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Papers - Suzuki, Sayo

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Three Kampo medicines—bofutsushosan, boiogito, and daisaikoto—have different effects on host fat accumulation and the intestinal microbiota in a high-fat-diet–induced mouse model of obesity

Nakamichi K., Yoshino T., Akiyama M., Jibiki A., Yokoyama Y., Kawazoe H., Suzuki S., Watanabe K., Kim Y.G., Nakamura T.

Journal of Natural Medicines 79 ( 5 ) 1044 - 1056 2025.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 13403443

Inhibiting body fat accumulation is important for the prevention of obesity. In Japan, three Kampo medicines are commonly used to treat obesity: bofutsushosan, boiogito, and daisaikoto. To compare the influences of these Kampo medicines on the intestinal microbiota, it is necessary to conduct a simultaneous investigation using the same mouse model under the same experimental conditions. C57BL/6J mice were divided into five groups: normal chow (NC), high-fat diet (HFD), HFD + 3% bofutsushosan extract (BTS), HFD + 3% boiogito extract (BOT), and HFD + 3% daisaikoto extract (DST). Epididymal white adipose tissue (WAT) weight, mesenteric WAT weight, serum triglyceride levels, and serum total cholesterol levels were measured. Additionally, total bacteria, alpha diversity, beta diversity, and bacterial composition in stool samples were measured. Body weight and epididymal WAT weight gain were significantly inhibited in the BTS-treated group and DST-treated group, but not in the BOT-treated group, compared with the HFD control group. Additionally, serum total cholesterol levels were significantly lower in the DST-treated group than in the HFD group. Specific intestinal bacteria, Clostridium sensu stricto 1, Erysipelatoclostridium, Roseburia, and the Lachnospiraceae NK4A136 group, were significantly changed in the Kampo-treated groups compared with the HFD group, and each of them was correlated with body weight gain, body fat rate, epididymal WAT weight, or mesenteric WAT weight. Our simultaneous investigation of BTS, BOT, and DST under the same conditions clearly demonstrated different changes in the intestinal microbiota and different effects on fat accumulation as well as their association among the three Kampo medicines.

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Identification of risk factors and development of a predictive model in patients using cefmetazole for international normalized ratio elevation

Namiki T., Yokoyama Y., Kimura M., Fukuda S., Seyama S., Iketani O., Samura M., Ishikawa H., Jibiki A., Kawazoe H., Ohtani H., Hasegawa N., Matsumoto K., Hashi H., Suzuki S., Nakamura T.

Plos One 20 ( 7 July ) e0322909 2025.07

Research paper (scientific journal), Joint Work, Accepted

Patient risk factors related to coagulopathy and bleeding when using cefmetazole (CMZ) have not yet been identified, and no models exist to predict side effects during CMZ treatment. Moreover, reports that examine which patients should be careful when using CMZ to ensure safety are lacking. Our objective was to understand risk factors for elevated international normalized ratio (INR) in patients using CMZ and to develop a predictive model for INR elevation using a risk score to enable safe administration of CMZ. This multicenter, retrospective, and observational study was conducted in Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital using data from patients being treated with CMZ. Patients were classified into INR-elevated or non-INR-elevated groups. Univariate and multivariate analyses were performed to calculate the adjusted odds ratios (aOR) and 95% confidence intervals (CI). The actual probability of an elevated INR and probability of an elevated INR predicted by the regression β coefficients were calculated and classified into four categories according to the risk score. Binomial logistic regression analysis revealed that liver disorder (aOR, 5.65; 95% CI, 1.69–18.91; risk scores, 2), nutritional risk (aOR, 6.32; 95% CI, 3.14–12.74; risk scores, 2), no-diabetes mellitus (aOR, 4.53; 95% CI, 1.34–15.26; risk scores, 2), and warfarin use (aOR, 98.44; 95% CI, 7.05–1375.50; risk scores, 5) were significantly associated with INR elevation. The predicted incidence probabilities of INR elevation were<5% (low risk), 5–<30% (medium risk), 30–<90% (high risk), and ≥ 90% (very high risk). The model validity showed a good fit (AUC, 0.79; 95% CI, 0.73–0.85, P<0.001). We identified risk factors that contribute to INR elevation and constructed a model to predict INR elevation using the risk score. Using this predictive model enables the appropriate use of CMZ in a safe manner.

