Details of a Researcher - Matsumoto, Kazuaki

Papers - Matsumoto, Kazuaki

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External validation of a flowchart related to achieving the target area under the concentration-time curve for vancomycin: A retrospective multicenter study

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

Journal of Infection and Chemotherapy 31 ( 5 ) 102701 2025.05

Joint Work, ISSN 1341321X

During therapeutic drug monitoring (TDM) for vancomycin (VCM), the area under the concentration-time curve (AUC) is important for balancing efficacy versus toxicity. In a previous study, we developed a decision tree (DT) model to achieve the target AUC during TDM over the follow-up period (AUCfollow-up). This study aimed to validate the DT model for achieving the target AUCfollow-up. Patients who received VCM for at least 72 h and had an initial TDM within four doses between January 2023 and December 2023 were analyzed. The AUC of the initial TDM was calculated over 2-point (peak/trough) concentrations via Bayesian estimation. The target AUCfollow-up was defined as 400–600 μg h/mL. Among 188 patients (median age [interquartile range], 66 [56, 79] years; 50 % female), the target AUCfollow-up was achieved in 70 % (132/188). When the predicted AUC was 400–600 μg h/mL, 84 % (102/121) achieved the target AUCfollow-up. In a 12 h dosing interval subgroup, 86 % (88/102) achieved the target AUCfollow-up. Conversely, when the predicted AUC was <400 or >600 μg h/mL, the proportion who achieved the target AUCfollow-up dropped to 44 % (30/67). Only 30 % (3/10) of those with creatinine clearance rates of >130 mL/min/1.73 m2 achieved the target. The area under the receiver operating characteristics curve was 0.74, and the R2 value was 0.15. Our findings confirmed the external validity of the DT model and supported its use for optimizing VCM dosing. Overall, the DT model offers a reliable framework for achieving target AUC values during follow-up for TDM, aiding safe and effective treatment.

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Efficacy of De-Escalation to Cefmetazole in Patients with Bacteremic Urinary Tract Infections Caused by Extended-Spectrum β-Lactamase-Producing Escherichia coli

Namiki Takaya, Yokoyama Yuta, Kimura Motonori, Fukuda Shogo, Seyama Shoji, Iketani Osamu, Uwamino Yoshifumi, Jibiki Aya, Kawazoe Hitoshi, Ohtani Hisakazu, Hasegawa Naoki, Matsumoto Kazuaki, Oda Rentaro, Hashi Hideki, Suzuki Sayo, Nakamura Tomonori

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 48 ( 5 ) 537 - 544 2025.05

Joint Work, ISSN 09186158

This study aimed to clarify the optimal value for the unbound cefmetazole concentration to remain above the minimum inhibitory concentration (MIC) (fT ≥ MIC) for efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing Escherichia coli. This double-center retrospective observational study was conducted at Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital from January 2012 to October 2022. Efficacy was determined via clinical evaluation (mortality rate, recurrence rate, vital changes) and bacteriological evaluation, and the optimal fT ≥ MIC was calculated via receiver operating characteristic curve analysis. As a result, the number of patients evaluated were 40 (35 and 5 in the treatment success and treatment failure groups, respectively). Univariate analysis showed that fT ≥ MIC, recurrence rate, and MIC for cefmetazole against bacteria were significantly different for the two groups (p < 0.05). Receiver operating characteristic curve analysis showed that the optimal fT ≥ MIC indicating efficacy was 57% (area under the curve: 0.94, 95% confidence interval: 0.86–1.00, p = 0.002). All patients with fT ≥ MIC ≥ 57% had successful treatment, whereas the frequency of treatment failure was high among those with fT ≥ MIC <57%. The optimal fT ≥ MIC for the clinical efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing E. coli was fT ≥ MIC ≥ 57%. This finding would be useful for optimal dosing of cefmetazole.

Methemoglobin-Encapsulating Liposome: A Low-Risk Intravascular Contrast Agent for Magnetic Resonance Imaging

Taguchi K., Sumiyoshi A., Suzuki Y., Ozawa Y., Iiyama M., Gao S., Sakai H., Osada K., Matsumoto K., Aoki I.

ACS Applied Bio Materials 8 ( 4 ) 2838 - 2846 2025.04

Joint Work

Hemoglobin shows different contrasts on magnetic resonance imaging (MRI) depending on the iron and oxygenation states of heme. Functional brain MRI utilizes the differences in the concentrations of oxyhemoglobin and deoxyhemoglobin in cerebral blood vessels; blood clots produce strong magnetic susceptibility effects. We hypothesized that methemoglobin (MetHb)-based nanoparticles can act as MRI contrast agents because MetHb levels in red blood cells affect relaxivity and are strictly regulated to <1% in the blood. Herein, we describe the synthesis of methemoglobin-encapsulated liposomes (Met-HbVs) as contrast agents for MRI. Met-HbV, with a size of approximately 200 nm, increased longitudinal relaxivity (r1) by 2.44-fold compared with hemoglobin-encapsulated liposomes in vitro. In contrast, the transverse relaxation capacity (r2) of Met-HbVs was similar to that of the hemoglobin-encapsulated liposomes. Owing to its relaxivity, Met-HbV enhanced the signal intensity on T1-weighted images and angiography, especially in the veins. Furthermore, deleterious biological responses were seldom observed after Met-HbV administration in mice with chronic renal failure. In conclusion, Met-HbV possesses potential as a vascular contrast agent in MRI for angiography, with advantages over gadolinium-based contrast agents in terms of safety for patients with renal failure. To the best of our knowledge, this is the first report demonstrating the potential of MetHb as a biomaterial for contrast agents in MRI.

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Influence factors of metronidazole-related CNS disorders: an analysis of the Japan adverse drug event report and FDA adverse event reporting system.

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

Expert opinion on drug safety 1 - 7 2025.04

Joint Work, ISSN 1474-0338

Background: Metronidazole (MNZ) can be administered for various infections. The impact of comorbidities/concomitant drugs on MNZ-induced central nervous system (CNS) disorders remains unclear. Research design and methods: We assessed the risk of metronidazole-related CNS disorders using the Japan Adverse Drug Event Report (JADER, May 2023) and the US Food and Drug Administration Adverse Event Reporting System (FAERS, Q1 2023), excluding comorbidities/concomitant drugs. Clonazepam and diazepam were evaluated as potential prophylactics based on the efficacy of benzodiazepines for MNZ-related CNS disorders. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated. Additionally, sensitivity analysis by sex and age was conducted. Results: The ROR (95% CI) of CNS disorders associated with MNZ in JADER and FAERS were 3.16 (2.69–3.72) and 1.69 (1.64–1.73), respectively. MNZ was significantly related to CNS disorders after excluding comorbidities (brain/spinal cord or liver abscesses) and concomitant drugs (glucocorticoids, antiepileptic, antiparkinson, and schizophrenia drugs). In sensitivity analysis, MNZ was significantly related to CNS disorders, despite sex and age. The ROR in the concomitant with clonazepam (CZP) was 0.70 (0.53–0.92) in FAERS. Conclusion: MNZ may be associated with CNS disorders, even if comorbidities/concomitant drugs that are potential risk factors for CNS disorders are excluded. Additionally, CZP may suppress CNS disorders.

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Direct comparison of the effects of first- and second-generation H(1) -receptor blockers on motor functions in mice.

Taguchi K, Tenjin K, Sakamoto Y, Shimada A, Hara R, Iketani O, Okamoto Y, Enoki Y, Kizu J, Hori S, Matsumoto K

Die Pharmazie 80 ( 1 ) 24 - 28 2025.03

Joint Work, ISSN 0031-7144

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Development and validation of a population pharmacokinetic model of vancomycin for patients of advanced age.

Takada K, Samura M, Igarashi Y, Suzuki A, Ishigo T, Fujii S, Ibe Y, Yoshida H, Tanaka H, Ebihara F, Maruyama T, Hamada Y, Komatsu T, Tomizawa A, Takuma A, Chiba H, Yagi Y, Nishi Y, Enoki Y, Taguchi K, Tanikawa K, Kunishima H, Matsumoto K

Journal of pharmaceutical health care and sciences 11 ( 1 ) 18 2025.03

Joint Work, ISSN 2055-0294

Background: Population pharmacokinetic (PPK) models of vancomycin (VCM) commonly use creatinine clearance (CLcr) as a covariate for clearance (CL). However, relying on CLcr in patients of advanced age may lead to inaccuracies in estimating VCM clearance. Therefore, this study aimed to develop and validate a new PPK model specifically for patients aged 75 years and older. Methods: PPK analysis was performed based on the blood concentrations of VCM (n = 159 patients). The predictive performance of the developed model was compared with that of previous models using mean absolute error (MAE) and mean squared error (MSE) for another dataset. Results: The PPK analysis optimized a two-compartment model using CLcr and the Alb levels as covariates at the central compartment of VCM clearance. The final model was as follows: CL (L/h) = 1.96 × (CLcr/3.09) 0.63 × (Serum albumin (Alb) /2.3) 0.22 × exponential (0.11). Clearance between the central and peripheral compartments (L/h) = 4.86. Central compartment volume of distribution (L) = 31.78. Peripheral compartment volume of distribution (L) = 53.64. The validation study revealed that compared with those of previous models (ranging from 0.67 to 0.79 L/h and from 0.81 to 1.11 (L/h)2, respectively), the final model demonstrated the smallest MAE of 0.60 L/h and MSE of 0.65 (L/h)2 for patients of advanced age with serum creatinine levels of < 0.6 mg/dL. Conclusion: The PPK model of VCM for patients of advanced age was optimized by adding the Alb levels and CLcr as covariates for CL. The predictive accuracy of the PPK model for patients with an SCr of < 0.6 mg/dL tended to be higher than those of previous models based just on CLcr. Thus, dosage is suggested to be adjusted based on CLcr and Alb levels for patients with an SCr of < 0.6 mg/dL.

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Carbon monoxide alleviates endotoxin-induced acute lung injury via NADPH oxidase inhibition in macrophages and neutrophils

Watabe Y., Giam Chuang V.T., Sakai H., Ito C., Enoki Y., Kohno M., Otagiri M., Matsumoto K., Taguchi K.

Biochemical Pharmacology 233 116782 2025.03

Joint Work, ISSN 00062952

Sepsis is a life-threatening condition caused by severe infection and often complicates acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) due to the collapse of the oxidative and inflammatory balance induced by microbial pathogens, including lipopolysaccharides (LPS). In sepsis-related ARDS/ALI, NADPH oxidase (NOX) and toll-like receptors (TLR) in neutrophils and macrophages are key players in initiating oxidative and inflammatory imbalances. Although NOX and TLR activation has been linked to carbon monoxide (CO), the mechanism by which CO affects sepsis-related ARDS/ALI through NOX and TLR remains unknown. Here, we demonstrate that CO reduces sepsis-related ARDS/ALI by inhibiting NOX in neutrophils and macrophages, which in turn suppresses the production of reactive oxygen species (ROS), TLR4-associated inflammatory responses, and macrophage polarization toward M1-like macrophages. CO-bound hemoglobin vesicle (CO-HbV) therapy, a hemoglobin-based CO donor, exerts a protective effect against LPS-induced ALI by suppressing exaggerated oxidative and inflammatory responses and neutrophil and M1-like macrophage infiltration in the bronchoalveolar lavage fluid (BALF). Through suppression of NOX activity, CO decreased ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization toward M1-like macrophages, according to cellular experiments conducted with peripheral neutrophils, BALF cells, and Raw264.7 cells. Moreover, ALI was found to be more severe in Hmox1+/- mice (mice with decreased endogenous CO production) than in the wild-type mice. Our findings suggest that both endogenously generated and exogenously supplied CO inhibit NOX-associated ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization, thereby eliciting antioxidant and anti-inflammatory responses that prevent the onset and progression of LPS-induced ALI.

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The combined dual β-lactams and diazabicyclooctane β-lactamase inhibitor is highly effective against Mycobacterium abscessus species in vitro.

Misawa K, Nishimura T, Yoshikawa M, Shimamura R, Kashimura S, Enoki Y, Taguchi K, Matsumoto K, Hasegawa N

Journal of global antimicrobial resistance 42 142 - 150 2025.02

Joint Work, ISSN 2213-7165

Objective: Mycobacterium abscessus pulmonary disease is a refractory infectious disease. Developing an effective treatment is urgent as the number of patients infected with M. abscessus species (MABS) is increasing worldwide. We previously reported that nacubactam, a diazabicyclooctane (DBO) β-lactamase inhibitor, could inhibit MABS β-lactamase. Few reports have indicated that dual β-lactams are effective with a DBO β-lactamase inhibitor against MABS. The objective of this study was to determine which dual β-lactams have high antibacterial activity against MABS in the presence and absence of nacubactam. Methods: Antimicrobial susceptibility tests were conducted through a checkerboard assay of 27 β-lactams using the broth microdilution method for three subspecies-type strains and 20 clinical isolates of MABS. The number of intracellular and extracellular bacteria was measured using human macrophages infected with M. abscessus treated with effective combinations confirmed in susceptibility tests. Results: In antimicrobial susceptibility tests, 91 combinations of dual β-lactams with nacubactam exhibited synergistic effects on M. abscessus JCM13569. Among them, the combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam exhibited highly synergistic effects, resulting in low MICs against MABS clinical isolates. Without nacubactam, the combination of imipenem and cefoxitin showed the lowest MIC. In experiments using human macrophages infected with M. abscessus, these dual β-lactam combinations reduced the number of intracellular and extracellular bacteria compared with those of single β-lactams. Conclusions: The combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam was highly effective against MABS. Without nacubactam, the combination of cefoxitin and imipenem was effective.

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In Vitro Activity of Aztreonam in Combination with Relebactam against Gram-Negative Pathogens Producing Various Serine and Metallo-β-Lactamases.

Hayashi K, Suzuki M, Ishii Y, Matsumura Y, Matsumoto K, Saito S, Doi Y

Journal of global antimicrobial resistance 42 73 - 79 2025.02

Joint Work, ISSN 2213-7165

Objectives: Infections caused by carbapenemase-producing Gram-negative pathogens have become a significant global public health challenge due to limited treatment options. Pathogens producing metallo-β-lactamase are particularly problematic since they are not inhibited by conventional β-lactamase inhibitors. Herein, we assess the in vitro activity of aztreonam in combination with relebactam against a collection carbapenemase producing organisms, including strains producing both serine‑β-lactamase and IMP-type metallo-β-lactamase that are commonly encountered in Japan. Methods: A total of 119 carbapenemase-producing clinical isolates were used in this study. Minimum inhibitory concentrations (MICs) of aztreonam and imipenem alone and aztreonam/relebactam, aztreonam/avibactam and imipenem/relebactam combinations were determined by the broth microdilution method. Results: Aztreonam MICs were reduced in combination with relebactam for strains producing ESBL or AmpC in addition to IMP-type, NDM-type, GES-type or OXA-48 carbapenemases and for Stenotrophomonas spp. Additionally, aztreonam/relebactam combination MICs were significantly lower than MICs of aztreonam alone among IMP producers, NDM producers and Stenotrophomonas spp. Significant differences between aztreonam/relebactam and aztreonam MICs were also observed for strains of E. coli, K. pneumoniae and Enterobacter spp., many of which produced both metallo-β-lactamase and serine‑β-lactamase. The aztreonam/relebactam combination showed comparable to higher MICs compared with the aztreonam/avibactam combination. Conclusion: The addition of relebactam has a potential to restore the activity of aztreonam against strains that produce metallo-β-lactamase and serine‑β-lactamase. The combination may have a role in the treatment of infections due to these strains in countries without access to ceftazidime-avibactam.

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Reply to Mitsuboshi, "Enhancing result reliability by addressing potential confounding factors".

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

Microbiology spectrum 13 ( 3 ) e0149924 2025.02

Joint Work

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Evaluation of lung epithelial lining fluid concentrations of lascufloxacin against Streptococcus pneumoniae in a hollow-fiber infection model

Kamura H.N., Yamaguchi T., Kasama T., Hayashi Y., Hamada M., Matsumoto K., Miyake R., Ishii Y.

Journal of Antibiotics 2025

Joint Work, ISSN 00218820

Lascufloxacin (LSFX) achieves concentrations in epithelial lining fluid (ELF) that are more than 15 times higher than those in the bloodstream, making it a promising candidate for respiratory and otorhinolaryngological infections. These concentrations were replicated using the Hollow-Fiber Infection Model and demonstrated bactericidal efficacy of LSFX against levofloxacin-sensitive and -resistant Streptococcus pneumoniae. The study confirms that LSFX’s elevated concentration in ELF plays a significant role in its bactericidal activity.

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Treatment success prediction in patients with methicillin-resistant coagulase-negative staphylococci infections, using vancomycin AUC24/MIC ratio: a multicentre retrospective cohort study.

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

The Journal of antimicrobial chemotherapy 80 ( 2 ) 538 - 546 2024.12

Joint Work, ISSN 0305-7453

Background: Although vancomycin is commonly used to treat methicillin-resistant coagulase-negative staphylococci (MRCoNS) infections, there are no clear guidelines for the optimal 24 h AUC24/MIC ratio. This study aimed to determine the target AUC24/MIC ratio associated with vancomycin-treated MRCoNS infection outcomes. Methods: This multicentre retrospective cohort study included adult patients who received vancomycin for ≥5 days for bloodstream infections caused by MRCoNS between January 2018 and December 2023. Primary outcome was treatment success, defined as a composite of survival beyond 30 days, clinical success and microbiological eradication. Secondary outcomes included 30-day mortality, clinical success, microbiological eradication and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cut-off for treatment success. Multivariate regression analysis was used to determine the association between AUC24/MIC and outcomes. Results: This study included 147 patients. ROC analysis identified a target AUC24/MIC ≥373 for treatment success. The overall treatment success rate (70.1%) was significantly higher in the above-average AUC24/MIC cutoff group (83.1%) than that in the below AUC24/MIC cut-off group (57.9%). Multivariate analysis confirmed that AUC24/MIC ≥373 was an independent predictor (adjusted OR = 10.227; 95% CI = 3.585–29.171). The 30-day mortality and microbiological eradication rates differed significantly between the below- and above-cut-off groups, whereas nephrotoxicity rates were comparable among the groups. Conclusions: In treating MRCoNS infections, vancomycin AUC24/MIC ratio ≥373 was independently associated with favourable treatment outcomes. However, further prospective studies are required to confirm this target owing to the retrospective nature of this study.

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Simulated achievement rate of β-lactams/nacubactam treatment in humans using instantaneous MIC-based PK/PD analysis.

Igarashi Y, Taguchi K, Enoki Y, Chuang VTG, Matsumoto K

The Journal of antimicrobial chemotherapy 80 ( 2 ) 547 - 553 2024.12

Joint Work, ISSN 0305-7453

Background: Nacubactam (NAC), a new diazabicyclooctane β-lactamase inhibitor, is being developed for use together with aztreonam (AZT) and cefepime (CFPM). However, the effective clinical dosages of AZT/NAC and CFPM/NAC have not yet been established. We have previously shown that free time above instantaneous MIC (fT > MICi) is a valuable pharmacokinetic (PK)/pharmacodynamic parameter for β-lactam (BL)/NAC in a mouse thigh infection model. Objectives: This study simulated the fT > MICi (%) for AZT/NAC and CFPM/NAC against carbapenemase-producing Enterobacterales (CPE) with different MIC in humans to estimate the clinical efficacy at practically achievable combination doses of AZT/NAC and CFPM/NAC. Methods: Using previously reported PK parameters of each drug in humans and chequerboard MIC data, we calculated the fT > MICi (%) for AZT/NAC and CFPM/NAC in 10 000 simulated patients to predict the percentages of target attainment of bacteriostatic and bactericidal efficacies at various combined doses. Results: The results predicted that both BL/NAC combinations could achieve 100% 2 log10-kill against CPE strains at the lowest combination dose (0.5 g/0.5 g q8h). Additionally, in MIC studies examining BLs/NAC at a 1:1 ratio, the dosage regimen for strains with MICcomb ≤ 1 mg/L was expected to offer 100% bactericidal efficacy (2 log10-kill) at 0.5 g/0.5 g q8h or higher doses. For strains with 1 mg/L < MICcomb ≤ 16 mg/L, BLs/NAC at a 2 g/2 g q8h was predicted to produce bactericidal efficacy (1 log10-kill). At MICcomb = 32 mg/L, some bacteriostatic effect was expected at high BL doses. Conclusions: AZT/NAC and CFPM/NAC are bactericidal against CPE at practically achievable dosages.

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Bacteremia and meningitis caused by penicillin-resistant Streptococcus pneumoniae serotype 35B successfully treated with ceftriaxone combined with vancomycin followed by linezolid: A case report

Tomioka Mifumi, Nakamura Kiwamu, Duan Shaoqing, Matsumoto Kazuaki, Shindo Takahiro, Hoshi Keisuke, Nagao Mika, Oshima Fuminari, Hara Yasuka, Namai Yoshiyuki

Internal Medicine (The Japanese Society of Internal Medicine) advpub ( 0 ) 2024.11

Joint Work, ISSN 0918-2918

We herein report a case of bacterial meningitis and bacteremia in a 3-month-old boy caused by Streptococcus pneumoniae serotype 35B multidrug resistance. Intravenous ampicillin was administered on admission. However, when pneumococcal meningitis was suspected, the antibiotic treatment was changed to ceftriaxone (CTRX) and vancomycin (VCM). However, owing to difficulties in achieving sufficient serum trough levels of VCM, this treatment was again switched to linezolid (LZD). The patient recovered without complications after 16 days of CTRX and LZD treatment. This case suggests that LZD is a viable treatment option for bacterial meningitis.

Development of a pharmacokinetic/pharmacodynamic evaluation model for osteomyelitis and usefulness of tedizolid as an alternative to vancomycin against MRSA osteomyelitis.

Liu X, Enoki Y, Taguchi K, Matsumoto K

The Journal of pharmacy and pharmacology 77 ( 2 ) 291 - 298 2024.11

Joint Work, ISSN 0022-3573

Objectives: This study aimed to develop a suitable osteomyelitis model for pharmacokinetic/pharmacodynamic (PK/PD) evaluation and to investigate the target PK/PD values of vancomycin and tedizolid against methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. Methods: An osteomyelitis model was established by implanting an MRSA-exposed sterilized suture in the tibia of normal mice and mice with cyclophosphamide-induced neutropenia. The suitability of the osteomyelitis mouse model for PK/PD evaluation was assessed using vancomycin as an indicator. The target PK/PD values for tedizolid were determined using this model. Key findings: In neutropenic mice, to achieve a static effect and 1 log10 kill against MRSA, the ratios of the area under the free drug concentration-time curve for 24 h to the minimum inhibitory concentration (fAUC24/MIC) of vancomycin were 91.29 and 430.03, respectively, confirming the validity of the osteomyelitis model for PK/PD evaluation. In immunocompetent mice, the target fAUC24/MIC values of tedizolid for achieving a static effect and 1 log10 kill against MRSA were 2.40 and 49.20, respectively. Additionally, only a 0.28 log10 kill was achieved in neutropenic mice with 20 times the human equivalent dose of tedizolid. Conclusions: In patients with restored immunity, tedizolid can potentially be used as an alternative to intravenous vancomycin therapy.

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Investigating the hypothermic effects of fluoroquinolone antimicrobials on non-bacterial fever model mice.

