Yasufumi Sawada

The University of Tokyo, 白山, Tōkyō, Japan

Are you Yasufumi Sawada?

Claim your profile

Publications (410)901.25 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: A patient presented with convulsive seizures when sodium valproate (VPA) and tebipenem pivoxil (Orapenem) were co-administered accidentally. The seizures were suspected to be caused by a reduced concentration of VPA in the blood. Case summary: A 6-year-old boy (weight: 16 kg, at the start of treatment) began sodium valproate (valproate syrup 5%) treatment for epilepsy in February 2012. At a dose of 350 mg/day, he experienced no convulsive seizures and maintained stable symptoms for the past 9 months. In December, he was prescribed 160 mg/day tebipenem pivoxil by an otolaryngologist for inflammation of the tympanic membrane. He experienced convulsive seizures the day after beginning co-administration. The concentration of VPA in his blood at this time was 30.0 μg/mL, which was lower than the optimal blood concentration. Discussion: Marked reduction of VPA concentration in the blood due to co-administration of VPA and injectable carbapenem antibiotics has been well-documented; however, this is the first report of such an interaction with tebipenem, which is an orally-administered carbapenem antibiotic. Although the mechanism of drug interaction between VPA and carbapenem antibiotics is not fully understood, it is thought that VPA blood concentrations decrease due to production of valproic acid glucuronic acid conjugates (VPA-Gluc) being promoted directly or indirectly by carbapenem antibiotics. When we assessed the patient according to the DIPS system, we calculated a score of +4 (possibility of interaction). Conclusions: The results suggest that co-administration of oral carbapenem antibiotics and VPA should be avoided.
    International journal of clinical pharmacology and therapeutics 11/2014; 53(01). DOI:10.5414/CP202188 · 1.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Among the adverse effects of anticancer drugs, critical effects have attracted the most attention. However, non-critical adverse effects that lower the quality of life of cancer patients have been gaining recognition. For example, the package insert of tegafur・gimeracil・oteracil potassium (S-1) was modified and lacrimal duct obstruction was added to the list of critical adverse effects on September 25, 2012. In a similar vein, this study aimed to examine the awareness of healthcare professionals regarding the adverse effects of anticancer drugs on the eyes. A web-based questionnaire survey was administered to medical doctors and pharmacists. We received responses from 38 doctors and 123 pharmacists. Only 39.5% (15) of the doctors and 33.3% (41) of the pharmacists were aware of the adverse effects of anticancer drugs on the eyes. Among respondents who had observed these adverse effects, only 12.5% (1/8) of doctors and 11.1% (2/18) of pharmacists reported them to the authorities or the pharmaceutical companies. The results suggest that the adverse effects of anticancer drugs on the eyes should gain more recognition among healthcare professionals. Therefore, we would like to encourage them in obtaining information concerning the safety of medicines and to report all observed adverse effects regardless of their severity.
    01/2014; 40(6):360-368. DOI:10.5649/jjphcs.40.360
  • [Show abstract] [Hide abstract]
    ABSTRACT: We conducted a workshop that aimed to address the problems of collaboration between community and hospital pharmacists to provide safe outpatient chemotherapy and promote continuous collaboration. Thirty-nine pharmacists in Gunma were enrolled in the workshop and divided into five groups. Each group comprised similar number of community and hospital pharmacists in the neighboring area. Participants in these groups discussed using the KJ method and identified the following important and urgent problems; "lack of collaboration between hospitals and pharmacies" and "lack of exchanging patients' information, including regimen". To improve collaboration, the participants recommended a workshop or a study group and setting up a hotline, and to exchange patients' information, they proposed to utilize a medicine notebook and reconfirm how to use these notebook. Furthermore, usage of cloud storage as a means to exchange patients' information was discussed. Post-workshop questionnaire revealed that 97% participants acknowledged an increased awareness toward collaboration, and 90% participants were motivated to take more aggressive action for promoting collaboration; whereas, only 53% participants believed that they could summarize the problems and corrective measures in promoting collaboration. The workshop seemed to be productive in identifying the problems of collaboration and improving the awareness and motivation toward collaboration. However, it served only as a "trigger", and therefore it is important for valuable "results" to continuously collaborate face-to-face between community and hospital pharmacists.
