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Mariko Kozaru, Hiroko Kambara, Akari Higuchi, Tatsuki Kagatsume, Keiko Hosohata Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, JapanCorrespondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan, Tel +81-72-690-1271, Fax +81-72-690-362, Email keiko.hosohata@ompu.ac.jpBackground: The P2Y12 receptor inhibitors clopidogrel and prasugrel are widely used. Clopidogrel and prasugrel have different metabolic pathways, but whether their adverse event (AE) profiles differ significantly is unclear.Objective: This study aimed to compare the possible AEs induced by clopidogrel and prasugrel and to assess the rank-order of their AEs submitted to a spontaneous reporting database.Materials and Methods: Data were extracted from the Japanese Adverse Drug Event Report database (JADER). Reports of AEs associated with clopidogrel and prasugrel were analyzed to calculate the reporting odds ratios (RORs) and 95% confidence intervals (CIs).Results: Based on 5869 reports for clopidogrel (69.6%, men) and 513 reports for prasugrel (74.1%, men), 703 and 135 different AEs were identified, respectively. Bleeding complications including hemorrhage were commonly reported for both clopidogrel and prasugrel. As for AEs related to clopidogrel, unexpected AEs such as interstitial lung disease (227 reports; ROR, 1.77; 95% CI, 1.49– 2.10), abnormal hepatic function (137 reports; ROR, 1.27; 95% CI, 1.07– 1.51), and hepatocellular injury (96 reports; ROR, 120.0; 95% CI, 94.9– 151.8) ranked at relatively high positions based on the number of occurrences, unlike prasugrel.Conclusion: This analysis of the national pharmacovigilance database highlights distinct AE profiles for clopidogrel and prasugrel. Unexpected AEs associated with clopidogrel were identified, providing valuable insights for clinical monitoring and patient safety.Keywords: P2Y12 platelet inhibitor, pharmacovigilance, adverse events, reporting odds ratio, signal detection, spontaneous reporting system

Kazuhiro Furumachi,1 Tatsuki Kagatsume,2 Akari Higuchi,2 Mariko Kozaru,2 Etsuko Kumagai,1 Keiko Hosohata2 1Department of Nephrology, Kenwakai Hospital, Nagano, Japan; 2Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, JapanCorrespondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, Japan, Tel +81-72-690-1271, Fax +81-72-690-1023, Email keiko.hosohata@ompu.ac.jpPurpose: The aim of the study was to determine the association between coronavirus disease 2019 (COVID-19) infection and diabetes management indices in patients with type 2 diabetes mellitus.Patients and Methods: A single-center, retrospective, observational study of patients with type 2 diabetes mellitus at Kenwakai Hospital (Nagano, Japan) was conducted. Data of 95 patients (mean age, 72 ± 12 years; men, 67.4%) who visited between March 1, 2019 and February 28, 2022 were obtained from the hospital’s electronic information system. COVID-19 was diagnosed by a chemiluminescent enzyme immunoassay (CLEIA).Results: There was no association between COVID-19 infection and age, sex, hemodialysis treatment status, or the Charlson Comorbidity Index. After adjustment for possible confounding factors, the incidence of COVID-19 infection was significantly correlated with HbA1c ≥ 7.0% (odds ratio [OR], 5.51; 95% confidence interval [CI], 1.30– 23.26).Conclusion: The results suggest an association between high HbA1c levels and COVID-19 infection in patients with type 2 diabetes mellitus. Appropriate management of diabetes mellitus, focusing on HbA1c levels, may help prevent COVID-19 infection and severe disease after infection.Keywords: Type 2 diabetes mellitus, COVID-19, risk factors, HbA1c, Japanese

