Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease

The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended‐release formulation of carbidopa‐levodopa, with an immediate‐release carbidopa‐levodopa formulation in advanced Parkinson's disease. We performed an open‐label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate‐release carbidopa‐levodopa followed by IPX066 or IPX066 followed by immediate‐release carbidopa‐levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple‐dose administration). Following a single dose of IPX066 or immediate‐release carbidopa‐levodopa, plasma levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate‐release carbidopa‐levodopa (P < .0001). Multiple‐dose data showed IPX066 substantially reduced variability in plasma levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in levodopa C_max was approximately 30% compared with immediate‐release carbidopa‐levodopa. Both products were well tolerated. IPX066 provided more sustained plasma levodopa concentrations than immediate‐release carbidopa‐levodopa. Larger, longer‐term, well‐controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066. © 2011 Movement Disorder Society     

Quality of life in early Parkinson's disease treated with levodopa/carbidopa/entacapone

We aimed to investigate whether treatment with levodopa/carbidopa/entacapone when compared with levodopa/carbidopa improves quality of life in Parkinson's disease (PD) patients with no or minimal, nondisabling motor fluctuations. This is a multicenter, randomized, double‐blind study. One hundred eighty‐four patients on 3 to 4 equal doses of 100/25 to 200/50 mg levodopa/carbidopa or levodopa/benserazide, 0 to 3 hours of nondisabling OFF time over a 48 hour period and no dyskinesia were randomized to levodopa/carbidopa/entacapone or levodopa/carbidopa treatment for 12 weeks. The primary outcome measure was quality of life as assessed by the PDQ‐8. Secondary outcome measures were the UPDRS parts I–IV, and the Wearing Off Card. Treatment with levodopa/carbidopa/entacapone resulted in significantly greater improvements in PDQ‐8 scores compared to treatment with levodopa/carbidopa (mean difference 1.4 points, P = 0.021). Statistically significant improvements were seen predominantly in nonmotor domains (depression, personal relationships, communication, stigma, all P < 0.05; dressing P = 0.056). Patients who were randomly assigned to levodopa/carbidopa/entacapone also showed significantly greater improvement in UPDRS part II scores (P = 0.032) with UPDRS part III scores showing borderline significance. Differences in UPDRS parts I and IV and Wearing Off Card scores were not significant. Treatment with levodopa/carbidopa/entacapone results in improved quality of life compared with levodopa/carbidopa in PD patients with mild or minimal, nondisabling motor fluctuations. © 2007 Movement Disorder Society     

Pharmacokinetic‐pharmacodynamic crossover comparison of two levodopa extension strategies

Controlled‐release carbidopa and levodopa (CL‐CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L ‐dopa) effects. In a randomized, open‐label crossover study of 17 PD subjects with wearing‐off responses, we compared 8‐hour L ‐dopa pharmacokinetics (PK) and clinical effects after two doses of CL‐CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near‐equivalent mean L ‐dopa area‐under‐the‐concentration‐curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL‐CR, P = 0.86). The mean hourly fluctuation index for L ‐dopa concentration was 235% for CLE and 196% for CL‐CR (P = 0.004). The mean maximal concentration for the first CLE dose was 1,926 ± 760 ng/mL and for CL‐CR, 1,840 ± 889 (P = 0.33). During the PK studies, the mean time that L ‐dopa concentration was ≥1,000 ng/mL for CLE was 291 ± 88 minutes and for CL‐CR, 306 ± 86 (P = 0.33). The mean percent‐time in “off” state was 18% for CLE and 28% for CL‐CR (P = 0.017), “on state without dyskinesia” was 64% for CLE and 65% for CL‐CR (P = 0.803), and “on state with nontroublesome dyskinesia” was 18% for CLE and 7% for CL‐CR (P = 0.03). Despite less “off” time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability. © 2009 Movement Disorder Society     

Melevodopa/carbidopa effervescent formulation in the treatment of motor fluctuations in advanced Parkinson's disease

