Details of a Researcher

Yuki Yanagisawa, Satoshi Watabe, Sakura Yokoyama, Kyoko Sayama, Hayato Kizaki, Masami Tsuchiya, Shungo Imai, Mitsuhiro Someya, Ryoo Taniguchi, Shuntaro Yada, Eiji Aramaki, Satoko Hori

JMIR cancer 11 e69663 2025.03

Research paper (scientific journal), Joint Work, Accepted

Improving Systematic Review Updates with Natural Language Processing: A Study on Screening Model Efficiency Through Component Classification and Selection

Tatsuki Hasegawa, Hayato Kizaki, Keisho Ikegami, Shungo Imai, Yuki Yanagisawa, Shuntaro Yada, Eiji Aramaki, Satoko Hori

JMIR Med Inform 13 e65371 2025.03

Research paper (scientific journal), Accepted

Natural language processing of electronic medical records identifies cardioprotective agents for anthracycline induced cardiotoxicity.

Yoshimasa Kawazoe, Masami Tsuchiya, Kiminori Shimamoto, Tomohisa Seki, Emiko Shinohara, Shuntaro Yada, Shoko Wakamiya, Shungo Imai, Eiji Aramaki, Satoko Hori

Sci Rep 15 ( 1 ) 6678 - 6678 2025.02

Research paper (scientific journal), Accepted

Actual use of budesonide enteric-coated capsules for Crohn's disease in Japan: analysis of health insurance big data

Keiji Yagisawa, Atsuhito Kubota, Shungo Imai, Shunsuke Nashimoto, Yuki Sato, Hitoshi Kashiwagi, Atsuo Maemoto, Mitsuru Sugawara, Yoh Takekuma

Biological & pharmaceutical bulletin 48 ( 1 ) 33 - 38 2025.01

Research paper (scientific journal), Joint Work, Accepted

Vertebral artery dissection in a patient with migraine treated with calcitonin gene-related peptide monoclonal antibody: a case report and FAERS database analysis

Daiki Tokuyasu, Shungo Imai, Shin-Pin Chen, Keiko Ihara, Narumi Watanabe, Yoshikane Izawa, Jin Nakahara, Satoko Hori, Tsubasa Takizawa

BMC Neurology 25 ( 1 ) 1 2025.01

Research paper (scientific journal), Joint Work, Accepted

ソーシャルメディアにおける過量服薬（オーバードーズ）に関連する発信の解析

佐藤隆哉，土屋雅美，市山凜太郎，久村颯海，渡部哲，柳澤友希，西山智弘，矢田竣太郎，荒牧英治，木﨑速人，今井俊吾，堀　里子

薬学雑誌 144 ( 12 ) 1125 - 1135 2025.01

Research paper (scientific journal), Joint Work, Accepted

Association between mineralocorticoid receptor antagonists and kidney harm: A systematic review and meta-analysis of randomized controlled trials

Satoru Mitsuboshi, Makoto Morizumi, Shungo Imai, Satoko Hori, Kazumasa Kotake

Pharmacotherapy 45 ( 1 ) 43 - 53 2025.01

Research paper (scientific journal), Joint Work, Accepted

病院における医薬品関連のインシデントレポート分析の現状と課題に関する全国調査

江原沙也加, 柳澤友希, 木﨑速人, 今井俊吾, 安室修, 舟越亮寛, 堀里子

医療薬学 51 ( 1 ) 10 - 19 2025.01

Research paper (scientific journal), Joint Work, Accepted

Validity and Utility of a Risk Prediction Model for Wound Infection After Lower Third Molar Surgery in Oral Diseases has the following publication status

Akira Yamagami, Katsuya Narumi, Yoshitaka Saito, Ayako Furugen, Shungo Imai, Keisuke Okamoto, Yoshimasa Kitagawa, Yoichi Ohiro, Ryo Takagi, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi

Oral Diseases in press 2025.01

Research paper (scientific journal), Joint Work, Accepted

Factors Affecting Delayed Recovery From Neutropenia In Patients With Pancreatic Cancer Receiving Gemcitabine Plus Nab-Paclitaxel

Naoko Yoshida, Shungo Imai, Kazuyoshi Kawakami, Takashi Yokokawa, Masashi Nakamura, Takeshi Aoyama, Hisanori Shimizu, Ryoichi Naito, Minori Teramae, Masami Tsuchiya, Hayato Kizaki, Masato Ozaka, Naoki Sasahira, Masakazu Yamaguchi, Satoko Hori

Journal of Cancer 16 ( 5 ) 1413 - 1419 2025.01

Research paper (scientific journal), Joint Work, Accepted

Real-world Efficacy of Erenumab on Migraine-associated Symptoms and Patient-reported Satisfaction Levels: A Retrospective Study in Japan

Keiko Ihara, Nobuyuki Takahashi, Seiya Ohtani, Narumi Watanabe, Kei Ishizuchi, Ryo Takemura, Daiki Tokuyasu, Koji Sekiguchi, Naoki Miyazaki, Shungo Imai, Satoko Hori, Jin Nakahara, Tsubasa Takizawa

Internal Medicine 64 ( 6 ) 825 - 831 2025

Research paper (scientific journal), Joint Work, Accepted

薬名類似に起因する薬剤誤処方の傾向分析 ‐薬剤師による誤調剤事例との比較‐

森部詩月，今井俊吾，佐山杏子，上村忠聖，林　誠一，木﨑速人，堀　里子

医薬品情報学 26 ( 4 ) 178 - 185 2025

Research paper (scientific journal), Joint Work, Accepted

診療情報データベースを用いた非小細胞肺がん患者に対するペメトレキセド含有化学療法における血液毒性へのメトホルミン併用の影響評価

早船真弘, 今井俊吾, 木﨑速人, 土屋雅美, 堀里子

薬学雑誌 145 ( 1 ) 61 - 70 2025

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

Identifying the Relative Importance of Factors Influencing Medication Compliance in General Patients Using Regularized Logistic Regression and LightGBM: Web-Based Survey Analysis.

Haru Iino, Hayato Kizaki, Shungo Imai, Satoko Hori

JMIR formative research 8 e65882 2024.12

Research paper (scientific journal), Accepted

Exploration of factors affecting denosumab-induced hypocalcemia in male patients with osteoporosis using a hospital-based administrative claims database

Yuto Kamimura, Keisuke Ikegami, Hayato Kizaki, Shungo Imai, Satoko Hori

Maturitas 193 108190 2024.12

Research paper (scientific journal), Joint Work, Accepted

Exploring the factors associated with difficulties in extracting tablets or capsules from press-through-package sheets

Masami Tsuchiya, Shungo Imai, Masaki Asano, Yuri Shimizu, Hayato Kizaki, Yukiko Ito, Makoto Tsuchiya, Ryoko Kuriyama, Nao Yoshida, Masanori Shimada, Takanori Sando, Tomo Ishijima, Satoko Hori

British journal of clinical pharmacology 91 ( 2 ) 479 - 484 2024.11

Research paper (scientific journal), Joint Work, Accepted

Medication Management Initiatives Using Wearable Devices: Scoping Review

Haru Iino, Hayato Kizaki, Shungo Imai, Satoko Hori

JMIR human factors 11 e57652 2024.11

Research paper (scientific journal), Joint Work, Accepted

Post-marketing surveillance of anticancer drugs using natural language processing of electronic medical records

Yoshimasa Kawazoe, Kiminori Shimamoto, Tomohisa Seki, Masami Tsuchiya, Emiko Shinohara, Shuntaro Yada, Shoko Wakamiya, Shungo Imai, Satoko Hori, Eiji Aramaki

npj Digital Medicine 7 ( 1 ) 315 2024.11

Research paper (scientific journal), Joint Work, Accepted

Development and validation of the prediction score for augmented renal clearance in critically Ill Japanese adults

Ryusei Mikami, Shungo Imai, Mineji Hayakawa, Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Mitsuru Sugawara, Yoh Takekuma

Journal of pharmaceutical health care and sciences 10 ( 1 ) 69 2024.11

Research paper (scientific journal), Joint Work, Accepted

Data-Driven Clinical Pharmacy Research: Utilizing Machine Learning and Medical Big Data

Shungo Imai

Biological & pharmaceutical bulletin 47 ( 10 ) 1594 - 1599 2024.10

Research paper (scientific journal), Single Work, Lead author, Corresponding author, Accepted

Association between gastroprotective agents and acute kidney injury in patients receiving non-steroidal anti-inflammatory drugs: Analysis of a Japanese hospital-based database

Satoru Mitsuboshi, Shungo Imai, Hayato Kizaki, Satoko Hori

Pharmacotherapy 44 ( 11 ) 851 - 860 2024.10

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

Utility analysis and demonstration of real-world clinical texts: A case study on Japanese cancer-related EHRs

Shuntaro Yada, Tomohiro Nishiyama, Shoko Wakamiya, Yoshimasa Kawazoe, Shungo Imai, Satoko Hori, Eiji Aramaki

PLoS ONE 19 ( 9 ) e0310432 2024.09

Research paper (scientific journal), Joint Work, Accepted

Development of a risk prediction model for surgical site infection after lower third molar surgery

Akira Yamagami, Katsuya Narumi, Yoshitaka Saito, Ayako Furugen, Shungo Imai, Yoshimasa Kitagawa, Yoichi Ohiro, Ryo Takagi, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi

Oral Diseases 30 ( 5 ) 3202 - 3211 2024.07

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Construction of a Multi-label Classifier for Extracting Multiple Incident Factors from Medication Incident Reports in Residential Care Facilities Using Natural Language Processing

Hayato Kizaki, Hiroki Satoh, Sayaka Ebara, Satoshi Watabe, Yasufumi Sawada, Shungo Imai, Satoko Hori

JMIR medical informatics 12 e58141 2024.07

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

External Validation and Update of the Risk Prediction Model for Denosumab-Induced Hypocalcemia Developed from a Hospital-Based Administrative Database

Keisuke Ikegami, Shungo Imai, Osamu Yasumuro, Masami Tsuchiya, Naomi Henmi, Mariko Suzuki, Katsuhisa Hayashi, Chisato Miura, Haruna Abe, Hayato Kizaki, Ryohkan Funakoshi, Yasunori Sato, Satoko Hori

JCO Clinical Cancer Informatics 8 e2400078 2024.07

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Concomitant use of lansoprazole and ceftriaxone is associated with an increased risk of ventricular arrhythmias and cardiac arrest in a large Japanese hospital database

Satoru Mitsuboshi, Shungo Imai, Hayato Kizaki, Satoko Hori

(Journal of Infection) 89 ( 2 ) 106202 2024.06

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

Access to Document (DOI)

病院における造影剤による即時型アレルギー対策の現状と課題：病院薬剤部門を対象とした質問紙調査

鈴木信也，木﨑速人，上村忠聖，男全昭紀，今井俊吾，堀　里子

医薬品情報学 26 ( 1 ) 19 - 27 2024.05

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Factor Analysis of Patients Who Find Tablets or Capsules Difficult to Swallow Due to Their Large Size: Using the Personal Health Record Infrastructure of Electronic Medication Notebooks

Masaki Asano, Shungo Imai, Yuri Shimizu, Hayato kizaki, Yukiko Ito, Makoto Tsuchiya, Ryoko Kuriyama, Nao Yoshida, Masanori Shimada, Takanori Sando, Tomo Ishijima, Satoko Hori