Hara R, Taguchi K, Ogino H, Okamoto Y, Enoki Y, Kizu J, Hori S, Matsumoto K

Journal of pharmaceutical health care and sciences 10 ( 1 ) 68 2024.11

Joint Work, ISSN 2055-0294

Background: Fluoroquinolone (FQ) antimicrobials have antipyretic effects during the treatment of bacterial infections; however, it is not clear whether these are due to their antimicrobial activities or their hypothermic effects. In this study, we investigated the hypothermic effects of FQ antimicrobials (ciprofloxacin [CPFX], gatifloxacin [GFLX], and levofloxacin [LVFX]) on fever by evaluating rectal body temperature changes in a mouse model of non-bacterial fever. Methods: CPFX, GFLX, and LVFX were administered intraperitoneally to non-bacterial fever model mice induced by yeast. Rectal body temperature was measured up to 180 min after administration. Results: A decrease in rectal body temperature of up to 1.2 °C for CPFX, 3.4 °C for GFLX, and 1.0 °C for LVFX was observed. The decrease in temperature was induced by an increase in the plasma concentration of FQ antimicrobials, suggesting that they are responsible for the temperature reduction. Focusing on glucocorticoids, one thermoregulation mechanism, we investigated the substances responsible for the reduction in rectal body temperature induced by FQ antimicrobials. Aminoglutethimide (an inhibitor of glucocorticoid production) were premedicated, followed by intraperitoneal administration of GFLX in the yeast-induced fever mouse model, resulting in attenuated GFLX-induced hypothermic effects. Conclusions: These results suggest that certain antipyretic effects of CPFX, GFPX, and LVFX during fever may contribute to their hypothermic effects; certain mechanisms are glucocorticoid-mediated.

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Optimal Teicoplanin Trough Concentration With Therapeutic Drug Monitoring in Children: A Systematic Review and Meta-analysis.

Hanai Y, Oda K, Ueda T, Matsumoto K, Murakami L, Uekusa S, Ohashi H, Nishimura K, Takesue Y, Matsuo K

Therapeutic drug monitoring 46 ( 6 ) 699 - 709 2024.07

Joint Work, ISSN 0163-4356

Background: Teicoplanin is used to treat serious Gram-positive bacterial infections. However, the optimal trough concentrations for pediatric patients remain unclear owing to the lack of monitoring guidelines. This study aimed to determine the optimal teicoplanin trough concentration for treating Gram-positive bacterial infections in children. Methods: A systematic review was conducted using 4 databases. Stepwise cutoffs within the range of 10–30 mcg/mL were used for efficacy and safety. Studies were included if they reported treatment success rates and/or all-cause mortality, nephrotoxicity, hepatotoxicity, and thrombocytopenia according to the trough concentration. Results: The meta-analysis included 12 studies involving 830 pediatric patients. Teicoplanin cutoff values of 10, 15, 20, and 30 mcg/mL were reported in 9, 8, 9, and 2 studies, respectively. Trough concentrations,10 mcg/mL significantly reduced the treatment success rate, with an odds ratio of 0.07 and a 95% confidence interval ranging from 0.01 to 0.40. The overall treatment success rate was 50.0% versus 95.7% observed at concentrations $10 mcg/mL. However, no significant difference was observed at the 15-, 20-, and 30-mcg/mL cutoffs, when compared with lower concentrations. Trough concentrations,20 mcg/mL were associated with a decreased risk of nephrotoxicity (odds ratio = 0.21; 95% confidence interval, 0.08–0.55). However, hepatotoxicity and thrombocytopenia showed no significant associations with trough concentration ranges between 10 and 30 mcg/mL. Conclusions: Although further prospective studies are required for validation, the authors’ findings suggest that 10- to 20-mcg/mL teicoplanin is the optimal trough concentration for enhanced clinical success and reduced toxicity in pediatric patients.

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Anti-edematous effects of epinastine, cetirizine and its enantiomers in λ-carrageenan-induced edema in rat hind paw

Taguchi K., Chuang V.T.G., Ozawa M., Sakamoto Y., Hara R., Iketani O., Enoki Y., Kizu J., Hori S., Matsumoto K.

Pharmazie (Pharmazie) 79 ( 6 ) 98 - 100 2024.06

Joint Work, ISSN 00317144

Urticaria is induced by the histamine released from mast cells which develops wheals (edema) as a visual feature. In clinical practice, second-generation histamine H1-receptor blockers are routinely used as the first-line symptomatic treatment for urticaria. Nevertheless, not much research has directly examined the second-generation histamine H1-receptor blockers’ ability to reduce edema. In this study, we directly evaluated the anti-edematous activities of three second-generation histamine H1-receptor blockers available in the market (epinastine hydrochloride, cetirizine hydrochloride, and levocetirizine hydrochloride) using a λ-carrageenan-induced footpad edema model. One hour before the induction of edema with 1% λ-carrageenan injection, all second-generation histamine H1-receptor blockers (5, 10, 50 and 100 mg/kg) were subcutaneously administered to rats. At 0.5 and 3 hours after λ-carrageenan administration, the edema volume was evaluated using a Plethysmometer. Epinastine hydrochloride significantly suppressed the edema growth in a dose-dependent manner. Cetirizine hydrochloride showed a slight anti-edematous effect, while levocetirizine significantly inhibited the development of edema in a dose-dependent manner. On the other hand, dextrocetirizine did not prevent edema from growing. In summary, second-generation histamine H1-receptor blockers, at least those examined in this study, may be able to reduce the clinical symptoms of urticaria associated with edema. Levocetirizine hydrochloride is also anticipated to have stronger anti-edematous effects than cetirizine hydrochloride because levocetirizine is responsible for cetirizine’s anti-edematous activity.

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Relationship between nephrotoxicity and area under the concentration-time curve of vancomycin in critically ill patients: a multicenter retrospective study.

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

Microbiology spectrum (Microbiology spectrum) 12 ( 7 ) e0373923 2024.05

Joint Work

We aimed to assess the frequency of acute kidney injury (AKI) in different areas under the concentration-time curve (AUC) values of vancomycin (VAN) using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. This multicenter retrospective observational study was conducted in eight hospitals. We retrospectively analyzed the data of patients who had received VAN in an intensive care unit (ICU) between January 2020 and December 2022. The primary outcome was the incidence of AKI. Patients were classified into three groups according to the AUC24-48h at the initial therapeutic drug monitoring (TDM) as follows: <500, 500-600, and ≥600 µg·h/mL. The AUC24-48h values were calculated using the Bayesian estimation software Practical AUC-guided TDM. Among 146 patients [median age (interquartile range), 67 (56-78) years; 39% women], the AUC24-48h <500 µg·h/mL had an AKI rate of 6.5% (7/107), the AUC24-48h 500-600 µg·h/mL had an AKI rate of 28.0% (7/25), and the AUC24-48h ≥600 µg·h/mL had an AKI rate of 42.9% (6/14). In multivariate Cox proportional hazard analysis, the AUC24-48h 500-600 µg·h/mL [hazard ratio 5.4, 95% confidence interval (CI) 1.64-17.63] and the AUC24-48h ≥600 μg·h/mL (hazard ratio 7.0, 95% CI 2.31-21.18) significantly correlated with a higher incidence of AKI compared with the AUC24-48h <500 μg·h/mL. In conclusion, we identified an association between AUC on day 2 and the risk of AKI in ICU patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. IMPORTANCE: Vancomycin (VAN) is a glycopeptide antibiotic and one of the most commonly used antibiotics for severe infections caused by methicillin-resistant Staphylococcus aureus. However, higher VAN concentrations have been associated with an increased risk of acute kidney injury (AKI). Herein, we aimed to assess the frequency of AKI in different areas under the concentration-time curve (AUC) values of VAN using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. We identified an association between AUC on day 2 and the risk of AKI in intensive care unit patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. Therefore, individualized dosing is feasible, with pharmacists being able to optimize VAN doses to attain appropriate targets.

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Direct comparison of anti-inflammatory effects of 14-, 15-, and 16-membered macrolide antibiotics in experimental inflammation model induced by carrageenan in rats.

Taguchi K, Chuang VTG, Ogino H, Hara R, Iketani O, Enoki Y, Kizu J, Hori S, Matsumoto K

Die Pharmazie (Pharmazie) 79 ( 3 ) 64 - 66 2024.05

Joint Work, ISSN 0031-7144

Some macrolide antibiotics, which share a basic lactone ring structure, also exhibit anti-inflammatory actions in addition to their antibacterial activities. However, no study has directly compared anti-inflammatory effects on acute inflammation among macrolide antibiotics with the distinct size of the lactone ring. In this study, we evaluated and compared the anti-inflammatory activities of four 14-membered macrolides (erythromycin, clarithromycin, roxithromycin, oleandomycin), one 15-membered macrolide (azithromycin), and three 16-membered macrolides (midecamycin, josamycin, leucomycin) using a rat carrageenan-induced footpad edema model. All macrolide antibiotics were intraperitoneally administered to rats one hour before the induction of inflammatory edema with 1% λ-carrageenan. The anti-inflammatory effects on acute inflammation were evaluated by changing the edema volume. All 14-membered and 15-membered macrolide antibiotics significantly suppressed the development of edema. Conversely, none of the 16-membered macrolide antibiotics inhibited the growth of edema. In conclusion, compared to 16-membered macrolide antibiotics, 14-membered and 15-membered macrolide antibiotics have stronger anti-inflammatory effects. Further research should be done to determine why different lactone ring sizes should have distinct anti-inflammatory effects.

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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

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.

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

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.

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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Polysarcosine-Coated liposomes attenuating immune response induction and prolonging blood circulation.

Hu M, Taguchi K, Matsumoto K, Kobatake E, Ito Y, Ueda M

Journal of colloid and interface science (Journal of Colloid and Interface Science) 651 273 - 283 2023.07

Joint Work, ISSN 0021-9797

Hypothesis: Liposomes coated with long polysarcosine (PSar) chains at a high density might enable long blood circulation and attenuate accelerated blood clearance (ABC) phenomenon. Experiments: In this study, we controlled the length (23, 45, 68 mers) and density (5, 10, 15 mol%) of PSar on liposomal coatings and, furthermore, investigated the effects of PSar length and density on the blood circulation time, biodistribution, immune response, and ABC phenomenon induction. Length-controlled PSar-bound lipids (PSar-PEs) were synthesized using a click reaction and inserted into bare liposomes at different combinations of chain lengths and proportions. Findings: Although all PSar-coated liposomes (PSar-lipos) had similar morphological, physical, and chemical properties, they had different blood circulation times and biodistribution, and exerted varied effects on the immune system. All PSar-lipos with different PSar length and density showed a similar anti-PSar IgM response. Liposomes modified with the longest PSar chain (68 mers) at a high density (15 mol%) showed the longest blood circulation time and, additionally, attenuated ABC phenomenon compared with PEG-lipo. The ex vivo analysis of the biodistribution of liposomes revealed that a thick PSar layer enhanced the blood circulation time of liposomes due to the reduction of the accumulation of liposomes in the liver and spleen. These findings provide new insights into the relationship between IgM expression and ABC phenomenon inhibition.

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The anti-inflammatory effect of tedizolid on carrageenan-induced footpad edema rat model.

Isobe N, Chuang VTG, Liu X, Enoki Y, Taguchi K, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 29 ( 11 ) 1088 - 1090 2023.07

Joint Work, ISSN 1341-321X

Tedizolid (TZD) is an oxazolidinone anti-methicillin-resistant Staphylococcus aureus (MRSA) drug. Linezolid (LZD), another oxazolidinone, has been shown to have an anti-inflammatory effect. TZD has been shown to exhibit an anti-inflammatory effect in a murine model of hematogenous pulmonary infection. In this study, we further investigated the anti-inflammatory effect of TZDs using a carrageenan-induced rat footpad edema model. TZD was administered at 0, 10, 20, and 40 mg/kg to the carrageenan-induced rat footpad edema model, and the edema rate was measured over time up to 9 h later. The area under the time curve of the edema rate profile (AUCedema0→9) decreased in a TZD dose-dependent manner. In addition, the correlation between AUCedema0→9 and the area under the time curve of free TZD plasma concentration (fAUCblood) obtained from the pharmacokinetic study of TZD in the carrageenan-induced rat footpad edema model was examined. fAUCblood and AUCedema0→9 showed a good negative correlation. These results indicate that TZD suppresses carrageenan-induced footpad edema and that TZD exerts its anti-inflammatory effects in a plasma concentration-dependent manner.

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Anti-Inflammatory Actions of Expectorants in a Rat Carrageenan-Induced Footpad Edema Model.

Ito M, Liu X, Taguchi K, Enoki Y, Kuroda Y, Kizu J, Matsumoto K

Die Pharmazie (Pharmazie) 78 ( 6 ) 86 - 88 2023.07

Joint Work, ISSN 0031-7144

S-Carboxymethyl-L-cysteine (SCMS) exhibits sputum-regulating and anti-inflammatory actions. Previous studies reported the anti-inflammatory effects of SCMS on chronic inflammatory diseases, but no study has examined these effects on acute inflammatory diseases. In this study, we investigated the anti-inflammatory effects of SCMS in a rat carrageenan-induced footpad edema model, which is routinely used as an acute inflammation model. Expectorants were administered to rats with footpad edema induced by subcutaneously administering 1% λ-carrageenan to the footpad of the left posterior limb, and the dose dependency of the anti-inflammatory effects was evaluated. As a result, even when the dose of SCMS was increased to 400 mg/kg, there were no inhibitory effects on edema. Furthermore, we examined the inhibitory effects of other expectorants (ambroxol hydrochloride, N-acetyl-L-cysteine, L-cysteine ethylester hydrochloride, and L-cysteine methylester hydrochloride), which were reported to exhibit anti-inflammatory effects on chronic inflammation, on edema. However, none of these expectorants inhibited edema.

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Pharmaceutical Integrity of Lyophilized Methemoglobin-Albumin Clusters after Reconstitution

Suzuki Yuto, Taguchi Kazuaki, Okamoto Wataru, Enoki Yuki, Komatsu Teruyuki, Matsumoto Kazuaki

ACS OMEGA (ACS Omega) 8 ( 25 ) 22589 - 22595 2023.06

Joint Work, ISSN 2470-1343

Covalent attachment of a ferric hemoglobin (metHb) core to three human serum albumin molecules to form metHb-albumin clusters has previously been used to develop an antidote for hydrogen sulfide poisoning. Lyophilization is one of the most effective approaches to preserve protein pharmaceuticals with minimum contamination and decomposition. However, there is concern that lyophilized proteins may undergo pharmaceutical alteration on reconstitution. This study investigated the pharmaceutical integrity of metHb-albumin clusters on lyophilization and reconstitution with three clinically available reconstitution fluids, (i) sterile water for injection, (ii) 0.9% sodium chloride injection, and (iii) 5% dextrose injection. The metHb-albumin clusters retained their physicochemical properties and structural integrity on lyophilization and reconstitution with sterile water for injection or 0.9% sodium chloride injection, along with comparable hydrogen sulfide scavenging ability compared to non-lyophilized metHb-albumin clusters. The reconstituted protein completely rescued lethal hydrogen sulfide poisoning in mice. On the other hand, lyophilized metHb-albumin clusters reconstituted with 5% dextrose injection showed physicochemical changes and a higher mortality rate in mice subjected to lethal hydrogen sulfide poisoning. In conclusion, lyophilization represents a potent preservation method for metHb-albumin clusters if either sterile water for injection or 0.9% sodium chloride injection is used for reconstitution.

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Polyoxazoline-conjugated porcine serum albumin as an artificial plasma expander for dogs.

Okamoto W, Usui T, Hasegawa M, Kobayashi T, Fujisawa J, Taguchi K, Matsumoto K, Kohno M, Iwazaki M, Shimano S, Nagao I, Toyoda H, Matsumura N, Tomiyasu H, Tochinai R, Komatsu T.

Scientific Reports (Scientific Reports) 13 ( 1 ) 9512 2023.06

Joint Work, ISSN 2045-2322

Veterinary medicine has made tremendous progress for domestic dogs, which are irreplaceable family members enriching human life. Nevertheless, no adequate supply system exists for their blood products. This study examined the synthesis, structure, safety, and efficacy of poly(2-ethyl-2-oxazoline)-conjugated porcine serum albumin (POx-PSA) as an artificial plasma expander for dogs. The aqueous POx-PSA solution showed moderately high colloid osmotic pressure and good blood cell compatibility. Actually, lyophilized powder stored for 1 year can regenerate into a homogeneous solution. The circulation half-life of POx-PSA in rats was 2.1-fold longer than that of naked PSA. Rats produced neither anti-PSA IgG antibody nor anti-POx IgG antibody, which suggests excellent immunological stealth properties of POx-PSA. Complete resuscitation of hemorrhagic shock in rats was achieved soon after injection of POx-PSA solution. Serum biochemistry tests and histopathological observations indicated no abnormality in the related organs. When POx-PSA was administered to dogs intravenously, (i) no serum biochemical or hematological alteration was observed, also (ii) no overt deterioration of animal health was observed. These results indicate that POx-PSA has potential as an artificial plasma expander for dogs.

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In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model.

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

Pharmaceutical research 2023.05

Joint Work, ISSN 0724-8741

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Antimicrobial Efficacy Evaluations of Metronidazole against Clostridioides difficile Infection using Fecal Pharmacokinetic and Pharmacodynamic Analyses.

Tashiro S, Taguchi K, Enoki Y, Matsumoto K

Pharmaceutical research (Pharmaceutical Research) 40 ( 7 ) 1799 - 1806 2023.05

Joint Work, ISSN 0724-8741

Objectives: The pharmacokinetics/pharmacodynamics (PK/PD) characteristics of metronidazole (MNZ) in Clostridioides difficile infection (CDI) remain unclear. We aimed to determine the PK/PD characteristics of MNZ using a fecal PK/PD analysis model. Methods: Susceptibility testing, time-kill studies, and post-antibiotic effect (PAE) measurements were performed to evaluate in vitro PD profiles. MNZ was subcutaneously administered to mice infected with C. difficile ATCC® 43255 to evaluate in vivo PK and PD profiles, followed by determining fecal PK/PD indices with target value. Results: MNZ exerted concentration-dependent bactericidal activities with minimum inhibitory concentration (MIC) and PAE being 0.79 µg/mL and 4.8 h, respectively, against C. difficile ATCC® 43255. The reduction in vegetative cells in feces and treatment outcomes were most closely correlated with the ratio of the area under the fecal drug concentration–time curve from 0 to 24 h to the MIC (fecal AUC24/MIC). The target value of fecal AUC24/MIC to achieve a 1 log10 reduction in vegetative cells was 188. Upon meeting the target value, high survival rates (94.5%) and low clinical sickness score grading (5.2) were achieved in the CDI mouse models. Conclusions: The PK/PD index and its target value of MNZ for CDI treatment was fecal AUC24/MIC ≥ 188. These findings may contribute to the effective clinical use of MNZ.

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Methemoglobin-albumin clusters for cyanide detoxification

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

Toxicology and Applied Pharmacology (Toxicology and Applied Pharmacology) 466 116472 2023.05

Joint Work, ISSN 0041008X

Sodium nitrite (NaNO2) is a universal antidote for patients with cyanide poisoning. However, its use has serious drawbacks in terms of efficacy and safety. Herein, we present a promising antidote: methemoglobin (metHb)-albumin clusters. The metHb-albumin cluster is made by a metHb core wrapped by covalently bound human serum albumin. Spectral analyses proved that the metHb-albumin clusters possessed cyanide-binding properties similar to those of naked metHb. In vitro cell experiments showed that metHb-albumin clusters prevented the cyanide-induced inhibition of cytochrome c oxidase activity, resulting in a strong cytoprotective effect. In mice subjected to cyanide poisoning, metHb-albumin clusters reduced mortality and alleviated metabolic acidosis, while maintaining the activity of cytochrome c oxidase in organs; their efficacy was better than that of NaNO2. Furthermore, the oxygen carrying capacity was maintained in poisoned mice treated with metHb-albumin clusters and was low in those treated with NaNO2. These results indicate that metHb-albumin clusters could be a more effective and safer antidote against cyanide poisoning than NaNO2.

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Optimal therapeutic recommendation for Clostridioides difficile infection in pediatric and adolescent populations: a systematic review and meta-analysis.

Tashiro S, Mihara T, Okawa R, Tanaka Y, Samura M, Enoki Y, Taguchi K, Matsumoto K, Yamagishi Y

European journal of pediatrics (European Journal of Pediatrics) 182 ( 6 ) 2673 - 2681 2023.03

Joint Work, ISSN 0340-6199

We conducted a systematic review and meta-analysis to examine the efficacy profiles of metronidazole (MNZ) and vancomycin (VCM) in pediatric and adolescent patients with Clostridioides difficile infection (CDI). A systematic review and meta-analysis was conducted using four electronic databases (PubMed, Cochrane Library, Web of Science, and Clinicaltrials.gov) through July 6, 2022. We analyzed the clinical cure and recurrence rates to determine the efficacy of MNZ and VCM. The clinical cure rates in all included studies were not significantly different between MNZ and VCM (OR = 0.63; 95% CI = 0.36–1.10; I2 = 0%; P = 0.10). Subgroup analyses were performed separately for each region to account for regional differences in the CDI. MNZ treatment achieved significantly lower clinical cure rates than did VCM in the United States of America (USA) and Europe (OR = 0.42, 95% CI = 0.19–0.93, I2 = 0%, P = 0.03). Recurrence rates were not significantly different between MNZ and VCM (OR = 1.48, 95% CI = 0.62–3.53, I2 = 28%, P = 0.38). Conclusion: MNZ exhibited significantly lower clinical cure rates than did VCM in the US and Europe; therefore, it is not recommended for the management of CDI in pediatric and adolescent populations.What is Known:• The unavailability of robust data on recommendations of therapeutic agents for the management of Clostridioides difficile infections in children precludes effective antibiotic choice.What is New:• Metronidazole exhibited significantly lower clinical cure rates than did vancomycin in the United States of America and Europe and recurrence rate was not significantly different between metronidazole and vancomycin; therefore, it is not recommended for the management of Clostridioides difficile infection in children.

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Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae.

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

The Journal of antimicrobial chemotherapy (The Journal of antimicrobial chemotherapy) 78 ( 4 ) 991 - 999 2023.02

Joint Work, ISSN 0305-7453

BACKGROUND: Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains challenging. We aimed to establish a practical PK/PD analysis method for aztreonam/nacubactam that incorporates instantaneous MIC (MICi). METHODS: Based on chequerboard MIC measurements, MICi of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. RESULTS: The mean change in the bacterial count of thigh-infected mice in an in vivo PD study was plotted based on %fT>MICi and analysed using the inhibitory effect sigmoid Imax model. fT>MICi calculated from the PK experiments showed a high correlation with the in vivo bactericidal effect, suggesting that fT>MICi is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT>MICi achieving growth inhibition, 1 log10 kill and 2 log10 kill, were 22, 38% and 75%, respectively. CONCLUSIONS: The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in combination therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against NDM-producing K. pneumoniae.

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Model-informed precision dosing of teicoplanin for the rapid achievement of the 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 ( 4 ) 704 - 713 2023.02

Joint Work, ISSN 1752-8054

Teicoplanin, a glycopeptide antimicrobial, is recommended for therapeutic drug monitoring, but it remains unclear how to target the area under the concentration-time curve (AUC). This simulation study purposed to demonstrate the potential of the Bayesian forecasting approach for the rapid achievement of the target AUC for teicoplanin. We generated concordant and discordant virtual populations against a Japanese population pharmacokinetic model. The predictive performance of the Bayesian posterior AUC in limited sampling on the first day against the reference AUC was evaluated as an acceptable target AUC ratio within the range of 0.8–1.2. In the concordant population, the probability for the maximum a priori or Bayesian posterior AUC on the first day (AUC0–24) was 61.3% or more than 77.0%, respectively. The Bayesian posterior AUC on the second day (AUC24–48) was more than 75.1%. In the discordant population, the probability for the maximum a priori or Bayesian posterior AUC0–24 was 15.5% or 11.7–80.7%, respectively. The probability for the maximum a priori or Bayesian posterior AUC24–48 was 23.4%, 30.2–82.1%. The AUC at steady-state (AUCSS) was correlated with trough concentration at steady-state, with a coefficient of determination of 0.930; the coefficients on days 7 and 4 were 0.442 and 0.125, respectively. In conclusion, this study demonstrated that early sampling could improve the probability of AUC0–24 and AUC24–48 but did not adequately predict AUCSS. Further studies are necessary to apply early sampling-based model-informed precision dosing in the clinical settings.

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Comparison of the efficacy and safety of standard- and high-dose daptomycin: a systematic review and meta-analysis.

