Details of a Researcher - Nakamura, Tomonori

Papers - Nakamura, Tomonori

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Efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli

Namiki T, Yokoyama Y, Kimura M, Fukuda S, Seyama S, Iketani O, Jibiki A, Kawazoe H, Ohtani H, Hasegawa N, Mastumoto K, Oda R, Hashi H, Suzuki S, Nakamura T

Biol Pharm Bull (The Pharmaceutical Society of Japan) 2025.02

Joint Work, Last author, Accepted

Three Kampo medicines-bofutsushosan, boiogito, and daisaikoto- have different effects on host fat accumulation and the intestinal microbiota in a high-fat-diet–induced mouse model of obesity

Nakamichi K, Yoshino T, Akiyama M, Jibiki A, Yokoyama Y, Kawazoe H, Suzuki S, Watanabe K, Kim Y, Nakamura T

Journal of Natural Medicines (Springer Nature) In press 2025

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

Treating refractory pediatric spastic quadriparesis with alcohol neurosurgery: a case report

Williams NL, John-Yung Lin M, Nakamura T

Annals of Clinical Case Reports (Remedy Publication) 9 ( 1 ) 2681 2024.10

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 2474-1655

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Evaluation of Medication Adherence Among Prevalent Users in Hypertension, Dyslipidemia, and Diabetes Using Health Insurance Claims: A Population-Based Cohort Study in Japan

Minako Matsumoto, Sei Harada, Harufumi Ikuta, Miho Iida, Suzuka Kato, Mizuki Sata, Takuma Shibuki, Yoshiki Ishibashi, Naoko Miyagawa, Moeko Hisamatsu, Aya Hirata, Kazuyo Kuwabara, Ayano Takeuchi, Daisuke Sugiyama, Sayo Suzuki, Tomonori Nakamura, Tomonori Okamura, Toru Takebayashi

Pharmacoepidemiology and Drug Safety (Wiley) 33 e5855 2024.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1053-8569

Interprofessional competency in clinical students: validating the clinical student version of the Japanese Self-assessment Scale of Interprofessional Competency (C-JASSIC)

Junji Haruta, Etsuko Tomizaki, Takashi Horiguchi, Tomonori Nakamura, Satoko Ishikawa, Toshiaki Monkawa

J Interprof Care 38 ( 5 ) 875 - 882 2024.07

Research paper (scientific journal), Joint Work, Accepted

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お薬手帳と比較した自記式質問紙による服薬情報の妥当性研究

矢嶋里菜, 松元美奈子, 飯田美穂, 原田成, 澁木琢磨, 平田あや, 桑原和代, 宮川尚子, 中村智徳, 岡村智教, 武林亨

日本公衆衛生雑誌 (日本公衆衛生学会) 71 ( 8 ) 430 - 437 2024.06

Research paper (scientific journal), Joint Work, Accepted

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Proton pump inhibitors and cyclin-dependent kinase 4/6 inhibitors in patients with breast cancer

Takahashi K, Uozumi R, Mukohara T, Hayashida T, Iwabe M, Iihara H, Kusuhara-Mamishin K, Kitagawa Y, Tsuchiya M, Kitahora M, Nagayama A, Kosaka S, Asano-Niwa Y, Seki T, Ohnuki K, Suzuki A, Ono F, Futamura M, Kawazoe H, Nakamura T

The Oncologist (Oxford University Press) 29 ( 6 ) e741 - e749 2024.06

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 10837159

Pharmacokinetics/pharmacodynamics analysis and establishment of optimal dosing regimens using unbound cefmetazole concentration for patients infected with Extended-Spectrum β-lactamase producing Enterobacterales (ESBL-E)

Namiki T., Yokoyama Y., Hashi H., Oda R., Jibiki A., Kawazoe H., Matsumoto K., Suzuki S., Nakamura T.

Pharmacotherapy (Pharmacotherapy) 44 ( 2 ) 149 - 162 2024.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 02770008

Study Objective: Establish methods for measuring cefmetazole (CMZ) concentrations conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis using unbound CMZ concentrations for extended-spectrum β-lactamase producing enterobacterales (ESBL-E) and investigate optimal dosing regimens for not undergoing hemodialysis (non-HD) and undergoing hemodialysis (HD) patients. Design: Prospective observational study. Patients: Included patients treated with CMZ who provided written informed consent and were admitted to the Tokyo Bay Urayasu Ichikawa Medical Center between August 2021 and July 2022. Measurements: Total and Unbound CMZ concentration was measured by high-performance liquid chromatography (HPLC) with solid-phase extraction and ultrafiltration. Setting: Determining the CMZ dosing regimen involved modified creatinine clearance (CLCR) with measured body weight (BW) using the Cockcroft–Gault equation. For non-HD patients, blood samples were collected during at least three points. For patients undergoing HD, 1 g was administered via intravenous infusion, or rapid intravenous injection after HD, or 30 min before the end of HD. Blood samples were collected before HD (pre-HD), and 1 and 3 h after starting HD and post-HD. All blood samples were collected at steady-state. Patient information was collected from electronic medical records. An unbound PK model was constructed for the non-HD patients. A nomogram was constructed using Monte Carlo simulations with a 90% probability of target attainment at 70% free time above the minimum inhibitory concentration (MIC). For the HD patients, a nomogram was used to determine the optimal dosing regimen for each HD schedule. Main Results: CMZ measurement methods were established. A model analysis of unbound PK in 37 non-HD patients incorporated creatinine clearance (CLCR) using the Cockcroft–Gault equation, albumin (ALB) for clearance and body weight (BW) for the volume of distribution. In Monte Carlo simulations, nomograms corresponding to the MIC (known and unknown) were generated for each covariate. Using the nomogram, non-HD patients with an ESBL-E MIC of 8 mg/L, a BW of 60 kg, an ALB of 25 g/L, and a CLCR of 60 mL/min required administration of 2 g every 6 h (1- and 3-h infusions). Unbound PK model parameters were calculated for 7 HD patients, and the optimal dosing regimens following PK/PD were determined for each HD schedule. In HD patients, the regimen after and during HD was established using a treatment that was effective up to an ESBL-E MIC of 4 mg/L. Conclusions: The nomogram for CMZ regimens established by PK/PD analysis of measured CMZ concentrations enables optimal CMZ dosing for ESBL-E-infected patients.

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Drug repositioning study on the antiemetic efficacy of anamorelin for cisplatin-induced nausea and vomiting in rats

Nishino H, Kawazoe H, Sekiguchi M, Jibiki A, Yokoyama Y, Suzuki S, Nakamura T

BPB Reports (The Pharmaceutical Society of Japan) 7 ( 1 ) 1 - 6 2024.01

Joint Work, Last author, Accepted

Patient prognosis and prediction model for taking Kampo formulas in dysmenorrhea An observational study

Maeda-Minami A, Kawamoto A, Yoshino T, Yokoyama Y, Suzuki S, Horiba Y, Nakamura T, Mimura M, Watanabe K

Medicine (Wolters Kluwer) 102 ( 48 ) e36191 2023.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 00257974

Two representative Kampo formulas, keishibukuryogan and tokishakuyakusan, are frequently prescribed for patients with dysmenorrhea. We previously constructed a model that could predict which of these 2 formulas was most suitable, which is based on 4 subjective symptoms and 3 objective signs. To evaluate the prognosis of patients with dysmenorrhea using the established prediction model and assess the treatment outcomes between those treated in accordance with the prediction model and those who received various other treatments. In this retrospective, observational study, we included patients with menstrual pain who visited the Kampo Clinic at the Keio University Hospital for the first time between October 2014 and December 2020. These patients were monitored over a 90-day follow-up period. Participants were categorized into 2 groups: model-accordance and various-options. The progression of visual analogue scale (VAS) values was evaluated by determining the slopes from regression analysis between these 2 groups, with changes corroborated by the medical records. The study comprised 57 patients: 37 in the model-accordance group and 20 in the various-options group. Notably, the various-options group reported a significantly higher number of subjective symptoms (P = .03). The VAS value showed a decline, as indicated by the negative slope value of the regression line, across both groups - irrespective of their classification. There were no significant differences in the occurrence of adverse events between the 2 groups. The prognosis of patients with dysmenorrhea and the incidence of adverse events remained consistent, regardless of whether the treatment approach was in accordance with the prediction model or varied. Further studies are warranted to assess the prognosis when Kampo formulas are chosen based on the prediction model in the various-options population.

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Influence of menopause on chemotherapy-induced nausea and vomiting in highly emetogenic chemotherapy for breast cancer: A retrospective observational study.

Yokokawa T, Suzuki K, Tsuji D, Hosonaga M, Kobayashi K, Kawakami K, Kawazoe H, Nakamura T, Suzuki W, Sugisaki T, Aoyama T, Hashimoto K, Hatori M, Tomomatsu T, Inoue A, Azuma K, Asano M, Takano T, Ohno S, Yamaguchi M

Cancer Medicine (Wiley) 12 ( 18 ) 18745 - 18754 2023.09

Research paper (scientific journal), Joint Work, Accepted

Background: Female sex and younger age are reported risk factors for chemotherapy-induced nausea and vomiting (CINV) in highly emetogenic chemotherapy, but the underlying mechanism has not been elucidated. The purpose of this study was to clarify the impact of menopause on CINV. Methods: This retrospective observational study analyzed data from consecutive patients who received their first cycle of perioperative anthracycline-based chemotherapy for breast cancer between January 2018 and June 2020. The endpoints were association between CINV (vomiting, ≥Grade 2 nausea, complete response [CR] failure) and menopause as well as the association between CINV and follicle-stimulating hormone [FSH]/estradiol [E2]. Results: Data for 639 patients were analyzed. Among these patients, 109 (17.1%) received olanzapine (four antiemetic combinations) and 530 (82.9%) did not (three antiemetic combinations). Premenopausal state (amenorrhea lasting ≥12 months) was significantly associated with ≥Grade 2 nausea and CR failure in univariate analysis but not in multivariate analysis. The premenopausal FSH/E2 group (defined by serum levels; FSH <40 mIU/mL and E2 ≥20 pg/mL) had a significantly higher rate of ≥Grade 2 nausea than the postmenopausal FSH/E2 group (FSH ≥40 mIU/mL and E2 <20 pg/mL) (48.8% vs. 18.8%, p = 0.023). Conclusions: Our results suggest that changes in FSH and E2 due to menopause may affect the severity of nausea and that FSH and E2 (especially FSH) levels might be useful indicators for CINV risk assessment.

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Development of a novel drug information provision system for Kampo medicine using natural language processing technology

Maeda-Minami A, Yoshino T, Yumoto T, Sato K, Sagara A, Inaba K, Kominato H, Kimura T, Takishita T, Watanabe G, Nakamura T, Mano Y, Horiba Y, Watanabe K, Kamei J

BMC Med Inform Decis Mak (BioMed Central Ltd) 23 ( 1 ) 119 2023.07

Research paper (scientific journal), Joint Work, Accepted

Background: Kampo medicine is widely used in Japan; however, most physicians and pharmacists have insufficient knowledge and experience in it. Although a chatbot-style system using machine learning and natural language processing has been used in some clinical settings and proven useful, the system developed specifically for the Japanese language using this method has not been validated by research. The purpose of this study is to develop a novel drug information provision system for Kampo medicines using a natural language classifier® (NLC®) based on IBM Watson. Methods: The target Kampo formulas were 33 formulas listed in the 17th revision of the Japanese Pharmacopoeia. The information included in the system comes from the package inserts of Kampo medicines, Manuals for Management of Individual Serious Adverse Drug Reactions, and data on off-label usage. The system developed in this study classifies questions about the drug information of Kampo formulas input by natural language into preset questions and outputs preset answers for the questions. The system uses morphological analysis, synonym conversion by thesaurus, and NLC®. We fine-tuned the information registered into NLC® and increased the thesaurus. To validate the system, 900 validation questions were provided by six pharmacists who were classified into high or low levels of knowledge and experience of Kampo medicines and three pharmacy students. Results: The precision, recall, and F-measure of the system performance were 0.986, 0.915, and 0.949, respectively. The results were stable even with differences in the amount of expertise of the question authors. Conclusions: We developed a system using natural language classification that can give appropriate answers to most of the validation questions.

