論文 - 河添　仁

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 （SPRINGER）  77   343 - 351 2023年01月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

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 （SPRINGER）  41   122 - 133 2023年01月

研究論文（学術雑誌）, 共著, 査読有り

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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年10月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り

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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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Vonoprazan-associated nephrotoxicity: extensive real-world evidence from spontaneous adverse drug reaction reports

Ishida M, Tsuchiya M, Naito J, Kawazoe H, Watanabe D, Nonaka Y, Sano M, Sakai H, Suzuki A, Kumada K, Okura H, Shimizu M, Iihara H

Kidney International （ELSEVIER）  102 （ 3 ） 666 - 668 2022年09月

研究論文（学術雑誌）, 共著, 査読有り

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

Yokoyama Y, Nozawa E, Morita M, Ishikawa E, Mori T, Sakurai M, Kikuchi T, Matsuki E, Yamazaki R, Kataoka K, Jibiki A, Kawazoe H, Suzuki S, Nakamura T

Journal of Clinical Laboratory Analysis （WILEY）  36 （ 8 ） e24598 2022年08月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0887-8013

　概要を見る


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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Association between the Co-administration of Histamine H2 Receptor Antagonists and the Effectiveness of Capecitabine in Patients with Colorectal Cancer: Propensity Score Analysis

Yamazaki T, Uozumi R, Kawazoe H*, Kitazume Y, Iihara H, Fujii H, Takahashi M, Arai T, Murachi Y, Sato Y, Mikami T, Hashiguchi K, Yoshizawa T, Takahashi K, Fujita Y, Hosokawa Y, Morozumi I, Tsuchiya M, Yokoyama A, Hashimoto H, Furukawa T

Journal of Cancer （IVYSPRING INTERNATIONAL PUBLISHER）  13 （ 10 ） 3073 - 3083 2022年08月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  1837-9664

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Background: The association between the effectiveness of capecitabine and the concomitant administration of gastric acid suppressants remains controversial. We aimed to clarify whether the effectiveness of capecitabine is affected by the co-administration of histamine H2 receptor antagonists (H2RAs) in early-stage colorectal cancer (CRC) patients using real-world data.
Methods: This multicenter, retrospective, observational study included consecutive patients with stage II-III CRC who received either capecitabine monotherapy or the CapeOX regimen (capecitabine and oxaliplatin) as adjuvant therapy between January 2009 and December 2014 in Japan. Relapse-free survival (RFS) and overall survival were estimated using the Kaplan-Meier method. Additionally, multivariable Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting analyses were performed.
Results: In total, 552 patients were included in this study, of which 30 were co-administered H2RAs. RFS at five years was 76.7% (95% confidence interval [CI]: 57.2-88.1%) and 79.8% (95% CI: 76.0-83.0%) in the H2RA and non-H2RA groups, respectively. Multivariable Cox proportional hazards model and propensity score-adjusted analyses showed that the co-administration of H2RAs was associated with a poor RFS among those receiving capecitabine monotherapy (hazard ratio [HR], 2.01; 95% CI: 0.86-4.70 and HR, 1.81; 95% CI: 0.77-4.22, respectively). In contrast, these results were inconsistent with the group receiving the CapeOX regimen.
Conclusions: The study findings suggest that the co-administration of H2RAs may not reduce the effectiveness of capecitabine therapy in patients with early-stage CRC. To confirm this relationship, a prospective study with a pharmacokinetic approach is needed.

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多様な進路・働き方における薬剤師のキャリアパスに対する意識調査

土屋雅美†, 河添　仁†*, 大西友美子, 島田美樹, 堀　里子

医療薬学 （(一社)日本医療薬学会）  48 （ 6 ） 249 - 258 2022年06月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  1346-342X