J Med Internet Res 26 e54645 2024.04

Research paper (scientific journal), Accepted

Access to Document (DOI)

A cross-sectional survey of hepatitis B virus screening in patients who received immunosuppressive therapy for rheumatoid arthritis in Japan

Yuki Yanagisawa, Shungo Imai, Hayato Kizaki, Satoko Hori

J Pharm Health Care Sci 10 18 2024.04

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

Adverse Event Signal Detection Using Patients' Concerns in Pharmaceutical Care Records: Evaluation of Deep Learning Models

Satoshi Nishioka, Satoshi Watabe, Yuki Yanagisawa, Kyoko Sayama, Hayato Kizaki, Shungo Imai, Mitsuhiro Someya, Ryoo Taniguchi, Shuntaro Yada, Eiji Aramaki, Satoko Hori

J Med Internet Res 26 e55794 2024.04

Research paper (scientific journal), Joint Work, Accepted

Serious bacterial infections associated with eculizumab: A pharmacovigilance study

Shohei Okusa, Tsubasa Takizawa, Shungo Imai, Munenori Oyama, Kei Ishizuchi, Jin Nakahara, Satoko Hori, Shigeaki Suzuki

Internal Medicine 63 ( 8 ) 1061 - 1066 2024.04

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Immunoregulatory Effects of Elemental Diet and Its Ingredient, Tryptophan, via Activation of the Aryl Hydrocarbon Receptor in Mice

Atsuhito Kubota, Shungo Imai, Ryoichi Aoyagi, Wataru Murase, Masaru Terasaki, Mitsuru Sugawara, Yoh Takekuma, Hiroyuki Kojima

Int J Mol Sci 25 ( 6 ) 3448 2024.03

Research paper (scientific journal), Joint Work, Accepted

Platelets affect the activity of amino acid transporter SNAT4 in HuH-7 human hepatoma cells

Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Shungo Imai, Yoh Takekuma, Mitsuru Sugawara

(Biol pharm bull) 47 ( 3 ) 652 - 659 2024.03

Research paper (scientific journal), Joint Work, Accepted

Evaluation of Patient Outcomes after Pharmacological Intervention in Home Health Care Utilizing Pharmaceutical Care Records

Yuki Yanagisawa, Yuki Yokokawa, Hayato Kizaki, Kyoko Sayama, Sakura Yokoyama , Tsuyoshi Sasaki, Mitsuhiro Someya, Ryoo Taniguchi, Shungo Imai, Satoko Hori

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 144 ( 8 ) 839 - 845 2024

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

マスメディアの「医薬品」に関する報道が患者に及ぼす影響―インターネットパネルと保険薬局の来局者を対象としたアンケート調査―

今井俊吾，小野貴登，阿部真也，松井洸，卯田健太，佐山杏子，木﨑速人，山口　浩，野村和彦，堀　里子

医療薬学 50 ( 7 ) 319 - 327 2024

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted

Comparison of the incidence of nausea and vomiting between linezolid and vancomycin using a claims database: a retrospective cohort study

Takezo Tsutsumi, Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma

International Journal of Clinical Pharmacy 46 ( 2 ) 421 - 428 2023.12

Research paper (scientific journal), Joint Work, Accepted

Effects of body composition on renal function estimates in older patients

Soyoko Kaburaki, Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma

Biological and Pharmaceutical Bulletin 46 ( 11 ) 1609 - 1618 2023.11

Research paper (scientific journal), Joint Work, Accepted

Influence of voiced and semi-voiced sounds on the subjective similarity of different drug names: A cognitive psychological experiment

Kodai Yoshikawa, Hayato Kizaki, Shungo Imai, Satoko Hori

Biological and Pharmaceutical Bulletin 46 ( 11 ) 1630 - 1634 2023.11

Research paper (scientific journal), Accepted

Comparison of different sustained-release opioids and acute respiratory conditions in patients with cancer and chronic kidney disease

Satoru Mitsuboshi, Shungo Imai, Hayato Kizaki, Satoko Hori

Pharmacotherapy 44 ( 2 ) 122 - 130 2023.11

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

A survey of the status of methadone switching in Japan using a hospital-based administrative claims database

Shungo Imai, Natsumi Aoki, Keisuke Ikegami, Hayato Kizaki, Satoko Hori

The Journal of Clinical Pharmacology 64 ( 2 ) 189 - 195 2023.09

Research paper (scientific journal), Lead author, Accepted

Access to Document (DOI)

Risk factor analysis of vancomycin-induced nephrotoxicity in paediatric patients aged 0 - 1 year using Japanese medical database

Takayuki Miyai, Yoh Takekuma, Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Mitsuru Sugawara, Shungo Imai

Biological & pharmaceutical bulletin 46 ( 6 ) 817 - 823 2023.06

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

Access to Document (DOI)

A Novel Approach to Analyze the Factors Affecting Adverse Drug Reactions by Combination of Electronic Medical Record Database and Machine Learning Method

Shungo Imai

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 143 ( 6 ) 485 - 489 2023.06

Research paper (conference, symposium, etc.), Single Work, Lead author, Last author, Corresponding author

Access to Document (DOI)

Detection of vaccine adverse events before package insert revisions using a Japanese spontaneous reporting system

Shimon Suzuki, Shungo Imai, Satoru Mitsuboshi, Hayato Kizaki, Masayuki Hashiguchi, Satoko Hori

The Journal of Clinical Pharmacology 63 ( 8 ) 903 - 908 2023.05

Research paper (scientific journal), Joint Work, Corresponding author, Accepted

Exploring factors affecting the occurrence of hypersensitivity reactions induced by nonionic iodine contrast media

Ryouichi Chatani, Sakura Kondo, Tadamasa Kamimura, Shinya Suzuki, Eriko Komatsubara, Seiichi Hayashi, Masayuki Hashiguchi, Hayato Kizaki, Shungo Imai, Satoko Hori

The Journal of Clinical Pharmacology 63 ( 9 ) 1002 - 1008 2023.04

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Onset timing and duration of augmented renal clearance in a mixed intensive care unit

Ryusei Mikami, Mineji Hayakawa, Shungo Imai, Mitsuru Sugawara, Yoh Takekuma

Journal of Intensive Care 11 ( 1 ) 13 - 13 2023.03

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Dysautonomia associated with immune checkpoint inhibitors

Toshiki Tezuka, Shinichi Okuzumi, Chiho Nakajima, Toshihiro Ide, Shungo Imai, Satoru Mitsuboshi, Yuki Kuwahara, Tsubasa Takizawa, Morinobu Seki, Naoto Minematsu, Naoko Aragane, Jin Nakahara, Satoko Hori, Shunya Nakane, Shigeaki Suzuki

Journal of Neurology 270 ( 7 ) 3413 - 3423 2023.03

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Usefulness of the Albumin–Bilirubin Score in Determining the Initial Dose of Voriconazole for Patients with Liver Cirrhosis

Shunsuke Nashimoto, Shungo Imai, Mitsuru Sugawara, Yoh Takekuma

Biological and Pharmaceutical Bulletin 46 ( 2 ) 230 - 236 2023.02

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Increased risk of Lambert-Eaton myasthenic syndrome (LEMS) in small cell lung cancer patients treated with immune checkpoint inhibitor

Shungo Imai, Satoru Mitsuboshi, Satoko Hori, Shigeaki Suzuki

European Journal of Cancer 180 1 - 3 2023.02

Research paper (scientific journal), Joint Work, Lead author, Accepted

Use of Japanese big data from electronic medical records to investigate risk factors and identify their high-risk combinations for linezolid-induced thrombocytopenia

Yuki Inoue, Yoh Takekuma, Takayuki Miyai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Shungo Imai

European journal of clinical pharmacology 79 ( 3 ) 415 - 425 2023.01

Research paper (scientific journal), Joint Work, Last author, Corresponding author, Accepted

Prediction and Implications of Edoxaban-Associated Bleeding in Patients after Critical Illness

Ryusei Mikami, Mineji Hayakawa, Shungo Imai, Kunihiko Maekawa, Kojiro Yamazaki, Mitsuru Sugawara, Yoh Takekuma

Journal of Clinical Medicine 12 ( 3 ) 860 2023.01

Research paper (scientific journal), Accepted

病院における造影剤副作用マネジメントと薬剤部門の関わり方に関する実態調査

近藤咲良，鈴木信也，上村忠聖，木﨑速人，今井俊吾，堀　里子

医薬品情報学 25 ( 1 ) 31 - 37 2023.01

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

薬局におけるリフィル処方箋への対応に関する実態と薬剤師の意識 – 横断的質問紙調査 –

平田彩乃，木﨑速人，矢野良太郎，山村真一，吉岡ゆうこ，鈴木順子，今井俊吾，堀　里子

医薬品情報学 25 ( 1 ) 1 - 11 2023.01

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Investigation of Prescription Status and Exploration of Risk Factors Related to Denosumab-Induced Hypocalcemia in Combination Therapy with 1α,25-Dihydroxy-vitamin D3.

Keisuke Ikegami, Megumi Saito, Shungo Imai, Hayato Kizaki, Osamu Yasumuro, Ryohkan Funakoshi, Satoko Hori

Biological and Pharmaceutical Bulletin 46 ( 1 ) 95 - 101 2023.01

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Hepatic drug metabolism in older people with body composition changes.

Soyoko Kaburaki, Eri Yoshimura, Yasushi Miyamoto, Shungo Imai, Hitoshi Kashiwagi, Hidefumi Ueno, Mitsuru Sugawara, Yoh Takekuma

Geriatrics & gerontology international (Wiley) 22 ( 5 ) 449 - 454 2022.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 1444-1586

AIM: Dosage adjustment is essential in older individuals because they are prone to experience a decline in liver function and changes in body composition. However, quantitative tests or equations for evaluating the activity of hepatic drug metabolism have not yet been clearly established. We examined hepatic drug metabolism activities in older individuals, focusing on changes in body composition parameters. METHODS: Lansoprazole and nifedipine, substrates of the metabolic enzymes cytochrome P450 (CYP) 2C19 and 3A4, respectively, were selected to study hepatic drug metabolism. Residual samples from blood test for older patients were evaluated to determine drug metabolism. The body composition of relevant patients was determined by analyzing characteristic parameters of skeletal muscle mass index (SMI), handgrip strength (HGS) and hepatic steatosis index (HSI). The differences in hepatic drug metabolism were studied statistically among categories in terms of the cut-off value of these parameters. RESULTS: Older male patients receiving lansoprazole and nifedipine in the low SMI (<7.0 kg/m2 ) category showed an 85-90% reduction in respective CYP2C19 and CYP3A4 metabolic activities compared with the normal SMI category. For the female patients, CYP2C19 and CYP3A4 metabolic activities showed no significant correlation with SMI and HGS. Fatty liver disease (HSI ≥36) was found to reduce CYP2C19 metabolic activity particularly in older female patients. CONCLUSIONS: Low CYP2C19 metabolic activity was statistically correlated with low SMI in male patients and high HSI in female patients, whereas low CYP3A4 metabolic activity was statistically correlated with low HGS in male patients.

