White matter hyperintensity predicts independent walking function at 6 months after stroke: A retrospective cohort study.

BACKGROUND: White matter hyperintensity (WMH) is reported to have a potential prevalence in healthy people and is a predictor of walking disability. However, WMH has not been adequately considered as a predictor of independent walking after stroke. OBJECTIVE: To investigate the effects of WMH severity on walking function in patients with acute stroke. METHODS: The retrospective cohort study included 422 patients with acute stroke. The WMH severity from magnetic resonance images was evaluated using the Fazekas scale. Age, type of stroke, Fazekas scale, Brunnstrom motor recovery stage, Motricity Index, and Mini-Mental State Examination were used as independent variables. Multivariable logistic regression analysis was conducted on the factors of independent walking at discharge and 6 months after onset, respectively. RESULTS: Multivariable analysis revealed that the Fazekas scale is not a predictive factor of independent walking at discharge (odds ratio [OR] = 0.89, 95% confidence intervals [CI] = 0.65-1.22), but at 6 months (OR = 0.54, 95% CI = 0.34-0.86). CONCLUSION: The WMH severity was a predictive factor of independent walking in patients with acute stroke after 6 months. WMH is a factor that should be considered to improve the accuracy of predicting long-term walking function in patients with stroke.

Risk factors for developing dyskinesia among Parkinson's disease patients with wearing-off: J-FIRST.

BACKGROUND: Dyskinesia frequently occurs during long-term treatment with levodopa in patients with Parkinson's disease (PD) and impacts quality of life. Few studies have examined risk factors for developing dyskinesia in PD patients exhibiting wearing-off. Therefore, we investigated the risk factors and impact of dyskinesia in PD patients exhibiting wearing-off. METHODS: We investigated the risk factors and impact of dyskinesia in a 1-year observational study of Japanese PD patients exhibiting wearing-off (J-FIRST). Risk factors were assessed by logistic regression analyses in patients without dyskinesia at study entry. Mixed-effect models were used to evaluate the impact of dyskinesia on changes in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Part I and PD Questionnaire (PDQ)-8 scores from one timepoint before dyskinesia was observed. RESULTS: Of 996 patients analyzed, 450 had dyskinesia at baseline, 133 developed dyskinesia within 1 year, and 413 did not develop dyskinesia. Female sex (odds ratio [95% confidence interval]: 2.636 [1.645-4.223]) and administration of a dopamine agonist (1.840 [1.083-3.126]), a catechol-O-methyltransferase inhibitor (2.044 [1.285-3.250]), or zonisamide (1.869 [1.184-2.950]) were independent risk factors for dyskinesia onset. MDS-UPDRS Part I and PDQ-8 scores increased significantly after the onset of dyskinesia (least-squares mean change [standard error] at 52 weeks: 1.11 [0.52], P = 0.0336; 1.53 [0.48], P = 0.0014; respectively). CONCLUSION: Female sex and administration of a dopamine agonist, a catechol-O-methyltransferase inhibitor, or zonisamide were risk factors for dyskinesia onset within 1 year in PD patients exhibiting wearing-off. Nonmotor symptoms and quality of life deteriorated after dyskinesia onset.

The Assessment of the Diagnostic Delay in Japanese People with Parkinson's Disease Using a Web-based Survey of Patients and Physicians.

