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矢野 育子医学部附属病院 薬剤部教授
研究活動情報
■ 受賞- 2024年11月 日本医療薬学会, JPHCS 誌論文賞, Significance of pharmacist intervention to oral antithrombotic therapy in the pharmaceutical outpatient clinic of cardiovascular internal medicine: a retrospective cohort study
- 2023年11月 日本医療薬学会, 第33回日本医療薬学会年会 優秀演題賞（International Session）, Effect of early dose reduction of osimertinib on efficacy in the first-line treatment for EGFR-positive non-small cell lung cancer
- 2023年11月 日本医療薬学会, JPHCS 誌論文賞, Effectiveness of pharmacist intervention for deprescribing potentially inappropriate medications: a prospective observational study
- 2023年03月 日本臨床腫瘍薬学会, 最優秀演題賞, 免疫チェックポイント阻害薬投与患者の好中球リンパ球比による層別化とプロトンポンプ阻害薬の併用による生命予後への影響
- 2023年03月 日本薬学会, 日本薬学会第143年会学生優秀発表賞（ポスター発表の部）, ユビキチンリガーゼHRD1を誘導する化合物の探索と神経細胞死抑制効果の検討
- 2022年 日本病院薬剤師会, 第10回（令和4年度）江口記念がん優秀論文賞, Safety and Efficacy of Bis-Glyceryl Ascorbate as Prophylaxis for Hand-Foot Skin Reaction: A Single-Arm, Open-Label Phase I/II study (DGA study)
- 2021年02月 第27回日本がんチーム医療研究会優秀演題賞, 抗がん薬調製ロボット導入前後における抗がん薬関連業務の比較
- 2019年03月 日本薬学会, 第42回佐藤記念国内賞, 医薬品適正使用のためのクリニカルファーマコメトリクス国内外の国際的学術賞
- 2018年03月 神戸大学医学部附属病院, 神戸大学医学部附属病院病院長賞, 院外処方箋における疑義照会簡素化プロトコール実行チームその他の賞
- 2017年09月 日本TDM学会, 日本TDM学会「国際TDM会議」派遣賞（海老原賞）, Molecular cornifying mechanisms of multi-targeted tyrosine kinase inhibitors-induced hand-foot skin reaction based on genetic differences of STAT3国内学会・会議・シンポジウム等の賞
- 2016年05月 神戸大学医学部附属病院薬剤部, 第10回日本ファーマシューティカルコミュニケーション学会大会 優秀発表賞, ひょっとして副作用!?見逃さない薬剤師になるための第一歩国内学会・会議・シンポジウム等の賞
- 2011年06月 日本TDM学会, 日本TDM学会「国際TDM会議」派遣賞（海老原賞）, Significance of trough monitoring of tacrolimus blood concentration and calcineurin activity in living-donor liver transplant patients.国内学会・会議・シンポジウム等の賞
- 2008年11月 公益財団法人 臨床薬理研究振興財団, 第1回臨床薬理研究振興財団研究大賞, カルシニューリン阻害剤の体内動態と薬効の速度論的解析に基づく個別化投与設計法出版社・新聞社・財団等の賞
- 2005年10月 日本薬物動態学会, 日本薬物動態学会奨励賞, 薬物動態と薬効の速度論的解析に基づく個別投与設計法の確立国内学会・会議・シンポジウム等の賞
- 2001年09月 日本医療薬学会, 日本医療薬学会奨励賞, 緑内障治療薬アセタゾラミドの体内動態と薬効の速度論的解析国内学会・会議・シンポジウム等の賞
- BACKGROUND: Torasemide, a loop diuretic, is rarely used for pregnant women because of the risk of reduced placental blood flow resulting from decreased circulating plasma volume. We experienced a case of a newborn with metabolic alkalosis and mild polyuria. The mother was suspected of self-medicating as we detected torasemide in the neonatal serum by LC-MS/MS method. CASE PRESENTATION: A Japanese pregnant woman in her 20s with mental illness, symptoms of panic and eating disorders, and a history of overdosing on over-the-counter medications, was referred to our hospital for birth control. She presented with vomiting following bulimia nervosa and hypokalemia. Her baby was delivered vaginally at 36 weeks and 4 days of gestation. The baby's blood gas analysis on day 0 revealed metabolic alkalosis (pH > 7.42, HCO3- > 28 mmHg). Up to 16 h after birth, mild polyuria and a urine output of 3.3 mL/kg/h were observed without the administration of diuretics. We suspected diuretic intake by the mother before delivery, because she had a history of taking torasemide before being referred to the hospital. As expected, torasemide was detected in the baby's serum. The serum concentration on the first day after delivery (4.80 ng/mL) gradually decreased to 0.45 ng/mL on day 5, whereas torasemide was not detected in the maternal serum. Neonatal metabolic alkalosis improved by day 3 following birth. CONCLUSIONS: This case suggests close counseling and monitoring of pregnant women before childbirth regarding their past and present use of drugs, particularly in those with mental illness.2025年04月, Journal of pharmaceutical health care and sciences, 11(1) (1), 31 - 31, 英語, 国際誌研究論文（学術雑誌）
- Japanese Society of Pharmaceutical Health Care and Sciences, 2025年04月, Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 51(4) (4), 203 - 212研究論文（学術雑誌）
- A woman in her 70s who was taking warfarin 3.75 mg/day had a prothrombin time-international normalized ratio (PT-INR) within the therapeutic range. Her medication for pulmonary hypertension was changed from bosentan to macitentan. After 40 days, she developed respiratory distress, anorexia, and vomiting caused by common cold. When she visited the pharmaceutical outpatient clinic without reservation, the pharmacist suspected that bosentan discontinuation, which cancelled cytochrome P450 (CYP) 2C9 and CYP3A4 enzyme induction, and decreased vitamin K intake due to appetite loss had enhanced warfarin effect, causing PT-INR prolongation. The pharmacist requested the physician to examine the patient's PT-INR. Results showed that her PT-INR was >7. Hence, she was urgently hospitalized. Warfarin and macitentan were discontinued, and the patient's PT-INR decreased to 1.77 after the intravenous administration of vitamin K. Her appetite improved, and warfarin 2 mg/day was resumed. Additionally, when she had been administered macitentan, her hemoglobin levels decreased from 10.8 to 6.6 mg/dL. Therefore, the pharmacist and the physician during hospitalization planned to resume treatment with bosentan, but not with macitentan. The pharmacist proposed to increase the warfarin dose to 3.75 mg since the bosentan and warfarin interaction could lower PT-INR. Thereafter, the patient's PT-INR was controlled within the therapeutic range, and her hemoglobin level was 8-9 mg/dL. The patient was discharged on day 17 of admission. Thus, pharmacist intervention plays a significant role in warfarin control with consideration of drug-drug interaction in patients receiving pulmonary hypertension treatment.2025年02月, The Kobe journal of medical sciences, 70(4) (4), E125-E129, 英語, 国内誌研究論文（学術雑誌）
- BACKGROUND: Valganciclovir (VGCV) is administered at a dose of 16 mg/kg 2 times daily for 6 months to treat symptomatic congenital cytomegalovirus (CMV) infections. During the treatment period, approximately 20% of the patients developed grade 3 or higher neutropenia. Currently, information on the pharmacokinetics and pharmacodynamics of ganciclovir, an active metabolite of VGCV, in infants is limited. In the current study, the relationship between ganciclovir concentration and neutropenia was investigated, and a population pharmacokinetic (PPK) model of ganciclovir in infants with symptomatic congenital CMV infection was developed. METHODS: Japanese infants who were prescribed oral VGCV for symptomatic congenital CMV infections between July 2017 and January 2021 were included. The relationship between the observed trough ganciclovir concentrations and neutrophil counts was examined. PPK analysis was performed to evaluate the covariates affecting the pharmacokinetics of ganciclovir. RESULTS: Twenty-seven ganciclovir serum samples from 8 patients were analyzed. A moderate negative correlation was observed between the observed trough ganciclovir concentration and neutrophil count. PPK model analysis showed that postmenstrual age (PMA) affected the total body clearance of ganciclovir after correcting for the empirical allometric scaling of body weight. Based on PMA and body weight, a nomogram to achieve the target area under the concentration-time curve from 0 to 24 hours of 40-60 mcg·h·mL-1 of ganciclovir was calculated. CONCLUSIONS: The relationship between neutrophil count and ganciclovir trough concentration in infants was clarified. The PPK model showed that the dose of VGCV should be reduced in patients with a low PMA to achieve target exposure.2024年09月, Therapeutic drug monitoring, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: While nirmatrelvir/ritonavir (NMV-r) has been positioned as a first-line treatment for mild to moderate COVID-19, it has multiple and significant drug-drug interactions (DDIs). The use of NMV-r in Japan has been limited compared to the United States. This study aimed to describe the distribution of DDIs with NMV-r and their management in patients with COVID-19 under the control of a management system for the appropriate use of NMV-r. METHODS: A retrospective observational study was conducted at a Japanese university hospital. The management system included a flowchart for selecting antivirals and a list for reviewing DDI management, based on the National Institutes of Health guidelines and the guidance of the Japanese Society of Pharmaceutical Health Care and Sciences. Patients with mild to moderate COVID-19 and prescribed NMV-r or molnupiravir (MOV) were included. The primary outcome was DDI management practices, including the selected COVID-19 medications. The secondary outcome included the distribution of DDI classification and the 30-day all-cause mortality. RESULTS: This study included 241 patients (median age of 60 years, 112 [46.5%] females), of whom 126 and 115 received NMV-r and MOV, respectively. Of the 241 patients, 145 (60.2%) received concomitant medications that have DDIs with NMV-r. All 30 patients with severe renal impairment or insufficient details on concomitant medications received MOV. Forty-nine patients with concomitant medications required alternative COVID-19 therapy consideration due to DDIs, of whom 42 (85.7%) patients received MOV. Eighty-one patients had concomitant medications requiring temporary adjustment, of whom 44 (54.3%) patients received NMV-r, and 42 of these patients temporarily adjusted these concomitant medications. Five patients with concomitant medications that can continued by monitoring the effects/adverse effects, of whom 4 (80.0%) patients received NMV-r. Seventy-six patients without concomitant medications requiring DDI management, of whom 71 (93.4%) patients received NMV-r. The 30-day all-cause mortality for eligible patients was 0.9% [95% confidence interval, 0.1-3.1]. CONCLUSIONS: Most patients received appropriate antivirals according to the classification of DDIs, and most patients with concomitant medications requiring temporary adjustment received the recommended DDI management. Our management system is effective in promoting the use of NMV-r in the appropriate patients and managing problematic DDIs.2024年09月, Journal of pharmaceutical health care and sciences, 10(1) (1), 54 - 54, 英語, 国際誌研究論文（学術雑誌）
- オピオイド鎮痛薬を入院中に開始した外来頭頸部がん患者を対象とした病院薬剤師による電話サポート介入の効果入院中にオピオイド鎮痛薬(オピオイド)を導入し外来移行した頭頸部がん患者に対し,病院薬剤師が電話で定期的に疼痛評価やオピオイド副作用評価を行い(電話サポート),必要時に薬剤調整などを医師に提案する取組みを行い,その効果を評価したので報告する.解析対象患者は10名,電話サポートの期間と回数の中央値はそれぞれ123日と5回であり,患者から薬剤師への相談は40件,薬剤師から医師への提案は53件であった.疼痛強度を示す1日平均numerical rating scaleは介入前後で5.5から1.0と有意に低下し,エドモントン症状評価システム改訂版による副作用評価では倦怠感と便秘の項目で介入前後の変化量がそれぞれ-2.5,-4.5と有意に低下した.以上,外来頭頸部がん患者への薬剤師による電話サポートはオピオイドによる疼痛緩和や副作用回避に有用であり,オピオイド適正使用に繋がることが示唆された.(著者抄録)(一社)日本緩和医療薬学会, 2024年09月, 日本緩和医療薬学雑誌, 17(3) (3), 87 - 94, 日本語
- (一社)日本TDM学会, 2024年07月, TDM研究, 41(2) (2), 158 - 158, 日本語
- Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.2024年06月, Investigational new drugs, 42(3) (3), 281 - 288, 英語, 国際誌研究論文（学術雑誌）
- 院外処方における臨床検査値を用いた2段階チェック機能の有用性 処方禁忌警告システムと処方箋への検査値印字院外処方における処方禁忌チェックシステムと院外処方箋における検査値印字による2段階チェックの有用性について評価した。処方禁忌チェックは2018年8月から稼働し、その17ヵ月後の2020年1月から院外処方箋への検査値印字を開始したことを踏まえ、17ヵ月間を1期間として対象期間を設定した。各調査期間における禁忌アラート該当件数は第1期が9850件(3.62%)、第2期が9464件(3.29%)、第3期が9460件(3.41%)、第4期が9823件(3.34%)であり、第1期に比べて第2、3、4期の割合はいずれも有意に低下した。検査値関連の疑義照会による処方変更件数は第2期が5件、第3期が66件、第4期が47件であり、第2期に比べて第3期と第4期で検査値関連の疑義照会による処方変更件数は約10倍に増えており、割合としても有意に増加した。院外処方箋に検査値印字を行う2段階チェックは医薬品の適正使用の推進に有用であることが示された。(一社)日本医療薬学会, 2024年06月, 医療薬学, 50(6) (6), 277 - 286, 日本語
- Elsevier BV, 2024年06月, Drug Metabolism and Pharmacokinetics, 56, 101009 - 101009研究論文（学術雑誌）
- BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.2024年04月, Therapeutic drug monitoring, 46(5) (5), 687 - 691, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 一包化錠剤仕分け装置の運用過程でテルミサルタン錠の変色を経験した。まず,テルミサルタン錠とドパミン誘導体を含む錠剤(レボドパ/カルビドパ錠,ドロキシドパ錠または粉砕したメチルドパ錠)との接触実験を行ったところ着色を確認した。一方で,テルミサルタンとドパミン誘導体が構造的に化学反応する可能性は低いため,テルミサルタン錠の添加剤であるメグルミンに着目し,メチルドパと混合下で基礎的検討を行った。水分存在下では着色が加速し,着色成分の質量分析を行った結果,複数のメチルドパ分解産物の生成が示された。すなわちドパミン誘導体は水分存在下でメグルミンと接触することで酸化的に分解され,さらに重合することでメラニン類似物質となり,それがテルミサルタン錠の変色原因であることが示唆された。以上,添加剤としてメグルミンを含有する薬剤では,無包装下でドパミン誘導体との接触による製剤学的相互作用に注意を要する。(著者抄録)(一社)日本病院薬剤師会, 2024年04月, 日本病院薬剤師会雑誌, 60(4) (4), 395 - 401, 日本語
- Introduction In our previous work, we investigated the analgesic effects of ibuprofen gargle after mandibular third molar extractions. However, a subsequent detailed review of individual patient data revealed variations in postoperative pain reduction among patients. Consequently, the present study was designed to conduct post-hoc subanalyses that identified factors contributing to variation in the analgesic response to ibuprofen gargle after third molar extractions. Materials and methods This study involved thirty-five Japanese patients from a prior randomized, double-blind, placebo-controlled, crossover study, which focused on the analgesic effects of ibuprofen gargle after mandibular third molar extractions. Participants were categorized as responders (n = 13) and non-responders (n = 22) based on the within-subject difference (ibuprofen-placebo, IP) of visual analog scale (VAS) changes. Baseline characteristics were compared, along with variables, such as age, sex, the reason for extraction, extraction site, Pell Gregory (space and depth) classification, Winter's classification, surgeon's experience, and surgery time. Baseline characteristics predicting responder status were examined using multivariate logistic regression. Results In the univariate analysis, variables such as age, sex, and baseline VAS scores with p-values <0.2 were evaluated using a stepwise approach. This analysis identified age (per -10 years) with an odds ratio of 4.163 (95% confidence interval (CI): 1.170-31.952, p = 0.0233) and sex (female) with an odds ratio of 9.977 (95% CI: 1.336-208.256, p = 0.0213) as significant predictors of responder status. Conclusions In young and female patients, ibuprofen gargle decreased postoperative pain after mandibular third molar extractions.2024年04月, Cureus, 16(4) (4), e57516, 英語, 国際誌研究論文（学術雑誌）
- INTRODUCTION: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. MATERIALS AND METHODS: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. RESULTS: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). CONCLUSIONS: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.2024年03月, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 30(10) (10), 971 - 977, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody, can cause infusion reactions (IRs), especially during the initial rituximab infusion therapy. Generally, patients are administered a histamine H1-receptor antagonist before the rituximab infusion, along with an antipyretic analgesic, to prevent or reduce IRs. Multiple retrospective case-control studies indicate that the second generation of histamine H1-receptor antagonists might be more effective than the first generation in suppressing IRs caused by the rituximab infusion. OBJECTIVE: This study aimed to assess the efficacy of first- and second-generation histamine H1-receptor antagonists for preventing IRs resulting from the initial infusion of rituximab in patients diagnosed with non-Hodgkin lymphoma. METHODS: This is a phase II, double-blind, active-controlled randomized trial. It will be a multicenter study conducted across 3 facilities that aims to enroll a total of 40 patients diagnosed with non-Hodgkin lymphoma who will receive their initial rituximab infusion. Participating patients will be administered hydroxyzine pamoate or bepotastine besilate, representing first- or second-generation histamine H1-receptor antagonists, respectively. This will be combined with 400-mg acetaminophen tablets taken approximately 30 minutes before the first infusion of rituximab. The primary end point of this trial is to assess severe IRs, equivalent to grade 2 or higher as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, that occur within a 4-hour period after the initiation of rituximab infusion. The secondary end points include assessing the severity of the initial IR, the maximum severity of the IR, and the duration between rituximab infusion initiation and the onset of the first IR within a 4-hour period. Additionally, the trial will evaluate histamine H1-receptor antagonist-induced drowsiness using the visual analogue scale, with each patient providing their individual response. RESULTS: This study began with patient recruitment in April 2023, with 17 participants enrolled as of November 12, 2023. The anticipated study completion is set for February 2026. CONCLUSIONS: This study is the first randomized controlled trial comparing the effects of oral first- and second-generation histamine H1-receptor antagonists in preventing IRs induced by the initial administration of rituximab. The findings from this study hold the potential to establish the rationale for a phase III study aimed at determining the standard premedication protocol for rituximab infusion. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051220169; https://jrct.niph.go.jp/latest-detail/jRCTs051220169. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54882.2024年02月, JMIR research protocols, 13, e54882, 英語, 国際誌研究論文（学術雑誌）
- 退院時薬剤情報提供が入院中に中止した潜在的不適切処方(PIMs)の中止維持に有用であるかについて検討するため、入院中にPIMsを中止して退院した65歳以上の循環器内科・心臓血管外科病棟患者について後方視的調査を行った。その結果、お薬手帳を用いた退院時薬剤情報提供を実施した群におけるPIMsの中止維持薬剤割合は86.1%と高く、薬剤情報提供が個別のPIMsの中止維持に有効であることが示唆された。PIMsの再開と関連する因子として中止維持の評価時点が再入院時であることが特定され、お薬手帳を介して退院時薬剤情報が共有されないまま他院へ通院することがPIMs再開のリスクとなることが示唆された。退院時の薬剤情報提供は、診療情報が共有されない他院への通院患者において一般的に回避すべきPIMsの中止維持に有効であり、より安全で一貫性のある薬物治療の提供に貢献できると考えられた。(一社)日本医療薬学会, 2024年02月, 医療薬学, 50(2) (2), 75 - 83, 日本語
- Parkinson's Disease (PD) is caused by many factors and endoplasmic reticulum (ER) stress is considered as one of the responsible factors for it. ER stress induces the activation of the ubiquitin-proteasome system to degrade unfolded proteins and suppress cell death. The ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) and its stabilizing molecule, the suppressor/enhancer lin-12-like (SEL1L), can suppress the ER stress via the ubiquitin-proteasome system, and that HRD1 can also suppress cell death in familial and nonfamilial PD models. These findings indicate that HRD1 and SEL1L might be key proteins for the treatment of PD. Our study aimed to identify the compounds with the effects of upregulating the HRD1 expression and suppressing neuronal cell death in a 6-hydroxydopamine (6-OHDA)-induced cellular PD model. Our screening by the Drug Gene Budger, a drug repositioning tool, identified luteolin as a candidate compound for the desired modulation of the HRD1 expression. Subsequently, we confirmed that low concentrations of luteolin did not show cytotoxicity in SH-SY5Y cells, and used these low concentrations in the subsequent experiments. Next, we demonsrated that luteolin increased HRD1 and SEL1L mRNA levels and protein expressions. Furthermore, luteolin inhibited 6-OHDA-induced cell death and suppressed ER stress response caused by exposure to 6-OHDA. Finally, luteolin did not reppress 6-OHDA-induced cell death when expression of HRD1 or SEL1L was suppressed by RNA interference. These findings suggest that luteolin might be a novel therapeutic agent for PD due to its ability to suppress ER stress through the activation of HRD1 and SEL1L.2024年01月, Neurochemical research, 49(1) (1), 117 - 128, 英語, 国際誌研究論文（学術雑誌）
- OBJECTIVE: This study was designed to evaluate the postoperative efficacy and safety of using an ibuprofen gargle as a pain management strategy for patients who have undergone mandibular third molar extraction. We also ensured that the quality of treatment was not compromised throughout the study. MATERIAL AND METHODS: Patients were randomized in a 1:1 ratio into two groups: the ibuprofen-placebo (IP) group and the placebo-ibuprofen (PI) group. On postoperative Day (POD) 1, the IP group initiated ibuprofen administration, while the PI group started taking placebo. On POD 2, the IP group switched to using placebo, whereas the PI group switched to ibuprofen. From PODs 3-5, both groups were prescribed ibuprofen gargle. The primary endpoint was within-subject visual analog scale (VAS) score before and 5 min after the first use of the ibuprofen or placebo gargle on PODs 1 and 2 (ΔVAS5_ibuprofen - ΔVAS5_placebo ). The incidence and severity of adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0 and a subjective rating scale. RESULTS: This study enrolled 40 patients. The within-subject VAS5 of the IP and PI groups were 1.25 ± 12.0 and -5.26 ± 8.93 mm, respectively. The treatment effect of ibuprofen gargle was -2.01 ± 10.62 mm (p = .246). None of the patients in each group presented with serious adverse events or clinically significant complications (including dry sockets) after extraction. Transient adverse events, such as throat tingling and oral discomfort (grade 1), were observed in each group. CONCLUSION: Ibuprofen gargle was safe but did not provide significant pain relief when used after mandibular third molar extraction.2023年11月, Clinical and experimental dental research, 9(6) (6), 1058 - 1068, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Optimised antithrombotic therapy requires clinical experience and an understanding of the current guidelines. This retrospective study aimed to evaluate whether pharmacist interviews and interventions with patients taking oral antithrombotic drugs in the pharmaceutical outpatient cardiology clinic had favourable clinical outcomes including decreased bleeding. METHODS: The participants included patients visiting the outpatient clinic of cardiovascular internal medicine at the Kobe University Hospital from January-December 2017, and were taking oral antithrombotic medication. The observation period was from the first visit to the outpatient clinic to October 2021 or death. Patients who received pharmacist intervention more than twice were defined as the pharmacist intervention group. Two control patients per one pharmacist intervention group individual were selected from the non-intervention pool matched for age, gender and antithrombotic medication type. RESULTS: Of the 895 eligible patients, 132 were in the pharmacist intervention group and 264 were selected for the matched non-intervention group. Bleeding events according to the Bleeding Academic Research Consortium criteria over type 2 were significantly lower in the pharmacist intervention group compared with the non-intervention group (17.4% versus 28.4%, P = 0.019). There were no significant differences in mortality and heart failure hospitalisation frequency, stroke, or cardiovascular events between the groups. Multivariate analysis identified age (≥ 65 years) and pharmacist intervention as factors associated with bleeding (odds ratio = 2.29 and 0.51, respectively). CONCLUSION: Pharmacist intervention in the outpatient clinic of cardiovascular internal medicine was effective in reducing the risk of bleeding in patients undergoing antithrombotic therapy.2023年09月, Journal of pharmaceutical health care and sciences, 9(1) (1), 28 - 28, 英語, 国際誌研究論文（学術雑誌）
- 神戸大学医学部附属病院では,緩和ケアチーム担当薬剤師がWHO方式がん疼痛治療法の鎮痛薬リストの強オピオイド鎮痛薬が処方された入院患者をモニタリングしている.今回,非がん性疼痛患者への強オピオイド使用に際して,薬剤師が検出した緩和薬物療法に関する薬物関連問題(Drug Related Problem,以下DRP)とその転帰について後方視的評価を行った.解析対象患者82名のうち47名(57.3%)にDRPを検出し,うち31名に対して病棟薬剤師を介して介入を行った結果,27名のDRPが解消された.初回モニタリング時に検出し,介入したDRPとしては,ガイドラインからみた不適切使用・禁忌(15件)や,適応のない薬剤の選択(18件)が多かった.緩和ケアチーム薬剤師が非がん性疼痛に対するオピオイド処方患者を一元的にモニタリングすることで,DRPを効率的に検出し,その解消につながる可能性がある.(著者抄録)(一社)日本緩和医療薬学会, 2023年09月, 日本緩和医療薬学雑誌, 16(3) (3), 65 - 71, 日本語
- 非がん性疼痛を有する患者のオピオイド使用状況モニタリングにおける薬剤師介入の効果神戸大学医学部附属病院では,緩和ケアチーム担当薬剤師がWHO方式がん疼痛治療法の鎮痛薬リストの強オピオイド鎮痛薬が処方された入院患者をモニタリングしている.今回,非がん性疼痛患者への強オピオイド使用に際して,薬剤師が検出した緩和薬物療法に関する薬物関連問題(Drug Related Problem,以下DRP)とその転帰について後方視的評価を行った.解析対象患者82名のうち47名(57.3%)にDRPを検出し,うち31名に対して病棟薬剤師を介して介入を行った結果,27名のDRPが解消された.初回モニタリング時に検出し,介入したDRPとしては,ガイドラインからみた不適切使用・禁忌(15件)や,適応のない薬剤の選択(18件)が多かった.緩和ケアチーム薬剤師が非がん性疼痛に対するオピオイド処方患者を一元的にモニタリングすることで,DRPを効率的に検出し,その解消につながる可能性がある.(著者抄録)(一社)日本緩和医療薬学会, 2023年09月, 日本緩和医療薬学雑誌, 16(3) (3), 65 - 71, 日本語
- 2023年09月, Drug Metabolism and Pharmacokinetics, 53, 100529[査読有り]研究論文（学術雑誌）
- Pharmaceutical Society of Japan, 2023年06月, Biological and Pharmaceutical Bulletin, 46(6) (6), 788 - 795研究論文（学術雑誌）
- BACKGROUND: Sarcopenia is defined as the loss of skeletal muscle mass and function and is associated with increased mortality. Certain genetic polymorphisms represent risk factors used to assess the incidence of sarcopenia; however, few studies have evaluated the association between genetic polymorphisms and sarcopenia after kidney transplantation (KTx). We examined single-nucleotide polymorphisms (SNPs) in the genes involved in sarcopenia after KTx. METHODS: Sixty-five patients who underwent KTx were enrolled in this study. We used the psoas mass index (PMI; the cross-sectional area of the bilateral psoas muscle/height) as a surrogate marker for assessing the extent of sarcopenia. We determined the PMI before KTx and 1 year after KTx, and we identified 5 SNPs in 5 genes associated with sarcopenia in the general population. Finally, the link between the changes in PMI 1 year after KTx and each SNP was examined. RESULTS: The median PMI before KTx and 1 year after KTx was 7.4 (4.6-13.2) and 7.0 (3.6-13.6), respectively. The PMI decreased in 43 patients (66.2%). The alpha-actinin-3 rs1815739 genotype was associated with changes in PMI; the distribution of CT+TT genotypes in the PMI decrease group was significantly higher than that of the CC genotype (odds ratio, 4.23; 95% CI 0.05-0.97; P = 0.025). Moreover, the T allele frequency was significantly higher in the PMI decrease group than in the PMI increase group (odds ratio, 2.34; 95% CI 0.18-0.950; P = 0.025). CONCLUSION: The alpha-actinin-3 rs1815739 genotype may represent a genetic risk factor for sarcopenia after KTx.2023年05月, Transplantation proceedings, 55(4) (4), 824 - 828, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND/AIM: Osimertinib is a key drug for treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Genetic differences may be associated to adverse events (AEs) induced by osimertinib. This retrospective observational multicenter study evaluated the association of genotypes, including STAT3 -1697C>G, CYP3A5 6986A>G, and ABCG2 421C>A, with the incidence of osimertinib-induced AEs in patients with EGFR mutation-positive NSCLC. PATIENTS AND METHODS: A total of 85 patients treated with osimertinib (Institution A: 33 patients, Institution B: 52 patients) were enrolled in the study. Single nucleotide polymorphisms were determined by real-time PCR, and the incidence of AEs was compared for each genotype. RESULTS: Paronychia incidence was 59% for the CC genotype, 19% for the CG genotype, and 19% for the GG genotype at STAT3 -1697C>G. A genotype-related trend was observed (Cochran-Armitage test, p=0.009). Multivariate analysis showed that the CC genotype at STAT3 -1697C>G and female sex were significant independent factors associated with paronychia [odds ratio (OR)=6.41, 95% confidence interval (CI)=1.94-21.20 and OR=3.40, 95%CI=1.03-11.22, respectively]. The incidence of diarrhea was 53% for the CC genotype, 30% for the AC genotype, and 29% for the AA genotype at ABCG2 421C>A, and a genotype-related trend was observed (p=0.048). However, the CC genotype at ABCG2 421C>A was not a significant independent factor associated with diarrhea in multivariate analysis. No significant associations were detected between other polymorphisms and the incidence of AEs. CONCLUSION: STAT3 -1697C>G may be a novel risk factor for osimertinib-induced paronychia in patients with NSCLC.2023年04月, Anticancer research, 43(4) (4), 1775 - 1783, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND/AIM: Lenvatinib is a multiple-tyrosine kinase inhibitor used to treat hepatocellular carcinoma (HCC), and its systematic concentration varies according to liver function. The albumin-bilirubin (ALBI) grade is a novel indicator for predicting liver function in patients with hepatic disease. This study aimed to investigate the relationship between ALBI grade and HCC patients' lenvatinib treatment duration. PATIENTS AND METHODS: This is a retrospective cohort study of patients with HCC and Child-Pugh A treated with lenvatinib between April 2018 and December 2019. The baseline liver function was determined using the ALBI grade. The primary outcome was discontinuation owing to adverse events. The risk factors for discontinuation owing to adverse effects were analyzed using logistic regression. RESULTS: This investigation included 48 HCC patients. Patients with ALBI grade 2 had a significantly shorter time of discontinuation due to adverse events than those with grade 1 (p=0.036). However, the time of treatment failure did not differ between the groups. Multiple logistic regression analysis showed that ALBI grade 2 and non-use of antihypertensive drugs were independent factors for discontinuation due to adverse events [odds ratio (OR)=14.1, 95% confidence interval (CI)=1.46-135, p=0.022 and OR=5.48, 95% CI=1.13-23.9, p=0.024, respectively]. CONCLUSION: The ALBI grades may be useful in predicting adverse events caused by lenvatinib in patients with HCC and Child-Pugh A.2023年03月, Anticancer research, 43(3) (3), 1317 - 1323, 英語, 国際誌研究論文（学術雑誌）
- This study aimed to determine the effects of pregnancy and ontogeny on risperidone and paliperidone pharmacokinetics by assessing their serum concentrations in two subjects and constructing a customized physiologically-based pharmacokinetic (PBPK) model. Risperidone and paliperidone serum concentrations were determined in a pregnant woman and her newborn. PBPK models for risperidone and paliperidone in adults, pediatric, and pregnant populations were developed and verified using the Simcyp simulator. These models were then applied to our two subjects, generating their "virtual twins." Effects of pregnancy on both drugs were examined using models with fixed pharmacokinetic parameters. In the neonatal PBPK simulation, 10 different models for estimating the renal function of neonates were evaluated. Risperidone was not detected in the serum of both pregnant woman and her newborn. Maternal and neonatal serum paliperidone concentrations were between 2.05-3.80 and 0.82-1.03 ng/ml, respectively. Developed PBPK models accurately predicted paliperidone's pharmacokinetics, as shown by minimal bias and acceptable precision across populations. The individualized maternal model predicted all observed paliperidone concentrations within the 90% prediction interval. Fixed-parameter simulations showed that CYP2D6 activity largely affects risperidone and paliperidone pharmacokinetics during pregnancy. The Flanders metadata equation showed the lowest absolute bias (mean error: 22.3% ± 6.0%) and the greatest precision (root mean square error: 23.8%) in predicting paliperidone plasma concentration in the neonatal population. Our constructed PBPK model can predict risperidone and paliperidone pharmacokinetics in pregnant and neonatal populations, which could help with precision dosing using the PBPK model-informed approach in special populations.2023年01月, Clinical and translational science, 16(4) (4), 618 - 630, 英語, 国際誌研究論文（学術雑誌）
- Oral lichen planus (OLP) is a type of chronic and refractory stomatitis characterized by abnormal keratinization, which is often painful. There is no consensus regarding treatment options for OLP, particularly in the presence of pain. The current study protocol focuses on the short-term efficacy and long-term safety of an ibuprofen gargle for pain management in patients with OLP. Patients (n = 24) with painful OLP will be enrolled. During a crossover study period, patients in the ibuprofen–placebo (IP) group will receive an ibuprofen gargle (0.6%) on day 1, a placebo gargle on day 2, and an ibuprofen gargle on days 3–5 at least once daily. Patients in the placebo–ibuprofen (PI) group will receive a placebo gargle on day 1, an ibuprofen gargle on day 2, and an ibuprofen gargle on days 3–5 at least once daily. The primary endpoint of the crossover study period is the change in pain level as measured by a visual analogue scale score from before gargle administration to 5 min after gargle administration on days 1 and 2. The primary endpoint of the long-term extension study is assessment of long-term safety. The results of this study may support existing evidence regarding the effectiveness of ibuprofen rinses in treating OLP.MDPI AG, 2023年01月, Methods and Protocols, 6(1) (1), 7 - 7[査読有り]研究論文（学術雑誌）
- Wiley, 2022年11月, Clinical and Translational Science, 15(11) (11), 2652 - 2662[査読有り]研究論文（学術雑誌）
- 神戸大学医学部附属病院では、2019年8月より抗がん薬調製ロボット(以下、調製ロボット)の日常業務での運用を開始した。そこで、調製ロボット導入前後の評価期間として2019年5～7月および2020年8～10月の各3ヵ月間を設定し、薬剤師のがん薬物療法関連業務を比較した。調製ロボット導入後に抗がん薬調製総件数は有意に増加したが、調製ロボットの調製率は調製総件数の29.2%を占め、薬剤師による抗がん薬調製件数は導入前に比べて導入後に有意に減少した(1,653±51 vs.1,330±20件/月、平均値±標準偏差、p<0.01)。また、薬剤師の対患者業務に関して、初回抗がん薬治療時の治療説明件数は導入前後で35±10件/月から55±5件/月へと有意に増加した(p=0.04)。調製ロボットの導入は、薬剤師による調製件数の減少とそれに伴うマンパワーの対患者業務へのシフトに有用である。(著者抄録)(一社)日本病院薬剤師会, 2022年06月, 日本病院薬剤師会雑誌, 58(6) (6), 627 - 632, 日本語
- BACKGROUND: Extraction of mandibular third molars is one of the most commonly performed oral surgical procedures, and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management. Oral NSAIDs are associated with adverse events such as gastrointestinal disorders, renal and hepatic dysfunction, and platelet dysfunction. Topical analgesics have been proposed as alternatives to oral and injectable medications to safely improve postoperative pain relief. We will conduct a single-center, placebo-controlled, double-blind, randomized crossover trial to assess the pain-relieving effect of an ibuprofen-containing gargle in patients undergoing extraction of mandibular third molars when compared with a placebo gargle. OBJECTIVE: This will be the first clinical study to compare the efficacy of an ibuprofen gargle with that of a placebo for relieving postoperative pain in addition to loxoprofen after mandibular third molar extraction. METHODS: This study will be performed at Kobe University Hospital. Participants (N=40) will be randomized equally to 1 of 2 groups. The ibuprofen-placebo group will receive an ibuprofen gargle on postoperative day (POD) 1 and a placebo gargle on POD 2. The placebo-ibuprofen group will receive a placebo gargle on POD 1 and an ibuprofen gargle on POD 2. Both groups will receive ibuprofen gargles on PODs 3-5 at least once daily. The primary objective is to estimate the within-subject difference on a visual analog scale (VAS) before and 5 minutes after using the ibuprofen or placebo gargle on PODs 1 and 2. The secondary objectives are to estimate the within-subject differences in ΔVAS before and 15 minutes after using the ibuprofen or placebo gargle on PODs 1 and 2, ΔVAS before and 5 or 15 minutes after using the ibuprofen gargle on PODs 3-5, overall efficacy (self-completion, 5 scales) on PODs 1-5, daily frequency of use (ibuprofen or placebo gargle and analgesics) on PODs 1-7, and the occurrence of adverse events. RESULTS: The Certified Review Board of Kobe University approved the study. The intervention was implemented in May 2021. For the primary analysis, we will calculate the mean and SD of ΔVAS5 on PODs 1 and 2 and the within-study difference in ΔVAS5. The treatment effect will be estimated by dividing the mean ΔVAS5 in the within-subject difference by 2 and calculating the P value using an unpaired t test. For the secondary analysis, we will calculate the mean and SD of ΔVAS15 on PODs 1 and 2 and the within-study difference in ΔVAS15. The treatment effect will be estimated as in the primary analysis. CONCLUSIONS: This trial will provide exploratory evidence of the efficacy and safety of an ibuprofen gargle for pain reduction after mandibular third molar extraction. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051210022; https://tinyurl.com/39ej23zu. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35533.2022年05月, JMIR research protocols, 11(5) (5), e35533, 英語, 国際誌研究論文（学術雑誌）
- Abstract Background Potentially inappropriate medications (PIMs) and polypharmacy in older adults lead to increase the risk of adverse drug events. This study aimed to evaluate the effectiveness of pharmacist intervention combining the criteria for detecting PIMs with the deprescribing algorithm on correcting PIMs, reducing the number of medications, and readmissions. Methods A prospective observational study was conducted at a Japanese University Hospital enrolling new inpatients aged ≥65 years prescribed ≥1 daily medication. Pharmacists detected PIMs based on the criteria combined the screening tool of older persons’ potentially inappropriate prescriptions criteria version 2 with the screening tool for older persons’ appropriate prescriptions for Japanese, examined changes using the deprescribing algorithm, and suggested changes to the physician. The proportion of patients whose number of medications was reduced at discharge and the rate of readmissions within 30 and 90 days were compared between patients without PIMs (without PIMs group), patients who were not suggested to change PIMs (no suggestions group), and patients who were suggested to change PIMs (suggested group). Results The study enrolled 544 patients (median age 75.0 years, 54.4% males, median number of medications 6.0/patient). The number of patients with PIMs was 240 (44.1%), and 304 patients had no PIMs (without PIMs group). Among the patients with PIMs, 125 (52.1%) patients received pharmacist suggestions to change ≥1 PIMs (suggested group), and 115 patients received no suggestions for change (no suggestions group). The total number of PIMs was 432, of which changes were suggested for 189 (43.8%). Of these 189 cases, 172 (91.0%) were changed. The proportion of patients whose number of medications was reduced was significantly higher in the suggested group than in the without PIMs group and the no suggestions group [56.8% (71/125) vs. 26.6% (81/304) and 19.1% (22/115), respectively; P < 0.001 in both comparisons]. There were no significant differences in the rates of readmissions within 30 and 90 days among the three groups. Conclusions Pharmacist intervention combining the criteria for detecting PIMs with the deprescribing algorithm was effective for correcting PIMs and may be associated with a reduction in the number of medications.Springer Science and Business Media LLC, 2022年04月, Journal of Pharmaceutical Health Care and Sciences, 8(1) (1), 12[査読有り]研究論文（学術雑誌）
- Abstract Background Hand-foot skin reaction (HFSR) induced by multiple tyrosine kinase inhibitors (TKIs) is a serious side effect that can cause treatment interruption or decreased dosing. This study was conducted to evaluate the safety and efficacy of bis-glyceryl ascorbate (Amitose bis(di)-glyceryl ascorbate [DGA])-containing cream (DGA cream) for the prevention of sunitinib-induced HFSR. Methods A single-arm, open-label phase I/II study was conducted, targeting patients with metastatic renal cell carcinoma (mRCC) who were receiving sunitinib therapy with a schedule of 2 weeks on/1 week off. The participants applied DGA cream to both palmar and plantar surfaces in combination with a moisturizing agent as standard-of-care prophylaxis during two sunitinib treatment cycles (6 weeks). The primary endpoint in phase I was safety defined as dermatological abnormalities and it was determined in the first five participants. The primary endpoint in phase II was efficacy defined as development of grade 1 or higher HFSR defined by Common Terminology Criteria for Adverse Events within 6 weeks and it was determined on a full analysis set (FAS) defined as the population including all participants who used DGA cream once in the study duration. Efficacy in the per protocol set (PPS) defined as the population excluding seven patients whose study treatment was interrupted was evaluated as a secondary endpoint. Results Twenty-four patients were enrolled as a FAS. No dermatological abnormalities occurred in the first 5 patients enrolled in the phase I study. Three patients developed HFSR (grade 1: n = 2, grade 2: n = 1) in the observation period. The HFSR incidence rate was 12.5% (3/24; 95% confidence interval [CI]: 2.7%-32.4%) in the FAS, which was significantly lower than the incidence rate predefined as a threshold of 33.3% by a previous report from our hospital (P = .030). The incidence rate in the 17 patients of the PPS was 17.6% (3/17; 95%CI: 3.8%-43.4%). Conclusion DGA cream may be safe and effective in the prophylaxis of HFSR in mRCC patients who receive sunitinib therapy (Trial ID: jRCTs051180051).Oxford University Press (OUP), 2022年03月, The Oncologist, 27(5) (5), e384 - e392研究論文（学術雑誌）
- Elsevier BV, 2022年02月, Drug Metabolism and Pharmacokinetics, 42, 100423 - 100423研究論文（学術雑誌）
- Our antimicrobial pharmacist-led intervention included: (a) a structured review of antibiotic prescriptions; (b) educating prescribers on antimicrobial therapy; (c) monthly reporting of department-level rates of blood sampling for culture. Daily review began in May 2018 and was discontinued after 10 months; however, the other interventions were conducted throughout the study period. This study aimed to evaluate the sustained impact of pharmacist's interventions on antimicrobial therapy and clinical outcomes between the baseline (May-December 2017), intervention (May-December 2018), and post-intervention (May-December 2019) periods. The rate of blood culture collections before starting antipseudomonal agent therapy was significantly increased from the baseline to post-intervention periods (71% vs. 85%, p < 0.001). Antipseudomonal agent therapy was more frequently de-escalated in the post-intervention period than in the baseline period (73% vs. 54%, p = 0.038). Total use of antipseudomonal agents was reduced from the baseline to intervention periods and persisted during the post-intervention period (50.5 vs. 41.8 and 42.6 DDD per 1000 patient-days, p = 0.016 and p = 0.022, respectively). During the study period, there were significant reductions in the incidence of hospital-acquired Clostridioides difficile infection (1.12, 0.54, and 0.51 per 10,000 patient-days, respectively, p = 0.031) and 30-day mortality with bacteremia (19%, 18%, and 12%, respectively, p = 0.005). Our pharmacist-led interventions sustainably achieved appropriate antimicrobial therapy and improved clinical outcomes.2022年01月, Journal of clinical medicine, 11(3) (3), 566, 英語, 国際誌研究論文（学術雑誌）
- We evaluated the association of signal transducer and activator of transcription 3 (STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTOR inhibitors were genotyped for the STAT3 polymorphism, rs4796793 (-1697C/G). We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome. In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the GG genotype compared with those with other genotypes (77.8% versus 23.1%, odds ratio = 11.67, 95% confidential interval = 3.06-44.46). Meanwhile, there were no significant differences in progression-free survival or time-to-treatment failure between the patients with the GG genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the GG genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the GG genotype of the STAT3 -1697C/G polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.2022年01月, Oncology research, 29(1) (1), 11 - 23, 英語, 国際誌研究論文（学術雑誌）
- The gut microbiome influences tumor response to immune checkpoint inhibitors (ICIs). The proton pump inhibitors (PPI) significantly impair diversity of the gut microbiota and can affect the efficacy of ICIs. Therefore, the present study aimed to evaluate the influence of PPI on survival in patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. We conducted a retrospective cohort study of patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. The use of PPI was defined as any administration for ≥30 d within 60 d prior and/or 30 d after treatment initiation. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and Cox proportional hazards regression analysis was performed to investigate prognostic factors based on patient characteristics. Seventy-nine patients were included in the analysis, and 34 patients (43.0%) received PPI. There were no significant differences in OS and PFS between PPI users and nonusers (median OS: 8.2 months vs. 11.2 months, hazard ratio (HR): 1.36, 95% confidence interval (CI): 0.75-2.42, p = 0.296; median PFS: 3.5 months vs. 5.1 months, HR: 1.63, 95% CI: 0.95-2.80, p = 0.069). In the multivariable analysis, PPI use was not associated with OS (HR 0.80, 95% CI 0.40-1.56, p = 0.526) or PFS (HR 1.44, 95% CI 0.79-2.60, p = 0.233). In conclusion, the estimated effect size of PPI use on survival in Japanese patients with metastatic or unresectable urothelial carcinoma treated with pembrolizumab was not reproducible.2022年, Biological & pharmaceutical bulletin, 45(5) (5), 590 - 595, 英語, 国内誌研究論文（学術雑誌）
- Invasive Aspergillus infection is a major factor for poor prognosis in patients receiving lung transplantation (LT). An antifungal agent, itraconazole (ITCZ), that has antimicrobial activity against Aspergillus species, is used as a prophylactic agent against Aspergillus infection after LT. ITCZ and its metabolite, hydroxyitraconazole (OH-ITCZ), potently inhibit CYP3A and P-glycoprotein that metabolize or excrete calcineurin inhibitors (CNIs), which are the first-line immunosuppressants used after LT; thus, concomitant use of ITCZ and CNIs could induce an increase in the blood concentration of CNIs. However, no criteria for dose reduction of CNIs upon concomitant use with ITCZ in LT recipients have been defined. In this study, the effect of ITCZ and OH-ITCZ on the blood concentrations of two CNIs, tacrolimus and cyclosporine, after LT were retrospectively evaluated. A total of 39 patients who received LT were evaluated. Effects of ITCZ and OH-ITCZ on the concentration/dosage (C/D) ratio of tacrolimus and cyclosporine were analyzed using linear mixed-effects models. The plasma concentrations of OH-ITCZ were about 2.5-fold higher than those of ITCZ. Moreover, there was a significant correlation between the plasma concentrations of ITCZ and OH-ITCZ. Based on parameters obtained in the linear regression analysis, the C/D ratios of cyclosporine and tacrolimus increase by an average of 2.25- and 2.70-fold, respectively, when the total plasma concentration of ITCZ plus OH-ITCZ is 1000 ng/mL. In conclusion, the plasma levels of ITCZ and OH-ITCZ could be key factors in drawing up the criterion for dose reduction of CNIs.2022年, Biological & pharmaceutical bulletin, 45(4) (4), 397 - 402, 英語, 国内誌研究論文（学術雑誌）
- Endoplasmic reticulum (ER) stress has been reported as a cause of Parkinson’s disease (PD). We have previously reported that the ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and its stabilizing factor suppressor/enhancer lin-12-like (SEL1L) participate in the ER stress. In addition, we recently demonstrated that neuronal cell death is enhanced in the cellular PD model when SEL1L expression is suppressed compared with cell death when HRD1 expression is suppressed. This finding suggests that SEL1L is a critical key molecule in the strategy for PD therapy. Thus, investigation into whether microRNAs (miRNAs) regulate SEL1L expression in neurons should be interesting because relationships between miRNAs and the development of neurological diseases such as PD have been reported in recent years. In this study, using miRNA databases and previous reports, we searched for miRNAs that could regulate SEL1L expression and examined the effects of this regulation on cell death in PD models created by 6-hydroxydopamine (6-OHDA). Five miRNAs were identified as candidate miRNAs that could modulate SEL1L expression. Next, SH-SY5Y cells were exposed to 6-OHDA, following which miR-101 expression was found to be inversely correlated with SEL1L expression. Therefore, we selected miR-101 as a candidate miRNA for SEL1L modulation. We confirmed that miR-101 directly targets the SEL1L 3′ untranslated region, and an miR-101 mimic suppressed the 6-OHDA–induced increase in SEL1L expression and enhanced cell death. Furthermore, an miR-101 inhibitor suppressed this response. These results suggest that miR-101 regulates SEL1L expression and may serve as a new target for PD therapy.Frontiers Media SA, 2021年12月, Frontiers in Molecular Neuroscience, 14研究論文（学術雑誌）
- Since 2014, several global and national guidelines have been introduced to address the problem of antimicrobial resistance. We conducted a campaign in a tertiary hospital to promote appropriate quinolone use through educational lectures in 2018. The aim of this retrospective study was to evaluate the changes in the following: prescription characteristics, trend of oral quinolone use, and antibiotic susceptibility of bacteria from 2013 to 2020. Antimicrobial use was assessed as days of therapy per 1000 patient-days. We found a significant reduction in unnecessary antibiotic prescriptions between December 2013 and December 2020. Significant negative trends were detected in the use of quinolones over 8 years (outpatients, coefficient = -0.15655, p < 0.001; inpatients, coefficient = -0.004825, p = 0.0016). In particular, the monthly mean use of quinolones among outpatients significantly decreased by 11% from 2013 to 2014 (p < 0.05) and reduced further by 31% from 2017 to 2020 (p < 0.001). A significant positive trend was observed in the susceptibility of Pseudomonas aeruginosa to levofloxacin (p < 0.001). These results demonstrate that the use of oral quinolones was further reduced following educational intervention and the bacterial susceptibility improved with optimal quinolone usage compared to that in 2013.2021年11月, Antibiotics (Basel, Switzerland), 10(11) (11), 1426, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- WHAT IS KNOWN AND OBJECTIVE: Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule). METHODS: Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis. RESULTS: The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F. WHAT IS NEW AND CONCLUSION: Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib.2021年10月, Journal of clinical pharmacy and therapeutics, 47(1) (1), 81 - 88, 英語, 国際誌研究論文（学術雑誌）
- Cefazolin is an essential antibiotic used for treating bacteremia; in particular, it is recommended as a first-line agent for infections caused by methicillin-susceptible Staphylococcusaureus (MSSA). In March 2019, problems with a major antibiotic supplier caused a critical shortage of cefazolin in Japan; however, the impact of the cefazolin shortage on clinical outcomes remains unknown. This study aimed to evaluate the effect of the cefazolin shortage in patients with MSSA bacteremia. Data from 75 patients were compared between the pre-shortage (March 2018-January 2019, n = 39) and post-shortage (March 2019-January 2020, n = 36) periods. There were no significant differences in the demographic characteristics between the two groups, and the cefazolin shortage did not worsen clinical outcomes such as adverse drug reactions, treatment failure, and 30-day mortality. In the post-shortage group, ampicillin/sulbactam and benzylpenicillin were more frequently administered as alternative antibiotics for empirical and definitive therapy (10% vs. 31%, p = 0.042; 0% vs. 19%, p = 0.004, respectively). Multivariate analysis revealed that the broad-spectrum antibiotics for definitive therapy, such as antipseudomonal penicillin, were associated with treatment failure in patients with MSSA bacteremia (OR = 17, p = 0.003). Hence, narrow-spectrum antibiotics should be prescribed for MSSA bacteremia as alternatives during a cefazolin shortage.2021年10月, Antibiotics (Basel, Switzerland), 10(10) (10), 1247, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Anticancer Research USA Inc., 2021年09月, Anticancer Research, 41(9) (9), 4239 - 4248研究論文（学術雑誌）
- (一社)日本TDM学会, 2021年05月, TDM研究, 38(2) (2), 180 - 180, 日本語
