Details of a Researcher - Matsumoto, Kazuaki

Papers - Matsumoto, Kazuaki

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Dual delivery of carbon monoxide and doxorubicin using haemoglobin-albumin cluster: proof of concept for well-tolerated cancer therapy.

Ito C, Taguchi K, Yamada T, Hanaya K, Enoki Y, Sugai T, Komatsu T, Matsumoto K

Journal of materials chemistry. B (Journal of Materials Chemistry B) 12 ( 23 ) 5600 - 5608 2024.05

Joint Work, ISSN 2050-750X

A serious concern of doxorubicin (DOX) therapy is that it causes severe adverse effects, particularly cardiotoxicity. Carbon monoxide (CO) possesses powerful cytoprotective effects against drug-induced organ injury and is expected to ameliorate DOX-induced cardiotoxicity. In this study, a dual carrier of DOX and CO (CO-HemoAct-DOX) was fabricated based on a haemoglobin-albumin cluster (HemoAct), which is a protein cluster with a haemoglobin core structure wrapped by serum albumin. CO-HemoAct-DOX was synthesised by binding CO to a haemoglobin core and covalently conjugating (6-maleimidocaproyl)hydrazone derivative of DOX to an albumin shell. The average DOX/cluster ratio was about 2.6. In the in vitro cytotoxicity assay against cancer cells, the anti-tumour activity of CO-HemoAct-DOX was 10-fold lower than that of DOX in a 2D-cultured model, whereas CO-HemoAct-DOX suppressed the growth of tumour spheroids to the same extent as DOX in the 3D-cultured model. In colon-26 tumour-bearing mice, CO-HemoAct-DOX achieved DOX delivery to the tumour site and alleviated tumour growth more effectively than DOX. Furthermore, CO-HemoAct attenuated DOX-induced cardiomyocyte atrophy in H9c2 cells and elevated the levels of cardiac biomarkers in mice exposed to DOX. These results suggest that the dual delivery of CO and DOX using HemoAct is a promising strategy as an anti-tumour agent to realise well-tolerated cancer therapy with minimal cardiotoxicity.

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Japanese Society for infection prevention and control guide to Clostridioides difficile infection prevention and control.

Kunishima H, Ichiki K, Ohge H, Sakamoto F, Sato Y, Suzuki H, Nakamura A, Fujimura S, Matsumoto K, Mikamo H, Mizutani T, Morinaga Y, Mori M, Yamagishi Y, Yoshizawa S

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 30 ( 8 ) 673 - 715 2024.05

Joint Work, ISSN 1341-321X

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Efficacy of hemodialysis and plasma exchange for ceftriaxone-induced antibiotic-associated encephalopathy：A case report of severe acute kidney injury due to rapidly progressive glomerulonephritis

Nagayama Shohei, Tashiro Sho, Kawai Yuki, Kunii Ayana, Baba Kenji, Kawasaki Keiko, Komiya Shiro, Yuto Jun, Matsumoto Kazuaki, Iwamoto Tamio, Tamura Kouichi

Nihon Toseki Igakkai Zasshi (The Japanese Society for Dialysis Therapy) 57 ( 2 ) 93 - 98 2024

Joint Work, ISSN 13403451

<p>An 88-year-old woman was admitted to our hospital with a diagnosis of acute kidney injury (AKI, stage 3) in May 20XX, attributed to rapidly progressive glomerulonephritis caused by anti-glomerular basement membrane disease. Emergent hemodialysis (HD) was performed for the rapidly progressing AKI, and she was also treated with PSL combined with plasma exchange (PE). On the fifth day of hospitalization, she showed a decreased level of consciousness. We suspected antibiotic-associated encephalopathy (AAE) due to ceftriaxone (CTRX), which had been administered since admission. The next day, plasma CTRX concentration was high (198.7 μg/mL). We discontinued CTRX. We predicted that PE would promote the removal of CTRX due to its low distribution volume and high protein-binding affinity rate；however, plasma CTRX concentration did not decrease after PE. Although a temporary decrease in plasma CTRX concentration was observed after HD, effective drug elimination was not achieved the next day due to redistribution of the drug from the tissue to the blood (rebound phenomenon). After discontinuation of CTRX, the patientʼs level of consciousness improved to the same level as on admission on the 13th day. Hypoalbuminemia and the presence of the rapidly progressing AKI in the present patient may have led to a decrease in the protein-binding affinity rate of CTRX, resulting in the plasma CTRX concentration being unchanged after HD and PE. As elderly AKI patients have multiple risks for AAE, we need to take this background into account.</p>

