Papers - Matsumoto, Kazuaki

Favorable Effects of Voriconazole Trough Concentrations Exceeding 1 μg/mL on Treatment Success and All-Cause Mortality: A Systematic Review and Meta-Analysis.

Hanai Y, Hamada Y, Kimura T, Matsumoto K, Takahashi Y, Fujii S, Nishizawa K, Miyazaki Y, Takesue Y

Journal of fungi (Basel, Switzerland) (Journal of Fungi)  7 ( 4 )  2021.04

Research paper (scientific journal), Joint Work, Accepted

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This systematic review and meta-analysis examined the optimal trough concentration of voriconazole for adult patients with invasive fungal infections. We used stepwise cutoffs of 0.5–2.0 µg/mL for efficacy and 3.0–6.0 µg/mL for safety. Studies were included if they reported the rates of all-cause mortality and/or treatment success, hepatotoxicity, and nephrotoxicity according to the trough concentration. Twenty-five studies involving 2554 patients were included. The probability of mortality was significantly decreased using a cutoff of ≥1.0 µg/mL (odds ratio (OR) = 0.34, 95% confidence interval (CI) = 0.15–0.80). Cutoffs of 0.5 (OR = 3.48, 95% CI = 1.45–8.34) and 1.0 µg/mL (OR = 3.35, 95% CI = 1.52–7.38) also increased the treatment success rate. Concerning safety, significantly higher risks of hepatotoxicity and neurotoxicity were demonstrated at higher concentrations for all cutoffs, and the highest ORs were recorded at 4.0 µg/mL (OR = 7.39, 95% CI = 3.81–14.36; OR = 5.76, 95% CI 3.14–10.57, respectively). Although further high-quality trials are needed, our findings suggest that the proper trough concentration for increasing clinical success while minimizing toxicity is 1.0–4.0 µg/mL for adult patients receiving voriconazole therapy.

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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 2021.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  13474367

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© 2020 The Japanese Society for the Study of Xenobiotics 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)3, LaCO3, and the polycation polymers bixalomer (Bxl) and sevelamer (Svl). Prior to oral administration of DTG (5 mg/kg), rats were orally administered Al(OH)3 (150 or 300 mg/kg), LaCO3 (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)3, LaCO3, 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)3, LaCO3, Bxl, and Svl affect the pharmacokinetics of DTG and indicate the need for caution when combining any of the above preparations with DTG.

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Performance of Area under the Concentration-Time Curve Estimations of Vancomycin with Limited Sampling by a Newly Developed Web Application.

Oda K, Hashiguchi Y, Kimura T, Tsuji Y, Shoji K, Takahashi Y, Matsumoto K, Kawamura H, Saito H, Takesue Y

Pharmaceutical research (Pharmaceutical Research)  38 ( 4 ) 637 - 646 2021.03

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

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Purpose: Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation. Methods: PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUC ) was evaluated against the reference AUC (AUC ) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUC ) calculated using an evaluated available software with clinical data. Results: Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept −15.57, median AUC /AUC 0.93 [range 0.81–1.24]), where only one estimation (6%) was out of the predetermined acceptable range of 0.8–1.2. Employment of only a trough concentration was more biased (AUC /AUC range 0.73–1.30 for 11 h, AUC /AUC range 0.62–1.40 for 23 h). In comparison with the evaluated software, AUC was not biased against the AUC (slope 1.04, intercept −15.80, median AUC /AUC 1.00 [range 0.86–1.10]). Conclusions: The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin. PAT REF BM-P PAT REF PAT REF PAT REF PAT BM-P PAT BM-P

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When Albumin Meets Liposomes: A Feasible Drug Carrier for Biomedical Applications.

Taguchi K, Okamoto Y, Matsumoto K, Otagiri M, Chuang VTG

Pharmaceuticals (Basel, Switzerland) (Pharmaceuticals)  14 ( 4 )  2021.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1424-8247

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Albumin, the most abundant protein in plasma, possesses some inherent beneficial structural and physiological characteristics that make it suitable for use as a drug delivery agent, such as an extraordinary drug-binding capacity and long blood retention, with a high biocompatibility. The use of these characteristics as a nanoparticle drug delivery system (DDS) offers several advantages, including a longer circulation time, lower toxicity, and more significant drug loading. To date, many innovative liposome preparations have been developed in which albumin is involved as a DDS. These novel albumin-containing liposome preparations show superior deliverability for genes, hydrophilic/hydrophobic substances and proteins/peptides to the targeting area compared to original liposomes by virtue of their high biocompatibility, stability, effective loading content, and the capacity for targeting. This review summarizes the current status of albumin applications in liposome-based DDS, focusing on albumin-coated liposomes and albumin-encapsulated liposomes as a DDS carrier for potential medical applications.