Objective Although diagnostic criteria of Parkinson's disease (PD) have been established, the details of the process by which patients notice symptoms, visit a physician, and receive a diagnosis of PD is unclear. We therefore explored factors influencing latency in diagnosing PD. Methods We performed an internet-based survey of patients with PD and their families as well as physicians treating patients with PD to identify any diagnostic latency and its determinants. Evaluated factors included motor and non-motor symptoms, the diagnosis history and symptoms, patients' feelings toward PD prior to the diagnosis, and physician-determined reasons for the diagnostic delay. Results Among the 186 eligible patient respondents (including 87 responses from family members of patients), 24% received a PD diagnosis >1 year after the onset of PD-related symptoms, 58.6% had mid- or late-stage PD at the diagnosis, and 29% of patients had initially thought their symptoms were common age-related phenomena. Tremor (42%) was the most frequent symptom that led patients to visit a medical institution, whereas gait disturbance (14%) was the least frequent. More patients diagnosed with early-stage PD than those diagnosed with mid- or late-stage PD consulted a neurologist at their first visit. Among the 331 eligible physicians, patients' misinterpretation of their symptoms as being age-related was deemed one of or the most common cause (s) of a diagnostic delay by 67% and 36%, respectively. Conclusion Patients' insufficient or misinterpreted information about PD may cause delays in accessing healthcare services, leading to diagnostic delay.

Long-term effects of safinamide adjunct therapy on levodopa-induced dyskinesia in Parkinson's disease: post-hoc analysis of a Japanese phase III study.

This post-hoc analysis investigated the long-term effects of safinamide on the course of dyskinesia and efficacy outcomes using data from a phase III, open-label 52-week study of safinamide 50 or 100 mg/day in Japanese patients with Parkinson's disease (PD) with wearing-off. Patients (N = 194) were grouped using the UPDRS Part IV item 32: with and without pre-existing dyskinesia (pre-D subgroup; item 32 > 0 at baseline [n = 81], without pre-D subgroup; item 32 = 0 at baseline [n = 113]). ON-time with troublesome dyskinesia (ON-TD) increased significantly from baseline to Week 4 in the pre-D subgroup (+ 0.25 ± 0.11 h [mean ± SE], p = 0.0355) but gradually decreased up to Week 52 (change from baseline: - 0.08 ± 0.17 h, p = 0.6224); ON-TD did not change significantly in the Without pre-D subgroup. UPDRS Part IV item 32 score increased significantly at Week 52 compared with baseline in the Without pre-D subgroup, but no UPDRS Part IV dyskinesia related-domains changed in the pre-D subgroup. Both subgroups improved in ON-time without TD, UPDRS Part III, and Part II [OFF-phase] scores. The cumulative incidence of new or worsening dyskinesia (adverse drug reaction) at Week 52 was 32.5 and 5.0% in the pre-D and Without pre-D subgroups, respectively. This study suggested that safinamide led to short-term increasing dyskinesia but may be not associated with marked dyskinesia at 1-year follow-up in patients with pre-existing dyskinesia, and that it improved motor symptoms regardless of the presence or absence of dyskinesia at baseline. Further studies are warranted to investigate this association in more details.Trial registration: JapicCTI-153057 (Registered: 2015/11/02).

Collective Expert Perspectives on the Use of Safinamide as Adjunctive Therapy for Parkinson's Disease: Online-Based Delphi Survey.

Background: Safinamide is a selective, reversible monoamine oxidase-B inhibitor with a sodium channel inhibitory effect. Published clinical evidence supports safinamide as an effective therapy for Parkinson's disease (PD) with wearing-off. However, to date, no consensus recommendations have been available to guide physicians in Asia on the optimal use of safinamide in clinical practice. To summarize opinions on the optimal patient profile and methods of using safinamide in common clinical scenarios, Japanese movement disorder specialists with expertise in PD investigated the perspectives of neurologists and neurosurgeons. Methods: The Delphi panel approach was used to summarize the opinions of panelists. The panel comprised doctors from Japan with extensive clinical practice experience in the use of safinamide (n = 46 at the final round). The consensus was defined as 80% or more agreement between panelists for each scenario at the final round. Results: There was a high level of agreement that patients with the following symptoms are suitable for safinamide treatment such as bradykinesia (100%), rigidity (95.7%), and/or gait disorder (89.1%) based on motor symptoms and PD-related pain (97.8%) and/or depression or apathy (93.5%) based on non-motor symptoms. Morning-off (95.7%), but not dyskinesia (71.7%), also reached consensus. The use of high-dose safinamide (100 mg/day) was recommended when the improvement in PD symptoms is insufficient and increasing the doses of other anti-PD medications is difficult (97.8%) or when the abovementioned non-motor symptoms adversely affect daily life (93.5%). Conclusions: This report provides expert perspectives on the use of safinamide for a wide range of clinical scenarios in Japan.

