated with improvement in dyskinesia.Trial registrationClinicalTrials.gov identifiers: NCT02136914 and NCT02274766.
| S-EPMC8140024 | biostudies-literature
Project description:The HiBalance program is a progressive and highly challenging balance training intervention incorporating Parkinson's disease (PD) specific balance components. The program improves balance and gait and increases the amount of ambulation in short-term, in older adults with PD. Yet, potential short- and long-term effects on habitual physical activity and sedentary behavior are currently unidentified. The aim of this study was to conduct preplanned secondary analyses of short- and long-term effects of the HiBalance program on objectively measured amount and bouts of brisk walking, sedentary behavior, and total physical activity in older adults with PD. Further, our aim was to investigate demographic, intervention-related, disease-related, and function-related factors potentially related to a difference in activity after intervention. A total of 100 older adults with mild-moderate PD were recruited. The intervention group participated in the HiBalance program, and the control received care as usual and was offered the HiBalance program after study termination. Physical activity data were collected using accelerometers at baseline, after intervention and after 6 and 12 months. A multilevel model was utilized to investigate the postintervention and long-term (6 and 12 months) effects on total physical activity, amount and bouts of brisk walking (i.e., moderate intensity physical activity), and sedentary behavior. Between-group difference for the main outcome brisk walking was at postintervention: Δ -10, CI -23.78 to 3.69 min/day (p < 0.05); 6 months: Δ -10, CI -23.89 to 3.89 min/day (p < 0.05); and 12 months: Δ -4, CI -16.81 to 8.81 min/day (p=0.43). Being part of the intervention group as well as finishing training during spring/summer showed an independent association to increased brisk walking after the intervention period. In conclusion, the HiBalance program increases the physical activity on moderate intensity after intervention and at 6 months but not at 12 months, independently of improved balance. Season seems to influence the effect on the physical activity.
| S-EPMC6702829 | biostudies-literature