Details of a Researcher - KAWAZOE Hitoshi

Papers - KAWAZOE Hitoshi

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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

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) in press. 2025.02

Research paper (scientific journal), Joint Work, Accepted

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

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

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

Background: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment.
Patients and Methods: This multicenter, retrospective, observational study, conducted across four medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan–Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio.
Results: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival periods were 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% confidence interval [CI], 0.70–2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61–2.47). Consistent results were obtained for subgroups receiving palbociclib (n = 177) and abemaciclib (n = 63) without propensity score matching. Moreover, adverse event incidence and severity were similar in both groups.
Conclusion: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.

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Mirtazapine plus granisetron and dexamethasone for carboplatin-induced nausea and vomiting in patients with thoracic cancers: A prospective multicenter phase II trial

Iihara H, Iwai M, Morita R, Fujita Y, Ohgino K, Ishihara T, Hirose C, Suzuki Y, Masubuchi K, Kawazoe H, Kawae D, Aihara K, Endo S, Fukunaga K, Yamazaki M, Tamura T, Kitamura Y, Fukui S, Endo J, Suzuki A

Lung Cancer (ELSEVIER IRELAND LTD) 192 107801 2024.04

Research paper (scientific journal), Joint Work, Accepted

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Using an online journal club to improve Asian speakers’ comfort in using English to discuss and understand research papers written in English

Tsuchiya M, Saeteaw M, Subongkot S, Tharnpanich T, Konmun J, Nasu I, Shimanuki Y, Tsuchitani T, Ezura M, Hashiguchi K, Bryan JC, Kawazoe H*

Journal of Oncology Pharmacy Practice (SAGE PUBLICATIONS LTD) in press. 2024.03

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

Introduction: This study aimed to evaluate the participants’ comfort in understanding research papers written in English and discussing such research in English via an Asian online journal club.
Methods: A self-administered online survey was delivered to seven journal club meeting attendees from July 2020 to July 2021. A customer satisfaction analysis was performed to assess the association between the participants’ perspectives on program logistics and satisfaction.
Results: The recovery rate was 37.0% (44/119). After participating in the journal club, the median scores of critical appraisal skills, knowledge and/or pharmaceutical care skills in clinical practice, and discussion skills in English (assessed using a seven-point Likert scale) improved significantly (compared to pre-participation median scores) from 4 (interquartile range [IQR]: 3–5) to 5 (IQR: 4–6), 5 (IQR: 4–5) to 5 (IQR: 5–6), and 4 (IQR: 2–5) to 5 (IQR: 3–5), respectively (P < 0.0001). The respondents also expressed great appreciation for the benefits and overall qualities of the journal club. Additionally, regarding patient care behavior after participation in the journal club, 34 (77.3%), 17 (38.6%), 16 (36.4%), and 14 (31.8%) respondents reported improvement in “drug information services,” “patient assessments,” “patient counseling,” and “multidisciplinary rounds,” respectively. Customer satisfaction analysis revealed that sharing information, mutual discussion, a shift system of presenters and co-chairs, and session duration should be improved as a matter of highest priority.
Conclusion: The findings suggest that our program could be helpful for Asian pharmacists, pharmacy students, and faculty members of the department of pharmacy.

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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 (WILEY) 44 ( 2 ) 149 - 162 2024.02

Research paper (scientific journal), Joint Work, Accepted

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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

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

Objective: Platinum- and anthracycline-based chemotherapy regimens cause nausea and vomiting in clinical practice, resulting in the deterioration of patients’ QoL, discontinuation of chemotherapy, and reduced therapeutic outcomes. Using pica behavior as an indicator, we aimed to clarify whether anamorelin, an orally active ghrelin receptor agonist, exerts antiemetic effects against cisplatin-induced nausea and vomiting in rats.
Materials and methods: Sprague–Dawley rats were treated with cisplatin (5 mg/kg, i.p.), three-drug or four-drug antiemetics (granisetron [0.3 mg/kg, p.o.], dexamethasone [1.5 mg/kg, p.o.], fosaprepitant [12.5 mg/kg, i.p.], with or without anamorelin [30 mg/kg, p.o.]). Data on kaolin intake, normal food intake, and spontaneous motor activity (SMA) were recorded 1 d before and 5 d after cisplatin administration. Body weight (BW) was measured daily, and the percentage change in BW from baseline was calculated.
Results: At the primary endpoint, kaolin intake was significantly higher in the cisplatin-only group than in the pretreatment and vehicle groups (p < 0.05). Additionally, kaolin food intake was not significantly low in cisplatin-treated mice treated with three-drug antiemetics with or without anamorelin. At the secondary endpoints, normal food intake, SMA, and percentage change in BW were significantly lower in the cisplatin-only group than in the vehicle group.
Conclusion: Our findings suggest that the prophylactic administration of standard three-drug antiemetics, besides anamorelin, may not improve cisplatin-induced nausea and vomiting. Further studies using methods suitable for evaluating anamorelin levels are required.

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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 2023.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 2045-7634

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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病院薬剤師のキャリアビジョンに対する意識調査

河添　仁*, 土屋雅美, 藤堂真紀, 原　梓, 大西友美子, 大里洋一, 堀　里子

Yakugaku Zasshi ((公社)日本薬学会) 143 ( 8 ) 683 - 691 2023.08

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

This study aimed to clarify diverse values toward career visions for hospital pharmacists. A self-administered online questionnaire survey was delivered to live and on-demand release attendees at a symposium about sustainable career paths for pharmacists at the 32nd annual meeting of the Japanese Society of Pharmaceutical Health Care and Sciences between September 23rd and November 14th, 2022. Correspondence analyses of text mining were conducted to assess the association between the participants’ perspectives on career visions and their backgrounds consisting of sex and generation. The recovery rate was 81.9% (136/166). The majority of respondents were women (61.4%), aged ≥40 years (66.1%). Correspondence analysis of career vision for pharmacists showed that respondents who were ≥20–30 years were associated with the research topic, whereas those who were ≥40 years were associated with the director of a pharmacy and worked until retirement age. In contrast, there was no difference in career visions for pharmacists based on sex. The median satisfaction score of the symposium was 6 [interquartile range (IQR): 5–6] in the entire population, as conveyed using a seven-point Likert scale. Interestingly, the median satisfaction scores of the symposium were significantly higher for men in management positions than women in non-management and management positions (p=0.0106 and p=0.0031, respectively). In conclusion, we believe that career support tailored to everyone’s values could enable hospital pharmacists to realize their career visions.

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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 PORTFOLIO) 13 11962 2023.07

Research paper (scientific journal), Joint Work, Corresponding 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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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 ((一社)日本医療薬学会) 49 ( 4 ) 173 - 182 2023.04

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

2021年度の当大学薬学部の5年次生146名を対象に、実務実習事前学習の学業成績を調査し、実務実習における到達度評価の向上に関わる因子を評価した。146名の実務実習事前学習の学業成績は81.2±2.0点、最大値は86.0点、最小値は74.0点であった。平均値で本学が目標とするスコア3に到達していた項目は薬局実習では10項目中6項目、病院実習では11項目中4項目であり、薬局実習よりも病院実習で目標到達率が低かった。なかでも、「処方箋に基づく調剤」のうち「患者情報の把握」はスコア3以上に到達していた実習生が146人中85人(38.2%)と目標到達率の低い項目であった。今回の検討から、代表的8疾患への関わりを増やすことで到達度評価を向上させる可能性が示唆された。すなわち、少数の患者であっても代表的8疾患に幅広く関わりを経験させる目標を優先させた方が実習生の到達度評価が向上することが示された。

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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, Corresponding 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 (SPRINGER) 77 343 - 351 2023.01

Research paper (scientific journal), Joint Work, Accepted

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 2023.01

Research paper (scientific journal), Joint Work, Accepted

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, Corresponding 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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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 2022.09

Research paper (scientific journal), Joint Work, Accepted

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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 2022.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0887-8013

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 2022.08

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

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 2022.06

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

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 2022.05

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

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 2022.04

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

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 2022.04

Research paper (scientific journal), Joint Work, Accepted

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 2022.03

Research paper (scientific journal), Joint Work, Accepted

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 2022.03

Research paper (scientific journal), Joint Work, Accepted

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 2022.02

Research paper (scientific journal), Joint Work, Accepted

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 2021.11

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

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

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

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

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

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

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

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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 2021.10

Research paper (scientific journal), Joint Work, Accepted

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)

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 2021.09

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

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 2021.07

Research paper (scientific journal), Joint Work, Accepted

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 2021.06

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

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 2021.06

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

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

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

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

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

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

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

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

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

Frontiers in Oncology (FRONTIERS MEDIA SA) 11 618570 2021.05

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

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

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Low-Dose Olanzapine Plus Graniseteron and Dexamethasone for Carboplatin-Induced Nausea and Vomiting in Patients with Thoracic Malignancies: A Prospective Multicenter Phase II Trial

Sakai C, Shimokawa M, Iihara H, Fujita Y, Ikemura S, Hirose C, Kotake M, Funaguchi N, Gomyo T, Imai H, Hakamata J, Kaito D, Minato K, Arai T, Kawazoe H, Suzuki A, Ohno Y, Okura H

Oncologist (WILEY) 26 ( 6 ) e1066 - e1072 2021.04

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

Background: Olanzapine is an inexpensive and durable agent for the treatment of chemotherapy-induced nausea and vomiting and is also superior to neurokinin-1 receptor antagonists in the control of nausea. This study aimed to investigate the efficacy and safety of a low dose of 5 mg olanzapine plus granisetron and dexamethasone for treatment of carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic malignancies.
Materials and Methods: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four centers in Japan. Registered patients were scheduled to receive area under the curve (AUC) ≥5 mg/mL per minute of CBDCA and had never received moderately to highly emetogenic chemotherapy. Patients received olanzapine 5 mg/day orally after supper for 4 days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the overall phase (0–120 hours).
Results: Between February 2018 and June 2020, 51 patients were enrolled, and 50 patients were evaluated. The CR rates in the overall (0–120 hours), acute (0–24 hours), and delayed phases (24–120 hours) were 94.0%, 100%, and 94.0%, respectively. No grade 3 or higher adverse effects of olanzapine were observed.
Conclusion: Prophylactic antiemetic therapy with a low dose of 5 mg olanzapine plus granisetron and dexamethasone showed durable efficacy with an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic malignancies receiving an AUC ≥5 mg/mL per minute of CBDCA-based regimen. Clinical trial identification number: UMIN000031267.
Implications for Practice: The results of this phase II trial indicated that the prophylactic administration of low-dose of 5 mg olanzapine combined with granisetron and dexamethasone has promising activity with acceptable safety profile in patients with thoracic malignancy receiving high-dose carboplatin chemotherapy.

