研究者詳細 - 中村　智徳

論文 - 中村　智徳

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3EZ, 20Ac-ingenol-induced apoptosis in chemoresistant cancers with cyclin D1 accumulation

Miyata S., Nakamura T., Kitanaka S.

Anticancer Research （Anticancer Research） 40 （ 11 ） 6237 - 6246 2020年11月

研究論文（学術雑誌）, 査読有り, ISSN 02507005

Background/Aim: The topoisomerase 1 catalytic inhibitor 3EZ, 20Ac-ingenol specifically induces apoptosis through the activation of ATR and the up-regulation of PTEN by enhancing the DNA damage response (DDR) in human B lymphoma (BALL-1) cells. The accumulation of cyclin D1 in cancer is known to be related to chemoresistance to DNA damage agents and nuclei of BALL-1 cells exhibit high levels of cyclin D1. However, 3EZ, 20Ac-ingenol effectively induced apoptosis of BALL-1 cells. Materials and Methods: Cell growth, protein levels, and apoptosis were determined by an MTT assay, immunoblotting and DNA fragmentation assay, respectively. Results: 3EZ, 20Ac-ingenol strongly induced inhibition of cell proliferation and apoptosis in Jeko-1 and Panc-1 cell lines through the activation of tumor suppressor proteins and caspase 3. Conclusion: 3EZ, 20Ac-ingenol-induced apoptosis might occur in cells with cyclin D1 accumulation through enhancing DDR, regardless of the cancer cell type.

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

Clinical Therapeutics （Elsevier） 42 （ 10 ） 1975 - 1982 2020年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01492918

© 2020 Elsevier Inc. Purpose: This study aimed to identify patient-related risk factors for chemotherapy-induced nausea and vomiting (CINV) in patients with cancer receiving carboplatin in addition to standard antiemetics, using real-world data. Methods: In this single-center, observational study, data from electronic medical records of consecutive patients with solid tumors who had received their first cycle of a carboplatin-based regimen and were treated with a 2- or 3-drug combination of antiemetics from January 2014 to January 2019 at Toranomon Hospital were retrospectively analyzed. The primary end point was the occurrence of a complete response (CR) within 5 days after the first cycle, which was defined as no vomiting and no use of rescue medication for CINV. A receiver operating characteristic curve, univariable, and multivariable logistic regression analyses were used. Findings: A total of 314 patients were evaluated in this study. The proportion of patients who had a CR in the overall, acute, and delayed phases was 76.8% (n = 241), 98.7% (n = 310), and 77.4% (n = 243), respectively. Similar to univariable logistic regression analysis, multivariable logistic regression analysis revealed that age ≥70 years and total dexamethasone dose ≥14.6 mg were significantly associated with a non-CR in the overall phase, whereas female sex, history of habitual alcohol intake, and history of smoking were not associated with a non-CR in the overall phase. Implications: Our study findings suggest that a patient age of <70 years and a total dexamethasone dose of <14.6 mg are high-risk factors for carboplatin-induced CINV

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虚実中間証を含む虚実証の予測モデル

前田絢子, 吉野鉄大, 片山琴絵, 堀場裕子, 引網宏彰, 嶋田豊, 並木隆雄, 田原英一,南澤潔, 村松慎一, 山口類, 井元清哉, 宮野悟, 美馬秀樹, 三村將, 中村智徳, 渡辺賢治

日本東洋医学雑誌（日本東洋医学会） 71 （ 4 ） 315 - 325 2020年07月

研究論文（学術雑誌）, 共著, 査読有り

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

菊山史博, 鈴木小夜，地引　綾，横山雄太，河添　仁, 中村智徳

薬学雑誌（日本薬学会） 140 （ 6 ） 799 - 808 2020年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00316903

