Objective: To assess the effects of adjunctive perampanel on myoclonic and absence seizures in IG... more Objective: To assess the effects of adjunctive perampanel on myoclonic and absence seizures in IGE. Background: Perampanel is a selective, non-competitive AMPA receptor antagonist, approved for adjunctive treatment of focal seizures, with or without secondarily generalized seizures, and for primary generalized tonic-clonic (PGTC) seizures in patients with epilepsy aged ≥12 years. Approval for PGTC seizures was based on the placebo-controlled Phase III Study 332 in patients with PGTC seizures and IGE. Since some AEDs can aggravate seizures in IGE, a post-hoc analysis was performed to assess myoclonic and absence seizure outcomes in the Extension Phase of Study 332. Design/Methods: Study 332 methodology has been published (French et al. Neurology 2015;85:950–957). Patients completing the Double-blind study could receive perampanel during an Extension Phase, including a 6-week blinded Conversion Period (dose optimized to maximum of 12 mg/day) and up to 136 weeks’ unblinded Maintenance....
Objective: Present an overview of efficacy and safety for adjunctive rufinamide in LGS patients a... more Objective: Present an overview of efficacy and safety for adjunctive rufinamide in LGS patients aged 1–30 years. Background: LGS, a rare epilepsy syndrome, affects 1–4% of children with epilepsy. Limited treatment options demonstrate inadequate seizure control and unfavorable tolerability. Design/Methods: Studies 022 (Glauser et al. Neurology 2008;70:1950–1958) and 304 (Ohtsuka et al. Epilepsy Res 2014;108:1627–1636) were Phase III, double-blind, placebo-controlled studies of adjunctive rufinamide in LGS patients aged 4–30 years (28-day Baseline; 84-day Treatment Phase). Rufinamide maintenance dose: 022, ≤45 mg/kg/day; 304, 800–3200 mg/day by body weight (15.0 to ≥70.1 kg). Patients completing 022 or 304 could enter an open-label extension (022E [Kluger et al. Acta Neurol Scand 2010;122:202–208]; 305 [Ohtsuka et al. Epilepsy Res 2016;121:1–7], respectively). The Phase III, randomized, open-label Study 303 (Arzimanoglou et al. EJPN 2016;20:393–402) assessed adjunctive rufinamide (45 ...
Objective: Many antiepileptic drugs (AEDs) have been reported to lose efficacy during prolonged t... more Objective: Many antiepileptic drugs (AEDs) have been reported to lose efficacy during prolonged treatment.1 This analysis examines response durability with rufinamide. Background: Rufinamide is a triazole derivative, structurally unrelated to other AEDs, approved for adjunctive treatment of seizures associated with LGS in patients aged ≥1year. Design/Methods: Subjects with LGS were aged 4-37 years, taking fixed-dose regimens of 1-3 concomitant AEDs. Following prospective baseline (28 days), subjects were randomized to a double-blind phase (Titration=14 days; Maintenance=70 days) and received rufinamide (45mg/kg/day maximum dose) or placebo. Subjects completing the double-blind phase were eligible for the open-label extension (OLE), which lasted up to 3 years; all subjects received adjunctive rufinamide treatment. Patients who received placebo during the double-blind phase started conversion on ~10mg ⁄kg ⁄day rufinamide. This was gradually up-titrated to a total dosage of ~25-60mg ⁄...
Objective: To examine efficacy by age, sex, and race of adjunctive perampanel for primary general... more Objective: To examine efficacy by age, sex, and race of adjunctive perampanel for primary generalized tonic-clonic seizures (PGTCS) from a Phase III study. Background: PER, a non-competitive AMPA receptor antagonist, is approved for adjunctive treatment of partial seizures with or without secondarily generalized seizures and for PGTCS in patients with epilepsy aged ≥12 years. Design/Methods: Patients (≥12 years) had a confirmed PGTCS clinical diagnosis and were receiving 13 concomitant antiepileptic drugs. Following baseline (48 weeks), patients were randomized to perampanel or placebo for the double-blind phase (4-week titration, 13-week maintenance, 4-week follow-up) with a maximum dose of 8 mg/day. Median percent change from baseline in PGTCS frequency and 50[percnt] responder rate were examined by age, sex, and race. Results: In the full analysis set (N=162; 81 perampanel, 81 placebo), the majority of patients (85.8[percnt]) were ≥18−<65 years of age (n=139) [<18y: n=22 (1...