[Late-Onset Dyskinesia Occurring During Antipsychotic Treatment for Schizophrenia: Treatments for Tardive Dyskinesia].

Tardive dyskinesia is recognized as buccolingual dyskinesia, but also includes various involuntary movements, such as chorea, dystonia, myoclonus, and tremor. Tardive dyskinesia can be treated depending on the type of movement disorder present. Antipsychotics causing tardive dyskinesia should be reduced in dosage or should be discontinued. However, the treatment of schizophrenia is important, and neurologists must treat tardive dyskinesia in collaboration with psychiatrists taking care of patients with tardive dystonia. Various treatments, such as VMAT-2 inhibitors or tetrabenazine, reserpine, dopamine receptor antagonists, botulinum toxin therapy, anticholinergic agents, or deep brain stimulation, are trialed, depending on the type of movement disorder and the degree of severity of the disorder.

Treatment Satisfaction and Its Influencing Factors in Parkinson's Disease: A Web-Based Survey of Patients and Physicians in Clinical Practice in Japan.

OBJECTIVE: This study aimed to gain an understanding of patient and physician satisfaction with overall treatment and routine consultations for Parkinson's disease in clinical practice. METHODS: This observational, cross-sectional, web-based survey was conducted in Japan from February to March 2019. Eligible patients with Parkinson's disease (N = 186) and physicians who treat patients with Parkinson's disease (N = 331) were asked to evaluate their satisfaction with treatment, consultation, symptom control, and use of a symptom diary. RESULTS: Patients had a mean age of 62.7 years, 54.8% were male, and most (75.8%) had Hoehn and Yahr stage ≥3 symptoms. Physicians were mostly male (93.1%) and had treated 52 patients with Parkinson's disease in the last 6 months, and 34.1% were certified neurologists. There were significant gaps between patient and physician satisfaction with treatment and consultations. Patient and physician satisfaction with overall treatment was significantly lower for patients with Hoehn and Yahr stage ≥3 symptoms than stage 1-2 symptoms (patients: 53.9% vs. 71.1%; physicians: 43.2% vs. 69.7%, respectively). The proportion of patients who were satisfied with symptom control was lower than that of physicians (26.4% vs. 51.5%). Influencing factors for patient satisfaction with treatment were nonmotor symptoms (e.g., insomnia and depression). Satisfaction tended to be higher for patients and physicians when symptom diaries were used. CONCLUSION: Significant gaps in perceptions of treatment and consultation exist between patients and physicians in Parkinson's disease. Physicians should participate in shared decision making with their patients and consider strategies for management of nonmotor symptoms and nonpharmacological therapies and encourage the use of symptom diaries.

Characteristics of wearing-off and motor symptoms improved by safinamide adjunct therapy in patients with Parkinson's disease: A post hoc analysis of a Japanese phase 2/3 study.

INTRODUCTION: Patients with Parkinson's disease (PD) experience various motor and non-motor symptoms. We conducted a post hoc analysis of a Japanese phase 2/3 study of safinamide (50 or 100 mg/day) in patients with Parkinson's disease and wearing-off to evaluate response according to background factors. Safinamide efficacy against major motor symptoms was also assessed. METHODS: Multiple regression analyses in safinamide-treated patients (50 or 100 mg/day) assessed changes in daily ON-time without troublesome dyskinesia (hereafter referred to as ON-time) according to baseline clinical variables. Subgroup analyses by baseline Unified Parkinson's Disease Rating Scale (UPDRS) part III score were also conducted. We evaluated cardinal motor symptoms using the UPDRS. RESULTS: In the multiple regression analysis, changes in ON-time were related to baseline non-motor symptoms (UPDRS part I score) and ON-time in the 50-mg group, but no relationships with non-motor symptoms were observed in the 100-mg group. Additionally, in the subgroup analysis of patients with more severe motor symptoms (UPDRS part III score > 20), a significant improvement in ON-time was observed only with 100 mg/day (p = 0.01). At both doses, safinamide significantly improved cardinal motor symptom scores (bradykinesia, rigidity, tremor, axial symptoms, and gait disturbances). CONCLUSIONS: The observed response profile to the 50-mg/day dose may be related to baseline non-motor symptoms, but this was not true for the 100-mg/day dose. Both safinamide doses improved major motor symptoms in levodopa-treated patients with PD.

