Published papers

【目的】基質特異性拡張型β-ラクタマーゼ産生腸内細菌目細菌（ESBL-E）感染症治療において、カルバペネム系抗菌薬の代替薬としてセフメタゾール（CMZ）が注目されている。CMZは腎排泄型で蛋白結合率が高い薬剤であり、ESBL-Eに対して、fT≧MICが70％になるように投与設計することにより、有効な殺菌効果が得られると報告されている。しかし、ESBL-E感染患者に対する遊離形薬物動態（PK）パラメータを用いた最適投与法は不明である。本研究は、ESBL-E感染患者における遊離形CMZ濃度を用いた母集団薬物動態／薬力学（PPK/PD）解析を実施し、最適投与法を構築する。【方法】本研究は倫理審査委員会の承認を得て、CMZ投与患者よりインフォームドコンセントを取得した。血液サンプルはCMZ投与前、点滴終了直後、点滴終了１時間後時点等から採取した。2020年9月～2022年3月のESBL-E株のMICは、臨床検査標準協会のガイドラインに従い、微量液体希釈法より測定した。PPK解析は、PhoenixR NLMETMより、遊離形CMZ濃度を用いて、ベースモデルを構築、共変量探索、最終モデルの適格性評価を行った。組み込まれた共変量ごとに各投与法（投与量、投与間隔、点滴時間）に応じてモンテカルロシミュレーションを実施し、目標達成確率(PTA)を算出した。PTAは、10,000回のシミュレーション結果のうち70％ fT≧MICを達成する確率を示し、PTA(％)≧90％を達成する投与法を検討した。また、各菌の全株数に占める各MICの分率に、各MICでのPTAを乗じた値を総計した有効反応期待確率として算出し、投与法を検討した。【結果・考察】対象患者37人が組み込まれ、血液サンプル146検体の遊離形CMZ濃度を測定した。ESBL-E株のMIC50値及びMIC90値はそれぞれ2、4 mg/Lだった。ベースモデルは1コンパートメントモデル、混合誤差モデルが選択された。PPK解析後の遊離形CMZの最終モデル式は、CL = 16.2 × (CLCR/4.36)0.781 × (アルブミン/28)1.2 L/h、V = 47.1 × (体重/62.8)0.751 Lであった。適格性評価より、最終モデルの妥当性が示された。患者個々のCLCR、アルブミン及び体重ごとの最適投与法のノモグラムを作成し、投与量及び投与回数の増加もしくは点滴時間を延長することでPTA及び有効反応期待確率を増加することが示された。【結論】遊離形CMZ濃度を用いたPPK/PD解析を実施し、ESBL-E感染患者に対するCLCR、アルブミン及び体重ごとの最適投与法のノモグラムを構築した。

It is necessary to determine the expiration date and storage methods for in-hospital preparations. However, data on the physical properties and stability of in-hospital preparations for eye drops, especially in long-term storage, are limited. Therefore, the stability of in-hospital preparations for eye drops, 0.5％ vancomycin (VCM), 0.25％ DENOSINE® (GCV), 0.1％ Funguard® (MCFG), 1％ VFEND® (VRCZ), and 5％ sodium chloride (NaCl), were evaluated for long-term storage.All eye drops were stored for 12 weeks under the following conditions: cool (4℃)/darkness, room temperature(approximately 23℃)/darkness, room temperature (approximately 24℃)/scattered light (approximately 1,500 lx), or high temperature (37℃)/darkness. The concentration of eye drops over time was measured by high-performance liquid chromatography and automated clinical chemistry analyzer, and pH, appearance, and sterility were evaluated.As a result, 0.5％ VCM eye drops can be stored for 3 weeks at room temperature when placed in a light-shielding bag or for 12 weeks at 4℃. The 0.25％ GCV, 1％ VRCZ, and 5％ NaCl eye drops can be stored for 12 weeks at 4 - 37℃. The 0.1％ MCFG eye drops can be stored for 6 weeks at 37℃, or for 12 weeks at room temperature or 4℃.The stability of in-hospital preparations for eye drops during long-term storage under varying conditions was demonstrated. Therefore, the use of in-hospital preparations for eye drops is considered to be safer and more effective.

