研究等業績 - 原著論文 - 菊地 正史
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Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients.
Masaki Tanaka, Masafumi Kikuchi, Shinya Takasaki, Tensei Hirasawa, Kensuke Sigeta, Aoi Noda, Miki Akiba, Yasushi Matsuda, Hisashi Oishi, Tetsu Sado, Masafumi Noda, Yoshinori Okada, Nariyasu Mano, Hiroaki Yamaguchi
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 22 ( 1 ) 407 - 417 2019年 [査読有り]
研究論文（学術雑誌）
PURPOSE: The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. METHODS: Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). RESULTS: The best three time-point equation was 4.04 + 1.64·C1 + 3.08·C4 + 5.17·C8 for MPA, and -0.13 + 3.01·C1 + 3.51·C4 + 5.74·C8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC0-12 within ± 15% of the observed AUC0-12 was 77.27% for MPA and 81.82% for AcMPAG. CONCLUSION: LSS using three time-point (C1, C4, and C8) provides the most reliable and accurate simultaneous estimation of the AUC0-12 of MPA and AcMPAG in Japanese lung transplant patients.
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Long-term relationship between everolimus blood concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma: a prospective study.
Shinya Takasaki, Hiroaki Yamaguchi, Yoshihide Kawasaki, Masafumi Kikuchi, Masaki Tanaka, Akihiro Ito, Nariyasu Mano
Journal of pharmaceutical health care and sciences 5 6 - 6 2019年 [査読有り]
研究論文（学術雑誌）
Background: Everolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC. Methods: Patients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated. Results: The median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1-28.0) ng/mL and 14.8 (6.4-58.4) ng/mL, respectively, with no significant difference between these values (P = 0.3594). Patients (n = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients (n = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; P = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; P = 0.0142). Median TTF and PFS of the total patients (n = 10) were 96 days (95% confidence interval [CI], 26-288) and 235 days (95% CI, 28-291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL (n = 5) was not significantly different from that of the patients with ≤15.3 ng/mL (n = 5; P = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL (P = 0.3436). Conclusions: This study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.
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Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma.
Shinya Takasaki, Yoshihide Kawasaki, Masafumi Kikuchi, Masaki Tanaka, Masato Suzuka, Aoi Noda, Yuji Sato, Shinichi Yamashita, Koji Mitsuzuka, Hideo Saito, Akihiro Ito, Hiroaki Yamaguchi, Yoichi Arai, Nariyasu Mano
International journal of clinical oncology 23 ( 5 ) 936 - 943 2018年10月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: The aim was to investigate the relationships between total sunitinib plasma concentrations (sunitinib plus its active metabolite; N-desethyl sunitinib) and clinical outcomes in Japanese patients with metastatic renal cell carcinoma (mRCC). METHODS: Twenty patients with mRCC were enrolled following treatment with sunitinib. To assess safety, the total sunitinib concentration range up to discontinuation of treatment and dosage reduction associated with adverse events within 6 weeks from initiating administration were analyzed. The longest administered sunitinib dosage was defined as the maintenance dose, and the relationship between total sunitinib concentration at the maintenance dosage and sunitinib efficacy was investigated. RESULTS: Total sunitinib concentration was significantly higher in patients who discontinued treatment or had dosage reduction due to adverse events within 6 weeks after initiation of sunitinib than in patients who continued treatment with the initial dosage. The time to treatment failure, progression-free survival, and overall survival were better in patients with total sunitinib concentrations < 50 ng/mL than in those with concentrations ≥ 50 ng/mL. CONCLUSIONS: The present study demonstrated that the effective range of total sunitinib concentration in Japanese patients with mRCC was lower than 50-100 ng/mL which was previously reported. These results indicate that therapeutic drug monitoring could maintain the therapeutic effect of sunitinib while minimizing adverse events by personalizing sunitinib dosages for Japanese patients with mRCC.
