Biol. Pharm. Bull. [JOURNAL]
Sun
200 papers
CAMK2 Expression and Its Regulation on Testosterone Synthesis in Mouse Testis.
Zhang D, Guo H, Wang M … +2 more , Liao J, Cui S
Biol Pharm Bull · 2026 · PMID 41638654 · Publisher ↗
Leydig cells are testosterone synthesis cells in testes, a process tightly regulated by luteinizing hormone (LH) through the activation of steroidogenic enzymes such as steroidogenic acute regulatory protein (StAR) and 3...
Leydig cells are testosterone synthesis cells in testes, a process tightly regulated by luteinizing hormone (LH) through the activation of steroidogenic enzymes such as steroidogenic acute regulatory protein (StAR) and 3-beta-hydroxy-Delta5-steroid dehydrogenase (3β-HSD). While calcium/calmodulin-dependent protein kinase 2 (CAMK2) is known to modulate diverse cellular processes, including hormone signaling, its role in testosterone production remains unclear. In this study, we investigated the expression and functions of CAMK2 in mouse testes, focusing on its potential involvement in testosterone synthesis. Our findings demonstrate that CAMK2 expression progressively increases from postnatal day 1 (PND 1) to adulthood. Pharmacological inhibition of CAMK2 with KN-62 markedly reduced serum testosterone levels and downregulated the expression of key steroidogenic enzymes, including StAR and 3β-HSD, at both mRNA and protein levels. In vitro experiments using primary Leydig cells further confirmed that CAMK2 inhibition suppressed testosterone production and steroidogenic enzyme expression, particularly after prolonged (12-24 h) KN-62 treatment. Additionally, CAMK2 expression was upregulated in response to LH stimulation, suggesting its involvement in LH-mediated signaling pathways, potentially through modulation of the epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase 1/2 (ERK1/2) cascade. These findings demonstrate that CAMK2 positively regulates testosterone synthesis in Leydig cells, likely via the EGFR/ERK1/2 cascade. The results of this study enhance our understanding of the regulation of testosterone synthesis and identifies CAMK2 as a potential therapeutic target for male reproductive endocrine disorders.
The NAMPT Inhibitor FK866 Attenuates DEN-Induced Liver Fibrosis in Mice.
Ren D, Wang S, Li L … +3 more , Fan Z, Li M, Li L
Biol Pharm Bull · 2026 · PMID 41638653 · Publisher ↗
Chronic liver disease (CLD) poses a significant global health challenge, and liver fibrosis is a crucial process in the pathogenesis of CLD. However, effective interventions to halt and reverse the progression of liver f...
Chronic liver disease (CLD) poses a significant global health challenge, and liver fibrosis is a crucial process in the pathogenesis of CLD. However, effective interventions to halt and reverse the progression of liver fibrosis remain elusive. This study investigated the potential of the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 in treating diethylnitrosamine (DEN)-induced liver fibrosis in mice. We first demonstrated that DEN-induced hepatic fibrosis in mice was accompanied by upregulation of hepatic NAMPT and poly (ADP-ribose) polymerase 1 (PARP1) expression. Administration of FK866 inhibited the increase in alanine aminotransferase and aspartate aminotransferase levels and reversed the histopathological changes associated with DEN-induced liver fibrosis. It also suppressed the elevated expression of fibrotic markers, such as fibronectin, collagen IV, laminin, and α-smooth muscle actin. Further studies revealed that this therapeutic effect was achieved by inhibiting the NAD level, as well as the protein expression of NAMPT, PARP1, and inflammatory factors, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α, and P65. In conclusion, FK866 exhibits therapeutic potential for the treatment of liver fibrosis.
Development of a Data-Driven Prediction Model of Adverse Drug Reactions Using Large-Scale Medical Information and Machine Learning.
Ambe K
Biol Pharm Bull · 2026 · PMID 41621853 · Publisher ↗
In the development of pharmaceuticals and other chemical substances, it is important to evaluate their efficacy and safety. There is a growing trend toward reducing reliance on traditional in vivo testing using animals f...
In the development of pharmaceuticals and other chemical substances, it is important to evaluate their efficacy and safety. There is a growing trend toward reducing reliance on traditional in vivo testing using animals for safety assessments and utilizing new evaluation methods, such as in vitro and in silico testing, to refine human safety assessments. Furthermore, in medical and environmental fields, there is a growing demand for the utilization of vast amounts of information. This has led to the development of data-driven approaches that utilize large-scale medical information and artificial intelligence (AI). Machine learning enables computers to learn from known data, discover new patterns, and predict unknown data. This technology is also useful for in silico prediction of chemical toxicity and adverse reactions in humans. Recently, explainable AI, which presents the basis for forecasts obtained from machine learning models in a user-understandable manner, has attracted attention and is a useful technology for decision-making support. We have developed machine learning models focusing on a quantitative structure-activity relationship approach to predict toxicity and adverse reactions based on the structural information of chemical substances. Furthermore, we have begun to develop a model to predict package insert revisions based on post-marketing adverse reaction information. These efforts will contribute to solving regulatory science issues regarding the appropriate use of chemical substances such as pharmaceuticals.
