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Papers - Enoki, Yuki

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リネゾリド血中濃度上昇に伴い低ナトリウム血症が発現した症例

田口和明, 榎木裕紀, 松元一明, 池谷修, 宇野俊介, 上蓑義典, 長谷川直樹

日本化学療法学会雑誌 ((公社)日本化学療法学会) 67 ( Suppl.A ) 292 - 292 2019.03

ISSN 1340-7007

Age-Associated Theophylline Metabolic Activity Corresponds to the Ratio of 1,3-Dimethyluric Acid to Theophylline in Mice

Kuroda Yuko, Taguchi Kazuaki, Enoki Yuki, Matsumoto Kazuaki, Hori Seiji, Kizu Junko

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 42 ( 8 ) 1423 - 1427 2019

Research paper (scientific journal), Accepted, ISSN 09186158

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 2–28-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.

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

Research paper (scientific journal), Accepted, 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 p

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Sarcopenia in Chronic Kidney Disease: Factors, Mechanisms, and Therapeutic Interventions

Watanabe Hiroshi, Enoki Yuki, Maruyama Toru

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 42 ( 9 ) 1437 - 1445 2019

Research paper (scientific journal), Accepted, ISSN 09186158

Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and decreased muscle endurance. Many insights into the molecular mechanisms of muscle wasting in CKD have been obtained. A persistent imbalance between protein degradation and synthesis in muscle causes muscle wasting. During muscle wasting, high levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The myostatin binding to its receptor activin A receptor type IIB stimulates the expression of atrogenes such as atrogin-1 and muscle ring factor 1, members of the muscle-specific ubiquitin ligase family. Impaired mitochondrial function also contributes to reducing muscle endurance. The increased protein-bound uremic toxin, parathyroid hormone, glucocorticoid, and angiotensin II levels that are observed in CKD all have a negative effect on muscle mass and endurance. Among the protein-bound uremic toxins, indoxyl sulfate, an indole-containing compound has the potential to induce muscle atrophy by stimulating ROS-mediated myostatin and atrogenes expression. Indoxyl sulfate also impairs mitochondrial function. Some potential therapeutic approaches based on the muscle wasting mechanisms in CKD are currently in the testing stages.

Evaluation of the Expression Time of Ganciclovir-Induced Adverse Events Using JADER and FAERS

Ando Go, Taguchi Kazuaki, Enoki Yuki, Yokoyama Yuta, Kizu Junko, Matsumoto Kazuaki

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 42 ( 11 ) 1799 - 1804 2019

Research paper (scientific journal), Accepted, ISSN 09186158

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 ganciclovir-induced 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.

Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research.

Yajima; Ryo; Matsumoto, Kazuaki; Yokono, Kanako; Watabe, Yuki; Enoki, Yuki; Taguchi, Kazuaki; Ise, Yuya; Katayama, Shiro; Kizu, Junko

Journal of pharmacy and pharmacology (Journal of Pharmacy and Pharmacology) 71 ( 5 ) 746 - 752 2018.12

Research paper (scientific journal), Joint Work, Accepted, 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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Oral vancomycin versus metronidazole for the treatment of Clostridioides difficile infection: Meta-analysis of randomized controlled trials

Igarashi, Yuki, Tashiro, Sho, Enoki, Yuki, Taguchi, Kazuaki, Matsumoto, Kazuaki, Ohge, Hiroki, Suzuki, Hiromichi, Nakamura, Atsushi, Mori, Nobuaki, Morinaga, Yoshitomo, Yamagishi, Yuka, Yoshizawa, Sadako, Yanagihara, Katsunori, Mikamo, Hiroshige, Kunishima, Hiroyuki

JOURNAL OF INFECTION AND CHEMOTHERAPY (Journal of Infection and Chemotherapy) 24 ( 11 ) 907 - 914 2018.12

Research paper (scientific journal), Joint Work, Accepted, 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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Stability of benzylpenicillin potassium and ampicillin in an elastomeric infusion pump

Nakamura, Tomomi, Enoki, Yuki, Uno, Shunsuke, Uwamino, Yoshifumi, Iketani, Osamu, Hasegawa, Naoki, Matsumoto, Kazuaki

JOURNAL OF INFECTION AND CHEMOTHERAPY (Journal of Infection and Chemotherapy) 24 ( 10 ) 856 - 859 2018.10

