Naohito Shirai

Hamamatsu University School of Medicine, Hamamatu, Shizuoka, Japan

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Publications (89)392.83 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of therapeutic regimens using proton pump inhibitors (PPIs) in patients with acid-related diseases is to potently inhibit acid secretion for the full 24 h. However, optimum treatment is still unclear because the pharmacodynamics of PPIs differ among CYP2C19 genotypes and most of the previous studies have had loss of sample power.
    European Journal of Clinical Pharmacology 07/2014; · 2.74 Impact Factor
  • Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 01/2013; 110(2):210-7.
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    ABSTRACT: Standard dosing (i.e. once daily) of proton pump inhibitors (PPIs) cannot inhibit acid secretion for a full 24 h. Better therapeutic regimens using PPIs are required to sustain potent acid inhibition for the full 24 h in all patients with acid-related diseases. To evaluate acid inhibitory effects by different dosing times of a PPI at the same daily dosage, in a study involving 70 rounds of pH monitoring. Using pH monitoring, we evaluated the efficacy of different divided treatment regimens with the same total daily dose of rabeprazole (40 mg o.m., 15 rounds; 20 mg b.d., 20 rounds; 10 mg q.d.s., 35 rounds) on day 7 or 8 of PPI dosing. In the study of divided treatment, the median pH (when administered once, twice or four times to achieve a daily dose of 40 mg) was 4.8 (3.6-6.4), 5.7 (4.1-7.4), 6.6 (4.9-8.4), respectively. When comparing the median pHs at the same CYP2C19 genotype among different dosing times of rabeprazole, the median pH attained with 10 mg q.d.s. was significantly higher than that in 40 mg o.m. or 20 mg b.d. Increase in the frequency of dosing effectively increased pH [median percent time of pH > 4.0 with q.d.s. therapy: 95.5% (63.2-100.0%)], irrespective to CYP2C19 genotype. Four times daily dosing with rabeprazole 10 mg achieved potent acid inhibition, including during the night-time, suggesting its potential usefulness as a regimen for patients who are refractory to standard once daily PPI treatment.
    Alimentary Pharmacology & Therapeutics 08/2012; 36(7):627-34. · 4.55 Impact Factor
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    ABSTRACT: The main therapeutic agent for gastroesophageal reflux disease (GERD) is a proton pump inhibitor (PPI). Plasma levels and the acid inhibitory effect of PPIs depend on the activity of cytochrome P450 (CYP) 2C19, which is polymorphic. Genotypes of CYP2C19 are classified into three groups: rapid metabolizers (RMs: *1/*1), intermediate metabolizers (IMs: *1/*X), and poor metabolizers (PMs: *X/*X), where *1 and X represent the wild type and the mutant allele, respectively. RMs include ultra-rapid metabolizers, who possess the CYP2C19*17 allele. The pharmacokinetics and pharmacodynamics of PPIs differ among different CYP2C19 genotype groups. Plasma PPI levels and intragastric pH values during PPI treatment are lowest in the RM group, intermediate in the IM group, and highest in the PM group. These CYP2C19-genotype-dependent differences in the pharmacokinetics and pharmacodynamics of PPIs influence the healing and recurrence of GERD during PPI treatment, suggesting the need for CYP2C19 genotype-based tailored therapy for GERD. CYP2C19 pharmacogenetics should be taken into consideration for the personalization of PPI-based therapy. However, the clinical usefulness of CYP2C19 genotype testing in GERD therapy should be verified in clinical studies.