Objective: To characterize relationships between perampanel exposure, PGTCS outcomes, and TEAEs i... more Objective: To characterize relationships between perampanel exposure, PGTCS outcomes, and TEAEs in patients with uncontrolled PGTCS. Background: PER, a non-competitive AMPA receptor antagonist, is approved for adjunctive treatment of partial seizures with or without secondarily generalized seizures and for PGTCS in patients with epilepsy aged ≥12 years. Design/Methods: Enrolled patients were aged ≥12yrs with uncontrolled PGTCS receiving 1-3 concomitant antiepileptic drugs (AEDs). Following baseline (4 or 8wks), patients were randomized into perampanel or placebo groups for DB treatment (Titration, 4wks; Maintenance, 13wks), with an 8mg maximum dose. Primary endpoints were percent change in PGTC seizure frequency/28days and 50[percnt] responder rate. Pharmacokinetic/pharmacodynamics (PK/PD) models were used to describe relationships between perampanel exposure and seizure outcomes, and neuropsychiatric TEAEs of special interest (e.g., hostility/aggression-related TEAEs using Standard...
Journal of Comparative Effectiveness Research, 2021
Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulat... more Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. ClinicalTrials.gov registration : NCT01557400 .
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, Jan 27, 2018
Evaluate the long-term safety, tolerability, and behavioral effects of adjunctive rufinamide in p... more Evaluate the long-term safety, tolerability, and behavioral effects of adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with inadequately controlled seizures associated with Lennox-Gastaut syndrome (LGS). Study 303 (ClinicalTrials.gov identifier NCT01405053) was a multicenter, randomized, open-label, Phase III trial. Patients were randomized (2:1) to oral suspension rufinamide (≤45 mg/kg/day) or any other investigator-chosen antiepileptic drug (AED) for a 2-year treatment period. Primary safety/tolerability assessments included monitoring of treatment-emergent adverse events (TEAEs) and serious TEAEs. Behavioral effects were assessed via the Child Behavior Checklist (CBCL) using the Total Problems score and change from baseline in CBCL Total Problems score. CBCL subscores were also evaluated. The Safety Analysis Set included 37 patients (rufinamide: n = 25; any other AED: n = 12). TEAE incidence was similar between the rufinamide (88.0%) and any-other-AED groups (...
