研究者詳細 - 米澤　淳

論文 - 米澤　淳

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Oxicam-derived non-steroidal anti-inflammatory drugs suppress 1-methyl-4-phenyl pyridinium-induced cell death via repression of endoplasmic reticulum stress response and mitochondrial dysfunction in SH-SY5Y cells

Omura T., Sasaoka M., Hashimoto G., Imai S., Yamamoto J., Sato Y., Nakagawa S., Yonezawa A., Nakagawa T., Yano I., Tasaki Y., Matsubara K.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications） 503 （ 4 ） 2963 - 2969 2018年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006291X

We have previously reported that oxicam-derived non-steroidal anti-inflammatory drugs (oxicam-NSAIDs), including meloxicam, piroxicam and tenoxicam, elicit protective effects against 1-methyl-4-phenyl pyridinium (MPP+)-induced cell death in a fashion independent of cyclooxygenase (COX) inhibition. We have also demonstrated that oxicam-NSAIDs suppress the decrease in phosphorylation of Akt caused by MPP+. The molecular mechanism through which oxicam-NSAIDs provide cytoprotection remains unclear. In this study, we speculated a possibility that endoplasmic reticulum (ER) stress and/or mitochondrial dysfunction, which are both causative factors of Parkinson's disease (PD), may be involved in the neuroprotective mechanism of oxicam-NSAIDs. We demonstrated here that oxicam-NSAIDs suppressed the activation of caspase-3 and cell death caused by MPP+ or ER stress-inducer, tunicamycin, in SH-SY5Y cells. Furthermore, oxicam-NSAIDs suppressed the increases in the ER stress marker CHOP (apoptosis mediator) caused by MPP+ or tunicamycin, beside suppressing eukaryotic initiation factor 2α (eIF2α) phosphorylation and the increase in ATF4 caused by MPP+. Taken together, these results suggest that oxicam-NSAIDs suppress the eIF2α-ATF4-CHOP pathway, one of the three signaling pathways in the ER stress response. Oxicam-NSAIDs suppressed the decrease in mitochondrial membrane potential depolarization caused by MPP+, indicating they also rescue cells from mitochondrial dysfunction. Akt phosphorylation levels were suppressed after the incubation with MPP+, whereas phosphorylation of eIF2α was enhanced. These results suggest that oxicam-NSAIDs prevented eIF2α phosphorylation and mitochondrial dysfunction by maintaining Akt phosphorylation (reduced by MPP+), thereby preventing cell death.

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Application of nSMOL coupled with LC-MS bioanalysis for monitoring the Fc-fusion biopharmaceuticals Etanercept and Abatacept in human serum

Iwamoto N., Yokoyama K., Takanashi M., Yonezawa A., Matsubara K., Shimada T.

Pharmacology Research and Perspectives （Pharmacology Research and Perspectives） 6 （ 4 ） e00422 2018年07月

研究論文（学術雑誌）, 共著, 査読有り

The principle of nano-surface and molecular-orientation limited (nSMOL) proteolysis has a unique characteristic Fab-selective proteolysis for antibody bioanalysis that is independent of a variety of monoclonal antibodies by the binding antibody Fc via Protein A/G in a pore with 100 nm diameter and modified trypsin immobilization on the surface of nanoparticles with 200 nm diameter. Since minimizing peptide complexity and protease contamination while maintaining antibody sequence specificity enables a rapid and broad development of optimized methods for liquid chromatography-mass spectrometry (LC-MS) bioanalysis, the application of regulatory LC-MS for monitoring antibody biopharmaceuticals is expected. nSMOL is theoretically anticipated to be applicable for representative Fc-fusion biopharmaceuticals, because Protein A/G-binding site Fc exists on the C-terminus, and its functional domain is available to orient and interact with the reaction solution. In this report, we describe the validated LC-MS bioanalysis for monitoring Ethanercept and Abatacept using nSMOL technology. The quantitation range of Ethanercept in human serum was from 0.195 to 100 μg/mL using the signature peptide VFCTK (aa.43-47), and that of Abatacept was from 0.391 to 100 μg/mL using the signature peptide MHVAQPAVVLASSR (aa.1-14). Both proteins fulfilled the guideline criteria for low-molecular-weight drug compounds. The results indicate that the clinical and therapeutic monitoring for antibody and Fc-fusion biopharmaceuticals are adequately applicable using nSMOL proteolysis coupled with LC-MS bioanalysis.

