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Papers - Enoki, Yuki

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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

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 Yuto, Taguchi Kazuaki, Hanyu Satomi, Kure Tomoko, Enoki Yuki, Otagiri Masaki, Sakai Hiromi, Matsumoto Kazuaki

JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY (Journal of Drug Delivery Science and Technology) 71 2022.05

ISSN 1773-2247

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&amp;nbsp;aureus with Vancomycin Minimum Inhibitory Concentration &gt; 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 ) 2022.03

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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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

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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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 (MDPI AG) 14 ( 1 ) 57 - 57 2021.12

Research paper (scientific journal), 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 renoprotectant 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.

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 (Wiley) 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.

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 (Elsevier BV) 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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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 2021.12

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

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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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 (Oxford University Press (OUP)) 8 ( 12 ) ofab568 2021.12

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

Abstract

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 &lt;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 &lt;10% (low risk), 10%–&lt;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.

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 (Basel, Switzerland) (Journal of Fungi) 7 ( 11 ) 975 - 975 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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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 - 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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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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Advanced oxidation protein products contribute to chronic kidney disease-induced muscle atrophy by inducing oxidative stress via CD36/NADPH oxidase pathway.

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

Journal of cachexia, sarcopenia and muscle (Journal of Cachexia, Sarcopenia and Muscle) 12 ( 6 ) 1832 - 1847 2021.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 2190-5991

Background: Sarcopenia with chronic kidney disease (CKD) progression is associated with life prognosis. Oxidative stress has attracted interest as a trigger for causing CKD-related muscular atrophy. Advanced oxidation protein products (AOPPs), a uraemic toxin, are known to increase oxidative stress. However, the role of AOPPs on CKD-induced muscle atrophy remains unclear. Methods: In a retrospective case–control clinical study, we evaluated the relationship between serum AOPPs levels and muscle strength in haemodialysis patients with sarcopenia (n = 26, mean age ± SEM: 78.5 ± 1.4 years for male patients; n = 22, mean age ± SEM: 79.1 ± 1.5 for female patients), pre-sarcopenia (n = 12, mean age ± SEM: 73.8 ± 2.0 years for male patients; n = 4, mean age ± SEM: 74.3 ± 4.1 for female patients) or without sarcopenia (n = 12, mean age ± SEM: 71.3 ± 1.6 years for male patients; n = 7, mean age ± SEM: 77.7 ± 1.6 for female). The molecular mechanism responsible for the AOPPs-induced muscle atrophy was investigated by using 5/6-nephrectomized CKD mice, AOPPs-overloaded mice, and C2C12 mouse myoblast cells. Results: The haemodialysis patients with sarcopenia showed higher serum AOPPs levels as compared with the patients without sarcopenia. The serum AOPPs levels showed a negative correlation with grip strength (P < 0.01 for male patients, P < 0.01 for female patients) and skeletal muscle index (P < 0.01 for male patients). Serum AOPPs levels showed a positive correlation with cysteinylated albumin (Cys-albumin), a marker of oxidative stress (r2 = 0.398, P < 0.01). In the gastrocnemius of CKD mice, muscle AOPPs levels were also increased, and it showed a positive correlation with atrogin-1 (r2 = 0.538, P < 0.01) and myostatin expression (r2 = 0.421, P < 0.05), but a negative correlation with PGC-1α expression (r2 = 0.405, P < 0.05). Using C2C12 cells, AOPPs increased atrogin-1 and myostatin expression through the production of reactive oxygen species via CD36/NADPH oxidase pathway, and decreased myotube formation. AOPPs also induced mitochondrial dysfunction. In the AOPPs-overloaded mice showed that decreasing running time and hanging time accompanied by increasing AOPPs levels and decreasing cross-sectional area in gastrocnemius. Conclusions: Advanced oxidation protein products contribute to CKD-induced sarcopenia, suggesting that AOPPs or its downstream signalling pathway could be a therapeutic target for the treatment of CKD-induced sarcopenia. Serum AOPPs or Cys-albumin levels could be a new diagnostic marker for sarcopenia in CKD.

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 ) 938 - 938 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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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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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 Q2W. 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 due to 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 We demonstrated that nivolumab was rapidly eliminated from the circulation in chronic kidney disease model rats compared to 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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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 ) 596 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.

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。

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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