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Clinical and biomarker factors affecting survival in patients with platinum-sensitive relapsed ovarian cancer receiving olaparib monotherapy: A multicenter retrospective study

Tashiro R, Kawazoe H, Mamishin K, Seto K, Udagawa R, Saito Y, Hashimoto H, Shimoi T, Yonemori K, Yonemura M, Terakado H, Nishimura T, Kawasaki T, Furukawa T, Nakamura T

Scientific Reports (NATURE RESEARCH) 13 ( 1 ) 11962 2023.07

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

The standard treatment for platinum-sensitive relapsed ovarian cancer (PSROC) is platinum-based chemotherapy followed by olaparib monotherapy. A retrospective study was conducted to identify factors affecting the survival of patients with PSROC undergoing olaparib monotherapy in real-world clinical settings. The study enrolled 122 patients who received olaparib monotherapy between April 2018 and December 2020 at three national centers in Japan. The study used the Kaplan–Meier method and univariable and multivariable Cox proportional hazards models to evaluate the associations between factors and progression-free survival (PFS). Patients with BRCA1/2 mutations had a significantly longer median PFS than those without these mutations. Both the BRCA1/2 mutation-positive and mutation-negative groups exhibited a prolonged PFS when the platinum-free interval (PFI) was ≥ 12 months. Cancer antigen 125 (CA-125) level within reference values was significantly linked to prolonged PFS, while a high platelet-to-lymphocyte ratio (≥ 210) was significantly associated with poor PFS in the BRCA1/2 mutation-negative group. The study suggests that a PFI of ≥ 12 months may predict survival after olaparib monotherapy in patients with PSROC, regardless of their BRCA1/2 mutation status. Additionally, a CA-125 level within reference values may be associated with extended survival in patients without BRCA1/2 mutations. A larger prospective study should confirm these findings.

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In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model

Igarashi Y., Kojima N., Takemura W., Liu X., Morita T., Mizukami Y., Enoki Y., Taguchi K., Yokoyama Y., Nakamura T., Matsumoto K.

Pharmaceutical Research (Pharmaceutical Research) 40 ( 7 ) 1789 - 1797 2023.07

ISSN 07248741

Purpose: Cefditoren, the active form of cefditoren pivoxil, is an oral cephalosporin antimicrobial drug. Although cefditoren exhibits high antimicrobial activity against Streptococcus pneumoniae, its pharmacokinetics/pharmacodynamics (PK/PD) characteristics remain unknown. This study aimed to determine its PK/PD parameter with target values for cefditoren against S. pneumoniae in S. pneumoniae lung-infected mice and to simulate MIC range of S. pneumoniae that can be expected to be treated at approved cefditoren doses in human using population pharmacokinetic (PPK) data from patients. Methods: Susceptibility testing and time-kill assays against S. pneumoniae ATCC® 49619 were performed for in vitro PD evaluation. Based on the results of a PK study in healthy mice and PD studies in S. pneumoniae lung-infected mice, optimal PK/PD parameters were determined using the correlation curve between the PK/PD parameters and lung bacterial count changes. The target value was calculated to achieve a 2 log10 reduction in the lung bacterial counts. Results: In vitro PD evaluation showed that cefditoren had a potent antimicrobial effect against S. pneumoniae in a time-dependent manner at concentrations above the MIC. In PK/PD analyses, both fAUC24/MIC and fCmax/MIC were well correlated with bactericidal efficacy, achieving 2 log10-kill with fAUC24/MIC ≥ 63 and fCmax/MIC ≥ 16. Conclusions: Cefditoren pivoxil has good therapeutic efficacy against acute pneumonia caused by S. pneumoniae with a MIC ≤ 0.031–0.063 mg/L at approved doses in adults and children.

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実務実習終了時における到達度評価を向上させる要因は何か？

石川春樹, 河添仁, 岩田紘樹, 中村友紀, 地引綾, 横山雄太, 小林典子, 鈴木小夜, 山浦克典, 中村智徳

医療薬学 (日本医療薬学会) 49 ( 4 ) 173 - 182 2023.04

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 1346-342X

Prognostic Model of Baseline Medications plus Neutrophil-to-lymphocyte Ratio in Patients with Advanced Non-small-cell Lung Cancer Receiving Immune Checkpoint Inhibitor plus Platinum Doublet: A Multicenter Retrospective Study

Nasu I, Kondo M, Uozumi R, Takada S, Nawata S, Iihara H, Okumura Y, Takemoto M, Mino K, Sasaki T, Hirose C, Aomori T, Shimano R, Maeno K, Oizumi S, Kusumoto S, Ohno Y, Ikemura S, Takai D, Hara A, Kawazoe H, Nakamura T

Journal of Cancer (IVYSPRING INTERNATIONAL PUBLISHER) 14 ( 5 ) 676 - 688 2023.03

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 1837-9664

Background: Association between baseline medications plus neutrophil-to-lymphocyte ratio (NLR) and the effectiveness of immune checkpoint inhibitor (ICI) plus platinum doublet remains unknown, despite several reported prognostic models. We used real-world data to investigate whether baseline medications plus NLR predict survival outcomes in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICI plus platinum doublet. Methods: This multicenter, retrospective, observational study conducted in Japan between December 2018 and March 2021 used real-world data of consecutive patients with advanced NSCLC who received ICI (pembrolizumab or atezolizumab) plus platinum doublet as first-line treatment. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The prognostic score for baseline medications plus NLR was weighted by regression β coefficients and used to categorize patients into good, intermediate, and poor prognoses groups. In addition, time-dependent receiver operating characteristic curve analyses and univariable and multivariable Cox proportional hazards models were constructed. Results: Overall, 241 patients were included. Poor prognosis was significantly associated with worse PFS (hazard ratio [HR]: 1.78; 95% confidence interval [CI]: 1.08–2.94; P = 0.025) and OS (HR: 3.59; 95% CI: 2.05–6.28; P < 0.001) than good prognosis. Harrell’s C-index for this prognostic model was 0.648. Conclusions: Baseline medication plus NLR could predict progressively worse survival outcomes in patients with advanced NSCLC receiving ICI plus platinum doublet and could be used as a prognostic index for poor outcomes.

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Ingenol mebutate inhibits the growth of pancreatic cancer cells in vitro via STING with an efficacy comparable to that of clinically used anticancer agents

Kikuyama F, Suzuki S, Jibiki A, Yokoyama Y, Kawazoe H, Kitanaka S, Nakamura T

Journal of Natural Medicines (Sringer) 77 ( 2 ) 343 - 351 2023.01

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 13403443

Pancreatic cancer is associated with a poor prognosis; thus, there is an urgent need to develop new and effective treatments. Ingenol mebutate (IM), which is isolated from the latex of Euphorbia peplus, was recently shown to be effective against pancreatic cancer cell lines; however, its mechanism of action has not been fully elucidated. In this study, we focused on the less drug-sensitive pancreatic cancer cell line Panc-1 and compared IM to commercially available anticancer drugs using cell survival assays. In addition, we aimed to identify novel biomolecules that may be involved in the mechanism of action of IM using RNA sequencing, western blotting, and inhibition assays. The IC50 values after 72 h of exposure to IM and SN-38, drugs to which the Panc-1 cells are most sensitive among the tested anticancer agents, were 43.1 ± 16.8 nM and 165 ± 37 nM, respectively. IM showed a cytostatic effect equal to or greater than that of the clinically used pancreatic cancer therapeutic drugs. RNA sequencing and protein expression analysis revealed that expression of stimulator of interferon genes (STING) increased at low IM concentration, whereas cell viability decreased. Co-exposure of IM and STING inhibitor, H-151, to Panc-1 or MIA PaCa-2 cell lines canceled the growth-inhibitory effects of IM alone. In conclusion, IM may have an efficacy comparable to that of existing pancreatic cancer therapeutic agents on the less drug-sensitive Panc-1 cell line and the immune-related molecule STING plays a role in the mechanism of action of IM.

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Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small-cell Lung Cancer: A Prospective Observational Study

Ishikawa E, Yokoyama Y, Chishima H, Kasai H, Kuniyoshi O, Kimura M, Hakamata J, Nakada H, Suehiro N, Nakaya N, Nakajima H, Ikemura S, Kawada I, Yasuda H, Terai H, Jibiki A, Kawazoe H, Soejima K, Muramatsu H, Suzuki S, Nakamura T

Investigational New Drugs (Sringer) 41 ( 1 ) 122 - 133 2023.01

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 01676997

Background: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. Methods: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration–time curve from 0 to 24 h (AUC0–24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. Results: There was a significant association between the AUC0–24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0–24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). Conclusion: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

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Patient-Associated Risk Factors for Severe Anemia in Patients with Advanced Ovarian or Breast Cancer Receiving Olaparib Monotherapy: A Multicenter Retrospective Study

Tashiro R, Kawazoe H, Mamishin K, Seto K, Udagawa R, Saito Y, Hashimoto H, Shimoi T, Yonemori K, Yonemura M, Terakado H, Kawasaki T, Furukawa T, Nakamura T

Frontiers in Oncology (Frontiers Media SA) 12 898150 2022.10

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

Background: Olaparib-induced anemia is a frequently occurring complication in patients with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and is associated with a marked deterioration in patients’ health-related quality of life. This study aimed to clarify patient-specific risk factors for severe anemia in patients with advanced ovarian or breast cancer receiving olaparib monotherapy in a real-world setting. Methods: This multicenter, retrospective, observational study enrolled consecutively presenting patients with advanced ovarian or breast cancer who received olaparib monotherapy as maintenance or palliative treatment between April 2018 and December 2020 at three participating medical institutions in Japan. The primary endpoint was patient-associated risk factors underlying the onset of grade ≥3 anemia from olaparib treatment initiation to 90 days after treatment. Receiver operating characteristic curves were constructed and univariable and multivariable logistic regression analyses were performed to evaluate the association between patient-associated risk factors and grade ≥3 anemia. Results: Of 113 patients evaluated in this study, 32.7% (n = 37) had grade ≥3 anemia. Multivariable logistic regression analysis revealed that low baseline red blood cell (RBC) count (<3.3 × 106 cells/μL), low baseline hematocrit level (<35%), low baseline hemoglobin level (<11.6 g/dL), and breast cancer susceptibility (BRCA1/2) mutation were significantly associated with the onset of grade ≥3 anemia (adjusted odds ratio [OR], 3.39; 95% confidence interval [CI], 1.28–9.62; P = 0.017, adjusted OR, 3.63; 95% CI, 1.28–11.64; P = 0.021, adjusted OR, 3.89; 95% CI, 1.39–12.21; P = 0.014, and adjusted OR, 4.09; 95% CI, 1.55–11.67; P = 0.006, respectively). Conclusions: Our findings suggest that low baseline RBC count, low baseline hematocrit level, and low baseline hemoglobin level might be the patient-associated risk factors for severe anemia induced by olaparib monotherapy. Additionally, BRCA1/2 mutation was suggested to be a patient-related risk factor for anemia regardless of severity. Therefore, applying these patient-associated risk factors would help classify and screen patients at risk of severe anemia.

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Design, Synthesis, and Monoamine Oxidase B Selective Inhibitory Activity of N-Arylated Heliamine Analogues.

Yamada Makito, Hirose Yu, Lin Bangzhong, Fujimoto Megumi, Nunomura Kazuto, Sirimangkalakitti Natchanun, Takahashi Naoyuki, Ohki, Yuuta, Sako Makoto, Murai Kenichi, Harada Kazuo, Arai Masayoshi, Suzuki Sayo, Nakamura Tomonori, Haruta Junichi, Arisawa Mitsuhiro

ACS Medicinal Chemistry Letters (American Chemical Society) 13 ( 10 ) 1582 - 1590 2022.08

Research paper (scientific journal), Joint Work, Accepted

Monoamine oxidase B (MAO-B) metabolizes monoamines such as dopamine regarding neural transmission and controls its level in the mammalian's brain. When MAO-B metabolizes dopamine abnormally, normal neurotransmission does not occur, and central nervous system disorders such as Parkinson's disease may develop. Although several MAO inhibitors have been developed, most of them have no selectivity between monoamine oxidase A (MAO-A) and MAO-B, or they work irreversibly against the enzyme. This report describes the first case of screening of N-arylated heliamine derivatives to develop novel MAO-B selective inhibitors that can be synthesized concisely by microwave-assisted Pd nanoparticle-catalyzed Buchwald-Hartwig amination. We discovered that the derivatives 4h, 4i, and 4j display inhibitory activity against MAO-B with IC50 values of 1.55, 13.5, and 5.08 μM, respectively.