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

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

Journal of Cancer (IVYSPRING INTERNATIONAL PUBLISHER) 12 ( 7 ) 2105 - 2112 2021.02

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

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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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 ((一社)日本医療薬学会) 46 ( 12 ) 715 - 721 2020.12

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

The Model Core Curriculum for Pharmacy Education (2013 version) presents eight disease areas as the minimum medical conditions that require student trainees to be continuously engaged in pharmacotherapy, during practical training at a community pharmacy followed by a hospital-based pharmacy. However, the relationship of the number of those who continuously experienced the minimum medical conditions and the outcome of rubric assessment that is newly introduced in this study remain unknown. We clarify the effect of the number of those who continuously experienced the minimum medical conditions and pharmacy training on rubric assessment using the uniquely developed “Individual Student Report Form.” Twenty inexperienced students and 21 experienced students in pharmacy practice were evaluated on the following subjects related to medication guidance: “(2)-2 Medication Order Review and Medication Therapy Management,” “(2)-4 Professional Attitudes and Behaviors of Practice, Patient Education, and Counseling,” “(3)-1 Collection of Patient Information,” “(3)-2 Management of Drug Information,” “(3)-3 Pharmaceutical Care Plans and Recommendations,” and “(3)-4 Evaluation of Effectiveness and Safety.” The number of eight disease experiences in any subjects were not shown to affect the students’ rubric evaluation. On the other hand, the pharmacy practice experiences were significantly increased in the “(3)-1 Collection of Patient Information” (partial regression coefficient B = 1.305, P = 0.044; 95％CI: 0.036-2.575). It is important to be flexible in the eight disease areas as the minimum medical conditions and to practice the problem solving of the patient with a certified pharmacist.

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医療従事者および医療系学生に対する国際ジャーナルクラブ活動とそのアウトカム

土屋雅美†, 河添　仁†, 江面美緒, 橋口宏司, 飯原大稔, 橋本浩伸

医療薬学 ((一社)日本医療薬学会) 46 ( 11 ) 664 - 671 2020.11

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

We developed an international journal club, using an online meeting tool, as an evidence-based medicine training program intended for healthcare professionals and students. This study aimed to evaluate the outcome of the journal club via a questionnaire survey. We administered the questionnaire to 53 healthcare professionals and students who participated in the journal club between February 2019 and April 2020. Respondents showed positive improvement scores after participating in the journal club, compared with those before, as conveyed through the use of a seven-point Likert scale. The median scores of critical thinking skills, discussion skills in English, evidence-based practice skills, and the sense of freedom to ask questions and make comments after participating in the journal club were significantly improved from 4 (interquartile range [IQR]: 2 - 5) to 5 (IQR: 4 - 6); 3 (IQR: 2 - 4) to 3 (IQR: 2 - 5); 3 (IQR: 2 - 5) to 4 (IQR: 3 - 6); and 3 (IQR: 1 - 5) to 3 (IQR: 2 - 6), respectively. Moreover, they expressed interest in the opportunity to share articles on topics of interest with other professionals from different disciplines, to exchange clinical practice ideas concerning topics of interest, and to explore differences in clinical settings between Asia and the MD Anderson Cancer Center. They also expressed great appreciation for the online meeting format, novelty, and overall qualities of the journal club. These findings suggest that an international journal club for healthcare professionals and students could be useful in an evidence-based medicine training program and communication in English.

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Patient-related Risk Factors for Nausea and Vomiting with Standard Antiemetics in Patients with Cancer Receiving Carboplatin: A Retrospective Study

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

Clinical Therapeutics (ELSEVIER) 42 ( 10 ) 1975 - 1982 2020.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0149-2918

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

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ヒノキ科花粉大量飛散年における2019年の花粉情報メール配信の評価

岡田啓司, 河添　仁, 高取真吾, 豊田芳彦, 清水秀樹, 宮野良隆, 難波弘行

日本花粉学会会誌 (日本花粉学会) 66 ( 1 ) 25 - 31 2020.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0387-1851

我々は,ヒノキ科花粉の飛散が多かった2019年の,メール配信の「登録群」と「非登録群」における初期療法の実施状況と花粉症症状の評価,および登録前後のセルフメディケーションを含めた花粉症治療の患者満足度を比較検討した.花粉症症状の評価が最も高かったのは,「登録+初期療法」群であり,「登録+非初期療法」群,「非登録+初期療法」群,「非登録+非初期療法」群の順であった.さらに,セルフメディケーションを含めた花粉症治療の患者満足度も,「登録後」が「登録前」より高かった.以上より,ヒノキ科花粉飛散情報メール配信は,ヒノキ科花粉大量飛散年においても,患者の花粉回避に対する意識を高め,患者満足度の向上に寄与すると考えられる.(著者抄録)

実務実習生の薬学専門科目に対する自己効力感は実務実習での成功体験に影響を与える

菊山史博, 鈴木小夜，地引　綾，横山雄太，河添　仁, 中村智徳

薬学雑誌 ((公社)日本薬学会) 140 ( 6 ) 799 - 808 2020.06

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

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

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タッチパネル式患者参画型問診票共有システムを用いた化学療法有害事象の把握と評価

中内香菜, 井門静香, 済川聡美, 河添　仁, 長谷部晋士, 朝井洋晶, 竹内一人, 松尾真由美, 薬師神芳洋

癌と化学療法 (癌と化学療法社) 47 ( 5 ) 801 - 806 2020.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 0385-0684

Screening for total pain and sharing of patient information including adverse events for patients receiving chemotherapy by medical staff is needed in clinical practice. We introduced a sharing system for patient-oriented outcome sheets via a touch panel at an outpatient chemotherapy clinic. This study aimed to assess whether the system contributes to the improved management of treatment-related adverse events. We retrospectively analyzed data from a total of 215 patients at Ehime University Hospital using their electronic medical records from April to August 2015. Forty of these patients had received interventions relating to treatment-related adverse events. The proportion of a total number of interventions before and after the sharing system was 42/282(14.9%)and 45/215(20.9%), respectively. The proportion of a total number of interventions at the first course of outpatient chemotherapy also increased from 9/40(22.5%)to 14/40(35%)compared with before the sharing system. The purpose of interventions were for insomnia, anorexia, and cancer-related pain, etc., listed in order of degree of frequency. These results suggest that a sharing system of patient-reported interview sheets contributes to tracking treatment -related adverse events and aids in ensuring interventions can be efficiently performed by multidisciplinary team members.

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

吉浦誠海, 河添　仁*, 鈴木小夜, 横山雄太, 地引　綾, 中村智徳

日本臨床腫瘍薬学会雑誌 ((一社)日本臨床腫瘍薬学会) 14 ( 4 ) 1 - 7 2020.04

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

ゲムシタビン誘発性血管痛は末梢静脈投与で生じ、臨床上未解決のままとなっている。エピルビシンとオキサリプラチンにおける先行研究によれば、抗炎症作用とpH調整目的にデキサメタゾンがオプションとなる。本研究の目的は、先発及び後発品のゲムシタビンとデキサメタゾン配合の製剤学的安定性を調査することであった。我々はデキサメタゾン配合後の凍結乾燥製剤及び液体製剤のゲムシタビン先発及び後発品11品目の濃度、pH及び外観変化を生理食塩液及び5%ブドウ糖液希釈において24時間後まで評価した。濃度とpHはそれぞれ高速液体クロマトグラフィーとpHメータで測定した。配合液の濃度及びpHは生理食塩液及び5%ブドウ糖液希釈において24時間後まで変化しなかった。ゲムシタビンの液体製剤のpHは凍結乾燥製剤と比較して、生理食塩液及び5%ブドウ糖液希釈においてわずかに低かった。さらに、生理食塩液及び5%ブドウ糖液希釈において外観変化はなかった。これらの結果は、すべての先発及び後発品のゲムシタビンの製剤学的安定性はデキサメタゾン配合によって影響を受けなかった。本研究は、実臨床においてゲムシタビン誘発性血管痛の可能性を減らすために、先発及び後発品のゲムシタビンはデキサメタゾンと配合投与できることを示唆する。(著者抄録)

Liquid Formulation of Gemcitabine Increases Venous Pain in Patients With Cancer: A Retrospective Study

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

Clinical Therapeutics (ELSEVIER) 42 ( 4 ) 712 - 719 2020.04

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

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

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A Nationwide, Multicenter Registry Study of Antiemesis for Carboplatin-Based Chemotherapy-Induced Nausea and Vomiting in Japan

Iihara H, Shimokawa M, Hayashi T, Kawazoe H, Saeki T, Aiba K, Tamura K.