© 2020 The Pharmaceutical Society of Japan Pharmacy practice experience (PPE) is essential in the six-year course of pharmaceutical education in Japan. We previously found that PPE reinforced students' self-efficacy for curriculums (SECs), leading robust acquisition and reconstruction of pharmaceutical expertise. In this study, we aimed to clarify whether students' SECs aŠect successful experiences as enactive attainments in PPE. We distributed survey questionnaires to the fifth-year students in Keio University in 2016-2017 before and after PPE. The students made a self-assessment of their psychological state ``expect to do well'' on a seven-point Likert scale for each curriculum (C1 to C18), and their successful experiences were also collected from free description type questionnaire. We could follow up 139 students. The SEC scores increased from prePPE to post I (p ＜ 0.001) and II terms (p ＜ 0.01). The increase in SEC scores during PPE was associated with the rate of students' successful experiences in the first-term PPE (p ＝ 0.04). The path analysis revealed the following as significant predictive factors of SECs for successful experiences: basic sciences (C1, C2, C3, C4, C5, and C6) with standardizing coefficient 0.35, health and environmental sciences (C11 and C12) with 0.39, and pharmaceutical sciences (C7, C8, C9, C10, C13, and C14) with － 0.51. Students in the first-term PPE tended to experience successful performance in medical professions by using their pharmaceutical expertise that they had learned. In this study, for the first time, we demonstrated that Japanese students' SECs for pharmaceutical expertise affected successful experiences, leading better outcomes of PPE.

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

吉浦誠海, 河添仁, 鈴木小夜, 横山雄太, 地引綾, 中村智徳

日本臨床腫瘍薬学会雑誌（日本臨床腫瘍薬学会） 14 1 - 7 2020年04月

研究論文（学術雑誌）, 共著, 査読有り

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

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

Clinical Therapeutics （Clinical Therapeutics） 42 （ 4 ） 712 - 719 2020年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01492918

© 2020 Elsevier Inc. Purpose: Venous pain induced by peripheral intravenous infusion of gemcitabine has remained an unresolved issue in clinical practice. This study aimed to identify differences between gemcitabine formulations as well as risk factors associated with gemcitabine-induced venous pain in patients with cancer. Methods: We retrospectively analyzed data from consecutive patients with cancer who had received chemotherapy including a lyophilized or liquid formulation of gemcitabine diluted with 5% glucose solution via a peripheral vein. The study was conducted at Ehime University Hospital using electronic medical records dated between January 2015 and July 2017. The primary end point was the prevalence of venous pain at the administration site during gemcitabine infusion, classified as injection site reaction of grade ≥2 according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate logistic regression analysis with generalized estimating equations for longitudinal data was used to identify risk factors for venous pain during all courses of gemcitabine treatment. Findings: A total of 1150 treatment courses in 141 Japanese patients were evaluated in this study. Venous pain occurred in 115 courses (10.0%) and in 49 patients (34.8%). The multivariate logistic regression analysis with generalized estimating equations revealed that a dose increase of gemcitabine and use of the liquid formulation of gemcitabine were significantly associated with an increased risk for venous pain (dose increase, adjusted odds ratio [OR] = 1.25; 95% CI, 1.11–1.40 [P < 0.001]; and liquid formulation, adjusted OR = 12.43, 95% CI, 5.61–27.51 [P < 0.001]), whereas age, course number of gemcitabine, and use of the soft-back product of 5% glucose solution were significantly associated with a reduced risk for venous pain (age, adjusted OR = 0.75; 95% CI, 0.57–0.98 [P = 0.037]; course number, adjusted OR = 0.96; 95% CI, 0.92–0.99 [P = 0.023]; and soft back, adjusted OR = 0.39; 95% CI, 0.21–0.74 [P = 0.004]). Implications: The use of the liquid formulation of gemcitabine was associated with a significant increase in the frequency of gemcitabine-induced venous pain despite dilution with 5% glucose solution compared to that with the lyophilized formulation. The lyophilized formulation of gemcitabine should hence be used in peripheral intravenous infusion for the treatment of patients with cancer.

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Discrimination of prediction models between cold-heat and deficiency-excess patterns

Maeda-Minami A., Yoshino T., Katayama K., Horiba Y., Hikiami H., Shimada Y., Namiki T., Tahara E., Minamizawa K., Muramatsu S., Yamaguchi R., Imoto S., Miyano S., Mima H., Mimura M., Nakamura T., Watanabe K.