Melevodopa hydrochloride plus carbidopa in effervescent tablets (M/C) is a readily soluble antiparkinsonian tablet formulation. A total of 221 patients with Parkinson's disease and motor fluctuations entered a randomized, double‐blind, double‐dummy, controlled parallel group study, which compared the effectiveness of oral M/C effervescent tablets with standard oral formulation levodopa/carbidopa tablets (L/C; Sinemet) in reducing total daily OFF time. The difference of total daily OFF time (intention‐to‐treat population) between the two groups was not statistically significant (P = 0.07): ?39.4 minutes (95%CI: ?67.08 to ?11.73) in M/C group vs. +3.5 minutes (95%CI: ?36.19 to +43.26) in the L/C group. In the intragroup analysis, M/C significantly reduced the baseline daily OFF, which remained unchanged in the L/C group. There were no unexpected adverse events in either treatment arms, and discontinuation rates due to adverse events did not differ between the two groups [M/C: 2 patients (1.3%); L/C: 1 patient (1.4%)]. This study failed to meet the primary endpoint (P = 0.07); however, there was a trend in favour of the M/C preparation, which deserves further attention. © 2010 Movement Disorder Society     

Double‐blind trial of levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Parkinson's disease

We performed a 39‐week, randomized, double‐blind, multicenter study to compare the efficacy, safety, and tolerability of levodopa/carbidopa/entacapone (LCE, Stalevo) with levodopa/carbidopa (LC, Sinemet IR) in patients with early Parkinson's disease (PD). Four hundred twenty‐three patients with early PD warranting levodopa were randomly assigned to treatment with LCE 100/25/200 or LC 100/25 three‐times daily. The adjusted mean difference in total Unified Parkinson's disease Rating Scale (UPDRS) Parts II and III between groups using the analysis of covariance model (prespecified primary outcome measure) was 1.7 (standard error = 0.84) points favoring LCE (P = 0.045). Significantly greater improvement with LCE compared with LC was also observed in UPDRS Part II activities of daily living (ADL) scores (P = 0.025), Schwab and England ADL scores (blinded rater, P = 0.003; subject, P = 0.006) and subject‐reported Clinical Global Impression (CGI) scores (P = 0.047). There was no significant difference in UPDRS Part III or investigator‐rated CGI scores. Wearing‐off was observed in 29 (13.9%) subjects in the LCE group and 43 (20.0%) in the LC group (P = 0.099). Dyskinesia was observed in 11 (5.3%) subjects in the LCE group and 16 (7.4%) in the LC group (P = 0.367). Nausea and diarrhea were reported more frequently in the LCE group. LCE provided greater symptomatic benefit than LC and did not increase motor complications. © 2008 Movement Disorder Society     

ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized,placebo-controlled phase 2 study

IntroductionND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations.MethodsThis was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h.ResultsND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC_0–10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of −2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H₀ of μ₀ ≤-1.6).ConclusionLevodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.     

Long‐term safety and efficacy of levodopa‐carbidopa intestinal gel in advanced Parkinson's disease

Background: Levodopa‐carbidopa intestinal gel (designated as carbidopa‐levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long‐term safety and efficacy outcomes from an open‐label phase 3 treatment program. Methods: PD patients (n = 262) who completed a 12‐week double‐blind study and its 52‐week open‐label extension or a separate 54‐week open‐label study were enrolled in this ongoing phase 3 open‐label, multinational study (NCT00660673). Safety and efficacy assessments were collected every 6 months. Results: Mean total duration of exposure to levodopa‐carbidopa intestinal gel was 4.1 years (range, 1.2 to 6.9 years). The overall discontinuation rate was 34% (average annual discontinuation rate, 10%). Although most patients (94%) reported an adverse event, the rate of adverse events decreased over time; 53% experienced a serious adverse event. Of patients in this extension study, 54% required jejunal tube replacement during the study, and 37% required percutaneous endoscopic gastrostomy tube replacement. Most patients were on levodopa monotherapy. Patients maintained reductions in “off” time and increases in mean “on” time without dyskinesia from initial levodopa‐carbidopa intestinal gel infusion to he study end point (P < 0.001; n = 81). Activities of daily living and quality‐of‐life assessments demonstrated significant improvements that persisted through the study. Conclusions: This long‐term study demonstrates sustained and clinically meaningful benefits from levodopa‐carbidopa intestinal gel in advanced PD patients. Although adverse event rates decreased over time, vigilance is required for device‐related complications and adverse events. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society     

Long-term exposure to duodenal levodopa/carbidopa infusion therapy improves quality of life in relation especially to mobility, activities of daily living, and emotional well-being