Characteristics of Outpatients Aged <65 Years Diagnosed with Nonbacterial Acute Infectious Diarrhea during Internal Medicine or Pediatric Clinic Consultation between 2019 and 2021 Based on a Large Japanese Medical Claims Database.
Mizuno K, Inose R, Kitada Y … +1 more , Muraki Y
Biol Pharm Bull · 2026 · PMID 41605659 · Publisher ↗
This study aimed to clarify comorbid diseases diagnosed concurrently with nonbacterial acute infectious diarrhea following the 2019 revision of the Manual of Antimicrobial Stewardship, and to examine prescription pattern...
This study aimed to clarify comorbid diseases diagnosed concurrently with nonbacterial acute infectious diarrhea following the 2019 revision of the Manual of Antimicrobial Stewardship, and to examine prescription patterns among outpatients who visited a clinic for this condition. We utilized a large Japanese medical claims database provided by IQVIA Japan. Between 2019 and 2021, outpatients aged <65 years who visited an internal medicine or pediatric clinic and were diagnosed with nonbacterial acute infectious diarrhea were selected. Patient characteristics, diseases diagnosed in the same month as that of nonbacterial acute infectious diarrhea, and prescriptions were investigated. Overall, 22590 patients were included in this analysis. Among the 5643 patients (25.0%) who received antibiotic prescriptions, acute bronchitis, acute pharyngitis, and pharyngitis were frequently reported simultaneously with nonbacterial acute infectious diarrhea. The antibiotic prescription rate was lowest among patients aged <6 years (internal medicine, 19.2%; pediatrics, 9.9%), compared with those aged 6-14 years (internal medicine, 25.0%; pediatrics, 14.4%) and 15-64 years (internal medicine, 28.5%; pediatrics, 26.2%). Notably, some patients diagnosed with nonbacterial acute infectious diarrhea also had comorbid conditions that required antibiotic use. Therefore, when assessing the appropriateness of antibiotic prescriptions, it is essential to consider these comorbidities. Furthermore, continued implementation of antimicrobial resistance countermeasures against nonbacterial acute infectious diarrhea remains important.
In Vivo and in Vitro Characterization of the Anti-inflammatory and Neuroprotective Effects of TPNA10168.
Izumi Y, Hirai K, Moro S … +9 more , Inoue S, Nonaka M, Ikawa S, Yamaki K, Takeda N, Yamada T, Ueda M, Kume T, Koyama Y
Biol Pharm Bull · 2026 · PMID 41605658 · Publisher ↗
Neuroinflammation contributes to the pathogenesis of various central nervous system disorders. TPNA10168, a novel nuclear factor erythroid 2-related factor 2 activator, exhibits neuroprotective effects in vitro and in vi...
Neuroinflammation contributes to the pathogenesis of various central nervous system disorders. TPNA10168, a novel nuclear factor erythroid 2-related factor 2 activator, exhibits neuroprotective effects in vitro and in vivo and anti-inflammatory activity in vitro. In this study, we examined the in vivo efficacy of TPNA10168 in a mouse model of systemic inflammation established by lipopolysaccharide (LPS) treatment. TPNA10168 attenuated the LPS-induced expression of several proinflammatory cytokines, such as tumor necrosis factor-α in the liver and interleukin-1β in the brain, and upregulated heme oxygenase-1 in both tissues. Although it did not suppress microglial activation in the brain, TPNA10168 reduced LPS-induced motor deficits without affecting anxiety-like or anhedonic behavior. In primary mesencephalic cultures, TPNA10168 inhibited microglial activation and nitric oxide production and protected dopaminergic neurons against LPS/interferon-γ-induced toxicity. The results suggest that TPNA10168 exerts partial anti-inflammatory effects in vivo and protects dopaminergic neurons from inflammation-induced damage in vitro, which indicates its potential as a therapeutic agent for inflammation-related neurological disorders.
Na/Ca Exchanger-Mediated Negative Inotropy of Na Channel Blockers Pilsicainide, Cibenzoline, and Propafenone in Guinea Pig Ventricular Myocardial Tissue Preparations.