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Using Japanese big data to investigate novel factors and their high-risk combinations that affect vancomycin-induced nephrotoxicity.

Shungo Imai, Shota Kadomura, Takayuki Miyai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma

British journal of clinical pharmacology 88 ( 7 ) 3241 - 3255 2022.02

Research paper (scientific journal), Lead author, Corresponding author, Accepted

AIMS: Several factors related to vancomycin-induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high-risk combinations that influence VIN. METHODS: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine ≥0.5 mg/dL or 1.5-fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. RESULTS: Of the 7,306 patients that were enrolled, VIN occurred in 14.2% of them (1,035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio; 0.701, 95% confidence interval; 0.512-0.959), ward pharmacy service (0.741, 0.638-0.861), duration of VCM <7 days (0.748, 0.623-0.899) and trough concentrations 10-15 mg/L (0.668, 0.556-0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin-tazobactam use (2.056, 1.754-2.409) and piperacillin use (2.868, 1.298-6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations ≥20 mg/L and concomitant piperacillin-tazobactam use was associated with the highest risk. CONCLUSIONS: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin-tazobactam but also piperacillin may increase the risk.

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Investigation of the risk factors of vomiting during linezolid therapy: a retrospective observational study.

Takezo Tsutsumi, Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma

European journal of clinical pharmacology (Springer Science and Business Media LLC) 78 ( 2 ) 279 - 286 2022.02

Research paper (scientific journal), Accepted, ISSN 0031-6970

PURPOSE: Some clinical studies have reported the occurrence of nausea and vomiting with linezolid (LZD) administration. However, no studies have evaluated nausea and vomiting as primary endpoints. In a previous study, we noted a possible relationship between LZD and vomiting, but risk factors were not identified. Therefore, the aim of the present study was to identify them. METHODS: Patients who received LZD 600 mg twice daily at Hokkaido University Hospital from September 2008 to April 2019 were enrolled in this retrospective observational study. Patient characteristics, concomitant medications, laboratory data, and the occurrence of vomiting were obtained from electronic medical records. Logistic regression analysis was performed to identify risk factors for vomiting, including age, sex, body weight, concomitant medications, and surgeries. RESULTS: A total of 496 patients were included in this study, of which 90 experienced vomiting. By multivariate logistic regression analysis, female sex (adjusted odds ratio [aOR], 2.69; 95% confidence interval [CI], 1.62-4.47), ≥ 10 days of LZD administration (aOR, 2.57; CI, 1.46-4.50), and hyponatraemia (aOR, 2.96; CI, 1.72-5.10) were identified as independent risk factors for vomiting; administration of serotonergic agents (aOR, 0.23; CI, 0.07-0.82) was negatively associated. CONCLUSIONS: This study is the first to successfully identify risk factors for LZD-induced vomiting. Careful monitoring of patients with these risk factors may lead to safer and sustainable LZD administration.

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Clinical applicability of urinary creatinine clearance for determining the initial dose of vancomycin in critically ill patients.

Ryusei Mikami, Shungo Imai, Mineji Hayakawa, Mitsuru Sugawara, Yoh Takekuma

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 ( 2 ) 199 - 205 2022.02

Research paper (scientific journal), Accepted

INTRODUCTION: The purpose of this study was to evaluate the clinical applicability of urinary creatinine clearance (CrCl) for determining the initial dose of vancomycin (VCM) in critically ill patients and to assess VCM trough plasma concentration/maintenance daily dose (C/D) ratio in patients with augmented renal clearance (ARC). METHODS: As the primary outcome measure, correlations between estimated renal function and the VCM C/D ratio were compared using the following formulas: CrCl, Cockcroft-Gault equation (eCrClC-G) and KineticGFR equation (KeGFR). Patients were divided into those with or without changes in renal function. The patients were further classified based on the presence or absence of ARC. The secondary outcome was the comparison of VCM C/D ratio between ARC and Non-ARC patients. RESULTS: A total of 65 patients were enrolled for analysis. In all groups, CrCl tended to correlate better with the VCM C/D ratio than eCrClC-G and KeGFR. A significantly lower VCM C/D ratio was observed in patients with persistent ARC than in the Non-ARC group (0.24 versus 0.52 kg/L). CONCLUSIONS: The clinical applicability of CrCl for the initial dosing design of VCM in critically ill patients was shown. Furthermore, the results indicated that patients with persistent ARC required a higher VCM dose than Non-ARC patients. Although our findings are limited, they have a value for further verification.

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Prescription and Therapeutic Drug Monitoring Status of Valproic Acid among Patients Receiving Carbapenem Antibiotics: A Preliminary Survey Using a Japanese Claims Database

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Annals of Clinical Epidemiology (Society for Clinical Epidemiology) 4 ( 1 ) 6 - 10 2022.01

Research paper (scientific journal), Lead author, Accepted

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Survey targeting community pharmacists regarding consultation requests from patients owing to media reports on “dangers of drugs”

Shungo Imai, Shinya Abe, Hikaru Matsui, Hitoshi Kashiwagi, Yuki Sato, Yoh Takekuma, Shouko Yoshimachi, Mitsuru Sugawara

Japanese Journal of Drug Informatics 24 ( 2 ) 75 - 87 2022

Research paper (scientific journal), Lead author, Corresponding author, Accepted

Organizing information on “dangerous drugs” published in weekly magazines and evaluating its relevance

Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Yoh Takekuma, Mitsuru Sugawara

Japanese Journal of Drug Informatics 24 ( 1 ) 1 - 10 2022

Research paper (scientific journal), Lead author, Corresponding author, Accepted

Clinical Research Using the Large Health Insurance Claims Database

Yoh Takekuma, Shungo Imai, Mitsuru Sugawara

YAKUGAKU ZASSHI (Pharmaceutical Society of Japan) 142 ( 4 ) 331 - 336 2022

Research paper (other academic), ISSN 0031-6903

The JMDC Claims Database® contains completely anonymized receipt information on the insured members of health insurance associations. The number of registered users is approximately 9.6 million (6% of the population) as of May 2020. In this database, it is possible to track even outpatient treatment, even if the patient changes the medical facility, as long as the insurer of the subscriber's health insurance does not change, so that long-term medical treatment could be targeted as a research theme. However, as the data do not contain medical record information, it is not possible to obtain laboratory values, although it is possible to know whether clinical tests have been performed. For pharmaceutics-related research, the most suitable use of the receipt database like JMDC Claims Database® seems to be the investigation of actual prescriptions. However, the research topics that pharmacists are interested in are probably comparisons of drug effects, drug-drug interactions, or causal analysis of drugs and side effects. However, laboratory data for evaluating drug efficacy is not available in the receipt database, and the accuracy of the disease name in the database becomes problematic when using the disease name as information indicating the occurrence of side effects. In this review, we introduce our studies performed by using JMDC Claims Database® and how to manage the above-described problems. We hope that this study will be helpful to those who are going to engage in research using medical big data.

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Construction of medical interviewing practice using video conferencing software

Ayako Mori, Izumi Kato, Hitoshi Kashiwagi, Shungo Imai, Katsuya Narumi, Yuki Sato, Ayako Furugen, Yuma Yamada, Masaki Kobayashi

YAKUGAKU ZASSHI 142 ( 6 ) 661 - 774 2022

Research paper (scientific journal), Accepted

Efficacy survey of Naldemedine in the Poor-Performance Status Group

Shintaro Kato, Yoshitaka Saito, Hiroko Onoda, Masayoshi Kumai, Shungo Imai, Kenkichi Tsuruga, Yoh Takekuma, Mitsuru Sugawar

YAKUGAKU ZASSHI 142 ( 7 ) 755 - 760 2022

Research paper (scientific journal), Accepted

Evaluation of the strategies to reduce third-generation oral cephalosporins in dentistry at a Japanese academic hospital: An interrupted time series analysis

Akira Yamagami, Katsuya Narumi, Yoshitaka Saito, Ayako Furugen, Shungo Imai, Yoshimasa Kitagawa, Yoichi Ohiro, Ryo Takagi, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi

Journal of Clinical Pharmacy and Therapeutics 47 ( 7 ) 1010 - 1019 2022

Research paper (scientific journal), Accepted

WHAT IS KNOWN AND OBJECTIVE: Third-generation oral cephalosporins, especially cefcapene-pivoxil (CFPN-PI), have been used frequently in the Japanese dental field. In December 2014 and April 2016, the newly published clinical guidelines recommended the use of amoxicillin (AMPC). Thus, it is important to evaluate the impact of these guidelines on the prescription profiles of prophylactic antibiotics, clinical outcomes and cost-effectiveness of antibiotics. METHODS: We conducted a retrospective study to analyse an interrupted time series analysis from April 2013 to March 2020 at the Department of Dentistry of Hokkaido University Hospital. A segmented regression model was used to estimate the changes in the incidence of infectious complications following tooth extraction. Prescribed antibiotic data were evaluated via days of therapy (DOT). Antibiotic costs were calculated in terms of the Japanese yen (JPY). RESULTS AND DISCUSSION: We identified 17,825 eligible patients. The incidence rates of infectious complications (SSI + dry socket) and SSI after tooth extraction were 3.2% and 2.2%, respectively, during the entire period. The extraction of impacted third molars corresponded to 5.0% and 3.4%, respectively. However, their incidence rates were not significantly different during this period. The use of prophylactic antibiotics and antibiotic cost showed consistent trends following the implementation of guidelines. The mean DOT of CFPN-PI decreased (ranging from 4893.6 DOTs/1000 patients [March 2013 to November 2014] to 3856.4 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3856.4 DOTs/1000 patients [December 2014 to March 2016] to 2293.9 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). In contrast, the mean DOT of AMPC was found to be increased (ranging from 1379.7 DOTs/1000 patients [March 2013 to November 2014] to 3236.3 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3236.3 DOTs/1000 patients [December 2014 to March 2016] to 4597.8 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). The mean monthly cost was decreased (ranging from 905.3 JPY [March 2013 to November 2014] to 788.7 JPY [December 2014 to March 2016]; p = 0.003, and from 788.7 JPY [December 2014 to March 2016] to 614.0 JPY [April 2016 to March 2020]; p < 0.001). WHAT IS NEW AND CONCLUSION: After December 2014, prophylactic antibiotics were switched from CFPN-PI to AMPC, and the incidence rate of infectious complications was not significantly different over time. However, changing antibiotics is useful from a cost-effectiveness perspective.

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Development of a method of liquid chromatography coupled with tandem mass spectrometry for simultaneous determination of linezolid and tedizolid in human plasma

Yuki Sato, Yoh Takekuma, Takayuki Daisho, Hitoshi Kashiwagi, Shungo Imai, Mitsuru Sugawara

Biological and Pharmaceutical Bulletin 45 ( 4 ) 421 - 428 2022

Research paper (scientific journal), Accepted

It is important to select appropriate antibiotics for infection control. Linezolid and tedizolid are newly developed and synthesized oxazolidinone antibacterial agents. It has been pointed out that there is a relationship between a high plasma concentration of the target drug and incidence of adverse effects, although it has been reported that neither linezolid nor tedizolid requires dose adjustment according to renal function. Due to the high incidence of adverse effects, both are often switched. Precise plasma concentration control by therapeutic drug monitoring (TDM) is desirable for reducing the adverse effects of both drugs and obtaining a better therapeutic effect. In this study, we aimed to establish a method for simultaneous quantification of linezolid and tedizolid in human plasma using LC coupled with tandem mass spectrometry. Sample preparation was performed by a simple operation with acetonitrile. Linezolid and tedizolid were separated by an octadecylsilyl column using a gradient elution of acetonitrile in aqueous 0.1% formic acid solution and were detected in the positive ion electrospray mode with multiple reaction monitoring. Quantification of linezolid and tedizolid ranged from 0.5 to 50 and 0.5 to 20 µg/mL, respectively. The intra-day and inter-day precision and accuracy of data were assessed and found to be acceptable. The developed method was successfully applied to measurement of the concentrations of linezolid and tedizolid. This simple method, which can simultaneously quantify both drug concentrations for daily TDM, could contribute to safer treatment of patients.