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乳がんFEC100療法におけるニューロキニン1受容体拮抗薬の費用効果分析の検討
中川 直人, 渡邊 桂子, 菊地 正史, 石田 孝宣, 木皿 重樹, Lai Leanne
医薬品相互作用研究 ( 医薬品相互作用研究会 ) 42 ( 2 ) 95 - 102 2018年06月 [査読有り]
研究論文（学術雑誌）
乳がんFEC100療法(Fluorouracil-Epirubicin-Cyclophosphamide)4コースを終えた外来患者62名(女性)を対象とし、アプレピタント(APR)を投与したA群、ホスアプレピタント(FOS)を投与したF群とした。A群1コースは合計9516円、F群1コースは合計12635円で、全体的にF群の方が直接医療費は高くなった。A群のCR率はF群よりも高く、また期待費用もF群より安価であることから、APRは優位(効果が大きく費用が安い)であった。感度分析を行い、FOSのCR率が仮に高くなっても、APRの優位性は揺るがないことが明らかとなった。
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Simultaneous analysis of oral anticancer drugs for renal cell carcinoma in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry.
Shinya Takasaki, Masaki Tanaka, Masafumi Kikuchi, Masamitsu Maekawa, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
Biomedical chromatography : BMC 32 ( 6 ) e4184 2018年06月 [査読有り]
研究論文（学術雑誌）
An analytical method using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry has been developed and validated for simultaneous measurement of four tyrosine kinase inhibitors used for renal cell carcinoma and their metabolites in human plasma. Despite their similar structures, it is difficult to measure plasma levels of these compounds simultaneously using optimal MS parameters for each compound because a quantitative range exceeding 50,000-fold is required. To overcome this problem, we used a linear range shift technique using in-source collision-induced dissociation. Linearity ranges of sorafenib, sorafenib N-oxide, sunitinib, N-desethyl sunitinib, axitinib and pazopanib were 100-10,000, 10-1,000, 1-100, 1-100, 1-100 and 500-50,000 ng/mL, respectively. The intra- and inter-day precision and accuracy were high, and coefficients of variation and relative error were <10.3% and within ±11.8%, respectively. The matrix effects of all analytes ranged from 87.7 to 114.8%. Extraction recoveries and overall recoveries showed small extraction loss (<15.0%) for all analytes. Moreover, all cancer patient samples used in this study were successfully quantified and fell within the linear range of measurement. Therefore, this novel analytical system using in-source collision-induced dissociation has sufficient performance to measure plasma concentrations of these four tyrosine kinase inhibitors and their metabolites for therapeutic drug monitoring.
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M. Maekawa, M. Mori, M. Fujiyoshi, H. Suzuki, K. Yanai, A. Noda, M. Tanaka, S. Takasaki, M. Kikuchi, K. Akasaka, S. Kisara, M. Matsuura, K. Hisamichi, M. Sato, J. Goto, M. Shimada, H. Yamaguchi, N. Mano
Chromatography ( The Society for Chromatographic Sciences ) 39 ( 1 ) 41 - 47 2018年 [査読有り]
研究論文（学術雑誌）
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Comparison of PETINIA and LC-MS/MS for determining plasma mycophenolic acid concentrations in Japanese lung transplant recipients.
Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Akiko Takahashi, Miki Akiba, Yasushi Matsuda, Masafumi Noda, Kanehiko Hisamichi, Hiroaki Yamaguchi, Yoshinori Okada, Nariyasu Mano
Journal of pharmaceutical health care and sciences 4 7 - 7 2018年 [査読有り]
研究論文（学術雑誌）
Background: Mycophenolic acid (MPA) treatment requires therapeutic drug monitoring to improve the outcome after organ transplantation. The aim of this study was to compare two methods, a particle enhanced turbidimetric inhibition immunoassay (PETINIA) and a reference liquid chromatography tandem mass spectrometry (LC-MS/MS) for determining plasma MPA concentrations from Japanese lung transplant recipients. Methods: Plasma MPA concentrations were determined from 20 Japanese lung transplant recipients using LC-MS/MS and the PETINIA on the Dimension Xpand Plus-HM analyzer. Results: The mean MPA concentration measured by PETINIA was significantly higher than that measured by LC-MS/MS (3.26 ± 2.73 μg/mL versus 2.82 ± 2.71 μg/mL, P < 0.0001). The result of the Passing Bablok analysis was a slope of 1.104 (95% confidence interval [CI], 1.036-1.150) and an intercept of 0.229 (95%CI, 0.144-0.315). Bland-Altman analysis revealed PETINIA overestimates plasma MPA concentration by 26.25% and 95%CI from 21.43 to 31.07%. Conclusion: The measurement of MPA by the PETINIA in Japanese lung transplant patients should evaluate the result with attention to positive bias.
