Updated on 2026/08/27

写真a

 
TOYAMA Akira
 
Organization
University Medical and Dental Hospital Division of Pharmacy Professor
Graduate School of Medicine, Dentistry and Health Sciences Medicine and Dentistry Professor
Title
Professor
External link

Degree

  • 博士(薬学) ( 1999.11   東北大学 )

Research Interests

  • resonance Raman spectroscopy

  • 医療薬学

Research Areas

  • Life Science / Clinical pharmacy

Research History

  • Niigata University   University Medical and Dental Hospital Division of Pharmacy   Professor

    2015.7

  • Niigata University   Graduate School of Medical and Dental Sciences Community Disease Control   Professor

    2015.7

  • Niigata University   Graduate School of Medical and Dental Sciences Biomedical Sciences   Professor

    2015.7

  • Niigata University   University Medical and Dental Hospital   Associate Professor

    2005.6 - 2015.6

  • Niigata University   Graduate School of Medical and Dental Sciences Biomedical Sciences   Associate Professor

    2005.6 - 2015.6

  • Niigata University   Graduate School of Medical and Dental Sciences Community Disease Control   Associate Professor

    2005.6 - 2015.6

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Professional Memberships

 

Papers

  • Association Between Individualized Estimated Glomerular Filtration Rate and Cumulative Cisplatin Dose in Head and Neck Cancer. International journal

    Naoto Hoshino, Kensuke Yoshida, Yoshitomi Kanemitsu, Akira Toyama, Munetoshi Sugiura

    Anticancer research   46 ( 7 )   4055 - 4065   2026.7

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    BACKGROUND/AIM: In concurrent chemoradiotherapy (CCRT) for head and neck cancer, achieving a cumulative cisplatin dose of ≥200 mg/m2 is associated with improved outcomes. However, treatment modification due to toxicity remains a challenge. As cisplatin is primarily excreted by the kidneys, assessment of renal function is important. This study investigated the association between individualized estimated glomerular filtration rate (eGFR) and cumulative cisplatin dose in patients with head and neck cancer undergoing CCRT. PATIENTS AND METHODS: This retrospective study included patients with head and neck cancer who received CCRT with cisplatin (80 mg/m2 every three weeks for three cycles) at Niigata University Medical and Dental Hospital between April 2015 and March 2024. The primary endpoint was the cumulative cisplatin dose. Renal function was assessed using individualized eGFR, and patients were categorized into ≥200 mg/m2 and <200 mg/m2 groups. Logistic regression analysis was performed to identify factors associated with a cumulative cisplatin dose of <200 mg/m2. RESULTS: Among 158 patients, 27 (17%) received a cumulative cisplatin dose of <200 mg/m2. Although all patients had a Cockcroft-Gault creatinine clearance (CGCCr) ≥60 ml/min, 8 (5%) had an individualized eGFR <60 ml/min. The proportion of patients with an eGFR <60 ml/min was significantly higher in the <200 mg/m2 group (15% vs. 3%, p=0.03). In the multivariate analysis, eGFR <60 ml/min was associated with a cumulative cisplatin dose <200 mg/m2 (adjusted odds ratio=4.66; 95% confidence interval=1.06-20.5; p=0.041). CONCLUSION: In patients with head and neck cancer undergoing cisplatin-based CCRT, individualized eGFR <60 ml/min was associated with a reduced cumulative cisplatin dose despite adequate CGCCr. Assessment using eGFR may improve pre-treatment evaluation of renal function in this setting.

    DOI： 10.21873/anticanres.18265

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  • Clinical Factors Associated With Non-Completion of Durvalumab Maintenance Therapy After Chemoradiotherapy in Patients With Locally Advanced Non-Small Cell Lung Cancer: A Single-Center Retrospective Study. International journal

    Masaaki Kotake, Satoshi Watanabe, Yuki Sakai, Toshiaki Kikuchi, Akira Toyama

    Thoracic cancer   17 ( 12 )   e70329   2026.6

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    BACKGROUND: Durvalumab maintenance following concurrent chemoradiotherapy (CCRT) is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC); however, some patients discontinue treatment before completing 12 months. We explored whether pretreatment peripheral blood inflammatory and nutritional markers are associated with durvalumab non-completion. METHODS: We retrospectively reviewed patients with locally advanced NSCLC who initiated durvalumab between August 2018 and April 2024. Laboratory data obtained within 7 days before the first dose were analyzed. Completion was defined as 12 months (365 days) of treatment. Routine laboratory parameters and inflammatory/nutritional indices were compared between completers and non-completers. Exploratory multivariable logistic regression and clinically adjusted sensitivity analyses were performed. RESULTS: Eighty patients were included: 36 completers and 44 non-completers. Durvalumab was discontinued because of disease progression (n = 24), radiation pneumonitis (n = 14), immune-related adverse events (n = 5), and aspiration pneumonia (n = 1). Conventional inflammatory indices did not differ between groups. In the primary exploratory multivariable model, a higher albumin-to-globulin (A/G) ratio was associated with durvalumab completion (OR, 9.74; 95% CI, 1.01-93.9; p = 0.048), whereas RDW-SD showed a non-significant inverse association with completion (OR, 0.942; 95% CI, 0.883-1.01; p = 0.076). After adjustment for age, ECOG performance status, and histology, these associations were not statistically significant. CONCLUSIONS: Lower A/G ratio and higher RDW-SD before durvalumab initiation may be associated with non-completion. Given the exploratory design, limited sample size, attenuation after clinical adjustment, and heterogeneous reasons for discontinuation, these findings require external validation.

    DOI： 10.1111/1759-7714.70329

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  • Individualized Estimated Glomerular Filtration Rate-based Renal Function Association With Cisplatin Treatment Completion in Cervical Cancer

    Naoto Hoshino, Kensuke Yoshida, Yoshitomi Kanemitsu, Akira Toyama, Munetoshi Sugiura

    ANTICANCER RESEARCH   46 ( 1 )   273 - 281   2026.1

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    DOI： 10.21873/anticanres.17941

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  • 薬剤師を対象としたe-learningによるがん化学療法の口腔粘膜炎に関する教育

    星野 直人, 吉田 謙介, 矢吹 剛, 古賀 雅良, 多川 洋史, 貝瀬 眞由美, 冨原 圭, 外山 聡

    日本口腔ケア学会雑誌   20 ( 2 )   34 - 40   2025.12

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  • Patient-reported oral adverse events during cancer chemotherapy: longitudinal evaluation using patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) and concordance with clinician assessments

    Yuki Sakai, Kouji Katsura, Yoshitomi Kanemitsu, Masaaki Kotake, Akira Toyama

    SUPPORTIVE CARE IN CANCER   33 ( 12 )   2025.11

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    DOI： 10.1007/s00520-025-10126-3

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  • Investigation of non-completion factors for durvalumab maintenance therapy in locally advanced non-small cell lung cancer

    Masaaki Kotake, Yuki Sakai, Satoshi Watanabe, Toshiaki Kikuchi, Akira Toyama

    TRANSLATIONAL LUNG CANCER RESEARCH   14 ( 10 )   4256 - 4267   2025.10

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    DOI： 10.21037/tlcr-2025-739

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  • A Cross-Sectional Survey of Oral Adverse Events and Oral Management Needs in Outpatients Receiving Cancer Drug Therapy Reviewed

    Yuki Sakai, Kouji Katsura, Masaaki Kotake, Akira Toyama

    Cancers   17 ( 4 )   2025.2

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    DOI： 10.3390/cancers17040641

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  • A case series study on the safety of cefditoren pivoxil use during the first trimester of pregnancy in Japan. International journal

    Mariko Honma, Naoto Suzuki, Mikako Goto, Taku Obara, Yoshiyuki Saito, Ken Nakajima, Ritsuko Yamane, Kunihiko Takahashi, Takeo Nakayama, Masahiro Hayashi, Atsuko Murashima, Akira Toyama

    Congenital anomalies   65 ( 1 )   e12588   2025

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    We evaluated the teratogenic risk associated with exposure to cefditoren pivoxil during the first trimester of pregnancy using the integrated databases of the Toranomon Hospital and the National Center for Child Health and Development. Among 13 599 registered individuals, the analysis included 285 subjects who had taken cefditoren pivoxil during the first trimester of pregnancy. The rates of stillbirth, miscarriage, and elective terminations were 0.4%, 5.6%, and 2.1%, respectively. Among 262 live births, the rates of preterm birth, low birth weight, and major congenital malformations were 4.6%, 5.7%, and 1.2%, respectively. Our results suggest that exposure to cefditoren pivoxil during the first trimester of pregnancy does not significantly increase the risk of adverse pregnancy outcomes and infant outcomes.