Santos‐García D, Sanjurjo LF, Macías M, Llaneza M, Carpintero P, de la Fuente‐Fernández R. Long‐term exposure to duodenal levodopa/carbidopa infusion therapy improves quality of life in relation especially to mobility, activities of daily living, and emotional well‐being.
Acta Neurol Scand: 2012: 125: 187–191.
© 2011 John Wiley & Sons A/S. Background – Continuous duodenal levodopa infusion (DLI) is an effective therapy that improves quality of life (QoL) in advanced Parkinson′s disease (PD). However, in which aspects improve the patients their QoL has been poorly documented. Methods – We evaluated 39‐item Parkinson′s disease Quality of Life Questionnaire Summary Index score (PDQ‐39SI) changes analyzing its different domains in nine patients with advanced PD treated with DLI. Results – All the patients (64.7 ± 11.1 years, 55.5% men) improved PDQ‐39SI 6 months after beginning with DLI (29.7 ± 8.6, P = 0.008) and after median duration infusion of 25.3 ± 8.8 months (34.8 ± 11.2, P = 0.008) compared with baseline (55.6 ± 11.5). All domains except social support improved significantly at 6 months. Mobility (P = 0.012), activities of daily living (P = 0.015), and emotional well‐being (P = 0.008) improved significantly at the end of the follow‐up. Conclusions– DLI improves QoL in patients with advanced PD after short‐ and long‐term exposure. Whereas all domains except social support improve after 6 months under DLI, only mobility, activities of daily living and emotional well‐being improve significantly after long‐term exposure to DLI.     

The effect of peripheral enzyme inhibitors on levodopa concentrations in blood and CSF

Levodopa combined with a dopa‐decarboxylase inhibitor, such as carbidopa, shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing‐off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day 1; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg tid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C_max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C_max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa. © 2010 Movement Disorder Society     

Randomized trial of safinamide add‐on to levodopa in Parkinson's disease with motor fluctuations

Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add‐on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double‐blind, placebo‐controlled, parallel‐group study was to evaluate the efficacy and safety of safinamide, an α‐aminoamide with dopaminergic and nondopaminergic mechanisms, as add‐on to l ‐dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression‐Change (CGI‐C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI‐C were significantly greater in both safinamide groups versus placebo. There were no significant between‐group differences for incidences of treatment‐emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l ‐dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia. © 2013 International Parkinson and Movement Disorder Society     

A Double‐Blind,Randomized, Placebo and Active‐Controlled Study of Nebicapone for the Treatment of Motor Fluctuations in Parkinson's Disease

To determine the efficacy, safety and tolerability of nebicapone, a new catechol‐O‐methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8‐week double‐blind, placebo‐ and active‐controlled, parallel‐group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty‐two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4–8 daily doses) were enrolled and 250 patients were eligible for intention‐to‐treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8‐week change from baseline in absolute “Off” time duration noted in self‐scoring diaries. At 8 weeks of treatment the mean daily “Off” time decreased significantly compared to placebo for nebicapone 150 mg (?106 min; 95%CI: ?192; ?21) and entacapone 200 mg (?81 min; 95%CI: ?142; ?19). The decrease in “Off” time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment‐emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.     

Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005)

Objective

Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A_2A receptor antagonist, istradefylline, shows promise for the treatment of PD.

Methods

Istradefylline (40mg/day) was studied in levodopa‐treated PD subjects experiencing prominent wearing‐off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double‐blind, 12‐week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake “off” time, recorded by subjects using a patient PD diary. Secondary end points evaluated “on” time (including “on time with dyskinesia”), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression–Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring.

Results

After randomization, approximately 88% of subjects completed the double‐blind period. Compared with baseline, the decrease of daily awake “off” time for istradefylline was a mean (± standard deviation) of ?10.8 ± 16.6% (95% confidence interval, ?13.46 to ?7.52) and for placebo, ?4.0 ± 15.7% (95% confidence interval, ?7.73–0.31; p = 0.007 using two‐way analysis of variance). This effect corresponded to changes from baseline in total daily awake “off” time of ?1.8 ± 2.8 hours for istradefylline and ?0.6 ± 2.7 hours for placebo (p = 0.005). Treatment‐emergent adverse effects with istradefylline were generally mild.