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Pharmacokinetic and Pharmacodynamic Markers of Mycophenolic Acid Associated with Effective Prophylaxis for Acute Graft-Versus-Host Disease and Neutrophil Engraftment in Cord Blood Transplant Patients

Yoshimura K., Yano I., Yamamoto T., Kondo T., Kawanishi M., Isomoto Y., Yonezawa A., Takaori-Kondo A., Matsubara K.

Biology of Blood and Marrow Transplantation （Biology of Blood and Marrow Transplantation） 24 （ 7 ） 1441 - 1448 2018年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10838791

Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration–time curves from 0 to 24 hours (AUC 0-24 ) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage ≥I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC 0-24 at 1 week after the start of MMF treatments compared with those with slower neutrophil engraftment. Inosine-5′-monophosphate dehydrogenase activity in peripheral blood mononuclear cells and single nucleotide polymorphisms in genes that were previously associated with MPA pharmacokinetics and pharmacodynamics were not an independent predictor for the clinical outcomes. Receiver-operating characteristic model analyses showed that cutoff values of AUC 0-24 for successful GI aGVHD prevention were.689 and 15.6 µg⋅hour⋅mL −1 for free MPA and AcMPAG, respectively. In addition, the cut-off value of free MPA AUC 0-24 for neutrophil engraftment by day 25 was.405 µg⋅hour⋅mL −1 . In conclusion, free MPA AUC 0-24 may be a better predictor of the prevention of GI aGVHD and neutrophil engraftment compared with that of total MPA in patients receiving CBT. Hence, monitoring of the free MPA AUC 0-24 between.405 and.689 µg⋅hour⋅mL −1 could be considered informative of individualized MPA treatments in CBT patients.

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医師からの指示として「残薬調整」をプレ印字した処方せんの医療経済効果

深津祥央, 池見泰明, 米澤淳, 山本浩貴, 尾崎淳子, 淺野理子, 櫻井香織, 上杉美和, 吉田優子, 傳田将也, 大谷祐基, 大村友博, 今井哲司, 中川俊作, 中川貴之, 今井博久, 松原和夫

日本病院薬剤師会雑誌（(一社)日本病院薬剤師会） 54 （ 3 ） 307 - 312 2018年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-8815

2016年度の診療報酬の改定に伴い、処方せんの様式に残薬に関する指示項目が追加された。京都大学医学部附属病院(以下、京大病院)では、1.「保健医療機関へ疑義照会した上で調剤」と2.「保険医療機関へ情報提供」の指定選択項目に、京大病院の処方医が保険薬局薬剤師に対する指示(選択可能)の位置づけで、3.「残薬調整し調剤後にFAXで情報提供」を追加した。この変更によって、院外処方せんにおける残薬調整実施率は変更前の2.8倍に増加し、残薬調整に有効な手段であることを示した。その結果、薬剤費の削減効果も顕著であった。一方で、病院薬剤師の負担は多大で、保険薬局から病院に送付されるトレーシングレポートを電子カルテに取り込み医師にフィードバックしなければならない。今後は、残薬の発生そのものの減少を目指して、服薬アドヒアランスを向上させるための処方提案や服薬指導のさらなる充実に取り組む必要がある。(著者抄録)

Analysis of glycoforms and amino acids in infliximab and a biosimilar product using new method with LC/TOF-MS

