研究者詳細 - 米澤　淳

論文 - 米澤　淳

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Development of extended pharmacokinetic models for propofol based on measured blood and brain concentrations

Kawata M., Yonezawa A., Mineharu Y., Itohara K., Mizota T., Matsui Y., Kikuchi T., Yamao Y., Hattori E.Y., Hamada M., Hira D., Furukawa K., Miyamoto S., Terada T., Matsubara K., Arakawa Y.

Scientific Reports （Scientific Reports） 14 （ 1 ） 6326 - 6326 2024年12月

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

Propofol’s pharmacokinetics have been extensively studied using human blood samples and applied to target-controlled infusion systems; however, information on its concentration in the brain remains scarce. Therefore, this study aimed to simultaneously measure propofol plasma and brain concentrations in patients who underwent awake craniotomy and establish new pharmacokinetic model. Fifty-seven patients with brain tumors or brain lesions who underwent awake craniotomy were sequentially assigned to model-building and validating groups. Plasma and brain (lobectomy or uncapping margins) samples were collected at five time-points. The concentration of propofol was measured using high-performance liquid chromatography. Population pharmacokinetic analysis was conducted through a nonlinear mixed-effects modeling program using a first-order conditional estimation method with interactions. Propofol’s brain concentrations were higher than its plasma concentrations. The measured brain concentrations were higher than the effect site concentrations using the previous models. Extended models were constructed based on measured concentrations by incorporating the brain/plasma partition coefficient (Kp value). Extended models showed good predictive accuracy for brain concentrations in the validating group. The Kp value functioned as a factor explaining retention in the brain. Our new pharmacokinetic models and Kp value can predict propofol’s brain and plasma concentrations, contributing to safer and more stable anesthesia.

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Selection of anti-cytokine biologics by pretreatment levels of serum leucine-rich alpha-2 glycoprotein in patients with inflammatory bowel disease

Amano T., Yoshihara T., Shinzaki S., Sakakibara Y., Yamada T., Osugi N., Hiyama S., Murayama Y., Nagaike K., Ogiyama H., Yamaguchi T., Arimoto Y., Kobayashi I., Kawai S., Egawa S., Kizu T., Komori M., Tsujii Y., Asakura A., Tashiro T., Tani M., Otake-Kasamoto Y., Uema R., Kato M., Tsujii Y., Inoue T., Yamada T., Kitamura T., Yonezawa A., Iijima H., Hayashi Y., Takehara T.

Scientific Reports 14 （ 1 ） 29755 2024年12月

研究論文（学術雑誌）, 共著, 査読有り

Serum leucine-rich alpha-2 glycoprotein (LRG) can monitor disease activities during biologics treatment in patients with inflammatory bowel disease (IBD). It is unclear whether the pretreatment serum LRG level can predict clinical effectiveness including serum trough levels of ustekinumab in patients with IBD. This multicenter prospective cohort study included 184 patients (Crohn’s disease, 104; ulcerative colitis, 80) who received ustekinumab (n = 119) or anti-tumor necrosis factor (n = 65) between January 2019 and March 2023. Multivariate logistic regression analysis revealed serum LRG level at week 0 (0w-LRG, odds ratio 0.12, 95% confidence interval 0.02–0.68) as one of significant factors for clinical remission at week 8. We divided patients into the low- and the high-LRG groups by the median 0w-LRG (18.2 µg/mL) and compared the effectiveness. In patients who received ustekinumab, the proportion of clinical remission at week 8 was significantly different between in the low- (76.9%) and in the high-LRG group (59.3%, P = 0.038), and median serum trough level at week 8 was significantly different between in the low- (10.9 µg/mL, interquartile range 6.7–13.4) and the high-LRG group (5.3 µg/mL, interquartile range 2.4–8.3, P < 0.001). The 0w-LRG can predict the effectiveness including serum trough levels of ustekinumab during induction treatment for patients with IBD.

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Subjective symptoms are triggers for the detection of immune checkpoint inhibitor-induced interstitial lung disease and associate with disease severity: a single-center retrospective study

Yokoi M., Yonezawa A., Hira D., Handa T., Tanizawa K., Nakagawa S., Tsuda M., Ikemi Y., Itotani R., Yoshida H., Nomura M., Matsubara J., Murakami K., Ozasa H., Muto M., Terada T.

Journal of Pharmaceutical Health Care and Sciences （Springer Science and Business Media LLC） 10 （ 1 ） 52 2024年12月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 2055-0294

Background: Interstitial lung disease (ILD) is one of the most common fatal immune-related adverse events (irAEs). ILD development adversely affects the continuation of anticancer drug therapy, including immune checkpoint inhibitor (ICI) therapy and prognosis. There are no established useful clinical indicators for the early detection of ILD. Furthermore, the factors that lead the attending physician to suspect ICI-induced ILD (ICI-ILD) remain unclear. This study aimed to investigate the ICI-ILD detection based on subjective symptoms and their relationship with disease severity in patients receiving anti-PD-1/PD-L1 antibody. Methods: This was a retrospective observational study. We enrolled the patients who received anti-PD-1/PD-L1 antibody at Kyoto University Hospital between September 2014 and April 2021. Patients who developed ICI-ILD were stratified into two distinct groups based on factors that triggered the suspicion of ILD development. The “Subjective symptoms” group was defined as patients in whom ILD was detected based on subjective symptoms. Conversely, the “Routine examinations” group was defined as patients in whom ILD was suspected based on scheduled routine examinations. The severity of ILD in each group was assessed and its association with changes in the respiratory symptoms was examined. Results: Of 926 patients who received anti-PD-1/PD-L1 antibody, 51 patients (5.5%) developed ICI-ILD. The incidence of ICI-ILD in patients with lung cancer was significantly higher than that in patients with other cancers (P < 0.001). Among the patients with ICI-ILD, 27 patients (52.9%) were classified into the “Subjective symptoms” group. The “Subjective symptoms” group exhibited a significantly higher proportion of Grade 3–5 ICI-ILD cases than the “Routine examinations” group (76.2% vs. 23.8%, P = 0.010). At the last visit, before the suspected onset of ILD, 21 of the 27 patients (77.8%) had no symptoms or no change in the respiratory symptoms. Conclusion: Subjective symptoms triggered the suspicion of Grade 3–5 ICI-ILD. Enhanced monitoring and patient education could be essential for the early detection of ICI-ILD because ILD may develop rapidly. Our findings might help to manage ICI-ILD in clinical practice.

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Population Pharmacokinetic Modeling of Posaconazole in Japanese Patients Receiving Fungal Prophylaxis.

Sugimoto M, Yonezawa A, Kanda J, Itohara K, Hira D, Yamagiwa T, Taniguchi R, Hanyu Y, Watanabe M, Arai Y, Mizumoto C, Kitawaki T, Kondo T, Yamashita K, Takaori-Kondo A, Terada T

Therapeutic drug monitoring 46 （ 5 ） 611 - 618 2024年04月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 0163-4356

Background:Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases.Methods:The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output.Results:In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea.Conclusions:PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored.

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Comparison of safety and effectiveness between etanercept biosimilar LBEC0101 and reference in patients with rheumatoid arthritis in real-world data using the KURAMA cohort

Kawakami, T; Masui, S; Onishi, A; Onizawa, H; Fujii, T; Murakami, K; Murata, K; Tanaka, M; Shimada, T; Nakagawa, S; Matsuda, S; Morinobu, A; Terada, T; Yonezawa, A

MODERN RHEUMATOLOGY 34 （ 6 ） 1135 - 1141 2024年03月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り, ISSN 1439-7595

Objectives: Biosimilars are anticipated to be widely used in the treatment of rheumatoid arthritis (RA), owing to their cost efficiency; LBEC0101 was the first etanercept (ETN) biosimilar approved in Japan. However, there are limited real-world data comparing its safety and effectiveness with those of a reference product. Methods: This study used data from the Kyoto University Rheumatoid Arthritis Management Alliance cohort, including patients with RA who received ETN therapy—ETN reference product (ETN-RP) or LBEC0101—between 2015 and 2021. Serum ETN levels were measured using liquid chromatography–tandem mass spectrometry. Results: The 1-year continuation rates of ETN-RP and LBEC0101 were 58.7% and 74.4%, respectively. Effectiveness of treatment was evaluated in 18 patients; both products significantly reduced the 28-joint RA disease activity score and erythrocyte sedimentation rate (DAS28-ESR). Moreover, to determine equivalence, we analysed 11 patients who switched from ETN-RP to LBEC0101; the DAS28-ESR and serum ETN levels before and after switching were not significantly different. Conclusions: This real-world cohort study confirmed that the biosimilar of ETN, LBEC0101, was comparable to the reference product in terms of continuation rate, effectiveness at initiation of introduction, and effect persistence before and after switching in clinical practice.

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Clinical characteristics of cryopyrin-associated periodic syndrome and long-term real-world efficacy and tolerability of canakinumab in Japan: results of a nationwide survey.

Miyamoto T, Izawa K, Masui S, Yamazaki A, Yamasaki Y, Matsubayashi T, Shiraki M, Ohnishi H, Yasumura J, Tomohiro K, Miyamae T, Matsubara T, Arakawa N, Ishige T, Takizawa T, Shimbo A, Shimizu M, Kimura N, Maeda Y, Maruyama Y, Shigemura T, Furuta J, Sato S, Tanaka H, Izumikawa M, Yamamura M, Hasegawa T, Kaneko H, Nakagishi Y, Nakano N, Iida Y, Nakamura T, Wakiguchi H, Hoshina T, Kawai T, Murakami K, Akizuki S, Morinobu A, Ohmura K, Eguchi K, Sonoda M, Ishimura M, Furuno K, Kashiwado M, Mori M, Kawahata K, Hayama K, Shimoyama K, Sasaki N, Ito T, Umebayashi H, Omori T, Nakamichi S, Dohmoto T, Hasegawa Y, Kawashima H, Watanabe S, Taguchi Y, Nakaseko H, Iwata N, Kohno H, Ando T, Ito Y, Kataoka Y, Saeki T, Kaneko U, Murase A, Hattori S, Nozawa T, Nishimura K, Nakano R, Watanabe M, Yashiro M, Nakamura T, Komai T, Kato K, Honda Y, Hiejima E, Yonezawa A, Bessho K, Okada S, Ohara O, Takita J, Yasumi T, Nishikomori R, Japan CAPS working group

Arthritis & rheumatology (Hoboken, N.J.) （Arthritis and Rheumatology） 76 （ 6 ） 949 - 962 2024年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2326-5191

Objective: We assess the clinical characteristics of patients with cryopyrin-associated periodic syndrome (CAPS) in Japan and evaluate the real-world efficacy and safety of interleukin-1 (IL-1) inhibitors, primarily canakinumab. Methods: Clinical information was collected retrospectively, and serum concentrations of canakinumab and cytokines were analyzed. Results: A total of 101 patients were included, with 86 and 15 carrying heterozygous germline and somatic mosaic mutations, respectively. We identified 39 mutation types, and the common CAPS-associated symptoms corresponded with those in previous reports. Six patients (5.9% of all patients) died, with four of the deaths caused by CAPS-associated symptoms. Notably, 73.7% of patients (100%, 79.6%, and 44.4% of familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous articular syndrome/neonatal onset multisystem inflammatory disease, respectively) achieved complete remission with canakinumab, and early therapeutic intervention was associated with better auditory outcomes. In some patients, canakinumab treatment stabilized the progression of epiphysial overgrowth and improved height gain, visual acuity, and renal function. However, 23.7% of patients did not achieve inflammatory remission with crucial deterioration of organ damage, with two dying while receiving high-dose canakinumab treatment. Serological analysis of canakinumab and cytokine concentrations revealed that the poor response was not related to canakinumab shortage. Four inflammatory nonremitters developed inflammatory bowel disease (IBD)—unclassified during canakinumab treatment. Dual biologic therapy with canakinumab and anti–tumor necrosis factor-α agents was effective for IBD– and CAPS-associated symptoms not resolved by canakinumab monotherapy. Conclusion: This study provides one of the largest epidemiologic data sets for CAPS. Although early initiation of anti–IL-1 treatment with canakinumab is beneficial for improving disease prognosis, some patients do not achieve remission despite a high serum concentration of canakinumab. Moreover, IBD may develop in CAPS after canakinumab treatment. (Figure presented.).