Complementary Therapies in Medicine （Complementary Therapies in Medicine） 49 102353 2020年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09652299

© 2020 Elsevier Ltd Objective: The purpose of this study was to extract important patient questionnaire items by creating random forest models for predicting pattern diagnosis considering an interaction between deficiency-excess and cold-heat patterns. Design: A multi-centre prospective observational study. Setting: Participants visiting six Kampo speciality clinics in Japan from 2012 to 2015. Main outcome measure: Deficiency–excess pattern diagnosis made by board-certified Kampo experts. Methods: We used 153 items as independent variables including, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We sampled training data with an equal number of the different patterns from a 2 × 2 factorial combination of deficiency–excess and cold–heat patterns. We constructed the prediction models of deficiency–excess and cold–heat patterns using the random forest algorithm, extracted the top 10 essential items, and calculated the discriminant ratio using this prediction model. Results: BMI and blood pressure, and subjective symptoms of cold or heat sensations were the most important items in the prediction models of deficiency–excess pattern and of cold–heat patterns, respectively. The discriminant ratio was not inferior compared with the result ignoring the interaction between the diagnoses. Conclusions: We revised deficiency–excess and cold–heat pattern prediction models, based on balanced training sample data obtained from six Kampo speciality clinics in Japan. The revised important items for diagnosing a deficiency–excess pattern and cold–heat pattern were compatible with the definition in the 11th version of international classification of diseases.

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The reductive activity of human liver microsomes for vitamin K epoxides

Masashi Kawano, Takuya Araki, Hideaki Yashima , Tomonori Nakamura, Koujirou Yamamoto

Indonesian Journal of Pharmaceutics （Universitas Padjadjaran） 2 （ 1 ） 7 - 13 2020年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2597-8748

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Cardiac Pacemaker Cells Generate Cardiomyocytes from Fibroblasts in Long-Term Cultures

Kiuchi S., Usami A., Shimoyama T., Otsuka F., Yamaguchi S., Nakamura T., Suzuki S., Ono K.

Scientific Reports （Scientific Reports） 9 （ 1 ） 15174 2019年10月

研究論文（学術雑誌）, 共著, 査読有り

Because cardiomyocyte generation is limited, the turnover of cardiomyocytes in adult heart tissues is much debated. We report here that cardiac pacemaker cells can generate cardiomyocytes from fibroblasts in vitro. Sinoatrial node cells (SANCs) were isolated from adult guinea pig hearts and were cultured at relatively low cell densities. Within a week, a number of fibroblast-like cells were observed to gather around SANCs, and these formed spontaneously beating clusters with cardiomyocyte structures. The clusters expressed genes and proteins that are characteristic of atrial cardiomyocytes. Pharmacological blocking of pacemaker currents inhibited generation of action potentials, and the spontaneous beating were ceased by physically destroying a few central cells. Inhibition of beating during culture also hampered the cluster formation. Moreover, purified guinea pig cardiac fibroblasts (GCFs) expressed cardiac-specific proteins in co-culture with SANCs or in SANC-preconditioned culture medium under electrical stimulation. These results indicate that SANCs can generate cardiomyocytes from cardiac fibroblasts through the influence of humoral factor(s) and electrophysiological activities followed by intracellular Ca2+ oscillations. This potential of SANCs to generate cardiomyocytes indicates a novel mechanism by which cardiomyocytes turns over in the vicinity of pacemaker cells and could be exploited in the development of strategies for cardiac regenerative therapy in adult hearts.

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Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study

Takahashi K., Yoshino T., Maki Y., Ishiuchi K., Namiki T., Ogawa-Ochiai K., Minamizawa K., Makino T., Nakamura T., Mimura M., Watanabe K.

Archives of Toxicology （Archives of Toxicology） 93 （ 11 ） 3111 - 3119 2019年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03405761

Liquorice [main ingredient, glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18β-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM–1.8 µM) and 18β-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM–4.2 µM). 3-Monoglucuronyl 18β-glycyrrhetinic acid, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18β-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker.