Seki M, Iinuma A, Shiota Y … +3 more , Hamaguchi S, Namekata I, Tanaka H
Biol Pharm Bull · 2026 · PMID 41605657 · Publisher ↗
Involvement of the Na/Ca exchanger (NCX) in the negative inotropic effects of class I antiarrhythmic drugs, pilsicainide, cibenzoline, and propafenone, was examined in isolated guinea pig ventricular myocardium. The clas...
Involvement of the Na/Ca exchanger (NCX) in the negative inotropic effects of class I antiarrhythmic drugs, pilsicainide, cibenzoline, and propafenone, was examined in isolated guinea pig ventricular myocardium. The class I antiarrhythmic drugs, as well as tetrodotoxin, decreased contractile force in a concentration-dependent manner; the magnitude of the effect was propafenone > cibenzoline > pilsicainide. Under conditions of NCX inhibition with the NCX inhibitor SEA0400 or with a low-Na extracellular solution, the negative inotropic effects of the class I antiarrhythmic drugs were attenuated. While the effect of pilsicainide was almost abolished, the inhibition was only partial for cibenzoline and propafenone. These results suggest that NCX facilitation secondary to Na channel blockade constitutes a common mechanism underlying the negative inotropic effects of class I antiarrhythmic drugs. Drugs with stronger negative inotropic effects have additional mechanisms, and the overall magnitude of negative inotropy is determined by the sum of these actions.
Quercetin Ameliorates Glucose Metabolism Dysregulation in CUMS Model Rats via the Bile Acid-FXR/TGR5 Axis.
Zhang B, Li Y, Fan P … +1 more , Wang S
Biol Pharm Bull · 2026 · PMID 41605656 · Publisher ↗
Quercetin, a plant-derived flavonoid, has demonstrated therapeutic potential across metabolic and neuropsychiatric disorders. This study aimed to clarify the mechanisms by which quercetin mitigates glucose metabolic dysf...
Quercetin, a plant-derived flavonoid, has demonstrated therapeutic potential across metabolic and neuropsychiatric disorders. This study aimed to clarify the mechanisms by which quercetin mitigates glucose metabolic dysfunction in rats subjected to chronic unpredictable mild stress (CUMS), with a particular focus on its regulation of the bile acid-farnesoid x receptor (FXR)/takeda g protein-coupled receptor 5 (TGR5) signaling pathway. Behavioral assessments and histopathological, biochemical, immunofluorescence, Western blotting, and targeted metabolomics analyses showed that quercetin significantly alleviated depressive-like behaviors and ameliorated glucose metabolic dysregulation. Quercetin treatment modified bile acid composition in colonic contents, activated the FXR/TGR5 pathway, and enhanced glucagon-like peptide-1 (GLP-1) secretion, collectively contributing to improved glycemic and lipid homeostasis. These results indicate that quercetin attenuates CUMS-induced glucose metabolic disturbances via the bile acid-FXR/TGR5-GLP-1 axis, suggesting its potential as a dual-target therapeutic agent for stress-related metabolic and neurobehavioral disorders.
Effectiveness of Operating Room Pharmacists' Prescribing Intervention for Appropriate Use of Antimicrobial Prophylaxis in Otorhinolaryngology-Head and Neck Surgery: A Single-Center, Observational Study.
Tomizawa A, Kitagawa K, Seto Y … +4 more , Ogawa T, Komatsu T, Yamashita T, Otori K
Biol Pharm Bull · 2026 · PMID 41605655 · Publisher ↗
We investigated the impact of operating room pharmacists on the appropriate use of antimicrobial prophylaxis (AMP) in otorhinolaryngology-head and neck surgery. Patients without intervention by operating room pharmacists...
We investigated the impact of operating room pharmacists on the appropriate use of antimicrobial prophylaxis (AMP) in otorhinolaryngology-head and neck surgery. Patients without intervention by operating room pharmacists (April 1, 2017, to March 31, 2019) and those who underwent intervention by operating room pharmacists (October 1, 2019, to March 31, 2021) were compared. Additionally, an interrupted time-series (ITS) analysis was conducted as a sensitivity analysis to assess temporal trends. Overall, 1697 patients (999 in the non-intervention group and 698 in the intervention group) were included, and 213 matched pairs were analyzed after 1 : 1 propensity score matching. The compliance rate of AMP administered within 1 h prior to incision was significantly higher in the intervention group than in the non-intervention group (98.1 vs. 93.4%; p = 0.027). In the subgroup analysis, the compliance rate of the guideline-recommended initial dose in patients weighing ≥80 kg was significantly higher in the intervention group than in the non-intervention group (93.1 vs. 70.7%; p < 0.001). The compliance rate of additional doses administered at the guideline-recommended intervals in patients with an estimated glomerular filtration rate individualized body surface area (eGFR) <50 mL/min was significantly higher in the intervention group than in the non-intervention group (89.8 vs. 80.4%; p = 0.041). ITS analysis showed that the improvement trend in AMP compliance stabilized after the intervention, indicating sustained intraoperative management. No significant differences were observed in the postoperative or total hospital stay between the two groups. In conclusion, interventions by operating room pharmacists significantly improved the appropriate use of intraoperative AMP.