Akie Yoshida,1 Kazuhiro Furumachi,2 Etsuko Kumagai,2 Keiko Hosohata1 1Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, Japan; 2Department of Nephrology, Kenwakai Hospital, Nagano, JapanCorrespondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, Japan, Tel +81-72-690-1271, Fax +81-72-690-1023, Email keiko.hosohata@ompu.ac.jpPurpose: The aim of the study was to identify the characteristics of patients infected with coronavirus disease 2019 (COVID-19) and to determine risk factors for COVID-19 infection in Japanese patients.Patients and Methods: We conducted a single-center retrospective observational study in Japanese adult patients (≥ 20 years) who visited Kenwakai Hospital (Nagano Japan). We analyzed data of 378 patients (mean age, 75 ± 14 years; men, 54%) from the hospital’s electronic information system. COVID-19 was diagnosed by polymerase-chain reaction. Patients were divided into 2 groups based on diagnosis of COVID-19.Results: Patients infected with COVID-19 showed significantly higher rates of men (69.8 vs 51.6%, P = 0.025) than uninfected control patients. After adjustment for possible confounding factors, COVID-19 infection was significantly associated with BUN (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.01– 1.03) and serum creatinine (Scr) (OR, 1.14; 95% CI, 1.05– 1.24). This association was observed in men (BUN, P = 0.012; Scr, P = 0.012), but not in women (BUN, P = 0.43; Scr, P = 0.54).Conclusion: BUN and Scr are potential risk factors for infection of COVID-19 in Japanese patients, particularly in men. Our results suggest that renal parameters might be important in Japanese male patients for the early detection of COVID-19 infection.Keywords: adult patients, COVID-19, risk factors, kidney function, Japanese

Mariko Kozaru, Tatsuya Iida, Keiko Hosohata Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, JapanCorrespondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan, Tel +81-72-690-1271, Fax +81-72-690-362, Email hosohata@gly.oups.ac.jpPurpose: Clinically, glaucoma is a serious problem because it is asymptomatic until a relatively late stage in most cases, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of glaucoma with the causative drugs using a spontaneous reporting system database.Methods: Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on reports of glaucoma caused by all drugs, we calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for glaucoma.Results: Among 609 reports of adverse events corresponding to glaucoma (46%, women), the most frequently implicated drug were steroids (prednisolone, betamethasone sodium phosphate, triamcinolone acetonide, and fluorometholone), pregabalin, ranibizumab, crizotinib, tacrolimus hydrate, darbepoetin alfa, and foscarnet sodium hydrate. Among 207 reports involved in angle-closure glaucoma (86%, women), anticholinergic drug and antidepressants ranked high and showed signals. Signals were also detected in bromazepam (ROR, 69.7; 95% CI, 30.9– 157.5), oral brotizolam (ROR, 16.6; 95% CI, 6.18– 44.8), and oral milnacipran hydrochloride (ROR, 22.8; 95% CI, 8.46– 61.4) for angle-closure glaucoma.Conclusion: A national pharmacovigilance database enabled us to identify the drugs that frequently induce glaucoma. The likelihood of the reporting of glaucoma varied among the drugs, which should be used carefully in clinical practice to avoid it.Keywords: glaucoma, pharmacovigilance, adverse drug reactions, reporting odds ratio, spontaneous reporting system

Takeo Hata,1 Atsushi Hirata,2 Ryosuke Ota,2 Keiko Hosohata,3 Masami Nishihara,1 Masashi Neo,1 Takahiro Katsumata1 1Department of Pharmacy, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Osaka, Japan; 2Department of Pharmacy, Kindai University Nara Hospital, Ikoma, Nara, Japan; 3Education and Research Center for Clinical Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, JapanCorrespondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan, Tel +81-72-690-1271, Fax +81-72-690-1023, Email hosohata@gly.oups.ac.jpPurpose: Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are highly effective and safe against juvenile idiopathic arthritis (JIA), which is classified into systemic JIA (sJIA) and the other JIA categories (non-sJIA) according to differences in clinical symptoms and pathophysiology. The purpose of the current study was to investigate trends in patterns of prescribing bDMARDs for moderate-to-severe JIA using a relatively large sample size in Japan.Patients and Methods: A descriptive epidemiological study based on a nationwide claims database in Japan was conducted from 2012 to 2018 using the “JMDC Claims Database” to explain annual changes based on the number of patients prescribed bDMARDs. Study drugs were identified based on the Anatomical Therapeutic Chemical codes, such as methotrexate, glucocorticoids, non-steroidal anti-inflammatory drugs, and bDMARDs.Results: From a database of 6,862,244 patients, the following exclusion criteria were applied: aged ≥ 16 years, without “M08” in their ICD-10 code as disease, and missing the information of prescription date in the database during the study period, resulting in a final number of 111 JIA patients. We found an increasing trend for adalimumab and tocilizumab and a decreasing trend for methotrexate. Differences in medication use between sJIA and non-sJIA patients were also evident, being consistent with national and international guidelines.Conclusion: Although the introduction of bDMARDs has markedly improved the efficacy of JIA therapy, there are still many short- and long-term safety issues to be examined, including the risk of infection and potential risk of associated malignancy. Future studies are needed to clarify these issues.Keywords: arthritis, juvenile, antirheumatic agents, biological products, database

