Masahiro Nomoto - Academia.edu (original) (raw)

Papers by Masahiro Nomoto

Internal Medicine, 2018

Objective We conducted a study to obtain information that could be used to provide Parkinson's di... more Objective We conducted a study to obtain information that could be used to provide Parkinson's disease (PD) patients with appropriate advice on safe driving. Methods Consecutive PD patients who visited our office were studied. Among these patients, those who had experienced driving after being diagnosed with PD were interviewed by neurologists and a trained nurse to investigate their previous car accidents, motor function, cognitive function, sleepiness, levodopa equivalent dose (LED), and emotional dysregulation. The rates of major car accidents before and after the onset of PD were compared. Results Fifteen patients had experienced a major car accident resulting in human injury or serious property damage since the onset of PD. When the rates of major car accidents before and after the onset of PD were compared, the ratio was 4.3 [95% confidence interval (CI) 1.9-9.7]. The incidence of accidents after the onset of PD was correlated with age, disease duration, LED, the cognitive function Mini-Mental Scale Examination (MMSE), Japanese translation of the Montreal Cognitive Assessment (MoCA-J), but not the motor symptom score [Unified Pankinson's disease rating scale (UPDRS) part III at the time of the study]. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) score was also higher in patients with major car accidents. Conclusion The severity of symptoms (Hoehn-Yahr classification), cognitive function, and disease duration were expected to be risk factors for car accidents. However, the motor symptom score (UPDRS part III) was not associated with the incidence of major car accidents. In addition to a low cognitive function and the severity of symptoms, the QUIP score might be an independent factor that can be referenced when advising PD patients to refrain from driving.

eNeurologicalSci, 2018

We conducted a phase I study investigating the efficacy, safety, and tolerability of ONO-2160, a ... more We conducted a phase I study investigating the efficacy, safety, and tolerability of ONO-2160, a newly developed levodopa pro-drug, and carbidopa compared with levodopa and carbidopa to stabilize levodopa plasma concentration fluctuations in Japanese patients with Parkinson's disease. In an open-label two-period design, patients (n = 12) with Parkinson's disease received levodopa and carbidopa for 3 days before 7 days of treatment with ONO-2160 and carbidopa. Patients were primarily evaluated using the Unified Parkinson's Disease Rating Scale Part III, a Parkinson's disease symptom diary, and analysis of adverse events. Pharmacokinetic analysis of plasma levodopa concentration was also performed. ONO-2160 and carbidopa therapy stabilized effective plasma levodopa concentration. No adverse events with safety concerns were observed. The combination of ONO-2160 and carbidopa produced a prolonged and stable plasma levodopa concentration with a reduction in Unified Parkinson's Disease Rating Scale Part III total scores. The combination was well tolerated, with no safety concerns, when administered to Japanese patients with Parkinson's disease.

Journal of neurology, 2018

Rotigotine-a non-ergot dopamine agonist-has two advantages; it can stimulate all dopamine recepto... more Rotigotine-a non-ergot dopamine agonist-has two advantages; it can stimulate all dopamine receptors (D1-D5) like innate dopamine, and its transdermal administration provides continuous dopaminergic stimulation. The age of the patient impacts the effect and adverse events of anti-parkinsonian treatment. We conducted a post hoc analysis on three randomized, double-blind, placebo-controlled trials performed in Japan to clarify the difference of anti-parkinsonian treatment in elderly and non-elderly patients. Data from two combination therapy trials (with levodopa) in advanced stage Parkinson's disease patients and one monotherapy trial in early stage patients were pooled and grouped by age (non-elderly aged < 70, elderly aged 70 +). In each age group, efficacy of rotigotine was compared to placebo. In the combination therapy, total Unified Parkinson's Disease Rating Scale Part III scores and some subtotal scores, including those for tremor, akinesia and gait disturbance, sig...

Journal of neurology, 2018

Unfortunately, the online published article has errors in Table 1 and Table 2. The corrected tabl... more Unfortunately, the online published article has errors in Table 1 and Table 2. The corrected tables are given in the following page.