MA-T Activates Human TRPV4 in the Non-pigmented Ciliary Epithelial Cells.
Luo Q, Toriyama M, Hashimoto M … +3 more , Tominaga M, Inoue T, Fujita F
Biol Pharm Bull · 2026 · PMID 41581922 · Publisher ↗
Matching transformation system (MA-T), an on-demand aqueous chlorine dioxide production solution is utilized in various applications, including antibacterial and cancer therapies. Herein, we focused on the ability of MA-...
Matching transformation system (MA-T), an on-demand aqueous chlorine dioxide production solution is utilized in various applications, including antibacterial and cancer therapies. Herein, we focused on the ability of MA-T in oxidizing human transient receptor potential cation channel subfamily V member 4 (hTRPV4), which functions as a redox sensor, using Ca imaging and patch-clamp experiments. We found that 10 ppm MA-T activated hTRPV4 in HEK293T cells. Moreover, MA-T induced increase in cytosolic calcium concentration through hTRPV4 activation in human non-pigmented ciliary epithelial cells. Our study findings suggest MA-T as a potential agent for TRPV4-related diseases.
Role of Mitochondrial Protein, mitoNEET, in Impaired Intracellular Cholesterol Metabolism-Induced Neuronal Cell Death.
Nakata A, Takeo T, Mizuno H
Biol Pharm Bull · 2026 · PMID 41581919 · Publisher ↗
Parkinson's disease (PD) is a progressive neurological disorder with an unclear etiology. Nonetheless, abnormal cholesterol metabolism is considered an environmental risk factor. MitoNEET (mNT) is an iron-sulfur cluster...
Parkinson's disease (PD) is a progressive neurological disorder with an unclear etiology. Nonetheless, abnormal cholesterol metabolism is considered an environmental risk factor. MitoNEET (mNT) is an iron-sulfur cluster protein located in the outer mitochondrial membrane. mNT dysfunction is involved in the pathology of several diseases, including PD. However, the cause of mNT dysfunction remains unclear. Therefore, we hypothesized that increased intracellular cholesterol levels may reduce mNT function and increase reactive oxygen species (ROS) levels, resulting in neuronal cell death and PD progression. In this study, we investigated the effects of cholesterol on cell viability and mNT levels in human neuroblastoma (SH-SY5Y) cells. Cholesterol reduced cell viability and mNT protein levels and increased ROS generation. Pioglitazone, an mNT activator, decreased cholesterol-induced ROS generation but did not rescue cell viability, suggesting that reduced mNT levels may be involved but are not the sole cause of cholesterol-induced cell death. Additionally, the viability of cells treated with rotenone, 6-hydroxydopamine, and 1-methyl-4-phenylpyridinium in the presence of cholesterol was measured. However, no significant enhancement in cell death was observed. Moreover, the toxic compounds did not reduce mNT levels, indicating that mNT is not involved in toxic compound-induced cell death. In summary, these results indicate that cholesterol induces cell death, reduces mNT protein levels without suppressing transcription, and increases ROS generation, which may affect PD development. Further assessment of the mechanisms associated with abnormal intracellular cholesterol metabolism, reduced mNT levels, and cell death may lead to the discovery of novel treatments for PD.
Ionic Liquids Composed of Lactic Acid and Trometamol Enhance the Oral Absorption of 10 kDa Dextran, as a Model Compound of Mid-Sized Molecules.
Fukuda S, Takata H, Hayashi R … +7 more , Yamamoto H, Nakae T, Tatsumi N, Hamamoto H, Kobayashi S, Ando H, Ishida T
Biol Pharm Bull · 2026 · PMID 41565278 · Publisher ↗
Oral administration is the preferred route for drug administration owing to a high level of patient compliance and suitability for long-term treatment. However, drugs with a molecular weight of >1000 Da such as peptide-b...