Tomohito Wakabayashi, Keiko Hosohata, Saki Oyama, Ayaka Inada, Sayaka Ueno, Hiroko Kambara, Tatsuya Iida, Takahiro Nakatsuji, Mayako Uchida, Kazunori Iwanaga Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, JapanCorrespondence: Keiko HosohataEducation and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, JapanTel +81-72-690-1271Fax +81-72-690-1023Email hosohata@gly.oups.ac.jpIntroduction: Concerns over safety profiles of tumor necrosis factor (TNF)-alfa inhibitors have been raised. The purpose of this study was to clarify the adverse events associated with TNF-alfa inhibitors using a spontaneous reporting system database.Materials and Methods: A retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated.Results: Among the 34,031 reports of adverse events associated with TNF-alfa inhibitors, 65.8% were women, who were frequently in their 60s (28.2%). Signals were detected for pneumonia (ROR, 5.36; 95% CI, 5.14– 5.6), interstitial lung disease (ROR, 2.04; 95% CI, 1.95– 2.15), pneumocystis jirovecii pneumonia (ROR, 11.8; 95% CI, 11.1– 12.5), and herpes zoster (ROR, 6.4; 95% CI, 5.92– 6.91) for TNF-alfa inhibitors as a class. There was variability in their signal strength across individual TNF-alfa inhibitors.Conclusion: The strength of the associations of TNF-alfa inhibitors with adverse events is variable, and further studies are required to evaluate the identified signals.Keywords: TNF-alfa inhibitors, adverse drug events, spontaneous reporting system, reporting odds ratio, Japanese Adverse Drug Event Report database

Ayaka Inada, Keiko Hosohata, Saki Oyama, Iku Niinomi, Yasuhiro Mori, Yuki Yamaguchi, Mayako Uchida, Kazunori Iwanaga Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka 569-1094, Japan Background: Bisphosphonates (BPs) and denosumab are widely used to treat osteoporosis and complications associated with bone metastases. However, medication-related osteonecrosis of the jaw (MRONJ) is a serious problem. Objective: The objective of this study was to evaluate the frequency, outcome, and characteristics of patients with drug-induced MRONJ. Methods: Retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database from the Pharmaceuticals and Medical Devices Agency. Adverse event reports submitted to JADER between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) was calculated. Results: Among the BPs that cause MRONJ, zoledronate was the most common; therefore, we compared the characteristics of cases of MRONJ induced by zoledronate with those induced by denosumab. Among the 3,875 (68.1% women) cases of MRONJ, zoledronate-related MRONJ accounted for 1,283 (56.0% women) and denosumab-related MRONJ accounted for 322 (55.3% women). MRONJ was more frequent after 70 years of age regardless of the use of either zoledronate or denosumab; onset occurred after 1 year from the denosumab treatment, but it is unknown when onset occurred after zoledronate treatment. The outcomes for MRONJ were poor, with 406 reports on zoledronate (31.6%) and 152 reports on denosumab (47.2%) demonstrating nonrecovery. Zoledronate (ROR: 319.3, 95% CI: 296.0–344.4) had the highest ROR among BP agents. Denosumab had a high ROR (ROR: 155.2, 95% CI: 136.5–176.3). Zoledronate and denosumab were used in similar patient backgrounds, and their use resulted in a similar frequency of MRONJ. Conclusion: The findings of this comprehensive evaluation of MRONJ using the JADER database will be helpful for prescribing medications to elderly patients. Keywords: medication-related osteonecrosis of the jaw, pharmacovigilance, spontaneous reporting system, reporting odds ratio, Japanese Adverse Drug Event Report database

Saki Oyama, Keiko Hosohata, Ayaka Inada, Iku Niinomi, Yasuhiro Mori, Yuki Yamaguchi, Mayako Uchida, Kazunori Iwanaga Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan Introduction: Tubulointerstitial nephritis (TIN) is a problem in clinical settings because drug therapy is the cause in most cases. Patients often present with nonspecific symptoms, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of TIN with the causative drugs using a spontaneous reporting system database. Materials and methods: Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on 5,195,890 reports of all adverse reactions, we obtained 3,088 reports of TIN caused by all drugs and calculated the reporting odds ratio (ROR) and 95% CI for TIN. Results: The 5 drugs with the highest RORs were gliclazide (ROR, 30.5; 95% CI, 17.4–53.2), tosufloxacin tosilate hydrate (ROR, 29.5; 95% CI, 21.3–41.0), piperacillin–tazobactam (ROR, 24.3; 95% CI, 19.4–30.5), cefteram pivoxil (ROR, 23.5; 95% CI, 12.5–44.2), and mefenamic acid (ROR, 22.5; 95% CI, 13.4–37.7). No sex-related difference was observed in drug-induced TIN. Most of the reports about TIN onset following the administration of culprit drugs were recorded within 12 weeks. Conclusion: Based on the results, a comprehensive study using a pharmacovigilance database enabled us to identify the dugs that most frequently induced TIN, so these drugs should be used carefully in clinical practice to avoid TIN. Keywords: tubulointerstitial nephritis, pharmacovigilance, spontaneous reporting system, reporting odds ratio, Japanese Adverse Drug Event Report database, JADER