Japanese Journal of Pharmacoepidemiology/Yakuzai ekigaku, 2015

Nihon Naika Gakkai Zasshi, 2013

Journal of General and Family Medicine, 2017

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Parkinsonism & related disorders, 2017

We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify f... more We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify factors affecting NMSs and the health-related quality of life of Japanese patients with Parkinson's disease (PD). A total of 1021 patients with PD who had one or more NMS and showed wearing-off under anti-parkinsonian treatment were enrolled from 35 medical centers in Japan for this observational study. The primary measurements were the Movement Disorder Society unified Parkinson's disease rating scale (MDS-UPDRS) part I and the Parkinson's Disease Questionnaire (PDQ-8). The relationships of MDS-UPDRS and PDQ-8 with the patient's clinical background and undertaken medical interventions were determined. Here, we report baseline data of our 52-week ongoing study. The mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively. The most common NMSs were constipation problems (85.4%), sleep problems (73.7%), pain and other sensations (72.7%) and daytime sleepiness (...

Electroencephalography and Clinical Neurophysiology, 1995

Neurology and Clinical Neuroscience, 2014

Background: There are two formulations of levodopa in Japan and a few other countries, levodopa/b... more Background: There are two formulations of levodopa in Japan and a few other countries, levodopa/benserazide 100/25 mg and levodopa/carbidopa 100/10 mg, which have been generally regarded as interchangeable in Parkinson's disease treatment. Aim: We investigated the pharmacokinetics of levodopa in the two kinds of levodopa/decarboxylase inhibitor (benserazide or carbidopa) formulations to study their equivalence. Methods: Population pharmacokinetic analysis was carried out using levodopa data from the healthy subject study and, additionally, for 70 plasma concentration data points from Parkinson's disease patients receiving either levodopa/decarboxylase inhibitor combination in clinical practice. Results: In healthy subjects, the mean AE standard deviation plasma levodopa maximum observed plasma concentration and area under the plasma concentration time curve from time 0 to 3 h (512 AE 139 vs 392 AE 49 lmol•h/L, P < 0.05) were significantly higher after levodopa/benserazide compared with levodopa/carbidopa. Levodopa time to maximum observed plasma concentration and plasma elimination half-life were not significantly different when comparing the respective formations. Levodopa pharmacokinetic parameters were the same between the Parkinson's disease patients and healthy subjects, except for levodopa apparent clearance, which was approximately two-thirds lower in Parkinson's disease patients compared with healthy subjects for both levodopa/decarboxylase inhibitor combinations, which might result in higher levodopa area under the curve in patients with Parkinson's disease than in healthy volunteers. Conclusion: Levodopa pharmacokinetics differ after administration of levodopa/ benserazide and levodopa/carbidopa. This information cold be useful for adjustment of medication in Parkinson's disease patients, especially with motor complications.

Nihon Naika Gakkai Zasshi, 2007

Clinical Neuropharmacology, 2015

† and for the PD Study Group Objectives: This study is the first controlled trial to evaluate the... more † and for the PD Study Group Objectives: This study is the first controlled trial to evaluate the efficacy and safety of subcutaneous apomorphine in Japanese patients with advanced Parkinson disease. Methods: A phase II, multicenter, randomized, double-blind, parallelgroup trial was undertaken in 16 patients with advanced Parkinson disease with wearing-off phenomenon to compare subcutaneous apomorphine versus placebo. The maintenance dose of apomorphine (1-6 mg per dose), determined individually for each patient by titration, was additionally administered 3 times at 2-hour intervals in the multiple-dose phase in which pharmacokinetics was evaluated. Results: The mean (SD) maintenance apomorphine dose was 3.4 (1.4) mg (range, 2-6 mg). The change in the Unified Parkinson's Disease Rating Scale motor score 20 minutes after maintenance dose administration was significantly greater in the apomorphine group than in the placebo group (least squares mean, −24.0 vs −4.1, P = 0.021). Apomorphine treatment resulted in an "on" state approximately 20 minutes after dose administration, lasting for approximately 60 minutes. Apomorphine was rapidly absorbed, with the maximum plasma concentration (C max) reached in 0.367 to 0.383 hour. It was quickly eliminated with a half-life of 0.520 to 0.793 hour, suggesting no accumulation during multiple-dose phase. The C max of apomorphine at effective dose was presumed to be approximately 20 ng/mL. Apomorphine was well tolerated. Conclusions: Subcutaneous apomorphine is expected to provide a new treatment option in Japan as a rescue therapy. Two-hour interval injections did not cause reduced responses, and effective blood concentration was presumed to be approximately 20 ng/mL similar, to the previous study conducted at North America.