    YAKUGAKU ZASSHI 01/2014; 134(4):563-74. DOI:10.1248/yakushi.13-00216 · 0.31 Impact Factor
  • Yakugaku zasshi journal of the Pharmaceutical Society of Japan 01/2014; 134(6):757-66. DOI:10.1248/yakushi.13-00244 · 0.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aims of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndrome in neonates after delivery by characterizing transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results, and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. Transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine, and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.
    Drug metabolism and disposition: the biological fate of chemicals 09/2013; 41(12). DOI:10.1124/dmd.113.052332 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To develop a pharmacokinetic model able to describe the nonlinear pharmacokinetics of paroxetine (PRX) and to predict the drug-drug interaction between PRX and metoprolol under various dosage regimens. Methods: A pharmacokinetic model of PRX incorporating mechanism-based inhibition was developed. This model was fitted to the drug concentration profiles obtained after single and repeated administrations of PRX to estimate the pharmacokinetic parameters of PRX and degradation rate constant of cytochrome P450 (CYP) 2D6. It was also fitted to the time profile of S-metoprolol after coadministration of metoprolol and PRX, and the fractional contribution of CYP2D6 to overall clearance of S-metoprolol was estimated. Using the developed model and estimated parameters, an optimal dosage regimen for metoprolol during withdrawal of PRX was simulated. Results: The developed model well described the time profiles of both PRX and metoprolol concentration during concomitant administration. The estimated parameters were consistent with reported values. The nonlinear and accumulation properties of PRX could be explained by mechanism-based inhibition of CYP2D6 by PRX. Upon tapering PRX from 20 mg/ day to 10 mg/day for 14 days then 5 mg/day for 14 days until cessation, the optimal dosage regimen to resume 120 mg/day of metoprolol based on the developed model was as follows: 30 mg/day during concomitant administration, 40 mg/day for the next 14 days, 60 mg/day for the next 14 days, and finally 120 mg/day. Conclusions: The developed model enabled us to quantitatively estimate drug-drug interactions of PRX and CYP2D6 substrate drugs, and to predict optimal dosage regimens.
    International journal of clinical pharmacology and therapeutics 01/2013; 51(5). DOI:10.5414/CP201798 · 1.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study was conducted among 252 inhabitants aged 16 years or older of small remote islands in Gotoh. The survey was conducted in a direct interview format based on a questionnaire. In the interview, the respondents were asked about the statuses of their Internet usage, purchase/use/storage of nonprescription drugs, acquisition of information regarding nonprescription drugs, as well as regulations pertaining to the sale of nonprescription drugs, including the use of postal services. Among the respondents, 7.5% were Internet users, whereas people who had past experiences in purchasing nonprescription drugs through Internet accounted for as few as 0.8% of the total number of respondents; 63.9% of the inhabitants of small remote islands did not use nonprescription drugs, additionally, most inhabitants of small remote islands did not express any need for nonprescription drugs sold through Internet. Further, the findings suggested that a large number of people felt the need for the presence of pharmacists and experts to provide them with explanations and information regarding nonprescription drugs. However, because a large number of these people were unaware of the existence of pharmacists, it is important that in the future, pharmacists should conduct "consultation meetings and briefings regarding medications." These meeting may be held in a continuous manner in these small remote islands, such that the inhabitants recognize the difference in a pharmacists' profession. It is essential that "family pharmacies/pharmacists" play a central role in promoting the supply, management, and proper use of pharmaceutical products.