    Molecular diagnosis & therapy 08/2012; 16(4):223-34. · 1.69 Impact Factor
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    ABSTRACT: The renin-angiotensin system (RAS) plays an important role not only in homeostasis but also in carcinogenesis. Recent epidemiological studies suggest that hypertensive patients with upregulated systemic RAS functions are at a significantly increased risk for the subsequent development of cancers with poor outcomes, and moreover that RAS inhibitors reduce tumor development, progression, and metastasis. Notably, Helicobacter pylori infection, one of the major predictors of gastric carcinogenesis, generally leads to RAS component overexpression, as exemplified by that of angiotensin I, angiotensin II, angiotensin I converting enzyme and angiotensin II receptor. Gastric mucosal RAS expression gradually increases with time after H. pylori infection with respect to the severity of inflammatory cell infiltration. Gastric carcinogenic potential is therefore considered to relate to RAS component expression levels and activities. This hypothesis is supported by findings that RAS genotypic variation can lead to high component expression levels (e.g. angiotensin I converting enzyme, chymase and angiotensinogen), and thereby increase the risk of development of gastric cancer. Thus, the RAS may be potently associated with the pathogenesis of H. pylori-related gastric carcinogenesis, and RAS inhibitors may provide tools for specifically preventing this disease.
    Journal of Gastroenterology and Hepatology 11/2011; 27(3):442-51. · 3.33 Impact Factor
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    ABSTRACT: The preventive effects of lansoprazole and famotidine on low-dose aspirin-induced gastric mucosal injury in relation to gastric acidity were compared in healthy Japanese volunteers. Fifteen Helicobacter pylori-negative volunteers with different CYP2C19 genotypes were randomly administered aspirin 100 mg, aspirin plus famotidine 20 mg twice daily, or aspirin plus lansoprazole 15 mg once daily for 7 days each in a crossover fashion. Gastroscopy for the evaluation of mucosal injury based on modified Lanza score (MLS) and 24-hour intragastric pH monitoring were performed on day 7 of each regimen. Aspirin induced gastric mucosal injury (median MLS = 3). Lansoprazole significantly decreased MLS to 0, which was significantly lower than that by famotidine (MLS = 1) (P < .05). Medians of pH 3 holding time and mean 24-hour pH values with the lansoprazole regimen were significantly higher than those with famotidine (P < .05). No significant differences in MLS were observed among the different CYP2C19 genotype groups in any of the treatment regimens. In this 7-day study, lansoprazole appeared to be more protective than famotidine against low-dose aspirin-induced mucosal injury but a larger well-controlled study is necessary to establish a definitive clinical benefit.
    The Journal of Clinical Pharmacology 07/2011; 51(7):1079-86. · 2.84 Impact Factor
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    ABSTRACT: Most of patients who are refractory to usual standard eradication therapies for H. pylori infection have rapid metabolizer genotype of CYP2C19 and are infected with resistant strains to several antimicrobial agents. However, most of H. pylori strains are sensitive to amoxicillin. We tested whether dual therapy with the 4 times daily dosing of rabeprazole and amoxicillin was effective as the 3rd rescue regimen for eradication of H. pylori. 49 patients who failed in eradication of H. pylori after two (1st: proton pump inhibitor (PPI)/amoxicillin/clarithromycin and 2nd: PPI/amoxicillin/metronidazole) were enrolled to the study. They were treated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. At 4 weeks after the treatment, they underwent the [13C]-urea breath test. When the result of [13C]-urea breath test was negative, they underwent the endoscopy and the successful eradication was confirmed by rapid urease test. All patients completed the treatment. The eradication rate was 87.8% (43/49) (95% CI = 75.2%-95.4%). No undesirable severe adverse events were observed during the study period. The dual therapy with 4 times daily dosing of rabeprazole and amoxicillin is well tolerated and effective as the 3rd rescue regimen for eradication of H. pylori.
