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Papers - KONDO Shingo

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Sex Differences in Electrolyte Disturbances Among Diuretic Users According to Renal Function and Age.

Maida N, Kondo S, Hayashi N, Iwata H, Kobayashi N, Yamaura K

Drug safety 2025.06

ISSN 0114-5916

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Prescription Trends and Contributing Factors of Medications Causing Xerostomia in Elderly Patients

Kondo Shingo, Sano Kunihiro, Hayashi Naoko, Fujishima Seitaro, Iwata Hiroki, Kobayashi Noriko, Yamaura Katsunori

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 51 ( 6 ) 355 - 365 2025.06

ISSN 1346342X

Xerostomia is a syndrome characterized by subjective or objective findings of oral dryness. One quarter of the elderly population suffers from xerostomia owing to a decline in salivary secretion function with age and problems with oral closure. Additionally, many ethical drugs have xerostomia listed as an adverse drug reaction. Xerostomia reduces the self-cleansing action of the mouth and can cause problems in maintaining oral health. In this study, we created a list of drugs associated with xerostomia from these package inserts. Then, electronic medical record data from Keio University Hospital were analyzed to investigate prescribing trends among elderly patients and to identify patient characteristics associated with these drugs. Patients who received continuous prescriptions from April 2019 to March 2020 were included in this study based on age, prescribed drugs, and associated diseases. Among the 575 patients analyzed, 464 (80.7％) were prescribed at least one xerostomia-inducing medication. Compared with the early-stage elderly, a significantly higher proportion of late-stage elderly patients received these medications (P < 0.001) and had multiple prescriptions (P < 0.001). Logistic regression analysis examined the presence and multiple prescriptions of xerostomia-inducing drugs, showing significant associations with late-stage elderly patients and polypharmacy. The most common conditions among patients prescribed xerostomia-inducing drugs were endocrine, nutritional, metabolic, cardiovascular, and gastrointestinal diseases. Accordingly, vasodilators, peptic ulcer drugs, and hyperlipidemic drugs were frequently prescribed to these patients. The results suggest that the risk of xerostomia should be a point of consideration when prescribing multiple medicines to elderly patients.

Practical training reduces aspiration-linked gaps in pressure ulcer education for pharmacy students

Kondo Shingo, Mima Ririka, Okui Rira, Iwata Hiroki, Kawamoto Yoshiko, Kobayashi Noriko, Furuta Katsunori, Yamaura Katsunori

Drug Discoveries & Therapeutics (International Research and Cooperation Association for Bio & Socio-Sciences Advancement) advpub ( 0 ) 90 - 95 2025.04

ISSN 1881-7831

Expectations for pharmacists' contribution and involvement in pressure ulcer pharmacotherapy are growing. This study aimed to not only clarify the effects of incorporating practical training on the use of topical medications into clinical preparatory education but also examine the relationship between students' aspiration—or lack thereof—to pursue a career as a pharmacist. The percentage of positive responses to the questionnaire survey on knowledge, skills, and attitudes toward pressure ulcer treatment was significantly higher after the lecture than before and highest after the practical training. In addition, students who aspired to become pharmacists tended to provide a higher percentage of positive responses after the lecture. However, the gap between aspiring and non-aspiring pharmacists tended to narrow after practical training. These results suggest that incorporating practical training on pressure ulcer treatment into lectures improves students' knowledge, skills, and attitudes toward its treatment. Including practical training in pressure ulcer education may compensate for the difference in the educational effect of lectures between students who aspire to become pharmacists and those who do not, thereby improving the educational effect for the latter.

Identification of Issues Related to Enteral Nutrients Using a Database of Near-miss Events from Community Pharmacies.

Kondo S., Maese M., Iwata H., Kobayashi N., Yamaura K.