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Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high-performance liquid chromatography–Photodiode array detection

Yuta Yokoyama, Eiji Nozawa, Miho Morita, Emi Ishikawa, Takehiko Mori, Masatoshi Sakurai, Taku Kikuchi, Eri Matsuki, Rie Yamazaki, Keisuke Kataoka, Aya Jibiki, Hitoshi Kawazoe, Sayo Suzuki, Tomonori Nakamura

Journal of Clinical Laboratory Analysis (Wiley) 36 ( 8 ) e24598 2022.07

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 08878013

Background: Dasatinib, nilotinib, and bosutinib, second-generation tyrosine kinase inhibitors (TKIs), and ponatinib, a third-generation TKI, are approved pharmaceuticals used in the treatment of chronic myeloid leukemia (CML). Although liquid chromatography-tandem mass spectrometry assays for simultaneous quantification of the four TKIs in human serum have been reported in the literature, a high-performance liquid chromatography (HPLC) assay that simultaneously quantifies these compounds has not yet been developed. This study aims to establish and validate an efficient HPLC analytical method using a photodiode array (PDA) detector for the simultaneous quantification of the four TKIs. Methods: Calibration standards were prepared by serial dilution of serum samples containing the four TKIs, followed by solid-phase extraction. The four TKIs were eluted in order within 10 min using a binary HPLC gradient system. Results: The calibration ranges were 2–500 ng/ml for dasatinib, 100–5000 ng/ml for nilotinib, and 10–500 ng/ml for bosutinib and ponatinib. Intra-day and inter-day precision and accuracy values were found to be in accordance with the U.S. Food and Drug Administration guidelines. The recovery rates were 92.9%–96.0%, 80.7%–86.1%, 91.6%–99.0%, and 86.4%–92.6% for dasatinib, nilotinib, bosutinib, and ponatinib, respectively. Conclusion: To the best of our knowledge, this is the first report of an HPLC-PDA analytical method that allows efficient simultaneous quantification of the four TKIs in the serum of patients with CML. We believe that the method developed herein can improve the efficiency of therapeutic drug monitoring in patients with CML in clinical practice.

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Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum

Emi Ishikawa, Yuta Yokoyama, Haruna Chishima, Ouki Kuniyoshi, Itaru Sato, Naoki Nakaya, Hideo Nakajima, Motonori Kimura, Jun Hakamata, Naoya Suehiro, Hideo Nakada, Shinnosuke Ikemura, Aya Jibiki, Hitoshi Kawazoe, Hiroshi Muramatsu, Sayo Suzuki, Tomonori Nakamura

J Chromatogr B Analyt Technol Biomed Life Sci (Elsevier) 1199 123245 2022.05

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 15700232

Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 μL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5–125.0 ng/mL for afatinib, 2.5–125.0 ng/mL for dacomitinib, 4.0–800.0 ng/mL for osimertinib, 1.0–125.0 ng/mL for AZ5104, and 2.5–125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.

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Prognostic Value of Baseline Medications plus Neutrophil-to-Lymphocyte Ratio in the Effectiveness of Nivolumab and Pembrolizumab in Patients with Advanced Non-Small-Cell Lung Cancer: A Retrospective Study

Ogiwara T, Kawazoe H, Egami S, Hashimoto H, Saito Y, Sakiyama N, Ohe Y, Yamaguchi M, Furukawa T, Hara A, Hiraga Y, Jibiki A, Yokoyama Y, Suzuki S, Nakamura T

Frontiers in Oncology (Frontiers Media SA) 11 770268 2021.11

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

Background: Nivolumab and pembrolizumab are the standard treatments for patients with advanced non-small-cell lung cancer (NSCLC). While there are reports on several inflammatory indices and the prognosis of patients with cancer, no study has combined baseline medication with the neutrophil-to-lymphocyte ratio (NLR) to predict clinical outcomes. This study investigated the efficacy of baseline medications plus NLR to predict the effectiveness of nivolumab and pembrolizumab in a real-world clinical setting. Methods: We conducted a single-center retrospective observational study of consecutive patients with advanced NSCLC who received nivolumab or pembrolizumab as first-line, second-line, or beyond treatment between December 2015 and November 2018 at the National Cancer Center Hospital in Japan. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The drug-based prognostic score for baseline medications plus NLR was weighed based on the regression β coefficients. The multivariable Cox proportional hazard model was used to assess the association between the prognostic score-stratified groups and survival outcomes. Results: In total, 259 patients were evaluated in this study. A prognostic score calculated from the baseline medications plus NLR was used to categorize the patients into good (score 0), intermediate (scores 1–2), and poor (scores 3–6) -prognosis groups. The multivariable Cox proportional hazard model revealed a significant association between the poor-prognosis group and reduced OS. The hazard ratio of OS was 1.75 (95% confidence interval: 1.07–2.99; P = 0.031). In contrast, no association between these prognosis groups and PFS was observed. Conclusions: The findings suggest that the baseline medications with nivolumab or pembrolizumab plus NLR could lead to progressively shorter survival outcomes in patients with advanced NSCLC and could be used as a prognostic index for poor outcomes. However, to ascertain the clinical application of these findings, these concomitant medications need further validation in a large-scale multicenter study.

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Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments

Takemura W., Tashiro S., Hayashi M., Igarashi Y., Liu X., Mizukami Y., Kojima N., Morita T., Enoki Y., Taguchi K., Yokoyama Y., Nakamura T., Matsumoto K.

Pharmaceutical Research (Pharmaceutical Research) 38 ( 11 ) 1839 - 1846 2021.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 07248741

Purpose: Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. Methods: The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. Results: The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. Conclusion: CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve “fT>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.

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薬局薬剤師を対象とした漢方薬の書籍等情報源認知度調査

前田絢子, 湯本哲郎, 里香世子, 相良篤信, 稲葉健二郎, 小湊英範, 木村隆夫, 中村智徳, 吉野鉄大, 堀場裕子, 渡辺賢治, 亀井淳三

未病と抗老化 (博慈会老人病研究所) 30 52 - 58 2021.11

Research paper (scientific journal), Joint Work, Accepted

Drug repositioning of antipsychotic drugs for cisplatin-induced pica behavior in mice

Sekiguchi M, Sagano N, Kawazoe H*, Hiraga Y, Jibki A, Yokoyama Y, Suzuki S, Nakamura T

Pharmazie (Avoxa - Mediengruppe Deutscher Apotheker GmbH) 76 ( 10 ) 484 - 487 2021.10

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 0031-7144

We aimed to clarify whether various antipsychotics ameliorate cisplatin-induced pica behavior in mice using a drug repositioning approach. Mice were administered cisplatin (12.5 mg/kg, i.p.) with or without olanzapine (1 mg/kg, i.p.), asenapine (4 mg/kg, i.p.), mirtazapine (5 mg/kg, i.p.) or standard three-drug antiemetics (granisetron [0.5 mg/kg, i.p.], fosaprepitant [25 mg/kg, i.p.], and dexamethasone [3 mg/kg, i.p.]). Kaolin, food, and water intake, and spontaneous motor activity on the day before and seven consecutive days after the cisplatin administration were measured using a telemetry system. At the primary endpoint, kaolin intake was significantly higher at day three in the cisplatin group than in the pre-treatment and saline groups (p < 0.05). Additionally, kaolin intake was not significantly higher in cisplatin with olanzapine, asenapine, and mirtazapine groups for seven days than in the pre-treatment group. At the secondary endpoint, cisplatin decreased the food and water intake, and spontaneous motor activity in a time-dependent manner. Three antipsychotics failed to improve the cisplatin-induced decrease in food and water intake, and spontaneous motor activity. The findings suggest that prophylactic administration of antipsychotics besides olanzapine may improve cisplatin-induced nausea and vomiting in a delayed phase and de-escalate standard 3-drug antiemetics.

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薬学教育モデル・コアカリキュラムに基づく実務実習におけるルーブリック形式の概略評価は実習生のパフォーマンスレベルを測定できるか？

河添　仁, 鈴木小夜, 平賀ゆい, 横山雄太, 地引　綾, 岩田紘樹, 小林典子, 藤本和子, 中田英夫, 青森　達, 山浦克典, 中村智徳

医療薬学 (日本医療薬学会) 47 ( 9 ) 513 - 524 2021.09

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

院内製剤の抗微生物薬，抗ウイルス薬，塩化ナトリウム点眼液の長期保存における安定性の評価

武田真実, 横山雄太, 渡邉武明, 平賀ゆい, 地引　綾, 河添　仁, 鈴木小夜, 門田佳子, 中村智徳

医療薬学 (日本医療薬学会) 47 ( 6 ) 316 - 325 2021.06

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 1346-342X

Effect of renin-angiotensin system inhibitors on pemetrexed plus platinum-induced hematological toxicities: a multicenter retrospective study using three propensity score analyses

Arami T, Kawazoe H*, Uozumi R, Hashimoto H, Egami S, Sakiyama N, Ohe Y, Nakada H, Aomori T, Ikemura S, Yasuda H, Kawada I, Fukunaga K, Soejima K, Yamaguchi M, Nakamura T

Pharmazie (Avoxa - Mediengruppe Deutscher Apotheker GmbH) 76 ( 6 ) 266 - 271 2021.06

Research paper (scientific journal), Joint Work, Last author, Accepted, ISSN 0031-7144

Hematological toxicities induced by pemetrexed plus platinum therapy remain a critical issue in clinical practice. We hypothesized that inhibition of the renin-angiotensin system (RAS) can ameliorate pemetrexed-induced hematological toxicities through drug-drug interactions involving organic anion transporters. Thus, this study aimed to clarify whether RAS inhibitors (RASIs) could prevent pemetrexed plus platinum-induced hematological toxicities. We retrospectively analyzed data from 305 consecutive patients with non-small cell lung cancer or malignant pleural mesothelioma who received their first cycle of a pemetrexed plus platinum regimen and were treated with or without RASIs. The primary endpoint was the incidence of severe myelosuppression after the first cycle. Propensity score (PS)-matched, PS-adjusted, and inverse probability of treatment weighting (IPTW) analyses were used. The number of patients with grade ≥3 hematological toxicities was 27 (8.9%). PS-matched analyses revealed that the concomitant use of RASIs was slightly associated with a lower risk of grade ≥3 hematological toxicities (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.20-2.32; p = 0.536). Additionally, sensitivity analyses using PS-adjusted and IPTW methods demonstrated similar results (OR, 0.63; 95% CI, 0.19-2.15; p = 0.463 and OR, 0.37; 95% CI, 0.11-1.29; p = 0.117, respectively). These findings suggest that RASIs might prevent pemetrexed plus platinum-induced hematological toxicities.

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Preventive effects of self-administered cryotherapy on paclitaxel-induced peripheral neuropathy in patients with early-stage breast cancer: a propensity score analysis

Shimanuki Y, Hashimoto H, Kawazoe H*, Uozumi R, Udagawa R, Watabe D, Nakamura T, Yamaguchi M, Terakado H

Pharmazie (Avoxa - Mediengruppe Deutscher Apotheker GmbH) 76 ( 6 ) 261 - 265 2021.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-7144

We hypothesized that suppression of peripheral circulation via cryotherapy may be effective in preventing paclitaxel-induced peripheral neuropathy (PIPN). Therefore, this study aimed to clarify whether self-administered cryotherapy could prevent PIPN in patients with early-stage breast cancer, using real-world data. A single-center, retrospective, observational study was conducted. Data from the electronic medical records of consecutive patients aged ≥ 20 years with early-stage breast cancer who received a regimen containing paclitaxel for 12 cycles with or without self-administered cryotherapy at the National Cancer Center Hospital from March 2018 to May 2019 were evaluated. The primary endpoint was the cumulative dose of paclitaxel until the onset of grade ≥ 2 PIPN. To compare the difference between the two groups, multivariable Cox proportional hazards models adjusted for prognostically important variables were used. Ninety Japanese patients were included in this study. The estimated incidence of grade ≥ 2 PIPN was 26.9% and 37.7% in the self-administered cryotherapy group and control group, respectively (P = 0.314). The multivariable Cox proportional hazards model showed that the self-administered cryotherapy group had a decreased risk of onset of grade ≥ 2 PIPN (hazard ratio: 0.63, 95% confidence interval: 0.25 to 1.39; P = 0.281). Sensitivity analyses using multivariable Cox proportional hazards models along with two propensity score-adjusted methods demonstrated consistent results. The findings suggest that the methods of self-administered cryotherapy may prevent PIPN and should be reinforced appropriately in clinical practice. A randomized controlled multicenter trial of self-administered cryotherapy is warranted.