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Serum Leucine-rich Alpha-2 Glycoprotein Can be a Biomarker for Selecting Anti-Cytokine Biologics in Patients with Inflammatory Bowel Disease: A Multicentre Prospective Cohort Study

Amano, T; Yoshihara, T; Shinzaki, S; Sakakibara, Y; Yamada, T; Osugi, N; HIyama, S; Murayama, Y; Ogiyama, H; Nagaike, K; Tujii, Y; Asakura, A; Tashiro, T; Tani, M; Otake-Kasamoto, Y; Inoue, T; Yonezawa, A; Iijima, H; Hayashi, Y; Takehara, T

JOURNAL OF CROHNS & COLITIS 18 I1248 - I1248 2024年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1873-9946

Low serum concentrations of bevacizumab and nivolumab owing to excessive urinary loss in patients with proteinuria: a case series

Masuda T., Funakoshi T., Horimatsu T., Yamamoto S., Matsubara T., Masui S., Nakagawa S., Ikemi Y., Yanagita M., Muto M., Terada T., Yonezawa A.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 94 （ 4 ） 615 - 622 2024年

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り, ISSN 03445704

Purpose: Proteinuria can cause interindividual variability in the pharmacokinetics of therapeutic antibodies and may affect therapeutic efficacy. Here, we measured the serum and urinary concentrations of bevacizumab (BV) and nivolumab (NIVO) in patients with proteinuria and reported a case series of these patients. Methods: Thirty-two cancer patients who received BV every 3 weeks or NIVO every 2 weeks between November 2020 and September 2021 at Kyoto University Hospital were enrolled in this study. The serum and urinary concentrations of BV and NIVO were measured using liquid chromatography-tandem mass spectrometry. Results: We divided the BV-treated patients and the NIVO-treated patients into two groups based on the urine protein-creatinine ratio (UPCR): UPCR 1 g/g or higher (BV, n = 9; NIVO, n = 3) and UPCR less than 1 g/g (BV, n = 14; NIVO, n = 6). Serum concentrations of the therapeutic antibodies adjusted by their doses were significantly lower in both BV- and NIVO-treated patients with UPCR 1 g/g or higher compared to those with less than 1 g/g. In patients with UPCR 1 g/g or higher, urinary concentrations of the therapeutic antibodies adjusted by their serum concentrations and urinary creatinine concentrations tended to increase. Conclusion: This case-series study suggests a possibility of reduction in serum concentrations of BV and NIVO in patients with proteinuria by urinary excretion of these drugs.

A case report of a prolonged decrease in tacrolimus clearance due to co-administration of nirmatrelvir/ritonavir in a lung transplant recipient receiving itraconazole prophylaxis

Tsuzawa A., Katada Y., Umemura K., Sugimoto M., Nishikawa A., Sato Y.k., Yoshida Y., Kitada N., Yonezawa A., Nakajima D., Date H., Terada T.

Journal of Pharmaceutical Health Care and Sciences （Journal of Pharmaceutical Health Care and Sciences） 9 （ 1 ） 12 2023年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2055-0294

Background: Drug-drug interaction management is complex. Nirmatrelvir/ritonavir is a potent cytochrome P450 (CYP) 3A inhibitor and influences pharmacokinetics of co-administered drugs. Although there are several reports about drug-drug interactions of nirmatrelvir/ritonavir, an influence of a concomitant use of nirmatrelvir/ritonavir and another potent CYP3A inhibitor on tacrolimus remains unclear. Here, we experienced a lung transplant patient with the novel coronavirus disease 2019 (COVID-19). In this patient, nirmatrelvir/ritonavir was administered, and the inhibitory effect of itraconazole on CYP3A was prolonged. Case presentation: We present a case in forties who had undergone lung transplantation. He was administered itraconazole and tacrolimus 1.0 mg/d, with a trough value of 8–12 ng/mL. The patient contracted the COVID-19, and a nirmatrelvir/ritonavir treatment was initiated. During the antiviral treatment, tacrolimus administration was discontinued for 5 d. Tacrolimus was resumed at 1.0 mg/d after completion of the nirmatrelvir/ritonavir treatment, but the trough value after 7 d was high at 31.6 ng/mL. Subsequently, the patient was placed on another 36-h tacrolimus discontinuation, but the trough value decreased to only 16.0 ng/mL. Conclusions: Co-administration of ritonavir caused a prolonged decrease in tacrolimus clearance through its inhibitory effects on CYP3A in a patient taking itraconazole. Management of drug-drug interaction by pharmacists can be important for patients with multiple medications.

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Acute inhibition of AMPA receptors by perampanel reduces amyloid β-protein levels by suppressing β-cleavage of APP in Alzheimer's disease models

Ueda S., Kuzuya A., Kawata M., Okawa K., Honjo C., Wada T., Matsumoto M., Goto K., Miyamoto M., Yonezawa A., Tanabe Y., Ikeda A., Kinoshita A., Takahashi R.

FASEB Journal （FASEB Journal） 37 （ 11 ） e23252 2023年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 08926638

Hippocampal hyperexcitability is a promising therapeutic target to prevent Aβ deposition in AD since enhanced neuronal activity promotes presynaptic Aβ production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aβ-evoked neuronal hyperexcitability, the acute effects of PER on Aβ metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aβ40 and Aβ42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aβ40/Aβ42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP βCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPβ levels, a direct byproduct of β-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aβ-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aβ clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aβ, indicating that the acute effect of PER is predominantly on Aβ production. In conclusion, acute treatment of PER reduces Aβ production by suppressing β-cleavage of amyloid-β precursor protein effectively, indicating a potential effect of PER against Aβ pathology in AD.

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Chapter 3: Management of kidney injury caused by cancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022

Ando, Y; Nishiyama, H; Shimodaira, H; Takano, N; Sakaida, E; Matsumoto, K; Nakanishi, K; Sakai, H; Tsukamoto, S; Komine, K; Yasuda, Y; Kato, T; Fujiwara, Y; Koyama, T; Kitamura, H; Kuwabara, T; Yonezawa, A; Okumura, Y; Yakushijin, K; Nozawa, K; Goto, H; Matsubara, T; Hoshino, J; Yanagita, M

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY （International Journal of Clinical Oncology） 28 （ 10 ） 1315 - 1332 2023年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-9625

Cisplatin should be administered with diuretics and Magnesium supplementation under adequate hydration to avoid renal impairment. Patients should be evaluated for eGFR (estimated glomerular filtration rate) during the treatment with pemetrexed, as kidney injury has been reported. Pemetrexed should be administered with caution in patients with a CCr (creatinine clearance) < 45 mL/min. Mesna is used to prevent hemorrhagic cystitis in patients receiving ifosfamide. Febuxostat is effective in avoiding hyperuricemia induced by TLS (tumor lysis syndrome). Preventative rasburicase is recommended in high-risk cases of TLS. Thrombotic microangiopathy could be triggered by anticancer drugs and there is no evidence of efficacy of plasma exchange therapy. When proteinuria occurs during treatment with anti-angiogenic agents or multi-kinase inhibitors, dose reductions or interruptions based on grading should be considered. Grade 3 proteinuria and renal dysfunction require urgent intervention, including drug interruption or withdrawal, and referral to a nephrologist should be considered. The first-line drugs used for blood pressure elevation due to anti-angiogenic agents are ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin receptor blockers). The protein binding of drugs and their pharmacokinetics are considerably altered in patients with hypoalbuminemia. The clearance of rituximab is increased in patients with proteinuria, and the correlation with urinary IgG suggests similar pharmacokinetic changes when using other antibody drugs. AIN (acute interstitial nephritis) is the most common cause of ICI (immune checkpoint inhibitor)-related kidney injury that is often treated with steroids. The need for renal biopsy in patients with kidney injury that occurs during treatment with ICI remains controversial.

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医薬品情報を利活用したがん薬物療法に対する薬学的介入

川上恵, 北田徳昭, 米澤淳, 岡村みや子, 尾崎淳子, 池見泰明, 中川俊作, 今井哲司, 中川貴之, 土井恵太郎, 秋月修治, 武藤学, 寺田智祐

医薬品情報学（一般社団法人　日本医薬品情報学会） 25 （ 2 ） 83 - 90 2023年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13451464

Abstract
Objective: In patients with specific backgrounds, comprehensive identification of health problems and proactive pharmacist intervention are crucial to providing safe and effective medical care. However, there are insufficient reports on chemotherapy regimen selection and supportive care management in patients taking immunosuppressants. In this study, to circumvent adverse events, pharmacists intervened with a patient administering tacrolimus (TAC) using known information, focusing on multiple factors attributable to the patient in addition to drug interactions.
Methods: The patient was a male in their 70s who received palliative chemotherapy for gastric cancer during their dermatomyositis treatment with TAC. Pharmaceutical support for cancer chemotherapy was provided using the following four procedures: (1) Patient information was collected from interviews and electronic medical records to identify patient-specific problems; (2) Basic pharmacological information was collected from tertiary sources, focusing on the interaction between TAC and aprepitant (APR). Furthermore, clinical reports were collected, and the pharmacokinetic drug interaction significance classification system was used for quantitative predictions; (3) The information obtained in steps 1) and 2) was evaluated, and comprehensive proposals linked to the patient information were presented; (4) Adverse events, TAC blood level, and patient outcomes were monitored after treatment initiation.
Results: A chemotherapy regimen consisting of S-1/oxaliplatin therapy without APR was selected. The adverse effects were controllable, and the treatment was completed without many adverse events. Meanwhile, TAC adherence was unaffected by cancer chemotherapy, and the TAC blood concentration or dose ratios were controlled within the same range as previously reported.
Conclusion: In cancer chemotherapy, for cases with limited evidence or information, comprehensive pharmaceutical support was provided using known patient information, considering multiple patient factors. This report is beneficial as an example of supportive care management by a pharmacist and contributes to providing optimal service in cases with specific backgrounds.

Serum Concentrations of Infliximab and IL-6 for Predicting One-Year Discontinuation of Infliximab Treatment Owing to Secondary Non-response in Patients with Rheumatoid Arthritis

Masui S., Yonezawa A., Nakamura M., Onishi A., Hashimoto M., Onizawa H., Fujii T., Murakami K., Murata K., Tanaka M., Yokoyama K., Iwamoto N., Shimada T., Itohara K., Hira D., Nakagawa S., Imai S., Nakagawa T., Hayakari M., Matsuda S., Morinobu A., Terada T., Matsubara K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 46 （ 8 ） 1112 - 1119 2023年08月

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

Secondary non-response to infliximab (IFX) occurs in some patients with rheumatoid arthritis (RA). Although therapeutic drug monitoring (TDM) is a useful tool to optimize IFX therapy, it is unclear whether it can help to identify the risk of secondary non-response. This study aimed to explore the utility of serum levels of IFX or other biomarkers to predict IFX discontinuation owing to secondary non-response. A single-center, retrospective study was conducted using the Kyoto University Rheumatoid Arthritis Management Alliance cohort database between 2011 and 2020. Serum IFX levels were measured using liquid chromatography-tandem mass spectrometry. An electrochemiluminescence assay was used to quantify serum levels of tumor necrosis factor-α and interleukin-6 and detect anti-drug antibodies. Eighty-four out of 310 patients were eligible for this study. The cutoff levels of biomarkers were determined by receiver operating characteristic analysis. IFX persistence was similar between groups stratified using IFX levels, tumor necrosis factor-α levels, interleukin-6 levels, and anti-drug antibodies positivity. The group with lower IFX and higher interleukin-6 levels had the worst therapy persistence (p=0.017) and the most frequent disease worsening (90.0%, p<0.001). Evaluating both interleukin-6 and IFX levels, not just IFX alone, enabled us to identify patients at risk of discontinuing IFX treatment. These findings support the utility of measuring IFX and interleukin-6 levels for successful maintenance therapy for RA.