Oral administration is the preferred route for drug administration owing to a high level of patient compliance and suitability for long-term treatment. However, drugs with a molecular weight of >1000 Da such as peptide-based therapeutics generally exhibit poor absorption from the gastrointestinal tract. In this study, we evaluated the potential of ionic liquids to enhance the oral absorption of mid-sized molecules such as dextran, which has a size of 10 kDa. In this study, the ionic liquids we tested enhanced the oral absorption of 10 kDa mid-sized dextran. Among the ionic liquids we tested, d/l-Lactic acid-trometamol ([Lac][Tris])-based ionic liquids consistently yielded higher values for maximum concentration (C; 153.9 ± 11.0 nmol/L) of dextran as well as for the area under the curve representing 0-2 h (AUC; 228.9 ± 54.1 nmol × h/L) compared with that of the other ionic liquids tested. The [Lac][Tris] = 5 : 1 ionic liquid achieved relatively higher values for both C and AUC. Interestingly, the observed oral absorption enhancement effect by the [Lac][Tris] = 5 : 1 ionic liquid for mid-sized molecules depended on the concentration of dextran (10 kDa). These results show that ionic liquid formulations can overcome the intestinal barrier and lead to systemic absorption of mid-sized molecules with molecular weights. Although further optimizations aimed at translating ionic liquid technology to the oral delivery of peptide drugs must be required, our results could expand the utility and possibility of ionic liquids as an oral absorption enhancer for mid-sized molecules such as peptides.
Characterization of the Cytosolic Translocation of the CYP3A2 Protein with Ubiquitination in Male and Female Rats.
Honda M, Fujimori H, Aiba T
Biol Pharm Bull · 2026 · PMID 41565253 · Publisher ↗
The cytosolic translocation of the membrane-associated CYP3A2 protein was examined in male and female rats to evaluate the ubiquitin-dependent protein degradation. In the experiments, the cytosol and membrane fractions w...
The cytosolic translocation of the membrane-associated CYP3A2 protein was examined in male and female rats to evaluate the ubiquitin-dependent protein degradation. In the experiments, the cytosol and membrane fractions were prepared from pooled rat liver tissues, and the amount of CYP3A2 protein in those fractions was determined by Western immunoblotting. The CYP3A2 protein detected in the cytosol fraction was shown to be ubiquitinated, and the apparent translocation ratio of the CYP3A2 protein from the membrane to the cytosol was calculated to be 0.58 in male control rats. The translocation ratio was then evaluated in male rats undergoing CYP3A2 induction. When male rats were treated with 80 mg/kg of dexamethasone (DEX), the translocation ratio decreased to 0.05, but the ratio was barely affected in male rats treated with 1.6 mg/kg of DEX, indicating that the cytosolic translocation of the CYP3A2 protein had a saturable nature. After that, the CYP3A2 translocation was examined in female rats with induced CYP3A2 protein, as the protein was known to be expressed in a male-specific manner. In female rats treated with 80 mg/kg of DEX, the translocation ratio was 0.04, but in those treated with 1.6 mg/kg of DEX, the ratio increased to 1.24, approximately 2 times larger than that in male control rats. It appeared that the DEX-induced CYP3A2 protein in female rats underwent expeditious degradation, presumably reflecting a difference in the mechanisms regulating the hepatic expression of the CYP3A2 protein in male and female rats.
Evaluation of Drug-Induced Kidney Injury by Primary Culture of Rat Kidney Tissue Slices Using Oxygen-Permeable Polyolefin Plate with Low Drug Adsorption.
Kadoguchi M, Matsushita K, Esashika K … +4 more , Yang J, Takahashi J, Tamai I, Arakawa H
Biol Pharm Bull · 2026 · PMID 41565252 · Publisher ↗
Rat kidney tissue slices are expected to be useful for an in vitro evaluation of drug-induced kidney injury (DIKI). We previously established a primary culture of rat kidney tissue slices using gas-permeable plates. Howe...
Rat kidney tissue slices are expected to be useful for an in vitro evaluation of drug-induced kidney injury (DIKI). We previously established a primary culture of rat kidney tissue slices using gas-permeable plates. However, polydimethylsiloxane (PDMS) exhibits a significant adsorption of lipophilic drugs, leading to limitations in DIKI evaluation. The aim of the present study was to evaluate a gas-permeable InnoCell™ non-treated plate made of polyolefin with low adsorption of lipophilic compounds for the primary culture of rat kidney tissue slices as an in vitro DIKI evaluation system. Drug concentrations in the medium were measured 24 h after the addition of 9 drugs to PDMS plates and InnoCell™ non-treated plates. Intra-tissue ATP levels and histopathology of rat kidney tissue slices were examined on Day 3 of culture. As a result, the InnoCell™ non-treated plates exhibited lower adsorption rates for sunitinib, cyclosporine A, and alectinib than the PDMS plates. Intra-tissue ATP levels were maintained, and immunohistochemical staining of megalin and aquaporin 1 was observed for up to 3 d. Furthermore, exposure to nephrotoxic lipophilic drugs reduced the ATP content in slices compared to that in non-treated slices. These results suggest that the primary culture of rat kidney tissue slices using InnoCell™ non-treated plates is useful for the DIKI evaluation of lipophilic drugs compared with conventional PDMS plates.
