Hirotaka Iwaki

Ehime University, Matuyama, Ehime, Japan

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Publications (13)13.53 Total impact

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    ABSTRACT: BackgraoudThere are two formulation of levodopa, levodopa/benserazide 100/25 mg and levodopa/carbidopa 100/10 mg in Japan and a few other countries, which have been generally regarded as interchangeable in Parkinson's disease (PD) treatment.AimWe investigated the pharmacokinetics of levodopa in the two kinds of levodopa/DCI (benserazide or carbidopa) formulation to study their equivalenceMethods Population pharmacokinetic analysis was conducted using levodopa data from the healthy subject study and, additionally, for 70 plasma concentration data points from PD patients receiving either levodopa/DCI combination in clinical practice.ResultsIn healthy subjects, mean±SD plasma levodopa Cmax and AUC0-3hr (512±139 vs 392±49 μmol•hr/L, P < 0.05) were significantly higher after levodopa/benserazide compared to levodopa/carbidopa. Levodopa Tmax and t1/2 were not significantly different comparing the respective formations. Levodopa pharmacokinetic parameters were the same between the PD patients and healthy subjects except for levodopa apparent clearance which was about two-thirds lower in PD patients compared to healthy subjects for both levodopa/DCI combinations, which may result in higher levodopa AUC in patients with Parkinson's disease than in healthy volunteers.Conclusion Levodopa pharmacokinetics differ after administration of levodopa/benserazide and levodopa/carbidopa. This information may be useful for adjustment of medication in PD patients especially with motor complications.This article is protected by copyright. All rights reserved.
    Neurology and Clinical Neuroscience. 11/2014;
  • Hirotaka Iwaki, Masahiro Nomoto
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    ABSTRACT: Abstract Acetylcholine is one of the main neurotransmitters. It is involved in autonomic activities of the peripheral organs and forms a part of complicated neural networks in the central nervous system. Anticholinergic drugs are used in the treatment of various diseases, and many drugs have anticholinergic side effects. Thus, estimating the total burden of anticholinergic activity of drugs is important to assess the related adverse effects for patients taking such drugs. Serum anticholinergic activity (SAA) is measured using a competitive radioreceptor binding assay of muscarinic receptors. In addition to this direct measurement, several drug scales like the Anticholinergic Drug Scale (ADS), Anticholinergic Cognitive Burden Scale (ACB), and Anticholinergic Risk Scale (ARS) have been developed to estimate the total anticholinergic burden of drugs. These measurements have been used to demonstrate that certain drugs may be responsible for the cognitive impairment in the elderly or certain groups of patients with neurologic disorders. Clinicians should be aware of the impact of such drugs because central adverse effects are often obscure in these patient groups and are easily overlooked.
    Brain and nerve = Shinkei kenkyū no shinpo 05/2014; 66(5):551-560.
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    ABSTRACT: 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, placebo-controlled 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.
    International Journal of General Medicine 01/2014; 7:103-8.
  • Nihon Naika Gakkai Zasshi 08/2013; 102(8):2023-33; quiz 2034-42.
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    ABSTRACT: Some patients with Parkinson disease improved their symptoms on treatment with nicotine patch or gum. Nicotine has also been studied for its antidyskinetic effect on levodopa-induced dyskinesia. We determined the effects of nicotine on levodopa pharmacokinetics and gastric emptying in healthy subjects and on levodopa transport in Caco-2 monolayers in vitro. Healthy subjects received transdermal nicotine patch application followed by oral levodopa/benserazide, 100/25 mg, in a fasting state and with enteral nutrition. Levodopa pharmacokinetics was determined, and gastric emptying was evaluated by carbon 13 (C)-labeled acetic acid breath testing. In vitro studies using intestinal Caco-2 cell monolayers evaluated whether the intestinal transport of levodopa was affected by nicotine and its metabolite, cotinine. Nicotine did not increase mean plasma concentration significantly during fasting or with enteral nutrition, although the extent of levodopa absorption was reduced by 34% to 60% in some individuals and the mean plasma concentration of levodopa was statistically decreased by nicotine in subjects who received enteral nutrition. However, gastric parameters were not significantly affected by nicotine. Nicotine and cotinine at 0.1 μmol/L significantly reduced levodopa uptake by Caco-2 cells (P < 0.01). We found that nicotine reduced plasma levodopa concentration in some healthy subjects but with no alteration of gastric emptying rate. In vitro, nicotine inhibited levodopa transport by Caco-2 cell monolayers in an α-methyl amino isobutyric acid-independent, 2-amino-norbornanecarboxylic acid-dependent manner. These results suggest that nicotine may inhibit the transport of levodopa by the system L-amino acid transporter.