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Machine learning-based model for estimating vancomycin maintenance dose to target the area under the concentration curve of 400-600 mg・h/L in Japanese patients

Takayuki Miyai, Shungo Imai, Eri Yoshimura, Hitoshi Kashiwagi, Yuki Sato, Hidefumi Ueno, Yoh Takekuma, Mitsuru Sugawara

Biological and Pharmaceutical Bulletin 45 ( 9 ) 1332 - 1339 2022

Research paper (scientific journal), Corresponding author, Accepted

Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.

Shota Kadomura, Shungo Imai, Kenji Momo, Yuki Sato, Hitoshi Kashiwagi, Tatsuya Itoh, Mitsuru Sugawara, Yoh Takekuma

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners 10781552211034703 - 10781552211034703 2021.10

Research paper (scientific journal), Accepted

INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

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A cross-sectional survey of hospitalization and blood tests implementation status in patients who received tolvaptan under 75 years of age using a Japanese claims database.

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Expert opinion on drug safety 20 ( 10 ) 1257 - 1266 2021.10

Research paper (scientific journal), Lead author, Accepted

BACKGROUND: Hypernatremia and liver injury are typical adverse effects of tolvaptan. Therefore, hospitalization and frequent monitoring of serum sodium concentration and liver function are necessary for tolvaptan initiation. We performed a cross-sectional survey to evaluate these situations. RESEARCH DESIGN AND METHODS: We employed the Japanese claims database, which contains data of patients aged < 75 years. Patients who were newly prescribed tolvaptan for fluid accumulation induced by chronic heart failure (FA-CHF) or liver cirrhosis (FA-LC) from January 2011 to June 2017 were included. We evaluated the hospitalization status and implementation of serum sodium and liver function tests in the evaluation period, based on the Japanese package insert. RESULTS: Of 1,173 patients, 347 and 117 were enrolled in FA-CHF and FA-LC groups, respectively. Among them, 10.7% (FA-CHF group) and 5.13% (FA-LC group) were prescribed tolvaptan without hospitalization. In the FA-CHF group, 11.0% and 17.6% did not undergo serum sodium and liver function tests even once in the evaluation period, respectively, compared with 12.0% and 12.8% in the FA-LC group. CONCLUSIONS: Our results highlight the deviation from Japanese package insert recommendations. This approach can be applied to other drugs and provides important perspectives on pharmacovigilance research.

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Factors affecting creatine phosphokinase elevation during daptomycin therapy using combination of machine learning and conventional methods.

Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

British journal of clinical pharmacology 88 ( 3 ) 1211 - 1222 2021.08

Research paper (scientific journal), Lead author, Corresponding author, Accepted

AIMS: Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP-induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods. METHODS: A population-based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and > 200 IU/L, and (2) > 1,000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree (DT) analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk. RESULTS: Of the 2,970 patients who received DAP, 706 were included. Elevation of CPK values > 200 IU/L and > 1,000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In DT analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high-risk group. CONCLUSIONS: Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high-risk patients require frequent CPK monitoring.

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Survey Based on Claims Data of New Control-Released Budesonide for Crohn's Disease

Atsuhito Kubota, Shungo Imai, Kenji Momo, Mitsuru Sugawara, Yoh, Takekuma

the journal of community pharmacy and pharmaceutical sciences ((一社)日本薬局学会) 13 ( 1 ) 54 - 61 2021.04

Research paper (scientific journal), Accepted, ISSN 1884-3077

Contribution of pharmaceutical inquiries performed by community pharmacists based on “patient interviews”: Evaluation of current situation and patient safety

Shungo Imai, Masashi Nanba, Hitoshi Kashiwagi, Yuki Sato, Yoh Takekuma, Mitsuru Sugawara

The journal of community pharmacy and pharmaceutical sciences ((一社)日本薬局学会) 13 ( 1 ) 68 - 78 2021.04

Research paper (scientific journal), Lead author, Accepted, ISSN 1884-3077

薬剤師は安全な薬物療法の提供のために,患者から必要な情報を「聞き取る」ことが重要である.しかし,薬局薬剤師の「聞き取り」に対し,一部の一般市民は厳しい視線を投げかけており,患者の理解を促すためのエビデンス構築が急務である.本研究は「患者への聞き取り」に基づき実施された疑義照会に着目し,その実態解明と医療安全への貢献度評価を試みた.解析には北海道大学病院の近隣薬局の疑義照会データを用いた.その結果,聞き取りに基づく疑義照会は「薬学的疑義照会の33.3%を占め,高い許諾割合(98.5%)を有し,用法や用量などの疑義照会分類において,医療安全への貢献度が高い」ことが見いだされた.また,このうち「医師からの説明と処方内容が食い違う」ことが発端となった事例が,特に医療安全へ貢献していることが示された.「患者への聞き取り」に基づく疑義照会の有用性を広く調査するための基礎となる知見が創出された.(著者抄録)

Probiotic prescription status of pediatric patients with otitis media receiving oral amoxicillin or amoxicillin/clavulanate from April 2016 to March 2017 using a Japanese health insurance claims database

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Biological & pharmaceutical bulletin 44 ( 3 ) 448 - 452 2021.03

Research paper (scientific journal), Lead author, Accepted

Antibiotic-associated diarrhea (AAD) is a typical side effect of antibiotic treatment, especially in children. Amoxicillin (AMPC) and amoxicillin/clavulanate (AMPC/CVA) are associated with high risk of AAD; however, these antibiotics are important in the pediatric field. Recent research suggests that probiotics prevent pediatric AAD, including that caused by AMPC and AMPC/CVA. Indeed, guidelines for acute otitis media in children recommend the concomitant use of probiotics. However, the prescription status of probiotics for pediatric patients with otitis media receiving oral AMPC and AMPC/CVA remains unknown. We therefore conducted a survey to clarify the current status of these prescriptions and, in particular, to identify specific populations with a low proportion of probiotic prescriptions. Pediatric patients (≤15 years of age) newly prescribed oral AMPC or AMPC/CVA for otitis media between April 2016 and March 2017 were identified from a Japanese health insurance claims database. Eligible patients were divided into the AMPC (1303 patients) and AMPC/CVA (424 patients) groups, in which 659 (50.6%) and 293 (69.1%) patients were prescribed probiotics, respectively. Of the patients receiving probiotic prescriptions in the AMPC and AMPC/CVA groups, 632 (95.9%) and 286 (97.6%) patients received antibiotic-resistant probiotic prescriptions, respectively. When classified by the prescribing clinical department and patient age, the proportions of probiotic prescriptions in Internal Medicine and Pediatrics departments were lower than those in the Otorhinolaryngology department regardless of age. These results indicate the probability of insufficient probiotic prescriptions for pediatric patients with otitis media. Solving this issue may lead to the provision of safer antimicrobial therapy.

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Implementation status of voriconazole therapeutic drug monitoring: analysis of data from a large Japanese health insurance claims database

Takayuki Miyai, Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma

TDM研究 38 ( 3 ) 39 - 48 2021

Research paper (scientific journal), Accepted

Investigation of the Real-World Situation and Risk Factors Associated with Olanzapine Prescribed to Diabetes Patients by Using a Japanese Claims Database.

Shinsuke Yamashita, Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma

Biological & pharmaceutical bulletin 44 ( 8 ) 1151 - 1155 2021

Research paper (scientific journal), Accepted

Olanzapine is effective for schizophrenia management; however, it is contraindicated in diabetes patients. In addition, olanzapine is useful for treating nausea and vomiting, such as in the case of chemotherapy-induced nausea and vomiting (CINV). Therefore, we hypothesized that the contraindicated prescription of olanzapine likely occurs among cancer patients with diabetes, especially by non-psychiatric physicians. Hence, we conducted a nationwide survey to elucidate the situation of such contraindicated prescriptions and the associated risk factors. We extracted the data of patients who were newly prescribed olanzapine between April 2015 and March 2017 from the health insurance claims database developed by JMDC, Inc., Tokyo. The patients who were prescribed contraindicated olanzapine were defined as those who were prescribed olanzapine after a diagnosis of diabetes and diabetes drug prescription. In all, the data of 7181 patients were analyzed. We evaluated the proportion of diabetes patients who were prescribed contraindicated olanzapine from among those who were prescribed olanzapine. Furthermore, we investigated the background of patients who were prescribed olanzapine for information such as olanzapine prescribers and history of cancer chemotherapy. In all, 100 diabetes patients (1.39%) were prescribed olanzapine. In these patients, the frequency of olanzapine prescription was higher by non-psychiatry/neurology physicians than by psychiatry/neurology physicians (3.25 and 0.85%, respectively). Additionally, all olanzapine prescriptions in cancer chemotherapy-treated diabetes patients were issued by non-psychiatry/neurology physicians. Thus, our study revealed there were diabetes patients who were prescribed olanzapine. Additionally, olanzapine for CINV management was more likely to be a contraindicated prescription.

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Implementation Status of Liver Function Tests for Monitoring Benzbromarone-Induced Hepatotoxicity: An Epidemiological Survey Using the Japanese Claims Database.

Shungo Imai, Yasuyuki Nasuhara, Kenji Momo, Hiromitsu Oki, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Biological & pharmaceutical bulletin 44 ( 10 ) 1499 - 1505 2021

Research paper (scientific journal), Lead author, Accepted

A major adverse effect of benzbromarone is hepatotoxicity. Therefore, periodic liver function tests are required at least for the first 6 months of benzbromarone administration. However, it is not clear whether the relevant blood tests are implemented appropriately. Here, we performed a cross-sectional survey of the implementation status of liver function tests in patients who were newly prescribed benzbromarone, using the Japanese large claims database. Male patients who were newly prescribed benzbromarone from January 2010 to December 2016 were included. We targeted patients who continued benzbromarone during the observation period (up to 180 d from the start of administration). The primary endpoint was the proportion of patients in whom periodic liver function tests were implemented. A periodic liver function test was defined as one or more liver function tests performed during both 1-90 and 91-180 d of initial benzbromarone administration. We labeled the tests as a "periodic test" or "non-periodic test" based on whether periodic liver function tests were performed or not, respectively. Furthermore, factors influencing non-periodic test were analyzed. Periodic testing was implemented only in 28.7% of patients. Additionally, factors such as number of hospital beds ≤19 (compared to 100-199 beds) and duration of the first prescription of benzbromarone were associated with non-periodic testing. Our study revealed that periodic liver function tests are not performed sufficiently in Japan. Thus, clinicians prescribing benzbromarone should be educated about the test. Our blood-test-based approach should be applied to other drugs and countries in future research.