Validation and development of population pharmacokinetic model of vancomycin using a real-world database from a nationwide free web application

Oda K., Matsumoto K., Shoji K., Shigemi A., Kawamura H., Takahashi Y., Katanoda T., Hashiguchi Y., Jono H., Saito H., Takesue Y., Kimura T.

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 30 ( 12 ) 1244 - 1251 2024

Joint Work, ISSN 1341321X

Introduction: Vancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT). Methods: In this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC. Results: The modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age. Conclusions: This study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users.

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Predictive Value of Vancomycin AUC<inf>24</inf>/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study

Hanai Y., Hashi H., Hanawa K., Endo A., Miyazaki T., Yamaguchi T., Harada S., Yokoo T., Uekusa S., Namiki T., Yokoyama Y., Asakawa D., Isoda R., Enoki Y., Taguchi K., Matsumoto K., Matsuo K.

Pharmaceutical Research (Pharmaceutical Research) 41 ( 7 ) 1381 - 1389 2024

Joint Work, ISSN 07248741

Background: Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration–time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. Methods: This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. Results: This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335–18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. Conclusions: In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.

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T-cell immunosuppression in sepsis is augmented by sciatic denervation-induced skeletal muscle atrophy

Osa S., Enoki Y., Takahashi D., Chuang V.T.G., Taguchi K., Matsumoto K.

FEBS Letters 598 ( 20 ) 2581 - 2591 2024

Joint Work, ISSN 00145793

Skeletal muscle atrophy is a known risk factor for immunosuppressive conditions and for a poor prognosis in sepsis. However, its immunopathology has not been experimentally elucidated. This study investigated the effects of skeletal muscle atrophy on the immunopathology of sepsis. Male C57BL/6J mice were subjected to sciatic denervation (DN) and caecal ligation and puncture (CLP) to induce muscle atrophy or sepsis. The macrophages, myeloid-derived suppressor cells (MDSC), and T-cells in peritoneal and spleen were analysed using flow cytometry. DN-induced muscle atrophy did not affect macrophage and MDSC populations. In contrast, the percentage of cytotoxic T-lymphocyte-associated antigen (CTLA)-4+ CD4+ T-cells, programmed death (PD)-1+ CD8+ T-cells, regulatory T-cells, and the CTLA-4+ regulatory T-cells was statistically significantly higher in DN-CLP mice than in sham-CLP mice. Skeletal muscle atrophy before sepsis triggers excessive T cell immunosuppression, which may contribute to the exacerbation of sepsis under skeletal muscle atrophy.

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SARS-CoV-2 mRNA vaccine-related myocarditis and pericarditis: An analysis of the Japanese Adverse Drug Event Report database

Takada K., Taguchi K., Samura M., Igarashi Y., Okamoto Y., Enoki Y., Tanikawa K., Matsumoto K.

Journal of Infection and Chemotherapy 31 ( 1 ) 102485 2024

Joint Work, ISSN 1341321X

Background: The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines and myocarditis/pericarditis in the Japanese population has not been systematically investigated. This study was aimed at clarifying the association between SARS-CoV-2 mRNA vaccines (BNT162b2 and mRNA-1273) and myocarditis/pericarditis as well as influencing factors by using the Japanese Adverse Drug Event Report database. Methods: Reporting odds ratios (RORs) and 95 % confidence intervals (95 % CIs) for the association between the vaccines and myocarditis/pericarditis were calculated using data from the database (April 2004–December 2023). Age, sex, onset time, and outcomes in symptomatic patients were evaluated. Results: The total number of reports was 880,999 (myocarditis: 1846; pericarditis: 761). The adverse events associated with the vaccines included myocarditis (919 cases) and pericarditis (321 cases), with the ROR [95 % CIs] being significant for both (myocarditis: 30.51 [27.82–33.45], pericarditis: 21.99 [19.03–25.40]). Furthermore, the ROR [95 % CIs] of BNT162b2 and mRNA-1273 were 15.64 [14.15–17.28] and 54.23 [48.13–61.10], respectively, for myocarditis, and 15.78 [13.52–18.42] and 27.03 [21.58–33.87], respectively, for pericarditis. Furthermore, most cases were ≤30 years or male. The period from vaccination to onset was ≤8 days, corresponding to early failure type based on analysis using the Weibull distribution. Outcomes were recovery or remission for most cases; however, they were severe or caused death in some cases. Conclusion: In the Japanese population, SARS-CoV-2 mRNA vaccination was significantly associated with the onset of myocarditis/pericarditis. The influencing factors included age of ≤30 years and male. Furthermore, although most adverse events occurred early after vaccination, overall outcomes were good.