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Development of a Liquid Chromatography-Tandem Mass Spectrometric Method for Quantification of Mycophenolic Acid and Its Glucuronides in Dried Blood Spot Samples.
Hiromasa Iboshi, Hiroaki Yamaguchi, Hiroyuki Suzuki, Masafumi Kikuchi, Masaki Tanaka, Shinya Takasaki, Akiko Takahashi, Masamitsu Maekawa, Miki Shimada, Yasushi Matsuda, Yoshinori Okada, Nariyasu Mano
Therapeutic drug monitoring 39 ( 6 ) 648 - 653 2017年12月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Personalized immunosuppressive therapy, including accurate drug dosing based on the drug blood level, leads to better clinical outcomes, specifically regarding avoidance of drug-induced adverse effects and maintenance of efficacy. Mycophenolic acid (MPA) is used as an immunosuppressant in transplantation of various solid organs. The aim of this study was to develop a method for quantification of MPA and its metabolites, mycophenolic acid 7-O-glucuronide (MPAG) and mycophenolic acid acyl glucuronide, in dried blood spot (DBS) samples, using liquid chromatography/electrospray ionization/tandem mass spectrometry. METHODS: For sample preparation, a microwave-drying approach was used to deactivate enzymes and reduce drying time. Blood volume was calculated in a DBS disk of 3 mm diameter. Concentrations of analytes in plasma from patients receiving mycophenolate mofetil were compared with DBS samples after hematocrit correction. RESULTS: The method yielded good recoveries of all 3 analytes (90.3%-104.2%). Blood volume in the disk was calculated as 3.0 ± 0.2 μL. Linearity over concentration ranges of 0.1-30 mcg/mL MPA, 0.1-200 mcg/mL MPAG, and 0.125-10 mcg/mL mycophenolic acid acyl glucuronide was obtained with r ≥0.999. Intraday and interday variations were less than 14.6%, and accuracy was within ±11.9%. Passing-Bablok analysis showed no significant differences between plasma concentrations and DBS concentrations after hematocrit correction of MPA and MPAG. CONCLUSIONS: We developed and validated a liquid chromatography/electrospray ionization-tandem mass spectrometry method for analysis of MPA in DBS samples. The method is useful for monitoring the MPA blood level.
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Severe toxicity induced by accumulation of active sunitinib metabolite in a Japanese patient with renal cell carcinoma: a case report.
Shinya Takasaki, Masafumi Kikuchi, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
Journal of medical case reports 11 ( 1 ) 28 - 28 2017年02月 [査読有り]
研究論文（学術雑誌）
BACKGROUND: Sunitinib is a multi-targeted tyrosine kinase inhibitor that is approved for treatment of renal cell carcinoma as an oral anticancer drug. Therapeutic drug monitoring of total sunitinib (sunitinib and N-desethyl sunitinib) is used in our hospital to improve therapeutic efficacy, while preventing adverse effects. Here, we report the first case of a patient with metastatic renal cell carcinoma undergoing hemodialysis and presenting severe adverse events induced by the accumulation of N-desethyl sunitinib. CASE PRESENTATION: A 60-year-old Japanese man was diagnosed with metastatic renal cell carcinoma requiring hemodialysis. On day 26 of the first cycle of sunitinib therapy, our patient presented grade 3 thrombocytopenia and leukopenia, which required interruption of therapy although the plasma levels of total sunitinib in the patient were less than the effective concentration of 50 ng/mL. The elimination half-life of sunitinib was normal at 50.8 hours, but that of N-desethyl sunitinib was an extended 211.4 hours. Moreover, the N-desethyl sunitinib/sunitinib trough level ratio was higher than 1.0. We attribute our patient's severe adverse events to the excessive accumulation of N-desethyl sunitinib owing to its delayed excretion. Although the reason for the delayed excretion of N-desethyl sunitinib in this patient was unknown, it may have been caused by genetic polymorphisms related to the pharmacokinetics of sunitinib rather than the hemodialysis. In this case, the patient was homozygous for the ABCG2 421C allele, but was capable of potentially harboring polymorphisms in other genes, such as ABCB1, an efflux pump of sunitinib. In addition, even though there is no clear evidence, urinary excretion of the metabolic products of N-desethyl sunitinib could be inhibited by the interaction of transporters such as the organic ion transporter. CONCLUSIONS: The monitoring of not only total sunitinib concentration but also N-desethyl sunitinib concentration and their elimination half-lives during sunitinib therapy is recommended to avoid critical adverse events.
