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Papers - Enoki, Yuki

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Liposomal methemoglobin as a potent antidote for hydrogen sulfide poisoning

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

Toxicology and Applied Pharmacology (Elsevier BV) 450 116159 - 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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Influences of protein levels on the cerebrospinal fluid distribution of ceftazidime & ceftriaxone in the cerebrospinal fluid of patients with inflamed meningitis.

Ichinose N, Yoshikawa G, Fukao E, Takahata T, Ichisawa M, Enoki Y, Taguchi K, Oda T, Tsutsumi K, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 8 ) 1216 - 1219 2022.05

ISSN 1341-321X

Introduction: Ceftazidime and ceftriaxone are used to treat various gram-negative pathogens, such as Streptococcus pneumoniae and Pseudomonas aeruginosa, and have shown excellent therapeutic efficacy against bacterial meningitis. However, there is insufficient information on the pharmacokinetic characteristics of their cerebrospinal distribution. Here, we investigated the association of clinical laboratory data in cerebrospinal fluid with ceftazidime and ceftriaxone concentration in the cerebrospinal fluid of patients with inflamed meningitis. Methods: Cerebrospinal fluid samples were collected from eight adult patients with inflamed meningitis who intravenously received either ceftazidime or ceftriaxone (ceftazidime: a total of 25 samples from three patients, ceftriaxone: a total of 12 samples from five patients). Total cell number, protein concentration, and glucose concentration in the cerebrospinal fluid were retrospectively collected from electronic medical charts. All ceftazidime and ceftriaxone concentrations in the cerebrospinal fluid were determined using high-performance liquid chromatography. Results: Both ceftazidime and ceftriaxone concentrations in cerebrospinal fluid correlated with protein concentration in cerebrospinal fluid; however, no significant correlation was observed in total cell number and glucose concentration in cerebrospinal fluid. Conclusions: This is the first report on the relationship between the cerebrospinal distribution of these antibiotics and clinical laboratory data in cerebrospinal fluid of adult patients with meningitis.

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Oxidized liposomal artificial red blood cells rescue azide-poisoned mice from lethal toxidrome by recovering cytochrome c oxidase activity

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

Journal of Drug Delivery Science and Technology (Elsevier BV) 71 103282 - 103282 2022.05

ISSN 1773-2247

Exposure to azide compounds causes inhibition of cytochrome c oxidase in the mitochondria, leading to acute lethal poisoning. Although urgent pharmaceutical intervention is required for rescue from azide poisoning, no antidote exists worldwide. We hypothesized that methemoglobin (metHb) can be a promising material as an antidote for azide poisoning because metHb can strongly bind to azide. However, metHb administration is not feasible owing to in vivo instability and toxicity. We aimed to develop a feasible metHb-based antidote for azide poisoning, in which the inner hemoglobin of liposomal artificial red blood cells is oxidized by mixing with sodium nitrite. From the stopped-flow spectrophotometry analysis, as-prepared oxidized liposomal artificial red blood cells, which encapsulated metHb into the liposome (metHb@Lipo), the binding affinity of metHb@Lipo to azide was comparable to that of bare metHb. In addition, detoxification by metHb@Lipo increased the survival rate in lethal azide-poisoned model mice with recovery of cytochrome c oxidase activity, leading to the amelioration of acidosis and tissue oxidation. Furthermore, metHb@Lipo detoxification functioned even after 1 year of storage in a ready-to-use formulation. These results indicate that oxidized liposomal artificial red blood cells are a potent antidote for azide poisoning with favorable properties for use in critical care medicine.

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Efficacy and Safety of Daptomycin versus Vancomycin for Bacteremia Caused by Methicillin-Resistant Staphylococcus&nbsp;aureus with Vancomycin Minimum Inhibitory Concentration > 1 µg/mL: A Systematic Review and Meta-Analysis.