    DOI： 10.1111/cga.12588

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  • 頭頸部化学放射線療法の口腔粘膜炎対策における含嗽薬とジメチルイソプロピルアズレン軟膏の併用効果に関する検討 多施設共同事後解析研究

    吉田 謙介, 渡邉 真一, 星野 直人, 朴 慶純, 飛鷹 範明, 金野 昇, 中井 昌紀, 安藤 智七美, 矢吹 剛, 鈴木 直人, 勝良 剛詞, 冨原 圭, 外山 聡

    日本口腔ケア学会雑誌   19 ( 1 )   17 - 23   2024.6

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  • Effect of Yokukansan on preoperative anxiety and postoperative pain in mandibular third molar extraction: A pilot study

    Kensuke Yoshida, Yasumitsu Kodama, Anna Kiyomi, Kyongsun Pak, Takahiro Nagai, Chie Saito, Kyosuke Yamazaki, Munetoshi Sugiura, Akira Toyama, Kei Tomihara

    ORAL SCIENCE INTERNATIONAL   21 ( 2 )   191 - 197   2024.5

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    DOI： 10.1002/osi2.1202

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  • メサドンの服用タイミングの変更によって傾眠を軽減できた1症例

    吉田 謙介, 松本 吉史, 磯貝 和也, 工藤 範子, 佐々木 健太, 阿部 聡美, 外山 聡

    日本緩和医療薬学雑誌   17 ( 1 )   25 - 28   2024.3

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  • Hospital pharmacist interventions for the management of oral mucositis in patients with head and neck cancer receiving chemoradiotherapy: a multicenter, prospective cohort study. International journal

    Kensuke Yoshida, Shinichi Watanabe, Naoto Hoshino, Kyongsun Pak, Noriaki Hidaka, Noboru Konno, Masaki Nakai, Chinami Ando, Tsuyoshi Yabuki, Naoto Suzuki, Kouji Katsura, Kei Tomihara, Akira Toyama

    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer   31 ( 5 )   316 - 316   2023.5

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    PURPOSE: Oral mucositis is a severe adverse event in patients with head and neck cancer (HNC) receiving chemotherapy and radiotherapy that may cause the termination of cancer treatment. In this study, we aimed to reveal the benefits of pharmacist interventions in oral health care for patients with HNC receiving concurrent chemoradiotherapy (CCRT). METHODS: We conducted a multicenter, prospective cohort study on 173 patients from September 2019 to August 2022. We evaluated the association between the occurrence of oral mucositis during CCRT and various factors in the absence or presence of direct medication instructions from hospital pharmacists. RESULTS: Sixty-eight patients received medication instructions from pharmacists (the pharmacist intervention group), whereas 105 patients did not receive instructions (the control group). Logistic regression analysis showed that grade 2 (Gr 2) oral mucositis was significantly lower in patients receiving pharmacist interventions than in patients in the control group (adjusted odds ratio [aOR], 0.42; 95% confidence interval [CI], 0.18-0.96; P = 0.04). The time to onset of Gr 2 oral mucositis was significantly longer in the pharmacist intervention group than in the control group (hazard ratio, 0.53; 95% CI, 0.29-0.97; P = 0.04). CONCLUSION: Direct intervention, especially when provided by hospital pharmacists, can have a real effect in supporting patients with HNC experiencing severe side effects of treatments. Moreover, the integration of pharmacists into the oral healthcare team is becoming even more essential to reduce the severity of side effects.

    DOI： 10.1007/s00520-023-07784-6

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  • 切除不能膵がんに対するゲムシタビン+ナブパクリタキセル療法の長期継続に寄与する因子に関する調査

    小竹 正晃, 坂井 由紀, 新木 貴大, 鈴木 直人, 外山 聡

    日本病院薬剤師会雑誌   59 ( 5 )   519 - 524   2023.5

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  • HIV外来診療における協働意思決定に基づいた継続的な薬剤師介入の影響

    成田 綾香, 島田 泉, 鈴木 直人, 外山 聡

    医療薬学   49 ( 2 )   39 - 50   2023.2

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    ヒト免疫不全ウイルス(HIV)の外来診療における協働意思決定に基づいた継続的な薬剤師面談の有効性を評価した。2016年10月～2018年3月の間に当院HIV外来を定期受診した抗レトロウイルス療法(ART)継続中の患者49名を対象とした。このうち、処方変更が不要であると判断された11名(男性10名、女性1名、中央値48歳)を変更提案不要群、薬剤師面談において処方変更を提案した38名(男性30名、女性8名、中央値45.5歳)を変更提案群、変更提案群のなかで処方変更がなされた35名を変更群と定義した。ARTの錠数、併用服薬錠数、服薬総錠数、服薬種類数は処方変更後に有意に減少し、推奨ART、single table regimenの適応となった患者数は有意に増加した。ART変更理由は、多い順に副作用・長期毒性の回避・軽減、服薬負担軽減、薬物相互作用回避、薬価負担軽減であった。継続的な薬剤師面談によって、治療安全性の向上、服薬アドヒアランス維持、経済的負担軽減が得られることが示唆された。

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    Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J03520&link_issn=&doc_id=20230216220001&doc_link_id=%2Fdb5pharm%2F2023%2F004902%2F001%2F0039-0050%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdb5pharm%2F2023%2F004902%2F001%2F0039-0050%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • 薬に対する患者の意識 新潟県下多施設調査

    大瀧 翔太, 古川 智康, 清水 健一, 翁長 寛人, 俵山 悟, 細川 浩輝, 鈴木 光幸, 持田 知志, 八木 元広, 渡辺 重雄, 若林 聰一, 山田 徹, 稲月 幸範, 井上 幹雄, 関口 知行, 坂口 正幸, 藤井 星也, 山寺 徹, 根津 洋平, 阿部 佑一, 清水 英勇, 二階堂 雅一, 外山 聡, 宇野 勝次, 新潟医薬品安全性研究会

    医薬品安全性学   8 ( 2 )   109 - 118   2022.12

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  • 薬の副作用に関する患者アンケート多施設調査 1997年度と2019年度の比較検討

    俵山 悟, 古川 智康, 清水 健一, 翁長 寛人, 大瀧 翔太, 井上 幹雄, 関口 知行, 坂口 正幸, 藤井 星也, 山寺 徹, 根津 洋平, 細川 浩輝, 阿部 佑一, 鈴木 光幸, 持田 知志, 八木 元広, 清水 英勇, 渡辺 重雄, 若林 聰一, 二階堂 雅一, 山田 徹, 稲月 幸範, 外山 聡, 宇野 勝次, 新潟医薬品安全性研究会

    医薬品安全性学   8 ( 2 )   127 - 139   2022.12

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  • オピオイドで疼痛管理不良の放射線皮膚炎にリドカイン混合ワセリンが奏効した1例

    島田 泉, 工藤 範子, 外山 美央, 市川 紘将, 土田 裕子, 岩井 由樹, 鈴木 丈雄, 結城 明彦, 濱 菜摘, 外山 聡

    日本緩和医療薬学雑誌   15 ( 1 )   21 - 24   2022.3

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  • [Comparison between Single and Three Times Pre-operative Administration of Amoxicillin in the Prophylactic Effects for Surgical Site Infections in Japanese Patients with Mandibular Third Molars Extraction].