Samura M, Takada K, Hirose N, Kurata T, Nagumo F, Uchida M, Inoue J, Tanikawa K, Enoki Y, Taguchi K, Matsumoto K, Ueda T, Fujimura S, Mikamo H, Takesue Y, Mitsutake K

British journal of clinical pharmacology (British Journal of Clinical Pharmacology) 89 ( 4 ) 1291 - 1303 2023.01

Joint Work, ISSN 0306-5251

Aims: Standard doses of daptomycin at 4 and 6 mg/kg were used for the treatment of skin and soft tissue for infections and bacteraemia, respectively. However, increased doses of daptomycin are recommended for complicated infections by Gram-positive organisms. Methods: A systematic review was conducted using 4 databases. We compared treatment success between standard-dose (SD, 4–6 mg/kg) and high-dose (HD, >6 mg/kg) daptomycin in patients with all-cause bacteraemia, complicated bacteraemia, infective endocarditis, osteomyelitis and foreign body/prosthetic infection as the primary outcome. We also compared the success between SD and HD2 (≥8 mg/kg) daptomycin treatments in patients with these diseases as the secondary outcome. The incidence of creatine phosphokinase (CPK) elevation was evaluated as safety. Results: In patients with complicated bacteraemia and infective endocarditis, the treatment success was significantly lower in the SD group than in the HD group (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30–0.76 and OR 0.50, 95% CI 0.30–0.82) and HD2 group (OR 0.38, 95% CI 0.21–0.69 and OR 0.30, 95% CI 0.15–0.60), respectively. A significant difference was demonstrated only in the HD2 group in patients with bacteraemia, including simple infection. SD did not decrease the success rate for the treatment of osteomyelitis and foreign body/prosthetic infection. The incidence of elevated CPK was significantly lower in SD group than in HD group. Conclusion: SD daptomycin was associated with significantly lower treatment success than HD in patients with complicated bacteraemia/infective endocarditis. The CPK elevation should be considered in patients treated with high daptomycin doses.

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Optimal timing for therapeutic drug monitoring of voriconazole to prevent adverse effects in Japanese patients

Hanai Y., Ueda T., Hamada Y., Oda K., Takahashi Y., Nakajima K., Miyazaki Y., Kiriyama M., Uekusa S., Matsuo K., Matsumoto K., Kimura T., Takesue Y.

Mycoses (Mycoses) 66 ( 12 ) 1035 - 1044 2023

Joint Work, ISSN 09337407

Background: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels. Objectives: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. Patients/Methods: Trough levels (Cmin) were measured on days 3–5 (recommended timing, RT) and days 6–14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. Results: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 μg/mL [DT], p =.023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 μg/mL, p =.465), suggesting that Cmin close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p =.004); DT was an independent risk factor for hepatotoxicity. Conclusion: Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3–5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin.

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Analysis of Risk Factors for Developing Tuberculosis in Patients Who Received Prophylactic Latent Tuberculosis Infection Treatment with Experience of Biologic Medications

Itagaki Marina, Iketani Osamu, Enoki Yuki, Chuang Victor Tuan Giam, Taguchi Kazuaki, Uno Shunsuke, Uchida Sho, Namkoong Ho, Uwamino Yoshifumi, Takano Yaoko, Hasegawa Naoki, Matsumoto Kazuaki

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 46 ( 12 ) 1832 - 1837 2023

Joint Work, ISSN 0918-6158

Biologic medications have dramatically improved the treatment outcomes of immunological inflammatory diseases, but their immunosuppressive effects put patients at risk for tuberculosis (TB). We investigated the risk factors for developing TB in patients treated for latent tuberculosis infection (LTBI) who also had experience of using biologic medications. At Keio University Hospital, we retrospectively investigated patients treated with anti-mycobacterial drugs before or concurrently with biologic medications from January 2012 to August 2020. Patients in the ‘follow-on cases group’ who had a positive TB screening test after initiating biologic medications and subsequently started LTBI treatment were excluded. We researched and compared the patient characteristics for TB and non-TB patient groups. Of the 146 eligible patients, 5 (3.4%) developed TB. The incidence rate was 600/100000 person-years. There were no significant differences between TB and non-TB patient groups in the history of TB, interferon-gamma release assay (IGRA), duration of biologic medication therapy, LTBI treatment periods, concomitant use of calcineurin inhibitors or anti-rheumatic drugs. The percentage of patients who received prednisolone at a dose of ≥15 mg for more than 1 month was higher in those who developed TB than in those who did not (40.0 vs. 7.1%, p = 0.054); however, this difference was not statistically significant. Regular monitoring of TB is necessary for long-term concomitant use of high prednisolone doses during and after the administration of biologic medications.

Fecal pharmacokinetics/pharmacodynamics characteristics of fidaxomicin and vancomycin against Clostridioides difficile infection elucidated by in vivo feces-based infectious evaluation models.

Tashiro S, Taguchi K, Enoki Y, Matsumoto K

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases (Clinical Microbiology and Infection) 29 ( 5 ) 616 - 622 2022.12

Joint Work, ISSN 1198-743X

Objectives: The pharmacokinetics (PK)/pharmacodynamics (PD; PK/PD) characteristics of fidaxomicin (FDX) and vancomycin (VCM) against Clostridioides difficile infection (CDI) are yet to be elucidated because of the lack of an established PK/PD analysis method for intestinal infections and unabsorbed oral drugs. Here, we developed a feces-based PK/PD analysis method and determined the fecal PK/PD index, with target values of FDX and VCM against CDI. Methods: The antimicrobial susceptibility, time-kill curves, and post-antibiotic effects (PAEs) of FDX and VCM against C. difficile were determined in vitro. The optimal fecal PK/PD indices, with target values, were determined from the results of PK and PD studies involving 5-week-old female C57BL/6J mice infected with C. difficile ATCC® 43255. The minimum inhibitory concentration (MIC) breakpoints for C. difficile were estimated based on clinical data concerning fecal antibiotic concentrations in patients with CDI. Results: FDX and VCM inhibited C. difficile growth via time-dependent antibacterial activity and exerted PAEs. In the CDI mouse model experiments, the changes in C. difficile load and clinical cures (72-hour survival rates and clinical sickness score grading) were most highly correlated with the ratio of area under the fecal drug concentration-time curve to MIC (AUC0→∞/MIC). The target AUC0→∞/MIC values of FDX and VCM for 3 log10 reduction in C. difficile load was 13,173 and 8,308, respectively. The MIC breakpoints of FDX and VCM for C. difficile was estimated to be 1.0 and 2.0 μg/mL, respectively. Conclusions: The developed in vivo feces-based PK/PD analysis method elucidated the optimal fecal PK/PD index, with target values of FDX and VCM against CDI.

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The G protein-coupled receptor ligand apelin-13 ameliorates skeletal muscle atrophy induced by chronic kidney disease.

Enoki Y, Nagai T, Hamamura Y, Osa S, Nakamura H, Taguchi K, Watanabe H, Maruyama T, Matsumoto K

Journal of cachexia, sarcopenia and muscle (Journal of Cachexia, Sarcopenia and Muscle) 14 ( 1 ) 553 - 564 2022.12

Joint Work, ISSN 2190-5991

Background: Targeting of the apelin–apelin receptor (Apj) system may serve as a useful therapeutic intervention for the management of chronic kidney disease (CKD)-induced skeletal muscle atrophy. We investigated the roles and efficacy of the apelin–Apj system in CKD-induced skeletal muscle atrophy. Methods: The 5/6-nephrectomized mice were used as CKD models. AST-120, a charcoal adsorbent of uraemic toxins (8 w/w% in diet), or apelin (1 μmol/kg) was administered to CKD mice to investigate the mechanism and therapeutic potential of apelin on CKD-induced skeletal muscle atrophy. The effect of indoxyl sulfate, a uraemic toxin, or apelin on skeletal muscle atrophy was evaluated using mouse myoblast cells (C2C12 cells) in vitro. Results: Skeletal muscle atrophy developed over time following nephrectomy at 12 weeks, as confirmed by a significant increase of atrogin-1 and myostatin mRNA expression in the gastrocnemius (GA) muscle and a decrease of lower limb skeletal muscle weight (P < 0.05, 0.01 and 0.05, respectively). Apelin expression in GA muscle was significantly decreased (P < 0.05) and elabela, another Apj endogenous ligand, tended to show a non-significant decrease at 12 weeks after nephrectomy. Administration of AST-120 inhibited the decline of muscle weight and increase of atrogin-1 and myostatin expression. Apelin and elabela expression was slightly improved by AST-120 administration but Apj expression was not, suggesting the involvement of uraemic toxins in endogenous Apj ligand expression. The administration of apelin at 1.0 μmol/kg for 4 weeks to CKD mice suppressed the increase of atrogin-1 and myostatin, increased apelin and Apj mRNA expression at 30 min after apelin administration and significantly ameliorated weight loss and a decrease of the cross-sectional area of hindlimb skeletal muscle. Conclusions: This study demonstrated for the first time the association of the Apj endogenous ligand–uraemic toxin axis with skeletal muscle atrophy in CKD and the utility of therapeutic targeting of the apelin–Apj system.

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Safety of linezolid in patients with decreased renal function and trough monitoring: a systematic review and meta-analysis.

Liu X, Aoki M, Osa S, Ito C, Saiki R, Nagai T, Enoki Y, Taguchi K, Matsumoto K

BMC pharmacology & toxicology (BMC Pharmacology and Toxicology) 23 ( 1 ) 89 2022.11

Joint Work

Background: Linezolid causes hematological toxicity, mostly thrombocytopenia, which leads to treatment discontinuation and failure. Recent studies revealed that during linezolid therapy, the incidence of treatment-related hematological toxicity is significantly higher in patients with decreased renal function (DRF) than in those with normal renal function. Linezolid monitoring is necessary due to the high frequency of hematological toxicity in patients with DRF and the relationship between blood concentration and safety. We performed a systematic review and meta-analysis to evaluate the safety correlation between DRF and trough monitoring. Methods: Articles published before June 24, 2022, on MEDLINE, Web of Sciences, Cochrane Register of Controlled Trials, and ClinicalTrials.gov were systematically analyzed. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the Mantel–Haenszel method and the variable effects model. Results: The incidence of hematological toxicity was significantly higher in patients with DRF than in those without DRF (OR = 2.37; p < 0.001). Subgroup analysis, performed according to hematotoxicity classification, including thrombocytopenia, anemia, and pancytopenia, revealed a significantly higher incidence of thrombocytopenia (OR = 2.45; p < 0.001) and anemia (OR = 2.31; p = 0.006) in patients with DRF than in those without; pancytopenia (OR = 1.41; p = 0.80) incidences were not significantly higher. Based on a systematic review, linezolid trough concentrations > 6–7 μg/mL may be associated with an increased incidence of thrombocytopenia. However, no confidential threshold values for the development of thrombocytopenia were found in the area under the concentration curve values for children or adults. Conclusion: We observed a high frequency of hematological toxicity during linezolid therapy in patients with DRF. To ensure safety, linezolid trough concentrations should be ≤6–7 μg/mL.

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Sciatic denervation-induced skeletal muscle atrophy is associated with persistent inflammation and increased mortality during sepsis.

Osa S, Enoki Y, Miyajima T, Akiyama M, Fujiwara Y, Taguchi K, Kim YG, Matsumoto K

Shock (Augusta, Ga.) (Shock) 59 ( 3 ) 417 - 425 2022.11

Joint Work, ISSN 1073-2322

Background: Patients with underlying skeletal muscle atrophy are likely to develop aggravated sepsis. However, no study has experimentally verified the association between the prognosis of sepsis and muscle atrophy, and the mechanism of aggravation of sepsis under muscle atrophy remains unclear. In this study, we investigated the effect of skeletal muscle atrophy induced by sciatic denervation (DN), an experimental muscle atrophy model, on sepsis prognosis. Methods: Skeletal muscle atrophy was induced by DN of the sciatic nerve in C57BL/6J male mice. Cecal ligation and puncture (CLP) was performed to induce sepsis. Results: The survival rates of the sham and DN groups 7 days after CLP were 63% and 35%, respectively, wherein an approximately 30% reduction was observed in the DN group (P < 0.05, vs. sham-CLP). The DN group had a higher bacterial count in the blood 48 h after CLP (P < 0.05, vs. sham-CLP). Notably, NOx (a metabolite of nitric oxide) concentrations in DN mice were higher than those in sham mice after CLP (P < 0.05, vs. sham-CLP), whereas serum platelet levels were lower 48 h after CLP (P < 0.05, vs. sham-CLP). In organ damage analysis, DN mice presented increased protein expression of the kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), a kidney injury marker, after CLP (NGAL 48 h after CLP, P < 0.05, vs. sham-CLP; KIM-1 24 h after CLP, P < 0.01, vs. sham-CLP). Furthermore, nitro tyrosine levels in the kidneys of DN mice were higher 48 h after CLP compared with those in sham-CLP mice, indicating the accumulation of nitrative stress (P < 0.05, vs. sham-CLP). Serum cytokine levels were increased in both groups after CLP, but decreased in the sham group 48 h after CLP and remained consistently higher in the DN group (tumor necrosis factor [TNF]-α: P < 0.05, sham-CLP vs. DN-CLP; interleukin (IL)-1β: P < 0.01, sham-CLP vs. DN-CLP; IL-6: P < 0.05, DN vs. DN-CLP; IL-10: P < 0.05, sham-CLP vs. DN-CLP). Conclusions: We verified that skeletal muscle atrophy induced by DN is associated with poor prognosis after CLP-induced sepsis. Importantly, mice with skeletal muscle atrophy presented worsening sepsis prognosis at late onset, including prolonged infection, persistent inflammation, and kidney damage accumulation, resulting in delayed recovery.

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Clinical Practice Guideline for the Therapeutic Drug Monitoring of Voriconazole in Non-Asian and Asian Adult Patients: Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

Takesue Y, Hanai Y, Oda K, Hamada Y, Ueda T, Mayumi T, Matsumoto K, Fujii S, Takahashi Y, Miyazaki Y, Kimura T, Japanese Antimicrobial Therapeutic Drug Monitoring Guideline Committee

Clinical therapeutics (Clinical Therapeutics) 44 ( 12 ) 1604 - 1623 2022.11

Joint Work, ISSN 0149-2918

Purpose: Voriconazole, an antifungal drug, is metabolized by a cytochrome P450 isozyme. Increased adverse effects are observed in Asians because of the high rate of poor metabolizers. In this therapeutic drug monitoring (TDM) guideline, recommendations were made according to ethnic group. Methods: Five clinical questions were used. For the preparation of the guideline, the performance of TDM in multicenter studies was surveyed (study 1). We also conducted a systematic review and meta-analysis (study 2) to establish recommendations for non-Asians and Asians. Findings: In study 1, 401 patients were surveyed. A risk of supratherapeutic concentrations was found in Japanese patients who adhered to the recommended dose. Target trough levels were achieved in 87% of patients with dose reductions. Although the trough level measured at the onset of adverse effects (AEs) was significantly associated with hepatotoxicity, no significant correlation was found between the initial trough level and hepatotoxicity, which indicated that hepatotoxicity was successfully prevented by the trough-guided dosing. In study 2, 22 studies (11 Asian locations and 11 non-Asian locations) were included in meta-analysis for the relationship between trough cutoff level (3, 4, 5, 5.5, and 6 µg/mL) and AEs. Significant differences were found for all cutoff levels, with the highest odds ratio for 4.0 µg/mL in Asian locations. In contrast, in non-Asian locations, no more than 1 study was available for any trough cutoff level, except for 5.5 µg/mL, at which level a significant increase in AEs was found. These findings indicate that TDM is strongly recommended to prevent AEs in Asians, and TDM is generally recommended for non-Asians to address subtherapeutic concentrations. TDM on day 3 is recommended to assess pharmacokinetic properties, including loading and maintenance doses. If the patient condition permits, delaying until day 5 is suggested for Asians because of the prolonged t½ in poor metabolizers. A trough level ≥1.0 µg/mL is strongly recommended to improve efficacy. Trough levels ≥2.0 µg/mL are suggested for invasive aspergillosis. To decrease adverse effects, trough levels <4.0 µg/mL are strongly recommended in Asians, whereas trough levels <5.5 µg/mL are generally recommended in non-Asians. Maintenance doses of 4 and 3 mg/kg twice daily are recommended in non-Asians and Asians, respectively. Implications: Different indications, timings, and target trough levels for TDM and different regimens are suggested for Asians and non-Asians.

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Differences in Pharmacokinetic/Pharmacodynamic Parameters of Tedizolid Against VRE and MRSA.

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

Pharmaceutical research (Pharmaceutical Research) 40 ( 1 ) 187 - 196 2022.11

Joint Work, ISSN 0724-8741

Purpose: Vancomycin-resistant enterococci (VRE) have recently become a major cause of nosocomial infections and a global public health concern. Tedizolid exhibits powerful antibacterial activity against VRE in vitro, but its pharmacokinetic/pharmacodynamic (PK/PD) parameters remain unclear. Therefore, we aimed to determine the PK/PD indices of tedizolid action on VRE and the mechanisms underlying the PK/PD indices differences of tedizolid against VRE and methicillin-resistant Staphylococcus aureus (MRSA). Methods: Optimal PK/PD target values of tedizolid were determined in vitro, based on time-kill curves and post-antibiotic effects (PAEs), and in vivo, using mouse models of thigh infection with VRE and MRSA strains. Results: The tedizolid bactericidal activity on VRE and MRSA was time-dependent. Correlations were closest between fAUC24/MIC and the tedizolid PK/PD index against MRSA and VRE. To achieve 1 log10 kill tedizolid fAUC24/MIC in neutropenic mouse models of thigh infection with VRE and MRSA should be 14.2 and 138.5, respectively. The PAEs of tedizolid against VRE and MRSA were 2.39 and 0.99 h, respectively. Conclusion: Tedizolid showed bactericidal effects against VRE even in neutropenic mice unlike MRSA, which could be attributed to its longer PAE against VRE. Hence, we hypothesize that tedizolid treatment against VRE infections is promising for achieving therapeutic success in clinical.

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In vitro effects of diazabicyclooctane β-lactamase inhibitors relebactam and nacubactam against three subspecies of Mycobacterium abscessus complex.

Misawa K, Nishimura T, Kashimura S, Enoki Y, Taguchi K, Uno S, Uwamino Y, Matsumoto K, Hasegawa N

International journal of antimicrobial agents (International Journal of Antimicrobial Agents) 60 ( 5-6 ) 106669 2022.09

Joint Work, ISSN 0924-8579

Background: Mycobacterium abscessus complex (MABC) pulmonary disease is notoriously difficult to treat due to intrinsic resistance to many common antibiotics. MABC is β-lactam-resistant as it produces class A β-lactamases, such as blaMab, which are inhibited by diazabicyclooctane (DBO) β-lactamase inhibitors. Objectives: To investigate the microbiological effects of the combination of β-lactam and DBO β-lactamase inhibitors (relebactam and nacubactam) against MABC and determine if the effects are associated with the MABC subspecies and colony morphotype. Methods: The antimicrobial susceptibility of three type strains and 20 clinical isolates of MABC to the combination of seven β-lactams with relebactam or nacubactam was evaluated using broth microdilution checkerboard assays. For these strains, expression levels of blaMab were assessed using quantitative real-time polymerase chain reaction and genotypic diversity was evaluated using 18-locus variable number tandem repeat assay. Results: Relebactam and nacubactam lowered the minimum inhibitory concentrations of β-lactams, particularly imipenem, meropenem, and tebipenem, against MABC. There was no difference in efficacy of combination treatment between three subspecies, but rough morphotypes tended to be less susceptible than smooth morphotypes. There were no differences in blaMab expression levels and genotypic diversity between the morphotypes. Conclusions: The combination of β-lactam with relebactam or nacubactam improved the efficacy of β-lactams against all MABC subspecies, but higher concentrations of β-lactams were needed for rough morphotypes.

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Efficacy of surgical skin preparation with chlorhexidine in alcohol according to the concentration required to prevent surgical site infection: meta-analysis.

Hasegawa T, Tashiro S, Mihara T, Kon J, Sakurai K, Tanaka Y, Morita T, Enoki Y, Taguchi K, Matsumoto K, Nakajima K, Takesue Y

BJS open (BJS open) 6 ( 5 ) 2022.09

Joint Work, ISSN 2474-9842

BACKGROUND: A combination of chlorhexidine gluconate and alcohol (CHG-alcohol) is recommended for surgical skin preparation to prevent surgical site infection (SSI). Although more than 1 per cent CHG-alcohol is recommended to prevent catheter-related bloodstream infections, there is no consensus regarding the concentration of the CHG compound for the prevention of SSI. METHODS: A systematic review and meta-analysis was performed. Four electronic databases were searched on 5 November 2020. SSI rates were compared between CHG-alcohol and povidone-iodine (PVP-I) according to the concentration of CHG (0.5 per cent, 2.0 per cent, 2.5 per cent, and 4.0 per cent). RESULTS: In total, 106 of 2716 screened articles were retrieved for full-text review. The risk ratios (RRs) of SSI for 0.5 per cent (6 studies) and 2.0 per cent (4 studies) CHG-alcohol were significantly lower than those for PVP-I (RR = 0.71, 95 per cent confidence interval (c.i.) 0.52 to 0.97; RR = 0.52, 95 per cent c.i 0.31 to 0.86 respectively); however, no significant difference was observed in the compounds with a CHG concentration of more than 2.0 per cent. CONCLUSIONS: This meta-analysis is the first study that clarifies the usefulness of an alcohol-based CHG solution with a 0.5 per cent or higher CHG concentration for surgical skin preparation to prevent SSI.

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Ceftazidime encephalopathy developed without the elevation of cerebrospinal fluid concentration of ceftazidime: A case report of two cases.

Toda M, Yoshifuji A, Hosoya K, Taguchi K, Komatsu M, Kobayashi E, Fujii K, Kato A, Hasegawa N, Matsumoto K, Ryuzaki M

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 12 ) 1667 - 1671 2022.08

Joint Work, ISSN 1341-321X

Background: Ceftazidime encephalopathy is reported to be caused by the repeated administration of ceftazidime in patients with renal impairment because of the high serum concentration of ceftazidime. Ceftazidime encephalopathy has been considered to be caused by the elevation of the cerebrospinal fluid (CSF) concentration. However, as no reports have measured CSF concentrations, the relationship with ceftazidime encephalopathy and CSF concentration has not been clarified. Case presentation: Case 1: An 80-year-old Japanese man under a combination therapy with peritoneal dialysis and hemodialysis, who had been treated for a cellulitis with ceftazidime, developed altered consciousness and was diagnosed as ceftazidime encephalopathy. His serum concentration of ceftazidime was elevated, but CSF concentration was only under 0.1 μg/mL. Case 2: An 88-year-old Japanese man with chronic kidney disease, who had been treated for a urinary tract infection with ceftazidime, developed altered consciousness and was diagnosed as ceftazidime encephalopathy. His serum concentration of ceftazidime was elevated, but CSF concentration was within the therapeutic range. However, his serum and CSF concentration of quinolinic acid was markedly increased. Conclusions: Patients with renal failure are more likely to develop ceftazidime encephalopathy. We need to pay attention to the dosage of ceftazidime and to the appearance of neurological symptoms. Ceftazidime encephalopathy was considered to be caused by the high CSF concentration, but it could be caused by quinolinic acid as neurotoxic substance.

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Oral fidaxomicin versus vancomycin for the treatment of Clostridioides difficile infection: A systematic review and meta-analysis of randomized controlled trials.