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Analysis of the Stability of 0.04% Mitomycin C Ophthalmic Solution under Various Storage Conditions

Nonomiya Yuma, Yamaguchi Koki, Yokoyama Yuta, Nakajima Isana, Hara Ryusei, Shoji Daigo, Takiguchi Tomomi, Takehana Kazumi, Jibiki Aya, Suzuki Sayo, Nakamura Tomonori, Tsuji Hideki, Yamaguchi Masakazu

The Keio Journal of Medicine (The Keio Journal of Medicine) 74 ( 4 ) 214 - 220 2025.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 00229717

A 0.04% mitomycin C (MMC) ophthalmic solution is not commercially available and is prepared in hospitals as required. The physical properties and stability of the MMC ophthalmic solution have not been clarified because of a lack of data. This study aimed to assess the stability of the MMC ophthalmic solution under various storage conditions. The MMC ophthalmic solution was prepared by dissolving 2 mg of MMC in 5 mL of saline solution. Each batch of ophthalmic solution was stored under three conditions [cold/shaded light, room temperature/shaded light, and room temperature/scattered light (approximately 4000 lx)], and MMC concentration was determined using high-performance liquid chromatography on days 0, 1, 3, 5, 7, 14, and 21. The expiry date was calculated based on the results of the degradation analysis. pH measurements and bacterial culture tests were conducted for each storage condition. The MMC concentrations on day 21 under cold/shaded light, room temperature/shaded light, and room temperature/scattered light were 340, 287, and 227 µg/mL, respectively. MMC concentrations decreased over time, and the decrease was highest when the samples were stored at room temperature and exposed to light, and lowest under cold conditions and protected from light. The pH of MMC solutions was 5.8 after preparation, which increased to 6.9 with time under all storage conditions. Culture tests did not detect any bacteria under any storage conditions. The MMC ophthalmic solution was most stable under cold/shaded conditions, and our study clarifies its expiry date for clinical use.

Efficacy of De-Escalation to Cefmetazole in Patients with Bacteremic Urinary Tract Infections Caused by Extended-Spectrum β-Lactamase-Producing Escherichia coli

Namiki Takaya, Yokoyama Yuta, Kimura Motonori, Fukuda Shogo, Seyama Shoji, Iketani Osamu, Uwamino Yoshifumi, Jibiki Aya, Kawazoe Hitoshi, Ohtani Hisakazu, Hasegawa Naoki, Matsumoto Kazuaki, Oda Rentaro, Hashi Hideki, Suzuki Sayo, Nakamura Tomonori

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 48 ( 5 ) 537 - 544 2025.05

Research paper (scientific journal), Accepted, ISSN 09186158

This study aimed to clarify the optimal value for the unbound cefmetazole concentration to remain above the minimum inhibitory concentration (MIC) (fT ≥ MIC) for efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing Escherichia coli. This double-center retrospective observational study was conducted at Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital from January 2012 to October 2022. Efficacy was determined via clinical evaluation (mortality rate, recurrence rate, vital changes) and bacteriological evaluation, and the optimal fT ≥ MIC was calculated via receiver operating characteristic curve analysis. As a result, the number of patients evaluated were 40 (35 and 5 in the treatment success and treatment failure groups, respectively). Univariate analysis showed that fT ≥ MIC, recurrence rate, and MIC for cefmetazole against bacteria were significantly different for the two groups (p < 0.05). Receiver operating characteristic curve analysis showed that the optimal fT ≥ MIC indicating efficacy was 57% (area under the curve: 0.94, 95% confidence interval: 0.86–1.00, p = 0.002). All patients with fT ≥ MIC ≥ 57% had successful treatment, whereas the frequency of treatment failure was high among those with fT ≥ MIC <57%. The optimal fT ≥ MIC for the clinical efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing E. coli was fT ≥ MIC ≥ 57%. This finding would be useful for optimal dosing of cefmetazole.

A simulated interprofessional team conference using cross-training in interprofessional education: A qualitative content analysis.

Etsuko Tomizaki, Junji Haruta, Takashi Horiguchi, Tomoko Arahata, Rika Fukui, Shunsuke Uno, Takayuki Ando, Tetsuhiro Yoshino, Satoko Ishikawa, Sayo Suzuki, Katsunori Yamaura, Toshiaki Monkawa.

