研究者詳細 - 松元　一明

論文 - 松元　一明

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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年11月

共著, 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年11月

共著, 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年09月

共著, 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年09月

共著, 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年08月

共著, 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年08月

共著, 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 <i>Pseudomonas aeruginosa</i>: 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年07月

共著, 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年07月

共著, 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年07月

共著, 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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人口動態統計に基づいたセルフメディケーション税制に関する実態調査と課題抽出

田口和明, 榎木裕紀, 堀里子, 山浦克典, 松元一明

医療薬学（(一社)日本医療薬学会） 48 （ 7 ） 276 - 283 2022年07月

共著, ISSN 1346-342X

Webリサーチシステムを活用して、日本の人口動態に則した割付でセルフメディケーション税制(本税制)に関する無記名自己記入式質間紙調査を実施し、本税制を取り巻く実状と課題を調べた。2021年3月91日〜2021年3月11日に無記名自己記入式質問紙を配信し、国内在往の20〜89歳の男女3000人より回答を得た。医療用医薬品の常用薬を使用していた調査対象は43.6%(n=1307)であった。約75%がドラッグストアを1ヵ月間に1回以上利用していた。半数以上が本税制を認知しており、性別、年代で認知度に差はほとんどなかった。本税制を認知していた1621人に対して本税制の申請経験と理解度を調査した。その結果、これまでに本税制による所得控除を受けた割合は6.4%と医療費控除を受けた割合(28%)に比べて低かった。68.1%が本税制の申請要件のいずれか一つを申請要件と認識しており、4項目すべてが必要要件であることを認識していたのは6.0%とわずかであり、理解度に差があった。

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年06月

共著

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年06月

共著, 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年06月

共著, 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年05月

共著, 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年05月

共著, 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年05月

共著, 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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