Tashiro S, Mihara T, Sasaki M, Shimamura C, Shimamura R, Suzuki S, Yoshikawa M, Hasegawa T, Enoki Y, Taguchi K, Matsumoto K, Ohge H, Suzuki H, Nakamura A, Mori N, Morinaga Y, Yamagishi Y, Yoshizawa S, Yanagihara K, Mikamo H, Kunishima H

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 11 ) 1536 - 1545 2022.08

Joint Work, ISSN 1341-321X

Background: Fidaxomicin (FDX) has received considerable attention as a novel therapeutic alternative agent to vancomycin (VCM) for Clostridioides difficile infection (CDI). However, the superiority and efficacy profile of FDX are not sufficiently determined by high-quality evidence. This study aimed to clarify the superiority of FDX for CDI treatment through a systematic review and meta-analysis. Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) which evaluated the efficacy and safety of FDX and VCM in patients with CDI. Electronic databases (PubMed, Cochrane Library, Web of Science, and Clinicaltrials.gov) were searched for studies published until October 15, 2021. The primary endpoint was global cure. The secondary endpoints were clinical cure, recurrence, and adverse event. Risk ratios (RRs), risk differences (RDs), and 95% confidence intervals were calculated using Mantel-Haenszel random-effects model. The risk of bias was assessed using Cochrane Handbook for Systematic Reviews of Interventions and Assessment Criteria. Results: Six RCTs were included in this meta-analysis. Compared to VCM, FDX was associated with significantly higher global cure rates (RR = 1.18, P < 0.00001; RD = 0.11, 95% CI = 0.07–0.16). In addition, clinical cure rates were comparable between FDX and VCM (P = 0.31). FDX was associated with significantly lower recurrence rates compared to VCM (RR = 0.59, P < 0.0001). In addition, adverse event rates were not significantly different between the drugs (P = 0.41). Conclusion: FDX achieves significantly higher global cure rates and lower recurrence rates and is comparable to VCM in clinical cure rates and adverse event rates in patients with CDI. Collectively, FDX is superior to VCM as a therapeutic agent for CDI.

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Concentration-Dependent Activity of Pazufloxacin against Pseudomonas aeruginosa: An In Vivo Pharmacokinetic/Pharmacodynamic Study.

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

Antibiotics (Basel, Switzerland) (Antibiotics) 11 ( 7 ) 2022.07

Joint Work, ISSN 2079-6382

The bacterium Pseudomonas aeruginosa is known to be associated with nosocomial infections around the world. Pazufloxacin, a potent DNA gyrase inhibitor, is known to be an effective drug candidate. However, it has not been clarified whether the pharmacokinetic (PK)/pharmacodynamic (PD) of pazufloxacin was effective against P. aeruginosa. Herein, we demonstrated that the PK/PD index of pazufloxacin against P. aeruginosa infection is used to optimize the dosing regiments. We constructed an in vivo infection model by infecting P. aeruginosa into the thigh of a mouse to determine the PD, and we measured the serum concentration of pazufloxacin to construct the PK model using high-performance liquid chromatography. The therapeutic efficacy of pazufloxacin was correlated with the ratio of the area under the free concentration time curve at 24 h to the minimum inhibitory concentration (fAUC24/MIC), and the maximum free concentration to the MIC (fCmax/MIC). Each contribution rate (R2) was 0.72 and 0.65, respectively, whereas the time at which the free drug concentration remained above the MIC (R2 = 0.28). The target value of pazufloxacin fAUC24/MIC for stasis was 46.1, for 1 log10 it was 63.8, and for 2 log10 it was 100.8. Moreover, fCmax/MIC for stasis was 5.5, for 1 log10 it was 7.1, and for 2 log10 it was 10.8. We demonstrated that the in vivo concentration-dependent activity of pazufloxacin was effective against the P. aeruginosa infection, and successfully made the PK/PD model sufficiently bactericidal. The PK/PD model will be beneficial in preventing the spread of nosocomial infections.

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Methemoglobin-albumin clusters for the treatment of hydrogen sulfide intoxication.

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

Journal of controlled release : official journal of the Controlled Release Society (Journal of Controlled Release) 349 304 - 314 2022.07

Joint Work, ISSN 0168-3659

Hydrogen sulfide (H2S) has attracted significant attention as a seed in drug development. However, H2S is toxic and induces lethal acute intoxication. Here, we developed methemoglobin (metHb)-albumin clusters as detoxifying agents for H2S intoxication, which were designed based on the inherent binding property of metHb with H2S. The metHb-albumin clusters comprising an autoxidized ferric Hb center wrapped covalently with an average of three human serum albumins showed a similar H2S binding affinity to that of naked metHb. Owing to the H2S binding capability, metHb-albumin clusters suppressed cell death induced by H2S exposure while maintaining mitochondrial function in H9c2 cells. In addition, lethal H2S intoxication model mice were rescued by a single administration of metHb-albumin clusters, resulting from the recovery of cytochrome c oxidase activity. Furthermore, the metHb-albumin clusters possessed essential characteristics, such as adequate pharmacokinetic properties and biocompatibility, for their use as detoxifying agents against H2S intoxication. In conclusion, the results obtained in this study suggest that metHb-albumin clusters are promising detoxifying agents for H2S intoxication and that harnessing the inherent H2S binding properties of metHb is an innovative approach to develop detoxifying agents for H2S intoxication.

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Liposomal methemoglobin as a potent antidote for hydrogen sulfide poisoning.

Suzuki Y, Taguchi K, Kure T, Enoki Y, Otagiri M, Sakai H, Matsumoto K

Toxicology and applied pharmacology (Toxicology and Applied Pharmacology) 450 116159 2022.07

Joint Work, ISSN 0041-008X

Hydrogen sulfide (H2S) induces acute and lethal toxicity at high concentrations. However, no specific antidotes for H2S poisoning have been approved. Liposomal methemoglobin (metHb@Lipo) was developed as an antidote for cyanide poisoning. As the toxic mechanism of H2S poisoning is the same as that of cyanide poisoning, metHb@Lipo could potentially be used as an antidote for H2S poisoning. In this study, we evaluated the antidotal efficacy of metHb@Lipo against H2S poisoning. Stopped-flow rapid-scan spectrophotometry clearly showed that metHb@Lipo scavenged H2S rapidly. Additionally, metHb@Lipo showed cytoprotective effects against H2S exposure in H9c2 cells by maintaining mitochondrial function. MetHb@Lipo treatment also improved the survival rate after H2S exposure in vivo, with the maintenance of cytochrome c oxidase activity and suppression of metabolic acidosis. Moreover, metHb@Lipo therapy maintained significant antidotal efficacy even after 1-year-storage at 4–37 °C. In conclusion, metHb@Lipo is a candidate antidote for H2S poisoning.

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Self-medication Tax System Based on Vital Statistics: Exploration through Survey

Taguchi Kazuaki, Enoki Yuki, Hori Satoko, Yamaura Katsunori, Matsumoto Kazuaki

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 48 ( 7 ) 276 - 283 2022.07

Joint Work, ISSN 1346-342X

The self-medication tax system is a new tax policy system that came into effect in 2017. The dissemination of this tax system is expected to promote changes in the people’s behavior toward self-medication and contribute to the optimization of healthcare costs. This study aimed to conduct an anonymous self-administered questionnaire survey on the self-medication tax system for 3,000 people, assigned based on vital statistics in an online survey system, and extract the reality of and issues surrounding the tax system. The results showed that approximately 55％ of the survey participants were aware of the self-medication tax system, but only 6％ were aware of all the application requirements for the tax system. This indicated that there was a misunderstanding among those who were familiar with the tax system. In addition, among the conditions for applying the system, the percentage of switch from over the counter drug purchases that met the application requirements was significantly lower than those of the other two requirements. Furthermore, 103 survey participants had received income deductions under the self-medication tax system, indicating that some potential applicants meet all the application requirements. The self-medication tax system was partially revised on January 1, 2022, with the application procedure partially simplified and the target products expanded. It is expected that these revisions will henceforth serve as a driving force to promote self-medication and popularize this tax system.

Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system.

Ozawa T, Namkoong H, Takaya R, Takahashi Y, Fukunaga K, Enoki Y, Taguchi K, Kizu J, Matsumoto K, Hasegawa N

BMC infectious diseases (BMC Infectious Diseases) 22 ( 1 ) 580 2022.06

Joint Work

Background: In Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database. Methods: We included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution. Results: The total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181–300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3–7.44), 2.61 (95% CI, 1.39–4.91), and 2.38 (95% CI, 1.04–5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62–351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35–14.77) and 6.99 (95% CI, 3.22–15.18). The β value of EB was 2.07 (95% CI, 1.48–2.76), which was classified as a wear-out failure type. Conclusions: For MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

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Current Aspects of Pediatric Pharmacokinetics and Pharmacodynamics of Antimicrobials in Japan: Importance of the Promotion of Population PK/PD Analysis.

Shoji K, Saito J, Nakamura H, Matsumoto K, Oda K, Takesue Y, Miyairi I

The Pediatric infectious disease journal (Pediatric Infectious Disease Journal) 41 ( 10 ) e418 - e423 2022.06

Joint Work, ISSN 0891-3668

Pharmacologic knowledge is important for pediatricians conducting feasible pharmacokinetic or pharmacodynamic (PK/PD) studies or applying effective antimicrobial therapies in children. Because of the difficulties in conducting PK/PD studies in children, antimicrobial PK/PD data in children are still limited. To fill in the lack of knowledge, promotion of population PK/PD analysis, which allows us to handle sparse sampling data from individual patients, is important because it is considered a suitable methodology to conduct PK/PD studies in children with limited blood drug concentration data for PK/PD analysis. Population PK/PD analysis is also useful in the clinical setting to provide individualized optimal dosage for each patient with various conditions. Here we summarized the current aspects of pediatric PK/PD studies of antimicrobials in Japan from clinical and research perspectives, specifically focusing on the importance of population PK/PD analysis.

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Single-step N-terminal modification of proteins via a bio-inspired copper(II)-mediated aldol reaction.

Hanaya K, Yamoto K, Taguchi K, Matsumoto K, Higashibayashi S, Sugai T

Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry - A European Journal) 28 ( 47 ) e202201677 2022.06

Joint Work, ISSN 0947-6539

The chemical modification of proteins is an effective technique for manipulating the properties and functions of proteins, and for creating protein-based materials. The N-terminus is a promising target for single-site modification that provides modified proteins with uniform structures and properties. In this paper, a copper(II)-mediated aldol reaction with 2-pyridinecarboxaldehyde (2-PC) derivatives is proposed as an operationally simple method to selectively modify the N-terminus of peptides and proteins at room temperature and physiological pH. The copper(II) ion activates the N-terminal amino acids by complexation with an imine of the N-terminal amino acid and 2-PCs, realizing the selective formation of the nucleophilic intermediate at the N-terminus. This results in a stable carbon-carbon bond between the 2-PCs and the α-carbon of various N-terminal amino acids. The reaction is applied to four different proteins, including biopharmaceuticals such as filgrastim and trastuzumab. The modified trastuzumab retains the human epidermal growth factor receptor 2 recognition activity.

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Japanese Clinical Practice Guidelines for Management of Clostridioides (Clostridium) difficile infection.

Kunishima H, Ohge H, Suzuki H, Nakamura A, Matsumoto K, Mikamo H, Mori N, Morinaga Y, Yanagihara K, Yamagishi Y, Yoshizawa S

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 8 ) 1045 - 1083 2022.05

Joint Work, ISSN 1341-321X

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Trimethoxy trityl groups as a potent substituent for anti-cancer cytidine analog prodrugs.

Ito C, Taguchi K, Moroi Y, Enoki Y, Tokuda R, Yamasaki K, Imoto S, Matsumoto K

Journal of pharmaceutical sciences (Journal of Pharmaceutical Sciences) 111 ( 8 ) 2201 - 2209 2022.05

Joint Work, ISSN 0022-3549

Methoxy trityl groups are acid-responsive protecting groups that are routinely used in the process of nucleoside analog synthesis. This study investigated the potential of methoxy trityl groups, monomethoxy trityl (MMT), dimethoxy trityl (DMT), and trimethoxy trityl (TMT), as acid-responsive substituents for designing anti-cancer cytidine analog prodrugs. For this purpose, we synthesized six gemcitabine (GEM) derivatives, which were modified either 4-(N)- or 5′-(O)-sites with MMT, DMT, and TMT, as candidates for anti-cancer cytidine analog prodrugs. In vitro dissociation test of methoxy trityl groups clearly showed that the acid responsivity of the methoxy trityl moieties was in the order TMT>DMT>MMT. Furthermore, the rate of 5′-(O)-methoxy tritylation was higher than that of 4-(N)-methoxy tritylation. Along with high acid-responsivity, trimethoxy trityl-O-GEM (TMT-O-GEM) showed superior cytotoxicity against 2D cultured human breast cancer cells (MCF-7 and MDA-MB-231) and human pancreatic cancer cells (AsPC-1) compared to other methoxy-tritylated GEM derivatives. Moreover, TMT-O-GEM suppressed the growth of MCF-7 spheroids compared with trimethoxy trityl-N-GEM (TMT-N-GEM). Both TMT-O-GEM and TMT-N-GEM were negligibly deprotected and metabolized in mouse or human serum after 72 h, indicating that trimethoxy tritylation inhibits deamination by cytidine deaminase. These results indicate that 5′-(O)-trimethoxy tritylation is a potent approach for the development of anti-cancer cytidine analog prodrugs.

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Influences of protein levels on the cerebrospinal fluid distribution of ceftazidime & ceftriaxone in the cerebrospinal fluid of patients with inflamed meningitis.

Ichinose N, Yoshikawa G, Fukao E, Takahata T, Ichisawa M, Enoki Y, Taguchi K, Oda T, Tsutsumi K, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 8 ) 1216 - 1219 2022.05

Joint Work, ISSN 1341-321X

Introduction: Ceftazidime and ceftriaxone are used to treat various gram-negative pathogens, such as Streptococcus pneumoniae and Pseudomonas aeruginosa, and have shown excellent therapeutic efficacy against bacterial meningitis. However, there is insufficient information on the pharmacokinetic characteristics of their cerebrospinal distribution. Here, we investigated the association of clinical laboratory data in cerebrospinal fluid with ceftazidime and ceftriaxone concentration in the cerebrospinal fluid of patients with inflamed meningitis. Methods: Cerebrospinal fluid samples were collected from eight adult patients with inflamed meningitis who intravenously received either ceftazidime or ceftriaxone (ceftazidime: a total of 25 samples from three patients, ceftriaxone: a total of 12 samples from five patients). Total cell number, protein concentration, and glucose concentration in the cerebrospinal fluid were retrospectively collected from electronic medical charts. All ceftazidime and ceftriaxone concentrations in the cerebrospinal fluid were determined using high-performance liquid chromatography. Results: Both ceftazidime and ceftriaxone concentrations in cerebrospinal fluid correlated with protein concentration in cerebrospinal fluid; however, no significant correlation was observed in total cell number and glucose concentration in cerebrospinal fluid. Conclusions: This is the first report on the relationship between the cerebrospinal distribution of these antibiotics and clinical laboratory data in cerebrospinal fluid of adult patients with meningitis.

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Oxidized liposomal artificial red blood cells rescue azide-poisoned mice from lethal toxidrome by recovering cytochrome c oxidase activity

Suzuki Y., Taguchi K., Hanyu S., Kure T., Enoki Y., Otagiri M., Sakai H., Matsumoto K.

Journal of Drug Delivery Science and Technology (Journal of Drug Delivery Science and Technology) 71 2022.05

Joint Work, ISSN 17732247

Exposure to azide compounds causes inhibition of cytochrome c oxidase in the mitochondria, leading to acute lethal poisoning. Although urgent pharmaceutical intervention is required for rescue from azide poisoning, no antidote exists worldwide. We hypothesized that methemoglobin (metHb) can be a promising material as an antidote for azide poisoning because metHb can strongly bind to azide. However, metHb administration is not feasible owing to in vivo instability and toxicity. We aimed to develop a feasible metHb-based antidote for azide poisoning, in which the inner hemoglobin of liposomal artificial red blood cells is oxidized by mixing with sodium nitrite. From the stopped-flow spectrophotometry analysis, as-prepared oxidized liposomal artificial red blood cells, which encapsulated metHb into the liposome (metHb@Lipo), the binding affinity of metHb@Lipo to azide was comparable to that of bare metHb. In addition, detoxification by metHb@Lipo increased the survival rate in lethal azide-poisoned model mice with recovery of cytochrome c oxidase activity, leading to the amelioration of acidosis and tissue oxidation. Furthermore, metHb@Lipo detoxification functioned even after 1 year of storage in a ready-to-use formulation. These results indicate that oxidized liposomal artificial red blood cells are a potent antidote for azide poisoning with favorable properties for use in critical care medicine.

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Efficacy and Safety of Daptomycin versus Vancomycin for Bacteremia Caused by Methicillin-Resistant Staphylococcus aureus with Vancomycin Minimum Inhibitory Concentration > 1 µg/mL: A Systematic Review and Meta-Analysis

Samura M., Kitahiro Y., Tashiro S., Moriyama H., Hamamura Y., Takahata I., Kawabe R., Enoki Y., Taguchi K., Takesue Y., Matsumoto K.

Pharmaceutics (Pharmaceutics) 14 ( 4 ) 2022.04

Joint Work, ISSN 1999-4923

This systematic review and meta-analysis compares the efficacy of daptomycin and van-comycin in adult patients with bacteremia by methicillin-resistant Staphylococcus aureus (MRSA) with vancomycin minimum inhibitory concentration (MIC) > 1 µg/mL. We searched the PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov databases on 12 May 2020. All-cause mortality (primary outcome) and treatment success rates were compared and subgroups stratified by infection source risk level and method of vancomycin susceptibility testing were also analyzed. Seven studies (n = 907 patients) were included in this efficacy analysis. Compared with vancomycin, daptomycin treatment was associated with significantly lower mortality (six studies, odds ratio (OR) 0.53, 95% confidence interval (CI) 0.29–0.98) and higher treatment success (six studies, OR 2.20, 95% CI 1.63–2.96), which was consistent regardless of the vancomycin MIC test method used. For intermediate-risk sources, daptomycin was a factor increasing treatment success compared with vancomycin (OR 4.40, 95% CI 2.06–9.40), and it exhibited a trend toward a higher treatment success rate for high-risk sources. In conclusion, daptomycin should be considered for the treatment of bacteremia caused by MRSA with vancomycin MIC > 1 µg/mL, especially in patients with intermediate-and high-risk bacteremia sources.

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Clinical Practice Guidelines for Therapeutic Drug Monitoring of Vancomycin in the Framework of Model-Informed Precision Dosing: A Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring

Matsumoto K., Oda K., Shoji K., Hanai Y., Takahashi Y., Fujii S., Hamada Y., Kimura T., Mayumi T., Ueda T., Nakajima K., Takesue Y.

Pharmaceutics (Pharmaceutics) 14 ( 3 ) 2022.03

Joint Work, ISSN 1999-4923

Background: To promote model-informed precision dosing (MIPD) for vancomycin (VCM), we developed statements for therapeutic drug monitoring (TDM). Methods: Ten clinical questions were selected. The committee conducted a systematic review and meta-analysis as well as clinical studies to establish recommendations for area under the concentration-time curve (AUC)-guided dosing. Results: AUC-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 µg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom VCM was administered with q12h. To increase the concentration on days 1–2, the routine use of a loading dose is required. TDM on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI. Conclusions: These VCM TDM guidelines provide recommendations based on MIPD to increase treatment response while preventing adverse effects.

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Validation of Vancomycin Area under the Concentration-Time Curve Estimation by the Bayesian Approach Using One-Point Samples for Predicting Clinical Outcomes in Patients with Methicillin-Resistant Staphylococcus aureus Infections.

Ueda T, Takesue Y, Nakajima K, Ichiki K, Ishikawa K, Yamada K, Tsuchida T, Otani N, Takahashi Y, Ishihara M, Takubo S, Ikeuchi H, Uchino M, Kimura T, Matsumoto K, Oda K, Kimura T

Antibiotics (Basel, Switzerland) (Antibiotics) 11 ( 1 ) 2022.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 2079-6382

Area under the concentration–time curve (AUC)-guided vancomycin treatment is asso-ciated with decreased nephrotoxicity. It is preferable to obtain two samples to estimate the AUC. This study examined the usefulness of AUC estimation via trough concentration (Cmin )-only sampling of 260 adults infected with methicillin-resistant Staphylococcus aureus (MRSA) who received vancomycin. The exact Cmin sampling time was used for Bayesian estimation. A significantly higher early treatment response was observed in patients with a day 2 AUC ≥ 400 µg·h/mL than those with <400 µg·h/mL, and a significantly higher early nephrotoxicity rate was observed in patients with a day 2 AUC ≥ 600 µg·h/mL than those with <600 µg·h/mL. These AUC cutoff values constituted independent factors for each outcome. In sub-analysis, the discrimination ability for early clinical outcomes using these AUC cutoffs was confirmed only in patients with q12 vancomycin administra-tion. A significant difference in early treatment response using the 400 µg·h/mL cutoff was obtained only in patients with low-risk infections. The usefulness of the vancomycin AUC target to decrease nephrotoxicity while assuring clinical efficacy was even confirmed with a single Cmin measurement. However, assessment with two samples might be required in patients with q24 administration or high/moderate-risk MRSA infections.

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Clinical practice guidelines for therapeutic drug monitoring of teicoplanin: a consensus review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

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

The Journal of antimicrobial chemotherapy (Journal of Antimicrobial Chemotherapy) 77 ( 4 ) 869 - 879 2022.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0305-7453

Background: Owing to its low risk of adverse effects, teicoplanin has been extensively used in patients with infections caused by MRSA. To promote the better management of patients receiving teicoplanin, we have updated the guidelines for therapeutic drug monitoring (TDM). Methods: The guidelines were developed by a committee following the methodology handbook published by the Japanese Medical Information Distribution Service. Nine clinical questions were selected. The committee conducted a systematic review and meta-analysis to establish evidence-based recommendations for the target trough concentration (Cmin). An initial electronic database search returned 515 articles, and 97 articles qualified for a full review. Four and five studies were included for the efficacy evaluation of cut-off Cmin values of 15 and 20 mg/L, respectively. Results: Compared with Cmin < 15 mg/L, a target Cmin value of 15-30 mg/L resulted in increased clinical efficacy in patients with non-complicated MRSA infections (OR = 2.68; 95% CI = 1.14-6.32) without an increase in adverse effects. Although there was insufficient evidence, target Cmin values of 20-40 mg/L were suggested in patients with complicated or serious MRSA infections. A 3 day loading regimen followed by maintenance treatment according to renal function was recommended to achieve the target trough concentrations. Because of the prolonged half-life of teicoplanin, measurement of the Cmin value on Day 4 before reaching steady state was recommended. Conclusions: The new guideline recommendations indicate the target Cmin value for TDM and the dosage regimen to achieve this concentration and suggest practices for specific subpopulations.

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Liposomal artificial red blood cell-based carbon monoxide donor is a potent renoprotectant against cisplatin-induced acute kidney injury

Taguchi K, Suzuki Y, Tsutsuura M, Hiraoka K, Watabe Y, Enoki Y, Otagiri M, Sakai H, Matsumoto K

Pharmaceutics (Pharmaceutics) 14 ( 1 ) 2022.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 1999-4923

Cisplatin (CDDP) is an essential anti-tumor agent for chemotherapeutic regimens against various types of cancer. However, the progression of nephrotoxicity, which is the main adverse effect of CDDP, leads to discontinuation of CDDP chemotherapy. Therefore, development of a renopro-tectant against CDDP-induced nephrotoxicity is crucial. Here, the potential of a carbon monoxide (CO)-loaded hemoglobin-vesicle (CO-HbV) as a renoprotectant for CDDP-induced nephrotoxicity was evaluated for its renoprotective effects against CDDP-induced nephrotoxicity, inhibitory effects on the anti-tumor activity of CDDP, and anti-tumor activity. In healthy mice, after pretreatment with either saline, HbV, or CO-HbV prior to CDDP administration, only the CO-HbV pretreatment group ameliorated the progression of CDDP-induced nephrotoxicity by suppressing apoptosis via caspase-3. In experiments using B16-F10 melanoma cells, the half-maximal inhibitory concentration of CDDP decreased with co-incubation with CO-HbV, owing to the anti-tumor activity of CO. CO-HbV pretreatment had no impact on the anti-tumor activity of CDDP in B16-F10 melanoma cell-bearing mice, which was consistent with the results of the cell experiment. Furthermore, CO-HbV pretreatment improved body growth and survival rates. In conclusion, CO-HbV pretreatment is a potent renoprotectant for CDDP-induced nephrotoxicity, allowing treatment with CDDP to be conducted without failure of cancer treatment.

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Neurotoxicity associated with colistin methanesulfonate treatment is enhanced by concomitant sevoflurane inhalation

Gotoda M., Enoki Y., Shishido S., Taguchi K., Matsumoto K.