Oncologist (WILEY) 25 ( 2 ) e373 - e380 2020.02

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

© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press. Background: We previously reported the results of a prospective study of chemotherapy-induced nausea and vomiting (CINV) in a cohort of patients who received carboplatin-based chemotherapy and were selected from a nationwide registry of those scheduled for moderately (MEC) or highly emetogenic chemotherapy (HEC) by the CINV Study Group of Japan. Of 1,910 previously registered patients (HEC: 1,195; MEC: 715), 400 patients received carboplatin-based chemotherapy. The frequency of CINV was determined, and the risk factors for CINV were assessed. Materials and Methods: CINV data were collected from 7-day diaries. Risk factors for CINV were identified using logistic regression models. Results: Of 400 patients scheduled for carboplatin-based chemotherapy, 267 patients received two antiemetics (5-hydroxytryptamine-3 receptor antagonist [5-HT3 RA] and dexamethasone [DEX]), 118 patients received three antiemetics (5-HT3 RA, DEX, and neurokinin-1 receptor antagonist [NK1 RA]), and 15 were nonadherent to the treatment. In these patients, the CINV overall, acute, and delayed phase rates of complete response (CR), defined as no vomiting with no rescue medication, were 67.0%, 98.2%, and 67.5%, respectively. The rates of no nausea were 55.6%, 94.0%, and 56.1%, respectively, and those of no vomiting were 81.3%, 99.0%, and 81.8%, respectively. Older age was associated with a decreased non-CR, whereas female sex, history of pregnancy-related emesis, and dual antiemetic therapy were associated with an increased non-CR during the overall period. Conclusion: In a clinical practice setting, in patients who received carboplatin-based chemotherapy, adherence is quite high and appropriate antiemetic prophylaxis requires a triple antiemetic regimen including NK1 RA. Implications for Practice: For patients receiving carboplatin-based chemotherapy, triple antiemetic therapy with 5-hydroxytryptamine-3 receptor antagonist, dexamethasone, and neurokinin-1 receptor antagonist should be given prophylactically regardless of risk factor status.

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外来がん化学療法患者に対する診察後から診察前への薬剤師面談の変更とその効果

芳野知栄, 田坂友紀, 小池香苗, 矢野安樹子, 白石沙弥, 河添　仁, 山本祐司, 井門敬子, 田中　守, 飛鷹範明, 田中亮裕, 渡部祐司, 荒木博陽

日本臨床腫瘍薬学会雑誌 ((一社)日本臨床腫瘍薬学会) 10 ( 4 ) 1 - 7 2019.04

Research paper (scientific journal), Joint Work, Accepted

愛媛大学医学部附属病院では、2016年6月より消化管・腫瘍外科の外来がん化学療法施行患者を対象に、薬剤師による面談を診察後から前へ変更した。そこで、診察前面談の有用性を評価し、改善点を明らかにすることを目的に変更前後6ヵ月間(前:2015年12月〜2016年5月、後:2016年7月〜12月)を比較検討した。変更前は延べ84名中47名、変更後は延べ139名中70名に面談を実施した。提案割合は変更前(23.4%、11/47名)と比較して変更後(40.0%、28/70名)で増加し、医師に当日採択された割合も変更後有意に上昇した(診察後面談:54.5%、6/11件vs診察前面談:100.0%、39/39件、p<0.001)。また、医師へのインタビューからも薬剤師の診察前面談内容が医師の診察時に共有されることで医師の業務負担軽減にも繋がり、患者の安全な薬物療法遂行に早期から貢献できていることが考えられた。(著者抄録)

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

鈴木小夜†, 河添　仁†, 地引　綾, 横山雄太, 中村智徳

医療薬学 ((一社)日本医療薬学会) 45 ( 4 ) 228 - 239 2019.04

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

To prepare for a new practical training scheme starting in 2019 based on a revised-model core curriculum for pharmaceutical education that incorporates outcome-based education, rubric-based assessment of student performance was implemented in practical training between May and July of 2018. The goals were to evaluate the rubric-based assessment to identify ways to improve it for appraising pharmaceutical students. All fifth-year students of the Keio University Faculty of Pharmacy in 2018 (n = 160) self-assessed their performance during practical training using evaluation sheets in a rubric form comprising three general instructional objectives with 10 task descriptions developed by the Japanese Pharmaceutical Association or Japanese Society of Hospital Pharmacists. Compared to the commencement of the training, the median evaluations in all tasks significantly increased at the completion of the practical training in the community pharmacy and the hospital settings. Survey questionnaires were administered to the students after the practical training. Customer satisfaction analysis identified two main areas for improvement of the rubric-based assessment for student growth: (1) students' lack of understanding of the rubric-based assessment in hospitals and (2) mentors' lack of understanding of it in both settings. The results suggest that rubric-based assessment is a feasible method for assessing pharmaceutical student performance during practical training. Additionally, the Faculty of Pharmacy should provide and disseminate information to students and mentors about rubric-based assessment and support mentors' efforts for student progress during practical training.

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Impact of e-mail-delivered Cupressaceae pollen dispersal data on prophylactic treatment and patient satisfaction

Okada K, Takatori S, Kawazoe H, Toyota Y, Ishida N, Shimizu H, Obana E, Kashiwagi S, Miyano Y, Namba H

Japanese Journal of Palynology (The Palynological Society of Japan) 64 ( 2 ) 55 - 62 2019.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0387-1851

Association Between Immune-Related Adverse Events and Clinical Efficacy in Patients with Melanoma Treated With Nivolumab: A Multicenter Retrospective Study

Okada N, Kawazoe H, Takechi K, Matsudate Y, Utsunomiya R, Zamami Y, Goda M, Imanishi M, Chuma M, Hidaka N, Sayama K, Kubo Y, Tanaka A, Ishizawa K.

Clinical Therapeutics (ELSEVIER) 41 ( 1 ) 59 - 67 2019.01

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

© 2018 Elsevier Inc. Purpose: Nivolumab, an anti–programmed death 1 antibody, produces antitumor effects by activating host immunity, which also causes immune-related adverse events (irAEs). The aim of this study was to analyze the association between antitumor effect and irAEs induced by nivolumab in patients with melanoma. Methods: Fifteen patients with melanoma who had received nivolumab at Tokushima University Hospital or Ehime University Hospital between January 2015 and December 2016 were enrolled in this study. Patients who had and did not have irAEs during nivolumab treatment were classified into an irAEs-positive group (n = 8) and an irAEs-negative group (n = 7), respectively. We compared the disease control rate (DCR) and overall survival (OS) between the 2 groups. Data on blood cell counts were also analyzed. Findings: After a median of 4 cycles of nivolumab treatment, irAEs occurred. The DCRs were 75% and 14% in the irAEs-positive and irAEs-negative groups, respectively (p < 0.05). OS in the irAEs-positive group was higher than that in the irAEs-negative group (p < 0.05). Multivariable Cox proportional hazards regression analysis revealed that irAE occurrence affected OS with nivolumab treatment. Moreover, the increase in baseline peripheral lymphocyte count at the time of onset of irAEs was significantly greater in the irAEs-positive group than in the irAEs-negative group after 4 cycles of nivolumab treatment (p < 0.05). Implications: Our study indicated that clinical response with nivolumab treatment improves with irAE occurrence in patients with melanoma. Moreover, the early increase in peripheral lymphocyte count may act as a biomarker for predicting the occurrence of irAEs induced by nivolumab.

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Patient-related Risk Factors for Nausea and Vomiting with Standard Antiemetics in Patients with Breast Cancer Receiving Anthracycline-based Chemotherapy: A Retrospective Observational Study

Kawazoe H, Murakami A, Yamashita M, Nishiyama K, Kobayashi-Taguchi K, Komatsu S, Aoki R, Kusakabe E, Yamasawa H, Yakushijin Y, Nakamura T, Kamei Y.

Clinical Therapeutics (ELSEVIER) 40 ( 12 ) 2170 - 2179 2018.12

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

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

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

Kawazoe H, Uozumi R, Murakami A, Yamashita M, Kobayashi-Taguchi K, Kusakabe E, Yamasawa H, Yakushijin Y, Nakamura T, Kamei Y.

Scientific Reports (NATURE PORTFOLIO) 8 16232 2018.11

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

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

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改訂薬学教育モデル・コアカリキュラムに向けた外来化学療法室実習プログラムに対する実習生からのフィードバック評価

白石沙弥, 河添　仁, 矢野安樹子, 済川聡美, 安永大輝, 飛鷹範明, 井門敬子, 田中　守, 田中亮裕, 荒木博陽

愛媛県病薬会誌 ((一社)愛媛県病院薬剤師会) 124 ( 2 ) 5 - 12 2018.09

Research paper (scientific journal), Joint Work, Accepted

Preventive Effects of Renin-angiotensin System Inhibitors on Oxaliplatin-induced Peripheral Neuropathy: A Retrospective Observational Study

Uchida M†, Kawazoe H†, Takatori S, Namba H, Uozumi R, Tanaka A, Kawasaki H, Araki H.

Clinical Therapeutics (ELSEVIER ) 40 ( 7 ) 1214 - 1222 2018.07

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

© 2018 Elsevier Inc. Purpose: Oxaliplatin-induced peripheral neuropathy has remained an unresolved issue in clinical practice. Our previous study hypothesized that inhibition of the renin-angiotensin system (RAS) may produce a preventive effect on oxaliplatin-induced neuropathy. The aim of this study was to clarify whether RAS inhibitors prevent oxaliplatin-induced peripheral neuropathy. Methods: This study retrospectively analyzed data from cancer patients who had received chemotherapy including oxaliplatin and were treated with or without RAS inhibitors. This retrospective observational study was conducted at Ehime University Hospital using electronic medical records from May 2009 to December 2016. The primary end point was the incidence of severe peripheral neuropathy during or after oxaliplatin treatment, according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate Cox proportional hazards model analysis was used to identify risk factors. Findings: A total of 150 patients were included in the study. The estimated incidence of peripheral neuropathy was 36.9% and 91.7% in the RAS inhibitor group and the non–RAS inhibitor group, respectively. The multivariate analysis using a Cox proportional hazards model showed that the RAS inhibitor group was slightly associated with a decreased risk of neurotoxicity (adjusted hazard ratio, 0.42 [95% CI, 0.18–0.99]; P = 0.048). Implications: The present findings suggest that RAS inhibitors have the ability to prevent oxaliplatin-induced peripheral neuropathy.