    YAKUGAKU ZASSHI 01/2013; 133(8):913-22. DOI:10.1248/yakushi.12-00268 · 0.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: For drug fostering and evolution, it is important to collect information directly from patients on the efficacy and safety of drugs as well as patient needs. At present, however, information gathered by healthcare professionals, pharmaceutical companies, or governments is not sufficient. There is concern that patients may fail to recognize the importance of providing information voluntarily. The present study was conducted to provide drug information to patients/consumers, to enlighten them on the importance of providing drug information by themselves, and to develop an Internet website, called "Minkusu," for collecting drug information from patients. This website is based on a registration system (free of charge). It is designed to provide information on proper drug use, and to collect opinions about drugs. As of May 31, 2012, a total of 1149 people had been registered. The male/female ratio of registered members was approximately 1:1, and patients/consumers accounted for 23%. According to the results of a questionnaire survey, several patient/consumer members appreciated the usefulness of the information service, and they took an opportunity to know of the concepts of drug development and evolution (Ikuyaku, in Japanese) through the information services provided by this site. In conclusion, the developed information system would contribute to the proper use of drugs by patients/consumers and to the promotion of drug development and evolution.
    YAKUGAKU ZASSHI 01/2013; 133(9):1023-34. DOI:10.1248/yakushi.13-00008 · 0.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: We report a case of sequential interaction of phenytoin (PHT) and phenobarbital (PB) with fluorouracil (5-FU). Case report: A male patient aged 60 under treatment with PHT and PB in which serum concentrations of PHT (32.8 mu g/ml) and PB (26.7 mu g/ml) increased similar to 2-fold after the start of postoperative adjuvant therapy with calcium levofolinate (1-LV) and fluorouracil (5-FU). When the drug interactions of this case evaluated using the Drug Interaction Probability Scale, was assessed as "probable". Discussion: In this case, 5-FU increased PHT, which in turn may have increased the PB concentration, suggesting that when fluoropyrimidine antitumor agents are administered to patients receiving PHT in combination with other drugs, some measures should be taken in consideration of secondary effects of antitumor agents on other drugs that may possibly interact with PHI, including frequent monitoring of blood drug concentration.
    International journal of clinical pharmacology and therapeutics 12/2012; 50(12):862-866. DOI:10.5414/CP201677 · 1.04 Impact Factor
  • Hiroki Satoh, Yasufumi Sawada
    Nippon rinsho. Japanese journal of clinical medicine 08/2012; 70 Suppl 6:310-5.
  • Yasuko Asahina, Satoko Hori, Yasufumi Sawada
    [Show abstract] [Hide abstract]
    ABSTRACT: There is little information about Japanese pharmacists' perceived facilitators and barriers to communication with patients about orally taken health products, including herbs and dietary supplements. To explore Japanese pharmacists' attitudes relating to patients' use of health products. Qualitative study involving focus group interviews with pharmacists was conducted. Data were analyzed using the constant comparative method. Focus group interviews with community pharmacists were conducted in Japan. Main outcome measure Pharmacists' views and experiences about patients' health product use and their perceived facilitators and barriers to communication. Sixteen pharmacists participated and were asked to describe their views and experiences about patients' health product use. Some were uncomfortable inquiring about and being asked about patients' health product use, due to lack of scientific evidence for their efficacy and safety, lack of knowledge to advise patients properly, and fear that they could not answer patients' questions. Other pharmacists had similar views or experiences, but those who were proactive in communicating with patients were motivated by certain predisposing factors, such as their professional responsibility for ensuring patients' health and safety. This study showed that differences in opinion about their roles might create differences in pharmacists' attitudes toward patients' health product use. This highlights the importance of reconsidering pharmacists' roles in community settings. Further studies and debate are needed in order to clarify the pharmacists' roles and to ensure the design of educational objectives that would enable pharmacists to support their patients in using health products and prescription drugs safely.
