研究者詳細 - 松元　一明

論文 - 松元　一明

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Carbon monoxide rescues the developmental lethality of experimental rat models of rhabdomyolysis-induced acute kidney injury

Taguchi K., Ogaki S., Nagasaki T., Yanagisawa H., Nishida K., Maeda H., Enoki Y., Matsumoto K., Sekijima H., Ooi K., Ishima Y., Watanabe H., Fukagawa M., Otagiri M., Maruyama T.

Journal of Pharmacology and Experimental Therapeutics （Journal of Pharmacology and Experimental Therapeutics） 372 （ 3 ） 355 - 365 2020年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00223565

© 2020 by The American Society for Pharmacology and Experimental Therapeutics Many victims, after being extricated from a collapsed building as the result of a disaster, suffer from disaster nephrology, a term that is referred to as the crush syndrome (CS). Recommended treatments, which include dialysis or the continuous administration of massive amounts of fluid are not usually easy in cases of such mass natural disasters. In the present study, we examined the therapeutic performance of a biomimetic carbon monoxide (CO) delivery system, CO-enriched red blood cells (CO-RBCs), on experimental animal models of an acute kidney injury (AKI) induced by traumatic and nontraumatic rhabdomyolysis, including CS and rhabdomyolysis with massive hemorrhage shock. A single CO-RBC treatment was found to effectively suppress the pathogenesis of AKI with the mortality in these model rats being improved. In addition, in further studies using glycerol-induced rhabdomyolysis model rats, the pathogenesis of which is similar to that for the CS, AKI and mortality were also reduced as the result of a CO-RBC treatment. Furthermore, CO-RBCs were found to have renoprotective effects via the suppression of subsequent heme protein-associated renal oxidative injury; the oxidation of myoglobin in the kidneys, the generation of reactive oxygen species by free heme produced from degraded-cytochrome P450 and hemoglobin-associated renal injury. Because CO-RBCs can be prepared and used at both hospitals and at a disaster site, these findings suggest that CO-RBCs have the potential for use as a novel cell therapy against both nontraumatic and traumatic rhabdomyolysis including CS-induced AKI.

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ヘモグロビンの生理活性ガス運搬能を利用した創薬戦略

田口和明, 松元一明, 丸山徹, 小田切優樹.

Yakugaku Zasshi （Yakugaku Zasshi） 140 （ 2 ） 141 - 146 2020年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00316903

© 2020 The Pharmaceutical Society of Japan. Bioactive gas molecules, including oxygen, nitric oxide and carbon monoxide (CO), exhibit a variety of physiological activities, and are associated with the onset and progress of some disorders. These facts have led researchers to the development of bioactive gas donors for the treatment of intractable disorders. Hemoglobin is likely an ideal carrier of bioactive gases, since hemoglobin in red blood cells innately carries oxygen in the form of oxyhemoglobin, nitric oxide in the form of S-nitrosohemoglobin, and CO in the form of carbonylhemoglobin. In this study, we attempted to develop a biomimetic CO delivery system using a preparation of hemoglobin. Our strategy for the preparation of this hemoglobin-based CO carrier involves CO being exogenously bound to red blood cells or hemoglobin-encapsulated liposomes, called hemoglobin-vesicles (HbV), which mimic the structure and function of red blood cells. We accumulated evidence that the CO donors-CO-bound red blood cells and CO-bound HbV-showed therapeutic efficacy against intractable disorders in animal models. Here, we describe the potential of hemoglobin-based CO donors, especially CO-bound red blood cells and CO-bound HbV, for the treatment of certain disorders. Hemoglobin-based strategies for the delivery of other bioactive gases for novel drug development are also discussed.