Impact of Chronic Kidney Disease on the Onset of Sepsis: A Systematic Review.
Osa S, Enoki Y, Endo A … +8 more , Kumamoto K, Kobayashi K, Komiya C, Satake N, Kawakami J, Yagi T, Taguchi K, Matsumoto K
Biol Pharm Bull · 2026 · PMID 41548931 · Publisher ↗
Patients with chronic kidney disease (CKD) who develop sepsis experience worse prognoses; however, the impact of CKD on the incidence of sepsis has not been systematically investigated. A systematic review was conducted...
Patients with chronic kidney disease (CKD) who develop sepsis experience worse prognoses; however, the impact of CKD on the incidence of sepsis has not been systematically investigated. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of Medical Literature Analysis and Retrieval System Online, Web of Science, the Cochrane Register of Controlled Trials, and ClinicalTrials.gov was performed for literature published prior to May 22, 2025, comparing the onset of sepsis in patients with or without CKD. The risk of bias was determined using the Risk of Bias in Nonrandomized Studies of Interventions tool. This study was registered with the International Prospective Register of Systematic Reviews (CRD42023465075). A total of 14 studies met the inclusion criteria for the systematic review. Of these, 5 examined community-acquired sepsis, 2 focused on intensive care unit-acquired sepsis, and the rest investigated surgery-acquired sepsis. Most studies enrolled populations aged over 65 years; 2 assessed age-related sepsis risk. One study evaluated sepsis occurrence in patients with end-stage CKD, while 3 studies stratified this association by estimated glomerular filtration rate (eGFR). Nearly all studies demonstrated an increased risk of sepsis among patients with CKD, with the risk progressively increasing as eGFR declined. Additionally, 2 studies reported that CKD elevated the risk of sepsis regardless of age, and all included studies indicated a low risk of bias. We indicate that patients with CKD may have a higher risk of developing sepsis than individuals without CKD.
Drug-Induced Liver Injury with Eosinophilia: A Case-Control Study Using Electronic Medical Records.
Minagawa K, Akimoto H, Hayakawa T … +3 more , Nagashima T, Takahashi Y, Asai S
Biol Pharm Bull · 2026 · PMID 41548930 · Publisher ↗
Idiosyncratic drug-induced liver injury (iDILI) is an unpredictable and potentially severe adverse drug reaction, in which immune-mediated mechanisms are suspected to play a central role. Although eosinophilia is often c...
Idiosyncratic drug-induced liver injury (iDILI) is an unpredictable and potentially severe adverse drug reaction, in which immune-mediated mechanisms are suspected to play a central role. Although eosinophilia is often considered a marker of hypersensitivity reactions, the role of eosinophils in iDILI, including drug-specific risks, remains poorly understood. We conducted a case-control study using electronic medical records to evaluate drug-specific risks associated with drug-induced liver injury with eosinophilia (DILI-Eos). Among 17129 Japanese adult patients who underwent serial liver function tests and eosinophil counts, we extracted 631 DILI-Eos cases and 16498 non-DILI-Eos controls. Multivariable logistic regression analysis was performed for 38 drugs that were newly prescribed in more than 50 DILI-Eos cases within 60 d prior to liver injury onset. Sulbactam/cefoperazone showed the strongest association with DILI-Eos (adjusted odds ratio (OR) 14.51; 95% confidence interval (CI) 10.09-20.85), followed by meropenem (OR 5.68; 95% CI 4.10-7.82) and tazobactam/piperacillin (OR 3.55; 95% CI 2.63-4.75). Several commonly used drugs, such as mosapride, lansoprazole, furosemide, and ambroxol, were also significantly associated with increased risk. These findings suggest that DILI-Eos can be triggered by a wide range of drugs across various therapeutic classes potentially via immune-mediated pathways. Notably, substantial variability in risk was observed even within the same drug classes, such as β-lactam antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), underscoring the importance of drug-specific evaluation. Further studies are needed to clarify the causality and mechanisms underlying eosinophilic responses in DILI.
HPLC-UV Analysis of Fruquintinib in Plasma of a Patient with Colorectal Cancer.