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Construction of a Risk Prediction Model of Extended Release Oxycodone Tablet-Induced Nausea and Clarification of Predictive Factors.

Masayoshi Kumai, Shungo Imai, Shintaro Kato, Ryo Koyanagi, Kenkichi Tsuruga, Takehiro Yamada, Yoh Takekuma, Mitsuru Sugawara

Biological & pharmaceutical bulletin 44 ( 4 ) 593 - 598 2021

Research paper (scientific journal), Accepted

Nausea is a typical adverse event associated with opioids. In this study, we performed logistic regression analysis with the aim of clarifying the risk factors for nausea induced by extended-release oxycodone (ER-OXY). Furthermore, we constructed a decision tree (DT) model, a typical data mining method, to estimate the risk of oxycodone-induced nausea by combining multiple factors. A retrospective study was conducted on patients who newly received ER-OXY for cancer pain during hospitalization at Hokkaido University Hospital in Japan from April 2015 to March 2018. In logistic regression and DT analyses, the dependent variable was the presence or absence of nausea. Independent variables were the potential risk factors. First, univariate analyses were performed to screen potential factors associated with oxycodone-induced nausea. Then, multivariate and DT analyses were performed using factors with p-values <0.1 in the univariate analysis. Of 267 cases included in this study, nausea was observed in 30.3% (81/267). In multivariate logistic regression analysis, only female sex was extracted as an independent factor affecting nausea (odds ratio, 1.98). In the DT analysis, we additionally revealed that an age <50 years was a risk factor for nausea in female patients. Thus, our DT model indicated that the risk of ER-OXY-induced nausea was highest in the subgroup comprising females <50 years of age (66.7%) and lowest in male patients (25.1%). The DT model suggested that the factor of young women may be an increased risk of ER-OXY-induced nausea.

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cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability.

Tsuyoshi Aoyama, Hiroki Kuriyama, Yuki Sato, Shungo Imai, Hitoshi Kashiwagi, Mitsuru Sugawara, Yoh Takekuma

Biological & pharmaceutical bulletin 44 ( 8 ) 1101 - 1110 2021

Research paper (scientific journal), Accepted

Dasatinib is a first-line pharmacotherapeutic treatment for chronic myeloid leukemia (CML). It is more effective than traditional treatments but causes adverse effects such as pleural effusion that limits its effective treatment cycle. Since pleural effusion is caused by vascular hyperpermeability and causes discontinuation of treatment with dasatinib, it is important to explore the mechanism of pleural effusion caused by dasatinib and how to prevent it. In this study, we investigated how dasatinib increase vascular permeability, and how it can be prevented. Cytotoxicity was observed in vascular endothelial cells or epithelial cells were exposed to high concentrations of dasatinib. Thus, it was observed in vascular endothelial cells such as human umbilical vascular endothelial cell (HUVEC). Vascular endothelial (VE)-cadherin is one of the important factors that control vascular permeability. When VE-cadherin expression decreases, vascular permeability increases, but it did not change with tyrosine kinase inhibitor exposure. Monolayer permeability significantly increased only with high concentration of dasatinib, but this increase was prevented by cAMP activation. Furthermore, dasatinib affects the cell morphology of HUVEC, with increased inter celluar space compared to control and bosutinib, which were also attenuated by cAMP activation. Dasatinib significantly affected permeability control of vascular endothelial cells compared to bosutinib and imatinib. These results indicated that the cAMP signaling pathway may be involved in the pleural effusion caused by dasatinib in CML patients.

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A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study

Takayuki Miyai, Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Shota Kadomura, Kenji Yoshida, Eri Yoshimura, Toshiaki Teraya, Takashi Tsujimoto, Yukari Kawamoto, Tatsuya Itoh, Hidefumi Ueno, Yoshikazu Goto, Yoh Takekuma, Mitsuru Sugawara

Antibiotics (MDPI AG) 9 ( 12 ) 920 - 920 2020.12

Research paper (scientific journal), Corresponding author, Accepted

We previously constructed a risk prediction model of vancomycin (VCM)-associated nephrotoxicity for use when performing initial therapeutic drug monitoring (TDM), using decision tree analysis. However, we could not build a model to be used at the time of initial administration due to insufficient sample size. Therefore, we performed a multicenter study at four hospitals in Japan. We investigated patients who received VCM intravenously at a standard dose from the first day until the initial TDM from November 2011 to March 2019. Acute kidney injury (AKI) was defined according to the criteria established by the “Kidney disease: Improving global outcomes” group. We extracted potential risk factors that could be evaluated on the day of initial administration and constructed a flowchart using a chi-squared automatic interaction detection algorithm. Among 843 patients, 115 (13.6%) developed AKI. The flowchart comprised three splitting variables (concomitant drugs (vasopressor drugs and tazobactam/piperacillin) and body mass index ≥ 30) and four subgroups. The incidence rates of AKI ranged from 9.34 to 36.8%, and they were classified as low-, intermediate-, and high-risk groups. The accuracy of flowchart was judged appropriate (86.4%). We successfully constructed a simple flowchart predicting VCM-induced AKI to be used when starting VCM administration.

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Comparison of interactions between warfarin and cephalosporins with and without the N-methyl-thio-tetrazole side chain.

Shungo Imai, Shota Kadomura, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Elsevier BV) 26 ( 11 ) 1224 - 1228 2020.11

Research paper (scientific journal), Lead author, Accepted, ISSN 1341-321X

Cephalosporins with an N-methyl-thio-tetrazole (NMTT) side chain interact with warfarin by reducing the production of blood clotting factors. However, cephalosporins without the NMTT side chain also enhance the effects of warfarin. Thus, we aimed to compare the effects of warfarin modified by cephalosporins with and without the NMTT side chain, using a Japanese health insurance claims database. The inclusion criteria were patients who (1) intravenously received second- or third-generation cephalosporins between April 2010 and March 2017 and (2) received warfarin during cephalosporin therapy. Patients were administered either cephalosporins with the NMTT side chain (NMTT group) or those without NMTT (non-NMTT group). After matching patient data by propensity score, the following outcomes were compared between the two groups: (1) proportion of patients administered vitamin K, (2) proportion of bleeding events, and (3) changes in the daily dose of warfarin. Among 203 patients, 100 patients (50 per group) were matched by the propensity score. The proportion of patients administered vitamin K was 6.0% in both groups. These patients intravenously received a single dose of menatetrenone; no bleeding was observed. The proportion of patients subjected to a reduction in the daily dose of warfarin was 6.5% and 4.3% in the NMTT and non-NMTT groups, respectively. As our study had a small sample size, we could not determine whether the risk of over anticoagulation of warfarin is affected by cephalosporins with or without NMTT side chain. However, we showed the bleeding risk was sufficiently low regardless of the presence/absence of the NMTT side chain.

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A cross-sectional exploratory survey on occurrence of triple-whammy prescription pattern in Japan.

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

International journal of clinical pharmacy (Springer Science and Business Media LLC) 42 ( 5 ) 1369 - 1373 2020.10

Research paper (scientific journal), Lead author, Accepted, ISSN 2210-7703

Background The concurrent use of nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system blockers, and diuretics, known as a "triple-whammy," is related to the occurrence of acute kidney injury. However, there are few reports regarding the prescription pattern of the triple-whammy. Objective To elucidate the patterns of the triple-whammy prescription in Japan. Methods A cross-sectional study was performed using a health-insurance-claims database that included Japanese people under 75 years of age, and enrolled outpatients that were prescribed any nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system blockers, and diuretics between April 2017 and June 2017. As an outcome, the proportion of triple-whammy prescriptions was evaluated. Among the patients who received triple-whammy prescriptions, we evaluated the prevalence of chronic kidney disease and the proportion of prescriptions provided for these three drugs from different clinical departments and institutions. Results Overall, 730 of 246,721 (0.3%) patients received triple-whammy prescriptions. Among these patients, 13.3% had underlying chronic kidney disease. The proportions of any of the three drug types prescribed by different clinical departments and institutions was 48.2% and 61.8%, respectively. Conclusions We examined the patterns of triple-whammy prescriptions and concluded that pharmacists need to pay attention to triple-whammy prescriptions if the prescriptions are provided by multiple clinical departments or institutions.

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Nonsteroidal anti-inflammatory drugs use in patients with chronic kidney disease are often prescribed from different clinicians than those who diagnosed them.

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Pharmacoepidemiology and drug safety 29 ( 8 ) 873 - 880 2020.08

Research paper (scientific journal), Lead author, Accepted

PURPOSE: When prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic kidney disease (CKD), patients' pathology and concomitant medications should be considered. In our pharmaceutical experience, NSAIDs are often prescribed by departments that are different from those that diagnosed CKD. That is, NSAIDs may be prescribed for patients without the advice of the clinicians who diagnosed them. In this study, we aimed to elucidate how frequently such cases occur. METHODS: We used the large health insurance claims database constructed by JMDC Inc., Tokyo. We evaluated the proportions of CKD diagnosis and NSAID prescription by different clinical departments and institutions. RESULTS: A total of 224 014 out-patients were included in the analysis; they were divided into CKD (n = 1501) and non-CKD groups (n = 222 513). The internal medicine departments diagnosed CKD most frequently (74.8% of the patients) and surgical departments rarely diagnosed CKD. However, the proportion of prescribed NSAIDs was high in other departments, especially surgical departments. In the CKD group, 50.4% of the patients received CKD diagnosis and NSAID prescription from different clinical departments; 72.8% of the patients received a diagnosis and prescription from different medical institutions. CONCLUSION: Our study revealed that NSAIDs are often prescribed to patients with CKD from different clinicians than those who diagnosed them.

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Interaction between piperacillin/tazobactam and warfarin: a single-center retrospective single-arm cohort study

Shota Kadomura, Yoh Takekuma, Shungo Imai, Hitoshi Kashiwagi, Kotaro Kawamoto, Tatsuya Itoh, and Mitsuru Sugawara

BPB reports 3 ( 2 ) 65 - 69 2020.02

Research paper (scientific journal), Accepted

A New Algorithm Optimized for Initial Dose Settings of Vancomycin Using Machine Learning.

Shungo Imai, Yoh Takekuma, Takayuki Miyai, Mitsuru Sugawara

Biological & pharmaceutical bulletin 43 ( 1 ) 188 - 193 2020

Research paper (scientific journal), Lead author, Corresponding author, Accepted

This study aimed to construct an optimal algorithm for initial dose settings of vancomycin (VCM) using machine learning (ML) with decision tree (DT) analysis. Patients who were administered intravenous VCM and underwent therapeutic drug monitoring (TDM) at the Hokkaido University Hospital were enrolled. The study period was November 2011 to March 2019. In total, 654 patients were included in the study. Patients were divided into two groups, training (patients who received VCM from November 2011 to December 2017; n = 496) and testing (patients who received VCM from January 2018 to March 2019; n = 158) groups. For the training group, DT analysis of the classification and regression tree algorithm was performed to construct an algorithm (called DT algorithm) for the initial dose settings of VCM. For the testing group, the rates of attaining the VCM therapeutic range (trough value = 10-15 and 10-20 mg/L) with the DT algorithm and three conventional dose-setting methods were compared for model evaluation. The DT algorithm was constructed to be used for patients with estimated glomerular filtration rate ≥50 mL/min and body weight ≥40 kg. As a result, the recommended daily doses ranged from 20.0 to 58.1 mg/kg. In model evaluation, the DT algorithm obtained the highest rates of attaining the VCM therapeutic range compared to conventional dose-setting methods. Therefore, our DT algorithm can be applied to clinical practice. In addition, ML is useful for setting drug doses.