Toxicology Reports (Toxicology Reports) 9 1255 - 1260 2022.01

Joint Work, ISSN 22147500

Colistin methanesulfonate (CMS) is a cyclic polypeptide antibiotic with neurotoxic side effects. Sevoflurane (Sevo), an inhaled anesthetic, is known to enhance the non-depolarizing effect of neuromuscular relaxants; however, its mechanism of action is unclear. In this study, we investigated the augmentation effect of Sevo on CMS-induced neurotoxicity. We prepared a sciatic nerve-skeletal muscle stimulation model using Sprague-Dawley male rats administered CMS with or without Sevo. The muscle contraction inhibition rate was determined from electromyogram measurements. Furthermore, we simulated the pharmacokinetics of CMS and colistin using previous reports, and the relationship between the effect of muscle contraction inhibition and pharmacokinetic parameters was evaluated. We observed a dose-dependent neuromuscular inhibitory effect of Sevo under CMS administration. The 50 % inhibitory dose (ID50) values for CMS and CMS+Sevo were 167 ± 12 and 85 ± 5 mg/kg, respectively. The combination of CMS with Sevo showed a 49 % decrease in the ID50 compared with CMS alone. The simulated area under the time–concentration curve (AUC) values for CMS and colistin administration in rats at 200 mg/kg were 219 and 16.0 mg·h/L, respectively. The predicted AUC values of colistin corresponding to the ID50 at 0–45 min for CMS alone and CMS+Sevo were 12.0 and 7.0 mg·h/L, respectively. We revealed that the neurotoxic effect of CMS was enhanced by the concomitant use of Sevo. Based on the simulated AUC values, we concluded that this neurotoxic effect may also occur in clinical settings, and concomitant use of CMS and Sevo should be avoided.

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Target Therapeutic Ranges of Anti-MRSA Drugs, Linezolid, Tedizolid and Daptomycin, and the Necessity of TDM

Matsumoto Kazuaki, Samura Masaru, Tashiro Sho, Shishido Shino, Saiki Reika, Takemura Wataru, Misawa Kana, Liu Xiaoxi, Enoki Yuki, Taguchi Kazuaki

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 45 ( 7 ) 824 - 833 2022

Joint Work, ISSN 0918-6158

The target therapeutic ranges of vancomycin, teicoplanin, and arbekacin have been determined, and therapeutic drug monitoring (TDM) is performed in clinical practice. However, TDM is not obligatory for daptomycin, linezolid, or tedizolid. In this study, we examined whether TDM will be necessary for these 3 drugs in the future. There was no significant difference in therapeutic effects on acute bacterial skin and skin structure infection between linezolid and tedizolid by meta-analysis. Concerning the therapeutic effects on pneumonia, the rate of effectiveness after treatment with tedizolid was significantly lower than with linezolid. With respect to safety, the incidences of gastrointestinal adverse events and blood/lymphatic system disorders related to tedizolid were significantly lower than those related to linezolid. Linezolid exhibits potent therapeutic effects on pneumonia, but the appearance of adverse reactions is indicated as a problem. There was a dose-dependent decrease in the platelet count, and the target trough concentration (Ctrough) was estimated to be 4–6 or 2–7 µg/mL in accordance with the patient’s condition. The efficacy of linezolid may be obtained while minimizing the appearance of adverse reactions by performing TDM. The target therapeutic range of tedizolid cannot be achieved in immunocompromised or severe patients. Therefore, we concluded that TDM was unnecessary, considering step-down therapy with oral drugs, use in non-severe patients, and high-level safety. Concerning daptomycin, high-dose administration is necessary to achieve an area under the curve (AUC) of ≥666 as an index of efficacy. To secure its safety, Ctrough (<20 µg/mL) monitoring is important. Therefore, TDM is necessary.

Exploring the Factors Affecting the Transferability of Vancomycin to Cerebrospinal Fluid in Postoperative Neurosurgical Patients with Bacterial Meningitis

Ichinose Naoki, Shinoda Kozue, Yoshikawa Gakushi, Fukao Eri, Enoki Yuki, Taguchi Kazuaki, Oda Toshimi, Tsutsumi Kazuo, Matsumoto Kazuaki

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 45 ( 9 ) 1398 - 1402 2022

Joint Work, ISSN 0918-6158

Vancomycin (VCM) is a standard treatment for bacterial meningitis. However, little is known about the transferability of VCM to cerebrospinal fluid (CSF), thus evidence of the transferability of VCM to CSF during bacterial meningitis is needed. In this study, we evaluated the concentration of VCM in the plasma and CSF of postoperative neurosurgical patients with bacterial meningitis and evaluated the factors that affect the transferability of VCM to CSF. The concentrations of VCM in plasma (trough) and CSF were determined in eight patients (four males and four females) with bacterial meningitis who were treated with VCM using HPLC. The ratio of the VCM concentrations in CSF/plasma was also calculated by estimating the blood VCM concentration at the same time as the VCM concentration in CSF was measured. The results showed that the VCM concentration in CSF was 0.9–12.7 µg/mL and the CSF/plasma VCM concentration ratio was 0.02–0.62. We examined the effect of drainage on the transferability of VCM to CSF, which showed that the VCM concentration in CSF and the CSF/plasma VCM concentration ratio were significantly higher in patients not undergoing drainage than in patients who were undergoing drainage. The CSF protein and glucose concentrations, which are diagnostic indicators of meningitis, were positively correlated with the VCM concentration in CSF and the CSF/plasma VCM concentration ratio. Thus, VCM transferability to CSF may be affected by changes in the status of the blood–brain barrier and blood–cerebrospinal fluid barrier due to drainage or meningitis.

Incidence of elevated creatine phosphokinase between daptomycin alone and concomitant daptomycin and statins: a systematic review and meta-analysis.

Samura M, Takada K, Hirose N, Kurata T, Nagumo F, Koshioka S, Ishii J, Uchida M, Inoue J, Enoki Y, Taguchi K, Tanikawa K, Matsumoto K

British journal of clinical pharmacology (British Journal of Clinical Pharmacology) 88 ( 5 ) 1985 - 1998 2021.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0306-5251

Aims: The present systematic review and meta-analysis evaluated the incidence of elevated creatine phosphokinase (CPK) levels between daptomycin alone and concomitant daptomycin and statin use. Methods: We searched the PubMed, Web of Sciences, Cochrane Library and ClinicalTrials.gov databases. We analysed the incidence of elevated CPK between daptomycin alone and concomitant daptomycin and statins among studies defining CPK elevation as levels ≥ the upper limit of normal (ULN) or ≥5× ULN. We also analysed the incidence of rhabdomyolysis between the groups. We then calculated the odds ratios (ORs) and 95% confidence intervals (CIs) based on the included studies. Results: Comparing CPK elevation defined as CPK levels ≥ULN, a significantly higher incidence of CPK elevation was observed with concomitant daptomycin and statin use than with daptomycin alone (OR = 2.55, 95% CI 1.78–3.64, P <.00001, I2 = 0%). Likewise, when CPK elevation was defined as CPK levels ≥5× ULN, a significantly higher incidence of CPK elevation was detected with concomitant daptomycin and statin use than with daptomycin alone (OR = 1.89, 95% CI 1.06–3.35, P =.03, I2 = 48%). The incidence of rhabdomyolysis was significantly higher following concomitant daptomycin and statin use than with daptomycin alone (OR = 11.60, 95% CI 1.81–74.37, P =.01, I2 = 0%). Conclusion: The combined use of daptomycin and statins were significant risk factors for the incidence of CPK elevation defined as levels ≥ULN or ≥5× ULN and rhabdomyolysis.

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Bioinspired carbon monoxide delivery using artificial blood attenuates the progression of obliterative bronchiolitis via suppression of macrophage activation by IL-17A.

Watabe Y, Taguchi K, Sakai H, Enoki Y, Maruyama T, Otagiri M, Kohno M, Matsumoto K

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (European Journal of Pharmaceutics and Biopharmaceutics) 170 43 - 51 2021.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0939-6411

Carbon monoxide (CO) is expected to attenuate the progression of obliterative bronchiolitis (OB), which is a serious complication after lung transplantation. However, issues in terms of feasible exogenous CO supply, such as continuousness and safety, remain unsolved. Here, we applied nano red blood cells, namely hemoglobin vesicles (Hb-V), as a CO cargo based on the biomimetic concept and investigated the therapeutic potential of CO-loaded Hb-V on OB in orthotopic tracheal transplant model mice. The CO-loaded Hb-V was comprised of negatively charged liposomes encapsulating carbonylhemoglobin with a size of ca. 220 nm. The results of histological evaluation showed that allograft luminal occlusion and fibrosis were significantly ameliorated by treatment with CO-loaded Hb-V compared to treatment with saline, cyclosporine, and Hb-V. The therapeutic effects of CO-loaded Hb-V on OB were due to the suppression of M1 macrophage activation in tracheal allografts, resulting from decreased IL-17A production. Furthermore, the expression of TNF-α and TGF-β in tracheal allografts was decreased by CO-loaded Hb-V treatment but not saline and Hb-V treatment, indicating that CO liberated from CO-loaded Hb-V inhibits epithelial-mesenchymal transition. These findings suggest that CO-loaded Hb-V exerts strong therapeutic efficacy against OB via the regulation of macrophage activation by IL-17A and TGF-β-driven epithelial-mesenchymal transition.

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Identification of Risk Factors for Daptomycin-Associated Creatine Phosphokinase Elevation and Development of a Risk Prediction Model for Incidence Probability.

Samura M, Hirose N, Kurata T, Takada K, Nagumo F, Koshioka S, Ishii J, Uchida M, Inoue J, Enoki Y, Taguchi K, Higashita R, Kunika N, Tanikawa K, Matsumoto K

Open forum infectious diseases (Open Forum Infectious Diseases) 8 ( 12 ) ofab568 2021.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 2328-8957

Background: In this study, we investigated the risk factors for daptomycin-associated creatine phosphokinase (CPK) elevation and established a risk score for CPK elevation. Methods: Patients who received daptomycin at our hospital were classified into the non-elevated or elevated CPK group based on their peak CPK levels during daptomycin therapy. Univariable and multivariable analyses were performed, and a risk score and prediction model for the incidence probability of CPK elevation were calculated based on logistic regression analysis. Results: The non-elevated and elevated CPK groups included 181 and 17 patients, respectively. Logistic regression analysis revealed that concomitant statin use (odds ratio [OR], 4.45 [95% confidence interval {CI}, 1.40-14.47]; risk score 4), concomitant antihistamine use (OR, 5.66 [95% CI, 1.58-20.75]; risk score 4), and trough concentration (Cmin) between 20 and <30 μg/mL (OR, 14.48 [95% CI, 2.90-87.13]; risk score 5) and ≥30.0 μg/mL (OR, 24.64 [95% CI, 3.21-204.53]; risk score 5) were risk factors for daptomycin-associated CPK elevation. The predicted incidence probabilities of CPK elevation were <10% (low risk), 10%-<25% (moderate risk), and ≥25% (high risk) with total risk scores of ≤4, 5-6, and ≥8, respectively. The risk prediction model exhibited a good fit (area under the receiver operating characteristic curve, 0.85 [95% CI,. 74-.95]). Conclusions: These results suggested that concomitant use of statins with antihistamines and Cmin ≥20 μg/mL were risk factors for daptomycin-associated CPK elevation. Our prediction model might aid in reducing the incidence of daptomycin-associated CPK elevation.

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Long-term pharmaceutical stability of liposome-encapsulated methemoglobin as an antidote for cyanide poisoning.

Suzuki Y, Taguchi K, Kure T, Enoki Y, Otagiri M, Sakai H, Matsumoto K

International journal of pharmaceutics (International Journal of Pharmaceutics) 610 121260 2021.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0378-5173

Liposome-encapsulated methemoglobin (metHb@Lipo) has been developed as a novel antidote for cyanide poisoning. Antidotes for lethal acute poisoning should be capable of being easily stored as ready-to-use formulations without temperature restrictions. Here, we investigated the pharmaceutical stability of the metHb@Lipo suspension after one-year storage as a ready-to-use formulation at 4 °C, room temperature (23–28 °C) and 37 °C. The liposomal integrity of metHb@Lipo was observed after one year of storage at all storage temperatures with no physicochemical change or methemoglobin leakage outside the liposome. Furthermore, the encapsulated methemoglobin remained intact without aggregation, fragmentation, denaturation, or dissociation of heme. Fresh and stored metHb@Lipo were equivalent in their binding affinity against cyanide. Moreover, all one-year stored metHb@Lipo suspensions improved the mortality rates of lethal cyanide poisoning mice comparable to fresh metHb@Lipo suspension. Additionally, all stored metHb@Lipo suspensions preserved high biocompatibility, including blood compatibility and the lack of organ toxicity. In conclusion, the metHb@Lipo suspension was a pharmaceutically stable antidote for cyanide poisoning for at least one year without any temperature restrictions.

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Population pharmacokinetic analysis and dosing optimization of prophylactic fluconazole in japanese patients with hematological malignancy

Sakamoto Y, Isono H, Enoki Y, Taguchi K, Miyazaki T, Kunimoto H, Koike H, Hagihara M, Matsumoto K, Nakajima H, Sahashi Y, Matsumoto K

Journal of Fungi (Journal of Fungi) 7 ( 11 ) 2021.11

Research paper (scientific journal), Joint Work, Accepted

We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40–140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5–1.0 µg/mL and 1.0–2.0 µg/mL for 200 mg/day and 1.0–2.0 µg/mL and 2.0–4.0 µg/mL for 400 mg/day, respectively. The recommended dose was 400–700 mg/day for the loading dose and 200–400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.

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低体重な血液透析患者において非常に高いセフトリアキソン血中濃度を認めた抗菌薬関連脳症と考えられる1例

内田裕之, 坂口隆志, 本郷偉元, 篠田こずえ, 田代渉, 松元一明, 佐村優, 加藤智之, 関口愛, 中島美治, 満田正樹, 河井良智

日本化学療法学会雑誌 ((公社)日本化学療法学会) 69 ( 6 ) 433 - 439 2021.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 1340-7007

われわれは第3世代セファロスポリン系抗菌薬であるセフトリアキソン(CTRX)による抗菌薬関連脳症(AAE)を疑う症例を経験した。83歳女性、身長140cm、体重37kgの透析患者の菌血症に対して第3病日からCTRX1日2gを投与した。第8病日に一過性の意識変調を認め、頭部核磁気共鳴画像法検査を実施したが、有意な所見はなかった。第14病日に再びGlasgow Coma Scale(GCS)E1V1M1の意識障害を認めた。感染症、ビタミン欠乏症、てんかん発作などの可能性とともに、CTRXによるAAEの可能性を考え、CTRXの投与を中止した。第16病日の脳波は徐波化に加えて三相波の混入を認めたが、第23病日には高振幅徐波は完全消失した。その後の検査で、第8病日のCTRXトラフ血中濃度は1,077.6μg/mLと非常に高い値であった。CTRX血中濃度の低下とともに、意識レベルは改善したが、投与中止から6日を要した。非常に高い血中濃度の原因は、高度腎機能障害患者であること、低効率な透析条件による排泄低下の可能性があること、低体重な患者に相対的に高投与量を継続投与したことが考えられた。このような特徴を有する患者においては、投与量設定に注意し、AAEを疑った際には血中濃度測定を含めた適切な検査を実施して、早期対応に努める必要性が示唆された。(著者抄録)

Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection.

Iketani O, Komeya A, Enoki Y, Taguchi K, Uno S, Uwamino Y, Matsumoto K, Kizu J, Hasegawa N

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 1 ) 61 - 66 2021.10

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

Introduction: Clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hydroxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy. Methods: CAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated. Results: Median area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4–1.8) μg·h/mL vs. 21.5 (IQR, 17.7–32.3) μg·h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9–10.9) μg·h/mL] and CAM monotherapy [8.2 (IQR, 6.3–9.3) μg·h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy. Conclusions: When RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.

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Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination.

Moriyama M, Liu X, Enoki Y, Matsumoto K, Tanabe Y

Pharmaceuticals (Basel, Switzerland) (Pharmaceuticals) 14 ( 9 ) 2021.09

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

Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)4/(S)-BINOL or Ti(OiPr)4/(R)-BINOL catalysis to afford the corresponding (R)-and (S)-δ-hydroxy-β-ketoesters, respectively, with highly enantiomeric excess (> 98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)-and (S)-plymuthipyranones B and three (R)-and (S)-synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 μg/mL, respectively, and those of vancomycin (reference) were 1 μg/mL. (ii) The natural (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyra-none B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class.

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Candidates for area under the time-concentration curve-guided dosing and risk reduction based on analyses of risk factors associated with nephrotoxicity in vancomycin-treated patients.

Hashimoto N, Kimura T, Hamada Y, Niwa T, Hanai Y, Chuma M, Fujii S, Matsumoto K, Shigemi A, Kawamura H, Takahashi Y, Takesue Y

Journal of global antimicrobial resistance (Journal of Global Antimicrobial Resistance) 27 12 - 19 2021.08

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

Objectives:: Compared with vancomycin trough concentration (Cmin)-guided dosing, area under the concentration–time curve (AUC)-guided dosing is associated with decreased acute kidney injury (AKI). However, whether Cmin-guided or AUC-guided dosing should be used in patients other than those with serious MRSA infections remains uncertain. The purposes of this multicentre study were to identify risk factors for early- and late-phase vancomycin-induced AKI and to identify candidates for AUC-guided dosing, rather than Cmin-guided dosing, who require a more accurate dose titration to reduce the AKI risk. Methods:: A multivariate logistic regression analysis was applied to identify risk factors for AKI. Additionally, the cut‑off day for AKI onset, cut-off Cmin for AKI, safe Cmin for reduced AKI risk and probability of AKI were calculated. Results:: In total, 8.4% (159/1882) of patients developed AKI. AKI occurred within the first 7 days of therapy (early phase) in the vast majority of patients. Significant risk factors for AKI during the early phase were identified as Cmin > 20 mg/L, ICU stay, concurrent diuretic or piperacillin/tazobactam use, and pre-existing renal dysfunction. A temporarily elevated Cmin (>15–20 mg/L) was not associated with a greater risk of AKI. In patients with risk factors, the cut-off Cmin for AKI and the estimated safe Cmin for reduced AKI risk were 18.8–21.0 mg/L and <11.7–13.5 mg/L, respectively. Conclusion:: Patients with known AKI risk factors require a low target Cmin. The presence of several risk factors for AKI may indicate a need for more accurate dose titration using AUC-guided dosing.

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Augmented clearance of nivolumab is associated with renal functions in chronic renal disease model rats.

Taguchi K, Hayashi Y, Ohuchi M, Yamada H, Yagishita S, Enoki Y, Matsumoto K, Hamada A

Drug metabolism and disposition: the biological fate of chemicals (Drug metabolism and disposition: the biological fate of chemicals) 50 ( 6 ) 822 - 826 2021.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0090-9556

The clinically approved dose of nivolumab is 240 mg every 2 weeks. However, previous studies have shown that baseline nivolumab clearance (CL) is associated with treatment outcomes in patients with solid cancers, thus motivating researchers to identify prognostic factors and indices influencing nivolumab CL. This study used chronic kidney disease model rats to investigate whether chronic renal impairment affected nivolumab CL and explored the surrogate markers associated with nivolumab CL. We observed that the total CL for nivolumab (CLtot) was approximately 1.42 times higher in chronic kidney disease model rats than that in sham rats with an increased urinary excretion. Additionally, CLtot showed positive correlation with renal CL for nivolumab (CLR) but not with extrarenal CL. Furthermore, the baseline levels of creatinine, blood urea nitrogen, creatinine CL, and urinary albumin/creatine ratio based on laboratory data were also significantly correlated with CLR Our findings suggest that nivolumab CL increases as renal function deteriorates because of an increased excretion of nivolumab in the urine; additionally, laboratory data reflecting renal function may be a feasible index to qualitatively estimate nivolumab CL prior to nivolumab treatment under conditions of renal impairment. SIGNIFICANCE STATEMENT: This study demonstrated that nivolumab was rapidly eliminated from the circulation in chronic kidney disease model rats compared with sham rats with an increased urinary nivolumab excretion. Moreover, nivolumab clearance was significantly correlated with the baseline levels of certain laboratory parameters reflecting renal functions. These results indicate the potential applicability of baseline renal function as a prognostic index to qualitatively estimate nivolumab clearance prior to nivolumab treatment under conditions with renal impairment.

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Different intra-cerebrospinal distribution of linezolid in patients with inflammatory meningitis.

Ichinose N, Yoshikawa G, Fukao E, Ichisawa M, Takahata T, Enoki Y, Taguchi K, Oda T, Tsutsumi K, Matsumoto K

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases (International Journal of Infectious Diseases) 110 382 - 384 2021.08

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

Linezolid has excellent antibiotic activity against gram-positive organisms and is expected to be an alternative to vancomycin for the treatment of bacterial meningitis. Accumulated evidence has shown the superior pharmacokinetic characteristics of linezolid to vancomycin, such as cerebrospinal fluid penetration. However, in the treatment of meningitis, pharmacokinetic information regarding the intra-cerebrospinal distribution of linezolid and the effects of drainage on the linezolid concentration in the cerebrospinal fluid are unclear. This report describes two patient cases, in which the linezolid concentrations in the cerebrospinal fluid were in the following order: subarachnoid space (cisternal drainage and lumbar puncture) ≥ third ventricle > lateral ventricle. In addition, the linezolid concentration in the cerebrospinal fluid, collected via lumbar puncture, tended to increase after removal of the drainage. This report is novel in presenting two cases of meningitis that showed different intra-cerebrospinal distribution of linezolid in various parts of the central nervous system and an increased linezolid concentration in the cerebrospinal fluid after removal of the drainage.

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Species Distribution of Candidemia and Their Susceptibility in a Single Japanese University Hospital: Prior Micafungin Use Affects the Appearance of Candida parapsilosis and Elevation of Micafungin MICs in Non-parapsilosis Candida Species.

Sakamoto Y, Kawabe K, Suzuki T, Sano K, Ide K, Nishigaki T, Enoki Y, Taguchi K, Koike H, Kato H, Sahashi Y, Matsumoto K

Journal of fungi (Basel, Switzerland) (Journal of Fungi) 7 ( 8 ) 2021.07

Research paper (scientific journal), Joint Work, Accepted

Introduction: Micafungin is a recommended echinocandin antifungal agent for can-didemia treatment and prophylaxis. However, overuse of echinocandin antifungals may cause re-sistance. There is currently no information available regarding the low susceptibility associated with using micafungin. This study investigated the effect of micafungin use on changes in the detected Candida species and low susceptibility. Methods: We conducted a retrospective survey and included records of Candida spp. detected in blood cultures from January 2010 to December 2018 in our hospital. Survey items included clinical outcomes at 30 days after positive cultures, patient char-acteristics, and drug prescription status. Patient background information included gender, previous hospitalization, stay in the intensive care unit, comorbidities, and history of surgery (within 90 days before candidemia onset) and drug exposure. Species detected and their minimum inhibitory concentrations (MICs) and amount of antifungal prescriptions by department were investigated. Risk factors for detecting C. parapsilosis and for low susceptibility to micafungin were evaluated using multivariate analysis. Results: A total of 153 Candida clinical blood isolates were collected and C. albicans was the most prevalent species, followed by C. parapsilosis and C. glabrata. In the analysis by department, antifungal use and non‐albicans Candida species were most frequently detected in the hematology department. Multivariate analysis showed that prior micafungin use increased the risk of C. parapsilosis (odds ratio (OR) 4.22; 95% confidence interval (CI) 1.39–12.79; p = 0.011). MIC90 of micafungin on C. glabrata and C. parapsilosis was 1.0 μg/mL. Prior micafungin use was clarified as a risk factor resulting in MIC > 0.06 μg/mL for micafungin in non‐parapsilosis Candida species (OR 13.2; 95% CI 3.23–54.2; p < 0.01). Conclusion: Prior micafungin use increased the risk of C. parapsilosis and the MIC > 0.06 μg/mL of micafungin in non‐parapsilosis Candida species. Since there are only a few antifungal options, further antifungal stewardship considering azole antifungal agents use is re-quired.