    04/2012; 34(4):529-37. DOI:10.1007/s11096-012-9640-4
  • Yasufumi Sawada, Hiroki Satoh
    [Show abstract] [Hide abstract]
    ABSTRACT: For the appropriate use of psychotropic drugs, such as hypnotics, antidepressants and antipsychotics, knowledge of the pharmacokinetic characteristics and the interactions of these drugs are required. The mechanisms of drug interaction can be subdivided into pharmacokinetic interactions and pharmacodynamic interactions. Among the former, interactions involving inhibition or induction of cytochrome P450 (CYP) enzymes are clinically very important. If such interactions cause an increase of systemic exposure to psychotropic drugs, adverse effects are likely, while a decrease exposure may lead to treatment failure. In this article, we review drug interactions of psychotropic drugs from the viewpoints of clinical evidence, mechanism, and management.
    Nippon rinsho. Japanese journal of clinical medicine 01/2012; 70(1):27-41.
  • 01/2012; 38(9):592-598. DOI:10.5649/jjphcs.38.592
  • [Show abstract] [Hide abstract]
    ABSTRACT: Confusion of drug names is one of the most common causes of drug-related medical errors. A similarity measure of drug names, "vwhtfrag", was developed to discriminate whether drug name pairs are likely to cause confusion errors, and to provide information that would be helpful to avoid errors. The aim of the present study was to evaluate and improve vwhtfrag. Firstly, we evaluated the correlation of vwhtfrag with subjective similarity or error rate of drug name pairs in psychological experiments. Vwhtfrag showed a higher correlation to subjective similarity (college students: r=0.84) or error rate than did other conventional similarity measures (htco, cos1, edit). Moreover, name pairs that showed coincidences of the initial character strings had a higher subjective similarity than those which had coincidences of the end character strings and had the same vwhtfrag. Therefore, we developed a new similarity measure (vwhtfrag+), in which coincidence of initial character strings in name pairs is weighted by 1.53 times over coincidence of end character strings. Vwhtfrag+ showed a higher correlation to subjective similarity than did unmodified vwhtfrag. Further studies appear warranted to examine in detail whether vwhtfrag+ has superior ability to discriminate drug name pairs likely to cause confusion errors.
    YAKUGAKU ZASSHI 01/2012; 132(4):525-9. DOI:10.1248/yakushi.132.525 · 0.31 Impact Factor
  • Keisuke Awa, Hiroki Satoh, Satoko Hori, Yasufumi Sawada
    [Show abstract] [Hide abstract]
    ABSTRACT: Topical dermatological formulations of non-steroidal anti-inflammatory drugs (NSAIDs) are reported to show their pharmacological effect partially through the systemic circulation, and to induce systemic side effects. However, pharmaceutical equivalence and pharmacokinetic bioequivalence between brand-name and generic products are not required. Therefore, we aimed to predict systemic drug exposure from brand-name and nine generic ketoprofen tapes. In vitro release profiles were examined using the paddle-over-disk method, then analyzed by the W. I. Higuchi equation incorporating an initial burst effect. Pharmacokinetic parameters were estimated from observed release profiles and the reported time-plasma concentration profile of the brand-name product. Plasma concentration profiles of generic products were predicted from the observed release profiles and the pharmacokinetic parameters of the brand-name product. In vitro release profiles differed markedly, and estimated release rates for initial burst effect and at 24 hours ranged from 4.20 to 88.75% and from 45.27 to 95.83%, respectively. The predicted plasma concentration profile of each product reflected its release profile, and estimated C(max) ranged from 61.70 to 290.30 ng/mL (0.46- to 2.15-fold vs. brand-name product). Generic products were classified into three types, i.e., systemic exposure comparable with, higher than and lower than that of brand-name product. C(max) was predicted to increase with enhanced skin permeability for all products, but the increase rates differed among products. These results suggest that safety and efficacy differ between brand-name and generic ketoprofen tapes. Healthcare professionals should carefully monitor systemic side effects, especially when switching from brand-name to generic products for which higher systemic exposure is predicted.
