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Papers - Enoki, Yuki

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Methemoglobin-albumin clusters for cyanide detoxification

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

Toxicology and Applied Pharmacology 466 116472 2023.05

ISSN 0041008X

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

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

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

Journal of Antimicrobial Chemotherapy 78 ( 4 ) 991 - 999 2023.04

ISSN 03057453

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

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

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

British Journal of Clinical Pharmacology 89 ( 4 ) 1291 - 1303 2023.04

ISSN 03065251

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

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

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

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

ISSN 09186158

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

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

Tashiro S, Taguchi K, Enoki Y, Matsumoto K

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

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 (Wiley) 14 ( 1 ) 553 - 564 2022.12

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.

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 2022.12

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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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 23 ( 1 ) 89 2022.11

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.) (Ovid Technologies (Wolters Kluwer Health)) 59 ( 3 ) 417 - 425 2022.11

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.

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 40 ( 1 ) 187 - 196 2022.11

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 2022.11

ISSN 09248579

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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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 (Journal of Infection and Chemotherapy) 28 ( 11 ) 1536 - 1545 2022.11

ISSN 1341321X

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

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

BJS open (BJS open) 6 ( 5 ) 2022.09

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.

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 2022.09

ISSN 0041008X

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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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 (Journal of Controlled Release) 349 304 - 314 2022.09

ISSN 01683659

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

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

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 45 ( 9 ) 1398 - 1402 2022.09

ISSN 09186158

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.

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

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

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

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

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

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 45 ( 7 ) 824 - 833 2022.07

ISSN 09186158

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.

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

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

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

ISSN 1346-342X

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

Trimethoxy Trityl Groups as a Potent Substituent for Anti-cancer Cytidine Analog Prodrugs.

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

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

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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