Protein redistribution diet and antiparkinsonian response to levodopa

Sixteen parkinsonian patients with daily fluctuations in the clinical response to levodopa have been placed on a redistribution protein diet. The diet was virtually protein-free until the evening meal and then unrestricted until bedtime. While on the redistribution protein diet, a group of patients (5 out of 16) had a clear and significant benefit from dietary therapy showing a definite reduction of diurnal motor performance fluctuations. In addition, all patients tended to show an improvement and a more constant response to levodopa treatment. A trial of redistribution protein diet appears a simple, reasonable, worthwhile approach to PD patients who begin to experience oscillating clinical response to levodopa treatment.     

Effects of a NR2B selective NMDA glutamate antagonist,CP‐101,606, on dyskinesia and parkinsonism

Glutamate antagonists decrease dyskinesia and augment the antiparkinsonian effects of levodopa in animal models of Parkinson's disease (PD). In a randomized, double‐blind, placebo‐controlled clinical trial, we investigated the acute effects of placebo and two doses of a NR2B subunit selective NMDA glutamate antagonist, CP‐101,606, on the response to 2‐hour levodopa infusions in 12 PD subjects with motor fluctuations and dyskinesia. Both doses of CP‐101,606 reduced the maximum severity of levodopa‐induced dyskinesia ～30% but neither dose improved Parkinsonism. CP‐101,606 was associated with a dose‐related dissociation and amnesia. These results support the hypothesis that glutamate antagonists may be useful antidyskinetic agents. However, future studies will have to determine if the benefits of dyskinesia suppression can be achieved without adverse cognitive effects. © 2008 Movement Disorder Society     

Major nutritional issues in the management of Parkinson's disease

As with other neurodegenerative diseases, neurologic and nutritional elements may interact affecting each other in Parkinson's disease (PD). However, the long‐term effects of such interactions on prognosis and outcome have not been given much attention and are poorly addressed by current research. Factors contributing to the clinical conditions of patients with PD are not only the basic features of PD, progression of disease, and the therapeutic approach but also fiber and nutrient intakes (in terms of both energy and protein content), fluid and micronutrient balance, and pharmaconutrient interactions (protein and levodopa). During the course of PD nutritional requirements frequently change. Accordingly, both body weight gain and loss may occur and, despite controversy, it seems that both changes in energy expenditure and food intake contribute. Nonmotor symptoms play a significant role and dysphagia may be responsible for the impairment of nutritional status and fluid balance. Constipation, gastroparesis, and gastro‐oesophageal reflux significantly affect quality of life. Finally, any micronutrient deficiencies should be taken into account. Nutritional assessments should be performed routinely. Optimization of pharmacologic treatment for both motor and nonmotor symptoms is essential, but nutritional interventions and counseling could and should also be planned with regard to nutritional balance designed to prevent weight loss or gain; optimization of levodopa pharmacokinetics and avoidance of interaction with proteins; improvement in gastrointestinal dysfunction (e.g., dysphagia and constipation); prevention and treatment of nutritional deficiencies (micronutrients or vitamins). A balanced Mediterranean‐like dietary regimen should be recommended before the introduction of levodopa; afterward, patients with advanced disease may benefit considerably from protein redistribution and low‐protein regimens. © 2009 Movement Disorder Society     

Special low-protein foods ameliorate postprandial off in patients with advanced Parkinson's disease.

Protein intake interferes with levodopa therapy. Patients with advanced Parkinson's disease (PD) should restrict daily protein intake and shift protein intake to the evening. For further reduction of protein intake in the first part of the day, special low-protein products (LPP) should be used instead of normal food products at breakfast and lunch. We studied the efficacy of LPP on postprandial off periods, in PD patients on levodopa therapy. The methods included a randomized, cross-over, single-blind, pilot clinical trial comparing a 2-month balanced diet with a 2-month LPP diet in 18 PD patients with motor fluctuations. The off phases were significantly shorter after LPP diet than after balanced diet (postprandial off, 49 +/- 73 min vs. 79 +/- 72 min and total off, 164 +/- 148 min vs. 271 +/- 174 min, both P < 0.0001). Moreover, a reduction in total off time during LPP diet (3.3 +/- 2.7 hr vs. 4.7 +/- 3.3 hr, P < 0.0001), occurred also in the 9 patients who did not experience subjective benefit. No significant changes in hematological and biochemical variables or body composition were recorded; a slight reduction in body weight (mean, -1.8%) was observed. Consumption of LPP in the first part of the day ameliorates off periods in PD patients, but additional studies including pharmacokinetics are needed.     