Interpretation

Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in “off” time without increased troublesome dyskinesia. Ann Neurol 2008

     

Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations

The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW‐6002) is an adenosine A_2A receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12‐week, multicenter, double‐blind, placebo‐controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti‐Parkinson's medications. Istradefylline‐treated subjects had significant placebo‐corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline‐treated and 7 (6.1%) placebo‐treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations. © 2008 Movement Disorder Society     

Longitudinal study of levodopa in Parkinson's disease: Effects of the advanced disease phase

Thirty‐four patients have been studied from the time of initiation of pharmacological treatment in a long‐term prospective study of levodopa effects and disease progression in Parkinson's disease. Objective motor scoring of the response to levodopa in defined off states was performed every 3 years. The mean time from the initiation of levodopa treatment to the most recent measurements was 18.2 years. Of 8 patients who are still alive, only 3 had none of the features of the advanced disease phase (dementia, hallucinations, frequent falling). Off‐phase motor function worsened at a yearly rate of 1.9% of the maximum disability score, although the plots of the serial scores showed that the magnitude of the levodopa response is well preserved. There was little difference in the rate of progression between patients with tremor‐dominant and non‐tremor‐dominant motor subtypes. Those who developed dementia had more rapid deterioration of motor scores, with significantly worse off‐phase (P = .008) and on‐phase (P = .03) motor function. A graph of serial scores of patients who have died, aligned for time of death, showed an upward curving trend of motor disability in the last 5 years of the disease course. Its advanced phase may reveal that Parkinson's disease has an exponential pattern of progression. © 2013 Movement Disorder Society     

Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson’s disease

Background: The 24‐week, double‐blind Efficacy and Safety Evaluation in PD–Adjunct (EASE‐PD Adjunct) study randomized patients with advanced Parkinson’s disease (PD) suboptimally controlled with levodopa to once‐daily placebo or adjunctive ropinirole prolonged release (2–24 mg/day). We investigated the effect of ropinirole prolonged release on nocturnal symptoms in these patients. Methods: Total and grouped item PD Sleep Scale (PDSS) scores were analyzed post hoc in patients with baseline PDSS total scores ≤ 100 (troublesome nocturnal symptoms) and >100. Results: Baseline PDSS total score was ≤ 100 in 93 of 198 (47%) and 89 of 189 (47%) patients receiving ropinirole prolonged release and placebo, respectively; this subgroup displayed evidence at baseline of greater daily awake ‘off’ time, reduced night‐time sleep and worse quality of life, than the PDSS >100 subgroup. Significant improvements with ropinirole prolonged release versus placebo in PDSS score from baseline to Week 24 last observation carried forward were observed for those with baseline PDSS ≤ 100 [adjusted mean treatment difference 9.0 (95% CI: 2.76, 15.33; P = 0.0051)], but not >100. The PDSS ≤ 100 subgroup demonstrated treatment benefits for PDSS groupings of motor symptoms on waking and global quality of sleep. Changes in daytime sleepiness were similar between treatment groups. The PDSS >100 subgroup demonstrated significant treatment benefit for global quality of sleep. The unadjusted odds ratio for a positive response with ropinirole prolonged release relative to placebo, for the PDSS ≤ 100 subgroup, was 2.90 (95% CI: 1.42, 5.95, P = 0.004). Conclusions: Once‐daily ropinirole prolonged release improves nocturnal symptoms in patients with advanced PD not optimally controlled with levodopa who suffer troublesome nocturnal disturbance.     

Placebo‐controlled,double‐blind dose‐finding study of entacapone in fluctuating parkinsonian patients

We conducted a multicenter randomized, placebo‐controlled double‐blind parallel‐group study in Japanese Parkinson's disease (PD) patients with wearing‐off motor fluctuations to determine the clinical efficacy and safety of entacapone as an adjunct to concomitant treatment with levodopa and a dopa decarboxylase inhibitor (DCI). We randomized 341 patients to receive entacapone 100 or 200 mg or placebo per dose of levodopa/DCI for 8 weeks. The primary efficacy variable was on time change while awake, determined by patients' diaries. Mean baseline on time in each group was approximately 8 hours. Mean on time change at final assessment was 1.4 hours each for entacapone 100‐mg and 200‐mg groups and by 0.5 hours for the placebo group (P < 0.05). The two entacapone doses were equally efficacious. Adverse events occurred in 79 patients (69.9%) in placebo, 82 (72.6%) in 100 mg, and 98 (86.0%) in 200 mg. The most common adverse event with entacapone was an increase in dyskinesias. The overall safety profile was satisfactory in both entacapone groups. In conclusion, both entacapone 100 and 200 mg were equally effective in increasing on time of PD patients with wearing‐off fluctuations, although the safety and tolerability profile appeared more favorable for the 100‐mg dose. © 2006 Movement Disorder Society     