- OBJECTIVE: It was reported that the administration of tramadol in patients with cancer pain who have a higher interleukin 6 (IL-6) serum level led to insufficient pain relief. Cytokines produced by tumors, including IL-6, are associated with cancer cachexia. However, whether nonresponse to tramadol is related to cancer cachexia is unknown. The purpose of this study was to examine the relationship between tramadol response and cancer cachexia in patients with cancer pain. METHODS: We conducted a retrospective cohort study of patients with cancer who received tramadol treatment for mild to moderate pain from January 2016 to June 2019. Patients who experienced <20% pain reduction based on the numeric rating scale from baseline to day 7 after treatment with tramadol were defined as nonresponders. Univariate and multivariate logistic regression analyses were conducted to examine the relationships between tramadol response and various patient characteristics, including cancer cachexia. RESULTS: Of 115 patients, 79 were included in the analysis. A total of 24 patients experienced cancer cachexia, and 22 patients were nonresponders. In the univariate logistic analysis, cancer cachexia (odds ratio [OR]: 6.04, 95% confidence interval [CI]: 2.06-17.7), higher white blood cell counts (× 103/μL; OR: 1.28, 95% CI: 1.04-1.61), and lower body mass index (OR: 0.79, 95% CI: 0.66-0.96) were significantly associated with nonresponse to tramadol. The multivariate logistic analysis revealed that cancer cachexia (OR: 5.27, 95% CI: 1.75-15.9) was the only significant factor associated with nonresponse to tramadol. CONCLUSIONS: Cancer cachexia in patients with cancer pain can be associated with nonresponse to tramadol.2021年03月, The American journal of hospice & palliative care, 38(3) (3), 276 - 282, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Hand-foot skin reaction (HFSR) is a common side effect caused by several tyrosine kinase inhibitors, including sunitinib. However, the nature of the cornifying factors related to the molecular biological mechanisms underlying HFSR remains poorly understood. We used human keratinocyte models to investigate the key cornifying factors for dermatological and biological abnormalities induced by sunitinib. On the basis of the results of microarray analysis using the three-dimensional (3D) human epidermal model, keratin (KRT)6A, serine protease inhibitor (SERPIN)B1, KRT5, and SERPIN Kazal-type 6 were selected as candidate genes related to HFSR. Sunitinib treatment significantly decreased the expression of SERPINB1 and KRT6A in the immunohistochemical staining of the 3D epidermal model. In PSVK1 cells, but not in normal human epidermal keratinocyte cells, both of which are human normal keratinocyte cell lines, sunitinib decreased the expression of KRT6A with a concomitant decrease in levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated p38 mitogen-activated protein kinase (MAPK). Inhibitors of the ERK and p38 MAPK signal pathways also significantly decreased KRT6A expression. Sunitinib-induced decrease in KRT6A expression was suppressed by the inhibition of glycogen synthase kinase-3β by enhancing ERK1/2 and p38 MAPK phosphorylation. Thus, sunitinib reduces the expression of KRT6A and SERPINB1 by inhibiting the ERK1/2 and p38 MAPK signalling pathways in the skin model. These changes in expression contribute to the pathology of HFSR.2021年03月, Experimental dermatology, 30(3) (3), 337 - 346, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- The incidence of bacteremia caused by Enterococcus faecium, which is highly resistant to multiple antibiotics, is increasing in Japan. However, risk factors for the acquisition of E. faecium infection and mortality due to enterococcal bacteremia are not well known. We compared demographic, microbiological, and clinical characteristics using a Cox regression model and univariate analysis. We performed a multivariate analysis to identify risk factors for patients treated between 2014 and 2018. Among 186 patients with enterococcal bacteremia, two groups included in the Kaplan-Meier analysis (E. faecalis (n = 88) and E. faecium (n = 94)) showed poor overall survival in the E. faecium group (HR: 1.92; 95% confidence interval: 1.01-3.66; p = 0.048). The median daily antibiotic cost per patient in the E. faecium group was significantly higher than that in the E. faecalis group ($23 ($13-$34) vs. $34 ($22-$58), p < 0.001). E. faecium strains were more frequently identified with previous use of antipseudomonal penicillins (OR = 4.04, p < 0.001) and carbapenems (OR = 3.33, p = 0.003). Bacteremia from an unknown source (OR = 2.79, p = 0.025) and acute kidney injury (OR = 4.51, p = 0.004) were associated with higher risks of 30-day mortality in patients with enterococcal bacteremia. Therefore, clinicians should provide improved medical management, with support from specialized teams such as those assisting antimicrobial stewardship programs.2021年01月, Antibiotics (Basel, Switzerland), 10(1) (1), 64, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (一社)日本医療薬学会, 2020年12月, 医療薬学, 46(12) (12), 681 - 691, 日本語経口抗がん薬治療における情報共有ツールおよびチーム基盤型学習を用いた病診薬連携の有用性の評価[査読有り]研究論文（学術雑誌）
- The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.2020年10月, Drug metabolism and pharmacokinetics, 35(5) (5), 405 - 409, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2020年05月, Pharmazie, 75(5) (5), 218 - 222Association between dexamethasone treatment and alterations in serum concentrations of trace metals.[査読有り]研究論文（学術雑誌）
- Antimicrobial stewardship teams (ASTs) have been well-accepted in recent years; however, their clinical outcomes have not been fully investigated in urological patients. The purpose of this study was to evaluate the outcomes of intervention via a retrospective review of urological patients, as discussed in the AST meetings, who were treated with broad-spectrum antibiotics between 2014 and 2018 at the Department of Urology, Kobe University Hospital in Japan. Interventions were discussed in AST meetings for patients identified by pharmacists as having received inappropriate antibiotic therapy. The annual changes in numbers of inappropriate medications and culture submissions over five years at the urology department were statistically analyzed. Among 1,033 patients audited by pharmacists, inappropriate antibiotic therapy was found in 118 cases (11.4%). The numbers of inappropriate antibiotic use cases and of interventions for indefinite infections had significantly decreased during the study period (p = 0.012 and p = 0.033, respectively). However, the number of blood and drainage culture submissions had significantly increased (p = 0.009 and p = 0.035, respectively). Our findings suggest that urologists have probably become more familiar with infectious disease management through AST intervention, leading to a decrease in inappropriate antibiotic use and an increase in culture submissions.2020年02月, Antibiotics (Basel, Switzerland), 9(2) (2), 63, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Background: Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chemoradiotherapy (CRT). This study examined the safety and efficacy of ibuprofen gargle in healthy volunteers and patients with chemotherapy- and concomitant CRT-induced oral mucositis. Methods: We enrolled healthy volunteers and patients with chemotherapy- and CRT-induced oral mucositis. In cohort I, single and multiple doses of ibuprofen gargle (0.6% or 1.0%) were administered to healthy volunteers on day 1 and days 4-10. In cohort II, multiple doses of ibuprofen gargle (0.6%) were administered to patients with complicated grade 2-3 oral mucositis based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoint of cohort I was the treatment-related adverse events (TRAEs) as defined by CTCAE version 4.0. The primary endpoint of cohort II was the change in the visual analogue scale (VAS) pain score from before to 15 min after gargle use on day 3. The incidence and severity of TRAEs were assessed based on the CTCAE version 4.0 and a subjective rating scale completed by healthy volunteers and patients. Results: In cohort I, 9 of 10 healthy volunteers were evaluable for safety. All 9 healthy volunteers reported the TRAE of oral irritation with single or multiple use of the gargle. In cohort II, 10 patients were enrolled and evaluable for safety and 7 of 10 patients were evaluable for efficacy. The mean change in the VAS pain score from before to 15 min after using the gargle on day 3 was - 1.28 (95% confidence interval: - 2.06, - 0.51), and all patients experienced some degree of pain relief (range: - 0.2 to - 2.5). All 10 patients reported the TRAE of oral irritation. No other TRAEs of ibuprofen gargle were observed in the healthy volunteers and patients. Conclusion: Despite oral irritation, the ibuprofen gargle appeared to be safe and effective for the pain related to chemo- or CRT-induced oral mucositis. However, ibuprofen-related oral irritation warrants further formulation improvement. Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000014433).2020年, Journal of pharmaceutical health care and sciences, 6, 12 - 12, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2012年は薬剤師の臨床業務にとって極めて大きな転機であった。すなわち、六年制薬学教育を受けた薬剤師の誕生と、薬剤師の病棟専任に対する診療報酬加算の実施の2つである。しかし、これら2つの転機が薬剤師の臨床業務の質に影響を及ぼしたかの評価はされていない。そこで、併用薬剤との相互作用が多いリファンピシンに焦点を絞り、病棟薬剤師がその処方に適切に介入できていたかを調査し、薬剤師の病棟業務の質を評価した。2012年(加算前)、2013年(加算直後)、2018年(加算5年後)において、該当薬剤の処方を病棟薬剤師が認識した割合は、調査年を追うごとに増加した。薬学的介入のなかで適切な提案ができている割合は、それぞれ75.0、87.5および86.6%であった。これらの結果から、病棟薬剤師業務加算の実施は、薬剤師の病棟業務の質的向上に寄与していると考えられる。一方で、薬学教育年数の延長が及ぼす効果を評価するために、卒後4年以内の病棟薬剤師の四年および六年制教育課程修了者について精査したところ、六年制修了者のほうが有意に処方介入度合いが高かった。このことから卒業直後は教育年数の延長効果が認められることが示唆された。しかし、今回の調査のみで、六年制薬学教育を修了した薬剤師の質を測ることは困難であり、今後様々な角度からの調査が必要である。(著者抄録)(一社)日本病院薬剤師会, 2020年, 日本病院薬剤師会雑誌, 56(6) (6), 643 - 650, 日本語[査読有り]研究論文（学術雑誌）
- PETINIA法による血中ミコフェノール酸測定試薬の基準測定法LC-MS/MS法との比較ミコフェノール酸モフェチル(mycophenolate mofetil;MMF)は臓器移植において主に用いられている免疫抑制薬で、ミコフェノール酸(mycophenolic acid;MPA)のプロドラッグである。MPAのAUC0-12が臨床効果や拒絶反応に相関することから、薬物血中濃度モニタリング(therapeutic drug monitoring;TDM)が推奨されている。血漿中MPA濃度測定には従来LC-MS/MS法やEMIT法などが用いられていたが、前者は操作が煩雑で多大な時間を要すること、後者は代謝産物との交差反応により偽高値を示す可能性があることが知られている。今回、PETINIA法による血漿中MPA測定試薬の基本性能および各種検体条件による影響について検討するとともに、高濃度領域も含めたLC-MS/MS法との相関性について評価した。PETINIA法によるMPA血中濃度測定は、感度や再現性、特異性において良好な性能を示した。血清分離剤による測定値への影響は認められず、保存安定性は試薬添付文書上の期間内で保たれていた。LC-MS/MS法との相関は良好であるが(y=1.18x-0.09、r=0.980、p<0.01)、15μg/mL以上の高濃度領域ではPETINIA法が高値を示すことが明らかとなった。以上より、PETINIA法による血漿中MPA濃度測定は低濃度領域では臨床的に有用性であるが、高濃度領域においては、解釈に注意が必要であることが示唆された。(著者抄録)(一社)日本臨床衛生検査技師会, 2020年01月, 医学検査, 69(1) (1), 36 - 43, 日本語[査読有り]
- PURPOSE: This study aimed to evaluate the efficacy of an educational intervention on reducing the inappropriate use of oral third-generation cephalosporins, the prevalence of resistant bacteria, and clinical outcomes. METHODS: A before-after study was conducted to compare the data for 1 year before and after intervention at a Japanese university hospital. Educational intervention included lectures for all medical staff on oral antibiotics and educational meetings with each medical department. The primary outcome was the use of oral third-generation cephalosporins in inpatients as measured by the monthly median days of therapy (DOTs) per 1000 patient days. Secondary outcomes included the use of each oral antibiotic in inpatients and outpatients, proportion of β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (BLNAR), penicillin-resistant Streptococcus pneumoniae (PRSP) and extended-spectrum β-lactamase producing Escherichia coli (ESBLEC), the incidence of hospital-acquired Clostridioides difficile infection (HA-CDI), and hospital mortality. RESULTS: The use of oral third-generation cephalosporins in inpatients was significantly decreased after intervention [DOTs (interquartile range): 24.2 (23.5-25.1) vs. 3.7 (0.0-7.1), P < 0.001], and the value in outpatients was also decreased significantly. The use of fluoroquinolones and macrolides did not increase after intervention. The proportion of BLNAR, PRSP and ESBLEC did not change significantly during the study period. The incidence of HA-CDI was significantly decreased, and hospital mortality did not change after intervention. CONCLUSION: Educational intervention was effective in reducing the use of oral third-generation cephalosporins without increasing the use of broad-spectrum antibiotics and worsening clinical outcome. The prevalence of resistant bacteria did not change during the study period.2019年12月, Infection, 47(6) (6), 1037 - 1045, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Sustained benzodiazepine use during pregnancy can induce neonatal abstinence syndrome (NAS). In this study, the association between NAS and plasma alprazolam concentration was examined using the measured neonatal concentrations in the time series as well as simulated plasma concentrations of pregnant woman and neonate by physiologically based pharmacokinetic (PBPK) modeling. A neonate born to a mother taking alprazolam daily throughout pregnancy exhibited symptoms such as apnea and vomiting from 9 h to 4 days after birth. Finnegan score was 7 at birth and decreased to 0 by day 4. Apnea improved by 24 h post-delivery and gastrointestinal symptoms disappeared by day 4. The plasma alprazolam concentration in the neonate was 15.2 ng/mL immediately after birth and gradually decreased over 3 days. Measured neonate and estimated maternal plasma alprazolam concentrations were within the 90% prediction intervals of each concentration by PBPK simulation using "pregnancy" and "pediatrics" population parameters including in Simcyp population-based ADME simulator. In conclusion, NAS symptoms such as apnea and digestive events disappeared in parallel with the decrease of the neonate's plasma alprazolam concentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data.2019年12月, Drug metabolism and pharmacokinetics, 34(6) (6), 400 - 402, 英語, 国際誌[査読有り]
- Background De-escalation therapy is recommended as an effective antibiotic treatment strategy for several infectious diseases. While there is limited evidence supporting its clinical and cost-effective outcomes in patients with community-acquired bacteremic pneumonia, there is no evidence in patients with nonbacteremic pneumonia. Objective This study aimed to evaluate the antibiotic costs in patients who did and did not receive de-escalation therapy, based on the 2017 Japanese guidelines for the management of community-acquired nonbacteremic pneumococcal pneumonia of the Japanese Respiratory Society (JRS). Setting Kobe university hospital, Japan. Methods A retrospective case series review including antibiotic use and length of hospital stay was conducted using the medical records from April 2008 to May 2019 at a university hospital in Japan. Main outcome measure Impact of antibiotic de-escalation therapy on the antibiotic costs. Results Among 55 patients who were eligible, the treating physicians de-escalated antibiotics in 28 (51%). The differences in the median length of hospital stay and the incidence of adverse drug reactions between the two groups were not statistically significant (p = 0.67 and 1.0, respectively). However, the median total antibiotic cost per infected patient in the de-escalated group was significantly lower than that in the non-de-escalated group [$269.8 ($195-$389) vs. $420.5 ($221-$799), p = 0.048]. Conclusion Antibiotic de-escalation based on the 2017 JRS guidelines leads to a reduction in total antibiotic costs for the management of community-acquired nonbacteremic pneumococcal pneumonia.2019年12月, International journal of clinical pharmacy, 41(6) (6), 1611 - 1617, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 疑義照会における検査値連動型の処方チェックシステムの有用性疑義照会における腎機能以外の電解質等の検査値も含めた処方チェックシステムの有用性について評価した。調査期間は2009年6〜11月の6ヵ月間(検査値印字未実施期間;I群)、2010年6〜11月の6ヵ月間(検査値印字実施期間;II群)、2016年9月〜2017年8月の12ヵ月間(チェックシステム導入期間;III群)とした。検査値を根拠とした疑義照会による処方変更件数は1ヵ月あたりI群が0件(0%)、II群が13.8件(6.6%)、III群が22.7件(8.9%)であり、II群と比べてIII群で有意に増加した。変更となった処方の内訳はII群では腎機能関連が最も多かったが、III群では電解質関連の占める割合が大きく増加した。薬剤別では、III群における腎機能関連の疑義照会のうち、レボフロキサシン、ファモチジン、レボセチリジン、セフカペン等が多かった。(一社)日本医療薬学会, 2019年12月, 医療薬学, 45(12) (12), 698 - 705, 日本語[査読有り]
- AIM: This study aimed to evaluate the efficacy of pharmacists' assessment and intervention using the Screening Tool for Older Persons' Appropriate Prescriptions for Japanese (STOPP-J) to detect and correct potentially inappropriate medications (PIM) compared with the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (STOPP) criteria version 2. METHODS: A prospective observational study was carried out at a medical unit of Cardiovascular Surgery and Cardiovascular Internal Medicine in a Japanese university hospital involving new inpatients aged ≥65 years prescribed one or more daily medication. Pharmacists detected PIM based on STOPP-J and STOPP criteria version 2, and corrected them with physicians. The number of patients with PIM, the content and changes in PIM were compared between both criteria. RESULTS: Overall, 230 patients were included (mean age 75.4 years, 162 men, mean number of medications 8.3). STOPP-J detected significantly more patients with PIM than STOPP criteria version 2 (122 [53%] vs 75 [33%], P < 0.001). The number of PIM based on STOPP-J was 232, the physicians were recommended to change 61 (26%) and 50 (22%) were changed. Meanwhile, the number of PIM based on STOPP criteria version 2 was 133, the physicians were recommended to change 61 (46%) and 54 (41%) were changed. Several medications detected as PIM using STOPP-J were not detected using STOPP criteria version 2. CONCLUSIONS: STOPP-J detected significantly more patients with PIM than STOPP criteria version 2, and pharmacists' assessment and intervention based on STOPP-J were suggested to be effective for detecting and correcting PIM. Geriatr Gerontol Int 2019; 19: 1101-1107.2019年11月, Geriatrics & gerontology international, 19(11) (11), 1101 - 1107, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: Hand-foot skin reaction (HFSR) is a serious side effect induced by multiple-tyrosine kinase inhibitors (TKIs). HFSR can cause treatment interruption or decreased dosing. HFSR also markedly decreases quality of life and is associated with the therapeutic efficacy of multiple-TKIs. Therefore, the management and prevention of HFSR is an important issue; however, an effective method for its prevention has not been established. Specific ascorbic acid derivatives can reverse multiple-TKI-induced keratinocyte growth and pathological changes in vitro. OBJECTIVE: This study was designed to evaluate the safety of bis-glyceryl ascorbate (Amitose DGA), a novel, hydrosoluble, and moisturizing ascorbic acid derivative, in patients with renal cell carcinoma (RCC) receiving sunitinib therapy. This study was also designed to evaluate Amitose DGA's preventive efficacy for sunitinib-induced HFSR. METHODS: This is a Phase I/II, single-center, uncontrolled, single-arm, open-label trial. We will recruit a total of 30 patients with RCC receiving sunitinib therapy, with a 2-week-on and 1-week-off schedule. The participants will apply Amitose DGA-containing cream over both palmar and plantar surfaces within two treatment cycles (ie, 6 weeks) of sunitinib in combination with a general moisturizing agent, in addition to standard-of-care processes. Safety assessments will include dermatological abnormalities, clinical laboratory tests, and incidence of adverse events. Efficacy assessments will include development of HFSR and therapeutic outcomes associated with sunitinib. RESULTS: Recruitment to the study began in August 2017 and is ongoing in Japan. To date, 21 subjects have been recruited. Study completion is expected in 2021. CONCLUSIONS: This is the first clinical study of Amitose DGA-containing cream in patients with RCC who are receiving sunitinib therapy. The single-center, single-arm, open-label design was selected to maximize subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable and preliminary evidence of the effects of Amitose DGA-containing cream on HFSR. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000027209; https://upload.umin.ac.jp/cgi-open-bin/ctr /ctr_view.cgi?recptno=R000031174. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14636.2019年08月, JMIR research protocols, 8(8) (8), e14636, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Antimicrobial Stewardship Team専従薬剤師による抗菌薬適正使用への介入効果薬剤師を抗菌薬適正使用支援チーム(AST)に専従配置し、抗菌薬適正使用に関する早期介入と病院職員を対象とした教育活動を行うことにより、注射用抗菌薬の使用状況や微生物検査の実施状況、医療経済的な面でさらなる効果が得られるかどうかを検証した。注射用抗菌薬全体の投与患者数は介入前が9868名、介入後が9921名となり、抗菌薬使用前に血液培養を採取した患者の割合は介入前が71.9%であったのに対して、介入後は82.1%と有意に上昇した。注射用抗菌薬全体の薬剤費用は介入前が114287580円、介入後が106050901円であり、介入後に8236679円減少した。監視対象抗菌薬の薬剤費用は介入前が86048445円、介入後が76960570円、非監視対象抗菌薬は介入前が28239135円、介入後が29090331円であった。院内CDIの発生率は介入前が1.41件/10000patient-days、介入後が0.75件/10000patient-daysであり有意に低下していた。(一社)日本医療薬学会, 2019年08月, 医療薬学, 45(8) (8), 460 - 469, 日本語[査読有り]
- オピオイド服用患者における酸化マグネシウムの緩下作用に対してプロトンポンプ阻害薬併用が与える影響胃酸分泌抑制剤の併用により酸化マグネシウム(magnesium oxide:以下、MgO)の効果が減弱することが報告されている。本研究では、オピオイド服用患者における便秘改善に要したMgO投与量に対するプロトンポンプ阻害薬(proton pump inhibitor:以下、PPI)併用の影響について調査した。対象は、神戸大学医学部附属病院緩和ケアチームが介入し、モルヒネまたはオキシコドンを定時内服している患者37名とした。便秘改善に要したMgO投与量は、PPI併用群、非併用群ともに平均約20mg/kg/dayであり、有意差は認められなかった。しかし、65歳未満の患者における便秘改善に要したMgO投与量は、PPI併用群で非併用群と比べて有意に多かった(27.4±10.2mg/kg/day vs 19.2±2.5mg/kg/day、p=0.03)。以上、65歳未満の非高齢患者においてはPPIの併用がMgOの効果減弱に寄与する可能性がある。(著者抄録)(一社)日本病院薬剤師会, 2019年08月, 日本病院薬剤師会雑誌, 55(8) (8), 964 - 968, 日本語[査読有り]
- In adult patients after living-donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically-based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living-donor liver transplantation. The clearance was about 1.35-fold higher in the recipients who had a liver with the CYP3A5*1 allele than in those with the CYP3A5*3/*3 genotype, whereas bioavailability was ~0.7-fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP3A5*3/*3. In conclusion, the constructed physiologically-based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent.2019年08月, CPT: pharmacometrics & systems pharmacology, 8(8) (8), 587 - 595, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 全自動錠剤ハーフカッターカセットの導入による調剤業務の効率性および経済性に関する検討投与量調整の手法として半錠調剤は依然として多い。この半錠調剤は薬剤師による手作業となることから、調剤過誤の増加や業務効率低下を招く要因となっている。安全で効率的な調剤業務を構築するべく、自動錠剤分包機内に自動ハーフカット機能を搭載した全自動錠剤ハーフカッターカセット(全自動ハーフカッター)を導入し調剤業務の効率性および経済性について検討したので報告する。全自動ハーフカッターの導入により、調査期間の11ヵ月間において、全自動ハーフカッター実装薬品の7,801処方(錠剤数38,980錠)にかかる作業時間を92時間削減した。手撒きおよび全自動ハーフカッターによる半錠の精度はほぼ同等であり、神戸大学医学部附属病院では5.8年継続使用することで人件費削減額が導入費用を上回ると試算された。全自動ハーフカッター導入により安全性のみならず作業の効率性並びに経済的効果が期待できる。(著者抄録)(一社)日本病院薬剤師会, 2019年06月, 日本病院薬剤師会雑誌, 55(6) (6), 643 - 648, 日本語[査読有り]
- PURPOSE: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. METHODS: Twenty B cell non-Hodgkin's lymphoma patients who were treated with rituximab for the first time or after more than one year's abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. RESULTS: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. CONCLUSION: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.2019年04月, Pharmaceutical research, 36(6) (6), 82 - 82, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: Warfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and pharmacodynamics. Sufficient understanding of factors affecting the response to warfarin is necessary to achieve improved outcomes for warfarin therapy. In this study, we evaluated effects of fasting on the anticoagulant properties of warfarin. METHODS: We conducted a retrospective observational study involving a total of 58 patients, who received cardiovascular surgeries and subsequent warfarin therapy. The effect of dietary intake on the anticoagulant properties with warfarin was assessed by measurement of the international normalized ratio of prothrombin time (PT-INR): the anticoagulant activities of warfarin were expressed as the warfarin sensitivity index (WSI). Additionally, fluctuations in WSI during the study period were obtained as differences between the maximum and minimum WSI. RESULTS: The maximum PT-INR and WSI values were significantly higher for patients who were fasting for different reasons during the postoperative period than those in the group without reduced dietary intake. The differences between maximum and minimum WSI in the fasting group significantly increased compared with those in the groups with moderate or no reduced dietary intake. Meanwhile, effects of other markers of clinical conditions including the baseline Child-Pugh score and Charlson Comorbidity Index on WSI were not significant. CONCLUSIONS: Our results indicate that postoperative fasting was significantly associated with the anticoagulation activity of warfarin. In patients fasting for different reasons during the postoperative period, closer control of PT-INR values and warfarin adjustments may be required to avoid adverse effects such as bleeding in warfarin treatment.2019年04月, European journal of clinical pharmacology, 75(4) (4), 561 - 568, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- The purpose of the study was to evaluate the ability of different beverages to mask the bitterness of zopiclone and eszopiclone in tablet formulations using the artificial taste sensor and human gustatory sensation testing. The beverages tested for bitterness-masking effects were: Mugicha, Sports beverage, Lactic acid drink, Orange juice and a diluted simple syrup (an 8.5% sucrose solution). The bitterness intensities estimated by the taste sensor of zopiclone or eszopiclone one-tablet solutions mixed with the various beverages, corresponded well with the observed bitterness intensities measured by gustatory sensation testing. The Sports beverage, Lactic acid drink and Orange juice significantly suppressed the bitterness intensity of both zopiclone and eszopiclone 1-tablet solutions compared with water when tested in the artificial taste sensor. Sports beverage, Lactic acid drink and Orange juice all contain citric acid as acidifier, so it was postulated that citric acid was involved in the mechanism of bitterness intensity suppression of zopiclone and eszopiclone 1-tablet solutions by these three beverages. It was then shown that citric acid suppressed the bitterness intensity of a zopiclone one-tablet sample solution in a dose-dependent manner. 1H-NMR spectroscopic analysis of mixtures of citric acid with zopiclone suggested that the carboxyl groups of citric acid interact with the amine group on zopiclone. This study therefore showed that the bitterness intensities of zopiclone and eszopiclone can be suppressed by citric-acid-contained beverages and suggests that this bitterness suppression is due to a direct electrostatic interaction between citric acid and the two drugs.2019年, Chemical & pharmaceutical bulletin, 67(5) (5), 404 - 409, 英語, 国内誌[査読有り]
- 2018年12月, Ther Drug Monit, 40(6) (6), 675 - 681, 英語Pharmacokinetics and Pharmacodynamics of Once-Daily Tacrolimus Compared With Twice-Daily Tacrolimus in the Early Stage After Living Donor Liver Transplantation[査読有り]研究論文（学術雑誌）
- 2018年11月, Biochem Biophys Res Commun, 506(3) (3), 516 - 521, 英語Ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) prevents cell death in a cellular model of Parkinson's disease[査読有り]研究論文（学術雑誌）
- Background: Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy. Methods: Schizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan® assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs). Results: A total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0-6.0) vs. 4.0 (2.0-7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5-6.5) vs. 0.0 (0.0-3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05). Conclusion: Special attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.2018年11月, J Pharm Health Care Sci, 4, 28 - 28, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- We have previously reported that oxicam-derived non-steroidal anti-inflammatory drugs (oxicam-NSAIDs), including meloxicam, piroxicam and tenoxicam, elicit protective effects against 1-methyl-4-phenyl pyridinium (MPP+)-induced cell death in a fashion independent of cyclooxygenase (COX) inhibition. We have also demonstrated that oxicam-NSAIDs suppress the decrease in phosphorylation of Akt caused by MPP+. The molecular mechanism through which oxicam-NSAIDs provide cytoprotection remains unclear. In this study, we speculated a possibility that endoplasmic reticulum (ER) stress and/or mitochondrial dysfunction, which are both causative factors of Parkinson's disease (PD), may be involved in the neuroprotective mechanism of oxicam-NSAIDs. We demonstrated here that oxicam-NSAIDs suppressed the activation of caspase-3 and cell death caused by MPP+ or ER stress-inducer, tunicamycin, in SH-SY5Y cells. Furthermore, oxicam-NSAIDs suppressed the increases in the ER stress marker CHOP (apoptosis mediator) caused by MPP+ or tunicamycin, beside suppressing eukaryotic initiation factor 2α (eIF2α) phosphorylation and the increase in ATF4 caused by MPP+. Taken together, these results suggest that oxicam-NSAIDs suppress the eIF2α-ATF4-CHOP pathway, one of the three signaling pathways in the ER stress response. Oxicam-NSAIDs suppressed the decrease in mitochondrial membrane potential depolarization caused by MPP+, indicating they also rescue cells from mitochondrial dysfunction. Akt phosphorylation levels were suppressed after the incubation with MPP+, whereas phosphorylation of eIF2α was enhanced. These results suggest that oxicam-NSAIDs prevented eIF2α phosphorylation and mitochondrial dysfunction by maintaining Akt phosphorylation (reduced by MPP+), thereby preventing cell death.2018年09月, Biochem Biophys Res Commun, 503(4) (4), 2963 - 2969, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Background: The expression level of signal transducer and activator of transcription 3 (STAT3) in tumor cells is reported to associate with response to therapy and with survival time in various types of cancer. Objective: This retrospective study aimed to elucidate the association of STAT3 expression in tumor cells with the therapeutic outcomes of sunitinib in patients with renal cell carcinoma (RCC). Patients and Methods: Patients with metastatic RCC who received sunitinib therapy were enrolled in this study. All patients underwent nephrectomy for RCC, and nephrectomy specimens were stained for STAT3 and phosphorylated STAT3 (p-STAT3) by immunohistochemistry. Results: We assessed 51 patients receiving sunitinib as a first-line therapy. STAT3 expression levels did not influence progression-free survival (PFS) and overall survival (OS) however, patients with p-STAT3-positive tumors exhibited significantly worse PFS compared with those with p-STAT3-negative tumors (log-rank test, P = 0.034). OS tended to be prolonged in patients with p-STAT3-negative tumors. Objective response rate or disease control rate based on the best overall response did not show a significant association with STAT3 or p-STAT3 expression. Univariate Cox proportional hazard regression analyses for clinical predictors revealed that p-STAT3 positivity significantly correlated with shorter PFS (hazard ratio [HR], 2.22, P = 0.041), whereas p-STAT3 expression was not related to the OS. Conclusions: Activated STAT3 in tumor tissues shows a significant association with poor prognosis in patients with RCC who received sunitinib as a first-line therapy, and positive p-STAT3 expression could be a potential biomarker for refractoriness to sunitinib therapy. [Figure not available: see fulltext.].Springer-Verlag France, 2018年06月, Targeted Oncology, 13(3) (3), 371 - 378, 英語[査読有り]研究論文（学術雑誌）
- 薬剤師歴が1〜8年目の薬剤師29名を対象とした。参加者を2群に分け、チーム基盤型学習(TBL)群と講義群に割り当てた。ジャーナルクラブの実施前に行ったプレテストのスコアと薬剤師歴、ジャーナルクラブに参加する前のモチベーションは、講義群とTBL群で有意差は認めなかった。ジャーナルクラブ参加前の予習時間は、TBL群において有意に短かった。主要評価項目であるプレテストとジャーナルクラブ直後のポストテストのスコア差は、講義群とTBL群で有意差は認めなかったが、プレテストのスコアで調整したプレテストとジャーナルクラブ直後のポストテストのスコア差は、TBL群で有意に高かった。ジャーナルクラブ直後のポストテストのスコアはTBL群で有意に高かった。ジャーナルクラブ1ヵ月後のポストテストのスコアは講義群とTBL群で有意差は認めないものの、TBL群においてスコアは高い傾向にあった。アンケートの結果、ジャーナルクラブに対する満足度は講義群とTBL群で有意差は認めなかった。TBLについてジャーナルクラブの満足度に対する顧客満足度分析を行い、重要維持項目は、「司会者の熱意」および「論文内容の解説」であった。(一社)日本医療薬学会, 2018年05月, 医療薬学, 44(5号) (5号), 236 - 243, 日本語[査読有り]研究論文（学術雑誌）
- 2018年04月, 医療薬学, 44(4号) (4号), 157 - 164, 日本語院外処方せんにおける疑義照会簡素化プロトコールの運用とアンケートによる評価[査読有り]研究論文（学術雑誌）
- OBJECTIVE: To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes. DESIGN: Before-after study. SETTING: National university hospital with 934 beds. INTERVENTION: Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration. METHODS: The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia. RESULTS: The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibility to levofloxacin was significantly increased from 2009 to 2016 (P = 0.01 for trend). Its susceptibility to other antibiotics remained over 84% and did not change significantly during the study period. The proportion of patients isolated MRSA and the incidence of MRSA decreased significantly from 2009 to 2016 (P < 0.001 and = 0.02 for trend, respectively). There were no significant changes in the 30-day mortality attributable to bacteremia during the study period (P = 0.57 for trend). CONCLUSION: The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome.2018年04月, Infection, 46(2) (2), 215 - 224, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting and disabling side effect of taxane anticancer agents. We prospectively evaluated the efficacy of cryotherapy for CIPN prevention. Breast cancer patients treated weekly with paclitaxel (80 mg/m(2) for one hour) wore frozen gloves and socks on the dominant side for 90 minutes, including the entire duration of drug infusion. Symptoms on the treated sides were compared with those on the untreated (nondominant) sides. The primary end point was CIPN incidence assessed by changes in tactile sensitivity from pretreatment baseline in a monofilament test at a cumulative dose of 960 mg/m(2). We also assessed thermosensory deficits, subjective symptoms (Patient Neuropathy Questionnaire [PNQ]), manipulative dexterity, and the time to events and hazard ratio by PNQ. All statistical tests were two-sided. Among the 40 patients, four did not reach the cumulative dose (due to the occurrence of pneumonia, severe fatigue, severe liver dysfunction, and macular edema), leaving 36 patients for analysis. None dropped out due to cold intolerance. The incidence of objective and subjective CIPN signs was clinically and statistically significantly lower on the intervention side than on the control (hand: tactile sensitivity = 27.8% vs 80.6%, odds ratio [OR] = 20.00, 95% confidence interval [CI] = 3.20 to 828.96, P < .001; foot: tacile sensitivity = 25.0% vs 63.9%, OR = infinite, 95% CI = 3.32 to infinite, P < .001; hand: warm sense = 8.8% vs 32.4%, OR = 9.00, 95% CI = 1.25 to 394.48, P = .02; foot: warm sense: 33.4% vs 57.6%, OR = 5.00, 95% CI = 1.07 to 46.93, P = .04; hand: PNQ = 2.8% vs 41.7%, OR = infinite, 95% CI = 3.32 to infinite, P < .001; foot: PNQ = 2.8% vs 36.1%, OR = infinite, 95% CI = 2.78 to infinite, P < .001; hand: hazard ratio [HR] = 0.13, 95% CI = 0.05 to 0.34; foot: HR = 0.13, 95% CI = 0.04 to 0.38, dexterity mean delay = -2.5 seconds, SD = 12.0 seconds, vs + 8.6 seconds, SD = 25.8 seconds, P = .005). Cryotherapy is useful for preventing both the objective and subjective symptoms of CIPN and resultant dysfunction.OXFORD UNIV PRESS INC, 2018年02月, JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 110(2) (2), 141 - 148, 英語[査読有り]研究論文（学術雑誌）
- Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is used to suppress GvHD in patients undergoing hematopoietic stem cell transplantation (HCT). The purpose of this study was to construct a population pharmacokinetic and pharmacodynamic model in HCT patients for individualized MPA therapy. Blood samples were obtained from 49 HCT patients after starting MMF therapy. Population pharmacokinetic and pharmacodynamic parameters were obtained using the program NONMEM. MPA was described via a one-compartment model with a first-order elimination, and 30.9% of MPA glucuronide (MPAG) was found in the enterohepatic circulation. Inosine-5Œ-monophosphate dehydrogenase (IMPDH) activity was modeled as a maximal inhibitory model with a half-maximal inhibitory concentration (IC50) of 3.59 μg/mL against MPA concentrations. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters revealed that decreased creatinine clearance increases the MPAG concentration followed by an increased MPA concentration therefore, IMPDH activity decreases. Diarrhea decreases the enterohepatic circulation of MPAG and consequently reduces MPA concentration. The IC50 for MPA exhibited a positive association with C-reactive protein. Dosage adjustment based on plasma MPA concentration is required especially for patients with renal dysfunction and/or diarrhea.Nature Publishing Group, 2018年, Bone Marrow Transplantation, 53(1) (1), 44 - 51, 英語[査読有り]研究論文（学術雑誌）
- Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration–time curves from 0 to 24 hours (AUC0-24) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage ≥I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC0-24 at 1 week after the start of MMF treatments compared with those with slower neutrophil engraftment. Inosine-5′-monophosphate dehydrogenase activity in peripheral blood mononuclear cells and single nucleotide polymorphisms in genes that were previously associated with MPA pharmacokinetics and pharmacodynamics were not an independent predictor for the clinical outcomes. Receiver-operating characteristic model analyses showed that cutoff values of AUC0-24 for successful GI aGVHD prevention were.689 and 15.6 µg⋅hour⋅mL−1 for free MPA and AcMPAG, respectively. In addition, the cut-off value of free MPA AUC0-24 for neutrophil engraftment by day 25 was.405 µg⋅hour⋅mL−1. In conclusion, free MPA AUC0-24 may be a better predictor of the prevention of GI aGVHD and neutrophil engraftment compared with that of total MPA in patients receiving CBT. Hence, monitoring of the free MPA AUC0-24 between.405 and.689 µg⋅hour⋅mL−1 could be considered informative of individualized MPA treatments in CBT patients.Elsevier Inc., 2018年, Biology of Blood and Marrow Transplantation, 24(7) (7), 1441 - 1448, 英語[査読有り]研究論文（学術雑誌）
- 2017年12月, くすりと糖尿病, 6(2号) (2号), 207 - 211, 日本語インスリンカートリッジの破損により著明な血糖上昇を来した1型糖尿病の1例[査読有り]研究論文（学術雑誌）
- What is known and objectiveAnticoagulation therapy with warfarin requires periodic monitoring of prothrombin time-international normalized ratio (PT-INR) and adequate dose adjustments based on the data to minimize the risk of bleeding and thromboembolic events. In our hospital, we have developed protocol-based pharmaceutical care, which we called protocol-based pharmacotherapy management (PBPM), for warfarin therapy. The protocol requires pharmacists to manage timing of blood sampling for measuring PT-INR and warfarin dosage determination based on an algorithm. This study evaluated the efficacy of PBPM in warfarin therapy by comparing to conventional pharmaceutical care. METHODSFrom October 2013 to June 2015, a total of 134 hospitalized patients who underwent cardiovascular surgeries received post-operative warfarin therapy. The early series of patients received warfarin therapy as the conventional care (control group, n=77), whereas the latter received warfarin therapy based on the PBPM (PBPM group, n=68). These patients formed the cohort of the present study and were retrospectively analysed. RESULTSThe indications for warfarin included aortic valve replacement (n=56), mitral valve replacement (n=4), mitral valve plasty (n=22) and atrial fibrillation (n=29). There were no differences in patients' characteristics between both groups. The percentage time in therapeutic range in the first 10days was significantly higher in the PBPM group (47.1%) than that in the control group (34.4%, P<.005). The average time to reach the steady state was significantly (P<.005) shorter in the PBPM group compared to the control group (7.3 vs 8.6days). What is new and conclusionWarfarin therapy based on our novel PBPM was clinically safe and resulted in significantly better anticoagulation control compared to conventional care.WILEY, 2017年10月, JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS, 42(5) (5), 591 - 597, 英語[査読有り]研究論文（学術雑誌）
- Hand foot skin reaction is recognized as one of the most common adverse events related to multiple tyrosine kinase inhibitors, but an effective prevention method has not been identified. The chief aim of this study was to find a mechanism-based preventive method for the skin toxicity induced by sorafenib using vitamin C derivatives. The effects of ascorbyl-2-phosphate magnesium (P-VC-Mg) on the molecular and pathological changes induced by sorafenib were investigated in human keratinocyte HaCaT cells. The cell growth inhibition and apoptotic effects of sorafenib were attenuated by P-VC-Mg. Moreover, P-VC-Mg inhibited the decrease of signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of apoptosis suppressors treated by sorafenib. HaCaT cells transfected with the STAT3 dominant-negative form (STAT3DN) and STAT3 small interfering RNA (siRNA) combined with P-VC-Mg did not exhibit the attenuation of cell growth inhibition. Interestingly, after exposure to sorafenib in a three dimensional (3D) skin model assay, the basal layer was significantly thickened and the granular and spinous layers became thinner. In contrast, after exposure to sorafenib with P-VC-Mg, the thickness of the basal, granular, and spinous layers was similar to that of the control image. These findings suggest that P-VC-Mg attenuates sorafenibinduced apoptosis and pathological changes in human keratinocyte cells and in the 3D skin model mediated by the maintenance of STAT3 activity.PHARMACEUTICAL SOC JAPAN, 2017年09月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 40(9) (9), 1530 - 1536, 英語[査読有り]研究論文（学術雑誌）
- Albumin-bound paclitaxel (Abraxane®, nab-paclitaxel) is not recommended to be administered concurrently or sequentially with other drugs due to concern for instability. The need to administer drugs separately increases infusion time. We evaluated the comp神戸大学医学部, 2017年07月, Kobe J Med Sci, 63(1) (1), E9 - E16, 英語[査読有り]研究論文（学術雑誌）
- 日本医薬品情報学会, 2017年05月, 医薬品情報学, 19(1号) (1号), 1 - 7, 日本語[査読有り]研究論文（学術雑誌）
- Signal transducer and activator of transcription (STAT) 3 is a key factor in homeostasis of the oral mucosa by regulating the production of inflammatory cytokines. Sunitinib is a substrate of P-glycoprotein (multidrug resistance (MDR)-1/ABCB1) and breast-cancer resistance protein (BCRP/ABCG2). In this retrospective study, we evaluated the association between sunitinib-induced stomatitis and STAT3, ABCB1, and ABCG2 polymorphisms in patients with metastatic renal cell carcinoma (mRCC). Fifty-two Japanese patients with RCC treated with sunitinib were retrospectively genotyped to elucidate a potential association between STAT3, ABCB1, and ABCG2 polymorphisms and stomatitis development. Stomatitis occurred in 22 out of 52 patients. The TT+TC genotypes at STAT3 rs744166 had an odds ratio of 5.00 against CC genotype for the stomatitis development (95% confident interval, 0.97-25.8). In the Kaplan-Meier method for the cumulative incidence of stomatitis, a statistically significant difference was observed between the TT+TC and CC genotypes in STAT3 rs744166 (p=0.037). Both multiple logistic regression analysis and Cox proportional-hazards regression analysis show STAT3 rs744166 TT+TC genotypes and serum creatinine in each patient were significant independent factors for stomatitis development. In conclusion, STAT3 polymorphism may be a novel risk factor for sunitinib-induced stomatitis in patients with mRCC.PHARMACEUTICAL SOC JAPAN, 2017年04月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 40(4) (4), 458 - 464, 英語[査読有り]研究論文（学術雑誌）
- Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase inhibitors (mTKIs). HFSR can necessitate dose reductions or interruption of therapy owing to its negative effect on the quality of life. Therefore, effective use of mTKIs requires measures to prevent HFSR. We evaluated the effect of prostaglandin El (PGE(1)) on HFSR, because PGE(1) is already used to treat bed sores and skin ulcers and has established angiogenic and antiproliferative effects in keratinocytes. We found that the patho-genesis of sorafenib-induced HFSR is characterized by a decrease in levels of a phosphorylated signal transducer and activator of transcription 3 (STAT3). We investigated the effect of PGE(1) on the sorafenib-mediated reduction in phosphorylated STAT3 levels in HaCaT human epidermal keratinocytes. In cells treated with sorafenib, phosphorylated STAT3 levels decreased in a concentration-dependent manner, and this effect was blocked in cells treated with sorafenib and PGE(1). Furthermore, the expression of phosphorylated STAT3, the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) and survivin decreased in cells pretreated with an inhibitor of CAMP response element binding protein (CREB). Cell viability increased in cells treated with sorafenib and PGE(1) compared with that in cells treated with sorafenib alone, and these effects were not observed in STAT3 knockdown HaCaT cells. Collectively, these findings indicate that PGE1 blocks the inhibitory effects of sorafenib on cell growth by maintaining the activity of STAT3 and enhancing the CREB activity. Therefore, PGE(1) might represent an effective treatment for the prevention of sorafenib-induced HFSR. (C) 2017 Elsevier Inc. All rights reserved.ACADEMIC PRESS INC ELSEVIER SCIENCE, 2017年04月, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 485(2) (2), 227 - 233, 英語[査読有り]研究論文（学術雑誌）
- What is known and objectivesThe Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (stopp) criteria were updated in 2014 (stopp criteria ver.2), but few studies have evaluated the usefulness of stopp criteria in elderly patients. This prospective observational study evaluated the prevalence of potentially inappropriate medications (PIMs), and the efficacy of hospital pharmacists' assessment and intervention based on stopp criteria ver.2. MethodsThe study was conducted at three medical units of Kobe University Hospital between April 2015 and March 2016. Pharmacists assessed and detected PIMs based on stopp criteria ver.2 and considered the patient's intention to change the prescription at the time of admission of each patient. If the pharmacists judged that benefits outweighed risks of prescription change and the patients consented to change the medications, they recommended the doctor to change the prescription. If there was a risk of exacerbation of disease by the change of medications and the pharmacists judged it to be difficult to adjust medications during hospitalization or the patients did not consent to change the medications, they did not recommend to change it. The pharmacists and the doctors discussed and finally decided whether to change the PIMs or not. The number of patients prescribed PIMs, the number and contents of PIMs, and the number of medications changed after pharmacists' intervention were calculated. ResultsTotally, 822 new inpatients aged >= 65 years prescribed >= 1 daily medicine were included. Their median (interquartile range) age was 75.0 (71.0-80.0) years, and 54.9% were male. According to the criteria, 346 patients (42.1%) were prescribed >= 1 PIMs. Patients prescribed PIMs took significantly more medications than others: 10.0 (7.0-13.0) vs. 60 (4.0-9.0), P < 0001. The total number of PIMs was 651%, 47.6% of which (n = 310) were recommended the doctors to change, and 292 of 651 PIMs (44.9%) were finally discontinued/changed after pharmacists' assessment and intervention. PIMs related to benzodiazepines, including Z-drugs, were most frequent, with a detailed classifications as follows (changed/total): (i) benzodiazepines for 4 or more weeks (75/205), (ii) drugs that predictably increase the risk of falls in older people (benzodiazepines) (30/67) and (iii) drugs that predictably increase the risk of falls in older people (hypnotic Z-drugs) (15/31). ConclusionOver 40% elderly patients were prescribed PIMs, and pharmacists' assessments and interventions based on stopp criteria ver.2 were useful in detecting and correcting prescription of PIMs.WILEY, 2017年04月, JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS, 42(2) (2), 209 - 214, 英語[査読有り]研究論文（学術雑誌）
- Population Pharmacokinetics of Topiramate in Japanese Pediatric and Adult Patients With Epilepsy Using Routinely Monitored DataBackground: Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. Methods: Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. Results: A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L.h(-1).70 kg(-1) without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L.h(-1).70 kg(-1). Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults. Conclusions: The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.LIPPINCOTT WILLIAMS & WILKINS, 2017年04月, THERAPEUTIC DRUG MONITORING, 39(2) (2), 124 - 131, 英語[査読有り]研究論文（学術雑誌）
- 日本ファーマシューティカルコミュニケーション学会, 2017年04月, 日本ファーマシューティカルコミュニケーション学会会誌, 15(1号) (1号), 6 - 12, 日本語DVDを用いた副作用研修会の取り組みと評価[査読有り]研究論文（学術雑誌）
- 「薬剤師外来」における薬学的処方介入とその評価「薬剤師外来」は、総合内科外来担当医1名と心臓血管外科外来担当医1名を対象に行い、薬剤師歴12年の薬剤師1名が専任で担当した。総合内科外来または心臓血管外科外来の「薬剤師外来」を受診した全ての患者を対象とした。「薬剤師外来」を受診した群(介入群)と比較するため、「薬剤師外来」を担当している医師と経験歴や専門領域が同様の総合内科医および心臓血管外科医各1名の外来を同一期間に受診した患者を非介入群とした。介入群は延べ517名であり、うち総合内科が338名、心臓血管外科が179名であった。介入群全体での中止および減量に関する処方変更件数および変更率は93件(18.0%)で、うち中止が64件(12.4%)、減量が29件(5.6%)であった。非介入群では、中止および減量が76件(10.1%)、うち中止が57件(7.6%)、減量が19件(2.5%)で、処方変更率はいずれも介入群が非介入群と比較して有意に高かった。介入群で中止・減量した薬剤に起因すると思われる症状の再発・再燃を5件認め、消化性潰瘍治療薬で3件、抗アレルギー薬で2件であった。非介入群では中止・減量に伴う有害事象の発現が6件あった。(一社)日本医療薬学会, 2017年03月, 医療薬学, 43(3) (3), 169 - 175, 日本語[査読有り]
- Therapeutic monoclonal antibodies (mAbs) have heterogeneities in their structures. Multiple studies have reported that the variety of post-translational modifications could affect the pharmacokinetic profiles or pharmacological potencies of therapeutic mAbs. Taking into the account that the structural modification of mAbs would affect the efficacy, it is worth investigating the structural alteration of therapeutic mAbs in the blood and the relationship between their structures and pharmacological effects. Herein, we have developed the method to isolate rituximab from plasma in which endogenous IgGs interfere the detection of rituximab, and successfully developed the analytical method with a liquid chromatograph time-of-flight mass spectrometer to detect the structure of rituximab in plasma with errors less than 30 parts per millions. Eight types of carbohydrate chains in rituximab were detected by this method. Interestingly, time-dependent changes in carbohydrate chains such as AAF (G2F) and GnGn (G0) were observed in rats, although the amino acids were stable. Additionally, these structural changes were observed via incubation in plasma as in the rat experiment, suggesting that a certain type of enzyme in plasma caused the alterations of the carbohydrate chains. The present analytical methods could clarify the actual pharmacokinetics of therapeutic mAbs, and help to evaluate the interindividual variations in pharmacokinetics and efficacy.PUBLIC LIBRARY SCIENCE, 2017年01月, PLOS ONE, 12(1) (1), e0169588, 英語[査読有り]研究論文（学術雑誌）
- Background: Everolimus has been used for the treatment of unresectable or metastatic renal cell carcinoma (RCC). Here, we measured blood concentrations of everolimus to obtain the population pharmacokinetic parameters and to examine the relationship between blood concentration and clinical outcomes. Methods: Twenty-two Japanese patients were enrolled. Blood samples were collected before and 2, 4, 8, and 24 hours after drug administration on days 1 and 8 of everolimus therapy (5 or 10 mg) from inpatients; occasional samples were collected from outpatients. Blood concentrations of everolimus were measured by high-performance liquid chromatography with tandem mass spectrometry. Population pharmacokinetic analysis was conducted using the NONMEM software. Results: Everolimus pharmacokinetics was best described by a 2-compartment model with population mean estimates of apparent oral clearance of 10.0 L/h and an interindividual variability of 42.4%. There was no relationship between overall best responses and the predicted trough concentrations at day 8. The predicted trough concentration in patients who terminated everolimus treatment owing to adverse drug reactions (ADRs) was significantly higher than in patients who stopped the treatment owing to disease progression or other reasons (27.6 +/- 3.1 versus 15.7 +/- 2.3 ng/mL; mean +/- SEM). Patients who terminated the treatment owing to ADRs had significantly shorter time-to-treatment failure than other patients (112 versus 187 days, median). Conclusions: This study reports the first population pharmacokinetic parameters of everolimus in patients with RCC. Individual dose adjustment based on everolimus blood concentrations helps to avoid early drug cessation due to ADRs.LIPPINCOTT WILLIAMS & WILKINS, 2016年12月, THERAPEUTIC DRUG MONITORING, 38(6) (6), 663 - 669, 英語[査読有り]研究論文（学術雑誌）
- 2016年09月, 日本病院薬剤師会雑誌, 52(9号) (9号), 1140 - 1143, 日本語テモゾロミド点滴静注用製剤の輸液希釈時における安定性の検討[査読有り]研究論文（学術雑誌）
- 一般社団法人日本医療薬学会, 2016年09月, 医療薬学, 42(9号) (9号), 613 - 619, 日本語
Many biosimilars have been launched recently, however, a precise analytical method to evaluate their characteristics has not been developed. In this study, we established a new qualitative analysis technology for biomedicines using liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (LC/QTOF-MS), and assessed the original product and 4 biosimilars of filgrastim. Three peaks (Peak 1-3) appeared in total ion chromatogram by LC/QTOF-MS in the original brand-named drug. Filgrastim appeared as the main peak (Peak 1), and its molecular weight was calculated to be 18798.96 ± 0.02. When the original product was reduced by dithiothreitol, the molecular weight was 18802.19 ± 0.47, which was identical to the theoretical value based on amino acid sequence. These results indicate that it is possible to measure and distinguish molecular weights of untreated and reduced forms of filgrastim by LC/QTOF-MS. In addition, main peaks from all products including biosimilars showed exactly the same mass spectra and calculated molecular weights, suggesting that the main components (filgrastim) in these 4 products were considered to be qualitatively equal. On the other hand, the area ratios of 2 secondary peaks (Peaks 2 and 3) against the main peak (Peak 1) in 2 biosimilars were higher than those in the original product. The calculated molecular weights in Peaks 2 and 3 corresponded to that of polysorbate 80, which was one of the additives in the formulation. In conclusion, LC/QTOF-MS is a useful technique for qualitative component analysis of biomedicines.