Long‐term outcomes of surgical therapies for Parkinson's disease

The surgical lesion of different brain structures has been used as a treatment for Parkinson's disease (PD) for several decades. More recently, the favored therapeutic approach has involved the administration of levodopa and the use of DBS. These two major therapeutic advances have greatly modified both the clinical condition of patients and the history of the disease. With the introduction of L ‐dopa in 1967, patients could regain mobility, because their akinesia, tremor, and rigidity were greatly improved, with consequent significant improvement in quality of life and increased life expectancy. However, after the so‐called “honeymoon” period in which the disease seemed to be controlled, motor fluctuations and L ‐dopa‐induced dyskinesias mitigated the initial enthusiasm. In the 1990s, unilateral pallidotomy and DBS of the globus palllidus internus and STN reduced these motor fluctuations and dyskinesias remarkably, thereby inaugurating a new era in the surgical treatment of PD. Short‐ and medium‐term follow‐up studies of patients who underwent surgery have documented sustained, significant motor benefits. However, given the progressive nature of PD and the purely symptomatic effects of pallidotomy and DBS, the long‐term clinical evolution of these surgical patients currently seems to be associated with a new PD phenotype, mainly characterized by axial motor problems and cognitive impairment. Here, we analyze the long‐term clinical outcomes of surgical PD patients with at least 5‐year follow‐up, focusing on the long‐term motor symptoms that were initially responsive to surgery. © 2012 Movement Disorder Society     

Standard and controlled-release levodopa/carbidopa in patients with fluctuating Parkinson's disease on a protein redistribution diet. A preliminary report

Ten patients with Parkinson's disease (PD) with motor fluctuations that responded to a protein redistribution diet were studied. All 10 patients were receiving standard Sinemet (levodopa/carbidopa). Five randomly selected patients were changed from standard Sinemet to a controlled-release form of Sinemet. The other five patients continued to receive standard Sinemet. To maintain the same degree of control of PD in the five patients switched to the controlled-release form of Sinemet, the daily levodopa intake increased. While receiving optimal therapy (standard Sinemet or controlled-release Sinemet) and a protein redistribution diet, all 10 patients then underwent hourly videotaping and blood sampling (for plasma levodopa levels) during 2 consecutive days. Videotapes were blindly reviewed for PD disability, dyskinesia, and the time required to walk a measured distance. Comparing the two groups, standard Sinemet with controlled-release Sinemet, respectively, mean levodopa requirements were 505 and 1895 mg, plasma levodopa levels were 6.1 and 17.6 mumol/L, and abnormal involuntary movement scale scores were 14 and 26. Their mean PD disability scores did not differ statistically or clinically. Also no statistically significant differences were noted in either their mean walking times or their mean daily dose frequencies.     

Low‐fat versus ketogenic diet in Parkinson's disease: A pilot randomized controlled trial

Background : Preliminary evidence suggests that diet manipulation may influence motor and nonmotor symptoms in PD, but conflict exists regarding the ideal fat to carbohydrate ratio. Objectives : We designed a pilot randomized, controlled trial to compare the plausibility, safety, and efficacy of a low‐fat, high‐carbohydrate diet versus a ketogenic diet in a hospital clinic of PD patients. Methods : We developed a protocol to support PD patients in a diet study and randomly assigned patients to a low‐fat or ketogenic diet. Primary outcomes were within‐ and between‐group changes in MDS‐UPDRS Parts 1 to 4 over 8 weeks. Results : We randomized 47 patients, of which 44 commenced the diets and 38 completed the study (86% completion rate for patients commencing the diets). The ketogenic diet group maintained physiological ketosis. Both groups significantly decreased their MDS‐UPDRS scores, but the ketogenic group decreased more in Part 1 (?4.58 ± 2.17 points, representing a 41% improvement in baseline Part 1 scores) compared to the low‐fat group (?0.99 ± 3.63 points, representing an 11% improvement) (P < 0.001), with the largest between‐group decreases observed for urinary problems, pain and other sensations, fatigue, daytime sleepiness, and cognitive impairment. There were no between‐group differences in the magnitude of decrease for Parts 2 to 4. The most common adverse effects were excessive hunger in the low‐fat group and intermittent exacerbation of the PD tremor and/or rigidity in the ketogenic group. Conclusions : It is plausible and safe for PD patients to maintain a low‐fat or ketogenic diet for 8 weeks. Both diet groups significantly improved in motor and nonmotor symptoms; however, the ketogenic group showed greater improvements in nonmotor symptoms. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Motor complications in Parkinson's disease: Ten year follow‐up study