　概要を見る

This study aimed to clarify the attitudes toward career paths for pharmacists in Japan. A self-administered online questionnaire survey was delivered to the live and on-demand release attendees at the 31st annual meeting of the Japanese Society of Pharmaceutical Health Care and Sciences between October 14th and December 7th, 2021. A customer satisfaction (CS) analysis was performed to assess the association between the participants’ perspectives on career paths and satisfaction. The recovery rate was 90.3％ (65/72). The number of females and males was 57 and 8, respectively. The respondents were from diverse backgrounds of age, workplace, and position, etc. The median satisfaction scores of job, education & training system, research activities, relationships, management’s consideration of women, the presence of role models, salary, career path support by colleagues, career path support by supervisors, career path support by a family member, work-life balance, and career paths was 4 (interquartile range [IQR]: 3 - 5), 3 (IQR: 2 - 4), 3 (IQR: 2 - 4), 4 (IQR: 3 - 5), 4 (IQR: 2.5 - 5), 2 (IQR: 1 - 4), 4 (IQR: 2 - 5), 4 (IQR: 3 - 5), 4 (IQR: 2.5 - 5), 5 (IQR: 5 - 7), 4 (IQR: 3 - 5), and 4 (IQR: 3 - 5), respectively. CS analysis revealed that the education & training system, work-life balance, and research activities should be improved as a matter of highest priority for a career path. In conclusion, the findings may provide useful information to develop career paths for Japanese pharmacists in diverse careers and work styles in the future.

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薬学生の自己理解を支援する性格検査MBTI®研修会とそのアウトカム

河添　仁*, 大里洋一

医療薬学 （(一社)日本医療薬学会）  48 （ 5 ） 218 - 227 2022年05月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り,  ISSN  1346-342X

　概要を見る

We newly introduced an on-site workshop of personality inventory, using the Myers-Briggs Type Indicator® (MBTI®) intended for pharmacy students in January 2022. The aim of this study was to evaluate the outcome of the MBTI® workshop to support pharmacy studentsʼ self-understanding via an online questionnaire survey. All third- to ?fth-year students of the Keio University Faculty of Pharmacy (n = 17) assessed the self-understanding, clarity of career path, and their own MBTI® type during the pre-workshop phase, and after the lecture of MBTI®, personality inventory of the MBTI®, and the MBTI® workshop. The recovery rate of the questionnaire was 100％. Notably, the self-guessed MBTI® typeafter the lecture of MBTI® was different from that after the personality inventory of the MBTI® and the MBTI® workshop (94.1％ and 88.2％, respectively). Respondents showed positive scores after participating in the workshop, compared with those before, as conveyed through the use of a seven-point Likert scale. The median scores of self-understanding and clarity of career path after participating in the workshop were signi?cantly improved from 5 (interquartile range [IQR]: 3.5 - 5.5) to 6 (IQR: 6 - 6) and 4 (IQR: 2 - 5) to 5 (IQR: 4 - 6), respectively. They also expressed high overallsatisfaction on the workshop (median 7 [IQR: 6.5 - 7]). In conclusion, this study demonstrated the usefulness of the MBTI® workshop as an educational program to support pharmacy studentsʼ self-understanding. The evaluation of their career path after the MBTI® workshop is warranted in the future.

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Proton pump inhibitors affect capecitabine efficacy in patients with stage II–III colorectal cancer: a multicenter retrospective study

Kitazume Y, Kawazoe H*, Uozumi R, Yoshizawa T, Iihara H, Fujii H, Takahashi M, Arai T, Murachi Y, Sato Y, Mikami T, Hashiguchi K, Yamazaki T, Takahashi K, Fujita Y, Hosokawa Y, Morozumi I, Tsuchiya M, Yokoyama A, Hashimoto H, Yamaguchi M

Scientific Reports （NATURE PORTFOLIO）  12   6561 2022年04月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り

　概要を見る

The association between capecitabine efficacy and proton pump inhibitors (PPIs) is controversial. Here, we determined whether co-administration of PPIs affects the real-world effectiveness of capecitabine. This retrospective observational study included consecutive patients with stage II–III colorectal cancer (CRC) who received adjuvant capecitabine monotherapy or CapeOX (capecitabine and oxaliplatin) between January 2009 and December 2014 at nine participating institutions. The primary endpoint was the difference in relapse-free survival (RFS) between patients who received PPIs and those who did not and was estimated using the Kaplan–Meier method. Overall survival (OS) was the secondary endpoint. Multivariable analysis of RFS and OS was performed using a Cox proportional hazards model, propensity score adjustment, and inverse probability of treatment weighting (IPTW) analyses. Data from 606 patients were evaluated, 54 of whom had received a PPI. PPI-treated patients tended to have poorer RFS and OS than patients treated without PPIs. The hazard ratio for RFS with capecitabine monotherapy was 2.48 (95% confidence interval: 1.22–5.07). These results were consistent with sensitivity analyses performed using propensity score adjustment and IPTW methods. Co-administration of PPIs may reduce the effectiveness of capecitabine and negatively impact patients with stage II–III CRC.