医薬品情報を利活用したがん薬物療法に対する薬学的介入　タクロリムスとアプレピタントの薬物相互作用に着目し薬学的支援を行った皮膚筋炎併発胃がんの1例

川上恵, 北田徳昭, 米澤淳, 岡村みや子, 尾崎淳子, 池見泰明, 中川俊作, 今井哲司, 中川貴之, 土井恵太郎, 秋月修治, 武藤学, 寺田智祐

医薬品情報学（(一社)日本医薬品情報学会） 25 （ 2 ） 83 - 90 2023年08月

筆頭著者, 最終著者, 責任著者, 査読有り, ISSN 1345-1464

医薬品情報を利活用した癌薬物療法に対する薬学的介入として、薬剤師がタクロリムスとアプレピタントの薬物相互作用に着目し薬学的支援を行った、皮膚筋炎併発胃癌患者の症例(70代男性)について報告した。薬剤師が収集した既知情報、文献的考察および定量評価結果を医師に示し、医師と治療レジメンおよび制吐療法を協議した。その結果、本患者が男性であること、および年齢が70代であり、催吐性リスクが必ずしも高くないことに鑑み、アプレピタントの使用は必須でないと判断された。これらの協議内容を踏まえ、総合的に判断した。その結果、制吐療法としてアプレピタントを使用せず、SOX療法を施行することが決定された。その結果、化学療法開始後の嘔気はコントロール可能な範囲であり、タクロリムスのアドヒアランスに影響はなかった。本症例のように、エビデンスや情報が少ないケースであっても、薬剤師が相互作用という単一的要因だけでなく、特定の背景を有する患者側に起因する複数の因子を同時に考慮し、情報収集、評価、提案およびモニタリングを行うことが、安全で適切な化学療法の提供つながることが示唆された。

Chapter 1: Evaluation of kidney function in patients undergoing anticancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022

Muto, S; Matsubara, T; Inoue, T; Kitamura, H; Yamamoto, K; Ishii, T; Yazawa, M; Yamamoto, R; Okada, N; Mori, K; Yamada, H; Kuwabara, T; Yonezawa, A; Fujimaru, T; Kawano, H; Yokoi, H; Doi, K; Hoshino, J; Yanagita, M

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY （International Journal of Clinical Oncology） 28 （ 10 ） 1259 - 1297 2023年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-9625

The prevalence of CKD may be higher in patients with cancer than in those without due to the addition of cancer-specific risk factors to those already present for CKD. In this review, we describe the evaluation of kidney function in patients undergoing anticancer drug therapy. When anticancer drug therapy is administered, kidney function is evaluated to (1) set the dose of renally excretable drugs, (2) detect kidney disease associated with the cancer and its treatment, and (3) obtain baseline values for long-term monitoring. Owing to some requirements for use in clinical practice, a GFR estimation method such as the Cockcroft–Gault, MDRD, CKD-EPI, and the Japanese Society of Nephrology’s GFR estimation formula has been developed that is simple, inexpensive, and provides rapid results. However, an important clinical question is whether they can be used as a method of GFR evaluation in patients with cancer. When designing a drug dosing regimen in consideration of kidney function, it is important to make a comprehensive judgment, recognizing that there are limitations regardless of which estimation formula is used or if GFR is directly measured. Although CTCAEs are commonly used as criteria for evaluating kidney disease-related adverse events that occur during anticancer drug therapy, a specialized approach using KDIGO criteria or other criteria is required when nephrologists intervene in treatment. Each drug is associated with the different disorders related to the kidney. And various risk factors for kidney disease associated with each anticancer drug therapy.

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Preparation and pharmaceutical properties of Hangeshashinto oral ointment and its safety and efficacy in Syrian hamsters with 5-fluorouracil-induced oral mucositis

Ogihara T., Kagawa M., Yamanaka R., Imai S., Itohara K., Hira D., Nakagawa S., Yonezawa A., Ito M., Nakagawa T., Terada T., Matsubara K.

Journal of Natural Medicines （Journal of Natural Medicines） 77 （ 1 ） 53 - 63 2023年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13403443

Chemotherapy-induced oral mucositis (COM) is a common adverse effect of cancer chemotherapy. Several clinical studies reported that repetitive use of mouthwashes containing 2.5–6.25% Hangeshashinto (HST), a Kampo formula, relieves COM, but the effect is insufficient. To solve this problem, we produced an oral ointment of 12% HST extract (considered quantitatively equivalent to 20% commercially available HST), which will increase the local concentrations of its active ingredients and prolong the contact time with COM. In this study, we evaluated the pharmaceutical properties (spreadability and stability) of HST oral ointment. In addition, its safety (oral mucosal irritation) and therapeutic effects on 5-fluorouracil-induced oral mucositis were evaluated in male Syrian hamsters. The HST ointment showed good spreadability and stability for more than 8 weeks at 4 °C. In the oral mucosal irritation test, topical application of HST ointment (0.2 g) three times per day for 14 days had no adverse effect on the oral mucosa of hamsters. In hamsters treated with 5-fluorouracil (60 mg/kg) twice, COM was induced by a submucosal injection of 5% acetic acid into the cheek pouch. When HST ointment (50 µg) was topically applied to the mucositis area once per day for 12 days, the area and macroscopic score of mucositis were significantly decreased, and the depth of the wound tended to be reduced compared with the lactose ointment-treated control animals. These findings suggest that HST oral ointment shows good properties in spreadability, stability, and safety, and elicits a therapeutic effect in an animal model of COM. Graphical abstract: [Figure not available: see fulltext.]

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Effect of Severe Renal Dysfunction on the Plasma Levels of DNA-Reactive Platinum after Oxaliplatin Administration

Nakagawa S., Shimazaki A., Funakoshi T., Yonezawa A., Kataoka S., Horimatsu T., Hira D., Itohara K., Imai S., Nakagawa T., Matsubara T., Yanagita M., Muto M., Matsubara K., Terada T.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 46 （ 2 ） 194 - 200 2023年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09186158

Higher amounts of circulating ultrafilterable platinum (fPt) are found in patients with renal dysfunction receiving a constant dose of oxaliplatin. However, the increased systemic fPt levels do not increase oxaliplatin-induced toxicities. We hypothesized that renal dysfunction has minimal effect on the elimination rate of reactive fPt, and that the DNA-binding capacity is one of the properties of reactive Pt species. This study aimed to quantify DNA-reactive fPt in plasma and to evaluate the impact of severe renal dysfunction on its pharmacokinetics. The pharmacokinetics of oxaliplatin was assessed in rats with bilateral nephrectomy (BNx) and in a hemodialysis patient who received mFOLFOX7 therapy for advanced metastatic gastric cancer. The platinum concentrations were determined using inductively coupled plasma-mass spectrometry. The amount of DNA-reactive fPt in the plasma was evaluated by the reaction between plasma and calf thymus DNA. Compared to the sham group in rats, the BNx group had significantly higher plasma total fPt concentrations at 24 h after drug administration. However, there was no significant difference in the plasma levels of DNA-reactive fPt between the two groups. In a hemodialysis patient, the plasma levels of total fPt decreased to 35.9 and 7.3% at 2 and 14 d after treatment, respectively. The plasma level of DNA-reactive fPt also decreased to 1.9 and 0.6%, respectively, on these days. This study showed that severe renal dysfunction has a limited effect on the plasma levels of DNA-reactive fPt after oxaliplatin administration.

Pharmacokinetics of GS-441524, the active metabolite of remdesivir, in patients receiving continuous renal replacement therapy: A case series

Nishikawa A., Ito I., Yonezawa A., Itohara K., Matsubara T., Sato Y., Matsumura K., Hamada S., Tanabe N., Kai S., Imoto E., Yoshikawa K., Ohtsuru S., Yanagita M., Hirai T., Terada T.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 30 （ 4 ） 348 - 351 2023年

研究論文（学術雑誌）, 責任著者, 査読有り, ISSN 1341321X

Remdesivir plays a key role in the treatment of coronavirus disease in 2019 (COVID-19). Haemodialysis is sometimes required for hospitalised patients with COVID-19, and patients undergoing haemodialysis are at an increased risk of severe COVID-19. In the present study, we report the serum concentrations of GS-441524, the active metabolite of remdesivir, in four patients undergoing continuous renal replacement therapy (CRRT). Patient 1, a male aged 70s, received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg remdesivir from day 2, according to the package insert as in non-haemodialysis patients. The mean trough serum concentration of GS-441524 was 783.5 ng/mL, which was approximately 7-fold higher than the mean for patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min. Patients 2-4 received a loading dose of 200 mg remdesivir on day 1, followed by 100 mg once every 2 days from day 2. The mean trough serum concentrations of GS-441524 were 302.2 ng/mL, 585.8 ng/mL and 677.3 ng/mL, respectively. These were 3 to 6-fold higher than the mean for patients with eGFR ≥60 mL/min. The target doses for patients 1, 2, 3, and 4 receiving CRRT were 13.6 mL/kg/h, 6.0–12.5 mL/kg/h, 20.1 mL/kg/h, and 15.1 mL/kg/h, respectively, using a polysulphone membrane. The package insert dose of remdesivir is an overdose for CRRT patients with a target dose of 10–20 mL/kg/h. In low-intensity CRRT, as in Japan, it may be necessary to extend the interval between the doses of remdesivir.

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Removal rate of 5-fluorouracil and its metabolites in patients on hemodialysis: a report of two cases of colorectal cancer patients with end-stage renal failure

Imamaki H., Oura M., Oguro F., Nishikawa Y., Nakagawa S., Funakoshi T., Kataoka S., Horimatsu T., Yonezawa A., Matsubara T., Watanabe N., Muto M., Yanagita M., Ozaki Y.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 93 （ 2 ） 161 - 167 2023年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03445704

Purpose: Hyperammonemia is a serious adverse effect of 5-fluorouracil (5FU) administration. Hemodialysis can be used for its management, but detailed data on the concentrations and removal rate of 5FU and its metabolites during hemodialysis remain unclear. Here, we present two cases of hemodialysis patients with end-stage renal disease who received concurrent 5FU infusion. Methods: Blood samples were collected from the hemodialysis circuit before and after the dialyzer during day 2 hemodialysis sessions, and from the internal shunt just before and after day 4 hemodialysis sessions. The serum levels of 5FU and its metabolites—α-fluoro-β-alanine (FBAL) and monofluoroacetate (FA)—were measured using liquid chromatography-tandem mass spectrometry. Results: Seven sets of blood samples were collected for case 1; the removal rates (mean ± standard deviation) of 5FU and FBAL by the dialyzer were 81.2 ± 23.2% and 96.1 ± 8.6%, respectively (p < 0.001). Three sets of blood samples were collected for case 2; the removal rates of 5FU and FBAL were 81.7 ± 3.9% and 94.8 ± 2.7%, respectively (p = 0.03). Twenty-seven sets of blood samples were collected for case 1; reductions in blood FBAL and FA levels were 49.3 ± 8.8% (p < 0.001) and 64.2 ± 30.3% (p = 0.04), respectively. Bayesian estimation yielded similar results. Three sets of blood samples were collected for case 2; reductions in the blood FBAL and FA levels were 49.9 ± 6.9% and 50.6 ± 33.0%, respectively. Conclusion: In this study, 5FU and its metabolite FBAL were directly removed from the blood by approximately 90% during hemodialysis, and the blood levels of FBAL and FA were reduced by approximately 50% with a single hemodialysis session.

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Comparison of cisplatin-based versus standard preoperative chemotherapy in patients with operable triple-negative breast cancer: propensity score matching and inverse probability of treatment weighting analysis

Yamaguchi A., Kawaguchi K., Kawanishi K., Maeshima Y., Nakakura A., Kataoka T.R., Takahara S., Nakagawa S., Yonezawa A., Takada M., Kawashima M., Kawaguchi-Sakita N., Kotake T., Suzuki E., Shimizu H., Torii M., Morita S., Ishiguro H., Toi M.

Breast Cancer Research and Treatment （Breast Cancer Research and Treatment） 204 （ 2 ） 261 - 275 2023年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01676806

Purpose: The efficacy of carboplatin is non-equivalent to that of cisplatin (CDDP) for various tumor types in curative settings. However, the role of CDDP in operable triple-negative breast cancer (TNBC) patients remains unknown. We conducted a multicenter observational study to examine the effects of CDDP added to preoperative chemotherapy in patients with TNBC. Methods: This retrospective study consecutively included previously untreated patients with stage I–III TNBC treated with preoperative chemotherapy with or without CDDP. The primary endpoint was distant disease-free survival (DDFS). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimize confounding biases in comparisons between the two groups. Results: A total of 138 patients were enrolled in the study. Of these, 52 were in the CDDP group and 86 in the non-CDDP group. DDFS was significantly better in the CDDP group than in the non-CDDP group (unadjusted hazard ratio (HR) 0.127 and p < 0.001, PSM HR 0.141 and p < 0.003, IPTW HR 0.123 and p = < 0.001). Furthermore, among the patients with residual cancer burden (RCB) class II/III, DDFS was better in the CDDP group than in the non-CDDP group (unadjusted HR 0.192 and p = 0.013, PSM HR 0.237 and p = 0.051, IPTW HR 0.124 and p = 0.059). Conclusion: Our study showed that CDDP-containing regimens achieved favorable prognoses in patients with operable TNBC, especially for the RCB class II/III population. Confirmative studies are warranted to elucidate the role of CDDP in TNBC treatment.

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Association between time in therapeutic range of tacrolimus blood concentration and acute rejection within the first three months after lung transplantation

Katada Y., Nakagawa S., Itohara K., Suzuki T., Kato R., Endo H., Sugimoto M., Yonezawa A., Nakagawa T., Ohsumi A., Nakajima D., Date H., Terada T.