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エベロリムス誘発肝機能障害により血中エベロリムス濃度高値と高血糖を示した腎細胞癌患者の1例
高崎 新也, 菊地 正史, 川崎 芳英, 伊藤 明宏, 荒井 陽一, 山口 浩明, 眞野 成康
癌と化学療法 ( (株)癌と化学療法社 ) 44 ( 1 ) 87 - 89 2017年01月 [査読有り]
研究論文（学術雑誌）
エベロリムス誘発肝機能障害により、血中エベロリムス濃度高値と高血糖を示した腎細胞癌患者の1例を経験したので報告する。症例は74歳、男性。右腎細胞癌、多発肺転移の診断で右腎摘除術後、インターフェロン、ソラフェニブにより治療されたが病勢進行となり、エベロリムスを開始した。エベロリムス投与15日目にgrade 3の肝機能障害および高血糖が認められ、血中エベロリムス濃度が58.4ng/mLと高値を示したことから、エベロリムスを休薬した。肝機能検査値の回復後にエベロリムスを減量して再開したが、再び肝機能障害が認められたため、エベロリムスの血中濃度が高値を示す前に投与を中止した。肝機能検査値の回復後にアキシチニブへ変更し、その後は肝機能障害および高血糖を認めなかった。腎細胞癌患者に対するエベロリムス治療において肝機能障害が認められた場合、血中エベロリムス濃度が高値を示す可能性が示唆された。したがって、血中エベロリムス濃度測定は有害事象の管理に重要であると考えられた。(著者抄録)
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[A Case of Renal Cell Carcinoma with High Everolimus Blood Concentrations and Hyperglycemia Due to Everolimus-Induced Hepatic Dysfunction].
Shinya Takasaki, Masafumi Kikuchi, Yoshihide Kawasaki, Akihiro Ito, Yoichi Arai, Hiroaki Yamaguchi, Nariyasu Mano
Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 1 ) 87 - 89 2017年01月 [査読有り]
研究論文（学術雑誌）
We report the case of a patient who had renal cell carcinoma with high everolimus blood concentrations and hyperglycemia due to everolimus-induced hepatic dysfunction. A 74-year-old man who underwent right nephrectomy for renal cell carcinoma was administered everolimus for multiple lung metastases. Everolimus caused grade 3 hepatic dysfunction and hyperglycemia; hence, high blood levels of everolimus were observed. Although the patient was re-administrated everolimus after recovering from hepatic dysfunction, hepatic function test values worsened again. Everolimus was discontinued before its blood concentration increased, and the patient was switched to axitinib treatment. Therefore, the measurement of everolimus blood level is considered useful for the management of adverse events in renal cell carcinoma.