Gando Y, Yamada M, Okano Y … +4 more , Ishikawa Y, Shirota M, Nomura S, Yasu T
Biol Pharm Bull · 2026 · PMID 41548929 · Publisher ↗
Fruquintinib is a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR) used in patients with metastatic colorectal cancer. Fruquintinib reportedly inhibits the phosphorylation...
Fruquintinib is a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR) used in patients with metastatic colorectal cancer. Fruquintinib reportedly inhibits the phosphorylation of VEGFR-2 by >80% at plasma trough concentrations >176 ng/mL. Therefore, maintaining a stable trough concentration of fruquintinib is clinically necessary. To date, the only reported method for quantifying fruquintinib concentrations in human plasma is LC-MS/MS, which is challenging to use routinely in clinical settings given its high cost and technical demands. Therefore, in this study, we aimed to develop a method for determining fruquintinib levels in human plasma and validate it for therapeutic drug monitoring (TDM). For the analysis, a 50-μL human plasma sample was obtained, and protein precipitation was performed using acetonitrile extraction. Fruquintinib and acetanilide (internal standard) were separated on a reversed-phase column using a mobile phase consisting of 0.5% KHPO (pH 2.6) and acetonitrile (69/31, v/v), pumped at a flow rate of 1.0 mL/min. The detection wavelength was set at 237 nm. The calibration curves for fruquintinib were linear (r = 0.999) in the range of 50-2000 ng/mL. The accuracy and precision in all validation experiments adhered to the guidelines of the U.S. Food and Drug Administration. Using the validated method, we successfully measured fruquintinib concentrations in the plasma of a patient. This article presents a simple, novel, and sensitive HPLC-UV-based method for determining the plasma concentration of fruquintinib and confirms its applicability in the TDM of fruquintinib in the clinical setting.
Effects of Oxygen-Permeable Plates on Cytochrome P450 and Flavin-Containing Monooxygenase in HepaRG Spheroid Cultures.
Takaoka N, Morita M, Takahashi J … +3 more , Esashika K, Ohta S, Sanoh S
Biol Pharm Bull · 2026 · PMID 41535012 · Publisher ↗
Three-dimensional (3D) hepatocyte spheroid cultures offer an advanced in vitro model for investigating liver function and drug metabolism; however, oxygen diffusion limitations restrict spheroid size and functionality. I...
Three-dimensional (3D) hepatocyte spheroid cultures offer an advanced in vitro model for investigating liver function and drug metabolism; however, oxygen diffusion limitations restrict spheroid size and functionality. In the present study, we developed a 3D spheroid culture system using HepaRG, a human hepatoma-derived cell line that retains drug-metabolizing enzymes, and oxygen-permeable plates composed of 4-polymethyl-1-pentene (PMP) to improve oxygen availability and metabolic performance. Morphological analysis showed enhanced spheroid circularity and compactness in the PMP culture, implying enhanced cell-cell adhesion. Hypoxic imaging revealed that PMP plate-based cultures markedly reduced central hypoxia, enabling the formation of spheroids with up to 20000 cells. Using clozapine, a low-clearance antipsychotic drug with limited metabolic elimination that is metabolized by monooxygenases, including CYP3A4 and flavin-containing monooxygenase (FMO), we observed an enhanced decline in clozapine levels in PMP plates compared with the clozapine levels seen in the conventional polystyrene plates. Furthermore, the mRNA and protein-expression levels of CYP3A4 and FMO3 were upregulated in the spheroids cultured on PMP plates. These results suggest that improved oxygenation enhances hepatic functionality in 3D cultures by maintaining cell viability and promoting the expression of drug-metabolizing enzymes. Therefore, the PMP plate-based spheroid model offers a practical and physiologically relevant platform for investigating drug metabolism and hepatotoxicity.
Long-Term Use of Proton Pump Inhibitors Affects Blood Levels of Indoxyl Sulfate in Japanese Patients with Chronic Kidney Disease.
Kawamoto K, Kadomura S, Nabeki M … +7 more , Sasaki H, Yamada K, Noda M, Masuda H, Tsuchida S, Itoh T, Kobayashi M
Biol Pharm Bull · 2026 · PMID 41526228 · Publisher ↗
Proton pump inhibitors (PPIs) are implicated in the progression of chronic kidney disease (CKD), but the mechanism behind this is unclear. PPIs are known to inhibit organic anion transporters (OATs) and affect intestinal...