Journal of Pharmaceutical Health Care and Sciences （Journal of Pharmaceutical Health Care and Sciences） 8 （ 1 ） 25 - 25 2022年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2055-0294

Background: Tacrolimus is a key drug in immunosuppressive therapy following lung transplantation. The blood tacrolimus levels are likely to fluctuate in the early postoperative period, and failure to maintain the tacrolimus trough level in target ranges is a risk factor for rejection. However, there is little information about the relationship between the time in therapeutic range (TTR) of the tacrolimus trough level (tacrolimus TTR) and clinical outcomes. This study aimed to evaluate the association between tacrolimus TTR and acute rejection (AR) within the first three months after lung transplantation. Methods: This was a retrospective study of patients who underwent lung transplantation at a single center. The target tacrolimus trough levels were 10–15 ng/mL, and tacrolimus TTR was calculated using the Rosendaal method. The cut-off value of the tacrolimus TTR was estimated by receiver operating characteristic analysis based on AR. Results: The study included 90 patients. AR was observed in 26 patients. In this study, ‘‘early-AR’’ was defined as any AR within 2 weeks post-transplant (n = 22) and ‘‘late-AR’’ was defined as any AR after 1-month post-transplant (n = 4). For early AR, the relationship between tacrolimus TTR and the onset of AR was examined. There were no differences in the tacrolimus TTR between the early-AR group and non-AR group (35.7 ± 22.4 vs 31.5 ± 19.9%, P = 0.416). For late-AR, the relationship with tacrolimus TTR was examined every 10 d. The tacrolimus TTR during postoperative days (POD) 21–30 and POD 31–onset was significantly lower in the late-AR group than the no-AR group (50.0 ± 7.1 vs. 71.8 ± 18.0% and 37.0 ± 26.6 vs. 68.9 ± 31.5%, P < 0.05, respectively). The cutoff value of the tacrolimus TTR during POD 21–30 was estimated as 55.0%. Conclusions: Our findings suggest that a lower tacrolimus TTR is a predictor of late AR. A tacrolimus TTR of 55% or higher is necessary to reduce the risk of AR during this period after lung transplantation.

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Use of proton pump inhibitors and macrolide antibiotics and risk of acute kidney injury: a self-controlled case series study

Ikuta K., Nakagawa S., Yamawaki C., Itohara K., Hira D., Imai S., Yonezawa A., Nakagawa T., Sakuragi M., Sato N., Uchino E., Yanagita M., Terada T.

BMC Nephrology （BMC Nephrology） 23 （ 1 ） 383 - 383 2022年12月

研究論文（学術雑誌）, 共著, 査読有り

Background: Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal disorders such as peptic ulcer disease and dyspepsia. However, several studies have suggested that PPI use increases the risk of acute kidney injury (AKI). PPIs are often concomitantly used with antibiotics, such as macrolides and penicillins for Helicobacter pylori eradication. Although macrolide antibiotics are considered to have relatively low nephrotoxicity, they are well known to increase the risk of AKI due to drug-drug interactions. In this study, we aimed to investigate the association between PPI use and the development of AKI. We also evaluated the effect of concomitant use of PPIs and macrolide antibiotics on the risk of AKI. Methods: This self-controlled case series study was conducted using electronic medical records at Kyoto University Hospital. We identified patients who were prescribed at least one PPI and macrolide antibiotic between January 2014 and December 2019 and underwent blood examinations at least once a year. An adjusted incident rate ratio (aIRR) of AKI with PPI use or concomitant use macrolide antibiotics with PPIs was estimated using a conditional Poisson regression model controlled for the estimated glomerular filtration rate at the beginning of observation and use of potentially nephrotoxic antibiotics. Results: Of the 3,685 individuals who received PPIs and macrolide antibiotics, 766 patients with episodes of stage 1 or higher AKI were identified. Any stage of AKI was associated with PPI use (aIRR, 1.80 (95% confidence interval (CI) 1.60 to 2.04)). Stage 2 or higher AKI was observed in 279 cases, with an estimated aIRR of 2.01 (95% CI 1.57 to 2.58, for PPI use). For the period of concomitant use of macrolide antibiotics with PPIs compared with the period of PPIs alone, an aIRR of stage 1 or higher AKI was estimated as 0.82 (95% CI 0.60 to 1.13). Conclusions: Our findings added epidemiological information for the association between PPI use and an increased risk of stage 1 or higher AKI. However, we did not detect an association between the concomitant use of macrolide antibiotics and an increased risk of AKI in PPI users.

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Population pharmacokinetics of everolimus in adult liver transplant patients: Comparison to tacrolimus disposition and extrapolation to pediatrics

Itohara K., Yano I., Nakagawa S., Sugimoto M., Hirai M., Yonezawa A., Imai S., Nakagawa T., Hira D., Ito T., Hata K., Hatano E., Terada T., Matsubara K.

Clinical and Translational Science （Clinical and Translational Science） 15 （ 11 ） 2652 - 2662 2022年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17528054

Everolimus has recently been used to prevent graft rejection in liver transplantation and reduces the incidence of kidney dysfunction caused by calcineurin inhibitors. In this study, a population pharmacokinetic analysis was conducted to improve the individualization of everolimus therapy. Japanese post-liver transplant patients whose blood everolimus concentrations were measured between March 2018 and December 2020 were included in this study. A nonlinear mixed-effect modeling program was used to explore covariates that affect everolimus pharmacokinetics. Individual everolimus pharmacokinetic parameters estimated by the post-hoc Bayesian analysis using the final model were compared with the tacrolimus dose per trough concentration (D/C) ratio in each patient. The final model was extrapolated to pediatric liver transplant patients for external evaluation. A total of 937 concentrations from 87 adult patients were used in the model-building process. Everolimus clearance was significantly affected by the estimated glomerular filtration rate, concomitant use of fluconazole, sex, as well as total daily dose of everolimus (TDM effect). The estimated individual apparent clearance of everolimus by the post-hoc Bayesian analysis was moderately correlated with the D/C ratio of tacrolimus in each patient (R2 = 0.330, p < 0.0001). The estimation accuracy in pediatric patients was considerably high, except for one infant out of 13 patients. In conclusion, population pharmacokinetic analysis clarified several significant covariates for everolimus pharmacokinetics in liver transplant patients. Everolimus pharmacokinetics moderately correlated with tacrolimus pharmacokinetics and could be extrapolated from adult to pediatric patients by body size correction, except for infants.

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UNIVERSAL LCMS-BASED ASSAY PLATFORM, REFMAB-Q NSMOL, FOR MONITORING MONOCLONAL ANTIBODY THERAPEUTICS USING ONE REFERENCE ANTIBODY

Iwamoto, N; Koguchi, Y; Yokoyama, K; Hamada, A; Yonezawa, A; Piening, B; Tran, E; Fox, B; Redmond, W; Shimada, T

JOURNAL FOR IMMUNOTHERAPY OF CANCER 10 A9 - A9 2022年11月

研究論文（学術雑誌）, 共著, 査読有り

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N-terminus of Etanercept is Proteolytically Processed by Dipeptidyl Peptidase-4

Masui S., Yonezawa A., Yokoyama K., Iwamoto N., Shimada T., Onishi A., Onizawa H., Fujii T., Murakami K., Murata K., Tanaka M., Nakagawa S., Hira D., Itohara K., Imai S., Nakagawa T., Hayakari M., Matsuda S., Morinobu A., Terada T., Matsubara K.

Pharmaceutical Research （Pharmaceutical Research） 39 （ 10 ） 2541 - 2554 2022年10月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 07248741

Purpose: Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties. Methods: An analytical method using liquid chromatography-mass spectrometry (LC–MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-β was investigated using an in-house enzyme-linked immunosorbent assay. Results: In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-β and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro. Conclusions: ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins.

抗うつ薬併用下における直接経口抗凝固薬による出血リスクの検討

小島悠輔, 片田佳希, 中川俊作, 重面雄紀, 圓東寛基, 山本将太, 米澤淳, 中川貴之, 松原和夫, 杉田尚子, 村井俊哉, 寺田智祐

医療薬学（(一社)日本医療薬学会） 48 （ 9 ） 419 - 428 2022年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

直接経口抗凝固薬(DOAC)使用中に選択的セロトニン再取り込み阻害薬(SSRI)やセロトニン・ノルアドレナリン再取り込み阻害薬(SNRI)を併用した入院患者17名(女性12例、男性5例、年齢67.9±12.6歳)における出血性有害反応の発現状況を後方視的に調査し、大出血の発現が確認された患者背景の傾向について検討した。REPLACE-2出血基準、RE-LY出血基準を用いて定義した大出血は、抗うつ薬併用時の4例(23.5%)に認められ、患者背景に起因するリスク因子については大出血との関連性が小さいことが示唆されたが、出血性有害反応の発現時期の傾向はみられなかった。

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics

Iwamoto N., Koguchi Y., Yokoyama K., Hamada A., Yonezawa A., Piening B.D., Tran E., Fox B.A., Redmond W.L., Shimada T.

Analyst （Analyst） 147 （ 19 ） 4275 - 4284 2022年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00032654

Accurate quantitation of antibodies is critical for development of monoclonal antibody therapeutics (mAbs). Therapeutic drug monitoring has been applied to measure levels of mAbs in clinics for dose adjustment for autoimmune disease. Trough levels of mAbs can be a biomarker for cancer immunotherapy. Thus, the deployment of a rapid and universal platform for mAb monitoring may benefit processes ranging from drug development to clinical practice for a wide spectrum of diseases. However, mAb monitoring often requires development and conduct of an individual ligand binding assay such as ELISA, which is impractical to scale. We streamlined quantitation of antibody therapeutics by a nano-surface and molecular-orientation limited (nSMOL) proteolysis assay using LC-MS with a universal reference antibody (refmAb-Q), for accurate multiplexed quantitation of unique signature peptides derived from mAbs. This innovative refmAb-Q nSMOL platform may provide a practical solution for quantitating an ever-increasing number of mAbs from developmental to clinical use settings.

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Improved absorption of itraconazole tablet by co-administration with lemon beverages in a lung transplant recipient: A case report

Umemura K., Katada Y., Nakagawa S., Sugimoto M., Matsumura K., Yonezawa A., Nagao M., Ohsumi A., Date H., Terada T.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 28 （ 8 ） 1203 - 1207 2022年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341321X

After lung transplantation, itraconazole (ITCZ) is used as a prophylaxis for aspergillosis. ITCZ is a weak base with high lipophilicity, and the dissolution and absorption of ITCZ tablets and capsules are pH dependent. Therefore, ITCZ may not achieve sufficient serum concentrations in patients with higher gastric pH because of its poor bioavailability. We report a case of a woman in fifties with post-COVID-19 respiratory failure who successfully underwent lung transplantation, followed by improved bioavailability of ITCZ tablets when given with acidic lemon beverages. The patient was initially administered ITCZ oral solution; this was discontinued because of its unpleasant taste, nausea, and vomiting. The ITCZ oral solution was replaced with ITCZ tablets 78 days after transplantation; however, serum concentrations of ITCZ and hydroxy-ITCZ were below the detection limit (100 ng/mL). We co-administered ITCZ tablets with commercially available lemon beverages. Subsequently, serum concentrations of ITCZ and hydroxy-ITCZ increased to 341 and 673 ng/mL, respectively, on the 125th day after transplantation. Infection with fungi, including Aspergillus spp., was not observed in this case. The patient had no adverse events such as gastric ulcer or hyperglycemia. These results suggest that the co-administration of lemon beverages and ITCZ tablets may help achieve better absorption of ITCZ in patients taking acid suppressants.

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Therapeutic Drug Monitoring of Antibody Drugs

Yonezawa A.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 45 （ 7 ） 843 - 846 2022年07月

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

In recent years, many antibody drugs that play an important role in the pharmacotherapy of several diseases have been developed. Antibody drugs exhibit immunogenicity in vivo leading to the development of antibodies against the antibody drug (anti-drug antibody). Nonetheless, other factors also affect the pharmacokinetics of antibody drugs. Recently, therapeutic drug monitoring (TDM) of infliximab was introduced for personalized medicine. However, the usefulness of TDM in antibody therapy remains unclear. In addition to intervention studies, real-world data analysis is important. Unlike small-molecule drugs, antibody drugs do not have a uniform molecular weight; therefore, using the conventional analysis methods, it is impossible to determine the true pharmacokinetic outcomes of these agents. To analyze structural changes of antibody drugs in the body, new technologies are necessary. In the future, along with the development of new drugs, the establishment of novel analytical methods is essential to facilitate the promotion of personalized medicine.

Assessment of Suvorexant and Eszopiclone as Alternatives to Benzodiazepines for Treating Insomnia in Patients With Major Depressive Disorder

Shigetsura Y., Imai S., Endo H., Shimizu Y., Ueda K., Murai T., Itohara K., Nakagawa S., Yonezawa A., Ikemi Y., Fukatsu S., Kitada N., Terada T., Nakagawa T., Matsubara K.