Journal of Neurology, Neurosurgery & Psychiatry, 2016
Purpose To review psychiatric and behavioural events in a study conducted to evaluate the efficac... more Purpose To review psychiatric and behavioural events in a study conducted to evaluate the efficacy and safety of adjunctive perampanel in patients with uncontrolled primary generalised tonic-clonic seizures (PGTCS). Method Following baseline (4 or 8 weeks), patients aged ≥12 years were randomised to double-blind treatment with perampanel or placebo (titration 4 weeks; maintenance 13 weeks; maximum dose 8 mg). Treatment-emergent adverse events (TEAEs) were evaluated using MedDRA search terms for psychiatric disorders and MedDRA SMQs for hostility/aggression-related events. Results In the Safety Analysis Set (perampanel n=81; placebo n=82), psychiatric TEAEs occurred in 20 (24.7%) perampanel- and 16 (19.5%) placebo-treated patients. Most TEAEs were of mild or moderate intensity. Frequency of TEAEs related to hostility/aggression was 18.5% for perampanel and 4.9% for placebo, largely due to a higher rate of irritability with perampanel (11.1%) versus placebo (2.4%). Incidences of serious adverse events and discontinuations due to TEAEs related to hostility/aggression for perampanel versus placebo were 1.2% versus 0% and 3.7% versus 1.2%, respectively. Conclusion Consistent with results from Phase III trials in partial epilepsy, hostility/aggression-related TEAEs occurred at a higher rate in perampanel-treated patients with PGTCS than in those treated with placebo, driven mainly by irritability. Supported by Eisai Inc.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, Jan 11, 2016
A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (A... more A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (AEDs) in young pediatric patients is of great importance in clinical practice. This paper presents 6-month interim safety and PK from an ongoing 2-year open-label study (Study 303) of adjunctive rufinamide treatment in pediatric subjects ≥1 to <4 years with inadequately controlled epilepsies of the Lennox-Gastaut syndrome (LGS) spectrum. Subjects (N = 37) were randomized to either rufinamide or any other approved AED chosen by the investigator as adjunctive therapy to the…
Journal of Neurology, Neurosurgery & Psychiatry, 2015
We assessed efficacy and safety of perampanel (selective noncompetitive AMPA receptor antagonist)... more We assessed efficacy and safety of perampanel (selective noncompetitive AMPA receptor antagonist) for primary generalised tonic-clonic (PGTC) seizures. Patients ≥12years with confirmed IGE; ≥3 PGTC seizures/8 weeks prior to randomization; receiving 1–3 concomitant AEDs were recruited. Trial consisted of 4–week screening; 4–8 week Baseline, 1:1 Randomization (perampanel titrated over 4 weeks to 8mg or highest tolerated dose versus placebo), 13–week Maintenance, 4–week Follow-up and Extension Phases. 164 patients were randomized; full analysis set included 81 patients each on perampanel and placebo. Median percent change in PGTC seizure frequency/28 days during Titration/Maintenance versus Baseline was –76.5% with perampanel versus –38.4% placebo; P<0.0001. 50% PGTC seizure responder rate was 64.2% with perampanel versus 39.5% placebo; P=0.0019. During Maintenance, 30.9% of perampanel patients were free of PGTC seizures versus 12.3% placebo. Treatment-emergent AEs (TEAEs) occurred ...
Chronic levodopa treatment of Parkinson's disease (PD) patients ultimately produces motor res... more Chronic levodopa treatment of Parkinson's disease (PD) patients ultimately produces motor response complications (MRCs) that include response fluctuations and dyskinesias. Recent nonhuman primate studies suggest that MRCs from the pulsatile nonphysiological stimulation of dopaminergic receptors on striatal spiny neurons increase the sensitivity of corticostriatal glutamatergic synaptic transmission. Changes to the glutamatergic signaling pathways and adenosinergic and serotonergic pathways both intrinsic and extrinsic to the striatal dopaminoceptive medium-spiny neurons may also contribute to the pathogenesis of motor dysfunction in advanced PD. Because of these alterations, basal ganglia output the changes in ways that favor the appearance of Parkinsonian signs and motor complications. While MRCs associated with chronic levodopa therapy are a major cause of treatment failure, the biochemical mechanisms underlying this phenomenon remain yet unclear. Based on recent behavioral and pharmacological data, the pathogenesis of PD motor complications in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primates may be influenced by increased synaptic efficacy of corticostriatal glutamatergic synaptic transmission associated with changes in medium spiny neuron signaling pathways. In addition to delivery systems that provide more continuous and physiological dopaminergic receptor stimulation, future goals of primate research in MRCs should include developing pharmacological agents that normalize striatal glutamatergic dysfunction by interacting with striatal N-methyl-D-aspartate and amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptors or other surface receptors. The MPTP-lesioned nonhuman primate, therefore, serves as an invaluable tool for discovering more novel and salutary treatment approaches to attenuate levodopa-induced motor complications and to prevent a loss of its therapeutic efficacy during the course of the disease.