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薬学実務実習が実習生の薬学専門教育の知識定着及び再構築に与える影響

菊山文博, 鈴木小夜, 中村智徳

薬学雑誌（日本薬学会） 139 （ 9 ） 1201 - 1209 2019年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00316903

Long-term practical training in the 6-year course of pharmaceutical education is a program for students after acquiring basic knowledge on pharmaceutical sciences and preclinical training. However, it remains unproved whether practical training affects students' robust acquisition and reconstruction of pharmaceutical expertise which they had learned before starting practical training. To address this issue, we administered survey questionnaires to 5th-year students (n=149) of Keio University in 2016 both before and after practical training. From the viewpoint of self-efficacy, psychological approach was applied to evaluate respondents' psychological state "to do well" on a 7-point Likert scale (1=disagree, 4=neither, 7=agree) for specific subjects C1-C18 (18 core units of pharmaceutical expertise in the current Model Core Curriculum for Pharmaceutical Education), mainly including basic pharmaceutical sciences, public health, clinical pharmacology and pharmacotherapy. C1-C18 total score values, which reflect the strength of certainty to acquire expertise, were significantly higher after the first term of practical training compared to before training, regardless of the pharmacy and the hospital (p<0.001), but not after the second term. Specific factors associated with increased score values for "to do well" were not extracted from other questionnaire answers concerning students' mentors or their self-learning during practical training. These results demonstrated that practical training at least partly reinforced students' feeling of "to do well", contributing to their robust acquisition and reconstruction of pharmaceutical expertise. Giving students recognition individually of their learning process themselves encourages more effective practical training toward their development of resources as a pharmacist.

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Prediction of deficiency-excess pattern in Japanese Kampo medicine: Multi-centre data collection

Complementary Therapies in Medicine （Complementary Therapies in Medicine） 45 228 - 233 2019年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09652299

Objective: The purpose of the present study was to compare important patient questionnaire items by creating a random forest model for predicting deficiency-excess pattern diagnosis in six Kampo specialty clinics. Design: A multi-centre prospective observational study. Setting: Participants who visited six Kampo specialty clinics in Japan from 2012 to 2015. Main outcome measure: Deficiency-excess pattern diagnosis made by board-certified Kampo experts. Methods: To predict the deficiency-excess pattern diagnosis by Kampo experts, we used 153 items as independent variables, namely, age, sex, body mass index, systolic and diastolic blood pressures, and 148 subjective symptoms recorded through a questionnaire. We extracted the 30 most important items in each clinic's random forest model and selected items that were common among the clinics. We integrated participating clinics’ data to construct a prediction model in the same manner. We calculated the discriminant ratio using this prediction model for the total six clinics’ data and each clinic's independent data. Results: Fifteen items were commonly listed in top 30 items in each random forest model. The discriminant ratio of the total six clinics’ data was 82.3%; moreover, with the exception of one clinic, the independent discriminant ratio of each clinic was approximately 80% each. Conclusions: We identified common important items in diagnosing a deficiency-excess pattern among six Japanese Kampo clinics. We constructed the integrated prediction model of deficiency-excess pattern.

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Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study

Komatsu A., Yoshino T., Suzuki T., Nakamura T., Kanai T., Watanabe K.

Basic and Clinical Pharmacology and Toxicology （Basic and Clinical Pharmacology and Toxicology） 124 （ 5 ） 607 - 614 2019年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17427835

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society) Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct bilirubin, glycyrrhizin and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia is defined as a serum potassium level of ≤3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of ≥0.5 mEq/L or an increase of ≥0.5 mEq/L after discontinuing the glycyrrhizin-containing medication was examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy-nine patients received glycyrrhizin (exposed group; mean age: 60.5 ± 14.2) and 1313 did not receive glycyrrhizin (control group; mean age: 58.3 ± 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct-bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin.

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

鈴木小夜, 河添仁, 地引綾, 横山雄太, 中村智徳

医療薬学（日本医療薬学会） 45 （ 4 ） 228 - 239 2019年04月

研究論文（学術雑誌）, 単著, 査読有り

Renal dysfunction and anemia associated with long-term imatinib treatment in patients with chronic myelogenous leukemia

Sakurai M., Kikuchi T., Karigane D., Kasahara H., Matsuki E., Hashida R., Yamane Y., Abe R., Koda Y., Toyama T., Kato J., Shimizu T., Yokoyama Y., Suzuki S., Nakamura T., Okamoto S., Mori T.