Research paper (scientific journal), Single Work, Accepted, 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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【ここまでは必ず押さえておきたい高齢者の低栄養と薬】高齢者が低栄養になるとどうなる?体内動態の変化と服薬上のリスク

榎木裕紀, 松元一明

調剤と情報 ((株)じほう) 24 ( 14 ) 2126 - 2130 2018.10

ISSN 1341-5212

Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions

Minayoshi, Yuki, Maeda, Hitoshi, Yanagisawa, Hiroki, Hamasaki, Keisuke, Mizuta, Yuki, Nishida, Kento, Kinoshita, Ryo, Enoki, Yuki, Imafuku, Tadasi, Chuang, Victor Tuan Giam, Koga, Tomoaki, Fujiwara, Yukio, Takeya, Motohiro, Sonoda, Kayoko, Wakayama, Tomohiko, Taguchi, Kazuaki, Ishima, Yu, Ishida, Tatsuhiro, Iwakiri, Yasuko, Tanaka, Motohiko, Sasaki, Yutaka, Watanabe, Hiroshi, Otagiri, Masaki, Maruyama, Toru

DRUG DELIVERY (Drug Delivery) 25 ( 1 ) 1067 - 1077 2018.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 1071-7544

Because of its multifaceted anti-inflammatory and immunomodulatory effects, delivering type-I interferon to Kupffer cells has the potential to function as a novel type of therapy for the treatment of various types of hepatitis. We report herein on the preparation of a Kupffer cell targeting type-I interferon, an albumin-IFNα2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFNα2b, attached by combining albumin fusion technology and site-directed mutagenesis. The presence of this unique oligosaccharide permits the protein to be efficiently, rapidly and preferentially distributed to Kupffer cells. Likewise IFNα2b, Man-HSA(D494N)-IFNα2b caused a significant induction in the mRNA levels of IL-10, IL-1Ra, PD-L1 in RAW264.7 cells and mouse isolated Kupffer cells, and these inductions were largely inhibited by blocking the interferon receptor. These data indicate that Man-HSA(D494N)-IFNα2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFNα2b significantly inhibited liver injury in Concanavalin A (Con-A)-induced hepatitis model mice, and consequently improved their survival rate. Moreover, the post-administration of Man-HSA(D494N)-IFNα2b at 2 h after the Con-A challenge also exerted hepato-protective effects. In conclusion, this proof-of-concept study demonstrates the therapeutic effectiveness and utility of Kupffer cell targeting type-I interferon against hepatitis via its anti-inflammatory and immunomodulatory actions.

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肺非結核性抗酸菌症に対するクラリスロマイシン、エサンブトール、リファンピシン3剤併用療法におけるPK/PD解析

池谷修, 米屋安佳里, 松元一明, 榎木裕紀, 藤原宏, 上蓑義典, 宇野俊介, 長谷川直樹

日本化学療法学会雑誌 ((公社)日本化学療法学会) 66 ( Suppl.A ) 259 - 259 2018.04

Accepted, ISSN 1340-7007

外来静注抗菌薬療法(OPAT)導入に向けたペニシリンGカリウムおよびアンピシリンの各種輸液製剤溶解後の安定性に関する検討

榎木裕紀, 中村友美, 宇野俊介, 上蓑義典, 池谷修, 長谷川直樹, 松元一明

日本化学療法学会雑誌 ((公社)日本化学療法学会) 66 ( Suppl.A ) 311 - 311 2018.04

Accepted, ISSN 1340-7007

Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery

Ichimizu, S., Watanabe, H., Maeda, H., Hamasaki, K., Nakamura, Y., Chuang, V. T. G., Kinoshita, R., Nishida, K., Tanaka, R., Enoki, Y., Ishima, Y., Kuniyasu, A., Kobashigawa, Y., Morioka, H., Futaki, S., Otagiri, M. and Maruyama, T.

