研究者詳細 - 松元　一明

論文 - 松元　一明

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

Tashiro S, Taguchi K, Enoki Y, Matsumoto K

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases （Clinical Microbiology and Infection） 29 （ 5 ） 616 - 622 2022年12月

共著, ISSN 1198-743X

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

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

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

Journal of cachexia, sarcopenia and muscle （Journal of Cachexia, Sarcopenia and Muscle） 14 （ 1 ） 553 - 564 2022年12月

共著, ISSN 2190-5991

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

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

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

BMC pharmacology & toxicology （BMC Pharmacology and Toxicology） 23 （ 1 ） 89 2022年11月

共著

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

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

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

Shock (Augusta, Ga.) （Shock） 59 （ 3 ） 417 - 425 2022年11月

共著, ISSN 1073-2322

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

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

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

Clinical therapeutics （Clinical Therapeutics） 44 （ 12 ） 1604 - 1623 2022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

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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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