International Journal of Hematology （International Journal of Hematology） 109 （ 3 ） 292 - 298 2019年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09255710

© 2019, Japanese Society of Hematology. Knowledge of the toxicity profile of long-term treatment with imatinib is limited. In the present study, we sought to evaluate renal function and hemoglobin levels during long-term imatinib treatment. Eighty-two patients with chronic myelogenous leukemia in chronic phase who had been on imatinib for over 5 years were retrospectively analyzed. The mean estimated glomerular filtration rate (eGFR) was significantly decreased over 5 years (77 ± 17 to 62 ± 14 ml/min/1.73m², P < 0.001). Higher age and lower eGFR value at initiation of imatinib were significantly associated with development of renal dysfunction by multivariate analyses. Mean hemoglobin levels also significantly decreased over the 5-year period (12.9 ± 1.7 to 12.4 ± 1.3 g/dl, P < 0.01). The rate of decrease in eGFR correlated significantly with hemoglobin levels (correlation coefficient = − 0.249, P < 0.05). Serum erythropoietin (EPO) levels did not increase in 16 patients with both renal dysfunction and anemia (median, 31.9 mIU/ml). In patients who participated in a clinical trial of imatinib discontinuation, mean eGFR (50.0 ± 6.5 to 56.0 ± 10.2 ml/min/1.73m², P < 0.05) and hemoglobin levels (12.0 ± 1.7 to 14.0 ± 1.6 g/dl, P < 0.01) improved significantly at 1 year after discontinuation. These findings suggest that long-term imatinib results in a partially reversible continuous decline in renal function and decreased hemoglobin levels.

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

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

Scientific Reports （Scientific Reports） 8 （ 1 ） 16232 2018年11月

研究論文（学術雑誌）, 共著, 査読有り

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

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

Clinical Therapeutics （Clinical Therapeutics） 40 （ 12 ） 2170 - 2179 2018年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01492918

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

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Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients

Nagano D., Araki T., Yanagisawa K., Ogawa Y., Gohda F., Uchiumi H., Handa H., Nakamura T., Yamamoto K.

European Journal of Clinical Pharmacology （European Journal of Clinical Pharmacology） 74 （ 8 ） 1055 - 1060 2018年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00316970

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: The clinical efficacies of some antiretroviral drugs are known to not depend on its concentration in blood. To establish a method of dosage adjustment for darunavir (DRV) based on pharmacokinetic theory, we analyzed the correlation between DRV levels in peripheral blood mononuclear cells (PBMCs) and plasma. Methods: The concentrations of DRV and ritonavir (RTV) in plasma and PBMCs of 31 samples obtained from 19 patients were analyzed. An in vitro kinetic study using MOLT-4 cells was performed to assess the contribution of RTV to the intracellular accumulation of DRV. Results: DRV levels in PBMCs varied between 7.91 and 29.36 ng/106 cells (CV 37.5%), while those in plasma were greater. No significant correlation was found between the trough level of DRV in plasma and that in PBMCs (p = 0.575). The inter-day difference in DRV levels in PBMCs seemed smaller than that in plasma (− 41.6–23.0% vs − 83.3–109.1%). In the in vitro study, the elimination half-life of cellular efflux of DRV was 15.7 h in the absence of RTV and extended to 47.6 h in the presence of RTV. Conclusions: We found a poor correlation between intracellular DRV and plasma DRV levels in patients receiving highly active antiretroviral therapy. The efflux rate of DRV from cells was slow; therefore, the concentration of DRV in PBMCs may reflect average exposure to the drug and clinical efficacy.

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Effect of a Dietary Supplement Containing Raspberry Ketone on CYP3A Activity in Healthy Women.

Tohru Aomori, JingWei Qi, Yuko Okada, Katsunori Nakamura, Haruhiko Hiraoka, Takuya Araki, Tomonori Nakamura, Ryuya Horiuchi, Koujirou Yamamoto

Pharmaceutica Analytica Acta 9 （ 6 ） 1000587 2018年06月

共著, 査読有り, ISSN 2153-2435

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学生のニーズに基づき学生主体で構築した新たなアドバンスト服薬指導事前実習の実施とその評価

鈴木小夜, 青野いづみ，今井奈津美，桑原亜記，剱田侑希，松元美奈子，吉田彩，渡邊明日香，高木彰紀，小林典子，佐伯晴子，大谷壽一，中村智徳，木津純子

薬学雑誌（日本薬学会） 137 （ 11 ） 1391 - 1408 2017年11月

研究論文（学術雑誌）, 共著, 査読有り

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