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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, Satou 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 （ELSEVIER ）  1199   123245 2022年04月

研究論文（学術雑誌）, 共著, 査読有り

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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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Effects of adding a neurokinin-1 receptor antagonist to 5 mg olanzapine, a 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone for preventing carboplatin-induced nausea and vomiting: a propensity score-matched analysis

Yamamoto S, Iihara H, Uozumi R, Kawazoe H, Tanaka K, Fujita Y, Abe M, Imai H, Karayama M, Hayasaki Y, Hirose C, Suda T, Nakamura K, Suzuki A, Ohno Y, Morishige K, Inui N

BMC Cancer （BMC）  22   310 2022年03月

研究論文（学術雑誌）, 共著, 査読有り

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Background: Olanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK1RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK1RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy.
Methods: Data were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK1RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK1RA (non-NK1RA group: 31 patients) and with NK1RA (NK1RA group: 31 patients). The patients were selected using propensity score matching.
Results: The complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0–120 h post carboplatin administration) was 93.5% in the non-NK1RA group and 96.8% in the NK1RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine.
Conclusions: The findings suggest that antiemetic regimens consisting of olanzapine, 5HT3RA, and DEX without NK1RA may be a treatment option for patients receiving carboplatin-based chemotherapy.

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Study protocol for a double-blind, comparative, randomized Japanese trial of triplet standard antiemetic therapies with or without 5 mg olanzapine to prevent chemotherapy-induced nausea and vomiting for patients with breast cancer treated with an anthracycline/cyclophosphamide regimen (JTOP-B)

Ozeki R, Iihara H, Shimokawa M, Hashimoto H, Abe M, Mukohara T, Bando H, Hayashi T, Kawazoe H, Komoda M, Yanai-Takahashi T, Saito M

BMJ Open （BMJ PUBLISHING GROUP ）  12   e058755 2022年03月

研究論文（学術雑誌）, 共著, 査読有り

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Introduction: Triple antiemetic therapy with neurokinin-1 receptor antagonist, 5-hydroxytryptamine type 3 receptor antagonist, and dexamethasone has been widely recommended for high emetogenic chemotherapeutic (HEC) agents and regimens, including anthracycline combined with cyclophosphamide (AC). The addition of olanzapine (OLZ) 5 mg or 10 mg to the recommended triple antiemetic therapy has demonstrated superiority in antiemetic efficacy compared with the standard triplet therapy for a cisplatin-based HEC regimen. Although OLZ plus the triple antiemetic treatment may also be effective for patients on an AC-based HEC regimen, no study has investigated its efficacy at a lower dose of 5 mg.
Methods and analysis: To assess whether 5 mg OLZ, as compared with placebo, in combination with triple combination therapy, significantly improves nausea and vomiting, we are conducting a randomised, parallel-group controlled clinical trial with a total of 500 patients at 15 study centres in Japan. The primary outcome is the complete response rate, defined as no emetic episodes and no use of rescue medication during 120 hours after the initiation of chemotherapy. Treatment group comparison for the primary endpoint will be done by using the Cochran-Mantel-Haenszel test.
Ethics and dissemination: The study was approved by the institutional review board of Juntendo University Hospital and relevant approval was obtained from all participating centres. All participants will be required to provide written informed consent. The trial results will be reported at conferences and in peer-reviewed journals.
Trial registration number: Japan Registry of Clinical Trials (jRCT) jRCT1031200134; protocol date: 30 July 2020, version: 1.3, approval: 25 August 2020.