Azoles versus conventional amphotericin B for the treatment of candidemia: A meta-analysis of randomized controlled trials

Osa S., Tashiro S., Igarashi Y., Watabe Y., Liu X., Enoki Y., Taguchi K., Mayumi T., Miyazaki Y., Takesue Y., Matsumoto K.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 26 （ 11 ） 1232 - 1236 2020年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341321X

© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Because exclusive use of echinocandins can induce the drug-resistant strains, appropriate use of azoles and polyenes is still necessary in the treatment of candidemia. In this study, we conducted a meta-analysis of randomized controlled trials regarding the efficacy and safety of azole and polyene antifungals in the treatment of candidemia. MEDLINE and the Cochrane Register of Controlled Trials were used as reference databases, and papers published up to June 10, 2019 were searched. The search results were carefully scrutinized, duplicate references were removed, and the study was ultimately carried out using three reports. Among azole antifungals, fluconazole and voriconazole were extracted, however; only conventional amphotericin B (AMPH-B) was extracted among polyene antifungals. Treatment successes with the use of azoles and AMPH-B were compared, and findings showed that AMPH-B was significantly superior (RR = 0.90, 95% CI 0.82–1.00, p = 0.04). However, there was no significant difference in mortality (RR = 0.87, 95% CI 0.72–1.07, p = 0.19). Analysis of adverse events showed that renal disorders were significantly less common with azoles than with AMPH-B (RR = 0.26, 95% CI 0.10–0.68, p = 0.006). In conclusion, AMPH-B were superior to azoles in terms of efficacy, but had a risk of causing renal disorders.

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Echinocandins versus non-echinocandins for the treatment of invasive candidiasis: A meta-analysis of randomized controlled trials

Tashiro S., Osa S., Igarashi Y., Watabe Y., Liu X., Enoki Y., Taguchi K., Mayumi T., Miyazaki Y., Takesue Y., Matsumoto K.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 26 （ 11 ） 1164 - 1176 2020年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341321X

© 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Introduction: Echinocandins are frequent use antifungals in the treatment of invasive candidiasis, and it is important to update information on their efficacy and safety for optimal antifungal drug treatment. The aim of this study is to clarify whether echinocandins are superior to non-echinocandins for the treatment of invasive candidiasis. Methods: We conducted a meta-analysis of RCTs of echinocandins and non-echinocandins for adult invasive candidiasis. The MEDLINE, Web of Sciences, Cochrane Register of Controlled Trials, and ClinicalTrials.gov databases before June 2019 were used. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel method random-effects model. Results: We identified 14,846 articles and screened, and five studies were included meta-analysis. The treatment success ratio for echinocandins was significantly higher than that for non-echinocandins (RR = 1.14, 95% CI 1.06–1.22, p = 0.0003). In regard to adverse events, there was no significant difference between the two treatment groups. A subgroup analysis showed that the treatment success ratio for echinocandins was significantly higher than that for azoles (RR = 1.20, 1.08–1.34, p = 0.001), whereas no significant differences were observed between echinocandins and polyenes. In safety analysis, the incidence ratio of electrolyte disorder (RR = 0.50, 0.33–0.76, p = 0.001), renal disorder (RR = 0.19, 0.09–0.40, p < 0.0001), and fever (RR = 0.46, 0.23–0.93, p = 0.03) were significantly lower in patients receiving echinocandins than in those receiving polyenes. Conclusions: This meta-analysis based on RCTs was first to show that use of echinocandins was associated with improved clinical success. Echinocandins may be useful as a first-line drug for invasive candidiasis.

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Characterization of Bovine Lactoferrin Nanoparticle Prepared by Desolvation Technique.

Taguchi K, Chuang VTG, Hashimoto M, Nakayama M, Sakuragi M, Enoki Y, Nishi K, Matsumoto K, Seo H, Otagiri M, Yamasaki K

Chemical & pharmaceutical bulletin （Chemical and Pharmaceutical Bulletin） 68 （ 8 ） 766 - 772 2020年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-2363