Proton pump inhibitors (PPIs) are implicated in the progression of chronic kidney disease (CKD), but the mechanism behind this is unclear. PPIs are known to inhibit organic anion transporters (OATs) and affect intestinal microbiota. PPI use may influence serum concentrations of indoxyl sulfate (IS), a uremic toxin that contributes to CKD. This study compares serum IS concentrations between Japanese patients receiving long-term PPI prescriptions and those receiving non-PPIs, evaluating the effect of long-term PPI therapies on serum IS concentrations. This single-center, cross-sectional study included patients with an estimated glomerular filtration rate (eGFR) of 15 to 44 mL/min/1.73 m, who attended an outpatient visit at a nephrology and/or diabetes department between October 2022 and December 2023. Serum IS concentrations were measured by HPLC. The analysis included 29 patients in the PPI group and 28 in the non-PPI group; serum IS concentrations were significantly higher in the PPI group [median (interquartile range) 15.37 (9.69-19.80) µM] and non-PPI group [median (interquartile range) 10.66 (6.97-14.19) µM], p = 0.03. Multiple regression analysis was performed, linking prescription of PPIs and lower eGFR to higher serum IS levels. This study highlights an apparent association of long-term prescriptions of PPIs with high serum IS concentrations. However, more detailed studies are required to evaluate the contribution of intestinal microbiota and diet to this phenomenon.
SMTP-44D Improves High Glucose-Induced Vascular Endothelial Dysfunction.
Jono S, Shinouchi R, Obama T … +3 more , Itabe H, Hasumi K, Nobe K
Biol Pharm Bull · 2026 · PMID 41526227 · Publisher ↗
Chronic diabetic complications are mostly caused by vascular disorders, with only a few effective treatments or preventive measures currently available. In this study, we investigated the effects of Stachybotrys microspo...
Chronic diabetic complications are mostly caused by vascular disorders, with only a few effective treatments or preventive measures currently available. In this study, we investigated the effects of Stachybotrys microspora triprenyl phenol-44D (SMTP-44D), a fungus-derived compound that inhibits both the epoxide hydrolase and phosphatase activities of soluble epoxide hydrolase (sEH), using human umbilical vein endothelial cells (HUVECs) in a high glucose treatment model. When HUVECs were treated with high glucose (30 mM) for 24 h, cell viability decreased to 69% compared with that under normal glucose (5.6 mM) conditions. When SMTP-44D was added, cell viability increased to 111%. In addition, nitric oxide levels in HUVECs decreased to 52% after 24 h of high-glucose treatment but increased to 82% after SMTP-44D treatment. Under the same conditions, high-glucose treatment increased intracellular reactive oxygen species levels and reduced Akt activation. SMTP-44D significantly improved both these changes, compared with the high glucose group. Under high glucose conditions, it is likely that oxidative stress and the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway are involved in endothelial dysfunction, and that SMTP-44D restores vascular function by acting on these pathways. In this study, we demonstrated, for the first time, SMTP-44D improves diabetic vascular endothelial dysfunction, suggesting that it may be a novel therapeutic and preventive candidate for the treatment of chronic complications of diabetes.
Exploratory Analysis for Development Predictive Models of Immune Checkpoint Inhibitor-Induced Myocarditis Using a Nationwide Claims Database.
Yamamoto R, Hamano H, Nakagomi K … +7 more , Uchiyama M, Michihara A, Ozaki AF, Patel PM, Tanioka M, Zamami Y, Uehara T
Biol Pharm Bull · 2026 · PMID 41526226 · Publisher ↗
Immune checkpoint inhibitors (ICIs), essential in cancer therapy, can cause severe immune-related adverse events (irAEs), including myocarditis with a high fatality rate. Currently, the pathogenesis, biomarkers, and risk...
Immune checkpoint inhibitors (ICIs), essential in cancer therapy, can cause severe immune-related adverse events (irAEs), including myocarditis with a high fatality rate. Currently, the pathogenesis, biomarkers, and risk factors of ICI-induced myocarditis (ICIM) are not fully understood. This exploratory study aimed to develop machine learning-based models to predict the onset of ICIM within 3 months of starting ICI therapy, using a large health insurance database. The models were constructed using the Light Gradient Boosting Machine (LightGBM) and Random Forest algorithms, incorporating clinical variables such as comorbidities and prior medication classifications. In this study, a strategy combining undersampling and bagging was used to minimize the impact of highly imbalanced datasets. The Random Forest model demonstrated superior performance compared with the LightGBM model, and the SHapley Additive exPlanations (SHAP) analysis for the Random Forest model revealed that the concurrent use of ICIs was the most important variable for predictions. Although predictive performance remains limited (AUROC ≈ 0.63), this exploratory framework demonstrates the feasibility of developing data-driven risk prediction models for ICIM. Future studies with expanded datasets and integration of laboratory parameters are warranted to improve predictive accuracy and potential clinical applicability.
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