The Keio journal of medicine (The Keio Journal of Medicine) advpub ( 0 ) 2025.03

Accepted, ISSN 0022-9717

Undernutrition is a common risk after surgery or during periods when oral dietary intake is challenging. Enteral nutrients, frequently utilized in nutritional management, are drugs associated with multiple contraindications involving pathology and allergy, and they require careful attention in dispensing. However, the occurrence of nutrition-related incidents in community pharmacies remains unknown. This study aimed to identify issues regarding the safety of pharmacotherapy in patients requiring enteral nutrition using the database of Project to Collect and Analyze Pharmaceutical Near-Miss Event Information. We highlighted the critical information that pharmacists should focus on to prevent accidents and elucidated the details and prescription drugs of cases that matched the search for “Nutrition (all included)” in Japanese. There were 475 cases reported between January 2009 and September 2023. Of these, 347 cases (73%) were classified as “inquiry about prescription and provision of information to prescribing physician” (Category II) and 115 cases (24%) were classified as “drug dispensing” (Category I). In both cases, the top five drugs were enteral nutrients. Among the life-threatening Category II cases, 9 cases were for pathological contraindications including severe liver or renal dysfunction, 6 cases were for adverse reactions including diarrhea, and 5 cases were for allergies or patient constitutions. Notably, the incidence of adverse reactions was higher than in data for the latest annual reports. Therefore, pharmacists should be mindful while dealing with prescriptions involving possible contraindications in patients requiring enteral nutrition. Pharmacists should contribute to the provision of safe pharmacotherapy by remaining vigilant against dispensing errors.

腎機能の低下者に対して注意が必要なOTC医薬品の解析

近藤慎吾, 前瀬鞠, 古堅彩子, 岩田紘樹, 小林典子, 山浦克典

薬局薬学 (Pharmacy Society of Japan) advpub ( 0 ) 126 - 135 2024.12

Lead author, Accepted, ISSN 18843077

Obtaining laboratory data on renal function in community pharmacies is challenging, as pharmacists rarely perform pharmaceutical interventions based on the patient’s renal function during over-the-counter (OTC) medication sales. This study aimed to identify OTC medications requiring caution in patients with impaired renal function using the Pharmaceuticals and Medical Devices Agency (PMDA) database. Moreover, we compared renal function-related cautionary notes in the package inserts of prescription drugs having the same composition. The analysis focused on the package inserts of OTC medications sold exclusively by pharmacists. Among these, 64% (9/14 cases) of pharmaceuticals requiring guidance (yo-shidou medication) and 80% (107/134 cases) of Category 1 OTC medications had renal function-related warnings in the “precautions for use (what you should not do/who should seek consultation)” section. For OTC medications containing famotidine and nizatidine, the dosage and administration were set lower than those for prescription drugs. Although these drugs can be used for patients with impaired renal function on prescription, their use is restricted as OTC medications. We believe that enabling self-checks of renal function at community pharmacies could expand the range of indications for OTC medications and promote notified self-medication.

Fujimoto T., Iwata H., Kobayashi N., Kondo S., Yamaura K.

BMC research notes 17 ( 1 ) 203 2024.07

Purpose: The prevalence of migraine headache is higher in women. Low barometric pressure is a factor in headache triggering, but sex-related differences have not been identified. The purpose of this study was to examine sex-related differences in headache triggered by low barometric pressure. Methods: Study subjects aged 20–49 years were randomly selected from a research company’s (Macromill, Inc.) web panel. Those with chronic migraine or tension-type headache invited to complete a web-based self-administered questionnaire. Logistic regression analysis was performed with the objective variable as the Headache Impact Test-6 (HIT-6) high scores (56 or more) or headache triggered by low barometric pressure. Results: Participants were 332 women and 337 men in the headache population. HIT-6 high scores were associated with age at headache occurrence 20 years or younger (OR: odds ratio 1.85, 95% CI: confidence interval 1.15–2.99, p = 0.012) and headache triggered by low barometric pressure (OR 2.11, 95%CI 1.51–2.94, p < 0.001). Headache triggered by low barometric pressure was significantly associated with women (OR 2.92, 95%CI 2.12–4.02, p < 0.001). Conclusions: Headache triggered by low barometric pressure were related to sex-related differences. It was suggested that a sex-specific treatment approach for headache triggering is needed.

