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Papers - Enoki, Yuki

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Population Pharmacokinetic Analysis and Dosing Optimization Based on Unbound Daptomycin Concentration and Cystatin C in Nonobese Elderly Patients with Hypoalbuminemia and Chronic Kidney Disease.

Samura M, Takada K, Yamamoto R, Ito H, Nagumo F, Uchida M, Kurata T, Koshioka S, Enoki Y, Taguchi K, Higashita R, Kunika N, Tanikawa K, Matsumoto K

Pharmaceutical research (Pharmaceutical Research) 38 ( 6 ) 1041 - 1055 2021.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 0724-8741

Purpose: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. Methods: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration–time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. Results: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05–0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20–60 mL/min and aged 65–95 years were calculated as 200–500 mg q24h. Conclusion: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

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Surveying health seminar participants on the self-medication tax deduction system and extracting challenges associated with tax reform

Kazuaki Taguchi, Yuki Enoki, Satomi Aruga, Mikio Sakakibara, Satoko Hori, Katsunori Yamaura, Kazuaki Matsumoto

Japanese Journal of Pharmaceutical Health Care and Sciences (Japanese Scoiety of Pharmaceutical Health Care and Science) 47 ( 5 ) 256 - 263 2021.05

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

健康セミナー参加者247名を対象に、セルフメディケーション税制に対する認知、理解度や関心などの実情に関するアンケートを実施し、本税制を取り巻く国民の実状と本税制の課題を明らかにすることを目的とした。調査の結果、過半数の調査対象者がドラッグストアを1ヵ月間に複数回利用しており、ドラッグストアを頻繁に利用している現状が示された。しかし、1年間のOTC医薬品の合計購入額が1万2千円以上10万円未満の調査対象者は11.8%(29人)と少なく、1年間のOTC医薬品の合計購入額が10万円以上の調査対象者はいなかった。セルフメディケーション税制の認知度について調査したところ、理解度に差はあるものの60%以上の調査対象者が本税制を認知していた。さらに、OTC医薬品の年間合計購入金額別に認知度を集計した。その結果、合計購入金額が1万2千円未満の調査対象者と合計購入金額が1万2千円以上の調査対象者で認知度は変わらなかったものの、合計購入金額が1万2千円以上の調査対象者のほうがセルフメディケーション税制について「知っている」と回答した割合が多かった。しかし、認知度に比べて申告件数は著しく少なかった。セルフメディケーション税制については、約50%(43人)が興味を示すとともに申告要件が揃っていれば控除を受けたいと回答した。

The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing.

Tsutsuura M, Moriyama H, Kojima N, Mizukami Y, Tashiro S, Osa S, Enoki Y, Taguchi K, Oda K, Fujii S, Takahashi Y, Hamada Y, Kimura T, Takesue Y, Matsumoto K

BMC infectious diseases (BMC Infectious Diseases) 21 ( 1 ) 153 2021.02

Research paper (scientific journal), Joint Work, Accepted

Background: This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety. Methods: We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs). Results: Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 μg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47–0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 μg/mL compared to those at 15–20 μg/mL (OR 2.39, 95% CI 1.78–3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18–0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13–3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28–1.01); however, it was not significant in the analysis of mortality. Conclusions: We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity.

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The optimal trough-guided monitoring of vancomycin in children: Systematic review and meta-analyses.

Moriyama H, Tsutsuura M, Kojima N, Mizukami Y, Tashiro S, Osa S, Enoki Y, Taguchi K, Oda K, Fujii S, Takahashi Y, Hamada Y, Kimura T, Takesue Y, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 27 ( 5 ) 781 - 785 2021.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-321X

We carried out a systematic review and meta-analysis exploring the relationship between vancomycin (VCM) trough concentrations and its effectiveness and nephrotoxicity in pediatric patients. We conducted our analysis using MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials as electronic databases (June 29, 2019). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We identified 16 studies that were eligible for the meta-analysis. A total of 351 and 3,266 patients were included in the analysis for effectiveness and nephrotoxicity, respectively. Pediatric MRSA infection patients with VCM trough concentrations ≥ 10 μg/mL had significantly lower treatment failure rates (OR 0.54, 95% CI 0.30–0.96). The incidence of nephrotoxicity was significantly higher in trough concentrations ≥ 15 μg/mL than when they were < 15 μg/mL (OR 3.02, 95% CI 2.08–4.38). We identified the optimal VCM trough concentrations associated with effectiveness and nephrotoxicity in pediatric patients with MRSA infection. Further prospective studies are needed to find optimal dosing and monitoring strategy on VCM in pediatric population.