Clinical neuropharmacology （Clinical neuropharmacology） 45 （ 3 ） 52 - 60 2022年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03625664

OBJECTIVES: We investigated the utility of switching from benzodiazepines to suvorexant or eszopiclone to manage benzodiazepine-unresponsive insomnia in patients with major depressive disorder (MDD) in a randomized, open-label study. METHODS: Patients with MDD who have insomnia symptoms (a score of >7 on the Insomnia Severity Index Japanese version [ISI-J]), who had received benzodiazepine treatment for more than 2 weeks (n = 18) were randomized to 4 weeks of suvorexant (20 or 15 mg/d) or eszopiclone (3 or 2 mg/d) treatment. The primary endpoint was an improvement in insomnia severity from baseline assessed by the ISI-J score at 2 and 4 weeks after switching from benzodiazepines. The secondary endpoints included changes in the scores of the Pittsburgh Sleep Quality Index Japanese version, the Beck Depression Inventory II, Generalized Anxiety Disorder 7, the digit span test, and the digit symbol substitution test from baseline. Adverse events were recorded throughout the study. RESULTS: Patients taking suvorexant or eszopiclone had improved ISI-J scores (-4.3 for suvorexant and -4.1 for eszopiclone at week 4; P = 0.04 for eszopiclone). Both drugs tended to improve the Beck Depression Inventory II and Generalized Anxiety Disorder 7 scores 2 and 4 weeks after switching. The Pittsburgh Sleep Quality Index Japanese version, digit symbol substitution test, and digit span test scores and the incidence of adverse events did not change from baseline. CONCLUSIONS: Switching to suvorexant or eszopiclone was well tolerated and improved the severity of benzodiazepine-unresponsive insomnia in MDD patients. Both drugs could be beneficial alternatives to benzodiazepines for treating insomnia in MDD patients.

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Recent advances in riboflavin transporter RFVT and its genetic disease

Jin C., Yonezawa A.

Pharmacology and Therapeutics （Pharmacology and Therapeutics） 233 108023 - 108023 2022年05月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者, 査読有り, ISSN 01637258

Riboflavin (vitamin B2) is essential for cellular growth and function. It is enzymatically converted to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which participate in the metabolic oxidation-reduction reactions of carbohydrates, amino acids, and lipids. Human riboflavin transporters RFVT1, RFVT2, and RFVT3 have been identified and characterized since 2008. They are highly specific transporters of riboflavin. RFVT3 has functional characteristics different from those of RFVT1 and RFVT2. RFVT3 contributes to absorption in the small intestine, reabsorption in the kidney, and transport to the fetus in the placenta, while RFVT2 mediates the tissue distribution of riboflavin from the blood. Several mutations in the SLC52A2 gene encoding RFVT2 and the SLC52A3 gene encoding RFVT3 were found in patients with a rare neurological disorder known as Brown-Vialetto-Van Laere syndrome. These patients commonly present with bulbar palsy, hearing loss, muscle weakness, and respiratory symptoms in infancy or later in childhood. A decrease in plasma riboflavin levels has been observed in several cases. Recent studies on knockout mice and patient-derived cells have advanced the understanding of these mechanisms. Here, we summarize novel findings on RFVT1–3 and their genetic diseases and discuss their potential as therapeutic drugs.

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Effect of Itraconazole and Its Metabolite Hydroxyitraconazole on the Blood Concentrations of Cyclosporine and Tacrolimus in Lung Transplant Recipients

Matsuda Y., Nakagawa S., Yano I., Masuda S., Imai S., Yonezawa A., Yamamoto T., Sugimoto M., Tsuda M., Tsuzuki T., Omura T., Nakagawa T., Chen-Yoshikawa T.F., Nagao M., Date H., Matsubara K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 45 （ 4 ） 397 - 402 2022年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09186158

Invasive Aspergillus infection is a major factor for poor prognosis in patients receiving lung transplantation (LT). An antifungal agent, itraconazole (ITCZ), that has antimicrobial activity against Aspergillus species, is used as a prophylactic agent against Aspergillus infection after LT. ITCZ and its metabolite, hydroxyitraconazole (OH-ITCZ), potently inhibit CYP3A and P-glycoprotein that metabolize or excrete calcineurin inhibitors (CNIs), which are the first-line immunosuppressants used after LT; thus, concomitant use of ITCZ and CNIs could induce an increase in the blood concentration of CNIs. However, no criteria for dose reduction of CNIs upon concomitant use with ITCZ in LT recipients have been defined. In this study, the effect of ITCZ and OH-ITCZ on the blood concentrations of two CNIs, tacrolimus and cyclosporine, after LT were retrospectively evaluated. A total of 39 patients who received LT were evaluated. Effects of ITCZ and OH-ITCZ on the concentration/dosage (C/D) ratio of tacrolimus and cyclosporine were analyzed using linear mixed-effects models. The plasma concentrations of OH-ITCZ were about 2.5-fold higher than those of ITCZ. Moreover, there was a significant correlation between the plasma concentrations of ITCZ and OH-ITCZ. Based on parameters obtained in the linear regression analysis, the C/D ratios of cyclosporine and tacrolimus increase by an average of 2.25- and 2.70-fold, respectively, when the total plasma concentration of ITCZ plus OH-ITCZ is 1000ng/mL. In conclusion, the plasma levels of ITCZ and OH-ITCZ could be key factors in drawing up the criterion for dose reduction of CNIs.

ロフラゼプ酸エチル活性代謝物の褥婦母乳およびその児の血中濃度を測定した2症例

森田真樹子, 米澤淳, 大村友博, 中川俊作, 志田あゆみ, 今井哲司, 河井昌彦, 松倉崇, 丹羽房子, 岩永甲午郎, 伊尾紳吾, 近藤英治, 松原和夫

医療薬学（(一社)日本医療薬学会） 48 （ 4 ） 149 - 153 2022年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

鬱病に対しロフラゼプ酸エチル(LOF)を妊娠中に服用しており、産後も必要と判断された患者2名とその児を対象として、LOFの活性代謝物の母乳中濃度と血中濃度を測定した。母乳移行率は2例とも約0.3であった。相対的乳児薬物摂取量(RID)は症例1が2.3%、症例2が3.9%で、出産直後の期間は母乳を介してLOFが乳児に及ぼす影響は軽微であった。日齢が進み、哺乳量が100mL以上に増加するとRIDが10%を超えると予想されるため、母親の希望で退院後は両症例とも人工ミルクを併用した。

Infliximab Treatment Persistence among Japanese Patients with Chronic Inflammatory Diseases: A Retrospective Japanese Claims Data Study

Masui S., Yonezawa A., Momo K., Nakagawa S., Itohara K., Imai S., Nakagawa T., Matsubara K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 45 （ 3 ） 323 - 332 2022年03月

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

Infliximab (IFX) has contributed to the treatment of several chronic inflammatory diseases, including Crohn's disease (CD), ulcerative colitis (UC), psoriasis (Pso), and rheumatoid arthritis (RA). However, the loss of response in some patients with long-term IFX therapy has been a major problem. Randomized controlled trials (RCTs) are limited in their short duration and lack of generalizability to the real-world population. We aimed to describe the persistence rates of IFX therapy to estimate its long-term effectiveness in clinical practice. Claims data from the Japan Medical Data Center database from January 2005 to June 2017 were used. The study population was identified based on the International Classification of Diseases, 10th Revision and the Anatomical Therapeutic Chemical Classification System. The 5-year persistence rates of IFX therapy were estimated using the Kaplan-Meier method. Overall, 281, 235, 41, and 222 patients with CD, UC, Pso, and RA, respectively, were selected. The 5-year persistence rates for IFX claims were 62.9, 38.9, 22.1, and 28.1% in patients with CD, UC, Pso, and RA, respectively. Patients with CD and UC administered IFX beyond the median dose had higher persistence rates. In patients with RA, female sex and no prior use of other biologics were associated with longer persistence. In conclusion, IFX persistence rates differed across chronic inflammatory diseases, which did not correspond to the results of the major RCTs. Factors associated with longer IFX persistence were identified in each disease group. Our findings may provide useful information to facilitate the proper use of IFX.

抗真菌剤併用下で多剤併用がん化学療法による有害反応を回避できた肺移植後リンパ増殖性疾患の1例

梅山遥, 北田徳昭, 片田佳希, 杉本充弘, 櫻井香織, 野口葉子, 池見泰明, 中川俊作, 米澤淳, 中川貴之, 菱澤方勝, 高折晃史, 松原和夫

日本病院薬剤師会雑誌（(一社)日本病院薬剤師会） 58 （ 3 ） 325 - 329 2022年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-8815

がん化学療法における薬物相互作用はときにがん化学療法の効果や副作用に影響をもたらすことがある。我々は移植後リンパ増殖性疾患患者に対し、シクロホスファミド、ピンクリスチン、プレドニゾロン併用療法(CVP療法)を施行するにあたり、抗がん薬、抗真菌薬および免疫抑制薬の相互作用による有害反応を回避するため、感染予防目的に投与したアゾール系抗真菌薬の変更および一時的休薬、免疫抑制薬の精密な投与設計を行うことで化学療法を完遂できた症例を経験した。これまでに免疫抑制薬、抗真菌薬を併用し、薬物相互作用を検討しつつ、がん化学療法を安全に施行した報告は少ない。今回の知見は、免疫抑制療法施行中という特殊条件下にある患者で、がん化学療法の副作用および合併症を制御しながら化学療法を施行するうえで有用と考えられる。(著者抄録)

Extrapolation of physiologically based pharmacokinetic model for tacrolimus from renal to liver transplant patients

Itohara K., Yano I., Nakagawa S., Yonezawa A., Omura T., Imai S., Nakagawa T., Sawada A., Kobayashi T., Tochio A., Sakai K., Taura K., Ogawa O., Matsubara K.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics） 42 100423 - 100423 2022年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

Physiologically based pharmacokinetic (PBPK) modeling is useful for evaluating differences in drug exposure among special populations, but it has not yet been employed to evaluate the absorption process of tacrolimus. In this study, we developed a minimal PBPK model with a compartmental absorption and transit model for renal transplant patients using available data in the literature and clinical data from our hospital. The effective permeability value of tacrolimus absorption and parameters for the single adjusting compartment were optimized via sensitivity analyses, generating a PBPK model of tacrolimus for renal transplant patients with good predictability. Next, we extrapolated the pharmacokinetics of tacrolimus for liver transplant patients by changing the population demographic parameters of the model. When the physiological parameters of a population with normal liver function were changed to those of a population with impaired hepatic function (Child-Pugh class A) in the constructed renal transplant PBPK model, the predicted tacrolimus concentrations were consistent with the observed concentrations in liver transplant patients. In conclusion, the constructed tacrolimus PBPK model for renal transplant patients could predict the pharmacokinetics in liver transplant patients by slightly reducing the hepatic function, even at three weeks post-transplantation.

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Risk factors of breakthrough aspergillosis in lung transplant recipients receiving itraconazole prophylaxis

Katada Y., Nakagawa S., Nagao M., Yoshida Y., Matsuda Y., Yamamoto Y., Itohara K., Imai S., Yonezawa A., Nakagawa T., Matsubara K., Tanaka S., Nakajima D., Date H., Terada T.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 28 （ 1 ） 54 - 60 2022年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341321X

Introduction: Invasive Aspergillus infection (IA) in lung transplantation can result in poor outcomes. Itraconazole has been shown to be effective for fungal prophylaxis in lung transplant recipients. However, IA remains a major cause of death after lung transplantation. Therefore, we aimed to clarify the risk factors for IA on itraconazole prophylaxis. Methods: We examined 120 recipients to uncover their IA epidemiology, clinical characteristics, and outcomes. In addition, a case-control study was performed to identify risk factors of IA. Results: Of the 120 patients, 12 developed IA under itraconazole prophylaxis. The patient demographics and clinical characteristics were compared among the following two groups: IA group, 12 patients, and control group, 108 patients. Significant differences were observed in age (p = 0.004), history of interstitial pneumonia (p = 0.032), and CMV infection (p < 0.001) between the groups. Before the onset of IA, 92% (11/12) of the patients received itraconazole with trough concentrations above the therapeutic range. IA developed at 272.9 ± 114.1 days after lung transplantation. Of the 12 patients who developed IA, 66.7% (8/12) had early cessation of cytomegalovirus (CMV) prophylaxis due to toxicity of valganciclovir, as follows: leukocytopenia in 4 patients, and renal dysfunction in 4 patients. Of the 8 patients who stopped valganciclovir, 75% (6/8) developed CMV infection subsequently. Conclusion: This study suggests that older age, history of interstitial pneumonia, and CMV infection may be important risk factors for IA on itraconazole prophylaxis. These results may help clinicians optimize prophylactic strategies for IA.

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Population pharmacokinetic modeling of GS-441524, the active metabolite of remdesivir, in Japanese COVID-19 patients with renal dysfunction

Sukeishi A., Itohara K., Yonezawa A., Sato Y., Matsumura K., Katada Y., Nakagawa T., Hamada S., Tanabe N., Imoto E., Kai S., Hirai T., Yanagita M., Ohtsuru S., Terada T., Ito I.