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Renin-Angiotensin-Aldosterone System Inhibitors Prevent the Onset of Oxaliplatin-Induced Peripheral Neuropathy: A Retrospective Multicenter Study and in Vitro Evaluation

Uchida M, Ushio S, Niimura T, Takechi K, Kawazoe H, Hidaka N, Tanaka A, Araki H, Zamami Y, Ishizawa K, Kitamura Y, Sendou T, Kawasaki H, Namba H, Shibata K, Tanaka M, Takatori S

Biological and Pharmaceutical Bulletin （The Pharmaceutical Society of Japan）  45 （ 2 ） 226 - 234 2022年02月

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

Oxaliplatin (OXA) is used in chemotherapy for various cancer types and is associated with acute and chronic neurotoxicity. However, a preventive strategy for OXA-induced peripheral neuropathy (OIPN) and its underlying mechanism remain unclear. We examined the effects of renin-angiotensin-aldosterone system inhibitors (RAASIs) on OIPN by performing a retrospective multicenter study and an in vitro assay. We retrospectively evaluated electronic medical records of 976 patients who underwent one or more courses of OXA-containing regimens at Ehime, Okayama, and Tokushima University Hospitals. The primary endpoint was the incidence of OIPN during or after OXA administration. The effects of RAASIs and OXA on the neurite length in PC12 cells were determined. The combined administration of an OXA-containing regimen and RAASI significantly inhibited the cumulative incidence grade-2 or higher OIPN (log-rank test; p = 0.0001). RAASIs markedly suppressed the development of both acute and chronic OIPN (multivariate analysis; p = 0.017 and p = 0.011). In an in vitro assay, 10 µM OXA suppressed the neurite length; treatment with 1 µM aliskiren, spironolactone, 10 µM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1 µM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500 µM SQ22536 (a cell-permeable adenylate cyclase (AC) inhibitor) markedly abolished neurite-extending effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may increase in the activity of ERK1/2 and AC in PC12 cells.

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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, 責任著者, 査読有り

　概要を見る

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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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, 責任著者, 査読有り,  ISSN  0031-7144

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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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新型タバコの主観的有害性認識度の評価　松山大学在校生への喫煙防止・禁煙教育の結果

黒田　普, 河添　仁, 山内真央子, 井上捷人, 高橋芹奈, 武智研志, 高取真吾, 柴田和彦, 難波弘行

禁煙科学 （日本禁煙科学会）  15 （ 10 ） 1 - 8 2021年10月

研究論文（学術雑誌）, 共著, 査読有り

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目的:紙巻タバコや新型タバコ(加熱式タバコ、電子タバコ)に対する大学生の主観的有害性認識度(以下、認識度)が、喫煙防止・禁煙教育を行うことでどの様に変化するか講義前後で評価した。方法:共通教育科目において、癌疾患、慢性閉塞性肺疾患等の喫煙が関係する病態や禁煙補助剤の説明、さらに紙巻きタバコや新型タバコの有害性に関する90分の講義を3回行った。講義終了後、学生にアンケートを配布し、年齢、性別、3種類のタバコに関する認識度の変化(1:少ない〜5:多いの5段階)の記載を求めた。結果と考察:大学生への喫煙防止・禁煙教育において、講義後に喫煙に対する認識度は上昇しており有意差が認められた。3種類のタバコの中で認識度が最も高いのは、紙巻タバコであり、加熱式タバコ、電子タバコの順であった。紙巻タバコの有害性に関しては、小学校より継続的に教育されているが、新型タバコは近年販売されたばかりであり、毒性が低い等の宣伝が原因と考えられる。また、全ての種類のタバコの有害性に関して、女性の方が男性よりも認識度が高い傾向にあった。この理由として、女性は妊娠・出産等の健康面を考慮しているためと考えられる。一方、講義前の加熱式タバコや電子タバコの認識度が紙巻タバコよりも低い結果であった。特にニコチンやタールが入っていない電子タバコに関しては、講義前の認識度が最も低いため、電子タバコなら喫煙しても良いと考える多くの学生がいると懸念される。結論:大学生に対する紙巻きタバコや新型タバコに関する有害性認識度の調査から、大学生への新型タバコの有害性に関して教育する必要がある。(著者抄録)

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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 （(一社)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, 筆頭著者, 査読有り,  ISSN  1346-342X