    Kensuke Yoshida, Yasumitsu Kodama, Chie Saito, Kei Tomihara, Akira Toyama

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   142 ( 12 )   1391 - 1398   2022

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    Although the dosage of oral antibiotics (OA) for the mandibular third molar extraction (MTME) varies among the administration periods according to the current guideline, our previous reports suggested that it might be possible to further shorten the administration period without increasing the incidence of surgical site infection (SSI). In the present study, we retrospectively evaluated the relationship between the incidence of SSI and the administration period of OA in patients who underwent the MTME in our hospital. This retrospective cohort study included 348 patients who underwent the MTME in our dental outpatient clinic from June 2020 to March 2022. The administrated antibiotic was amoxicillin (AMPC) in all patients. Patients were divided into two groups based on the administration period of AMPC single and three times before the surgery. The following information was collected: (1) patient factors (age, gender, body mass index, diagnosis, mandibular third molar status); (2) surgical factors (operation time, presence/absence of wound closure, presence/absence of hemostat, experience of surgeons); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. There were 217 cases in the single group and 131 cases in the three times group. The incidence of SSI was 1.1% (4/348), with 1.4% (3/217) in the single group and 0.8% (1/131) in the three times group; there was no significant difference between the two groups. Our result suggests that single administration of AMPC before the MTME would be sufficient for the prevention of SSI in Japanese patients without risk factors.

    DOI： 10.1248/yakushi.22-00163

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  • Salivary inflammatory mediators as biomarkers for oral mucositis and oral mucosal dryness in cancer patients: A pilot study. International journal

    Anna Kiyomi, Kensuke Yoshida, Chie Arai, Risa Usuki, Kyosuke Yamazaki, Naoto Hoshino, Akira Kurokawa, Shinobu Imai, Naoto Suzuki, Akira Toyama, Munetoshi Sugiura

    PloS one   17 ( 4 )   e0267092   2022

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    Oral mucositis (OM) is a common side effect in patients with cancer receiving chemotherapy and radiotherapy; however, no salivary mediator is known to be associated with OM. We aimed to determine candidate salivary inflammatory mediators potentially associated with OM in patients with cancer. To this end, we compared the relationships between OM grade, oral mucosal dryness, and inflammatory mediators (Interleukin (IL)-1β, IL-6, IL-10, IL-12p70, tumor necrosis factor (TNF), prostaglandin E2, and vascular endothelial growth factor) in patients with cancer and in healthy volunteers (HV). We collected saliva samples from 18 patients with cancer according to the following schedule: 1) within 14 days of treatment initiation, 2) within 3 days of OM occurrence, 3) when OM was improved or got worsened, and 4) within 7 days after chemotherapy completion. The oral care support team determined the OM grade at each sample collection point based on CTCAE version 5.0. Salivary inflammatory mediator concentrations were detected using cytometric bead array or enzyme-linked immunoassay. We compared oral mucosal dryness in pre- and post-index patients with cancer to that in HV (n = 33) using an oral moisture-checking device. Fourteen of eighteen patients experienced OM (four, grade 3 OM; four, grade 2 OM; six, grade 1 OM). IL-6, IL-10, and TNF salivary concentrations were significantly increased in the post-index group compared to those in the pre-index group (p = 0.0002, p = 0.0364, and p = 0.0160, respectively). Additionally, salivary IL-6, IL-10, and TNF levels were significantly higher in the post-index group than in the HV group (p < 0.0001, p < 0.05, and p < 0.05, respectively). Significant positive correlations were observed between OM grade and salivary IL-6, IL-10, and TNF levels (p = 0.0004, r = 0.4939; p = 0.0171, r = 0.3394; and p = 0007, r = 0.4662, respectively). Oral mucosal dryness was significantly higher in the HV than in the pre- and post-index groups (p < 0.001). Our findings suggest that salivary IL-6, IL-10, and TNF levels may be used as biomarkers for OM occurrence and grade in patients with cancer. Furthermore, monitoring oral mucosal dryness and managing oral hygiene before cancer treatment is essential.

    DOI： 10.1371/journal.pone.0267092

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  • Comparison between the prophylactic effects of amoxicillin 24 and 48 hours pre-operatively on surgical site infections in Japanese patients with impacted mandibular third molars: A prospective cohort study. International journal

    Kensuke Yoshida, Yasumitsu Kodama, Atsushi Nishikawa, Andrea Rei Estacio Salazar, Akira Toyama, Ritsuo Takagi

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 6 )   845 - 851   2021.6

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    INTRODUCTION: According to the guidelines, the dosage for mandibular wisdom tooth extraction (MWTE) varies within the administration period. There is a 24-fold difference between the minimum and maximum doses. If an appropriate antimicrobial can be administered without increasing incidence of surgical site infection (SSI), it may lead to a global action plan on antimicrobial resistance (AMR). Therefore, we prospectively surveyed incidence of SSI post-operatively and use of oral antibiotics (OA) for MWTE. METHODS: Subjects were patients who underwent MWTE in our dental outpatient clinic from May 2019 to April 2020. Two groups were formed depending on type of administration period they received: 24 h and 48 h after surgery. The following information was collected: (1) patient factors (age, gender, body mass index, presence/absence of preoperative medication, diagnosis, impacted wisdom tooth status; (2) surgical factors (operative time, presence/absence of closure, presence/absence of hemostat, doctor career, type and frequency of painkiller); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. RESULTS: Three hundred forty subjects were analyzed, all of which used amoxicillin. There were 106 cases in 24 h group and 234 cases in 48 h group. The total incidence of SSI was 1.1% (4/340 cases), with 0.9% (1/106 cases) in 24 h group and 1.3% (3/234 cases) in 48 h group; there was no difference between the two groups. CONCLUSION: Our study suggests that amoxicillin (250 mg/dose every 8 h x 3 doses beginning 1 h before surgery) might be sufficient in preventing SSI in Japanese dental patients without SSI risk factors.

    DOI： 10.1016/j.jiac.2021.01.018

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  • Clinico-statistical survey of oral antimicrobial prophylaxis and surgical site infection regarding ordinary tooth extraction and mandibular wisdom tooth extraction in the dental outpatient clinic. International journal

    Kensuke Yoshida, Yasumitsu Kodama, Takahiro Nagai, Andrea Rei Estacio Salazar, Syouta Kaneko, Chie Saito, Akira Toyama, Ritsuo Takagi

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 2 )   192 - 197   2021.2

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    INTRODUCTION: We investigated the use of oral antibiotics (OA) and surgical site infection (SSI) related to extractions of ordinary teeth and mandibular wisdom teeth in a dental outpatient clinic from January 2015 to December 2019. METHODS: The following information were surveyed: (1) presence/absence of OA, (2) timing, (3) type, (4) administration period, and (5) SSI rates. RESULTS: The use of OA during ordinary tooth extraction decreased from 68.3% to 41.3%, but SSI rate did not change during this period of time. Total SSI rate was 0.8% (122/14,832) on average. For mandibular wisdom tooth extraction, preoperative administration of third-generation cephalosporins decreased from 70.4% to 0.3% while that of penicillin (AMPC) increased from 0% to 98%. SSI rate was not changed after these improvements. Total SSI rate was 3.5% (180/5106) on average. The duration of OA was slightly decreased to two days in 2018 and 2019, and it was found that there was no significant difference in SSI rates between 2- and 3-day durations. Preoperative administration had 0.37 odds ratio (OR) (95% confidence interval (95%CI): 0.22-0.63) of SSI compared with postoperative administration. AMPC had 0.76 OR (95% CI: 0.55-1.04) of SSI compared with Third-generation cephalosporins and others. Timing of OA was P < 0.01. CONCLUSIONS: SSI rates did not change over time, administration period of OA decreased and the use of AMPC increased. Therefore, it seems necessary to continue to investigate the effects of SSI risk factors proactively in the future and to make efforts in the advocacy of appropriate antimicrobial use.