    Hepato-gastroenterology 01/2010; 57(102-103):1314-9. · 0.77 Impact Factor
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    ABSTRACT: Gastric acid plays an important role in the pathogenesis of gastric mucosal lesions. We investigated whether aspirin-induced gastric mucosal injury might have any association with the intragastric pH. Fifteen healthy, Helicobacter pylori-negative volunteers randomly underwent the four different 7-day regimens: (1) aspirin 100 mg, (2) rabeprazole 10 mg, (3) aspirin 100 mg + rabeprazole 10 mg, and (4) aspirin 100 mg + rabeprazole 40 mg. Gastric mucosal injury based on the modified Lanza score (MLS), 24-h intragastric pH, and histopathology of gastric mucosa were evaluated prior to the start and on day 7 of each regimen. The median MLSs were 0 in the baseline and the rabeprazole 10 mg regimen. The median MLS in the aspirin regimen was 3, while those in both aspirin + rabeprazole 10 mg and aspirin + rabeprazole 40 mg regimens were 0. Rabeprazole significantly prevented the gastric mucosal injury by aspirin (P = 0.001 for rabeprazole 10 mg and P = 0.005 for rabeprazole 40 mg). The MLSs were negatively correlated with the 24-h intragastric pH (P = -0.711, < 0.001), whereas aspirin had no effect on the intragastric pH. Aspirin expanded the mean diameter of the microvessels of the gastric mucosa, which, in turn, was negatively correlated with the intragastric pH. Aspirin might induce gastric mucosal injury by affecting the mucosal microvessels in an acid-dependent manner. Sustained maintenance of the intragastric pH at an elevated value is necessary to prevent gastric mucosal damage induced by aspirin.
    Digestive Diseases and Sciences 09/2009; 55(6):1627-36. · 2.26 Impact Factor
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    ABSTRACT: Maintenance therapy of gastroesophageal reflux disease (GERD) is usually performed with a low dose of a proton-pump inhibitor (PPI). Because PPIs are metabolized by CYP2C19 in the liver, we investigated whether a patient's CYP2C19 genotype was associated with symptomatic recurrence of GERD during maintenance therapy with a low dose of a PPI. We enrolled 124 patients with erosive GERD whose esophageal mucosal breaks were endoscopically proven to be cured after treatment with lansoprazole 30 mg/day for 8 weeks. When reflux symptoms occurred less than once per week, the dose of lansoprazole was decreased to 15 mg/day, but if symptoms then occurred more than once per week, it was restored to 30 mg/day. CYP2C19 genotypes were classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). In 18 of 54 RMs, 28 of 56 IMs, and 8 of 14 PMs, the maintenance dose of lansoprazole was decreased to 15 mg/day, but in 16 (88.9%), 22 (78.6%), and 4 (50%), respectively, there was symptomatic recurrence of GERD and the dose was restored to 30 mg/day. The hazard ratios of symptomatic recurrence of GERD in IMs and PMs compared with RMs were 0.40 (95%CI: 0.19-0.87, P = 0.021) and 0.19 (95%CI: 0.05-0.69, P = 0.011). When the dose of lansoprazole is decreased, the RM genotype of CYP2C19 appears to be a risk factor for symptomatic recurrence of GERD. The CYP2C19 genotyping test would be useful for determining the optimal dose of a PPI for maintenance therapy of GERD.
    European Journal of Clinical Pharmacology 04/2009; 65(7):693-8. · 2.74 Impact Factor
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    ABSTRACT: The effect of multidrug resistance transporter gene 1 (MDR1) on the bioavailability and kinetics of several substrates has not yet been fully elucidated. We evaluated the influence of MDR1 C3435T polymorphism on the pharmacokinetics and pharmacodynamics of lansoprazole in Japanese subjects. Fifteen healthy volunteers with the rapid extensive metabolizer genotype of CYP2C19 were classified into three MDR1 C3435T genotype groups: C/C (n = 5), C/T (n = 5), and T/T (n = 5). Lansoprazole 30 mg was administered orally for 15 days. The intragastric pH and plasma lansoprazole levels were determined on days 1 and 15. On day 1, the mean C(max) of lansoprazole in the T/T group was significantly higher than that in the C/C or C/T groups (T/T 1,248, C/C 618, C/T 607 ng/ml; P = 0.038). On day 15, similar MDR1 genotype-dependent differences were observed in the C(max) of lansoprazole, although smaller than the differences observed on day 1. In contrast, the intragastric pH attained after lansoprazole administration did not differ among MDR1 genotype groups on either day 1 or day 15. Although the sample size was small, our study demonstrated that the MDR1 C3435T polymorphism influenced the pharmacokinetics, but not the pharmacodynamics (i.e., intragastric pH), of lansoprazole in rapid metabolizers of CYP2C19.