J Control Release (Journal of Controlled Release) 277 23 - 34 2018.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 1873-4995

Human serum albumin (HSA) is a superior carrier for delivering extracellular drugs. However, the development of a cell-penetrating HSA remains a great challenge due to its low membrane permeability. We report herein on the design of a series of palmitoyl-poly-arginine peptides (CPPs) and an evaluation of their cell-penetrating effects after forming a complex with HSA for use in intracellular drug delivery. The palmitoyl CPPs forms a stable complex with HSA by anchoring itself to the high affinity palmitate binding sites of HSA. Among the CPPs evaluated, a cyclic polypeptide composed of D-dodecaarginines, palmitoyl-cyclic-(D-Arg)12 was the most effective for facilitating the cellular uptake of HSA by HeLa cells. Such a superior cell-penetrating capability is primarily mediated by macropinocytosis. The effect of the CPP on pharmacological activity was examined using three drugs loaded in HSA via three different methods: a) an HSA-paclitaxel complex, b) an HSA-doxorubicin covalent conjugate and c) an HSA-thioredoxin fusion protein. The results showed that cell-penetrating efficiency was increased with a corresponding and significant enhancement in pharmacological activity. In conclusion, palmitoyl-cyclic-(D-Arg)12/HSA is a versatile cell-penetrating drug delivery system with great potential for use as a nano-carrier for a wide diversity of pharmaceutical applications.

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【新薬展望2018】(第III部)治療における最近の新薬の位置付け<薬効別>～新薬の広場～　抗菌薬

松元一明, 榎木裕紀

医薬ジャーナル ((株)医薬ジャーナル社) 54 ( 増刊 ) 495 - 501 2018.02

ISSN 0287-4741

＜文献概要＞2017年に承認申請が行われた多剤耐性結核菌(MDR-TB)治療薬のベダキリンフマル酸塩の概要,作用機序,体内動態,用法・用量,相互作用および副作用について,最近の知見を元に概説した。また,2017年10月現在,国内第III相試験が行われている新規フルオロケトライド系抗菌薬のT-4288(ソリスロマイシン)の概要と海外での開発状況について述べた。またさらに,国内第I相試験段階ではあるが,β-ラクタマーゼ阻害剤のOP0595について,そのユニークな薬剤特性を概説した。

Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-kappaB signaling pathway in secondary hyperparathyroidism

Watanabe, H., Sugimoto, R., Ikegami, K., Enoki, Y., Imafuku, T., Fujimura, R., Bi, J., Nishida, K., Sakaguchi, Y., Murata, M., Maeda, H., Hirata, K., Jingami, S., Ishima, Y., Tanaka, M., Matsushita, K., Komaba, H., Fukagawa, M., Otagiri, M. and Maruyama, T.

Biochem Pharmacol (Biochemical Pharmacology) 145 192 - 201 2017.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 0006-2952

Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1-34). In Caco-2 cells, PTH (1-34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13-34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-kappaB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-kappaB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment.

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Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction

Enoki, Y., Watanabe, H., Arake, R., Fujimura, R., Ishiodori, K., Imafuku, T., Nishida, K., Sugimoto, R., Nagao, S., Miyamura, S., Ishima, Y., Tanaka, M., Matsushita, K., Komaba, H., Fukagawa, M., Otagiri, M. and Maruyama, T.

J Cachexia Sarcopenia Muscle (Journal of Cachexia, Sarcopenia and Muscle) 8 ( 5 ) 735 - 747 2017.10

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

BACKGROUND: Chronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS-targeted intervention using AST-120, which inhibits IS accumulation, or mitochondria-targeted intervention using L-carnitine or teneligliptin, a dipeptidyl peptidase-4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice. METHODS: The in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6-nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non-treatment group and AST-120, L-carnitine, or teneligliptin treatment groups. RESULTS: In C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC-1alpha and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co-incubation with an anti-oxidant, ascorbic acid, L-carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin-6 and atrophy-related factors such as myostatin and atrogin-1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG-1alpha and increased muscular autophagy, as reflected by decreased mitochondria-rich type I fibres. An AST-120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L-carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level. CONCLUSIONS: Our results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS-targeted and mitochondria-targeted interventions for treating CKD-induced muscle atrophy and decreased exercise endurance.

Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism

Sugimoto, R., Watanabe, H., Ikegami, K., Enoki, Y., Imafuku, T., Sakaguchi, Y., Murata, M., Nishida, K., Miyamura, S., Ishima, Y., Tanaka, M., Matsushita, K., Komaba, H., Fukagawa, M., Otagiri, M. and Maruyama, T.