Parkinson's disease (PD) can be symptomatically controlled with standard treatments; however, after a few years, this response typically declines and most patients develop motor complications. We carried out a prospective practice‐based study to evaluate the evolution appearance and evolution of motor complications in 64 de novo PD patients over 5 years and in 38 PD patients over 10 years. We studied untreated patients from initial assessment at basal conditions and evaluated every 6 months thereafter with treatment (levodopa versus other drugs). The follow‐up assessments were performed with the Unified Parkinson's Disease Rating Scale (UPDRS). At each assessment, patients were monitored regarding the development of dyskinesias, motor fluctuations, freezing, loss of postural reflexes, and cognitive impairment. We observed a significant improvement in UPDRS scores during the first year, then a progressive decline, more evident after the third year. Motor complications increased after the third year, and at the end of the survey (tenth year); drug‐induced dyskinesias and motor fluctuations were experienced (71.1 and 94.7%, respectively). After the first decade, many complications arose from the non‐levodopa–responsive features of the disease (cognitive impairment was present in 52.6% and gait freezing in 71.1%). Initial medication may influence medium‐term complications but not long‐term problems. Most long‐term disabling problems of PD were related to non‐levodopa‐responsive features. © 2010 Movement Disorder Society.     

A balanced carbohydrate: protein diet in the management of Parkinson's disease

Although restricting dietary protein is a proposed adjunct to treating Parkinson's disease (PD), the effect of carbohydrate consumption is unknown. We measured plasma levodopa and large neutral amino acid (LNAA) levels in nine PD patients treated with carbidopa/levodopa and different isocaloric meals containing high protein-low carbohydrate, low protein-high carbohydrate, and balanced 5:1 carbohydrate:protein mixtures. We found that levodopa levels increased significantly regardless of the type of diet, but that plasma LNAA levels varied less and motor performance was superior after the balanced diet than after the other two meals. We conclude that PD patients can consume nutritionally adequate meals and still maintain a stable plasma levodopa:LNAA ratio.     

Protein intake in Parkinsonian patients using the EPIC food frequency questionnaire.

The dietary habits of 45 Italian patients with Parkinson's disease (PD) and their spouses were investigated using the EPIC food frequency questionnaire. Average daily energy intake was similar, but PD patients consumed significantly more vegetable proteins and carbohydrates (both +18%; P = 0.01 and P = 0.001, respectively). Daily protein intake, which interferes with levodopa absorption, was 50% higher than the recommended daily allowance (1.2 vs. 0.8 g/kg) in both PD patients and spouses and was significantly higher in patients with moderate/severe symptoms (1.27 +/- 0.29 vs. 1.07 +/- 0.28 g/kg; P < 0.001). In patients taking levodopa, there was a correlation between daily levodopa dosage and protein intake (P = 0.027). Dietary habits of patients with advanced and/or fluctuating PD should always be checked, with particular reference to protein intake.     

Early versus delayed initiation of entacapone in levodopa‐treated patients with Parkinson’s disease: a long‐term,retrospective analysis

Background: We analysed data from three clinical trials in Parkinson’s disease (PD) patients with wearing‐off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long‐term outcomes than delayed entacapone treatment. Methods: Post‐hoc analysis of pooled data from three randomized, double‐blind, placebo‐controlled studies and their long‐term, open‐label extension phases. In all three studies, patients on levodopa/dopa‐decarboxylase inhibitor (DDCI) were first randomized to entacapone (‘early‐start’ group) or placebo (‘delayed‐start’ group) for the initial 6‐month double‐blind phase, after which all patients received open‐label levodopa/DDCI and entacapone treatment for up to 5 years. Results: A total of 488 PD patients with wearing‐off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and entacapone was found, with an improvement in Unified Parkinson’s Disease Rating Scale Part III (motor) score of ?1.66 (95% confidence intervals [?3.01, ?0.31]) points compared with the delayed‐start treatment group (P < 0.05). Levodopa/DDCI and entacapone therapy was well tolerated. There was no excess of dyskinesia in the early‐start group. Conclusions: These data suggest that early rather than delayed addition of entacapone to levodopa/DDCI in PD patients with wearing‐off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years.     