Objective: To assess the effects of adjunctive perampanel on myoclonic and absence seizures in IG... more Objective: To assess the effects of adjunctive perampanel on myoclonic and absence seizures in IGE. Background: Perampanel is a selective, non-competitive AMPA receptor antagonist, approved for adjunctive treatment of focal seizures, with or without secondarily generalized seizures, and for primary generalized tonic-clonic (PGTC) seizures in patients with epilepsy aged ≥12 years. Approval for PGTC seizures was based on the placebo-controlled Phase III Study 332 in patients with PGTC seizures and IGE. Since some AEDs can aggravate seizures in IGE, a post-hoc analysis was performed to assess myoclonic and absence seizure outcomes in the Extension Phase of Study 332. Design/Methods: Study 332 methodology has been published (French et al. Neurology 2015;85:950–957). Patients completing the Double-blind study could receive perampanel during an Extension Phase, including a 6-week blinded Conversion Period (dose optimized to maximum of 12 mg/day) and up to 136 weeks’ unblinded Maintenance....
Objective: Present an overview of efficacy and safety for adjunctive rufinamide in LGS patients a... more Objective: Present an overview of efficacy and safety for adjunctive rufinamide in LGS patients aged 1–30 years. Background: LGS, a rare epilepsy syndrome, affects 1–4% of children with epilepsy. Limited treatment options demonstrate inadequate seizure control and unfavorable tolerability. Design/Methods: Studies 022 (Glauser et al. Neurology 2008;70:1950–1958) and 304 (Ohtsuka et al. Epilepsy Res 2014;108:1627–1636) were Phase III, double-blind, placebo-controlled studies of adjunctive rufinamide in LGS patients aged 4–30 years (28-day Baseline; 84-day Treatment Phase). Rufinamide maintenance dose: 022, ≤45 mg/kg/day; 304, 800–3200 mg/day by body weight (15.0 to ≥70.1 kg). Patients completing 022 or 304 could enter an open-label extension (022E [Kluger et al. Acta Neurol Scand 2010;122:202–208]; 305 [Ohtsuka et al. Epilepsy Res 2016;121:1–7], respectively). The Phase III, randomized, open-label Study 303 (Arzimanoglou et al. EJPN 2016;20:393–402) assessed adjunctive rufinamide (45 ...
Objective: Many antiepileptic drugs (AEDs) have been reported to lose efficacy during prolonged t... more Objective: Many antiepileptic drugs (AEDs) have been reported to lose efficacy during prolonged treatment.1 This analysis examines response durability with rufinamide. Background: Rufinamide is a triazole derivative, structurally unrelated to other AEDs, approved for adjunctive treatment of seizures associated with LGS in patients aged ≥1year. Design/Methods: Subjects with LGS were aged 4-37 years, taking fixed-dose regimens of 1-3 concomitant AEDs. Following prospective baseline (28 days), subjects were randomized to a double-blind phase (Titration=14 days; Maintenance=70 days) and received rufinamide (45mg/kg/day maximum dose) or placebo. Subjects completing the double-blind phase were eligible for the open-label extension (OLE), which lasted up to 3 years; all subjects received adjunctive rufinamide treatment. Patients who received placebo during the double-blind phase started conversion on ~10mg ⁄kg ⁄day rufinamide. This was gradually up-titrated to a total dosage of ~25-60mg ⁄...
Objective: To examine efficacy by age, sex, and race of adjunctive perampanel for primary general... more Objective: To examine efficacy by age, sex, and race of adjunctive perampanel for primary generalized tonic-clonic seizures (PGTCS) from a Phase III study. Background: PER, a non-competitive AMPA receptor antagonist, is approved for adjunctive treatment of partial seizures with or without secondarily generalized seizures and for PGTCS in patients with epilepsy aged ≥12 years. Design/Methods: Patients (≥12 years) had a confirmed PGTCS clinical diagnosis and were receiving 13 concomitant antiepileptic drugs. Following baseline (48 weeks), patients were randomized to perampanel or placebo for the double-blind phase (4-week titration, 13-week maintenance, 4-week follow-up) with a maximum dose of 8 mg/day. Median percent change from baseline in PGTCS frequency and 50[percnt] responder rate were examined by age, sex, and race. Results: In the full analysis set (N=162; 81 perampanel, 81 placebo), the majority of patients (85.8[percnt]) were ≥18−<65 years of age (n=139) [<18y: n=22 (1...