Replacement of Phe[sup 3] in the endogenous δ-opioid selective peptide deltorphin I with four optically pure stereoisomers of the topographically constrained, highly hydrophobic novel amino acid β-isopropylphenylalanine (β-iPrPhe) produced four pharmacologically different deltorphin I peptidomimetics. Radiolabeled ligand-binding assays and in vitro biological evaluation indicate that the stereoconfiguration of the iPrPhe residue plays a crucial role in determining the binding affinity, bioactivity and selectivity of [β-iPrPhe[sup 3]]deltorphin I analogs: a (2S,3R) configuration of the iPrPhe[sup 3] residue in [β-iPrPhe[sup 3]]deltorphin I provided the most desirable biological properties with binding affinity (IC[sub 50] = 2 nm), bioassay potency (IC[sub 50] = 1.23 nm in MVD assay) and exceptional selectivity for the δ-opioid receptor over the µ-opioid receptor (30 000). Further conformational studies based on two-dimensional NMR and computer-assisted molecular modeling suggested a model for the possible bioactive conformation in which the Tyr[sup 1] and (2S,3R)-β-iPrPhe[sup 3] residues adopt trans side-chain conformations, and the linear peptide backbone favors a distorted β-turn conformation. [ABSTRACT FROM AUTHOR]

Zinc supplementation may ameliorate zinc deficiency in maintenance hemodialysis patients; however, no standard protocol has been established. This study aimed to investigate the effects of zinc acetate hydrate (ZAH) and polaprezinc (PPZ) as zinc supplements in hemodialysis patients. We enrolled 75 hemodialysis patients with serum zinc levels <60  μ g/dL for this study and randomly assigned Zinc supplementation to these 75 patients: 37 received ZAH (50 mg/day), and 38 received PPZ (34 mg/day). Serum zinc levels of both groups were compared every 4 weeks for 1 year. In both groups, serum zinc levels significantly increased at 4-52 weeks. Serum zinc levels were significantly higher in the ZAH group at 4-12 weeks; however, no significant differences were observed between the groups at 16-52 weeks. Adverse events requiring a reduction in the zinc dose, including copper deficiency, occurred significantly more frequently in the ZAH group. In conclusion, PPZ can safely maintain serum zinc levels for 1 year. ZAH provides rapid zinc supplementation but can cause adverse events., Competing Interests: The authors declare no conflicts of interest regarding the publication of this paper., (Copyright © 2023 Etsuko Kumagai et al.)