[査読有り]研究論文（学術雑誌） - 2016年08月, J Pharm Health Care Sci, 2, 17, 英語Effect of vitamin K2 on the anticoagulant activity of warfarin during the perioperative period of catheter ablation: Population analysis of retrospective clinical data[査読有り]研究論文（学術雑誌）
- Docetaxel is frequently used in the treatment of a wide variety of solid tumors, including breast cancer. The aim of this study is to obtain the population pharmacokinetic parameters of docetaxel in Japanese female patients with breast cancer. Blood samples from 24 patients were collected sequentially before and after docetaxel infusion. Genomic DNA was isolated from the peripheral blood and genotyped for the selected polymorphisms in the candidate genes of drug transporters and metabolizing enzymes. The influence of patient characteristics on the pharmacokinetics of docetaxel was evaluated using the nonlinear-mixed-effect modeling program, NONMEM. As a basis for comparison, the pharmacokinetics of another taxane paclitaxel in 41 separate female patients with breast cancer was calculated. A two-compartment model adequately described the pharmacokinetic profiles of docetaxel. The population mean estimates of the total body clearance for patients aged 58 years or less and the central volume of distribution for docetaxel were 32.6 L/h and 5.77 L, respectively. In patients over 58 years, the clearance was 24 % higher than that in the younger patients. No influences of the genotypes examined were noted on the clearance of docetaxel. The clearance of paclitaxel was not affected by patient age. Patients over the age of 58 years showed significantly higher clearance of docetaxel than that in patients aged 58 years or less. Since the clearance of paclitaxel was not affected by the age, it is possible that the pharmacokinetic mechanisms of docetaxel might be specifically affected by age in females.SPRINGER HEIDELBERG, 2016年06月, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 72(6) (6), 703 - 710, 英語[査読有り]研究論文（学術雑誌）
- Background:Levetiracetam, a second-generation antiepileptic drug, is frequently used for managing partial-onset seizures. About 70% of the administered dose is excreted in urine unchanged, and dosage adjustment is recommended based on the individual's renal function. In this study, a population pharmacokinetic model of levetiracetam was developed using routinely monitored serum concentration data for individualized levetiracetam therapy.Methods:Patients whose serum concentrations of levetiracetam at steady-state were routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were enrolled. The influence of patient characteristics on levetiracetam pharmacokinetics was evaluated using the nonlinear mixed-effects modeling (NONMEM) program.Results:A total of 583 steady-state concentrations from 225 patients were used for the analysis. The median patient age and estimated glomerular filtration rate (eGFR) were 38 (range: 1-89) years and 98 (15-189) mLmin(-1)1.73 m(-2), respectively. Serum concentration-time data of levetiracetam were well described by a 1-compartment model with first-order absorption. Oral clearance was allometrically related to the individual body weight and eGFR. An increase in the dose significantly increased oral clearance. No improvement in model fit was observed by including the covariate of any concomitant antiepileptic drugs. The population mean clearance for an adult weighing 70 kg and with a normal renal function was 4.8 and 5.9 L/h for 500 mg bis in die (bid) and 1500 mg bid, respectively.Conclusions:Oral clearance allometrically related with body weight and eGFR can well predict the routine therapeutic drug monitoring data from pediatric to aged patients with varying renal function. Dosage adjustments based on renal function are effective in controlling the trough and peak concentrations in similar ranges.LIPPINCOTT WILLIAMS & WILKINS, 2016年06月, THERAPEUTIC DRUG MONITORING, 38(3) (3), 371 - 378, 英語[査読有り]研究論文（学術雑誌）
- Homeostasis of riboflavin should be maintained by transporters. Previous in vitro studies have elucidated basic information about riboflavin transporter RFVT3 encoded by SLC52A3 gene. However, the contribution of RFVT3 to the maintenance of riboflavin homeostasis and the significance in vivo remain unclear. Here, we investigated the physiological role of RFVT3 using Slc52a3 knockout (Slc52a3-/-) mice. Most Slc52a3-/- mice died with hyperlipidemia and hypoglycemia within 48 hr after birth. The plasma and tissue riboflavin concentrations in Slc52a3-/- mice at postnatal day 0 were dramatically lower than those in wild-type (WT) littermates. Slc52a3-/- fetuses showed a lower capacity of placental riboflavin transport compared with WT fetuses. Riboflavin supplement during pregnancy and after birth reduced neonatal death and metabolic disorders. To our knowledge, this is the first report to indicate that Rfvt3 contributes to placental riboflavin transport, and that disruption of Slc52a3 gene caused neonatal mortality with hyperlipidemia and hypoglycemia owing to riboflavin deficiency.NATURE PUBLISHING GROUP, 2016年06月, SCIENTIFIC REPORTS, 6, 英語[査読有り]研究論文（学術雑誌）
- 病院と薬局の合意に基づく院外処方せんにおける疑義照会簡素化プロトコルとその効果について検討した。通常の疑義照会を含む全体の処方変更に占めるプロトコルに基づく変更の割合は、プロトコル改定前は12.3±1.3%で、改定後は16.8±4.1%と有意に増加した。改定前のプロトコルにおいては、処方変更内容として剤形・規格の変更が74%と最も多かった。プロトコルからの逸脱の割合は、2014年9月においては20%と多かったが、プロトコル改定後の2015年3月において7%に有意に減少した。2014年9月において、院外処方せんにおける変更は369件で、そのうち、プロトコルに基づく処方変更の割合は13%、疑義照会による変更のうちプロトコルに該当する内容の変更は12%あった。プロトコルに基づき薬剤師が残薬調整を行うことにより、最大で10940円の薬剤費が削減された。(一社)日本医療薬学会, 2016年05月, 医療薬学, 42(5号) (5号), 336 - 342, 日本語[査読有り]研究論文（学術雑誌）
- 日本エイズ学会, 2016年05月, 日本エイズ学会誌, 18(2号) (2号), 163 - 167, 日本語抗てんかん薬との薬物相互作用を検討したエファビレンツおよびドルテグラビル服用症例[査読有り]研究論文（学術雑誌）
- Everolimus blood concentrations did not predict interstitial lung disease in patients with metastatic renal cell carcinomaエベロリムス(EVE)投与(5〜10mg/日)を受けた転移性腎細胞癌患者22名のカルテを基に、間質性肺疾患(ILD)と定常状態のEVE血中濃度との関連を後ろ向きに検討した。EVEトラフ血中濃度は投薬8日目に測定し、血清乳酸デヒドロゲナーゼ(LDH)とKrebs von den Lungen 6(KL-6)の濃度も測定した。その結果、治療中に22名のうち7名にILDを認めた。その発症の中央値は158日で、この有害反応の重症度はグレードIが5名、グレードIIとIIIが各1名であった。これらの患者7名では血清LDHとKL-6の濃度がILD発症後に有意に上昇したが、EVEトラフ濃度の中央値はILD患者と非ILD患者の間で有意な差を認めなかった。以上より、転移性腎細胞癌患者のうち、EVE誘発性ILD患者では血清LDHとKL-6の濃度が有意に上昇するが、定常状態のEVE濃度からILDの発症を予測することはできないと考えられた。(一社)日本TDM学会, 2016年03月, TDM研究, 33(1) (1), 1 - 8, 英語[査読有り]
- 薬剤師の介入による向精神薬適正使用と転倒・転落事故数への影響2012年4月から多職種合同(医師、薬剤師、看護師、精神保健福祉士)の入院時初回面談を行い、薬剤師による介入を開始したが、介入後の睡眠薬、抗不安薬、抗精神病薬、抗鬱薬および抗パーキンソン病薬の処方動向と病棟での転倒・転落事故数を調査し、薬剤師介入が及ぼした影響について検討した。睡眠薬、抗不安薬、抗精神病薬については薬剤師が介入開始した2012年度以降に継続して使用量が減少していた。使用量および使用薬剤の変化の要因として、全国的に向精神薬による治療が単剤化へ移行していることに加え、処方医師の異動による交代等の様々な要因も考えられた。しかし京大病院精神科神経科では2014年度診療報酬改定以前より単剤化が進んでおり、経年的な減少がみられることから、入院時初回面談や入院中の処方変更提案など薬剤師による積極的な処方介入が向精神薬の適正使用に貢献したと考えられた。(一社)日本医療薬学会, 2016年03月, 医療薬学, 42(3) (3), 174 - 184, 日本語[査読有り]研究論文（学術雑誌）
- 心臓血管外科病棟におけるバンコマイシン(VCM)治療に焦点を当てて、プロトコルの基づく薬物治療管理(PBPM)の臨床的アウトカムを定量化し、VCM治療における薬剤師介入の効果について検討した。VCMが開始され治療薬物モニタリング(TDM)を行った54例を対象とし、プロトコル導入以前にVCM治療を行った29例(男性21名、女性8名、70±18歳)(I群)、プロトコル導入後にVCM治療を行った25例(男性17名、女性8名、67±15歳)(II群)に分けた。急性腎障害発現はI群9例(31.0%)、II群2例(8.0%)であった。治療域維持率の中央値は、I群50%、II群80%、中毒域到達率の中央値は、I群17%、II群0%であった。治療域維持率及び中毒域到達率に関する2群間の差は、敗血症、肺炎、感染性心内膜炎の背景を有する場合において大きい値であった。VCM血中濃度の日内変動はI群で大きい傾向があった。(一社)日本医療薬学会, 2016年01月, 医療薬学, 42(1号) (1号), 14 - 22, 日本語[査読有り]研究論文（学術雑誌）
- This study aimed to examine the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in Nagase analbuminemic rats (NARs) to evaluate the effect of protein binding on the associated inosine-5'-monophosphate dehydrogenase (IMPDH) activity. Free fractions of MPA in the control rats and NARs were 2.09 and 24.8%, respectively. Pharmacokinetic and pharmacodynamic parameters simultaneously obtained by the nonlinear mixed effects modeling program NONMEM explained reasonably well the concentrations of MPA and MPA glucuronide as well as IMPDH activity in both rats. NARs showed a higher clearance and a smaller volume of distribution based on the free MPA concentration than the controls did, besides the increase in free fraction. The half-maximal inhibitory concentration based on free MPA was estimated as 163 ng/mL for both rats. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters showed that the area under the IMPDH activity-time curve decreased non-linearly according to the increase in free fraction of MPA. In conclusion, the experimental data obtained from NARs followed by the modeling and simulation approach quantitatively clarified that the free MPA concentration was suitable for the biomarker of immunosuppressive effect of MPA. Dose adjustments based on the total MPA may cause unnecessary overexposure to MPA in patients with hypoalbuminemia. Copyright (C) 2015, The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.JAPANESE SOC STUDY XENOBIOTICS, 2015年12月, DRUG METABOLISM AND PHARMACOKINETICS, 30(6) (6), 441 - 448, 英語[査読有り]研究論文（学術雑誌）
- Monitoring of pharmacodynamics in addition to pharmacokinetics is one of strategies to individualize mycophenolate mofetil therapy. The purpose of this study was to develop sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for evaluation of the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA). Concentrations of mycophenolic acid glucuronide (MPAG), mycophenolic acid acyl-glucuronide, as well as unbound MPA and MPAG, were determined, and inosine-5-monophosphate dehydrogenase activity was calculated by measuring concentrations of produced xanthosine-5-monophosphate (XMP) and intracellular adenosine-5-monophosphate after incubation of peripheral blood mononuclear cell (PBMC) lysates. A metal-free Mastro(TM) column and two gradient patterns were used to improve the quantification limit of XMP to 0.1 m. In the clinical MPA concentration range, the linearity of the calibration curve, inter- and intra-day precision and accuracy satisfied the relevant US Food and Drug Administration guidelines. The MPA concentrations in hematopoietic stem cell transplant (HSCT) patients determined by the enzyme assay and the present LC-MS/MS method showed a good correlation (r(2) = 0.95, p < 0.001). In this study, we report sensitive and validated LC-MS/MS methods to evaluate the pharmacokinetics and pharmacodynamics of MPA, which are sufficiently sensitive to assess small quantities of PBMC lysates collected shortly after HSCT. Copyright (c) 2015 John Wiley & Sons, Ltd.WILEY-BLACKWELL, 2015年09月, BIOMEDICAL CHROMATOGRAPHY, 29(9) (9), 1309 - 1316, 英語[査読有り]研究論文（学術雑誌）
- Gefitinib and erlotinib are anticancer agents, which inhibit epidermal growth factor receptor (EGFR) tyrosine kinase. Interstitial lung disease (ILD) occurs in patients with non-small cell lung cancer receiving EGFR inhibitors. In the present study, we examined whether gefitinib- and erlotinib-induced lung injury related to ILD through endoplasmic reticulum (ER) stress, which is a causative intracellular mechanism in cytotoxicity caused by various chemicals in adenocarcinomic human alveolar basal epithelial cells. These two EGFR inhibitors increased Parkinson juvenile disease protein 2 and C/EBP homologous protein mRNA expressions, and activated the eukaryotic initiation factor (eIF) 2 alpha/activating transcription factor 4 pathway without protein kinase R-like ER kinase activation in A549 cells. Gefitinib and erlotinib caused neither ER stress nor cell death; however, these agents inhibited cell growth via the reduction of cyclin-D1 expression. Tauroursodeoxycholic acid, which is known to suppress eIF2 alpha phosphorylation, cancelled the effects of EGFR inhibitors on cyclin-D1 expression and cell proliferation in a concentration-dependent manner. The results of an EGFR-silencing study using siRNA showed that gefitinib and erlotinib affected eIF2 alpha phosphorylation and cyclin-D1 expression independent of EGFR inhibition. Therefore, the inhibition of cell growth by these EGFR inhibitors might equate to impairment of the alveolar epithelial cell repair system via eIF2 alpha phosphorylation and reduced cyclin-D1 expression.PUBLIC LIBRARY SCIENCE, 2015年08月, PLOS ONE, 10(8) (8), 英語[査読有り]研究論文（学術雑誌）
- In 2012 we conducted a questionnaire survey to clarify the current state of pharmacy-related universities and clinical faculties and identify problem areas in pharmacy education and research. The survey was sent to 74 universities nationwide; responses were received from 488 out of 530 faculties distributed at 59 universities. The male/female ratio of the respondents was 3:1 and the age breakdown was 24% aged 30-years or younger, 61% aged 40-50-years. Regarding interest in education and research, 62% of the respondents emphasized education over research; the weekly average time devoted to these respective activities was 21 hours for education and 13 hours for research. Of the respondents, 46% had not even practiced once in 2012, while 61% out of the responders who had practiced (52%) had engaged in practice in a clinical setting one day per week or more. As for research, 83% and 20% of respondents supervised undergraduate and PhD students, respectively. Despite the fact that roughly half of all respondents do not fully engage in practice and research, satisfaction with the current situation on a 5-point scale was 35% for "satisfied" and "somewhat satisfied" combined, and 40% for "acceptable." Clinical faculties should not be content with the present situation and should strive to advance education and research by enhancing motivation to train the next generation. It is hoped that future discussions will lead to the revitalization of practice/education/research among clinical faculties, and also to the training of staff in clinical faculties, in whose footsteps the pharmacy students and/or next generation pharmacists can aspire to follow.一般社団法人日本医療薬学会, 2015年04月, 医療薬学, 41(4号) (4号), 223 - 235, 日本語[査読有り]研究論文（学術雑誌）
- NATURE PUBLISHING GROUP, 2015年02月, BONE MARROW TRANSPLANTATION, 50(2) (2), 312 - 314, 英語[査読有り]研究論文（学術雑誌）
- 造影CT時における水分摂取推奨の有用性について検討するため、水分摂取推奨前1年9ヵ月間および推奨後2年間におけるヨード造影剤によるアレルギー様症状の有害事象発現率に関して院内インシデント報告を基に後方視的な調査を行った。院内インシデント報告を基に調査した結果、積極的な水分摂取はヨード造影剤による呼吸器および消化器系有害反応の予防に有用で、その予防効果は夏季に顕著であることが示唆された。(公社)日本薬学会, 2015年, 薬学雑誌, 135(10) (10), 1177 - 1184, 日本語[査読有り]
- Clobazam (CLB) is metabolized by cytochrome P450 (CYP) 3A4 to yield N-desmethylclobazam (N-CLB), which is further inactivated by CYP2C19. The aim of this study was to retrospectively evaluate the relationship between CYP2C19 polymorphisms and the efficacy of low-dose, add-on CLB therapy in Japanese patients with epilepsy. Fifty patients were divided into three groups according to their CYP2C19 polymorphism. CLB and N-CLB serum concentrations and seizure frequency before and after starting CLB were analyzed. Extensive metabolizers (EMs, n = 11), intermediate metabolizers (IMs, n = 22), and poor metabolizers (PMs, n = 17) were included. Although the dose-normalized CLB serum concentrations were not significantly different, the dose-normalized N-CLB serum concentrations were significantly higher in PMs than in EMs or IMs. Seizure frequency was significantly decreased by the CLB therapy in PMs (p < 0.01), but not in EMs or IMs. CLB serum concentrations did not correlate with seizure reduction rate, but median N-CLB serum concentrations were significantly higher in patients with excellent seizure control (a parts per thousand 90 % seizure reduction) compared to those with a parts per thousand 50 % seizure reduction or with < 50 % seizure reduction (1103, 341, and 570 ng/mL, respectively). The efficacy of low-dose CLB therapy was significantly influenced by CYP2C19 polymorphisms. Ideally, CLB therapy should be started with a low dose (2.5 mg/day) and dosage increased until N-CLB serum concentration reaches 1100 ng/mL or until the desired effect is acquired, a recommendation that is particularly important for PMs.SPRINGER HEIDELBERG, 2015年01月, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 71(1) (1), 51 - 58, 英語[査読有り]研究論文（学術雑誌）
- Acute kidney injury (AKI) often correlates with poor prognosis and is followed by various severe unfavorable systemic outcomes. It is important to understand the pathophysiology of AKI for the development of novel therapeutic approaches toward promoting renal regeneration after injury. Recent studies have indicated that AKI-induced tubular cell death plays an active role in the onset of tissue regeneration however, the mechanisms underlying renal tubular repair after injury have yet to be understood. In the present study, we explored molecules that might serve as “danger” signals in mediating tubular regeneration. Kidneys of rats systemically administered the nephrotoxicant cisplatin (to induce AKI) exhibited massive cell proliferation. The proportion of proliferating cells in the total cell distribution was highest in the outer stripe of the outer medulla coincided with where the tubular damage was the most severe in this study. This finding suggests that soluble factors may have been released from damaged cells to stimulate the proliferation of neighboring tubular epithelial cells. In elucidating the mechanism of dying cell-to-surviving cell communication using normal rat kidney NRK-52E epithelial cells, we found a significant increase in ATP levels in supernatants of these cells after the induction of cell death using ultraviolet irradiation. Furthermore, treatment of conditioned supernatants with apyrase or suramin, which inhibits purinergic signaling, resulted in significant decreases in cell proliferation and migration activities. These results demonstrate a novel role for extracellular nucleotides, probably as danger signals in aggravating tubular regeneration after AKI.American Physiological Society, 2014年12月, American Journal of Physiology - Renal Physiology, 307(12) (12), F1404 - F1411, 英語[査読有り]研究論文（学術雑誌）
- Comparison of the Effects of Azole Antifungal Agents on the Anticoagulant Activity of WarfarinThe package insert of the antithrombotic agent warfarin warns users of its interaction with azole anti-fungals. However, information on the frequency or degree of these interactions is limited. In particular, the time to onset of azole-mediated prothrombin time prolongation, expressed as the international normalized ratio (INR), is poorly characterized. Therefore, we retrospectively examined the INR in 29 patients administered warfarin with fluconazole (FLCZ), voriconazole (VRCZ), or itraconazole (ITCZ). INRs in 18 patients taking FLCZ and in 5 patients taking VRCZ significantly increased from 1.40 to 2.94 and from 1.95 to 2.89, respectively. The warfarin sensitivity index (WSI), calculated as INR/daily warfarin dose, also significantly increased from 1.06 to 1.89 with FLCZ and showed an upward trend from 1.13 to 2.23 with VRCZ. ITCZ had no influence on the INR or WSI in 6 patients. The INRs observed when warfarin was coadministered with azoles (Y) correlated significantly with those observed in the absence of azoles (X): FLCZ, Y=4.94X-3.96, r(2)=0.80; VRCZ, Y=2.13X-1.27, r(2)=0.93. Moreover, in all 8 patients with closely monitored INRs, the WSI increased within 1 week of FLCZ or VRCZ coadministration. In conclusion, FLCZ and VRCZ augmented the anticoagulant activity of warfarin. The INR should be closely monitored within 1 week of initiating FLCZ or VRCZ coadministration with warfarin, especially in patients with high INRs.PHARMACEUTICAL SOC JAPAN, 2014年12月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 37(12) (12), 1990 - 1993, 英語[査読有り]研究論文（学術雑誌）
- Acute kidney injury (AKI) often correlates with poor prognosis and is followed by various severe unfavorable systemic outcomes. It is important to understand the pathophysiology of AKI for the development of novel therapeutic approaches toward promoting renal regeneration after injury. Recent studies have indicated that AKI-induced tubular cell death plays an active role in the onset of tissue regeneration; however, the mechanisms underlying renal tubular repair after injury have yet to be understood. In the present study, we explored molecules that might serve as "danger" signals in mediating tubular regeneration. Kidneys of rats systemically administered the nephrotoxicant cisplatin (to induce AKI) exhibited massive cell proliferation. The proportion of proliferating cells in the total cell distribution was highest in the outer stripe of the outer medulla coincided with where the tubular damage was the most severe in this study. This finding suggests that soluble factors may have been released from damaged cells to stimulate the proliferation of neighboring tubular epithelial cells. In elucidating the mechanism of dying cell-to-surviving cell communication using normal rat kidney NRK-52E epithelial cells, we found a significant increase in ATP levels in supernatants of these cells after the induction of cell death using ultraviolet irradiation. Furthermore, treatment of conditioned supernatants with apyrase or suramin, which inhibits purinergic signaling, resulted in significant decreases in cell proliferation and migration activities. These results demonstrate a novel role for extracellular nucleotides, probably as danger signals in aggravating tubular regeneration after AKI.AMER PHYSIOLOGICAL SOC, 2014年12月, AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 307(12) (12), F1404 - F1411, 英語[査読有り]研究論文（学術雑誌）
- OXFORD UNIV PRESS INC, 2014年07月, JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 106(7) (7), 英語[査読有り]
- 2014年05月, 医療薬学, 40(5号) (5号), 297 - 303, 日本語プロトコルに基づいた薬物治療管理の実践 病棟専任薬剤師が参画したチーム医療による持参薬管理[査読有り]研究論文（学術雑誌）
- 2014年04月, Transplant Proc., 71(1) (1), 51 - 58, 英語[査読有り]
- Therapeutic drug monitoring (TDM) and subsequent dosage adjustment for individual patients in the treatment with tacrolimus are required after liver transplantation to prevent rejection and over-immunosuppression, which leads to severe infection and adverse reactions including nephrotoxicity. The purpose of this study was to evaluate the analytical performance among commercially available immunoassay methods, which were microparticle enzyme immunoassay (MEIA), chemiluminescent enzyme immunoassay (CLIA), and affinity column-mediated immunoassay (ACMIA), compared with an assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, the flow injection assay (FIA-MS/MS) was also evaluated to determine whether it could be available as a new method of analysis in tacrolimus therapy. The blood tacrolimus concentrations in samples from liver transplant recipients (n = 102) were measured using MEIA, CLIA, ACMIA, and LC-MS/MS. Additional blood samples from liver transplant recipients (n = 54) were analyzed using both FIA-MS/MS and LC-MS/MS. Because the assay performance and characteristics of MEIA, CLIA, ACMIA, and FIA-MS/MS are relatively different, the measured data should be carefully considered depending on the methodology.ELSEVIER SCIENCE INC, 2014年04月, TRANSPLANTATION PROCEEDINGS, 46(3) (3), 758 - 760, 英語[査読有り]研究論文（学術雑誌）
- 2014年03月, 日本病院薬剤師会雑誌, 50(3号) (3号), 299 - 304, 日本語悪性神経膠腫患者に対するtemozolomide・放射線併用療法における有害反応解析[査読有り]研究論文（学術雑誌）
- Effectiveness of Everolimus in Combination with Cyclosporine as Treatment for Chronic Rejection in a Pediatric Patient Undergoing Liver Transplantation生後6ヵ月の女児。激症型の高熱と黄疸が出現した。他院で急性肝不全と診断されたが治療が奏効しないため、5日後に当院に転院となり、生体肝移植を施行した。術後1日目から免疫抑制薬としてタクロリムスを開始した。術後60日目のアスパラギン酸アミノトランスフェラーゼ(AST)、アラニンアミノトランスフェラーゼ(ALT)、総ビリルビン(T-Bil)はそれぞれ120U/L、145U/L、10.8mg/dLで、病理検査より、線維形成と胆管の変性を認め、慢性拒絶反応と診断した。高用量ステロイドパルス療法によりASTとALTは低下したが、T-Bilはパルス療法開始後11日目まで低下しなかった。慢性拒絶反応治療のため、術後62日目にタクロリムスを中止し、シクロスポリン(12時間毎に25mg)+エベロリムス(12時間毎に0.5mg)併用を開始した。投与量は、エベロリムス(12〜13ng/mL)とシクロスポリン(180ng/mL)の標的トラフ濃度に基づいて調整した。術後77日目にT-Bilは3.0mg/dLまで低下し、慢性拒絶反応の改善を認めた。(一社)日本TDM学会, 2014年01月, TDM研究, 31(1) (1), 1 - 5, 英語[査読有り]
- 2013年12月, 日本病院薬剤師会雑誌, 49(12号) (12号), 1305 - 1309, 日本語胆道がんに対するゲムシタビン シスプラチン療法の有害反応解析と治療継続に関する影響因子の検討[査読有り]研究論文（学術雑誌）
- 非小細胞肺がん患者に対する簡易懸濁法を用いたエルロチニブ投与について検討した。嚥下障害を有する非小細胞肺がん患者3例を対象とした。2次治療としてエルロチニブ療法を導入することとなり、簡易懸濁法によってエルロチニブ投与液を調製した。エルロチニブ錠は30分後には約80%の懸濁率が得られた。懸濁初期には、イオン水に対する懸濁率が高い傾向を示したが、10分以降pHの影響は受けず、30分後には全てのpHで約80%の懸濁率が得られた。エルロチニブ錠を簡易懸濁法にて投与開始8日目の血中濃度は、ばらつきは大きく、投与前1130±720、2時間後2260±1250、4時間後2290±1370、24時間後1120±460ng/mLであった。AUCは、62800、44800、18700ng・hr/mLで、平均42100±17400ng・hr/mLであった。(一社)日本医療薬学会, 2013年09月, 医療薬学, 39(9号) (9号), 565 - 570, 日本語[査読有り]研究論文（学術雑誌）
- Refractory epilepsy is reportedly associated with an overexpression of ATP-binding cassette transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (Bcrp). In this study, we examined the contribution of Pgp and Bcrp to the brain distribution of 12 antiepileptic drugs (AEDs) in Mdr1a/1b(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice within a therapeutic concentration range. The blood concentrations were sequentially determined, and the brain concentrations were measured at 60 min after intravenous administration. The plasma concentration profiles for each AED in the Mdr1a/1b(-/-) mice were equivalent to those in the wild-type mice. In contrast, the plasma concentration profiles of phenytoin, lamotrigine, topiramate, tiagabine, and levetiracetam in the Mdr1a/1b(-/-)/Bcrp(-/-) mice were significantly lower than the corresponding ones in the wild-type mice. The brain-to-plasma concentration ratio (Kpbrain) values of phenytoin, topiramate, and tiagabine in the Mdr1a/1b(-/-) mice were significantly higher than the corresponding ones in the wild-type mice. In contrast, the Kp brain values of phenobarbital, clobazam, zonisamide, gabapentin, tiagabine, and levetiracetam in the Mdr1a/1b(-/-)/Bcrp(-/-) mice were significantly higher than the corresponding ones in Mdr1a/1b(-/-) mice. The Kpbrain values of the 12 AEDs in the Mdr1a/1b(-/-)/Bcrp(-/-) mice, but not wild-type mice, significantly correlated with the corresponding molecular weight values. These findings suggest that both Pgp and Bcrp restrict brain access for several AEDs. Taken together, information on the contribution of each transporter may be useful in the development of strategic treatments of refractory epilepsy. © 2013 Elsevier B.V.2013年06月, European Journal of Pharmacology, 710(1-3) (1-3), 20 - 28, 英語[査読有り]研究論文（学術雑誌）
- (一社)日本泌尿器科学会, 2013年03月, 日本泌尿器科学会雑誌, 104(2) (2), 372 - 372, 日本語腎移植後の維持免疫抑制患者におけるカルシニューリン活性の検討
- The purpose of this study was to develop an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method of 22 antiepileptics for routine therapeutic monitoring. The antiepileptics used in the analyses were carbamazepine, carbamazepine-10,11-epoxide, clobazam, N-desmethylclobazam, clonazepam, diazepam, N-desmethyldiazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, N-desmethylmesuximide, nitrazepam, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide. After protein precipitation of 50?mu L plasma with methanol, the supernatant was diluted with water or was evaporated to dryness and reconstituted with mobile phase in the case of benzodiazepines. Separation was achieved on an Acquity UPLC BEH C18 column with a gradient mobile phase of 10?mm ammonium acetate containing 0.1% formic acid and methanol at a flow rate of 0.4?mL/min. An Acquity TQD instrument in multiple reaction monitoring mode with ion mode switching was used for detection. All antiepileptics were detected and quantified within 10?min, with no endogenous interference. All the calibration curves showed good linearity in the therapeutic range (r2?<?0.99). The precision and accuracy values for intra- and inter-assays were within +/- 15% except for phenobarbital and tiagabine. A good correlation was observed between the concentration of clinical samples measured by the new method described here and the conventional methods. The values of carbamazepine and phenytoin by UPLC-MS/MS were lower than those detected by the immunoassays, which might be caused by the cross-reaction of antibodies with their metabolites. In conclusion, we developed a simple and selective UPLC-MS/MS method suitable for routine therapeutic monitoring of antiepileptics. Copyright (c) 2012 John Wiley & Sons, Ltd.WILEY-BLACKWELL, 2012年12月, BIOMEDICAL CHROMATOGRAPHY, 26(12) (12), 1519 - 1528, 英語[査読有り]研究論文（学術雑誌）
- The purpose of this study was to develop an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method of 22 antiepileptics for routine therapeutic monitoring. The antiepileptics used in the analyses were carbamazepine, carbamazepine-10,11-epoxide, clobazam, N-desmethylclobazam, clonazepam, diazepam, N-desmethyldiazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, N-desmethylmesuximide, nitrazepam, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, vigabatrin and zonisamide. After protein precipitation of 50?mu L plasma with methanol, the supernatant was diluted with water or was evaporated to dryness and reconstituted with mobile phase in the case of benzodiazepines. Separation was achieved on an Acquity UPLC BEH C18 column with a gradient mobile phase of 10?mm ammonium acetate containing 0.1% formic acid and methanol at a flow rate of 0.4?mL/min. An Acquity TQD instrument in multiple reaction monitoring mode with ion mode switching was used for detection. All antiepileptics were detected and quantified within 10?min, with no endogenous interference. All the calibration curves showed good linearity in the therapeutic range (r2?<?0.99). The precision and accuracy values for intra- and inter-assays were within +/- 15% except for phenobarbital and tiagabine. A good correlation was observed between the concentration of clinical samples measured by the new method described here and the conventional methods. The values of carbamazepine and phenytoin by UPLC-MS/MS were lower than those detected by the immunoassays, which might be caused by the cross-reaction of antibodies with their metabolites. In conclusion, we developed a simple and selective UPLC-MS/MS method suitable for routine therapeutic monitoring of antiepileptics. Copyright (c) 2012 John Wiley & Sons, Ltd.WILEY-BLACKWELL, 2012年12月, BIOMEDICAL CHROMATOGRAPHY, 26(12) (12), 1519 - 1528, 英語[査読有り]研究論文（学術雑誌）
- Frozen gloves (FG) are effective in preventing docetaxel-induced nail toxicity (DNT), but uncomfortable. The preventive effect of FG for DNT was compared using a standard (-25 to -30A degrees C) or more comfortable (-10 to -20A degrees C) preparation. Breast cancer patients receiving docetaxel were eligible. Each patient wore an FG (prepared at -10 to -20A degrees C for 90 min) for 60 min without replacement on the right hand. The left hand was protected by standard methods (FG prepared at -25 to -30A degrees C overnight and worn for 90 min with replacement at 45 min). The primary endpoint was DNT occurrence at 5 months. Secondary endpoints included docetaxel exposure [cumulative dose and area under the blood concentration time curve (AUC)] until DNT occurrence and discomfort from FG. The pharmacokinetics of docetaxel was assessed. From 23 patients enrolled between December 2006 and June 2010, seven who received docetaxel for less than 5 months were excluded from evaluation. The median accumulated docetaxel dose was 700 mg/m(2) (340-1430 mg/m(2)). Within 5 months of FG use, none developed protocol-defined DNT in either hand. Two patients (13%) developed DNT at 7.2 and 7.3 months, respectively, both at -10 to -20A degrees C. In the control hand (-25 to -30A degrees C), discomfort occurred in 92% of the cycles, compared to 15% in the experimental hand (-10 to -20A degrees C). Five patients (22%) experienced pain at -25 to -30A degrees C, but none did at -10 to -20A degrees C. The degree of docetaxel exposure was not related to DNT occurrence in our study. A convenient preparation of FG at -10 to -20A degrees C is almost as effective as a standard preparation at -25 to -30A degrees C, with significantly less discomfort.SPRINGER, 2012年09月, SUPPORTIVE CARE IN CANCER, 20(9) (9), 2017 - 2024, 英語[査読有り]研究論文（学術雑誌）
- Purpose Tacrolimus pharmacokinetics and calcineurin activity in peripheral blood mononuclear cells (PBMCs) were investigated in adult patients undergoing primary living-donor liver transplantation (LDLT) in order to clarify the significance of monitoring the tacrolimus blood trough concentration during the early post-transplantation period. Methods Fourteen patients were enrolled in this study, and time-course data following the oral administration of a conventional tacrolimus formulation twice daily were obtained at 1 and 3 weeks post-transplantation. The concentration of tacrolimus in whole blood and calcineurin activity in PBMCs were measured. Results The apparent clearance of tacrolimus significantly increased at 3 weeks versus 1 week post-transplantation, although the trough concentration did not significantly differ at these time points. The concentration at each sampling time, except at 1 h post-dose, correlated well with the area under the concentration-time curve from 0 to 12 h (AUC(0-12)). Neither the concentration at the trough time point nor AUC(0-12) was correlated with the area under the calcineurin activity-time curve from 0 to 12 h; however, calcineurin activity at the trough time point was strongly correlated with the latter (r(2)>0.92). Conclusions Based on these results, trough concentration monitoring can be considered an appropriate procedure for routine tacrolimus dosage adjustment in adult LDLT patients. Monitoring of calcineurin activity at the trough time point was also found to be potentially useful for predicting the immunological status of the patient during the tacrolimus dosing interval.SPRINGER HEIDELBERG, 2012年03月, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 68(3) (3), 259 - 266, 英語[査読有り]研究論文（学術雑誌）
- 2012年, 移植, 47(1) (1), 75 - 81タクロリムス血中濃度測定法の差異に関する臨床的評価：M E I A，C L I A，A C M I A，E M I T 間の比較検討[査読有り]
- The anticoagulant drug warfarin is used to prevent conditions such as venous thrombosis and so on. Since warfarin has many interactions with other drugs and a large inter-individual pharmacodynamic variability, its dosage must be adjusted based on the prothrombin time international normalized ratio (PT-INR) in each patient. Oxycodone is often used to control cancer pain. In the drug package insert, care should be taken when co-administering oxycodone with warfarin, but the mechanism of the interaction between the two remains unknown. In addition, there have been no reports on interaction between oxycodone and warfarin in patients.In this study, we retrospectively investigated the effect of oxycodone on the blood coagulation activity in 9 cancer patients who were treated with warfarin. After combination with oxycodone, the total dosage of warfarin in two weeks was significantly decreased to 78.6% of that without oxycodone. The median of PT-INR was also significantly increased from 2.03 to 2.30 compared to that without oxycodone. Moreover, the median of the warfarin sensitivity index, which was defined as PT-INR/warfarin dose (mg/day), was also significantly increased from 0.78 to 0.Japanese Society of Pharmaceutical Health Care and Sciences, 2012年, 医療薬学, 38(4) (4), 258 - 264, 日本語
- (一社)日本臨床薬理学会, 2011年10月, 臨床薬理, 42(Suppl.) (Suppl.), S229 - S229, 日本語難治性てんかん患者のクロバザム治療におけるCYP2C19遺伝子多型の寄与[査読有り]
- (一社)日本TDM学会, 2011年06月, TDM研究, 28(3) (3), s196 - s196, 日本語新規抗てんかん薬ラモトリギンの血中濃度測定と相互作用に関する検討[査読有り]
- Sorafenib is an oral multikinase inhibitor for the treatment of patients with advanced hepatocellular carcinoma (HCC). However, it produces various adverse reactions (hand-foot syndrome, hypertension, diarrhea, etc.) that often lead to discontinuation of treatment, a clinical problem that needs to be addressed.In this study, we retrospectively reviewed the medical records of 50 patients with HCC who had been treated with sorafenib at Kyoto University Hospital to investigate factors influencing discontinuation of treatment continuation as well as development of adverse events. The overall rate for discontinuation of treatment (including treatment termination and dose reduction/interruption) due to adverse events was 56%, and that for treatment termination due to progressive disease was 30%. The frequency of discontinuation due to any reason within the first month was significantly higher in patients starting with 800 mg / day (19/35, 54.3%) than with 400 mg/day (3/15, 20.0%). In addition, the median duration of successful treatment with the starting dose was longer in patients on 400 mg/day than 800 mg/day (89 days vs. 29 days). The development of hand-foot syndrome (grade>2)or diarJapanese Society of Pharmaceutical Health Care and Sciences, 2011年, 医療薬学, 37(11) (11), 631 - 636, 日本語
- Pharmacokinetics of Vancomycin after Intravenous Administration in 3 Patients Implanted with Vancomycin-loaded Cement Beadsバンコマイシン(VAN)負荷セメントビーズ移植を受け、VAN静注も受けた患者3名中1名に顕著な薬物動態(PK)の変化を認めた。患者1は後方腰椎椎体間固定術(PLIF)を受けた67歳男性で、VAN静注を受けていたが25日目にVAN負荷ビーズの移植を受け、PK(VANクリアランス、terminal half-life、CCr)が大きく変化した。患者2はPLIFを受けた73歳女性で、VAN静注を受けた3日目にVAN負荷ビーズを移植したが、PKに大きな変化は見られなかった。患者3は人工膝関節全置換術を受けた69歳男性で、VAN静注後のVAN負荷ビーズ移植前後でPKに大きな差は見られなかった。上記3例中で患者1が予期以上に高いVAN濃度を示したことから、VAN負荷ビーズはある程度PKに影響を及ぼすことが示唆された。VAN負荷ビーズ移植患者へのVAN静注時にはVANパラメータを詳細に観察する必要がある。(一社)日本医療薬学会, 2010年11月, 医療薬学, 36(11) (11), 826 - 831, 英語[査読有り]
- Multidrug and toxin extrusions (MATE1/SLC47A1 and MATE2-K/SLC47A2) play important roles in the renal excretion of metformin. We have previously identified the nonsynonymous MATE variants with functional defects at low allelic frequencies. The purpose of this study was to evaluate the effects of heterozygous MATE variants on the disposition of metformin in mice and humans. Pharmacokinetic parameters of metformin in Mate1(+/-) heterozygous mice were comparable with those in Mate1(+/+) wild-type mice. Among 48 Japanese diabetic patients, seven patients carried heterozygous MATE variant and no patient carried homozygous MATE variant There was no significant difference in oral clearance of metformin with or without heterozygous MATE variants. In addition, creatinine clearance, but not heterozygous MATE variants, significantly improved the model fit of metformin clearance by statistical analysis using the nonlinear mixed-effects modeling program. In conclusion, heterozygous MATE variants could not influence the disposition of metformin in diabetic patients. Pharmacogenetics and Genomics 20:135-138 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.LIPPINCOTT WILLIAMS & WILKINS, 2010年02月, PHARMACOGENETICS AND GENOMICS, 20(2) (2), 135 - 138, 英語[査読有り]研究論文（学術雑誌）