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Pharmacokinetics/Pharmacodynamics Evaluation of Flomoxef against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli In Vitro and In Vivo in a Murine Thigh Infection Model.

Tashiro S, Hayashi M, Takemura W, Igarashi Y, Liu X, Mizukami Y, Kojima N, Enoki Y, Taguchi K, Yokoyama Y, Nakamura T, Matsumoto K

Pharmaceutical research (Pharmaceutical Research) 38 ( 1 ) 27 - 35 2021.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0724-8741

Purpose: Although flomoxef (FMOX) has attracted substantial attention as an antibiotic against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli), the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of FMOX against ESBL-producing E. coli is unclear. The aim of this study was to determine the PK/PD index of FMOX against ESBL-producing E. coli. Methods: In vitro time-kill curve studies and in vivo PK/PD experiments were carried out. Results: Time–kill curves exhibited a unique bactericidal activity: time-dependent activity at low concentrations and concentration-dependent activity at high concentrations. In neutropenic murine thigh infection experiments, the antibacterial activity of FMOX correlated with the time that the free drug concentration remaining above the minimum inhibitory concentration (MIC) (fT>MIC) and the ratio of the area under the free drug concentration–time curve for a 24 h period to the MIC (fAUC /MIC). However, the burden of ESBL producing E. coli significantly reduced when the time intervals for administration were shorter among three dosage regimens with same magnitude of fAUC /MIC, indicating that fT>MIC is significant PK/PD index. The target value of fT>MIC for 1 log kill reduction was 35.1%. Conclusions: fT>MIC is the most significant PK/PD index of FMOX against ESBL-producing E. coli and its target value is ≥ 40%. 24 24 10

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Dosing Optimization of Ampicillin-Sulbactam Based on Cystatin C in Elderly Patients with Pneumonia.

Matsubara K, Matsumoto K, Yokoyama Y, Watanabe E, Enoki Y, Shigemi A, Ikawa K, Terazono H, Morikawa N, Ohshige T, Takeda Y

Biological & pharmaceutical bulletin (Biological and Pharmaceutical Bulletin) 44 ( 5 ) 732 - 736 2021

Research paper (scientific journal), Joint Work, Accepted, ISSN 0918-6158

Ampicillin-sulbactam is a first-line therapy for pneumonia and is mainly excreted by the kidney. It is important to optimize the dose and dosing interval of ampicillin-sulbactam because in patients with decreased renal function and low skeletal muscle mass, such as the elderly, excess drug may burden renal function. In this study, we evaluated indices of renal function and optimized the dose and dosing interval of ampicillin-sulbactam based on pharmacokinetics (PK) and pharmacodynamics theory in elderly patients. The serum concentrations of ampicillin and sulbactam were measured by HPLC, and PK parameters were calculated. Correlations between the clearance of ampicillin or sulbactam and renal function were evaluated, and dosing optimization was calculated based on PK parameters. The PK parameters of ampicillin were CL=6.5±4.0L/h, Vd=19.3±0.2L, Ke=0.4±0.2, and t1/2=2.7±1.6h. The most correlated renal function index was estimated glomerular filtration rate (eGFRcys-c) calculated by serum cystatin-c (r=0.7374, correlation formula; CL of ampicillin=0.1937×eGFRcys-c-0.6726). Based on this formula, we calculated the clearance of ampicillin and developed dosing regimens for the elderly. Serum cystatin-c concentration is an ideal index to optimize ampicillin-sulbactam antimicrobial therapy in elderly patients with pneumonia.

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Rational dosage regimens for cephalothin and cefazolin using pharmacokinetics and pharmacodynamics analysis in healthy horses.