Masaru Samura, Yuki Kitahiro, Sho Tashiro, Hiromu Moriyama, Yuna Hamamura, Isamu Takahata, Rina Kawabe, Yuki Enoki, Kazuaki Taguchi, Yoshio Takesue, Kazuaki Matsumoto

Pharmaceutics (Pharmaceutics) 14 ( 4 ) 2022.03

ISSN 1999-4923

This systematic review and meta-analysis compares the efficacy of daptomycin and vancomycin in adult patients with bacteremia by methicillin-resistant Staphylococcus aureus (MRSA) with vancomycin minimum inhibitory concentration (MIC) > 1 µg/mL. We searched the PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov databases on 12 May 2020. All-cause mortality (primary outcome) and treatment success rates were compared and subgroups stratified by infection source risk level and method of vancomycin susceptibility testing were also analyzed. Seven studies (n = 907 patients) were included in this efficacy analysis. Compared with vancomycin, daptomycin treatment was associated with significantly lower mortality (six studies, odds ratio (OR) 0.53, 95% confidence interval (CI) 0.29-0.98) and higher treatment success (six studies, OR 2.20, 95% CI 1.63-2.96), which was consistent regardless of the vancomycin MIC test method used. For intermediate-risk sources, daptomycin was a factor increasing treatment success compared with vancomycin (OR 4.40, 95% CI 2.06-9.40), and it exhibited a trend toward a higher treatment success rate for high-risk sources. In conclusion, daptomycin should be considered for the treatment of bacteremia caused by MRSA with vancomycin MIC > 1 µg/mL, especially in patients with intermediate- and high-risk bacteremia sources.

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Neurotoxicity associated with colistin methanesulfonate treatment is enhanced by concomitant sevoflurane inhalation

Gotoda M., Enoki Y., Shishido S., Taguchi K., Matsumoto K.

Toxicology Reports (Toxicology Reports) 9 1255 - 1260 2022.01

ISSN 22147500

Colistin methanesulfonate (CMS) is a cyclic polypeptide antibiotic with neurotoxic side effects. Sevoflurane (Sevo), an inhaled anesthetic, is known to enhance the non-depolarizing effect of neuromuscular relaxants; however, its mechanism of action is unclear. In this study, we investigated the augmentation effect of Sevo on CMS-induced neurotoxicity. We prepared a sciatic nerve-skeletal muscle stimulation model using Sprague-Dawley male rats administered CMS with or without Sevo. The muscle contraction inhibition rate was determined from electromyogram measurements. Furthermore, we simulated the pharmacokinetics of CMS and colistin using previous reports, and the relationship between the effect of muscle contraction inhibition and pharmacokinetic parameters was evaluated. We observed a dose-dependent neuromuscular inhibitory effect of Sevo under CMS administration. The 50 % inhibitory dose (ID50) values for CMS and CMS+Sevo were 167 ± 12 and 85 ± 5 mg/kg, respectively. The combination of CMS with Sevo showed a 49 % decrease in the ID50 compared with CMS alone. The simulated area under the time–concentration curve (AUC) values for CMS and colistin administration in rats at 200 mg/kg were 219 and 16.0 mg·h/L, respectively. The predicted AUC values of colistin corresponding to the ID50 at 0–45 min for CMS alone and CMS+Sevo were 12.0 and 7.0 mg·h/L, respectively. We revealed that the neurotoxic effect of CMS was enhanced by the concomitant use of Sevo. Based on the simulated AUC values, we concluded that this neurotoxic effect may also occur in clinical settings, and concomitant use of CMS and Sevo should be avoided.

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Liposomal Artificial Red Blood Cell-Based Carbon Monoxide Donor Is a Potent Renoprotectant against Cisplatin-Induced Acute Kidney Injury.