- We describe the longitudinal follow-up of calcineurin activity and its clinical relevance in 4 de novo living-donor kidney transplant recipients treated with cyclosporine (n = 1) or tacrolimus (n = 3) The calcineurin activity in peripheral blood mononuclear cells was measured in combination with therapeutic drug monitoring during hospitalization. Serial blood samplings were performed after the oral administration of each drug to evaluate the temporal pharmacokinetic and pharmacodynamic profiles. Significant changes in enzyme activity were evaluated in relation to clinical outcomes. A nadir of calcineurin activity occurred at the maximum blood drug concentration within 4 h post-dose in most cases. Unlike cyclosporine, tacrolimus partially suppressed calcineurin activity throughout the dosing interval compared to the pre-dose level (cyclosporine, 62-67% inhibition. tacrolimus. 13-35% inhibition). Notably, calcineurin activity rapidly increased a few days before the onset of acute rejection in 2 patients, 1 receiving cyclosporine and 1 receiving tacrolimus, despite the achievement of therapeutic trough blood concentrations. These preliminary findings indicate that therapeutic monitoring of calcineurin activity in addition to the measurement of blood drug concentrations may be helpful to evaluate the pharmacodynamic effects of cyclosporine and tacrolimus early after renal transplantationJAP SOC STUDY XENOBIOTICS, 2010年, DRUG METABOLISM AND PHARMACOKINETICS, 25(5) (5), 411 - 417, 英語[査読有り]研究論文（学術雑誌）
- 2006年11月から外来化学療法施行中のTS-1併用患者を対象に、TS-1を適正・安全に服用されるための薬学的管理(薬剤指導)を点滴日に毎回継続的に実施、TS-1だけでなく併用している内服・注射を含めた総合的な薬剤チェックを含めた包括的な患者教育の実施システムを構築した。今回、構築したシステムについて概説し、システム導入によって得られたファーマシューティカルケアの質的向上について評価した。その結果、点滴実施フロアでのベットサイドの指導がレジメン変更時のみの場合と比べ約3.3倍に増加、薬剤師が患者と直接面談する機会が増えた。また、TS-1服用期間の確認・副作用モニターと同時に患者からの質問や症状の訴えを聴く双方向のやりとりが頻繁に行える機会が得られ、TS-1服用の自己管理ノートの確認欄の記載率も100%に向上した。以上より、TS-1併用患者への患者教育システムによる継続的な薬剤指導により、TS-1の内服が適正に改善し安全な投与に貢献したと考えられた。(一社)日本医療薬学会, 2009年12月, 医療薬学, 35(12) (12), 866 - 874, 日本語
- The effect of itraconazole on the pharmacokinetics of everolimus was investigated in rats. Ten minutes after an intravenous or intraintestinal administration of itraconazole, everolimus was delivered intravenously (0.2 mg/kg) or intraintestinally (0.5 mg/kg). Blood concentrations of everolimus were measured up to 240 min, and pharmacokinetic parameters were calculated. Intraintestinally administered itraconazole (20 mg/kg)significantly increased the area under the concentration-time curve (AUC) of intraintestinally administered everolimus about 4.5-fold, but even at 50 mg/kg did not affect the AUC of intravenously administered everolimus. However, intravenously administered itraconazole (50 mg/kg) increased the AUC of both intraintestinally and intravenously administered everolimus approximately 2-fold. Using a value for hepatic blood flow from the literature (50 ml/min/kg), the apparent intestinal and hepatic extraction of everolimus without itraconazole was calculated as about 80% and 13%, respectively. Intraintestinally administered itraconazole (20 mg/kg) changed the apparent intestinal extraction by 0.26-fold from 0.829 to 0.215, but the hepatic availability of everolimus was almost unchanged after the intravenous or intraintestinal administration of itraconazole even at a dose of 50 mg/kg from 0.871 to 0.923 or 0.867, respectively. In conclusion, intraintestinally administered itraconazole dramatically increased the AUC of everolimus delivered intraintestinally by inhibiting the intestinal first-pass extraction of this drug. Copyright (C) 2009 John Wiley & Sons, Ltd.JOHN WILEY & SONS LTD, 2009年12月, BIOPHARMACEUTICS & DRUG DISPOSITION, 30(9) (9), 517 - 523, 英語[査読有り]研究論文（学術雑誌）
- We propose a simple and practical modeling approach for analysis of the data for myelosuppression after cancer chemotherapy, which can be applied when pharmacokinetic data are not available and several anticancer drugs were simultaneously administered. The model equation is based on the probability density function for the Erlang distribution. The data for cell counts of leukocytes (white blood cell, WBC), platelets (PLT), and reticulocytes (RET) obtained in routine clinical laboratory tests after the ICE (ifosfamide/carboplatin/etoposide) regimen for cancer chemotherapy were retrospectively collected from 28 patients, and a population analysis was applied. The time course profiles could be well explained by the proposed model. The individual values of the time to reach the nadir were obtained by the Bayesian method, and their medians (days) were 16.8 for WBC, 12.8 for PLT, and 8.2 for RET. Such information would be useful to determine the day of visit for outpatients especially for additional treatment to prevent side effects such as infections. The model is simple and applicable to explain the time course profiles for myelosuppression irrespective of cell types, and also practical because it requires only the data from routine clinical laboratory tests without any additional burden to patients. (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4402-4412, 2009JOHN WILEY & SONS INC, 2009年11月, JOURNAL OF PHARMACEUTICAL SCIENCES, 98(11) (11), 4402 - 4412, 英語[査読有り]研究論文（学術雑誌）
- Tacrolimus is widely used to prevent acute rejection after transplantation, but achieving therapeutic blood concentrations of tacrolimus is often difficult because of large pharmacokinetic variability. In this study, the applicability of the Bayesian method to individualize tacrolimus dose was prospectively examined. Twenty adult recipients (Bayesian group) and another 20 adult patients (control group), all of whom underwent living-donor liver transplantation, were enrolled in this study. In the Bayesian group, the dose of tacrolimus during the first 3 and 4 weeks after surgery was adjusted with the Bayesian method using a population pharmacokinetic model, targeting a trough level of 5 to 12 ng/mL. The interindividual variability in tacrolimus concentrations was significantly reduced in the Bayesian group compared with the control group (average percentage coefficient of variation for all occasions, 32% vs 44% and 31% vs 39% in the first 3 and 4 weeks, respectively). In addition, more patients achieved the target concentrations in the Bayesian group than in the control group (average for all occasions, 85% vs 59% and 83% vs 70% in the first 3 and 4 weeks, respectively). These findings suggest that the Bayesian method can be used to calculate maintenance doses of tacrolimus in adult patients early after living-donor liver transplantation.SAGE PUBLICATIONS INC, 2009年07月, JOURNAL OF CLINICAL PHARMACOLOGY, 49(7) (7), 789 - 797, 英語[査読有り]研究論文（学術雑誌）
- Tacrolimus is widely used to prevent acute rejection after transplantation, but achieving therapeutic blood concentrations of tacrolimus is often difficult because of large pharmacokinetic variability. In this study, the applicability of the Bayesian method to individualize tacrolimus dose was prospectively examined. Twenty adult recipients (Bayesian group) and another 20 adult patients (control group), all of whom underwent living-donor liver transplantation, were enrolled in this study. In the Bayesian group, the dose of tacrolimus during the first 3 and 4 weeks after surgery was adjusted with the Bayesian method using a population pharmacokinetic model, targeting a trough level of 5 to 12 ng/mL. The interindividual variability in tacrolimus concentrations was significantly reduced in the Bayesian group compared with the control group (average percentage coefficient of variation for all occasions, 32% vs 44% and 31% vs 39% in the first 3 and 4 weeks, respectively). In addition, more patients achieved the target concentrations in the Bayesian group than in the control group (average for all occasions, 85% vs 59% and 83% vs 70% in the first 3 and 4 weeks, respectively). These findings suggest that the Bayesian method can be used to calculate maintenance doses of tacrolimus in adult patients early after living-donor liver transplantation.SAGE PUBLICATIONS INC, 2009年07月, JOURNAL OF CLINICAL PHARMACOLOGY, 49(7) (7), 789 - 797, 英語[査読有り]研究論文（学術雑誌）
- 2009年05月, 日本病院薬剤師会雑誌, 45(5号) (5号), 681 - 684, 日本語ビンカアルカロイド系抗がん剤の物理化学的特性に及ぼす温度変化の影響[査読有り]研究論文（学術雑誌）
- 2009年03月, 薬学雑誌, 129(3号) (3号), 353 - 357, 日本語新規抗悪性腫瘍薬テモゾロミドのカプセル開封後の溶液中での安定性に関する評価[査読有り]研究論文（学術雑誌）
- With the introduction of 6-year pharmacy educational program in 2006, a provision was made to assign pharmacist faculties having working experience as pharmacists in pharmacy schools. In October 2007, we conducted a survey to investigate the situation of pharmacist faculties. We sent a questionnaire to 247 pharmacist faculties in 66 pharmacy schools and the response rate was 84.9%. The faculties consisted of professors (43%), associate professors (23%) and lecturers (23%), and 77% of them had a Ph.D. degree. In a typical week, the major activities they engaged in were educational activities (20.6hrs), research (12.2hrs) and management (9.6hrs). While the average time they were occupied by clinical practice was 3.5hrs, 67% of them did not do any. Half of the faculties did not conduct any research with students or graduate students in their own schools, and in 2007 only 55% applied for Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Twenty-six percent said they were very satisfied or satisfied with their work on a five-point scale, and 44% rated their degree of satisfaction as fair. In conclusion, our survey showe日本医療薬学会, 2009年01月, 医療薬学, 35(1) (1), 43 - 49, 日本語
- At Kyoto University Hospital,we introduced an electronic medical recording system in October 2005.We then investigated interventions in the dispensing room as well as the usage of electronic medical records in our satellite-like pharmacy from June through August 2007.The number of prescriptions in this period was 29,618,and we had questions concerning 840 of them,a quarter of which could be answered using electronic medical records.Of the 640 prescriptions that we contacted physicians about,either asking questions or making recommendations,82.5% were changed.On comparing the pharmaceutical interventions in the dispensing room made this time with those made in the course of conducting pharmaceutical care services in our previous report of 2003,when an electronic medical recording system had not be introduced,pharmacists mainly made recommendations to physicians based on standard pharmacotherapy,such as those concerning inappropriate dosages,indications and drug interactions (69%),and pointed out errors in prescriptions (15%).However,pharmaceutical care interventions had also been based on standard therapy in consideration of individual patient backgrounds,such as those concerning doJapanese Society of Pharmaceutical Health Care and Sciences, 2009年, 医療薬学, 35(8) (8), 558 - 564, 日本語
- Calcineurin inhibitors are used as immunosuppressive agents for graft-versus-host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation.Since azole antifungals are frequently used for prophylaxis and treatment of infection under immunosuppressive therapy,it is highly possible that azole antifungals will affect blood concentrations of calcineurin inhibitors by inhibiting the drug metabolizing enzyme cytochrome P450 (CYP) 3A4.However,dosage adjustment with individual azole antifungals when administered by different routes has yet to be fully examined.In this study,we examined the effect of azole antifungals on blood concentrations of tacrolimus administered by intravenous constant infusion and cyclosporine administered orally in hematopoietic stem cell transplant patients.Oral voriconazole increased the blood concentration/dose (C/D) ratio of tacrolimus 2.7-fold,a significant increase.Oral itraconazole and intravenous voriconazole increased the C/D ratio 2.4-fold and 2-fold,respectively,but these changes were not statistically significant.The effects of oral and intravenous fluconazole were less potent than those of voriconazole and itraconazole,and tended to increaseJapanese Society of Pharmaceutical Health Care and Sciences, 2009年, 医療薬学, 35(4) (4), 233 - 239, 日本語
- It has been reported that antiemetic therapy based on the guidelines produced by the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) is effective in reducing emetic risk.However,while the effect of antiemetic therapy has been much reported for the intermittent administration of anticancer drugs,there have been few reports on such therapy in the case of the daily administration of anticancer drugs.In the present study,we investigated antiemetic therapy used for the prevention of nausea and vomiting induced by the daily administration of ICE combination chemotherapy (ifosphamide,carboplatin,and etoposide : ICE group) or DeVIC combination chemotherapy (dexamethasone,etoposide,ifosphamide,and carboplatin : DeVIC group) in 30 eligible patients.All patients received 5-HT3 serotonin receptor antagonists prophylactically during the daily administration of both types of chemotherapy but no patient received such prophylactic therapy after the administration of the anticancer drugs.The incidences of nausea and vomiting during chemotherapy for the ICE group (60.0% and 46.7%,respectively) were significantly higher than that in the DeVIC group (6.7%Japanese Society of Pharmaceutical Health Care and Sciences, 2009年, 医療薬学, 35(9) (9), 609 - 614, 日本語
- Larger Dosage Required for Everolimus than Sirolimus to Maintain Same Blood Concentration in Two Pancreatic Islet Transplant Patients with TacrolimusWe attempted a switch of mammalian target of rapamycin (mTOR) inhibitors from sirolimus to everolimus, a derivative of sirolimus and now on the market in Japan, in two pancreatic islet transplant patients. Both patients were administered tacrolimus with sirolimus or everolimus. They had been administered 5 or 9 mg sirolimus once a day and had maintained a trough concentration of about 15 ng/mL as measured by high performance liquid chromatography with ultraviolet detection. After the switch from sirolimus to everolimus, they were given 10 or 12 mg/day of everolimus twice a day to maintain a trough concentration of 12-15 ng/mL as measured by a fluorescence polarization immunoassay (FPIA) method. Afterward, the blood concentrations of everolimus and sirolimus after the conversion were measured by high performance liquid chromatography with mass spectrometry and everolimus concentrations were found to be 5-10 ng/mL. These data show that a larger dosage is needed for everolimus than sirolimus to maintain the same trough blood concentration. Data obtained by the FPIA for everolimus should be carefully evaluated after switching from sirolimus to everolimus because of the cross-reactivity of the antibody with sirolimus.JAP SOC STUDY XENOBIOTICS, 2009年, DRUG METABOLISM AND PHARMACOKINETICS, 24(2) (2), 175 - 179, 英語[査読有り]研究論文（学術雑誌）
- The pharmacokinetics of vancomycin was retrospectively examined based on trough concentrations obtained during routine therapeutic drug monitoring to examine possible pharmacokinetic differences between adult Japanese cancer and non-cancer patients with various degrees of renal function. A total of 231 data points from 65 cancer patients and 41 non-cancer patients were collected, and patients' background, vancomycin dose, and vancomycin clearance estimated by an empirical Bayesian method were summarized. Regarding the patients' characteristics and clinical laboratory test data, no clear differences were found between the two groups. The relationship between vancomycin clearance and creatinine clearance were similar between the groups, suggesting little effect of malignancy on vancomycin clearance. After the sub-group comparisons regarding fluid retention and cancer type, no clear differences were found in the vancomycin clearance versus creatinine clearance relationship. We conclude that the initial dose of vancomycin should not necessarily be adjusted for cancer patients. For individualized vancomycin-based therapy, dose adjustment at the appropriate time is important according to information from routine therapeutic drug monitoring and clinical laboratory tests, and to observations of the efficacy, nephrotoxicity, and other conditions in each patient.PHARMACEUTICAL SOC JAPAN, 2009年01月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 32(1) (1), 99 - 104, 英語[査読有り]研究論文（学術雑誌）
- We attempted a switch of mammalian target of rapamycin (mTOR) inhibitors from sirolimus to everolimus, a derivative of sirolimus and now on the market in Japan, in two pancreatic islet transplant patients. Both patients were administered tacrolimus with sirolimus or everolimus. They had been administered 5 or 9 mg sirolimus once a day and had maintained a trough concentration of about 15 ng/mL as measured by high performance liquid chromatography with ultraviolet detection. After the switch from sirolimus to everolimus, they were given 10 or 12 mg/day of everolimus twice a day to maintain a trough concentration of 12-15 ng/mL as measured by a fluorescence polarization immunoassay (FPIA) method. Afterward, the blood concentrations of everolimus and sirolimus after the conversion were measured by high performance liquid chromatography with mass spectrometry and everolimus concentrations were found to be 5-10 ng/mL. These data show that a larger dosage is needed for everolimus than sirolimus to maintain the same trough blood concentration. Data obtained by the FPIA for everolimus should be carefully evaluated after switching from sirolimus to everolimus because of the cross-reactivity of the antibody with sirolimus.JAP SOC STUDY XENOBIOTICS, 2009年, DRUG METABOLISM AND PHARMACOKINETICS, 24(2) (2), 175 - 179, 英語[査読有り]研究論文（学術雑誌）
- 2009年, Frontiers in Drug Design and Discovery, 4(1) (1), 97 - 121, 英語Important drug interactions for clinical oncologists[査読有り]
- 2009年, Frontiers in Drug Design and Discovery, 4(1) (1), 122 - 134, 英語Pharmacogenomic considerations in breast cancer management[査読有り]
- A Retrospective Analysis of Vancomycin Pharmacokinetics in Japanese Cancer and Non-cancer Patients Based on Routine Trough Monitoring DataThe pharmacokinetics of vancomycin was retrospectively examined based on trough concentrations obtained during routine therapeutic drug monitoring to examine possible pharmacokinetic differences between adult Japanese cancer and non-cancer patients with various degrees of renal function. A total of 231 data points from 65 cancer patients and 41 non-cancer patients were collected, and patients' background, vancomycin dose, and vancomycin clearance estimated by an empirical Bayesian method were summarized. Regarding the patients' characteristics and clinical laboratory test data, no clear differences were found between the two groups. The relationship between vancomycin clearance and creatinine clearance were similar between the groups, suggesting little effect of malignancy on vancomycin clearance. After the sub-group comparisons regarding fluid retention and cancer type, no clear differences were found in the vancomycin clearance versus creatinine clearance relationship. We conclude that the initial dose of vancomycin should not necessarily be adjusted for cancer patients. For individualized vancomycin-based therapy, dose adjustment at the appropriate time is important according to information from routine therapeutic drug monitoring and clinical laboratory tests, and to observations of the efficacy, nephrotoxicity, and other conditions in each patient.PHARMACEUTICAL SOC JAPAN, 2009年01月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 32(1) (1), 99 - 104, 英語[査読有り]研究論文（学術雑誌）
- 2008年11月, 日本病院薬剤師会雑誌, 44(11号) (11号), 1629 - 1632, 日本語薬学教育六年制に向けた外来薬剤交付実習の取り組みとその評価[査読有り]研究論文（学術雑誌）
- 2008年10月, TDM研究, 25(4号) (4号), 165 - 169, 日本語成人難治性てんかん患者におけるクロバザムおよび活性代謝物の体内動態に関する解析[査読有り]研究論文（学術雑誌）
- サイバーオンコロジーを用いて、外来癌化学療法の副作用である悪心・嘔吐の発現における性差の関与をレトロスペクティブに解析した。レベル5となるレジメンの化学療法を施行した日本人患者117例(男性70例、女性47例)を対象とした。対象レジメンによる治療でグレード2以上の悪心は11%(13/117例)、嘔吐は14%(16/117例)に発現した。FEC及びABVD施行症例で、悪心・嘔吐の発現割合が高かった。癌の種類別では、乳癌や悪性リンパ腫でグレード2以上の悪心・嘔吐の発現割合が高く、胃癌では少なかった。グレード2以上の発現割合は悪心・嘔吐共に女性で有意に高かった。悪心のオッズ比は8.77で、有意に女性が高く、嘔吐のオッズ比は3.26で、女性の発現割合がやや高かった。(一社)日本医療薬学会, 2008年08月, 医療薬学, 34(8) (8), 742 - 747, 日本語
- Patients admitted for surgical procedures have often taken a variety of medicines for heart disease or hypertension in addition to those for their underlying diseases. In this study, we examined the withdrawal periods for anticoagulants and antihypertensive medicines before surgery, and investigated the effect of angiotensin II receptor (ATII) antagonists on blood pressure during surgery. In July 2005, 300 patients underwent surgical procedures in the Day-Surgery Unit and 314 in the surgical wards (excluding ophthalmology). We prepared a chart of recommended withdrawal periods before surgery, and based on it investigated the withdrawal periods for these patients. Furthermore, patients were assigned to 2 groups : Group I in which ATII antagonists were withdrawn 24 hours prior to surgery or earlier (n=10) ; and Group II, in which ATII antagonists were administered in the morning of the day of surgery day (n=9), and compared blood pressures between two groups. Forty-four patients (16.7%) in the Day-Surgery Unit and 47 patients (15.0%) in the surgery wards had been taking anticoagulants, angiotensin converting enzyme inhibitors or ATII antagonists. In the case of 10 patients in the Day-Surgery Unit and 12 patients in the surgery wards, anticoagulants were not discontinued sufficiently long enough before surgery. Further, patients who had been taking ATII antagonists had lower systemic blood pressures and more frequent episodes of hypotension than those not on ATII antagonists, although these differences were not statistically significant. In conclusion, pharmacists should provide doctors with adequate information regarding times of drug withdrawal to reduce risks while patients are under anesthesia.日本医療薬学会, 2008年08月, 医療薬学, 34(8号) (8号), 773 - 780, 日本語[査読有り]研究論文（学術雑誌）
- 2008年05月, 日本病院薬剤師会雑誌, 44(5号) (5号), 744 - 746, 日本語高眼圧患者におけるアセタゾラミド投与量と副作用発現の危険因子に関する検討[査読有り]研究論文（学術雑誌）
- Objective The potential influence of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes, CYP3A4 and CYP3A5, on the oral clearance (CL/F) of tacrolimus in adult living-donor liver transplant patients was examined. Furthermore, the development of renal dysfunction was analyzed in relation to the CYP3A5 genotype. Methods Sixty de novo adult liver transplant patients receiving tacrolimus were enrolled in this study. The effects of various covariates (including intestinal and hepatic mRNA levels of MDR1 and CYP3A4, measured in each tissue taken at the time of transplantation, and the CYP3A5*3 polymorphism) on CL/F during the first 50 days after surgery were investigated with the nonlinear mixed-effects modeling program. Results CL/F increased linearly until postoperative day 14, and thereafter reached a steady state. The initial CL/F immediately after liver transplantation was significantly affected by the intestinal MDR1 mRNA level (P<0.005). Furthermore, patients carrying the CYP3A5*1 allele in the native intestine, but not in the graft liver, showed a 1.47 times higher (95% confidence interval, 1.17-1.77 times, P<0.005) recovery of CL/F with time than patients having the intestinal CYP3A5*3/*3 genotype. The cumulative incidence of renal dysfunction within 1 year after transplantation, evaluated by the Kaplan-Meier method, was significantly associated with the recipient's but not donor's CYP3A5 genotype (*1/*1 and *1/*3 vs. *3/*3: recipient, 17 vs. 46%, P<0.05; donor, 35 vs. 38%, P=0.81). Conclusion These findings suggest that the CYP3A5*1 genotype as well as the MDR1 mRNA level in enterocytes contributes to interindividual variation in the CL/F of tacrolimus in adult recipients early after living-donor liver transplantation. Furthermore, CYP3A5 in the kidney may play a protective role in the development of tacrolimus-related nephrotoxicity.LIPPINCOTT WILLIAMS & WILKINS, 2008年05月, PHARMACOGENETICS AND GENOMICS, 18(5) (5), 413 - 423, 英語[査読有り]研究論文（学術雑誌）
- 2008年02月, 日本病院薬剤師会雑誌, 44(2号) (2号), 265 - 267, 日本語電子カルテ導入に伴う疑義照会の質的向上と薬剤師の役割[査読有り]研究論文（学術雑誌）
- Calcineurin inhibitors, tacrolimus and cyclosporine, have been widely used to prevent the rejection or graft-versus-host disease after transplantations. Since these drugs have a narrow therapeutic range and show large inter- and intraindividual pharmacokinetic variability, frequent therapeutic drug monitoring is required to control their blood concentrations. Even with blood concentrations within the therapeutic range, some patients still experience acute rejection or infections. Tacrolimus and cyclosporine form a complex with their respective binding proteins, immunophilins, which in turn inhibit the phosphatase activity of calcineurin, a key enzyme in the activation of T lymphocytes. Pharmacodynamic assessment of calcineurin phosphatase activity in combination with the monitoring of blood concentrations has been studied. The inhibitory effects on calcineurin activity in peripheral blood mononuclear cells differed between tacrolimus and cyclosporine in transplant patients. The pharmacodynamics of both drugs shows great inter- as well as intraindividual variation, and acute rejection was associated with calcineurin activity. Calcineurin activity at trough time points was suggested as a single surrogate predictor for overall calcineurin activity throughout dosing periods. Monitoring of calcineurin phosphatase activity might be useful to determine the therapeutic range of tacrolimus and cyclosporine concentrations for an individual patient treated with a calcineurin inhibitor.JAP SOC STUDY XENOBIOTICS, 2008年, DRUG METABOLISM AND PHARMACOKINETICS, 23(3) (3), 150 - 157, 英語[査読有り]
- The aim of this study was to quantitatively evaluate the effects of intestinal and hepatic extraction on the pharmacokinetics of everolimus in rats. Everolimus was administered intravenously, intraportally or intraintestinally in order to separately evaluate the intestinal and hepatic first-pass extraction. Cyclosporine or tacrolimus was administered into rat intestines, and after 10 min everolimus pharmacokinetics were evaluated. The blood concentrations of everolimus were measured by the high-performance liquid chromatography with tandem mass spectrometry. Total body clearance of everolimus was constant in the dosage from 0.2 to 1.0 mg/kg. The bioavailability after intraportal and intraintestinal administration were 48.0% and 21.2%, respectively. Concomitantly administered cyclosporine (5 mg/kg), but not tacrolimus (1 mg/kg), significantly decreased the total body clearance of everolimus compared with the control, and also increased the bioavailabilty of everolimus after intraintestinal administration 1.75-fold. Cyclosporine significantly increased the area under the blood concentration-time curve of everolimus after the intraintestinal constant infusion 3-fold, and increased that after the intraportal constant infusion only 1.35-fold. In conclusion, the intestine as well as liver contributes to the first-pass extraction for everolimus in rats. Intestinally administered cyclosporine inhibited the intestinal extraction of everolimus more than its hepatic extraction.JAP SOC STUDY XENOBIOTICS, 2008年, DRUG METABOLISM AND PHARMACOKINETICS, 23(6) (6), 469 - 475, 英語[査読有り]研究論文（学術雑誌）
- 2007年10月, 日本病院薬剤師会雑誌, 43(10号) (10号), 1377 - 1380, 日本語加齢黄斑変性症の光線力学的療法における薬剤業務 ベルテポルフィンの調製と患者指導[査読有り]研究論文（学術雑誌）
- Background We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel. Methods. Paclitaxel was administered at 175mg/m(2) or 150mg/m(2) to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1 (ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated. Results. Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-mu M concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel. Conclusion. The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.SPRINGER TOKYO, 2007年08月, INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 12(4) (4), 284 - 290, 英語[査読有り]研究論文（学術雑誌）
- EMIT,a homogeneous enzyme immunoassay for the quantitative analysis of mycophenolic acid (MPA) in human plasma,was evaluated in comparison with high-performance liquid chromatography (HPLC).For EMIT,coefficients of variation (CV) for within-run measurements (1~12μg/mL,n=20)varied from 4.07% to 5.16% and CVs for between-day measurements (1~12μg/mL,n=20)ranged from 2.23% to 5.63%.The lower limit of detection was 0.20μg/mL.When MPA plasma concentrations were simultaneously measured using EMIT and HPLC,there was a good linear relationship between the 2 assay methods showing a high degree of correlation : EMIT=1.13×HPLC+0.164 ; r2=0.967,51 points in 16 liver transplant recipients,EMIT=1.10×HPLC+0.305 ; r2=0.948,55 points in 15 renal transplant recipients and EMIT=1.06×HPLC-0.014 ; r2=0.887,300 points in 8 islet transplant recipients.These results indicate that EMIT is a convenient means of measuring MPA in plasma.Japanese Society of Pharmaceutical Health Care and Sciences, 2007年, 医療薬学, 33(9) (9), 804 - 808, 日本語
- Gefitinib (Iressa®), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is effective in patients with advanced non-small cell lung cancer (NSCLC). However, since interstitial lung disease, a fatal adverse event, has occurred more frequently since gefitinib came on to the market, and ISEL and SWOG 0023 examinations have not shown any significant life-extending efficacy, patients have started to feel uneasy about being treated with it. In these circumstances, in the present study, we created a system under which pharmacists can be directly involved in treatment with gefitinib and monitor for adverse events. The subjects were 98 patients with NSCLC who were treated at our hospital, and received gefitinib at a dose of 250 mg once daily. We made a leaflet describing gefitinib and a check sheet for adverse events, and using them, explained the expected adverse events to patients and monitored their conditions. Common drug-related adverse events occurring were rash (54%), pruritus (29%) and diarrhea (23%), and most were graded as mild in degree (grade 1 or 2). Interstitial lung disease was observed in 10 of the 98 patients (10.2%), but none died. Liver injuryJapanese Society of Pharmaceutical Health Care and Sciences, 2007年, 医療薬学, 33(1) (1), 1 - 7, 日本語
- Proton-pump inhibitors (PPIs, e. g. omeprazole and rabeprazole) are often administered to transplant patients as a treatment or prophylaxis for ulcers after surgery. Since tacrolimus and PPIs share the CYP3A4 system for metabolism, pharmacokinetic interactions are anticipated when they are administered simultaneously. We present a Japanese male patient who underwent a living-donor kidney transplantation having received tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression. The concentration/dose (C/D) ratio for tacrolimus was markedly higher during the period of treatment with omeprazole than ranitidine or rabeprazole. The results of liver functional tests were within the normal range during the use of these three antacid drugs. Since the higher C/D ratio for tacrolimus when omeprazole was being administered did not result from a decrease in the elimination of tacrolimus due to hepatic dysfunction, drug interaction between omeprazole and tacrolimus was strongly suspected. The present case indicates that rabeprazole can be used safely in place of omeprazole in kidney transplant recipients receiving tacrolimus.JAP SOC STUDY XENOBIOTICS, 2007年, DRUG METABOLISM AND PHARMACOKINETICS, 22(6) (6), 441 - 444, 英語[査読有り]研究論文（学術雑誌）
- 新規抗精神病薬の臨床導入に伴う処方内容の変化 大学病院精神科外来における検討当院においてリスペリドン導入後5年の2001年とクエチアピン、ペロスピロン、オランザピン追加導入後3年の2004年における新規抗精神病薬の処方動向を調査した。対象は外来の統合失調症患者で2001年262名、2004年203名であった。その結果、2001年から2004年で新規抗精神病薬の単剤処方率は17.2%から35%に増加し、併用例も含めると30.9%から70%に増加していたが、新規抗精神病薬処方患者に占める新規抗精神病薬の単剤使用率は55.6%から50%に減少し、2004年の併用患者の多くが従来型抗精神病薬との併用であった。2004年における新規抗精神病薬の単剤使用率はオランザピン58.1%、リスペリドン44.9%、ペロスピロン46.7%、クエチアピン16.7%であった。抗パーキンソン薬の処方率は83.6%から69%に低下し、新規向精神病薬の単剤群では抗パーキンソン薬の併用は新規従来併用群や従来群と比較して有意に低く、抗パーキンソン薬の処方量は新規単剤群で有意に少なかった。従来型抗精神病薬の併用により新規抗精神病薬の特性が損なわれる可能性が示唆された。(一社)日本医療薬学会, 2007年01月, 医療薬学, 33(1) (1), 60 - 65, 日本語[査読有り]研究論文（学術雑誌）
- Distinct effects of omeprazole and rabeprazole on the tacrolimus blood concentration in a kidney transplant recipientProton-pump inhibitors (PPIs, e. g. omeprazole and rabeprazole) are often administered to transplant patients as a treatment or prophylaxis for ulcers after surgery. Since tacrolimus and PPIs share the CYP3A4 system for metabolism, pharmacokinetic interactions are anticipated when they are administered simultaneously. We present a Japanese male patient who underwent a living-donor kidney transplantation having received tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression. The concentration/dose (C/D) ratio for tacrolimus was markedly higher during the period of treatment with omeprazole than ranitidine or rabeprazole. The results of liver functional tests were within the normal range during the use of these three antacid drugs. Since the higher C/D ratio for tacrolimus when omeprazole was being administered did not result from a decrease in the elimination of tacrolimus due to hepatic dysfunction, drug interaction between omeprazole and tacrolimus was strongly suspected. The present case indicates that rabeprazole can be used safely in place of omeprazole in kidney transplant recipients receiving tacrolimus.JAP SOC STUDY XENOBIOTICS, 2007年, DRUG METABOLISM AND PHARMACOKINETICS, 22(6) (6), 441 - 444, 英語[査読有り]研究論文（学術雑誌）
- Objective: Our objective was to investigate the population pharmacokinetics of tacrolimus in pediatric living-donor liver transplant recipients and examine the effects of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 on the oral clearance of tacrolimus. Methods. Data were collected retrospectively from 130 de novo pediatric liver transplant recipients treated with tacrolimus during the first 50 postoperative days. Pharmacogenomic data including both the CYP3A5*3 polymorphism and messenger ribonucleic acid (mRNA) expression levels of MDR1, CYP3A4, and CYP3A5 in the native intestine and the graft liver at transplantation were obtained from 65 of the recipients. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modeling program NONMEM to estimate population mean parameters of apparent clearance (CL/F) and apparent volume of distribution (V/F). Results. Both CL/F and V/F were allometrically related to body weight, and CL/F decreased when the AST value was elevated. CL/F increased linearly in the immediate postoperative period but did not change with time after postoperative day 21. The intestinal MDR1 mRNA level significantly influenced the initial CL/F (P < .005). Furthermore, the increase in CL/F over time was 2 times higher (95% confidence interval, 1.19-2.81 times; P < .005) in recipients of a CYP3A5*1-carrying graft liver than in patients with the hepatic CYP3A5*3/*3 genotype. The Bayesian prediction for tacrolimus concentrations was not significantly biased on any postoperative day, and the mean absolute prediction error was lower than 3 ng/mL after the first 2 weeks of transplantation. Conclusions. The enterocyte MDR1 mRNA level and the CYP3A5*1 allele in the graft liver contribute differently to the interindividual variability in the oral clearance of tacrolimus after living-donor liver transplantation.MOSBY, INC, 2006年10月, CLINICAL PHARMACOLOGY & THERAPEUTICS, 80(4) (4), 331 - 345, 英語[査読有り]研究論文（学術雑誌）
- For hormone refractory prostate carcinoma, a combination therapy of paclitaxel and carboplatin is used to expect life extention. We investigated the pharmacokinetics of carboplatin in Japanese prostate cancer patients. (n=10, 55-72 years), and evaluated the usefulness of Calvert's formula in the individualized dosing adjustment. They were intravenously administered carboplatin (area under the free plasma concentration versus time curve (AUC)=5mg(.)min/ml), following the intravenous administration of paclitaxel (175mg/m(2)). The dosage of carboplatin for each patient was determined with Calvert's formula using individual creatinine clearance values. Plasma concentration of total platinum was measured sequentially and the pharmacokinetic parameters of carboplatin were determined in each patient. Plasma concentration of total carboplatin after intravenous infusion well fitted the two-compartment model. Carboplatin clearance was 62.0 +/- 12.7 ml/min (mean +/- S.D.), and linearly related to the individual creatinine clearance (r(2) = 0.64, p < 0.01). The actual AUC for total carboplatin was 8.20 +/- 1.11 mg (.) min/ml, and its inter-individual variability was decreased to 65% of that in carboplatin clearance, indicating the effectiveness of Calvert's formula for dosage adjustment of carboplatin. Leucopenia of grade 4 according to the National Cancer Institute's Common Toxicity Criteria was found in one patient, but no patient demonstrated thrombocytopenia. In conclusion, determining carboplatin dosage based on Calvert's formula decreased the inter-individual variability in the actual AUC compared with that in the carboplatin clearance, and a target AUC of 5 mg (.) min/ml of carboplatin was comparatively safe for Japanese patients with prostate cancer.PHARMACEUTICAL SOC JAPAN, 2006年07月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 29(7) (7), 1441 - 1444, 英語[査読有り]研究論文（学術雑誌）