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Validation of the usefulness of artificial neural networks for risk prediction of adverse drug reactions used for individual patients in clinical practice.

Shungo Imai, Yoh Takekuma, Hitoshi Kashiwagi, Takayuki Miyai, Masaki Kobayashi, Ken Iseki, Mitsuru Sugawara

PloS one 15 ( 7 ) e0236789 2020

Research paper (scientific journal), Lead author, Corresponding author, Accepted

Artificial neural networks are the main tools for data mining and were inspired by the human brain and nervous system. Studies have demonstrated their usefulness in medicine. However, no studies have used artificial neural networks for the prediction of adverse drug reactions. We aimed to validate the usefulness of artificial neural networks for the prediction of adverse drug reactions and focused on vancomycin -induced nephrotoxicity. For constructing an artificial neural network, a multilayer perceptron algorithm was employed. A 10-fold cross validation method was adopted for evaluating the resultant artificial neural network. In total, 1141 patients who received vancomycin at Hokkaido University Hospital from November 2011 to February 2019 were enrolled. Among these patients, 179 (15.7%) developed vancomycin -induced nephrotoxicity. The top three risk factors of vancomycin -induced nephrotoxicity which are relatively important in the artificial neural networks were average vancomycin trough concentration ≥ 13.0 mg/L and concomitant use of piperacillin-tazobactam and vasopressor drugs. The predictive accuracy of the artificial neural network was 86.3% and that of the multiple logistic regression model (conventional statistical method) was 85.1%. Moreover, area under the receiver operating characteristic curve (AUROC) of the artificial neural network was 0.83. In the 10-fold cross-validation, the accuracy obtained was 86.0% and AUROC was 0.82. The artificial neural network model predicting the vancomycin -induced nephrotoxicity showed good predictive performance. This appears to be the first report of the usefulness of artificial neural networks for an adverse drug reactions risk prediction model.

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Prescription of Colchicine with Other Dangerous Concomitant Medications: A Nation-Wide Survey Using the Japanese Claims Database.

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Biological & pharmaceutical bulletin 43 ( 10 ) 1519 - 1525 2020

Research paper (scientific journal), Lead author, Accepted

The anti-inflammatory agent colchicine may cause toxic effects such as rhabdomyolysis, pancytopenia, and acute respiratory distress syndrome in cases of overdose and when patients have renal or liver impairment. As colchicine is a substrate for CYP3A4 and P-glycoprotein (P-gp), drug-drug interactions are important factors that cause fatal colchicine-related side effects. Thus, we conducted a nation-wide survey to determine the status of inappropriate colchicine prescriptions in Japan. Patients prescribed the regular use of colchicine from April 2014 to March 2017 were identified using the Japanese large health insurance claims database. As the primary endpoint, we evaluated the concomitant prescription proportions of strong CYP3A4 and/or P-gp inhibitors classified as "contraindications for co-administration" with colchicine in patients with renal or liver impairment. We defined these cases as "inappropriate colchicine prescriptions." Additionally, factors affecting inappropriate colchicine prescriptions were analyzed. Among the 3302 enrolled patients, 43 (1.30%) were inappropriately prescribed colchicine. Of these 43 patients, 11 had baseline renal and/or liver impairment. By multiple regression analysis, the primary diseases "gout" and "Behçet's disease" were extracted as independent factors for inappropriate colchicine prescriptions with odds ratios of 0.40 (95% confidence interval: 0.19-0.84) and 4.93 (95% confidence interval: 2.12-11.5), respectively. We found that approximately 1% of patients had important colchicine interactions. Particularly, Behçet's disease was a risk factor for inappropriate prescriptions, with approximately 25% of patients showing renal and/or liver impairment (classified as "contraindications for co-administration"). These findings may be useful for medical professionals who prescribe colchicine therapy.

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Association of the ward pharmacy service with active implementation of therapeutic drug monitoring for vancomycin and teicoplanin-an epidemiological surveillance study using Japanese large health insurance claims database.

Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma

Journal of pharmaceutical health care and sciences 6 18 - 18 2020

Research paper (scientific journal), Lead author, Accepted

Background: Ward pharmacists are required for the active implementation of therapeutic drug monitoring (TDM). This epidemiological study verified whether Japanese ward pharmacists contribute to improving the TDM implementation proportions of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents using the large health insurance claims database. Methods: The patients who received intravenous anti-MRSA agents from April 2012 to March 2017 were enrolled. We defined ward pharmacy service as the "drug management and guidance fee" and/or "inpatient pharmaceutical services premium". In addition, implementation of TDM was identified by "the specific drug treatment management fee". We compared the proportions of TDM implementation for vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK) in the ward and non-ward pharmacy service groups. To avoid confounding, the propensity score method was employed. Moreover, the clinical variables affecting TDM implementation in each anti-MRSA agent were analyzed by using a multiple logistic regression model. Results: The following number of patients were included in the study: VCM (n = 2138), TEIC (n = 596), and ABK (n = 142). After propensity score matching, the proportions of TDM implementation for VCM and TEIC were higher in the ward pharmacy service group than in the non-ward pharmacy service group (VCM: 69.2% vs 60.3%, TEIC: 51.4% vs 34.7%), while no significant difference was observed for ABK (21.2% vs 23.1%). As independent clinical variables affecting TDM implementation for VCM and TEIC, several clinical variables, including ward pharmacy services, were extracted. In contrast, no clinical variables were extracted for ABK. Conclusions: We found that the ward pharmacy service is associated with the active implementation of TDM for anti-MRSA agents, such as VCM and TEIC.

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Comparison of predictive performance of drug dose settings using renal function estimation equations based on the Japanese population: a preliminary retrospective study using vancomycin dosing data.

Shungo Imai, Soyoko Kaburaki, Takayuki Miyai, Hitoshi Kashiwagi, Mitsuru Sugawara, Yoh Takekuma

BPB Reports 2 ( 5 ) 80 - 85 2019.10

Research paper (scientific journal), Lead author, Accepted

Construction of a flow chart-like risk prediction model of ganciclovir-induced neutropaenia including severity grade: A data mining approach using decision tree.

Shungo Imai, Takehiro Yamada, Kumiko Kasashi, Nobuhisa Ishiguro, Masaki Kobayashi, Ken Iseki

Journal of clinical pharmacy and therapeutics 44 ( 5 ) 726 - 734 2019.10

Research paper (scientific journal), Lead author, Accepted, ISSN 0269-4727

WHAT IS KNOWN AND OBJECTIVE: Haematological toxicities such as neutropaenia are a common side effect of ganciclovir (GCV); however, risk factors for GCV-induced neutropaenia have not been well established. Decision tree (DT) analysis is a typical technique of data mining consisting of a flow chart-like framework that shows various outcomes from a series of decisions. By following the flow chart, users can estimate combinations of risk factors that may increase the probability of certain events. In our previous study, we demonstrated the usefulness of this approach in the evaluation of adverse drug reactions. Therefore, we aimed to construct a risk prediction model of GCV-induced neutropaenia including severity grade. METHODS: We performed a retrospective study at the Hokkaido University Hospital and enrolled patients who received GCV between April 2008 and March 2018. Neutropaenia was defined as an absolute neutrophil count (ANC) <1500 cells/mm3 and a decrease to <75% relative to baseline. We classified the patients who developed neutropaenia in three groups (Grades 2-4) based on the National Cancer Institute-Common Terminology Criteria for Adverse Events. Data collection was achieved through the retrieval of medical records. We employed a chi-squared automatic interaction detection algorithm to construct the DT model and compared the accuracies to the logistic regression model (a conventional statistical method) to evaluate the established model. RESULTS AND DISCUSSION: In total, 396 adult patients were included in the study; 61 (15.4%) developed neutropaenia. Three predictive factors (hematopoietic stem cell transplantation, baseline ANC <3854 cells/mm3 and duration of therapy ≥15 days) were extracted using the DT analysis to produce five subgroups, the incidence of neutropaenia ranged between 1.7% and 52.8%. In each subgroup, patients who developed neutropaenia were categorized based on the severity. The accuracies of each model were the same (84.6%), which indicated precision. WHAT IS NEW AND CONCLUSION: We successfully built a risk prediction model of GCV-induced neutropaenia including severity grade. This model is expected to assist decision-making in the clinical setting.

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Safety of administering a loading dose of vancomycin in patients with renal impairment.

Yusuke Niinuma, Shungo Imai, Takehiro Yamada, Keisuke Kagami, Akira Yamagami, Takayuki Miyai, Kumiko Kasashi, Masaki Kobayashi, Ken Iseki

The Japanese Journal of Therapeutic Drug Monitoring ((一社)日本TDM学会) 36 ( 3 ) 117 - 124 2019.09

Research paper (scientific journal), Accepted, ISSN 0911-1026

腎機能低下患者におけるバンコマイシン(VCM)初回負荷投与の安全性は十分に検証されていない。そこで今回、腎機能低下患者に対するVCM初回負荷投与の安全性を明らかにするために、単施設(n=1489)後ろ向き観察研究を実施した。初回負荷投与実施群(n=86)と非実施群(n=206)では、腎機能障害発現割合に有意差は認めなかった。(初回負荷投与実施群:非実施群=6.98%:9.71%、P=0.46)ベースラインの腎機能別でも同様の結果であった。また、VCMの初回トラフ値(中央値)はいずれの群も推奨濃度範囲内であり、両群間に有意差はなかった。多変量ロジスティック回帰分析で腎機能障害発現の危険因子として、投与日数9日以上、フロセミド、ピペラシリン・タゾバクタムの併用、ICU入室、初回トラフ値12.2μg/mL以上が抽出され、初回負荷投与の実施は抽出されなかった。以上より、VCMの初回負荷投与は腎機能低下患者に対しても安全に行える可能性が示唆された。(著者抄録)

Analysis of risk factors for ganciclovir-induced thrombocytopenia and construction of risk-prediction models using a decision tree analysis

Shungo Imai, Takehiro Yamada, Kumiko Kasashi, Masaki Kobayashi, Ken Iseki

Japanese Journal of Drug Informatics ((一社)日本医薬品情報学会) 21 ( 1 ) 9 - 19 2019.05

Research paper (scientific journal), Lead author, Accepted, ISSN 1345-1464

ガンシクロビル(GCV)による血小板減少症の発現因子を従来の手法であるロジスティック回帰分析を用いて探索した。さらに、2種の決定木(DT)分析アルゴリズムを用いて血小板減少症発現割合の推定モデルを構築し、そのモデルの妥当性について検討した。GCVの点滴静注製剤の投与を受けた患者386例を対象とした。血小板減少症の発現は12.2%(386例中47例)に認められ、多変量解析において白血球数7000cells/mm3未満、血小板数101000cells/mm3未満、総ビリルビン値0.8mg/dL以上が血小板減少症発現に影響する独立因子として抽出された。CHAID法で構築したDTモデルでは、ツリーは3段階、六つのサブグループに分枝し、五つのリスク因子が抽出された。また、CRT法で構築したモデルでは、ツリーは3段階、七つのサブグループに分枝し、五つのリスク因子が抽出された。ロジスティック回帰モデルならびにCHAID法で構築されたDTモデルの精度は87.8%、CRT法で構築されたDTモデルの精度は88.3%であった。