Tsuda M., Otani Y., Yonezawa A., Masui S., Ikemi Y., Denda M., Sato Y., Nakagawa S., Omura T., Imai S., Nakagawa T., Hayakari M., Matsubara K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 41 （ 11 ） 1716 - 1721 2018年

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 09186158

Biosimilar products of therapeutic antibodies have been launched all over the world. They can relieve some of the economic burden of medicines. Although clinical trials have demonstrated the equivalency of biosimilar products with their reference product, biosimilar products are not commonly used in clinical practice. One reason is that the structural difference between the reference product and a biosimilar one remains unclear. We analyzed glycoforms and amino acids of an infliximab biosimilar product approved in Japan compared to that of the reference product (Remicade®). By combination of papain digestion and LC/ time-of-flight (TOF)-MS, we established a valuable method to analyze these therapeutic antibodies. Nine glycoforms were detected in infliximab, and a difference in amino acids was observed. In the glycoforms of MMF, MGnF/GnMF, GnGn, GnGnF, AGnF/GnAF, and AAF, the relative intensities were significantly different between the reference and biosimilar product. Furthermore, we elucidated that the content rate of the C-terminal lysine was different among glycoforms. In conclusion, our analytical method can analyze not only amino acids but also carbohydrate chains of therapeutic antibodies, and will provide a useful strategy to evaluate bio-medicines including biosimilar antibodies.

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Population pharmacokinetics and pharmacodynamics of mycophenolic acid using the prospective data in patients undergoing hematopoietic stem cell transplantation

Yoshimura K., Yano I., Yamamoto T., Kawanishi M., Isomoto Y., Yonezawa A., Kondo T., Takaori-Kondo A., Matsubara K.

Bone Marrow Transplantation （Bone Marrow Transplantation） 53 （ 1 ） 44 - 51 2018年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 02683369

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is used to suppress GvHD in patients undergoing hematopoietic stem cell transplantation (HCT). The purpose of this study was to construct a population pharmacokinetic and pharmacodynamic model in HCT patients for individualized MPA therapy. Blood samples were obtained from 49 HCT patients after starting MMF therapy. Population pharmacokinetic and pharmacodynamic parameters were obtained using the program NONMEM. MPA was described via a one-compartment model with a first-order elimination, and 30.9% of MPA glucuronide (MPAG) was found in the enterohepatic circulation. Inosine-5Œ-monophosphate dehydrogenase (IMPDH) activity was modeled as a maximal inhibitory model with a half-maximal inhibitory concentration (IC 50 ) of 3.59 μg/mL against MPA concentrations. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters revealed that decreased creatinine clearance increases the MPAG concentration followed by an increased MPA concentration; therefore, IMPDH activity decreases. Diarrhea decreases the enterohepatic circulation of MPAG and consequently reduces MPA concentration. The IC50 for MPA exhibited a positive association with C-reactive protein. Dosage adjustment based on plasma MPA concentration is required especially for patients with renal dysfunction and/or diarrhea.

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Verification between original and biosimilar therapeutic antibody infliximab using nSMOL coupled LC-MS bioanalysis in human serum

Iwamoto N., Yokoyama K., Takanashi M., Yonezawa A., Matsubara K., Shimada T.

Current Pharmaceutical Biotechnology （Current Pharmaceutical Biotechnology） 19 （ 6 ） 495 - 505 2018年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13892010