CPT: Pharmacometrics and Systems Pharmacology （CPT: Pharmacometrics and Systems Pharmacology） 11 （ 1 ） 94 - 103 2022年01月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 2163-8306

Remdesivir, a prodrug of the nucleoside analog GS-441524, plays a key role in the treatment of coronavirus disease 2019 (COVID-19). However, owing to limited information on clinical trials and inexperienced clinical use, there is a lack of pharmacokinetic (PK) data in patients with COVID-19 with special characteristics. In this study, we aimed to measure serum GS-441524 concentrations and develop a population PK (PopPK) model. Remdesivir was administered at a 200 mg loading dose on the first day followed by 100 mg from day 2, based on the package insert, in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 ml/min. In total, 190 concentrations from 37 Japanese patients were used in the analysis. The GS-441524 trough concentrations were significantly higher in the eGFR less than 60 ml/min group than in the eGFR greater than or equal to 60 ml/min group. Extracorporeal membrane oxygenation in four patients hardly affected the total body clearance (CL) and volume of distribution (Vd) of GS-441524. A one-compartment model described serum GS-441524 concentration data. The CL and Vd of GS-441524 were significantly affected by eGFR readjusted by individual body surface area and age, respectively. Simulations proposed a dose regimen of 200 mg on day 1 followed by 100 mg once every 2 days from day 2 in patients with an eGFR of 30 ml/min or less. In conclusion, we successfully established a PopPK model of GS-441524 using retrospectively obtained serum GS-441524 concentrations in Japanese patients with COVID-19, which would be helpful for optimal individualized therapy of remdesivir.

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レテルモビルの中止によりボリコナゾールの血中濃度が著明に上昇した造血幹細胞移植後の1症例

石村裕樹, 片田佳希, 梅山遥, 杉本充弘, 北田徳昭, 米澤淳, 中川貴之, 新井康之, 高折晃史, 寺田智祐

日本病院薬剤師会雑誌（(一社)日本病院薬剤師会） 58 （ 1 ） 35 - 39 2022年01月

共著, 査読有り, ISSN 1341-8815

ボリコナゾール(voriconazole:以下、VRCZ)はチトクロームP450(cytochrome P450:以下、CYP)を介した併用薬剤との相互作用が多数報告されている。一方、併用薬中止後のVRCZ投与量や血中濃度の推移、および副作用を詳細に記述した報告は限られる。今回、CYP誘導作用を有するレテルモビル(letermovir:以下、LMV)中止後に、VRCZのトラフ値が著明に上昇した症例を経験した。40歳代の女性で、造血幹細胞移植後にLMVとVRCZの投与を開始した。VRCZのトラフ値は1.1～1.9μg/mLで推移していたが、LMV中止7日後に視覚障害、29日後に肝障害を認め、33日後にトラフ値が9.0μg/mLに上昇していた。LMV中止後は、酵素誘導解除に伴うCYP発現量の減少により、VRCZ血中濃度が上昇する可能性が高いため、きめ細やかなモニタリングが必要と考えられる。(著者抄録)

A Nationwide Questionnaire Survey on Awake Craniotomy in Japan

Kawata M., Fukui A., Mineharu Y., Kikuchi T., Yamao Y., Yamamoto Hattori E., Shiraki A., Mizota T., Furukawa K., Miyamoto S., Yonezawa A., Arakawa Y.

Neurologia Medico-Chirurgica （Neurologia Medico-Chirurgica） 62 （ 6 ） 278 - 285 2022年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 04708105

The number of awake craniotomies is increasing because of its beneficial features. However, not enough information is available regarding the current status of awake craniotomy in Japan. To evaluate the current status of awake craniotomy in institutes, a nationwide questionnaire survey was conducted. From June to August 2019, we conducted a questionnaire survey on awake craniotomy in the neurosurgery department of 45 institutes that perform awake craniotomies in Japan. Responses were obtained from 39 institutes (response rate, 86.7%). The main methods of awake craniotomy were almost the same in all institutes. Twenty-six institutes (66.7%) had fewer than 10 awake craniotomies (low-volume institutes) per year, and 13 high-volume institutes (33.3%) performed more than 10 awake craniotomies annually. Some institutes experienced a relatively high frequency of adverse events. In 11 institutes (28.2%), the frequency of intraoperative seizures was more than 10%. An intraoperative seizure frequency of 1%-9%, 10%-29%, and over 30% was identified in 12 (92%), 0 (0%), and 1 (8%) of the high-volume institutes, which was significantly less than in 16 (62%), 10 (38%), and 0 (0%) of the lowvolume institutes (p = 0.0059). The routine usage of preoperative antiepileptic drugs was not different between them, but the old type was used more often in the low-volume institutes (p = 0.0022). Taken together, the annual number of awake craniotomies was less than 10 in over two-thirds of the institutes. Fewer intraoperative seizures were reported in the high-volume institutes, which tend not to preoperatively use the old type of antiepileptic drugs.

MicroRNA-101 Regulates 6-Hydroxydopamine-Induced Cell Death by Targeting Suppressor/Enhancer Lin-12-Like in SH-SY5Y Cells

Omura T., Nomura L., Watanabe R., Nishiguchi H., Yamamoto K., Imai S., Nakagawa S., Itohara K., Yonezawa A., Nakagawa T., Kunimasa J., Yano I., Matsubara K.

Frontiers in Molecular Neuroscience （Frontiers in Molecular Neuroscience） 14 748026 2021年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 16625099

Endoplasmic reticulum (ER) stress has been reported as a cause of Parkinson’s disease (PD). We have previously reported that the ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and its stabilizing factor suppressor/enhancer lin-12-like (SEL1L) participate in the ER stress. In addition, we recently demonstrated that neuronal cell death is enhanced in the cellular PD model when SEL1L expression is suppressed compared with cell death when HRD1 expression is suppressed. This finding suggests that SEL1L is a critical key molecule in the strategy for PD therapy. Thus, investigation into whether microRNAs (miRNAs) regulate SEL1L expression in neurons should be interesting because relationships between miRNAs and the development of neurological diseases such as PD have been reported in recent years. In this study, using miRNA databases and previous reports, we searched for miRNAs that could regulate SEL1L expression and examined the effects of this regulation on cell death in PD models created by 6-hydroxydopamine (6-OHDA). Five miRNAs were identified as candidate miRNAs that could modulate SEL1L expression. Next, SH-SY5Y cells were exposed to 6-OHDA, following which miR-101 expression was found to be inversely correlated with SEL1L expression. Therefore, we selected miR-101 as a candidate miRNA for SEL1L modulation. We confirmed that miR-101 directly targets the SEL1L 3′ untranslated region, and an miR-101 mimic suppressed the 6-OHDA–induced increase in SEL1L expression and enhanced cell death. Furthermore, an miR-101 inhibitor suppressed this response. These results suggest that miR-101 regulates SEL1L expression and may serve as a new target for PD therapy.

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Pharmacist-physician collaborative care for outpatients with left ventricular assist devices using a cloud-based home medical management information-sharing system: a case report

Katada Y., Yonezawa A., Utsumi M., Kitada N., Sato Y.k., Matsumura K., Sukeishi A., Nakagawa S., Imai S., Nakagawa T., Minakata K., Kanemitsu H., Minatoya K., Nomoto S., Matsubara K.

Journal of Pharmaceutical Health Care and Sciences （Journal of Pharmaceutical Health Care and Sciences） 7 （ 1 ） 5 - 5 2021年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2055-0294

Background: The standard anticoagulation therapy for patients implanted with left ventricular assist devices (LVADs) includes warfarin therapy. We developed a cloud-based home medical management information-sharing system named as LVAD@home. The LVAD@home system is an application designed to be used on iPad tablet computers. This system enables the sharing of daily information between a patient and care providers in real time. In this study, we reported cases of outpatients with LVADs using this system to manage anticoagulation therapy. Case presentation: The patient, a man in his 40s with end-stage heart failure owing to non-ischemic dilated cardiomyopathy, underwent LVAD implantation and warfarin was started on postoperative day 1. He started to use LVAD@home to manage warfarin therapy after discharge (postoperative day 47). He sent his data to care providers daily. By using this system, the pharmacist observed his signs of reduced dietary intake 179 days after discharge, and after consulting the physician, told the patient to change the timing of the next measurement earlier than usual. On the next day, the prothrombin time-international normalized ratio increased from 2.0 to 3.0, and thus the dose was decreased by 0.5 mg. Four patients used this system to monitor warfarin therapy from October 2015 to March 2018. In these patients, the time in therapeutic range was 90.1 ± 1.3, which was higher than that observed in previous studies. Additionally, there were no thromboembolic events or bleeding events. Conclusions: The cloud-based home management system can be applied to share real-time patient information of factors, including dietary intake that interact with warfarin. It can help to improve long-term anticoagulation outcomes in patients implanted with LVAD.

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投稿論文紹介覚醒下開頭術麻酔管理の現況　全国アンケート調査

溝田敏幸, 濱田美帆, 菊池隆幸, 峰晴陽平, 山尾幸広, 服部悦子[山本], 川内豪, 米澤淳, 福井彩香, 松井馨大, 古川恵子, 荒川芳輝

麻酔（克誠堂出版(株)） 70 （ 11 ） 1244 - 1248 2021年11月

筆頭著者, 最終著者, 責任著者, 査読有り, ISSN 00214892

覚醒下開頭術麻酔管理の現況全国アンケート調査

溝田敏幸, 濱田美帆, 菊池隆幸, 峰晴陽平, 山尾幸広, 服部悦子[山本], 川内豪, 米澤淳, 福井彩香, 松井馨大, 古川恵子, 荒川芳輝

麻酔（克誠堂出版(株)） 70 （ 11 ） 1244 - 1248 2021年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-4892

わが国における覚醒下開頭術の麻酔管理の実態を明らかにするため、全国アンケート調査を行った。国内で覚醒下開頭術を実施している45施設にアンケートを実施し、19施設(42.2%)から回答を得た。覚醒前(開頭時)にプロポフォールとレミフェンタニルによる全身麻酔を施行しラリンジアルマスクによる気道確保を行う点はほとんどの施設で共通していた一方で、頭部浸潤に使用する局所麻酔薬の種類・濃度・投与量や、覚醒後(閉頭時)の麻酔管理方法などは施設により大きく異なることが明らかになった。今後これらの管理方法を検証しガイドラインに反映していくことが必要と考えられる。(著者抄録)

Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data

Nakae K., Masui S., Yonezawa A., Hashimoto M., Watanabe R., Murata K., Murakami K., Tanaka M., Ito H., Yokoyama K., Iwamoto N., Shimada T., Nakamura M., Denda M., Itohara K., Nakagawa S., Ikemi Y., Imai S., Nakagawa T., Hayakari M., Matsubara K.

PLoS ONE （PLoS ONE） 16 （ 10 October ） e0258601 2021年10月

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

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use.

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Antibiotic-induced microbiome depletion alters renal glucose metabolism and exacerbates renal injury after ischemia-reperfusion injury in mice

Osada Y., Nakagawa S., Ishibe K., Takao S., Shimazaki A., Itohara K., Imai S., Yonezawa A., Nakagawa T., Matsubara K.

American Journal of Physiology - Renal Physiology （American Journal of Physiology - Renal Physiology） 321 （ 4 ） F455 - F465 2021年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1931857X

Recent studies have revealed the impact of antibiotic-induced microbiome depletion (AIMD) on host glucose homeostasis. The kidney has a critical role in systemic glucose homeostasis; however, information regarding the association between AIMD and renal glucose metabolism remains limited. Hence, we aimed to determine the effects of AIMD on renal glucose metabolism by inducing gut microbiome depletion using an antibiotic cocktail (ABX) composed of ampicillin, vancomycin, and levofloxacin in mice. The results showed that bacterial 16s rRNA expression, luminal concentrations of short-chain fatty acids and bile acids, and plasma glucose levels were significantly lower in ABX-treated mice than in vehicle-treated mice. In addition, ABX treatment significantly reduced renal glucose and pyruvate levels. mRNA expression levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the renal cortex were significantly higher in ABX-treated mice than in vehicle-treated mice. We further examined the impact of AIMD on the altered metabolic status in mice after ischemia-induced kidney injury. After exposure to ischemia for 60min, renal pyruvate concentrations were significantly lower in ABX-treated mice than in vehicle-treated mice. ABX treatment caused a more severe tubular injury after ischemia-reperfusion. Our findings confirm that AIMD is associated with decreased pyruvate levels in the kidney, which may have been caused by the activation of renal gluconeogenesis. Thus, we hypothesized that AIMD would increase the vulnerability of the kidney to ischemia-reperfusion injury.