Objective: To characterize relationships between perampanel exposure, PGTCS outcomes, and TEAEs i... more Objective: To characterize relationships between perampanel exposure, PGTCS outcomes, and TEAEs in patients with uncontrolled PGTCS. Background: PER, a non-competitive AMPA receptor antagonist, is approved for adjunctive treatment of partial seizures with or without secondarily generalized seizures and for PGTCS in patients with epilepsy aged ≥12 years. Design/Methods: Enrolled patients were aged ≥12yrs with uncontrolled PGTCS receiving 1-3 concomitant antiepileptic drugs (AEDs). Following baseline (4 or 8wks), patients were randomized into perampanel or placebo groups for DB treatment (Titration, 4wks; Maintenance, 13wks), with an 8mg maximum dose. Primary endpoints were percent change in PGTC seizure frequency/28days and 50[percnt] responder rate. Pharmacokinetic/pharmacodynamics (PK/PD) models were used to describe relationships between perampanel exposure and seizure outcomes, and neuropsychiatric TEAEs of special interest (e.g., hostility/aggression-related TEAEs using Standard...
Journal of Comparative Effectiveness Research, 2021
Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulat... more Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. ClinicalTrials.gov registration : NCT01557400 .
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, Jan 27, 2018
Evaluate the long-term safety, tolerability, and behavioral effects of adjunctive rufinamide in p... more Evaluate the long-term safety, tolerability, and behavioral effects of adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with inadequately controlled seizures associated with Lennox-Gastaut syndrome (LGS). Study 303 (ClinicalTrials.gov identifier NCT01405053) was a multicenter, randomized, open-label, Phase III trial. Patients were randomized (2:1) to oral suspension rufinamide (≤45 mg/kg/day) or any other investigator-chosen antiepileptic drug (AED) for a 2-year treatment period. Primary safety/tolerability assessments included monitoring of treatment-emergent adverse events (TEAEs) and serious TEAEs. Behavioral effects were assessed via the Child Behavior Checklist (CBCL) using the Total Problems score and change from baseline in CBCL Total Problems score. CBCL subscores were also evaluated. The Safety Analysis Set included 37 patients (rufinamide: n = 25; any other AED: n = 12). TEAE incidence was similar between the rufinamide (88.0%) and any-other-AED groups (...