    European Journal of Clinical Pharmacology 03/2009; 65(6):593-600. · 2.74 Impact Factor
  • Digestive Diseases and Sciences 01/2009; · 2.26 Impact Factor
  • Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics 01/2009; 40(6):267-272.
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    ABSTRACT: To examine whether the sedative effects assessed by psychomotor tests would depend on the cytochrome P450 (CYP) 2C19 genotypes after an infusion regimen of diazepam commonly used for gastrointestinal endoscopy in Japan. Fifteen healthy Japanese volunteers consisting of three different CYP2C19 genotype groups underwent a critical flicker fusion test, an eye movement analysis and a postural sway test as a test for physical sedative effects, and a visual analog scale (VAS) symptom assessment method as a test for mental sedative effects during the 336 h period after the intravenous infusion of diazepam (5 mg). The physical sedative effects assessed by the critical flicker test continued for 1 h (t values of 5 min, 30 min and 60 min later: 4.35, 5.00 and 3.19, respectively) and those by the moving radial area of a postural sway test continued for 3 h (t values of 5 h, 30 h, 60 min and 3 h later: -4.05, -3.42, -2.17 and -2.58, respectively), which changed significantly compared with the baseline level before infusion (P<0.05). On the other hand, the mental sedative effects by the VAS method improved within 1 h. The CYP2C19 genotype-dependent differences in the postinfusion sedative effects were not observed in any of the four psychomotor function tests. With the psychomotor tests, the objective sedative effects of diazepam continued for 1 h to 3 h irrespective of CYP2C19 genotype status and the subjective sedative symptoms improved within 1 h. Up to 3 h of clinical care appears to be required after the infusion of diazepam, although patients feel subjectively improved.
    World Journal of Gastroenterology 09/2008; 14(33):5197-203. · 2.55 Impact Factor
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    ABSTRACT: P-glycoprotein, the gene product of multidrug-resistant transporter-1 (MDR1), confers multidrug resistance against antineoplastic agents but also affects the kinetic disposition of some drugs and carcinogens. MDR1 C3435T polymorphism influences the development of colon cancer and adult acute myeloid leukemia by the association with transporting carcinogen. The aim of this study was to clarify the association of MDR1 C3435T polymorphism with susceptibility to gastric cancer and peptic ulcers in patients with Japanese H. pylori infection. We assessed the MDR1 C3435T polymorphism in H. pylori-positive gastritis alone patients (n=150), gastric cancer (n=292), gastric ulcer (n=215), and duodenal ulcer (n=163) and H. pylori-negative subjects (n=168) as control by a PCR-based method. No significant difference existed in frequencies of MDR1 C3435T polymorphisms between H. pylori-negative controls and H. pylori-positive gastritis alone patients. Moreover, MDR1-3435 T allele carriage didn't affect the risk of gastric cancer or peptic ulcer development. The age- and sex-adjusted odds ratios (ORs) of MDR1 3435 T allele carriers relative to the C/C genotype group for gastric cancer, gastric ulcer and duodenal ulcer risk were 0.96 (95%CI: 0.56-1.66), 1.16 (95%CI: 0.72-1.84) and 1.00 (95%CI: 0.61-1.62), respectively. In this preliminary data, the association with MDR1 C3435T polymorphism and risk for developing H. pylori-related gastric cancer and peptic ulcer in Japanese was low. P-glycoprotein might not be involved in the carcinogenesis of H. pylori-related gastric cancer.