Advances in Medical Education and Practice. 16 583 - 594 2025.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1179-7258

Purpose: In 2021, we introduced a new simulation-based learning program focusing on a roleplay conference before patient discharge. This study aimed to evaluate the program’s effectiveness and highlight the significance of cross-training in interprofessional education (IPE). Methods: In September 2023, the program included 346 students (98 medical, 110 nursing, and 138 pharmacy students). The students’ reflective writing was analyzed using inductive content analysis to describe their learning and perspectives. The original items, subcategories, and main categories were extracted. The simulation involved the students role-playing various healthcare professionals during a discharge-planning conference for a stroke patient. This allowed them to experience the challenges and dynamics of interprofessional collaboration. Results: Student feedback emphasized the importance of understanding what constitutes a good healthcare team. A total of 203 items were grouped into eight main categories and 17 subcategories, including patient-centered care (related to the importance of patient-centered care, supporting patient decision-making, communicating with patients during conferences, and facilitating decision-making processes), contrasts in patient and interprofessional communication, conference communication (challenge of building consensus, the way to proceed conferences, importance of conference preparation, and process of information aggregation and realization of outcomes), mutual recognition and role contribution, building relationships (importance of daily interprofessional communication), understanding one’s profession (reflection on one’s own profession, understanding the roles of different professions, and communication within one’s own professional context), recursion into learning (motivation for continuous learning and improvement), and understanding other professions (understanding the role and perspectives of other professions and recognizing professional differences). Specific feedback highlighted improved empathy and communication skills. Students recognized the value of each profession’s contribution to patient care. Moreover, students reported a deeper appreciation of patient-centered approaches and the complexities of coordinating care across different healthcare roles. Conclusion: Simulated interprofessional team conferences using cross-training effectively taught junior students to understand the essence of a good healthcare team and the importance of a patient-centered approach. Cross-training significantly enhanced students’ interprofessional competencies, communication skills, and empathy toward other professions. This case underscores the necessity of incorporating cross-training into IPE to prepare healthcare professionals for collaborative practice and improve patient outcomes. Future research should consider expanding the scope to include more diverse scenarios and longitudinal assessments to measure longterm impacts on professional practice.

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Evaluation of Medication Adherence Among Prevalent Users in Hypertension, Dyslipidemia, and Diabetes Using Health Insurance Claims: A Population-Based Cohort Study in Japan.

Matsumoto M., Harada S., Ikuta H., Iida M., Kato S., Sata M., Shibuki T., Ishibashi Y., Miyagawa N., Hisamatsu M., Hirata A., Kuwabara K., Takeuchi A., Sugiyama D., Suzuki S., Nakamura T., Okamura T., Takebayashi T.

Pharmacoepidemiology and Drug Safety 33 ( 8 ) e5855 2024.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 10538569

Purpose: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined. Methods: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression. Results: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications. Conclusion: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support.

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Considering Medical Professionalism from the Standpoint of Pharmacy Education

Suzuki Sayo

YAKUGAKU ZASSHI (The Pharmaceutical Society of Japan) 144 ( 6 ) 615 - 624 2024.06

Research paper (scientific journal), Single Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0031-6903

Worldwide interest in teaching medical professionalism has increased drastically over the past two decades and is recognized as an important core competency. It is also essential in pharmacy education. However, there is no single definition of medical professionalism owing to its multifaceted nature, leading to difficulty in understanding it. The foundational concept of professionalism are the social contract and accountability, which describe the relationship between the profession and the society which it serves. Profession must understand expectations from the society, which is trustworthy, assures competence, and devoted to the public good for the contract based on their mutual trust. In “teaching,” three basic educational actions (“setting expectations,” “providing experiences,” and “evaluating outcomes”) are required. There are two learning goals of professionalism education: the minimum goal of not doing unprofessional acts and the aspirational goal of pursuing a higher level of interiorized professionalism which leads to the professional identity formation. The true professionals are “reflective practitioners,” who have the ability to manage ambiguous problems using their interiorized professionalism in complicated situations. Therefore, reflection is one of the central concepts of professionalism education. The Professionalism Mini-Evaluation Exercise (P-MEX), an observational tool to evaluate medical professionalism, has some favorable aspects; the Japanese version is available and is a guide to specific actions for professionalism through its items, although some cautions must be exercised when using it. Considering that teaching professionalism includes not only formal but informal and hidden curricula, all of the staff in the educational environments should consider professionalism education by understanding professionalism.