Journal of Neurology, Neurosurgery & Psychiatry, 2016
Purpose To review psychiatric and behavioural events in a study conducted to evaluate the efficac... more Purpose To review psychiatric and behavioural events in a study conducted to evaluate the efficacy and safety of adjunctive perampanel in patients with uncontrolled primary generalised tonic-clonic seizures (PGTCS). Method Following baseline (4 or 8 weeks), patients aged ≥12 years were randomised to double-blind treatment with perampanel or placebo (titration 4 weeks; maintenance 13 weeks; maximum dose 8 mg). Treatment-emergent adverse events (TEAEs) were evaluated using MedDRA search terms for psychiatric disorders and MedDRA SMQs for hostility/aggression-related events. Results In the Safety Analysis Set (perampanel n=81; placebo n=82), psychiatric TEAEs occurred in 20 (24.7%) perampanel- and 16 (19.5%) placebo-treated patients. Most TEAEs were of mild or moderate intensity. Frequency of TEAEs related to hostility/aggression was 18.5% for perampanel and 4.9% for placebo, largely due to a higher rate of irritability with perampanel (11.1%) versus placebo (2.4%). Incidences of serious adverse events and discontinuations due to TEAEs related to hostility/aggression for perampanel versus placebo were 1.2% versus 0% and 3.7% versus 1.2%, respectively. Conclusion Consistent with results from Phase III trials in partial epilepsy, hostility/aggression-related TEAEs occurred at a higher rate in perampanel-treated patients with PGTCS than in those treated with placebo, driven mainly by irritability. Supported by Eisai Inc.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, Jan 11, 2016
A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (A... more A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (AEDs) in young pediatric patients is of great importance in clinical practice. This paper presents 6-month interim safety and PK from an ongoing 2-year open-label study (Study 303) of adjunctive rufinamide treatment in pediatric subjects ≥1 to <4 years with inadequately controlled epilepsies of the Lennox-Gastaut syndrome (LGS) spectrum. Subjects (N = 37) were randomized to either rufinamide or any other approved AED chosen by the investigator as adjunctive therapy to the…
Journal of Neurology, Neurosurgery & Psychiatry, 2015
We assessed efficacy and safety of perampanel (selective noncompetitive AMPA receptor antagonist)... more We assessed efficacy and safety of perampanel (selective noncompetitive AMPA receptor antagonist) for primary generalised tonic-clonic (PGTC) seizures. Patients ≥12years with confirmed IGE; ≥3 PGTC seizures/8 weeks prior to randomization; receiving 1–3 concomitant AEDs were recruited. Trial consisted of 4–week screening; 4–8 week Baseline, 1:1 Randomization (perampanel titrated over 4 weeks to 8mg or highest tolerated dose versus placebo), 13–week Maintenance, 4–week Follow-up and Extension Phases. 164 patients were randomized; full analysis set included 81 patients each on perampanel and placebo. Median percent change in PGTC seizure frequency/28 days during Titration/Maintenance versus Baseline was –76.5% with perampanel versus –38.4% placebo; P<0.0001. 50% PGTC seizure responder rate was 64.2% with perampanel versus 39.5% placebo; P=0.0019. During Maintenance, 30.9% of perampanel patients were free of PGTC seizures versus 12.3% placebo. Treatment-emergent AEs (TEAEs) occurred ...
Chronic levodopa treatment of Parkinson's disease (PD) patients ultimately produces motor res... more Chronic levodopa treatment of Parkinson's disease (PD) patients ultimately produces motor response complications (MRCs) that include response fluctuations and dyskinesias. Recent nonhuman primate studies suggest that MRCs from the pulsatile nonphysiological stimulation of dopaminergic receptors on striatal spiny neurons increase the sensitivity of corticostriatal glutamatergic synaptic transmission. Changes to the glutamatergic signaling pathways and adenosinergic and serotonergic pathways both intrinsic and extrinsic to the striatal dopaminoceptive medium-spiny neurons may also contribute to the pathogenesis of motor dysfunction in advanced PD. Because of these alterations, basal ganglia output the changes in ways that favor the appearance of Parkinsonian signs and motor complications. While MRCs associated with chronic levodopa therapy are a major cause of treatment failure, the biochemical mechanisms underlying this phenomenon remain yet unclear. Based on recent behavioral and pharmacological data, the pathogenesis of PD motor complications in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primates may be influenced by increased synaptic efficacy of corticostriatal glutamatergic synaptic transmission associated with changes in medium spiny neuron signaling pathways. In addition to delivery systems that provide more continuous and physiological dopaminergic receptor stimulation, future goals of primate research in MRCs should include developing pharmacological agents that normalize striatal glutamatergic dysfunction by interacting with striatal N-methyl-D-aspartate and amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid receptors or other surface receptors. The MPTP-lesioned nonhuman primate, therefore, serves as an invaluable tool for discovering more novel and salutary treatment approaches to attenuate levodopa-induced motor complications and to prevent a loss of its therapeutic efficacy during the course of the disease.
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