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.     

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     

International Parkinson and movement disorder society evidence‐based medicine review: Update on treatments for the motor symptoms of Parkinson's disease

Objective: The objective of this review was to update evidence‐based medicine recommendations for treating motor symptoms of Parkinson's disease (PD). Background: The Movement Disorder Society Evidence‐Based Medicine Committee recommendations for treatments of PD were first published in 2002 and updated in 2011, and we continued the review to December 31, 2016. Methods: Level I studies of interventions for motor symptoms were reviewed. Criteria for inclusion and quality scoring were as previously reported. Five clinical indications were considered, and conclusions regarding the implications for clinical practice are reported. Results: A total of 143 new studies qualified. There are no clinically useful interventions to prevent/delay disease progression. For monotherapy of early PD, nonergot dopamine agonists, oral levodopa preparations, selegiline, and rasagiline are clinically useful. For adjunct therapy in early/stable PD, nonergot dopamine agonists, rasagiline, and zonisamide are clinically useful. For adjunct therapy in optimized PD for general or specific motor symptoms including gait, rivastigmine is possibly useful and physiotherapy is clinically useful; exercise‐based movement strategy training and formalized patterned exercises are possibly useful. There are no new studies and no changes in the conclusions for the prevention/delay of motor complications. For treating motor fluctuations, most nonergot dopamine agonists, pergolide, levodopa ER, levodopa intestinal infusion, entacapone, opicapone, rasagiline, zonisamide, safinamide, and bilateral STN and GPi DBS are clinically useful. For dyskinesia, amantadine, clozapine, and bilateral STN DBS and GPi DBS are clinically useful. Conclusions: The options for treating PD symptoms continues to expand. These recommendations allow the treating physician to determine which intervention to recommend to an individual patient. © 2018 International Parkinson and Movement Disorder Society     

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     

Increased prefrontal volume in PD with levodopa‐induced dyskinesias: A voxel‐based morphometry study

Levodopa‐induced dyskinesias represent disabling complications from long‐term therapy with dopaminergic drugs for treating Parkinson's disease (PD). Although several neuroimaging studies have reported altered striatofrontal function that contributes to the emergence of these motor complications, the neuroanatomical correlates of this disorder are still unknown. Optimized voxel‐based morphometry (VBM) was applied to the MRI brain images of 36 PD patients with levodopa‐induced dyskinesias, 36 PD patients without levodopa‐induced dyskinesias, and 32 age‐ and sex‐matched controls. The VBM analysis comparing dyskinetic and nondyskinetic groups provided evidence of increased gray matter volume of the bilateral inferior frontal gyrus in dyskinetic patients, a finding that was more evident in patients with early‐onset PD. No significant differences were detected in the dyskinetic and nondyskinetic groups when compared with the controls. Our findings suggest that the presence of dyskinesias in patients with PD is characterized by an aberrant neural plasticity that could play a role in the pathophysiology of these motor complications. © 2011 Movement Disorder Society     

Levodopa response differs in Parkinson's motor subtypes: A task‐based effective connectivity study

Parkinson's disease (PD) is a circuit‐level disorder with clinically‐determined motor subtypes. Despite evidence suggesting each subtype may have different pathophysiology, few neuroimaging studies have examined levodopa‐induced differences in neural activation between tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtype patients during a motor task. The goal of this functional MRI (fMRI) study was to examine task‐induced activation and connectivity in the cortico‐striatal‐thalamo‐cortical motor circuit in healthy controls, TD patients, and PIGD patients before and after levodopa administration. Fourteen TD and 12 PIGD cognitively‐intact patients and 21 age‐ and sex‐matched healthy controls completed a right‐hand, paced tapping fMRI paradigm. Collectively, PD patients off medication (OFF) showed hypoactivation of the motor cortex relative to healthy controls, even when controlling for performance. After levodopa intake, the PIGD patients had significantly increased activation in the left putamen compared with TD patients and healthy controls. Psychophysiological interaction analysis revealed that levodopa increased effective connectivity between the posterior putamen and other areas of the motor circuit during tapping in TD patients, but not in PIGD patients. This novel, levodopa‐induced difference in the neural responses between PD motor subtypes may have significant implications for elucidating the mechanisms underlying the distinct phenotypic manifestations and enabling the classification of motor subtypes objectively using fMRI.     