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Antimicrobial Stewardship of Oral Third-Generation Cephalosporins in Community Pharmacy: A Single-Center Quasi-Experimental Study

Nakamura Koyo, Matsumoto Kazuaki, Enoki Yuki, Taguchi Kazuaki, Yamashita Shuji, Kai Junko, Hayashi Hideki

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 47 ( 8 ) 1447 - 1451 2024

Joint Work, ISSN 0918-6158

<p>Proper use of antimicrobials in hospital and outpatient settings is critical for minimizing the occurrence of antimicrobial resistance. Some hospitals have intervened in the inappropriate use of third-generation oral cephalosporins. However, there have been no such studies in community pharmacy settings. This study aimed to investigate how the use of oral third-generation cephalosporins in community pharmacies affects the amount of antimicrobials used. Patients who visited Nakanomaru Pharmacy after being prescribed antimicrobials at target medical institutions between February 2021 and January 2023 were identified. The number of oral antimicrobials used, duration of use, number of prescriptions, patient age and sex, and infectious diseases in the target patients before and after the intervention for the proper use of oral third-generation cephalosporins were retrospectively investigated based on the patients’ medication history and prescription receipts. Through efforts to ensure the proper use of oral third-generation cephalosporins, the amount of oral third-generation cephalosporins used has decreased, and the use of penicillins and oral first-generation cephalosporins has increased. There was no increase in the antimicrobial change or relapse rates associated with treatment failure before and after the initiation of appropriate antimicrobial use. By working toward the proper use of oral third-generation cephalosporins in community pharmacies, we were able to reduce the doses of oral third-generation cephalosporins without compromising their therapeutic efficacy. We believe that recommending the selection of narrow-spectrum antimicrobials based on these guidelines will contribute to their proper use.</p>

Identification of Patients Who Require Two-Point Blood Sampling for the Peak and Trough Values Rather Than One-Point Blood Sampling for the Trough Value for the Evaluation of AUC of Vancomycin Using Bayesian Estimation

Suzuki A., Samura M., Ishigo T., Fujii S., Ibe Y., Yoshida H., Tanaka H., Ebihara F., Maruyama T., Hamada Y., Fujihara H., Yamaguchi F., Nagumo F., Komatsu T., Tomizawa A., Takuma A., Chiba H., Nishi Y., Enoki Y., Taguchi K., Matsumoto K.

Pharmaceutical Research 41 ( 11 ) 2161 - 2171 2024

Joint Work, ISSN 07248741

Objectives: It is recommended to adjust the dose of vancomycin (VCM) with a target area under the concentration–time curve (AUC) of 400–600 μg·h/mL. Factors that affect the deviation between AUCs are estimated from the trough value alone and the trough and peak values using practical AUC-guided therapeutic drug monitoring (PAT) for vancomycin. In this study, factors that affect AUC were evaluated. Methods: AUCs were estimated from a single trough value and trough and peak values, and the patients were classified into those who showed a 10% or greater deviation (deviation group) and those in whom the deviation was less than 10% (no-deviation group). Risk factors related to ≥ 10% deviation of AUC were identified by univariate and multivariate analysis. Results: As a result of univariate and multivariate analysis of 30 patients in the deviation group and 344 patients in the no-deviation group, a creatinine clearance (CLcr) of ≥ 110 mL/min (odds ratio (OR) = 3.697, 95% confidence interval (CI) = 1.616–8.457, p = 0.002), heart failure with a brain natriuretic peptide (BNP) of ≥ 300 pg/mL (OR = 4.854, 95%CI = 1.199–19.656, p = 0.027), and the concomitant use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker (ACE-I/ARB) (OR = 2.544, 95%CI = 1.074–6.024, p = 0.034) were identified as risk factors of ≥ 10% deviation of AUC. Conclusions: Estimation of AUC by two-point blood sampling for the trough and peak values rather than one-point blood sampling for the trough value is suggested to improve the prediction accuracy in patients with enhanced renal function, severe heart failure, and patients using ACE-I/ARB.

