perampanel and Parkinson-Disease

L-Dopa represents the mainstay of therapy of Parkinson's disease (PD), but its effectiveness is reduced with continued treatment and disease progression. Accordingly, there remains a need to explore novel treatment strategies to manage the signs and symptoms of the later disease stages. The aim of the study was to evaluate the efficacy and safety of adjunctive perampanel (PER) in patients with PD through a meta-analysis of existing trials.. Randomized, placebo-controlled, double- or single-blind, add-on studies of PER in patients with PD were identified through a systematic literature search. The following outcomes were assessed: changes from baseline to final efficacy visit in total daily OFF time, activities of daily living during OFF time and motor function during ON time, incidence of adverse events (AEs), and treatment withdrawal.. Four trials were included involving 2266 participants, 1449 and 817 for PER and placebo treatment groups, respectively. Four PER daily doses were tested, namely 0.5, 1, 2 and 4 mg. There were no significant differences in any efficacy outcome between PER and placebo treated patients. The risk ratios (RRs) for AEs, severe AEs and treatment withdrawal were similar between placebo and PER at 0.5, 1 and 2 mg; the 4 mg daily dose was associated with an increased risk of AEs [RR 1.118 (1.047-1.193)], and withdrawal for AEs [RR 1.345 (1.034-1.749)] and for any reason [RR 1.197 (1.020-1.406)].. In PD patients experiencing motor fluctuations, adjunctive PER did not improve the motor state and was well-tolerated at the lower doses.

Topics: Activities of Daily Living; Antiparkinson Agents; Clinical Trials as Topic; Double-Blind Method; Humans; Nitriles; Parkinson Disease; Pyridones; Single-Blind Method

To identify adverse events (AEs) significantly associated with perampanel treatment in double-blind clinical studies (RCTs). Serious AEs, study withdrawals due to AEs and dose-effect responses of individual AEs were also investigated.. All placebo controlled, double-blind RCTs investigating therapeutic effects of oral perampanel were searched. AEs were assessed for their association with perampanel after exclusion of synonyms, rare AEs and non-assessable AEs. Risk difference (RD) was used to evaluate the association of any AE (99% confidence intervals) and withdrawals or serious AEs (95% confidence intervals) with perampanel.. Nine RCTs (five in pharmacoresistant epilepsy and four in Parkinson's disease) were included in our study. Almost 4000 patients had been recruited, 2627 of whom were randomized to perampanel and treated with drug doses of 0.5 mg/day (n = 68), 1 mg/day (n = 65), 2 mg/day (n = 753), 4 mg/day (n = 1017), 8 mg/day (n = 431) or 12 mg/day (n = 293). Serious AEs were not significantly associated with perampanel treatment. The experimental drug was significantly associated with an increased risk of AE-related study withdrawals at 4 mg/day [RD (95% confidence interval) 0.03 (0.00, 0.06)] and 12 mg/day [RD (95% confidence interval) 0.13 (0.07, 0.18)]. Of 15 identified AEs, five (dizziness, ataxia, somnolence, irritability and weight increase) were found to be significantly associated with perampanel and one (seizure worsening) was significantly associated with placebo.. Vestibulocerebellar AEs (dizziness, ataxia), sedative effects (somnolence), irritability and weight increase were significantly associated with perampanel treatment.

Topics: Anticonvulsants; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance; Epilepsies, Partial; Epilepsy; Humans; Nitriles; Parkinson Disease; Pyridones; Randomized Controlled Trials as Topic; Risk Assessment; Seizures

Perampanel is a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist. Two multicenter randomized, double-blind, placebo-controlled, parallel-group phase III studies assessed the efficacy and safety of adjunctive perampanel in patients with Parkinson's disease and motor fluctuations.. In both phase III studies (301 and 302), levodopa-treated patients were randomized and treated with once-daily oral placebo (n = 504), perampanel 2 mg (n = 509), or perampanel 4 mg (n = 501). The primary end point was change in daily "off" time from baseline. The treatment period was 30 weeks in study 301 and 20 weeks in study 302.. For any efficacy end point, perampanel 2 or 4 mg was not superior to placebo. Perampanel was well tolerated up to 4 mg/day.. Perampanel failed to significantly improve motor symptoms versus placebo. There was also no effect on the duration or disability of levodopa-induced dyskinesia.

Topics: Aged; Dose-Response Relationship, Drug; Double-Blind Method; Excitatory Amino Acid Antagonists; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitriles; Parkinson Disease; Pyridones

Perampanel, a novel, noncompetitive, selective AMPA-receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of "wearing off" motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once-daily add-on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose-response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least-squares (LS) mean change from baseline to week 12 in percent "off" time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1-sided Williams test for dose-response trend at the 0.025 level of significance. At week 12, dose-response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent "off" time during the waking day (P = 0.061, with significance defined as P

Topics: Adult; Aged; Antiparkinson Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Nitriles; Parkinson Disease; Pyridones; Receptors, AMPA; Treatment Outcome

The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity.. The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α-synuclein transmission in cultured cells and mouse models of Parkinson's disease.. Mouse primary hippocampal neurons were transduced with α-synuclein preformed fibrils to examine the effect of perampanel on the development of α-synuclein pathology and its mechanisms of action. An α-synuclein preformed fibril-injected mouse model was used to validate the effect of oral administration of perampanel on the α-synuclein pathology in vivo.. Perampanel inhibited the development of α-synuclein pathology in mouse hippocampal neurons transduced with α-synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α-synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity-dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α-synuclein pathology in wild-type mice inoculated with α-synuclein preformed fibrils.. Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease-modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Mice; Nitriles; Parkinson Disease; Pyridones; Synucleinopathies