Background: Infliximab (IFX) is a chimeric therapeutic monoclonal antibody targeting tumor necrosis factor alpha (TNFα)-mediated inflammatory immune diseases. However, despite of an initial good clinical response, decrease in response to long-term treatment is a common observation. Objective: Recent studies suggest that IFX level in circulation has a correlation with clinical bioavailability. Therefore, the management of IFX dosage for individual manifestation by IFX monitoring may be valuable for the improvement of therapeutic response and outcomes. Method: In order to develop a broad IFX therapeutic monitoring in human serum, we have developed the validated IFX bioanalysis for Remicade™ and its biosimilar product using our nano-surface and molecular-orientation limited proteolysis (nSMOL) technology coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The nSMOL chemistry has a unique property of Fab-selective proteolysis, and makes it possible a global bioanalysis for many monoclonal antibodies. Results: The quantitation range of IFX in serum was from 0.293 to 300 μg/ml with good linearity. Quantitation verification at the concentrations of 0.293, 0.879, 14.1 and 240 μg/ml was within 1.56-7.53% of precision and 98.9-111% of accuracy using H-chain signature peptide SINSATHYAESVK. Moreover, cross-verified bioanalysis of Remicade quantitation using biosimilar standard, and its opposite combination, obtained an identical and inter-comparative results. Conclusion: The nSMOL strategy has the potential as a practical therapeutic monitoring technology in IFX therapeutic applications.

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Taxanes and platinum derivatives impair Schwann cells via distinct mechanisms

Imai S., Koyanagi M., Azimi Z., Nakazato Y., Matsumoto M., Ogihara T., Yonezawa A., Omura T., Nakagawa S., Wakatsuki S., Araki T., Kaneko S., Nakagawa T., Matsubara K.

Scientific Reports （Scientific Reports） 7 （ 1 ） 5947 2017年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2045-2322

Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy-induced peripheral neuropathy (CIPN), however, the precise underlying mechanisms are not fully understood. Here, we examined the direct effects of anti-cancer agents on Schwann cells. Exposure of primary cultured rat Schwann cells to paclitaxel (0.01 μM), cisplatin (1 μM), or oxaliplatin (3 μM) for 48 h induced cytotoxicity and reduced myelin basic protein expression at concentrations lower than those required to induce neurotoxicity in cultured rat dorsal root ganglion (DRG) neurons. Similarly, these anti-cancer drugs disrupted myelin formation in Schwann cell/DRG neuron co-cultures without affecting nerve axons. Cisplatin and oxaliplatin, but not paclitaxel, caused mitochondrial dysfunction in cultured Schwann cells. By contrast, paclitaxel led to dedifferentiation of Schwann cells into an immature state, characterized by increased expression of p75 and galectin-3. Consistent with in vitro findings, repeated injection of paclitaxel increased expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerve. These results suggest that taxanes and platinum derivatives impair Schwan cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, which may be important in the development of CIPN in conjunction with their direct impairment in peripheral neurons.

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Efficacy of protocol-based pharmacotherapy management on anticoagulation with warfarin for patients with cardiovascular surgery

Katada Y., Nakagawa S., Minakata K., Odaka M., Taue H., Sato Y., Yonezawa A., Kayano Y., Yano I., Nakatsu T., Sakamoto K., Uehara K., Sakaguchi H., Yamazaki K., Minatoya K., Sakata R., Matsubara K.

Journal of Clinical Pharmacy and Therapeutics （Journal of Clinical Pharmacy and Therapeutics） 42 （ 5 ） 591 - 597 2017年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 02694727

What is known and objective: Anticoagulation therapy with warfarin requires periodic monitoring of prothrombin time-international normalized ratio (PT-INR) and adequate dose adjustments based on the data to minimize the risk of bleeding and thromboembolic events. In our hospital, we have developed protocol-based pharmaceutical care, which we called protocol-based pharmacotherapy management (PBPM), for warfarin therapy. The protocol requires pharmacists to manage timing of blood sampling for measuring PT-INR and warfarin dosage determination based on an algorithm. This study evaluated the efficacy of PBPM in warfarin therapy by comparing to conventional pharmaceutical care. METHODS: From October 2013 to June 2015, a total of 134 hospitalized patients who underwent cardiovascular surgeries received post-operative warfarin therapy. The early series of patients received warfarin therapy as the conventional care (control group, n=77), whereas the latter received warfarin therapy based on the PBPM (PBPM group, n=68). These patients formed the cohort of the present study and were retrospectively analysed. RESULTS: The indications for warfarin included aortic valve replacement (n=56), mitral valve replacement (n=4), mitral valve plasty (n=22) and atrial fibrillation (n=29). There were no differences in patients' characteristics between both groups. The percentage time in therapeutic range in the first 10 days was significantly higher in the PBPM group (47.1%) than that in the control group (34.4%, P<.005). The average time to reach the steady state was significantly (P<.005) shorter in the PBPM group compared to the control group (7.3 vs 8.6 days). What is new and conclusion: Warfarin therapy based on our novel PBPM was clinically safe and resulted in significantly better anticoagulation control compared to conventional care.