© 2020 The Pharmaceutical Society of Japan Lactoferrin (Lf) nanoparticles have been developed as a carrier of drugs and gene. Two main methods, desolvation technique and emulsification method, for preparation of protein nanoparticles have been reported so far, but most of the previous reports of Lf nanoparticles preparation are limited to emulsification method. In this study, we investigated the optimal conditions by desolvation technique for the preparation of glutaraldehyde-crosslinked bovine Lf (bLf) nanoparticles within the size range of 100–200nm, and evaluated their properties as a carrier for oral and intravenous drug delivery. The experimental results of dynamic light scattering and Transmission Electron Microscope suggested that glutaraldehyde-crosslinked bLf nanoparticles with 150nm in size could be produced by addition of 2-propanol as the desolvating solvent into the bLf solution adjusted to pH 6, followed by crosslinking with glutaraldehyde. These cross-linked bLf nanoparticles were found to be compatible to blood components and resistant against rapid degradation by pepsin. Thus, cross-linked bLf nanoparticles prepared by desolvation technique can be applied as a drug carrier for intravenous administration and oral delivery.

Factorial Analysis of Clostridioides Difficile Colitis and Pseudomembranous Colitis Using JADER

Takaya Risako, Misawa Kana, Tashiro Sho, Enoki Yuki, Taguchi Kazuaki, Matsumoto Kazuaki

BPB Reports （公益社団法人日本薬学会） 3 （ 1 ） 1 - 6 2020年

研究論文（学術雑誌）, 共著, 査読有り

Clostridioides difficile (C. difficile) colitis and pseudomembranous colitis are known as healthcare-associated intestinal infections. In this study, the incidence of C. difficile colitis and pseudomembranous colitis was investigated using the Japanese Adverse Drug Event Report (JADER). Using JADER data between April 2004 and September 2017, the patient who developed C. difficile colitis and pseudomembranous colitis were investigated. During the study period, 375 cases of C. difficile colitis and 903 cases of pseudomembranous colitis were reported. The numbers of reported cases of both C. difficile colitis and pseudomembranous colitis were largest in those in their 70s, accounting for 24.7% and 25.6%, respectively. Patients in their 60s-90s comprised the majority of all patients with both C. difficile colitis and pseudomembranous colitis. Both C. difficile colitis and pseudomembranous colitis were caused by antibiotics in many patients, and signals of all antibiotics were detected. In C. difficile colitis, signals of immunosuppressants, corticosteroids, and alkylating drugs were also detected among drugs other than antibiotics. For pseudomembranous colitis, the use of molecularly targeted drugs, antimetabolic drugs, and corticosteroids was reported other than antibiotics. Using JADER, we revealed risk factors for the development of C. difficile colitis and pseudomembranous colitis, and firstly revealed that molecularly targeted drugs other than antibiotics could also be potential risk factors. Our findings may be useful for the early detection of drug-induced C. difficile colitis and pseudomembranous colitis.

フルコナゾールの血中濃度が定常状態に達するまでに時間を要した移植後患者の一例

坂本靖宜, 磯野ひかる, 小池博文, 榎木裕紀, 田口和明, 萩原真紀, 松本憲二, 中島秀明, 佐橋幸子, 松元一明

日本薬理学会年会要旨集（公益社団法人日本薬理学会） 93 （ 0 ） 2-O-036 2020年

共著

[Introduction]Fluconazole is anti-fungal agent widely used to prophylaxis and treatment. In the ECIL6 Guidelines, it is recommended that the dose of FLCZ for treatment should be established as ≥10 to 15 mg/mL, which is a trough level. We report a patient in whom a specific interval was required until the blood concentration of FLCZ reached a steady state.[Case]The patient was a 50-year-old male. To treat acute lymphocytic leukemia, remission induction and consolidation therapies were performed. After remission was achieved, umbilical cord blood transplantation was conducted. On Day 18, graft survival was confirmed. A blood culture test on Day 27 detected yeast-like fungus. Micafungin (MCFG) at 150 mg, used for empiric therapy, was switched to liposomal amphotericin B (L-AMB) at 3 mg/kg. On Day 36, renal hypofunction was noted, and L-AMB was switched to MCFG at 150 mg. On Day 65, there was a decrease in the β-D-glucan level from ≥600 to 375.2 pg/mL, and MCFG at 150 mg was switched to FLCZ at 200 mg. On Day 71, the trough level of FLCZ was 21.0 mg/mL, and its concentration 2 hours after administration was 24.4 mg/mL. The β-D-glucan level was 232.1 pg/mL. On Day 79, the trough and 2-hour levels of FLCZ were 30.6 and 32.1 mg/mL, respectively, and the β-D-glucan level was 167.6 pg/mL. On Day 85, the trough level of FLCZ was 38.4 mg/mL, and the β-D-glucan level was 161.4 pg/mL. Subsequently, blood culture was negative, and FLCZ administration was continued until Day 229. During the administration period, the creatinine clearance ranged from 33.0 to 45.9 mL/min.[Discussion]The half-life of FLCZ is approximately 30 hours. Its clearance depends on the renal function. In the present case, a target trough level was achieved in the early phase, but the blood concentration of FLCZ increased with the prolongation of the administration period. Therefore, the appearance of central nervous toxicity must be considered. In the future, it may be necessary to establish individualized, optimized FLCZ dosimetry in accordance with the renal function for the optimal use of FLCZ.