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非小細胞肺がん患者におけるオシメルチニブのPK/PD/PGxに基づく治療最適化

横山雄太, 石川恵海, 国吉央城, 中村智徳

臨床薬理の進歩 (臨床薬理研究振興財団) 42 134 - 140 2021.06

Research paper (scientific journal), Last author, Accepted

Absolute Lymphocyte Count Predicts Immune-related Adverse Events in Patients with Non-small-cell Lung Cancer Treated with Nivolumab Monotherapy: A Multicenter Retrospective Study

Egami S, Kawazoe H, Hashimoto H, Uozumi R, Arami T, Sakiyama N, Ohe Y, Nakada H, Aomori T, Ikemura S, Fukunaga K, Yamaguchi M, Nakamura T

Frontiers in Oncology (Frontiers Media SA) 11 618570 2021.05

Research paper (scientific journal), Joint Work, Accepted

Background: Among patients with advanced non-small-cell lung cancer who were treated with nivolumab monotherapy, the association of peripheral blood count data (at baseline and 2 weeks after treatment initiation) with the early onset of immune-related adverse events (irAEs) and treatment efficacy has not been clearly established. This study aimed to identify peripheral blood count data that may be predictive of the development of nivolumab-induced irAEs in a real-world clinical setting. Materials and Methods: This multicenter observational study retrospectively evaluated consecutive patients with advanced non-small-cell lung cancer undergoing nivolumab monotherapy in the second- or later-line setting between December 2015 and November 2018 at the National Cancer Center Hospital and Keio University Hospital in Japan. The primary endpoint was the association between peripheral blood count data and irAEs during the 6-week study period. Receiver operating characteristic curve and multivariable logistic regression analyses were performed. Results: Of the 171 patients evaluated, 73 (42.7%) had ≥1 irAE during the first 6 weeks following treatment initiation. The median time to irAEs from the initiation of nivolumab was 15 (interquartile range: 13–28) days. Receiver operating characteristic curve analyses revealed that the optimal cut-off values of the absolute lymphocyte count, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio 2 weeks after treatment initiation for early irAE onset were 820, 4.3, and 2.2, respectively. In multivariable logistic regression analyses, absolute lymphocyte count >820 at 2 weeks after treatment initiation was significantly associated with an increased risk of early onset of any irAE. In contrast, no significant association was observed for the neutrophil-to-lymphocyte ratio (>4.3) or the lymphocyte-to-monocyte ratio (>2.2) at 2 weeks following treatment initiation. Conclusions: The absolute lymphocyte count >820 at 2 weeks following nivolumab initiation predicts early onset of irAEs during a 6-week study period. Routinely available absolute lymphocyte count, which is measured after the initiation of nivolumab, may be useful for identifying patients at risk of early onset of irAEs.

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Inter-rater Reliability of Kampo Diagnosis for Chronic Diseases.

Maeda-Minami A, Yoshino T, Horiba Y, Nakamura T, Watanabe K

Journal of Alternative and Complementary Medicine (Mary Ann Liebert) 27 ( 7 ) 613 - 616 2021.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 10755535

This single-center observational study aimed to assess the inter-rater reliability (IRR) of Kampo medicine pattern diagnosis, which is modularized into three modules for chronic diseases, using 64 participants' information documents. The linearly weighted percentage of agreement and Gwet's agreement coefficient (AC) 2 for the deficiency-excess module, among three specialists, were 85.9% and 0.708, respectively. The unweighted percentage of agreement and Gwet's AC1 were 64.6% and 0.542 for the cold-heat, and 35.9% and 0.254 for the qi-blood-fluid modules, respectively. Our findings suggest that our modularization method may improve the IRR of Kampo medicine pattern diagnosis.

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Peripheral blood biomarkers predict immune-related adverse events in non-small cell lung cancer patients treated with pembrolizumab: a multicenter retrospective study

Egami S, Kawazoe H, Hashimoto H, Uozumi R, Arami T, Sakiyama N, Ohe Y, Nakada H, Aomori T, Ikemura S, Fukunaga K, Yamaguchi M, Nakamura T

Journal of Cancer ( IVYSPRING INT PUBL) 12 ( 7 ) 2105 - 2112 2021.02

Research paper (scientific journal), Joint Work, Accepted

Background: Pembrolizumab is currently the standard treatment for patients with advanced non-small cell lung cancer (NSCLC). However, the association between immune-related adverse events (irAEs) and peripheral blood cell counts remains unclear. We aimed at identifying peripheral blood cell counts that may predict the development of pembrolizumab-induced irAEs. Methods: We retrospectively analyzed data on consecutive patients with advanced NSCLC who received pembrolizumab monotherapy as first-line or later-line therapy at the National Cancer Center Hospital and Keio University Hospital. We used data between December 2015 and November 2018. The primary endpoint was the relationship between peripheral blood cell count data and early-onset irAEs during the 6-weeks study period. Receiver operating characteristic (ROC) curve and multivariable logistic regression analyses were performed. Results: In total, 92 patients were evaluated, of whom 45 (48.9%) had at least one irAE during the first 6-weeks after treatment initiation. The ROC curves revealed that the optimal cutoff of pretreatment absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) for onset of irAEs were 1459, 2.320, 1.538, and 165, respectively. Multivariable logistic regression analyses revealed that pretreatment ALC>1450 and LMR>1.6 were significantly associated with a reduced risk for onset of any irAEs, whereas pretreatment NLR>2.3 and PLR>165 were significantly associated with an increased risk. Conclusions: The findings suggest that considering the routine availability of blood cell count data before the initiation of treatment with pembrolizumab, it may be useful in identifying early-onset irAEs during the 6-weeks study period in clinical practice.

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Pharmacokinetic/pharmacodynamic evaluation of flomoxef against extended-spectrum beta-lactamase-producing Escherichia coli in vitro and in vivo in a murine thigh infection model

Tashiro S, Hayashi M, Takemura W, Igarashi Y, Liu X, Mizukami Y, Kojima N, Enoki Y, Taguchi K, Yokoyama Y, Nakamura T, Matsumoto K

Pharmaceutical Research (Springer) 38 ( 1 ) 83 - 87 2021.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 07248741

Purpose: Although flomoxef (FMOX) has attracted substantial attention as an antibiotic against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli), the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of FMOX against ESBL-producing E. coli is unclear. The aim of this study was to determine the PK/PD index of FMOX against ESBL-producing E. coli. Methods: In vitro time-kill curve studies and in vivo PK/PD experiments were carried out. Results: Time–kill curves exhibited a unique bactericidal activity: time-dependent activity at low concentrations and concentration-dependent activity at high concentrations. In neutropenic murine thigh infection experiments, the antibacterial activity of FMOX correlated with the time that the free drug concentration remaining above the minimum inhibitory concentration (MIC) (fT>MIC) and the ratio of the area under the free drug concentration–time curve for a 24 h period to the MIC (fAUC24/MIC). However, the burden of ESBL producing E. coli significantly reduced when the time intervals for administration were shorter among three dosage regimens with same magnitude of fAUC24/MIC, indicating that fT>MIC is significant PK/PD index. The target value of fT>MIC for 1 log10 kill reduction was 35.1%. Conclusions: fT>MIC is the most significant PK/PD index of FMOX against ESBL-producing E. coli and its target value is ≥ 40%.

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Design, synthesis, and monoamine oxidase inhibitory activity of (+)-cinchonaminone and its simplified derivatives

Sato Yuta, Oyobe Naoko, Ogawa Takao, Suzuki Sayo, Aoyama Hiroshi, Nakamura Tomonori, Fujioka Hiromichi, Shuto Satoshi, Arisawa Mitsuhiro

ACS Medicinal Chemistry Letters (American Chemical Society) 12 ( 9 ) 1464 - 1469 2021

Research paper (scientific journal), Joint Work, Accepted

The absolute structure of an indole alkaloid (+)-cinchonaminone by total synthesis of both (+)-cinchonaminone and its enantiomer was determined. The main focus of the study was the enantioselective synthesis of both enantiomers of a chiral cis-3,4-disubstituted piperidine. We also evaluated monoamine oxidase (MAO) inhibitory activities of these enantiomers. Furthermore, its structurally simplified derivatives were synthesized that did not have any chiral center. Two of these derivatives showed stronger MAO inhibitory activities than that of (+)-cinchonaminone.

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急性期病院における腎機能別酸化マグネシウムの使用実態と薬剤師介入の有用性について

森裕也、小谷遥、伊藤知行、枦秀樹、横山雄太、中村智徳、太田哲徳

日本腎臓病薬物療法学会誌 (日本腎臓病薬物療法学会) 10 ( 2 ) 165 - 170 2021

Research paper (scientific journal), Joint Work, Accepted

代表的8疾患と薬局実習が病院実習の到達度に与える影響

清宮啓介, 津田壮一郎, 池淵由香, 鈴木小夜, 地引　綾, 岩田紘樹，横山雄太, 河添　仁, 小林典子, 藤本和子, 山浦克典, 中村智徳, 村松　博, 青森　達, 望月眞弓

医療薬学 (日本医療薬学会) 46 ( 12 ) 715 - 721 2020.11

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

平成31年度より導入された改訂薬学教育モデル・コアカリキュラムによる実務実習では、実習生が代表的8疾患に継続して関わることが求められ、また実習は薬局、病院の順で行うことを原則としているが、それらの教育効果が新たに導入された概略評価に与える影響は明らかにされていない。そこで本研究では、慶應義塾大学病院薬剤部で独自に作成した「学生個別記録用紙」を用い、代表的8疾患の継続的関わりと薬局実習経験が病院実習における概略評価到達度に与える影響について検討した。平成30年度I期実習生20名（薬局実習未経験）、II期21名（薬局実習経験済）を対象とし、服薬指導と関連した評価項目「（2）-2 処方せんと疑義照会」、「（2）-4 患者・来局者対応、服薬指導、患者教育」、「（3）-1 患者情報の把握」、「（3）-2 医薬品情報の収集と活用」、「（3）-3 処方設計と提案」、「（3）-4 薬物療法における効果と副作用の評価」の概略評価到達度をアウトカムとした。いずれの項目も代表的8疾患の継続経験疾患数は、実習生の概略評価到達度に影響するとは示されなかった。一方で、薬局実習経験は「（3）-1 患者情報の把握」において、病院実習の概略評価到達度を有意に上昇させた（偏回帰係数1.305, P = 0.044; 95%CI, 0.036–2.575）。代表的8疾患には柔軟に対応し、指導薬剤師と共に患者の問題を解決する実習を行うことが重要である。

3EZ, 20Ac-ingenol-induced apoptosis in chemoresistant cancers with cyclin D1 accumulation

Shohei Miyata, Tomonori Nakamura, Susumu Kitanaka

Anticancer Res (The International Institute of Anticancer Research) 40 ( 11 ) 6237 - 6246 2020.11

Research paper (scientific journal), Accepted, ISSN 02507005

Background/Aim: The topoisomerase 1 catalytic inhibitor 3EZ, 20Ac-ingenol specifically induces apoptosis through the activation of ATR and the up-regulation of PTEN by enhancing the DNA damage response (DDR) in human B lymphoma (BALL-1) cells. The accumulation of cyclin D1 in cancer is known to be related to chemoresistance to DNA damage agents and nuclei of BALL-1 cells exhibit high levels of cyclin D1. However, 3EZ, 20Ac-ingenol effectively induced apoptosis of BALL-1 cells. Materials and Methods: Cell growth, protein levels, and apoptosis were determined by an MTT assay, immunoblotting and DNA fragmentation assay, respectively. Results: 3EZ, 20Ac-ingenol strongly induced inhibition of cell proliferation and apoptosis in Jeko-1 and Panc-1 cell lines through the activation of tumor suppressor proteins and caspase 3. Conclusion: 3EZ, 20Ac-ingenol-induced apoptosis might occur in cells with cyclin D1 accumulation through enhancing DDR, regardless of the cancer cell type.

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Nasu I, Shimano R, Kawazoe H, Nakamura T, Miura Y, Takano T, Hayashi M

Clin Ther (Elsevier) 42 ( 10 ) 1975 - 1982 2020.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 01492918

© 2020 Elsevier Inc. Purpose: This study aimed to identify patient-related risk factors for chemotherapy-induced nausea and vomiting (CINV) in patients with cancer receiving carboplatin in addition to standard antiemetics, using real-world data. Methods: In this single-center, observational study, data from electronic medical records of consecutive patients with solid tumors who had received their first cycle of a carboplatin-based regimen and were treated with a 2- or 3-drug combination of antiemetics from January 2014 to January 2019 at Toranomon Hospital were retrospectively analyzed. The primary end point was the occurrence of a complete response (CR) within 5 days after the first cycle, which was defined as no vomiting and no use of rescue medication for CINV. A receiver operating characteristic curve, univariable, and multivariable logistic regression analyses were used. Findings: A total of 314 patients were evaluated in this study. The proportion of patients who had a CR in the overall, acute, and delayed phases was 76.8% (n = 241), 98.7% (n = 310), and 77.4% (n = 243), respectively. Similar to univariable logistic regression analysis, multivariable logistic regression analysis revealed that age ≥70 years and total dexamethasone dose ≥14.6 mg were significantly associated with a non-CR in the overall phase, whereas female sex, history of habitual alcohol intake, and history of smoking were not associated with a non-CR in the overall phase. Implications: Our study findings suggest that a patient age of <70 years and a total dexamethasone dose of <14.6 mg are high-risk factors for carboplatin-induced CINV

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虚実中間証を含む虚実証の予測モデル

前田絢子, 吉野鉄大, 片山琴絵, 堀場裕子, 引網宏彰, 嶋田豊, 並木隆雄, 田原英一,南澤潔, 村松慎一, 山口類, 井元清哉, 宮野悟, 美馬秀樹, 三村將, 中村智徳, 渡辺賢治

日本東洋医学雑誌 (日本東洋医学会) 71 ( 4 ) 315 - 325 2020.07

Research paper (scientific journal), Joint Work, Accepted

Pharmacy Students' Self-efficacy for Pharmaceutical Expertise Affects Successful Experiences as Enactive Attainments in Pharmacy Practice Experience in Japan

Kikuyama F, Suzuki S, Jibiki A, Yokoyama Y, Kawazoe H, Nakamura T

Yakugaku Zasshi (日本薬学会) 140 ( 6 ) 799 - 808 2020.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 00316903

© 2020 The Pharmaceutical Society of Japan Pharmacy practice experience (PPE) is essential in the six-year course of pharmaceutical education in Japan. We previously found that PPE reinforced students' self-efficacy for curriculums (SECs), leading robust acquisition and reconstruction of pharmaceutical expertise. In this study, we aimed to clarify whether students' SECs aŠect successful experiences as enactive attainments in PPE. We distributed survey questionnaires to the fifth-year students in Keio University in 2016-2017 before and after PPE. The students made a self-assessment of their psychological state ``expect to do well'' on a seven-point Likert scale for each curriculum (C1 to C18), and their successful experiences were also collected from free description type questionnaire. We could follow up 139 students. The SEC scores increased from prePPE to post I (p ＜ 0.001) and II terms (p ＜ 0.01). The increase in SEC scores during PPE was associated with the rate of students' successful experiences in the first-term PPE (p ＝ 0.04). The path analysis revealed the following as significant predictive factors of SECs for successful experiences: basic sciences (C1, C2, C3, C4, C5, and C6) with standardizing coefficient 0.35, health and environmental sciences (C11 and C12) with 0.39, and pharmaceutical sciences (C7, C8, C9, C10, C13, and C14) with － 0.51. Students in the first-term PPE tended to experience successful performance in medical professions by using their pharmaceutical expertise that they had learned. In this study, for the first time, we demonstrated that Japanese students' SECs for pharmaceutical expertise affected successful experiences, leading better outcomes of PPE.