Pharmacokinetics/pharmacodynamics analysis and establishment of optimal dosing regimens using unbound cefmetazole concentration for patients infected with Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E).

Takaya Namiki, Yuta Yokoyama, Hideki Hashi, Rentaro Oda, Aya Jibiki, Hitoshi Kawazoe, Kazuaki Matsumoto, Sayo Suzuki, Tomonori Nakamura.

Pharmacotherapy. (Pharmacotherapy) 44 ( 2 ) 149 - 162 2024.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 0277-0008

Study Objective: Establish methods for measuring cefmetazole (CMZ) concentrations conduct a pharmacokinetic/pharmacodynamic (PK/PD) analysis using unbound CMZ concentrations for extended-spectrum β-lactamase producing enterobacterales (ESBL-E) and investigate optimal dosing regimens for not undergoing hemodialysis (non-HD) and undergoing hemodialysis (HD) patients. Design: Prospective observational study. Patients: Included patients treated with CMZ who provided written informed consent and were admitted to the Tokyo Bay Urayasu Ichikawa Medical Center between August 2021 and July 2022. Measurements: Total and Unbound CMZ concentration was measured by high-performance liquid chromatography (HPLC) with solid-phase extraction and ultrafiltration. Setting: Determining the CMZ dosing regimen involved modified creatinine clearance (CLCR) with measured body weight (BW) using the Cockcroft–Gault equation. For non-HD patients, blood samples were collected during at least three points. For patients undergoing HD, 1 g was administered via intravenous infusion, or rapid intravenous injection after HD, or 30 min before the end of HD. Blood samples were collected before HD (pre-HD), and 1 and 3 h after starting HD and post-HD. All blood samples were collected at steady-state. Patient information was collected from electronic medical records. An unbound PK model was constructed for the non-HD patients. A nomogram was constructed using Monte Carlo simulations with a 90% probability of target attainment at 70% free time above the minimum inhibitory concentration (MIC). For the HD patients, a nomogram was used to determine the optimal dosing regimen for each HD schedule. Main Results: CMZ measurement methods were established. A model analysis of unbound PK in 37 non-HD patients incorporated creatinine clearance (CLCR) using the Cockcroft–Gault equation, albumin (ALB) for clearance and body weight (BW) for the volume of distribution. In Monte Carlo simulations, nomograms corresponding to the MIC (known and unknown) were generated for each covariate. Using the nomogram, non-HD patients with an ESBL-E MIC of 8 mg/L, a BW of 60 kg, an ALB of 25 g/L, and a CLCR of 60 mL/min required administration of 2 g every 6 h (1- and 3-h infusions). Unbound PK model parameters were calculated for 7 HD patients, and the optimal dosing regimens following PK/PD were determined for each HD schedule. In HD patients, the regimen after and during HD was established using a treatment that was effective up to an ESBL-E MIC of 4 mg/L. Conclusions: The nomogram for CMZ regimens established by PK/PD analysis of measured CMZ concentrations enables optimal CMZ dosing for ESBL-E-infected patients.

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Drug repositioning study on the antiemetic efficacy of anamorelin for cisplatin-induced nausea and vomiting in rats.

Nishino Haruto, Kawazoe Hitoshi, Sekiguchi Mayu, Jibiki Aya, Yokoyama Yuta, Suzuki Sayo, Nakamura Tomonori.