ヘパリン類似物質含有製剤の選択に有用な情報構築に関する検討.

石渡涼子，榎木裕紀，横山雄太，田口和明, 木津純子, 松元一明.

日本老年薬学会雑誌（(一社)日本老年薬学会） 2 （ 2 ） 19 - 26 2019年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2433-4065

保湿剤として臨床現場で汎用されているヘパリン類似物質ソフト軟膏5銘柄(A、B、C、D、E)とクリーム6銘柄(F、G、H、I、J、K)を用いて、患者に適した薬剤を選択する際に役立つ情報を構築するために、製剤学的特性(展延性、稠度)、使用感および角質水分量の変化に関する研究を行った。ソフト軟膏ではAの延びが最も低く、最も軟らかい製剤はEであった。クリーム製剤ではFの延びが最も低く、最も硬い製剤はFであった。ソフト軟膏製剤間の使用感比較では、最も使いやすいとされた製剤、使いにくいとされた製剤はいずれもDであり、クリーム製剤では最も使いやすいとされたのはJ、最も使いにくいとされたのはHであった。ソフト軟膏塗布後の角質水分量の変化量に関して銘柄間で差はみられず、クリーム製剤では銘柄Fが銘柄JおよびKと比較して有意に角質水分量の増加がみられた。

Support for fungal infection treatment mediated by pharmacist-led antifungal stewardship activities

Samura M., Hirose N., Kurata T., Ishii J., Nagumo F., Takada K., Koshioka S., Uchida M., Yamamoto S., Inoue J., Enoki Y., Taguchi K., Ishida A., Sekine H., Kunika N., Kunishima H., Matsumoto K.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 26 （ 3 ） 272 - 279 2019年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341321X

© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Objective: At the Yokohama General Hospital, pharmacist-led antimicrobial stewardship programs (ASP) including antifungal stewardship programs (AFP) were started in 2012. To investigate the efficacy of the programs, we compared several parameters that are recommended for the measurement of ASP in Japan based on pre- and post-AFP activities. Patients and methods: The subjects were inpatients who developed candidemia between April 2008 and March 2016. They were divided into two groups: pre-AFP (April 2008 until March 2012) and post-AFP (April 2012 until March 2016). The results were compared between the two groups. Results: The cumulative optimal antifungal drug usage rate, as a process parameter, significantly increased in the post-AFP group (p = 0.025). Furthermore, the days of therapy of antifungal drugs in the pre- and post-AFP groups was median 6.0 (interquartile range [IQR] 0.3–15.7) and median 3.4 (IQR 1.9–3.4) per 1,000 patient-days, respectively; there was a significant decrease in the post-AFP group (p < 0.001). Expenditure on antifungal drugs, as an outcome parameter, in the pre- and post-AFP groups was 9390.5 ± 5687.1 and 5930.8 ± 4687.0 US dollars, respectively; there was a significant decrease in the post-AFP group (p = 0.002). Conclusions: These results suggest that pharmacist-led antifungal stewardship activities improve both outcome and process parameters.