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病棟薬剤師の持参薬服薬計画提案によるポリファーマシー改善と医療者負担軽減効果

中山佳代子, 米澤淳, 杉本充弘, 櫻井香織, 野口葉子, 山本将太, 吉田優子, 池見泰明, 深津祥央, 萱野勇一郎, 松原和夫

日本病院薬剤師会雑誌（(一社)日本病院薬剤師会） 53 （ 9 ） 1109 - 1114 2017年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-8815

服薬されずに破棄される医薬品(残薬)とともに、臨床的に必要以上の薬剤が処方される「ポリファーマシー」が社会問題視されている。本研究では、病棟薬剤師の持参薬確認と服薬計画提案による、他職種の業務負担軽減効果およびポリファーマシー改善効果を検証した。持参薬確認業務により、内科・外科の医師および看護師ともに、患者1人あたりの持参薬確認にかかる業務時間が4.1〜8.5分短縮した。調査期間中の入院患者数694人のうち約9割に持参薬があり、平均持参薬数は6.8種類であった。そのうち17.1%の患者に対して病棟薬剤師による服薬計画変更提案がされ、74.8%の提案が医師に受け入れられた。薬剤の中止提案が最も多く、平均服用薬剤数は6.78種から6.71種へと有意に減少した。病棟薬剤師による持参薬の服薬計画提案が、医師および看護師の負担軽減とポリファーマシー改善に貢献すると考えられる。(著者抄録)

Accumulation of alpha-fluoro-beta-alanine and fluoro mono acetate in a patient with 5-fluorouracil-associated hyperammonemia

Nishikawa Y., Funakoshi T., Horimatsu T., Miyamoto S., Matsubara T., Yanagita M., Nakagawa S., Yonezawa A., Matsubara K., Muto M.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 79 （ 3 ） 629 - 633 2017年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03445704

Purpose High-dose 5-fluorouracil (5-FU) containing chemotherapy occasionally causes hyperammonemia and can be lethal. However, the mechanism of 5FU-associated hyperammonemia has not been known. The aim of this study was to reveal the pharmacokinetics of 5-FU-asso-ciated hyperammonemia in a recurrent colorectal cancer patient with end-stage renal disease (ESRD). Methods We experienced a case of hyperammonemia during mFOLFOX6 plus bevacizumab therapy for recurrent colorectal cancer. He was a dialyzed patient due to diabetic nephropathy and was registered to prospective blood sampling for pharmacokinetics analysis during chemotherapy. Blood concentrations of 5-FU and its catabolites were determined by inductively coupled plasma-mass spectrometry. Results The patient developed hyperammonemia encephalopathy 41 h after the initiation of continuous 5-FU infusion (on the third day). Before onset of hyperammonemia encephalopathy, serum alpha-fluoro-beta-alanine (FBAL, 59.2 qg/ml) and fluoro mono acetate (FMA, 905.8 ng/ml) were gradually increased. After hemodialysis for hyperammonemia, FBAL and FMA were collaterally decreased and his symptom was improved. Other intermediate catabolites of 5-FU, dihydrofluorouracil, and alpha-fluoro-beta-ureido-propionic acid were not changed. Conclusion We found increases of serum FBAL and FMA under the condition of hyperammonemia in the patient with ESRD during mFOLFOX6 plus bevacizumab therapy. This research supported the hypothesis that impairment of tricarboxylic acid (TCA) cycle by FMA would cause 5-FU-associated hyperammonemia.