Taguchi K, Suzuki Y, Tsutsuura M, Hiraoka K, Watabe Y, Enoki Y, Otagiri M, Sakai H, Matsumoto K

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

Research paper (scientific journal), Accepted, ISSN 1999-4923

Cisplatin (CDDP) is an essential anti-tumor agent for chemotherapeutic regimens against various types of cancer. However, the progression of nephrotoxicity, which is the main adverse effect of CDDP, leads to discontinuation of CDDP chemotherapy. Therefore, development of a renoprotectant against CDDP-induced nephrotoxicity is crucial. Here, the potential of a carbon monoxide (CO)-loaded hemoglobin-vesicle (CO-HbV) as a renoprotectant for CDDP-induced nephrotoxicity was evaluated for its renoprotective effects against CDDP-induced nephrotoxicity, inhibitory effects on the anti-tumor activity of CDDP, and anti-tumor activity. In healthy mice, after pretreatment with either saline, HbV, or CO-HbV prior to CDDP administration, only the CO-HbV pretreatment group ameliorated the progression of CDDP-induced nephrotoxicity by suppressing apoptosis via caspase-3. In experiments using B16-F10 melanoma cells, the half-maximal inhibitory concentration of CDDP decreased with co-incubation with CO-HbV, owing to the anti-tumor activity of CO. CO-HbV pretreatment had no impact on the anti-tumor activity of CDDP in B16-F10 melanoma cell-bearing mice, which was consistent with the results of the cell experiment. Furthermore, CO-HbV pretreatment improved body growth and survival rates. In conclusion, CO-HbV pretreatment is a potent renoprotectant for CDDP-induced nephrotoxicity, allowing treatment with CDDP to be conducted without failure of cancer treatment.

Incidence of elevated creatine phosphokinase between daptomycin alone and concomitant daptomycin and statins: A systematic review and meta-analysis.

Samura M, Takada K, Hirose N, Kurata T, Nagumo F, Koshioka S, Ishii J, Uchida M, Inoue J, Enoki Y, Taguchi K, Tanikawa K, Matsumoto K

British journal of clinical pharmacology (Wiley) 88 ( 5 ) 1985 - 1998 2021.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0306-5251

Aims

The present systematic review and meta‐analysis evaluated the incidence of elevated creatine phosphokinase (CPK) levels between daptomycin alone and concomitant daptomycin and statin use.

Methods

We searched the PubMed, Web of Sciences, Cochrane Library and ClinicalTrials.gov databases. We analysed the incidence of elevated CPK between daptomycin alone and concomitant daptomycin and statins among studies defining CPK elevation as levels ≥ the upper limit of normal (ULN) or ≥5× ULN. We also analysed the incidence of rhabdomyolysis between the groups. We then calculated the odds ratios (ORs) and 95% confidence intervals (CIs) based on the included studies.

Results

Comparing CPK elevation defined as CPK levels ≥ULN, a significantly higher incidence of CPK elevation was observed with concomitant daptomycin and statin use than with daptomycin alone (OR = 2.55, 95% CI 1.78–3.64, P < .00001, I2 = 0%). Likewise, when CPK elevation was defined as CPK levels ≥5× ULN, a significantly higher incidence of CPK elevation was detected with concomitant daptomycin and statin use than with daptomycin alone (OR = 1.89, 95% CI 1.06–3.35, P = .03, I2 = 48%). The incidence of rhabdomyolysis was significantly higher following concomitant daptomycin and statin use than with daptomycin alone (OR = 11.60, 95% CI 1.81–74.37, P = .01, I2 = 0%).

Conclusion

The combined use of daptomycin and statins were significant risk factors for the incidence of CPK elevation defined as levels ≥ULN or ≥5× ULN and rhabdomyolysis.

Bioinspired carbon monoxide delivery using artificial blood attenuates the progression of obliterative bronchiolitis via suppression of macrophage activation by IL-17A.