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Evaluation of the expression time of ganciclovir-induced adverse events using JADER and FAERS

Ando G., Taguchi K., Enoki Y., Yokoyama Y., Kizu J., Matsumoto K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 42 （ 11 ） 1799 - 1804 2019年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09186158

© 2019 The Pharmaceutical Society of Japan. Investigation of the occurrence time of adverse drug reactions helps to prevent the development and aggravation of adverse reactions, but the expression time of ganciclovir-induced adverse events has not been elucidated. In this study, using databases of spontaneous adverse event reports, the Japanese Adverse Drug Event Report database (JADER) and the U.S. Food and Drug Administration (FDA)'s Adverse Event Reporting System (FAERS), the incidence of adverse reactions due to ganciclovir and their expression time were analyzed. As a result of calculation of the reporting odds ratio (ROR) and 95% confidence interval for individual main adverse reactions of ganciclovir (cytopenia, leukopenia, thrombocytopenia, liver damage, and acute renal failure), a signal was detected for all adverse reactions in both databases, except for liver damage in JADER. Furthermore, the Weibull distribution was performed for the analysis of onset time of each ganciclovir-induced adverse event. The results of Weibull parameter α and β values of each adverse event in both JADER and FAERS suggested that most adverse events occurred within 30 d and classified into the early failure type, except that thrombocytopenia and acute renal failure in JADER classified into the random failure type. Based on these findings, it concluded that the paying attention to signs of each ganciclovirinduced adverse event is required from the early phase after ganciclovir administration. However, in FAERS, development after a long-term course also accounted for 11%, suggesting that long-term periodic monitoring of adverse reactions would be also required.

Evaluation for optimal dosing of vancomycin in patients with different physical types

Hashimoto M., Iketani O., Ichinose N., Enoki Y., Taguchi K., Uno S., Uwamino Y., Hasegawa N., Matsumoto K.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 25 （ 9 ） 735 - 737 2019年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341321X

© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases The sufficient dose to obtain an optimal trough concentration of vancomycin (VCM) in patients with non-standard physical types remains controversial. In this study, we examined the relationship between the dose and physical type in patients in whom an optimal trough concentration was obtained among VCM-treated patients. We retrospectively investigated the dose of VCM and physical type in patients treated with VCM between January 2012 and January 2017 at two medical institutions (n = 272). The physical type was classified using the body mass index (BMI). Patients with a BMI of <18.5 kg/m 2 were assigned to the lean group, those with a BMI of 18.5–24.9 kg/m 2 were assigned to the standard group, and those with a BMI of ≥25 kg/m 2 were assigned to the obesity group. The mean doses of VCM per time (mg/kg) to achieve the target trough concentration of VCM, 15–20 μg/mL, were 19.8 ± 4.3, 16.5 ± 3.7, and 13.7 ± 2.7 mg/kg in the lean, standard, and obesity groups, respectively. The dose per time to achieve the target trough concentration decreased significantly in association with an increase of BMI. The upper limit of the recommended dose (15–20 mg/kg) or higher in lean patients, and the lower dose in obese patients than the recommended dose might be appropriate to achieve the target trough concentration when we calculated the dose per time based on actual body weight.

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Experimental verification of factors influencing calcium salt formation based on a survey of the development of ceftriaxone-induced gallstone-related disorder

Ito R., Yoshida A., Taguchi K., Enoki Y., Yokoyama Y., Matsumoto K.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 25 （ 12 ） 972 - 978 2019年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341321X

© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Ceftriaxone (CTRX) forms salts with calcium (Ca) in the gall bladder and bile duct, and induces the formation of gallstones. In this study, factors of CTRX-induced gallstone formation were extracted from the results of a retrospective survey using the Japanese Adverse Drug Event Report (JADER), and the causal relationship between the factors and gallstone formation was investigated. From JADER, 136 patients who developed ‘gallstone-related disorder’ with CTRX as a suspected drug were extracted. The incidence of gallstone-induced adverse effects was high in patients treated with CTRX at a dose exceeding the normal daily dose and in children younger than 10 years old, suggesting that CTRX at a high level is a factor for gallstone formation. Thus, after mixing CTRX and Ca2+ at different concentrations under different pH condition, the number of particles in the solutions was measured using a Coulter counter. As a result, the number of minute particles significantly increased at all pH values when Ca2+ and CTRX were mixed at a concentration of 10 mEq/L or higher and 1.5 g/L or higher, respectively. At pH 6.5 or 7.0, visible crystals were detected when 25 mEq/L of Ca2+ and 2.0 g/L of CTRX were mixed. Based on these findings, attention should be sufficiently paid to the development of ‘gallstone-related disorder’ in pediatric patients and in patients treated with CTRX at a dose exceeding the normal dose. Furthermore, gallstone formation and growth may be promoted when CTRX and Ca2+ coexist at high concentrations under low pH conditions.

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Age-associated theophylline metabolic activity corresponds to the ratio of 1,3-dimethyluric acid to theophylline in mice

Kuroda Y., Taguchi K., Enoki Y., Matsumoto K., Hori S., Kizu J.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 42 （ 8 ） 1423 - 1427 2019年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09186158

© 2019 The Pharmaceutical Society of Japan. Age is known as one of influencing factor for theophylline (TP)-metabolizing capacity. In a previous our study, the ratio of TP and its major metabolite 1,3-dimethyluric acid (DMU) in serum (DMU/TP) is a useful index to estimate TP-metabolizing capacity, and this value markedly increased by influencing factor, such as the history of smoking. However, it is unknown whether DMU/TP values in serum reflect age-associated changes of TP-metabolizing capacity. In this study, the effect of age on the DMU/TP values in serum were investigated using mice of different age due to the limited blood sampling in human. The concentrations of TP and its metabolites in mouse serum were simultaneously measured using HPLC. As observed in human serum, serum TP concentrations were closely correlated with DMU concentration in mice, which indicates that the DMU/TP ratio is a good indicator of TP metabolic ability in mice. When TP was administered subcutaneously in 2?8-week-old mice, age-associated changes in the DMU/TP ratio in mice were observed. In conclusion, age-associated changes in TP-metabolizing capacity can be estimated by the DMU/TP ratio in serum.

Clostridioides（Clostridium）difficile感染症診療ガイドライン.

國島広之, 大毛宏喜, 鈴木広道, 中村敦, 松元一明, 三鴨廣繁, 森伸晃, 森永芳智, 栁原克紀, 山岸由佳, 吉澤定子.

感染症学雑誌 92 819 - 854 2018年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0387-5911

Oral vancomycin versus metronidazole for the treatment of Clostridioides difficile infection: Meta-analysis of randomized controlled trials

Igarashi Y., Tashiro S., 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） 24 （ 11 ） 907 - 914 2018年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-321X

© 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases At present, vancomycin (VCM) and metronidazole (MNZ) are used for the first-line standard treatment of Clostridioides difficile infection (CDI). However, their differential use has not been sufficiently investigated. In this study, a meta-analysis on differences in the efficacy for CDI between VCM and MNZ was performed. Reports of randomized controlled studies using VCM or MNZ to treat CDI were surveyed. Meta-analysis was performed using the Mantel-Haenszel method and random-effects model, and the risk ratio and 95% confidence interval were calculated. Excluding overlapping reports, 1043 reports were extracted and 5 randomized controlled studies were extracted. There was no difference in therapeutic effects for CDI between VCM and MNZ (RR = 1.08, 95% CI (0.99–1.17), p = 0.09, I2 = 37%). On subgroup analysis by the severity, there was no difference in the clinical effects for CDI between VCM and MNZ in non-severe cases (risk ratio: 1.09, 95% confidence interval: 1.00–1.19, p = 0.06), but the clinical effects of VCM were significantly higher than those of MNZ in severe cases (risk ratio: 1.19, 95% confidence interval: 1.02–1.39, p = 0.03). No significant difference was noted in the recurrence rate, incidence of adverse event, time to exhibit therapeutic effects, or judgment of the bacteriological effects. As the therapeutic effects of VCM were superior in severe CDI cases, VCM should be considered first in severe cases.