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Liposome-encapsulated methemoglobin as an antidote against cyanide poisoning.

Suzuki Y, Taguchi K, Kure T, Sakai H, Enoki Y, Otagiri M, Matsumoto K

Journal of controlled release : official journal of the Controlled Release Society (Journal of Controlled Release) 337 59 - 70 2021.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 0168-3659

Cyanide induces acute lethal poisoning resulting from inhibition of cytochrome c oxidase located in the complex IV (Complex IV) of mitochondria. However, current therapies for cyanide poisoning using hydroxocobalamin and nitrous acid compounds remain a clinical issue. Here, we show that liposome-encapsulated methemoglobin (metHb@Lipo), nanosized biomimetic red blood cells, replicate the antidotal mechanism of nitrous acid compounds against cyanide poisoning, achieving superior efficacy and fast action with no adverse effects. The structure of metHb@Lipo, which consists of concentrated methemoglobin in its aqueous core and a lipid membrane resembling the red blood cell membrane, provides favorable characteristics as a cyanide antidote, such as binding properties and membrane permeability. Upon cyanide exposure, metHb@Lipo maintained the mitochondrial function in PC12 cells, resulting in a cell viability comparable to treatment with nitrous acid compounds. In a mouse model of cyanide poisoning, metHb@Lipo treatment dramatically improved mortality with a rapid recovery from the symptoms of cyanide poisoning compared to treatment with nitrous acid compounds. Furthermore, metHb@Lipo also possesses satisfactory pharmacokinetic properties without long-term bioaccumulation and toxicity. Our findings showed a novel concept to develop drugs for cyanide poisoning and provide a promising possibility for biomimetic red blood cell preparations for pharmaceutical applications.

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セルフメディケーション税制に対する新人薬局薬剤師の認知・見解実態把握調査

田口和明, 榎木裕紀, 有賀聡美, 榊原幹夫, 堀里子, 山浦克典, 松元一明

医療薬学 ((一社)日本医療薬学会) 47 ( 7 ) 358 - 363 2021.07

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

ドラッグストアまたはドラッグストア併設の保険薬局に勤務し、在学中にセルフメディケーション税制(以下、本税制)が施行されていた薬剤師を対象に、本税制に関する認知・見解実態把握調査(アンケート)を実施した。調査対象者は、男性138名(44.5%)、女性172名(55.5%)の合計310名であった。本税制の認知度と理解度について調査したところ、284名(91.6%)の調査対象者が「よく知っている(説明できる)」または「聞いたことはあるが、内容はよく知らない」と回答し、理解度に差はあるものの、ほとんどの調査対象者が本税制について見聞があった。これらの調査対象者は、主に「テレビ」、「雑誌本」、「インターネット」などのメディアを通して本税制に関する情報を得ていた。また、教育現場や職場で本税制について知った調査対象者も多かった。調査対象者の97名(31.3%)が本税制に関する講義を受講したと回答した。本税制の認知度を集計した結果、大学で本税制の講義を受けたことのあると回答した調査対象者において、「よく知っている(説明できる)」と回答した割合が顕著に高かった。今後、薬剤師として働くうえで、多くの調査対象者(86.4%)が本税制の知識が必要だと感じており、半数の調査対象者が本税制に関する情報を収集するうえで携帯アプリを活用したいと回答した。

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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Retrospective study of the efficacy and safety of metronidazole and vancomycin for Clostridioides difficile infection.

Misawa K, Iketani O, Enoki Y, Taguchi K, Uno S, Uwamino Y, Hasegawa N, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 27 ( 10 ) 1407 - 1412 2021.05

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

Introduction: According to the Japanese guidelines for the management of Clostridioides difficile infection (CDI), the first choice is metronidazole (MNZ) for non-severe cases and vancomycin (VCM) for severe cases. However, the appropriateness of this first choice in Japanese patients is unclear. We therefore evaluated the appropriateness of the CDI management guidelines and the incidence of adverse drug reactions. Methods: The electronic chart data at Keio University Hospital between January 2012 and June 2019 were retrospectively reviewed. The response rate, the relapse rate, and the adverse reaction rate of treatment for CDI using MNZ or VCM were investigated according to the disease severity. Factorial analysis associated with the response, relapse, and adverse reaction was also performed. Results: In the 352 patients surveyed, no significant difference was observed in the response rate between MNZ and VCM regardless of the severity of CDI. The presence of cancer was a factor related to the persistence of diarrheal symptoms and older age was a risk factor for relapse. MNZ induced nausea significantly more frequently than VCM, and young age and female sex were risk factors for nausea. Conclusion: As no significant difference was observed in the response rate of CDI between MNZ and VCM, the Japanese CDI management guidelines, which recommend MNZ as the first choice, were demonstrated to be appropriate. Attention to nausea was also suggested to be necessary when administering MNZ to young females.

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健康セミナー参加者におけるセルフメディケーション税制に関する実態調査と税制改定に向けた課題の抽出

田口和明, 榎木裕紀, 有賀聡美, 榊原幹夫, 堀里子, 山浦克典, 松元一明

医療薬学 ((一社)日本医療薬学会) 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。

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

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

© 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

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

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

© 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

© 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

© 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

© 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

© 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

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

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

© 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

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

© 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

© 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

© 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

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

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

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 S-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.

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 (Journal of Infection and Chemotherapy) 26 ( 11 ) 1232 - 1236 2020

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

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

Sho Tashiro, Sumika Osa, Yuki Igarashi, Yuki Watabe, Xiaoxi Liu, Yuki Enoki, Kazuaki Taguchi, Toshihiko Mayumi, Yoshitsugu Miyazaki, Yoshio Takesue, Kazuaki Matsumoto

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 26 ( 11 ) 1164 - 1176 2020

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

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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Characterization of Bovine Lactoferrin Nanoparticle Prepared by Desolvation Technique

Taguchi Kazuaki, Nakayama Mayuki, Yamasaki Keishi, Sakuragi Mina, Enoki Yuki, Nishi Koji, Matsumoto Kazuaki, Seo Hakaru, Otagiri Masaki

Chemical and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 68 ( 8 ) 766 - 772 2020

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

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.

Factorial Analysis of Clostridioides Difficile Colitis and Pseudomembranous Colitis Using JADER

Takaya Risako, Misawa Kana, Tashiro Sho, Enoki Yuki, Taguchi Kazuaki, Matsumoto Kazuaki

BPB Reports (公益社団法人日本薬学会) 3 ( 1 ) 1 - 6 2020

Research paper (scientific journal), Joint Work, Accepted

Clostridioides difficile (C. difficile) colitis and pseudomembranous colitis are known as healthcare-associated intestinal infections. In this study, the incidence of C. difficile colitis and pseudomembranous colitis was investigated using the Japanese Adverse Drug Event Report (JADER). Using JADER data between April 2004 and September 2017, the patient who developed C. difficile colitis and pseudomembranous colitis were investigated. During the study period, 375 cases of C. difficile colitis and 903 cases of pseudomembranous colitis were reported. The numbers of reported cases of both C. difficile colitis and pseudomembranous colitis were largest in those in their 70s, accounting for 24.7% and 25.6%, respectively. Patients in their 60s-90s comprised the majority of all patients with both C. difficile colitis and pseudomembranous colitis. Both C. difficile colitis and pseudomembranous colitis were caused by antibiotics in many patients, and signals of all antibiotics were detected. In C. difficile colitis, signals of immunosuppressants, corticosteroids, and alkylating drugs were also detected among drugs other than antibiotics. For pseudomembranous colitis, the use of molecularly targeted drugs, antimetabolic drugs, and corticosteroids was reported other than antibiotics. Using JADER, we revealed risk factors for the development of C. difficile colitis and pseudomembranous colitis, and firstly revealed that molecularly targeted drugs other than antibiotics could also be potential risk factors. Our findings may be useful for the early detection of drug-induced C. difficile colitis and pseudomembranous colitis.

A post-transplantation patient in whom a specific interval was required until the blood concentration of fluconazole reached a steady state

Sakamoto Yasutaka, Isono Hikaru, Koike Hirofumi, Enoki Yuki, Taguchi Kazuaki, Hagihara Maki, Matsumoto Kenji, Nakajima Hideaki, Sahashi Yukiko, Matsumoto Kazuaki

Proceedings for Annual Meeting of The Japanese Pharmacological Society (Japanese Pharmacological Society) 93 ( 0 ) 2-O-036 2020

Joint Work

[Introduction]Fluconazole is anti-fungal agent widely used to prophylaxis and treatment. In the ECIL6 Guidelines, it is recommended that the dose of FLCZ for treatment should be established as ≥10 to 15 mg/mL, which is a trough level. We report a patient in whom a specific interval was required until the blood concentration of FLCZ reached a steady state.[Case]The patient was a 50-year-old male. To treat acute lymphocytic leukemia, remission induction and consolidation therapies were performed. After remission was achieved, umbilical cord blood transplantation was conducted. On Day 18, graft survival was confirmed. A blood culture test on Day 27 detected yeast-like fungus. Micafungin (MCFG) at 150 mg, used for empiric therapy, was switched to liposomal amphotericin B (L-AMB) at 3 mg/kg. On Day 36, renal hypofunction was noted, and L-AMB was switched to MCFG at 150 mg. On Day 65, there was a decrease in the β-D-glucan level from ≥600 to 375.2 pg/mL, and MCFG at 150 mg was switched to FLCZ at 200 mg. On Day 71, the trough level of FLCZ was 21.0 mg/mL, and its concentration 2 hours after administration was 24.4 mg/mL. The β-D-glucan level was 232.1 pg/mL. On Day 79, the trough and 2-hour levels of FLCZ were 30.6 and 32.1 mg/mL, respectively, and the β-D-glucan level was 167.6 pg/mL. On Day 85, the trough level of FLCZ was 38.4 mg/mL, and the β-D-glucan level was 161.4 pg/mL. Subsequently, blood culture was negative, and FLCZ administration was continued until Day 229. During the administration period, the creatinine clearance ranged from 33.0 to 45.9 mL/min.[Discussion]The half-life of FLCZ is approximately 30 hours. Its clearance depends on the renal function. In the present case, a target trough level was achieved in the early phase, but the blood concentration of FLCZ increased with the prolongation of the administration period. Therefore, the appearance of central nervous toxicity must be considered. In the future, it may be necessary to establish individualized, optimized FLCZ dosimetry in accordance with the renal function for the optimal use of FLCZ.

A Selection Table for Information on Heparinoid-Containing Preparation

Ishiwatari Ryoko, Enoki Yuki, Yokoyama Yuta, Taguchi Kazuaki, Kizu Junko, Matsumoto Kazuaki

Journal of Geriatric Pharmacy (Japanese Society of Geriatric Pharmacy) 2 ( 2 ) 19 - 26 2019.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 2433-4065

We evaluated heparinoid-containing soft ointments and heparinoid-containing creams to develop information useful to select drugs. Spreadability, consistency and the water content of stratum corneum was measured. A selection table focusing on impression of the use was prepared. Spreadability of the semi-original soft ointment and cream were lower than those of all generic drugs. Regarding hardness, one generic soft ointment was softer than the semi-original drug, but the semi-original cream was harder than all generic creams. Regarding the impression of the use, a significant difference was noted in smell in soft ointments, and 6 items in creams. Correlation was found between the spreadability and consistency test results and impression of the use. A significant difference was noted in the water content of stratum corneum in creams. The selection table prepared based on the impression of the use may provide information that helps selection of preparations in clinical practice.

Support for fungal infection treatment mediated by pharmacist-led antifungal stewardship activities

Samura M, Hirose N, Kurata T, Ishii J, Nagumo F, Takada K, Koshioka S, Uchida M, Yamamoto S, Inoue J, Enoki Y, Taguchi K, Ishida A, Sekine H, Kunika N, Kunishima H, Matsumoto K

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 26 ( 3 ) 272 - 279 2019

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

© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Objective: At the Yokohama General Hospital, pharmacist-led antimicrobial stewardship programs (ASP) including antifungal stewardship programs (AFP) were started in 2012. To investigate the efficacy of the programs, we compared several parameters that are recommended for the measurement of ASP in Japan based on pre- and post-AFP activities. Patients and methods: The subjects were inpatients who developed candidemia between April 2008 and March 2016. They were divided into two groups: pre-AFP (April 2008 until March 2012) and post-AFP (April 2012 until March 2016). The results were compared between the two groups. Results: The cumulative optimal antifungal drug usage rate, as a process parameter, significantly increased in the post-AFP group (p = 0.025). Furthermore, the days of therapy of antifungal drugs in the pre- and post-AFP groups was median 6.0 (interquartile range [IQR] 0.3–15.7) and median 3.4 (IQR 1.9–3.4) per 1,000 patient-days, respectively; there was a significant decrease in the post-AFP group (p < 0.001). Expenditure on antifungal drugs, as an outcome parameter, in the p

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Evaluation of the expression time of ganciclovir-induced adverse events using JADER and FAERS

Ando G, Taguchi K, Enoki Y, Yokoyama Y, Kizu J, Matsumoto K

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 42 ( 11 ) 1799 - 1804 2019

Research paper (scientific journal), Joint Work, Accepted, ISSN 09186158

© 2019 The Pharmaceutical Society of Japan. Investigation of the occurrence time of adverse drug reactions helps to prevent the development and aggravation of adverse reactions, but the expression time of ganciclovir-induced adverse events has not been elucidated. In this study, using databases of spontaneous adverse event reports, the Japanese Adverse Drug Event Report database (JADER) and the U.S. Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), the incidence of adverse reactions due to ganciclovir and their expression time were analyzed. As a result of calculation of the reporting odds ratio (ROR) and 95% confidence interval for individual main adverse reactions of ganciclovir (cytopenia, leukopenia, thrombocytopenia, liver damage, and acute renal failure), a signal was detected for all adverse reactions in both databases, except for liver damage in JADER. Furthermore, the Weibull distribution was performed for the analysis of onset time of each ganciclovir-induced adverse event. The results of Weibull parameter α and β values of each adverse event in both JADER and FAERS suggested that most adverse events occurred within 30 d and classified into t

Evaluation for optimal dosing of vancomycin in patients with different physical types

Hashimoto M, Iketani O, Ichinose N, Enoki Y, Taguchi K, Uno S, Uwamino Y, Hasegawa N, Matsumoto K

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 25 ( 9 ) 735 - 737 2019

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

© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases The sufficient dose to obtain an optimal trough concentration of vancomycin (VCM) in patients with non-standard physical types remains controversial. In this study, we examined the relationship between the dose and physical type in patients in whom an optimal trough concentration was obtained among VCM-treated patients. We retrospectively investigated the dose of VCM and physical type in patients treated with VCM between January 2012 and January 2017 at two medical institutions (n = 272). The physical type was classified using the body mass index (BMI). Patients with a BMI of <18.5 kg/m 2 were assigned to the lean group, those with a BMI of 18.5–24.9 kg/m 2 were assigned to the standard group, and those with a BMI of ≥25 kg/m 2 were assigned to the obesity group. The mean doses of VCM per time (mg/kg) to achieve the target trough concentration of VCM, 15–20 μg/mL, were 19.8 ± 4.3, 16.5 ± 3.7, and 13.7 ± 2.7 mg/kg in the lean, standard, and obesity groups, respectively. The dose per time to achieve the target trough concentration decreased significantly in association with an increase of BMI. The upper limit of the recommended dose (15–20 mg/kg) or higher in lean patients, and the lower dose in obese patients than the recommended dose might be appropriate to achieve the target trough concentration when we calculated the dose per time based on actual body weight.

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Experimental verification of factors influencing calcium salt formation based on a survey of the development of ceftriaxone-induced gallstone-related disorder

Ito R, Yoshida A, Taguchi K, Enoki Y, Yokoyama Y, Matsumoto K

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 25 ( 12 ) 972 - 978 2019

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

© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Ceftriaxone (CTRX) forms salts with calcium (Ca) in the gall bladder and bile duct, and induces the formation of gallstones. In this study, factors of CTRX-induced gallstone formation were extracted from the results of a retrospective survey using the Japanese Adverse Drug Event Report (JADER), and the causal relationship between the factors and gallstone formation was investigated. From JADER, 136 patients who developed ‘gallstone-related disorder’ with CTRX as a suspected drug were extracted. The incidence of gallstone-induced adverse effects was high in patients treated with CTRX at a dose exceeding the normal daily dose and in children younger than 10 years old, suggesting that CTRX at a high level is a factor for gallstone formation. Thus, after mixing CTRX and Ca2+ at different concentrations under different pH condition, the number of particles in the solutions was measured using a Coulter counter. As a result, the number of minute particles significantly increased at all pH values when Ca2+ and CTRX were mixed at a concentration of 10 mEq/L or higher and 1.5 g/L or higher, respectively. At pH 6.5 or 7.0, visible crystals were detected when 25 mEq/L of Ca2+ and 2.0 g/L of CTRX were mixed. Based on these findings, attention should be sufficiently paid to the development of ‘gallstone-related disorder’ in pediatric patients and in patients treated with CTRX at a dose exceeding the normal dose. Furthermore, gallstone formation and growth may be promoted when CTRX and Ca2+ coexist at high concentrations under low pH conditions.

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Age-associated theophylline metabolic activity corresponds to the ratio of 1,3-dimethyluric acid to theophylline in mice

Kuroda Y, Taguchi K, Enoki Y, Matsumoto K, Hori S, Kizu J

Biological and Pharmaceutical Bulletin (Biological and Pharmaceutical Bulletin) 42 ( 8 ) 1423 - 1427 2019

Research paper (scientific journal), Joint Work, Accepted, ISSN 09186158

© 2019 The Pharmaceutical Society of Japan. Age is known as one of influencing factor for theophylline (TP)-metabolizing capacity. In a previous our study, the ratio of TP and its major metabolite 1,3-dimethyluric acid (DMU) in serum (DMU/TP) is a useful index to estimate TP-metabolizing capacity, and this value markedly increased by influencing factor, such as the history of smoking. However, it is unknown whether DMU/TP values in serum reflect age-associated changes of TP-metabolizing capacity. In this study, the effect of age on the DMU/TP values in serum were investigated using mice of different age due to the limited blood sampling in human. The concentrations of TP and its metabolites in mouse serum were simultaneously measured using HPLC. As observed in human serum, serum TP concentrations were closely correlated with DMU concentration in mice, which indicates that the DMU/TP ratio is a good indicator of TP metabolic ability in mice. When TP was administered subcutaneously in 2?8-week-old mice, age-associated changes in the DMU/TP ratio in mice were observed. In conclusion, age-associated changes in TP-metabolizing capacity can be estimated by the DMU/TP ratio in serum.

Clostridioides（Clostridium）difficile感染症診療ガイドライン.

國島広之, 大毛宏喜, 鈴木広道, 中村敦, 松元一明, 三鴨廣繁, 森伸晃, 森永芳智, 栁原克紀, 山岸由佳, 吉澤定子.

感染症学雑誌 92 819 - 854 2018.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0387-5911

Oral vancomycin versus metronidazole for the treatment of Clostridioides difficile infection: meta-analysis of randomized controlled trials.

Yuki Igarashi, Sho Tashiro, Yuki Enoki, Kazuaki Taguchi, Kazuaki Matsumoto, Hiroki Ohge, Hiromichi Suzuki, Atsushi Nakamura, Nobuaki Mori, Yoshitomo Morinaga, Yuka Yamagishi, Sadako Yoshizawa, Katsunori Yanagihara, Hiroshige Mikamo, Hiroyuki Kunishima.

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 24 ( 11 ) 907 - 914 2018.11

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

© 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases At present, vancomycin (VCM) and metronidazole (MNZ) are used for the first-line standard treatment of Clostridioides difficile infection (CDI). However, their differential use has not been sufficiently investigated. In this study, a meta-analysis on differences in the efficacy for CDI between VCM and MNZ was performed. Reports of randomized controlled studies using VCM or MNZ to treat CDI were surveyed. Meta-analysis was performed using the Mantel-Haenszel method and random-effects model, and the risk ratio and 95% confidence interval were calculated. Excluding overlapping reports, 1043 reports were extracted and 5 randomized controlled studies were extracted. There was no difference in therapeutic effects for CDI between VCM and MNZ (RR = 1.08, 95% CI (0.99–1.17), p = 0.09, I2 = 37%). On subgroup analysis by the severity, there was no difference in the clinical effects for CDI between VCM and MNZ in non-severe cases (risk ratio: 1.09, 95% confidence interval: 1.00–1.19, p = 0.06), but the clinical effects of VCM were significantly higher than those of MNZ in severe cases (risk ratio: 1.19, 95% confidence interval: 1.02–1.39, p = 0.03). No significant difference was noted in the recurrence rate, incidence of adverse event, time to exhibit therapeutic effects, or judgment of the bacteriological effects. As the therapeutic effects of VCM were superior in severe CDI cases, VCM should be considered first in severe cases.

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Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research.

Ryo Yajima , Kazuaki Matsumoto, Kanako Yokono, Yuki Watabe, Yuki Enoki, Kazuaki Taguchi, Yuya Ise, Shiro Katayama, Junko Kizu.

Journal of Pharmacy and Pharmacology (Journal of Pharmacy and Pharmacology) 71 ( 5 ) 746 - 752 2018.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 2042-7158

© 2018 Royal Pharmaceutical Society Objectives: As commercially available pregabalin preparations are limited to oral administration, it is impossible to use it as an adjuvant analgesic for neuropathic cancer-related pain in terminally ill cancer patients with oral feeding difficulties. The objective of this study was to develop a pregabalin suppository to be available at hospitals. Methods: Pregabalin suppositories were prepared using bases comprising six different compositions of Witepsol H-15, Witepsol S-55, and Witepsol E-75. The suppository release test and stability test were performed in vitro. The pharmacokinetics and pharmacodynamics of the suppositories were assessed in rats. Key findings: In the in vitro releasing test, the pregabalin suppositories with H-15, H-15 : S-55 = 1 : 1, H-15 : S-55 = 2 : 1, H-15 : S-55 = 1 : 2 released approximately 100% of the pregabalin within 180 min. Among these pregabalin suppositories, only the suppository with H-15 : S-55 = 2 : 1 demonstrated an equivalent AUC 0−∞ with the oral administration group. Consistent with the results of the pharmacokinetic study, the pregabalin suppository with H-15 : S-55 = 2 : 1 exhibited antinociceptive effects. In addition, the pregabalin suppository with H-15 : S-55 = 2 : 1 was stable for 12 weeks when refrigerated with light shielding. Conclusions: The pregabalin suppositories prepared in this study may be applicable for pain control for terminally cancer ill patients with oral feeding difficulties.

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Stability of benzylpenicillin potassium and ampicillin in an elastomeric infusion pump.

Tomomi Nakamura, Yuki Enoki, Shunsuke Uno, Yoshifumi Uwamino, Osamu Iketani, Naoki Hasegawa, Kazuaki Matsumoto.

Journal of Infection and Chemotherapy (Elsevier B.V.) 24 ( 10 ) 856 - 859 2018.10

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

Some infectious diseases, such as infective endocarditis, osteomyelitis, and abscesses, require treatment with long-term intravenous antimicrobial treatment. Therefore, the patient is required to stay in the hospital to receive therapy, which lowers their quality of life. Establishing an outpatient parenteral antimicrobial therapy (OPAT) by continuous infusion pump is desired in Japan to overcome these issues. However, the 24-h stability of antimicrobial agents dissolved in infusion solutions is unclear. Thus, we investigated the stability of antimicrobial agents in five different infusion solutions in a clinical setting. Benzylpenicillin potassium (PCG) and ampicillin (ABPC) were dissolved separately in five different infusion solutions and kept at 25 or 31.1 °C for 24 h. The residual ratios were determined by high-performance liquid chromatography (HPLC). Dissolved PCG in acetate ringer solution remained stable for 24 h at temperatures of 25 and 31.1 °C (101.7 ± 1.4% and 92.9 ± 1.3%, respectively). In addition, the PCG solution did not adsorb onto the elastomeric infusion pump after 24 h at 31.1 °C. PCG dissolved in acetate ringer solution was also stable for 10 days after being kept in an elastomeric infusion pump at 4 °C (99.7 ± 0.5%). ABPC was unstable in all of the tested infusion solutions and temperatures. Based on our results, PCG in acetate ringer solution can be used in OPAT with continuous infusion pumps.