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がんの治療手帳の作成とセミナーの開催による多職種連携への取り組み
菊地 正史, 小林 美奈子, 中川 直人, 木皿 重樹, 松浦 正樹, 久道 周彦, 山田 卓郎, 佐々木 孝雄, 石岡 千加史, 眞野 成康
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 52 ( 12 ) 1493 - 1498 2016年12月 [査読有り]
研究論文（学術雑誌）
がん化学療法の外来化が進むなかで、安全で安心ながん治療の提供には、保険薬局を含めた地域における多職種連携が重要となっている。東北大学病院では、患者情報とがん化学療法の基礎知識の共有を目的に、がんの治療手帳(以下、治療手帳)を作成するとともに、宮城県薬剤師会と宮城県各地域における多職種連携セミナー(以下、セミナー)を開催した。治療手帳は、アンケート調査に基づく保険薬局薬剤師が必要とする情報ばかりか、患者自らが副作用の発現状況や経口抗がん薬の服薬状況を記入できる情報共有ツールとなった。また、セミナーの平均参加人数は約137名/回であり、アンケート調査の結果、参加者の約97%が内容に満足またはやや満足と回答し、90%以上がセミナーで得られた情報は抗がん薬の調剤や服薬指導時に有益であると回答した。今回の取り組みは、地域における多職種連携を強化し、安全で質の高いがん化学療法を実施するうえで役立つものと期待される。(著者抄録)
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イトラコナゾールの併用によりシロリムスの全血中トラフ濃度が高値を示したリンパ脈管筋腫症患者の2例
菊地 正史, 野田 あおい, 田中 雅樹, 高橋 阿希子, 秋場 美紀, 松田 安史, 星川 康, 久道 周彦, 山口 浩明, 岡田 克典, 眞野 成康
TDM研究 ( (一社)日本TDM学会 ) 33 ( 3 ) 104 - 108 2016年09月 [査読有り]
研究論文（学術雑誌）
症例1:49歳、女性。リンパ脈管筋腫症(LAM)の進行に伴う右片肺移植施行後、シロリムス(SRL)を開始し、2mg/日の連日投与で全血中トラフ濃度は6.7〜7ng/mLで安定していた。深在性真菌症の予防にイトラコナゾール(ITCZ)50mg/日の連日投与を開始するため、SRL1mg/日の連日投与に減量したが、併用13日目に治療濃度域の上限(15ng/mL)に近い13.2ng/mLまで上昇した。SRLを1mg/日の隔日投与に変更し、併用17日目に8.6ng/mLまで低下した。症例2:40歳、女性。LAMの進行に伴う両肺移植施行後、深在性真菌症の予防にITCZを50mg/日で連日投与していた。SRLを1mg/日の連日投与で開始したところ、併用6日目の全血中トラフ濃度は治療濃度域の上限を超える28.4ng/mLとなった。SRLを1mg/日の3日毎投与に変更し、併用9日目に11.3ng/mLまで低下した。肺移植後のLAM患者において、SRLとITCZを併用する場合、SRLの減量や投与間隔の延長を検討し、全血中トラフ濃度を頻回に測定しながら投与量を調節することが重要である。(著者抄録)
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肺移植後患者におけるミコフェノール酸モフェチル血中濃度測定の検討
矢吹 皓, 船橋 淳一, 岡田 克典, 渡邉 龍秋, 菊地 正史, 野津田 泰嗣, 新井川 弘道, 松田 安史, 野田 雅史, 桜田 晃, 星川 康
Organ Biology ( 一般社団法人 日本臓器保存生物医学会 ) 23 ( 2 ) 141 - 144 2016年
研究論文（学術雑誌）
Mycophenolate mofetil (MMF) has been used as a standard immunosuppressive agent after lung transplantation. MMF is rapidly metabolized to active constituent, mycophenolic acid (MPA), after intake. Gastrointestinal side- effects and leukocytopenia are common adverse effects of MMF. Although, therapeutic drug monitoring (TDM) for calcineurin inhibitors is widely used, the role of TDM for MPA is unclear in lung transplantation. We investigated the correlation among the blood concentration of MPA, the dosage of MMF and the number of leukocyte in lung transplant recipients. The correlation coefficient between the blood concentration of MPA and the dosage of MMF was not significant, so MMF might require TDM. On the other hand, neither the correlation coefficients between the number of leukocyte and the blood concentration of MPA nor the correlation coefficients between the number of leukocyte and the dosage of MMF were not significant. Further investigation is necessary to find the meanings of TDM for MPA after lung transplantation.