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Hydrosulphide-methaemoglobin-albumin cluster: a hydrogen sulphide donor

Suzuki Y., Yamada T., Enoki Y., Matsumoto K., Komatsu T., Taguchi K.

Journal of Materials Chemistry B 12 ( 44 ) 11515 - 11522 2024

Joint Work, ISSN 2050750X

Methaemoglobin (metHb) possesses inherent characteristics that facilitate reversible binding to hydrogen sulphide. Exogenous hydrogen sulphide supplementation imparts beneficial bioactive effects, including antioxidant and anti-inflammatory; hence, we hypothesized that the metHb-hydrogen sulphide complex could act as a hydrogen sulphide donor for medication. In this study, we prepared a hydrosulphide-metHb-albumin (H2S-metHb-albumin) cluster and examined its applicability as a hydrogen sulphide donor in the mice model of hepatic ischemia-reperfusion injury. Structural analysis revealed that the H2S-metHb-albumin cluster exhibited a nanostructure wherein one metHb was wrapped by an average of three albumins, and hydrogen sulphide was bound to the haem. Additionally, the H2S-metHb-albumin cluster exhibited low-pH responsiveness, leading to sustained release of hydrogen sulphide. Owing to these structural and pharmaceutical characteristics, the severity of hepatic ischemia-reperfusion injury was alleviated via antioxidant and anti-inflammatory effects of the H2S-metHb-albumin cluster treatment. The protective effects were more potent in the H2S-metHb-albumin cluster compared to that in a conventional hydrogen sulphide donor (sodium hydrogen sulphide). No abnormal signs of toxic and biological responses were observed after the H2S-metHb-albumin cluster administration, confirming high biological compatibility. These results successfully establish the proof of concept that the H2S-metHb-albumin cluster is a promising hydrogen sulphide donor. To the best of our knowledge, this is the first report demonstrating the remarkable potential of metHb as a biomaterial for hydrogen sulphide donors.

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

Namiki T, Yokoyama Y, Hashi H, Oda R, Jibiki A, Kawazoe H, Matsumoto K, Suzuki S, Nakamura T

Pharmacotherapy (Pharmacotherapy) 44 ( 2 ) 149 - 162 2023.11

Joint Work, ISSN 0277-0008

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

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Elucidating the binding properties of methemoglobin in red blood cell to cyanide, hydrosulfide, and azide ions using artificial red blood cell.

Suzuki Y, Arakida Y, Sakai H, Enoki Y, Matsumoto K, Taguchi K

Toxicology and applied pharmacology (Toxicology and Applied Pharmacology) 481 116752 2023.11

Joint Work, ISSN 0041-008X

Methemoglobin (metHb), the oxidized form of hemoglobin, lacks the ability of reversible oxygen binding; however, it has a high binding affinity to toxic substances such as cyanide, hydrosulfide, and azide. This innate property of metHb offers the clinical option to treat patients poisoned with these toxins, by oxidizing the endogenous hemoglobin in the red blood cells (RBCs). The binding properties of naked metHb (isolated from RBC) with these toxins has been studied; however, the binding behaviors of metHb under the intracellular conditions of RBC are unclear because of the difficulty in detecting metHb status changes in RBC. This study aimed to elucidate the binding properties of metHb in RBC under physiological and poisoned conditions using artificial RBC, which was hemoglobin encapsulated in a liposome. The mimic-circumstances of metHb in RBC (metHb-V) was prepared by oxidizing the hemoglobin in artificial RBC. Spectroscopic analysis indicated that the metHb in metHb-V exhibited a binding behavior different from that of naked metHb, depending on the toxic substance: When the pH decreased, (i) the cyanide binding affinity of metHb-V remained unchanged, but that of naked metHb decreased (ii) the hydrosulfide binding affinity was increased in metHb-V but was decreased in naked metHb. (iii) Azide binding was increased in metHb-V, which was similar to that in naked metHb, irrespective of the pH change. Thus, the binding behavior of intracellular metHb in the RBC with cyanide, hydrosulfide, and azide under physiological and pathological conditions were partly elucidated using the oxidized artificial RBC.