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Analysis of Clinical Factors and Mortality in Diffuse Large B-cell Lymphoma Patients Over or Under 80 Years of Age

Hasebe S, Tanaka K, Miyake Y, Asai H, Takeuchi K, Fujii T, Kawazoe H, Tanimoto K, Yamanouchi J, Azuma T, Yasukawa M, Yakushijin Y.

International Journal of Gerontology (TAIWAN SOC GERIATRIC EMERGENCY & CRITICAL CARE MEDICINE-TSGECM ) 12 ( 2 ) 100 - 104 2018.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 18739598

© 2017 Background: The prognosis of diffuse large B-cell lymphoma (DLBCL) is remarkably improved after R-CHOP therapy. However, there are few detailed reports regarding very elderly DLBCL patients. We investigated relationships between prognostic factors and mortality risk in DLBCL patients, especially those aged 80 years or more. Methods: The study subjects consisted of 141 patients newly-diagnosed with de novo DLBCL. Information regarding age, sex, stage, performance status (PS), lactate dehydrogenase (LDH), extranodal (EN) involvement, and therapies was available. Results: For the 141 patients, the female sex was significantly inversely related to mortality, whereas age ≥80 years, PS ≥2, and non-standard therapy were significantly positively associated with death. No associations were observed between death and stage, LDH, or EN. When classifying patients by age (<80 [n = 108] and ≥80 [n = 33] years), a significant inverse association between female sex and mortality was found only in the latter (very elderly) group. Positive relationships of PS ≥2 with mortality was more pronounced in patients ≥80 years of age than in those <80 years of age. A significant positive relationship with non-standard therapy was found only in patients <80 years of age. Conclusion: PS ≥2 may be positively associated with mortality, regardless of age. Female sex may be inversely related to mortality only in DLBCL patients aged 80 years or more, possibly due to the difference in rituximab clearance between the two study groups.

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全入院患者に対する抗がん剤の閉鎖式薬物移送システム導入とその評価

沖野真季, 河添　仁*, 泉　智基, 矢野安樹子, 白石沙弥, 芳野知栄, 渡邉真一, 田坂友紀, 飛鷹範明, 田中　守, 田中亮裕, 荒木博陽

医療薬学 ((一社)日本医療薬学会) 44 ( 1 ) 37 - 48 2018.01

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

A Japanese guideline for the safe handling of anticancer drugs recommends a closed system drug transfer device (CSTD). We gradually introduced the PhaSealTM system from preparation to administration of all anticancer drugs to inpatients on holidays as well as weekdays. We evaluated whether the CSTD handling of 36 pharmacists was appropriate or not and also retrospectively compared outcomes before and after the introduction of CSTD. In nine pharmacists who had more than 4 items of an inappropriate handling of CSTD, the median noncompliance ratio after re-training was significantly improved from 4 to 1 items (P = 0.008). We subsequently administered a questionnaire for 36 pharmacists. The customer satisfaction analysis indicated two issues for improvement: anxiety over appropriate preparation on the double audit system of pharmacists and anxiety over miss priming after liquid sensor. On the other hand, the median introduction ratio per day of CSTD between February and April 2016 and between September and October 2016 was significantly increased on weekdays and holidays (P < 0.001 and P < 0.001, respectively). In addition, the median preparation time per day between February and April 2016 and between September and October 2016 was not significantly increased on weekdays and holidays (P = 0.514 and P = 0.423, respectively). These results suggest that our training for pharmacists contributed to an appropriate handling of CSTD, resulting in the safe handling of all anticancer drugs to inpatients on weekdays as well as holidays and the risk management of pharmacists without increase of the preparation time.

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Preventive effect of pre-warming, hot compress, and pH adjustment in oxaliplatin-induced venous pain

Kawazoe H, Sumikawa S, Nakauchi K, Yakushijin Y, Yamamoto Y, Watanabe Y, Tanaka A, Araki H

International Journal of Clinical Pharmacy (SPRINGER) 39 ( 6 ) 1291 - 1297 2017.12

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

Background Venous pain induced by peripheral intravenous administration of oxaliplatin remains clinically unresolved. Objective The aim of this study was to determine the efficacy of comprehensive intervention care for venous pain in colorectal cancer patients receiving oxaliplatin. Setting A Japanese tertiary hospital. Method We treated all outpatients after April 2012 with comprehensive intervention care including pre-warming of the oxaliplatin solution, use of a hot compress, and pH adjustment by combination with dexamethasone. We retrospectively reviewed the electronic medical records from colorectal cancer patients who had received oxaliplatin via a peripheral vein between December 2009 and June 2014. Main outcome measures The primary endpoint of this study was the incidence of venous pain at the administration site during oxaliplatin infusion, according to injection site reaction grade ≥ 2. Results We evaluated 271 treatment courses in 59 patients. Venous pain occurred in 42 courses (15.5%) among 26 patients. Multivariate logistic regression analysis revealed that female gender and body mass index ≥ 25 kg/m2 were significantly associated with an increased risk of venous pain during all courses (adjusted odds ratio [OR]: 3.18, 95% confidence interval [CI] 1.35–7.92; P < 0.01; and adjusted OR: 3.37, 95% CI 1.26–9.40; P = 0.02, respectively), whereas comprehensive intervention care were significantly associated with reduced risk of venous pain during all courses (adjusted OR: 0.10, 95% CI 0.02–0.44; P < 0.01). Conclusion Comprehensive intervention care is a clinical treatment option for oxaliplatin-induced peripheral venous pain in patients with colorectal cancer, especially females with obesity.

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Psychiatric Patients with Antipsychotic Drug-Induced Hyperprolactinemia and Menstruation Disorders

Takechi K, Yoshioka Y, Kawazoe H, Tanaka M, Takatori S, Kobayashi M, Matsuoka I, Yanagawa H, Zamami Y, Imanishi M, Ishizawa K, Tanaka A, Araki H

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 40 ( 10 ) 1775 - 1778 2017.10

Research paper (scientific journal), Joint Work, Accepted

Treatment with antipsychotic drugs has been associated with hyperprolactinemia. The same antipsychotic drugs have also been associated with side effects such as menstruation disorders. The aim of this study was to evaluate the prevalence of hyperprolactinemia and menstruation disorders in women undergoing antipsychotic treatment. We performed a retrospective chart review study of psychiatric patients who underwent laboratory testing for serum prolactin (PRL) level between March 2011 and March 2015 in Ehime University Hospital. Patients presenting with and without menstruation disorders were evaluated to determine if they presented concomitant hyperprolactinemia. Patients with menstrual disorders had a significant increase in serum PRL level with a mean of approximately 90 ng/mL. Those with menstrual disorders presented increased PRL levels by 2-fold that of patients without menstrual disorder. However, there was no significant difference in the equivalent dose of chlorpromazine between these two groups. Additionally, about 70% of patients with menstrual disorders received risperidone treatment. The receiver operating characteristic curve showed that the optimal cutoff point of serum PRL level associated with the development of menstrual disorders was 60 ng/mL. Based on these results, we concluded that patients with menstrual disorders presented increased serum PRL, and that most of them underwent treatment with risperidone.

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Antiemetic Effectiveness and Cost-Saving of Aprepitant plus Granisetron Is Superior to Palonosetron in Gastrointestinal Cancer Patients Who Received Moderately Emetogenic Chemotherapy

Toda H†, Kawazoe H†*, Yano A, Yamamoto Y, Watanabe Y, Yamamoto Y, Hiasa Y, Yakushijin Y, Tanaka H, Araki H

Journal of Cancer (IVYSPRING INTERNATIONAL PUBLISHER) 8 ( 8 ) 1371 - 1377 2017.05

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

Purpose: The therapeutic benefit of a three-drug combination of antiemetics has not been established in moderately emetogenic chemotherapy (MEC). The aim of this study was to compare the antiemetic effectiveness and cost-saving of palonosetron plus dexamethasone (control group) with aprepitant, granisetron, and dexamethasone (study group) in cancer patients who received MEC.
Methods: We switched the standard antiemetic treatment from the control group to the study group in gastrointestinal cancer patients who received MEC after October 2015. The antiemetics in both groups were modified using salvage antiemetic therapy at the clinicians' discretion, according to the severity of chemotherapy-induced nausea and vomiting. We retrospectively reviewed the electronic medical records from patients, before and after switching groups, from between April 2014 and March 2016.
Results: We evaluated 443 treatment courses in 83 patients. The proportion of courses that included salvage antiemetic therapy in the control group and the study group was 34.8 % (116/333) and 8.2 % (9/110), respectively, and was statistically significant (p < 0.001). The mean integrated costs of antiemetics per course in the control group and the study group were 193 ± 55 USD and 143 ± 38 USD, respectively. Multivariate logistic regression analysis revealed that the study group was significantly associated with a reduced risk of requiring salvage antiemetic therapy (p = 0.038).
Conclusions: These results suggest that the antiemetic effectiveness and cost-saving of a three-drug combination of aprepitant, generic granisetron, and dexamethasone was superior to a two-drug combination of palonosetron plus dexamethasone in gastrointestinal cancer patients who received MEC.