This study aimed to clarify whether the performance levels of pharmaceutical students could be measured by a rubric-based performance evaluation, which consists of a four-point score, during pharmacy practice experiences (PPEs) at both community and hospital pharmacies on a revised model core curriculum for pharmaceutical education in Japan. We assessed the changes in performance evaluation by mentors and students during PPEs, the correlation of their total scores, and those between community pharmacies and hospitals. Data from the electronic records of fifth-year students of the Keio University Faculty of Pharmacy, who did PPEs in 2019, were retrospectively analyzed. A total of 144 students were included in this study. The median scores of performance evaluation by mentors and students in all tasks significantly increased from the commencement to the end of training in community pharmacies and hospitals (P < 0.05). Consequently, there was a significant association of total scores of performance evaluation between mentors and students in the community pharmacies (ρ = 0.755) or hospitals (ρ = 0.724). In contrast, there was a poor association of total scores of performance evaluation by mentors between community pharmacies or hospitals (ρ = 0.209) and those between community pharmacies and hospitals (ρ = 0.409). In conclusion, these findings suggest that performance evaluation by mentors and students reflects the latter’s performance level and can measure their growth in the PPEs at a community pharmacy and a hospital.

Background: Nivolumab and pembrolizumab are the standard treatments for patients with advanced non-small-cell lung cancer (NSCLC). While there are reports on several inflammatory indices and the prognosis of patients with cancer, no study has combined baseline medication with the neutrophil-to-lymphocyte ratio (NLR) to predict clinical outcomes. This study investigated the efficacy of baseline medications plus NLR to predict the effectiveness of nivolumab and pembrolizumab in a real-world clinical setting. Methods: We conducted a single-center retrospective observational study of consecutive patients with advanced NSCLC who received nivolumab or pembrolizumab as first-line, second-line, or beyond treatment between December 2015 and November 2018 at the National Cancer Center Hospital in Japan. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The drug-based prognostic score for baseline medications plus NLR was weighed based on the regression β coefficients. The multivariable Cox proportional hazard model was used to assess the association between the prognostic score-stratified groups and survival outcomes. Results: In total, 259 patients were evaluated in this study. A prognostic score calculated from the baseline medications plus NLR was used to categorize the patients into good (score 0), intermediate (scores 1–2), and poor (scores 3–6) -prognosis groups. The multivariable Cox proportional hazard model revealed a significant association between the poor-prognosis group and reduced OS. The hazard ratio of OS was 1.75 (95% confidence interval: 1.07–2.99; P = 0.031). In contrast, no association between these prognosis groups and PFS was observed. Conclusions: The findings suggest that the baseline medications with nivolumab or pembrolizumab plus NLR could lead to progressively shorter survival outcomes in patients with advanced NSCLC and could be used as a prognostic index for poor outcomes. However, to ascertain the clinical application of these findings, these concomitant medications need further validation in a large-scale multicenter study.

© 2017, Govi-Verlag Pharmazeutischer Verlag GmbH. All rights reserved. Azathioprine (AZA) is increasingly being prescribed to rheumatoid arthritis (RA) patients. Following oral administration, AZA is converted into its active form. Inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE) patients with low thiopurine (S)-methyltransferase (TPMT) activity tend to respond well to AZA therapy. In a previous study of Japanese SLE patients under low-dose AZA therapy, the group with the 94C>A mutation in inosine triphosphatase (ITPA) showed greater improvement in their disease activity index. However, it is not yet clear how genotypes relate to responsiveness to RA treatment. The genotypes ITPA 94C>A, TPMT∗3C, NUDT15 595C>T, GST-M1, GST-T1 and MRP4/ABCC4 2269G>A of Japanese patients with RA were determined. The relationship between these genotypes and response to AZA therapy was evaluated using the Disease Activity Score 28 (DAS28) and various medical data. Of the 22 patients 15 had the ITPA 94C/C genotype, 7 had the ITPA 94C/A genotype, none had the TPMT∗3C mutation, 4 had the NUDT15 595C>T mutation, 8 had the GST-M1 and T1 null genotypes and 9 had the MRP4/ABCC4 2269G>A mutation. Changes in DAS28 at 6 months after baseline were similar in both ITPA genotype groups. However, the maintenance dose of AZA was significantly lower in the C/A group than in the C/C group (0.85±0.30 mg/kg/day vs. 1.2±0.46 mg/kg/day, respectively; p = 0.043). The ITPA 94C/A group showed the same response to RA treatment as the C/C group, but at a lower dose. This demonstrates that RA patients with the ITPA 94C>A mutation are more responsive to AZA.

