研究者詳細 - 中村　智徳

論文 - 中村　智徳

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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年10月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り

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 M., Hirose Y., Lin B., Fumimoto M., Nunomura K., Natchanun S., Takahashi N., Ohki Y., Sako M., Murai K., Harada K., Arai M., Suzuki S., Nakamura T., Haruta J., Arisawa M.

ACS Medicinal Chemistry Letters （ACS Medicinal Chemistry Letters） 13 （ 10 ） 1582 - 1590 2022年08月

研究論文（学術雑誌）, 共著, 査読有り

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年07月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り, 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

Ishikawa E., Yokoyama Y., Chishima H., Kuniyoshi O., Sato I., Nakaya N., Nakajima H., Kimura M., Hakamata J., Suehiro N., Nakada H., Ikemura S., Jibiki A., Kawazoe H., Muramatsu H., Suzuki S., Nakamura T.

Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences （Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences） 1199 123245 2022年05月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り, 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年11月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り

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年11月

研究論文（学術雑誌）, 共著, 査読有り, 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年11月

研究論文（学術雑誌）, 共著, 査読有り

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年10月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り, 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年09月

研究論文（学術雑誌）, 共著, 査読有り, 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年06月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り, 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年06月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り, 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年06月

研究論文（学術雑誌）, 共著, 査読有り, 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年06月

研究論文（学術雑誌）, 最終著者, 査読有り

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年05月

研究論文（学術雑誌）, 共著, 査読有り

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 （Journal of Alternative and Complementary Medicine） 27 （ 7 ） 613 - 616 2021年03月

研究論文（学術雑誌）, 共著, 査読有り, 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 （Journal of Cancer） 12 （ 7 ） 2105 - 2112 2021年02月

研究論文（学術雑誌）, 共著, 査読有り

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年01月

研究論文（学術雑誌）, 共著, 査読有り, 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年

研究論文（学術雑誌）, 共著, 査読有り

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年

研究論文（学術雑誌）, 共著, 査読有り

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年11月

研究論文（学術雑誌）, 共著, 査読有り, 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。

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