    DOI： 10.1016/j.jiac.2020.08.022

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  • Pharmacist involved education program in a multidisciplinary team for oral mucositis: Its impact in head-and-neck cancer patients. International journal

    Kensuke Yoshida, Yasumitsu Kodama, Yusuke Tanaka, Kyongsun Pak, Marie Soga, Akira Toyama, Kouji Katsura, Ritsuo Takagi

    PloS one   16 ( 11 )   e0260026   2021

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    OBJECTIVES: This retrospective study examined how a pharmacist-involved education program in a multidisciplinary team (PEMT) for oral mucositis (OM) affected head-and-neck cancer (HNC) patients receiving concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Total samples data of 53 patients during the stipulated timeframe were retrospectively collected from electronic medical records from February 2017 to January 2019. We compared the presence/absence of OM (OM: yes/no) between patients with and without PEMT (PEMT: yes/no) as the primary endpoint and OM severity as the secondary endpoint. The following information was surveyed: age, gender, weight loss, steroid or immunosuppressant use, hematological values (albumin, white blood cell count, blood platelets, and neutrophils), cancer grade, primary cancer site, type and use of mouthwash and moisturizer, opioid use (yes/no, days until the start of opioid use, and dose, switch to tape), and length of hospital day (LOD). The two groups were compared using Fisher's exact test for qualitative data and the Mann-Whitney U test for quantitative data, and a significance level of p<0.05 was set. RESULTS: The group managed by PEMT had significantly lower weight loss and a significantly lower incidence of local anesthetic and opioid use and switch to tape compared with the group not managed by PEMT (p<0.05). The two groups showed no significant difference in OM (yes/no) or OM severity. The PEMT group had significantly shorter LOD at 57 (53-64) days compared with the non-PEMT group at 63.5 (57-68) days (p<0.05). CONCLUSIONS: Our results showed that PEMT did not improve OM (yes/no) or OM severity in HNC patients undergoing CCRT. However, the PEMT group had a lower incidence of grades 3 and 4 OM than the non-PEMT group, although not significantly. In addition, PEMT contributed to oral pain relief and the lowering of the risk for OM by reduction in weight loss.

    DOI： 10.1371/journal.pone.0260026

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  • Prediction of Postoperative Infection for Patients Undergoing Gastrointestinal Surgery: Findings from Electronic Health Records

    Kyoko Nakazawa, Takashi Ishikawa, Akira Toyama, Toshifumi Wakai, Kohei Akazawa

    Gastroenterology Insights   11 ( 2 )   36 - 46   2020.11

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    Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

    Introduction: Postoperative infection is a major cause of morbidity and prolonged hospitalization in patients undergoing gastrointestinal surgery. This observational study aimed to investigate the risk factors associated with postoperative infection and to develop a prediction model for postoperative infections that occur after gastrointestinal surgery. Methods: The study population comprised 1637 patients who underwent gastrointestinal surgery at Niigata University Medical and Dental Hospital between June 2013 and May 2017. Observational data from 1883 surgical procedures were used in the statistical analyses (including 198 patients who underwent several operations). Results: The generalized estimating equation (GEE) was used to detect significant risk factors, including older age, history of smoking, body temperature greater than 38 °C, non-endoscopic surgical procedures, surgery in the thoracic or lower gastrointestinal tract, and use of medical nutritional products during surgery. The sensitivity and specificity of the GEE model were 88.2% and 55.1%, respectively. Conclusion: This study established a predictable GEE model, incorporating the data of patients who were hospitalized several times into a prediction analysis, even though the sensitivity was not sufficiently high. The GEE model, which is considered clinically useful, can be constructed using a variety of variables, including those obtained from electronic health records.

    DOI： 10.3390/gastroent11020007

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  • A case of severe hepatotoxicity induced by cisplatin and 5-fluorouracil. International journal

    Ayaka Yaegashi, Kensuke Yoshida, Naoto Suzuki, Izumi Shimada, Yusuke Tani, Yasuo Saijo, Akira Toyama

    International cancer conference journal   9 ( 1 )   24 - 27   2020.1

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    Severe hepatotoxicity from combination chemotherapy with cisplatin and 5-fluorouracil is a rare adverse effect. In this case report, we present a case with severe hepatotoxicity immediately following chemotherapy with cisplatin and 5-fluorouracil. This female patient had previously been treated with this combination with no hepatotoxicity. The elevated liver enzymes quickly normalized after chemotherapy was stopped. There were no specific changes in liver imaging. As hepatotoxicity occurred after repeated administration of cisplatin, we suggest that this hepatotoxicity might represent a case of allergic hepatitis caused by cisplatin. Severe hepatotoxicity should be watched for with repeated administration of cisplatin.

    DOI： 10.1007/s13691-019-00394-2

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  • Age-Based Comparison of Hematological Toxicity in Patients with Lung Cancer. International journal

    Yuki Sakai, Qiliang Zhou, Yoshifumi Matsumoto, Takuro Saiki, Masato Moriyama, Akira Toyama, Yasuo Saijo

    Oncology   98 ( 11 )   771 - 778   2020

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    INTRODUCTION: Because of the increasing age of the general population, there is an increasing number of older patients with lung cancer. Cancer chemotherapy often causes severe hematological toxicity in older patients. OBJECTIVE: This study aimed to explore the risk factors affecting the hematological toxicity of cytotoxic anticancer drugs in patients with lung cancer. METHODS: Data were retrospectively collected from 194 patients with lung cancer at Niigata University Medical and Dental Hospital, Japan, between April 2011 and March 2016, when the patients underwent their first round of cytotoxic chemotherapy. The patients were divided into three groups on the basis of age: <65, 65-74, and ≥75 years. Physiological functions and laboratory data before treatment, as well as hematological adverse events following chemotherapy, were compared among the groups. RESULTS: Patients aged ≥75 years were significantly more likely to experience grade 3 or 4 neutropenia, compared with patients aged <65 years. However, there were no differences in the incidence of anemia or thrombocytopenia among the age groups. The frequency of febrile neutropenia tended to increase with age. Multivariate analysis showed that age ≥75 years, male sex, and a performance status of ≥2 were independent factors for grade 3 or 4 neutropenia. Patients with 2 or 3 of these factors had a significantly higher frequency of neutropenia, compared with patients who had 0 or 1 of these factors. CONCLUSION: We found that age ≥75 years, male sex, and a performance status of ≥2 were independent risk factors for grade 3 or 4 neutropenia.

    DOI： 10.1159/000507864

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  • 歯科領域における周術期患者の抗菌薬使用実態調査 経口スイッチ療法の評価

    吉田 謙介, 田村 隆, 磯辺 浩和, 新木 貴大, 中川 裕介, 石田 みなみ, 鈴木 直人, 西川 敦, 船山 昭典, 児玉 泰光, 小林 正治, 高木 律男, 田邊 嘉也, 外山 聡

    医薬品相互作用研究   41 ( 3 )   174 - 177   2017.11

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    Language：Japanese   Publisher：(一社)医薬品相互作用研究会  

    当院歯科領域では周術期患者に対し、術後感染予防として注射用抗菌薬セファゾリン(CEZ)が推奨されているが、CEZ投与終了翌日から経口抗菌薬へ切り替えて投与する治療(経口スイッチ療法)が経験的に行われる場合がある。「術後感染予防抗菌薬適正使用のための実践ガイドライン」では、推奨投与期間を超えた経口抗菌薬の追加は不要であるとされている。そこで今回、経口スイッチ療法の必要性について検討するため、2015年1月～6月に当院歯科領域でCEZを使用された患者213例を対象とし、経口スイッチ療法実施群(111例)と非実施群(102例)に分けて諸データの群間比較を行った。結果、実施群の背景として、「入院期間の短縮」や「剤形変更による費用削減」などを期待して経口スイッチ療法が行われていたと考えられたが、実際には「入院期間の短縮」「費用削減」とも認められなかった。このことから経口スイッチ療法の必要性は低い可能性が示唆された。

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  • ICT介入による予防的抗菌薬の変更が口腔外科手術におけるSSI発生率と医療費に与える影響

    吉田 謙介, 鈴木 直人, 新木 貴大, 西川 敦, 児玉 泰光, 高木 律男, 田邊 嘉也, 外山 聡

    日本病院薬剤師会雑誌   53 ( 6 )   671 - 674   2017.6

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  • Immune monitoring with a lymphocyte adenosine triphosphate assay in kidney transplant recipients treated with a calcineurin inhibitor. International journal