Levodopa‐carbidopa intestinal gel in advanced Parkinson's disease: Final 12‐month,open‐label results

Motor complications in Parkinson's disease (PD) are associated with long‐term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l ‐dopa‐carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG‐J), which reduces l‐ dopa‐plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54‐week, open‐label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post‐LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary‐assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health‐related quality‐of‐life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG‐J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty‐seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l‐ dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

1‐[2‐(4‐Benzyloxyphenoxy)Ethyl]Imidazole inhibits monoamine oxidase B and protects against neuronal loss and behavioral impairment in rodent models of Parkinson's disease

Monoamine oxidase B (MAO‐B) is well known as a therapeutic target for Parkinson's disease (PD). MAO‐B inhibitors retain antiparkinsonism abilities to improve motor function and prevent neuronal loss by decreasing dopamine metabolism and oxidative stress in the brain. From the study to find novel antiparkinsonism drugs that can inhibit MAO‐B activity, neuronal loss, and behavioral deficits in the mouse model of PD, we identified that 1‐[2‐(4‐benzyloxyphenoxy)ethyl]imidazole (BPEI) or safinamide strongly and selectively inhibited MAO‐B activities in a dose‐dependent manner (IC₅₀ of BPEI and safinamide for MAO‐B were 0.016 and 0.0021 µM and for MAO‐A were 70.0 and 370 µM, respectively). In ex vivo studies after an administration (30 mg/kg, i.p.) of BPEI or safinamide to normal mice, the MAO‐B activity in the brain was reduced by up to 90.6% or 82.4% at 1.0 hr. BPEI (20 mg/kg, i.p.) or safinamide (20 mg/kg, i.p.) significantly reversed the behavioral impairments, dopamine levels in the striatum, and neuronal loss in the substantia nigra of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated mice compared with the MPTP‐alone‐treated group. In the 6‐hydroxydopamine‐induced PD rat model, behavioral improvement by levodopa sparing activity was observed in the BPEI‐ or safinamide‐treated (20 mg/kg, i.p.) rats. Moreover, BPEI revealed additional curative activities for nonmotor symptoms of PD such as pain, anxiety, epilepsy, and depression in rodent disease models. Therefore, BPEI has broad therapeutic potential for treating motor symptoms via strong and selective inhibitory effects on MAO‐B, with additional benefits for comorbid symptoms in PD. © 2015 Wiley Periodicals, Inc.     

Compulsive use of dopaminergic drug therapy in Parkinson's disease: Reward and anti‐reward

A few Parkinson patients develop a disabling pattern of compulsive dopaminergic drug use (“dopamine dysregulation syndrome”—DDS). DDS patients commonly identify aversive dysphoric “OFF” mood‐states as a primary motivation to compulsively use their drugs. We compared motoric, affective, non‐motor symptoms and incentive arousal after overnight medication withdrawal and after levodopa in DDS and control PD patients. Twenty DDS patients were matched to 20 control PD patients for age, gender, and disease duration and underwent a standard levodopa challenge. Somatic symptomatology, positive and negative affective states, drug effects, reward responsivity, motor disability, and dyskinesias were tested in the “OFF”‐state after overnight withdrawal of medications, and then after a challenge with a standard dose of levodopa, after a full “ON”‐state was achieved. In the “OFF”‐state, DDS patients reported lower positive affect, and more motor and non‐motor disability. In the “ON”‐state, DDS patients had higher expressions of drug “wanting,” reward responsivity, and dyskinesias. Positive and negative affect, non‐motor symptomatology, and motor disability were comparable. These findings suggest that affective, motivational, and motoric disturbances in PD are associated with the transition to compulsive drug use in individuals who inappropriately overuse their dopaminergic medication. © 2010 Movement Disorder Society