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乳がんFEC100療法におけるホスアプレピタント注とアプレピタントカプセルの有効性と安全性の比較
渡邊 桂子, 菊地 正史, 木皿 重樹, 小笠原 喜美代, 久道 周彦, 石田 孝宣, 鈴木 直人, 村井 ユリ子, 島田 美樹, 富岡 佳久, 石岡 千加史, 眞野 成康
医薬品相互作用研究 ( 医薬品相互作用研究会 ) 39 ( 1 ) 29 - 35 2015年08月 [査読有り]
研究論文（学術雑誌）
乳がんFEC100療法におけるホスアプレピタント注(FOS)とアプレピタントカプセル(APR)の有効性と安全性について比較検討した。乳がんFEC100療法を施行し、FOSを末梢静脈から投与、またはAPRを内服し、制吐療法を施行した32例を対象とした。FOSを投与したFOS群19例、APRを内服したAPR群13例であった。急性および遅発性悪心は、それぞれFOS群7例、APR群5例およびFOS群13例、APR群6例に発現し、重症度は最大でgrade 2であった。急性嘔吐は、両群ともに0例で、遅発性嘔吐はFOS群の2例に発現し、重症度は最大でgrade 2であった。CR率は、FOS群36.8%、APR群76.9%で有意差を認めた。注射部位反応はFOS群の17例で発現し、血管痛や静脈炎が有意に高値であった。
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PTX療法におけるラニチジン注とファモチジン注のアレルギー発現率の後方視的コホート研究
片岡 佑太, 菊地 正史, 中川 直人, 木皿 重樹, 高橋 哉子, 小笠原 喜美代, 我妻 恭行, 久道 周彦, 鈴木 直人, 村井 ユリ子, 富岡 佳久, 石岡 千加史, 島田 美樹, 眞野 成康
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 49 ( 10 ) 1091 - 1095 2013年10月 [査読有り]
研究論文（学術雑誌）
パクリタキセル注(以下、PTX)を用いるがん化学療法においては、アレルギー予防のためH2受容体拮抗薬のラニチジン注またはファモチジン注が前投薬されるが、ラニチジン注を用いた場合にしばしばそう痒感、蕁麻疹などが発現し、東北大学病院のがん化学療法に関するプロトコル審査委員会で問題提起された。そこで、ラニチジン注投与群175例(以下、R群)とファモチジン注投与群97例(以下、F群)について、両群間のアレルギー発現率を後方視的に比較検討した。その結果、前投薬中に発現したアレルギーはR群が12例(6.9%)、F群が0例(0%)であり、R群において有意に高頻度に発現していた(p<0.01)。一方、PTX投与中に発現したアレルギーは、R群で1例(0.6%)、F群で2例(2.1%)であり、両群に有意差は認められなかった。以上より、PTXの前投薬にはラニチジン注よりもファモチジン注のほうが安全に使用できることが示唆された。(著者抄録)
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Structure and Cytotoxic Activity of Enzymatic Hydrolysis Products of Secoiridoid Glucosides, Isoligustroside and Isooleuropein
Masafumi Kikuchi, Yasunori Yaoita, Nariyasu Mano, Masao Kikuchi
CHEMISTRY & BIODIVERSITY ( WILEY-BLACKWELL ) 8 ( 4 ) 651 - 657 2011年04月 [査読有り]
研究論文（学術雑誌）
Hydrolysis of isoligustroside (1) and isooleuropein (2), secoiridoid glucosides, in the presence of beta-glucosidase provided 2-(4-hydroxyphenyl)methyl (2R,3S,4S)-3-formyl-3,4-dihydro-4-(2-methoxy-2-oxoethyl)-2-methyl-2H-pyran-5-carboxylate (3) and 2-(3,4-dihydroxyphenyl)methyl (2R,3S,4S)-3-formyl-3,4-dihydro-4-(2-methoxy-2-oxoethyl)-2-methyl-2H-pyran-5-carboxylate (4), respectively. The structures of 3 and 4 were elucidated on the basis of extensive spectral analyses, including 2D-NMR experiments. Compounds 3 and 4 were found to be new rearrangement products of the aglycones of 1 and 2. The cytotoxic activities of 3 and 4 were evaluated using a disease-oriented panel of 39 human cancer cell lines and showed moderate cytotoxic activity for 4, while 3 exhibited weaker activity compared to that of 4.
