Takashi Moritoyo

ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (FALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions.

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.

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.

Accelerating Regulatory Science Initiatives for the Development of Drugs for Alzheimer’s Disease in Japan

PURPOSE The Ministry of Health, Labour and Welfare (MHLW) of Japan launched a regulatory science research project in which the aim is to promote the establishment of guidelines for the development of innovative drugs thorough interactions between academia and Japans regulatory agency, the Pharmaceuticals and Medical Devices Agency (PMDA). In this project, a research system with the aim of developing a guideline for the clinical evaluation of drugs intended for the treatment of Alzheimers disease (AD) was established. METHODS Two research groups were set up: (1) the Biomarker and Clinical Evaluation Group to establish biomarker-based criteria for the clinical evaluation of drugs for AD, and (2) the Modeling and Simulation (M&S) Group to create a disease model of AD using M&S techniques based on data from the Alzheimers Disease Neuroimaging Initiative (ADNI). Furthermore, a human resource exchange between the University of Tokyo Hospital and the PMDA is conducted to establish a guideline that is suitable for regulatory use. FINDINGS As an interim report of this project, issues that require consideration for the clinical evaluation and development were summarized, including topics such as the use of biomarkers in the inclusion criteria, the efficacy endpoint, and the clinical data package required for application in Japan. IMPLICATIONS As the result of collaboration between the University of Tokyo Hospital and PMDA, this document is the first to summarize perspectives on the development of drugs for AD in Japan.

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

Pharmacokinetics of teriparatide after subcutaneous administration to volunteers with renal failure: a pilot study.

BACKGROUND AND OBJECTIVE Teriparatide acetate was developed in the form of a synthetic analogue of the Nterminal peptide (1-34) of human parathyroid hormone for the treatment of osteoporosis; it is administered subcutaneously once weekly. However, it is not known whether the pharmacokinetics (PK) of this drug is affected by renal impairment, and this study was conducted to look into this question. METHODS A multi-center study was conducted at six hospitals in Japan. Subjects were enrolled and grouped on the basis of renal function stratified as: normal function to mild renal impairment (estimated GFR(e-GFR): ≥ 60.0 mL/min/1.73 m2) (8 subjects), moderate impairment (eGFR: 30.0 - 59.9 mL/min/1.73 m2) (5 subjects), and severe impairment (eGFR: 15.0 - 29.9 mL/min/1.73 m2) (5 subjects). The PK parameters, blood and urine electrolytes concentrations, and safety profiles were assessed following a single subcutaneous injection of teriparatide acetate (56.5 μg as teriparatide). RESULTS The elimination half-life (t1/2) and the mean residence time extrapolated to infinity were significantly prolonged in the group with severe renal impairment (t1/2: 5.0 hours) compared with normal to mild and moderate impairment groups (t1/2: 1.5 hours and 1.2 hours, respectively). However, virtually all of the teriparatide was eliminated from the blood after 24 hours. Given that the drug is administered once weekly, it appeared highly unlikely that accumulation of the drug in the body would become a problem even with repeated administration. There were no particular problems with safety or tolerability. CONCLUSIONS In treatment with teriparatide acetate once-per week formulation, prescription at the usual dosage appears to be appropriate even in renally impaired 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.

Effect of grapefruit juice on cabergoline pharmacokinetics in patients with Parkinson's disease

Cabergoline is one of the synthetic ergoline dopamine agonists, which is widely used for the treatment of Parkinsons disease (PD). Cytochrome P‐450 (CYP) 3A4 contributes to metabolize Cabergoline. It has been well known that grapefruit juice inhibits CYP3A4 enzyme located in the gut wall. To investigate whether grapefruit juice influences the pharmacokinetics of cabergoline, plasma level of cabergoline in patients of PD was evaluated.

Effect of short-term treatment with sitagliptin or glibenclamide on daily glucose fluctuation in drug-naïve Japanese patients with type 2 diabetes mellitus

To compare the effect of a dipeptidyl peptidase‐4 inhibitor (DPP4‐i) and a sulfonylurea (SU) on daily glucose fluctuation in drug‐naïve Japanese patients with type 2 diabetes mellitus (T2DM).