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デキサメタゾン配合後における先発及び後発医薬品のゲムシタビン注射剤の製剤学的安定性の評価

吉浦誠海, 河添仁, 鈴木小夜, 横山雄太, 地引綾, 中村智徳

日本臨床腫瘍薬学会雑誌 (日本臨床腫瘍薬学会) 14 1 - 7 2020.04

Research paper (scientific journal), Joint Work, Accepted

Liquid formulation of gemcitabine increases venous pain in patients with cancer: a retrospective study

Kawazoe H, Mori N, Ido S, Uozumi R, Tsuneoka K, Takeuchi A, Matsuo M, Yamauchi M, Nakai M, Sumikawa S, Nakamura T, Yakushijin Y

Clinical Therapeutics (Elsevier Inc.) 42 ( 4 ) 712 - 719 2020.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 01492918

© 2020 Elsevier Inc. Purpose: Venous pain induced by peripheral intravenous infusion of gemcitabine has remained an unresolved issue in clinical practice. This study aimed to identify differences between gemcitabine formulations as well as risk factors associated with gemcitabine-induced venous pain in patients with cancer. Methods: We retrospectively analyzed data from consecutive patients with cancer who had received chemotherapy including a lyophilized or liquid formulation of gemcitabine diluted with 5% glucose solution via a peripheral vein. The study was conducted at Ehime University Hospital using electronic medical records dated between January 2015 and July 2017. The primary end point was the prevalence of venous pain at the administration site during gemcitabine infusion, classified as injection site reaction of grade ≥2 according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate logistic regression analysis with generalized estimating equations for longitudinal data was used to identify risk factors for venous pain during all courses of gemcitabine treatment. Findings: A total of 1150 treatment courses in 141 Japanese patients were evaluated in this study. Venous pain occurred in 115 courses (10.0%) and in 49 patients (34.8%). The multivariate logistic regression analysis with generalized estimating equations revealed that a dose increase of gemcitabine and use of the liquid formulation of gemcitabine were significantly associated with an increased risk for venous pain (dose increase, adjusted odds ratio [OR] = 1.25; 95% CI, 1.11–1.40 [P < 0.001]; and liquid formulation, adjusted OR = 12.43, 95% CI, 5.61–27.51 [P < 0.001]), whereas age, course number of gemcitabine, and use of the soft-back product of 5% glucose solution were significantly associated with a reduced risk for venous pain (age, adjusted OR = 0.75; 95% CI, 0.57–0.98 [P = 0.037]; course number, adjusted OR = 0.96; 95% CI, 0.92–0.99 [P = 0.023]; and soft back, adjusted OR = 0.39; 95% CI, 0.21–0.74 [P = 0.004]). Implications: The use of the liquid formulation of gemcitabine was associated with a significant increase in the frequency of gemcitabine-induced venous pain despite dilution with 5% glucose solution compared to that with the lyophilized formulation. The lyophilized formulation of gemcitabine should hence be used in peripheral intravenous infusion for the treatment of patients with cancer.

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Discrimination of prediction models between cold-heat and deficiency-excess patterns

Maeda-Minami A, Yoshino T, Katayama K, Horiba Y, Hikiami H, Shimada Y, Namiki T, Tahara E, Minamizawa K, Muramatsu S, Yamaguchi R, Imoto S, Miyano S, Mima H, Mimura M, Nakamura T, Watanabe K

Complement Ther Med (Elsevier) 49 102353 2020.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 09652299

© 2020 Elsevier Ltd Objective: The purpose of this study was to extract important patient questionnaire items by creating random forest models for predicting pattern diagnosis considering an interaction between deficiency-excess and cold-heat patterns. Design: A multi-centre prospective observational study. Setting: Participants visiting six Kampo speciality clinics in Japan from 2012 to 2015. Main outcome measure: Deficiency–excess pattern diagnosis made by board-certified Kampo experts. Methods: We used 153 items as independent variables including, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We sampled training data with an equal number of the different patterns from a 2 × 2 factorial combination of deficiency–excess and cold–heat patterns. We constructed the prediction models of deficiency–excess and cold–heat patterns using the random forest algorithm, extracted the top 10 essential items, and calculated the discriminant ratio using this prediction model. Results: BMI and blood pressure, and subjective symptoms of cold or heat sensations were the most important items in the prediction models of deficiency–excess pattern and of cold–heat patterns, respectively. The discriminant ratio was not inferior compared with the result ignoring the interaction between the diagnoses. Conclusions: We revised deficiency–excess and cold–heat pattern prediction models, based on balanced training sample data obtained from six Kampo speciality clinics in Japan. The revised important items for diagnosing a deficiency–excess pattern and cold–heat pattern were compatible with the definition in the 11th version of international classification of diseases.

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The reductive activity of human liver microsomes for vitamin K epoxides

Masashi Kawano, Takuya Araki, Hideaki Yashima , Tomonori Nakamura, Koujirou Yamamoto

Indonesian Journal of Pharmaceutics (Universitas Padjadjaran) 2 ( 1 ) 7 - 13 2020.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 2597-8748

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Cardiac pacemaker cells generate cardiomyocytes from fibroblasts in long-term cultures

Kiuchi S., Usami A., Shimoyama T., Otsuka F., Yamaguchi S., Nakamura T., Suzuki S., Ono K.

Sci Rep (Nature Publishing) 9 ( 1 ) 15174 2019.10

Research paper (scientific journal), Joint Work, Accepted

© 2019, The Author(s). Because cardiomyocyte generation is limited, the turnover of cardiomyocytes in adult heart tissues is much debated. We report here that cardiac pacemaker cells can generate cardiomyocytes from fibroblasts in vitro. Sinoatrial node cells (SANCs) were isolated from adult guinea pig hearts and were cultured at relatively low cell densities. Within a week, a number of fibroblast-like cells were observed to gather around SANCs, and these formed spontaneously beating clusters with cardiomyocyte structures. The clusters expressed genes and proteins that are characteristic of atrial cardiomyocytes. Pharmacological blocking of pacemaker currents inhibited generation of action potentials, and the spontaneous beating were ceased by physically destroying a few central cells. Inhibition of beating during culture also hampered the cluster formation. Moreover, purified guinea pig cardiac fibroblasts (GCFs) expressed cardiac-specific proteins in co-culture with SANCs or in SANC-preconditioned culture medium under electrical stimulation. These results indicate that SANCs can generate cardiomyocytes from cardiac fibroblasts through the influence of humoral factor(s) and electrophysiological activities followed by intracellular Ca2+ oscillations. This potential of SANCs to generate cardiomyocytes indicates a novel mechanism by which cardiomyocytes turns over in the vicinity of pacemaker cells and could be exploited in the development of strategies for cardiac regenerative therapy in adult hearts.

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Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study.

Takahashi K, Yoshino T, Maki Y, Ishiuchi K, Namiki T, Ogawa-Ochiai K, Minamizawa K, Makino T, Nakamura T, Mimura M, Watanabe K

Arch Toxicol (Springer ) 93 ( 11 ) 3111 - 3119 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 03405761

© 2019, Springer-Verlag GmbH Germany, part of Springer Nature. Liquorice [main ingredient, glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18β-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM–1.8 µM) and 18β-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM–4.2 µM). 3-Monoglucuronyl 18β-glycyrrhetinic acid, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker.

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Educational effect of practical training on students’ robust acquisition and reconstruction of expertise on pharmaceutical sciences they had learned before practical training.

Fuminiro Kikuyama, Sayo Suzuki, Tomonori Nakamura

Yakugaku-Zasshi (The Pharmaceutical Society of Japan) 139 ( 9 ) 1201 - 1209 2019.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 00316903

© 2019 The Pharmaceutical Society of Japan. Long-term practical training in the 6-year course of pharmaceutical education is a program for students after acquiring basic knowledge on pharmaceutical sciences and preclinical training. However, it remains unproved whether practical training affects students' robust acquisition and reconstruction of pharmaceutical expertise which they had learned before starting practical training. To address this issue, we administered survey questionnaires to 5th-year students (n=149) of Keio University in 2016 both before and after practical training. From the viewpoint of self-efficacy, psychological approach was applied to evaluate respondents' psychological state "to do well" on a 7-point Likert scale (1=disagree, 4=neither, 7=agree) for specific subjects C1-C18 (18 core units of pharmaceutical expertise in the current Model Core Curriculum for Pharmaceutical Education), mainly including basic pharmaceutical sciences, public health, clinical pharmacology and pharmacotherapy. C1-C18 total score values, which reflect the strength of certainty to acquire expertise, were significantly higher after the first term of practical training compared to before training, regardless of the pharmacy and the hospital (p<0.001), but not after the second term. Specific factors associated with increased score values for "to do well" were not extracted from other questionnaire answers concerning students' mentors or their self-learning during practical training. These results demonstrated that practical training at least partly reinforced students' feeling of "to do well", contributing to their robust acquisition and reconstruction of pharmaceutical expertise. Giving students recognition individually of their learning process themselves encourages more effective practical training toward their development of resources as a pharmacist.

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Prediction of deficiency-excess pattern in Japanese Kampo medicine: Multi-centre data collection.

Maeda-Minami A, Yoshino T, Katayama K, Horiba Y, Hikiami H, Shimada Y, Namiki T, Tahara E, Minamizawa K, Muramatsu S, Yamaguchi R, Imoto S, Miyano S, Mima H, Mimura M, Nakamura T, Watanabe K

Complemen Ther Med (Elsevier) 45 228 - 233 2019.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 09652299

© 2019 Elsevier Ltd Objective: The purpose of the present study was to compare important patient questionnaire items by creating a random forest model for predicting deficiency-excess pattern diagnosis in six Kampo specialty clinics. Design: A multi-centre prospective observational study. Setting: Participants who visited six Kampo specialty clinics in Japan from 2012 to 2015. Main outcome measure: Deficiency-excess pattern diagnosis made by board-certified Kampo experts. Methods: To predict the deficiency-excess pattern diagnosis by Kampo experts, we used 153 items as independent variables, namely, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We extracted the 30 most important items in each clinic's random forest model and selected items that were common among the clinics. We integrated participating clinics’ data to construct a prediction model in the same manner. We calculated the discriminant ratio using this prediction model for the total six clinics’ data and each clinic's independent data. Results: Fifteen items were commonly listed in top 30 items in each random forest model. The discriminant ratio of the total six clinics’ data was 82.3%; moreover, with the exception of one clinic, the independent discriminant ratio of each clinic was approximately 80% each. Conclusions: We identified common important items in diagnosing a deficiency-excess pattern among six Japanese Kampo clinics. We constructed the integrated prediction model of deficiency-excess pattern.

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Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study

Akihiro Komatsu, Tetsuhiro Yoshino, Takeshi Suzuki, Tomonori Nakamura, Takanori Kanai, Kenji Watanabe

Basic Clin Pharmacol Toxicol (Wiley) 124 ( 5 ) 607 - 614 2019.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 17427835

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society) Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct bilirubin, glycyrrhizin and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia is defined as a serum potassium level of ≤3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of ≥0.5 mEq/L or an increase of ≥0.5 mEq/L after discontinuing the glycyrrhizin-containing medication was examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy-nine patients received glycyrrhizin (exposed group; mean age: 60.5 ± 14.2) and 1313 did not receive glycyrrhizin (control group; mean age: 58.3 ± 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct-bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin.