Kuroda T, Minamijima Y, Niwa H, Tamura N, Mita H, Fukuda K, Kaimachi M, Suzuki Y, Enoki Y, Taguchi K, Matsumoto K, Toutain PL, Bousquet-Melou A, Kasashima Y

Equine veterinary journal (Equine Veterinary Journal) 2020.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0425-1644

Background: First-generation cephalosporins have good activity against gram-positive bacteria and are extensively used in horses. There are few reports of pharmacokinetics and pharmacodynamics (PK/PD) analysis of cephalosporins in horses. Objective: To optimise the dosages of the two first-generation cephalosporins cephalothin (CET) and cefazolin (CEZ) in horses using PK/PD concepts. Study design: Experimental study with single administration. Methods: Drug plasma concentrations following a single intravenous (i.v.) administration of 22 mg/kg bodyweight (bwt) CET in 12 horses and of 10 mg/kg bwt CEZ in six horses were measured using LC-MS/MS. Data were modelled using a nonlinear mixed effect modelling followed by Monte Carlo simulations. Minimum inhibitory concentrations (MICs) against Streptococcus zooepidemicus and Staphylococcus aureus isolated from horses were determined by the microbroth dilution method. Results: The percentages of CET and CEZ binding to serum proteins were 19.9% ± 8.4% and 15.2% ± 8.5% respectively. For both CET and CEZ, the MIC against S. zooepidemicus was 0.12 mg/L and against S. aureus was 0.5 mg/L. For CET, to achieve a probability of target attainment (PTA) of 90% for a PK/PD target of a free serum plasma concentration exceeding the MIC for 40% of the dosing interval, an empirical CET dosage regimen of 22 mg/kg bwt q8h and 22 mg/kg bwt q4h i.v. administration were required for S. zooepidemicus and S. aureus respectively. For CEZ, the corresponding dosage regimens were 10 mg/kg bwt q12h and 10 mg/kg bwt q8h. Main limitations: Small sample size only in healthy horses. Conclusions: For CET, more frequent administration than that currently recommended (22 mg/kg bwt q6–12h) is required to empirically control S. aureus infection in horses. For CEZ, less frequent administration compared to the dosage regimen currently proposed (10–22 mg/kg bwt q6h) could control S. zooepidemicus and S. aureus infections in horses. 90 90

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Remdesivir for the treatment of coronavirus COVID-19: A meta-analysis of randomised controlled trials.

Enoki Y, Igarashi Y, Watabe Y, Honma K, Suzuki Y, Hayashi Y, Hiraoka K, Taguchi K, Matsumoto K

Journal of global antimicrobial resistance (Journal of Global Antimicrobial Resistance) 24 81 - 82 2020.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2213-7165

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Use of an alternative signature peptide during development of a LC-MS/MS assay of plasma nivolumab levels applicable for multiple species.

Ohuchi M, Yagishita S, Taguchi K, Goto Y, Fukahori M, Enoki Y, Shimada T, Yamaguchi M, Matsumoto K, Hamada A

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences (Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences) 1162 122489 2020.12

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

Recently, immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1) antibodies, have dramatically changed treatment strategies for several cancers. In pharmacokinetic/pharmacodynamic studies, experiments using a variety of animal species are assumed. We have identified optimal multiple reaction monitoring transitions for signature candidate peptides of nivolumab in human, mouse, and rat plasma and developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify nivolumab (an anti-PD-1 antibody) using trastuzumab as the internal standard. Calibration curves were linear in the range of 1–200 µg/mL. The intra- and inter-day precision and accuracy in human plasma fulfilled Food and Drug Administration guideline criteria for bioanalytical validation. There was no need to change the measurement method in mouse plasma. On the other hand, in rat plasma, an interference peak was observed at a retention time similar to that of the surrogate peptide ASGITFSNSGMHWVR (550.75 > 661.50) employed in human and mouse plasma. Therefore, we confirmed that ASQSVSSYLAWYQQKPGQAPR (785.0 > 940.2) can be used as an alternate nivolumab surrogate peptide in rat plasma at the same concentration range as used in human and mouse plasma. Using our method, the concentration range and a gradual increase in trough value were confirmed in clinical samples from two antibody-treated patients, including one with gastric cancer and one with non-small-cell lung cancer. The time course and blood concentration transition also were evaluated in nivolumab administration experiments in mouse and rat. The present study showed that the selection of the optimal peptide is essential for accurate LC-MS/MS measurement of nivolumab concentration in human, mouse, and rat plasma. The method developed here is expected to be of use in non-clinical and clinical pharmacokinetic studies.