- We prepared data sheets to consolidate information on adverse reactions occurring in combination chemotherapy. Using them, we monitored adverse reactions due to combination therapy consisting of vincristine, nimustine, carboplatin, interferon-β and radiation therapy (VAC-F-R) in 50 patients with brain tumors, and evaluated their severity using the Common Terminology Criteria for Adverse Events v.3.0. The incidences of adverse reactions due to the VAC-F-R protocol were then compared with that for adverse reactions due to existing monotherapy. With VAC-F-R, a high incidences were observed for appetite loss (86%), nausea (68%) and vomiting (34%), and the incidences of leucopenia and thrombocytopenia with grade 3 or higher were 60% and 24%, respectively. Vomiting and fever could be prevented by pretreatment with a 5HT_3 receptor antagonist and non-steroidal anti-inflammatory drugs. While the incidences of the unpreventable adverse reactions were 1.5-to 5-fold greater than those seen with monotherapy, there was no difference in the time of the nadir for leucopenia and thrombocytopenia as compared to monotherapy with nimusitine. Our efforts to consolidate information on adverse reactions due to a particular chemotherapy regimen have helped decrease their severity in cancer patients and improve their quality of life.日本医療薬学会, 2006年07月, 医療薬学, 32(7号) (7号), 599 - 606, 日本語[査読有り]研究論文（学術雑誌）
- For hormone refractory prostate carcinoma, a combination therapy of paclitaxel and carboplatin is used to expect life extention. We investigated the pharmacokinetics of carboplatin in Japanese prostate cancer patients. (n=10, 55-72 years), and evaluated the usefulness of Calvert's formula in the individualized dosing adjustment. They were intravenously administered carboplatin (area under the free plasma concentration versus time curve (AUC)=5mg(.)min/ml), following the intravenous administration of paclitaxel (175mg/m(2)). The dosage of carboplatin for each patient was determined with Calvert's formula using individual creatinine clearance values. Plasma concentration of total platinum was measured sequentially and the pharmacokinetic parameters of carboplatin were determined in each patient. Plasma concentration of total carboplatin after intravenous infusion well fitted the two-compartment model. Carboplatin clearance was 62.0 +/- 12.7 ml/min (mean +/- S.D.), and linearly related to the individual creatinine clearance (r(2) = 0.64, p < 0.01). The actual AUC for total carboplatin was 8.20 +/- 1.11 mg (.) min/ml, and its inter-individual variability was decreased to 65% of that in carboplatin clearance, indicating the effectiveness of Calvert's formula for dosage adjustment of carboplatin. Leucopenia of grade 4 according to the National Cancer Institute's Common Toxicity Criteria was found in one patient, but no patient demonstrated thrombocytopenia. In conclusion, determining carboplatin dosage based on Calvert's formula decreased the inter-individual variability in the actual AUC compared with that in the carboplatin clearance, and a target AUC of 5 mg (.) min/ml of carboplatin was comparatively safe for Japanese patients with prostate cancer.PHARMACEUTICAL SOC JAPAN, 2006年07月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 29(7) (7), 1441 - 1444, 英語[査読有り]研究論文（学術雑誌）
- The Outpatient Oncology Unit of Kyoto University Hospital, which has a full-time staff, was established in October 2003. Before it was established, different kinds of regimens for outpatient chemotherapy were independently used by various departments for the same types of cancer. In order to further improve the safety of chemotherapy for outpatients, we unified the regimens under the control of the oncology Unit and registered the set prescriptions for them in the ordering system. These regimens were checked by pharmacists as to whether they were suitable as infusions and complied with health insurance indications. Sixty-three regimens were registered when the Unit was established. There was a further increase in the number of prescriptions during the half-year period after the Unit was established, and they were registered between June and December 2004, bringing the total number of registered regimens to 79. The registration of chemotherapy regimens has enabled all the medical staff of the Unit to have access to the same information, and pharmacists are able to check them easily. The use of such set prescriptions has helped prevent simple mistakes and allowed chemotherapy to be conducted more safely. In addition, the rate of questions about prescriptions decreased from 10% at the time of establishing the Unit to 3% in January 2005 due to the introduction of a prescription support system. In conclusion, the registration of the regimens has helped the Outpatient Oncology Unit to conduct standard chemotherapy more safely and improve cooperation with each department on outpatient chemotherapy.日本医療薬学会, 2006年04月, 医療薬学, 32(4号) (4号), 327 - 333, 日本語[査読有り]研究論文（学術雑誌）
- Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: Twice daily vs. once daily dosingWe have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once- and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n = 5) or once daily in the morning (QD, n = 9) after transplantation. On postoperative day (POD) 6, the OD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C-2) and area under the concentration-time curve (AUC) for 4 hours (AUC(0-4)), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA(0-12)) and 24 hours (AUA(0-21)) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C2 level was significantly correlated with the AUC(0-4) (r(2) = 0.95), which was negatively related to the AUA(0-12) with a large interindividual variability (r(2) = 0.59). However, a significant correlation was found between the AUA(0-1)2 or AUA(0-24), and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (E-max) model, the mean estimates of E-max and the C-b value that gives a half-maximal effect (EC50) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Furthermore, CaN activity at trough time points would be a single surrogate predictor for the overall CaN activity throughout dosing intervals following cyclosporine administration.JOHN WILEY & SONS INC, 2006年02月, LIVER TRANSPLANTATION, 12(2) (2), 292 - 300, 英語[査読有り]研究論文（学術雑誌）
- Tacrolimus is a calcineurin inhibitor that has been widely used to prevent allograft rejection after transplantation. We report a case of a living-donor liver transplant recipient experiencing a considerable increase in the trough blood concentration of tacrolimus after concomitant ingestion of grapefruit juice (250 mL) 4 times for 3 days. The trough blood concentrations of tacrolimus were not changed during or immediate after the repeated intake of grapefruit juice. However, almost 1 week after the final ingestion, the blood concentration of tacrolimus markedly increased to as much as 47.4 ng/mL from 4.7 ng/mL before the ingestion, resulting in a profound reduction of calcineurin phosphatase activity in peripheral blood mononuclear cells. Furthermore, headache and nausea, but not nephrotoxicity or hyperglycemia, took place throughout the period of the elevated blood concentrations. Grapefruit juice may have a clinically significant effect on the pharmacokinetics and pharmacodynamics of tacrolimus. It is recommended to avoid the consumption of grapefruit juice in transplant recipients treated with tacrolimus.JAP SOC STUDY XENOBIOTICS, 2006年, DRUG METABOLISM AND PHARMACOKINETICS, 21(2) (2), 122 - 125, 英語[査読有り]研究論文（学術雑誌）
- Pancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.JAP SOC STUDY XENOBIOTICS, 2006年, DRUG METABOLISM AND PHARMACOKINETICS, 21(6) (6), 492 - 500, 英語[査読有り]研究論文（学術雑誌）
- 2006年01月, 日本病院薬剤師会雑誌, 42(1号) (1号), 49 - 52, 日本語全診療科を対象とした「がん化学療法説明書」の作成とその運用[査読有り]研究論文（学術雑誌）
- Temporal decline in Sirolimus elimination immediately after pancreatic islet transplantationPancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.JAP SOC STUDY XENOBIOTICS, 2006年, DRUG METABOLISM AND PHARMACOKINETICS, 21(6) (6), 492 - 500, 英語[査読有り]研究論文（学術雑誌）
- Cisplatin is an effective anticancer drug, but has its severe adverse effects, especially nephrotoxicity. The molecular mechanism of cisplatin-induced nephrotoxicity is still not clear. In the present study, we examined the role of rat (r)OCT2, an organic cation transporter predominantly expressed in the kidney, in the tubular toxicity of cisplatin. Using HEK293 cells stably expressing rOCT2 (HEK-rOCT2), we evaluated the cisplatin-induced release of lactate dehydrogenase and the uptake of cisplatin. The release of lactate dehydrogenase and the accumulation of platinum were greater in HEK-rOCT2 cells treated with cisplatin than in mock-transfected cells. Moreover, cimetidine and corticosterone, OCT2 inhibitors, inhibited the cytotoxicity and the transport of cisplatin in HEK-rOCT2 cells. Pharmacokinetics of cisplatin was investigated in male and female rats because the renal expression level of rOCT2 was higher in male than female rats. The renal uptake clearance of cisplatin was greater in male than female rats, while the hepatic uptake clearance was similar between the sexes. In addition, glomerular filtration rate and liver function were unchanged, but N-acetyl-beta-(D)-glucosaminidase activity in the bladder urine and the urine volume were markedly increased 2 days after the administration of 2 mg/kg of cisplatin in male rats. Moreover, cisplatin did not induce the elevation of urinary N-acetyl-beta-(D)-glucosaminidase activity in the castrated male rats whose renal rOCT2 level was lower than that of the sham-operated rats. In conclusion, the present results indicated that renal rOCT2 expression was the major determinant of cisplatin-induced tubular toxicity. (c) 2005 Elsevier Inc. All rights reserved.PERGAMON-ELSEVIER SCIENCE LTD, 2005年12月, BIOCHEMICAL PHARMACOLOGY, 70(12) (12), 1823 - 1831, 英語[査読有り]研究論文（学術雑誌）
- Background: The calcineurin inhibitors tacrolimus and cyclosporine (INN, ciclosporin) have been widely used to prevent allograft rejection after transplantation. We investigated pharmacodynamic properties of the 2 drugs and their clinical relevance in liver transplantation. Methods: Forty de novo living-donor liver transplant patients participated in this study, and they were treated with either tacrolimus (N = 30) or cyclosporine (N = 10). We simultaneously measured blood drug concentrations and calcineurin phosphatase activity in peripheral blood mononuclear cells during the first 14 postoperative days. Nephrotoxicity and acute rejection were also examined in relation to the blood drug concentrations and calcineurin activity. Results: Calcineurin activity was only partially inhibited by tacrolimus concentrations greater than 20 ng/ mL, although it could be almost completely inhibited by cyclosporine concentrations greater than 700 ng/mL. According to a maximum effect model, the population mean estimates of the EC50 (blood concentration that yields a half-maximal effect) for tacrolimus and cyclosporine were 26.4 ng/mL (95% confidence interval [CI], 15.7-37.1 ng/mL) and 200 ng/mL (95% CI, 127-274 ng/mL), respectively. Patients with nephrotoxicity in both groups had significantly higher trough concentrations compared with those without this adverse event. In addition, patients with acute rejection in the tacrolimus group had significantly lower trough concentrations and higher calcineurin activity than those without a rejection episode. Conclusions: The inhibitory effects on calcineurin activity in peripheral blood mononuclear cells differed between tacrolimus and cyclosporine in living-donor liver transplant patients. Pharmacodynamic assessment in combination with blood concentration monitoring may be useful for determining the individual therapeutic range of tacrolimus and cyclosporine.MOSBY, INC, 2005年08月, CLINICAL PHARMACOLOGY & THERAPEUTICS, 78(2) (2), 168 - 181, 英語[査読有り]研究論文（学術雑誌）
- 外来化学療法加算が新設されたことを契機に,外来化学療法部設置に向けた検討を始めた.抗癌剤投与の安全管理体制の構築,運用について開設後4ヵ月間の実績に基づいた評価を含めて報告した.4診療科にわたる63レジメンを事前登録した.レジメンに基づき処方のセット化を行ったことにより,処方せんおよびラベルにレジメン名を記載することが可能となり,処方点検の際の有用な情報源となった.疑義照会内容を翌日の患者リストに記載し,専任医師に直接照会することで,実施前日中に処方を修正できた.外来化学療法部に薬剤師2名が常駐する体制をとり,午前中の患者の来院が集中する時間帯は,3人での調製体制をとることで,より安全に業務を行うことができた(一社)日本医療薬学会, 2005年04月, 医療薬学, 31(4) (4), 301 - 306, 日本語
- We previously reported that in hyperuricemic rats, renal impairment occurred and organic ion transport activity decreased, accompanied with a specific decrease in the expression of rat organic anion transporters, rOAT1 and rOAT3, and organic cation transporter, rOCT2. In the present study, we investigated the reversibility of the organic ion transport activity and expression of organic ion transporters (slc22a) during recovery from hyperuricemia. Hyperuricemia was induced by the administration of a chow containing uric acid and oxonic acid, an inhibitor of uric acid metabolism. Four days after discontinuance of the chow, the plasma uric acid concentration returned to the normal level, and renal functions such as creatinine clearance and BUN levels were restored, although the recovery of tubulointerstitial injury was varied in sites of the kidney. Basolateral uptake of p-aminohippurate (PAH) and tetraethylammonium (TEA), and both protein and mRNA levels of rOAT1, rOAT3 and rOCT2 in the kidney gradually improved during 14 days of recovery from hyperuricemia. Basolateral PAH transport showed a higher correlation with the protein level of rOAT1 (r(2) = 0.80) than rOAT3 (r(2) = 0.34), whereas basolateral TEA transport showed a strong correlation with rOCT2 protein (r(2) = 0.91). The plasma testosterone concentration, which is a dominant factor in the regulation of rOCT2, was gradually restored during the recovery from hyperuricemia, but the correlation between the plasma testosterone level and rOCT2 protein expression in the kidney was not significant. These results suggest that the regulation of organic ion transporters, rOAT1, rOAT3 and rOCT2, by hyperuricernia is reversible, and the organic ion transport activity restores according to the expression levels of these transporters. (c) 2005 Elsevier Inc. All rights reserved.PERGAMON-ELSEVIER SCIENCE LTD, 2005年03月, BIOCHEMICAL PHARMACOLOGY, 69(6) (6), 993 - 999, 英語[査読有り]研究論文（学術雑誌）
- We have compared the pharmacodynamic properties of calcineurin inhibitors tacrolimus and cyclosporin A in rats to clarify the different therapeutic drug monitoring strategy of both drugs in a clinical situation. In various tissue extracts, the inhibition of calcineurin activity by cyclosporin A was significantly greater than that by tacrolimus at the same drug concentration ( 1 muM) in the thymus, heart, liver, spleen, kidney, and testis ( p < 0.05). The time profiles of blood concentrations and calcineurin activity in whole blood were examined after single or repeated administration of each drug in rats. A substantial time delay in the inhibition was observed following the single administration of tacrolimus or cyclosporin A, resulting in an anticlockwise hysteresis in the relationship between blood concentrations and calcineurin inhibition in whole blood. In contrast, such a hysteresis loop diminished after the repeated administration of each drug, and the recovery rate of calcineurin activity was greater for the inhibition induced by cyclosporin A than by tacrolimus. Furthermore, tacrolimus produced a comparable inhibition of calcineurin activity in whole blood at lower blood concentrations than cyclosporin A. Overall, the effect compartment model well described the time profiles of calcineurin activity in whole blood after the single and repeated administrations of each drug. These findings suggest that the properties of calcineurin inhibition differ between tacrolimus and cyclosporin A. Distinct pharmacodynamics may partly contribute to the therapeutic drug monitoring strategy in transplant patients receiving calcineurin inhibitors.AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2005年02月, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 312(2) (2), 816 - 825, 英語[査読有り]研究論文（学術雑誌）
- Purpose. The aim of this study was to investigate the effect of hepatic or renal insufficiency on the pharmacokinetics of paclitaxel in rats. Methods. Rats were treated with carbon tetrachloride (CCl4; 0.5 ml/kg) to induce hepatic failure or were subjected to 5/6 nephrectomy (5/6 Nx) to induce renal failure. Paclitaxel (3 mg/kg) was administered intravenously or intraportally. Testosterone 6 beta-hydroxylase activity, which is a marker of CYP3A activity, was measured in rat liver microsomes from CCl4-treated or 5/6 Nx rats. Results. After paclitaxel was administered intravenously, total body clearance was significantly reduced by 73% and 34% relative to each control value in CCl4-treated and 5/6 Nx rats, respectively (control, 1.82 +/- 0.42 vs. CCl4-treated, 0.49 +/- 0.11; sham, 1.54 +/- 0.07 vs. 5/6 Nx, 1.01 +/- 0.12 L h(-1) kg(-1); mean SE, n = 5 to 6). Testosterone 6 beta-hydroxylase activity was reduced by 92% and 59% relative to each control value in rat liver microsomes from CCl4-treated and 5/6 Nx rats, respectively. After the intraportal administration of paclitaxel, apparent clearance was reduced by 85% relative to control value in rats with hepatic failure. while that in rats with renal failure was the same as the reduction in systemic clearance. Conclusions. These results suggested that not only hepatic failure but also renal failure could modify the pharmacokinetics of paclitaxel in vivo.SPRINGER/PLENUM PUBLISHERS, 2005年02月, PHARMACEUTICAL RESEARCH, 22(2) (2), 228 - 234, 英語[査読有り]研究論文（学術雑誌）
- 2005年, Japanese Journal of Clinical Pharmacology and Therapeutics, 36(2) (2), 58 - 62, 英語Clinical pharmacokinetics of immunosuppressants: Tacrolimus[査読有り]
- 2004年10月, TDM研究, 21(4号) (4号), 313 - 319, 日本語チオペンタール血中濃度測定と脳死判定時の緊急体制システムの整備[査読有り]研究論文（学術雑誌）
- Purpose. The aim of this study was to clarify the effects of renal failure on intestinal secretion of quinolone antibacterial drugs. Methods. Pharmacokinetics of grepafloxacin, levofloxacin, and ciprofloxacin in cisplatin-induced acute renal failure (ARF) rats were evaluated, and intestinal and biliary clearance studies were examined. Transport experiments using culture cells were performed. Results. The bioavailability of grepafloxacin in ARF rats was 1.2-fold higher than that in normal rats. On the other hand, the bioavailability of ciprofloxacin in ARF rats was markedly decreased to half of that in normal rats, and that of levofloxacin was not changed. Intestinal clearance of grepafloxacin in ARF rats was 75% of that in normal rats, whereas that of ciprofloxacin was 1.4-fold higher than in normal rats, and that of levofloxacin was comparable between normal and ARF rats. Transport experiments using P-glycoprotein-expressing LLC-GA5-COL150 cells and human intestinal Caco-2 cells suggested that grepafloxacin and levofloxacin were substrates of P-glycoprotein and that ciprofloxacin was not, and that intestinal secretion of ciprofloxacin was mediated by a specific transport system distinct from organic cation and anion transporters and multidrug resistance-associated protein 2. Conclusions. Cisplatin-induced ARF differentially modulated the bioavailability and intestinal secretion of quinolones in rats.KLUWER ACADEMIC/PLENUM PUBL, 2004年02月, PHARMACEUTICAL RESEARCH, 21(2) (2), 330 - 338, 英語[査読有り]研究論文（学術雑誌）
- It is important for the clinical pharmacist to maintain the safety and efficacy of drug therapy for individual patients. In order to improve prescribing and help patients to understand their medication better, we began checking prescriptions and providing medicines to patients individually in the oncology surgery ward of our hospital in January 2003. Before preparing medications, we investigated the compliance of each patient through counseling, checked their prescriptions, and pointed out prescription errors to physicians. On the following day, after filling the prescriptions, we handed them to individual patients and explained the medication to each patient. Half a year after introducing this system, we calculated pharmacist prescription intervention rates and analyzed the results. We found a 49% error rate in prescriptions and pointed out the errors to physicians, 93% of which they acknowledged. To evaluate our system, we conducted a questionnaire survey of the doctors and nurses in the oncology surgery ward on the provision of medication by clinical pharmacists. We obtained a 95% response rate and the results were very satisfactory. The checking of prescriptions by clinical phaJapanese Society of Pharmaceutical Health Care and Sciences, 2004年, 医療薬学, 30(7) (7), 445 - 450, 日本語
- Cyclosporin A pharmacokinetics was studied in rats with cisplatin-induced acute renal failure (ARF) using microemulsion preconcentrate (MEPC) and completely dissolved formulations. Although the pharmacokinetics of cyclosporin A was unchanged after intravenous administration, maximum concentration of cyclosporin A in ARF rats was significantly reduced to 608+/-62 and 999+/-189ng/ml compared with 1720+/-142 and 1832+/-250 ng/ml in controls after oral administration of MEPC and completely dissolved formulations, respectively. In an in situ intestinal loop sac study, the amount absorbed plus metabolized and the blood concentration of cyclosporin A were similar between control and ARF rats, and taurocholic acid, one of the bile acids, significantly increased absorption of cyclosporin A using the MEPC formulation in both control and ARF rats; the amount absorbed plus metabolized with taurocholic acid was increased to 137 and 186%, and simultaneously the blood concentration was increased to 155 and 158% of that without taurocholic acid in control and ARF rats, respectively. The bile flow in ARF rats was decreased compared with that in controls. These results suggested that renal dysfunction decreased the absorption of cyclosporin A in spite of the MEPC formulation, and the alternation of bile secretion partly affected the absorption rate of cyclosporin A in the gastrointestinal tract.PHARMACEUTICAL SOC JAPAN, 2003年11月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 26(11) (11), 1591 - 1595, 英語[査読有り]研究論文（学術雑誌）
- 2003年10月, 日本病院薬剤師会雑誌, 39(10号) (10号), 1251 - 1254, 日本語高カロリー輸液(TPN)無菌調製の完全実施とその評価[査読有り]研究論文（学術雑誌）
- We investigated organic anion and cation transport activity and the expression of several organic ion transporters in hyperuricemic rat kidney. Feeding oxonic acid, an inhibitor of uric acid metabolism, and uric acid for 10 days significantly increased plasma uric acid level. Plasma creatinine and blood urea nitrogen concentrations also increased in hyperuricemic rats, indicating impaired renal function. The accumulation of organic anions, p-ammohippurate (PAH) and methotrexate, and cations, tetraethylammonium (TEA) and cimetidine, into renal slices was markedly decreased, suggesting decreased transport activity for organic anions and cations at the basolateral membrane in the kidney. The expression levels of basolateral organic anion transporters rOAT1 and rOAT3, and organic cation transporter, rOCT2, significantly decreased in hyperuricemic rat kidney as assessed by mRNA and protein levels. In contrast, the expression of rOCT1 was unaltered by hyperuricemia at both mRNA and protein levels. Moreover, the mRNA expression of kidney-specific organic anion transporters, OAT-K1 and OAT-K2, and organic anion transporting polypeptide (oatp) 1, which localize at the brush-border membrane in the kidney, was unchanged in hyperuricemic rats. In conclusion, we showed decreased basolateral organic anion and cation transport activity, accompanied by a specific decrease in rOAT1, rOAT3 and rOCT2 expression in hyperuricemic rat kidney. These phenomena partly contribute to the changed renal disposition of organic anions and cations in hyperuricemia. (C) 2003 Elsevier Inc. All rights reserved.PERGAMON-ELSEVIER SCIENCE LTD, 2003年09月, BIOCHEMICAL PHARMACOLOGY, 66(6) (6), 1107 - 1114, 英語[査読有り]研究論文（学術雑誌）
- Although clinical pharmacists participate in delivering safe and effective drug therapy to individual patients, there has so far been little assessment of the importance and quality of clinical pharmacy services. Physicians need drug information in order to practice safe and effective drug therapy. Previously, pharmacists provided drug information to physicians at the drug information section of the hospital pharmacy. At present, clinical pharmacists in most hospitals consult with patients regarding the drug therapy, and sometimes recommend the dosage regimen and provide drug information regarding the drug therapy to the physicians directly. We analyzed the records providing drug information to physicians and clinical interventions from March through May in 2002, and evaluated the acceptance ratio of pharmacists' recommendation for drug therapy. Clinical interventions included advice regarding drug therapy and pointing out prescription errors, inappropriate dosage, adverse drug reactions, drug interactions, and other aspects. In our survey, 73.8% of all interventions by the pharmacists were accepted by the physicians. For advice based on therapeutic drug monitoring, pharmacokineticJapanese Society of Pharmaceutical Health Care and Sciences, 2003年, 医療薬学, 29(4) (4), 415 - 420, 日本語
- Objective: To evaluate Bayesian prediction of blood tacrolimus concentrations in adult patients receiving living-donor liver transplantation (LDLT) using previously obtained population pharmacokinetic parameters. Patients and methods: Data were retrospectively collected from 47 adult patients receiving LDLT who were not included in the estimation of population pharmacokinetic parameters. Blood tacrolimus concentrations were predicted without or with the empirical Bayesian method using sparse samples obtained in the previous week. Predictive performance of the concentrations was evaluated by the mean prediction error (ME), mean absolute prediction error (MAE) and root mean square error (RMSE) as well as the percentage of successful predictions (percentage of absolute prediction error less than 3 mug/L, %PRED3). Results: Concentrations predicted by the population mean pharmacokinetic parameter values coincided well with observed concentrations during the period of tacrolimus infusion immediately after the operation. For concentrations during subsequent oral therapy with tacrolimus, predictability by the population mean pharmacokinetic parameter values alone was not satisfactory. Bayesian forecasting using one or two blood concentrations obtained in the previous week significantly decreased (p < 0.05) MAE and RMSE compared with predictions based on the population mean pharmacokinetic parameters on postoperative days 21 and 28, but not on day 14. During postoperative days 15-21, %PRED3 was increased to 68.6% or 71.2% with the Bayesian method using one or two blood concentrations, respectively, from 44.9% with the population mean pharmacokinetic parameter values. Conclusion: The present study demonstrated the applicability of the Bayesian method with use of one or two samples for prediction of blood tacrolimus concentrations in adult patients receiving LDLT.ADIS INTERNATIONAL LTD, 2003年, CLINICAL PHARMACOKINETICS, 42(13) (13), 1161 - 1178, 英語[査読有り]
- Purpose. We investigated the characteristics of transport of an organic anion, p- aminohippurate (PAH), at the apical membrane in a kidney epithelial cell line OK. Methods. Efflux and uptake of [C-14] PAH across the apical membrane were measured using OK cell monolayers grown on microporous membrane filters. Results. PAH efflux to the apical side was greater than that to the basolateral side and significantly inhibited by probenecid. Diethyl pyrocarbonate (DEPC), an inhibitor of potential- sensitive organic anion transport, significantly decreased PAH efflux to the apical side. Moreover, PAH efflux to the apical side was significantly decreased on incubation with high potassium buffer, as compared with control condition. Extracellular pH and Cl- had no effect on PAH efflux across the apical membrane. PAH uptake from the apical side was inhibited by various organic anions, and the inhibition patterns of PAH uptake from the apical and basolateral sides by various dicarboxylates were similar. Conclusions. These results suggested that PAH efflux to the apical side in OK cells was mediated by a potential- sensitive transport system, but not by an anion exchanger. Moreover, PAH uptake from the apical side was mediated by a specific transport system, which interacts with various organic anions and dicarboxylates.KLUWER ACADEMIC/PLENUM PUBL, 2002年12月, PHARMACEUTICAL RESEARCH, 19(12) (12), 1822 - 1826, 英語[査読有り]研究論文（学術雑誌）
- Purpose. The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. Methods. The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun(R) capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral(R) capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. Results. The area under the blood concentration-time curve (AUC) after the administration of Sandimmun(R) (corn oil) and Neoral(R) (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral(R) (saline), it was unchanged. The terminal elimination rate constant was not affected by probucol in any type of cyclosporin A solution. The solubility of cyclosporin A or tacrolimus in water dropped to 49% or 16% of the respective control in the presence of probucol. Conclusion. The interaction between cyclosporin A and probucol is caused by the decreased absorption of cyclosporin A partly based on the lowered solubility in the presence of probucol.KLUWER ACADEMIC/PLENUM PUBL, 2002年09月, PHARMACEUTICAL RESEARCH, 19(9) (9), 1362 - 1367, 英語[査読有り]研究論文（学術雑誌）
- The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of grepafloxacin and levofloxacin in vivo. Plasma concentrations of grepafloxacin and levofloxacin after intravenous and intraintestinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of grepafloxacin were significantly decreased to 60 and 63% of the corresponding control values by cyclosporin A. The apparent oral clearance of grepafloxacin was decreased to 33% of the control, and the bioavailability of grepafloxacin was increased to 95% by cyclosporin A from 53% in the controls. Intestinal clearance of grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance of grepafloxacin was also decreased to one-third with cyclosporin A in rats. Intestinal secretion of grepafloxacin in mdr1a/1b (-/-) mice, which lack mdr1-type P-glycoproteins, was significantly decreased compared with wild-type mice, although the biliary secretion was similar. Intestinal secretion of grepafloxacin in wild-type mice treated with cyclosporin A was comparable to those in mdr1a/1b (-/-) mice with or without cyclosporin A, indicating that cyclosporin A completely inhibited P-glycoprotein-mediated intestinal transport of grepafloxacin. In conclusion, our results indicated that P-glycoprotein mediated the intestinal secretion of grepafloxacin and limited the bioavailability of this drug in vivo.AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2002年03月, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 300(3) (3), 1063 - 1069, 英語[査読有り]研究論文（学術雑誌）
- Although acetazolamide, a carbonic anhydrase inhibitor, has an effect of lowering the intraocular pressure, a number of side effects have been reported with its use. We therefore investigated the pharmacokinetics and pharmacodynamics of acetazolamide in patients with an intraocular pressure (IOP) elevation. The plasma acetazolamide concentration and IOP in 17 patients with a transient IOP elevation were simultaneously measured after the last acetazolamide administration, and the findings were analyzed by nonlinear mixed effect modeling using the NONMEM software program. The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption. The apparent oral clearance (L/hr) showed a correlation with the creatinine clearance (CCR, mL/min), as estimated by the Cockcroft and Gault equation, as follows:0. 0468・CCR. The estimated apparent oral volume of the distribution, first-order absorption rate constant, and absorption lag time were 0.231 L/kg, 0.821 hr^-1, and 0.497 hr, respectively. The intraocular pressure after oral acetazolamide administration was characterized by an E_max model. The maximal effect in lowering the IOP (E_max)was 7.2 mmHg, and the concentration corresponding to 50% of E_max (EC_50) was 1.64 μg/mL. We next investigated the relationship between the acetazolamide concentration and its side effects in 23 glaucomatous patients who received repeated doses of oral acetazolamide for one week or more. The serum concentration of chloride ion was found to be higher than the normal range, and also showed a significant correlation with the acetazolamide concentration in the erythrocytes. The patients with an erythrocyte acetazolamide concentration of more than 20μg/mL had higher incidents of the side effects. Based on these results, the recommended dosage of acetazolamide was calculated so that the minimum plasma concentration at steady-state exceeded 4 μg/mL. The dosage regimen desired in this study is expected to contribute to the safe and effective pharmacotherapeutic use of acetazolamide.日本医療薬学会, 2002年, 医療薬学, 28(1) (1), 1 - 8, 日本語
- The effects of renal failure on the hepatic and intestinal extraction of tacrolimus were evaluated to examine the mechanisms for the increased bioavailability of this drug in cisplatin-induced renal failure model rats. Tacrolimus extractions in the liver and intestine were evaluated by intravenous, intraportal and intraintestinal infusion. The intestinal metabolism and absorption rate were estimated by incubating the isolated intestine with drug solution and by an in situ loop method, respectively. Blood concentrations of tacrolimus following the intraintestinal infusion were significantly increased in rats with renal failure compared with those in normal rats. The blood concentration of tacrolimus during intraportal infusion in rats with renal failure showed non-linearity against dose, and was increased as compared with that in normal rats. The intestinal metabolism was not altered, but the absorption rate was significantly increased in the intestine from rats with renal dysfunction. These results suggest that the hepatic metabolism of tacrolimus is impaired in rats with renal failure, and that the accelerated absorption rate in the intestine in renal dysfunction is followed by partial saturation of hepatic extraction, which may be one of the mechanisms of increased bioavailability of tacrolimus.ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 2002年01月, JOURNAL OF PHARMACY AND PHARMACOLOGY, 54(1) (1), 65 - 70, 英語[査読有り]研究論文（学術雑誌）
- Transport characteristics of grepafloxacin and levofloxacin across the apical membrane of Caco-2 cells were examined. Both grepafloxacin and levofloxacin uptakes increased rapidly, and were temperature-dependent. Grepafloxacin and levofloxacin uptakes showed concentration-dependent saturation with Michaelis constants of 3.9 and 9.3 nM, respectively. Uptake of grepafloxacin and levofloxacin increased in Cl--free and ATP depleted conditions, suggesting the involvement of an efflux transport system different from the uptake mechanism. However, cyclosporin A, a typical inhibitor of P-glycoprotein, did not affect the uptake of these drugs. Unlabeled grepafloxacin, unlabeled levofloxacin and quinidine inhibited the uptake of grepafloxacin and levofloxacin under Cl--free conditions. Tetraethylammonium, cimetidine, p-aminohippurate, probenecid, amino acids, beta -lactam antibiotic or monocarboxylates did not inhibit the uptake of grepafloxacin and levofloxacin under the same conditions. In conclusion, our results suggested that grepafloxacin and levofloxacin uptakes were mediated by a specific transport system distinct from those for organic cations and anions, amino acids, dipeptides and monocarboxylates. (C) 2001 Elsevier Science B.V. All rights reserved.ELSEVIER SCIENCE BV, 2001年11月, EUROPEAN JOURNAL OF PHARMACOLOGY, 431(3) (3), 297 - 303, 英語[査読有り]研究論文（学術雑誌）
- Objective: To characterize the pharmacokinetics of tacrolimus in adult recipients receiving living-donor liver transplantation (LDLT). Methods: Thirty-five patients were given tacrolimus as 18- to 60-h intravenous infusions after surgery, followed by a 4-week course of oral dose therapy (at 0900 hours and 2100 hours). Blood samples were collected daily in the morning (0800 hours) beginning the day after surgery. Whole blood concentration data were evaluated by nonlinear mixed-effect modeling using the program NONMEM and were characterized using a one-compartment model. Results: The clearance (CL, 1 h(-1)) was related to the grafted hepatic weight, postoperative days (POD), and hepatic and renal dysfunction. Interindividual variabilities in CLI, volume of distribution (V), and bioavailability (F) were 57.4%, 39.7%, and 63.0%, respectively, and the correlation between individual CL and F was 0.776. Residual intraindividual variability was 2.9 ng ml(-1). Based on the estimated final parameters, a typical recipient of LDLT with grafted hepatic weight of 600 g and normal hepatic and renal function would have a CL of 0.737 1 h(-1) on POD 0 and 1.14 1 h(-1) on POD 30, V of 1.52 1 kg(-1) and F of 6.8%. Conclusions: Nonlinear mixed-effect modeling was useful for analysis of pharmacokinetic characteristics of tacrolimus in LDLT patients. Immediately after surgery, patients receiving LDLT showed a smaller CL value than other transplant patients, and CL value increased with POD within 30 days after surgery. The estimated population pharmacokinetic parameters can be applied for a priori dosage calculations in adult patients with LDLT.SPRINGER-VERLAG, 2001年09月, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 57(6-7) (6-7), 479 - 484, 英語[査読有り]研究論文（学術雑誌）