Watabe Y, Taguchi K, Sakai H, Enoki Y, Maruyama T, Otagiri M, Kohno M, Matsumoto K

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V (Elsevier BV) 170 43 - 51 2021.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0939-6411

Carbon monoxide (CO) is expected to attenuate the progression of obliterative bronchiolitis (OB), which is a serious complication after lung transplantation. However, issues in terms of feasible exogenous CO supply, such as continuousness and safety, remain unsolved. Here, we applied nano red blood cells, namely hemoglobin vesicles (Hb-V), as a CO cargo based on the biomimetic concept and investigated the therapeutic potential of CO-loaded Hb-V on OB in orthotopic tracheal transplant model mice. The CO-loaded Hb-V was comprised of negatively charged liposomes encapsulating carbonylhemoglobin with a size of ca. 220 nm. The results of histological evaluation showed that allograft luminal occlusion and fibrosis were significantly ameliorated by treatment with CO-loaded Hb-V compared to treatment with saline, cyclosporine, and Hb-V. The therapeutic effects of CO-loaded Hb-V on OB were due to the suppression of M1 macrophage activation in tracheal allografts, resulting from decreased IL-17A production. Furthermore, the expression of TNF-α and TGF-β in tracheal allografts was decreased by CO-loaded Hb-V treatment but not saline and Hb-V treatment, indicating that CO liberated from CO-loaded Hb-V inhibits epithelial-mesenchymal transition. These findings suggest that CO-loaded Hb-V exerts strong therapeutic efficacy against OB via the regulation of macrophage activation by IL-17A and TGF-β-driven epithelial-mesenchymal transition.

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Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments.

Takemura W, Tashiro S, Hayashi M, Igarashi Y, Liu X, Mizukami Y, Kojima N, Morita T, Enoki Y, Taguchi K, Yokoyama Y, Nakamura T, Matsumoto K

Pharmaceutical research (Pharmaceutical Research) 38 ( 11 ) 1839 - 1846 2021.12

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

Purpose: Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. Methods: The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. Results: The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. Conclusion: CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve “fT>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.

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Identification of Risk Factors for Daptomycin-Associated Creatine Phosphokinase Elevation and Development of a Risk Prediction Model for Incidence Probability.

Samura M, Hirose N, Kurata T, Takada K, Nagumo F, Koshioka S, Ishii J, Uchida M, Inoue J, Enoki Y, Taguchi K, Higashita R, Kunika N, Tanikawa K, Matsumoto K

Open forum infectious diseases (Oxford University Press (OUP)) 8 ( 12 ) ofab568 2021.12

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

Abstract

Background

In this study, we investigated the risk factors for daptomycin-associated creatine phosphokinase (CPK) elevation and established a risk score for CPK elevation.

Methods

Patients who received daptomycin at our hospital were classified into the non-elevated or elevated CPK group based on their peak CPK levels during daptomycin therapy. Univariable and multivariable analyses were performed, and a risk score and prediction model for the incidence probability of CPK elevation were calculated based on logistic regression analysis.

Results

The non-elevated and elevated CPK groups included 181 and 17 patients, respectively. Logistic regression analysis revealed that concomitant statin use (odds ratio [OR], 4.45 [95% confidence interval {CI}, 1.40–14.47]; risk score 4), concomitant antihistamine use (OR, 5.66 [95% CI, 1.58–20.75]; risk score 4), and trough concentration (Cmin) between 20 and &lt;30 µg/mL (OR, 14.48 [95% CI, 2.90–87.13]; risk score 5) and ≥30.0 µg/mL (OR, 24.64 [95% CI, 3.21–204.53]; risk score 5) were risk factors for daptomycin-associated CPK elevation. The predicted incidence probabilities of CPK elevation were &lt;10% (low risk), 10%–&lt;25% (moderate risk), and ≥25% (high risk) with total risk scores of ≤4, 5–6, and ≥8, respectively. The risk prediction model exhibited a good fit (area under the receiver operating characteristic curve, 0.85 [95% CI, .74–.95]).

Conclusions

These results suggested that concomitant use of statins with antihistamines and Cmin ≥20 µg/mL were risk factors for daptomycin-associated CPK elevation. Our prediction model might aid in reducing the incidence of daptomycin-associated CPK elevation.

Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy.