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改訂薬学教育モデル・コアカリキュラムに準拠した実務実習に向けたルーブリック形式の概略評価を用いたパフォーマンス評価の先行導入　学生視点に基づくアウトカム評価と教育効果向上のための提案

鈴木小夜, 河添仁, 地引綾, 横山雄太, 中村智徳

医療薬学 (日本医療薬学会) 45 ( 4 ) 228 - 239 2019.04

Research paper (scientific journal), Single Work, Accepted

Renal dysfunction and anemia associated with long-term imatinib treatment in patients with chronic myelogenous leukemia.

Sakurai M, Kikuchi T, Karigane D, Kasahara H, Matsuki E, Hashida R, Yamane Y, Abe R, Koda Y, Toyama T, Kato J, Shimizu T, Yokoyama Y, Suzuki S, Nakamura T, Okamoto S, Mori T

International Journal of Hematology (Springer) 109 ( 3 ) 292 - 298 2019.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 09255710

© 2019, Japanese Society of Hematology. Knowledge of the toxicity profile of long-term treatment with imatinib is limited. In the present study, we sought to evaluate renal function and hemoglobin levels during long-term imatinib treatment. Eighty-two patients with chronic myelogenous leukemia in chronic phase who had been on imatinib for over 5 years were retrospectively analyzed. The mean estimated glomerular filtration rate (eGFR) was significantly decreased over 5 years (77 ± 17 to 62 ± 14 ml/min/1.73m², P < 0.001). Higher age and lower eGFR value at initiation of imatinib were significantly associated with development of renal dysfunction by multivariate analyses. Mean hemoglobin levels also significantly decreased over the 5-year period (12.9 ± 1.7 to 12.4 ± 1.3 g/dl, P < 0.01). The rate of decrease in eGFR correlated significantly with hemoglobin levels (correlation coefficient = − 0.249, P < 0.05). Serum erythropoietin (EPO) levels did not increase in 16 patients with both renal dysfunction and anemia (median, 31.9 mIU/ml). In patients who participated in a clinical trial of imatinib discontinuation, mean eGFR (50.0 ± 6.5 to 56.0 ± 10.2 ml/min/1.73m², P < 0.05) and hemoglobin levels (12.0 ± 1.7 to 14.0 ± 1.6 g/dl, P < 0.01) improved significantly at 1 year after discontinuation. These findings suggest that long-term imatinib results in a partially reversible continuous decline in renal function and decreased hemoglobin levels.

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Olanzapine plus aprepitant, palonosetron, and dexamethasone for nausea and vomiting in patients with breast cancer receiving anthracycline: A retrospective study.

Hitoshi Kawazoe, Ryuji Uozumi, Akari Murakami, Michiko Yamashita, Kana Kobayashi-Taguchi, Erina Kusakabe, Haruna Yamasawa, Yoshihiro Yakushijin, Tomonori Nakamura, Yoshiaki Kamei

Scientific Reports (Nature Publishing) 8 ( 1 ) 16232 2018.11

Research paper (scientific journal), Joint Work, Accepted

© 2018, The Author(s). This study aimed to compare the antiemetic efficacy and safety of a four-drug combination with those of a standard three-drug combination in Japanese patients with breast cancer treated with anthracycline. We retrospectively analyzed data from Japanese patients with breast cancer, who had received their first cycle of anthracycline and were treated with aprepitant, palonosetron, and dexamethasone with or without olanzapine. This retrospective observational study was performed at Ehime University Hospital using the electronic medical records. Multivariable and propensity score-adjusted analyses were performed to compare the onset of complete response (CR) failure between the groups. One-hundred and thirty patients were included in this study and the four- and three-drug group had 22 and 108 patients, respectively. Similar to multivariable logistic regression analysis, propensity-adjusted logistic regression analysis revealed that the four-drug group was markedly associated with a decreased odds of CR failure in the overall, acute, and delayed phases (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.10–0.73; OR: 0.28, 95% CI: 0.10–0.76; and OR: 0.15, 95% CI: 0.04–0.57, respectively). Additionally, treatment-related adverse events were well tolerated in both the groups. These findings suggest that the antiemetic efficacy of the four-drug combination is superior to that of the standard three-drug combination.

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Hitoshi Kawazoe, Akari Murakami, Michiko Yamashita, Kanako Nishiyama, Kana Kobayashi-Taguchi, Saaya Komatsu, Reina Aoki, Erina Kusakabe, Haruna Yamasawa, Yoshihiro Yakushijin, Tomonori Nakamura, Yoshiaki Kamei

Clinical Therapeutics (Elsevier) 40 ( 12 ) 2170 - 2179 2018.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 01492918

© 2018 Elsevier Inc. Purpose: The aim of this study was to identify a high-risk or low-risk population for chemotherapy-induced nausea and vomiting among patients with breast cancer treated with a current standard 3-drug antiemetic regimen and receiving anthracycline. Methods: We analyzed data from chemotherapy-naive Japanese patients with breast cancer, who had received the first cycle of anthracycline-based regimen and were treated with a 3-drug combination of aprepitant, palonosetron, and dexamethasone. This study was carried out at Ehime University Hospital (Toon, Japan) using electronic medical records from May 2011 to June 2017. The primary end point was complete response (CR), which was defined as no emesis and no use of rescue medication. Findings: A total of 103 patients were included in this study. The percentages of patients who had a CR in the overall, acute, and delayed phases were 35.0%, 40.8%, and 50.5%, respectively. Multivariate logistic regression analysis revealed that age <55 years and body mass index <27.5 kg/m2 were significantly associated with an increased risk for CR failure in the overall and acute phases. In contrast, a history of alcohol habit was significantly associated with a decreased risk for CR failure in overall phase. Implications: The present findings suggest that, among patients with breast cancer receiving anthracycline and treated with aprepitant, palonosetron, and dexamethasone, patients younger than 55 years and having a body mass index <27.5 kg/m2 are high-risk populations for chemotherapy-induced nausea and vomiting, whereas those with a history of habitual alcohol consumption is a low-risk one.

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Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients

Daisuke Nagano, Takuya Araki, Kunio Yanagisawa, Yoshiyuki Ogawa, Fumito Gohda, Hideki Uchiumi, Hiroshi Handa, Tomonori Nakamura, Koujirou Yamamoto

European Journal of Clinical Pharmacology (Springer) 74 ( 8 ) 1055 - 1060 2018.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 00316970

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: The clinical efficacies of some antiretroviral drugs are known to not depend on its concentration in blood. To establish a method of dosage adjustment for darunavir (DRV) based on pharmacokinetic theory, we analyzed the correlation between DRV levels in peripheral blood mononuclear cells (PBMCs) and plasma. Methods: The concentrations of DRV and ritonavir (RTV) in plasma and PBMCs of 31 samples obtained from 19 patients were analyzed. An in vitro kinetic study using MOLT-4 cells was performed to assess the contribution of RTV to the intracellular accumulation of DRV. Results: DRV levels in PBMCs varied between 7.91 and 29.36 ng/106 cells (CV 37.5%), while those in plasma were greater. No significant correlation was found between the trough level of DRV in plasma and that in PBMCs (p = 0.575). The inter-day difference in DRV levels in PBMCs seemed smaller than that in plasma (− 41.6–23.0% vs − 83.3–109.1%). In the in vitro study, the elimination half-life of cellular efflux of DRV was 15.7 h in the absence of RTV and extended to 47.6 h in the presence of RTV. Conclusions: We found a poor correlation between intracellular DRV and plasma DRV levels in patients receiving highly active antiretroviral therapy. The efflux rate of DRV from cells was slow; therefore, the concentration of DRV in PBMCs may reflect average exposure to the drug and clinical efficacy.

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Effect of a Dietary Supplement Containing Raspberry Ketone on CYP3A Activity in Healthy Women.

Tohru Aomori, JingWei Qi, Yuko Okada, Katsunori Nakamura, Haruhiko Hiraoka, Takuya Araki, Tomonori Nakamura, Ryuya Horiuchi, Koujirou Yamamoto

Pharmaceutica Analytica Acta 9 ( 6 ) 1000587 2018.06

Joint Work, Accepted, ISSN 2153-2435

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学生のニーズに基づき学生主体で構築した新たなアドバンスト服薬指導事前実習の実施とその評価

鈴木小夜, 青野いづみ，今井奈津美，桑原亜記，剱田侑希，松元美奈子，吉田彩，渡邊明日香，高木彰紀，小林典子，佐伯晴子，大谷壽一，中村智徳，木津純子

薬学雑誌 (日本薬学会) 137 ( 11 ) 1391 - 1408 2017.11

Research paper (scientific journal), Joint Work, Accepted

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電子味覚システムとヒト官能試験によるクリンダマイシンの苦味抑制飲食物の探索

NAKAMURA Tomonori

医療薬学 (日本医療薬学会) 43 ( 9 ) 492 - 501 2017.09

Research paper (other academic), Joint Work, Accepted

事前学習および薬局実習における OTC 実習の問題点と満足度向上のための提案

栗原智香，青森　達，鈴木小夜，高木彰紀，大塚尚子，地引　綾，中村智徳

薬学教育 (日本薬学教育学会) 1 51 - 58 2017.08

Research paper (scientific journal), Joint Work, Accepted

Signiﬁcant decreases in blood propofol concentrations during adrenalectomy for phaeochromocytoma

Tatsunori Watanabe, Haruhiko Hiraoka, Takuya Araki, Daisuke Nagano, Tohru Aomori, Tomonori Nakamura, Koujirou Yamamoto, Hiroshi Baba

Br J Clin Pharmacol. (Wiley) 83 ( 10 ) 2205 - 2213 2017.07

Research paper (scientific journal), Joint Work, Accepted

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Development and evaluation of an overseas clinical rotation program for undergraduate pharmacy students in Japan.

Hisakazu Ohtani⁎, Rieko Mitsui, Takeshi Akiyoshi, Ayuko Imaoka, Yoshihiro Abe, Motoko Kanke, Tomonori Nakamura, Patrick Foster, Mayumi Mochizuki

Currents in Pharmacy Teaching and Learning (Elsevier) 9 ( 3 ) 452 - 459 2017.03

Research paper (scientific journal), Joint Work, Accepted

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Sex differences in the blood concentration of tacrolimus in systemic lupus erythematosus and rheumatoid arthritis patients with CYP3A5*3/*3

Ayano Ito, Yuko Okada, Tadahiro Hashita, Tohru Aomori, Keiju Hiromura, Yoshihisa Nojima, Tomonori Nakamura, Takuya Araki, Koujirou Yamamoto

Biochem Genet (Springer) 55 ( 3 ) 268 - 277 2017.03

Research paper (scientific journal), Joint Work, Accepted

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Suppression of antibody to infliximab by azathioprine in a patient with rheumatoid arthritis.

Aomori Tohru, Tsuchiya Ayumi, Suzuki Sayo, Jibiki Aya, Otsuka Naoko, Ishioka Eriko, Kaneko Yuko, Takeuchi Tsutomu, Tomonori Nakamura

Die Pharmazie 72 ( 2 ) 95 - 97 2017.02

Research paper (scientific journal), Joint Work, Accepted

Effect of genetic polymorphisms of azathioprine-metabolizing enzymes on response to rheumatoid arthritis treatment

Tsuchiya Ayumi, Aomori Tohru, Mami Sakamoto, Suzuki Sayo, Jibiki Aya, Otsuka Naoko, Ishioka Eriko, Kaneko Yuko, Takeuchi Tsutomu, Tomonori Nakamura

Die Pharmazie 72 ( 1 ) 22 - 28 2017.01

Research paper (scientific journal), Joint Work, Accepted

Elevated direct bilirubin: Possible predictors for pseudoaldosteronism: Case–control study

Tetsuhiro Yoshino, Haruka Nakamura, Megumi Sano, Yuko Horiba, Tomonori Nakamura, Kenji Watanabe

Traditional & Kampo Medicine 3 ( 2 ) 174 - 176 2016.07

Research paper (scientific journal), Joint Work, Accepted

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生物学的製剤のリウマチ治療効果予測モデルの構築

NAKAMURA Tomonori

上原生命科学財団研究報告集 29 1 - 4 2015.12

Research paper (bulletin of university, research institution), Single Work

Determination of Intracellular Darunavir by Liquid Chromatography Coupled with Fluorescence Detection.

Daisuke Nagano, Takuya Araki, Tomonori Nakamura, Koujirou Yamamoto

J Chromatog Sci 52 ( 9 ) 1021 - 1025 2014.10

Research paper (scientific journal), Joint Work, Accepted

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Quantitative evaluation of biliary elimination of gadoxetate, a magnetic resonance imaging contrast agent, via geometrical isomer-specific transporting system in rats.