    YAKUGAKU ZASSHI 01/2012; 132(1):135-44. DOI:10.1248/yakushi.132.135 · 0.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aggravation of asthmatic response (asthmatic attack, 2 cases) and adverse events (tremor, 1 case) due to a switch from a brand-name tulobuterol tape to a generic tape were recently reported. These changes disappeared after reformulation from generic to the brand-name tape. To investigate this issue, we conducted a questionnaire survey on changes of asthmatic response, adverse events and product usability due to a switch between tulobuterol tapes. We identified 44 cases (18 from doctors, 26 from pharmacists) in which changes of asthmatic response or adverse events had occurred due to a switch between tulobuterol tapes. Aggravation of asthmatic response had occurred in 30 cases and adverse events in 21 cases due to switch from brand-name tulobuterol tape to generic tape. As regards change of product usability, we obtained 96 relevant responses (18 from doctors, 78 cases pharmacists), and the major response was that generic tulobuterol tape peeled off the skin more easily than did the brand-name tape (60 cases). These results suggest that changes of asthmatic response, adverse events and product usability should be carefully monitored when switching tulobuterol tapes.
    YAKUGAKU ZASSHI 01/2012; 132(5):617-27. DOI:10.1248/yakushi.132.617 · 0.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The remote islands in Nagasaki Prefecture have medical institutions such as no pharmaceutical wholesaler offices (“wholesalers”). This has caused concerns about the supply of prescription drugs (“drugs”), resulting in disadvantages for patients (such as health risks caused by not being able to take medicine). In order to clarify the condition concerning the availability of drugs on remote islands, we conducted a survey on the “availability of drugs” involving member pharmacies of the Nagasaki Pharmaceutical Association.In the survey, we collected and analyzed cases whereby a prescription drug could not be supplied to the patient on the day of prescription. In over 70% of cases, we received answers stating that they “had patients wait for a few days”. Among them, cases in which drugs were supplied within two days amounted to 80%, while there were also cases requiring seven or more days to supply the drug, making up approximately 3%. On remote islands, especially those without wholesalers, the supply is dependent on boatlift. The problem could be partly due to the present distribution system. Furthermore, since the generic drugs amounted to 78% of the cases whereby the drug could not be obtained within a day on remote islands, there were cases of failure to supply drugs, such as antineoplastic, antibiotic, and antitubercular agents. It is necessary to request the administration to increase the number of vessels in service between the mainland and remote islands, as well as to establish a more stable and prompt pharmaceutical supply system on remote islands.
    01/2012; 38(10):656-663. DOI:10.5649/jjphcs.38.656
  • 01/2012; 38(7):449-460. DOI:10.5649/jjphcs.38.449
  • [Show abstract] [Hide abstract]
    ABSTRACT: The objectives were to investigate the ability of population-based in vitro-in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus. A population-based pharmacokinetic simulator (Simcyp) was used to simulate tacrolimus clearance from in vitro metabolism data and demographic characteristics of Japanese liver transplant patients (JLTs). The relationship between haematocrit and dose-to-concentration (D/C) ratio was validated using seven JLTs, whose highly variable haematocrit and D/C ratio were previously analysed. This validation was used as a surrogate for establishing 'interindividual' variability and to assess the power of clinical studies to discern the effect of haematocrit, sex and CYP3A5 genotype on tacrolimus clearance in a virtual JLT population. The relationship between haematocrit and D/C ratio was reproducible by Simcyp and corresponded well to those observed in seven JLTs. The number of JLTs required to detect the influence of CYP3A5 genotype and sex were estimated to be about 50 and > 600, respectively, which was consistent with the results of previous population pharmacokinetic studies for tacrolimus. In conclusion, population-based IVIVE is considered to be a useful approach to assess the influence of covariates a priori before conducting clinical studies. This is also helpful with study design and assessment of the statistical power of clinical studies involving population-based pharmacokinetics to detect the effects of covariates.