    Kentaro Sugiyama, Mahoto Tsukaguchi, Akira Toyama, Hiroshi Satoh, Kazuhide Saito, Yuki Nakagawa, Kota Takahashi, Sachiko Tanaka, Kenji Onda, Toshihiko Hirano

    Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation   12 ( 3 )   195 - 9   2014.6

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    OBJECTIVES: The adenosine triphosphate assay using peripheral lymphocytes may be useful to evaluate the risks of acute rejection and infection in kidney transplant patients. We used the adenosine triphosphate assay to evaluate differences between recipients who were treated with cyclosporine- or tacrolimus-based immunosuppressive therapy. MATERIALS AND METHODS: Adenosine triphosphate levels were measured in peripheral CD4+ cells before and after transplant and were correlated with clinical outcomes in 45 kidney transplant recipients. These recipients received immunosuppressive therapy with either cyclosporine (23 patients) or tacrolimus (22 patients). RESULTS: Adenosine triphosphate levels were significantly lower in the cyclosporine- than tacrolimus-based therapy groups from 2 to 6 weeks after transplant. Adenosine triphosphate levels were similar between these groups before and 1 week after transplant. The frequency of cytomegalovirus infection was greater in the recipients who received cyclosporine (17 patients [74%]) than tacrolimus (6 patients [27%]; P ≦ .003). The frequency of acute rejection episodes was similar between the cyclosporine and tacrolimus groups. CONCLUSIONS: These observations suggest that cyclosporine-based immunosuppressive therapy causes excessive immunosuppression compared with tacrolimus-based therapy, evidenced by the lymphocyte adenosine triphosphate levels. The adenosine triphosphate assay using peripheral CD4+ cells may be a useful method for predicting the occurrence of cytomegalovirus infections in kidney transplant recipients.

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  • Peripheral Lymphocyte Response to Mycophenolic Acid In Vitro and Incidence of Cytomegalovirus Infection in Renal Transplantation. International journal

    Kentaro Sugiyama, Hiroyasu Sasahara, Mahoto Tsukaguchi, Kazuya Isogai, Akira Toyama, Hiroshi Satoh, Kazuhide Saitoh, Yuki Nakagawa, Kota Takahashi, Sachiko Tanaka, Kenji Onda, Toshihiko Hirano

    Cell medicine   6 ( 1-2 )   47 - 55   2013.12

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    The lymphocyte immunosuppressant sensitivity test (LIST) with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay procedure has been used to predict the pharmacological efficacy of immunosuppressive agents to prevent acute rejection episodes for renal transplant recipients. In this study, mycophenolic acid (MPA) pharmacological efficacies were evaluated by LIST at both prior to and just after renal transplantation. We compared the efficacies to the clinical outcome of these recipients. MPA's pharmacological efficacy was evaluated by LIST not only before the operation but also at 2, 4, and 6 weeks after transplantation in 16 renal transplant recipients. These recipients were divided into high- and low-sensitivity groups according to peripheral blood mononuclear cell (PBMC) sensitivity to MPA in vitro. The MPA sensitivities were compared to cytomegalovirus (CMV) infection and acute rejection episodes in these recipients under MPA immunosuppressive therapy. The rate of CMV infection episodes in the low-MPA pharmacological efficacy group categorized at 2 weeks after renal transplantation was 5/6 (83.3%), which was significantly higher than the rate of 1/10 (10.0%) (p < 0.01) in the high-MPA sensitivity group. However, the MPA pharmacological efficacy evaluated both before and after transplantation had no relationship with the incidence of rejection episodes. These findings suggest that the MPA pharmacological efficacy evaluated by LIST at 2 weeks after operation is a useful biomarker for predicting the following occurrence of CMV infection episodes in renal transplant recipients.

    DOI： 10.3727/215517913X674216

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  • Comparison of the Pharmacological Efficacies of Immunosuppressive Drugs Evaluated by the ATP Production and Mitochondrial Activity in Human Lymphocytes. International journal

    Hiroyasu Sasahara, Kentaro Sugiyama, Mahoto Tsukaguchi, Kazuya Isogai, Akira Toyama, Hiroshi Satoh, Kazuhide Saitoh, Yuki Nakagawa, Kota Takahashi, Sachiko Tanaka, Kenji Onda, Toshihiko Hirano

    Cell medicine   6 ( 1-2 )   39 - 45   2013.12

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    The lymphocyte immunosuppressant sensitivity test (LIST) using patient peripheral lymphocytes can predict the therapeutic efficacy of immunosuppressive drugs used in renal transplantation. We have evaluated the pharmacological efficacy of drugs by using the LIST with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, which measures the cellular mitochondrial activity. The LIST with the MTT assay requires a relatively large amount of blood. As such, we developed a new assay for examining drug sensitivity with a CellTiter-Glo assay, which measures the amount of cellular ATP to help increase the assay's sensitivity and reduce the amount of blood needed. Renal transplant recipients generally receive either cyclosporine or tacrolimus, in addition to mycophenolate mofetil and methylprednisolone, as an immunosuppressive therapy to prevent acute rejection. We evaluated the pharmacological efficacy of these immunosuppressive agents with both the MTT and CellTiter-Glo assays using the peripheral blood mononuclear cells of 21 healthy volunteers. Furthermore, we also examined the relationship between these immunosuppressive agents' pharmacological efficacy and the results of the MTT and CellTiter-Glo assays. The IC50 values for cyclosporine, tacrolimus, mycophenolic acid, and methylprednisolone were significantly correlated between the MTT and CellTiter-Glo assays. The amount of blood cells required for LIST with the CellTiter-Glo assay was able to be reduced to 25% of the amount required for the previously established LIST with the MTT assay procedure. We concluded from these observations that the LIST with the CellTiter-Glo assay should be used instead of the MTT assay for carrying out individualized immunosuppressive therapy in renal transplantation patients.

    DOI： 10.3727/215517913X674207

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  • 歯科病棟における注射用抗菌薬の使用状況とカルバペネム系薬の起炎菌に対する適合性に関する調査

    齋藤 直美, 田村 隆, 西川 敦, 児玉 泰光, 内山 正子, 田邊 嘉也, 高木 律男, 外山 聡, 佐藤 博

    日本病院薬剤師会雑誌   49 ( 1 )   73 - 76   2013.1

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  • Clinical Significance of the Pharmacological Efficacy of Tacrolimus Estimated by the Lymphocyte Immunosuppressant Sensitivity Test (LIST) Before and After Renal Transplantation. International journal

    Kentaro Sugiyama, Kazuya Isogai, Akira Toyama, Hiroshi Satoh, Kazuhide Saito, Yuki Nakagawa, Masayuki Tasaki, Kota Takahashi, Toshihiko Hirano

    Cell medicine   3 ( 1-3 )   81 - 88   2012.1

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    The lymphocyte immunosuppressant sensitivity test (LIST) with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay procedure can predict the pharmacological efficacy of immunosuppressive agents. A previous study reported the pharmacological efficacy of tacrolimus evaluated by LIST just before renal transplantation significantly correlated with the incidence of acute rejection episodes. However, the pharmacological efficacy of tacrolimus has not been estimated after renal transplantation. Therefore, the present study evaluated the pharmacological efficacy of tacrolimus by LIST using the MTT assay procedure before and 1, 3, and 12 months after transplantation in 17 renal transplant recipients that received tacrolimus-based immunosuppressive therapy. The tacrolimus pharmacological efficacies before and after the procedure were also compared with incidence of acute rejection and cytomegalovirus (CMV) infection episodes. The individual values of tacrolimus 50% inhibition of lymphocyte proliferation (IC50) varied widely before transplantation, and the mean value of the IC50 was 126.4 ± 337.7 ng/ml. The patients were divided into two groups according to the tacrolimus IC50 values evaluated before transplantation. The rate of acute rejection episodes in the tacrolimus high-sensitivity group was significantly lower than that in the tacrolimus low-sensitivity group (p = 0.005). The tacrolimus IC50 deviation between patients expanded further at one and three months after surgery. However, the sensitivity deviation almost converged at 1 year after surgery. Moreover, the pharmacological efficacy of tacrolimus evaluated at 1, 3, and 12 months after transplantation did not significantly correlate with the incidence of acute rejection episodes. The pharmacological efficacies of tacrolimus evaluated at both before and after surgery were not significantly correlated with the episodes of CMV infection. These findings suggest that the pharmacological efficacy of tacrolimus evaluated with LIST before surgery is a useful biomarker for predicting the occurrence of acute allograft rejection in renal transplantation.