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Optimal trough concentration of teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus infection: A systematic review and meta-analysis.

Hanai Y, Takahashi Y, Niwa T, Mayumi T, Hamada Y, Kimura T, Matsumoto K, Fujii S, Takesue Y

Journal of clinical pharmacy and therapeutics (Journal of Clinical Pharmacy and Therapeutics)  46 ( 3 ) 622 - 632 2021.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0269-4727

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© 2021 John Wiley & Sons Ltd What is known and objective: It has been recommended that the trough concentration (Cmin) of teicoplanin should be maintained at ≥20 μg/ml for difficult-to-treat complicated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Conversely, Cmin of teicoplanin of at least 10 μg/ml is required for non-complicated MRSA infections. Considering the low incidence of nephrotoxicity for teicoplanin, Cmin = 15–30 μg/ml has been suggested for most MRSA infections. Thus, we assessed the clinical efficacy and adverse effects of teicoplanin at this target Cmin. Methods: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials and Ichushi-Web) to identify eligible studies. Studies were included if they provided the incidence of treatment success, mortality in patients with MRSA infection, and/or hepatotoxicity and nephrotoxicity according to the Cmin range. Results and discussion: Four trials assessing clinical success (n = 299) and three studies assessing adverse effects (n = 546) were included. Cmin = 15–30 μg/ml significantly increased the probability of treatment success compared with Cmin < 15 μg/ml (odds ratio [OR] = 2.68, 95% confidence interval [CI] = 1.14–6.32, p = 0.02). The all-cause mortality rate did not differ between the groups (OR = 0.46, 95% CI = 0.13–1.61, p = 0.22). Cmin = 15–30 μg/ml did not increase the risks of nephrotoxicity (OR = 0.91, 95% CI = 0.49–1.69, p = 0.76) or hepatotoxicity (OR = 0.67, 95% CI = 0.18–2.44, p = 0.54). What is new and conclusion: Teicoplanin therapy using a Cmin target of 15–30 μg/ml is likely to be associated with better clinical responses than Cmin < 15 μg/ml without increasing the risk of adverse effects.

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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

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© 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 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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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 - 153 2021.02

Research paper (scientific journal), Joint Work, Accepted

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© 2021, The Author(s). 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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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

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© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature. 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 (fAUC24/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 fAUC24/MIC, indicating that fT>MIC is significant PK/PD index. The target value of fT>MIC for 1 log10 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%.

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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 - 122489 2021.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15700232

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© 2020 Elsevier B.V. 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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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

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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 t =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. 1/2

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Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments

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

Pharmaceutical Research (Pharmaceutical Research)  38 ( 11 ) 1839 - 1846 2021

Research paper (scientific journal), Joint Work, Accepted,  ISSN  07248741

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Purpose: Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. Methods: The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. Results: The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. Conclusion: CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve “fT>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.

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Optimal trough concentration of voriconazole with therapeutic drug monitoring in children: A systematic review and meta-analysis.

Hanai Y, Hamada Y, Kimura T, Matsumoto K, Takahashi Y, Fujii S, Nishizawa K, Takesue Y

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  27 ( 2 ) 151 - 160 2020.12

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

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© 2020 Objectives: This systematic review and meta-analysis was designed to determine the optimal trough concentration of voriconazole for children with invasive fungal infections (IFIs). Methods: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and Japana Centra Revuo Medicina) for clinical studies describing the voriconazole trough concentration. We used stepwise cut-off values of 1.0–2.0 mg/L for efficacy and 3.0–6.0 mg/L for safety. The efficacy outcomes were treatment success and all-cause mortality, and the safety outcomes were hepatotoxicity, neurotoxicity and all-cause adverse events. Results: Nine studies involving 211 patients were included in the analysis. The probability of treatment success against IFIs was significantly increased at cut-off values of ≥1.0 mg/L (odds ratio [OR] = 2.65, 95% confidence interval [CI] = 1.20–5.87). Our analysis did not find any relationship between the trough concentration and survival. Concerning safety, the occurrence of any outcomes did not significantly differ according to the voriconazole trough concentrations at any cut-off value. However, in a subgroup analysis of Asian study locations, a significantly higher risk of hepatotoxicity was demonstrated at voriconazole trough cut-off values ≥ 3.0 mg/L (OR = 8.40, 95% CI = 1.36–51.92). Although a significant correlation between the voriconazole concentration and hepatotoxicity was evident in regression curve analysis, (y = 0.1198e0.2298x), no correlation was demonstrated for neurotoxicity (y = 0.3913e−0.008x). Conclusion: Our findings suggest that the optimal trough concentration for increasing clinical success and minimizing hepatotoxicity during voriconazole therapy in children with IFIs, particularly for Asian populations, is 1.0–3.0 mg/L.