Comparative examination of levodopa pharmacokinetics during simultaneous administration with lactoferrin in healthy subjects and the relationship between lipids and COMT inhibitory activity in vitro.

Background: Lactoferrin (bLF) is an iron-binding multifunctional protein that is abundant in milk. In mice, it inhibits catechol-O-methyltransferase (COMT) activity and increases blood levodopa levels. However, the clinical effects are unknown.Objective: The objective of this study was to determine the effect of bLF on the kinetics of levodopa in blood.Design: The effects of the concomitant administration of a combined formulation of levodopa and an aromatic amino acid decarboxylase inhibitor and bLF on the concentration of levodopa in blood and its metabolism were assessed in eight healthy subjects. In addition, we analyzed the association with clinical factors and evaluated whether clinical factors affected the COMT inhibitory activity of bLF in vitro.Results: Although not statistically significant, the peak plasma concentration (Cmax) of levodopa increased by 18.5%. From the results of the stratified analysis of total cholesterol, a relationship with ΔCmax was predicted. Therefore, bLF was reacted with cholesterol in the presence of lecithin and sodium deoxycholate in vitro to evaluate COMT inhibitory activity, and an increase in inhibitory activity was observed. By contrast, the ester compound cholesteryl oleate had no effect. The inhibitory activity of free fatty acids, which are known to interact with bLF, was also enhanced.Conclusion: The COMT inhibitory activity of bLF is not effective in elevating blood levodopa levels. However, in humans with high lipid levels, such as cholesterol, interactions may enhance the inhibitory effect, resulting in the enhanced absorption of levodopa.Trial registration: ID, UMIN000026787, registered 30 March 2017; URL, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000030749Trial registration: UMIN Japan identifier: UMIN000026787.

Influence of istradefylline on non-motor symptoms of Parkinson's disease: A subanalysis of a 1-year observational study in Japan (J-FIRST).

INTRODUCTION: The non-motor symptoms (NMSs) of Parkinson's disease (PD) significantly impact the patient's health-related quality of life. This subanalysis of the J-FIRST study evaluated the effect of istradefylline, a selective adenosine A2A receptor antagonist, on NMSs in istradefylline-naïve Japanese patients with PD. METHODS: Patients with PD and ≥1 NMS and 'wearing-off' with their current antiparkinsonian treatment were observed for up to 52 weeks. The effect of istradefylline on NMSs was measured in terms of changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 total, individual sub-items scores and the 8 item PD questionnaire (PDQ-8) estimated by the marginal structural model. RESULTS: Overall, 732 patients were istradefylline-naïve prior to the study, of whom 171 were treated with istradefylline for ≥8 weeks during the observation period (istradefylline-treated patients). At baseline, istradefylline-treated patients were more likely to have a dyskinesia (49.7% vs 40.8%) and received a significantly higher daily dose of levodopa (462.8 mg vs 413.0 mg) than those who did not receive istradefylline (n = 561). MDS-UPDRS Part 1 total score at the end of the 52-week observational period slightly increased in patients who received istradefylline and those who did not (0.49 ± 0.41 vs 0.07 ± 0.20; P = 0.36). There were no statistically significant differences between the two groups of patients in terms of changes in the MDS-UPDRS Part 1 total score or any sub-items, or in the PDQ-8 total score. CONCLUSION: NMSs remained generally controlled in istradefylline-treated Japanese patients with PD who exhibited wearing-off with their current antiparkinsonian treatment. Istradefylline could be a feasible treatment option for patients with advanced PD, without worsening existing NMSs.