    Life Sciences 08/2008; 83(7-8):301-4. · 2.56 Impact Factor
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    ABSTRACT: The hypothesis that non-erosive reflux disease (NERD) patients comprise various subgroups is gaining popularity. This study was conducted to investigate the possibility of categorizing NERD patients according to symptom types and response to acid-suppressive drug rabeprazole (RPZ) 10 mg/day. NERD patients were classified as grade N (endoscopically normal), M (minimal change), or erosive GERD, and answered a 51-item, yes-or-no questionnaire pre and post-treatment. Compared to erosive GERD, clear differences existed in pretreatment prevalence of symptoms and responsiveness to RPZ in grades N and M; the results suggested stomachaches (especially at night) were significant symptoms in grade N and dysmotility-like symptoms like bloated stomach were significant in grade M while gastroesophageal reflux symptoms were significant in erosive GERD. Clinical significance of classifying NERD was indicated from different symptoms and responsiveness to PPI.
    Digestive Diseases and Sciences 06/2008; 53(12):3082-94. · 2.26 Impact Factor
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    ABSTRACT: Helicobacter pylori (H. pylori) eradication increases the serum pepsinogen I/ pepsinogen II ratio and the percentage change in pepsinogen I/pepsinogen II ratios is a useful marker of H. pylori eradication. We studied whether the pepsinogen method could be an early diagnostic marker of H. pylori eradication even in patients persistently treated with a proton pump inhibitor. Sixty-two H. pylori-positive patients underwent H. pylori-eradication therapy, followed by treatment with a proton pump inhibitor to cure ulcers. Serum levels of pepsinogen I and pepsinogen II were measured before, at the end of, and at 4 weeks after the eradication therapy. The cut-off values of percentage changes in pepsinogen I/pepsinogen II ratios for the diagnosis of eradication of H. pylori were set in proportion to pepsinogen I/pepsinogen II ratios before eradication in accordance with a previous report. Using the results of 13C-urea breath test as the standard, the sensitivity, specificity and validity of the pepsinogen method were 100.0%, 89.8% and 90.3%, respectively, at 4 weeks after eradication therapy. The percentage change in serum pepsinogen I/pepsinogen II ratios is useful as an early diagnostic marker for judgment of H. pylori eradication irrespective of proton pump inhibitor treatment.
    Hepato-gastroenterology 01/2008; 55(82-83):486-90. · 0.77 Impact Factor
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    ABSTRACT: Increasing evidence suggests that eradication therapy of Helicobacter pylori (H. pylori) may be an effective treatment for gastric lymphoma of mucosa-associated lymphoid tissue (MALToma), but it remains unclear whether a similar therapeutic effect may be obtained for MALToma at other sites. We describe here a case of regression of gastroduodenal MALToma after eradication therapy for H. pylori. A 39-year-old man underwent gastroscopy at a routine check-up, which demonstrated protruding lesions like a raised erosion in the antrum and multiple whitish granular lesions in the fornix. Simultaneously, multiple coarse nodular lesions were also found in the duodenal bulb. Forceps biopsy specimens obtained from both the stomach and bulb showed infiltration of small- to medium-sized lymphocytes with cleaved nuclei, centrocyte-like cells, together with atypical large lymphoid cells into the glandular lesion, and the rearrangement of immunoglobulin was positive, thereby allowing diagnosis of low grade MALToma with large cell transformation. H. pylori was positive in the stomach, while the presence of H, pylori was not detected microscopically in the bulb, although ectopic gastric mucosa was identified in the bulb. Regression of multiple coarse or granular lesions in both the stomach and bulb were observed three months after eradication of H. pylori. Thereafter the disappearance of MALToma was verified histologically a further six months later. There was no recurrence of MALToma detected over a two-year follow-up period. These findings suggest that eradication of H. pylori could be a treatment of first choice for MALToma occurring in the gastrointestinal tract outside the stomach.