Comparisons between prophylactic effects of cefcapene-pivoxil and amoxicillin on surgical site infection after impacted mandibular third molar surgery

Akira Yamagami, Takehiro Yamada, Yoshimasa Kitagawa, Yoichi Ohiro, Jun Sato, Nobuhisa Ishiguro, Shungo Imai, Masaki Kobayashi, Ken Iseki

Japanese Journal of Pharmaceutical Health Care and Sciences ((一社)日本医療薬学会) 45 ( 5 ) 254 - 261 2019.05

Research paper (scientific journal), Accepted, ISSN 1346-342X

下顎埋伏智歯抜歯術においてセフカペンピボキシル(CFPN-PI)またはアモキシシリン(AMPC)の予防投与を受けた患者の手術部位感染(SSI)発生率を比較した。解析対象となったのはCFPN-PI群129例(男性50例、女性79例、中央値24.0歳)、AMPC群164例(男性75例、女性89例、中央値25.0歳)であった。SSI発生率はCFPN-PI群において11.6%(15/129)、AMPC群において2.4%(4/164)であり、CFPN-PI群のSSI発生率は有意に高かった。次いで、SSI発生に影響する要因分析を行った。単変量解析において抗菌薬(CFPN-PIの使用)、性別(女性)、術後入院、手術難易度、反対側下顎埋伏智歯抜歯の有無、Pell-Gregory分類がP≦0.2となり、これらを多変量解析における解析対象因子として抽出した。解析対象因子のvariance inflation factorはいずれも4未満であり多重共線性はみられなかった。多変量解析の結果、抗菌薬(CFPN-PIの使用)および術後入院がそれぞれオッズ比5.61、4.66を示し、SSIに影響する独立因子として抽出された。

Construction of a risk prediction model of vancomycin-associated nephrotoxicity to be used at the time of initial therapeutic drug monitoring: A data mining analysis using a decision tree model.

Shungo Imai, Takehiro Yamada, Kumiko Kasashi, Yusuke Niinuma, Masaki Kobayashi, Ken Iseki

Journal of evaluation in clinical practice 25 ( 1 ) 163 - 170 2019.02

Research paper (scientific journal), Lead author, Accepted, ISSN 1356-1294

OBJECTIVES: In our previous study, we built a risk prediction model of vancomycin (VCM)-associated nephrotoxicity using decision tree (DT) analysis. However, this has several limitations in clinical applications. Our objective here was to construct a clinically applicable risk prediction model to be used at the time of initial therapeutic drug monitoring (TDM), in patients with uncomplicated infections. METHOD: A retrospective study was conducted at Hokkaido University Hospital. Subjects that had received VCM were extracted between November 2011 and April 2017. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dL or 50% or higher from baseline. The additional inclusion criteria in this study were as follows: (1) the target trough level of VCM was set to 10 to 15 mg/L, and (2) the duration of therapy was 7 to 14 days. Patients were assumed to have uncomplicated infections. Risk factors for nephrotoxicity were evaluated, which could be extracted at the initial TDM. In the DT analysis, a chi-squared automatic interaction detection algorithm was constructed. RESULTS: A total of 402 patients were enrolled, and 56 (13.9%) patients developed nephrotoxicity. In the DT analysis, concomitant medications (furosemide, piperacillin-tazobactam, and vasopressor drugs) and an initial VCM trough concentration ≥ 15.0 mg/L were extracted as predictive variables by which patients were divided into six subgroups. The incidence of nephrotoxicity was 5.2% to 70.0%, with subgroups classified as low to high risk of nephrotoxicity. The accuracy of DT model was favourable (87.1%). CONCLUSION: We propose that the DT model built in this study is applicable to clinical practice.

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[Verification of Relationship between Administration of Linezolid and Vomiting].

Takezo Tsutsumi, Shungo Imai, Katsuhisa Yamada, Takehiro Yamada, Kumiko Kasashi, Masaki Kobayashi, Ken Iseki

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 139 ( 7 ) 1055 - 1061 2019

Research paper (scientific journal), Accepted, ISSN 0031-6903

Linezolid (LZD), an antimicrobial agent against methicillin-resistant Staphylococcus aureus, demonstrates good bone and joint penetration, and is used for prosthetic bone and joint infections. Recently, we observed vomiting in several patients administered LZD. However, there are few reports on the incidence rate of, and risk factors for, LZD-induced nausea and vomiting. In this study, we aimed to verify the relationship between LZD administration and vomiting. Patients administered LZD at the Department of Orthopedic Surgery of Hokkaido University Hospital between November 2008 and December 2017 were enrolled in the study. The primary endpoint was the comparison of the vomiting rate between patients administered LZD (LZD group) and those administered other antibiotics (non-LZD group). For the secondary endpoint, to verify the risk factors of vomiting, a univariate logistic regression analysis was performed. In total, 130 patients were included in this study; 77 patients in the LZD group, and 53 in the non-LZD group. Vomiting occurred in 18 patients in the LZD group and 4 patients in the non-LZD group (23.4% and 7.5%, respectively); this was significantly higher in the LZD group. In the univariate logistic regression analysis, LZD administration, gender (female), age ≥65 years, renal impairment (creatinine clearance <60 mL/min) and concomitant use of rifampicin were extracted as potential risk factors of vomiting. The results of this study reveal a possible relationship between LZD administration and vomiting.

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Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients with Severe Liver Cirrhosis (Child-Pugh Class C).

Takehiro Yamada, Shungo Imai, Yasuyuki Koshizuka, Yuki Tazawa, Keisuke Kagami, Naoki Tomiyama, Ryosuke Sugawara, Akira Yamagami, Tsuyoshi Shimamura, Ken Iseki

Biological & pharmaceutical bulletin 41 ( 7 ) 1112 - 1118 2018.07

Research paper (scientific journal), Accepted, ISSN 0918-6158

Therapeutic drug monitoring for voriconazole, an antifungal agent, is essential for maximizing efficacy and preventing toxicity. The aim of this study was to elucidate the optimal maintenance dose of voriconazole in patients with severe liver cirrhosis (Child-Pugh class C) by reviewing the plasma trough concentrations obtained by therapeutic drug monitoring and daily doses of voriconazole. We retrospectively evaluated 6 patients with Child-Pugh class C cirrhosis who received oral voriconazole treatment and were liver transplant recipients or were awaiting liver transplantation. We compared their voriconazole trough concentrations and daily maintenance doses to those of patients who did not have liver cirrhosis (n=56). We found that plasma voriconazole trough concentrations in all patients with Child-Pugh class C were almost within therapeutic range, and the median plasma trough concentration at steady state was not significantly different from that of patients who did not have liver cirrhosis. In addition, the median daily maintenance dose of voriconazole was significantly lower (2.13 mg/kg/d) than that of the control patients (6.27 mg/kg/d), suggesting that trough voriconazole concentrations are elevated in Child-Pugh class C patients. Thus, we conclude that oral voriconazole maintenance doses in patients with Child-Pugh class C should be reduced to approximately one-third that of patients with normal liver function, with the follow-up dose adjusted by therapeutic drug monitoring.

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The use of broad-spectrum antibiotics reduces the incidence of surgical site infection after pancreatoduodenectomy

Kimitaka Tanaka, Toru Nakamura, Shungo Imai, Hiroki Kushiya, Daisuke Miyasaka, Yoshitsugu Nakanishi, Toshimichi Asano, Takehiro Noji, Takahiro Tsuchikawa, Keisuke Okamura, Toshiaki Shichinohe, Satoshi Hirano

Surgery Today (Springer Tokyo) 48 ( 9 ) 1 - 10 2018.04

Research paper (scientific journal), Accepted, ISSN 1436-2813

Purpose: The development of surgical site infection (SSI) after biliary reconstruction is highly influenced by the presence of preoperative bacteria in the bile juice. We selected vancomycin and piperacillin/tazobactam (VCM + PIPC/TAZ) as perioperative prophylactic antibiotics for patients undergoing pancreaticoduodenectomy. This study aimed to retrospectively analyze the effectiveness of VCM + PIPC/TAZ compared to cefmetazole. Methods: Seventy-two patients who underwent pancreaticoduodenectomy between April 2015 and March 2017 at our department were evaluated. Forty patients were administered cefmetazole as the perioperative prophylactic antibiotic, and 32 were administered VCM + PIPC/TAZ. The intraoperative VCM blood concentration (incision, biliary reconstruction, and wound closure) was measured during surgery to confirm the hemodynamics. Results: The frequency of SSIs was significantly lower in the VCM + PIPC/TAZ group (8/32 patients) than in the cefmetazole group (20/40 patients, P = 0.031). Postoperatively, significantly fewer patients in the VCM + PIPC/TAZ group (4/32 patients) required ≥ 15 days of additional antibiotic administration compared to those in the cefmetazole group (14/40 patients, P = 0.033). Six of 32 patients in the VCM + PIPC/TAZ group showed redneck syndrome symptoms. There was no significant difference in the VCM blood concentration between patients with and without SSIs. Conclusions: The use of VCM + PIPC/TAZ can reduce the incidence of SSI after pancreaticoduodenectomy and also reduce the need for the additional administration of antibiotics for ≥ 15 days after surgery.

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[Possibility of Poor Outcomes after Treatment Using Teicoplanin at the Minimum Inhibitory Concentration of >2 μg/mL in Methicillin-resistant Staphylococcus aureus Bacteremia].

Keisuke Kagami, Shungo Imai, Yuki Tazawa, Sumio Iwasaki, Tatsuya Fukumoto, Koji Akizawa, Takehiro Yamada, Nobuhisa Ishiguro, Ken Iseki

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 138 ( 9 ) 1181 - 1189 2018

Research paper (scientific journal), Accepted, ISSN 0031-6903

Only minimal information exists regarding the treatment outcomes of patients suffering from methicillin-resistant Staphylococcus aureus (MRSA) bacteremia treated with teicoplanin (TEIC) when the TEIC minimum inhibitory concentration (MIC) is close to the upper limit of the "susceptibility range" according to the Clinical Laboratory Standards Institute (CLSI). We investigated the outcome of TEIC-treated patients in MRSA bacteremia, focusing on TEIC MIC against MRSA. A retrospective cohort study was conducted on patients with MRSA bacteremia. TEIC treatment failure was defined as any of the following: (1) all-cause 60-day mortality, (2) persistent bacteremia until the end of TEIC treatment, or (3) 30-day recurrence of MRSA bacteremia. Nineteen patients were enrolled, of whom 15 exhibited TEIC MICs ≤2 μg/mL and the remaining 4 exhibited >2 μg/mL. The rate of treatment failure and all-cause 60-day mortality in patients with MIC >2 μg/mL were significantly higher than those in patients with MIC ≤2 μg/mL [4 patients (100%) versus 4 patients (26.7%) (p=0.018) and 4 patients (100%) versus 2 patients (13.3%) (p=0.004), respectively]. Three of four patients (75%) with MIC >2 μg/mL had persistent bacteremia, which was quantitatively higher than in patients with MIC ≤2 μg/mL (1 of 7 patients, 14.3%). Our finding suggests that TEIC MIC >2 μg/mL may be related to poor treatment outcome in MRSA bacteremia, and that TEIC should not be used in this case.