    DOI： 10.3727/215517912X639360

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  • Comparative study of the cellular pharmacodynamics of tacrolimus in renal transplant recipients treated with and without basiliximab. International journal

    Kentaro Sugiyama, Kazuya Isogai, Satoshi Horisawa, Akira Toyama, Hiroshi Satoh, Kazuhide Saito, Yuki Nakagawa, Masayuki Tasaki, Kota Takahashi, Toshihiko Hirano

    Cell transplantation   21 ( 2-3 )   565 - 70   2012

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    Basiliximab is a recently developed immunosuppressive agent for the prevention of acute allograft rejection in renal transplant recipients. The combination use of basiliximab and a calcineurin inhibitor was suggested to be more effective in comparison to immunosuppressive therapy using calcineurin inhibitor without basiliximab. Cyclosporine has been generally administered with basiliximab for renal transplant recipients. However, in cases of tacrolimus-based immunosuppressive regimen, the clinical efficacy and safety of combined use of tacrolimus and basiliximab remains to be elucidated. This study evaluated the tacrolimus pharmacological efficacy using a lymphocyte immunosuppressant sensitivity test (LIST) with MTT assay procedures in 16 cases of renal transplant recipients treated by tacrolimus without basiliximab and in 13 cases treated by tacrolimus in combination with basiliximab. The rate of acute rejection episodes in the recipients treated with tacrolimus plus basiliximab was 1/13 (7.7%), whereas the rate in the recipients treated with tacrolimus without basiliximab was 6/16 (37.5%). The recipients were divided into two groups according to their peripheral blood mononuclear cell (PBMC) sensitivity to tacrolimus [i.e., including a tacrolimus high sensitivity group (IC(50) <1.0 ng/ml) and a low sensitivity group (IC(50) >1.0 ng/ml). In the recipients treated with tacrolimus without basiliximab, the rate of acute rejection episodes in the tacrolimus high sensitivity group was 1/10 (10.0%), which was significantly lower than the rate in the low sensitivity group of 5/6 (83.3%; p = 0.008). The incidence of cytomegalovirus infection was not significantly different between the tacrolimus high and the low sensitivity groups of the recipients treated with tacrolimus with and without basiliximab. Therefore, in the case of selected tacrolimus-based immunosuppressive therapy for renal transplant recipients, the tacrolimus pharmacological efficacy should be evaluated using LIST at a time just before the transplant procedure in order to accurately predict allograft rejection. The data also suggested that low tacrolimus sensitivity recipients should be treated with tacrolimus-based immunosuppressive therapy in combination with basiliximab.

    DOI： 10.3727/096368911X605493

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  • [Longer working hours of pharmacists in the ward resulted in lower medication-related errors--survey of national university hospitals in Japan].

    Kazuo Matsubara, Akira Toyama, Hiroshi Satoh, Hiroshi Suzuki, Toshio Awaya, Yoshikazu Tasaki, Toshiaki Yasuoka, Ryuya Horiuchi

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   131 ( 4 )   635 - 41   2011.4

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    It is obvious that pharmacists play a critical role as risk managers in the healthcare system, especially in medication treatment. Hitherto, there is not a single multicenter-survey report describing the effectiveness of clinical pharmacists in preventing medical errors from occurring in the wards in Japan. Thus, we conducted a 1-month survey to elucidate the relationship between the number of errors and working hours of pharmacists in the ward, and verified whether the assignment of clinical pharmacists to the ward would prevent medical errors between October 1-31, 2009. Questionnaire items for the pharmacists at 42 national university hospitals and a medical institute included the total and the respective numbers of medication-related errors, beds and working hours of pharmacist in 2 internal medicine and 2 surgical departments in each hospital. Regardless of severity, errors were consecutively reported to the Medical Security and Safety Management Section in each hospital. The analysis of errors revealed that longer working hours of pharmacists in the ward resulted in less medication-related errors; this was especially significant in the internal medicine ward (where a variety of drugs were used) compared with the surgical ward. However, the nurse assignment mode (nurse/inpatients ratio: 1 : 7-10) did not influence the error frequency. The results of this survey strongly indicate that assignment of clinical pharmacists to the ward is critically essential in promoting medication safety and efficacy.

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  • The pharmacological efficacy of mycophenolic acid before and after renal transplantation as estimated by the lymphocyte immunosuppressant sensitivity test (LIST). International journal

    Kentaro Sugiyama, Kazuya Isogai, Satoshi Horisawa, Akira Toyama, Hiroshi Satoh, Kazuhide Saito, Yuki Nakagawa, Masayuki Tasaki, Kota Takahashi, Toshihiko Hirano

    Immunopharmacology and immunotoxicology   32 ( 3 )   430 - 6   2010.9

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    The lymphocyte immunosuppressant sensitivity test (LIST) can predict the pharmacological efficacy of immunosuppressive agents. We herein estimated the mycophenolic acid efficacy using LIST before and 1, 3, and 12 months after the operation in 15 renal transplant recipients. The pharmacological efficacy of mycophenolic acid as assessed before transplantation showed small individual variations, whereas the variability greatly increased at 1 and 3 months after transplantation. Furthermore, the individual IC50 variation among these subjects at 1-year after operation was closely similar to that observed before surgery. No significant implications of these individual differences in the mycophenolic acid sensitivity were noted in regard to the clinical courses of these recipients.

    DOI： 10.3109/08923970903490478

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  • Pharmacodynamic parameters of immunosuppressive drugs are not correlated with age, duration of dialysis, percentage of lymphocytes or lymphocyte stimulation index in renal transplant recipients.

    Kentaro Sugiyama, Kazuya Isogai, Akira Toyama, Hiroshi Satoh, Kazuhide Saito, Yuki Nakagawa, Masayuki Tasaki, Kota Takahashi, Noriko Saito, Toshihiko Hirano

    Biological & pharmaceutical bulletin   31 ( 11 )   2146 - 9   2008.11

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    The lymphocyte immunosuppressant-sensitivity test (LIST) has been reported extensively as being able to estimate the pharmacological efficacy of immunosuppressive drugs in individual patients. This study measured the IC50 values for 6 drugs, cyclosporine, tacrolimus, methylprednisolone, 6-mercaptopurine, mycophenolic acid, and mizoribine, against mitogen-induced proliferation of peripheral-blood lymphocytes in 29 renal transplant recipients. We also examined relationship between the IC50 values and 4 factors; age, duration of dialysis, percentage of lymphocytes in total white blood cells, and blastogenesis stimulation index by mitogen. There were no significant correlations between the IC50 values and these factors, except that the tacrolimus IC50 value was correlated weakly with the stimulation index (p<0.05, r=-0.429). It was concluded that the pharmacological efficacy of immunosuppressive drugs cannot be inferred from the patient characteristics or their laboratory data. LIST is an effective method to elucidate the pharmacodynamic properties of immunosuppressive agents in individual renal transplant recipients without being influenced by the recipient clinical data.