© 2017, Govi-Verlag Pharmazeutischer Verlag GmbH. All rights reserved. In rheumatoid arthritis (RA) treatment, the concomitant use of methotrexate has been shown to reduce the incidence of antibodies to infliximab (ATI), on the other hand, it is unclear whether azathioprine can reduce ATI production. We enrolled a total of 10 Japanese adult patients with RA who were treated with infliximab concomitantly with methotrexate or azathioprine. Serum concentrations of infliximab and ATI of these patients were measured. The mean serum infliximab concentrations was 1.6±1.3 μg/ml in patients with methotrexate and 1.0±0.5 μg/ml in patients with azathioprine. Serum ATI concentrations were below the limit of quantitation in 4 of 5 patients in each group. The results from the present study suggest that azathioprine suppresses ATI production.

薬局実務実習を終えた薬学部5年生151人と、実務実習を受け入れた延べ125薬局を対象とした。OTC薬の実習内容は、「販売」44名、「RP+見学」39名、「見学のみ」26名、「RPのみ」28名、「いずれも実施せず」13名、無回答1名であった。OTC薬実習に対して「興味」、「十分」、「満足度」を問う質問に対して「そう思う」と回答した学生は、それぞれ110名、54名、69名であった。OTC薬の種類に関する知識の必要性を感じた学生は131名、OTC薬の成分や薬理作用に関する知識の必要性を感じた学生は126名、疾患や病態の知識の必要性を感じた学生は137名であった。OTC薬実習の総合満足度を改善する因子の探索をCS分析で行い、改善度が高かった順に「学生による実際の販売(相談販売)」、「薬剤師がOTC薬を販売しているところの見学」、「OTC薬選択となる疾患や症状の基準」「学生による実際の販売(指名販売)」であった。8割以上の薬局薬剤師はOTC薬実習に関するSBOsを達成することに困難を感じていた。指導薬剤師は学生のコミュニケーションスキルの不足を感じていた。

© 2017 The Pharmaceutical Society of Japan. Long-term practical on-site training, based on the Model Core Curriculum for Pharmaceutical Education, is a core program of the 6-year course of pharmaceutical education, introduced in Japan in 2010. In particular, medication counseling in practical training in 5th-year provides valuable opportunities for communication with real patients rather than simulated patients (SPs). However, it can also cause anxiety in 4th-year students before practical training. To address such concerns, upperclassmen (5th-and 6th-year students), who have already completed practical training, constructed and conducted a new educational program for medication counseling practice in preclinical training based on their experiences. They also developed case scenarios and played the role of patients themselves to create more realistic clinical settings. Advice from professional SPs was also provided. The 5-step program is composed of 1st counseling, 1st small group discussion (SGD) for improving counseling, 2nd revised counseling based on the 1st SGD, 2nd SGD, and development of a counseling plan and presentation. Educational effects of the program were evaluated by questionnaire survey after preclinical training in 4th-year students and after their practical training in 5th-year students. This new program, the Advanced Medication Counseling Practice, was found to be useful to reduce anxiety about communication with patients among 4th-year students (about 90%). Even after their practical training in 5th-year, they still appreciated usefulness of this program (about 80%). This program is still valued 4 years after its development. We developed the Advanced Medication Counseling Practice in preclinical training for junior students by senior students.