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Factors associated with somnolence during brain function mapping in awake craniotomy

Mizota T., Hamada M., Shiraki A., Kikuchi T., Mineharu Y., Yamao Y., Hattori E.Y., Yonezawa A., Furukawa K., Arakawa Y.

Journal of Clinical Neuroscience （Journal of Clinical Neuroscience） 89 349 - 353 2021年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09675868

Somnolence during brain function mapping is one of the factors that inhibit the accomplishment of the goals of awake craniotomy. We examined the effect of anesthesia depth measured by bispectral index (BIS) during pre-awake phase on somnolence during brain function mapping and also explored the factors associated with somnolence. We examined the association between BIS values during pre-awake phase and somnolence during the first 30 min of brain function mapping in 55 patients who underwent awake craniotomy at Kyoto University Hospital from 2015 to 2018. The pre-awake BIS value was defined as the mean BIS value for 60 min before the removal of the airway. Somnolence during brain function mapping was the primary outcome, defined as either of the following conditions: inability to follow up, disorientation, or inability to assess speech function. Additionally, we compared patient or perioperative variables between patients with/without somnolence. Somnolence occurred in 14 patients (25.5%), of which 6 patients (10.9%) were unable to complete brain function mapping. There was no significant difference in the pre-awake BIS value between patients with/without somnolence (median: 46 vs. 49, P = 0.192). Somnolence was not significantly associated with age, gender, and the number of preoperative anticonvulsive drugs, but patients with somnolence had a significantly lower preoperative Western Aphasia Battery (WAB) aphasia quotient score (median 93.8 vs. 98.6, P = 0.011). We did not find an association between pre-awake BIS value and somnolence during brain function mapping. Somnolence likely occurs in patients with a low preoperative WAB aphasia quotient score.

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Cilostazol is an effective causal therapy for preventing paclitaxel-induced peripheral neuropathy by suppression of Schwann cell dedifferentiation

Koyanagi M., Imai S., Iwamitsu Y., Matsumoto M., Saigo M., Moriya A., Ogihara T., Nakazato Y., Yonezawa A., Nakagawa S., Nakagawa T., Matsubara K.

Neuropharmacology （Neuropharmacology） 188 108514 - 108514 2021年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00283908

Chemotherapy-induced peripheral neuropathy (CIPN) can lead to discontinuation of chemotherapy and is consequently a serious impediment to effective cancer treatment. Due to our limited understanding of mechanisms underlying the pathogenesis of CIPN, no causal therapy has been approved for relief of this condition. We previously demonstrated that taxanes (paclitaxel and docetaxel) induce Schwann cell dedifferentiation, characterized by increased expression of p75 and galectin-3, ultimately leading to demyelination. These changes appear to be responsible for CIPN pathogenesis. This study was designed to identify a novel candidate therapeutic for CIPN with the ability to suppress paclitaxel-induced Schwann cell dedifferentiation. Given that elevation of cyclic adenosine monophosphate (cAMP) signaling participates in Schwann cell differentiation, we performed immunocytochemical screening of phosphodiesterase (PDE) inhibitors. We found that the PDE3 inhibitor cilostazol strongly promoted differentiation of primary cultures of rat Schwann cells via a mechanism involving cAMP/exchange protein directly activated by cAMP (Epac) signaling. Co-treatment with cilostazol prevented paclitaxel-induced dedifferentiation of Schwann cell cultures and demyelination in a mixed culture of Schwann cells and dorsal root ganglia neurons. Notably, continuous oral administration of cilostazol suppressed Schwann cell dedifferentiation within the sciatic nerve and the development of mechanical hypersensitivity in a mouse model of paclitaxel-related CIPN. Importantly, cilostazol potentiated, rather than inhibited, the anti-cancer effect of paclitaxel on the human breast cancer cell line MDA-MB-231. These findings highlight the potential utility of cilostazol as a causal therapeutic that avoids the development of paclitaxel-related CIPN without compromising anti-cancer properties.

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Pronociceptive roles of schwann cell-derived galectin-3 in taxane-induced peripheral neuropathy

Koyanagi M., Imai S., Matsumoto M., Iguma Y., Kawaguchi-Sakita N., Kotake T., Iwamitsu Y., Ntogwa M., Hiraiwa R., Nagayasu K., Saigo M., Ogihara T., Yonezawa A., Omura T., Nakagawa S., Nakagawa T., Matsubara K.

Cancer Research （Cancer Research） 81 （ 8 ） 2207 - 2219 2021年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00085472

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of taxanes such as paclitaxel and docetaxel. Despite the high medical needs, insufficient understanding of the complex mechanism underlying CIPN pathogenesis precludes any endorsed causal therapy to prevent or relieve CIPN. In this study, we report that elevation of plasma galectin-3 level is a pathologic change common to both patients with taxane-treated breast cancer with CIPN and a mouse model of taxane-related CIPN. Following multiple intraperitoneal injections of paclitaxel in mice, galectin-3 levels were elevated in Schwann cells within the sciatic nerve but not in other peripheral organs or cells expressing galectin-3. Consistent with this, paclitaxel treatment of primary cultures of rat Schwann cells induced upregulation and secretion of galectin-3. In vitro migration assays revealed that recombinant galectin-3 induced a chemotactic response of the murine macrophage cell lineRAW264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxelinduced macrophage infiltration and mechanical hypersensitivity. By contrast, chemical depletion of macrophages by clodronate liposomes suppressed paclitaxel-induced mechanical hypersensitivity despite the higher level of plasma galectin-3. Deficiency (Galectin-3-/- mice) or pharmacologic inhibition of galectin-3 inhibited paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. In conclusion, we propose that Schwann cell- derived galectin-3 plays a pronociceptive role via macrophage infiltration in the pathogenesis of taxane-induced peripheral neuropathy. Therapies targeting this phenomenon, which is common to patients with CIPN and mouse models, represent a novel approach to suppress taxane-related CIPN.

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Association of proton pump inhibitors and concomitant drugs with risk of acute kidney injury: A nested case-control study

Ikuta K., Nakagawa S., Momo K., Yonezawa A., Itohara K., Sato Y., Imai S., Nakagawa T., Matsubara K.

BMJ Open （BMJ Open） 11 （ 2 ） e041543 2021年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2044-6055

Objectives This study aimed to assess whether the combined use of proton pump inhibitors (PPIs) with non-steroidal anti-inflammatory drugs (NSAIDs) or antibiotics (penicillins, macrolides, cephalosporins or fluoroquinolones) was associated with an increased risk of acute kidney injury (AKI). Design A nested case-control study. Setting A health insurance claims database constructed by the Japan Medical Data Center. Participants Patients were eligible if they were prescribed a PPI, NSAID and antibiotic at least once between January 2005 and June 2017. The patients who were new PPI users and did not have any history of renal diseases before cohort entry were included (n=219 082). The mean age was 45 and 44% were women. Interventions Current use of PPIs, NSAIDs, or antibiotics. Primary outcome measures Acute kidney injury. Results During a mean follow-up of 2.4 (SD, 1.7) years, 317 cases of AKI were identified (incidence rate of 6.1/10 000 person-years). The current use of PPIs was associated with a higher risk of AKI compared with past PPI use (unadjusted OR, 4.09; 95% CI, 3.09 to 5.44). The unadjusted ORs of AKI for the current use of PPIs with NSAIDs, cephalosporins and fluoroquinolones, compared with the current use of PPIs alone, were 3.92 (95% CI, 2.40 to 6.52), 2.57 (1.43 to 4.62) and 3.08 (1.50 to 6.38), respectively. The effects of concurrent use of PPIs with NSAIDs, cephalosporins or fluoroquinolones remain significant in the adjusted model. The analyses on absolute risk of AKI confirmed the results from the nested case-control study. Conclusions Concomitant use of NSAIDs with PPIs significantly increased the risk for AKI. Moreover, the results suggested that concomitant use of cephalosporins or fluoroquinolones with PPIs was associated with increased risk of incident AKI.

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Complete deletion of Slc52a2 causes embryonic lethality in mice

Jin C., Matsui Y., Yonezawa A., Imai S., Ogihara T., Itohara K., Nakagawa S., Nakagawa T., Matsubara K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 44 （ 2 ） 283 - 286 2021年02月

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

Riboflavin (vitamin B2) plays an important role in cellular growth and function. Riboflavin transporter 2 (RFVT2) is widely expressed in several tissues, especially in the brain and salivary glands, and plays an important role in the tissue disruption of riboflavin. During the last 10 years, mutations in SLC52A2 have been documented in patients with a rare neurological disorder known as Brown–Vialetto–Van Laere syndrome. However, no suitable animal model of this disease has been reported. Here, we aimed to clarify the physiological role of RFVT2 using Slc52a2-mutant mice. The appearance, body weight, and plasma riboflavin concentration of Slc52a2 heterozygous mutant (Slc52a2+/−) mice were similar to those of wild-type (WT) mice. However, intercrossing between Slc52a2+/− mice failed to generate Slc52a2 homozygous mutant (Slc52a2−/−) mice. This suggested that Slc52a2 gene deficiency results in early embryonic lethality. Our findings suggested that RFVT2 is essential for growth and development, and its deletion may influence embryonic survival.

Impact of the catechol-O-methyltransferase Val158Met polymorphism on the pharmacokinetics of l-dopa and its metabolite 3-O-methyldopa in combination with entacapone

Yamamoto J., Omura T., Kasamo S., Yamamoto S., Kawata M., Yonezawa A., Taruno Y., Endo H., Aizawa H., Sawamoto N., Matsubara K., Takahashi R., Tasaki Y.

Journal of Neural Transmission （Journal of Neural Transmission） 128 （ 1 ） 27 - 36 2021年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03009564

In the pharmacotherapy of patients with Parkinson’s disease (PD), entacapone reduces the peripheral metabolism of l-dopa to 3-O-methyldopa (3-OMD), thereby prolonging the half-life (t1/2) of l-dopa and increasing the area under the concentration curve (AUC). The effect of entacapone on the pharmacokinetics of l-dopa differs between patients with high-activity (H/H) and low-activity (L/L) catechol-O-methyltransferase (COMT) Val158Met polymorphisms, but the effects are unclear in heterozygous (H/L) patients. 3-OMD has a detrimental effect and results in a poor response to l-dopa treatment in patients with PD; however, the influence of this polymorphism on the production of 3-OMD remains unknown. Therefore, the present study aimed to clarify the effect of the COMT Val158Met polymorphism on the concentrations of l-dopa and 3-OMD in the presence of entacapone. We performed an open-label, single-period, single-sequence crossover study at two sites in Japan. The study included 54 Japanese patients with PD, who underwent an acute l-dopa administration test with and without 100 mg entacapone on two different days. Entacapone increased l-dopa AUC0–infinity by 1.59 ± 0.26-fold in the H/H group, which was significantly higher than that in the H/L (1.41 ± 0.36-fold) and L/L (1.28 ± 0.21-fold) groups (p < 0.05). The concurrent administration of l-dopa with entacapone suppressed the increase in 3-OMD levels compared with l-dopa alone in all genotypes. Our results suggest that the COMT Val158Met polymorphism may be an informative biomarker for individualized dose adjustment of COMT inhibitors in the treatment of PD.

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STAT3 Polymorphism Associates With mTOR Inhibitor-Induced Interstitial Lung Disease in Patients With Renal Cell Carcinoma

Yamamoto K., Ioroi T., Shinomiya K., Yoshida A., Harada K., Fujisawa M., Omura T., Ikemi Y., Nakagawa S., Yonezawa A., Ogawa O., Matsubara K., Iwamoto T., Nishikawa K., Hayashi S., Tohara D., Murakami Y., Motoshima T., Jono H., Yano I.

Oncology Research （Oncology Research） 29 （ 1 ） 11 - 23 2021年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09650407

We evaluated the association of signal transducer and activator of transcription 3 (STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTOR inhibitors were genotyped for the STAT3 polymorphism, rs4796793 (−1697C/G). We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome. In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the GG genotype compared with those with other genotypes (77.8% vs. 23.1%, odds ratio = 11.67, 95% confidential interval = 3.06–44.46). There were no significant differences in progression-free survival or time-to-treatment failure between the patients with the GG genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the GG genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin, and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the GG genotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.

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Effect of riboflavin deficiency on development of the cerebral cortex in Slc52a3 knockout mice

Jin C., Yonezawa A., Yoshimatsu H., Imai S., Koyanagi M., Yamanishi K., Nakagawa S., Itohara K., Omura T., Nakagawa T., Nagai J., Matsubara K.