- The need for mixed-effects modeling with population dichotomous dataOver the past 25 years sophisticated data analytic techniques have been developed which can lead to improved analyses, but at additional computational cost. In particular, this applies to the approach where interindividual random effects are included in a data analytic model for population pharmacokinetic data, which can often lead to substantially improved estimates of fixed-effect parameters. However, there are also commonly occurring situations, notably with some types of pharmacodynamic data, where such improvement is not realized. This study simulates some simple population dichotomous data, and secondarily, some related continuous data. These data are analyzed using both mixed-effect (ME) models that include interindividual random effects and naive (NA) models that do not include interindividual random effects, and it is seen that use of an ME model does not inevitably lead to gains over use of an NA model. In fact, using maximum likelihood estimation with both types of models, the root mean square estimation errors for fixed effect parameters can actually be larger with an ME model than with the corresponding NA model. Using a form of restricted maximum likelihood estimation with the ME model, the two types of models yield root mean square errors which are comparable, but which still do not suggest that there is always marked advantage in using the ME model.KLUWER ACADEMIC/PLENUM PUBL, 2001年08月, JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 28(4) (4), 389 - 412, 英語[査読有り]研究論文（学術雑誌）
- Purpose. To evaluate the mechanism of renal transport of quinolone antibacterial drugs, we examined the interaction of levofloxacin with p-aminohippurate (PAH) transport systems and the transport of levofloxacin in renal epithelial cells. Methods. Transport of [C-14]PAH or [C-14]levofloxacin was measured using OK cell monolayers grown on microporous membrane filters. Results. Transcellular transport from the basolateral to the apical side and cellular accumulation of [C-14]PAH were inhibited by levofloxacin. Both the initial uptake of [C-14]PAH from the basolateral side and the efflux to the apical side were inhibited by levofloxacin. The basolateral-to-apical transcellular transport of [C-14]levofloxacin was greater than that in the opposite direction. [C-14]Levofloxacin efflux to the apical side was greater than that to the basolateral side. Unlabeled levofloxacin and grepafloxacin inhibited the transcellular transport of [C-14]levofloxacin, accompanied by an increase of cellular accumulation. However, neither PAH nor an anion transport inhibitor 4-4 ' -diisothiocyanostilbene-2,2 ' -disulfonic acid (DIDS) affected the basolateral-to-apical transport of [C-14]levofloxacin nor its uptake from the basolateral side. Conclusions. These results indicated that levofloxacin inhibits PAH transport across both the basolateral and apical membranes of OK cells, but are not transported via the systems for PAH transport. The existence of a specific transport system for quinolones was indicated in OK cells.KLUWER ACADEMIC/PLENUM PUBL, 2001年05月, PHARMACEUTICAL RESEARCH, 18(5) (5), 573 - 578, 英語[査読有り]研究論文（学術雑誌）
- Itraconazole is known to interact with digoxin, a substrate of P-glycoprotein, in clinical situations. In this study, the interactions of the azole antifungal agents, miconazole, fluconazole, ketoconazole as well as itraconazole, with P-glycoprotein were examined using a transfected kidney epithelial cell line, LLC-GA5-COL150, which expresses human P-glycoprotein on the apical membrane.The Japanese Society for the Study of Xenobiotics, 2001年01月, 薬物動態, 16(1) (1), 5 - 11, 英語
Itraconazole decreased the transcellular transport of digoxin from the basolateral to apical side in LLC-GA5-COL150 cell monolayers, that was accompanied by increased cellular accumulation. The basolateralto-apical transcellular transport of digoxin in the host LLC-PK1 cell monolayers was not affected by itraconazole. Ketoconazole and fluconazole also significantly inhibited P-glycoprotein-mediated transport of digoxin, although miconazole was not effective. The inhibitory effects of itraconazole and ketoconazole on digoxin transport in LLC-GA5-COL150 monolayers were as strong as that of cyclosporin A, a typical P-glycoprotein modulator, and neither quinidine nor cimetidine inhibited digoxin transport at the same concentration (10 μM). In addition, the viability of LLC-GA5-COL150 cells against itraconazole was higher than that of LLC-PK1 cells, but viability against the other three azoles was similar to that of LLC-PK1 cells.
In conclusion, ketoconazole and fluconazole as well as itraconazole inhibited the transport of digoxin via human P-glycoprotein, and itraconazole could be a substrate of P-glycoprotein.[査読有り] - Secretory mechanisms of grepafloxacin and levofloxacin in the human intestinal cell line caco-2.Grepafloxacin and levofloxacin transport by Caco-2 cell monolayers was examined to characterize the intestinal behavior of these quinolones. The levels of transcellular transport of [(14)C]grepafloxacin and [(14)C]levofloxacin from the basolateral to the apical side were greater than those in the opposite direction. The unidirectional transport was inhibited by the presence of excess unlabeled quinolones, accompanied by increased accumulation. The inhibitory effects of cyclosporin A plus grepafloxacin on basolateral-to-apical transcellular transport and cellular accumulation of [(14)C]grepafloxacin were comparable to those of cyclosporin A alone, indicating that the transport of grepafloxacin across the apical membrane was mainly mediated by P-glycoprotein. On the other hand, basolateral-to-apical transcellular transport of [(14)C]levofloxacin in the presence of cyclosporin A was decreased by unlabeled levofloxacin, grepafloxacin, and enoxacin, accompanied by significantly increased cellular accumulation. The organic cation cimetidine, organic anion p-aminohippurate, and the multidrug resistance-related protein (MRP) modulator probenecid did not affect the transcellular transport of [(14)C]grepafloxacin or [(14)C]levofloxacin in the presence of cyclosporin A. The basolateral-to-apical transcellular transport of levofloxacin in the presence of cyclosporin A showed concentration-dependent saturation with an apparent Michaelis constant of 5.6 mM. In conclusion, these results suggested that basolateral-to-apical flux of quinolones was mediated by P-glycoprotein and a specific transport system distinct from organic cation and anion transporters and MRP.2000年10月, The Journal of pharmacology and experimental therapeutics, 295(1) (1), 360 - 6, 英語, 国際誌[査読有り]
- We showed a digoxin-itraconazole interaction in three patients in whom digoxin serum concentrations were increased. Their electrocardiograms revealed arrhythmias such as ventricular premature contraction, atrioventricular block, and ST depression. The elimination half-life of digoxin in case 3 patient who continued itraconazole therapy was 8.4 days, which was estimated by nonlinear least squares method from the serum concentrations of digoxin versts time curve. In order to evaluate the influence of itraconazole on pharmacokinetic parameters of digoxin, we estimated digoxin clearance by the Bayesian method using the population pharmacokinetic parameters in Japanese patients. During the concomitant use of itraconazole and digoxin, the digoxin clearance in all patients decreased to 50.5 +/- 8.8% (mean +/- S.D.) of the clearance without itraconazole. When digoxin and itraconazole are used concomitantly, careful monitoring of digoxin serum concentrations is necessary. Based on our results of digoxin clearance evaluation, the dose of digoxin should be reduced to 50% of original dose after itraconazole is started, and digoxin serum concentration might be controlled at the same level before the concomitant use.PHARMACEUTICAL SOC JAPAN, 2000年09月, YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 120(9) (9), 807 - 811, 日本語[査読有り]研究論文（学術雑誌）
- 2000年09月, Pharmaceutical research, 17(9) (9), 1155 - 7, 英語, 国際誌[査読有り]
- Purpose. The transepithelial transport of levofloxacin was evaluated in the isolated perfused kidney to investigate its renal secretory mechanisms. Methods. Levofloxacin was instantaneously administered into the renal artery together with inulin and Evans blue-labeled albumin, and the single-pass dilution curves of the renal venous and urinary outflow were determined in the absence or presence of various compounds. Kinetic parameters were computed based on non-compartment moment analysis. Results. The ratio of fractional excretion to filtration fraction (FE/FF) for levofloxacin was 2.99 +/- 0.is, indicating the involvement of tubular secretion. In the presence of cimetidine and quinolones, the FE/FF of levofloxacin was significantly decreased and the transepithelial mean transit time ((T) over bar(cell)) of levofloxacin was prolonged. The (T) over bar(cell) showed a negative correlation with renal secretion of levofloxacin, while the volume of distribution of levofloxacin showed no correlation. Conclusions. Transport on the brush-border membrane plays a determining step in the renal secretion of levofloxacin, and cimetidine and quinolones interact with levofloxacin transport on the brush-border membrane.KLUWER ACADEMIC/PLENUM PUBL, 2000年02月, PHARMACEUTICAL RESEARCH, 17(2) (2), 236 - 241, 英語[査読有り]研究論文（学術雑誌）
- Inhibitory effect of KW-3902, an adenosine A(1) receptor antagonist, on p-aminohippurate transport in OK cells.KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine) is a novel potent and selective adenosine A(1) receptor antagonist. We examined the effect of KW-3902 on p-aminohippurate (PAH) transport in opossum kidney (OK) epithelial cells. Pretreatment for 3 h with KW-3902 inhibited the transcellular transport of PAH across OK cell monolayers from the basal to the apical side. The uptake of PAH across the basolateral membrane of OK cells was inhibited by KW-3902 pretreatment in a time- and concentration-dependent manner. A kinetic analysis revealed that the inhibitory effect of KW-3902 on the basolateral PAH uptake was due to an increase in the Michaelis constant (K(m)) as well as a decrease in the maximum uptake rate (V(max)), showing that the inhibition was a mixed type. Pretreatment with adenosine deaminase or 8-cyclopentyl-1,3-dipropylxanthine, another selective adenosine A(1) receptor antagonist, also decreased the basolateral PAH uptake. KW-3902 pretreatment had no effect on the concentration of intracellular alpha-ketoglutarate which exchanges for PAH across the basolateral membrane of OK cells. These results suggest that KW-3902 has an inhibitory effect on PAH transport in OK epithelial cells.1999年07月, Biochimica et biophysica acta, 1419(2) (2), 164 - 72, 英語, 国際誌研究論文（学術雑誌）
- KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine) is a novel patent and selective adenosine A(1) receptor antagonist. We examined the effect of KW-3902 on p-aminohippurate (PAH) transport in opossum kidney (OK) epithelial cells. Pretreatment for 3 h with KW-3902 inhibited the transcellular transport of PAR across OK cell monolayers from the basal to the apical side. The uptake of PAH across the basolateral membrane of OK cells was inhibited by KW-3902 pretreatment in a time- and concentration-dependent manner. A kinetic analysis revealed that the inhibitory effect of KW-3902 on the basolateral PAH uptake was due to an increase in the Michaelis constant (K-m) as well as a decrease in the maximum uptake rate (V-max), showing that the inhibition was a mixed type. Pretreatment with adenosine deaminase or 8-cyclopentyl-1,3-dipropylxanthine, another selective adenosine A(1) receptor antagonist, also decreased the basolateral PAH uptake. KW-3902 pretreatment had no effect on the concentration of intracellular alpha-ketoglutarate which exchanges for PAN: across the basolateral membrane of OK cells. These results suggest that KW-3902 has an inhibitory effect on PAH transport in OK epithelial cells. (C) 1999 Elsevier Science B.V. All rights reserved.ELSEVIER SCIENCE BV, 1999年07月, BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1419(2) (2), 164 - 172, 英語[査読有り]研究論文（学術雑誌）
- Although acetazolamide, a carbonic anhydrase inhibitor, has an effect of lowering intraocular pressure, a number of side effects have been reported. Therefore, we investigated the relationship between the concentration of acetazolamide and its side effects, including plasma electrolyte imbalance. This study was conducted on 23 glaucomatous patients who received repeated doses of oral acetazolamide for one week or more. The concentrations of total and unbound plasma acetazolamide, as well as in the whole blood from the patients, were measured by high-performance liquid chromatography. The serum creatinine concentration, electrolyte concentrations, and adverse reactions were monitored. We found that plasma concentrations of chloride ion after repeated doses became higher than the normal range. This chloride ion concentration significantly correlated with the acetazolamide concentration in the erythrocytes, but not with the plasma concentration. The patients with erythrocyte acetazolamide concentration more than 20 mu g/ml had higher incidences of the side effects. Periodical monitoring of erythrocyte acetazolamide concentration and plasma chloride ion can be easily and safely applied to elderly glaucomatous patients treated with acetazolamide for long periods to prevent overdosage and side effects.MARY ANN LIEBERT INC PUBL, 1999年04月, JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, 15(2) (2), 97 - 105, 英語[査読有り]研究論文（学術雑誌）
- PURPOSE: To elucidate the renal distribution of quinolones, we examined the uptake of levofloxacin and grepafloxacin in vivo and in rat renal cortical slices. METHODS: The plasma and various tissue concentrations of levofloxacin and grepafloxacin were measured after a bolus injection in rats, and tissue uptake clearance was calculated. Transport characteristics of quinolones in rat renal cortical slices were evaluated. RESULTS: The tissue distribution of levofloxacin and grepafloxacin in the kidney was greater than in any other tissue, and the tissue uptake clearances of levofloxacin and grepafloxacin in the kidney cortex were 1.2 and 4.6 ml/min/g tissue, respectively. The uptake of levofloxacin and grepafloxacin in rat renal cortical slices was concentrative, as indicated by slice/medium ratios of 2.3 and 9.6 at 60 min, respectively. The uptake of levofloxacin and grepafloxacin in rat renal cortical slices showed saturation, and was significantly inhibited in the presence of quinidine (p<.05), but not of tetraethylammonium or p-aminohippurate. CONCLUSIONS: Renal distribution of levofloxacin and grepafloxacin may be mediated by a specific transport system for quinolones, distinct from the organic cation and organic anion transport systems in the kidney.1999年04月, Pharmaceutical research, 16(4) (4), 534 - 9, 英語, 国際誌[査読有り]
- Transport of quinolone antibacterial drugs in a kidney epithelial cell line, LLC-PK1The transport of quinolone antibacterial drugs by LLC-PK1 monolayers was examined to characterize the renal tubular secretion of these drugs. The transcellular transport of levofloxacin and grepafloxacin from the basolateral to apical side was larger than the transport in the opposite direction. The basal-to-apical transcellular transport and uptake from the basolateral side of levofloxacin showed concentration dependent saturation with an apparent Michaelis constant (K-m) of 0.6 and 13 mM, respectively. Various quinolones (1 mM) inhibited the transcellular transport of levofloxacin, and this inhibition was accompanied by a marked increase of cellular accumulation. These results indicated that quinolones interacted more strongly with the transport system on the apical than the basolateral membrane. Neither tetraethylammonium nor cyclosporin A affected the basal-to-apical transcellular transport and accumulation of levofloxacin. The basal-to-apical transcellular transport of levofloxacin was not influenced by either lowering the pH of the apical side or pretreatment of apical membrane with p-chloromercuribenzene sulfonate. These findings indicate that quinolones are specifically transported from the basolateral to apical side by LLC-PK1 monolayers and have higher affinity for the transport system in the apical membrane, a system distinct from H+/organic cation antiport system.AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 1998年11月, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 287(2) (2), 672 - 678, 英語[査読有り]研究論文（学術雑誌）
- We present a digoxin-clarithromycin interaction in two patients in whom digoxin concentrations were unexpectedly increased. The ratio of renal digoxin clearance to creatinine clearance in one patient was lower during the concomitant administration of clarithromycin (0.64 and 0.73) than that after cessation of clarithromycin administration (1.30 +/- 0.20; mean +/- SD), Because P-glycoprotein could play an important role in the renal secretion of digoxin, we hypothesized that clarithromycin decreases renal digoxin excretion by inhibiting P-glycoprotein-mediated transport. Digoxin transport was evaluated with use of a kidney epithelial cell line, which expresses the human P-glycoprotein on the apical membrane by transfection with MDR1 complementary deoxyribonucleic acid, Clarithromycin inhibited the transcellular transport of digoxin from the basolateral to the apical side in a concentration-dependent manner and concomitantly increased the cellular accumulation of digoxin, These results suggest that clarithromycin may inhibit the P-glycoprotein-mediated tubular secretion of digoxin, and this interaction mechanism may contribute to an increase in the serum digoxin concentration.MOSBY-YEAR BOOK INC, 1998年07月, CLINICAL PHARMACOLOGY & THERAPEUTICS, 64(1) (1), 123 - 128, 英語[査読有り]研究論文（学術雑誌）
- Efflux of intracellular alpha-ketoglutarate via p-aminohippurate/dicarboxylate exchange in OK kidney epithelial cellsThe involvement of intracellular alpha-ketoglutarate (alpha-KG) in p-aminohippurate (PAH) transport was investigated in OK kidney epithelial cells. Efflux of intracellular alpha-KG from the OK cells to the basolateral side was increased by applying PAH to the basolateral side of the cells. In contrast, the intracellular alpha-KG concentration was not influenced by the addition of PAH. The alpha-KG efflux across the basolateral membrane induced by PAH was higher than that across the apical membrane. Probenecid inhibited the PAM-dependent alpha-KG efflux. The alpha-KG efflux to the basolateral side was saturable with increasing concentration of PAH in the basolateral medium. Antimycin A, a metabolic inhibitor, inhibited [C-14]PAH uptake across the basolateral membrane of OK cells in a dose-dependent manner. In addition, both the alpha-KG efflux induced by PAH and the intracellular alpha-KG concentration were decreased by antimycin A dose-dependently. These results directly show that alpha-KG generated by intracellular metabolism is effluxed via PAH/dicarboxylate exchange in the basolateral membrane of OK cells.AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 1998年05月, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 285(2) (2), 422 - 427, 英語[査読有り]研究論文（学術雑誌）
- Objective: To characterize the pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure (IOP) elevation and to provide individual patients with the optimal dosage regimen for this drug. Methods: We studied 17 patients with transient IOP elevation, who were given 62.5-500 mg acetazolamide orally as single or repetitive doses. Plasma acetazolamide concentration and IOP were measured at approximately 1, 3, 5, and 9 h after the last acetazolamide administration. Pharmacokinetics and pharmacodynamics were analyzed by nonlinear mixed-effect modeling using the program NONMEM. Results: The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption. The apparent oral clearance was related to the creatine clearance (CCR) which was estimated by the Cockcroft and Gault equation, as follows: 0.0468.CCR1.h(-1). The estimated apparent oral volume of distribution, first-order absorption rate constant, and absorption lag time were 0.231 1.kg(-1) 0.821.h(-1), and 0.497 h, respectively. IOP after oral acetazolamide administration was characterized by an E-max model. The maximal effect in lowering the IOP (E-max) was 7.2 mmHg, and the concentration corresponding to 50% of the maximal effect (EC50) was 1.64 mu g.ml(-1). As 70% of E-max was achieved at a plasma concentration of 4 mu g.ml(-1), this concentration was considered satisfactory for lowering IOP. The recommended dosage nias calculated so that the minimum plasma concentration at steady state exceeded this target concentration; 350 mg t.i.d., 135 mg t.i.d., 125 mg b.i.d., and 115 mg once daily for the patients with CCR values of 70, 50, 30, and 10 ml.min(-1) respectively. Conclusion: Measuring plasma concentrations of acetazolamide and subsequent pharmacokinetic and pharmacodynamic analyses are useful for estimating its concentration-dependent effectiveness in lowering the IOP in individual patients. The dosage regimen presented in this study is expected to improve the benefits of acetazolamide pharmacotherapy in most elderly patients with transient rises in IOP following intraocular surgery.SPRINGER VERLAG, 1998年03月, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 54(1) (1), 63 - 68, 英語[査読有り]研究論文（学術雑誌）
- Inhibition PAH transport by parathyroid hormone in OK cells: involvement of protein kinase C pathwayWe have previously shown that the p-aminohippurate (PAH) transport system in OK kidney epithelial cell line is under the regulatory control of protein kinase C. Parathyroid hormone (PTH) could activate protein kinase C, as well as protein kinase A, in OK cells. In the present study, the effect of PTH on PAH transport was studied in OK cells. PTH inhibited the transcellular transport of PAH from the basal to the apical side, as well as the accumulation of PAH in OK cells. Basolateral PAH uptake was inhibited by PTH in a dose-and time-dependent manner. Protein kinase A activators did not affect the transcellular transport or the accumulation of PAH. The PTH-induced inhibition of the accumulation of PAH was blocked by a protein kinase C inhibitor staurosporine. These results suggest that PTH inhibits the PAH transport in OK cells and that the messenger system mediated by protein kinase C, not protein kinase A, plays an important role in the regulation of PAH transport by PTH.AMER PHYSIOLOGICAL SOC, 1997年11月, AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 273(5) (5), F674 - F679, 英語[査読有り]研究論文（学術雑誌）
- Transport of quinolone antibacterial drugs by human P-glycoprotein expressed in a kidney epithelial cell line, LLC-PK1The purpose of this study was to characterize the transport mechanisms involved in the renal tubular secretion of quinolones. The contribution of P-glycoprotein to the transport of quinolones was elucidated using a kidney epithelial cell line, LLC-PK1, and its transfectant derivative cell line, LLC-GA5-COL 150, which expresses human P-glycoprotein on the apical membrane. The transcellular transport of levofloxacin, a quinolone antibacterial drug, from the basolateral to apical side was increased in LLC-GA5-COL 150 compared with that in LLC-PK, monolayers. The apparent Michaelis constant and maximum velocity values for the saturable transcellular transport of levofloxacin from the basolateral to apical side in LLC-GA5-COL 150 monolayers were 3.0 mM and 45 nmol/mg protein per 15 min, respectively. The increased basolateral-to-apical transport in LLC-GA5-COL 150 monolayers was completely inhibited by cyclosporin A and quinidine to the level observed in LLC-PK1 monolayers. In addition, 3 mM levofloxacin inhibited the basolateral-to-apical transport of daunorubicin in LLC-GA5-COL 150 monolayers. The basolateral-to-apical transport of another quinolone antibacterial drug, DU-6859a, in LLC-GA5-COL 150 monolayers greatly exceeded than that in LLC-PK1 monolayers, and was inhibited by levofloxacin. These findings suggest that quinolone antibacterial drugs are transported by P-glycoprotein, and that P-glycoprotein may contribute at least in part to the renal tubular secretion of quinolones.WILLIAMS & WILKINS, 1997年08月, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 282(2) (2), 955 - 960, 英語[査読有り]研究論文（学術雑誌）
- Purpose. Levofloxacin, a quinolone antibacterial drug, is a zwitterion at physiological pH. We examined the effect of cationic and anionic drugs on renal excretion of levofloxacin by means of in vivo clearance to characterize the mechanisms of renal excretion of this drug. Methods. In vivo clearance was studied in male Wistar albino rats. A bolus dose of 2.85 mg/kg of levofloxacin was administered, followed by a constant infusion of 7.08 mu g/min. Cimetidine, tetraethylammonium, or p-aminohippurate was administered as a bolus and incorporated into the infusion solution. After reaching steady state, urine and blood concentrations were measured, and pharmacokinetic parameters were calculated. Results. Renal clearance was 2.56 +/- 0.42 ml/min in control, which accounted for 34% of the total body clearance. Renal clearance was significantly decreased to 0.83 +/- 0.25 ml/min by cimetidine (p<.05), corresponding to 32% of the control value. The cationic drug, tetraethylammonium also reduced the renal clearance of levofloxacin, but the effect of the anionic drug, p-aminohippurate, was slight. The clearance ratio of levofloxacin, which was calculated by renal clearance divided by the plasma unbound fraction and the glomerular filtration rate, was 1.60 +/- 0.38 in the control and it was decreased to 0.68 +/- 0.17 and 1.11 +/- 0.22 by cimetidine and tetraethylammonium, respectively. Conclusions. The present results suggest that the renal excretion of levofloxacin in rats involves tubular secretion and reabsorption, in addition to glomerular filtration, and that tubular secretion is inhibited by cimetidine.PLENUM PUBL CORP, 1997年04月, PHARMACEUTICAL RESEARCH, 14(4) (4), 508 - 511, 英語[査読有り]研究論文（学術雑誌）
- Inhibition of PAH transport by parathyroid hormone in OK cells: Involvement of protein kinase C pathwayWe have previously shown that the p-aminohippurate (PAH) transport system in OK kidney epithelial cell line is under the regulatory control of protein kinase C. Parathyroid hormone (PTH) could activate protein kinase C, as well as protein kinase A, in OK cells. In the present study, the effect of PTH on PAH transport was studied in OK cells. PTH inhibited the transcellular transport of PAH from the basal to the apical side, as well as the accumulation of PAH in OK cells. Basolateral PAH uptake was inhibited by PTH in a dose- and time-dependent manner. Protein kinase A activators did not affect the transcellular transport or the accumulation of PAH. The PTH- induced inhibition of the accumulation of PAH was blocked by a protein kinase C inhibitor staurosporine. These results suggest that PTH inhibits the PAH transport in OK cells and that the messenger system mediated by protein kinase C, not protein kinase A, plays an important role in the regulation of PAH transport by PTH.1997年, American Journal of Physiology - Renal Physiology, 273(5) (5), F674 - F679, 英語[査読有り]研究論文（学術雑誌）
- LIPPINCOTT-RAVEN PUBL, 1996年02月, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 37(3) (3), 5075 - 5075, 英語Clinical significance of monitoring plasma concentrations of acetazolamide[査読有り]
- The present paper reports theoretical equations for the predictive performance of the Bayesian forecasting method. The precision of parameter estimates and predicted concentrations for an individual was described by general equations with the aid of a variance-covariance matrix of parameter estimates that involved the Bayes theorem. The equations were applied to assess the predictive performance of the one-point Bayesian method in association with blood sampling time, the population parameters, and the pharmacostatistical model. The simulation study showed that the prediction error in parameter estimates essentially depended upon the sampling time but the magnitude of dependency was affected by the size of inter- and intraindividual variances. With a smaller value of interindividual variance, the dependency on sampling time was less apparent. Effects of sampling time were further examined using clinical data obtained from 20 patients taking theophylline, and the results were in good agreement with the theoretical consideration. The present general equations are useful to investigate the sampling strategy as well as structural and variance modeling on the predictive performance of the Bayesian method.PLENUM PUBL CORP, 1994年02月, JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS, 22(1) (1), 59 - 71, 英語[査読有り]研究論文（学術雑誌）
- The population pharmacokinetics of theophylline were studied in 55 patients with stable chronic airway obstruction. Two hundred and seventy six theophylline serum concentrations after intravenous short infusion were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, smoking habit, age and the measurement of arterial blood gases (oxygen tension: PaO2, carbon dioxide tension: PaCO2, blood pH) and clinical laboratory tests (serum albumin concentration, haematocrit) on the pharmacokinetic parameters of theophylline was examined by the likelihood ratio test. Assessment of each factor was made by a forward selection method. In the final regression model, the total body clearance (CL, l/h/kg) was related to the value of PaCO2 as well as to the presence of hepatic dysfunction, and the volume of distribution (V(d), l/kg) was related with the PaCO2 value as expressed in the following equations: CL = exp(-3.78-0.525.HF+0.0233.PaCO2) and V(d) = exp(-1.12+0.00934.PaCO2), where HF is a categorical variable with a value of unity if a patient has hepatic dysfunction otherwise zero. The interactions among blood gas measurements were observed and the CL and V(d) of theophylline would be inversely correlated with PaO2 or pH, if we selected PaO2 or blood pH to be a more important factor than PaCO2. The inter-individual variabilities in CL and V(d) were 38.5% and 12.5%, respectively, and the residual variability in theophylline serum concentrations was 10.6% as a coefficient of variation. This final model and the population parameters of theophylline will be useful for individualization of a drug dosage regimen by means of the Bayesian method. Significant correlation between arterial blood gas measurements and pharmacokinetic parameters observed in this study indicates that the pharmacokinetics of theophylline can vary in association with the severity of respiratory diseases.PHARMACEUTICAL SOC JAPAN, 1993年05月, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 16(5) (5), 501 - 505, 英語[査読有り]研究論文（学術雑誌）
- Population pharmacokinetics of theophylline. I: Intravenous infusion to children in the acute episode of asthma.The population pharmacokinetics of theophylline during constant-rate intravenous infusion has been studied in 66 children (8.7 +/- 4.7 year of age; 26.0 +/- 12.8 kg, mean +/- S.D.) with an episode of acute asthma. One hundred and twelve theophylline serum concentrations (13.9 +/- 4.8 micrograms/ml) collected retrospectively were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, age, gender, days after admission, blood gas measurements (PaO2, PaCO2, blood pH) and clinical analyses data (total serum protein, albumin concentration, haemoglobin concentration, haematocrit) on theophylline clearance was examined by the likelihood ratio test. A final estimate of population mean clearance was 58.6 ml/kg/h, which was decreased by 36% in patients with hepatic dysfunction. Other factors tested displayed no statistically significant effect on theophylline clearance. The inter-individual variability in clearance was 26% while the intra-individual variability in theophylline concentrations was 2.6 micrograms/ml as a standard deviation, which was almost double that observed for stable patients. Taking into account that the therapeutic window of this drug is 10-20 micrograms/ml, this value indicates a relatively large intra-individual variability and suggests that frequent (daily) monitoring of serum concentrations is necessary for patients with an episode of acute asthma.1993年01月, Biological & pharmaceutical bulletin, 16(1) (1), 59 - 62, 英語, 国内誌[査読有り]
- The pharmacokinetics of theophylline in acutely ill patients show wide intraindividual variability associated with the severity of clinical status. To investigate the mechanism of this variability, we studied the effects of leukotriene C4 (LTC4)-induced pathophysiologic changes on the disposition of theophylline. The plasma concentration-time profiles were measured after simultaneous intravenous bolus injection of theophylline and antipyrine in guinea pigs. The animals 5-mu-g/kg of LTC4 intravenously 60 min later. The plasma theophylline concentration 30 min after LTC4 treatment was significantly lower (p < 0.05) than that of nontreated control animals, whereas the plasma antipyrine concentration at that time was not affected. In addition, the significantly slower declines in plasma concentrations of both drugs (0.0805 +/- 0.0199 and 0.291 +/- 0.020 h-1 for theophylline and antipyrine, respectively, mean +/- SEM) than did controls (0.197 +/- 0.010 and 0.439 +/- 0.028 h-1). Leukotriene C4 treatment also induced moderate bronchoconstriction and metabolic acidosis, increased blood hemoglobin concentration and hematocrit, and decreased concentration of swum proteins. In connection with these changes, the plasma unbound fraction of theophylline increased significantly (p < 0.001, 94.4 +/- 3.3% in treatment versus 58.2 +/- 4.4% in control), but that of antipyrine was unchanged (94.9 +/- 3.0% in treatment versus 92.1 +/- 0.9% in control). These findings indicated that an increase in the volume of distribution was responsible for the abrupt change in plasma theophylline concentration following LTC4 treatment and the apparent change in the volume of distribution was estimated as 26.1 +/- 5.6%. Results showed that the LTC4 response can influence the disposition kinetics of theophylline and suggested a possible mechanism for the intraindividual variability in acutely ill patients.AMER LUNG ASSOC, 1992年09月, AMERICAN REVIEW OF RESPIRATORY DISEASE, 146(3) (3), 616 - 620, 英語[査読有り]研究論文（学術雑誌）
- Blood oxygen tension-related change of theophylline clearance in experimental hypoxemiaThe effects of arterial blood oxygen tension on the pharmacokinetics of theophylline were investigated using an experimental acute hypoxemia model in rats. Conscious rats were exposed to hypoxic gas composed of 8% O2-92% N2. After blood gas tensions and blood pH were stabilized, rats received 5 mg/kg i.v. theophylline, and urine and blood samples were collected. The steady-state volume of distribution, unbound free fraction and hematocrit were unaffected by hypoxemia. Total body clearance was significantly changed (P< .01) from 0.156 ± 0.020 l/kg/hr in control to 0.0556 ± 0.0067 l/kg/hr in hypoxemic rats due to the reduction of both hepatic and renal clearances. In another constant rate i.v. infusion study, the plateau plasma concentration of theophylline was elevated steeply as soon as animals had inspired hypoxic gas, and the elevated concentrations went down after returning to room air. The present results suggested that the variation of arterial oxygen tension is one possible mechanism for a rapid and large intraindividual variability in theophylline clearance in acutely ill patients with chronic obstructive pulmonary disease.1989年, Journal of Pharmacology and Experimental Therapeutics, 248(3) (3), 1237 - 1242, 英語[査読有り]研究論文（学術雑誌）
- The effects of medium-chain glyceride (MGK) on the intestinal absorption and the hepatobiliary transport of Phenol red (PR) were investigated in rats. The in situ recirculation experiment using the small intestine showed that disappearance of PR from the recirculated MGK emulsion at a lipid content of 4% was over 5 times greater than that from the buffer solution, although the effect diminished with the increase of the lipid content. On the contrary, in the everted sac experiments, mucosal to serosal transport of PR from MGK emulsion was reduced to about one half of the control, and the pretreatment with PR-free MGK emulsion could not enhance PR disappearance from the buffer solution recirculated successively. The effect of a polyoxyethylene derivative of castor oil (HCO-100) employed for emulsion preparation on the transport of PR was investigated by the everted sac experiments. The amount of PR transported was decreased with the increase of HCO-100 in the range of 0.1-2.0%. These results may suggest that other factors are related with the promoting effect except for the membrane permeability. When the absorption of MGK components was examined by in situ and in vitro studies, the disappearance of MGK components in the former was nearly twice of that in the latter. The inhibiting effect of MGK on the biliary excretion of PR was observed in the in situ recirculation study with MGK emulsion containing PR. The biliary excretion percent of PR was also significantly reduced by injecting the components of MGK into the mesenteric vein. © 1987.1987年, International Journal of Pharmaceutics, 36(2-3) (2-3), 131 - 139, 英語[査読有り]研究論文（学術雑誌）