Objective: Mineralocorticoid receptor antagonists (MRAs), eplerenone and esaxerenone, cause hyperkalemia dose-dependently. We investigated the cytochrome P450 3A4-mediated drug-drug interaction between the MRAs and clarithromycin., Methods: This retrospective observational study included adult hypertensive patients with MRA plus clarithromycin or MRA alone with a propensity score matching (1:1). The difference in serum potassium level (ΔK, maximum level - baseline level) between groups was compared using the Mann-Whitney U -test. Linear regression analysis was used to detect variables that correlated with ΔK in patients with MRA plus clarithromycin., Results: After propensity score matching (each nine patients), serum potassium level was elevated after treatment with MRA plus clarithromycin [4.3 (3.5 to 5.1) meq/l to 4.9 (4.0 to 5.5) meq/l, P  = 0.0234] and MRA alone [4.3 (4.0 to 4.7) meq/l to 4.6 (4.4 to 5.2) meq/l, P  = 0.0469]. Although there was no significant difference in ΔK between groups [MRA plus clarithromycin: 0.5 (0.1 to 1.1) meq/l vs. MRA alone: 0.3 (0.1 to 1.2) meq/l, P  = 0.7231], ΔK was significantly higher in esaxerenone plus clarithromycin than in esaxerenone alone [0.6 (0.5 to 1.1) meq/l vs. 0.1 (0.1 to 0.2) meq/l, P  = 0.0495]. Conversely, clarithromycin did not show a significant effect on ΔK in patients with eplerenone [0.4 (-0.2 to 1.2) meq/l vs. 0.8 (0.1 to 1.3) meq/l, P  = 0.5745]. A positive correlation was found between ΔK and age in patients with MRA plus clarithromycin ( y  = 0.03 ×  x - 1.38, r  = 0.71, P  = 0.0336)., Conclusion: The drug-drug interaction between MRAs and clarithromycin was evident, particularly in esaxerenone. Serum potassium levels should be closely monitored in older patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cyclosporine is widely used to prevent allograft rejection after transplantation. The purpose of this study was to clarify the adverse events profiles associated with cyclosporine in transplant patients using a spontaneous reporting system database., Methods: Retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database, with the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event., Results: The database comprised 3,327, 958, and 956 reports associated with cyclosporine in the kidney, stem cell, and heart transplant patients, respectively. Infectious and renal disorders were commonly detected in these transplant patients. The signal scores of cyclosporine for toxic nephropathy were noteworthy in the kidney (ROR: 15.1, 95% CI: 11-20.8) and stem cell (ROR, 216; 95% CI, 29.3-1593) transplantation. Cyclosporine in heart transplantation was strongly associated with gastric cancer (ROR, 39.4; 95% CI, 16.7-93.2), but not kidney or stem cell transplantation., Conclusion: It was suggested that there is a diversity in the strength of the association between cyclosporine and adverse events in the kidney, stem cell, and heart transplantation. Our results may provide useful information for treatment with cyclosporine, although further research with more data is needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Niinomi et al.)

Juvenile idiopathic arthritis (JIA) is a systemic inflammatory disease of childhood onset. The purpose of this study was to clarify the frequency of adverse events caused by drugs used in JIA treatment and characterize their safety profiles using a spontaneous reporting system database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports on drugs used for the treatment of JIA and which were submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for reports on each adverse event were calculated. A total of 5,748 reports were identified in the treatment of JIA, in which 35 different drugs were involved. Adverse events by drugs in JIA were frequently reported in females (64.3%) and in those younger than 10 (61.2%). Among the most frequently