Sakamoto Y, Isono H, Enoki Y, Taguchi K, Miyazaki T, Kunimoto H, Koike H, Hagihara M, Matsumoto K, Nakajima H, Sahashi Y, Matsumoto K

Journal of fungi (Basel, Switzerland) (Journal of Fungi) 7 ( 11 ) 975 - 975 2021.11

Research paper (scientific journal), Joint Work, Accepted

We conducted population pharmacokinetic (PPK) analysis and Monte Carlo simulations to determine the appropriate prophylactic dose of fluconazole to prevent invasive candidiasis in patients with hematological malignancies. Patients receiving chemotherapy or hematopoietic stem cell transplantation at Yokohama City University Hospital between November 2018 and March 2020 were included. Additionally, patients receiving oral fluconazole for prophylaxis were recruited. We set the free area under the curve/minimum inhibitory concentration (MIC) = 50 as the target and determined the largest MIC (breakpoint MIC) that could achieve more than 90% probability of target attainment. The blood fluconazole concentration of 54 patients (119 points) was used for PPK analysis. The optimal model was the one-compartment model with first-order administration and first-order elimination incorporating creatinine clearance (CLcr) as a covariate of clearance and body weight as a covariate of distribution volume. We conducted Monte Carlo simulation with fluconazole at 200 mg/day or 400 mg/day dosing schedules and patient body weight and CLcr ranging from 40 to 70 kg and 40–140 mL/min, respectively. The breakpoint MICs on the first dosing day and at steady state were 0.5–1.0 µg/mL and 1.0–2.0 µg/mL for 200 mg/day and 1.0–2.0 µg/mL and 2.0–4.0 µg/mL for 400 mg/day, respectively. The recommended dose was 400–700 mg/day for the loading dose and 200–400 mg/day for the maintenance dose. Our findings suggest that the optimal prophylactic dose of fluconazole in hematological malignancy patients depends on CLcr and body weight, and a sufficient loading and maintenance dose may be needed to completely prevent invasive candidiasis.

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Long-term pharmaceutical stability of liposome-encapsulated methemoglobin as an antidote for cyanide poisoning.

Suzuki Y, Taguchi K, Kure T, Enoki Y, Otagiri M, Sakai H, Matsumoto K

International journal of pharmaceutics (International Journal of Pharmaceutics) 610 121260 - 121260 2021.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0378-5173

Liposome-encapsulated methemoglobin (metHb@Lipo) has been developed as a novel antidote for cyanide poisoning. Antidotes for lethal acute poisoning should be capable of being easily stored as ready-to-use formulations without temperature restrictions. Here, we investigated the pharmaceutical stability of the metHb@Lipo suspension after one-year storage as a ready-to-use formulation at 4 °C, room temperature (23–28 °C) and 37 °C. The liposomal integrity of metHb@Lipo was observed after one year of storage at all storage temperatures with no physicochemical change or methemoglobin leakage outside the liposome. Furthermore, the encapsulated methemoglobin remained intact without aggregation, fragmentation, denaturation, or dissociation of heme. Fresh and stored metHb@Lipo were equivalent in their binding affinity against cyanide. Moreover, all one-year stored metHb@Lipo suspensions improved the mortality rates of lethal cyanide poisoning mice comparable to fresh metHb@Lipo suspension. Additionally, all stored metHb@Lipo suspensions preserved high biocompatibility, including blood compatibility and the lack of organ toxicity. In conclusion, the metHb@Lipo suspension was a pharmaceutically stable antidote for cyanide poisoning for at least one year without any temperature restrictions.

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Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection.

Iketani O, Komeya A, Enoki Y, Taguchi K, Uno S, Uwamino Y, Matsumoto K, Kizu J, Hasegawa N

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (Journal of Infection and Chemotherapy) 28 ( 1 ) 61 - 66 2021.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1341-321X

Introduction: Clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hydroxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy. Methods: CAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated. Results: Median area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4–1.8) μg·h/mL vs. 21.5 (IQR, 17.7–32.3) μg·h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9–10.9) μg·h/mL] and CAM monotherapy [8.2 (IQR, 6.3–9.3) μg·h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy. Conclusions: When RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.

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Advanced oxidation protein products contribute to chronic kidney disease-induced muscle atrophy by inducing oxidative stress via CD36/NADPH oxidase pathway.

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

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

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

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

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