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A cohort study of the risk factors and the target AUC to avoid vancomycin-associated acute kidney injury in pediatric patients.

Kanazawa N, Shigemi A, Amadatsu N, Arimura K, Shimono S, Oda K, Chuang VTG, Matsumoto K, Kawamura H, Terazono H

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 30 ( 4 ) 323 - 328 2023.11

Joint Work, ISSN 1341-321X

Objectives: In recent years, Vancomycin (VCM) dosing design using area under the concentration-time curve (AUC) has been recommended as a measure of efficacy and safety, but there are fewer reports on pediatric patients than on adults. In this study, we evaluated the threshold of AUC for AKI occurrence in pediatric patients and investigated the factors that contribute to the occurrence of AKI. Methods: Pediatric patients aged 1–15 years on VCM treatment who underwent TDM at Kagoshima University Hospital from April 2016 to March 2022 were included in the computation of AUC using pediatric population pharmacokinetic parameters. Results: The ROC curve showed that the AUC threshold for the risk of developing AKI was 583.0 μg・h/mL, and the AUC-ROC curve was 0.873 (sensitivity 0.930, specificity 0.750). Univariate analysis showed that factors associated with AKI incidence were the duration of VCM administration, ICU admission, and AUCSS. Concomitant medications identified as risk factors for AKI incidence were tazobactam/piperacillin, liposomal amphotericin B, calcineurin inhibitors, contrast agents, and H2-receptor blockers. The multivariate analysis showed that AUC ≧ 583.0 μg・h/mL (odds ratio 20.14, 95% CI 3.52–115.22, p < 0.001) and H2-receptor blockers (odds ratio 8.70, 95% confidence interval = 1.38–54.87, p = 0.02) were independent factors for AKI incidence. Conclusions: We showed that in pediatric patients receiving VCM, the risk of AKI increases as AUC increases. The findings imply that concurrent use of VCM and H2-receptor blockers may increase the risk of AKI.

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Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study.

Ishigo T, Fujii S, Ibe Y, Aigami T, Nakano K, Fukudo M, Yoshida H, Tanaka H, Ebihara F, Maruyama T, Hamada Y, Suzuki A, Fujihara H, Yamaguchi F, Samura M, Nagumo F, Komatsu T, Tomizawa A, Takuma A, Chiba H, Nishi Y, Enoki Y, Taguchi K, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 30 ( 4 ) 329 - 336 2023.11

Joint Work, ISSN 1341-321X

Introduction: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. Methods: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400–600 μg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). Results: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400–600 μg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). Conclusion: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

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Oral teicoplanin administration suppresses recurrence of Clostridioides difficile infection: Proof of concept.