reported drugs, prednisolone (36.8%) and tocilizumab (36.0%) were predominant. Prednisolone was significantly correlated with hematophagic histiocytosis (ROR, 1.37; 95% CI, 1.18 - 1.61). Tocilizumab was associated with a high ROR for pneumonia (ROR, 8.61: 95% CI, 5.81 - 12.7), a decreased neutrophil count (ROR, 6.1; 95% CI, 4.07 - 9.16), and lymphadenitis (ROR, 8.34; 95% CI, 4.2 - 16.6). Our results revealed the safety profile of drugs for the treatment of JIA patients. It was suggested that there is a diversity in drugs and their strength of association with adverse events in JIA patients. Our results may provide useful information for the treatment of JIA patients, although further research with more data is needed.

Introduction: Transthyretin (TTR) is a sensitive marker of nutritional status and independent risk factor for mortality in hemodialysis patients. However, its range associated with prognosis in Japanese hemodialysis patients is unknown., Methods: Maintenance hemodialysis Patients (n = 664) were enrolled, and their TTR levels were measured to assess 1-year mortality. Patients were assigned to four groups based on TTR levels: <20, 20 to <30 (control), 30 to <40, and ≥40 mg/dl. One-year mortality at each TTR range was analyzed using a Cox proportional hazards model after adjustment for prognostic factors., Results: Seventy-seven (11.6%) deaths were recorded during follow-up. The hazard ratio (HR) of TTR <20 mg/dl was significantly higher compared with the control group in terms of all-causes (HR: 3.14) and non-cardiovascular mortality (HR: 6.986)., Conclusion: TTR levels were independent and sensitive predictors of mortality in hemodialysis patients. TTR <20 mg/dl is a risk factor for 1-year mortality in Japanese hemodialysis patients., (© 2021 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Fourteen novel vanin-1 inhibitors coded OMP-# were designed from RR6 and successfully synthesized by a nucleophilic addition-elimination reaction of the pantetheinic acid-derived Weinreb amide as a key step under Barbier conditions. The synthesized OMP compounds exhibited inhibitory activity against human serum vanin-1 in vitro. Among the synthesized compounds, OMP-7, which possesses a trifluoromethoxy group at the para-position on the phenyl ring, exhibited the most potent activity, approximately 20 times that of the mother compound RR6. OMP-7 was further subjected to an in vivo assay using a normal hamster. More potent activity was observed than that of RR6 against both serum and renal vanin-1. The activity lasted for 4 h after injection against serum vanin-1 and 1 h after injection against renal vanin-1, whereas RR6 did not show the desired activity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ferroptosis is a recently recognized form of nonapoptotic cell death that is triggered by reactive oxidative species (ROS) due to iron overload, lipid peroxidation accumulation, or the inhibition of phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). Recent studies have reported that ferroptosis plays a vital role in the pathophysiological process of multiple systems such as the nervous, renal, and pulmonary systems. In particular, the kidney has higher rates of O 2 consumption in its mitochondria than other organs; therefore, it is susceptible to imbalances between ROS and antioxidants. In ischemia/reperfusion (I/R) injury, which is damage caused by the restoring blood flow to ischemic tissues, the release of ROS and reactive nitrogen species is accelerated and contributes to subsequent inflammation and cell death, such as ferroptosis, as well as apoptosis and necrosis being induced. At the same time, I/R injury is one of the major causes of acute kidney injury (AKI), causing significant morbidity and mortality. This review highlights the current knowledge on the involvement of ferroptosis in AKI via oxidative stress.