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Development of HPLC with fluorescent detection using NBD-F for the quantification of colistin sulfate in rat plasma and its pharmacokinetic applications.

Sui Ouchi, Kazuaki Matsumoto, Maki Okubo, Yuta Yokoyama, Junko Kizu.

Biomedical Chromatography (John Wiley and Sons Ltd) 32 ( 5 ) e4167 2018.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 1099-0801

Colistin sulfate, composed of a mixture of colistin A sulfate (CLA) and colistin B sulfate (CLB), is available for treating life-threatening infections caused by multidrug-resistant Gram-negative bacteria. In this study, the CLA and CLB were quantified separately. Colistin sulfate was extracted from rat plasma with a solid-phase extraction C18 cartridge and reacted with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), and the fluorescent derivatives were subjected to reversed-phase high-performance liquid chromatography analysis and used to investigate the pharmacokinetics of CLA and CLB in rat plasma. The recovery rates of CLA and CLB were 41.2 ± 4.4 and 45.5 ± 3.1%, respectively. The recovery rate calculated from the total area of CLA and CLB was 43.9 ± 3.6%. When 2 mm NBD-F and 10 mm boric acid buffer (pH 9.5) were added to colistin sulfate, the highest recovery rate was obtained. The best heating time was 5 min at 60°C. The lower limits of quantification for CLA, CLB and the total area of CLA and CLB were 0.05, 0.05 and 0.1 μg/mL
the coefficients of variations were 13.5, 14.5 and 14.1%, respectively. This method was found to have acceptable linearity, precision and accuracy, and has been successfully applied to a pharmacokinetic study in rat plasma.

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一包化調剤薬の鑑査業務における刻印錠と両面印字錠の比較.

松元一明, 大森栄, 石井伊都子, 川久保孝, 神田博仁, 鈴木貴明, 横山威一郎, 中澤一純, 木津純子

日本病院薬剤師会雑誌 ((一社)日本病院薬剤師会) 54 ( 4 ) 433 - 439 2018.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-8815

刻印錠と両面印字錠の一包化を行い、薬剤師と薬学部学生を対象に、調剤薬鑑査における鑑査時間、調剤ミスの発見の有無についてタイムスタディを実施し、その後、アンケートを行った。刻印錠の鑑査に、学生(40名)、薬剤師(98名)は平均517.2秒、505.6秒を要し、両面印字錠の平均298.9秒、277.5秒と比較して有意に長かった(p<0.001)。アンケートの結果、刻印錠では、"大変やりにくい"、"やりにくい"との回答が82.6%、両面印字錠では、"大変やりやすい"、"やりやすい"との回答が91.2%得られた。"鑑査の速さ"、"鑑査のしやすさ"、"鑑査の正確性"は71.7%、92.8%、89.9%が、両面印字錠のほうがよいと回答した。今後増え続けると思われる一包化の鑑査業務において、両面印字錠は、鑑査業務の負担軽減に貢献できるものと考える。(著者抄録)

Dosing optimization of meropenem based on a pharmacokinetic analysis in patients receiving hemodiafiltration and an in vitro model.

Yuta Yokoyama, Kakine Nishino, Kazuaki Matsumoto, Yuki Inomoto, Kaori Matsuda, Rin-nosuke Nakamura, Nobuhiro Yasuno, Junko Kizu.

JOURNAL OF INFECTION AND CHEMOTHERAPY (Journal of Infection and Chemotherapy) 24 ( 2 ) 92 - 98 2018.02

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

© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases The purpose of this study was to estimate the in vivo pharmacokinetics of meropenem during intermittent-infusion hemodiafiltration (I-HDF) and clarify its optimal dosage and dosing interval in patients receiving I-HDF. The clearance of meropenem by online hemodiafiltration (OL-HDF) and I-HDF was predicted using an in vitro system and assessed to establish whether the results obtained are applicable to clinical cases. In the in vivo study, the mean volume of distribution (Vd), non-I-HDF clearance (CLnon-I-HDF), and I-HDF clearance (CLI-HDF) were 15.80 ± 3.59 l, 1.05 ± 0.27 l/h, and 5.78 ± 1.03 l/h. Dosing regimens of 0.25 g once daily for a MIC of 8 μg/ml and of 0.5 g once daily for a MIC of 16 μg/ml achieved 40% T > MIC. In the in vitro and in vivo studies, observed CLHDF was similar to predictive CLHDF (= Cf/Cp × (QD + QSUB)). In conclusion, adjustments to the dose and interval of meropenem were developed based on the presumed susceptibility of pathogens to meropenem in patients receiving I-HDF. We suggest 0.5 g once daily as an appropriate regimen for empirical treatment.

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Analysis of Adverse Drug Events in Pulmonary Mycobacterium Avium Complex Disease Using the Japanese Adverse Drug Event Report (JADER) Database

Namkoong H, Takahashi Y, Ishii M, Asakura T, Suzuki S, Kamata H, Yagi K, Betsuyaku T, Matsumoto K, Kizu J, Hasegawa N

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 197 2018

Research paper (scientific journal), Joint Work, Accepted, ISSN 1073-449X

自動車運転に影響を及ぼす医薬品に対する病院薬剤師の対応.

松元一明, 市川楓子, 黒田裕子, 木津純子.

日本病院薬剤師会雑誌 53 1161 - 1167 2017.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-8815

Factorial analysis of hepatitis B virus reactivation-induced hepatitis B using JADER.

Ayako Hara, Kazuaki Matsumoto, Yuta Yokoyama, Junko Kizu.

BIOLOGICAL & PHARMACEUTICAL BULLETIN (PHARMACEUTICAL SOC JAPAN) 40 ( 6 ) 782 - 788 2017.06

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

Hepatitis B caused by chemotherapy- and immunosuppression-associated hepatitis B virus reactivation is likely to become fulminant, and a high mortality rate has been reported. In this study, using the Japanese adverse drug event report database (JADER), factorial analysis of patients who developed hepatitis B as an adverse event was performed. The number of reported cases of hepatitis B during the survey period was 781 and 185 of them (24%) died. Rituximab and prednisolone were administered to many cases (233, 216 cases, respectively), and the reporting odds ratios were high (65.35, 13.40, respectively), suggesting their strong association with the development of hepatitis B. Regarding the onset time, rituximab-induced hepatitis B developed within one year after administration in 83%, being a high frequency. Prednisolone-induced hepatitis B developed even after one year in 36%. Since prednisolone is used to treat rheumatoid arthritis at a dose <= 10mg/d, the patients were divided based on the prednisolone dose into the groups treated at >10 and <= 10 mg/d, and the onset time was investigated in each group. The median onset time was 113 and 330d, respectively, showing a significant difference. On time-to-event analysis using the Weibull distribution, rituximab was classified as the early failure type, and prednisolone and methotrexate for rheumatoid arthritis were classified as the wear out failure type. These findings are important information which may lead to early discovery of and taking actions against hepatitis B being helpful for providing appropriate medical care.

ラモトリギンの医薬品副作用データおよび医薬品副作用被害救済給付決定情報の調査解析.

横山雄太, 黒田裕子, 安藤剛, 松元一明, 木津純子.

日本病院薬剤師会雑誌 53 283 - 289 2017.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-8815

抗菌薬のTDM実施に関する実態調査－TDM実施率と感染制御体制との関連性およびTDMの実施方法の抗菌薬TDMガイドラインとの比較－.

松元一明, 磯田梨奈, 黒田裕子, 横山雄太, 木津純子.

日本化学療法学会雑誌 65 175 - 182 2017.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 1340-7007

Synthesis of linezolid metabolites PNU-142586 and PNU-142300 toward the exploration of metabolite-related events.

Kengo Hanaya, Kazuaki Matsumoto, Yuta Yokoyama, Junko Kizu, Mitsuru Shoji, Takeshi Sugai.

CHEMICAL & PHARMACEUTICAL BULLETIN 65 194 - 199 2017.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1347-5223

有害事象自発報告データベース（JADER）からみた医薬品による交通事故.

安藤剛, 松元一明, 横山雄太, 木津純子.

日本交通科学協議会誌 16 46 - 51 2017.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 13469282

CYP2C19遺伝子多型と代謝物濃度をふまえたTDMによるボリコナゾール投与量適正化が有用であった2例.

茂見茜里, 松元一明, 渡辺英里香, 猪川和朗, 金澤直子, 横山雄太, 梅﨑雄太, 池田龍二, 森川則文, 武田泰生

日本外科感染症学会雑誌 13 661 - 667 2016.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1349-5755

Pregabalin prescription for terminally ill cancer patients receiving specialist palliative care in an acute hospital.

Ryo Yajima, Kazuaki Matsumoto, Yuya Ise, Norihito Suzuki, Yuta Yokoyama, Junko Kizu, Shiro Katayama.

JOURNAL OF PHARMACEUTICAL HEALTH CARE AND SCIENCES 2 29 2016.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 2055-0294

Pharmaceutical studies on and clinical application of olanzapine suppositories prepared as a hospital preparation.

Kazuaki Matsumoto, Satoru Kimura, Kenichi Takahashi, Yuta Yokoyama, Masayuki Miyazawa, Satoko Kushibiki, Morio Katamachi, Junko Kizu.

JOURNAL OF PHARMACEUTICAL HEALTH CARE AND SCIENCES 2 20 2016.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 2055-0294

The pharmacokinetics of ampicillin-sulbactam in anuric patients: dosing optimization for prophylaxis during cardiovascular surgery.

Yuta Yokoyama, Kazuaki Matsumoto, Kazuro Ikawa, Erika Watanabe, Hiroyuki Yamamoto, Yutaka Imoto, Norifumi Morikawa, Yasuo Takeda.

INTERNATIONAL JOURNAL OF CLINICAL PHARMACY 38 771 - 775 2016.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 2210-7711

医薬品副作用被害救済制度からみた抗菌薬が関連した副作用被害の実態.

佐藤沙紀, 松元一明, 黒田裕子, 木津純子.

日本化学療法学会雑誌 64 656 - 662 2016.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 1340-7007

Therapeutic drug monitoring of voriconazole in Japanese patients: analysis based on clinical practice data.

Kazuaki Matsumoto, Kazuko Abematsu, Akari Shigemi, Naoko Kanazawa, Erika Watanabe, Yuta Yokoyama, Kazuro Ikawa, Norifumi Morikawa, Yasuo Takeda.

JOURNAL OF CHEMOTHERAPY 28 198 - 202 2016.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 1120-009X

抗菌薬TDMガイドライン2016.

竹末芳生, 大曲貴夫, 岡田賢二, 笠原敬, 関雅文, 髙倉俊二, 高橋佳子, 時松一成, 松元一明, 三鴨廣繁, 猪川和朗, 平田純生, 木村利美, 小林昌宏, 西圭史, 浜田幸宏.

日本化学療法学会雑誌 64 387 - 477 2016.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 1340-7007

Pharmacokinetics and brain penetration of carbapenems in mice.

Kazuaki Matsumoto, Yuji Kurihara, Yuko Kuroda, Seiji Hori, Junko Kizu.

JOURNAL OF INFECTION AND CHEMOTHERAPY 22 346 - 349 2016.04

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

Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections.

Kazuaki Matsumoto, Erika Watanabe, Naoko Kanazawa, Tomohide Fukamizu, Akari Shigemi, Yuta Yokoyama, Kazuro Ikawa, Norifumi Morikawa, Yasuo Takeda.

CLINICAL PHARMACOLOGY: ADVANCES AND APPLICATIONS 8 15 - 18 2016.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 1179-1438

自動車運転に影響を及ぼす医薬品の処方における薬局薬剤師の対応.

髙橋佑介, 松元一明, 黒田裕子, 大原整, 木津純子.

日本交通科学協議会誌 15 ( 3 ) 29 - 37 2016.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 13469282

A bundle that includes active surveillance, contact precaution for carriers, and cefazolin-based antimicrobial prophylaxis prevents methicillin-resistant Staphylococcus aureus infections in clean orthopedic surgery.

Hideki Kawamura, Kazuaki Matsumoto, Akari Shigemi, Michiyo Orita, Aya Nakagawa, Tomoko Nozima, Hiroyuki Tominaga, Setsuro Komiya, Koichi Tokuda, Junichiro Nishi.

AMERICAN JOURNAL OF INFECTION CONTROL (MOSBY-ELSEVIER) 44 ( 2 ) 210 - 214 2016.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 0196-6553

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of orthopedic surgical site infections (SSIs). The aim of this study was to evaluate the effect of a bundle approach in the prevention of orthopedic MRSA SSIs.
Material and Methods: MRSA active surveillance and decolonization were performed preoperatively at our institution from July 2004 until 2007. In January 2008, a bundle approach comprising contact precautions for MRSA-positive patients and cefazolin-based antimicrobial prophylaxis (AMP) stewardship was implemented. Data on the prevalence of MRSA SSIs, antimicrobial use density, duration of AMP, and the use of an alcohol antiseptic agent (L/1,000 patient-days) were evaluated during 2 periods: July 2004-December 2007 (period A) and January 2008-December 2012 (period B).
Results and Discussion: The MRSA SSI rate during period B (0.97%; 19 out of 1,966) was significantly lower than that during period A (2.17%; 29 out of 1,333; P =.003). The infection rate correlated negatively with both the cefazolin antimicrobial use density (r = -0.76; P = .0002) and the use of an alcohol antiseptic agent (r = -0.68; P = .002).
Conclusions: An infection-prevention bundle consisting of contact precautions for carriers and AMP stewardship in addition to active surveillance was associated with a significant decrease in the incidence of orthopedic MRSA SSIs. Copyright (c) 2016 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

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フレーバー添加レバミピド内用液剤の安定性に関する基礎検討.

矢島領, 今岡楓太, 輪湖哲也, 黒田裕子, 松元一明, 木津純子, 片山志郎.

YAKUGAKU ZASSHI 135 1397 - 1402 2015.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0031-6903

Anti-inflammatory effects of linezolid on carrageenan-induced paw edema in rats.

Kazuaki Matsumoto, Shigeaki Obara, Yuko Kuroda, Junko Kizu.

JOURNAL OF INFECTION AND CHEMOTHERAPY (Elsevier) 21 ( 12 ) 889 - 891 2015.12

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

The immunomodulatory activity of linezolid has recently been reported using in vitro experimental models. However, the anti-inflammatory activity of linezolid has not yet been demonstrated using in vivo experimental models. Therefore, the aim of the present study was to demonstrate the anti-inflammatory activity of linezolid and other anti-MRSA agents using the carrageenan-induced rat paw edema model.The pretreatment with 50 mg/kg linezolid significantly suppressed edema rates, compared with control (5% glucose), with edema rates at 0.5 and 3 h after the administration of carrageenan being 17.3 ± 3.5 and 30.8 ± 3.0%, respectively. On the other hand, edema rates were not suppressed by the pretreatments with 50 mg/kg vancomycin, teicoplanin, arbekacin, and daptomycin. Furthermore, we demonstrated that linezolid exhibited anti-inflammatory activity in a concentration-dependent manner. These effects were observed at linezolid concentrations that are achievable in human serum with conventional dosing.In conclusion, the results of the present study suggest that the anti-inflammatory activities of linezolid, in addition to its antimicrobial effects, have a protective effect against destructive inflammatory responses in areas of inflammation.

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Pharmacokinetics of prophylactic ampicillin-sulbactam and dosing optimization in patients undergoing cardiovascular surgery with cardiopulmonary bypass.

Yuta Yokoyama, Kazuaki Matsumoto, Kazuro Ikawa, Erika Watanabe, HiroyukiYamamoto, Yutaka Imoto, Norifumi Morikawa, Yasuo Takeda.

BIOLOGICAL & PHARMACEUTICAL BULLETIN 38 1817 - 1821 2015.11

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

Trough level monitoring of intravenous busulfan to estimate the area under the plasma drug concentration-time curve in pediatric hematopoietic stem cell transplant recipients.

Erika Watanabe, Takuro Nishikawa, Kazuro Ikawa, Hiroki Yamaguchi, Takanari Abematsu, Shunsuke Nakagawa, Koichiro Kurauchi, Yuichi Kodama, Takayuki Tanabe, Yuichi Shinkoda, Kazuaki Matsumoto, Yasuhiro Okamoto, Yasuo Takeda, Yoshifumi Kawano.

INTERNATIONAL JOURNAL OF HEMATOLOGY 102 611 - 616 2015.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0925-5710

溶出性・分割性からみた市販アセトアミノフェン坐剤の比較.

黒田裕子, 徳田真実, 井上舞鳥, 増田克哉, 寺島朝子, 前澤佳代子, 松元一明, 木津純子.

医療薬学 41 714 - 721 2015.10

Research paper (scientific journal), Joint Work, Accepted

Pharmacokinetics and dosing estimation of meropenem in Japanese patients receiving continuous venovenous hemodialysis.

Shinji Kawano, Kazuaki Matsumoto, Ryohei Hara, Yuko Kuroda, Kazuro Ikawa, Norifumi Morikawa, Tetsuya Horino, Seiji Hori, Junko Kizu.

JOURNAL OF INFECTION AND CHEMOTHERAPY 21 476 - 478 2015.06

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

Pharmacokinetics and skin tissue penetration of daptomycin in rats.

Kazuaki Matsumoto, Masashi Kitaoka, Yuko Kuroda, Kazuro Ikawa, Norifumi Morikawa, Junichi Sasaki, Osamu Iketani, Satoshi Iwata, Tetsuya Horino, Seiji Hori, Junko Kizu.

CLINICAL PHARMACOLOGY: ADVANCES AND APPLICATIONS 7 79 - 82 2015.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 1179-1438

医薬品副作用被害救済制度からみた一般用医薬品が関連した副作用被害の実態.

黒田裕子, 松元一明, 木津純子.

日本病院薬剤師会雑誌 51 425 - 428 2015.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-8815

Population pharmacokinetic-pharmacodynamic target attainment analysis of sulbactam in patients with impaired renal function: dosing considerations for Acinetobacter baumannii infections.

Yokoyama Yuta, Matsumoto Kazuaki, Ikawa Kazuro, Watanabe Erika, Morikawa Norifumi, Takeda Yasuo.

JOURNAL OF INFECTION AND CHEMOTHERAPY 21 284 - 289 2015.04

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

Risk factors for ganciclovir-induced thrombocytopenia and leukopenia.

Matsumoto Kazuaki, Shigemi Akari, Ikawa Kazuro, Kanazawa Naoko, Fujisaki Yuko, Morikawa Norifumi, Takeda Yasuo.

BIOLOGICAL & PHARMACEUTICAL BULLETIN 38 235 - 238 2015.02

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

バンコマイシン塩酸塩点滴静注用製剤の生理食塩液に対する溶解性比較.

松元一明, 黒田裕子, 寺島朝子, 前澤佳代子, 木津純子.

日本環境感染学会誌 30 ( 1 ) 29 - 32 2015.01

Research paper (scientific journal), Joint Work, Accepted

Linezolid dosage in pediatric patients based on pharmacokinetics and pharmacodynamics.

Matsumoto Kazuaki, Shigemi Akari, Takeshita Ayumi, Watanabe Erika, Yokoyama Yuta, Ikawa Kazuro, Morikawa Norifumi, Takeda Yasuo.

JOURNAL OF INFECTION AND CHEMOTHERAPY (SPRINGER JAPAN KK) 21 ( 1-2 ) 70 - 73 2015.01

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

Linezolid pharmacokinetic profile in pediatric patients has not been fully characterized, and the dose needed to achieve a pharmacokinetic-pharmacodynamic (PK-PD) target has yet to be established because its efficacy is associated with the area under the plasma drug concentration time curve (AUC(24))/minimum inhibitory concentration (MIC) ratio. The present study aimed to define the pharmacokinetic parameters of intravenous linezolid in pediatric patients and assess the rationale for the approved dosage recommendations. Linezolid was safe, tolerated well, and clinically effective for treating Gram-positive bacteria in five pediatric patients (3-11 years). The mean values for the volume of distribution, and total clearance (CL) in a one-compartment model were estimated to be 0.646 +/- 0.239 l/kg and 0.171 +/- 0.068 1/h/kg, respectively (mean +/- S.D.). Based on this analysis, the AUC(24) and trough drug concentration in plasma (C-min) for linezolid doses were predicted to be 175.4 mu g h/ml and 3.4 mu g/ml for 30 mg/kg/day, 204.7 mu g h/ml and 4.3 mu g/ml for 35 mg/kg/day, and 2632 mu g h/ml and 6.2 mu g/ml for 45 mg/kg/day, respectively. Taking into account that AUC(24) should be >= 200 mu g h/ml for MIC of 2.0 mu g/ml (to achieve an AUC(24)/MIC ratio of >= 100) and C-min should be approximately 7 mu g/ml (to avoid thrombocytopenia), we consider the approved dosage of 30 mg/kg/day to be fundamentally rational, but can be underdosed against bacteria with MIC of 2.0 mu g/ml; therefore, a dose of 35-45 mg/kg/day is more appropriate to ensure the efficacy and safety of linezolid in pediatric patients. (C) 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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カラゲニン足蹠浮腫モデルを用いた各種ケトプロフェンテープ剤の抗炎症効果比較.

松元一明, 河野倫也, 杉山哲也, 坂本靖宜, 島田亜由美, 黒田裕子, 寺島朝子, 前澤佳代子, 木津純子.

医療薬学 40 672 - 676 2014.11

Research paper (scientific journal), Joint Work, Accepted

Factors affecting treatment and recurrence of Clostridium difficile infections.

Matsumoto Kazuaki, Kanazawa Naoko, Shigemi Akari, Ikawa Kazuro, Morikawa Norifumi, Toyoyasu Koriyama, Orita Michiyo, Kawamura Hideki, Tokuda Koichi, Nishi Junichiro, Takeda Yasuo.

BIOLOGICAL & PHARMACEUTICAL BULLETIN (PHARMACEUTICAL SOC JAPAN) 37 ( 11 ) 1811 - 1815 2014.11

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

The antimicrobial agents vancomycin and metronidazole have been used to treat Clostridium difficile infections (CDIs). However, it remains unclear why patients are at risk of treatment failure and recurrence. Therefore, this study retrospectively examined 98 patients with CDIs who were diagnosed based on the detection of toxin-positive C. difficile to determine the risk factors affecting drug treatment responses and the recurrence of CDI. No significant difference was observed in the cure rate or dosage between the vancomycin and metronidazole groups. The 90-d mortality rate and total number of drugs associated with CDIs, including antiinfective agents used within 2 months before the detection of toxin-positive C. difficile, were significantly lower in the treatment success group than in the failure group. The total number of antiinfective agents and gastric acid-suppressive agents used during CDI therapy was also significantly lower in the success group than in the failure group. The period from the completion of CDI therapy to restarting the administration of anticancer agents and steroids was significantly longer in patients without than in patients with recurrence. These results indicate that the total number of drugs associated with CDIs should be minimized to reduce the risk of CDIs, that not only antibiotics but also gastric acid-suppressive agents should be discontinued during CDI therapy to increase therapeutic efficacy, and that the use of anticancer agents and steroids should be delayed as long as possible after patients are cured by CDI therapy to prevent recurrence.

複合型塩素系除菌・洗浄用製剤の安定性と色調の変化.

木津純子, 高木奏, 黒田裕子, 前澤佳代子, 松元一明, 堀誠治.

日本環境感染学会誌 29 ( 6 ) 411 - 416 2014.11

Research paper (scientific journal), Accepted

Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: A dosage strategy according to the trough concentration target and renal function in adult patients.