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再発・難治性悪性軟部腫瘍に対するpazopanib治療の検討

長谷部晋士, 木谷彰岐, 河添　仁, 竹内一人, 薬師神芳洋

愛媛医学 36 ( 1 ) 41 - 46 2017.03

Research paper (scientific journal), Joint Work, Accepted

Non-steroidal anti-inflammatory drugs induce severe hematologic toxicities in lung cancer patients receiving pemetrexed plus carboplatin: A retrospective cohort study

Kawazoe H, Yano A, Ishida Y, Takechi K, Katayama H, Ito R, Yakushijin Y, Moriguchi T, Tanaka M, Tanaka A, Araki H

PloS One (PUBLIC LIBRARY SCIENCE ) 12 ( 2 ) e0171066 2017.02

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

Purpose: As the major toxicity induced by pemetrexed plus carboplatin is severe hematologic toxicities, the aim of this study was to determine the risk factors for severe hematologic toxicities in lung cancer patients.
Methods: We retrospectively investigated data from lung cancer patients who had received pemetrexed plus carboplatin, with or without bevacizumab. This observational study was carried out at Ehime University Hospital using electronic medical records dating from July 2009 to March 2015. Severe hematologic toxicities were defined as grade 3 or 4, according to the Common Terminology Criteria for Adverse Events, version 4.0.
Results: Forty-two patients were included in the study. The incidence of grade 3 or 4 hematologic toxicities during the first cycle of chemotherapy and during all cycles was 19.0% and 16.1%, respectively. Multivariate time-depend generalized estimating equations logistic regression analysis revealed that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted odds ratio (OR): 8.32, 95% confidence interval (CI): 1.27–54.38; p = 0.03), whereas creatinine clearance of <45 mL/min was not significantly associated with an increased risk of severe hematologic toxicities during all cycles (adjusted OR: 0.91, 95% CI: 0.25–3.34; p = 0.88).
Conclusions: The results suggest that severe hematologic toxicities in patients receiving carboplatin-based pemetrexed may be significantly induced by the inhibition of renal tubular pemetrexed secretion through drug–drug interactions between NSAIDs and pemetrexed rather than through glomerular filtration of pemetrexed, even with moderate to sufficient renal function.

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S-1における副作用モニタリングシートを利用した病院と保険薬局の患者情報共有システム導入の副作用発見率への貢献

河添　仁, 岡田由季, 矢野安樹子, 白石沙弥, 酒井　瞳, 亀田慶太, 橋岡多津, 木下清司, 古川　清, 田中　守, 田中亮裕, 荒木博陽

医療薬学 ((一社)日本医療薬学会) 43 ( 2 ) 94 - 103 2017.02

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

Limited sharing of information occurs between hospitals and community pharmacies regarding outpatients receiving oral chemotherapy. We therefore developed the sharing system of patient information between hospital and community pharmacies using the monitoring sheet of tegafur/gimeracil/oteracil potassium (S-1). After October 2013, community pharmacies monitored adverse events in patients receiving S-1 using the monitoring sheet, and subsequently provided this information to our hospital by fax. A medical clerk entered the information into the electronic medical records, thus providing feedback to hospital physicians. In this study, we retrospectively investigated adverse events in outpatients who had received S-1 between September 2012 and October 2014. In total, sixty-seven patients were included in the study. The proportion of patients who experienced adverse events in the control group and the monitoring sheet group was 69.0％ and 76.0％, respectively. The proportion of patients who developed lacrimation in the control group and the monitoring sheet group was 11.9％ and 36.0％, respectively, which was statistically significant (P = 0.03). On the other hand, the proportion of patients who managed any adverse events in the control group and the monitoring sheet group was 45.2％ and 68.0％, respectively. The proportion of patients who managed lacrimation in the control group and the monitoring sheet group was 11.9％ and 32.0％, respectively, which was not statistically significant (P = 0.06). These results suggest that this sharing system contributed to the identification of adverse events induced by S-1, resulting in appropriate management for patients who developed these adverse events by hospital physicians and community pharmacists.

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アプレピタント併用によりデキサメタゾンの前投与を減量時にパクリタキセルの過敏症反応が生じた1例

佐々木優, 河添　仁, 村上　聡, 守口淑秀, 田中亮裕, 荒木博陽

日本臨床腫瘍薬学会雑誌 ((一社)日本臨床腫瘍薬学会) 5 19 - 22 2016.12

Research paper (scientific journal), Joint Work, Accepted

外来患者におけるハザーダス・ドラッグ調製から投与管理までの閉鎖式薬物移送システム導入の臨床的アウトカムと医療経済効果の推算

河添　仁, 中内香菜, 矢野安樹子, 白石沙弥, 薬師神芳洋, 竹内　茜, 井門静香, 恒岡菊江, 松尾真由美, 中井昌紀, 田中　守, 田中亮裕, 荒木博陽

医療薬学 ((一社)日本医療薬学会) 42 ( 7 ) 518 - 528 2016.07

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

Following the publication of a guideline on the safe handling of hazardous drugs (HDs) in Japan, the issue of cost-effectiveness has been become a problem. We introduced the PhaSeal™ system in June 2015, a closed system drug transfer devices (CSTD) used for all outpatients, from preparation to administration. We retrospectively compared clinical outcomes before and after the introduction of CSTD of HDs included chemotherapy. Furthermore, we evaluated the medical fee income and the cost of providing CSTD between July and December 2015. The mean number of outpatient chemotherapy treatments per day before and after CSTD introduction was 15 ± 6 and 14 ± 5, respectively (P = 0.947). The mean preparation time by pharmacists before and after introduction was 21 ± 9 and 24 ± 9 minutes, respectively (P = 0.002). The mean time of nursing preparation before and after introduction was 29 ± 16 and 25 ± 14 minutes, respectively (P = 0.068). The mean time of patients waiting for chemotherapy before and after introduction was 36 ± 17 and 37 ± 17 minutes, respectively (P = 0.735). Based on the mean differences between the medical fee income and the cost of CSTD per month, we estimated that the annual cost associated with the introduction of CSTD for all outpatient to administer HDs was approximately JPY 21,000,000. After April 2016, we estimated that the amount of increase of the medical fee income of CSTD was approximately JPY 2,000,000 per year. These results suggest that the medical fee income should be increased so CSTD can be implemented for all outpatients.

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外来化学療法におけるがん患者指導管理料3の臨床的アウトカムと医療経済効果の推算

河添　仁, 矢野安樹子, 田坂祐一, 中内香菜, 田中　守, 田中亮裕, 薬師神芳洋, 荒木博陽

医療薬学 ((一社)日本医療薬学会) 42 ( 4 ) 228 - 236 2016.04

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

We retrospectively evaluated the clinical outcomes of pharmaceutical interventions relating to outpatient chemotherapy and estimated their associated economic impact between August 2014 and August 2015. We developed a novel pharmaceutical system, involving JPY1,164,000 allocated to a total of 582 patients. There were 117 proposals for pharmaceutical interventions, 106 (90.6%) of which were accepted by physicians. The number of proposals for supportive therapy was 56, 29 (51.8%) of which significantly decreased the grade of chemotherapy-induced adverse events compared to before pharmaceutical interventions (P < 0.001). The number of reductions in grade 1, 2, and 3 events was 14, 11 and 4, respectively. In this study, the potential economic costs associated with reduction of grade 1, 2 and 3 chemotherapy-induced adverse events were calculated as JPY112,000, JPY112,000, and JPY2,140,000, respectively, based on the costs paid by the Adverse Drug Reaction Relief System of the Pharmaceuticals and Medical Devices Agency. According to this cost calculation, we estimated that the total cost saving associated with the clinical outcomes of pharmaceutical interventions was JPY11,360,000. This is the first study to estimate the economic impact associated with the clinical outcomes of pharmaceutical interventions for outpatient chemotherapy. These results suggest that pharmaceutical interventions contribute to the quality and safety of outpatient chemotherapy by decreasing chemotherapy-induced adverse events.

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トラマドール/アセトアミノフェン誘発悪心・嘔吐における予防対策の有用性と関連因子

芳野知栄, 河添　仁, 井門敬子, 田中亮裕, 田中　守, 荒木博陽

日本緩和医療薬学会雑誌 8 ( 4 ) 99 - 102 2015.12

Research paper (scientific journal), Joint Work, Accepted

抗がん剤の調製から投与までの医療従事者に対する抗がん剤曝露対策の評価

上野昌紀, 河添　仁, 済川聡美, 中内香菜, 竹内　茜, 井門静香, 恒岡菊江, 樋口則子, 岡本千恵, 田中　守, 田中亮裕, 朝井洋晶, 薬師神芳洋, 荒木博陽

医療薬学 ((一社)日本医療薬学会) 41 ( 11 ) 811 - 820 2015.11

Research paper (scientific journal), Joint Work, Accepted

The BD PhasealTM administration set, a new device for the BD PhasealTM closed system drug transfer device (CSTD), can prevent the occupational exposure of health caregivers to antineoplastic agents during all stages of the treatment process from preparation to administration. Further, a revised nursing approach for administration may prevent inadvertent antineoplastic agent spills. In this study, we compared the exposure levels of cyclophosphamide (CPA) and paclitaxel (PTX) between conventional methods and the new method described above; by sampling drug absorption sheets (a sampling sheet method) was used. In both methods, CPA was prepared using the BD PhasealTM CSTD and PTX was a plastic needle open system. For the new method, CPA was administered using the BD PhasealTM administration set and PTX was the revised nursing administration approach. Five pharmacists undertook the preparation process, and five nurses the administration process. Within the administration process using the conventional method, the following levels were detected: CPA 1.67 ng/cm2 and PTX 0.077 ng/cm2. No measurable levels were detected with the new method. For the preparation process, no CPA was detected, but PTX was detected. These results suggest that the use of the BD PhasealTM administration sets and the revised nursing administration approach is useful for preventing the occupational exposure of health caregivers to antineoplastic agents; this applies to both the preparation process and the administration processes.