- Effect of medium-chain glycerides (MGK) on the intestinal absorption and the hepatobiliary transport of bromthymol blue.The effect of medium chain glyceride (MGK) emulsion on the intestinal absorption and the biliary excretion of bromthymol blue (BTB) was investigated in rats. Extensive tissue accumulation of BTB was reduced when BTB was administered with MGK emulsion formulation. HCO-100, an emulsifier, was also important for the decrease in the tissue accumulation of BTB. The ratios of absorption percent to tissue accumulation percent and to free fraction, not contained in the droplet of emulsion, in MGK emulsion were much greater than that of the control. Pretreatment with BTB-free emulsion reduced BTB absorption under the control, although tissue accumulation was not affected. The absorption appeared to decrease with increase in the time of pretreatment. The effect of leaving treatment after pretreatment on the absorption of BTB was also investigated. With the increase in leaving time after pretreatment, reduced absorption tended to resume to the level of control. The change in monocaprylate content from 54 to 60% in MGK made a difference in BTB absorption and it was suggested that monocaprylate content in MGK was one of the significant factors of MGK emulsion on drug absorption. Bile recovery study was simultaneously carried out with an in situ recirculation experiment. The recovery of BTB into bile tended to decrease. The ratio of recovery percent of BTB into bile to the absorption percent of BTB also decreased extensively, which is possibly another effect of MGK on drug disposition.1986年06月, Journal of pharmacobio-dynamics, 9(6) (6), 532 - 9, 英語, 国内誌[査読有り]
- (一社)日本TDM学会, 2024年07月, TDM研究, 41(2) (2), 158 - 158, 日本語
- 2024年, 医療薬学フォーラム講演要旨集, 32nd錠剤同士の接触により生じるテルミサルタン錠の着色とそのメカニズムの解析
- (一社)日本TDM学会, 2023年06月, TDM研究, 40(2) (2), 176 - 176, 日本語
- (一社)日本医薬品情報学会, 2023年06月, 日本医薬品情報学会総会・学術大会講演要旨集, 25回, 147 - 147, 日本語ニルマトレルビル/リトナビル併用時にタクロリムス濃度の異常高値を認めた腎移植症例
- (一社)日本TDM学会, 2023年06月, TDM研究, 40(2) (2), 176 - 176, 日本語
- 2023年, 日本薬学会年会要旨集(Web), 143rdユビキチンリガーゼHRD1を誘導する化合物の探索と神経細胞死抑制効果の検討
- 2023年, 医療薬学フォーラム講演要旨集, 31stパーキンソン病発症に関連する小胞体ストレス関連分子SEL1Lを制御するmicroRNAの探索と血漿中microRNA発現量の検討
- (一社)日本臨床薬理学会, 2022年12月, 日本臨床薬理学会学術総会抄録集, 43回, 1 - 5, 日本語
- (一社)日本医学教育学会, 2022年07月, 医学教育, 53(Suppl.) (Suppl.), 187 - 187, 日本語基本的技術トレーニング研修における初期臨床研修医に対する医療安全教育の実践
- MDPI, 2021年09月15日, ECCM 2021, 9(1) (1), 12
- (公社)日本薬学会, 2021年03月, 日本薬学会年会要旨集, 141年会, 29P01 - 289, 日本語消化管上皮細胞モデルにおけるABCB1発現・機能に及ぼすエベロリムス長期曝露の影響
- 2021年03月, 日本病院薬剤師会雑誌, 57(3) (3), 305巻頭言：薬剤師が研究するということ[招待有り]
- 2021年, 日本緩和医療薬学会年会プログラム・要旨集, 14th薬剤師が主導する非がん疼痛患者へのオピオイド使用状況モニタリングの評価
- 2021年, 日本緩和医療薬学会年会プログラム・要旨集, 14thオピオイド鎮痛薬使用がん患者への薬剤師による外来電話サポートの介入効果
- 2020年12月, TDM研究, 37(4) (4)巻頭言：個別化投与設計から精密医療の時代に〜変わるものと変わらないもの〜[招待有り]
- (一社)日本臨床薬理学会, 2020年10月, 臨床薬理, 51(Suppl.) (Suppl.), S293 - S293, 日本語腎移植患者におけるタクロリムスPBPKモデル構築と肝移植患者の薬物動態との比較
- (公社)日本薬学会, 2020年03月, 日本薬学会年会要旨集, 140年会, 28P - am038, 日本語がん悪液質に対する補中益気湯による改善効果に関する調査
- (公社)日本薬学会, 2020年03月, 日本薬学会年会要旨集, 140年会, 28J - am02S, 日本語ナトリウム・グルコース共輸送体2(SGLT2)阻害剤ipragliflozinによる重篤な皮膚障害に関する基礎的検討
- 【調剤業務Update 薬剤師の貢献と発信されたエビデンス総まとめ】調剤の自動化とその効果＜Key Points＞◎調剤を自動化する意義は、生産性を高め、より安全性を向上させることにある。◎IT技術の進歩に伴い、調剤業務の各工程を自動化した新しい機器が市販されている。◎調剤の自動化には、各施設の特徴に応じた機器の選定と、機器の特徴を生かした業務の再構築が必要である。(著者抄録)(株)南山堂, 2020年02月, 薬局, 71(2) (2), 285 - 290, 日本語
- (一社)日本臨床薬理学会, 2019年11月, 臨床薬理, 50(Suppl.) (Suppl.), S297 - S297, 日本語新生児の先天性サイトメガロウイルス感染症患者におけるガンシクロビル血中濃度測定と生理学的薬物動態モデルを用いたシミュレーション
- (一社)日本臨床薬理学会, 2019年11月, 臨床薬理, 50(Suppl.) (Suppl.), S297 - S297, 日本語新生児の先天性サイトメガロウイルス感染症患者におけるガンシクロビル血中濃度測定と生理学的薬物動態モデルを用いたシミュレーション
- 医薬品適正使用のためのクリニカルファーマコメトリクスクリニカルファーマコメトリクスの目的は医薬品市販後の臨床データを数理モデルによって解析し、医薬品の適正使用や個別化投与設計に活かすことにある。筆者が取り組んできたクリニカルファーマコメトリクス研究について、次の項目に分けて概説した。1)新規抗てんかん薬の薬物動態と薬効の速度論的解析および薬物血中濃度モニタリングの有用性、2)電子カルテ情報を活用した医薬品使用評価の定量的解析、として述べた。(公社)日本薬学会, 2019年10月, 薬学雑誌, 139(10) (10), 1227 - 1234, 日本語
- 薬物動態学の観点から見る免疫抑制薬免疫抑制薬は薬物動態の個人差が大きいため、薬物治療モニタリングを用いて投与量調整が行われる。免疫抑制薬の個別化投与設計に向けて、これまで取り組んできたファーマコメトリクス(薬物動態、病態進行、治療効果などを定量的に扱う学問領域)研究を、タクロリムス、ミコフェノール酸、エベロリムスに分けて述べた。(一社)日本臓器保存生物医学会, 2019年07月, Organ Biology, 26(2) (2), 41 - 47, 日本語
- 【がん治療と薬物相互作用 ピットフォールに陥らないための基礎と実践】併存疾患のあるがん患者における薬物相互作用のピットフォール てんかん＜Key Points＞◎がん患者における併存疾患としてのてんかんには、既往症や悪性腫瘍の合併症(脳転移など)に伴うてんかんや、がん薬物療法の副作用としてのてんかんなどがある。◎てんかんの治療や発作の予防は重要で、がん薬物療法と並行して行う必要がある。◎抗てんかん薬は薬物相互作用を起こしやすいため注意が必要である。◎抗てんかん薬と抗がん薬がん薬物療法が互いにどう影響し合うかを十分に考慮した上で、おのおのの治療方針を定めることが重要である。(著者抄録)(株)南山堂, 2019年06月, 薬局, 70(7) (7), 1481 - 1487, 日本語
- (一社)日本TDM学会, 2019年05月, TDM研究, 36(2) (2), 49 - 49, 日本語抗てんかん薬TDMガイドライン
- (一社)日本TDM学会, 2019年05月, TDM研究, 36(2) (2), 188 - 188, 日本語ラモトリギンTDMの現状と血中濃度の変動因子に関する調査
- (公社)日本薬学会, 2019年03月, 日本薬学会年会要旨集, 139年会(4) (4), 133 - 133, 日本語新規Bcl-2選択的阻害剤の長期間曝露がヒト白血病細胞株に及ぼす影響
- 2019年02月, 薬局, 70(2号) (2号), 287 - 292, 日本語【高齢患者のOveruse/Underuse 過剰でも過少でもない薬剤の適正使用を考える】 Overuse/Underuseに対する薬学管理の実践ポイント 病院薬剤師のOveruse/Underuseへの関わり[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2019年, 日本医療薬学会年会講演要旨集(Web), 29クロザピン及び活性代謝物の母集団薬物動態解析:入院・外来の影響
- 2019年, 診断と治療, 107(2) (2), 173 - 179, 日本語【診療に活かす薬理・ブラッシュアップ】 日常診療に直結する薬理学 治療薬物モニタリング(TDM)記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- OXFORD UNIV PRESS, 2018年10月, ANNALS OF ONCOLOGY, 29, 英語Coverings avoid frostbites and do not reduce efficacy of cryotherapy for prevention of chemotherapy-induced neuropathy研究発表ペーパー・要旨（国際会議）
- WILEY, 2018年10月, INTERNATIONAL JOURNAL OF UROLOGY, 25, 240 - 240, 英語Risk factors for Pseudomonas aeruginosa-causing urosepsis: How does urological intervention contribute to lower mortality rate ?研究発表ペーパー・要旨（国際会議）
- 2018年08月, ファルマシア, 54(8号) (8号), 757 - 761, 日本語【専門・認定薬剤師を知る】 我が国における認定・専門薬剤師制度の現状と今後の展望[査読有り][招待有り]記事・総説・解説・論説等（学術雑誌）
- 2018年08月, Pharma Medica, 36(8号) (8号), 29 - 33, 日本語【てんかん診療Update】 薬物療法 臨床薬理学的解説[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年08月, 薬事新報, (3058号) (3058号), 19 - 22, 日本語ポリファーマシー対策の取り組み ポリファーマシー対策の取り組み[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年01月, Medical Science Digest, 44(1号) (1号), 49 - 53, 日本語シグナル伝達因子に起因する間質性肺炎発症メカニズム[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2018年01月, Med Oncol, 35(2) (2), 16, 英語Genetic polymorphisms associated with adverse reactions of molecular-targeted therapies in renal cell carcinoma[査読有り]記事・総説・解説・論説等（学術雑誌）
- (一社)日本臨床薬理学会, 2017年11月, 臨床薬理, 48(Suppl.) (Suppl.), S278 - S278, 日本語B細胞リンパ腫患者における、リツキシマブのPK/PD解析
- (一社)日本臨床薬理学会, 2017年11月, 臨床薬理, 48(Suppl.) (Suppl.), S274 - S274, 日本語小児におけるトリクロロエタノールの薬物動態・薬力学の発達・成長に伴う変化の解析
- (一社)日本臨床薬理学会, 2017年11月, 臨床薬理, 48(Suppl.) (Suppl.), S278 - S278, 日本語B細胞リンパ腫患者における、リツキシマブのPK/PD解析
- 医薬ジャーナル社, 2017年10月, 医薬ジャーナル, 53(10) (10), 131 - 135, 日本語薬剤師による処方設計(61)薬剤師主導のバンコマイシン処方設計に向けた取り組み
- OXFORD UNIV PRESS, 2017年10月, ANNALS OF ONCOLOGY, 28, 90 - 90, 英語The effects of icing on paclitaxel-induced peripheral neuropathy among breast cancer patients: a self-controlled trial研究発表ペーパー・要旨（国際会議）
- 薬剤師による処方設計 薬剤師主導のバンコマイシン処方設計に向けた取り組み薬剤の投与設計における薬剤師の介入は,医薬品の適正使用の推進において非常に重要な職務である。神戸大学医学部附属病院(以下,当院)では,バンコマイシンの血中濃度測定が実施された全例に対し,薬剤部からの介入を行っている。特に初回投与設計については,当院のニーズに合わせた初回投与ノモグラムを過去のデータを基に作成し,業務の標準化を図っている。今後は,バンコマイシンの処方支援プロトコールに基づいた薬物治療管理の運用を目指している。本稿では,バンコマイシン治療における当院での取り組みを紹介し,薬剤師主導のバンコマイシンの治療計画について考えたい。(著者抄録)(株)医薬ジャーナル社, 2017年10月, 医薬ジャーナル, 53(10) (10), 2315 - 2319, 日本語記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- (一社)日本医用マススペクトル学会, 2017年08月, JSBMS Letters, 42(Suppl.) (Suppl.), 43 - 43, 日本語質量分析法を駆使した最新薬物動態研究 LC/TOF-MSを用いた抗体医薬品の体内動態解析
- 2017年06月, 医療薬学フォーラム講演要旨集, 25th, 233, 日本語リツキシマブの体内動態とその変動因子の考察
- 小児集中治療室に入室した小児患者を対象に、年齢層毎にトリクロホスが経口投与または経胃管投与された患者の割合と体重あたりの投与量、投与時刻を調査した。トリクロホスおよび抱水クロラール(CH)とこれらの代謝産物であるトリクロロエタノール(TCE)とトリクロロ酢酸(TCA)について、血中濃度の同時測定法を開発した。小児集中治療室に入室した小児219人中132人(60%)に、2827回のトリクロホスが投与された。2827投与のうち570投与(20%)が入室30日以内、2257投与(80%)が入室31日以降に投与された。確立した血中濃度の測定方法において、CHの検出下限値・定量下限値は、TCE、TCA、トリクロホスと比べて高かった。小児集中治療室に入室した157入室・135人中、除外基準に該当した53人を除いた82人(61%)の家族が同意取得の対象となり、73人(89%)から同意を得た。不同意と関連する患者・家族要因の解析では、同意群と比較して不同意群で月齢が高く、同意取得時に父親が同席した割合が高かった。(公財)臨床薬理研究振興財団, 2017年06月, 臨床薬理の進歩, (38号) (38号), 71 - 78, 日本語[招待有り]記事・総説・解説・論説等（その他）
- (一社)日本TDM学会, 2017年06月, TDM研究, 34(2) (2), 67 - 95, 日本語抗てんかん薬TDM標準化ガイドライン(STATEMENT) 2017 Version 1.0[査読有り]記事・総説・解説・論説等（学術雑誌）
- (公社)日本薬学会, 2017年03月, 日本薬学会年会要旨集, 137年会(4) (4), 74 - 74, 日本語小児におけるテイコプラニンの薬物動態解析
- (公社)日本薬学会, 2017年03月, 日本薬学会年会要旨集, 137年会(4) (4), 74 - 74, 日本語小児におけるテイコプラニンの薬物動態解析
- 2017年03月, 別冊Bio Clinica: 慢性炎症と疾患, 6(1号) (1号), 121 - 125, 日本語シグナル伝達因子に起因する間質性肺炎発症メカニズム[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 医薬ジャーナル社, 2017年, 医薬ジャーナル, 53(3) (3), 899 - 903, 日本語小児および成人てんかん患者におけるトピラマートの母集団薬物動態解析とその臨床応用[招待有り]記事・総説・解説・論説等（学術雑誌）
- 日本病院薬剤師会, 2017年, 日本病院薬剤師会雑誌, 53(3) (3), 273 - 278, 日本語ポリファーマシーに関連する問題と、STOPP criteriaを活用した高齢者に対する不適切処方のスクリーニング[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2017年, 別冊Bio Clinica, 6(1) (1), 121 - 125, 日本語シグナル伝達因子に起因する間質性肺炎発症メカニズム[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2017年01月, 医薬ジャーナル, 53(増刊) (増刊), 463 - 470, 日本語【新薬展望2017】(第III部)治療における最近の新薬の位置付け＜薬効別＞ 新薬の広場 抗てんかん薬[招待有り]記事・総説・解説・論説等（学術雑誌）
- (一社)日本臨床薬理学会, 2016年10月, 臨床薬理, 47(Suppl.) (Suppl.), S214 - S214, 日本語生体肝移植術後における1日1回製剤のタクロリムス薬物動態と薬効
- (一社)日本臨床薬理学会, 2016年10月, 臨床薬理, 47(Suppl.) (Suppl.), S252 - S252, 日本語臍帯血移植患者におけるミコフェノール酸血中濃度と急性GVHD発症との関連
- 2016年09月, 薬局, 67(10号) (10号), 2820 - 2825, 日本語【処方箋検査値トレーシングレポート活用術 地域医療連携に薬立つ「知恵」と「コツ」】 まずはしっかりと押さえよう!臨床検査値Q&A 院外処方箋に記載されている検査項目にはどのようなものがありますか? またそれからどのような情報を得ることができるのでしょうか?[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2016年07月, 東京都病院薬剤師会雑誌, 65(4号) (4号), 287 - 294, 日本語待ったなし!求められるエビデンス 薬剤師が関わるチーム医療のアウトカム記事・総説・解説・論説等（学術雑誌）
- 2016年06月, 医療薬学フォーラム2016社会的敗北ストレス負荷によるうつ病モデルマウスにおけるブロチゾラム誘発睡眠作用の効力変化に関する行動薬理学的研究
- (一社)日本医薬品情報学会, 2016年05月, 日本医薬品情報学会総会・学術大会講演要旨集, 19回, 116 - 116, 日本語術前外来における薬剤師の取り組み 術前休薬基準の作成と運用
- (一社)日本TDM学会, 2016年05月, TDM研究, 33(2) (2), 135 - 135, 日本語生体肝移植術後のタクロリムス静脈内投与から経口投与への切り替え換算量に関する検討
- (公社)日本薬学会, 2016年03月, 日本薬学会年会要旨集, 136年会(4) (4), 79 - 79, 日本語シクロスポリンおよびタクロリムスの血中濃度測定系に対するアゾール系抗真菌薬の影響
- (公社)日本薬学会, 2016年03月, 日本薬学会年会要旨集, 136年会(4) (4), 79 - 79, 日本語シクロスポリンおよびタクロリムスの血中濃度測定系に対するアゾール系抗真菌薬の影響
- (公社)日本薬学会, 2016年03月, 日本薬学会年会要旨集, 136年会(4) (4), 79 - 79, 日本語小児及び成人てんかん患者におけるトピラマートの母集団薬物動態解析
- (公社)日本薬学会, 2016年03月, 日本薬学会年会要旨集, 136年会(4) (4), 82 - 82, 日本語インフリキシマブ先行品と後続品における糖鎖構造の比較
- (公社)日本薬学会, 2016年03月, 日本薬学会年会要旨集, 136年会(4) (4), 79 - 79, 日本語小児及び成人てんかん患者におけるトピラマートの母集団薬物動態解析
- (公社)日本薬学会, 2016年03月, 日本薬学会年会要旨集, 136年会(4) (4), 82 - 82, 日本語インフリキシマブ先行品と後続品における糖鎖構造の比較
- 2016年01月, 日本病院薬剤師会雑誌, 52(1号) (1号), 29 - 33, 日本語これからの院外処方せんの在り方[招待有り]記事・総説・解説・論説等（学術雑誌）
- (一社)日本臨床薬理学会, 2015年11月16日, 臨床薬理, 46(Supplement) (Supplement), S144 - S144, 日本語造血幹細胞移植患者におけるミコフェノール酸の母集団PK‐PDモデル解析
- TAYLOR & FRANCIS LTD, 2015年11月, DRUG METABOLISM REVIEWS, 47, 234 - 234, 英語EFFECT OF PROTEIN BINDING ON PHARMACOKINETICS AND PHARMACODYNAMICS OF MYCOPHENOLIC ACID USING A POPULATION-MODELING APPROACH研究発表ペーパー・要旨（国際会議）
- (一社)日本臨床薬理学会, 2015年11月, 臨床薬理, 46(Suppl.) (Suppl.), S149 - S149, 日本語潰瘍性大腸炎の治療効果に及ぼす患部組織中タクロリムス濃度及びCYP3A5多型の影響
- 2015年11月, 日本病院薬剤師会雑誌, 51(11号) (11号), 1305 - 1307, 日本語【ポリファーマシー】 ポリファーマシーとは[招待有り]記事・総説・解説・論説等（学術雑誌）
- 日本医療薬学会, 2015年10月23日, 日本医療薬学会年会講演要旨集, 25, 162 - 162, 日本語23-2-S35-1 大学病院の立場から : 外来患者におけるチーム医療の実践(外来において薬物治療マネージメントを考える,シンポジウム35,医療薬学の進歩と未来-次の四半世紀に向けて-)
- 日本医療薬学会, 2015年10月23日, 日本医療薬学会年会講演要旨集, 25, 242 - 242, 日本語22-8-O45-02 臨床検査値を印字した院外処方せんの有用性評価(薬薬連携,口頭発表,一般演題,医療薬学の進歩と未来-次の四半世紀に向けて-)
- 日本医療薬学会, 2015年10月23日, 日本医療薬学会年会講演要旨集, 25, 250 - 250, 日本語23-4-O52-06 イホスファミド脳症のリスク因子に関する調査(がん薬物療法(副作用対策),口頭発表,一般演題,医療薬学の進歩と未来-次の四半世紀に向けて-)
- 日本医療薬学会, 2015年10月23日, 日本医療薬学会年会講演要旨集, 25, 204 - 204, 日本語21-6-O9-03 院外処方せんにおける疑義照会一部不要プロトコルの効果(医療安全・薬学教育他,口頭発表,一般演題,医療薬学の進歩と未来-次の四半世紀に向けて-)
- 日本医療薬学会, 2015年10月23日, 日本医療薬学会年会講演要旨集, 25, 201 - 201, 日本語21-5-O6-09 非イオン性ヨード造影剤によるアレルギー様症状の有害事象に及ぼす水分摂取推奨の影響(有害事象・副作用,口頭発表,一般演題,医療薬学の進歩と未来-次の四半世紀に向けて-)
- 日本医療薬学会, 2015年10月23日, 日本医療薬学会年会講演要旨集, 25, 208 - 208, 日本語21-7-O13-04 悪性黒色腫に対するニボルマブ治療における免疫関連有害反応の検討(がん薬物療法(副作用対策),口頭発表,一般演題,医療薬学の進歩と未来-次の四半世紀に向けて-)
- 日本医療薬学会, 2015年10月23日, 日本医療薬学会年会講演要旨集, 25, 296 - 296, 日本語P0183-21-PM 円滑なC型肝炎治療薬の導入を目指した薬剤師外来の開設と有用性考察(外来薬剤師業務,ポスター発表,一般演題,医療薬学の進歩と未来-次の四半世紀に向けて-)
- 日本医療薬学会, 2015年10月23日, 日本医療薬学会年会講演要旨集, 25th, 330 - 330, 日本語小児におけるバンコマイシン血中濃度と治療効果の関連
- (一社)日本移植学会, 2015年09月, 移植, 50(総会臨時) (総会臨時), 336 - 336, 日本語生体肝移植術後のタクロリムス静脈内導入における点滴速度の適正化
- (一社)日本癌治療学会, 2015年09月, 日本癌治療学会誌, 50(3) (3), 2082 - 2082, 日本語血液・リンパ リンパ腫治療の将来展望 生体内におけるリツキシマブの経時的構造変化の解析
- 2015年06月, 医療薬学フォーラム講演要旨集, 23rd, 283, 日本語プロトコルに基づいた薬物治療管理の臨床アウトカム:心臓血管外科におけるワルファリンプロトコル
- 日本TDM学会, 2015年05月15日, TDM研究, 32(2) (2), 141 - 141, 日本語新規抗てんかん薬の使用状況と血中濃度モニタリングの実際
- 日本TDM学会, 2015年05月15日, TDM研究, 32(2) (2), 136 - 136, 日本語生体肝移植術後のタクロリムス静脈内導入における血中濃度の評価
- (一社)日本TDM学会, 2015年05月, TDM研究, 32(2) (2), 193 - 193, 日本語
- (公社)日本薬学会, 2015年03月, 日本薬学会年会要旨集(CD-ROM), 135th(4) (4), ROMBUNNO.27G-PM08 - 56, 日本語プロトコルに基づいた薬物治療管理が臨床アウトカムに与える影響:TDMオーダを含めた処方設計支援
- (公社)日本薬学会, 2015年03月, 日本薬学会年会要旨集(CD-ROM), 135th(4) (4), ROMBUNNO.27G-PM06 - 55, 日本語生体肝移植後C型肝炎再燃に対するシメプレビル+ペグインターフェロン+リバビリン療法の治療効果とタクロリムス血中濃度への影響
- 2015年, 日本脳腫瘍学会プログラム・抄録集, 33rd, 198, 日本語テモゾロミド長期服用患者の実態調査
- (一社)日本臨床薬理学会, 2014年11月, 臨床薬理, 45(Suppl.) (Suppl.), S236 - S236, 日本語乳癌患者におけるドセタキセルの母集団薬物動態解析とファーマコゲノミクス
- 2014年11月, 医薬ジャーナル, 50(11号) (11号), 2685 - 2691, 日本語薬剤師による処方設計 外来がん化学療法におけるトレーシングレポートを活用した病診薬連携の取り組み記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 日本医療薬学会, 2014年08月25日, 日本医療薬学会年会講演要旨集, 24, 175 - 175, 日本語27-O1PM-04 クロザピンによる副作用の実態調査と薬剤師による介入の効果(副作用(実態調査と対策),優秀演題候補セッション1,新時代を拓く医療薬学フロンティア)
- 日本医療薬学会, 2014年08月25日, 日本医療薬学会年会講演要旨集, 24, 168 - 168, 日本語28-WS-6 薬物療法専門薬剤師の認定申請のための症例サマリーの書き方 : 感染症領域(薬物療法専門薬剤師による薬物治療介入の実際と症例サマリーの纏め方,薬物療法専門薬剤師認定制度委員会企画ワークショップ,新時代を拓く医療薬学フロンティア)
- 日本医療薬学会, 2014年08月25日, 日本医療薬学会年会講演要旨集, 24, 216 - 216, 日本語27-O3PM-16 転倒・転落事故減少を目指した薬剤師による睡眠薬適正使用への介入(医療安全2,一般演題(口頭),新時代を拓く医療薬学フロンティア)
- 日本医療薬学会, 2014年08月25日, 日本医療薬学会年会講演要旨集, 24, 320 - 320, 日本語27-P3PM-010 授乳婦に対する母乳移行性情報情報データベースの作成(妊婦・授乳婦,一般演題(ポスター),新時代を拓く医療薬学フロンティア)
- 日本医療薬学会, 2014年08月25日, 日本医療薬学会年会講演要旨集, 24th, 189 - 189, 日本語保険薬局と協働で行う吸入指導外来の取り組みとその評価
- (一社)日本癌治療学会, 2014年06月, 日本癌治療学会学術集会(CD-ROM), 52nd(3) (3), ROMBUNNO.P82-3 - 2331, 日本語がん領域におけるプレガバリン使用実態に基づく効果と副作用に関する調査
- (一社)日本TDM学会, 2014年05月15日, TDM研究, 31(3) (3), 107 - 107, 日本語小児及び成人てんかん患者の日常診療におけるレベチラセタム血中濃度データの評価と母集団薬物動態解析
- (公社)日本薬学会, 2014年03月, 日本薬学会年会要旨集, 134年会(4) (4), 62 - 62, 日本語ヨード造影剤におけるアレルギー発現率の検討 水分摂取効果及び先発品・後発品間の比較
- (公社)日本薬学会, 2014年03月, 日本薬学会年会要旨集, 134年会(4) (4), 230 - 230, 日本語病院薬剤師を対象としたフィジカルアセスメント講習会の実施とその評価
- 2014年, 日本脳腫瘍学会プログラム・抄録集, 32nd, 75, 日本語神経膠腫患者における抗てんかん薬の血中濃度とてんかん発作出現との関連
- 医薬ジャーナル社, 2014年01月, 医薬ジャーナル, 50(1号) (1号), 77 - 81, 日本語【薬学教育モデル・コアカリキュラム改訂の目指すもの】 薬剤師教育の充実とは 病院薬剤師の立場から[招待有り]記事・総説・解説・論説等（学術雑誌）
- OXFORD UNIV PRESS, 2013年11月, ANNALS OF ONCOLOGY, 24, 英語研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2013年10月, THERAPEUTIC DRUG MONITORING, 35(5) (5), 693 - 693, 英語Impact of P-Glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Antiepileptic Drugs研究発表ペーパー・要旨（国際会議）
- 日本医療薬学会, 2013年08月28日, 日本医療薬学会年会講演要旨集, 23, 331 - 331, 日本語土-P3-476 胆道がんに対するゲムシタビン+シスプラチン療法の有害反応解析と治療継続に関する影響因子の検討(がん薬物療法(その他),ポスター発表,一般演題,再興、再考、創ろう最高の医療の未来)
- 日本医療薬学会, 2013年08月28日, 日本医療薬学会年会講演要旨集, 23rd, 427 - 427, 日本語リファンピシンの薬物相互作用に対する薬学的介入を指標とした病棟薬剤業務の質的評価
- 日本医療薬学会, 2013年08月28日, 日本医療薬学会年会講演要旨集, 23rd, 330 - 330, 日本語腎がん患者におけるエベロリムスの使用実態に関する調査
- (一社)日本医薬品情報学会, 2013年08月, 日本医薬品情報学会総会・学術大会講演要旨集, 16回, 68 - 68, 日本語電子カルテ端末から利用可能な注射薬配合変化情報検索システムの構築と評価
- 2013年04月, TDM研究, 30(2号) (2号), 53 - 108, 日本語抗てんかん薬TDMガイドライン[招待有り]記事・総説・解説・論説等（学術雑誌）
- (公社)日本薬学会, 2013年03月, 日本薬学会年会要旨集, 133年会(4) (4), 69 - 69, 日本語抗てんかん薬クロバザムの臨床効果に対するCYP2C19遺伝子多型の重要性[査読有り]
- (公社)日本薬学会, 2013年03月, 日本薬学会年会要旨集(CD-ROM), 133rd(4) (4), ROMBUNNO.30PMF-716 - 208, 日本語病棟専任薬剤師が参画したチーム医療による持参薬管理の実践~安全性向上と業務負担軽減~
- NATURE PUBLISHING GROUP, 2013年02月, CLINICAL PHARMACOLOGY & THERAPEUTICS, 93, S114 - S115, 英語BLOOD CONCENTRATION MONITORING OF EVEROLIMUS IN JAPANESE PATIENTS WITH RENAL CELL CARCINOMA研究発表ペーパー・要旨（国際会議）
- 2013年, 日本緩和医療薬学会年会プログラム・要旨集, 7th右股関節離断術後のプレガバリン無効の幻肢痛・幻肢覚に対してデュロキセチンが奏効した症例~がんサポートチームの介入~
- 日本医療薬学会, 2012年10月10日, 日本医療薬学会年会講演要旨集, 22, 269 - 269, 日本語P1-018 ベルテポルフィン使用後におけるLED照射の安全性に関する検討(薬剤管理指導・病棟薬剤業務,ポスター,一般演題,岐路に立つ医療〜千年紀の目覚め〜よみがえれ!ニッポン!薬の改革は我らが手で!)
- 日本医療薬学会, 2012年10月10日, 日本医療薬学会年会講演要旨集, 22nd, 346 - 346, 日本語新規抗凝固薬ダビガトランの出血性副作用発現因子の探索
- 日本臨床精神神経薬理学会・日本神経精神薬理学会, 2012年10月, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 22回・42回, 174 - 174, 日本語炭酸リチウム及びアデニンの投与によってクロザピン治療を継続できた治療抵抗性統合失調症の2症例
- (公社)日本薬学会, 2012年03月, 日本薬学会年会要旨集, 132年会(4) (4), 196 - 196, 日本語慢性拒絶反応を呈した肝移植患者におけるシロリムスの臨床効果
- 2011年11月24日, 生体膜と薬物の相互作用シンポジウム講演要旨集, 33rd, 76 - 77, 日本語メトホルミンのPK/PDにおけるMATEの役割
- 2011年10月, 臨床薬理, 42(Suppl.) (Suppl.)難治性潰瘍性大腸炎のタクロリムス治療における大腸粘膜のMDR1発現量とCYP3A5遺伝子多型の影響
- 日本医療薬学会, 2011年09月09日, 日本医療薬学会年会講演要旨集, 21, 132 - 132, 日本語ビノレルビン/シスプラチン併用療法中の嘔吐に対するアプレピタントの効果に関する検討(一般演題(口頭)1,がん薬物療法(副作用対策)(1),Enjoy Pharmacists' Lifestyles)
- 日本医療薬学会, 2011年09月09日, 日本医療薬学会年会講演要旨集, 21, 219 - 219, 日本語P-0226 進行肝細胞がん患者におけるソラフェニブの服薬継続並びに有害事象発現に及ぼす影響因子の検討(一般演題 ポスター発表,がん薬物療法(外来化学療法),Enjoy Pharmacists' Lifestyles)
- 日本医療薬学会, 2011年09月09日, 日本医療薬学会年会講演要旨集, 21, 212 - 212, 日本語P-0181 ドセタキセル、シスプラチン併用療法時の感染対策に関する調査(一般演題 ポスター発表,がん薬物療法(副作用対策),Enjoy Pharmacists' Lifestyles)
- 日本医療薬学会, 2011年09月09日, 日本医療薬学会年会講演要旨集, 21, 262 - 262, 日本語P-0485 新規疑義照会データベースの構築とその評価(一般演題 ポスター発表,調剤・処方鑑査・リスクマネジメント,Enjoy Pharmacists' Lifestyles)
- 日本医療薬学会, 2011年09月09日, 日本医療薬学会年会講演要旨集, 21, 348 - 348, 日本語P-1001 HIV感染妊婦の受け入れに対する薬剤部の取り組み(一般演題 ポスター発表,HIV,Enjoy Pharmacists' Lifestyles)
- LIPPINCOTT WILLIAMS & WILKINS, 2011年08月, THERAPEUTIC DRUG MONITORING, 33(4) (4), 494 - 495, 英語Association between biliary concentration of 13-O-demethylated tacrolimus and clinical course in liver transplant patients研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2011年08月, THERAPEUTIC DRUG MONITORING, 33(4) (4), 529 - 530, 英語Significance of trough monitoring of tacrolimus blood concentration and calcineurin activity in living-donor liver transplant patients研究発表ペーパー・要旨（国際会議）
- (一社)日本TDM学会, 2011年06月, TDM研究, 28(3) (3), s182 - s182, 日本語タクロリムス血中濃度管理における脳死全肝移植と生体肝移植との比較
- 2011年, 医療薬学フォーラム講演要旨集, 19th薬学6年制における病院実務実習の評価:学生に対するアンケート調査及び実習記録から
- 2010年11月10日, 臨床薬理, 41(Supplement) (Supplement), S204, 日本語H+/有機カチオンアンチポータMATEの遺伝子多型によるメトホルミンの体内動態変化
- (一社)日本臨床薬理学会, 2010年11月, 臨床薬理, 41(Suppl.) (Suppl.), S312 - S312, 日本語生体肝移植患者の術後経過に及ぼす遺伝的背景の影響
- (一社)日本臨床薬理学会, 2010年11月, 臨床薬理, 41(Suppl.) (Suppl.), S205 - S205, 日本語生体肝移植後のタクロリムス関連腎障害の発症におけるCYP3A5遺伝子多型の影響
- 日本医療薬学会, 2010年10月25日, 日本医療薬学会年会講演要旨集, 20, 487 - 487, 日本語P2-583 薬学実務実習における調剤室の取り組みとその評価(一般演題 ポスター発表,薬学教育(実務実習),臨床から学び臨床へと還元する医療薬学)
- 日本医療薬学会, 2010年10月25日, 日本医療薬学会年会講演要旨集, 20, 273 - 273, 日本語O8-04 パクリタキセル・カルボプラチン併用療法の副作用発現に関連する因子の検討(一般演題 口頭発表,がん薬物療法(副作用対策),臨床から学び臨床へと還元する医療薬学)
- 日本医療薬学会, 2010年10月25日, 日本医療薬学会年会講演要旨集, 20, 315 - 315, 日本語P1-170 進行非小細胞肺がんに対するエルロチニブの肝障害発症に関する検討(一般演題 ポスター発表,有害事象・副作用,臨床から学び臨床へと還元する医療薬学)
- 日本医療薬学会, 2010年10月25日, 日本医療薬学会年会講演要旨集, 20, 449 - 449, 日本語P2-357 質量分析法を用いた経口チロシンキナーゼ阻害薬6種の一斉定量法の確立(一般演題 ポスター発表,癌薬物療法(その他),臨床から学び臨床へと還元する医療薬学)
- 日本医療薬学会, 2010年10月25日, 日本医療薬学会年会講演要旨集, 20, 292 - 292, 日本語P1-032 NICUにおける薬剤師の新しい業務展開とその評価(一般演題 ポスター発表,薬剤管理指導・情報提供,臨床から学び臨床へと還元する医療薬学)
- 2010年, 日本緩和医療薬学会年会プログラム・要旨集, 4thワルファリン服用患者においてオキシコドン併用がプロトロンビン時間に及ぼす影響
- 2009年12月, 治療学, 43(12号) (12号), 1351 - 1355, 日本語免疫抑制薬とアゾール系抗真菌薬の薬物動態学的相互作用[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2009年07月, 医療薬学フォーラム講演要旨集, 17th, 212, 日本語小細胞肺がん治療におけるシスプラチンとカルボプラチンの副作用比較及びその危険因子の抽出
- 2009年07月, 医療薬学フォーラム講演要旨集, 17th, 222, 日本語脳神経外科大量化学療法レジメンにおける薬剤師の関わり
- (公社)日本薬剤学会, 2009年04月30日, 薬剤学, 69(Supplement) (Supplement), 111 - 111, 日本語腎排泄型カチオン性薬物メトホルミンのクリアランス予測因子の探索
- (公社)日本薬学会, 2009年03月, 日本薬学会年会要旨集, 129年会(4) (4), 206 - 206, 日本語イトラコナゾール内用液の小児患者における有用性に関する検討
- 2008年12月, 上原記念生命科学財団研究報告集, 22, 1 - 4, 日本語免疫抑制剤の体内動態と薬効の速度論的解析に基づく個別化投与設計システムの開発[招待有り]記事・総説・解説・論説等（学術雑誌）
- (一社)日本臨床薬理学会, 2008年11月, 臨床薬理, 39(Suppl.) (Suppl.), S189 - S189, 日本語癌化学療法における骨髄抑制作用の経時的変化に関する速度論的解析
- 日本医療薬学会, 2008年09月01日, 日本医療薬学会年会講演要旨集, 18, 381 - 381, 日本語21-P1-042 注射薬調剤における疑義照会データベースの構築と照会内容の解析(データベース,来るべき時代への道を拓く)
- 日本医療薬学会, 2008年09月01日, 日本医療薬学会年会講演要旨集, 18, 258 - 258, 日本語20H-05 病院実習における9年間のアンケート結果からみた治験教育の状況と今後の課題(薬学教育(モデル・コアカリキュラム)・卒後研修・研修制度,来るべき時代への道を拓く)
- 日本医療薬学会, 2008年09月01日, 日本医療薬学会年会講演要旨集, 18, 284 - 284, 日本語20-P1-010 調剤業務と薬剤管理指導業務における薬学的介入の比較(調剤・処方鑑査(内用薬),来るべき時代への道を拓く)
- 日本医療薬学会, 2008年09月01日, 日本医療薬学会年会講演要旨集, 18, 326 - 326, 日本語20-P2-260 腎機能低下時の大腸がん患者に対するOxaliplatinの使用調査(がん薬物療法(その他),来るべき時代への道を拓く)
- 日本医療薬学会, 2008年09月01日, 日本医療薬学会年会講演要旨集, 18, 410 - 410, 日本語21-P2-213 進行膵がんに対するTS-1とGemcitabine併用療法時の骨髄抑制に関する調査(がん薬物療法(外来化学療法),来るべき時代への道を拓く)
- 日本医療薬学会, 2008年09月01日, 日本医療薬学会年会講演要旨集, 18th, 250 - 250, 日本語温度変化に対するビンカアルカロイド系抗がん剤の物理化学的特性の検討
- 日本医療薬学会, 2008年09月01日, 日本医療薬学会年会講演要旨集, 18th, 423 - 423, 日本語脳神経外科病棟でのテモゾロミド・放射線併用療法における薬剤師の関わり
- 2008年07月, 臨床薬理の進歩, (29号) (29号), 113 - 119, 日本語カルシニューリン阻害剤の体内動態と薬効の速度論的解析に基づく個別化投与設計法[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2008年03月, 第128回日本薬学会成人肝移植患者におけるジピリダモール、アシクロビル、ST合剤の予防的投与に関する検討研究発表ペーパー・要旨（全国大会，その他学術会議）
- 2008年01月, 今日の移植, 21(1号) (1号), 17 - 23, 日本語タクロリムス血中濃度の調整メカニズム[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2007年12月, 日本医療薬学会会報, 11(4号) (4号), 24 - 29, 日本語これからの臨床薬剤師のあり方 薬剤師が変える薬物治療[招待有り]速報，短報，研究ノート等（学術雑誌）
- 日本てんかん学会, 2007年09月30日, てんかん研究, 25(3) (3), 377 - 377, 日本語P2-62 坑てんかん薬クロバザムおよび活性代謝物の体内動態に関する解析(薬物治療6,一般演題(ポスター),てんかん制圧:新たなステージに向けて,第41回日本てんかん学会)
- 日本医療薬学会, 2007年09月01日, 日本医療薬学会年会講演要旨集, 17, 152 - 152, 日本語29-S4-3 臓器移植に生かす免疫抑制剤のPK/PD(シンポジウム29-S4 一歩進んだ「がん薬物業務」,社会の期待に応える医療薬学を)
- 日本医療薬学会, 2007年09月01日, 日本医療薬学会年会講演要旨集, 17, 211 - 211, 日本語30-C1-09-2 小児脳腫瘍患者のコンプライアンス向上を目指したテモゾロミドの投与方法に関する検討(がん薬物療法,社会の期待に応える医療薬学を)
- 日本医療薬学会, 2007年09月01日, 日本医療薬学会年会講演要旨集, 17, 197 - 197, 日本語29-C1-14-1 外来患者に対する安全ながん薬物療法に向けたTS-1服薬指導の取り組み(がん薬物療法,社会の期待に応える医療薬学を)
- 日本医療薬学会, 2007年09月01日, 日本医療薬学会年会講演要旨集, 17, 195 - 195, 日本語29-B4-13-5 がん化学療法における医療経済学的視点に基づく薬剤使用評価(がん薬物療法,社会の期待に応える医療薬学を)
- じほう, 2007年09月, 薬事, 49(9号) (9号), 1359 - 1364, 日本語【薬学的視点から薬をみる力 薬物動態パラメータをどう読むか?】 薬物動態パラメータを活用した臨床事例 カルシニューリン阻害剤について記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- LIPPINCOTT WILLIAMS & WILKINS, 2007年08月, THERAPEUTIC DRUG MONITORING, 29(4) (4), 484 - 484, 英語Intestinal CYP3A5 genotype and MDR1 expression influence apparent clearance of tacrolimus in adult living-donor liver transplant recipients研究発表ペーパー・要旨（国際会議）
- BLACKWELL PUBLISHING, 2007年05月, AMERICAN JOURNAL OF TRANSPLANTATION, 7, 551 - 551, 英語Neoral once daily dosing utilizing trough and C2 monitoring in de novo living donor liver transplant recipients.研究発表ペーパー・要旨（国際会議）
- (公社)日本薬学会, 2007年03月, 日本薬学会年会要旨集, 127年会(3) (3), 199 - 199, 日本語電子カルテを活用したオピオイド鎮痛薬に関する薬剤管理指導の標準化
- (公社)日本薬学会, 2007年03月, 日本薬学会年会要旨集, 127年会(3) (3), 189 - 189, 日本語外来がん化学療法における性差に基づく副作用解析
- 日本肺癌学会, 2006年11月05日, 肺癌, 46(5) (5), 559 - 559, 日本語P-134 ゲフィチニブの臨床効果と副作用の背景因子に関する解析(分子標的治療2, 第47回日本肺癌学会総会)
- 2006年11月, 今日の移植, 19(6号) (6号), 658 - 660, 日本語【Ciclosporin Pharmaco-Clinical Forum 2006】 TDMによる臨床成績向上への更なる挑戦 カルシニューリン阻害剤のpharmacodynamicsと至適投与設計[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 日本医療薬学会, 2006年09月01日, 日本医療薬学会年会講演要旨集, 16, 347 - 347, 日本語01-H-08 mTOR阻害薬をシロリムスからエベロリムスに変更した膵島移植患者における血中濃度モニタリング(薬物動態(TDM・投与設計等),医療薬学の扉は開かれた)
- 日本医療薬学会, 2006年09月01日, 日本医療薬学会年会講演要旨集, 16, 429 - 429, 日本語30P2-150 膵島移植患者におけるミコフェノール酸の薬物動態学/薬力学的解析(薬物動態(TDM・投与設計等),医療薬学の扉は開かれた)
- 日本医療薬学会, 2006年09月01日, 日本医療薬学会年会講演要旨集, 16, 506 - 506, 日本語01P1-109 手術前の適切な休薬期間設定への取り組み(医薬品適正使用,医療薬学の扉は開かれた)
- LIPPINCOTT WILLIAMS & WILKINS, 2006年07月, INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY, 21(4) (4), A25 - A26, 英語Prescription survey of schizophrenia in the psychiatric outpatient unit of a university hospital (I): comparison between prescriptions before and after the introduction of novel antipsychotics[査読有り]研究発表ペーパー・要旨（国際会議）
- LIPPINCOTT WILLIAMS & WILKINS, 2006年07月, INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY, 21(4) (4), A11 - A11, 英語Major factors inhibiting spread of novel antipsychotic monotherapy for schizophrenia: prescription survey in the psychiatric outpatient unit of Kyoto University Hospital[査読有り]研究発表ペーパー・要旨（国際会議）
- じほう, 2006年07月, 薬事, 48(8号) (8号), 1289 - 1293, 日本語【薬剤師による臨床研究の進め方 日常業務から医療薬学研究のシーズを育てる】 臨床研究の実例と進め方のポイント 緑内障治療薬アセタゾラミドの体内動態と薬効の速度論的解析 着眼点と進め方のポイント[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- JOHN WILEY & SONS INC, 2006年05月, LIVER TRANSPLANTATION, 12(5) (5), C5 - C5, 英語Improved cyclosporine absorption and immunosuppression by a once daily dosing in living-donor liver transplant patients.研究発表ペーパー・要旨（国際会議）
- (一社)日本TDM学会, 2006年04月, TDM研究, 23(2) (2), 85 - 86, 日本語膵島移植患者におけるラパマイシンの体内動態と薬効・副作用に関する検討
- (一社)日本TDM学会, 2006年04月, TDM研究, 23(2) (2), 87 - 88, 日本語小児造血幹細胞移植におけるシクロスポリン間歇点滴法の血中濃度モニタリング
- じほう, 2006年02月, 薬事, 48(2号) (2号), 269 - 275, 日本語薬剤師が変える薬物治療 生体肝移植症例におけるカルシニューリン活性の測定に基づく薬効評価と個別化投与設計[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2005年12月27日, Drug metabolism and pharmacokinetics, 20(6) (6), 1 - 2, 日本語平成17年度日本薬物動態学会奨励賞を受賞して
- 2005年11月, 今日の移植, 18(6号) (6号), 721 - 724, 日本語【CPCF2005】 肝臓移植患者の小腸・肝組織を用いた遺伝子解析に基づく免疫抑制剤の投与設計[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2005年10月, Drug Metabolism and Pharmacokinetics, 20(5号) (5号), 25 - 28, 日本語薬物血中濃度モニタリングの現状と課題 免疫抑制剤の適正使用[招待有り]記事・総説・解説・論説等（学術雑誌）
- 日本医療薬学会, 2005年09月01日, 日本医療薬学会年会講演要旨集, 15, 389 - 389, 日本語P-643 バンコマイシンの目標血中濃度と副作用発現に関する検討 : ICTとの連携による取り組み(9.薬物動態(TDM・投与設計等)3,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
- 日本医療薬学会, 2005年09月01日, 日本医療薬学会年会講演要旨集, 15, 383 - 383, 日本語P-618 薬剤溶出ステント留置患者における抗血小板薬の適正使用について(8.有害事象・副作用(基礎と臨床)1,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
- 日本医療薬学会, 2005年09月01日, 日本医療薬学会年会講演要旨集, 15, 269 - 269, 日本語P-161 京大病院薬剤部における膵島移植に対する取り組み(6.服薬指導(入院・外来)3,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
- 日本医療薬学会, 2005年09月01日, 日本医療薬学会年会講演要旨集, 15, 345 - 345, 日本語P-465 癌化学療法の質的向上を目指した薬剤師の取り組み : 副作用結果に基づく危険因子の解析(2.癌薬物療法(外来化学療法、緩和ケア等)7,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
- 日本医療薬学会, 2005年09月01日, 日本医療薬学会年会講演要旨集, 15, 344 - 344, 日本語P-461 外来化学療法におけるレジメン登録と注射オーダー支援機能の導入(2.癌薬物療法(外来化学療法、緩和ケア等)7,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
- 日本医療薬学会, 2005年09月01日, 日本医療薬学会年会講演要旨集, 15, 368 - 368, 日本語P-558 ゲフィチニブ内服患者に対する服薬指導と副作用モニタリング(6.服薬指導(入院・外来)5,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
- 日本医療薬学会, 2005年09月01日, 日本医療薬学会年会講演要旨集, 15, 199 - 199, 日本語SP11-1 膵島移植患者における免疫抑制剤のTDM(SP11「移植医療とTDM」,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
- (一社)日本腎臓学会, 2005年05月, 日本腎臓学会誌, 47(3) (3), 298 - 298, 英語rOCT2(Slc22a2)に焦点を合わせたシスプラチンの腎毒性(Nephrotoxicity of cisplatin focusing on rOCT2 (Slc22a2))
- (一社)日本TDM学会, 2005年04月, TDM研究, 22(2) (2), 105 - 106, 日本語泌尿器系癌患者におけるパクリタキセルの体内動態と薬効・副作用に関する解析
- (公社)日本薬学会, 2005年03月, 日本薬学会年会要旨集, 125年会(2) (2), 180 - 180, 日本語前立腺癌患者におけるカルボプラチン体内動態と副作用の解析
- (公社)日本薬学会, 2005年03月, 日本薬学会年会要旨集, 125年会(2) (2), 214 - 214, 日本語新規抗精神病薬の普及と単剤化を阻害する要因 大学病院精神科外来における処方調査から
- The Japanese Society of Clinical Pharmacology and Therapeutics, 2005年03月, 臨床薬理, 36(2号) (2号), 58 - 62, 日本語[招待有り]記事・総説・解説・論説等（学術雑誌）
- 医薬ジャ-ナル社, 2005年01月, 医薬ジャーナル, 41(1号) (1号), 75 - 80, 日本語【臨床に活かすPK/PD 薬物の体内動態と薬効・毒性】 免疫抑制剤のPK/PD[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2004年11月, 今日の移植, 17(6号) (6号), 801 - 803, 日本語カルシニューリン阻害剤の薬効測定に基づく個別化投与設計[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2004年10月, 薬局, 55(10月臨増) (10月臨増), 173 - 175, 日本語【Q and Aで学ぶTDM活用ガイド】 TDM 実践Q and A 免疫抑制剤 免疫抑制剤のTDMを実施することによってどのようなメリットがあるのでしょうか?[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2004年10月, 薬局, 55(10月臨増) (10月臨増), 184 - 185, 日本語【Q and Aで学ぶTDM活用ガイド】 TDM 実践Q and A 免疫抑制剤 今まではシクロスポリンはトラフ値を測定していましたが,最近ピーク値も有用になってきたと聞きました.これについて教えてください[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2004年10月, 薬局, 55(10月臨増) (10月臨増), 186 - 187, 日本語【Q and Aで学ぶTDM活用ガイド】 TDM 実践Q and A 免疫抑制剤 シクロスポリンの有効治療域は疾患によって異なるのでしょうか?[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2004年10月, 薬局, 55(10月臨増) (10月臨増), 291 - 292, 日本語【Q and Aで学ぶTDM活用ガイド】 TDM 実践Q and A 遺伝子情報をTDMに活かすことはできますか?また逆にTDMで得られた情報を遺伝子多型に活かすことはできますか?[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 日本医療薬学会, 2004年09月01日, 日本医療薬学会年会講演要旨集, 14, 161 - 161, 日本語S7-4 生体腎移植患者におけるカルシニューリン阻害剤の体内動態と薬効の解析(一般講演,薬物治療に薬物動態情報を活かすには,(7)薬物動態情報の活用1:PK/PD,2.最近研究情報の現状と適用,"薬剤師がつくる薬物治療"-薬・薬・学の連携-)
- 日本医療薬学会, 2004年09月01日, 日本医療薬学会年会講演要旨集, 14, 220 - 220, 日本語P-13 パクリタキセルとカルボプラチンの少量分割投与による骨髄抑制の軽減 : 非小細胞肺癌を中心として(1.薬物療法(基礎と臨床),"薬剤師がつくる薬物治療"-薬・薬・学の連携-)
- 日本医療薬学会, 2004年09月01日, 日本医療薬学会年会講演要旨集, 14, 269 - 269, 日本語P-212 京大病院における外来化学療法レジメンの登録とその評価(14.調剤・処方管理・オーダリング(注射剤含む),"薬剤師がつくる薬物治療"-薬・薬・学の連携-)
- 日本医療薬学会, 2004年09月01日, 日本医療薬学会年会講演要旨集, 14, 243 - 243, 日本語P-107 開心術後肺高血圧症に対する経口シルデナフィル使用の薬学的検討(5.薬剤服用歴管理・服薬指導(入院患者服薬指導),"薬剤師がつくる薬物治療"-薬・薬・学の連携-)
- じほう, 2004年09月, 薬事, 46(10号) (10号), 1745 - 1749, 日本語【移植医療】 臓器移植に活かす薬剤師の専門性[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 一般社団法人 日本臨床薬理学会, 2004年01月31日, 臨床薬理 = JAPANESE JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 35(1) (1), 86S, 日本語
- 2004年01月, 薬剤学: 生命とくすり, 64(1号) (1号), 32 - 35, 日本語臨床薬剤業務と連携した薬物動態と薬効の母集団解析[招待有り]記事・総説・解説・論説等（学術雑誌）
- 日本医療薬学会, 2003年09月01日, 日本医療薬学会年会講演要旨集, 13, 146 - 146, 日本語28-02-15 高カロリー輸液 (TPN) の無菌調製完全実施と適応に関する検討
- 日本医療薬学会, 2003年09月01日, 日本医療薬学会年会講演要旨集, 13, 135 - 135, 日本語27-03-02 3 年次学生を対象とした医療薬学実習(1 ヶ月)の取り組みとその評価
- (公社)日本薬学会, 2003年03月, 日本薬学会年会要旨集, 123年会(4) (4), 179 - 179, 日本語ランソプラゾール併用がタクロリムス血中濃度に影響したと考えられた症例
- 2003年03月, 産婦人科治療, 86(増刊) (増刊), 377 - 384, 日本語【女性診療科医のための薬物療法マニュアル】 薬物動態を考慮した処方計画[招待有り]記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- The Japanese Society of Clinical Pharmacology and Therapeutics, 2003年01月31日, 臨床薬理, 34(1) (1), 25S - 26S, 日本語
- 日本医療薬学会, 2002年09月24日, 日本医療薬学会年会講演要旨集, 12, 228 - 228, 日本語P-335 生体肝移植後に発生した全身性皮膚掻痒感に対する薬剤管理指導
- 日本医療薬学会, 2002年09月24日, 日本医療薬学会年会講演要旨集, 12, 220 - 220, 日本語P-302 薬剤管理指導における医薬品情報のニーズと提供内容の解析
- 日本医療薬学会, 2002年09月24日, 日本医療薬学会年会講演要旨集, 12, 246 - 246, 日本語P-408 シクロスポリンとプロブコールの相互作用機序に関する検討
- 日本医療薬学会, 2002年09月24日, 日本医療薬学会年会講演要旨集, 12, 213 - 213, 日本語P-275 抗悪性腫瘍剤無菌調製のシステム化
- 2002年03月05日, 薬剤学, 62, 104 - 104, 日本語グレパフロキサシンのバイオアベイラビリティにおける P-糖蛋白質の役割
- (公社)日本薬学会, 2002年03月, 日本薬学会年会要旨集, 122年会(4) (4), 57 - 57, 日本語高尿酸血症モデルラットにおける腎尿細管薬物輸送活性と有機イオントランスポーターの発現量変動
- The Japanese Society of Clinical Pharmacology and Therapeutics, 2002年01月31日, 臨床薬理, 33(1) (1), 127S - 128S, 日本語
- 2001年09月17日, 薬物動態 = Xenobiotic metabolism and disposition, 16, S207, 日本語キノロン系抗菌薬の消化管分泌に及ぼす腎障害の影響
- 日本医療薬学会, 2001年09月01日, 日本医療薬学会年会講演要旨集, 11, 103 - 103, 日本語O-98 腎障害時におけるシクロスポリン体内動態の解析
- 2001年03月05日, 薬剤学 = Journal of Pharmaceutical Science and Technology, Japan, 61, 195 - 195, 日本語Caco-2細胞におけるグレパフロキサシン及びレボフロキサシンの取り込み特性
- (公社)日本薬学会, 2001年03月, 日本薬学会年会要旨集, 121年会(3) (3), 82 - 82, 日本語高尿酸血症モデルラットにおける有機イオン輸送系の活性と発現量変動
- 日本医療薬学会, 2000年09月01日, 日本病院薬学会年会講演要旨集, 10, 252 - 252, 日本語P-196 うっ血性心不全患者のジゴキシンクリアランスに及ぼすイトラコナゾール併用の影響
- 日本医療薬学会, 2000年09月01日, 日本病院薬学会年会講演要旨集, 10, 142 - 142, 日本語O-119 タクロリムスの体内動態に及ぼす腎障害の影響
- (一社)日本薬物動態学会, 2000年09月, 薬物動態, 15(Suppl.) (Suppl.), S215 - S215, 日本語腎障害ラットにおける有機イオントランスポータの輸送活性とその発現変動
- 2000年05月29日, 臨床薬理の進歩, (21) (21), 1 - 11, 日本語薬物相互作用の臨床薬理 薬物トランスポータ群の構造・機能解析に基づく薬物相互作用の評価
- (公社)日本薬学会, 2000年03月, 日本薬学会年会要旨集, 120年会(4) (4), 57 - 57, 日本語培養腎上皮細胞OKの頂側膜におけるPAH輸送
- (一社)日本薬物動態学会, 1999年09月, 薬物動態, 14(Suppl.) (Suppl.), S166 - S166, 日本語培養腎上皮細胞OKにおける有機アニオン輸送 アデノシンA1レセプターアンタゴニストKW-3902の影響
- (一社)日本薬物動態学会, 1998年10月, 薬物動態, 13(Suppl.) (Suppl.), S178 - S178, 日本語培養腎上皮細胞OKの有機アニオン輸送に及ぼすキノロン系抗菌薬の影響
- 1997年10月09日, 薬物動態 = Xenobiotic metabolism and disposition, 12, 193 - 193, 日本語キノロン系抗菌薬の腎移行特性
- 1997年10月09日, 薬物動態 = Xenobiotic metabolism and disposition, 12, 193 - 193, 日本語培養腎上皮細胞 LLC-PK_1におけるレボフロキサシンの輸送特性
- 日本医療薬学会, 1991年06月25日, 日本病院薬学会年会講演要旨集, 1, 108 - 109, 日本語28 Population Pharmacokinetics によるテォフィリン体内動態の変動要因解析
- The Japanese Society of Clinical Pharmacology and Therapeutics, 1991年, 臨床薬理, 22(1) (1), 193 - 194, 日本語
- 日本てんかん学会, 1990年, 日本てんかん学会プログラム・抄録集, (24) (24), 214 - 214, 日本語2B3-14 ACTH療法によるバルプロ酸血中濃度の変動について
- 共編者(共編著者), 1 薬剤業務の補助業務. 3 基本的な補助業務, 薬事日報社, 2024年11月, 日本語, ISBN: 9784840816472薬剤業務補助者育成ガイドブック : 実践!タスクシフト
- 分担執筆, 薬物代謝能の変動要因, 南江堂, 2024年03月, 日本語, ISBN: 9784524403813生物薬剤学
- α1遮断薬−ループ利尿薬, フェニトイン−ST合剤（スルファメトキサゾール−トリメトプリム）, ワルファリン−アミオダロン、ワルファリン−シプロフロキサシン、ワルファリン−マクロライド系抗菌薬、ワルファリン−ST合剤（スルファメトキサゾール−トリメトプリム）, 医学書院, 2024年02月, 日本語, ISBN: 9784260052733これだけは気をつけたい!高齢者への薬剤処方
- 編者(編著者), 月刊薬事（10月臨時増刊号）, 2023年10月ケーススタディで学ぶ処方提案：これが決め手！同効薬の使いどころ
- 分担執筆, 経皮吸収型製剤, 薬事日報社, 2022年08月, 日本語, ISBN: 9784840815963調剤指針
- 共編者(共編著者), Q56薬物の胎盤透過性はどのように予測する？Q57薬物の母乳移行性はどのように予測する？Q58薬剤の催奇性はどのように予測する？Q59更年期障害時に注意すべき薬剤は？, じほう, 2021年12月, 日本語, ISBN: 9784840754019できる薬剤師とよばれるために上手に使いたい薬学ナレッジ101
- 分担執筆, 第5章生殖器・婦人科疾患．A総論．1. 修得すべき知識の概要．2. 生殖器系の構造と機能．3. 妊娠・分娩・避妊に関する薬物．B疾患各論．1. 月経異常．2. 不妊症．3. 更年期障害．4．子宮内膜症．5. 子宮筋腫．6.異常妊娠．7.異常分娩．8. 性感染症．9．母子感染症．, 中山書店, 2020年05月, 日本語, ISBN: 9784521744544臨床薬学テキストシリーズ. 〔薬理・病態・薬物治療〕消化器/感覚器・皮膚/生殖器・産婦人科
- 共編者(共編著者), 金原出版, 2018年11月, 日本語, ISBN: 9784307470483抗てんかん薬TDM標準化ガイドライン
- その他, 中山書店, 2018年, 日本語臨床薬学テキストシリーズ．薬物治療総論/症候・臨床検査/個別化医療 / 薬物の副作用教科書・概説・概論
- その他, 中山書店, 2018年, 日本語臨床薬学テキストシリーズ．薬物治療総論/症候・臨床検査/個別化医療 / 薬害，薬物乱用と健康リスク教科書・概説・概論
- その他, 薬事日報社, 2018年, 日本語第十四改訂調剤指針 / 経皮吸収型製剤事典・辞書
- その他, 金原出版株式会社, 2018年, 日本語抗てんかん薬TDM標準化ガイドライン2018 / 抗てんかん薬TDM標準化ガイドライン2018その他
- その他, 南山堂, 2018年, 日本語ポリファーマシー見直しのための医師・薬剤師連携ガイド / ポリファーマシー見直しのための医師・薬剤師連携ガイドその他
- その他, 東京化学同人, 2018年, 日本語スタンダード薬学シリーズII 7. 臨床薬学III.チーム医療および地域の保健・医療・福祉への参画 / 第2章チーム医療と薬剤師2-1病院内のチームと構成員の役割教科書・概説・概論
- その他, 東京化学同人, 2018年, 日本語スタンダード薬学シリーズII 7. 臨床薬学III.チーム医療および地域の保健・医療・福祉への参画 / 第1章医療機関におけるチーム医療 1-1 チーム医療の基本的事項教科書・概説・概論
- 共著, 第2章 医療と薬剤師．第4章 処方せんと調剤．第10章10.5 臓器移植時の薬物療法と処方, 廣川書店, 2014年03月医療薬学第6版
- その他, 廣川書店, 2014年, 日本語医療薬学第6版 / 第4章 処方せんと調剤教科書・概説・概論
- その他, 廣川書店, 2014年, 日本語医療薬学第6版 / 第2章 医療と薬剤師教科書・概説・概論
- その他, 廣川書店, 2014年, 日本語医療薬学第6版 / 10.5 臓器移植時の薬物療法と処方教科書・概説・概論
- その他, 東京化学同人, 2012年, 日本語薬学用語辞典 / ?教科書・概説・概論
- その他, じほう, 2012年, 日本語疾患からみた臨床薬理学第3版 / 臓器移植と免疫抑制療法教科書・概説・概論
- 共著, 14. 臓器移植と免疫抑制療法, じほう, 2012年疾患からみた臨床薬理学第3版
- その他, 廣川書店, 2012年, 日本語最新薬剤学第10版 / 第 5 章 医療薬剤学 5.1 医療と薬剤師．5.2医薬品の有効性と安全性.教科書・概説・概論
- 共著, 第 5 章 医療薬剤学 5.1 医療と薬剤師, 廣川書店, 2012年最新薬剤学第10版
- 共著, 第5章 １．pharmacokineticsとpharmacodynamics, 西村書店, 2012年カラー版内科学
- 薬事日報社, 2011年, 日本語第十三改訂調剤指針 / 経皮吸収型製剤事典・辞書
- その他, 経皮吸収型製剤, 薬事日報社, 2011年第十三改訂調剤指針
- その他, 羊土社, 2009年, 日本語薬物トランスポーター活用ライブラリー 機能・輸送基質から創薬・臨床応用まで / ジゴキシンの薬物相互作用に関わるトランスポーター学術書
- その他, 廣川書店, 2009年, 日本語医療薬学第5版 / 第4章 処方せんと調剤教科書・概説・概論
- その他, 廣川書店, 2009年, 日本語医療薬学第5版 / 第2章 医療と薬剤師教科書・概説・概論
- その他, 廣川書店, 2009年, 日本語医療薬学第5版 / 10.5 臓器移植時の薬物療法と処方教科書・概説・概論
- その他, Bentham Science Publishers Ltd., 2009年, 英語Frontiers in drug design and discovery vol. 4 / Pharmacogenomic considerations in breast cancer management.学術書
- その他, Bentham Science Publishers Ltd., 2009年, 英語Frontiers in drug design and discovery vol. 4 / Important drug interactions for clinical oncologists.学術書
- その他, Thomson Reuters, 2008年, 英語Evolution of living-donor liver transplantation / Therapeutic drug monitoring and individualized therapy with tacrolimus in recipients of living-donor liver transplantation.学術書
- その他, じほう, 2007年, 日本語薬剤師が変える薬物治療２−安全ながん治療とテーラーメイド医療に向けて− / バルビツレート療法時のチオペンタール体内動態と脳死判定時における体制整備学術書
- その他, じほう, 2007年, 日本語薬剤師が変える薬物治療２−安全ながん治療とテーラーメイド医療に向けて− / カルシニューリン活性に基づく薬効評価と個別化投与設計学術書
- その他, 廣川書店, 2006年, 日本語最新薬剤学第9版 / 5.1 医療と薬剤師．5.2医薬品の有効性と安全性教科書・概説・概論
- 共訳, メディカル・サイエンス・インターナショナル, 2006年, 日本語ハーバード大学テキスト 病態生理に基づく臨床薬理学 / 薬力学教科書・概説・概論
- その他, 東京化学同人, 2006年, 日本語スタンダード薬学シリーズ10. 実務実習事前学習：病院・薬局実習に行く前に / 第2章 チーム医療に注目するSBO4-6教科書・概説・概論
- その他, じほう, 2004年, 日本語薬剤師・薬学生のための実践TDMマニュアル / 喘息治療薬(テオフィリン)学術書
- その他, じほう, 2004年, 日本語薬剤師・薬学生のための実践TDMマニュアル / タクロリムス学術書
- その他, 文光堂, 2004年, 日本語眼科薬物治療ガイド / 第 3 章 胃腸障害を避けるには, 併用薬・食事との折り合いと問題点学術書
- その他, 東京化学同人, 2004年, 日本語スタンダード薬学シリーズ9. 薬学と社会2 / 医療の担い手としての使命教科書・概説・概論
- 日本薬学会第144回年会, 2024年03月ニルマトレルビル/リトナビル適正使用に向けた体制の構築とその評価口頭発表（一般）
- 第51回日本集中治療医学会学術集会, 2024年03月ECU栄養プロトコールポスター発表
- 第45回日本病院薬剤師会近畿学術大会, 2024年01月ブレクスピプラゾール，クエチアピンおよびリスペリドンを服用中の妊婦とその児における薬物動態の評価口頭発表（一般）
- 全国自治体病院協議会 2023年度薬剤管理研修会プログラム, 2023年12月薬剤師の職能と生涯研鑽公開講演，セミナー，チュートリアル，講習，講義等
- 第97回日本薬理学会年会, 2023年12月妊婦および新生児におけるリスペリドンと活性代謝物パリペリドンの生理学的薬物動態モデル解析[招待有り]シンポジウム・ワークショップパネル（公募）
- 第33回日本医療薬学会年会, 2023年11月Impact of ALBI grade on lenvatinib treatment discontinuation due to adverse events in hepatocellular carcinoma patients口頭発表（一般）
- 第33回日本医療薬学会年会, 2023年11月Effect of early dose reduction of osimertinib on efficacy in the first-line treatment for EGFR-positive non-small cell lung cancer口頭発表（一般）
- 第33回日本医療薬学会年会, 2023年11月先天性サイトメガロウイルス感染症患者におけるガンシクロビルのPK/PD解析口頭発表（一般）
- 第33回日本医療薬学会年会, 2023年11月薬剤師外来が抗血栓薬服用患者の長期臨床アウトカムに与える影響口頭発表（一般）
- The 21st International Congress of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT 2023), 2023年11月A model-based pharmacokinetic analysis of drug-drug interaction between nirmatrelvir/ritonavir and tacrolimusポスター発表
- 令和5年度 兵庫県病院薬剤師会 新入局者研修会, 2023年10月薬剤師の職能と生涯研鑽〜プロフェッショナリズムを考える〜[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 第73回日本薬学会関西支部大会・総会, 2023年10月食道癌FP 療法施行患者における術後回復期以降のプラチナ血中濃度推移と臨床検査値との連関解析ポスター発表
- 第28回観三薬剤師会, 2023年09月PBPMを活用したチーム医療の推進と 薬物療法の質向上[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- The 21st International Congress of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT 2023), 2023年09月Physiologically-based pharmacokinetic modeling and simulation of fentanyl for treatment optimization in neonates口頭発表（一般）
- 第8回TDM-QC研究会, 2023年08月TDM-QC実施報告（抗てんかん薬）口頭発表（一般）
- トーアエイヨー株式会社 社内研修会, 2023年08月神戸大学における 薬剤部の取り組みについて[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 第65回秋田県臨床薬学研究会, 2023年07月薬剤師の専門性と職能将来像〜バイオシミラーを通じた病院経営への関わりを含めて〜公開講演，セミナー，チュートリアル，講習，講義等
- 第6回日本病院薬剤師会Future Pharmacist Forum, 2023年07月シンポジウム19「薬剤師のための臨床研究入門」趣旨説明公開講演，セミナー，チュートリアル，講習，講義等
- 第24回青森県臨床薬学研究会, 2023年07月薬剤師の専門性と研究について考える[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 2022年度神戸薬科大学学長裁量経費に基づく共同研究プログラム 公開報告会, 2023年07月microRNAを介した小胞体ストレス関連分子SEL1L/HRD1の機能解析とパーキンソン病治療への応用その他
- 医療薬学フォーラム2023／第31回クリニカルファーマシーシンポジウム, 2023年07月パーキンソン病発症に関連する小胞体ストレス関連分子SEL1Lを制御するmicroRNAの探索と血漿中microRNA発現量の検討ポスター発表
- 第25回日本医薬品情報学会総会・学術大会, 2023年06月ニルマトレルビル/リトナビル併用時にタクロリムス濃度の異常高値を認めた腎移植症例口頭発表（一般）
- 第39回日本TDM学会・学術大会, 2023年06月高度腎機能障害患者におけるバンコマイシンAUC-guided TDMの安全性に関する検討口頭発表（一般）
- 第8回日本がんサポーティブケア学会学術集会, 2023年06月マルチキナーゼ阻害薬による手足皮膚反応の予防軽減を目指した製剤開発ポスター発表
- 日本医療薬学会 第6回 フレッシャーズ・カンファランス, 2023年06月肺胞上皮細胞におけるエベロリムスの上皮間葉転換誘導とシグナル伝達因子の関連口頭発表（一般）
- 日本医療薬学会 第6回 フレッシャーズ・カンファランス, 2023年06月1%クロルヘキシジングルコン酸エタノールの使用促進による血液培養汚染率への影響口頭発表（一般）
- 第3回兵庫県薬剤師会・病院薬剤師会・薬系5大学連携学術大会, 2023年06月卒前・卒後における臨床薬学教育を考える[招待有り]シンポジウム・ワークショップパネル（指名）
- 大塚製薬工場 社内研修会, 2023年05月神戸大学における 薬剤部の取り組みについて[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 第16回日本緩和医療薬学会年会, 2023年05月非がん性疼痛に対して使用されるオピオイド性鎮痛薬の薬剤師による使用状況モニタリングとその効果口頭発表（一般）
- 第6回Kinki Epilepsy Summit -てんかんの新知見とパラダイムシフト-, 2023年04月抗てんかん薬の薬物動態と投与設計 up-to-date[招待有り]口頭発表（招待・特別）
- 日本薬学会第143年会, 2023年03月ユビキチンリガーゼHRD1を誘導する化合物の探索と神経細胞死抑制効果の検討
- 2023年03月非小細胞肺がん患者におけるオシメルチニブの有害事象に関する薬理遺伝学的解析
- 日本臨床腫瘍薬学会学術大会2023, 2023年03月免疫チェックポイント阻害薬投与患者の好中球リンパ球比による層別化とプロトンポンプ阻害薬の併用による生命予後への影響
- 近畿薬剤師合同学術大会2023（第25回近畿薬剤師学術大会・第44回日本病院薬剤師会近畿学術大会）, 2023年03月兵庫県下の病院施設における新人薬剤師の卒後研修に関する現状調査
- 公開シンポジウム：令和4年度厚生労働科学研究費補助金 （医薬品・医療機器等レギュラトリーサイエンス政策研究事業） 国民のニーズに応える薬剤師の 専門性のあり方に関する調査研究, 2023年02月薬剤師の専門性のあり方について： 研究班からの提案公開講演，セミナー，チュートリアル，講習，講義等
- 第44日本病院薬剤師会近畿学術大会, 2023年02月潜在的不適切処方の中止維持における退院時薬剤情報提供の有用性
- 神戸大学第18回 附属学校連携授業, 2022年12月薬と上手に付き合うために公開講演，セミナー，チュートリアル，講習，講義等