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Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research

Yajima R., Matsumoto K., Yokono K., Watabe Y., Enoki Y., Taguchi K., Ise Y., Katayama S., Kizu J.

Journal of Pharmacy and Pharmacology （Journal of Pharmacy and Pharmacology） 71 （ 5 ） 746 - 752 2018年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2042-7158

© 2018 Royal Pharmaceutical Society Objectives: As commercially available pregabalin preparations are limited to oral administration, it is impossible to use it as an adjuvant analgesic for neuropathic cancer-related pain in terminally ill cancer patients with oral feeding difficulties. The objective of this study was to develop a pregabalin suppository to be available at hospitals. Methods: Pregabalin suppositories were prepared using bases comprising six different compositions of Witepsol H-15, Witepsol S-55, and Witepsol E-75. The suppository release test and stability test were performed in vitro. The pharmacokinetics and pharmacodynamics of the suppositories were assessed in rats. Key findings: In the in vitro releasing test, the pregabalin suppositories with H-15, H-15 : S-55 = 1 : 1, H-15 : S-55 = 2 : 1, H-15 : S-55 = 1 : 2 released approximately 100% of the pregabalin within 180 min. Among these pregabalin suppositories, only the suppository with H-15 : S-55 = 2 : 1 demonstrated an equivalent AUC 0−∞ with the oral administration group. Consistent with the results of the pharmacokinetic study, the pregabalin suppository with H-15 : S-55 = 2 : 1 exhibited antinociceptive effects. In addition, the pregabalin suppository with H-15 : S-55 = 2 : 1 was stable for 12 weeks when refrigerated with light shielding. Conclusions: The pregabalin suppositories prepared in this study may be applicable for pain control for terminally cancer ill patients with oral feeding difficulties.

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Stability of benzylpenicillin potassium and ampicillin in an elastomeric infusion pump

Nakamura T., Enoki Y., Uno S., Uwamino Y., Iketani O., Hasegawa N., Matsumoto K.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 24 （ 10 ） 856 - 859 2018年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-321X

© 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Some infectious diseases, such as infective endocarditis, osteomyelitis, and abscesses, require treatment with long-term intravenous antimicrobial treatment. Therefore, the patient is required to stay in the hospital to receive therapy, which lowers their quality of life. Establishing an outpatient parenteral antimicrobial therapy (OPAT) by continuous infusion pump is desired in Japan to overcome these issues. However, the 24-h stability of antimicrobial agents dissolved in infusion solutions is unclear. Thus, we investigated the stability of antimicrobial agents in five different infusion solutions in a clinical setting. Benzylpenicillin potassium (PCG) and ampicillin (ABPC) were dissolved separately in five different infusion solutions and kept at 25 or 31.1 °C for 24 h. The residual ratios were determined by high-performance liquid chromatography (HPLC). Dissolved PCG in acetate ringer solution remained stable for 24 h at temperatures of 25 and 31.1 °C (101.7 ± 1.4% and 92.9 ± 1.3%, respectively). In addition, the PCG solution did not adsorb onto the elastomeric infusion pump after 24 h at 31.1 °C. PCG dissolved in acetate ringer solution was also stable for 10 days after being kept in an elastomeric infusion pump at 4 °C (99.7 ± 0.5%). ABPC was unstable in all of the tested infusion solutions and temperatures. Based on our results, PCG in acetate ringer solution can be used in OPAT with continuous infusion pumps.

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Development of HPLC with fluorescent detection using NBD-F for the quantification of colistin sulfate in rat plasma and its pharmacokinetic applications

Ouchi S., Matsumoto K., Okubo M., Yokoyama Y., Kizu J.