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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)  53 ( 6 ) 1239 - 1249 2020.12

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

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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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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

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© 2020 The Authors 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 offCmax/MIC (r2 = 0.94) of teicoplanin for static effect and 1 log10 kill against MSSA were 4.44 and 15.44, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MSSA were 30.4 and 70.56, respectively. Target values of fCmax/MIC (r2 = 0.91) of teicoplanin for static effect and 1 log10 kill against MRSA were 8.92 and 14.16, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MRSA were 54.8 and 76.4, respectively. Conclusion: These results suggest thatfCmax/MIC and fAUC24/MIC are useful PK/PD indices of teicoplanin against MSSA and MRSA.

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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

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© 2020 The Authors 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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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

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

Chizuru Yamashita, Yoshio Takesue, Kazuaki Matsumoto, Kazuhiro Ikegame, Yuki Enoki, Motoi Uchino, Taiga Miyazaki, Koichi Izumikawa, Tohru Takada, Keiji Okinaka, Takashi Ueda, Yoshitsugu Miyazaki, Toshihiko Mayumi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy)  26 ( 6 ) 596 - 603 2020.06

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

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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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Carbon Monoxide Rescues the Developmental Lethality of Experimental Rat Models of Rhabdomyolysis-Induced Acute Kidney Injury.

Kazuaki Taguchi, Shigeru Ogaki, Taisei Nagasaki, Hiroki Yanagisawa, Kento Nishida, Hitoshi Maeda, Yuki Enoki, Kazuaki Matsumoto, Hidehisa Sekijima, Kazuya Ooi, Yu Ishima, Hiroshi Watanabe, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama

The Journal of pharmacology and experimental therapeutics (Journal of Pharmacology and Experimental Therapeutics)  372 ( 3 ) 355 - 365 2020.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00223565

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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. SIGNIFICANCE STATEMENT: After mass natural and man-made disasters, people who are trapped in collapsed buildings are in danger of acute kidney injury (AKI), including crush syndrome (CS)-related AKI. This paper reports that carbon monoxide-enriched red blood cells (CO-RBCs), which can be prepared at both hospitals and disaster sites, dramatically suppressed the pathogenesis of CS-related AKI, thus improving mortality via suppressing heme protein-associated renal injuries. CO-RBCs have the potential for serving as a practical therapeutic agent against disaster nephrology associated with the CS.

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Strategy of drug development based on the bioactive gas-carrying capacity of hemoglobin

Taguchi K., Matsumoto K., Maruyama T., Otagiri M.

YAKUGAKU ZASSHI (The Pharmaceutical Society of Japan)  140 ( 2 ) 141 - 146 2020.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00316903

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<p>Bioactive gas molecules, including oxygen, nitric oxide and carbon monoxide (CO), exhibit a variety of physiological activities, and are associated with the onset and progress of some disorders. These facts have led researchers to the development of bioactive gas donors for the treatment of intractable disorders. Hemoglobin is likely an ideal carrier of bioactive gases, since hemoglobin in red blood cells innately carries oxygen in the form of oxyhemoglobin, nitric oxide in the form of <i>S</i>-nitrosohemoglobin, and CO in the form of carbonylhemoglobin. In this study, we attempted to develop a biomimetic CO delivery system using a preparation of hemoglobin. Our strategy for the preparation of this hemoglobin-based CO carrier involves CO being exogenously bound to red blood cells or hemoglobin-encapsulated liposomes, called hemoglobin-vesicles (HbV), which mimic the structure and function of red blood cells. We accumulated evidence that the CO donors—CO-bound red blood cells and CO-bound HbV—showed therapeutic efficacy against intractable disorders in animal models. Here, we describe the potential of hemoglobin-based CO donors, especially CO-bound red blood cells and CO-bound HbV, for the treatment of certain disorders. Hemoglobin-based strategies for the delivery of other bioactive gases for novel drug development are also discussed.</p>

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