Japanese Clinical Medicine, 2015

The number of patients with late-onset myasthenia gravis (MG) among patients ≥50 years has been i... more The number of patients with late-onset myasthenia gravis (MG) among patients ≥50 years has been increasing recently. We encountered three patients who developed elderly-onset MG at a particularly advanced age (≥80 years). All were female and positive for anti-acetylcholine receptor antibodies. About 4 years have passed since MG onset in all three patients and symptoms have been controlled without recurrence using a combination of oral low-dose prednisolone and tacrolimus. As many cases of elderly-onset MG do not require strong immunosuppression, we recommend minimum immunosuppressive treatment to avoid adverse events, particularly in patients at an advanced age of ≥80 years.

Nihon Naika Gakkai Zasshi, 2013

Movement Disorders Clinical Practice, 2014

The International Parkinson and Movement Disorder Society (MDS)-sponsored revision of the Unified... more The International Parkinson and Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been developed and is now available in English. Part of the overall program includes the establishment of official non-English translations of the MDS-UPDRS. We present the process for completing the official Japanese translation of the MDS-UPDRS with clinimetric testing results. In this trial, the MDS-UPDRS was translated into Japanese, underwent cognitive pretesting, and the translation was modified after taking the results into account. The final translation was approved as the Official Working Draft of the MDS-UPDRS Japanese version and tested in 365 native-Japanese-speaking patients with PD. Confirmatory analyses were used to determine whether the factor structure for the Englishlanguage MDS-UPDRS could be confirmed in data collected using the Official Working Draft of the Japanese translation. As a secondary analysis, we used exploratory factor analyses to examine the underlying factor structure without the constraint of a prespecified factor organization. Confirmatory factor analysis revealed that Comparative Fit Index for all parts of the MDS-UPDRS exceeded the minimal standard of 0.90, relative to the English version, and therefore the Japanese translation met the prespecified criterion to be designated, called an official MDS translation. Secondary analyses revealed some differences between the Englishlanguage MDS-UPDRS and the Japanese translation; however, these differences were considered to be within an acceptable range. The Japanese version of the MDS-UPDRS met the criterion as an Official MDS Translation and is now available for use (www.movementdisorders.org). The UPDRS has been widely used since the 1980s as a standard clinical rating scale for Parkinson's disease (PD). 1,2 However, increasing evidence indicates that several symptoms frequently experienced by PD patients that affect their quality of life, such as sleep problems, sensory disturbance, urinary problems, constipation, and fatigue, are not adequately evaluated in the original

Parkinsonism & Related Disorders, 2014

Objective: To confirm the superiority of transdermal rotigotine up to 16 mg/24 h over placebo, an... more Objective: To confirm the superiority of transdermal rotigotine up to 16 mg/24 h over placebo, and noninferiority to ropinirole, in Japanese Parkinson's disease (PD) patients on concomitant levodopa therapy. Methods: This trial was a randomized, double-blind, double-dummy, three-arm parallel group placeboand ropinirole-controlled trial. Four-hundred and twenty PD patients whose motor symptoms were not well controlled by levodopa treatment were randomized 2:2:1 to receive rotigotine, ropinirole (up to 15 mg/day) or placebo during a 16-week treatment period followed by a 4-week taper period. The primary variable was change in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON state) sum score from baseline to the end of the treatment period. Results: The difference in the change in the UPDRS Part III (ON state) sum score from baseline to the end of treatment between rotigotine and placebo groups was À6.4 ± 1.2 (95% CI: À8.7 to À4.1; p < 0.001), indicating superiority of rotigotine over placebo. The difference between rotigotine and ropinirole groups was À1.4 ± 1.0 (95% CI: À3.2 to 0.5), below the non-inferiority margin, indicating the non-inferiority of rotigotine to ropinirole. Application site reaction was seen in 57.7% of the patients in the rotigotine group and in 18.6% in the ropinirole group (P < 0.001). No other safety issue was noted. Conclusions: Rotigotine was well tolerated at doses up to 16 mg/24 h and showed similar efficacy to ropinirole except that the application site reaction was much higher in the rotigotine group.