Tanaka Y, Tashiro S, Ikegami S, Enoki Y, Taguchi K, Matsumoto K

Anaerobe (Anaerobe) 84 102789 2023.10

Joint Work, ISSN 1075-9964

Objectives: Teicoplanin is a potential antimicrobial candidate for Clostridioides difficile infection (CDI) treatment. However, the therapeutic potential of teicoplanin against severe CDI has not been clinically proven. In the present study, we investigated the efficacy of oral teicoplanin administration against severe CDI and the recurrence of severe CDI after teicoplanin treatment in a mouse model. Methods: A lethal CDI mouse model was established by colonizing the mice with C. difficile ATCC® 43255; they were orally administered teicoplanin (128 mg/kg/d) or vancomycin (160 mg/kg/d) for 10 d, 24 h after C. difficile spore challenge, and physiological and biological responses were monitored for 20 d after the initial antibiotic treatment. We also performed the in vitro time-kill assay and determined minimum inhibitory concentration (MIC), post-antibiotic effect, and toxin production with antibiotic exposure. Results: The therapeutic response (survival rates, body weight change, clinical sickness score grading, C. difficile load, and toxin titer in feces) of oral teicoplanin administration was comparable to that of oral vancomycin administration in the lethal CDI mouse model. Moreover, teicoplanin treatment suppressed the re-onset of diarrhea and re-increase in toxin titer 10 d after treatment compared with that by vancomycin treatment. In in vitro experiments, teicoplanin exhibited time-dependent antibacterial activity and possessed lower MIC and longer post-antibiotic effect than vancomycin against C. difficile. C. difficile toxin production was numerically lower with teicoplanin exposure than with vancomycin exposure. Conclusions: The results obtained from the present basic experiments could suggest that teicoplanin is a potential antibiotic for the treatment of severe CDI with recurrence-prevention activity.

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Pharmaceutical stability of methemoglobin-albumin cluster as an antidote for hydrogen sulfide poisoning after one-year storage in freeze-dried form

Suzuki Y., Taguchi K., Okamoto W., Enoki Y., Komatsu T., Matsumoto K.

International Journal of Pharmaceutics (International Journal of Pharmaceutics) 645 123433 2023.10

Joint Work, ISSN 03785173

Long-term stability during storage is an important requirement for pharmaceutical preparations. The methemoglobin (metHb)-albumin cluster, in which bovine metHb is covalently enveloped with an average of three human albumin molecules, is a promising antidote for hydrogen sulfide (H2S) poisoning. In this study, we investigated the pharmaceutical stability of metHb-albumin cluster after storage for one year in solution and as freeze-dried powder. The lyophilized powder of metHb-albumin cluster stored for one year was readily reconstituted in sterile water for injection, yielding a homogeneous brown solution. Physicochemical measurements revealed that the overall structure of the metHb-albumin cluster was still maintained after preservation. Results of the pharmacological study showed that 100 % of the H2S-poisoned mice survived after treatment with the reconstituted solution of metHb-albumin cluster powder. Furthermore, the solution did not cause any toxic reactions. The antidotal efficacy of metHb-albumin cluster for H2S poisoning was preserved in freeze-dried powder form for at least one year.

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In vivo Pharmacokinetic/Pharmacodynamic Analysis of the Efficacy of the Cefepime/Nacubactam Combination Against β-Lactamase-Producing Enterobacterales based on the Instantaneous MIC Concept.

Igarashi Y, Takemura W, Liu X, Kojima N, Morita T, Chuang VTG, Enoki Y, Taguchi K, Matsumoto K

Pharmaceutical research (Pharmaceutical Research) 40 ( 10 ) 2423 - 2431 2023.10

Joint Work, ISSN 0724-8741

Purpose: Nacubactam (NAC) is a novel diazabicyclooctane β-lactamase inhibitor used in combination with cefepime (CFPM). In this study, we aimed to determine the target pharmacokinetics (PK) and pharmacodynamics (PD) values of CFPM/NAC in mice infected with β-lactamase-producing Enterobacterales, such as the carbapenemase-producing Enterobacterales. Methods: Three strains of β-lactamase-producing Enterobacterales, Klebsiella pneumoniae MSC 21444, Escherichia coli MSC 20662, and K. pneumoniae ATCC BAA-1898, were used for checkerboard assays and fractionation studies and dose-range studies. A PK study was performed in neutropenic mice. Additionally, PK/PD analysis was performed based on the instantaneous minimum inhibitory concentration (MICi) concept. Results: Checkerboard measurements revealed that higher NAC concentrations decreased the CFPM MIC in a concentration-dependent manner. In all tested strains, fT > MICi calculated from the PK experiments showed a high correlation with the mean change in the bacterial count of thigh-infected mice in the in vivo PD study, suggesting that fT > MICi is an optimal PK/PD parameter for monitoring the CFPM/NAC combination. The target fT > MICi values for CFPM/NAC to achieve a bacteriostatic effect, 1-log10-kill, and 2-log10-kill values were 30, 49, and 94%, respectively. Conclusions: Our results indicate that fT > MICi is a PK/PD parameter is suitable for monitoring the CFPM/NAC combination. The minimum target value for achieving a static effect against β-lactamase-producing Enterobacterales is 30%.