    Digestive Endoscopy 12/2007; 11(4):327 - 331. · 1.61 Impact Factor
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    ABSTRACT: The eradication rates of Helicobacter pylori by the triple therapy consisting of a proton pump inhibitor (PPI) and two antimicrobial agents are mainly influenced by bacterial susceptibility to antimicrobial agents and magnitude of acid inhibition during the treatment with a PPI. Acid inhibition during the treatment is affected by the dosing schemes of acid inhibitory drugs (i.e., PPI), genotypes of drug-metabolizing enzymes (i.e., CYP450 2C19), drug transporters (i.e., multi-drug resistant transporter-1) and inflammatory cytokines (i.e., IL-1 beta). Modification of dosing schedules of a PPI, such as frequent PPI dosing and concomitant dosing with a histamine 2-receptor antagonist, could overcome these genetics-related differences in therapeutic effectiveness. For attaining higher eradication rates, the tailored regimen based on the relevant pharmacogenomics is preferable.
    Expert Opinion on Pharmacotherapy 12/2007; 8(16):2701-17. · 2.86 Impact Factor
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    ABSTRACT: Most clarithromycin-resistant strains of Helicobacter pylori have a mutation from adenine (A) to guanine (G) at position 2142 or 2143 of the 23S rRNA gene. Our aim in this study was to develop a polymerase chain reaction (PCR)-based assay that could determine these mutations in a single reaction tube. We designed the forward primer FP2143G and the reverse primer RP2142G, which specifically anneal with the 2143G- and 2142G-mutated sequences, respectively, of the 23S rRNA gene of H. pylori. We also designed the forward primer FP-1 and reverse primer RP-1 upstream and downstream from the positions 2142 and 2143, respectively, to distinguish the wild-type A2142G and A2143G mutations from each other by amplicon sizes. DNA was extracted from 292 gastric tissue samples positive for rapid urease test, and the DNA underwent the PCR reaction. The results were compared with minimum inhibitory concentrations (MIC) for clarithromycin. Helicobacter pylori strains with A2142G, A2143G and wild type could be distinguished by amplicon sizes by a single PCR reaction. The genotyping results were correlated well with the MIC values for clarithromycin. The median MIC for clarithromycin of the wild-type strains was <0.015 microg/mL. Those of strains with 2142G or 2143G were > or =1.0 microg/mL. Our new PCR-based assay for 23S rRNA mutations of H. pylori is a useful method for detecting clarithromycin-resistant strains of H. pylori easily.
    Journal of Gastroenterology and Hepatology 12/2007; 22(11):1810-5. · 3.33 Impact Factor
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    ABSTRACT: Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole and rabeprazole, are metabolized by CYP2C19 in the liver. There are genetic differences in the activity of this enzyme. Genotypes of CYP2C19 are classified into three groups, rapid metabolizer (RM: *1/*1), intermediate metabolizer (IM: *1/*X) and poor metabolizer (PM: *X/*X) (*1 and 'X' represent the wild-type and mutant allele, respectively). The pharmacokinetics and pharmacodynamics of PPIs differ among three different CYP2C19 genotype groups. Plasma PPI levels and intragastric pHs during PPI treatment in the RM group are lowest, those in the IM group come next, and those in the PM group are highest of the three groups. These CYP2C19 genotypic differences in pharmacokinetics and pharmacodynamics of PPIs influence the healing and eradication rates for the gastro-esophageal reflux disease and Helicobacter pylori infection by PPI-based regimens. Recently, the CYP2C19 genotype-based tailored therapy for H. pylori infection has been found to be effective. CYP2C19 pharmacogenetics should be taken into consideration for the personalization of a PPI-based therapy.
    Pharmacogenomics 10/2007; 8(9):1199-210. · 3.86 Impact Factor

Publication Stats

2k Citations
392.83 Total Impact Points

Institutions

  • 1999–2013
    • Hamamatsu University School of Medicine
      • • Center for Clinical Research
      • • Division of Laboratory Medicine (School of Medicine)
      • • Clinical Laboratories
      • • Division of Clinical Pharmacology and Therapeutics (School of Medicine)
      Hamamatu, Shizuoka, Japan
    • Seirei Hamamatsu General Hospital
      Hamamatu, Shizuoka, Japan
  • 2011
    • Shizuoka General Hospital
      Sizuoka, Shizuoka, Japan