Parkinsonism & Related Disorders, 2014

Background: This report presents data from one of the first trials of apomorphine rescue treatmen... more Background: This report presents data from one of the first trials of apomorphine rescue treatment for advanced Parkinson's disease (PD) conducted in Japan. This 3 month trial aimed to evaluate the sustainability of efficacy of intermittent apomorphine rescue treatment. Methods: A phase III, double-blind, placebo-controlled trial was conducted in PD patients (n = 31) with motor fluctuations in spite of individually titrated treatment with levodopa and other anti PD. Intermittent treatment was titrated to the maintenance dose with a subsequent unblind 12-week outpatient phase. At the week-12 visit, response to apomorphine or placebo was assessed as primary efficacy endpoint using the Unified Parkinson's Disease Rating Scale (UPDRS) part III (Motor Examination) under double-blind crossover conditions. Results: In the crossover phase (n = 28), least squares mean changes in the the UPDRS part III score from pre-dose were −24.5 points with apomorphine and −2.3 points with placebo, showing that apomorphine, compared with placebo, provided a significantly greater improvement in the UPDRS part III score change (difference between treatments:-22.1 [95% confidence interval,-27.8,-16.4]; P < 0.001). The most frequently reported adverse events during the study were increased eosinophil count (8 patients), nausea (7), somnolence (6), dyskinesia (5), yawning (5), and decreased blood pressure (3). Conclusions: Our results indicate that a 3-month use of intermittent apomorphine is an effective rescue therapy for "off" episodes in advanced PD patients.

International Journal of General Medicine, 2014

Pregabalin, a novel agent for treating partial epilepsy and peripheral neuropathic and central pa... more Pregabalin, a novel agent for treating partial epilepsy and peripheral neuropathic and central pain, was studied for its effect on driving performance in healthy volunteers. Sixteen healthy male volunteers who drove regularly were enrolled in a double-blind, parallel-group, placebocontrolled study assessing the effect of pregabalin on driving performance. Subjects received an oral dose of pregabalin 75 mg or placebo, and a second dose 12 hours later. A driving simulator was used to test simple and complicated braking reaction time, and simple and complicated steering-wheel techniques before the first dose, and 1 hour and 3 hours after the second dose of pregabalin or placebo. The effect of training during the driving test on the driving performance of each group was also evaluated. There were no statistically significant differences in driving performance between the pregabalin and the placebo groups. However, the pregabalin group showed no significant improvement in steering-wheel skills with training, whereas the placebo group showed a significant (P,0.05) improvement with training. In this study using a driving simulator, pregabalin did not impair driving performance but mildly reduced the training effects of driving experiments. Although pregabalin caused sleepiness, it had no severe effect on driving ability after a second dose of 75 mg after the initial introduction of pregabalin.

Internal Medicine, 2013

Objective For patients with Parkinson's disease (PD), driving is challenging due to an impaired m... more Objective For patients with Parkinson's disease (PD), driving is challenging due to an impaired motor function and decreased attention capabilities. This study assessed the driving capacity in PD patients by comparing neurological signs. Methods The driving ability of PD patients was evaluated using a driving simulator (Safety Master NT-932) that tested the reaction time in response to traffic signals and steering wheel errors. We studied the correlations between the total Unified Parkinson's Disease Rating Scale (UPDRS) score, the UPDRS part III score, the subscores of the UPDRS part III score, age, PD disease duration, braking reaction time, steering wheel errors and total scores for driving safety test results. 'On' state regular PD licensed drivers (n=42; mean age: 63 years) in Hoehn and Yahr stages II-III participated after their cognitive status was confirmed using mini-mental state examinations. Results The UPDRS scores, the UPDRS part III scores and the postural instability subscores exhibited significant (p<0.05) correlations with the number of steering wheel errors but not with the braking reaction time or the total safety scores of the test results. Conclusion The UPDRS is an established evaluation method used to estimate PD signs, although it is not sufficient alone for deciding whether PD patients should be allowed to drive. Our findings suggest that determining the driving ability using a driving simulator might be a useful adjunct to UPDRS scores in the assessment of PD patients who are active drivers. Estimating the driving ability requires complex measurements, including motor performance with perception of stimuli and attention.