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オキサリプラチンの静脈炎および血管痛の危険因子の解析と加温投与ならびに温罨法による予防効果の評価

中内香菜, 河添　仁, 宮嶋理沙, 和泉千恵子, 六角由紀, 恒岡菊江, 樋口則子, 藤原光子, 児島　洋, 薬師神芳洋

癌と化学療法 (癌と化学療法社) 42 ( 11 ) 1397 - 1400 2015.11

Research paper (scientific journal), Joint Work, Accepted

学習成果の定量的評価を用いた外来化学療法室実習プログラムの導入と評価

済川聡美, 河添　仁, 上野昌紀, 田中亮裕, 田中　守, 荒木博陽

医療薬学 ((一社)日本医療薬学会) 41 ( 6 ) 442 - 449 2015.06

Research paper (scientific journal), Joint Work, Accepted

A quantitative evaluation method has not yet been established for pharmacy students in relation to learning achievements and their hospital-based practical training. We therefore developed an outpatient chemotherapy educational program to address this issue. To assess the learning achievements quantitatively, we carried out four examinations - twice at the halfway point (first) and at the program's term-end (second); a perfect score was 100. This study was conducted between May and November 2013 and 24 pharmacy students participated. The results showed that the first and second mean scores relating to their cytotoxic agent handling knowledge were 91.5 ± 5.2 and 99.1 ± 1.8, respectively. The first and second mean scores relating to preparation skills for vials (how to handle anticancer drugs) were 68.5 ± 13.1 and 78.9 ± 18.5, respectively. For their preparation skills (using closed systems to handle anticancer drugs) the mean scores were 85.2 ± 13.1 (first) and 97.0 ± 3.7 (second). The first and second mean scores about the processes involved in solving chemotherapy-related patient problems were 52.1 ± 23.7 and 77.8 ± 21.9, respectively. All of the scores were significantly increased at the end of the program compared with scores halfway through. These results suggest that our program may be useful for supporting pharmacy students to learn more effectively during their hospital-based practical training in Japan.

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Risk Factors for Discontinuation of S-1 Adjuvant Chemotherapy for Gastric Cancer

Kawazoe H, Shimasaki M, Ueno M, Sumikawa S, Takatori S, Namba H, Yoshida M, Sato K, Kojima Y, Watanabe Y, Moriguchi T, Tanaka A, Araki H

Journal of Cancer (IVYSPRING INTERNATIONAL PUBLISHER) 6 ( 5 ) 464 - 469 2015.03

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

Purpose: The aim of this study was to clarify the risk factors for discontinuing tegafur/gimeracil/oteracil potassium (S-1) adjuvant chemotherapy following gastrectomy in patients with gastric cancer.
Methods: We retrospectively investigated patients with curatively-resected gastric cancer who received S-1 adjuvant chemotherapy. S-1 was administered orally at 80-120 mg/day, depending on body surface area, on days 1-28 every 6 weeks for 1 year. The dose and treatment schedule were modified at the clinicians' discretion, according to toxicity.
Results: Seventy-one patients were included in the study, 26 of whom discontinued S-1 therapy. The relapse-free survival rates in the S-1-completed and S-1-discontinuation groups at 5 years post-surgery were 88.1% and 55.8%, respectively. The overall survival rates in the S-1-completed and S-1-discontinuation groups at 5 years post-surgery were 89.4% and 59.8%, respectively. The hazard ratios for relapse and death were significantly lower in the S-1-completed group compared with those in the S-1-discontinuation group (0.18; p<0.001 and 0.19; p=0.002, respectively). Multivariate logistic regression analysis revealed that S-1 discontinuation was significantly associated with an initial overdose of S-1, having stage I cancer, creatinine clearance <66 mL/min, and a side effect of nausea.
Conclusions: These results suggest that assessing renal function to avoid initial overdose of S-1, together with the early management of side effects, may support the continuation of S-1 adjuvant chemotherapy in patients with gastric cancer.

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実務実習におけるがん化学療法レジメンの構成を学ぶ実習の試み

岡本千恵, 木村博史, 桝田麻矢, 安永大輝, 田坂祐一, 立川登美子, 河添　仁, 田中亮裕, 末丸克矢, 荒木博陽

日本病院薬剤師会雑誌 50 ( 9 ) 1122 - 1125 2014.09

Research paper (scientific journal), Joint Work, Accepted

S-1における院外処方せんを利用した双方向性の情報共有の取り組みとその評価

河添　仁, 上野昌紀, 済川聡美, 田中　守, 田中亮裕, 荒木博陽

医療薬学 ((一社)日本医療薬学会) 40 ( 8 ) 441 - 448 2014.08

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

Community pharmacies play a significant role in home healthcare. However, patient information from hospitals is not shared with community pharmacies. We attempted the bidirectional sharing of patient information regarding chemotherapy between hospitals and community pharmacies. We developed a “medicine message board,” which was a modified prescription format. Hospital pharmacists recorded information regarding patients taking tegafur/gimeracil/oteracil (S-1) on the message board. In turn, community pharmacists monitored side effects in the S-1 patients and returned the information by fax to our hospital also using the message board. A medical clerk entered the side effects into the electronic medical record, providing feedback to doctors. We distributed questionnaires to community pharmacies around our hospital between December 2013 and January 2014 and assessed their understanding using a five-point Likert scale (where 1 = insufficiency and 5 = sufficiency). The results showed that the mean scores on understanding about the presence or absence of cancer notification before and after the initiation of the message board were 2.10 ± 1.02 and 4.20 ± 1.06, respectively. The mean understanding about the name of a cancer patient's disease before and after the message board was 2.25 ± 0.91 and 4.45 ± 0.83, respectively. All these differences were significant. Understanding about the purpose of treatment, dose adjustments of S-1 due to body surface area and renal function, administration schedule, presence or absence of combination chemotherapy, pharmaceutical instructions, treatment adherence, and side effects monitoring were also significantly improved in community pharmacies after the initiation of the message board. These results suggest that there is scope to improve the support provided to oral chemotherapy patients by hospitals and community pharmacists.

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がん診療連携拠点病院に勤務する医師の「高額医療」と「限度額適応認定証」の認識

薬師神芳洋, 森田純子, 矢野琢也, 松久哲章, 河添　仁, 児島　洋, 岡田憲三, 亀井治人, 原　雅道, 藤井元廣, 松野　剛, 谷水正人, 新海　哲

癌と化学療法 (癌と化学療法社) 41 ( 5 ) 605 - 610 2014.05

Research paper (scientific journal), Joint Work, Accepted

病院実務実習における多職種間を想定したコミュニケーション・スキルアップ実習プログラムの導入と評価

河添　仁, 田中亮裕, 田中　守, 末丸克矢, 荒木博陽

医療薬学 ((一社)日本医療薬学会) 39 ( 12 ) 733 - 740 2013.12

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

There is a lack of opportunities in Japan to engage in communication skills education about effective interactions between pharmacists and medical staff. This is despite the fact that current pharmacy education programs should be producing clinical experts in this area. Because of this, we delivered an educational program relating to building communication skills when working in a multidisciplinary team; 29 pharmacy students took part between May and November 2011. The program was based on two components: a lecture about communication skills by a facilitator (including “active listening”, “assertiveness” and “conflict management”), and a small group discussion (SGD) relating to decisions about opioid increases/rotation using a cancer pain case as an alternative opioid treatment. After the students finished the SGD, we distributed questionnaires to them and assessed outcomes using a five-grade Likert scale. As a result of the questionnaires, their mean understanding about opioid increasing and opioid rotation were 4.59 ± 0.68 and 4.48 ± 0.69, respectively. The mean implementation score of communication skills relating to “assertiveness” was 3.62 ± 0.94, which was significantly worse when compared with that of “active listening” (4.31 ± 0.60, P = 0.003). In addition, the mean satisfaction levels of the SGD group work and the overall educational program were 4.31 ± 0.81 and 4.38 ± 0.62, respectively. Care is required when interpreting the results given the study was limited to a single institution. However, these results suggest that this type of program may be useful for supporting pharmacy students to learn about communication skills. Improved skills should result in more effective communication, when pharmacists interact with medical staff.

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外来化学療法における薬学的管理の業務展開と医療安全への質的貢献の評価

河添　仁, 井門敬子, 田中亮裕, 末丸克矢, 荒木博陽

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 49 ( 9 ) 981 - 985 2013.09

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

オキサリプラチン投与時の血管痛に対する加温ならびに温罨法の試み

宮嶋理沙, 河添　仁, 恒岡菊江, 藤原光子, 児島　洋, 薬師神芳洋

癌と化学療法 (癌と化学療法社) 40 ( 4 ) 537 - 540 2013.04

Research paper (scientific journal), Joint Work, Accepted

タクロリムス眼軟膏の製剤学的安定性の検討

公平恵崇, 渡邉真一, 河添　仁, 原　祐子, 末丸克矢, 荒木博陽

愛媛県病薬会誌 ((一社)愛媛県病院薬剤師会) 110 3 - 7 2012.04

Research paper (scientific journal), Joint Work, Accepted

Comparison of antiemetic efficacy between single and repeat treatment with dexamethasone in patients receiving carboplatin-based combination chemotherapy

Kawazoe H, Motoki Y, Takechi Y, Shishino Y, Ido K, Suemaru K, Araki H

Methods and Findings in Experimental and Clinical Pharmacology (THOMSON REUTERS) 32 ( 7 ) 499 - 505 2010.09

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

A retrospective study was carried out to compare the preventive effects of single and repeat treatment with dexamethasone (DEX) on delayed nausea and emesis in patients who had received carboplatin (CBDCA)-based combination chemotherapy. Sixty-four patients were evaluated. Efficacy was assessed using the nausea and emesis score, food intake score and the requirement for antiemetic medication. These forward scores were categorized as three-grade during the first 5 days after chemotherapy. Acute nausea and emesis were well controlled in both groups on day 1. Mean values of the nausea and emesis score on day 3 evening and the food intake score on day 4 morning in the repeat-treatment group was 1.31 ± 0.93 and 3.46 ± 1.03, respectively, which were significantly better when compared with the singletreatment group (2.00 ± 1.52; P = 0.028 and 2.79 ± 1.12; P = 0.018, respectively). Multivariate logistic regression analysis revealed that less frequent dispensing of antiemetic medication was significantly associated with the repeat-treatment group (adjusted odds ratio, 0.153; 95% confidence interval, 0.026-0.734; P = 0.018). These results suggest that repeat-dose DEX may be more effective than single-dose DEX for the prevention of delayed nausea and emesis after CBDCA-based combination chemotherapy.

