Published papers

Kikyo-to is a kampo medicine which is composed of Platycodi Radix (PR) and Glycyrrhizae Radix (GR), and used for Pharyngitis. As previous research in our laboratory has found the possibility that kikyo-to could influence cell viability of RAW264.7, we examined the effect of kikyo-to in detail. Decoction of both crude PR and GR, that is kikyo-to (K-D), or each crude herbal medicine, or aqueous solution of extract granule preparation of kikyo-to (K-G) were exposed to RAW264.7 mouse macrophage-derived cells, CACO-2 human colorectal cancer cells and K562 human blood cancer cells. Viability of these cells were evaluated after exposure of various dilution of these preparations.K-D decreased cell viability of RAW264.7 in a time and concentration-dependent manner and K-G also decreased cell viability of RAW264.7 in a concentration-dependent manner. In contrast, the viability of other cells did not change significantly. Decoction of GR alone decreased cell viability of RAW264.7, suggesting that components of GR may contribute to decrease in cell viability of RAW264.7, selectively. To confirm this hypothesis, further studies, functional analysis and clinical validations are needed.

© 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.

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

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.

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

The absolute structure of an indole alkaloid (+)-cinchonaminone by total synthesis of both (+)-cinchonaminone and its enantiomer was determined. The main focus of the study was the enantioselective synthesis of both enantiomers of a chiral cis-3,4-disubstituted piperidine. We also evaluated monoamine oxidase (MAO) inhibitory activities of these enantiomers. Furthermore, its structurally simplified derivatives were synthesized that did not have any chiral center. Two of these derivatives showed stronger MAO inhibitory activities than that of (+)-cinchonaminone.

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

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

Background: Dasatinib, nilotinib, and bosutinib, second-generation tyrosine kinase inhibitors (TKIs), and ponatinib, a third-generation TKI, are approved pharmaceuticals used in the treatment of chronic myeloid leukemia (CML). Although liquid chromatography-tandem mass spectrometry assays for simultaneous quantification of the four TKIs in human serum have been reported in the literature, a high-performance liquid chromatography (HPLC) assay that simultaneously quantifies these compounds has not yet been developed. This study aims to establish and validate an efficient HPLC analytical method using a photodiode array (PDA) detector for the simultaneous quantification of the four TKIs. Methods: Calibration standards were prepared by serial dilution of serum samples containing the four TKIs, followed by solid-phase extraction. The four TKIs were eluted in order within 10 min using a binary HPLC gradient system. Results: The calibration ranges were 2–500 ng/ml for dasatinib, 100–5000 ng/ml for nilotinib, and 10–500 ng/ml for bosutinib and ponatinib. Intra-day and inter-day precision and accuracy values were found to be in accordance with the U.S. Food and Drug Administration guidelines. The recovery rates were 92.9%–96.0%, 80.7%–86.1%, 91.6%–99.0%, and 86.4%–92.6% for dasatinib, nilotinib, bosutinib, and ponatinib, respectively. Conclusion: To the best of our knowledge, this is the first report of an HPLC-PDA analytical method that allows efficient simultaneous quantification of the four TKIs in the serum of patients with CML. We believe that the method developed herein can improve the efficiency of therapeutic drug monitoring in patients with CML in clinical practice.