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Pharmacokinetic/pharmacodynamic evaluation of teicoplanin against Staphylococcus aureus in murine thigh infection model.

Watanabe E, Matsumoto K, Ikawa K, Yokoyama Y, Shigemi A, Enoki Y, Umezaki Y, Nakamura K, Ueno K, Terazono H, Morikawa N, Takeda Y

Journal of global antimicrobial resistance (Journal of Global Antimicrobial Resistance) 24 83 - 87 2020.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2213-7165

Objectives: Pharmacokinetic/pharmacodynamic (PK/PD) analysis using murine infection models is a well-established methodology for optimising antimicrobial therapy. Therefore, we investigated the PK/PD indices of teicoplanin againstStaphylococcus aureus using a murine thigh infection model. Methods: Mice were rendered neutropenic by administration of a two-step dosing of cyclophosphamide. Then, isolates of methicillin-susceptibleS. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) were inoculated into the thighs of neutropenic mice. PK/PD analyses were performed by non-linear least-squared regression using the MULTI program. Results: Target values offC /MIC (r = 0.94) of teicoplanin for static effect and 1 log kill against MSSA were 4.44 and 15.44, respectively. Target values of fAUC /MIC (r = 0.92) of teicoplanin for static effect and 1 log kill against MSSA were 30.4 and 70.56, respectively. Target values of fC /MIC (r = 0.91) of teicoplanin for static effect and 1 log kill against MRSA were 8.92 and 14.16, respectively. Target values of fAUC /MIC (r = 0.92) of teicoplanin for static effect and 1 log kill against MRSA were 54.8 and 76.4, respectively. Conclusion: These results suggest thatfC /MIC and fAUC /MIC are useful PK/PD indices of teicoplanin against MSSA and MRSA. max 10 24 10 max 10 24 10 max 24 2 2 2 2

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Stability of antimicrobial agents in an elastomeric infusion pump used for outpatient parenteral antimicrobial therapy.

Akahane M, Enoki Y, Saiki R, Hayashi Y, Hiraoka K, Honma K, Itagaki M, Gotoda M, Shinoda K, Hanyu S, Hamamura Y, Miyajima T, Ito C, Taguchi K, Uno S, Uwamino Y, Iketani O, Hasegawa N, Matsumoto K

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases (International Journal of Infectious Diseases) 103 464 - 468 2020.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1201-9712

Objectives: The long-term stability of antimicrobials dissolved in infusion solution is necessary to establish and spread the outpatient parenteral antimicrobial therapy (OPAT). In this study, we evaluated the stability of antimicrobial agents dissolved in infusion solutions. Methods: The antimicrobial agents were dissolved in infusion solutions and kept at 25 °C and 31.1 °C for 24 h or 4 °C for 10 days in a polypropylene tube or an elastomeric infusion pump. The stability was measured by high-performance liquid chromatography. Results and conclusion: The residual ratio of cefazolin (CEZ), cefmetazole (CMZ), piperacillin (PIPC), and tazobactam (TAZ) at 31.1 °C for 24 h was as follows: 95.7 ± 3.0%, 94.8 ± 0.9%, 102.6 ± 1.8%, and 103.9 ± 3.6% in saline, respectively; 94.7 ± 3.0%, 94.3 ± 1.5%, 106.1 ± 3.0%, and 107.3 ± 2.4% in 5% dextrose solution, respectively. The residual ratio of these antimicrobials at 4 °C for 10 days was maintained above 90% in both saline and 5% dextrose solution. The residual ratio of all the above antimicrobials in an elastomeric infusion pump at 31.1 °C for 24 h was equivalent to that in the polypropylene tube. On the other hand, doripenem and meropenem were not stable in any infusion solution at 31.1 °C. CEZ, CMZ, and PIPC/TAZ dissolved in saline or 5% dextrose solution can be used in OPAT with continuous infusion pumps.

