Hayato Yabe

Mutations in MME cause an autosomal-recessive Charcot–Marie–Tooth disease type 2

The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.

Plasma amantadine concentrations in patients with Parkinson's disease

We determined plasma amantadine concentrations in patients with Parkinsons disease (PD) in daily clinical practice and investigated the relationship between plasma concentration and adverse reactions to clarify the safe therapeutic range. Seventy-eight consecutive PD patients on stable amantadine treatment were recruited. Plasma concentration of amantadine was measured 3h after the administration of morning amantadine dose. Serum creatinine was measured to estimate renal function. The mean daily dose of amantadine was 135.1+/-62.3mg/day, and the mean plasma amantadine concentration was 812.5+/-839.5 ng/ml (range, 91-4400 ng/ml). Plasma amantadine concentration increased according to increasing renal dysfunction. Three patients exhibited adverse reactions, such as myoclonus, hallucinations, and delirium, and all of them showed plasma amantadine concentration >3000 ng/ml. None of the three cases had previously shown such side effects. PD patients who have not developed any psychiatric symptoms as adverse reactions to the treatment may develop myoclonus, hallucination, or delirium when the plasma concentration of amantadine exceeds 3000 ng/ml. It is therefore recommended to use amantadine at the plasma concentration of less than 3000 ng/ml in the treatment of Parkinsons disease, especially in elderly patients.

Zonisamide-induced long-lasting recovery of dopaminergic neurons from MPTP-toxicity

Zonisamide is an antiepileptic drug that also improves the cardinal symptoms of Parkinsons disease. This study investigated the effects of zonisamide on dopaminergic neuronal degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Six groups of mice were treated as follows: 1) normal saline; 2) MPTP, 15 mg/kg×4 every 2h; 3) MPTP and zonisamide, 40 mg/kg×1, 1h after the last MPTP dose; 4) MPTP and zonisamide, 1 day after the last dose of MPTP; 5) MPTP and zonisamide, 1h before the first MPTP dose; and 6) zonisamide, 40 mg/kg. MPTP-treatment decreased the contents of dopamine as well as the number and area of tyrosine hydroxylase (TH)-positive neurons. Concurrent treatment of mice with zonisamide and MPTP did not show any inhibition of the toxic effect of MPTP towards dopamine contents at 1 week after treatment but it increased the number and area of TH-positive neurons compared to the MPTP-treated group. Surviving TH-positive neurons had recovery of dopamine production after several weeks. Moreover, zonisamide increased the number of S100β-positive and glial fibrillary acidic protein (GFAP)-positive astrocytes and dopamine turnover. These results suggest that zonisamide acts as a neuro-protectant against MPTP-induced dopaminergic neuronal degeneration as shown by an increase of TH-positive neurons and this may be mediated by increased S100β secretion.

Coadministration of domperidone increases plasma levodopa concentration in patients with Parkinson disease.

ObjectivesThe aim of this study was to examine the effects of the peripheral dopamine D2-receptor antagonist, domperidone, on the plasma kinetics of levodopa in patients with Parkinson disease (PD). MethodsIn a randomized crossover design, 18 hospitalized patients with PD received a single dose of levodopa/benserazide, 100/25 mg, with or without domperidone, 10 mg, under fasting conditions. Plasma levodopa concentrations were determined up to 3 hours after dose administration. ResultsMean ± SEM levodopa maximum plasma concentration (Cmax) (14.1 ± 2.9 vs 9.7 ± 1.6 &mgr;mol/L; P < 0.01), plasma concentration at 30 min (C30 min) (13.7 ± 3.0 vs 8.1 ± 2.0 &mgr;mol/L; P < 0.01), and area under the plasma concentration-time curve from 0 to 3 hours (AUC0–3 hr) (15.9 ± 3.1 vs 12.1 ± 2.4 &mgr;mol/L · hour; P < 0.05) were significantly higher after coadministration of levodopa with domperidone compared to levodopa alone. Thus, domperidone increased levodopa Cmax and AUC0–3 hr by 1.5- and 1.3-fold, respectively. There were no exacerbations of PD by concomitant domperidone administration. ConclusionsThe results demonstrate that coadministration of domperidone increased the bioavailability of levodopa. This may be the reason for no exacerbation of PD in concomitant administration of domperidone, a dopamine D2-receptor blocker.

Inter- and intra-individual variation in L-dopa pharmacokinetics in the treatment of Parkinson's disease

Parkinsons disease is a neurodegenerative, slowly progressive, age-related disorder. Numerous medications have been developed for its treatment and the prognosis of the disorder has improved greatly over recent years. However, the effects of medicines are variable among patients, and there are also daily fluctuations in the effects of medications in the same person. The factors that cause individual variations in the effects of medicines, the causes, and strategies to cope with these fluctuations are reviewed.