Kidney Int (ELSEVIER SCIENCE INC) 91 ( 3 ) 658 - 670 2017.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 0085-2538

Hyperuricemia occurs with increasing frequency among patients with hyperparathyroidism. However, the molecular mechanism by which the serum parathyroid hormone (PTH) affects serum urate levels remains unknown. This was studied in uremic rats with secondary hyperparathyroidism where serum urate levels were found to be increased and urate excretion in the intestine and kidney decreased, presumably due to down-regulation of the expression of the urate exporter ABCG2 in intestinal and renal epithelial membranes. These effects were prevented by administration of the calcimimetic cinacalcet, a PTH suppressor, suggesting that PTH may down-regulate ABCG2 expression. This was directly tested in intestinal Caco-2 cells where the expression of ABCG2 on the plasma membrane was down-regulated by PTH (1-34) while its mRNA level remained unchanged. Interestingly, an inactive PTH derivative (13-34) had no effect, suggesting that a posttranscriptional regulatory system acts through the PTH receptor to regulate ABCG2 plasma membrane expression. As found in an animal study, additional clinical investigations showed that treatment with cinacalcet resulted in significant reductions in serum urate levels together with decreases in PTH levels in patients with secondary hyperparathyroidism undergoing dialysis. Thus, PTH down-regulates ABCG2 expression on the plasma membrane to suppress intestinal and renal urate excretion, and the effects of PTH can be prevented by cinacalcet treatment.

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Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1

Enoki, Yuki, Watanabe, Hiroshi, Arake, Riho, Sugimoto, Ryusei, Imafuku, Tadashi, Tominaga, Yuna, Ishima, Yu, Kotani, Shunsuke, Nakajima, Makoto, Tanaka, Motoko, Matsushita, Kazutaka, Fukagawa, Masafumi, Otagiri, Masaki and Maruyama, Toru

Scientific Reports (NATURE PUBLISHING GROUP) 6 32084 2016.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 2045-2322

Skeletal muscle atrophy, referred to as sarcopenia, is often observed in chronic kidney disease ( CKD) patients, especially in patients who are undergoing hemodialysis. The purpose of this study was to determine whether uremic toxins are involved in CKD-related skeletal muscle atrophy. Among six protein-bound uremic toxins, indole containing compounds, indoxyl sulfate ( IS) significantly inhibited proliferation and myotube formation in C2C12 myoblast cells. IS increased the factors related to skeletal muscle breakdown, such as reactive oxygen species ( ROS) and inflammatory cytokines ( TNF-alpha, IL-6 and TGF-beta 1) in C2C12 cells. IS also enhanced the production of muscle atrophy-related genes, myostatin and atrogin-1. These effects induced by IS were suppressed in the presence of an antioxidant or inhibitors of the organic anion transporter and aryl hydrocarbon receptor. The administered IS was distributed to skeletal muscle and induced superoxide production in half-nephrectomized ( 1/2 Nx) mice. The chronic administration of IS significantly reduced the body weights accompanied by skeletal muscle weight loss. Similar to the in vitro data, IS induced the expression of myostatin and atrogin-1 in addition to increasing the production of inflammatory cytokines by enhancing oxidative stress in skeletal muscle. These data suggest that IS has the potential to accelerate skeletal muscle atrophy by inducing oxidative stress-mediated myostatin and atrogin-1 expression.

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CKD誘発骨格筋障害に対するAST-120の有効性評価

荒毛里歩, 榎木裕紀, 渡邊博志, 異島優, 田中元子, 松下和孝, 深川雅史, 小田切優樹, 丸山徹

日本腎臓学会誌 ((一社)日本腎臓学会) 58 ( 3 ) 315 - 315 2016.05

Accepted, ISSN 0385-2385

OAT-DEPENDENT CELLULAR ACCUMULATION OF P-CRESYL SULFATE, A UREMIC TOXIN, CAUSES VASCULAR ENDOTHELIAL AND SMOOTH MUSCLE CELL DAMAGES BY INDUCING OXIDATIVE STRESS

Watanabe Hiroshi, Miyamoto Yohei, Enoki Yuki, Ishima Yu, Fukagawa Masafumi, Otagiri Masaki, Maruyama Toru

DRUG METABOLISM REVIEWS 47 175 - 175 2015.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0360-2532

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