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Time-dependent structural alteration of rituximab analyzed by LC/TOF-MS after a systemic administration to rats

Otani Y., Yonezawa A., Tsuda M., Imai S., Ikemi Y., Nakagawa S., Omura T., Nakagawa T., Yano I., Matsubara K.

PLoS ONE （PLoS ONE） 12 （ 1 ） e0169588 2017年01月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 1932-6203

Therapeutic monoclonal antibodies (mAbs) have heterogeneities in their structures. Multiple studies have reported that the variety of post-translational modifications could affect the pharmacokinetic profiles or pharmacological potencies of therapeutic mAbs. Taking into the account that the structural modification of mAbs would affect the efficacy, it is worth investigating the structural alteration of therapeutic mAbs in the blood and the relationship between their structures and pharmacological effects. Herein, we have developed the method to isolate rituximab from plasma in which endogenous IgGs interfere the detection of rituximab, and successfully developed the analytical method with a liquid chromatograph time-of-flight mass spectrometer to detect the structure of rituximab in plasma with errors less than 30 parts per millions. Eight types of carbohydrate chains in rituximab were detected by this method. Interestingly, time-dependent changes in carbohydrate chains such as AAF (G2F) and GnGn (G0) were observed in rats, although the amino acids were stable. Additionally, these structural changes were observed via incubation in plasma as in the rat experiment, suggesting that a certain type of enzyme in plasma caused the alterations of the carbohydrate chains. The present analytical methods could clarify the actual pharmacokinetics of therapeutic mAbs, and help to evaluate the interindividual variations in pharmacokinetics and efficacy.

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Differential effects of taxanes and platinum derivatives on cultured Schwann cells

Satoshi Imai, Madoka Koyanagi, Ziauddin Azimi, Yui Nakazato, Mayuna Matsumoto, Takashi Ogihara, Atsushi Yonezawa, Tomohiro Omura, Shunsaku Nakagawa, Shuji Wakatsuki, Toshiyuki Araki, Shuji Kaneko, Takayuki Nakagawa, Kazuo Matsubara

Sci Rep In press 2017年

研究論文（学術雑誌）, 共著, 査読有り

Population pharmacokinetics of topiramate in Japanese pediatric and adult patients with epilepsy using routinely monitored data

Takeuchi M., Yano I., Ito S., Sugimoto M., Yamamoto S., Yonezawa A., Ikeda A., Matsubara K.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 39 （ 2 ） 124 - 131 2017年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01634356

Background: Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. Methods: Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. Results: A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L$h21$70 kg21 without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L$h21$70 kg21. Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults. Conclusions: The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.

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Riboflavin transporters RFVT/SLC52A mediate translocation of riboflavin, rather than FMN or FAD, across Plasma Membrane

Jin C., Yao Y., Yonezawa A., Imai S., Yoshimatsu H., Otani Y., Omura T., Nakagawa S., Nakagawa T., Matsubara K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 40 （ 11 ） 1990 - 1995 2017年

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 09186158

Riboflavin (vitamin B2) plays a role in various biochemical oxidation-reduction reactions. Flavin mononucleotide (FMN) and FAD, the biologically active forms, are made from riboflavin. Riboflavin transporters (RFVTs), RFVT1-3/Slc52a1-3, have been identified. However, the roles of human (h)RFVTs in FMN and FAD homeostasis have not yet been fully clarified. In this study, we assessed the contribution of each hRFVT to riboflavin, FMN and FAD uptake and efflux using in vitro studies. The transfection of hRFVTs increased cellular riboflavin concentrations. The uptake of riboflavin by human embryonic kidney cells transfected with hRFVTs was significantly increased, and the efflux was accelerated in a time-dependent manner. However, the uptake and efflux of FMN and FAD hardly changed. These results strongly suggest that riboflavin, rather than FMN or FAD, passes through plasma membranes via hRFVTs. Our findings could suggest that hRFVTs are involved in riboflavin homeostasis in the cells, and that FMN and FAD concentrations are regulated by riboflavin kinase and FAD synthase.