Effects of safinamide adjunct therapy on pain in patients with Parkinson's disease: Post hoc analysis of a Japanese phase 2/3 study.

INTRODUCTION: The non-dopaminergic and dopaminergic actions of safinamide may alleviate pain in patients with Parkinson's disease (PD). We investigated the efficacy of safinamide for pain when administered as an adjunct to levodopa in Japanese patients with PD. METHODS: This was a post hoc analysis of a phase 2/3 clinical study of safinamide in Japanese patients with PD who were experiencing wearing-off. Pain was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part II 'sensory symptoms' item 17, on a scale of 0-4, and the 39-item Parkinson's Disease Questionnaire (PDQ-39) 'bodily discomfort' domain score. Subgroup analyses, according to baseline symptoms and concomitant medications, were also performed. RESULTS: Least square (LS) mean changes in the UPDRS item 17 score from baseline to Week 24 in the placebo, safinamide 50-mg and safinamide 100-mg groups during the OFF phase were 0.08, -0.15 (p = 0.0133 vs placebo) and -0.18 (p = 0.0054), respectively, and during the ON phase were 0.04, -0.08 (p = 0.0529) and -0.08 (p = 0.0505), respectively. Changes from baseline to Week 24 in PDQ-39 'bodily discomfort' scores were not significantly different in safinamide groups vs placebo. The presence of moderate-to-severe bradykinesia or early-morning dystonia at baseline resulted in numerically greater effect sizes in UPDRS item 17 scores during the OFF phase. CONCLUSIONS: Safinamide 50 mg and 100 mg reduced the UPDRS item 17 score in patients with PD, especially during the OFF phase. Patients with moderate-to-severe bradykinesia and early-morning dystonia may benefit from safinamide treatment.

Long-term safety and efficacy of opicapone in Japanese Parkinson's patients with motor fluctuations.

The double-blind part of the COMFORT-PD (COMt-inhibitor Findings from Opicapone Repeated Treatment for Parkinson's Disease) study in Japanese levodopa-treated patients with Parkinson's disease and motor fluctuations found that both opicapone 25 and 50 mg were significantly more effective than placebo. This 52-week open-label extension study evaluated the long-term safety and efficacy of opicapone 50 mg tablets in patients who completed the double-blind part of the COMFORT-PD study. Safety was monitored via adverse events, laboratory testing, and physical, cardiovascular and neurological examinations. Efficacy was primarily assessed by change in OFF-time. Secondary efficacy measures included: ON-time, percentage of OFF/ON-time responders, other outcomes from the double-blind part. 391/437 patients were transferred to the open-label extension period and included in the safety analysis set (full analysis set, n = 387; open-label completers, n = 316). Adverse events were frequently reported (n = 338, 86.4%), but < 50% were considered drug-related (39.9%) and few were considered serious (2.6%) or led to discontinuation (2.8%). Decreased OFF-time was consistently observed over the open-label period regardless of initial randomization. Change [LSM (SE)] in OFF-time from the open-label baseline to the last visit showed a persistent effect in patients initially randomized to opicapone 25 mg [- 0.37 (0.20) h, P = 0.0689] and opicapone 50 mg [- 0.07 (0.21) h, P = 0.6913] whereas opicapone 50 mg led to a statistically significant reduction in the previous placebo group [- 1.26 (0.19) h, P < 0.05]. Once-daily opicapone 50 mg was generally well tolerated and consistently reduced OFF-time over 52 weeks in Japanese levodopa-treated patients with motor fluctuations.Trial registration JapicCTI-153112; date of registration: December 25, 2015.

Long-term study of ropinirole patch in Parkinson's disease patients with/without basal l-dopa.