BPB Reports (The Pharmaceutical Society of Japan) 7 ( 1 ) 1 - 6 2024.01

Research paper (scientific journal), Joint Work, Accepted

Objective: Platinum- and anthracycline-based chemotherapy regimens cause nausea and vomiting in clinical practice, resulting in the deterioration of patients’ QoL, discontinuation of chemotherapy, and reduced therapeutic outcomes. Using pica behavior as an indicator, we aimed to clarify whether anamorelin, an orally active ghrelin receptor agonist, exerts antiemetic effects against cisplatin-induced nausea and vomiting in rats. Materials and Methods: Sprague–Dawley rats were treated with cisplatin (5 mg/kg, i.p.), three-drug or four-drug antiemetics (granisetron [0.3 mg/kg, p.o.], dexamethasone [1.5 mg/kg, p.o.], fosaprepitant [12.5 mg/kg, i.p.], with or without anamorelin [30 mg/kg, p.o.]). Data on kaolin intake, normal food intake, and spontaneous motor activity (SMA) were recorded 1 d before and 5 d after cisplatin administration. Body weight (BW) was measured daily, and the percentage change in BW from baseline was calculated. Results: At the primary endpoint, kaolin intake was significantly higher in the cisplatin-only group than in the pretreatment and vehicle groups (p < 0.05). Additionally, kaolin food intake was not significantly low in cisplatin-treated mice treated with three-drug antiemetics with or without anamorelin. At the secondary endpoints, normal food intake, SMA, and percentage change in BW were significantly lower in the cisplatin-only group than in the vehicle group. Conclusion: Our findings suggest that the prophylactic administration of standard three-drug antiemetics, besides anamorelin, may not improve cisplatin-induced nausea and vomiting. Further studies using methods suitable for evaluating anamorelin levels are required.

Patient prognosis and prediction model for taking Kampo formulas in dysmenorrhea: An observational study.

Maeda-Minami, Ayako, Kawamoto Ayako, Yoshino Tetsuhiro, Yokoyama Yuta, Suzuki Sayo , Horiba Yuko, Nakamura Tomonor, Mimura Masaru, Watanabe Kenji.

Medicine (Medicine (United States)) 102 ( 48 ) e36191 2023.12

Research paper (scientific journal), Accepted, ISSN 0025-7974

Two representative Kampo formulas, keishibukuryogan and tokishakuyakusan, are frequently prescribed for patients with dysmenorrhea. We previously constructed a model that could predict which of these 2 formulas was most suitable, which is based on 4 subjective symptoms and 3 objective signs. To evaluate the prognosis of patients with dysmenorrhea using the established prediction model and assess the treatment outcomes between those treated in accordance with the prediction model and those who received various other treatments. In this retrospective, observational study, we included patients with menstrual pain who visited the Kampo Clinic at the Keio University Hospital for the first time between October 2014 and December 2020. These patients were monitored over a 90-day follow-up period. Participants were categorized into 2 groups: model-accordance and various-options. The progression of visual analogue scale (VAS) values was evaluated by determining the slopes from regression analysis between these 2 groups, with changes corroborated by the medical records. The study comprised 57 patients: 37 in the model-accordance group and 20 in the various-options group. Notably, the various-options group reported a significantly higher number of subjective symptoms (P = .03). The VAS value showed a decline, as indicated by the negative slope value of the regression line, across both groups - irrespective of their classification. There were no significant differences in the occurrence of adverse events between the 2 groups. The prognosis of patients with dysmenorrhea and the incidence of adverse events remained consistent, regardless of whether the treatment approach was in accordance with the prediction model or varied. Further studies are warranted to assess the prognosis when Kampo formulas are chosen based on the prediction model in the various-options population.

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優れた研究能力と高い専門性を活用し患者アウトカムを改善する！

山口浩明, 鈴木小夜

The Annual Meeting of Japanese Society of Pharmaceutical Health Care and Sciences (Japanese Society of Pharmaceutical Health Care and Sciences) 33 ( 0 ) 50 - 55 2023.11

Research paper (international conference proceedings), Joint Work, Last author, Accepted

What Factors Improve the Evaluation of Achievement at the End of Pharmacy Practice Experiences?

Ishikawa H, Kawazoe H, Iwata H, Nakamura Y, Jibiki A, Yokoyama Y, Kobayashi N, Suzuki S, Yamaura K, Nakamura T.