    Clinical neuropharmacology 03/2013; 36(2):46-51. · 2.35 Impact Factor
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    ABSTRACT: Objective The concentrations of neopterin and osteopontin in the cerebrospinal fluid (CSF) were measured in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in order to evaluate their utility as biomarkers for the treatment response. Methods Seven HAM/TSP patients were treated intravenously with high-dose methylprednisolone (1,000 mg/day) for 3 days. CSF samples were collected before and after the treatment. The neopterin and osteopontin concentrations were determined using high-performance liquid chromatography (HPLC) and an enzyme immunoassay, respectively. The clinical symptoms were evaluated using the Osame Motor Disability Score and the Urinary Disturbance Score. Results Four out of the seven patients showed an improvement in motor function with the treatment, and were therefore classed as responders. The pre-treatment CSF neopterin concentration exceeded the upper limit of normal in all seven of the patients, and tended to be higher in treatment responders as compared to non-responders. The CSF neopterin concentration was reduced following treatment in all patients. The mean CSF neopterin concentration significantly (p<0.01) decreased following treatment by almost 60% (from 124.1±79.9 nmol/L to 49.2±29.8 nmol/L). The mean CSF osteopontin concentration was significantly (p<0.01) higher in the HAM/TSP patients in comparison to the 18 HTLV-1-seronegative patients who were designated as controls (9.54±4.53 mg/L vs. 3.72±3.04 mg/L). No significant (p=0.47) reduction of the CSF osteopontin concentration was observed following the intravenous administration of high-dose methylprednisolone. Conclusion These results indicate that the CSF neopterin concentration, but not the osteopontin concentration, is a potentially valuable biomarker for monitoring the treatment response in HAM/TSP patients. Furthermore, high pre-treatment CSF neopterin concentrations may be a predictive biomarker for a response to intravenous high-dose methylprednisolone therapy.
    Internal Medicine 01/2013; 52(19):2203-2208. · 0.97 Impact Factor
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    ABSTRACT: In the last 30 years, a lot of drugs to treat neurological disorders have been developed. Now neurology is one of the fields where the medication is the most important factor deciding the prognosis of the treated patients. Neurologists are now required to have precise knowledge of drug metabolisms and interactions on the medication to treat neurological disorders. Insert Packages contain most useful and important information for medications, however, information for the drugs are not enough to prescribe some drugs, and even though in the same drugs, information offered is different especially on drug interactions. Pharmacists and physicians should choose the drugs which offer proper and useful drug information to treat patients. Developments of drugs to treat patients are important as a physician in Japan. It can also contribute to treat patients in the all of the world. The role of neurologists is especially big because the drugs of the brain are rapidly developed than any other fields in medicine.
    Rinshō shinkeigaku = Clinical neurology. 01/2013; 53(11):907-10.
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    ABSTRACT: 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 01/2013; 52(8):871-6. · 0.97 Impact Factor
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    ABSTRACT: Randomized clinical trials have shown that pramipexole has an antidepressant effect in patients with Parkinson's disease. We investigated the comparative efficacy of pramipexole toward dopamine receptor D(2) and D(3) expression in rat brain. Groups of rats were treated subacutely with pramipexole (1 mg/kg), imipramine (10 mg/kg), or bromocriptine (5 mg/kg), with appropriate controls. Using real-time RT-PCR and immunoblotting, dopamine receptor D(2) and D(3) expression was up-regulated in the striatum following pramipexole treatment, while imipramine and bromocriptine had no significant effects. These findings support that pramipexole exerts additional therapeutic benefits such as decreasing depression by increasing dopamine receptor D(3) expression in the striatum.