Neural substrates of levodopa‐responsive gait disorders and freezing in advanced Parkinson's disease: A kinesthetic imagery approach

Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H₂¹⁵0] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa‐responsive gait disorders and FoG, and eight age‐matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor‐parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor‐parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper‐limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa‐responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery. Hum Brain Mapp 36:959–980, 2015. © 2014 Wiley Periodicals, Inc.     

The duration of the motor response to apomorphine boluses is conditioned by the length of a prior infusion in Parkinson's disease

“Pulsatile” administration of levodopa has been invocated a relevant factor for motor fluctuations in Parkinson's disease (PD). We studied dopaminergic sensitivity to apomorphine in 10 parkinsonian patients with motor fluctuations. Patients were tested as follows: the minimal effective dose of apomorphine (MED‐1) was administered in the morning to induce an on response. Fifteen minutes after this motor response had disappeared, an apomorphine infusion was initiated and maintained to ensure on periods of three different durations on different days. Infusion lasted for ～30, 60 and 90 minutes. Subsequently, the infusion was stopped, and after 15 minutes in the off state, a second bolus of apomorphine (MED‐2) was given. The mean infusion doses were 49.2 ± 5.4, 108.4 ± 10.3, and 150 ± 8.2 mg. These elicited on periods of 48.2 ± 4.1, 110 ± 4.5, and 195 ± 3.8 minutes. The MED‐2 elicited on responses with a duration of 30 ± 4.5, 18.4 ± 3.2, and 11.2 ± 4.1 minutes. The duration of the on response induced by the apomorphine infusions correlated inversely (P < 0.01) with the on induced by the MED‐2 of apomorphine. Our findings indicate that a continuous dopaminergic stimulus may induce pharmacodynamic changes associated with tolerance in PD patients. © 2009 Movement Disorder Society     

Randomized,double‐blind,multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease

The objective of this study was to evaluate the efficacy and safety of pramipexole extended release (ER) administered once daily in early Parkinson's disease (PD). Pramipexole immediate release (IR) administered three times daily (TID) is an efficacious and generally well‐tolerated treatment for PD. A pramipexole ER formulation is now available. We performed a randomized, double‐blind, placebo and active comparator–controlled trial in subjects with early PD. The primary efficacy and safety evaluation of pramipexole ER compared with placebo took place at week 18. Two hundred fifty‐nine subjects were randomized 2:2:1 to treatment with pramipexole ER once daily, pramipexole IR TID, or placebo. Levodopa rescue was required by 7 subjects in the placebo group (14%), 3 subjects in the pramipexole ER group (2.9%, P = 0.0160), and 1 subject in the pramipexole IR group (1.0%, P = 0.0017). Adjusted mean [standard error (SE)] change in Unified Parkinson Disease Rating Scale (UPDRS) II [activities of daily living (ADL)] + III (motor) scores from baseline to week 18, including post‐levodopa rescue evaluations, was ?5.1 (1.3) in the placebo group, ?8.1 (1.1) in the pramipexole ER group (P = 0.0282), and ?8.4 (1.1) in the pramipexole IR group (P = 0.0153). Adjusted mean (SE) change in UPDRS ADL + motor scores, censoring post‐levodopa rescue data, was ?2.7 (1.3) in the placebo group, ?7.4 (1.1) in the pramipexole ER group (P = 0.0010), and ?7.5 (1.1) in the pramipexole IR group (P = 0.0006). Adverse events more common with pramipexole ER than placebo included somnolence, nausea, constipation, and fatigue. Pramipexole ER administered once daily was demonstrated to be efficacious compared with placebo and provided similar efficacy and tolerability as pramipexole IR administered TID. © 2010 Movement Disorder Society