Background/aim: High-dose chemotherapy is frequently administered to patients with hematologic malignancies, thereby causing severe adverse drug reactions (ADRs) at a relatively high frequency. To precisely monitor ADRs, we developed a medication instruction sheet (MIS) for patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) combination therapy for non-Hodgkin's lymphoma (NHL). Herein, we evaluated the usefulness of the MIS for managing ADRs in patients who received R-CHOP therapy., Patients and Methods: We included patients aged ≥20 years who received R-CHOP therapy as first-line treatment for NHL at the Department of Hematology, Kyushu University Hospital, between August 2014 and December 2018. Medical professionals evaluated the possible occurrence of ADRs according to the present MIS and ADRs were graded according to the Common Toxicity Criteria, version 4.0 (National Cancer Institute, Bethesda, MD, USA). Finally, the accuracy of the MIS in predicting the occurrence of ADRs of different grades and during definite periods was evaluated., Results: Seventy-five patients with NHL were included in the present study. Overall, 359 ADR events were monitored, which were predicted ADR items listed in the MIS. Among these, 254 (71%) events occurred during the same period as those listed in the MIS. The onset timing of any grade of an infusion reaction and peripheral neuropathy precisely matched those listed in the MIS. However, the accuracy of the MIS was reduced in patients with thrombocytopenia (42%)., Conclusion: The present MIS could be useful for monitoring ADRs in patients with cancer undergoing R-CHOP therapy., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The occurrence of chemotherapy-related serious adverse events (AEs) is associated with a poor prognosis of hematopoietic malignancies. We have developed a medication guidance sheet (MGS) for monitoring AEs occurring when combining chemotherapy with etoposide, methylprednisolone, cisplatin, cytarabine, and rituximab (ESHAP±R). In this study, the usefulness of MGS was investigated in non-Hodgkin's lymphoma patients., Patients and Methods: The MGS was used to monitor AEs in 48 adult patients receiving ESHAP±R. The prediction accuracy of the MGS was estimated before and after modification based on practical data., Results: A total of 246 AEs developed, all of which were predicted by the MGS. Among them, 149 events (61%) occurred during the same period as those predicted by the MGS. After modification of MGS for the onset and duration of AEs, the accuracy increased to 84%., Conclusion: The accuracy of the original MGS for ESHAP±R was insufficient but greatly improved after the AEs duration modification., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Teicoplanin is a glycopeptide antibiotic against methicillin-resistant Staphylococcus aureus infections. However, the impact of clinical characteristics on nephrotoxicity associated with teicoplanin has not been determined. This meta-analysis aimed to investigate the relationship between clinical characteristics and nephrotoxicity associated with teicoplanin. We identified clinical research published from January 1975 to June 2021 using PubMed, Cochrane Library, and Scopus, which described the nephrotoxicity associated with teicoplanin. Meta-analysis determined the incidence of nephrotoxicity. Using meta-regression analysis, we evaluated the impact of clinical characteristics on outcomes. Of the 567 articles, eight articles including 634 patients were analysed. The overall incidence of nephrotoxicity associated with teicoplanin was 11.0% (95% confidence interval: 8.0-13.0) for the fixed-effect model. Additionally, patients with >65 years had a high trend for the risk of nephrotoxicity compared to those with ≤65 years (>65 years; 12.0% [95% confidence interval: 9.0-15.0] vs. ≤65 years; 7.0% [95% confidence interval: 3.0-12.0], p = 0.09) for the fixed-effect model. Meta-regression analysis demonstrated that only serum albumin level negatively correlated with the risk of nephrotoxicity (y = -17.0 x + 56.7, r = 0.74, p = 0.01). This meta-analysis ascertained that hypoalbuminemia leads to nephrotoxicity associated with teicoplanin., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Background: Several studies reported that abnormal behavior was noted in pediatric patients receiving several drugs, including neuraminidase inhibitors (NIs). However, the information on drugs associated with abnormal behavior in a real-world setting remains limited. The purpose of this study was to clarify the drugs associated with abnormal behavior using a spontaneous reporting system database., Methods: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio at 95% confidence interval were calculated., Results: A total of 1,144 reports of abnormal behavior were identified. The signals were detected through the association of 4 neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) with the abnormal behaviour. These signals were stronger for oseltamivir than other neuraminidase inhibitors. The signals were also detected for acetaminophen and montelukast., Conclusion: Our results should be able to raise physicians' awareness of drugs associated with abnormal behavior, but further investigation of these medications is warranted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ischemia-reperfusion injury is one of the major causes of acute kidney injury (AKI), which is increasingly prevalent in clinical settings. Glaucocalxin A (GLA), a biologically ent-kauranoid diterpenoid, has various pharmacological effects like antioxidation, immune regulation, and antiatherosclerosis. In this study, the effect of GLA on AKI and its mechanism were studied in vitro. HK-2 human renal tubular epithelial cells were exposed to hypoxia/reoxygenation (H/R), which were established as an in vitro AKI model. Subsequently, the mRNA expressions of inflammatory and antioxidant factors were determined by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Reactive oxygen species (ROS) production and cell death were detected by fluorescence-activated cell sorting. GLA pre-treatment improved the cell viability of HK-2 cells exposed to H/R. GLA suppressed the H/R-induced ROS production in HK-2 cells. GLA also elevated the activities of superoxide dismutase of HK-2 cells exposed to H/R. Moreover, GLA prevented H/R-induced cell death in HK-2 cells. Furthermore, GLA ameliorated the activation of the protein kinase B (Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in HK-2 cells exposed to H/R. Our findings suggested that GLA protected HK-2 cells from H/R-induced oxidative damage, which was mediated by the Akt/Nrf2/HO-1 signaling pathway. These results indicate that GLA may serve as a promising therapeutic drug for AKI.