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Usefulness of a decision tree model for the analysis of adverse drug reactions: Evaluation of a risk prediction model of vancomycin-associated nephrotoxicity constructed using a data mining procedure.

Shungo Imai, Takehiro Yamada, Kumiko Kasashi, Masaki Kobayashi, Ken Iseki

Journal of evaluation in clinical practice 23 ( 6 ) 1240 - 1246 2017.12

Research paper (scientific journal), Lead author, Accepted, ISSN 1356-1294

OBJECTIVES: Several publications concerning decision tree (DT) analysis in medical fields have recently demonstrated its usefulness for defining prognostic factors in various diseases. However, there are minimal reports on the predictors of adverse drug reactions. We attempted to use DT analysis to discover combinations of multiple risk factors that would increase the risk of nephrotoxicity associated with vancomycin (VCM). To demonstrate the usefulness of DT analysis, we compared its predictive performance with that of multiple logistic regression analysis. METHOD: A single-centre, retrospective study was conducted at Hokkaido University Hospital. A total of 592 patients, who received intravenous administrations of VCM between November 2011 and April 2016, were enrolled. Nephrotoxicity was defined as an increase in serum creatinine of ≥0.5 mg/dL or a ≥50% increase in serum creatinine from the baseline. Risk factors for VCM nephrotoxicity were extracted from previous reports. In the DT analysis, a chi-squared automatic interaction detection algorithm was constructed. For evaluating the established algorithms, a 10-fold cross validation method was adopted to calculate the misclassification risk of the model. Moreover, to compare the accuracy of the DT analysis, multiple logistic regression analysis was conducted. RESULTS: Eighty-seven (14.7%) patients developed nephrotoxicity. A VCM trough concentration of ≥15.0 mg/L, concomitant medication (vasopressor drugs and furosemide), and a duration of therapy ≥14 days were extracted to build the DT model, in which the patients were divided into 6 subgroups based on variable rates of nephrotoxicity, ranging from 4.6 to 69.6%. The predictive accuracies of the DT and logistic regression models were similar (87.3%, respectively), indicating that they were accurate. CONCLUSION: This study suggests the usefulness of DT models for the evaluation of adverse drug reactions.

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データマイニング手法を用いたガンシクロビル誘発性好中球減少症の要因分析．

今井俊吾, 山田武宏, 笠師久美子, 小林正紀, 井関健

医療薬学 43 ( 10 ) 552 - 562 2017.11

Research paper (scientific journal), Lead author, Accepted

Improved Clinical Outcomes in Patients with Positive Blood Culture by Proactive Intervention of Antimicrobial Use-Impact of Antimicrobial Stewardship Program Implementation on Clinical Practice

Takehiro Yamada, Keisuke Kagami, Shungo Imai, Koji Akizawa, Sumio Iwasaki, Tatsuya Fukumoto, Nobuhisa Ishiguro, Ken Iseki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN (PHARMACEUTICAL SOC JAPAN) 137 ( 7 ) 917 - 925 2017.07

Research paper (scientific journal), Accepted, ISSN 0031-6903

Bacteremia is one of the most serious infectious illness resulting from nosocomial infection. Therefore, appropriate antimicrobial chemotherapy should be provided as soon as possible to patients exhibiting symptoms of infectious disease and having positive blood culture results. Antimicrobial stewardship (AS) guidelines were recently released by the Infectious Diseases Society of America. The guidelines recommend "proactive intervention and feedback" as one of the core strategies for implementing optimal antimicrobial drug use to improve patient outcomes in clinical settings. We began using the AS program for optimizing antimicrobial chemotherapy in patients with positive blood culture results. The results of blood cultures and antimicrobial prescriptions for the corresponding patients were daily reviewed by a pharmacist and a physician, members of the infection control team (ICT). If the antimicrobial agents selected were inappropriate, ICT made a recommendation to the attending physicians who prescribed the antibiotics. To evaluate the outcomes of this program, we conducted a single-center, retrospective investigation for near a hundred of patients who underwent intervention by infection-control physician and pharmacist. Resolution of bacteremia (determined by blood culture results) was 96.3% in the group that accepted intervention, whereas only 16.7% of the cases resolved in the group that did not accept intervention. These results strongly suggest the importance of the infection disease-specialist team intervention. This program could become an important method for improving clinical outcomes in patients with bacteremia.

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Validating the Effectiveness of Switching the Vancomycin TDM Analysis Software Based on the Predictive Accuracy.

Shungo Imai, Takehiro Yamada, Nobuhisa Ishiguro, Takenori Miyamoto, Keisuke Kagami, Naoki Tomiyama, Yusuke Niinuma, Daisuke Nagasaki, Koji Suzuki, Akira Yamagami, Kumiko Kasashi, Masaki Kobayashi, Ken Iseki

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan 137 ( 9 ) 1185 - 1192 2017

Research paper (scientific journal), Lead author, Accepted, ISSN 0031-6903

Based on the predictive performance in our previous study, we switched the therapeutic drug monitoring (TDM) analysis software for dose setting of vancomycin (VCM) from "Vancomycin MEEK TDM analysis software Ver2.0" (MEEK) to "SHIONOGI-VCM-TDM ver.2009" (VCM-TDM) in January 2015. In the present study, our aim was to validate the effectiveness of the changing VCM TDM analysis software in initial dose setting of VCM. The enrolled patients were divided into two groups, each having 162 patients in total, who received VCM with the initial dose set using MEEK (MEEK group) or VCM-TDM (VCM-TDM group). We compared the rates of attaining the therapeutic range (trough value; 10-20 μg/mL) of serum VCM concentration between the groups. Multivariate logistic regression analysis was performed to confirm that changing the VCM TDM analysis software was an independent factor related to attaining the therapeutic range. Switching the VCM TDM analysis software from MEEK to VCM-TDM improved the rate of attaining the therapeutic range by 21.6% (MEEK group: 42.6% vs. VCM-TDM group: 64.2%, p<0.01). Patient age ≥65 years, concomitant medication (furosemide) and the TDM analysis software used VCM-TDM were considered to be independent factors for attaining the therapeutic range. These results demonstrated the effectiveness of switching the VCM TDM analysis software from MEEK to VCM-TDM for initial dose setting of VCM.

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Three-day regimen of oseltamivir for postexposure prophylaxis of influenza in wards

N. Ishiguro, R. Oyamada, Y. Nasuhara, T. Yamada, T. Miyamoto, S. Imai, K. Akizawa, T. Fukumoto, S. Iwasaki, H. Iijima, K. Ono

JOURNAL OF HOSPITAL INFECTION (W B SAUNDERS CO LTD) 94 ( 2 ) 150 - 153 2016.10

Research paper (scientific journal), Accepted, ISSN 0195-6701

Inpatients who had been in close contact with patients with influenza were given oseltamivir [75 mg capsules once daily for adults or 2 mg/kg (maximum of 75 mg) once daily for children] for three days as postexposure prophylaxis (PEP). The index patients with influenza were prescribed a neuraminidase inhibitor and were discharged immediately or transferred to isolation rooms. The protective efficacy of oseltamivir for three days was 93% overall [95% confidence interval (CI) 53-99%; P = 0.023] and 94% for influenza A (95% CI 61-99%; P = 0.017), which is comparable to that of seven- to 10-day regimens of oseltamivir as PEP. (C) 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

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Factors Affecting the Timing of Signal Detection of Adverse Drug Reactions

Masayuki Hashiguchi, Shungo Imai, Keiko Uehara, Junya Maruyama, Mikiko Shimizu, Mayumi Mochizuki

PLOS ONE (PUBLIC LIBRARY SCIENCE) 10 ( 12 ) e0144263 2015.12

Research paper (scientific journal), Accepted, ISSN 1932-6203

We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release.

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Evaluation of Predictive Accuracy between Two Types of Vancomycin TDM Analysis Software

Imai Shungo, Yamada Takehiro, Nishimura Ayako, Oki Hiromitsu, Kumai Masayuki, Miyamoto Takenori, Kasashi Kumiko, Iseki Ken

Iyakuhin Johogaku (Japanese Society of Drug Informatics) 16 ( 4 ) 169 - 178 2015

Research paper (scientific journal), Lead author, Accepted, ISSN 1345-1464

Objective: To attain optimal blood concentration rapidly, it is needed to perform initial dose setting appropriately when vancomycin (VCM) used.  In order to design initial dose settings of VCM more currently, we compared the predictive performance of two types of VCM therapeutic drug monitoring (TDM) analysis software retrospectively. Method: We utilized two TDM analysis software, SHIONOGI-VCM-TDM ver.2009 (VCM-TDM) and “Vancomycin MEEK TDM analysis software Ver. 2.0” (MEEK), based on patient’s background. 112 patients who received VCM and performed TDM were analyzed during the period from October 2011 through September 2012 and compared the actual trough level with the predictive trough level.  The predictive performance was evaluated by calculating ME (mean prediction error), MAE (mean absolute prediction error), and RMSE (root mean squared error).  Age, gender, and a renal function were evaluated as patient’s background. Results: VCM-TDM gave good predictive performance for patients overall.  When classified patient’s background complexly (sex, age, and renal function), as for male patients, VCM-TDM showed good predictive performance except for the group over 65 years old and CCr over 85 mL/min.  For female patients, the difference of predictive performance was not accepted by all groups. Conclusion: These results suggest, for male patients, we should use VCM-TDM for initial dose settings except for the group over 65 years old and over CCr 85 mL/min.  For the other patients, we consider that both of software can be used.  These new findings seem to contribute to proper dosage settings of VCM.

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オーダリングシステムと連動した特定抗菌薬使用届出システムの導入とその有用性

山田武宏, 宮本剛典, 川岸亨, 今井俊吾, 沖洋充, 秋沢宏次, 笠師久美子, 石黒信久, 井関健

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 50 ( 3 ) 293 - 297 2014.03

Research paper (scientific journal), Accepted, ISSN 1341-8815

院内感染制御を適正に行うにあたって、抗methicillin-resistant Staphyrococcus aureus(以下、MRSA)薬および広域抗菌薬等の使用は、届出制等によりその適正使用を推進することが求められている。今回、より効率的かつ確実に特定抗菌薬(抗MRSA薬およびカルバペネム系薬)の使用を管理する目的で、処方オーダリングシステムと連動した特定抗菌薬使用届出システム(以下、本システム)の運用を開始した。本システム導入後では、導入前に比してリネゾリド錠の使用量および長期使用件数が著明に減少し、抗MRSA薬使用金額は年間で約2割減少した。また、本システムは、届出内容を臨床検査値や投与履歴と共に一括表示・外部出力する機能を有している。この機能を活用して、効率的な特定抗菌薬の使用状況把握が可能となった。以上より、本システムの活用は抗菌薬適正使用に有用であることが示唆された。(著者抄録)

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