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Cytotoxic and EGFR tyrosine kinase inhibitory activities of aglycone derivatives obtained by enzymatic hydrolysis of oleoside-type secoiridoid glucosides, oleuropein and ligustroside
Masafumi Kikuchi, Nariyasu Mano, Yoshimasa Uehara, Koichi Machida, Masao Kikuchi
JOURNAL OF NATURAL MEDICINES ( SPRINGER JAPAN KK ) 65 ( 1 ) 237 - 240 2011年01月 [査読有り]
研究論文（学術雑誌）
Hydrolysis of oleoside-type secoiridoid glucosides, oleuropein (1) and ligustroside (2), in the presence of beta-glucosidase provided their aglycones, named (5S,8R,9S)-7-3,4-dihydroxyphenethyl elenolate (3) and (5S,8R,9S)-7-4-hydroxyphenethyl elenolate (4), respectively. The structures of 3 and 4 were identified by spectroscopic means and optical rotation measurements. Evaluation of the cytotoxic and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activities of compounds 1-4 showed that compounds 3 and 4 exhibited moderate cytotoxicity against a disease-oriented panel of 39 human cancer cell lines in vitro, whereas compound 3 inhibited the enzyme.
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Masafumi Kikuchi, Yasunori Yaoita Nariyasu Mano, Masao Kikuchi
Shoyakugaku Zasshi ( 日本生薬学会 ) 64 ( 2 ) 104 - 105 2011年01月 [査読有り]
研究論文（学術雑誌）
From the leaves of Syringa vulgaris L. (Oleaceae), nine known glycosides were isolated and identified: 3,4-dihydroxyphenethyl β-D-glucopyranoside (1), acteoside (2), echinacoside (3), oleoacteoside (4), oleoechinacoside (5), isooleoacteoside (6), syringopicroside B (7), syringalactone B (8), and 2"-epi-frameroside (9). This is the first time that compounds 6, 7 and 9 have been isolated from the leaves of S. vulgaris. The growth inhibitory activity of compounds 1-9 against 39 human cancer cell lines was evaluated.
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New physiological function of secoiridoids: neuritogenic activity in PC12h cells
Kenzo Chiba, Matsumi Yamazaki, Masafumi Kikuchi, Rie Kakuda, Masao Kikuchi
JOURNAL OF NATURAL MEDICINES ( SPRINGER TOKYO ) 65 ( 1 ) 186 - 190 2011年01月 [査読有り]
研究論文（学術雑誌）
Previously, we have reported that geniposide isolated from an extract of Gardenia fructus has neuritogenic activity in PC12h cells, a subclone of rat pheochromocytoma cells. Furthermore, we have indicated that several geniposide-related iridoid compounds also had similar potent neuritogenic activity. In this study, we have examined the effects of various secoiridoid compounds [K-1, sweroside; K-2, swertiamarin; K-3, gentiopicroside; K-4, 6'-O-beta-d-glucopyranosylsweroside; K-5, 6'-O-beta-d-glucopyranosylgentiopicroside; K-6, 6'-O-beta-d-glucopyranosylswertiamarin; K-7, 5'-O-beta-d-glucopyranosylamarogentin; K-8, 5'-O-beta-d-glucopyranosylamaroswertin; H-1, n-butyl vogeloside; H-2, n-butyl epivogeloside; H-3, (7S)-secologanin butyl methyl acetal; H-4, (7R)-secologanin butyl methyl acetal; H-5, secologanin dimethyl acetal] isolated from various medicinal herbs. The secoiridoids H-1, H-2, H-3, H-4, and H-5 induced significant neurite outgrowth. Among these H-series compounds, H-2 was the most potent neuritogenic compound. Among the K-series compounds, K-1, K-2, K-3, and K-8 showed the most potent activity. These results suggest that secoiridoids have neuritogenic activity in PC12h cells and that these secoiridoid compounds are promising starting compounds for the development of neurotrophic factor-like and iridoid compounds.