Ogawa J, Yokota A, Araki T, Aomori T, Nakamura T, Yamamoto K, Koshiishi I*.

Biopharmaceutics & Drug Disposition 35 ( 6 ) 362 - 371 2014.08

Research paper (scientific journal), Joint Work, Accepted

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The Effect of a Dietary Supplement Containing Raspberry Ketone on CYP3A Activity.

Masayuki Sekizuka, Jing Wei Qi, Tohru Aomori, Yuko Okada1, Katsunori Nakamura, Takuya Araki, Ryuya Horiuchi, Shin Ohta, Tomonori Nakamura and Koujirou Yamamoto

Pharmaceutica Analytica Acta 5 ( 6 ) 302 2014.06

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

Case report: dose adjustment of warfarin using genetic information and plasma concentration monitoring.

Tohru Aomori*, Yukiyoshi Fujita, Kyoko Obayashi, Hiroaki Sato, Kazuma Kiyotani, Katsunori Nakamura, Tomonori Nakamura, Koujirou Yamamoto.

J Clin Pharm Ther 9 ( 6 ) 319 - 321 2014.06

Research paper (scientific journal), Joint Work, Accepted

Assessment of DDR2, BRAF, EGFR, and KRAS mutations as therapeutic markers in Japanese non-adenocarcinoma lung cancer patients.

14. Hideaki Yashima, Kimihiro Shimizu, Takuya Araki, Tohru Aomori, Yoichi Ohtaki, Toshiteru Nagashima, Yasuaki Enokida, Jun Atsumi, Tomonori Nakamura, Izumi Takeyoshi, Koujirou Yamamoto

Mol Clin Oncol 2 714 - 718 2014.06

Research paper (scientific journal), Joint Work, Accepted

OTC薬実習の問題点とその改善のための提案.

剱田侑希, 門田佳子, 鈴木小夜, 青森達, 小林典子, 高木彰紀, 手塚淑人, 大谷壽一, 中村智徳*.

医療薬学 40 117 - 123 2014.02

Research paper (scientific journal), Joint Work, Accepted

Risk of Falling and Hypnotic Drugs: Retrospective Study of Inpatients

Kyoko Obayashi, Takuya Araki, Katsunori Nakamura, Masahiko Kurabayashi, Yoshihisa Nojima, Katsuyuki Hara, NAKAMURA Tomonori, Koujirou Yamamoto

Drugs in R&D 13 159 - 164 2013.06

Research paper (scientific journal), Joint Work, Accepted

Sensitive and simple determination of vitamin K1 in human plasma by ultra-performance liquid chromatography coupled with a fluorescence detector.

Izumi Ohno, Takuya Araki, Masashi Kawano, Tomonori Nakamura*, Koujirou Yamamoto.

J Liquid Chromatography and Related Technology 36 ( 8 ) 1068 - 1077 2013.03

Research paper (scientific journal), Joint Work, Accepted

Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population.

Taofik Rusdiana, Takuya Araki, Tomonori Nakamura*, Anas Subarnas, Koujirou Yamamoto.

Eur J Clin Pharmacol 69 ( 3 ) 395 - 405 2013.03

Research paper (scientific journal), Joint Work, Accepted

Analysis of cytochrome P450 gene polymorphism in a lupus nephritis patient in whom tacrolimus blood concentration was markedly elevated after administration of azole anti-fungal agents.

Yukiyoshi Fujita, Takuya Araki, Yuko Okada, Tohru Aomori, Rie Shimizu, Tomizawa Takeshi, Keiju Hiromura, Yoshihisa Nojima, Tomonori Nakamura*, Koujirou Yamamoto.

J Clin Pharm Ther 38 ( 1 ) 74 - 76 2013.02

Research paper (scientific journal), Joint Work, Accepted

Effect of genetic polymorphisms (TPMT, ITPA, IMPDH1, XO and MRP4) on the efficacy of low-dose azathioprine therapy in Japanese patients with systemic lupus erythematosus.

Ayumu Nagamine, Miki Takenaka, Tohru Aomori, Yuko Okada, Keiju Hiromura, Yoshihisa Nojima Y, Takuya Araki, Tomonori Nakamura, Koujirou Yamamoto*.

Amer J Health-Sys Pharm 69 (23) 2072-2078 2012.12

Research paper (scientific journal), Joint Work, Accepted

Clinical efficacy of two intravenous iron, saccharated ferric oxide and cideferron, for iron deficiency anemia.

Takuya Araki, Mari Takaai, Ai Miyazaki, Sohei Ohshima, Taku Shibamiya, Tomonori Nakamura, Koujirou Yamamoto:

Die Pharmazie 67 ( 12 ) 1030-1032 2012.12

Research paper (scientific journal), Joint Work, Accepted

A patient with GIST modified dose by measurement of plasma concentration of sunitinib.

Tadahiro Hashita, Yoshihiko Katsuyama, Katsunori Nakamura, Yasuyuki Momose, Daisuke Komatsu, Naohiko Koide, Shinichi Miyagawa, Tomonori Nakamura, Koujirou Yamamoto, Shigeru Ohmori*.

Oncology Letters 4 (3) 501-504. 2012.09

Research paper (scientific journal), Joint Work, Accepted

Design and synthesis of indomethacin analoguesthat inhibit P-glycoprotein and/or multi-drug resistant protein without Cox inhibitory activity.

Mitsuhiro Arisawa, Yayoi Kasaya, Tohru Obata, Takuma Sasaki, Tomonori Nakamura, Takuya Araki, Koujirou Yamamoto, Akito Sasaki, Akihiro Yamano, Mika Ito, Hiroshi Abe, Yoshihiro Ito, Ssatoshi Shuto

J Med Chem 55 ( 18 ) 8152-8163 2012.09

Research paper (scientific journal), Joint Work, Accepted

Effect of ethanol contained in paclitaxel injection on the ethanol concentration in expiration.

Tohru Aomori, Hironori Makino, Masayuki Sekizuka, Takuya Araki, Keiko Iizuka, Tomonori Nakamura, Koujirou Yamamoto*.

Drugs R&D 12 (3) 165-170 2012.09

Research paper (scientific journal), Joint Work, Accepted

CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subjects.

Katsunori Nakamura, Kyoko Obayashi, Takuya Araki, Tohru Aomori, Yukiyoshi Fujita, Yuko Okada, Masahiko Kurabayashi, Akira Hasegawa, Shigeru Ohmori, Tomonori Nakamura, Koujirou Yamamoto

J. Clin. Pharmacy Ther 37 ( 4 ) 481-485 2012.08

Research paper (scientific journal), Joint Work, Accepted

Review of the treatment of non-small-cell lung cancer with gefitinib.

Takuya Araki, Hideaki Yashima, Kimihiro Shimizu, Tohru Aomori, Tadahiro Hashita, Kyoichi Kaira, Tomonori Nakamura, Koujirou Yamamoto

Clinical Medicine Insights: Oncology 12 ( 6 ) 407-421 2012.06

Research paper (scientific journal), Joint Work, Accepted

Ruthenium-catalyzed cycloisomerization of 1,3-dienes, for example, an N-dienyl-2-vinylaniline derivative, leading to a 3-Exomethylene-2-vinyl indole derivative and its application to the synthesis of (±)-cinchonaminone.

Takao Ogawa, Tomonori Nakamura, Takuya Araki, Koujiro Yamamoto, Satoshi Shuto, Mitsuhiro Arisawa*.

Eur J Organic Chemistry 2012 (16) 3084-3087 2012.04

Research paper (scientific journal), Joint Work, Accepted

Clinical screening assay of EGFR mutations by PNA-clamp Smart Amplification Process Version 2 in lung adenocarcinoma.

Takuya Araki, Kimihito Shimizu, Tomonori Nakamura, Masaru Baba, Yuki Kawai, Katsunori Nakamura, Yasumasa Mitani, Kyoko Obayashi, Tohru Aomori, Yukiyoshi Fujita, Yohei Miyamae, Seiichi Kakegawa, Kyoichi Kaira, Alexander Lezhava, Yoshihide Hayashizaki, Izumi Takeyoshi, Koujirou Yamamoto.

Oncology Reports 26 (5) 1213-1219 2011.11

Research paper (scientific journal), Joint Work, Accepted

Determination of landiolol in human plasma by high-performance liquid chromatography with fluorescence detection.

Tohru Aomori, Naoki Matsumoto, Katsunori Nakamura, Yukiyoshi Fujita, Masayuki, Sekizuka, Takuya Araki, Tomonori Nakamura, Koujirou Yamamoto*.

J Liquid Chromatography and Related Technology 34 (19) 2411-2419. 2011.11

Research paper (scientific journal), Joint Work, Accepted

Influence of CYP2C9 and VKORC1 polymorphisms on time to determine the warfarin maintenance dose.

Tohru Aomori, Kyoko Obayashi, Yukiyoshi Fujita, Takuya Araki, Katsunori Nakamura, Tomonori Nakamura, Koujirou Yamamoto*.

Pharmazie 66 (3) 222-225 2011.03

Research paper (scientific journal), Joint Work, Accepted

液体調製器具を用いた抗がん薬注射剤調製手技の未熟達者における評価.

藤田行代志, 関塚雅之, 中村智徳, 本徳理恵, 阿部正樹, 中村克徳, 荒木拓也, 飯塚惠子, 山本康次郎*.

医療薬学 37 (2) 91-96 2011.02

Research paper (scientific journal), Joint Work, Accepted

入院患者持参薬を含む内服指示書作成システムの確立.

金田亜季子, 大林恭子, 阿部正樹, 飯塚恵子, 中村智徳, 山本康次郎*.

医療薬学 36 (8) 599-604 2010.08

Research paper (scientific journal), Joint Work, Accepted

Pharmacokinetic individualization of high-dose methotrexate chemotherapy for treatment of localized osteocarcinoma.

Yukiyoshi Fujita, Tomonori Nakamura*, Hiromi Nishiba, Tetsuya Shinozaki, Takashi Yanagawa, H Watanabe, Kenji Takagishi, Yuko Okada, Katsunori Nakamura, Ryuya Horiuchi, Koujirou Yamamoto.

J Chemotherapy 22 (3) 186-190 2010.06

Research paper (scientific journal), Joint Work, Accepted

Inosine triphosphate pyrophosphatase 94C>A polymorphism: clinical implications for patients treated with low-dose azathioprine.

Koujirou Yamamoto*, Yuko Okada, Katsunori Nakamura, Keiju Hiromura, Yoshihis Nojima, Tomonori Nakamaura.

Exp Opin Drug Safety 9 (3) 447-457 2010.03

Research paper (scientific journal), Joint Work, Accepted

Usefulness of peptide nucleic acid (PNA)-clamp smart amplification process version 2 (SmartAmp2) for clinical diagnosis of KRAS codon 12 mutations in lung adenocarcinoma; comparison of PNA-clamp SmartAmp2 and PCR-related methods.

Takuya Araki, Kimihiro Shimizu, Katsunori Nakamura, Tomonori Nakamura, Yasumasa Mitani, Kyoko Obayashi, Yukiyoshi Fujita, Seiichi Kakegawa, Yohei Miyamae, Kyoichi Kaira, Takefumi Ishidao, Alexander Lezhava, Yoshihide Hayashizaki, Izumi Takeyoshi, Koujirou Yamamoto.

J. Molecular Diagnostics 12 (1) 118-124. 2010.01

Research paper (scientific journal), Joint Work, Accepted

アザチオプリンの治療効果に対するITPA94C＞A遺伝子多型の影響

山本康次郎，岡田裕子，中村智徳

医薬ジャーナル 45 ( 12 ) 149-154. 2009.12

Research paper (scientific journal), Joint Work

薬学的視点を踏まえたバイタルサイン教育: 薬剤師がバイタルサインの測定を習得するための環境と実践.

大林恭子, 金田亜季子, 飯塚恵子, 中村智徳, 山本康次郎

薬局 60 ( 10 ) 3287-3291 2009.10

Research paper (scientific journal), Joint Work

Isolation of β-sitosterol and digalactopyranosyldiacyl-glyceride from Citrus hystrix, a Thai traditional harb, as pancreatic lipase inhibitors.

Daisuke Watanabe, Rie Kerakawati, Tetsuo Morita, Tomonori Nakamura, Koichi Ueno, Takuya Kumamoto, Waka Nakanishi, Tsutomu Ishikawa*, Jun Uzawa, Hiroko Seki, Masahiko Tachi, Kenichi Harada, Yoshinori Higuchi, Chaiyo Chaichantipyuth.

Heterocycles 78 1497-1505 2009.05

Research paper (scientific journal), Joint Work, Accepted

Comparative antiulcer effect of bisdemethoxycurcumin and curcumin in a gastric ulcer model system.

Sirima Mahattanadul, Tomonori Nakamura, Panichayupakaranant P, Phdoongsombut N, Tungsinmunkong K, Bouking P.