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LC/QTOF‐MSによるフィルグラスチムバイオ後続品の定性・成分分析

松村健吾, 松村健吾, 大谷祐基, 大村友博, 米澤淳, 津田真弘, 池見泰明, 中川俊作, 今井哲司, 中川貴之, 矢野育子, 吉貴達寛, 松原和夫

医療薬学（一般社団法人日本医療薬学会） 42 （ 9 ） 613‐619 - 619 2016年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

<p>Many biosimilars have been launched recently, however, a precise analytical method to evaluate their characteristics has not been developed. In this study, we established a new qualitative analysis technology for biomedicines using liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (LC/QTOF-MS), and assessed the original product and 4 biosimilars of filgrastim. Three peaks (Peak 1-3) appeared in total ion chromatogram by LC/QTOF-MS in the original brand-named drug. Filgrastim appeared as the main peak (Peak 1), and its molecular weight was calculated to be 18798.96 ± 0.02. When the original product was reduced by dithiothreitol, the molecular weight was 18802.19 ± 0.47, which was identical to the theoretical value based on amino acid sequence. These results indicate that it is possible to measure and distinguish molecular weights of untreated and reduced forms of filgrastim by LC/QTOF-MS. In addition, main peaks from all products including biosimilars showed exactly the same mass spectra and calculated molecular weights, suggesting that the main components (filgrastim) in these 4 products were considered to be qualitatively equal. On the other hand, the area ratios of 2 secondary peaks (Peaks 2 and 3) against the main peak (Peak 1) in 2 biosimilars were higher than those in the original product. The calculated molecular weights in Peaks 2 and 3 corresponded to that of polysorbate 80, which was one of the additives in the formulation. In conclusion, LC/QTOF-MS is a useful technique for qualitative component analysis of biomedicines.</p>

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A pilot study of regenerative therapy using controlled release of recombinant human fibroblast growth factor for patients with pre-collapse osteonecrosis of the femoral head

Kuroda Y., Asada R., So K., Yonezawa A., Nankaku M., Mukai K., Ito-Ihara T., Tada H., Yamamoto M., Murayama T., Morita S., Tabata Y., Yokode M., Shimizu A., Matsuda S., Akiyama H.

International Orthopaedics （International Orthopaedics） 40 （ 8 ） 1747 - 1754 2016年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03412695

Purpose: We evaluated the safety and clinical outcomes of a single local administration of gelatin hydrogel impregnated with recombinant human fibroblast growth factor (rhFGF)-2 for the treatment of the precollapse stage of osteonecrosis of the femoral head (ONFH). Methods: Patients with ONFH (precollapse stage ≤2) received a single local administration of 800 μg of rhFGF-2-impregnated gelatin hydrogel and were followed up for one year. The surgery was performed using a minimally invasive technique involving a 1-cm skin incision, and walking was allowed from day one postoperatively. The primary outcomes included occurrence of adverse events and complications. The secondary outcomes included changes in the Harris hip scores, visual analog scale for pain scores, University of California, Los Angeles (UCLA) activity scores, and radiological images. Results: We included ten patients, of which five experienced 14 adverse events, including one complication from spinal anesthesia. However, patients completely recovered from all adverse events. The mean clinical scores significantly improved by one year postoperatively compared with the pre-operative scores (before vs. after: visual analog score for pain, 21.2 vs. 5.3 mm; UCLA activity score, 5.5 vs. 6.6; Harris hip score, 81.0 vs. 96.9 points). There was only one case of femoral head collapse; however, this occurred in a hip with extensive necrosis. Stage progression and collapse did not occur in the other nine cases. Computed tomography confirmed bone regeneration in the femoral heads. Conclusions: Clinical application of rhFGF-2-impregnated gelatin hydrogel for patients with precollapse ONFH was feasible and safe.