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Multivalent cation and polycation polymer preparations influence pharmacokinetics of dolutegravir via chelation-type drug interactions.

Enoki Y, Kishi N, Sakamoto K, Uchiyama E, Hayashi Y, Suzuki N, Ito M, Taguchi K, Yokoyama Y, Kizu J, Matsumoto K

Drug metabolism and pharmacokinetics (Drug Metabolism and Pharmacokinetics) 37 100371 2020.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1347-4367

Dolutegravir (DTG) is an integrase inhibitor, whose gastrointestinal absorption is impaired by the formation of chelates with multivalent metal cation preparations. However, little is known regarding the interactions of DTG with preparations containing other multivalent metal cations or with polycation polymer preparations. This study examined how the pharmacokinetics of DTG are affected by co-administration with Al(OH) , LaCO , and the polycation polymers bixalomer (Bxl) and sevelamer (Svl). Prior to oral administration of DTG (5 mg/kg), rats were orally administered Al(OH) (150 or 300 mg/kg), LaCO (50 or 75 mg/kg), Bxl (250 or 500 mg/kg), or Svl (300 or 600 mg/kg). Serum concentrations of DTG were then measured over the next 24 h. Compared to the administration of DTG alone, its co-administration with Al(OH) , LaCO , Bxl, and Svl led to reduced serum concentration of DTG, and consequently, a significantly reduced area under the curve. These comparisons also revealed a considerable reduction in the maximum concentration, suggesting that the interactions of these agents with DTG in the intestinal tract inhibit absorption of DTG. The above results demonstrate that Al(OH) , LaCO , Bxl, and Svl affect the pharmacokinetics of DTG and indicate the need for caution when combining any of the above preparations with DTG. 3 3 3 3 3 3 3 3

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Azoles versus conventional amphotericin B for the treatment of candidemia: A meta-analysis of randomized controlled trials.

Osa S, Tashiro S, Igarashi Y, Watabe Y, Liu X, Enoki Y, Taguchi K, Mayumi T, Miyazaki Y, Takesue Y, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 26 ( 11 ) 1232 - 1236 2020.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-321X

© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Because exclusive use of echinocandins can induce the drug-resistant strains, appropriate use of azoles and polyenes is still necessary in the treatment of candidemia. In this study, we conducted a meta-analysis of randomized controlled trials regarding the efficacy and safety of azole and polyene antifungals in the treatment of candidemia. MEDLINE and the Cochrane Register of Controlled Trials were used as reference databases, and papers published up to June 10, 2019 were searched. The search results were carefully scrutinized, duplicate references were removed, and the study was ultimately carried out using three reports. Among azole antifungals, fluconazole and voriconazole were extracted, however; only conventional amphotericin B (AMPH-B) was extracted among polyene antifungals. Treatment successes with the use of azoles and AMPH-B were compared, and findings showed that AMPH-B was significantly superior (RR = 0.90, 95% CI 0.82–1.00, p = 0.04). However, there was no significant difference in mortality (RR = 0.87, 95% CI 0.72–1.07, p = 0.19). Analysis of adverse events showed that renal disorders were significantly less common with azoles than with AMPH-B (RR = 0.26, 95% CI 0.10–0.68, p = 0.006). In conclusion, AMPH-B were superior to azoles in terms of efficacy, but had a risk of causing renal disorders.

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Indoxyl Sulfate Contributes to Adipose Tissue Inflammation through the Activation of NADPH Oxidase.