INTRODUCTION: A dopamine agonist patch could be an important treatment option for Parkinson's disease. This study evaluated the long-term efficacy and safety of the ropinirole hydrochloride patch. The steady state plasma ropinirole concentration was also assessed. METHODS: In a multicenter, open-label, uncontrolled study, Parkinson's disease patients with/without basal levodopa and with/without prior dopamine agonist therapy (any of these four regimens) received application of a ropinirole patch once daily for up to 52 weeks with unforced titration from 8 to 64 mg. For patients with prior dopamine agonist therapy, the initial dose of ropinirole patch was determined from the prior dopamine agonist dose by using a conversion table. RESULTS: Most adverse events were mild or moderate. All application site adverse events were mild, except for moderate application site erythema in one patient. In patients with prior dopamine agonist therapy, switching to ropinirole patch did not lead to a significant early increase of adverse events. A change from baseline in the UPDRS Part III total score, the primary efficacy endpoint, showed improvement until Week 16 compared with baseline, followed by little subsequent change until Week 52, indicating maintenance of efficacy. The plasma ropinirole concentration was at steady state throughout the study period and showed a dose-proportional increase. CONCLUSION: Once-daily application of ropinirole patch showed long-term efficacy and safety (52 weeks) for Parkinson's disease. Switching from other dopamine agonists to ropinirole patch was effective and safe. The plasma ropinirole concentration was at steady state throughout the study period and showed a dose-proportional increase.

PICALM mRNA Expression in the Blood of Patients with Neurodegenerative Diseases and Geriatric Depression.

BACKGROUND: Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a validated genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with other neurodegenerative diseases. However, PICALM expression in the blood of neurodegenerative diseases remains elusive. OBJECTIVE: This study aimed to assess the usefulness of PICALM expression levels in the blood of patients with AD, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and geriatric major depressive disorder (MDD) as a diagnostic biomarker. METHODS: In total, 45, 20, 21, and 19 patients with AD, PD, DLB, and geriatric MDD, respectively, and 54 healthy controls (HCs) were enrolled in the study. Expression data from Gene Expression Omnibus database (GSE97760), (GSE133347) and (GSE98793), (GSE48350), and (GSE144459) were used to validate the ability of biomarkers in the blood of patients with AD, PD, geriatric MDD, and a postmortem human AD brain and animal model of AD (3xTg-AD mouse), respectively. RESULTS: PICALM mRNA expression in human blood was significantly increased in patients with AD compared with that in HCs. PICALM mRNA expression and age were negatively correlated only in patients with AD. PICALM mRNA expression in human blood was significantly lower in patients with PD than in HCs. No changes in PICALM mRNA expression were found in patients with DLB and geriatric MDD. CONCLUSION: PICALM mRNA expression in blood was higher in patients with AD, but lower in patients with PD, which suggests that PICALM mRNA expression in human blood may be a useful biomarker for differentiating neurodegenerative diseases and geriatric MDD.

Pharmacokinetic Comparison of Capsule and Tablet Formulations of Opicapone in Healthy Japanese Subjects: Phase 1 Study.

Opicapone, a peripheral, long-acting catechol-O-methyltransferase inhibitor has been shown to improve wearing-off phenomenon in randomized, double-blind studies. This study compared the pharmacokinetic characteristics of opicapone small-tablet and size 1 capsule formulations after single oral administration to healthy Japanese subjects. In this open-label, randomized, 2-way and 2-period crossover phase 1 study, 48 healthy male subjects (aged 20 to 45 years; body mass index, 18.5 to <30.0 kg/m2 ) were randomly assigned to 2 cohorts (n = 24 each), which were administered opicapone 25 or 50 mg in a tablet-capsule or capsule-tablet sequence under fasted conditions. Blood samples were collected for pharmacokinetic analysis before opicapone capsule/tablet administration and at regular intervals over 24 hours after administration. Compared with capsules, tablets were associated with higher Cmax and AUClast/0-∞ values. However, t1/2 and tmax values were similar with opicapone 25- and 50-mg capsules/tablets. Geometric mean ratios (tablets/capsules) of Cmax , AUClast , and AUC0-∞ were 1.24, 1.18, and 1.19, respectively, for the 25-mg dose and 1.42, 1.28, and 1.27, respectively, for the 50-mg dose. Opicapone was well tolerated, and no serious adverse events occurred. A small tablet formulation of opicapone proposed for use in Japanese clinical trials was associated with apparent greater exposure compared with the existing hard capsule formulation, which should be considered when developing opicapone for Japanese patients.