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Disruption of Slc52a3 gene causes neonatal lethality with riboflavin deficiency in mice

Yoshimatsu H., Yonezawa A., Yamanishi K., Yao Y., Sugano K., Nakagawa S., Imai S., Omura T., Nakagawa T., Yano I., Masuda S., Inui K.I., Matsubara K.

Scientific Reports （Scientific Reports） 6 27557 2016年06月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 2045-2322

Homeostasis of riboflavin should be maintained by transporters. Previous in vitro studies have elucidated basic information about riboflavin transporter RFVT3 encoded by SLC52A3 gene. However, the contribution of RFVT3 to the maintenance of riboflavin homeostasis and the significance in vivo remain unclear. Here, we investigated the physiological role of RFVT3 using Slc52a3 knockout (Slc52a3-/-) mice. Most Slc52a3-/-mice died with hyperlipidemia and hypoglycemia within 48 hr after birth. The plasma and tissue riboflavin concentrations in Slc52a3-/-mice at postnatal day 0 were dramatically lower than those in wild-type (WT) littermates. Slc52a3-/-fetuses showed a lower capacity of placental riboflavin transport compared with WT fetuses. Riboflavin supplement during pregnancy and after birth reduced neonatal death and metabolic disorders. To our knowledge, this is the first report to indicate that Rfvt3 contributes to placental riboflavin transport, and that disruption of Slc52a3 gene caused neonatal mortality with hyperlipidemia and hypoglycemia owing to riboflavin deficiency.

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病院と薬局の合意に基づく院外処方せんにおける疑義照会簡素化プロトコルとその効果

櫻井香織, 尾崎淳子, 矢野育子, 安達昂一郎, 木村嘉彦, 松村勝之, 西脇布貴, 吉田優子, 池見泰明, 萱野勇一郎, 米澤淳, 深津祥央, 松原和夫

医療薬学 42 （ 5 ） 336‐342 2016年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

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Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia

Kumagai M., Marui A., Tabata Y., Takeda T., Yamamoto M., Yonezawa A., Tanaka S., Yanagi S., Ito-Ihara T., Ikeda T., Murayama T., Teramukai S., Katsura T., Matsubara K., Kawakami K., Yokode M., Shimizu A., Sakata R.

Heart and Vessels （Heart and Vessels） 31 （ 5 ） 713 - 721 2016年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09108327

As a form of therapeutic angiogenesis, we sought to investigate the safety and efficacy of a sustained-release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel in patients with critical limb ischemia (CLI). We conducted a phase I–IIa study that analyzed 10 CLI patients following a 200-μg intramuscular injection of bFGF-incorporated gelatin hydrogel microspheres into the ischemic limb. Primary endpoints were safety and transcutaneous oxygen pressure (TcO2) at 4 and 24 weeks after treatment. During the follow-up, there was no death or serious procedure-related adverse event. After 24 weeks, TcO2 (28.4 ± 8.4 vs. 46.2 ± 13.0 mmHg for pretreatment vs after 24 weeks, p < 0.01) showed significant improvement. Regarding secondary endpoints, the distance walked in 6 min (255 ± 105 vs. 318 ± 127 m, p = 0.02), the Rutherford classification (4.4 ± 0.5 vs. 3.1 ± 1.4, p = 0.02), the rest pain scale (1.7 ± 1.0 vs. 1.2 ± 1.3, p = 0.03), and the cyanotic scale (2.0 ± 1.1 vs. 0.9 ± 0.9, p < 0.01) also showed improvement. The blood levels of bFGF were within the normal range in all patients. A subanalysis of patients with arteriosclerosis obliterans (n = 7) or thromboangiitis obliterans (Buerger’s disease) (n = 3) revealed that TcO2 had significantly improved in both subgroups. TcO2 did not differ between patients with or without chronic kidney disease. The sustained release of bFGF from biodegradable gelatin hydrogel may offer a safe and effective form of angiogenesis for patients with CLI.

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