Phytomedicine 16 (4) 342-351 2009.04

Research paper (scientific journal), Joint Work, Accepted

The structure-activity relationship between oxycoumarin derivatives which show the inhibitory effect of iNOS in mouse macrophage RAW 264.7.

Tomonori Nakamura*, Naoko Kodama, Manabu Oda, Shizuko Tsuchiya, Yu Arai, Takuya Kumamoto, Tsutomu Ishikawa, Koichi Ueno, Shingo Yano.

J Natural Medicines 63 (1) 15-20 2009.01

Research paper (scientific journal), Joint Work, Accepted

Inhibitory effect of the extracts from Thai medicinal plants on iNOS expression in mouse macrophage RAW 264.7.

Tomonori Nakamura*, Naoko Kodama, Takuya Kumamoto, Yoshinori Higuchi, Chaiyo Chaichantipyuth, Koichi Ueno, Tsutomu Ishikawa, Shingo Yano.

J Natural Medicines 63 (1) 107-110 2009.01

Research paper (scientific journal), Joint Work, Accepted

Inhibitory effect of oxycoumarins isolated from Thai medicinal plant, Clausena guillauminii on the inflammation mediators, iNOS, TNF-α and COX-2 expression in mouse macrophage RAW264.7.

Tomonori Nakamura*, Naoko Kodama, Yu Arai, Takuya Kumamoto, Yoshinori Higuchi, Chaiyo Chaichantipyuth, Tsutomu Ishikawa, Koichi Ueno, Shingo Yano.

J Natural Medicines 63 (1) 21-27. 2009.01

Research paper (scientific journal), Joint Work, Accepted

Morphine-6-glucuronide induces contraction of the ileal circular muscle more potently than morphine in mice.

Hiroki Iwata, Shizuko Tsuchiya, Koichi Ueno, Tomonori Nakamura, Shingo Yano*.

Eur J Pharmacol 600 (1-3) 130-132 2008.12

Research paper (scientific journal), Joint Work, Accepted

一般用医薬品販売制度改革に対する薬学生の意識調査.

奥澤紘子, 鵜飼加奈子, 武藤奈々美, 草間美嘉, 中村智徳, 上野光一*.

医療薬学 34 (9) 891-897 2008.09

Research paper (scientific journal), Joint Work, Accepted

Functional analysis of the transcriptional activity of cytosine and adenine (CA) repeats polymorphism in the estrogen receptor β gene.

Kanako Ugai, Kazuhiro Nishimura, Katsumi Fukino, Tomonori Nakamura, Koichi Ueno*.

J Toxicol Sci 33 (2) 237-240 2008.05

Research paper (scientific journal), Joint Work, Accepted

甘味ステビア食品は糖尿病予備軍を救うことが出来るか―インスリンシグナル伝達増強作用.

矢野眞吾,土屋静子,中村智徳*.

日本アンチエイジング歯科学雑誌 1 13-18 2008.05

Research paper (scientific journal), Joint Work, Accepted

千葉大学医療系学部基礎教育課程における専門職連携教育の取組み ― 看護学部, 薬学部, 医学部必須教育プログラムの開発と実践.

酒井郁子*, 宮崎美砂子, 山本利江, 石井伊都子, 中村智徳, 根矢三郎, 田邉政裕, 田川まさみ, 朝比奈真由美.

千葉大学看護学部紀要 30 49-55 2008.05

Research paper (scientific journal), Joint Work, Accepted

砂糖代替甘味料－ステビア.

矢野眞吾, 中村智徳, 土屋静子

Functional Food 2 41-46 2008

Research paper (scientific journal), Joint Work

Contractile effect of TRPA1 receptor agonists in the isolated mouse intestine.

Angelica Rodories Penuelas, Kimihito Tashima, Tomonori Nakamura, Shizuko Tsuchiya, Syunji Horie, Shingo Yano

Eur J Pharmacol 576 ( 1-3 ) 143-150 2007.12

Research paper (scientific journal), Joint Work, Accepted

Morphine leads to contraction of ileal circular muscle via inhibition of nitergic pathway in mice.

Hiroki Iwata, Shizuko Tsuchiya, Tomonori Nakamura, Shingo Yano*.

Eur J Pharmacol 574 (1) 66-70 2007.11

Research paper (scientific journal), Joint Work, Accepted

Regionally differential effects of sennoside A on spontaneous contractions of colon in mice.

Michiko Kobayashi*, Taketo Yamaguchi, Takao Odaka, Tomonori Nakamura, Shizuko Tsuchiya, Shingo Yano.

Basic Clin Pharmacol Toxicol 101 (2) 121-126 2007.08

Research paper (scientific journal), Joint Work, Accepted

非ステロイド抗炎症薬と同時投与されたラフチジンのラット胃粘膜障害形成に対する抑制効果.

土屋静子, 中村智徳, 矢野眞吾*.

薬理と治療 35 (2) 159-164 2007.02

Research paper (scientific journal), Joint Work, Accepted

Association of hypoadiponectinemia in men with early onset of coronary heart disease and multiple coronary artery stenosis.

aotake Hashimoto, Junji Kanda, Tomonori Nakamura, Atsuya Horie, Hiroko Kurosawa, Toru Hashimoto*, Kazutoshi Sato, Syunichi Kushida, Masaru Suzuki, Shingo Yano, Rie Iwai, Hidenori Takahashi, Shouji Yoshida.

Metabolism 55 (12) 1653-1657 2006.12

Research paper (scientific journal), Joint Work, Accepted

Establishment and pathophysiological characterization of type 2 diabetic mice model produced by streptozotocin and nicotinamide.

Tomonori Nakamura*, Tomoko Terajima, Taeko Ogata, Koichi Ueno, Naotake Hashimoto, Kageyoshi Ono, Shingo Yano.

Biol Pharm Bull 29 (6) 1167-1174 2006.06

Research paper (scientific journal), Joint Work, Accepted

Isolation of new Gelsedine-type indole alkaloids from Gelsemium elegans and evaluation of cytotoxic activity of Gelaemium alkaloids on epidermoid carcinoma A431.

Mariko Kitajima*, Tomonori Nakamura, Noriyuki Kogure, Mio Ogawa, Yuka Mitsuno, Kageyoshi Ono, Shingo Yano, Norio Aimi, Hiromitsu Takayama.

J Natural Products 69 (4) 715-718 2006.04

Research paper (scientific journal), Joint Work, Accepted

Memory and learning-enhancing effect of Daikenchuto, a traditional Japanese herbal medicine, in mice.

Tomonori Nakamura, Nobuko Komai, Issei Isogami, Koichi Ueno, Fumio Ikegami, Kageyoshi Ono, Shingo Yano*.

J Natural Medicines 60 64-67 2006.01

Research paper (scientific journal), Joint Work, Accepted

Elucidation of anti-allergic activities of curcumin-related compounds with a special reference to their anti-oxidative activities.

Makoto Suzuki, Tomonori Nakamura, Sachi Iyoki, Akihiro Fujiwara, Yuhya Watanabe, Kunihiko Mohri, Kageyoshi Ono, Shingo Yano*.

Biol Pharm Bull 28 (8) 1438-1443 2005.08

Research paper (scientific journal), Joint Work, Accepted

A new lignin from Balanophora abbreviate and inhibition of lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression.

Akihiro Hosokawa, Megumi Sumino, Tomonori Nakamura, Shingo Yano, Toshikazu Sekine, Nijsri, Ruangrungsi, Kazuo Watanabe, Fumio Ikegami*.

Chem Pharm Bull 52 (10) 1265-1267 2004.10

Research paper (scientific journal), Joint Work, Accepted

Impaired glucose tolerance is accompanied by decreased insulin sensitivity in tissues of mice implanted with cells that over-express resistin.

Yutaka Kitagawa, Hideaki Bujo, Kazuo Takahashi, Manabu Shibasaki, Ko Ishikawa, Kazuo Yagui, Naotake Hashimoto, Kazuhiro Noda, Tomonori Nakamura, Shingo Yano, Yasushi Saito.

Diabetologia 47 (10) 1847-1853 2004.10

Research paper (scientific journal), Joint Work, Accepted

The histamine H2 receptor antagonist, cimetidine, inhibits the articular osteopenia in rats with adjuvant-induced arthritis by suppressing the osteoclast differentiation induced by histamine.

Katsunori Yamaura, Taeko Yonekawa, Tomonori Nakamura, Shingo Yano, Koichi Ueno*.

J Pharmacol Sci 92 (1) 43-49 2003.05

Research paper (scientific journal), Joint Work, Accepted

Abatement of morphine-induced constipation in mice by Dai-kenchu-to, a traditional Japanese herbal medicine.

Tomonori Nakamura, Akiko Sakai, Issei Isogami, Kazuhiro Noda, Koichi Ueno, Shingo Yano*.

Jpn J Pharmacol 88 (2) 217-221 2002.02

Research paper (scientific journal), Joint Work, Accepted

Inhibition of the antibody production by acetaminophen independent of liver injury in mice.

Katsunori Yamaura, Kohei Ogawa, Taeko Yonekawa, Tomonori Nakamura, Koichi Ueno*, Shingo Yano.

Biol Pharm Bull 25 (2) 201-205 2002.02

Research paper (scientific journal), Joint Work, Accepted

開局薬剤師の服薬情報提供による医師・患者間への介入がもたらす臨床効果に関する一考察.

山浦克典, 室谷裕司, 泉茂雄, 久津間信明, 春日一夫, 中村智徳, 矢野眞吾, 上野光一*.

千葉医療薬学研究会雑誌 2 3-8. 2001.02

Research paper (scientific journal), Joint Work, Accepted

癌患者におけるモルヒネ製剤の使用状況と消化器副作用.

水谷義勝, 酒井明子, 上野光一, 中村智徳, 高橋英世, 矢野眞吾*.

日本病院薬剤師会雑誌 37 (2) 233-236 2001.02

Research paper (scientific journal), Joint Work, Accepted

A new anti-influenza virus antibiotic, 10-norparvulenone from Microsphaeropsis sp. FO-5050.

Akiko Fukami, Tomonori Nakamura, Yon-Pil Kim, Kazuo Shiomi, Masahiko Hayashi, Takeshi Nagai, Hiroki Yamada, Kanki Komiyama, Satoshi Omura*.

J Antibiotics 53 (10) 1215-1218 2000.09

Research paper (scientific journal), Joint Work, Accepted

A new antimicrobial antibiotic from Actinoplanes capillaceus sp. K95-5561T.

Akiko Fukami, Tomonori Nakamura, Kanako Kawaguchi, Mun-Chual Rho, Atsuko Matsumoto, Yoko Takahashi, Kazuo Shiomi, Masahiko Hayashi, Kanki Komiyama, Satoshi Omura*.

J Antibiotics 53 (10) 1212-1214. 2000.09

Research paper (scientific journal), Joint Work, Accepted

透析患者における医薬品情報の提供方法と患者理解度に関する研究.

矢野眞吾*, 中嶋由紀子, 山浦克典, 中村智徳, 本庄美恵子, 小山一郎, 久津間信明, 上野光一.

医薬品情報学 2(4) 167-170 2000.04

Research paper (scientific journal), Joint Work, Accepted

Acetaminophen-induced immunosuppression associated with hepatotoxicity in mice

Koichi Ueno, Katsunori Yamaura, Tomonori Nakamura, Tetsuo Satoh, Shingo Yano

Res Commun Mol Pathol Pharmacol 108 ( 3-4 ) 237-251 2000.03

Research paper (scientific journal), Joint Work, Accepted

New members of the macrospherides from Microsphaeropsis sp. FO-5050 IV

Akiko Fukami, Yohei Taniguchi, Tomonori Nakamura, Mun-Chual Rho, Kanako Kawaguchi, Masahiko Hayashi, Kanki Komiyama, Satoshi Omura

J. Antibiotics 52 ( 5 ) 501-504 1999.05

Research paper (scientific journal), Joint Work, Accepted

Acteoside as the analgesic principle of CEDRON (Lippia triphylla (L’Her) O.Kuntze), a Peruvian medicinal plant

Tomonori Nakamura, Atsushi Tsukada, Emi Okuyama, Mikio Yamazaki, Motoyoshi Satake, Sansei Nishibe, Takeshi Deyama, Akira Moriya, Masao Maruno

Chem Pharm Bull 45 ( 3 ) 499-504 1997.03

Research paper (scientific journal), Joint Work, Accepted

Neurotropic compounds from star anise (Illicium. verum Hook. fil)

Tomonori Nakamura, Emi Okuyama, Mikio Yamazaki

Chem Pharm Bull 44 ( 10 ) 1908-1914 1996.10

Research paper (scientific journal), Joint Work, Accepted

Convulsants from star anise (Illicium verum Hook. f.).

Emi Okuyama, Tomonori Nakamura, Mikio Yamazaki

Chem Pharm Bull 41 ( 9 ) 1670-1671 1993.09

Research paper (scientific journal), Joint Work, Accepted

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