研究者詳細 - 松元　一明

論文 - 松元　一明

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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年05月

共著, 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年04月

共著, 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年03月

共著, 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 <i>Staphylococcus aureus</i> 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年01月

研究論文（学術雑誌）, 共著, 査読有り, 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年01月

研究論文（学術雑誌）, 共著, 査読有り, 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年01月

研究論文（学術雑誌）, 共著, 査読有り, 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年01月

共著, 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 K., Samura M., Tashiro S., Shishido S., Saiki R., Takemura W., Misawa K., Liu X., Enoki Y., Taguchi K.

Biological & pharmaceutical bulletin （Biological & pharmaceutical bulletin） 45 （ 7 ） 824 - 833 2022年

共著, 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 N., Shinoda K., Yoshikawa G., Fukao E., Enoki Y., Taguchi K., Oda T., Tsutsumi K., Matsumoto K.

Biological & pharmaceutical bulletin （Biological & pharmaceutical bulletin） 45 （ 9 ） 1398 - 1402 2022年

共著, 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年12月

研究論文（学術雑誌）, 共著, 査読有り, 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年12月

研究論文（学術雑誌）, 共著, 査読有り, 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年12月

研究論文（学術雑誌）, 共著, 査読有り, 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年11月

研究論文（学術雑誌）, 共著, 査読有り, 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年11月

研究論文（学術雑誌）, 共著, 査読有り

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年11月

研究論文（学術雑誌）, 共著, 査読有り, 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年10月

研究論文（学術雑誌）, 共著, 査読有り, 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 <i>anti</i>-MRSA Activity and Its Chiral Discrimination.

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

Pharmaceuticals (Basel, Switzerland) （Pharmaceuticals） 14 （ 9 ） 2021年09月

研究論文（学術雑誌）, 共著, 査読有り, 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年08月

研究論文（学術雑誌）, 共著, 査読有り, 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年08月

研究論文（学術雑誌）, 共著, 査読有り, 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年08月

研究論文（学術雑誌）, 共著, 査読有り, 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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