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学習成果基盤型の薬学教育モデル・コア・カリキュラムに基づく実務実習の先行導入から実装後の取り組み評価

河添仁, 岩田紘樹, 石川春樹, 近藤慎吾, 地引綾, 横山雄太, 小林典子, 鈴木小夜, 山浦克典, 中村智徳

医療薬学 (Japanese Society of Pharmaceutical Health Care and Sciences) 50 ( 9 ) 455 - 464 2024.06

Research paper (scientific journal), Accepted, ISSN 1346342X

Pharmacy practice experiences (PPEs) based on a revised model core curriculum for pharmaceutical education that incorporates outcome-based education have been implemented in Japan. PPEs is a 22-week period in both a community pharmacy and hospital and is characterized by “participatory and experiential learning,” “performance evaluation,” and “continuous involvement in eight representative diseases.” This mini-review describes the evaluation from preintroduction to implementation of PPEs. During the performance evaluation, using a rubric—consisting of a four-point score—for assessing pharmaceutical students’ performance instead of a rating scale of specific behavioral objectives was feasible. Pharmacist mentors and pharmaceutical students could measure the latter’s performance level and growth in PPEs at a community pharmacy or hospital using a rubric assessment. During the continuous involvement of eight representative diseases, sharing information tools between community pharmacies and hospitals substantially increased the implementation rate related to these eight diseases. Furthermore, experiences of eight representative diseases were considerably associated with the growth of pharmaceutical students’ performance. Results indicate that PPEs with which pharmaceutical students experience a wide range of involvement with eight representative diseases may effectively enhance their competencies.

Lack of information on gender differences in the package inserts of prescription drugs in Japan

Narumi Maida, Shingo Kondo, Masanori Ogawa, Naoko Hayashi, Hiroki Iwata, Noriko Kobayashi, Katsunori Yamaura

Drug Discov Ther. (International Research and Cooperation Association for Bio & Socio-Sciences Advancement) 17 ( 6 ) 396 - 403 2023.12

Research paper (scientific journal), Corresponding author, Accepted, ISSN 1881-7831

The package inserts of prescription drugs provide essential information for the proper administration of pharmacotherapy. The incidence of adverse reactions for several drugs is known to be higher in women than in men. However, no studies have examined whether information on gender differences is included in Japanese package inserts. Therefore, this study investigated information on gender differences in the package inserts of Japanese prescription drugs, using the drug information database JAMES provided by the Medical Information System Development Center and the Japan Pharmaceutical Information Center. Non-proprietary names of prescription drugs were yielded 1,679 in Japan. Of the 1,679 ingredients in package inserts of prescription drugs, 76 (4.5%) included information on gender differences. The number of inserts that contained information on gender differences in the "DOSAGE AND ADMINISTRATION," "ADVERSE REACTIONS," and "PHARMACOKINETICS" sections was 3, 16, and 62, respectively. Furthermore, in the "ADVERSE REACTIONS" section, 15 of the 16 inserts mentioned a higher frequency of adverse reactions in women compared with men. Importantly, most of the inserts with information on gender differences in the "PHARMACOKINETICS" section mentioned a higher area under the curve for women than for men. Most of the package inserts of prescription drugs with information on gender differences provide useful information aimed at preventing risks in women. However, there is an extreme lack of information on gender differences in the package inserts of prescription drugs in Japan, and we consider enhancing information on gender difference as an urgent issue.

Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells

Takahashi C, Kondo S, Sadaoka K, Ishizuka S, Noguchi K, Kato Y, Sugimoto Y

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 530 ( 1 ) 230 - 234 2020.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006291X

© 2020 Elsevier Inc. JQ1 disrupts the binding of bromodomain and extra-terminal (BET) family of proteins to acetylated histones, modulates the expression of various genes, and inhibits the proliferation of cancer cells. We established two JQ1-resistant sublines from human colorectal cancer HCT116 cells. These resistant cells showed an 8- to 9-fold higher resistance to JQ1, and a 2- to 4-fold higher resistance to various anti-cancer agents, such as doxorubicin, etoposide, mitoxantrone, SN-38, cisplatin, and methotrexate than the parental HCT116 cells. The JQ1-resistant cells expressed higher levels of TRAF2 and NCK-interacting protein kinase (TNIK), cyclin D1 (CCND1), cyclin E1 (CCNE1), and their corresponding mRNAs than the parental cells. TNIK is a regulator of Wnt/β-catenin signaling and is known to transactivate CCND1. Transient transfection of HCT116 cells with a TNIK expression plasmid resulted in the upregulation of cyclin D1, cyclin E1, and their corresponding mRNAs, as well as an increase in CCNE1 promoter activity. Furthermore, luciferase assay revealed that the JQ1-resistant cells showed high CCNE1 promoter activity. These results suggest that TNIK also transactivates CCNE1. Three stable TNIK transfectant clones of HEK293 cells expressed 1.5- to 2-fold higher levels of TNIK, cyclin D1, and cyclin E1 than the parental cells. The 293/TNIK-6 cells, which expressed the highest level of TNIK among the transfectants, showed a 2.3-fold higher resistance to JQ1 than the parental cells. These results suggest the possible involvement of TNIK in cellular resistance to JQ1.

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STAT1 upregulates glutaminase and modulates amino acids and glutathione metabolism

Kondo S., Kato Y., Minagawa S., Sugimoto Y.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications) 523 ( 3 ) 672 - 677 2020.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006291X

© 2020 Elsevier Inc. We previously reported the upregulation of cellular Glu and glutathione levels in human ABCB5- and murine Abcb5-transfected cells. Here, we demonstrate the upregulation of STAT1 and glutaminase (GLS) in ABCB5/Abcb5-transfected cells. Among a total of four ABCB5/Abcb5 high-expressing clones with docetaxel resistance, three of the clones expressed STAT1 and GLS highly and showed resistance to docetaxel and buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. Neither STAT1 nor GLS upregulation was observed in the remaining ABCB5 high-expressing clone, as well as in another two ABCB5 low-expressing clones; these three clones did not show BSO resistance. The ABCB5/STAT1 high-expressing clones showed higher cellular levels of Ala, Glu, and Asp and lower cellular levels of Phe, Trp, Leu, Ile, Gly, Met, Tyr, Val, and His compared to the ABCB5/STAT1 low-expressing clones. The former clones also showed a higher resistance to Glu. The STAT1-transfected clones expressed high levels of GLS and the corresponding mRNA, suggesting the transactivation of GLS by STAT1. These clones showed resistance to Glu and BSO, similar to the ABCB5/STAT1 high-expressing clones. The cellular glutathione levels of the STAT1-transfected clones were significantly higher than that of the control. The STAT1-transfected clones also showed greater resistance to the effect of BSO on the cellular glutathione depletion compared to the control. These results demonstrate that STAT1 upregulates GLS and modulates amino acids and glutathione metabolism. Although we were unable to directly prove STAT1 upregulation by ABCB5, our results suggest that ABCB5 expression, directly or indirectly, leads to the overexpression of STAT1.

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SNAIL- and SLUG-induced side population phenotype of HCT116 human colorectal cancer cells and its regulation by BET inhibitors.

Kato Y, Kondo S, Itakura T, Tokunaga M, Hatayama S, Katayama K, Sugimoto Y.