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Research Projects

  • Dynamic control of protein structure by cation-π interaction

    Grant number：16350003

    2004 - 2006

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    TAKEUCHI Hideo, MIURA Takashi, TOYAMA Akira

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    Grant amount：\15900000 （ Direct Cost: \15900000 ）

    We have studied the effects of interaction between a positive charge and π electrons, i.e. cation-π interaction, on the structural formation and dynamics of proteins by circular dichroism (CD), fluorescence, and UV resonance Raman spectroscopy. The peptides and proteins studied are neuromedin B, neuromedin C, and the transmembrane region of influenza B virus BM2 protein (BM2-TMP). The cation-π interaction between His^+ and Trp was found to be unable to control the secondary structures of neuromedin B and C, suggesting that such cation-π interactions do not so much contribute to protein structural stability. However, analogous cation-π interactions play an important role in gating a proton channel formed by BM2-TMP in lipid bilayers, demonstrating that cation-π interactions can control the functioning of a protein by modifying its local structure near functionally important regions. In addition, cation-π interaction between Cu^<2+> and Trp was found to cause not only a shift and intensity change of UV absorption of the Trp indole ring but also to generate a negative signal in CD spectra. The negative CD signal is expected to serve as a new marker of cation-π interaction between Cu^<2+> and Trp in proteins. As shown in the case of the proton channel formed by BM2-TMP, cation-π interactions could play important roles in structural dynamics of proteins associated with their functioning. Although the present proposal about the role of cation-a interaction in protein functioning need to be further tested in many other proteins, the present study has provided the basis of such future studies.

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  • Detection of DNA structural changes upon drug-binging by a combination of site-selective deutaretation and difference Raman intensity changes

    Grant number：15590036

    2003 - 2004

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    TOYAMA Akira

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    Grant amount：\3000000 （ Direct Cost: \3000000 ）

    The goal of my research is to understand the mechanism of drug-DNA interaction by using of"isotope-edited UV resonance Raman spectroscopy -a combination of site-selective isotope labeling and ultraviolet resonance Raman (UVRR) spectroscopy The aim of this project is to find the correlation between the structure and UVRR intensity of DNA bases.
    UV Raman spectra of adenine and guanine derivatives were recorded in several solvents and the intensities of UV Raman bands were analyzed by using three solvent parameters proposed by Kamlet and Taft : the hydrogen-bond donor acidy, hydrogen-bond acceptor basicity, and polarity-polarizability. As a result, we have found that the Raman intensity of the purine rings depends mostly on hydrogen bonding but little on environmental polarity-polarizability.
    However, it is also known that base stacking interactions suppress the Raman intensity of DNA bases (Raman hypochromism). In order to determine either hydrogen-bonding or stacking is dominant in Raman intensity, isotope-edited UVRR spectra were measured of a 22-mer oligonucleotide (LacDNA) bound by cyclic AMP (cAMP) receptor protein (CRP). CRP-(cAMP)2 complex forms strong hydrogen bonds with guanine residues of LacDNA, but base stacking of the guanine rings are not significantly altered by the complex. For isotope-edited UVRR spectra of the guanine residues of LacDNA, some Raman bands showed appreciable frequency changes but did not show meaningful intensity changes upon CRP-(cAMP)2 binding. It is indicated that the UVRR intensities of aqueous DNA must predominantly be determined by the strength of the base stacking. Isotope edited UVRR spectra of a 19-mer oligonucleotide containing a AC-mismatched base pair were also measured to evaluate the sensitivity of the UVRR intensity to the base stacking. A significant intensity change was detected at the pre-melting state of the DNA. This observation demonstrates the utility of isotope-edited UVRR spectroscopy as a probe of the base staking of DNA bases.

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  • Detection of small structural changes of DNA under physiological conditions by a combination of site-selective deuteration and Raman difference spectroscopy

    Grant number：13672248

    2001 - 2002

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (C)

    Awarding organization：Japan Society for the Promotion of Science

    TOYAMA Akira

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    Grant amount：\3500000 （ Direct Cost: \3500000 ）

    Small structural changes of selected guanine residues in DNA have been detected by a combination of site-selective isotope labeling and ultraviolet resonance Raman (UVRR) spectroscopy, I.e. isotope-edited Raman spectroscopy. UVRR spectra were measured for [8-^2H]guaninelabeled and unlabeled oligonucleotides excited at 251nm light. In the difference spectrum between the unlabeled and labeled DNA, Raman signals arise from the residue at the labeled position and the other components were canceled out. Thus, it becomes possible to extract the Raman signals of the selected guanine in olinonucleotides.
    To obtain basic data for applying isotope-edited Raman spectroscopy to guanine residues, vibrational modes of UVRR bands of the C8-deuterated guanine ring were studied by examining the wavenumber shifts upon seven isotopic substitutions (2-^<13>C, 2-^<15>N, 6-^<18>O, 7-^<15>N, 8-^<13>C, 9-^<15>N and 1'-^<13>C). The hydrogen bond sensitivities of the Raman bands were also investigated by comparing the Raman spectra recorded in several solvents of different hydrogen bonding properties. Some of the Raman bands have been found to be hydrogen bonding markers at specific donor or acceptor sites on the guanine ring, A negative peak around 1525 cm^<-1> a strong positive/negative peak pair around 1485/1465 cm^<-1>, and a weak positive/negative peak pair around 1025/1040cm^<-1> serve as markers of hydrogen bonding at N7, C6=O, and N1-H/C2-NH_2, respectively.
    The applicability of isotopeedited Raman spectroscopy has been tested by using a 22-mer oligonucleotide duplex. UVRR spectra of the labeled and unlabeled oligomers were measured in the absence and presence of cAMP receptor protein (CRP),Which is Known to hydrogen-bonded to guanine residues of duplex DNA. The isotope-edited spectra showed that CRP is hydrogen-bonded strongly to C6=O of guanine residues but not N7 atom. Isotope-edited Raman spectroscopy can provide structural information of a selected guanine residue for DNA-drug systems under physiological conditions.

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  • 重水素置換と共鳴ラマン分光法を併用した薬物-DNAオリゴマ-相互作用の構造研究

    Grant number：11771407

    1999 - 2000

    System name：科学研究費助成事業

    Research category：奨励研究(A)

    Awarding organization：日本学術振興会

    外山 聡

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    Grant amount：\2100000 （ Direct Cost: \2100000 ）

    本研究の目的は、共鳴ラマン分光法を用いて、DNA-薬物の相互作用様式を詳細に調べることである。ラマン分光法は、薬物が「どのように」結合するかという情報を与えるため、DNA-薬物の相互作用を調べる手段として有用である。しかし、ラマン分光法からは、薬物が「どこに」結合するか解らない。これを解決するために、昨年度開発した方法で合成した、1残基のみに重水素を導入したDNAオリゴマーを採用した。DNAオリゴマーと薬物の複合体のラマンスペクトルを、重水素化体と未置換体の双方について測定し、両者のスペクトルの差を計算する。この差スペクトルにおいては、重水素化されていない部分のスペクトルは相殺され、重水素化した残基のシグナルのみが残る。
    薬物としては、抗がん性抗生物質アクチノマイシンD(ActD)を用いた。DNAは、ActD結合部位を含む自己相補鎖d(AGTGCTCGA^9GCA^<12>CT)_2の、A^9またはA^<12>のみを重水素ラベルしたものを使用した(下線を付した部分にActDがインターカレートする)。DNAにActDが結合すると、A^9のラマンバンド強度は約40%減少したが、A^<12>のラマンバンドには有意な変化がなかった。A^9のラマンバンド強度減少の原因は、塩基のスタッキングが強まることによるラマン淡色効果である。この結果は、ActDの結合に伴うDNAの巻戻りが主に5'側のみに起こり、この巻戻りがA^9のスタッキングを増加させたことを示している。
    X線結晶解析によると、ActD結合に伴うDNAの構造変化には、結晶化の条件により、5'側が巻戻るもの、3'側が巻戻るもの、両側均等に巻戻る場合がある。本研究により、生理的条件では5'側のみに巻戻りが起こることを決定することができた。重水素置換と共鳴ラマン分光法を併用した本方法は、他の薬物のDNA結合様式の解明にも汎用できる、新規な方法であると考えている。

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  • 紫外共鳴ラマン分光法による蛋白質に結合したアデニンヌクレオチドの構造研究

    Grant number：08740436

    1996

    System name：科学研究費助成事業

    Research category：奨励研究(A)