Tanaka S, Watanabe H, Nakano T, Imafuku T, Kato H, Tokumaru K, Arimura N, Enoki Y, Maeda H, Tanaka M, Matsushita K, Fukagawa M, Maruyama T

Toxins (Toxins) 12 ( 8 ) 502 2020.08

Research paper (scientific journal), Joint Work, Accepted

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Adipose tissue inflammation appears to be a risk factor for the progression of chronic kidney disease (CKD), but the effect of CKD on adipose tissue inflammation is poorly understood. The purpose of this study was to clarify the involvement of uremic toxins (indoxyl sulfate (IS), 3-indoleacetic acid, p-cresyl sulfate and kynurenic acid) on CKD-induced adipose tissue inflammation. IS induces monocyte chemoattractant protein-1 (MCP-1) expression and reactive oxygen species (ROS) production in the differentiated 3T3L-1 adipocyte. An organic anion transporter (OAT) inhibitor, an NADPH oxidase inhibitor or an antioxidant suppresses the IS-induced MCP-1 expression and ROS production, suggesting the OAT/NADPH oxidase/ROS pathway is involved in the action of IS. Co-culturing 3T3L-1 adipocytes and mouse macrophage cells showed incubating adipocytes with IS increased macrophage infiltration. An IS-overload in healthy mice increased IS levels, oxidative stress and MCP-1 expression in epididymal adipose tissue compared to unloaded mice. Using 5/6-nephrectomized mice, the administration of AST-120 suppressed oxidative stress and the expression of MCP-1, F4/80 and TNF-α in epididymal adipose tissue. These collective data suggest IS could be a therapeutic target for the CKD-related inflammatory response in adipose tissue, and that AST-120 could be useful for the treatment of IS-induced adipose tissue inflammation.

Concurrent administration with multivalent metal cation preparations or polycationic polymer preparations inhibits the absorption of raltegravir via its chelation.

Enoki Y, Suzuki N, Ito M, Uchiyama E, Kishi N, Ito C, Kitahiro Y, Sakamoto K, Taguchi K, Yokoyama Y, Kizu J, Matsumoto K

The Journal of pharmacy and pharmacology (Journal of Pharmacy and Pharmacology) 72 ( 10 ) 1361 - 1369 2020.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-3573

© 2020 Royal Pharmaceutical Society Objectives: Raltegravir (RAL) that can form chelates with multivalent metal cations shows lateral interactions with multivalent metal cation and polycationic polymer. We investigated the interactions of RAL with multivalent metal cation preparations, Al(OH)3 and LaCO3, and polycationic polymer preparations, bixalomer (Bxl) and sevelamer (Svl). Methods: Immediately before the oral administration of 40 mg/kg RAL, the rats were administered orally with the vehicle, Al(OH)3, LaCO3, Bxl, or Svl, and the time course of RAL serum concentration was followed. The in vitro binding affinity of RAL with multivalent metal cation and polycationic polymer was also evaluated using isothermal titration calorimetry (ITC). Results: When Al(OH)3, LaCO3, Bxl, or Svl was concomitantly administered with RAL, the maximum concentration and area under the curve were significantly lower than those when RAL was administered alone. ITC showed the interaction of RAL with Al(OH)3 as an enthalpy-driven reaction and its interactions with LaCO3 and Bxl as entropy–enthalpy mixed reactions. Conclusions: The interaction of RAL with Al(OH)3, LaCO3, Bxl, or Svl can inhibit RAL absorption into the gastrointestinal tract, and thus, the multivalent metal cation and polycationic polymer are the modifying factors that can affect RAL pharmacokinetics.

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Carbon monoxide rescues the developmental lethality of experimental rat models of rhabdomyolysis-induced acute kidney injury.

Taguchi K, Ogaki S, Nagasaki T, Yanagisawa H, Nishida K, Maeda H, Enoki Y, Matsumoto K, Sekijima H, Ooi K, Ishima Y, Watanabe H, Fukagawa M, Otagiri M, Maruyama T

The Journal of pharmacology and experimental therapeutics (Journal of Pharmacology and Experimental Therapeutics) 372 ( 3 ) 355 - 365 2020.01