Effect of Opicapone Tablets on Levodopa and 3-O-Methyldopa Pharmacokinetics in Healthy Japanese Subjects: Phase 1 Study.

This study evaluated the effect of a small-tablet formulation of opicapone for use in clinical trials in Japan on the pharmacokinetics of levodopa (l-dopa) and 3-O-methyldopa (3-OMD). In an open-label, 3-period, single-sequence crossover phase 1 study in 80 healthy Japanese males (aged 20-45 years; body mass index, 18.5 to <30.0 kg/m2 ), 10 mg of l-dopa/carbidopa 100 was administered 3 times daily on day 0 (period 1) and day 12 (period 3), and opicapone tablets (5, 10, 25, or 50 mg; n = 20 each group) were administered once daily for 11 days (period 2). During periods 1 and 3, plasma concentrations of l-dopa and 3-OMD were measured and pharmacokinetic parameters (maximum observed plasma concentration, time at which maximum concentration was observed, area under the plasma concentration-time curve from time 0 to 5 hours [AUC5h ] and from time 0 to 24 hours [AUC24h ] following each dose, terminal half-life) of plasma l-dopa and 3-OMD were determined along with the geometric mean ratio (period 3/period 1) of AUC24h for l-dopa and 3-OMD. Maximum concentration of l-dopa for the first, second, or third doses of l-dopa/carbidopa did not significantly increase with increasing opicapone dose. The AUC of l-dopa increased with increasing opicapone dose but tended toward a peak plateau with opicapone doses of 25 mg and higher. Geometric mean ratios (90% confidence intervals) of AUC24h were 5 mg, 1.16 (1.10-1.21); 10 mg, 1.26 (1.23-1.30); 25 mg, 1.51 (1.44-1.57); 50 mg, 1.60 (1.54-1.66). Opicapone tablets were well tolerated. In Japanese healthy subjects, increases in plasma exposure to l-dopa appear to level off with opicapone doses of 25 mg and higher, which may be relevant for optimal dosing among Japanese patients with Parkinson disease.

The Effects of Safinamide Adjunct Therapy on Depression and Apathy in Patients With Parkinson's Disease: Post-hoc Analysis of a Japanese Phase 2/3 Study.

BACKGROUND AND PURPOSE: Neuropsychiatric symptoms in Parkinson's disease (PD) have been shown to significantly affect quality of life (QOL). We investigated the impact of safinamide on depression and apathy when administered as an adjunct to levodopa in Japanese patients with PD. METHODS: This was a post-hoc analysis of data from a phase 2/3 clinical study of safinamide in Japanese patients with PD experiencing wearing-off (JapicCTI-153056; https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-153056). Patients received placebo, safinamide 50 mg, or safinamide 100 mg as an adjunct therapy. The endpoints for this analysis were changes from baseline to Week 24 in the Unified Parkinson's Disease Rating Scale (UPDRS) Part I item 3 (depression) and item 4 (apathy) scores and the Parkinson's Disease Questionnaire (PDQ-39) "emotional well-being" domain score. Subgroup analyses investigated the relationship between neuropsychologic symptoms and improvements in motor fluctuation and assessed which patient populations might be expected to obtain neuropsychologic benefit from safinamide. RESULTS: Compared with placebo, safinamide (both doses) significantly improved UPDRS Part I item 3 scores in the overall analysis population, and the 100-mg dose improved UPDRS Part I item 4 scores in the population with apathy at baseline. Changes in the PDQ-39 "emotional well-being" score showed numerical, but not significant, dose-related improvements. Notable reductions in depression were associated with a change in daily ON-time ≥1 h, pain during OFF-time at baseline, and female sex. CONCLUSIONS: The results from this post-hoc analysis of the Japanese phase 2/3 study suggest that safinamide could bring benefits to patients with PD who have mild depression, pain during the OFF phase. In addition, safinamide might provide particular benefits for patients with PD who have mild apathy and female.