Internal Medicine, 2018

Objective We conducted a study to obtain information that could be used to provide Parkinson's di... more Objective We conducted a study to obtain information that could be used to provide Parkinson's disease (PD) patients with appropriate advice on safe driving. Methods Consecutive PD patients who visited our office were studied. Among these patients, those who had experienced driving after being diagnosed with PD were interviewed by neurologists and a trained nurse to investigate their previous car accidents, motor function, cognitive function, sleepiness, levodopa equivalent dose (LED), and emotional dysregulation. The rates of major car accidents before and after the onset of PD were compared. Results Fifteen patients had experienced a major car accident resulting in human injury or serious property damage since the onset of PD. When the rates of major car accidents before and after the onset of PD were compared, the ratio was 4.3 [95% confidence interval (CI) 1.9-9.7]. The incidence of accidents after the onset of PD was correlated with age, disease duration, LED, the cognitive function Mini-Mental Scale Examination (MMSE), Japanese translation of the Montreal Cognitive Assessment (MoCA-J), but not the motor symptom score [Unified Pankinson's disease rating scale (UPDRS) part III at the time of the study]. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) score was also higher in patients with major car accidents. Conclusion The severity of symptoms (Hoehn-Yahr classification), cognitive function, and disease duration were expected to be risk factors for car accidents. However, the motor symptom score (UPDRS part III) was not associated with the incidence of major car accidents. In addition to a low cognitive function and the severity of symptoms, the QUIP score might be an independent factor that can be referenced when advising PD patients to refrain from driving.

eNeurologicalSci, 2018

We conducted a phase I study investigating the efficacy, safety, and tolerability of ONO-2160, a ... more We conducted a phase I study investigating the efficacy, safety, and tolerability of ONO-2160, a newly developed levodopa pro-drug, and carbidopa compared with levodopa and carbidopa to stabilize levodopa plasma concentration fluctuations in Japanese patients with Parkinson's disease. In an open-label two-period design, patients (n = 12) with Parkinson's disease received levodopa and carbidopa for 3 days before 7 days of treatment with ONO-2160 and carbidopa. Patients were primarily evaluated using the Unified Parkinson's Disease Rating Scale Part III, a Parkinson's disease symptom diary, and analysis of adverse events. Pharmacokinetic analysis of plasma levodopa concentration was also performed. ONO-2160 and carbidopa therapy stabilized effective plasma levodopa concentration. No adverse events with safety concerns were observed. The combination of ONO-2160 and carbidopa produced a prolonged and stable plasma levodopa concentration with a reduction in Unified Parkinson's Disease Rating Scale Part III total scores. The combination was well tolerated, with no safety concerns, when administered to Japanese patients with Parkinson's disease.

Journal of neurology, 2018

Rotigotine-a non-ergot dopamine agonist-has two advantages; it can stimulate all dopamine recepto... more Rotigotine-a non-ergot dopamine agonist-has two advantages; it can stimulate all dopamine receptors (D1-D5) like innate dopamine, and its transdermal administration provides continuous dopaminergic stimulation. The age of the patient impacts the effect and adverse events of anti-parkinsonian treatment. We conducted a post hoc analysis on three randomized, double-blind, placebo-controlled trials performed in Japan to clarify the difference of anti-parkinsonian treatment in elderly and non-elderly patients. Data from two combination therapy trials (with levodopa) in advanced stage Parkinson's disease patients and one monotherapy trial in early stage patients were pooled and grouped by age (non-elderly aged < 70, elderly aged 70 +). In each age group, efficacy of rotigotine was compared to placebo. In the combination therapy, total Unified Parkinson's Disease Rating Scale Part III scores and some subtotal scores, including those for tremor, akinesia and gait disturbance, sig...

Journal of neurology, 2018

Unfortunately, the online published article has errors in Table 1 and Table 2. The corrected tabl... more Unfortunately, the online published article has errors in Table 1 and Table 2. The corrected tables are given in the following page.