Biochem Biophys Res Commun. (Biochemical and Biophysical Research Communications) 521 ( 1 ) 152 - 157 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006291X

© 2019 Elsevier Inc. Epithelial-mesenchymal transition (EMT) is associated with cancer malignancies such as invasion, metastasis, and drug resistance. In this study, HCT116 human colorectal cancer cells were transduced with SLUG or SNAIL retroviruses, and EMT cells with mesenchymal morphology were established. The EMT cells showed a high invasive activity and resistance to several anticancer agents such as methotrexate, SN-38, and cisplatin. Furthermore, they contained about 1–10% side population (SP) cells that were not stained by Hoechst 33342. This SP phenotype was not stable; the isolated SP cells generated both SP and non-SP cells, suggesting a potential for differentiation. Gene expression analysis of SP cells suggested the alteration of genes that are involved in epigenetic changes. Therefore, we examined the effect of 74 epigenetic inhibitors, and found that two inhibitors, namely I-BET151 and bromosporine, targeting the bromodomain and extra-terminal motif (BET) proteins, decreased the ratio of SP cells to <50% compared with the control, without affecting the immediate efflux of Hoechst 33342 by transporters. In addition, compared with the parental cells, the EMT cells showed a higher sensitivity to I-BET151 and bromosporine. This study suggests that EMT development and SP phenotype can be independent events but both are regulated by BET inhibitors in SLUG- or SNAIL-transducted HCT116 cells.

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Upregulation of cellular glutathione levels in human ABCB5- and murine Abcb5-transfected cells.

Kondo S., Hongama K., Hanaya K., Yoshida R., Kawanobe T., Katayama K., Noguchi K., Sugimoto Y.

BMC Pharmacol Toxicol. (BIOMED CENTRAL LTD) 16 2015.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2050-6511

Background: Previously, we have demonstrated that human ABCB5 is a full-sized ATP-binding cassette transporter that shares strong homology with ABCB1/P-glycoprotein. ABCB5-transfected cells showed resistance to taxanes and anthracyclines. Herein, we further screened ABCB5 substrates, and explored the mechanism of resistance.
Methods: Sensitivity of the cells to test compounds was evaluated using cell growth inhibition assay. Cellular levels of buthionine sulfoximine (BSO), glutathione and amino acids were measured using HPLC and an enzyme-based assay. Cellular and vesicular transport of glutathione was evaluated by a radiolabeled substrate. Expression levels of glutathione-metabolizing enzymes were assessed by RT-PCR.
Results: Human ABCB5-transfected 293/B5-11 cells and murine Abcb5-transfected 293/mb5-8 cells showed 6.5- and 14-fold higher resistance to BSO than the mock-transfected 293/mock cells, respectively. BSO is an inhibitor of gamma-glutamylcysteine ligase (GCL), which is a key enzyme of glutathione synthesis. 293/B5-11 and 293/mb5-8 cells also showed resistance to methionine sulfoximine, another GCL inhibitor. A cellular uptake experiment revealed that BSO accumulation in 293/B5-11 and 293/mb5-8 cells was similar to that in 293/mock cells, suggesting that BSO is not an ABCB5 substrate. The cellular glutathione content in 293/B5-11 and 293/mb5-8 cells was significantly higher than that in 293/mock cells. Evaluation of the BSO effect on the cellular glutathione content showed that compared with 293/mock cells the BSO concentration required for a 50 % reduction in glutathione content in 293/B5-11 and 293/mb5-8 cells was approximately 2- to 3-fold higher. This result suggests that the BSO resistance of the ABCB5- and Abcb5-transfected cells can be attributed to the reduced effect of BSO on the transfectants. Cellular and vesicular transport assays showed that the transport of radiolabeled glutathione in 293/B5-11 cells was similar to that in 293/mock cells. The mRNA expression of genes encoding glutathione-metabolizing enzymes in 293/B5-11 cells was similar to that in 293/mock cells. The cellular content of Glu, a precursor of glutathione, in 293/B5-11 and 293/mb5-8 cells was higher than that in 293/mock cells.
Conclusions: ABCB5/Abcb5-transfected cells showed resistance to BSO, which is not a substrate of ABCB5. Our results suggest that ABCB5/Abcb5 upregulates cellular glutathione levels to protect cells from various poisons.

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