Japanese Journal of Pharmaceutical Health Care and Sciences (Japanese Society of Pharmaceutical Health Care and Sciences) 49 ( 4 ) 173 - 182 2023.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

In the pharmacy practice experience (PPE) component of the pharmaceutical education model core curriculum, factors by which achievement can best be evaluated in rubric format have not been empirically determined. In this study, multivariate analysis was conducted based on characteristic information obtained from PPEs.Data were analyzed from a total of 146 fifth-year students of Keio University Faculty of Pharmacy who completed PPEs in 2021. Using “Learning Results Prior to PPE”, “Presence / Absence of Role Model in PPE”, “Number of Experience Areas focused on Representative Eight Diseases”, and “Number of People who were Provided Medication Instruction” as the explanatory variables, and “Number of Mentor-provided Performance Evaluations with Scores ≥3” and “Sum of Mentor-provided Performance Evaluation Scores” as the objective variables, multiple regression analysis was performed. For “Number of Mentor-provided Performance Evaluations with Scores ≥3” predictions in training at a pharmacy, training at a hospital, or both, the respective probability values were <0.001, 0.189, and 0.012. For “Sum of Mentor-provided Performance Evaluation Scores”, the respective probability values were 0.005, 0.046, and 0.048. The effect of “Number of Experience Areas focused on Representative Eight Diseases” on each objective variable was consistently large.Multivariate analysis using PPE-relevant collected information identified factors that improve the evaluation of achievement at the end of a PPE.

Ingenol mebutate inhibits the growth of pancreatic cancer cells in vitro via STING with an efficacy comparable to that of clinically used anticancer agents.

Kikuyama F, Suzuki S, Jibiki A, Yokoyama Y, Kawazoe H, Kitanaka S, Nakamura T

Journal of natural medicines (Journal of Natural Medicines) 77 ( 2 ) 343 - 351 2023.01

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 1340-3443

Pancreatic cancer is associated with a poor prognosis; thus, there is an urgent need to develop new and effective treatments. Ingenol mebutate (IM), which is isolated from the latex of Euphorbia peplus, was recently shown to be effective against pancreatic cancer cell lines; however, its mechanism of action has not been fully elucidated. In this study, we focused on the less drug-sensitive pancreatic cancer cell line Panc-1 and compared IM to commercially available anticancer drugs using cell survival assays. In addition, we aimed to identify novel biomolecules that may be involved in the mechanism of action of IM using RNA sequencing, western blotting, and inhibition assays. The IC50 values after 72 h of exposure to IM and SN-38, drugs to which the Panc-1 cells are most sensitive among the tested anticancer agents, were 43.1 ± 16.8 nM and 165 ± 37 nM, respectively. IM showed a cytostatic effect equal to or greater than that of the clinically used pancreatic cancer therapeutic drugs. RNA sequencing and protein expression analysis revealed that expression of stimulator of interferon genes (STING) increased at low IM concentration, whereas cell viability decreased. Co-exposure of IM and STING inhibitor, H-151, to Panc-1 or MIA PaCa-2 cell lines canceled the growth-inhibitory effects of IM alone. In conclusion, IM may have an efficacy comparable to that of existing pancreatic cancer therapeutic agents on the less drug-sensitive Panc-1 cell line and the immune-related molecule STING plays a role in the mechanism of action of IM.

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Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study.

Ishikawa E, Yokoyama Y, Chishima H, Kasai H, Kuniyoshi O, Kimura M, Hakamata J, Nakada H, Suehiro N, Nakaya N, Nakajima H, Ikemura S, Kawada I, Yasuda H, Terai H, Jibiki A, Kawazoe H, Soejima K, Muramatsu H, Suzuki S, Nakamura T

Investigational new drugs (Investigational New Drugs) 41 ( 1 ) 122 - 133 2023.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0167-6997

Background: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. Methods: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration–time curve from 0 to 24 h (AUC0–24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. Results: There was a significant association between the AUC0–24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0–24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). Conclusion: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

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基質特異性拡張型β-ラクタマーゼ産生腸内細菌目細菌感染患者に対する遊離形セフメタゾール濃度を用いたPPK/PD解析と最適投与法の構築

並木孝哉, 横山雄太, 枦秀樹, 織田錬太郎, 地引綾, 河添仁, 松元一明, 鈴木小夜, 中村智徳

Annual Scientific Meeting of The Japanese Society of Clinical Pharmacology and Therapeutics (The Japanese Society of Clinical Pharmacology and Therapeutics) 44 ( 0 ) 2-C-O12-5 2023

【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。

Design, Synthesis, and Monoamine Oxidase B Selective Inhibitory Activity of N-Arylated Heliamine Analogues.