Japanese Journal of Pharmacoepidemiology/Yakuzai ekigaku, 2015

Nihon Naika Gakkai Zasshi, 2013

Journal of General and Family Medicine, 2017

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Parkinsonism & related disorders, 2017

We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify f... more We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify factors affecting NMSs and the health-related quality of life of Japanese patients with Parkinson's disease (PD). A total of 1021 patients with PD who had one or more NMS and showed wearing-off under anti-parkinsonian treatment were enrolled from 35 medical centers in Japan for this observational study. The primary measurements were the Movement Disorder Society unified Parkinson's disease rating scale (MDS-UPDRS) part I and the Parkinson's Disease Questionnaire (PDQ-8). The relationships of MDS-UPDRS and PDQ-8 with the patient's clinical background and undertaken medical interventions were determined. Here, we report baseline data of our 52-week ongoing study. The mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively. The most common NMSs were constipation problems (85.4%), sleep problems (73.7%), pain and other sensations (72.7%) and daytime sleepiness (...

Electroencephalography and Clinical Neurophysiology, 1995

Neurology and Clinical Neuroscience, 2014

Background: There are two formulations of levodopa in Japan and a few other countries, levodopa/b... more Background: There are two formulations of levodopa in Japan and a few other countries, levodopa/benserazide 100/25 mg and levodopa/carbidopa 100/10 mg, which have been generally regarded as interchangeable in Parkinson's disease treatment. Aim: We investigated the pharmacokinetics of levodopa in the two kinds of levodopa/decarboxylase inhibitor (benserazide or carbidopa) formulations to study their equivalence. Methods: Population pharmacokinetic analysis was carried out using levodopa data from the healthy subject study and, additionally, for 70 plasma concentration data points from Parkinson's disease patients receiving either levodopa/decarboxylase inhibitor combination in clinical practice. Results: In healthy subjects, the mean AE standard deviation plasma levodopa maximum observed plasma concentration and area under the plasma concentration time curve from time 0 to 3 h (512 AE 139 vs 392 AE 49 lmol•h/L, P < 0.05) were significantly higher after levodopa/benserazide compared with levodopa/carbidopa. Levodopa time to maximum observed plasma concentration and plasma elimination half-life were not significantly different when comparing the respective formations. Levodopa pharmacokinetic parameters were the same between the Parkinson's disease patients and healthy subjects, except for levodopa apparent clearance, which was approximately two-thirds lower in Parkinson's disease patients compared with healthy subjects for both levodopa/decarboxylase inhibitor combinations, which might result in higher levodopa area under the curve in patients with Parkinson's disease than in healthy volunteers. Conclusion: Levodopa pharmacokinetics differ after administration of levodopa/ benserazide and levodopa/carbidopa. This information cold be useful for adjustment of medication in Parkinson's disease patients, especially with motor complications.

Nihon Naika Gakkai Zasshi, 2007

Clinical Neuropharmacology, 2015

† and for the PD Study Group Objectives: This study is the first controlled trial to evaluate the... more † and for the PD Study Group Objectives: This study is the first controlled trial to evaluate the efficacy and safety of subcutaneous apomorphine in Japanese patients with advanced Parkinson disease. Methods: A phase II, multicenter, randomized, double-blind, parallelgroup trial was undertaken in 16 patients with advanced Parkinson disease with wearing-off phenomenon to compare subcutaneous apomorphine versus placebo. The maintenance dose of apomorphine (1-6 mg per dose), determined individually for each patient by titration, was additionally administered 3 times at 2-hour intervals in the multiple-dose phase in which pharmacokinetics was evaluated. Results: The mean (SD) maintenance apomorphine dose was 3.4 (1.4) mg (range, 2-6 mg). The change in the Unified Parkinson's Disease Rating Scale motor score 20 minutes after maintenance dose administration was significantly greater in the apomorphine group than in the placebo group (least squares mean, −24.0 vs −4.1, P = 0.021). Apomorphine treatment resulted in an "on" state approximately 20 minutes after dose administration, lasting for approximately 60 minutes. Apomorphine was rapidly absorbed, with the maximum plasma concentration (C max) reached in 0.367 to 0.383 hour. It was quickly eliminated with a half-life of 0.520 to 0.793 hour, suggesting no accumulation during multiple-dose phase. The C max of apomorphine at effective dose was presumed to be approximately 20 ng/mL. Apomorphine was well tolerated. Conclusions: Subcutaneous apomorphine is expected to provide a new treatment option in Japan as a rescue therapy. Two-hour interval injections did not cause reduced responses, and effective blood concentration was presumed to be approximately 20 ng/mL similar, to the previous study conducted at North America.