    Journal of Pharmacological Sciences 09/2012; 120(2):133-7. · 2.15 Impact Factor
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    ABSTRACT: The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.
    Journal of Pharmacological Sciences 07/2012; 119(4):324-9. · 2.15 Impact Factor
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    ABSTRACT: The 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). In 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. Mean ± SEM levodopa maximum plasma concentration (Cmax) (14.1 ± 2.9 vs 9.7 ± 1.6 μmol/L; P < 0.01), plasma concentration at 30 min (C30 min) (13.7 ± 3.0 vs 8.1 ± 2.0 μmol/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 μmol/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. The 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.
    Clinical neuropharmacology 06/2012; 35(4):182-4. · 2.35 Impact Factor
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    ABSTRACT: Zonisamide has been proven as an effective drug for the recovery of degenerating dopaminergic neurons in the animal models of Parkinson's disease. However, several lines of evidence have questioned the neuroprotective capacity of zonisamide in animal models of Parkinson's disease. Although it suppresses dopaminergic neurodegeneration in animal models, the cellular and molecular mechanisms underlying the effectiveness of zonisamide are not fully understood. The current study demonstrates the effects of zonisamide on astrocyte cultures and two 6-hydroxydopamine-induced models of Parkinson's disease. Using primary astrocyte cultures, we showed that zonisamide up-regulated the expression of mRNA encoding mesencephalic astrocyte-derived neurotrophic factor, vascular endothelial growth factor, proliferating cell nuclear antigen, metallothionein-2, copper/zinc superoxide dismutase, and manganese superoxide dismutase. Similar responses to zonisamide were found in substantia nigra where the rats were pre-treated with 6-hydroxydopamine. Notably, pharmacological inhibition of 6-hydroxydopamine-induced toxicity by zonisamide pre-treatment was also confirmed using rat mesencephalic organotypic slice cultures of substantia nigra. In addition to this, zonisamide post-treatment also attenuated the nigral tyrosine hydroxylase-positive neuronal loss induced by 6-hydroxydopamine. Taken together, these studies demonstrate that zonisamide protected dopamine neurons in two Parkinson's disease models through a novel mechanism, namely increasing the expression of some important astrocyte-mediated neurotrophic and anti-oxidative factors.
    European journal of pharmacology 05/2012; 689(1-3):72-80. · 2.59 Impact Factor
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    ABSTRACT: We report a 33-year-old woman with myasthenia gravis (MG) who developed optic neuritis after the treatment of MG for 22 years. At 10 years of age, she was diagnosed with generalized MG (MGFA V) and at 11 years, she underwent thymectomy. She had been treated successfully only with anti-cholinesterase inhibitors for 22 years despite lasting high titer of anti-acetylcholine receptor antibody. She could manage everything in her life and had two children. At 33 years of age, she experienced acute visual loss in her left eye. Laboratory examination showed positive anti-acetylcholine receptor, antinuclear, anti-ssDNA, anti-dsDNA, anti-SS-A, and anti-aquaporin 4 (AQP4) antibodies. Brain MRI showed an enlarged left optic nerve with enhancement by gadolinium. Three courses of steroid pulse therapy did not show any effect on her visual acuity. However, plasma exchange therapy mildly ameliorated her visual acuity. Her MG symptoms were not exacerbated during the course of the optic neuritis. Furthermore blephalopstosis caused by MG has disappeared completely after the treatment with steroid pulse and plasma exchange. This case had 23 years of immunosuppressive treatment free durations with stable condition. The cause of development of optic neuritis would be her predisposed tendency other than thymectomy or treatment with immunosuppressive therapies.
    Rinshō shinkeigaku = Clinical neurology. 01/2012; 52(7):503-6.