- “がん”に関わる薬剤師の為のWebセミナー Vol.1, 2022年12月がん薬物療法におけるポリファーマシー対策
- ユーシービージャパンオンライン特別セミナー, 2022年11月抗てんかん薬のTDMと薬局との連携
- 第43回日本臨床薬理学会学術総会, 2022年11月成人肝移植患者におけるエベロリムスの母集団薬物動態解析および小児肝移植患者への外挿
- Transplantation Science Symposium Asian Regional Meeting 2022, 2022年11月Association of ACTN3 polymorphism with Sarcopenia in Kidney Transplant Recipients
- Neuroscience 2022, 2022年11月Mir-101 regulates neuronal cell death by targeting suppressor/enhancer lin-12-like (SEL1L) in a cellular model of Parkinson’s disease using 6-hydorxydopamineポスター発表
- 第72回日本薬学会関西支部総会・大会, 2022年10月分子標的型抗がん薬による間質性肺疾患発症の分子機構に基づく予測法の開発 -mTOR阻害薬による間質性肺疾患とSTAT3の関連-
- 日本医療薬学会 第86回医療薬学公開シンポジウム, 2022年10月クリニカルファーマコメトリクス概論：個別化投与設計の変遷[招待有り]口頭発表（基調）
- 第16回京都大学薬学部生涯教育講演会, 2022年09月医療現場で35年：「薬剤師が変われば医療が変わる」と言われたい[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 第32回医療薬学会年会, 2022年09月Effects of long-term multiple immunosuppressants on everolimus pharmacokinetics in patients after renal transplantation
- 第32回日本医療薬学会年会, 2022年09月ニルマトレルビル/リトナビルの適正使用に向けた予備的検討
- 第32回日本医療薬学会年会, 2022年09月薬剤師が変わると医療が変わる ～輝ける未来に向かって～シンポジウム・ワークショップパネル（公募）
- The 20th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT 2022), 2022年09月Effects of pregnancy and renal ontogeny on risperidone/paliperidone pharmacokinetics predicted by physiologically based pharmacokinetic modelポスター発表
- 第7回TDM-QC研究会, 2022年08月TDM-QC実施報告（抗てんかん薬）
- Inovative Pharmacist Seminar in Yamagata 2022, 2022年07月薬剤師が変わると医療が変わる：リサーチマインドを持とう！[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 旭化成ファーマ社内教育講演会, 2022年07月神戸大学医学部附属病院 薬剤部・薬剤師の業務について
- 医療薬学フォーラム2022・第30回クリニカルファーマシーシンポジウム, 2022年07月ユビキチンリガーゼHRD1を制御するマイクロRNAの探索とパーキンソン病との関連ポスター発表
- 医療薬学フォーラム2022・第30回クリニカルファーマシーシンポジウム, 2022年07月スニチニブ投与ラットを用いた手足皮膚反応の原因角化因子の探索とヒト表皮角化細胞株による検証
- 第5回 日本病院薬剤師会 Future Pharmacist Forum, 2022年07月「薬剤師の臨床研究計画から公表に至るまでのピットフォール」 クロージングその他
- 沖縄県病院薬剤師会講演会, 2022年06月薬の倫理とプロフェショナルオートノミー
- 第121回日本皮膚科学会, 2022年06月スニチニブによる手足皮膚反応の予防に対するAmitose-DGA含有クリームの第1/2相試験
- 第38回日本TDM学会学術大会, 2022年05月抗菌薬のTDMにおけるプレアボイド事例と入院期間に及ぼす影響口頭発表（一般）
- 第25回日本臨床救急医学会総会・学術集会, 2022年05月国民のニーズに応える専門薬剤師のあり方について[招待有り]シンポジウム・ワークショップパネル（指名）
- 北京華通国康公益基金会セミナー, 2022年04月日本の病院薬剤師の業務とがん薬物療法への関わり[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 日本薬学会第141年会, 2021年03月, 日本語, WEB開催, 国内会議消化管上皮細胞モデルにおけるABCB1発現・機能に及ぼすエベロリムス長期曝露の影響ポスター発表
- 日本薬学会第141年会, 2021年03月, 日本語, 国内会議セルトラリンに起因するセロトニン症候群関連症状のリスク因子の探索ポスター発表
- 第10回日本薬剤師レジデントフォーラム, 2021年03月, 日本語, 日本薬剤師レジデント制度研究会, WEB開催, 日本国, 国内会議粘度可変型流動食マーメッド®と胃酸分泌抑制薬の併用による下痢発現のリスクに関する検討ポスター発表
- 第10回日本薬剤師レジデントフォーラム, 2021年03月, 日本語, 日本薬剤師レジデント制度研究会, WEB開催, 日本国, 国内会議一包化錠剤仕分け装置TABSORT®の効率的かつ安全性の高い運用方法の検討ポスター発表
- 第10回日本薬剤師レジデントフォーラム, 2021年03月, 日本語, 日本薬剤師レジデント制度研究会, WEB開催, 日本国, 国内会議病院 - 保険薬局間のシームレスな吸入指導体制の構築に向けたツールの作成とその評価ポスター発表
- 第10回日本薬剤師レジデントフォーラム, 2021年03月, 日本語, 日本薬剤師レジデント制度研究会, WEB開催, 日本国, 国内会議薬剤師によるTDM関連オーダリング補助業務の有用性の検討ポスター発表
- 第10回日本薬剤師レジデントフォーラム, 2021年03月, 日本語, 日本薬剤師レジデント制度研究会, WEB開催, 日本国, 国内会議若年の腎機能正常患者におけるVCM有効血中濃度への到達に影響する因子の調査ポスター発表
- 第10回日本薬剤師レジデントフォーラム, 2021年03月, 日本語, 日本薬剤師レジデント制度研究会, WEB開催, 日本国, 国内会議院外処方箋への臨床検査値印字が保険薬局の処方介入に与える影響ポスター発表
- 第10回日本薬剤師レジデントフォーラム, 2021年03月, 日本語, 日本薬剤師レジデント制度研究会, WEB開催, 日本国, 国内会議セロトニン受容体拮抗型制吐薬投与患者における便秘発現の実態調査ポスター発表
- 日本臨床腫瘍薬学会学術大会2021, 2021年03月, 日本語, 国内会議病院と保険薬局の連携強化を目的とした研修会（Team Based Learning）による人材育成シンポジウム・ワークショップパネル（指名）
- 第7回兵庫県薬剤師会・兵庫県病院薬剤師会共催講演会, 2021年02月, 日本語, 国内会議持続可能な医療に向けて 〜薬剤師が変われば医療が変わる！〜[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 第27 回日本がんチーム医療研究会, 2021年02月, 日本語, 国内会議抗がん薬調製ロボット導入前後における抗がん薬関連業務の比較口頭発表（一般）
- 文部科学省科学技術人材育成費補助事業「ダイバーシティ研究環境実現イニシアティブ（連携型）清流の国輝くギフジョ支援プロジェクト」「キャリパス支援講演会」, 2021年02月, 日本語, 国内会議医薬品適正使用を目指した薬物動態研究の実践〜これまでのキャリアを振り返って〜[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- The 4th International Cancer Research Symposium of Training Plan for Oncology Professionals, 2021年02月, 英語, 国際会議Impact of sunitinib on the expression of cornifying factors in human epidermal 3D skin modelsポスター発表
- 第42回日本病院薬剤師会近畿学術大会, 2021年01月, 日本語, 国内会議進行固形がん患者を対象とした心血管疾患予防のための降圧薬の使用実態に関する調査ポスター発表
- Next Generation Leader Conference, 2021年01月, 日本語, 国内会議薬剤師が変われば医療が変わる 〜ハートフルに洞察しスキルで対応する〜[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 第41回日本臨床薬理学会学術総会, 2020年12月, 日本語, 国内会議腎移植患者におけるタクロリムスPBPKモデル構築と肝移植患者の薬物動態との比較ポスター発表
- 第41回日本臨床薬理学会学術総会, 2020年12月, 日本語, 国内会議腎細胞癌患者を対象とした2週投与1週休薬スケジュール下におけるスニチニブ至適血中濃度に関する検討ポスター発表
- 第30回日本医療薬学会年会, 2020年10月, 日本語, WEB開催, 国内会議薬剤師による抗菌薬血中濃度測定オーダー登録と注射薬仮登録がもたらす実践的有用性の評価ポスター発表
- 第30回日本医療薬学会年会, 2020年10月, 日本語, WEB開催, 国内会議レンバチニブによる有害事象の発生予測に対するALBI Gradeの有用性の検討ポスター発表
- 第30回日本医療薬学会年会, 2020年10月, 日本語, WEB開催, 国内会議人工弁置換術後のワルファリン導入下におけるPT-INR値に関する解析ポスター発表
- 第30回日本医療薬学会年会, 2020年10月, 日本語, 日本医療薬学会, WEB開催, 国内会議病棟薬剤師に対する手指衛生の教育効果と評価者としての薬学部実務実習生への波及効果口頭発表（一般）
- 第30回日本医療薬学会年会, 2020年10月, 英語, 一般社団法人日本医療薬学会, WEB開催, 日本国, 国内会議Reinforced collaboration between community pharmacies and hospital for the management of oral anti-cancer therapy using information sharing tools and team-based learningポスター発表
- 第30回日本医療薬学会年会, 2020年10月, 英語, WEB開催, 国内会議Effects of pharmacist-led antimicrobial stewardship programme in urological patientsポスター発表
- 第23回千葉TDMセミナー, 2020年10月, 日本語薬物動態モデル解析の変遷と薬剤師として想うこと[招待有り]公開講演，セミナー，チュートリアル，講習，講義等
- 第4回日本老年薬学会学術大会, 2020年06月, 日本語, 日本老年薬学会, WEB開催, 日本国, 国内会議全病棟を対象としたボリファーマシー対策の実践口頭発表（一般）
- 第4回日本老年薬学会学術大会, 2020年06月, 日本語, WEB開催, 国内会議薬剤師による転院時の診療情報提供書作成支援口頭発表（一般）
- 日本病院薬剤師会 東北ブロック第10回学術大会, 2020年06月, 日本語, 国内会議ポリファーマシーに対する薬剤師介入の取り組みシンポジウム・ワークショップパネル（指名）
- 日本薬学会第140年会, 2020年03月, 日本語, 京都, 国内会議腎移植後にスニチニブ治療を開始した腎癌患者におけるタクロリムス・エベロリムスの薬物動態モデル解析ポスター発表
- 第9回日本薬剤師レジデントフォーラム, 2020年03月, 日本語, 東京, 国内会議人工弁置換術後のワルファリン導入におけるプロトロンビン時間国際標準比推移の現状と課題ポスター発表
- 第9回日本薬剤師レジデントフォーラム, 2020年03月, 日本語, 東京, 国内会議薬剤師によるTDMオーダーと注射仮登録の有用性評価ポスター発表
- 第9回日本薬剤師レジデントフォーラム, 2020年03月, 日本語, 東京, 国内会議レンバチニブによる有害事象の発生予測に対するALBIスコアの有用性の検討ポスター発表
- 第9回日本薬剤師レジデントフォーラム, 2020年03月, 日本語, 東京, 国内会議神戸大学・神戸薬科大学薬剤師レジデントにおける教育関連業務ポスター発表
- 日本薬学会第140年会, 2020年03月, 日本語, 京都, 国内会議マウス血清中バイオメタル濃度に及ぼすシスプラチン、オキサリプラチンおよびデキサメタゾンの影響ポスター発表
- 日本薬学会第140年会, 2020年03月, 日本語, 京都, 国内会議がん悪液質に対する補中益気湯による改善効果に関する調査ポスター発表
- 日本薬学会第140年会, 2020年03月, 日本語, 京都, 国内会議Physiologically-based pharmacokinetic modeling and simulation of serum risperidone and paliperidone concentrations in pregnant woman taking risperidone and in her babyポスター発表
- 日本薬学会第140年会, 2020年03月, 日本語, 京都, 国内会議スニチニブによる表皮角化細胞のkeratin 6AおよびSERPINB1発現変動ポスター発表
- 第33回近畿小児科学会, 2020年03月, 日本語, 大阪, 国内会議生下時より経時的に薬物血中濃度を測定し得たリスペリドン内服母体児の１例口頭発表（一般）
- The 3rd International Cancer Research Symposium of Training Plan for Oncology Professionals, 2020年02月, 英語, 大阪, 国際会議Monitoring of concentrations of sunitinib, tacrolimus, and everolimus in the patient with metastatic renal cell carcinoma after renal transplantationポスター発表
- 第41回日本病院薬剤師会近畿学術大会, 2020年02月, 日本語, 神戸, 国内会議抗がん薬混合調製ロボットの導入と稼働状況ポスター発表
- 第41回日本病院薬剤師会近畿学術大会, 2020年02月, 日本語, 神戸, 国内会議乳児におけるテイコプラニン血中濃度の評価ポスター発表
- 兵庫県予防協会・神戸市主催：2019年度後期土曜健康科学セミナー, 2020年01月, 日本語, 神戸, 国内会議薬と上手に付き合うために公開講演，セミナー，チュートリアル，講習，講義等
- 第40回日本臨床薬理学会学術総会, 2019年12月, 日本語, 東京, 国内会議新生児の先天性サイトメガロウイルス感染症患者におけるガンシクロビル血中濃度測定と生理学的薬物動態モデルを用いたシミュレーションポスター発表
- 日本薬物動態学会第34回年会, 2019年12月, 英語, つくば, 国内会議Population pharmacokinetic modeling of everolimus in renal transplant patients with multiple immunosuppressive therapy.ポスター発表
- 第22回宝ヶ池セミナー, 2019年11月, 日本語, 京都, 国内会議免疫抑制薬のファーマコメトリクス公開講演，セミナー，チュートリアル，講習，講義等
- 三重大学大学院医科学専攻修士課程, 2019年11月, 日本語, 津, 国内会議医薬品開発及び個別化治療におけるファーマコメトリクス公開講演，セミナー，チュートリアル，講習，講義等
- 第39回医療情報学連合大会・第20回日本医療情報学会学術大会, 2019年11月, 日本語, 千葉, 国内会議医薬品不適切使用症例検出システムの構築口頭発表（一般）
- 第29回日本医療薬学会年会, 2019年11月, 日本語, 福岡, 国内会議クロザピン及び活性代謝物の母集団薬物動態解析：入院・外来の影響ポスター発表
- 第29回日本医療薬学会年会, 2019年11月, 日本語, 福岡, 国内会議再発・難治性悪性リンパ腫患者におけるフィルグラスチムバイオ後続品の有効性と安全性に関する検討口頭発表（一般）
- 第29回日本医療薬学会年会, 2019年11月, 日本語, 福岡, 国内会議プロトコルおよび 薬剤部門システムを活用した DOACの薬物相互作用マネジメント口頭発表（一般）
- 第29回日本医療薬学会年会, 2019年11月, 日本語, 福岡, 国内会議プロトンポンプ阻害薬の院内フォーミュラリー策定による後発医薬品の使用促進と薬剤費の削減効果口頭発表（一般）
- 第69回日本薬学会関西支部総会・大会, 2019年10月, 日本語, 神戸, 国内会議SGLT2阻害剤の皮膚障害に関する研究―ラット体内動態データの薬物動態学的解析とマイクロアレイ解析―口頭発表（一般）
- Neuroscience2019, 2019年10月, 英語, Chicago, 国際会議Oxicam-derived non-steroidal anti-inflammatory drugs protect against 1-methyl-4-phenyl pyridinium-induced cell death by suppressing of endoplasmic reticulum stress response and mitochondrial dysfunctionポスター発表
- 神戸薬科大学第91回リカレントセミナー, 2019年09月, 日本語, 神戸, 国内会議薬物動態を理解し、処方設計に活かす公開講演，セミナー，チュートリアル，講習，講義等
- The 17th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT 2019), 2019年09月, 英語, Iguazu, 国際会議PHARMACOKINETIC ASSESSMENT FOR A CASE OF ALPRAZOLAM-INDUCED NEONATAL ABSTINENCE SYNDROME USING PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELポスター発表
- The 17th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT 2019), 2019年09月, 英語, Iguazu, 国際会議Use of PBPK model simulator for the individualized therapyシンポジウム・ワークショップパネル（指名）
- 日本学術会議、日本薬学会共催公開シンポジウム：薬剤師が担う日本の医療と薬学教育, 2019年08月, 日本語, 東京, 国内会議認定・専門薬剤師制度のあり方公開講演，セミナー，チュートリアル，講習，講義等
- 広島大学薬学部主催：令和元年度ヒロシマ薬剤師研修会, 2019年07月, 日本語, 広島, 国内会議ポリファーマシーにおける薬剤師の取り組み〜病診薬連携の強化を目指して〜公開講演，セミナー，チュートリアル，講習，講義等
- 第17回日本臨床腫瘍学会学術集会, 2019年07月, 日本語, 京都, 国内会議通院治療室における急変時対応システムの構築と職員教育ポスター発表
- 医療薬学フォーラム2019 第27回 クリニカルファーマシーシンポジウム, 2019年07月, 日本語, 広島, 国内会議血清クレアチニン低値の患者におけるバンコマイシン母集団薬物動態解析ポスター発表
- 医療薬学フォーラム2019 第27回 クリニカルファーマシーシンポジウム, 2019年07月, 日本語, 広島, 国内会議肺由来細胞のエベロリムス反応性におけるSTAT3遺伝子多型の影響ポスター発表
- 医療薬学フォーラム2019 第27回 クリニカルファーマシーシンポジウム, 2019年07月, 日本語, 広島, 国内会議ICU入室患者における睡眠薬使用後のせん妄発現に対するリスク因子の探索ポスター発表
- 第22回日本医薬品情報学会総会・学術大会, 2019年06月, 日本語, 札幌, 国内会議処方オーダリングシステムにおける検査値に対応した処方禁忌チェック機能の導入と評価口頭発表（一般）
- 第81回大阪薬科大学公開教育講座, 2019年05月, 日本語, 大阪, 国内会議新規抗てんかん薬の薬物動態とTDMの有用性公開講演，セミナー，チュートリアル，講習，講義等
- 病院薬剤師セミナー in OSAKA, 2019年05月, 日本語, 大阪, 国内会議ポリファーマシーに対する薬剤師の取り組み公開講演，セミナー，チュートリアル，講習，講義等
- 第36回日本TDM学会・学術大会, 2019年05月, 日本語, 東京, 国内会議ラモトリギンTDMの現状と血中濃度の変動因子に関する調査ポスター発表
- 第36回日本TDM学会・学術大会, 2019年05月, 日本語, 東京, 国内会議抗てんかん薬TDMガイドラインシンポジウム・ワークショップパネル（指名）
- 医薬品情報研修会, 2019年04月, 日本語, 京都, 国内会議薬剤師のポリファーマシーに対する取り組みについて〜抗不安薬・睡眠薬・NSAIDsを中心に〜公開講演，セミナー，チュートリアル，講習，講義等
- 第7回つるまい医療薬学シンポジウム, 2019年03月, 日本語, 名古屋, 国内会議薬剤業務を科学する[招待有り]シンポジウム・ワークショップパネル（指名）
- 第2回神戸臨床薬学研究会, 2019年03月, 日本語, 神戸, 国内会議明日からの薬物治療を変える公開講演，セミナー，チュートリアル，講習，講義等
- 第8回日本薬剤師レジデントフォーラム, 2019年03月, 日本語, 福岡, 国内会議睡眠薬使用後にせん妄が出現した患者のICU入室中におけるリスク因子の探索ポスター発表
- 日本薬学会第139年会, 2019年03月, 日本語, 日本薬学会, 千葉, 国内会議新規Bcl-2選択的阻害剤の長期間曝露がヒト白血病細胞株に及ぼす影響ポスター発表
- 第8回日本薬剤師レジデントフォーラム, 2019年03月, 日本語, 福岡, 国内会議高度催吐性リスクの化学療法に伴う悪心・嘔吐に対するオランザピン投与量の検討ポスター発表
- 神戸大学医学部・近畿大学薬学部合同セミナー, 2019年03月, 日本語, 大阪, 国内会議抗がん薬の副作用マネジメントにおける地域薬局との連携[招待有り]シンポジウム・ワークショップパネル（指名）
- 第8回日本薬剤師レジデントフォーラム, 2019年03月, 日本語, 福岡, 国内会議経口抗がん薬を含む術後補助化学療法における薬薬協働支援の有用性ポスター発表
- 日本臨床腫瘍薬学会学術大会2019, 2019年03月, 日本語, 日本臨床腫瘍薬学会, 札幌, 国内会議経口抗がん薬を含む術後補助化学療法における病院および保険薬局薬剤師との協働支援の有用性評価ポスター発表
- 日本薬学会第139年会, 2019年03月, 日本語, 日本薬学会, 千葉, 国内会議化学療法誘発性の悪心・嘔吐予防目的のオランザピン投与量に関する検討ポスター発表
- 日本薬学会第139年会, 2019年03月, 日本語, 日本薬学会, 千葉, 国内会議医薬品適正使用のためのクリニカルファーマコメトリクス※佐藤記念国内賞受賞講演[招待有り]口頭発表（招待・特別）
- 日本臨床腫瘍薬学会学術大会2019, 2019年03月, 日本語, 日本臨床腫瘍薬学会, 札幌, 国内会議チーム基盤型学習を用いた経口抗がん薬に関する勉強会の有用性の検討口頭発表（一般）
- 京都薬科大学キャリアパスセミナー, 2019年02月, 日本語, 京都, 国内会議薬物治療の質的向上を目指して〜薬剤師に研究が必要な理由〜公開講演，セミナー，チュートリアル，講習，講義等
- 第34回日本静脈経腸栄養学会学術集会, 2019年02月, 日本語, 日本静脈経腸栄養学会, 東京, 国内会議低アルブミン血症の原因がPPIによるcollagenous colitisと考えられた1例ポスター発表
- 第34回日本静脈経腸栄養学会学術集会, 2019年02月, 日本語, 日本静脈経腸栄養学会, 東京, 国内会議低Mg血症による副甲状腺機能低下症を呈した2症例ポスター発表
- 第4回Hyogo Pharmacy Director Conference, 2019年02月, 日本語, 神戸, 国内会議神戸大学病院の現状分析とこれから公開講演，セミナー，チュートリアル，講習，講義等
- 神戸大学・神戸薬科大学合同シンポジウム, 2019年02月, 日本語, 神戸, 国内会議神戸大学・神戸薬科大学連携事業における薬剤部の役割[招待有り]シンポジウム・ワークショップパネル（指名）
- 第214回大阪薬品適正使用研究会, 2019年02月, 日本語, 大阪, 国内会議ポリファーマシー見直しのための多職種協働〜高齢者の安全な薬物療法への取り組み〜公開講演，セミナー，チュートリアル，講習，講義等
- The 2nd International Cancer Research Symposium of Training Plan for Oncology Professionals, 2019年02月, 日本語, Osaka, 国際会議Molecular characteristics of human leukemia cell line after the long-term exposure to the Bcl-2 inhibitor ABT-199ポスター発表
- 第40回日本病院薬剤師会近畿学術大会, 2019年01月, 日本語, 日本病院薬剤師会, 奈良, 国内会議免疫関連有害事象防止のための診療連携体制構築により有害事象の重症化を回避できた2症例口頭発表（一般）
- 神戸薬科大学大学院薬剤学特論, 2019年01月, 日本語, 神戸, 国内会議個別化投与設計のためのファーマコメトリクス公開講演，セミナー，チュートリアル，講習，講義等
- 平成30年度大学病院情報マネジメント部門連絡会議, 2019年01月, 日本語, 大学病院情報マネジメント部門連絡会議, 熊本, 国内会議検査値連動型の処方チェックシステムを用いた疑義照会の有用性シンポジウム・ワークショップパネル（公募）
- 第40回日本病院薬剤師会近畿学術大会, 2019年01月, 日本語, 日本病院薬剤師会, 奈良, 国内会議改訂薬学教育モデルコア・カリキュラムに準拠した病院実務実習のプログラムの作成と評価ポスター発表
- 第45回日本臓器保存生物医学会学術集会, 2018年11月, 日本語, 日本臓器保存生物医学会, 名古屋, 国内会議薬物動態学（PK）の観点から見る免疫抑制剤[招待有り]シンポジウム・ワークショップパネル（指名）
- 協和発酵キリン株式会社社内研修会, 2018年11月, 日本語, 神戸, 国内会議薬剤部における業務・教育・研究公開講演，セミナー，チュートリアル，講習，講義等
- 平成30年度大学院特別講義がんプロフェショナル養成特論, 2018年11月, 日本語, 神戸, 国内会議抗がん薬の薬物動態と薬効解析公開講演，セミナー，チュートリアル，講習，講義等
- 第28回日本医療薬学会年会, 2018年11月, 日本語, 日本医療薬学会, 神戸, 国内会議ポリファーマシー対策のための医薬連携合同勉強会の開催とアンケートによる現状調査ポスター発表
- 第28回日本医療薬学会年会, 2018年11月, 日本語, 日本医療薬学会, 神戸, 国内会議ポリファーマシーの効率的な検出と保険薬局との連携を目指したwebシステムの構築ポスター発表
- 第28回日本医療薬学会年会, 2018年11月, 日本語, 日本医療薬学会, 神戸, 国内会議シクロスポリン内服中に母乳育児を行なった２症例ポスター発表
- 第28回日本医療薬学会年会, 2018年11月, 日本語, 日本医療薬学会, 神戸, 国内会議STOPP criteria version 2と高齢者の安全な薬物療法ガイドライン2015を組み合わせた不適切処方への介入口頭発表（一般）
- Taiwan Society of Health-System Pharmacist (TSHP) Annual Conference, 2018年11月, 英語, 高雄, 国際会議Improvement of Patient Care Quality through Pharmacist Intervention as A Member of Multidisciplinary Team Creates New Roles in Japan[招待有り]口頭発表（招待・特別）
- 第55回日本糖尿病学会近畿地方会, 2018年10月, 日本語, 日本糖尿病学会, 神戸, 国内会議薬学部実務実習生へのチーム医療「糖尿病」に関する教育課題について口頭発表（一般）
- 第68回日本薬学会近畿支部総会・大会, 2018年10月, 日本語, 姫路, 国内会議Up-to-date 抗てんかん薬のTDMシンポジウム・ワークショップパネル（公募）
- 2018 International Meeting on 22nd MDO and 33rd JSSX, 2018年10月, 英語, 日本薬物動態学会, Kanazawa, 国際会議Physiologically based pharmacokinetic model for tacrolimus in living-donor liver transplantation considering liver regeneration and CYP3A5 genotype口頭発表（一般）
- 2018 International Meeting on 22nd MDO and 33rd JSSX, 2018年10月, 英語, 日本薬物動態学会, Kanazawa, 国際会議Drug metabolism in pediatric populations-Prediction of hepatic clearance-[招待有り]シンポジウム・ワークショップパネル（指名）
- The 16th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT 2018), 2018年09月, 英語, International Association of Therapeutic Drug Monitoring & Clinical Toxicology, Brisbene, 国際会議Influence of CYP2C19 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in the combination therapy with lansoprazole in Japanese renal transplant recipientsポスター発表
- The 16th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT 2018), 2018年09月, 英語, International Association of Therapeutic Drug Monitoring & Clinical Toxicology, Brisbene, 国際会議Association of pharmacokinetic and pharmacodynamic markers of mycophenolic acid and clinical outcomes in cord blood transplant patientsシンポジウム・ワークショップパネル（公募）
- 第16回日本臨床腫瘍学会学術集会, 2018年07月, 日本語, 日本臨床腫瘍学会, 神戸, 国内会議冷却療法は凍傷予防の手足カバー使用下においても化学療法誘発性末梢神経障害を予防する口頭発表（一般）
- 第2回フレッシャーズ・カンファランス, 2018年07月, 日本語, 一般社団法人 日本医療薬学会, 京都, 国内会議リスペリドンによる錐体外路症状とCYP2D6遺伝子多型の関連口頭発表（一般）
- 大阪府下市立病院薬剤部長会学術講演会, 2018年07月, 日本語, 大阪, 国内会議ポリファーマシーと薬剤師の役割[招待有り]シンポジウム・ワークショップパネル（指名）
- 18th World Congress of Basic and Clinical Pharmacology, 2018年07月, 英語, International Union of Basic and Clinical Pharmacology, Kyoto, 国際会議Effects of sunitinib on the expression of keratin 9 in human keratinocyte cell lines and a 3D skin modelポスター発表
- 第32回島根てんかん研究会, 2018年06月, 日本語, 島根, 国内会議新規抗てんかん薬のTDMは必要か？〜ラコサミドを含めて〜公開講演，セミナー，チュートリアル，講習，講義等
- 医療薬学フォーラム2018 第26回クリニカルファーマーシーシンポジウム, 2018年06月, 日本語, 日本薬学会, 東京, 国内会議ケラチン9の発現に及ぼす皮膚高次構造とスニチニブの影響ポスター発表
- 医療薬学フォーラム2018 第26回クリニカルファーマーシーシンポジウム, 2018年06月, 日本語, 日本薬学会, 東京, 国内会議エベロリムス長期曝露肺胞上皮細胞の上皮間葉転換に寄与するケモカインの探索ポスター発表
- 9 th Congress of World Federation of Pediatric Intensive and Critical Care Societies, 2018年06月, 英語, World Federation of Pediatric Intensive and Critical Care, Singapore, 国際会議Development of a pediatric dosing regimen of trichlofos and chloral hydrate based on population pharmacokinetics and pharmacodynamics in pediatric intensive care patients口頭発表（一般）
- 第35回日本ＴＤＭ学会・学術大会, 2018年05月, 日本語, 日本ＴＤＭ学会, 福岡, 国内会議ベンゾジアゼピン系薬剤（クロバザム）レベチラセタム[招待有り]シンポジウム・ワークショップパネル（指名）
- 第35回日本TDM学会・学術大会, 2018年05月, 日本語, 日本ＴＤＭ学会, 福岡, 国内会議アルプラゾラム服用妊婦から出生した児の薬物血中濃度測定を行った一症例ポスター発表
- 日本薬学会第138年会, 2018年03月, 日本語, 日本薬学会, 金沢, 国内会議薬剤師教育におけるチーム基盤型学習 (TBL) の導入とその有用性の検討口頭発表（一般）
- 第7回日本薬剤師レジデントフォーラム, 2018年03月, 日本語, 日本薬剤師レジデント研究会, 神戸, 国内会議薬剤師レジデントの学生教育機会に関する報告ポスター発表
- 第7回日本薬剤師レジデントフォーラム, 2018年03月, 日本語, 日本薬剤師レジデント研究会, 神戸, 国内会議造血器腫瘍の化学療法におけるフィルグラスチム先行品とバイオ後続品の有効性と安全性の比較ポスター発表
- 日本薬学会第138年会, 2018年03月, 日本語, 日本薬学会, 金沢, 国内会議持参薬確認業務における危険予知トレーニングツールの開発とその評価口頭発表（一般）
- 日本薬学会第138年会, 2018年03月, 日本語, 日本薬学会, 金沢, 国内会議ポリファーマシーに対する介入の長期的な評価口頭発表（一般）
- 第7回日本薬剤師レジデントフォーラム, 2018年03月, 日本語, 日本薬剤師レジデント研究会, 神戸, 国内会議グアーガム分解物含有経腸栄養剤使用患者に対する整腸剤の相加効果の検討ポスター発表
- 日本臨床腫瘍薬学会学術大会2018, 2018年03月, 日本語, 日本臨床腫瘍薬学会, 横浜, 国内会議Nab-Paclitaxelと併用薬混合時の安定性に関する検討ポスター発表
- 近畿薬剤師合同学術大会2018, 2018年02月, 日本語, 京都府薬剤師会, 京都, 国内会議統合失調症治療における頓用薬の使用に関する評価ポスター発表
- 近畿薬剤師合同学術大会2018, 2018年02月, 日本語, 京都府薬剤師会, 京都, 国内会議造血器腫瘍の化学療法におけるフィルグラスチム先行品とバイオ後続品の有効性と安全性の検討ポスター発表
- 近畿薬剤師合同学術大会2018, 2018年02月, 日本語, 川勝一雄, 京都府, 国内会議小児用量鑑査システム導入のための処方状況調査ポスター発表
- 近畿薬剤師合同学術大会2018, 2018年02月, 日本語, 京都府薬剤師会, 京都, 国内会議オピオイド服用患者における酸化マグネシウムの緩下作用に対してプロトンポンプ阻害薬併用が与える影響ポスター発表
- メディショナルナノテク研究会, 2017年12月, 日本語, テクノグローバルウェイブ, 神戸, 国内会議病院薬剤部からのメッセージ[招待有り]シンポジウム・ワークショップパネル（指名）
- 第38回日本臨床薬理学会学術集会, 2017年12月, 日本語, 日本臨床薬理学会, 横浜, 国内会議小児におけるトリクロロエタノールの薬物動態・薬力学の発達・成長に伴う変化の解析口頭発表（一般）
- 第38回日本臨床薬理学会学術集会, 2017年12月, 日本語, 日本臨床薬理学会, 横浜, 国内会議実臨床データを用いたファーマコメトリクス による個体間変動予測シンポジウム・ワークショップパネル（公募）
- 第17回日本クリニカルパス学会, 2017年12月, 日本語, 日本クリニカルパス学会, 大阪, 国内会議外国人患者受入れ医療機関認証制度と患者用クリニカルパスポスター発表
- 第18回日本クリニカルパス学会学術集会, 2017年12月, 日本語, 日本クリニカルパス学会, 大阪, 国内会議外国人患者受入れ医療機関認証制度と患者用クリニカルパス口頭発表（一般）
- 第38回日本臨床薬理学会学術集会, 2017年12月, 日本語, 日本臨床薬理学会, 横浜, 国内会議B細胞リンパ腫患者における，リツキシマブのPK/PD解析口頭発表（一般）
- 第27回日本医療薬学会年会, 2017年11月, 日本語, 日本医療薬学会, 千葉, 国内会議麻酔科術前外来患者を対象とした薬剤師の介入効果ポスター発表
- 第27回日本医療薬学会年会, 2017年11月, 日本語, 日本医療薬学会, 千葉, 国内会議統合失調症患者における錐体外路症状発現に及ぼすCYP2D6遺伝子多型の影響口頭発表（一般）
- 第27回日本医療薬学会年会, 2017年11月, 日本語, 日本医療薬学会, 千葉, 国内会議検査値連動型の処方チェックシステムを用いた疑義照会の有用性ポスター発表
- 第27回日本医療薬学会年会, 2017年11月, 日本語, 日本医療薬学会, 千葉, 国内会議院内製剤レボチロキシンナトリウム坐剤の至適投与量の探索と安定性の検討口頭発表（一般）
- 日本薬物動態学会第32年会, 2017年11月, 日本語, 日本薬物動態学会, 東京, 国内会議Population pharmacokinetics and pharmacodynamics of trichloroethanol in pediatric patients口頭発表（一般）
- 日本薬物動態学会第32年会, 2017年11月, 日本語, 日本薬物動態学会, 東京, 国内会議PK/PD analysis of rituximab in the patient with non-Hodgkin’s lymphoma口頭発表（一般）
- 第34回日本TDM学会・学術大会, 2017年09月, 日本語, 日本TDM学会, 京都, 国内会議腎移植患者における術後早期のタクロリムス血中濃度の評価ポスター発表
- the 15th Congress of the International Association of Therapeutic Drug Monitoring & Clinical Toxicology, 2017年09月, 英語, the International Association of Therapeutic Drug Monitoring & Clinical Toxicology, Kyoto, Japan, 国際会議TDM for a new class of anti-epileptic drugs, S-12 TDM for central nervous system drugs.[招待有り]シンポジウム・ワークショップパネル（指名）
- the 15th Congress of the International Association of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT), 2017年09月, 英語, the International Association of Therapeutic Drug Monitoring & Clinical Toxicology, Kyoto, Japan, 国際会議Population pharmacokinetic modeling and simulation of topiramate using the routinely monitored data for the individualized dosage adjustmentポスター発表
- the 15th Congress of the International Association of Therapeutic Drug Monitoring & Clinical Toxicology, 2017年09月, 英語, the International Association of Therapeutic Drug Monitoring & Clinical Toxicology, Kyoto, Japan, 国際会議Molecular cornifying mechanisms of multi-targeted tyrosine kinase inhibitors-induced hand-foot skin reaction based on genetic differences of STAT3ポスター発表
- the 15th Congress of the International Association of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT), 2017年09月, 英語, the International Association of Therapeutic Drug Monitoring & Clinical Toxicology, Kyoto, Japan, 国際会議Impact of STAT3 genetic polymorphism on sunitinib-induced stomatitis in Japanese renal cell carcinoma patientsポスター発表
- the 15th Congress of the International Association of Therapeutic Drug Monitoring & Clinical Toxicology (IATDMCT), 2017年09月, 英語, the International Association of Therapeutic Drug Monitoring & Clinical Toxicology, Kyoto, Japan, 国際会議CYP2C19 polymorphism affects the efficacy but not drowsiness in the low dose clobazam therapy口頭発表（一般）
- 第15回日本臨床腫瘍学会学術集会, 2017年07月, 日本語, 日本臨床腫瘍学会, 神戸, 国内会議冷却手袋靴下によるパクリタキセル起因性末梢神経障害の予防：乳癌化学療法患者に対する個体内比較試験口頭発表（一般）
- 医療薬学フォーラム2017 第25回クリニカルファーマシーシンポジウム, 2017年07月, 日本語, 日本薬学会医療薬科学部会, 鹿児島, 国内会議病棟薬剤師によるベンゾジアゼピン系薬剤の適正使用についての取り組みとその評価ポスター発表
- 医療薬学フォーラム2017 第25回クリニカルファーマシーシンポジウム, 2017年07月, 日本語, 日本薬学会医療薬科学部会, 鹿児島, 国内会議リツキシマブの体内動態とその変動因子の考察ポスター発表
- 第11回日本緩和医療薬学会年会, 2017年06月, 日本語, 日本緩和医療薬学会, 札幌, 国内会議薬剤師主導のオピオイド使用全入院患者を対象としたカルテ回診の評価と課題ポスター発表
- 第11回日本薬物動態学会ショートコース, 2017年05月, 日本語, 日本薬物動態学会, 東京, 国内会議生理学的薬物動態モデルを用いた生体肝移植患者におけるタクロリムスのモデリング&シミュレーション公開講演，セミナー，チュートリアル，講習，講義等
- 第1回日本老年薬学会学術大会, 2017年05月, 日本語, 日本老年薬学会, 東京, 国内会議高齢者の安全な薬物療法ガイドライン2015を 用いた高齢者のポリファーマシーに対する 薬剤師による介入とその評価 − STOPP criteria ver.2との比較−口頭発表（一般）
- 第64回日本生化学会近畿支部例会, 2017年05月, 日本語, 日本生化学会, 大阪, 国内会議ChREBPのグルコース濃度依存的なDNA結合はO-GlcNAc修飾により制御される口頭発表（一般）
- 日本薬学会第137年会, 2017年03月, 日本語, 日本薬学会, 仙台, 国内会議頭頸部がん患者におけるcisplatinと強度変調放射線同時併用療法の完遂率を低下させる因子の検討ポスター発表
- 日本薬学会第137年会, 2017年03月, 日本語, 日本薬学会, 仙台, 国内会議腎細胞癌患者のスニチニブ治療効果に及ぼす組織STAT3発現の影響ポスター発表
- 日本薬学会第137年会, 2017年03月, 日本語, 日本薬学会, 仙台, 国内会議小児におけるテイコプラニンの薬物動態解析口頭発表（一般）
- 日本薬学会第137年会, 2017年03月, 日本語, 日本薬学会, 仙台, 国内会議後方視的解析に基づくバンコマイシン初回投与ノモグラムの検討ポスター発表
- 第6回日本薬剤師レジデントフォーラム, 2017年03月, 日本語, 日本薬剤師レジデント制度研究会, 東京, 国内会議経口抗がん薬処方に対する保険薬局との連携強化のためのツールの評価と今後の課題ポスター発表
- 日本臨床腫瘍薬学会学術大会2017, 2017年03月, 日本語, 日本臨床腫瘍薬学会, 新潟, 国内会議経口抗がん薬処方に対する地域保険薬局との連携強化に向けた保険薬局薬剤師の意識調査と連携ツールの作成ポスター発表
- 第6回日本薬剤師レジデントフォーラム, 2017年03月, 日本語, 日本薬剤師レジデント制度研究会, 東京, 国内会議吸入指導外来の立ち上げとその評価についてポスター発表
- 第6回日本薬剤師レジデントフォーラム, 2017年03月, 日本語, 日本薬剤師レジデント制度研究会, 東京, 国内会議院外処方箋における疑義照会簡素化プロトコールの運用とその評価ポスター発表
- 日本薬学会第137年会, 2017年03月, 日本語, 日本薬学会, 仙台, 国内会議院外処方箋における疑義照会簡素化プロトコールの運用とその効果口頭発表（一般）
- 日本薬学会第137年会, 2017年03月, 日本語, 日本薬学会, 仙台, 国内会議エルロチニブによる皮膚障害におけるアクアポリン3の発現変動ポスター発表
- 日本薬学会第137年会, 2017年03月, 日本語, 日本薬学会, 仙台, 国内会議エベロリムスによる間質性肺疾患発症メカニズムにおけるTGF-βの関与ポスター発表
- 日本薬学会第137年会, 2017年03月, 日本語, 日本薬学会, 仙台, 国内会議mTOR阻害薬によるトリグリセリド合成亢進作用におけるACAA2の役割ポスター発表
- The 5th International Symposium of Training Plan for Oncology Professionals, 2017年03月, 英語, Training Plan for Oncology Professionals, Osaka, Japan, 国際会議Effects of Topical Cryotherapy on Chemotherapy-induced Peripheral Neuropathy among Breast Cancer Patients: A Self Controlled Clinical Trial.ポスター発表
- The 5th International Symposium of Training Plan for Oncology Professionals, 2017年03月, 英語, Training Plan for Oncology Professionals, Osaka, Japan, 国際会議Association of Single Nucleotide Polymorphisms in STAT3, ABCB1, and ABCG2 with Stomatitis in Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib: A Retrospective Analysis in Japanese Patientsポスター発表
- 第38回日本病院薬剤師会近畿学術大会, 2017年02月, 日本語, 日本病院薬剤師会, 大阪, 国内会議脳神経外科領域CARE療法におけるカルボプラチン推定AUCと抗腫瘍効果ならびに血液毒性の関連について口頭発表（一般）
- 第38回日本病院薬剤師会近畿学術大会, 2017年02月, 日本語, 日本病院薬剤師会, 大阪, 国内会議参加型を意識した糖尿病教室用ツール・薬物療法かるたとカードの開発口頭発表（一般）
- 平成28年度北海道薬科大学生涯学習センター：病態・薬物治療フォローアップ講座, 2017年02月, 日本語, 北海道薬科大学, 札幌, 国内会議抗てんかん薬のTDMとファーマコゲノミクス公開講演，セミナー，チュートリアル，講習，講義等
- Kobe Pharmacist Seminar, 2017年02月, 日本語, 兵庫県病院薬剤師会, 神戸, 国内会議院外処方箋における疑義照会簡素化について公開講演，セミナー，チュートリアル，講習，講義等
- 平成28年度熊本薬学教育部大学院「先端医療学特論」, 2017年01月, 日本語, 熊本薬学教育部大学院, 熊本, 国内会議ファーマコメトリクスを活用した医薬品開発と個別投与設計公開講演，セミナー，チュートリアル，講習，講義等
- 第37回日本臨床薬理学会, 2016年12月, 日本語, 日本臨床薬理学会, 米子, 国内会議臍帯血移植患者におけるミコフェノール酸血中濃度と急性GVHD発症との関連ポスター発表
- 第37回日本臨床薬理学会, 2016年12月, 日本語, 日本臨床薬理学会, 米子, 国内会議生体肝移植術後における1日1回製剤のタクロリムス薬物動態と薬効口頭発表（一般）
- 2016 ASHP Midyear Clinical Meeting and Exhibitions, 2016年12月, 英語, ASHP, Las Vegas, USA, 国際会議Effects of pharmacists' assessment and intervention based on screening tool of older persons' potentially inappropriate prescriptions criteria version 2ポスター発表
- 信州病棟薬剤師セミナー, 2016年11月, 日本語, 長野県病院薬剤師会, 松本, 国内会議薬物療法の適正化：クリニカルクエスチョンから臨床研究へ、そして再び臨床へ公開講演，セミナー，チュートリアル，講習，講義等
- 第66回日本薬学会近畿支部総会・大会, 2016年10月, 日本語, 日本薬学会, 大阪, 国内会議貧血時におけるタクロリムスの体内動態ポスター発表
- 日本薬物動態学会第31回年会, 2016年10月, 日本語, 日本薬物動態学会, 松本, 国内会議Physiologically-based pharmacokinetic modeling and simulation of tacrolimus in living-donor liver transplantation: Effects of liver regeneration and CYP3A5 genotype口頭発表（一般）
- 第26回日本医療薬学会年会, 2016年09月, 日本語, 日本医療薬学会, 京都, 国内会議白内障手術前後における患者の薬識に関する調査口頭発表（一般）
- 第26回日本医療薬学会年会, 2016年09月, 日本語, 日本医療薬学会, 京都, 国内会議全病棟での担当薬剤師による抗MRSA薬の投与設計体制の構築とその評価口頭発表（一般）
- 第26回日本医療薬学会年会, 2016年09月, 日本語, 日本医療薬学会, 京都, 国内会議集中治療室における薬剤師専従による薬物治療への安全性貢献の評価口頭発表（一般）
- 第26回日本医療薬学会年会, 2016年09月, 日本語, 日本医療薬学会, 京都, 国内会議甲状腺癌に対するレンバチニブ治療の現状と薬剤師の関わり口頭発表（一般）
- 第32回京都がん研究会, 2016年09月, 日本語, 京都がん研究会, 京都, 国内会議抗体医薬品の薬物動態評価とその変動因子の探索公開講演，セミナー，チュートリアル，講習，講義等
- 第26回日本医療薬学会年, 2016年09月, 日本語, 日本医療薬学会, 京都, 国内会議ファーマメトリクスに基づくタクロリムス投与個別適正化の実践シンポジウム・ワークショップパネル（公募）
- 第26回日本医療薬学会年会, 2016年09月, 日本語, 日本医療薬学会, 京都, 国内会議テンプレートを活用した周術期管理におけるシームレスな薬学的管理の導入と評価ポスター発表
- 第26回日本医療薬学会年会, 2016年09月, 日本語, 日本医療薬学会, 京都, 国内会議カバジタキセル投与患者における好中球減少のリスク因子の探索口頭発表（一般）
- 第37回三重てんかん研究会, 2016年09月, 日本語, 三重てんかん研究会, 三重, 国内会議Up-to-date 抗てんかん薬のTDM公開講演，セミナー，チュートリアル，講習，講義等
- 摂南大学薬学部臨床研究センター設立記念シンポジウム「日本の小児医療環境を考える」, 2016年07月, 日本語, 摂南大学薬学部, 大阪, 国内会議小児領域におけるファーマコメトリクスの活用公開講演，セミナー，チュートリアル，講習，講義等
- 医療薬学フォーラム2016, 2016年06月, 日本語, 日本薬学会, 滋賀, 国内会議腎機能低下時におけるフルオロウラシルの体内動態ポスター発表
- 第19回日本医薬品情報学会総会・学術大会, 2016年06月, 日本語, 日本医薬品情報学会, 東京, 国内会議術前外来における薬剤師の取り組み〜術前休薬基準の作成と運用口頭発表（一般）
- 医療薬学フォーラム2016, 2016年06月, 日本語, 日本薬学会, 滋賀, 国内会議社会的挫折ストレス負荷によるうつ病モデルマウスにおけるブロチゾラム誘発睡眠作用の効力変化に関する行動薬理学的研究ポスター発表
- 医療薬学フォーラム2016, 2016年06月, 日本語, 日本薬学会, 滋賀, 国内会議実臨床データを用いた新規抗てんかん薬のファーマコメトリクスシンポジウム・ワークショップパネル（公募）
- 医療薬学フォーラム2016, 2016年06月, 日本語, 日本薬学会, 滋賀, 国内会議ワルファリンの抗凝固作用に及ぼす食事摂取量の影響ポスター発表
- 第33回日本TDM学会・学術大会, 2016年05月, 日本語, 日本TDM学会, 宇都宮, 国内会議生体肝移植術後のタクロリムス静脈内投与から経口投与への切り替え換算量に関する検討口頭発表（一般）
- 第10回日本ファーマシューティカルコミュニケーション学会大会, 2016年05月, 日本語, 日本ファーマシューティカルコミュニケーション学会, 名古屋, 国内会議ひょっとして「副作用」!?見逃さない薬剤師になるための第一歩口頭発表（一般）
- 医療薬学フォーラム2015/第23回クリニカルファーマシーシンポジウム, 2015年07月免疫抑制剤のPK-PD解析と個別化投与設計[招待有り]
- 第22回クロマトグラフィーシンポジウム, 2015年05月京都大学におけるTDM分析事例〜抗てんかん薬について〜[招待有り]
- The13th CJK Joint Symposium for Clinical Information on Parenteral Drugs, 2015年04月Pharmacist Roles in the Individualized Pharmacotherapy[招待有り]
- 東邦大学大森病院TDM委員会勉強会, 2015年03月新規抗てんかん薬のTDM[招待有り]
- 第２１回「TDM研修会, 2015年02月新規抗てんかん薬のTDMとPK/PD[招待有り]
- 第36回日本病院薬剤師会近畿学術大会, 2015年01月臨床系教員の立場から[招待有り]
- 第35回日本臨床薬理学会学術総会, 2014年12月新規抗てんかん薬のTDMと臨床薬理[招待有り]
- 第31回日本TDM学会・学術大会, 2014年05月新規抗てんかん薬のTDM[招待有り]
- 薬物治療モニタリング研究会第102回例会, 2014年02月Up-to-date抗てんかん薬のTDM[招待有り]
- 第34回日本臨床薬理学会学術総会, 2013年12月小児医薬品評価におけるModeling and Simulationの活用について[招待有り]
- 6th Asian Association of Schools of Pharmacy Conference Pre-conference Pharmacy Education Forum and Workshops, 2013年11月From Bench to Bedside”-Application of Science to Clinical Practice[招待有り]
- The 13th Congress of the Asian Society of Transplantation, 2013年09月The role of pharmacists in organ transplantation[招待有り]
- 薬剤師レジデント交流会, 2012年03月これからの薬剤師レジデントプログラムに望む事〜大学の立場から〜[招待有り]
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2022年04月01日 - 2025年03月31日周産期母児における抗精神病薬治療の適正化のためのファーマコメトリクス
- 厚生労働省, 厚生労働科学研究費補助金（医薬品・医療機器等レギュラトリーサイエンス政策研究事業）, 神戸大学, 2024年04月 - 2025年03月, 研究分担者専門薬剤師が医療の質に与える効果とその評価に関する研究
- 神戸薬科大学, 学長裁量経費による学内共同研究経費, 2022年04月 - 2025年03月, 研究代表者microRNAを介した小胞体ストレス関連分子SEL1L/HRD1の機能解析とパーキンソン病治療への応用
- 厚生労働省, 医薬品・医療機器等レギュラトリーサイエンス政策研究事業, 2020年04月 - 2023年03月, 研究代表者国民のニーズに応える薬剤師の専門性のあり方に関する調査研究
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2019年04月 - 2022年03月妊婦における適正使用を目指した新規抗てんかん薬の数理学的モデル解析妊娠経過に伴う生理学的・薬物動態学的変化並びに新生児における臓器の発達がリスペリドン及びその活性代謝物であるパリペリドン薬物動態に与える影響について，生理学的薬物動態（PBPK）モデルを構築した。PBPKモデルによって，成人，小児並びに妊婦における両薬物の血中濃度を精度よく予測することができた。また感度分析の結果，アルブミン濃度の低下やCYP2D6活性の上昇，GFRの上昇及び胎児胎盤体積の増加が妊娠に伴う薬物動態変動の要因であることを定量的に示した。新生児のGFR予測においては，RhodinやSchwartzのモデルに比べて，Symcypモデルが優れていることが示唆された。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2016年04月01日 - 2019年03月31日, 研究代表者生体肝移植患者から得られたタクリムス血中濃度推移に適した生理学的薬物動態モデルを構築し，肝再生および肝臓・小腸CYP3A5遺伝子多型が薬物動態に与える影響を定量的に評価した．その結果，肝機能は生体肝移植後早期に回復し，タクロリムスの全身クリアランスへの寄与は移植後の限られた期間のみであることが判明した．また，見かけのクリアランスは肝および小腸のCYP3A5遺伝子多型の影響を同程度受けることが判明した．さらに，得られた薬物動態パラメータを用いて，肝・小腸CYP3A5遺伝子多型別の投与量ノモグラムを作成した．競争的資金
- 国立大学法人東京大学, 長寿・障害総合研究事業, 2017年, 研究代表者（AMED）高齢者の多剤処方見直しのための医師・薬剤師連携ガイド作成に関する研究/病院薬剤師主導による多剤処方の是正を目指した医師・薬剤師連携モデルの構築と医師・薬剤師連携ガイドの作成競争的資金
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 京都大学, 2013年04月01日 - 2016年03月31日ミコフェノール酸の薬物動態と薬効の速度論的解析と個別化投与設計無アルブミン血症ラットを用いて検討した結果、非結合型ミコフェノール酸（MPA）血中濃度が免疫抑制効果の指標となることが示された。また、シミュレーションの結果、同一血中濃度を目標にした場合に、MPAの非結合型分率の増加に応じて、非結合型濃度は直線的に増加するが、薬理活性のマーカーであるIMPDH活性の減少は非線形的であることが明らかとなった。 さらに、造血幹細胞移植患者から得られたMPA血中濃度及びIMPDH活性を用いて、速度論的解析を行った結果、腎機能障害時には蓄積した代謝物が腸肝循環する結果、MPA血中濃度が上昇することが明らかとなったが、IMPDHへの影響は限定的であることが示された。
- 日本学術振興会, 科学研究費助成事業 挑戦的萌芽研究, 挑戦的萌芽研究, 京都大学, 2013年04月01日 - 2015年03月31日進化的アルゴリズムによるPopPKモデリングの完全自動化ポピュレーション・ファーマコキネティック・モデルは、患者情報に基づく平均的な薬物動態パラメーター、個体間変動および個体内変動からなるモデルである。患者個人個人の血中薬物動態を予測するためには、より精度の高い患者情報と薬物動態パラメーターとの間の関係すなわち共変量モデルを見つけることが重要である。しかしながら、共変量候補の数が多いために、モデル開発は困難を極める。そこで本研究では、コンピューター上で数式を進化させることにより、臨床データから完全自動で共変量モデルを開発するシステムを完成させた。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 京都大学, 2009年 - 2011年難治性てんかん患者における薬物動態と薬効の母集団解析に基づく個別化処方設計支援チトクロームP450(CYP) 2C19遺伝子多型と併用抗てんかん薬が、クロバザム及び活性代謝物の薬物動態に与える影響について定量的評価を行った。CYP2C19遺伝子多型を有する患者では、活性代謝物の濃度が遺伝子多型を有さない患者に比べて3. 8倍上昇することから、CYP2C19遺伝子多型診断が低用量クロバザム治療における患者の選択に有用であることが示唆された。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 京都大学, 2007年 - 2011年薬物動態・薬理遺伝学に基づいたテーラーメイド抗がん剤治療の標準治療化に関する研究肝代謝型抗がん薬は治療域が狭いだけでなく薬物動態の個人間差異が大きい。遺伝子多型や併用薬および薬物動態などの情報を基に投与量を個別に調整する方法は、理論的に最も単純でかつ確実な方法である。京都大学大学院医学研究科・医の倫理委員会にて承認を得て、複数の臨床楽理学関連の医師主導臨床試験を行い、薬物動態の個人間差異を出来るだけ小さくするための手法の可能性を検討した。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 京都大学, 2007年 - 2008年免疫抑制剤の薬物動態と薬効の速度論的解析と相互作用を考慮した適正使用法の開発新規免疫抑制剤であるエベロリムス体内動態についてラットを用いて検討した結果、小腸での高い初回通過効果のためバイオアベイラビリティが低いこと、併用したタクロリムスとは相互作用しないが、シクロスポリンとは小腸部位で相互作用を起こすことが判明した.さらに、タクロリムス併用膵島移植患者では薬物間相互作用が期待できないため、エベロリムスではシロリムスに比べて約3倍の投与量を必要とすることが示唆された.
- 日本学術振興会, 科学研究費助成事業 萌芽研究, 萌芽研究, 京都大学, 2006年 - 2007年抗リン酸化ペプチド抗体を用いた高感度カルシニューリン活性測定法の開発と臨床応用研究代表者等はこれまでに、生体肝移植患者において、シクロスポリンやタクロリムスの標的分子であるカルシニューリンの酵素活性が、これら薬物の免疫抑制効果の指標となり得ることを明らかにしてきた。本研究では、臨床応用可能な迅速かつ高感度な新規カルシニューリン活性測定法の開発を目指して、ELISA法を用いた測定系について検討した。現在までに、カルシニューリンの特異的基質であるリン酸化RIIペプチドに対する抗リン酸化ペプチド抗体の作成に成功し、さらに抗体の特異性が確認された。続いて、抗リン酸化RIIペプチド抗体をプレートに固相化し、FLAG付リン酸化RIIペプチドを標準物質として、サンドイッチELISA測定系を確立した。FLAG付リン酸化RIIペプチドの定量性は、0.125-4ng/mLの範囲であった。本法は、カルシニューリンによるリン酸化RIIペプチドの脱リン酸化反応(ステップ1)と、FLAG付リン酸化RIIペプチドによる反応終了液中に含まれるリン酸化RIIペプチドの定量(ステップ2)を行うことを特徴とし、反応前後のリン酸化RIIペプチドの物質収支からカルシニューリンの脱リン酸化活性が算出できる。 本年度は、リン酸化RIIペプチド定量のための条件検討を実施した。まず、ステップ1の停止液のステップ2に対する影響を調べた結果、常用の5%トリクロロ酢酸/0.lMリン酸二水素カリウム溶液を用いた場合、FLAG付リン酸化RIIペプチド(4ng/mL)の検出が不可能であった。そこで次に、5mM EGTA(カルシニューリンの阻害剤)をステップ1の停止液として用いた場合、ステップ2には影響せず、FLAG付リン酸化RIIペプチドの検出が可能であることが示された。今後、開発したnon-RI ELISA測定系の臨床応用に向けて、カルシニューリン活性測定の最適化及び全自動化を目指す予定である。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 京都大学, 2005年 - 2006年カルシニューリン阻害剤の体内動態・薬効の母集団解析と個別化投与設計法の開発臓器移植時に汎用されるカルシニューリン阻害剤であるタクロリムスとシクロスポリンの薬効特性について比較するため、生体肝移植患者において薬物血中濃度と同時に末梢血単核球細胞中のカルシニューリン活性を測定した。非線形混合効果モデルプログラムNONMEMを用いた母集団薬効解析を行った結果、シクロスポリンの場合には、ピーク血中濃度付近の約700ng/mL以上でカルシニューリン活性はほぼ完全に抑制される一方、タクロリムスの場合には、治療域以上の血中濃度(>20ng/mL)においても部分的にしか阻害されないなど、カルシニューリン阻害特性に両薬剤で相違のあることが判明した。また、カルシニューリン阻害特性には大きな個体差があることも判明したため、薬物血中濃度モニタリングに加えて、薬効をモニタリングすることの有用性が示唆された。続いて、タクロリムス体内動態の変動要因を解明するため、生体肝移植患者を対象に小腸と肝臓における薬物排出トランスポータP-糖蛋白質(MDR1)や薬物代謝酵素(CYP3A4、CYP3A5)の影響について母集団薬物動態解析を行った。その結果、術直後の経口クリアランスにMDR1遺伝子の小腸におけるmRNA発現量が、また術後経過に伴う経口クリアランスの回復に移植肝に発現するCYP3A5*3アレルが有意に影響を及ぼすことが明らかとなった。以上、本研究成果に基づき、個々の患者におけるカルシニューリン活性の測定と遺伝子情報を含む体内動態変動因子を考慮することによって、より精緻なタクロリムスの個別化治療が可能になると考える
- 日本学術振興会, 科学研究費助成事業 基盤研究(A), 基盤研究(A), 京都大学, 2001年 - 2003年薬物排泄機構の遺伝子多型解析に基づく医薬品相互作用・動態個体間変動評価法の基盤構築異物処理臓器に発現する生体膜輸送システム(薬物トランスポータ)は、医薬品や劇・毒物等の低分子性異物や代謝老廃産物を体外へ排除する役割を担っている。本研究では、腎臓に発現するヒト型薬物トランスポータの遺伝子情報(一塩基多型(SNP))や発現情報と薬物体内動態パラメータとの定量的解析を行い、薬物動態個体間変動評価法の構築を試みた。 新たに遺伝子単離した腎特異的トランスポータhOCT2-A並びにNaGLT1を含む、多様な腎トランスポータの薬物輸送特性を明らかにした。さらに、有機イオントランスポータを中心にして各薬物トランスポータのヒト腎におけるmRNAプロファイルを作成するとともに、腎臓における膜局在を同定した。hOCT1やhPEPT2において機能変化を引き起こすcSNPを見出したが、これらSNPの発現頻度は少なく、個体間変動因子として機能している可能性は低いことが示唆された。またモデル動物や腎不全患者を対象にした腎薬物トランスポータの発現量解析と薬物体内動態解析の相関解析より、腎薬物トランスポータ発現量が薬物の腎排泄能を規定する因子となり得ることが判明した。 今後、ヒト型薬物トランスポータ群の発現量に影響を及ぼすと考えられるrSNPやiSNPなどの遺伝情報に加えて、加齢・病態・臓器障害時における発現変動のメカニズム、発現制御に関わる転写因子等の探索など、個人差をもたらす遺伝的・分子的要因の網羅的解析を行うことによって、ヒト薬物トランスポータ群の薬物体内動態個体間変動因子としての役割が明らかになり、テーラーメイド薬物療法の実践へと発展することが期待される。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 京都大学, 2002年 - 2002年免疫抑制剤の体内動態・薬効の母集団速度論的解析と個別化処方設計支援システムの開発
- 日本学術振興会, 科学研究費助成事業 奨励研究(A), 奨励研究(A), 京都大学, 2000年 - 2001年病態時における薬物腎排泄の変動とその分子機構に基づく科学的投与設計の構築生体に投与されたイオン性薬物の多くは、腎臓において尿細管分泌を受け尿中に排泄されることが知られているが、腎障害時におけるこれら薬物の腎排泄変化と薬物トランスポータの発現変動に関する情報は少ない。本研究課題では、平成12年度にシスプラチン惹起腎障害モデルラットを用いた検討を行い、このモデルにおいては有機アニオンの腎皮質切片への取り込みは有意に低下するものの、有機カチオンの取り込みは有意に変化していないこと、さらに側底膜有機アニオントランスポータrOAT1及び有機カチオントランスポータrOCT2の発現変動を伴わないことが判明した。本年度は、既報に準じ5%オキソン酸と2.5%尿酸の混合飼料を10日間与えることによって高尿酸血症モデルラットを作成し検討したところ、糸球体濾過速度の減少と共に、有機アニオンメトトレキサートや有機カチオンシメチジン腎クリアランスの減少が観察された。さらに腎切片へのこれら薬物の取り込みは減少したことから、血管側側底膜を介した輸送活性の低下が示唆された。ラット腎粗膜画分を調製し、側定膜有機アニオントランスポータrOAT1、rOAT3並びに有機カチオントランスポータrOCT1、rOCT2特異抗体を用いてウェスタンプロッティングを行ったところ、rOCT1蛋白量は変動していないものの、rOAT1、rOAT3、rOCT2蛋白量の減少が観察された。さらに、ラット腎total RNAを調製し、rOAT1、rOAT3、rOCT2の特異的プローブを用いノーザンブロッティングを行ったところ、rOAT1、rOCT2 mRNA発現量の有意な低下が認められた。従って、高尿酸血症モデルラットの腎側底膜における有機アニオン及び有機カチオン輸送活性の低下に、rOAT1、rOAT3及びrOCT2の特異的な発現量低下が寄与していることが示唆された。 以上の結果、腎障害時におけるイオン性薬物の腎排泄への影響は多様であるものの、一部は薬物トランスポータの特異的な発現変動で説明できると考えられる。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 1999年 - 2000年生体異物障壁としての小腸薬物代謝酵素とトランスポータの協働機能解析我々は最近、チトクロームP450(CYP)3A4で代謝される新規免疫抑制剤タクロリムスの体内動態を検討し、経口投与時の初回通過効果に対して、肝臓のみならず小腸が関与するとの知見を報告した。この知見は、肝臓における薬物代謝能を評価するのみでは、経口投与時のバイオアベイラビリティや相互作用の予測が難しいことを示唆する点で極めて重要である。そこで本研究では、薬物療法および医薬品開発における緊要性も考慮しつつ、生体異物(薬物)障壁としての小腸の機能に注目し、基礎的観点から詳細な解析を行なった。 小腸にはCYP3Aサブファミリーが存在するが、酵素活性は肝臓に比べ一桁以上低いため、薬物代謝に対する寄与は小さいと考えられてきた。一方、小腸には薬物を排出するトランスポータ(P-糖蛋白質など)が存在するが、膜透過性が高い薬物については、消化管吸収が不完全になることでバイオアベイラビリティが低下するとは考え難い。しかし、薬物代謝酵素とトランスポータが協働する場合には、小腸が薬物の初回通過効果に大きく関与する可能性がある。すなわち本研究では、「小腸におけるトランスポータが、薬物の小腸上皮細胞における滞留時間を延長させること、もしくは代謝物の蓄積による代謝阻害を回避させることによって、薬物代謝を顕著に促進させる」との仮説を定量的かつ速度論的に検証した。従って、本研究は薬物動態研究の新しい流れをリードするものであり、また得られた研究成果・情報は創薬や薬物療法の適正化に還元し得るものと期待される。
- 日本学術振興会, 科学研究費助成事業 特定領域研究(A), 特定領域研究(A), 京都大学, 1999年 - 1999年薬物トランスポータ分子認識を利用した薬物動態制御システムの構築本研究では、臓器特異的に発現する薬物トランスポータ群の分子認識能に基づき、薬物の生体内利用率を高めるドラックデリバリーの開発、あるいは薬物相互作用発現機構の分子的解明について検討を加えた。 1.H^+駆動型ペプチドトランスポータ(PEPT)とエステル型化合物との相互作用 従来ペプチド結合を待つ化合物のみPEPTの基質になると考えられてきたが、ペプチド結合をエステル結合にした化合物も、PEPTの基質になることを明らかにした。これらの結果より、経口吸収性の低い薬物をアミノ酸でエステル化し、小腸に発現するPEPT1の基質とすることによって、消化管吸収の改善が可能になった。従って、PEPTの分子認識能を利用した、新規薬物送達システムの実用化に向けて大きく前進したと考えられる。 2.PEPTと糖尿病治療薬との相互作用 新規経口血糖降下剤nateglinideは、D-フェニルアラニンを有するジペプチド様構造をしている。また、臨床上繁用されている経口血糖降下剤glibenclamideは、構造的に多様なイオンチャネルやトランスポータを阻害することが知られている。そこで、これら糖尿病治療薬とPEPTとの相互作用について検討した結果、両薬物ともPEPTの機能を非競合的に阻害すること、並びにPEPTを介して輸送されないことが判明した。従って、これら経口血糖降下剤がPEPTの生理及び薬物動態学的機能を阻害し、臨床的問題を引き起こす可能性が示唆された。 3.有機イオントランスポータを介する薬物相互作用発現機構の評価・解析 新規腎局在性有機アニオントランスポータOAT-K2のcDNAクローニングに成功し、OAT-K1並びにOAT-K2の機能的異同について検討した。その結果、両トランスポータは互いに異なる薬物認識特性を有することがわかった。また、有機カチオントランスポータOCT1及びOCT2の機能特性について比較したところ、両トランスポータは互いに類似した薬物認識能を有するものの、その発現調節において異なる調節を受けることが判明した。これらの分子的情報をもとに、現在、薬物相互作用発現機構の予測システムを構築中である。
- 日本学術振興会, 科学研究費助成事業 基盤研究(B), 基盤研究(B), 京都大学, 1997年 - 1999年遺伝子発現による薬物排泄系の再構築を基盤とした薬物相互作用の新評価・予測法の開発我々はこれまで、細胞膜小胞系・培養細胞系などの実験系を用い、小腸や腎における吸収・分泌機構に関する研究を行い、これら実験系が薬物吸収・分泌の評価系として有用であることを示してきた。本研究では、我々がクローン化した薬物トランスポー夕群の種々発現系を用いることにより、医薬品適正使用に還元しうる薬物間相互作用のin vitro評価・予測系の開発を目的として以下の検討を行った。 1.薬物トランスポータcDNAのクローニングとアフリカツメガエル卵母細胞を用いた薬物輸送解析 ラット腎有機アニオントランスポー夕OAR1並びにOAT-K2のcDNAクローニングを行った。また、遺伝子クローニング直後の機能解析・評価系として、アフリカツメガエル卵母細胞発現系の最適条件を設定し、種々アニオン型利尿剤がOAT1と相互作用することを明らかにした。 2.薬物トランスポータ安定発現細胞の作成と機能解析 OAT-K1安定発現細胞を用い、臨床上問題となっているメトトレキセートとNSAIDとの相互作用発現に対し、OAT-K1が少なくとも一部関わることを明らかにした。また、OAT-K1並びにOAT-K2安定発現MDCK細胞を作成し、これらトランスポータの輸送特性や膜局在性などの解析を行ったところ、アニオン性薬物の尿細管分泌に対して本細胞系が有用なモデル系であることが判明した。ラット腎有機カチオントランスポータOCT1並びにOCT2の安定発現細胞を作成し、カチオン性薬物の構造活性相関を中心に精査した。また、単層細胞シートを用いた薬物輸送解析や特異抗体を用いた免疫化学的解析の結果から、OCT安定発現細胞がカチオン性薬物の腎移行を考慮する上で有用なin vitroスクリーニング系であることを実証した。さらに、我々が既に作成したP-糖蛋白質安定発現細胞を用い、強心配糖体ジゴキシンの薬物相互作用をin vitro評価・予測するための最適条件の決定を行った。 本研究で開発した方法を薬物動態・薬物相互作用のスクリーニング系として用いることによって、薬物排泄系トランスポータ個々に着目した詳細な解析を行うことが可能になると考えられる。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 京都大学, 1997年 - 1998年母集団薬物動態および代謝酵素の遺伝子診断情報に基づく薬物個別投与設計法の開発我々はこれまでに、フェニトインを対象薬剤として選択し、日本人てんかん患者における母集団薬物動態パラメータを推定すると共に、フェニトインの体内動態におよぼすチトクロームP450(CYP)2C9/19の遺伝子多型の影響を検討してきた。本研究では、患者個別のフェニトイン血中濃度の予測精度を検討することによって、薬物個別投与設計における代謝酵素の遺伝子診断情報および薬物血中濃度情報の有用性を評価した。CYP2C9およびCYP2C19の遺伝子変異の影響を考慮しないフェニトインの母集団動態パラメータに基づいて患者の血中濃度を予測したところ、CYP2C9の遺伝子変異(Leu^<359>)を有する患者では実測値が大きく高濃度側へ偏ることが明らかとなった。一方、CYP2C9/19の遺伝子変異の影響を考慮したフェニトイン母集団動態パラメータを用いた場合、CYP2C9の遺伝子変異(Leu^<359>)を有する患者においても血中濃度の予測に偏りは認められなかった。本研究では、さらにベイジアン推計理論に基づく個別投与設計の精密化について検討を加えた。すなわち、CYP2C9/19の遺伝子変異の影響を考慮した母集団動態パラメータを事前情報とし、患者に対する事後情報として1〜2点の薬物血中濃度データを用いて速度論的解析を行ったところ、患者固有の動態パラメータに基づく血中濃度の予測精度は、母集団動態パラメータのみによる場合に比べ顕著に上昇することが認められた。従って、CYP2C9/19遺伝子診断情報はフェニトインの低代謝能患者の検出に極めて有用であること、また薬物血中濃度モニタリングに基づくベイジアン解析によって投与量の個別化と精密化が期待できることが明らかとなった。
- 日本学術振興会, 科学研究費助成事業 奨励研究(A), 奨励研究(A), 京都大学, 1996年 - 1996年緑内障治療剤投与の適正化を目指した薬物体内動態・薬効の母集団解析炭酸脱水酵素阻害剤であるアセタゾラミドは、唯一の内服用緑内障治療剤として眼科領域で広く使用されているものの、副作用の発現頻度は高く、その使用には困難を伴っていた。本研究では、アセタゾラミド投与の適正化を目指して、医師との連携により、患者におけるアセタゾラミドの体内動態と薬効の母集団解析を行った。 京都大学医学部附属病院眼科入院中でアセタゾラミド内服している一過性の高眼圧患者17名を対象に、経時的な眼圧測定と採血を行った。眼圧はGoldmann圧平眼圧計により測定し、アセタゾラミド血漿中濃度は、HPLC法により定量した。体内動態は繰り返し投与を含む1次吸収1-コンパートメントモデルを、薬効はEmaxモデルを仮定し、拡張最小二乗法プログラムNONMEMにより解析した。見かけのクリアランス(CL,L/hr)は、個々の患者の体重(BW)と血清クレアチニン値(Scr)と以下の関係にあった:CL=0.0255・BW/Scr。また、アセタゾラミドによる眼圧最大下降値(Emax)は、7.2±1.5mmHg(mean±SE)であり、Emaxの半分の薬効をもたらす濃度(EC50)は、1.64±1.43μg/mlであることから、アセタゾラミドによる十分な眼圧下降効果は、血漿中濃度5〜10μg/mlで期待でき、それ以上の血中濃度の上昇は薬効の増強にはつながらないことが明らかとなった。さらに、得られた体内動態・薬効の速度論パラメータに基づき、個々の患者の体重と血清クレアチニン値を用いたアセタゾラミド投与量のノモグラムを作成した。本研究で得られた知見は、個々の患者に適した安全かつ有効なアセタゾラミド治療を推進する上で有用な情報となると考える。
- 日本学術振興会, 科学研究費助成事業 基盤研究(B), 基盤研究(B), 京都大学, 1995年 - 1996年培養細胞系を用いた薬物輸送の速度論的解析に基づく消化管吸収・腎排泄評価法の開発医薬品開発の前臨床試験では薬剤の有効・安全性を確保するために、吸収・分布・代謝・排泄や毒性についての検討が必須であるが、実験用動物の大量消費に対して批判が強まりつつある。我々は、細胞膜小胞系・培養細胞系等の新しいin vitro実験系を用いて、小腸や腎尿細管における吸収・分泌機構や細胞毒性に関する研究を進めてきた。本研究では、代表的株化腎化皮細胞(LLC-PK_1, OK, MDCK)及び腸管上皮細胞(Caco-2)を用いて薬物輸送を速度論的に解析することにより、薬物経細胞輸送の律速過程と細胞内蓄積の関係を明らかにし、消化管吸収、腎排泄、腎毒性の新しいin vitro評価系を確立することを目的として、以下の検討を行った。 1.単層細胞シートを用いた薬物経細胞輸送実験:多孔性フィルター(Transwell)上に上皮細胞を培養して単層細胞シートを形成させた。頂側膜あるいは側底膜側のチャンバーに薬物を添加し、反対側チャンバーへの薬物の移行性について検討した。また、方向選択的経細胞輸送と細胞内蓄積の相関について解析し、培養細胞系を用いた薬物の消化管吸収・腎尿細管動態のin vitro評価法を確立した。 2.単層腎細胞シートを用いた薬物細胞毒性実験:細胞毒性の指標には刷子縁膜局在酵素やリソソーム酵素の変化等を測定した。種々の細胞培養条件や薬物添加条件で薬物の毒性を比較し、毒性評価のための最適条件を決定した。 3.薬物輸送の速度論的解析:刷子縁膜および側底膜における薬物輸送活性(influxおよびefflux clearance)を評価し得る薬物速度論モデルを開発し、細胞シートによる経細胞輸送の測定結果を解析した。その結果、薬物輸送の速度論的解析によって、薬物経細胞輸送に対する律速過程、および輸送担体の寄与を定量的に評価・予測できることが明らかとなった。