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This study aimed to clarify whether the performance levels of pharmaceutical students could be measured by a rubric-based performance evaluation, which consists of a four-point score, during pharmacy practice experiences (PPEs) at both community and hospital pharmacies on a revised model core curriculum for pharmaceutical education in Japan. We assessed the changes in performance evaluation by mentors and students during PPEs, the correlation of their total scores, and those between community pharmacies and hospitals. Data from the electronic records of fifth-year students of the Keio University Faculty of Pharmacy, who did PPEs in 2019, were retrospectively analyzed. A total of 144 students were included in this study. The median scores of performance evaluation by mentors and students in all tasks significantly increased from the commencement to the end of training in community pharmacies and hospitals (P < 0.05). Consequently, there was a significant association of total scores of performance evaluation between mentors and students in the community pharmacies (ρ = 0.755) or hospitals (ρ = 0.724). In contrast, there was a poor association of total scores of performance evaluation by mentors between community pharmacies or hospitals (ρ = 0.209) and those between community pharmacies and hospitals (ρ = 0.409). In conclusion, these findings suggest that performance evaluation by mentors and students reflects the latter’s performance level and can measure their growth in the PPEs at a community pharmacy and a hospital.

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Efficacy and safety of 5 mg olanzapine for nausea and vomiting management in cancer patients receiving carboplatin: integrated study of three prospective multicenter phase II trials

Yamamoto S, Iihara H, Uozumi R, Kawazoe H, Tanaka K, Fujita Y, Abe M, Imai H, Karayama M, Hayasaki Y, Hirose C, Suda T, Nakamura K, Suzuki A, Ohno Y, Morishige K, Inui N

BMC Cancer （BMC）  21   832 2021年07月

研究論文（学術雑誌）, 共著, 査読有り

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Background: The efficacy of olanzapine as an antiemetic agent in cancer chemotherapy has been demonstrated. However, few high-quality reports are available on the evaluation of olanzapine’s efficacy and safety at a low dose of 5 mg among patients treated with carboplatin regimens. Therefore, in this study, we investigated the efficacy and safety of 5 mg olanzapine for managing nausea and vomiting in cancer patients receiving carboplatin regimens and identified patient-related risk factors for carboplatin regimen-induced nausea and vomiting treated with 5 mg olanzapine.
Methods: Data were pooled for 140 patients from three multicenter, prospective, single-arm, open-label phase II studies evaluating the efficacy and safety of olanzapine for managing nausea and vomiting induced by carboplatin-based chemotherapy. Multivariable logistic regression analyses were performed to determine the patient-related risk factors.
Results: Regarding the endpoints of carboplatin regimen-induced nausea and vomiting control, the complete response, complete control, and total control rates during the overall study period were 87.9, 86.4, and 72.9%, respectively. No treatment-related adverse events of grade 3 or higher were observed. The multivariable logistic regression models revealed that only younger age was significantly associated with an increased risk of non-total control. Surprisingly, there was no significant difference in CINV control between the patients treated with or without neurokinin-1 receptor antagonist.
Conclusions: The findings suggest that antiemetic regimens containing low-dose (5 mg) olanzapine could be effective and safe for patients receiving carboplatin-based chemotherapy.

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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 （(一社)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, 査読有り,  ISSN  1346-342X

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It is necessary to determine the expiration date and storage methods for in-hospital preparations. However, data on the physical properties and stability of in-hospital preparations for eye drops, especially in long-term storage, are limited. Therefore, the stability of in-hospital preparations for eye drops, 0.5％ vancomycin (VCM), 0.25％ DENOSINE® (GCV), 0.1％ Funguard® (MCFG), 1％ VFEND® (VRCZ), and 5％ sodium chloride (NaCl), were evaluated for long-term storage.
All eye drops were stored for 12 weeks under the following conditions: cool (4℃)/darkness, room temperature(approximately 23℃)/darkness, room temperature (approximately 24℃)/scattered light (approximately 1,500 lx), or high temperature (37℃)/darkness. The concentration of eye drops over time was measured by high-performance liquid chromatography and automated clinical chemistry analyzer, and pH, appearance, and sterility were evaluated.
As a result, 0.5％ VCM eye drops can be stored for 3 weeks at room temperature when placed in a light-shielding bag or for 12 weeks at 4℃. The 0.25％ GCV, 1％ VRCZ, and 5％ NaCl eye drops can be stored for 12 weeks at 4 - 37℃. The 0.1％ MCFG eye drops can be stored for 6 weeks at 37℃, or for 12 weeks at room temperature or 4℃.
The stability of in-hospital preparations for eye drops during long-term storage under varying conditions was demonstrated. Therefore, the use of in-hospital preparations for eye drops is considered to be safer and more effective.

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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, 責任著者, 査読有り,  ISSN  0031-7144

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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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