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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