Objective: The calcineurin inhibitor tacrolimus has been widely used to prevent allograft rejection after transplantation. The purpose of this study was to clarify the adverse events associated with tacrolimus in solid organ transplantation using a spontaneous reporting system database., Materials and Methods: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated., Results: The database comprised 26,620 reports associated with tacrolimus, of which 2,014, 1,988, and 725 reports involved heart, kidney, and liver transplantation, respectively. Infectious disorder was commonly detected in these transplant patients. There was a significant association between tacrolimus use and colon cancer in patients undergoing heart transplantation (ROR: 3.33, 95% CI: 2.18 - 5.08), but not kidney or liver transplantation. Tacrolimus use in those undergoing kidney transplantation is strongly associated with bronchitis (ROR, 8.95; 95% CI, 6.34 - 12.6). A signal for seizure was detected in liver transplant patients with tacrolimus (ROR, 4.12; 95% CI, 1.77 - 9.59)., Conclusion: It was suggested that there is a diversity in the strength of the association between tacrolimus and adverse events in patients receiving heart, kidney, and liver transplantation. Our results may provide useful information for treatment with tacrolimus, although further research with more data is needed to clarify this.

Oxidative stress plays an important role in the pathophysiology of acute kidney injury (AKI). Previously, we reported that vanin-1, which is involved in oxidative stress, is associated with renal tubular injury. This study was aimed to determine whether urinary vanin-1 is a biomarker for the early diagnosis of AKI in two experimental models: in vivo and in vitro. In a rat model of AKI, ischemic AKI was induced in uninephrectomized rats by clamping the left renal artery for 45 min and then reperfusing the kidney. On Day 1 after renal ischemia/reperfusion (I/R), serum creatinine (SCr) in I/R rats was higher than in sham-operated rats, but this did not reach significance. Urinary N-acetyl-β-D-glucosaminidase (NAG) exhibited a significant increase but decreased on Day 2 in I/R rats. In contrast, urinary vanin-1 significantly increased on Day 1 and remained at a significant high level on Day 2 in I/R rats. Renal vanin-1 protein decreased on Days 1 and 3. In line with these findings, immunofluorescence staining demonstrated that vanin-1 was attenuated in the renal proximal tubules of I/R rats. Our in vitro results confirmed that the supernatant from HK-2 cells under hypoxia/reoxygenation included significantly higher levels of vanin-1 as well as KIM-1 and NGAL. In conclusion, our results suggest that urinary vanin-1 might be a potential novel biomarker of AKI induced by I/R.

We investigated the effectiveness of monitoring serum carnitine levels in hemodialysis patients receiving L-carnitine supplementation. One-hundred forty-five hemodialysis patients were divided into three groups. Group 1 consisted of patients (n = 30) who had been receiving supplementation before this study and then discontinued at the beginning. The remaining patients were divided into Group 2 (n = 13) and Group 3 (n = 102) based on their baseline free carnitine (FC) level, <20 or ≥ 20 μmol/L. Group 2 was started on supplementation, and Groups 1 and 3 were observed without any intervention for the first 6 months. FC was measured every 6 months in all three groups up to 18 months. All patients in whom FC was less than 20 μmol/L at 6 and 12 months were prescribed supplementation. After the first 6 months, the mean ± SD of FC changed from 262.5 ± 87.5 μmol/L at baseline to 70.8 ± 33.6 μmol/L (P < 0.001) in Group 1, from 17.4 ± 1.9 to 193.9 ± 43.3 μmol/L (P < 0.001) in Group 2, and from 49.2 ± 24.6 to 44.2 ± 19.8 μmol/L (P < 0.05) in Group 3. The acyl/free carnitine changed from 0.62 to 0.59 in Group 1 (P = 0.287), from 0.76 to 0.66 in Group 2 (P = 0.054) and from 0.57 to 0.60 in Group 3 (P < 0.05). Of the 145 patients, 126 continued follow-up for the full 18 months. FC remained in the normal range (36-74 μmol/L) within the 95% CI. FC was considered a strong predictor of carnitine deficiency after 6 months (AUC: 0.9146, cut-off value: 33.8 μmol/L). FC monitoring is essential for appropriate carnitine supplementation in hemodialysis patients., (© 2021 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Previously, the authors reported the utility of urinary vanin-1 as an early biomarker of kidney injury in spontaneously hypertensive rats and in humans. However, little is known about whether urinary vanin-1 can be used to predict the clinical outcome. This study aimed to evaluate the predictive power of urinary vanin-1 based on kidney function decline in hypertensive patients. The authors measured urinary vanin-1 in 147 patients at the baseline and examined its association with the incidence of ≥20% decline in the estimated glomerular filtration rate (eGFR) using the Cox regression analysis. The mean age of the patients averaged 72.9 ± 8.2 years, and 39% were women. Median (interquartile range) urinary vanin-1 was 0.33 (0-2.6) ng/mg Cr During a median follow-up of 12 months, 14 patients showed kidney function decline. A higher urinary vanin-1 level was associated with an increased risk of kidney function decline (hazard ratio, 9.87; 95% CI, 1.11-87.5) (p = .04) in the fully adjusted model. In conclusion, urinary vanin-1 is an independent risk factor for kidney function decline in hypertensive patients and it could be useful in clinical settings. The underlying pathophysiologic mechanisms warrant additional investigation., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Introduction: The development of new xanthine oxidase (XO) inhibitors, such as febuxostat and topiroxostat, could offer an alternative to treatment with allopurinol. The purpose of this study was to compare safety profiles of new XO inhibitors with allopurinol using a spontaneous reporting system database., Materials and Methods: A retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated., Results: Among 7,305 reports of adverse events associated with XO inhibitors, 64.5% involved males, who were frequently in their 70s (25.9%). A large number of skin-related adverse events were detected with the use of allopurinol, but not with febuxostat or topiroxostat. As for individual XO inhibitors, the signal values showing associations between drug reaction with eosinophilia and systemic symptoms (DRESS) and allopurinol, drug-induced liver injury and febuxostat, and blood urea increase and topiroxostat were noteworthy., Conclusion: The strength of the associations of XO inhibitors with adverse events is variable, and further studies are required to evaluate the identified signals.