Matsumoto Kazuaki, Shigemi Akari, Takeshita Ayumi, Watanabe Erika, Yokoyama Yuta, Ikawa Kazuro, Morikawa Norifumi, Takeda Yasuo.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS (ELSEVIER SCIENCE BV) 44 ( 3 ) 242 - 247 2014.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0924-8579

The pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is a 24-h area under the plasma drug concentration-time curve (AUC(24))/minimum inhibitory concentration (MIC) ratio of >= 100. The main adverse event associated with administration of linezolid is thrombocytopenia. Therefore, the aims of the present study were to define PD thresholds that would minimise linezolid-induced thrombocytopenia and to perform a population PK analysis to identify factors influencing the pharmacokinetics of linezolid. Population PK analysis revealed that creatinine clearance (CLCr) significantly affected linezolid pharmacokinetics: the mean parameter estimate of drug clearance (CL; in L/h)= 0.0258 x CLCr + 2.03. A strong correlation (r=0.970) was found between AUC(24) and trough plasma concentrations (C.) [AUC(24)=18.2 x C-min + 134.4]. The Cmin value for AUC(24)=200 (in the case of MIC=2 mu g/mL) was estimated to be 3.6 mu g/mL. Regarding safety, Cmin was a significant predictor of thrombocytopenia during treatment, and its threshold to minimise linezolid-induced thrombocytopenia was 8.2 mu g/mL. A Kaplan-Meier plot revealed that the median time from initiation of therapy to the development of thrombocytopenia was 15 days. Therefore, the target C. range was 3.6-8.2 mu g/mL. The following formula to achieve a target C. in patients with different degrees of renal function was proposed based on these results: initial daily dose (mg/day) = CL x AUC(24) = (0.0258 x CLCr + 2.03) x (18.2 x C-min + 134.4). This recommended initial dosage and subsequent dosage adjustment for the target concentration range should avoid adverse events, thereby enabling effective linezolid-based therapies to be continued. (C) 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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Pharmacokinetic/pharmacodynamic evaluation of sulbactam against Acinetobacter baumannii in in vitro and murine thigh and lung infection models.

Yokoyama Yuta, Matsumoto Kazuaki, Ikawa Kazuro, Watanabe Erika, Shigemi Akari, Umezaki Yasuhiro, Nakamura Koyo, Ueno Keiichiro, Morikawa Norifumi, Takeda Yasuo.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS 43 ( 6 ) 547 - 552 2014.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 0924-8579

九州山口地区における基質拡張型βラクタマーゼ産生菌の検出状況と抗菌薬使用状況に関する合同調査.

室高広, 北原隆志, 伊東弘樹, 入江利行, 野中敏治, 藤井裕史, 松元一明, 山崎博史, 柳原克紀, 佐々木均.

日本環境感染学会誌 29 32 - 39 2014.01

Research paper (scientific journal), Joint Work, Accepted

Clinical practice guidelines for therapeutic drug monitoring of arbekacin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

Okada Kenji, Kimura Toshimi, Mikamo Hiroshige, Kasahara Kei, Seki Masafumi, Takakura Shunji, Tokimatsu Issei, Ohmagari Norio, Takahashi Yoshiko, Matsumoto Kazuaki, Igarashi Masahiro, Kobayashi Masahiro, Hamada Yukihiro, Mochizuki Takahiro, Kimura Masao, Nishi Yoshifumi, Tanigawara Yusuke, Takesue Yoshio.

JOURNAL OF INFECTION AND CHEMOTHERAPY (ELSEVIER SCIENCE BV) 20 ( 1 ) 1 - 5 2014.01

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

Arbekacin (ABK) was approved and widely used in Japan for treatment of patients infected with MRSA, and TDM was introduced in clinical practice. The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons. First, although the daily dose of 150-200 mg was approved in Japan, recent PR-PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently. Second, although maximal concentrations that obtained immediately after the end of administration (C-max) was generally adopted, the serum concentration at 1 h after initiation of administration [peak serum concentration (C-peak)] proved to be more suitable as an efficacy indicator of aminoglycosides. Lastly, as ABK is approved only in Japan, no international practice guideline for TDM has not been available in ABK to date. This guideline evaluated the scientific data associated with serum ABK monitoring and provided recommendations based on the available evidence. Potential limitations of this guideline, however, include the findings that few prospective clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies. (C) 2013, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

Hamada Yukihiro, Tokimatsu Issei, Mikamo Hiroshige, Kimura Masao, Seki Masafumi, Takakura Shunji, Ohmagari Norio, Takahashi Yoshiko, Kasahara Kei, Matsumoto Kazuaki, Okada Kenji, Igarashi Masahiro, Kobayashi Masahiro, Mochizuki Takahiro, Nishi Yoshifumi, Tanigawara Yusuke, Kimura Toshimi, Takesue Yoshio.

JOURNAL OF INFECTION AND CHEMOTHERAPY 19 ( 3 ) 381 - 392 2013.06

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

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Development of Initial Loading Procedure for Teicoplanin in Critically Ill Patients with Severe Infections.

Matsumoto Kazuaki, Kanazawa Naoko, Watanabe Erika, Yokoyama Yuta, Fukamizu Tomohide, Shimodozono Yoshihiro, Maeda Chiharu, Yasuda Tomotsugu, kakihana Yasuyuki, Ikawa Kazuro, Morikawa Norifumi, Takeda Yasuo.

BIOLOGICAL & PHARMACEUTICAL BULLETIN 36 ( 6 ) 1024 - 1026 2013.06

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

Practice guidelines for therapeutic drug monitoring of vancomycin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

Matsumoto Kazuaki, Takesue Yoshio, Ohmagari Norio, Mochizuki Takahiro, Mikamo Hiroshige, Seki Masafumi, Takakura Shunji, Tokimatsu Issei, Takahashi Yoshiko, Kasahara Kei, Okada Kenji, Igarashi Masahiro, Kobayashi Masahiro, Hamada Yukihiro, Kimura Masao, Nishi Yoshifumi, Tanigawara Yusuke, Kimura Toshimi.

JOURNAL OF INFECTION AND CHEMOTHERAPY 19 ( 3 ) 365 - 380 2013.06

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

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大学病院でのICT病棟ラウンドにおける指摘事項の解析.

川村英樹, 折田美千代, 中川彩, 松元一明, 茂見茜里, 郡山豊泰, 西順一郎.

日本環境感染学会誌 28 25 - 28 2013.01

Research paper (scientific journal), Joint Work, Accepted

Pharmacokinetics of ampicillin-sulbactam and the renal function-based optimization of dosing regimens for prophylaxis in patients undergoing cardiovascular surgery.

Yokoyama Yuta, Matsumoto Kazuaki, Yamamoto Hiroyuki, Iguro Yoshifumi, Imoto Yutaka, Ikawa Kazuro, Morikawa Norifumi, Ishida Shiro, Okano Yoshiro, Watanabe Erika, Shimodozono Yoshihiro, Yamada Katsushi, Takeda Yasuo.

JOURNAL OF INFECTION AND CHEMOTHERAPY 18 ( 6 ) 878 - 882 2012.12

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

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The Development of Appropriate Dosage of Anti-bacterial and Anti-fungal Agents Based on Pharmacokinetics and Pharmacodynamics.

Matsumoto Kazuaki.

YAKUGAKU ZASSHI 132 ( 10 ) 1171 - 1177 2012.10

Research paper (scientific journal), Single Work, Accepted, ISSN 0031-6903

Characterization of the hepatic cellular uptake of alpha(1)-acid glycoprotein (AGP), part 1: A peptide moiety of human AGP is recognized by the hemoglobin beta-chain on mouse liver parenchymal cells.

Nishi Koji, Komori Hisakazu, Kikuchi Mari, Uehara Nao, Fukunaga Naoko, Matsumoto Kazuaki, Watanabe Hiroshi, Nakajou Keisuke, Misumi Shogo, Suenaga Ayaka, Maruyama Toru, Otagiri Masaki.

JOURNAL OF PHARMACEUTICAL SCIENCES (WILEY-BLACKWELL) 101 ( 4 ) 1599 - 1606 2012.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-3549

Human a1-acid glycoprotein (AGP), a serum glycoprotein, is known to have anti-inflammatory activity. We recently reported that AGP was mainly incorporated into the liver in mice via a receptor-mediated pathway, although the mechanism for this was largely unknown. The objective of this study was to identify the specific cellular surface protein that recognizes the peptide moiety of AGP. Pharmacokinetic studies of 111InAGP and 111In recombinant glycan-deficient AGP (rAGP) in mice demonstrated that both AGPs are mainly distributed to the liver and kidney, but hepatic and renal uptake clearance of rAGP was higher than that for AGP. Hepatic uptake of rAGP was inhibited in the presence of 100-fold excess of unlabeled AGP, indicating that the hepatic uptake of rAGP shared a common route with that of AGP and that it recognized the peptide moiety of AGPs. In ligand blotting analyses using crude cellular membrane fraction of mice liver, a band corresponding to a 16 kDa protein was observed to bind to both AGPs. Interestingly, matrix-assisted laser desorption ionizationtime-of-flight mass spectrometry MALDITOF-MS and western blotting analyses indicated that this 16 kDa protein is the hemoglobin beta-chain (HBB). It, therefore, appears that HBB is associated with the hepatic uptake of AGP via a direct interaction with its peptide moiety. (c) 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:15991606, 2012

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Reduction in the incidence of MRSA with use of alcohol-based hand rub solutions and gloves.

Matsumoto Kazuaki, Shigemi Akari, Yaji Keiko, Shimodozono Yoshihiro, Takeda Yasuo, Ikawa Kazuro, Morikawa Norifumi, Miyanohara Hiroaki, Kawamura Hideki, Orita Michiyo, Tokuda Koichi, Nishi Junichiro, Yamada Katsushi.

JOURNAL OF INFECTION AND CHEMOTHERAPY 18 ( 2 ) 269 - 271 2012.04

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

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抗菌薬TDMガイドライン.

竹末芳生, 大曲貴夫, 笠原敬, 関雅文, 髙倉俊二, 高橋佳子, 時松一成, 松元一明, 三鴨廣繁, 木村利美, 谷川原祐介, 五十嵐正博, 岡田賢二, 木村匡男, 小林昌宏, 西圭史, 浜田幸宏, 望月敬浩.

日本化学療法学会雑誌 60 501 - 505 2012

Research paper (scientific journal), Joint Work, Accepted, ISSN 1340-7007

抗MRSA薬投与時のTDMの実際.

松元一明, 深水知英, 金澤直子, 日髙伸之介, 棈松和子, 茂見茜里, 下堂薗権洋, 武田泰生.

日本外科感染症学会雑誌 9 113 - 123 2012

Research paper (scientific journal), Joint Work, Accepted, ISSN 1349-5755

テイコプラニンにおける血中トラフ濃度20μg/mL以上の臨床的効果、安全性.

髙倉俊二, 竹末芳生, 大曲貴夫, 笠原敬, 関雅文, 高橋佳子, 時松一成, 松元一明, 三鴨廣繁.

日本化学療法学会雑誌 60 501 - 505 2012

Research paper (scientific journal), Joint Work, Accepted, ISSN 1340-7007

Safety analysis of liposomal amphotericin B in adult patients: anaemia, thrombocytopenia, nephrotoxicity, hepatotoxicity and hypokalaemia.

Shigemi Akari, Matsumoto Kazuaki, Ikawa Kazuro, Yaji Keiko, Shimodozono Yoshihiro, Morikawa Norifumi, Takeda Yasuo, Yamada Katsushi.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS 38 ( 5 ) 417 - 420 2011.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0924-8579

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An initial dosing method for teicoplanin based on the area under the serum concentration time curve required for MRSA eradication.

Kanazawa Naoko, Matsumoto Kazuaki, Ikawa Kazuro, Fukamizu Tomohide, Shigemi Akari, Yaji Keiko, Shimodozono Yoshihiro, Morikawa Norifumi, Takeda Yasuo, Yamada Katsushi.

JOURNAL OF INFECTION AND CHEMOTHERAPY (SPRINGER TOKYO) 17 ( 2 ) 297 - 300 2011.04

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

Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum trough concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective trough concentration (a parts per thousand yen13 mu g/mL). A logistic regression analysis was performed to test whether the area under the concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory concentration (MIC) for the isolates was < 2 mu g/mL). Each AUC was estimated using individual dose, creatinine clearance (CL(cr)), and body weight data. The target value, which gives about a 0.9 microbiological eradication probability, was 750 mu g h/mL for AUC from zero to 24 h (AUC(0-24 h)). Using published population pharmacokinetic parameters, the dose required to achieve the AUC(0-24 h) target was calculated as dose (mg) = 750 x (0.00498 x CL(cr) (mL/min) + 0.00426 x body weight (kg). For various combinations of CL(cr) and body weight, we checked the calculated doses using a therapeutic drug monitoring (TDM)-supporting software and developed a nomogram. The nomogram would be useful for initial dose adjustment to promptly reach an effective serum trough concentration and avoid adverse events of teicoplanin.

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Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction.

Matsumoto Kazuaki, Takeshita Ayumi, Ikawa Kazuro, Shigemi Akari, Yaji Keiko, Shimodozono Yoshihiro, Morikawa Norifumi, Takeda Yasuo, Yamada Katsushi.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS (ELSEVIER SCIENCE BV) 36 ( 2 ) 179 - 181 2010.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0924-8579

The major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia. Recent studies have reported that the incidence of linezolid-induced thrombocytopenia was higher in patients with renal failure than in patients with normal renal function, although the underlying mechanisms of this toxicity are still unknown. The present study thus aimed to investigate the relationship between renal function and linezolid exposure as well as the effects of drug exposure on thrombocytopenia. A statistically significant (P < 0.01) strong correlation (r = 0.933) was observed between linezolid clearance and creatinine clearance. A negative correlation (r = -0.567) was also shown between linezolid clearance and blood urea nitrogen, although the correlation was not statistically significant. In thrombocytopenic patients, the trough concentration was 14.4-35.6 mg/L and the area under the plasma linezolid concentration-time curve for 24 h (AUC(24 h)) was 513.1-994.6 mg h/L; in non-thrombocytopenic patients, drug exposure was relatively low (6.9 mg/L and 7.2 mg/L for trough concentration and 294.3 mg h/L and 323.6 mg h/L for AUC(24 h)). These results provide a pharmacokinetic explanation for the mechanism of the adverse event that renal dysfunction increased linezolid trough concentration and AUC and that higher drug exposure induced thrombocytopenia. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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Determination of teicoplanin trough concentration target and appropriate total dose during the first 3 days: a retrospective study in patients with MRSA infections.

Matsumoto Kazuaki, Kanazawa Naoko, Ikawa Kazuro, Fukamizu Tomohide, Shigemi Akari, Yaji Keiko, Shimodozono Yoshihiro, Morikawa Norifumi, Takeda Yasuo, Yamada Katsushi.

JOURNAL OF INFECTION AND CHEMOTHERAPY (SPRINGER TOKYO) 16 ( 3 ) 193 - 199 2010.06

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

An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to retrospectively evaluate the pharmacokinetics and pharmacodynamics of teicoplanin to determine the therapeutic target for the teicoplanin trough concentration and an appropriate dosing method during the first 3 days. The mean trough concentrations were 13.2 mg/L for patients with eradication of MRSA. Moreover, logistic regression analysis showed that the teicoplanin trough concentration was 13 mg/L to achieve MRSA eradication with a probability of 89.0%. The rates of achieving a parts per thousand yen13 mg/L in a parts per thousand currency sign24, 24-36 and a parts per thousand yen36 mg/kg (total dose during the first 3 days) groups were 9.1, 48.4 and 87.5%, respectively. These results suggest that the administration of a parts per thousand yen36 mg/kg during the first 3 days is appropriate to promptly obtain a trough concentration target of a parts per thousand yen13 mg/L for the initial treatment of MRSA infections.

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腎機能障害を有する術後MRSA感染症患者2例におけるリネゾリドの体内動態.

竹下鮎美, 松元一明, 茂見茜里, 猪川和朗, 森川則文, 武田泰生, 山田勝士.

日本外科感染症学会雑誌 7 373 - 376 2010

Research paper (scientific journal), Joint Work, Accepted, ISSN 1349-5755

Receptor-Mediated Uptake of Human alpha 1-Acid Glycoprotein into Liver Parenchymal Cells in Mice.

Matsumoto Kazuaki, Nishi Koji, Kikuchi Mari, Watanabe Hiroshi, Nakajou Keisuke, Komori Hisakazu, Kadowaki Daisuke, Suenaga Ayaka, Maruyama Toru, Otagiri Masaki.

DRUG METABOLISM AND PHARMACOKINETICS 25 ( 1 ) 101 - 107 2010

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

Correlation between meropenem and doripenem use density and the incidence of carbapenem-resistant Pseudomonas aeruginosa.

Shigemi Akari, Matsumoto Kazuaki, Yaji Keiko, Shimodozono Yoshihiro, Takeda Yasuo, Miyanohara Hiroaki, Kawamura Hideki Orita Michiyo, Tokuda Koichi. Nishi Junichiro, Yamada Katsushi.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS (ELSEVIER SCIENCE BV) 34 ( 6 ) 589 - 591 2009.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0924-8579

Optimal use of carbapenems is an important issue in the prevention of resistance in Pseudomonas aeruginosa. In this study, we investigated the correlation between antimicrobial use density (AUD) of carbapenems and imipenem/cilastatin (IPM/CS) or meropenem (MEPM) susceptibility of P. aeruginosa strains. The AUD of five carbapenems [IPM/CS, panipenem/betamipron, biapenem, MEPM and doripenem (DRPM)] was examined every 6 months between 2006 and 2008. The AUD was calculated using the defined daily doses methodology developed by the World Health Organisation. A minimum inhibitory concentration of IPM/CS or MEPM of <= 4 mg/L was considered to be sensitive. There was a significant negative correlation between MEPM susceptibility and the total AUD of MEPM and DRPM [r = -0.823, 95% confidence interval (CI) -0.035 to -0.980; P = 0.044]. Furthermore, there was a significant correlation between MEPM susceptibility and IPM/CS susceptibility (r = 0.839, 95% CI 0.084 to 0.981; P = 0.037). Cross-resistance was therefore investigated and only 5.6% of MEPM-insensitive strains were susceptible to IPM/CS, although 43.3% of IPM/CS-insensitive strains were susceptible to MEPM. These results suggest that curtailing the use of MEPM and DRPM may curb the emergence not only of MEPM-resistant strains but also IPM/CS-resistant strains. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes.

Matsumoto Kazuaki, Ikawa Kazuro, Abematsu Kazuko, Fukunaga Naoko, Nishida Kentaro, Fukamizu Tomohide, Shimodozono Yoshihiro, Morikawa Norifumi, Takeda Yasuo, Yamada Katsushi.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS (ELSEVIER SCIENCE BV) 34 ( 1 ) 91 - 94 2009.07

Research paper (scientific journal), Joint Work, ISSN 0924-8579

Voriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60-70% of Asian populations. Because the voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity, this study investigated the effect of CYP2C19 polymorphism on the relationship between voriconazole trough concentrations and liver function abnormalities in 29 Japanese patients with fungal infections (CYP2C19 wild-type, n = 10; non-wild-type, n = 19). Hepatotoxicity, defined as liver enzyme abnormality according to the National Cancer Institute criteria, was observed in 10 (34.5%) of 29 patients with a trough concentration >= 3.9 mg/L. Logistic regression analysis suggested that the therapeutic range for the voriconazole trough concentration should be 2-4 mg/L. Non-linear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild-type and 4.4-6.5 mg/kg/day for the non-wild-type in Japanese patients. These recommended initial dosages and subsequent dose adjustment for the target concentration range by therapeutic drug monitoring should avoid adverse events and thus enable continued effective voriconazole therapy for Japanese patients with mycoses. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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Renal function as a predictor of linezolid-induced thrombocytopenia.

Matsumoto Kazuaki, Takeda Yasuo, Takeshita Ayumi, Fukunaga Naoko, Shigemi Akari, Yaji Keiko, Shimodozono Yoshihiro, Yamada Katsushi, Ikawa Kazuro, Morikawa Norifumi.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS 33 ( 1 ) 98 - 99 2009.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0924-8579

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シクロスポリンおよびタクロリムスのTDM支援ソフトウェアの開発.

金子生, 猪川和朗, 福原慶, 森川則文, 福永直子, 深水知英, 松元一明, 下堂薗権洋, 武田泰生, 山田勝士.

TDM研究 26 52 - 58 2009

Research paper (scientific journal), Joint Work, Accepted

A retrospective study of the relationship between high-dose methotrexate chemotherapy-related toxicity and concomitant drugs: non-steroidal anti-inflammatory drugs and sulfametoxazole.

Shibayama Yoshihiko, Sata Takuya, Furuno Yumiko, Motoya Toshiro, Matsumoto Kazuaki, Fukamizu Tomohide, Fukunaga Naoko, Shimodozono Yoshihiro, Takeda Yasuo, Yamada Katsushi

JOURNAL OF APPLIED THERAPEUTIC RESEARCH 7 11 - 14 2009

Research paper (scientific journal), Joint Work, Accepted

Relationship between methotrexate concentration in serum and half-life of methotrexate in high-dose methotrexate therapy: a retorospective study.

Shibayama Yoshihiko, Motoya Toshiro, Yoshikawa Yoshimi, Matsumoto Kazuaki, Fukamizu Tomohide, Fukunaga Naoko, Shimodozono Yoshihiro, Takeda Yasuo, Yamada, Katsushi.

JOURNAL OF APPLIED THERAPEUTIC RESEARCH 6 25 - 28 2008

Research paper (scientific journal), Joint Work, Accepted

alpha(1)-Acid glycoprotein suppresses rat acute inflammatory paw edema through the inhibition of neutrophils activation and prostaglandin E-2 generation.

Matsumoto Kazuaki, Nishi Koji, Kikuchi Mari, Kadowaki Daisuke, Tokutomi Yoshiko, Tokutomi Naofumi, Nishi Katsuhide, Suenaga Ayaka, Otagiri Masaki.

BIOLOGICAL & PHARMACEUTICAL BULLETIN 30 ( 7 ) 1226 - 1230 2007.07

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

A retrospective study of the relationship between methotrexate clearance and hyperuricemia following high-dose methotrexate therapy.

Shibayama Yoshihiko, Yoshikawa Yoshimi, Matsumoto Kazuaki, Shimodozono Yoshihiro, Miyagoe Taeko, Kurita Miho, Kusadome Chie, Yamaguchi Mariko, Nishi Yaeno, Motoya Toshiro, Takeda Yasuo, Yamada Katsushi.

JOURNAL OF APPLIED THERAPEUTIC RESEARCH 6 ( 1 ) 3 - 6 2006

Research paper (scientific journal), Joint Work, Accepted

テイコプラニン維持量設定ノモグラムの作成.

宮越妙子, 松元一明, 大磯茂, 下堂薗権洋, 武田泰生, 山田勝士.

日本病院薬剤師会雑誌 41 1267 - 1270 2005

Research paper (scientific journal), Joint Work, Accepted

Effects of alpha(1)-acid glycoprotein on isometric tension of mouse aorta.

Tokutomi Yoshiko, Okamoto Shigehiro, Matsumoto Kazuaki, Otagiri Masaki, Nishi Katsuhide, Tokutomi Naofumi.

EUROPEAN JOURNAL OF PHARMACOLOGY 477 ( 2 ) 137 - 141 2003.09

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

Effect of alpha(1)-acid glycoprotein on erythrocyte deformability and membrane stabilization.

Matsumoto Kazuaki, Nishi Katsuhide, Tokutomi Yoshiko, Irie Tetsumi, Suenaga Ayaka, Otagiri Masaki.

BIOLOGICAL & PHARMACEUTICAL BULLETIN 26 ( 1 ) 123 - 126 2003.01

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

α(1)-酸性糖蛋白質の血液循環系に及ぼす作用.

松元一明, 岡本茂洋, 徳冨芳子, 西勝英、丸山徹, 末永綾香, 小田切優樹.

人工血液 11 144 - 150 2003

Research paper (scientific journal), Joint Work, Accepted

Characterization of ligand binding sites on the alpha(1)-acid glycoprotein in humans, bovines and dogs.

Matsumoto Kazuaki, Sukimoto Katsuaki, Nishi Koji, Maruyama Toru, Suenaga Ayaka, Otagiri Masaki.

DRUG METABOLISM AND PHARMACOKINETICS 17 ( 4 ) 300 - 306 2002

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

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