Biomedical Chromatography （Biomedical Chromatography） 32 （ 5 ） e4167 2018年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1099-0801

Copyright © 2017 John Wiley & Sons, Ltd. Colistin sulfate, composed of a mixture of colistin A sulfate (CLA) and colistin B sulfate (CLB), is available for treating life-threatening infections caused by multidrug-resistant Gram-negative bacteria. In this study, the CLA and CLB were quantified separately. Colistin sulfate was extracted from rat plasma with a solid-phase extraction C18 cartridge and reacted with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), and the fluorescent derivatives were subjected to reversed-phase high-performance liquid chromatography analysis and used to investigate the pharmacokinetics of CLA and CLB in rat plasma. The recovery rates of CLA and CLB were 41.2 ± 4.4 and 45.5 ± 3.1%, respectively. The recovery rate calculated from the total area of CLA and CLB was 43.9 ± 3.6%. When 2 mm NBD-F and 10 mm boric acid buffer (pH 9.5) were added to colistin sulfate, the highest recovery rate was obtained. The best heating time was 5 min at 60°C. The lower limits of quantification for CLA, CLB and the total area of CLA and CLB were 0.05, 0.05 and 0.1 μg/mL; the coefficients of variations were 13.5, 14.5 and 14.1%, respectively. This method was found to have acceptable linearity, precision and accuracy, and has been successfully applied to a pharmacokinetic study in rat plasma.

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一包化調剤薬の鑑査業務における刻印錠と両面印字錠の比較.

松元一明, 大森栄, 石井伊都子, 川久保孝, 神田博仁, 鈴木貴明, 横山威一郎, 中澤一純, 木津純子.

日本病院薬剤師会雑誌（(一社)日本病院薬剤師会） 54 （ 4 ） 433 - 439 2018年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-8815

刻印錠と両面印字錠の一包化を行い、薬剤師と薬学部学生を対象に、調剤薬鑑査における鑑査時間、調剤ミスの発見の有無についてタイムスタディを実施し、その後、アンケートを行った。刻印錠の鑑査に、学生(40名)、薬剤師(98名)は平均517.2秒、505.6秒を要し、両面印字錠の平均298.9秒、277.5秒と比較して有意に長かった(p<0.001)。アンケートの結果、刻印錠では、"大変やりにくい"、"やりにくい"との回答が82.6%、両面印字錠では、"大変やりやすい"、"やりやすい"との回答が91.2%得られた。"鑑査の速さ"、"鑑査のしやすさ"、"鑑査の正確性"は71.7%、92.8%、89.9%が、両面印字錠のほうがよいと回答した。今後増え続けると思われる一包化の鑑査業務において、両面印字錠は、鑑査業務の負担軽減に貢献できるものと考える。(著者抄録)

Dosing optimization of meropenem based on a pharmacokinetic analysis in patients receiving hemodiafiltration and an in vitro model

Yokoyama Y., Nishino K., Matsumoto K., Inomoto Y., Matsuda K., Nakamura R., Yasuno N., Kizu J.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 24 （ 2 ） 92 - 98 2018年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-321X

© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases The purpose of this study was to estimate the in vivo pharmacokinetics of meropenem during intermittent-infusion hemodiafiltration (I-HDF) and clarify its optimal dosage and dosing interval in patients receiving I-HDF. The clearance of meropenem by online hemodiafiltration (OL-HDF) and I-HDF was predicted using an in vitro system and assessed to establish whether the results obtained are applicable to clinical cases. In the in vivo study, the mean volume of distribution (Vd), non-I-HDF clearance (CLnon-I-HDF), and I-HDF clearance (CLI-HDF) were 15.80 ± 3.59 l, 1.05 ± 0.27 l/h, and 5.78 ± 1.03 l/h. Dosing regimens of 0.25 g once daily for a MIC of 8 μg/ml and of 0.5 g once daily for a MIC of 16 μg/ml achieved 40% T > MIC. In the in vitro and in vivo studies, observed CLHDF was similar to predictive CLHDF (= Cf/Cp × (QD + QSUB)). In conclusion, adjustments to the dose and interval of meropenem were developed based on the presumed susceptibility of pathogens to meropenem in patients receiving I-HDF. We suggest 0.5 g once daily as an appropriate regimen for empirical treatment.

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