Japanese Clinical Medicine, 2015

The number of patients with late-onset myasthenia gravis (MG) among patients ≥50 years has been i... more The number of patients with late-onset myasthenia gravis (MG) among patients ≥50 years has been increasing recently. We encountered three patients who developed elderly-onset MG at a particularly advanced age (≥80 years). All were female and positive for anti-acetylcholine receptor antibodies. About 4 years have passed since MG onset in all three patients and symptoms have been controlled without recurrence using a combination of oral low-dose prednisolone and tacrolimus. As many cases of elderly-onset MG do not require strong immunosuppression, we recommend minimum immunosuppressive treatment to avoid adverse events, particularly in patients at an advanced age of ≥80 years.

Nihon Naika Gakkai Zasshi, 2013

Movement Disorders Clinical Practice, 2014

The International Parkinson and Movement Disorder Society (MDS)-sponsored revision of the Unified... more The International Parkinson and Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been developed and is now available in English. Part of the overall program includes the establishment of official non-English translations of the MDS-UPDRS. We present the process for completing the official Japanese translation of the MDS-UPDRS with clinimetric testing results. In this trial, the MDS-UPDRS was translated into Japanese, underwent cognitive pretesting, and the translation was modified after taking the results into account. The final translation was approved as the Official Working Draft of the MDS-UPDRS Japanese version and tested in 365 native-Japanese-speaking patients with PD. Confirmatory analyses were used to determine whether the factor structure for the Englishlanguage MDS-UPDRS could be confirmed in data collected using the Official Working Draft of the Japanese translation. As a secondary analysis, we used exploratory factor analyses to examine the underlying factor structure without the constraint of a prespecified factor organization. Confirmatory factor analysis revealed that Comparative Fit Index for all parts of the MDS-UPDRS exceeded the minimal standard of 0.90, relative to the English version, and therefore the Japanese translation met the prespecified criterion to be designated, called an official MDS translation. Secondary analyses revealed some differences between the Englishlanguage MDS-UPDRS and the Japanese translation; however, these differences were considered to be within an acceptable range. The Japanese version of the MDS-UPDRS met the criterion as an Official MDS Translation and is now available for use (www.movementdisorders.org). The UPDRS has been widely used since the 1980s as a standard clinical rating scale for Parkinson's disease (PD). 1,2 However, increasing evidence indicates that several symptoms frequently experienced by PD patients that affect their quality of life, such as sleep problems, sensory disturbance, urinary problems, constipation, and fatigue, are not adequately evaluated in the original

Parkinsonism & Related Disorders, 2014

Objective: To confirm the superiority of transdermal rotigotine up to 16 mg/24 h over placebo, an... more Objective: To confirm the superiority of transdermal rotigotine up to 16 mg/24 h over placebo, and noninferiority to ropinirole, in Japanese Parkinson's disease (PD) patients on concomitant levodopa therapy. Methods: This trial was a randomized, double-blind, double-dummy, three-arm parallel group placeboand ropinirole-controlled trial. Four-hundred and twenty PD patients whose motor symptoms were not well controlled by levodopa treatment were randomized 2:2:1 to receive rotigotine, ropinirole (up to 15 mg/day) or placebo during a 16-week treatment period followed by a 4-week taper period. The primary variable was change in the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON state) sum score from baseline to the end of the treatment period. Results: The difference in the change in the UPDRS Part III (ON state) sum score from baseline to the end of treatment between rotigotine and placebo groups was À6.4 ± 1.2 (95% CI: À8.7 to À4.1; p < 0.001), indicating superiority of rotigotine over placebo. The difference between rotigotine and ropinirole groups was À1.4 ± 1.0 (95% CI: À3.2 to 0.5), below the non-inferiority margin, indicating the non-inferiority of rotigotine to ropinirole. Application site reaction was seen in 57.7% of the patients in the rotigotine group and in 18.6% in the ropinirole group (P < 0.001). No other safety issue was noted. Conclusions: Rotigotine was well tolerated at doses up to 16 mg/24 h and showed similar efficacy to ropinirole except that the application site reaction was much higher in the rotigotine group.