    Awarding organization：日本学術振興会

    外山 聡

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    Grant amount：\1100000 （ Direct Cost: \1100000 ）

    本研究は、紫外共鳴ラマン分光を用いて、蛋白質(サイクリックAMP受容蛋白質(CRP)や乳酸脱水素酵素)と複合体を形成した状態のアデニンヌクレオチド(サイクリックAMP (cAMP)やNADH)の構造を明らかにすることである。これらヌクレオチドは蛋白質のアロステリックエフェクターとなっており、その構造を知ることは重要である。
    260nm励起光を用いることで,CRP-cAMP混合系において,cAMPに選択的な共鳴ラマンスペクトルを測定することができた。このスペクトルより,CRPに結合したcAMPについて,そのコンフォメーションとアデニン環の水素結合状態について詳細な知見が得られた。関連実験として,CRPに結合したcGMP (cAMPと同様にCRPに結合するが,CRPを活性化しない)の紫外共鳴ラマンスペクトルも測定した。これにより,CRPに結合したcGMPについても構造情報が得られた。CRPに結合したcAMPとcGMPの構造を比較することにより,アロステリックエフェクターの構造とCRPの活性にどのような関連があるかについて,議論することができた。
    一方,乳酸脱水素酵素に結合したNADHについては,蛍光の妨害により,260nm励起のスペクトルを測定することはできなかった。励起光を変化させる実験などを行ったが,現在のところ満足の行く結果は得られていない。
    本研究により,紫外共鳴ラマン分光法は,蛋白質に結合したヌクレオチドの構造を研究するのに優れた手段であることが明らかとなった。現在のところ,乳酸脱水素酵素のように本法を適用し難い蛋白質もあるが,測定法の改良などにより,紫外共鳴ラマン分光法は多くの蛋白質について,それに結合した核酸誘導体の構造を研究する手段になると期待される。

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  • Development of an Ultraviolet Raman Microspectrometer Applicable to Structural Analyzes of Cells

    Grant number：07554025

    1995 - 1996

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Scientific Research (A)

    Awarding organization：Japan Society for the Promotion of Science

    TAKEUCHI Hideo, TOYAMA Akira, HASHIMOTO Shinji, MIURA Takashi

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    Grant amount：\15900000 （ Direct Cost: \15900000 ）

    Raman microspectroscopy is a useful technique to investigate the structures of micrometer-sized particles in a non-destructive manner. On the other hand, ultraviolet resonance Raman spectroscopy provides key information on the structures of proteins and nucleic acids. In this study, we have developed an ultraviolet Raman microspectrometer to exploit the utilities of both spectroscopic methods. The microspectrometer consists of a continous-wave ultraviolet laser, an ultraviolet microscope, and a Raman spectrometer. The ultraviolet laser beam is obtained by frequency-doubling visible laser light from an Ar^+ laser. The ultraviolet microscope is specially designed for high throughput in the ultraviolet region and high spatial resolution of microscopic images. Samples under a microscope objective are irradiated with ultraviolet laser light and the Raman scattered light was collected with the same objective and then guided to the Raman spectrometer, which has already been developed in our laboratory. We have succeeded to record some Raman spectra by using newly developed ultraviolet Raman microspectrometer.
    However, the sensitivity of the microspectrometer is not enough to investigate the structures of microparticles in living cells. We are planning to use an ultra-high-sensitivity CCD detector to detect even extremely weak Raman light and to apply the ultraviolet Raman microspectrometer to structural analyzes of living cells.

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  • A High-Pereormance Ultraviolet Apparatus

    Grant number：02554018

    1990 - 1991

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for Developmental Scientific Research (B)

    Awarding organization：Japan Society for the Promotion of Science

    HARADA Issei, IKEDA Takeshi, TOYAMA Akira, HASHIMOTO Shinji

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    Grant amount：\14900000 （ Direct Cost: \14900000 ）

    A high-throughput and low stray-light multichannel ultraviolet Raman apparatus has been constructed. The apparatus is a Czerny Turner type single polychromator [Jasco, f = 575 mm, (F 6.3) ; a holographic grating, 4320 gr/mm (efficiency, 30% at 220 nm)] equipped with a fore-prism spectrometer (a Czerny Turner mount ; a synthetic 30ﾟ quartz prism, f = 200 mm ; reciprocal linear dispersion, ca. 1000 cm^<-1> at 240 nm) and a liquid-N_2 cooled CCD detector (Princeton Instruments, UV enhanced LN/CCD1152). The rpism spectrometer is used as a short-wavelength cut filter to reject the Rayleigh scattering by properly adjusting the exit slit width. The light passing through the filter spectrometer is further dispersed by the single grating polychromator and focused onto the CCD detector. The spectral range per 1152 channels is 1470 cm^<-1> at 240 nm (1.3 cm^<-1> per pixel of 22.5-muM width). UV radiation in the 213-266-nm range was generated by frequency conversion of 1064-nm pulses from a Nd : YAG laser (Quanta Ray DCR3G) operated at a 30-Hz repetition rate. For a suspension of bacteriorhodopsin, which is a retinoid membrane protein, spectra of high S/N ratios were obtained without saturation of the Raman bands and photochemical reaction.

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  • 紫外共鳴ラマン及びNMR分光法による薬物で誘起される核酸構造変化の研究

    Grant number：02771680

    1990

    System name：科学研究費助成事業

    Research category：奨励研究(A)

    Awarding organization：日本学術振興会

    外山 聡

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    Grant amount：\800000 （ Direct Cost: \800000 ）

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  • Ultraviolet Resonance Raman Spectroscopic Study on Regulatory Protein-Nucleic Acid Interactions

    Grant number：62430004

    1987 - 1990

    System name：Grants-in-Aid for Scientific Research

    Research category：Grant-in-Aid for General Scientific Research (A)

    Awarding organization：Japan Society for the Promotion of Science

    HARADA Issei, TOYAMA Akira, HASHIMOTO Shinji, UCHIDA Kiyoshi, TAKEUCHI Hideo

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    Grant amount：\24700000 （ Direct Cost: \24700000 ）

    The purpose of the research is threefold : construction of ultraviolet Raman apparatus, tabulation of UV Raman marker bands useful in structural study of proteins and nucleic acids, and UV resonance Raman (UVRR) spectroscopic study on cyclic AMP receptor protein (CRP) and the CRP-cAMP complex in solution.
    (1) UV Raman apparatus
    UV radiation is generated by a system consisting of a Nd : YAG laser (30 Hz), a harmonic generator (KDP or BBO), and an H_2-Raman shifter. Scattered light from a sample is dispersed (2nd order) by an f/6.8 80-cm double monochromator equipped with 600 g/mm gratings blazed at 500 nm and detected with a doubly intensified diode array of 700 pixels.
    (2) Table of UVRR marker bands and its applications
    UVRR spectra of peptides containing Pro, Trp, Tyr, Phe, and His, nucleosides, nucleotides, and the related compounds have been studied extensively and a list of useful structural marker bands is tabulated. Good-quality UVRR spectra of Cu, Zu-superoxide dismutase and bacteriorhodopsin have been recorded for the first time, and some pieces of structural information on the proteins are obtained on the basis of the table.
    (3) Structure of CRP and CRP-cAMP in dilute solution
    Upon uptake of a cAMP molecule in one of the two subunits of CRP, drastic change occurs in the beta-sheet structure of the other subunit as well as the bound subunit. The adenine-ribose bond conformation is syn in the bound cAMP and the binding form is stabilized by H-bonding at N7 and C6NH_2 with side chains of the protein.

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Teaching Experience

  • 医療薬剤学特論

    2026
    Institution name：新潟大学

  • 臨床薬効評価学

    2026
    Institution name：新潟大学

  • 薬剤評価学演習

    2026
    Institution name：新潟大学

  • 医療薬剤学演習

    2026
    Institution name：新潟大学

  • 統合臨床医学

    2022
    Institution name：新潟大学

  • 医学序説 II

    2022
    Institution name：新潟大学

  • 医学序説 I

    2021
    Institution name：新潟大学

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