Pharmacokinetics of levodopa/benserazide versus levodopa/carbidopa in healthy subjects and patients with Parkinson's disease

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 Parkinsons disease treatment.

Pharmacokinetic characteristics of agents applied in the treatment of Parkinson's disease

The efforts to treat Parkinson’s disease have resulted in the development of numerous medicines, including L-dopa, 3.4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitors, a monoamine oxidase (MAO) inhibitor, catechol-O-methyltransferase (COMT) inhibitors, dopamine receptor agonists, amantadine and anticholinergics. Patients with Parkinson’s disease respond to the agents with improvement in disease signs and symptoms. However, the effect of treatment varies greatly between cases. The factors causing individual differences in response comprise pharmacodynamics and pharmacokinetics. The individual pharmacokinetic characteristics of patients vary by around 4-fold. Factors causing pharmacokinetic variations, including food, drug-drug interactions, sympathetic activity and renal function, are evaluated to achieve better results for personalized therapy in the treatment of Parkinson’s disease. The safe total dose of dopamine receptor agonists should be investigated to avoid valvulopathy

One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan

BACKGROUND Epidemiological studies have repeatedly reported that increased serum urate level is associated with a slower progress of Parkinsons disease (PD). The urate precursor, inosine, raises the serum urate level and is therefore a candidate for a disease modifying treatment. However, an elevated serum urate level is a risk factor for gout, urolithiasis, and cardiovascular diseases. Although there have been previous clinical studies, the use of inosine in a clinical setting is still limited, and its safety is unclear, especially in an Asian population. METHODS We conducted a single-arm, single-center clinical trial to assess the safety of inosine for PD patients with relatively low urate levels. After informed consent, 10 subjects were orally administered inosine to maintain a target urate level between 6.0mg/dl and 8.0mg/dl for one year. All adverse effects were recorded and categorized by severity. Also, the efficacy of using inosine to raise the serum urate level was reported. RESULTS We did not observe any adverse events requiring termination or reduction of the study drug, although uric acid crystalluria was transiently observed in a single subject. An inosine dosage of 1070 (SD=501) mg/day significantly raises the urate level from 3.5 (0.84)mg/dl at baseline to 6.68 (1.11)mg/dl at the 52nd week. CONCLUSIONS Inosine was safely used for one year and effectively raised urate levels in a small group of subjects. Our study is the first report to use inosine for patients with PD in an Asian population.

Japanese version of the ALS-FTD-Questionnaire (ALS-FTD-Q-J)

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share common clinical, genetic and neuropathological features. Some ALS patients have behavioral/personality changes, which could result in significant obstacles in the care provided by family members and caregivers. An easy screening tool would contribute greatly to the evaluation of these symptoms. We translated the ALS-FTD-Questionnaire, developed in the Netherlands, into Japanese (ALS-FTD-Q-J) and examined the clinimetric properties (internal consistency, construct and clinical validity). Patients with ALS and/or behavioral variant FTD (bvFTD) were evaluated alongside healthy controls in this multicenter study. All ALS patients, regardless of bvFTD status, were further evaluated by the frontal behavioral inventory (FBI) and for frontal/executive function, cognition, anxiety/depression, and motor functions. Data from 146 subjects were analyzed: ALS (92), ALS-bvFTD (6), bvFTD (16), and healthy controls (32). The internal consistency of the ALS-FTD-Q-J was good (Cronbach α=0.92). The ALS-FTD-Q-J showed construct validity as it exhibited a high correlation with the FBI (r=0.79). However, correlations were moderate with anxiety/depression and low with cognitive scales, in contrast to the original report, i.e. a moderate correlation with cognition and a low correlation with anxiety/depression. The ALS-FTD-Q-J discriminated ALS patients from (ALS-)bvFTD patients and controls. Thus, the ALS-FTD-Q-J is useful for evaluating Japanese ALS/FTD patients.

Dopamine agonists and valvular heart disease in Japanese patients with Parkinson's disease

A high incidence of valvular heart disease in Parkinsons disease (PD) patients treated with ergot-derived dopamine agonists, such as cabergoline and pergolide, has been reported. However, the frequency of valvulopathy, including “restrictive” valvulopathy, in Japanese PD patients remains unclear.We have evaluated the frequency of valvulopathy in PD patients treated with ergot-derived dopamine agonists. Patients treated with either pergolide or cabergoline were prone to higher grades of valvular regurgitation than control patients. Left-sided heart valves (aortic and mitral valves) were more affected than the tricuspid valve. However, “restrictive” valvulopathy was not observed in our patients.These results indicate that pergolide and cabergoline are risk factors for valvular regurgitation even in Japanese patients with PD.