Yamada Makito, Hirose Yu, Lin Bangzhong, Fujimoto Megumi, Nunomura Kazuto, Sirimangkalakitti Natchanun, Takahashi Naoyuki, Ohki, Yuuta, Sako Makoto, Murai Kenichi, Harada Kazuo, Arai Masayoshi, Suzuki Sayo, Nakamura Tomonori, Haruta Junichi, Arisawa Mitsuhiro.

ACS Medicinal Chemistry Letters 13 ( 10 ) 1582 - 1590 2022.08

Research paper (scientific journal), Joint Work, Accepted

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Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high-performance liquid chromatography–Photodiode array detection

Yokoyama Y, Nozawa E, Morita M., Ishikawa E, Mori T, Sakurai M, Kikuchi T, Matsuki E, Yamazaki R, Kataoka K, Jibiki A., Kawazoe H, Suzuki S, Nakamura T.

Journal of Clinical Laboratory Analysis 36 ( 8 ) e24598 2022.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 08878013

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.

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Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum.

Ishikawa E, Yokoyama Y, Chishima H, Kuniyoshi O, Sato I, Nakaya N, Nakajima H, Kimura M, Hakamata J, Suehiro N, Nakada H, Ikemura S, Jibiki A, Kawazoe H, Muramatsu H, Suzuki S, Nakamura T

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 1199 123245 2022.05

Research paper (scientific journal), Accepted, ISSN 1570-0232

Reports on the therapeutic drug monitoring (TDM) of second- and third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer patients are limited and are required to improve the safety of EGFR-TKI therapy. Some EGFR-TKIs have active metabolites with similar or higher potency compared with the parent compounds; thus, monitoring the parent compound as well as its active metabolites is essential for truly effective TDM. In this study, we developed and validated a method that simultaneously quantifies second- and third-generation EGFR-TKIs (afatinib, dacomitinib, and osimertinib) and the active metabolites of osimertinib, AZ5104 and AZ7550, in the human serum using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The clinical application of the method was also evaluated. The analytes were extracted from a 100 μL serum sample using a simple protein precipitation method and analyzed using LC-MS/MS. Excellent linearity of calibration curves was observed at ranges of 2.5–125.0 ng/mL for afatinib, 2.5–125.0 ng/mL for dacomitinib, 4.0–800.0 ng/mL for osimertinib, 1.0–125.0 ng/mL for AZ5104, and 2.5–125.0 ng/mL for AZ7550. The precision and accuracy were below 14.9% and within ± 14.9% of the nominal concentrations, respectively. The mean recovery was higher than 94.7% and the coefficient of variation (CV) was lower than 8.3%. The mean internal-standard normalized matrix factors ranged from 94.6 to 111.9%, and the CVs were lower than 9.7%. This analytical method met the acceptance criteria of the U.S. Food and Drug Administration guidelines. The method was also successfully applied to the analysis of 45 clinical samples; it supports the efficient and valuable analysis for TDM investigations of EGFR-TKIs.

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Prognostic Value of Baseline Medications Plus Neutrophil-to-Lymphocyte Ratio in the Effectiveness of Nivolumab and Pembrolizumab in Patients With Advanced Non-Small-Cell Lung Cancer: A Retrospective Study.

Ogiwara T, Kawazoe H, Egami S, Hashimoto H, Saito Y, Sakiyama N, Ohe Y, Yamaguchi M, Furukawa T, Hara A, Hiraga Y, Jibiki A, Yokoyama Y, Suzuki S, Nakamura T

Frontiers in oncology (Frontiers in Oncology) 11 770268 2021.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 2234-943X

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.

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Can Rubric-based Performance Evaluation Measure Students’ Performance Levels in Pharmacy Practice Experiences?: Based on the Revised Model Core Curriculum for Pharmaceutical Education.

Kawazoe Hitoshi, Suzuki Sayo, Hiraga Yui, Yokoyama Yuta, Jibiki Aya, Iwata Hiroki, Kobayashi Noriko, Fujimoto Kazuko, Nakada Hideo, Aomori Tohru, Yamaura Katsunori, Nakamura Tomonori

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 47 ( 9 ) 513 - 524 2021.09

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 1346-342X

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.

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