Parkinsonism & Related Disorders, 2014

Background: This report presents data from one of the first trials of apomorphine rescue treatmen... more Background: This report presents data from one of the first trials of apomorphine rescue treatment for advanced Parkinson's disease (PD) conducted in Japan. This 3 month trial aimed to evaluate the sustainability of efficacy of intermittent apomorphine rescue treatment. Methods: A phase III, double-blind, placebo-controlled trial was conducted in PD patients (n = 31) with motor fluctuations in spite of individually titrated treatment with levodopa and other anti PD. Intermittent treatment was titrated to the maintenance dose with a subsequent unblind 12-week outpatient phase. At the week-12 visit, response to apomorphine or placebo was assessed as primary efficacy endpoint using the Unified Parkinson's Disease Rating Scale (UPDRS) part III (Motor Examination) under double-blind crossover conditions. Results: In the crossover phase (n = 28), least squares mean changes in the the UPDRS part III score from pre-dose were −24.5 points with apomorphine and −2.3 points with placebo, showing that apomorphine, compared with placebo, provided a significantly greater improvement in the UPDRS part III score change (difference between treatments:-22.1 [95% confidence interval,-27.8,-16.4]; P < 0.001). The most frequently reported adverse events during the study were increased eosinophil count (8 patients), nausea (7), somnolence (6), dyskinesia (5), yawning (5), and decreased blood pressure (3). Conclusions: Our results indicate that a 3-month use of intermittent apomorphine is an effective rescue therapy for "off" episodes in advanced PD patients.

International Journal of General Medicine, 2014

Pregabalin, a novel agent for treating partial epilepsy and peripheral neuropathic and central pa... more Pregabalin, a novel agent for treating partial epilepsy and peripheral neuropathic and central pain, was studied for its effect on driving performance in healthy volunteers. Sixteen healthy male volunteers who drove regularly were enrolled in a double-blind, parallel-group, placebocontrolled study assessing the effect of pregabalin on driving performance. Subjects received an oral dose of pregabalin 75 mg or placebo, and a second dose 12 hours later. A driving simulator was used to test simple and complicated braking reaction time, and simple and complicated steering-wheel techniques before the first dose, and 1 hour and 3 hours after the second dose of pregabalin or placebo. The effect of training during the driving test on the driving performance of each group was also evaluated. There were no statistically significant differences in driving performance between the pregabalin and the placebo groups. However, the pregabalin group showed no significant improvement in steering-wheel skills with training, whereas the placebo group showed a significant (P,0.05) improvement with training. In this study using a driving simulator, pregabalin did not impair driving performance but mildly reduced the training effects of driving experiments. Although pregabalin caused sleepiness, it had no severe effect on driving ability after a second dose of 75 mg after the initial introduction of pregabalin.

Internal Medicine, 2013

Objective For patients with Parkinson's disease (PD), driving is challenging due to an impaired m... more Objective For patients with Parkinson's disease (PD), driving is challenging due to an impaired motor function and decreased attention capabilities. This study assessed the driving capacity in PD patients by comparing neurological signs. Methods The driving ability of PD patients was evaluated using a driving simulator (Safety Master NT-932) that tested the reaction time in response to traffic signals and steering wheel errors. We studied the correlations between the total Unified Parkinson's Disease Rating Scale (UPDRS) score, the UPDRS part III score, the subscores of the UPDRS part III score, age, PD disease duration, braking reaction time, steering wheel errors and total scores for driving safety test results. 'On' state regular PD licensed drivers (n=42; mean age: 63 years) in Hoehn and Yahr stages II-III participated after their cognitive status was confirmed using mini-mental state examinations. Results The UPDRS scores, the UPDRS part III scores and the postural instability subscores exhibited significant (p<0.05) correlations with the number of steering wheel errors but not with the braking reaction time or the total safety scores of the test results. Conclusion The UPDRS is an established evaluation method used to estimate PD signs, although it is not sufficient alone for deciding whether PD patients should be allowed to drive. Our findings suggest that determining the driving ability using a driving simulator might be a useful adjunct to UPDRS scores in the assessment of PD patients who are active drivers. Estimating the driving ability requires complex measurements, including motor performance with perception of stimuli and attention.