Randomized, Controlled Study of Opicapone in Japanese Parkinson's Patients with Motor Fluctuations.

OBJECTIVES: This placebo-controlled, randomized study evaluated the efficacy and safety of opicapone 25-mg and 50-mg tablets in Japanese levodopa-treated patients with Parkinson's disease and motor fluctuations. METHODS: Japanese adults (n = 437, age 39-83 years) with Parkinson's disease (United Kingdom Parkinson's Disease Society criteria) received opicapone 25-mg (n = 145), opicapone 50-mg (n = 145), or placebo (n = 147) tablets over the double-blind treatment period (14-15 weeks). The primary efficacy assessment was change in OFF-time; secondary efficacy assessments included OFF/ON-time responders (≥1 hour change from baseline), total ON-time, ON-time with and without troublesome dyskinesia, and Unified Parkinson's Disease Rating Scale. RESULTS: The least squares mean (standard error) change in OFF-time from baseline to the last visit was -0.42 (0.21) hour for the placebo group, -1.16 (0.22) hour for the opicapone 25 mg group, and -1.04 (0.21) hour for the opicapone 50 mg group. The percentage of ON-time responders, changes in total ON-time/ON-time without troublesome dyskinesia, and Unified Parkinson's Disease Rating Scale II (at OFF) all showed statistically significant improvements versus placebo for both opicapone tablet doses (P < 0.05). Unified Parkinson's Disease Rating Scale III (at ON) was improved versus placebo in patients who received opicapone 50 mg (P < 0.05). Adverse events were more common in patients treated with opicapone 25 mg (60.0%) or opicapone 50 mg (54.5%) versus placebo (48.3%). The most commonly reported adverse event was dyskinesia (placebo, 2.7%; opicapone 25 mg, 9.0%; opicapone 50 mg, 12.4%). CONCLUSIONS: In Japanese patients, both opicapone 25 and 50 mg were significantly more effective than placebo with no dose-dependent difference in efficacy, and both doses were well tolerated. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Lister hooded rats as a novel animal model of attention-deficit/hyperactivity disorder.

Appropriate animal models are necessary to determine the molecular and cellular mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). This study used a battery of behavioral tests to compare Lister hooded rats (LHRs), an old outbred strain frequently used for autistic epilepsy research, with Wistar rats and spontaneously hypertensive rats (SHRs), a commonly used ADHD model. The open field, elevated plus maze, light/dark box, and drop tests demonstrated that LHRs were the most hyperactive animals and displayed the most inattentive- and impulsive-like behaviors, which are characteristics of ADHD. The radial arm maze, social interaction, and Morris water maze tests showed that LHRs did not display deficits characteristic of autism or intellectual disability. Although LHRs did not show different monoamine contents, the mRNA expression levels of various genes linked to ADHD (Cdh13, Drd5, Foxp2, Maoa, Sema6d, Slc9a9, and St3gal3) and tyrosine hydroxylase protein expression levels were lower in the prefrontal cortex of LHRs compared with that of Wistar rats or SHRs. c-Fos, synapsin I, and tau protein expression levels in the prelimbic region of the medial prefrontal cortex were also increased in LHRs compared with Wistar rats. Atomoxetine and guanfacine, commonly used non-stimulant treatments for ADHD, ameliorated ADHD-like behaviors in LHRs. These results suggest that LHRs can serve as a better ADHD model to develop novel pharmacological interventions.