Research paper (scientific journal), Accepted, ISSN 0022-3565

© 2020 by The American Society for Pharmacology and Experimental Therapeutics Many victims, after being extricated from a collapsed building as the result of a disaster, suffer from disaster nephrology, a term that is referred to as the crush syndrome (CS). Recommended treatments, which include dialysis or the continuous administration of massive amounts of fluid are not usually easy in cases of such mass natural disasters. In the present study, we examined the therapeutic performance of a biomimetic carbon monoxide (CO) delivery system, CO-enriched red blood cells (CO-RBCs), on experimental animal models of an acute kidney injury (AKI) induced by traumatic and nontraumatic rhabdomyolysis, including CS and rhabdomyolysis with massive hemorrhage shock. A single CO-RBC treatment was found to effectively suppress the pathogenesis of AKI with the mortality in these model rats being improved. In addition, in further studies using glycerol-induced rhabdomyolysis model rats, the pathogenesis of which is similar to that for the CS, AKI and mortality were also reduced as the result of a CO-RBC treatment. Furthermore, CO-RBCs were found to have renoprotective effects via the suppression of subsequent heme protein-associated renal oxidative injury; the oxidation of myoglobin in the kidneys, the generation of reactive oxygen species by free heme produced from degraded-cytochrome P450 and hemoglobin-associated renal injury. Because CO-RBCs can be prepared and used at both hospitals and at a disaster site, these findings suggest that CO-RBCs have the potential for use as a novel cell therapy against both nontraumatic and traumatic rhabdomyolysis including CS-induced AKI.

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Molecular mechanism of muscle wasting in CKD

Watanabe H, Enoki Y, Maruyama T

Recent Advances of Sarcopenia and Frailty in CKD (Recent Advances of Sarcopenia and Frailty in CKD) 15 - 33 2020.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 9789811523649

© Springer Nature Singapore Pte Ltd. 2020. Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and a decreased muscle endurance. Many insights have made into the molecular mechanisms of muscle atrophy in CKD. A persistent imbalance between protein synthesis and degradation causes a loss of muscle mass. A decrease in insulin/IGF-1-Akt-mTOR signaling and an increased ubiquitin-proteasome system (UPS) have emerged as inducers of muscle loss. During muscle wasting, abnormal levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in skeletal muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The binding of myostatin to its receptor ActRIIB stimulates the expression of Foxo-dependent atrogenes. An impaired mitochondrial function also contributes to reduced muscle endurance. Increased glucocorticoid, angiotensin II, parathyroid hormone, and protein-bound uremic toxin levels that are observed in CKD all have a negative effect on muscle mass and endurance. The loss of skeletal muscle mass during the progression of CKD further contributes to the development of renal failure. Some potential therapeutic approaches based on the molecular mechanisms of muscle wasting in CKD are currently in the testing stages using animal models and clinical settings.

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Echinocandins versus non-echinocandins for empirical antifungal therapy in patients with hematological disease with febrile neutropenia: A systematic review and meta-analysis

Yamashita C, Takesue Y, Matsumoto K, Ikegame K, Enoki Y, Uchino M, Miyazaki T, Izumikawa K, Takada T, Okinaka K, Ueda T, Miyazaki Y, Mayumi T

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 26 ( 6 ) 596 - 603 2020

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341321X

© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Empirical antifungal therapy is recommended in high-risk patients who have persistent febrile neutropenia (FN) despite broad-spectrum antibiotic therapy. Based on high-quality evidence, most guidelines recommend caspofungin. The aim of this study was to clarify whether echinocandins, including micafungin, are associated with improved clinical outcomes in patients with persistent FN. We conducted a meta-analysis of randomized controlled trials (RCTs) of empirical therapy with echinocandins and non-echinocandins for FN in patients with hematological disease. The primary outcome was all-cause mortality within 7 days after completion of therapy. Secondary outcomes included treatment success, and discontinuation of therapy because of adverse events. For subgroup analysis, we compared RCTs of echinocandins with liposomal amphotericin B. Six RCTs (four that evaluated caspofungin and two that evaluated micafungin) were included in the meta-analysis. Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with non-echinocandins [risk ratio (RR) 0.70, 95% confidence interval (CI) 0.49–0.99; RR 0.48, 95% CI 0.33–0.71, respectively]. There was no significant difference in treatment success (RR 1.09, 95% CI 0.87–1.36). Mortality and adverse events in echinocandin-treated patients were significantly lower than in those treated with liposomal amphotericin B (RR 0.68, 95% CI 0.46–0.99; RR 0.53, 95% CI 0.37–0.74, respectively). In conclusion, patients with persistent FN treated with echinocandins had decreased risk of death and adverse events. Both caspofungin and micafungin may be recommended as first-line empirical antifungal therapy in these patients. However, the small number of enrolled patients and the lack of RCTs involving pediatric patients should be considered when using micafungin.