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注射用抗がん剤調製の知識・手技の均てん化を目指した多施設共同研修

河添　仁, 刀根潤一, 吉田陽子, 木村博史, 村上　朋, 亀岡春菜, 武智宣佳, 小暮友毅, 村上通康, 浅川隆重, 井上智喜, 江口久恵, 末丸克矢, 荒木博陽

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 46 ( 8 ) 1086 - 1090 2010.08

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

Nephrotoxicity Induced by Repeated Cycles of Oxaliplatin in a Japanese Colorectal Cancer Patient with Moderate Renal Impairment

Kawazoe H, Sugishita H, Watanabe S, Tanaka A, Morioka J, Suemaru K, Watanabe Y, Kawachi K, Araki H

Japanese Journal of Cancer and Chemotherapy 37 ( 6 ) 1153 - 1157 2010.06

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

There have so far been few reports of the pharmacokinetics of oxaliplatin in patients with renal impairment. This report describes the nephrotoxicity induced by repeated cycles of oxaliplatin in a Japanese colorectal cancer patient with moderate renal impairment(creatinine clearance(Ccr): 20-30mL/min). The patient was a 77-year-old male who had chronic renal impairment and received the modified FOLFOX6 repeated every 2 weeks. In cycle 8, the blood concentration of oxaliplatin(66 mg/m2)was measured as the platinum level to confirm the patient's safety. The serum ultrafiltrate concentrations of platinum were 800, 1, 000, 300, <200, and <200 ng/mLat 1, 2, 3 hr, 1 week, and 2 weeks after the start of infusion, respectively, which were closely comparable with the population pharmacokinetic data in Japanese patients with normal renal function. On the other hand, the serum creatinine value was gradually increased after cycle 6, resulting in a decrease of Ccr. The mean Ccr during day 1-59 and day 240-299were significantly different at 26. 5+/-2. 8(mean+/-SD)and 9. 6+/-1. 9mL/min, respectively. Consequently, the chemotherapy showed a complete response after 10 cycles, but the patient got dialysis on day 311. In conclusion, the repeated cycles of oxaliplatin cumulatively damaged the renal function in a Japanese patient with a moderate renal impairment.

カルボプラチン併用化学療法による骨髄抑制の危険因子の探索～多変量解析を用いた症例対照研究～

河添　仁, 元木雄己, 飛鷹範明, 井門敬子, 末丸克矢, 荒木博陽

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 46 ( 6 ) 792 - 796 2010.06

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

注射用抗がん剤取扱い時における薬剤師の被曝認識―愛媛県下10施設におけるアンケート調査―

小暮友毅, 河添　仁*, 井門敬子, 村上通康, 浅川隆重, 井上智喜, 末丸克矢, 荒木博陽, 江口久恵

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 46 ( 5 ) 651 - 655 2010.05

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

Problems associated with prophylactic use of erythromycin in 1566 staff to prevent hospital infection during the outbreak of pertussis

Tanaka H, Kaji M, Higuchi K, Shinohara N, Norimatsu M, Kawazoe H, Ninomiya M, Fukuoka N, Ishii N, Fujita J, Okabe A, Houchi H

Journal of Clinical Pharmacy and Therapeutics (WILEY) 34 ( 6 ) 719 - 722 2009.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0269-4727

Background and objective: Pertussis developed in Kagawa University Medical School and University Hospital in May 2007. To control the outbreak and prevent the infection of hospital inpatients, the Infection Control Team (ICT) carried out the prophylactic administration of erythromycin (EM) to hospital staff (1566 staff) who might be exposed to Bordetella pertussis.
Methods: An oral dose of 1000 mg/day EM was given for 10 days. To assess compliance and estimate the frequency of adverse effect, the ICT conducted a questionnaire survey.
Results and discussion: Of 942 respondents (response rate: 60.2%), 264 (28.0%) experienced some form of EM adverse effects, of which the most commonly reported involved digestive organ symptoms, e.g. diarrhoea (15.6%), stomachache (7.5%), nausea (3.6%), epigastric distress (2.1%) and abdominal distention (1.8%). More importantly, 246 participants (26.1%) stopped taking the EM before completing 10 days because of perceived adverse effects.
Conclusion: These results indicate that EM appears to cause adverse effects more frequently than reported in the package insert in Japan. The prophylactic use of EM for pertussis infection is recognized in the guideline of the Centers for Disease Control and Prevention. However, this study suggests that attention should be paid to EM non-compliance during a pertussis outbreak, which could extend the duration of the outbreak and increase the number of affected patients.

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イトラコナゾール内用液がシクロスポリンの薬物動態に及ぼす影響

山口佳津騎, 河添　仁, 井上達也, 田中裕章, 二宮昌樹, 福岡憲泰, 芳地一

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 45 ( 11 ) 1494 - 1496 2009.11

Research paper (scientific journal), Joint Work, Accepted

Comparison of Antibacterial Activity of Fluoroquinolones with Their Sucralfate-complexes against Clinically-isolated Bacteria

Kawazoe H, Takaoka K, Shibata H, Arakaki N, Higuti T, Negayama K, Houchi H, Tsuchiya K, Takiguchi Y

Journal of Health Science (The Pharmaceutical Society of Japan) 55 ( 5 ) 790 - 795 2009.10

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

Oral fluoroquinolones are widely known to form chelate complexes with metal-containing drugs, resulting in inhibition of their intestinal absorption. However, for intestinal sterilization, the concomitant regimen may be a selective and effective strategy due to decreased absorption of fluoroquinolones result in the retainment of antibiotics at the intestine if the mixture still perpetuated antibacterial activity. Therefore, to clarify whether the mixture of fluoroquinolones and sucralfate affects their antibacterial activity or not, we conducted in vitro study. According from the checkerboard study using a microdilution method with Mueller-Hinton broth, the antibacterial activity of these fluoroquinolones-sucralfate mixtures equaled to the parent fluoroquinolones even in the presence of sucralfate at the molar ratio of [sucralfate: fluoroquinolone] was less than 166, and the minimal inhibitory concentrations for clinical isolated Escherichia coli and Pseudomonas aeruginosa strains were independent of the existence of sucralfate. These data imply that the chelated forms of each fluoroquinolone retain antibacterial activity even in the presence of the recommended therapeutic doses of sucralfate in clinical practice.

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薬学生の満足度調査から見えてきた薬剤師教育の不足項目 -実務実習事前教育の現状-

河添　仁, 福岡憲泰, 辻　繁子, 合田哲子, 安西英明, 芳地　一

医療薬学 ((一社)日本医療薬学会) 35 ( 7 ) 501 - 508 2009.07

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

Little information is available on the level of satisfaction of pharmacy students with pharmacist education before clinical pharmacy practice,although the current pharmacy education is rapidly changing to place more importance on nurturing clinical experts.In view of this,we performed a questionnaire survey to investigate deficiencies in pharmacist education that affected the satisfaction level of pharmacy students.A questionnaire was given to 59 pharmacy students between February 2007 and July 2008 and the responses were analyzed using categorical regression in order to objectively reflect the results in future pharmacist education.The survey revealed that pharmacist jobs that reduced the satisfaction level of pharmacy students included“making in-hospital pharmaceutical preparations”,“compliance management”,“clinical research coordination”,“drug purchasing management and stock control”,and“payment for injection drugs”,etc.,listed in order of degree of deficiency.Other items that influenced the satisfaction level were“nurturing medical professionals”,“team approach to medical treatment”,and“communication”.In this regard,75.4% of the pharmacy students responded that communication education between pharmacists and other medical staff was insufficient.The findings of our survey suggest that satisfaction level is a useful index to target in improving pharmacist education.

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Prospective Study to Assess the Optimal Blood Concentration of Tacrolimus in Japanese Patients with Rheumatoid Arthritis

Kawazoe H, Dobashi H, Kameda T, Susaki K, Kittaka K, Tokuda M, Fukuoka N, Ishida T, Takiguchi Y, Houchi H

Journal of Health Science (The Pharmaceutical Society of Japan) 55 ( 3 ) 435 - 440 2009.06

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

We performed a prospective study to assess the optimal blood concentration of tacrolimus in Japanese patients with rheumatoid arthritis (RA). The dose of tacrolimus (1-3mg/day) was administered orally once daily after the evening meal, and the blood concentration of tacrolimus 12 hr after administration was quantified. A total of 23 patients were enrolled. Clinical efficacy was assessed using the Disease Activity Score in 28 joints and European League Against Rheumatism (EULAR) response criteria at each outpatient visit during months 1-6. The ratio of patients who showed a moderate or good response was 47.8% (11/23). The mean blood concentrations of tacrolimus in EULAR responders and EULAR non-responders were 5.5±3.6 (mean±S.D.) and 3.1±1.9 ng/ml, respectively (p=0.069). Interestingly, although tacrolimus had lower mean blood concentrations (<5 ng/ml) compared with transplant fields (10-20 ng/ml), six (35.3%) of 17 patients showed sufficient response to tacrolimus. In addition, in five patients, tacrolimus was co-administered with methotrexate (MTX). On the other hand, the mean blood concentrations of tacrolimus in patients who did or did not develop adverse events were 4.8±4.4 (n=8) and 4.0±2.1 (n=15) ng/ml, respectively (p=0.624). We failed to clear the optimal blood concentration of tacrolimus in RA patients, but one of the most remarkable findings was the observation that patients in whom tacrolimus was combined with MTX reached a positive response at much lower tacrolimus concentrations compared to patients not co-treated with MTX.