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Ceftriaxone-Related Encephalopathy in a Patient With End-Stage Renal Disease and High Ceftriaxone Concentrations in Cerebrospinal Fluid and Plasma: A Case Report.

Takano T, Kaburagi M, Morikubo S, Ichikawa D, Matsumoto K

Cureus 15 ( 10 ) e46401 2023.10

Joint Work, ISSN 2168-8184

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Model-informed precision dosing of vancomycin for rapid achievement of target area under the concentration-time curve: A simulation study.

Oda K, Yamada T, Matsumoto K, Hanai Y, Ueda T, Samura M, Shigemi A, Jono H, Saito H, Kimura T

Clinical and translational science (Clinical and Translational Science) 16 ( 11 ) 2265 - 2275 2023.09

Joint Work, ISSN 1752-8054

In this study, we aimed to evaluate limited sampling strategies for achieving the therapeutic ranges of the area under the concentration-time curve (AUC) of vancomycin on the first and second day (AUC0–24, AUC24–48, respectively) of therapy. A virtual population of 1000 individuals was created using a population pharmacokinetic (PopPK) model, which was validated and incorporated into our model-informed precision dosing tool. The results were evaluated using six additional PopPK models selected based on a study design of prospective or retrospective data collection with sufficient concentrations. Bayesian forecasting was performed to evaluate the probability of achieving the therapeutic range of AUC, defined as a ratio of estimated/reference AUC within 0.8–1.2. The Bayesian posterior probability of achieving the AUC24–48 range increased from 51.3% (a priori probability) to 77.5% after using two-point sampling at the trough and peak on the first day. Sampling on the first day also yielded a higher Bayesian posterior probability (86.1%) of achieving the AUC0–24 range compared to the a priori probability of 60.1%. The Bayesian posterior probability of achieving the AUC at steady-state (AUCSS) range by sampling on the first or second day decreased with decreased kidney function. We demonstrated that second-day trough and peak sampling provided accurate AUC24–48, and first-day sampling may assist in rapidly achieving therapeutic AUC24–48, although the AUCSS should be re-estimated in patients with reduced kidney function owing to its unreliable predictive performance.

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A combination of 5/6-nephrectomy and unilateral ureteral obstruction model accelerates progression of remote organ fibrosis in chronic kidney disease

Homma Kyoka, Enoki Yuki, Uchida Sato, Taguchi Kazuaki, Matsumoto Kazuaki

FASEB BIOADVANCES (FASEB BioAdvances) 5 ( 10 ) 377 - 394 2023.08

Joint Work

Chronic kidney disease (CKD) involves progressive renal fibrosis, which gradually reduces kidney function and often causes various complications in extrarenal tissues. Therefore, we investigated fibrogenesis in extrarenal tissues (heart, liver, and lungs) in different experimental CKD models, such as the 5/6-nephrectomy (5/6 Nx), unilateral ureteral obstruction (UUO), and a combination (2/3 Nx + UUO). We evaluated the degree of fibrogenesis in kidneys and extrarenal tissues by histological analysis and quantification of fibrosis-related gene and protein expression. To elucidate the fibrosis mechanisms observed in 2/3 Nx + UUO mice, we evaluated the effect of indoxyl sulfate (IS), a typical uremic toxin accumulated in CKD, and transforming growth factor-β (TGF-β), a fibrosis-related factor, on fibrosis using human hepatoma (HepG2) and RAW264.7 cells. A significant decline in renal function was observed in the 5/6 Nx and 2/3 Nx + UUO models, whereas a significant increase in renal fibrosis was observed only in the obstructed kidneys. Notable amount of fibrosis was induced in the liver and heart in the 2/3 Nx + UUO model, with the induction of macrophage infiltration and increased tissue IS and TGF-β levels. In agreement with the results of in vivo experiments, co-stimulation with IS, TGF-β, and macrophage-conditioned medium increased the expression of fibrogenic genes in HepG2 cells. We demonstrated that the 2/3 Nx + UUO model induced both loss of renal function and renal fibrosis in the earlier stages, providing a novel CKD model that induces remote organ fibrosis in a shorter time.

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