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Characterization of Bovine Lactoferrin Nanoparticle Prepared by Desolvation Technique.

Taguchi K, Chuang VTG, Hashimoto M, Nakayama M, Sakuragi M, Enoki Y, Nishi K, Matsumoto K, Seo H, Otagiri M, Yamasaki K

Chemical & pharmaceutical bulletin (公益社団法人日本薬学会) 68 ( 8 ) 766 - 772 2020

Research paper (scientific journal), Joint Work, Accepted, ISSN 0009-2363

<p>Lactoferrin (Lf) nanoparticles have been developed as a carrier of drugs and gene. Two main methods, desolvation technique and emulsification method, for preparation of protein nanoparticles have been reported so far, but most of the previous reports of Lf nanoparticles preparation are limited to emulsification method. In this study, we investigated the optimal conditions by desolvation technique for the preparation of glutaraldehyde-crosslinked bovine Lf (bLf) nanoparticles within the size range of 100–200 nm, and evaluated their properties as a carrier for oral and intravenous drug delivery. The experimental results of dynamic light scattering and Transmission Electron Microscope suggested that glutaraldehyde-crosslinked bLf nanoparticles with 150 nm in size could be produced by addition of 2-propanol as the desolvating solvent into the bLf solution adjusted to pH 6, followed by crosslinking with glutaraldehyde. These cross-linked bLf nanoparticles were found to be compatible to blood components and resistant against rapid degradation by pepsin. Thus, cross-linked bLf nanoparticles prepared by desolvation technique can be applied as a drug carrier for intravenous administration and oral delivery.</p>

Echinocandins versus non-echinocandins for the treatment of invasive candidiasis: A meta-analysis of randomized controlled trials

Tashiro S, Osa S, Igarashi Y, Watabe Y, Liu X, Enoki Y, Taguchi K, Mayumi T, Miyazaki Y, Takesue Y, Matsumoto K

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 26 ( 11 ) 1164 - 1176 2020

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341321X

© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Introduction: Echinocandins are frequent use antifungals in the treatment of invasive candidiasis, and it is important to update information on their efficacy and safety for optimal antifungal drug treatment. The aim of this study is to clarify whether echinocandins are superior to non-echinocandins for the treatment of invasive candidiasis. Methods: We conducted a meta-analysis of RCTs of echinocandins and non-echinocandins for adult invasive candidiasis. The MEDLINE, Web of Sciences, Cochrane Register of Controlled Trials, and ClinicalTrials.gov databases before June 2019 were used. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel method random-effects model. Results: We identified 14,846 articles and screened, and five studies were included meta-analysis. The treatment success ratio for echinocandins was significantly higher than that for non-echinocandins (RR = 1.14, 95% CI 1.06–1.22, p = 0.0003). In regard to adverse events, there was no significant difference between the two treatment groups. A subgroup analysis showed that the treatment success ratio for echinocandins was significantly higher than that for azoles (RR = 1.20, 1.08–1.34, p = 0.001), whereas no significant differences were observed between echinocandins and polyenes. In safety analysis, the incidence ratio of electrolyte disorder (RR = 0.50, 0.33–0.76, p = 0.001), renal disorder (RR = 0.19, 0.09–0.40, p < 0.0001), and fever (RR = 0.46, 0.23–0.93, p = 0.03) were significantly lower in patients receiving echinocandins than in those receiving polyenes. Conclusions: This meta-analysis based on RCTs was first to show that use of echinocandins was associated with improved clinical success. Echinocandins may be useful as a first-line drug for invasive candidiasis.

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