    Biopharmaceutics & Drug Disposition 12/2011; 32(9):498-506. DOI:10.1002/bdd.777 · 2.18 Impact Factor
  • K Awa, H Satoh, S Hori, Y Sawada
    [Show abstract] [Hide abstract]
    ABSTRACT: Low-dose aspirin is widely used for prevention of thrombosis, but combined use of aspirin with non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, reduces the antiplatelet effect of aspirin. However, there has been no report describing the effects of the timing of the ibuprofen dose on the degree of interaction between low-dose aspirin and ibuprofen. The purpose of this study was to predict the time-course of the antiplatelet effect of low-dose aspirin when ibuprofen is administered as a single dose or repeatedly in combination with aspirin at various time intervals. We simulated ex vivo platelet aggregation using a previously developed pharmacokinetic (PK)/pharmacodynamic (PD) model. The antiplatelet effect of low-dose aspirin (81 mg) was predicted to be markedly reduced when ibuprofen (200 mg; the usual prescribed dose in Japan) was administered 1 h or less after aspirin, but not when it was administered more than 2 h after the administration of aspirin. Moreover, the administration of ibuprofen up to 12 h before aspirin completely abrogated the antiplatelet effect of aspirin. When ibuprofen (200 mg) was administered three times daily for 3 days (day 1 to day 3) on a background of continuous low-dose aspirin (81 mg) once daily, 2 h after aspirin, no reduction in the antiplatelet effect of aspirin was predicted on day 1, but a reduction is predicted from day 2, with no return to the initial level until more than 3 days after discontinuation of ibuprofen. A marked reduction in the antiplatelet effect of aspirin was also seen on the same schedule when the dosage of ibuprofen was 150 mg, which is the dose used in over-the-counter (OTC) preparations. This study indicates that the antiplatelet effect of low-dose aspirin can be markedly reduced with combined use of ibuprofen, depending on the timing of co-administration. As even the lower OTC dose of ibuprofen (150 mg) was enough to affect the antiplatelet effect of aspirin, health professionals should take into account patients' use of OTC ibuprofen when prescribing low-dose aspirin.
    Journal of Clinical Pharmacy and Therapeutics 11/2011; 37(4):469-74. DOI:10.1111/j.1365-2710.2011.01313.x · 1.53 Impact Factor

Publication Stats

6k Citations
901.25 Total Impact Points

Institutions

  • 1981–2014
    • The University of Tokyo
      • • Department of Pharmaceutical Sciences
      • • Graduate School of Interdisciplinary Information Studies
      • • Department of Pharmacy
      • • Department of Pharmaceutics
      白山, Tōkyō, Japan
  • 1996–2011
    • Kyushu University
      • • Faculty of Pharmaceutical Sciences
      • • Graduate School of Pharmaceutical Sciences
      Fukuoka-shi, Fukuoka-ken, Japan
  • 2008
    • Kyoto Pharmaceutical University
      Kioto, Kyōto, Japan
  • 2001–2007
    • Fukuoka University
      Hukuoka, Fukuoka, Japan
  • 2006
    • Astellas Pharmaceutical
      • Drug Metabolism Research Laboratories
      Northbrook, Illinois, Japan
  • 2005–2006
    • Fujita Health University
      • Department of Psychiatry
      Nagoya, Aichi, Japan
    • Shirasagi Hospital
      Ōsaka, Ōsaka, Japan
  • 2003
    • Tottori University
      TTJ, Tottori, Japan
  • 2002
    • Fukuoka Dental College
      • Department of Physiological Science and Molecular Biology
      Hukuoka, Fukuoka, Japan
    • Okinawa Chubu Hospital
      Okinawa, Okinawa, Japan
  • 1991–2001
    • Tokyo Medical University
      • Division of Pharmacy
      Edo, Tōkyō, Japan
  • 1993
    • Hokkaido University
      • Faculty of Pharmaceutical Sciences
      Sapporo-shi, Hokkaido, Japan