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精神科病棟における薬剤師の役割―医師・看護師への認識調査の前後比較による検証と再評価―

篠原尚樹, 河添　仁, 田中裕章, 二宮昌樹, 福岡憲泰, 芳地　一

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 45 ( 4 ) 511 - 514 2009.04

Research paper (scientific journal), Joint Work, Accepted

同種造血幹細胞移植患者における多剤耐性緑膿菌による感染症治療

河添　仁, 滝口祥令, 井上達也, 山口佳津騎, 田中裕章, 加地雅人, 辻　繁子, 二宮昌樹, 福岡憲泰, 大西宏明, 石田俊彦, 芳地　一

Yakugaku Zasshi ((公社)日本薬学会) 128 ( 4 ) 657 - 661 2008.04

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

Infections caused by multiple-drug-resistant Pseudomonas aeruginosa (MDRP) are a clinically significant problem. We reported here the effective use of combination therapy in a patient with infection caused by MDRP according to an interventional treatment strategy suggested by a pharmacist. The patient was a 70-year-old male who underwent allogeneic hematopoietic stem cell transplantation. On day 45 after transplant, MDRP was newly isolated from urine, but the diagnosis at that time was colonization. On day 61, the patient developed a fever (≥38.0°C). In addition, laboratory data showed that C-reactive protein (CRP) was also increased. At the medical team conference, the pharmacist proposed the following treatment strategy for this infection. Aztreonam and amikacin were intravenously administered at doses of 2 g/day and 800 mg/day, respectively. The subsequent clinical course was well controlled, but the infection recurred and was aggravated. Aztreonam and ciprofloxacin were then intravenously administered at doses of 4 g/day and 600 mg/day, respectively, resulting in the alleviation of fever in the patient as well as a decrease in CRP and disappearance of MDRP isolates from urine on day 67; that is, MDRP infection was consequently well controlled. In conclusion, the combination therapy between aztreonam and amikacin, or ciprofloxacin may be clinically useful for severe infections of MDRP in compromised hosts.

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院内製剤抗生物質点眼液の安定性

田中裕章, 朝倉正登, 土居智明, 河添　仁, 福岡憲泰, 玉井栄治, 宮田　茂, 松下　治, 岡部昭延, 芳地　一

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 43 ( 10 ) 1369 - 1372 2007.10

Research paper (scientific journal), Joint Work, Accepted

同種造血幹細胞移植患者におけるニューキノロン系抗菌薬による内因性感染の予防効果 —骨髄移植，末梢血幹細胞移植，臍帯血移植の比較—

河添　仁, 滝口祥令, 田中裕章, 二宮昌樹, 福岡憲泰, 大西宏明, 石田俊彦, 芳地　一

Yakugaku Zasshi ((公社)日本薬学会) 127 ( 8 ) 1301 - 1307 2007.08

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

We performed a retrospective study to examine the preventive effects of newquinolones for endogenous infection in patients receiving various allogeneic hematopoietic stem cell transplantation including bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT). Forty-nine patients were enrolled. Ciprofloxacin or norfloxacin was orally administered for intestinal sterilization from day -14 until engraftment. As a result, the period from transplantation until engraftment was significantly longer in CBT group than in BMT group. The febrile index (the ratio of the febrile (≥38.0°C) period during neutropenia (≤500 cells/mm3) and C-reactive protein (CRP)-positive index (the ratio of CRP-positive (≥2.0 mg/dl) period during neutropenia) were comparable among the three groups. In addition, no gram-negative bacteria in stool was isolated in the three groups; that is, an endogenous infection of gram-negative bacteria, a potential pathogen, was well controlled by newquinolones. We should be careful when interpreting the results of this small study; however, newquinolones are clinically effective for endogenous infection of gram-negative bacteria in patients receiving not only BMT, but also PBSCT and CBT.

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個々の患者の副作用予測のために開発された婦人科がん化学療法モニタリングシート

土居智明, 飯原なおみ, 河添　仁, 福岡憲泰, 芳地　一, 黒崎勇二, 森田修之

Yakugaku Zasshi ((公社)日本薬学会) 127 ( 6 ) 1027 - 1033 2007.06

Research paper (scientific journal), Joint Work, Accepted

Monitoring the adverse reaction patterns specific to individual patients is important to avoid subsequent reactions. Gynecologic cancer chemotherapy is often implemented repeatedly with an altered protocol during prolonged terms. The purpose of this study was to develop and assess the efficacy of a worksheet that pharmacists can use to analyze adverse reaction patterns in individual patients with gynecologic chemotherapy. The worksheet which we developed consisted of multiple sections. One section is for necessary drug information for the proper use of antineoplastic agents. Another section is for the following items recorded by the pharmacists: a) patients' basic information such as stage of disease and protocol, b) state of implementation and break of chemotherapy and supportive therapy on calendar, and c) laboratory data and symptoms. We arranged the last item below the calendar and enabled pharmacists to easily assess individual adverse reactions coupled with the treatment course. Reviews of the developed worksheet indicated that the worksheet led to the convenient detection of individual adverse reaction patterns and effective prevention of additional adverse reactions. This monitoring sheet covering long-term chemotherapy which was designed to predict individual adverse reaction patterns will improve the individualization and safety of gynecologic chemotherapy.

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Preventive Effects of Low-dose Dexamethasone for Delayed Adverse Events Induced by Carboplatin-based Combination Chemotherapy

Kawazoe H, Takiguchi Y, Tanaka H, Doi C, Fukuoka N, Kanaji N, Bandoh S, Ishida T, Houchi H

Yakugaku Zasshi ((公社)日本薬学会) 127 ( 6 ) 1001 - 1006 2007.06

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

We performed a retrospective study to examine the protective effect of low-dose dexamethasone (DEX) on delayed adverse events induced by carboplatin (CBDCA)-based combination chemotherapy in patients with thoracic tumors. Low-dose DEX (4-8 mg/day) was administered on day 1 and after, in addition to a serotonin 5-HT3 receptor antagonist. The acute adverse events (day 1) were well controlled in the patients with or without co-treatment of DEX. On the other hand, the delayed nausea, emesis, anorexia, and fatigue after day 2 failed to be controlled by 5-HT3 antagonist alone. Co-treatment with DEX significantly suppressed the grade of the delayed adverse events during days 2-10. The mean ratio of complete protection during days 2-10 were significantly higher in the DEX-treated group compared with the non-DEX-treated group. These results reveal that low-dose DEX is a clinically effective treatment for the prevention of delayed adverse events induced by CBDCA-based combination chemotherapy.

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Change of the Blood Concentration of Tacrolimus after the Switch from Fluconazole to Voriconazole in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Kawazoe H, Takiguchi Y, Tanaka H, Fukuoka N, Ohnishi H, Ishida T, Houchi H

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 29 ( 12 ) 2528 - 2531 2006.12

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

The purpose of this study was to assess the impact by switching co-administered triazole antifungal agent from fluconazole (FCZ) to voriconazole (VCZ) on the blood concentration of tacrolimus (FK506) in patients receiving allogeneic hematopoietic stem cell transplantation. We performed a retrospective study presented as case reports. The blood concentration of FK506 was increased after the switch from FCZ to VCZ, resulting in increase of the concentration/dose (C/D) ratio of FK506. Thus, the mean C/D ratios of FK506 with oral administration was surprisingly increased over 4.5-fold after the switch. Therefore, it was necessary to reduce the FK506 dose when co-administered FCZ is switched to VCZ. We should be careful when interpreting the results of these case reports; however, in some patients, it is recommended that the dose of FK506 be reduced to one-fifth after the switch.

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患者参加型癌化学療法副作用モニタリング—患者の治療参加と情報の共有化—

河添　仁, 久保智美, 飯原なおみ, 土居智明, 奥條真紀子, 福岡憲泰, 藤本さとし, 金地伸拓, 坂東修二, 石田俊彦, 滝口祥令, 芳地　一

Yakugaku Zasshi ((公社)日本薬学会) 126 ( 8 ) 629 - 642 2006.08

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

The purpose of this study was to assess patient participation in cancer therapy and the sharing of patient information among the medical care team (physicians, nurses, pharmacists, and especially patients). We monitored the side effects of cancer chemotherapy with patients, and developed two support tools: One scored the points of subjective symptoms (fatigue, anorexia, nausea, etc) by patients, and the other recorded objective symptoms (clinical examination data) by pharmacists. It is most important that they attend each patient at their bedside. At this time, the trial was evaluated by questionnaire survey by inpatients receiving cancer chemotherapy (n=15). As a result, all patients (15/15) responded that this trial was necessary. This trial addressed the following: 1) increased communication between patients and medical staff concerning side effects (14/15), 2) increased interest in side effects (10/15), 3) when a patient tells medical staff about side effects, they act on it (10/15). None of the patients felt inconvenienced by scoring every day (0/15), or anxiety about side effects (0/15). Furthermore, all patients (15/15) responded that “participation of pharmacists in cancer chemotherapy” was necessary. This trial revealed no problems and suggested that patients related to the center of medical care. We should be careful in interpreting results of this small sized trial; however, the following conclusions should be reached: 1) introduction of monitoring side effects of cancer chemotherapy with patients, 2) develop communication among the medical care team.

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診療報酬改訂に伴う「投与日数規制の原則廃止」の薬物療法管理に及ぼす影響

河添　仁, 飯原なおみ, 土居智明, 森田修之

Yakugaku Zasshi ((公社)日本薬学会) 125 ( 12 ) 959 - 969 2005.12

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

The proclamation of April 2002 of a Ministry of Health, Labor and Welfare ordinance has enabled doctors to prescribe drugs for an outpatient without a limit on the length of prescription terms except for a few drugs. There is a concern that the prescription-term deregulation could cause careless drug therapy management in order to extend the interval between patient hospital visits. The purpose of this study is to make pre- and post-deregulation comparisons of two items, prescription terms and implementation of clinical examination that complied with package-insert precautions, and to discuss the approaches to increase safety. Prescription terms have lengthened progressively. In the pre-regulation period of January to March 2002, the mean prescription term was 19.9 days; in the post-regulation period of July to September 2002, it was 24.9 days; and in July to September 2003, 28.6 days. Even for anti-tumor agents, there were prescriptions over 90 days after deregulation. There was no significant difference between the pre- and post-deregulation compliance ratios for the package-insert precautions in eight drugs of investigated nine. However, one case had a delay in detection of liver dysfunction, which was caused by deviation from the once-a-month testing indicated in the package-insert precautions for prolonged prescription terms. The evidence suggested that the deregulation led to negligent drug therapy management. To assure safe therapy, the following should be addressed: first, sufficient function of a computerized prescriber order entry system and second, creation of a new framework with pharmacists' active involvement such as collaborative therapy management with physicians.

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