Scientific Reports （Scientific Reports） 10 （ 1 ） 18443 2020年12月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り

Riboflavin transporter 3 (RFVT3), encoded by the SLC52A3 gene, is important for riboflavin homeostasis in the small intestine, kidney, and placenta. Our previous study demonstrated that Slc52a3 knockout (Slc52a3−/−) mice exhibited neonatal lethality and metabolic disorder due to riboflavin deficiency. Here, we investigated the influence of Slc52a3 gene disruption on brain development using Slc52a3−/− embryos. Slc52a3−/− mice at postnatal day 0 showed hypoplasia of the brain and reduced thickness of cortical layers. At embryonic day 13.5, the formation of Tuj1+ neurons and Tbr2+ intermediate neural progenitors was significantly decreased; no significant difference was observed in the total number and proliferative rate of Pax6+ radial glia. Importantly, the hypoplastic phenotype was rescued upon riboflavin supplementation. Thus, it can be concluded that RFVT3 contributes to riboflavin homeostasis in embryos and that riboflavin itself is required during embryonic development of the cerebral cortex in mice.

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Successful management of hyperammonemia with hemodialysis on day 2 during 5-fluorouracil treatment in a patient with gastric cancer: a case report with 5-fluorouracil metabolite analyses

Ozaki Y., Imamaki H., Ikeda A., Oura M., Nakagawa S., Funakoshi T., Kataoka S., Nishikawa Y., Horimatsu T., Yonezawa A., Matsubara T., Yanagita M., Muto M., Watanabe N.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 86 （ 5 ） 693 - 699 2020年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03445704

Purpose: Hyperammonemia is an important adverse event associated with 5-fluorouracil (5FU) from 5FU metabolite accumulation. We present a case of an advanced gastric cancer patient with chronic renal failure, who was treated with 5FU/leucovorin (LV) infusion chemotherapy (2-h infusion of LV and 5FU bolus followed by 46-h 5FU continuous infusion on day 1; repeated every 2 weeks) and developed hyperammonemia, with the aim of exploring an appropriate hemodialysis (HD) schedule to resolve its symptoms. Methods: The blood concentrations of 5FU and its metabolites, α-fluoro-β-alanine (FBAL), and monofluoroacetate (FA) of a patient who had hyperammonemia from seven courses of palliative 5FU/LV therapy for gastric cancer were measured by liquid chromatography–mass spectrometry. Results: On the third day of the first cycle, the patient presented with symptomatic hyperammonemia relieved by emergency HD. Thereafter, the 5FU dose was reduced; however, in cycles 2–4, the patient developed symptomatic hyperammonemia and underwent HD on day 3 for hyperammonemia management. In cycles 5–7, the timing of scheduled HD administration was changed from day 3 to day 2, preventing symptomatic hyperammonemia. The maximum ammonia and 5FU metabolite levels were significantly lower in cycles 5–7 than in cycles 2–4 (NH3 75 ± 38 vs 303 ± 119 μg/dL, FBAL 13.7 ± 2.5 vs 19.7 ± 2.0 μg/mL, FA 204.0 ± 91.6 vs 395.9 ± 12.6 ng/mL, mean ± standard deviation, all p < 0.05). After seven cycles, partial response was confirmed. Conclusion: HD on day 2 instead of 3 may prevent hyperammonemia in 5FU/LV therapy.

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Efficacy and safety of the initial dose of teicoplanin adjusted for the body weight

Katada Y., Nakagawa S., Yamashima H., Sugimoto M., Kimata M., Yoshida Y., Matsuda Y., Takahashi Y., Itohara K., Kitada N., Imai S., Fukatsu S., Tsuda M., Yonezawa A., Nakagawa T., Yamamoto M., Matsumura Y., Nagao M., Matsubara K.

Japanese Journal of Chemotherapy 68 （ 6 ） 608 - 618 2020年11月

筆頭著者, 最終著者, 責任著者, 査読有り, ISSN 13407007

Since teicoplanin (TEIC) has a long elimination half-life, it takes a long time for the steady state concentration to be achieved. Therefore, a loading dose is required for a therapeutic concentration (15-30 μg/mL) to be achieved rapidly. However, the optimal TEIC loading dose method needed to achieve therapeutic concentrations is not yet known. In the present study, we retrospectively investigated the relationship between the initial TEIC dosage based on the body weight and the serum concentration of the drug on the third day. Also, we studied the clinical efficacy and safety of TEIC in relation to the initial dose of TEIC used. From January 2016 to December 2016, a total of 109 adult inpatients received TEIC at Kyoto University Hospital, and the serum levels of the drug were measured on the third administration day. The patients were divided into three dose groups: the low-dose group: ≧10, <20 mg/kg/2 days (n=25); moderate-dose group: ≧20, <30 mg/kg/2 days (n=64); high-dose group: 30-50 mg/kg/2 days (n=20). The TEIC concentrations were significantly higher in the high-dose and moderate-dose groups than in the low-dose group (13.6±8.2, 22.7±7.4, and 27.6±5.24 μg/mL, respectively; P<0.01). The proportion of patients who failed to achieve serum TEIC levels of at least 15 μg/mL was 52% in the low-dose group, 20.3% in the moderate-dose group, and 0% in the low-dose group (P<0.001). There were no significant differences in the incidence of nephrotoxicity or hepatotoxicity among the three groups. The time to achieve a blood culture-negative state was significantly shorter in patients with serum TEIC concentrations of ≧15 μg/ mL than in those with <15 μg/mL (10±8.6 and 2.5±0.5 days, respectively; P<0.05). Thus, for rapid achievement of the target concentration, we strongly recommend that the initial loading dose should be over 30 mg/kg for 2 days (15-30 μg/mL).

Association of initial trough concentrations of vancomycin with outcomes in pediatric patients with gram-positive bacterial infection

Kondo M., Nakagawa S., Orii S., Itohara K., Sugimoto M., Omura T., Sato Y., Imai S., Yonezawa A., Nakagawa T., Matsubara K.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 43 （ 10 ） 1463 - 1468 2020年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09186158

Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive infections. For adult patients, treatment with vancomycin requires effective therapeutic drug-monitoring (TDM) to achieve clinical outcomes and reduce the incidence of adverse effects. However, it remains still unclear whether the TDM with vancomycin is beneficial in yielding better clinical outcomes in pediatrics. The objective of our study was to evaluate whether the clinical response to treatment was associated with initial trough concentrations of vancomycin in pediatric patients. A retrospective observation study of 60 patients (age: 1 month-15 years) who had completed and qualified for analysis was conducted at Kyoto University Hospital. The response to treatment was assessed by the time to resolution of fever and time to 50% decline in C-reactive protein (CRP). In addition, we explored whether vancomycin trough level was associated with the baseline characteristics. Trend analysis showed that there were significant correlations between vancomycin trough level and age, body weight, estimated glomerular filtration rate, and serum albumin levels. The time to resolution of fever of the patients with higher initial trough level (≥5µg/mL) was significantly lower than that of the patients with lower trough level (<5µg/mL). The higher vancomycin concentration tended to be associated with the shorter time to 50% decline in CRP. The findings suggest that initial trough concentration is important in achieving better outcomes with vancomycin treatment in pediatrics.

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抗インフルエンザ薬の適正使用指針(フォーミュラリ)導入のアウトカム評価

片田佳希, 米澤淳, 杉本充弘, 木全柾典, 吉田優子, 糸原光太郎, 中川俊作, 北田徳昭, 今井哲司, 池見泰明, 深津祥央, 中川貴之, 松村康史, 長尾美紀, 松原和夫

日本病院薬剤師会雑誌（(一社)日本病院薬剤師会） 56 （ 10 ） 1155 - 1160 2020年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-8815

京都大学医学部附属病院では、2019年11月より抗インフルエンザ薬を対象に適正使用指針(フォーミュラリ)を導入した。これまで、フォーミュラリ導入に関する過去の研究では医療経済を指標に検討されてきた。本研究では、医薬品の適正使用に焦点を当てて、フォーミュラリ導入の効果を検討した。2018年12月〜2019年1月および2019年12月〜2020年1月に抗インフルエンザ薬が投与された331名を対象とした。各薬剤の使用割合は導入前後によって、オセルタミビル:47.2→72.2%、ザナミビル:2.2→4.0%、ラニナミビル:19.4→7.3%、ペラミビル:19.4→16.5%、バロキサビル:11.6→0%に変化した。不適切投与は導入前後において21.6%から1.3%へ有意に低下した。1人当たりの薬剤費用は3,391円から2,685円へと減少した。フォーミュラリの導入は、医療経済だけでなく適正使用にも貢献することが明らかとなった。(著者抄録)

Schwann cell-derived CXCL1 contributes to human immunodeficiency virus type 1 gp120-induced neuropathic pain by modulating macrophage infiltration in mice

Ntogwa M., Imai S., Hiraiwa R., Koyanagi M., Matsumoto M., Ogihara T., Nakagawa S., Omura T., Yonezawa A., Nakagawa T., Matsubara K.

Brain, Behavior, and Immunity （Brain, Behavior, and Immunity） 88 325 - 339 2020年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 08891591

The neuroinflammatory responses to human immunodeficiency virus type 1 (HIV-1) coat proteins, such as glycoprotein 120 (gp120), are considered to be responsible for the HIV-associated distal sensory neuropathy. Accumulating evidences suggest that T-cell line tropic X4 gp120 increases macrophage infiltration into the peripheral nerves, and thereby induces neuroinflammation leading to pain. However, the mechanisms underlying X4 gp120-induced macrophage recruitment to the peripheral nervous systems remain unclear. Here, we demonstrated that perineural application of X4 gp120 from HIV-1 strains IIIB and MN elicited mechanical hypersensitivity and spontaneous pain-like behaviors in mice. Furthermore, flow cytometry and immunohistochemical studies revealed increased infiltration of bone marrow-derived macrophages into the parenchyma of sciatic nerves and dorsal root ganglia (DRG) 7 days after gp120 IIIB or MN application. Chemical deletion of circulating macrophages using clodronate liposomes markedly suppressed gp120 IIIB-induced pain-like behaviors. In in vitro cell infiltration analysis, RAW 264.7 cell (a murine macrophage cell line) was chemoattracted to conditioned medium from gp120 IIIB- or MN-treated cultured Schwann cells, but not to conditioned medium from these gp120-treated DRG neurons, suggesting possible involvement of Schwann cell-derived soluble factors in macrophage infiltration. We identified using a gene expression array that CXCL1, a chemoattractant of macrophages and neutrophils, was increased in gp120 IIIB-treated cultured Schwann cells. Similar to gp120 IIIB or MN, perineural application of recombinant CXCL1 elicited pain-like behaviors accompanied by macrophage infiltration to the peripheral nerves. Furthermore, the repeated injection of CXCR2 (receptor for CXCL1) antagonist or CXCL1 neutralizing antibody prevented both pain-like behaviors and macrophage infiltration in gp120 IIIB-treated mice. Thus, the present study newly defines that Schwann cell-derived CXCL1, secreted in response to X4 gp120 exposure, is responsible for macrophage infiltration into peripheral nerves, and is thereby associated with pain-like behaviors in mice. We propose herein that communication between Schwann cells and macrophages may play a prominent role in the induction of X4 HIV-1-associated pain.

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病診薬連携で行う吸入支援のアウトカムの評価

鋒山香苗, 杉本充弘, 米澤淳, 寺尾真琴, 山本浩貴, 吉田優子, 朝倉佳代子, 深津祥央, 谷村和哉, 佐藤晋, 松本久子, 中川俊作, 北田徳昭, 平井豊博, 松原和夫

医療薬学（(一社)日本医療薬学会） 46 （ 8 ） 405 - 413 2020年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

喘息や慢性閉塞性肺疾患(COPD)患者に対し吸入指導外来の支援体制開始によってもたらされる治療アウトカムについて、観察研究により評価を行った。2013年7月〜2019年7月末に呼吸器内科医師・病院薬剤師・保険薬局薬剤師との合同講習会を11回実施し、吸入デバイス、スペーサー、補助具の理解度が上昇したことがアンケート調査から分かった。当院では2013年12月に吸入指導外来を開設してから2018年12月まで、延べ3120回の吸入指導(月平均約50名)を行った。吸入薬説明手順、評価項目表の評価の内訳は、特に問題なしが88.9%(1642件)となっていたが、吸入方法不備・吸入意義の理解不足の報告も3.5%(65件)と一定数あった。吸入指導外来開設前後の緊急入院患者数、同時期の喘息またはCOPD外来受診患者数は、有意差はなかったものの開設前と比較して緊急入院患者数は減少傾向を示した。開設4年後、COPD(喘息合併を含む)の症例では、緊急入院患者数/外来受診患者数は、開設前と比較し、緊急入院患者数は有意に減少していた。また、緊急入院となったCOPD患者の重症度別では、Stage IV以外の比較的軽症のCOPD症例で緊急入院患者数が減少していた。一方、喘息のみの診断歴の患者では、緊急入院患者数の顕著な減少は認められなかった。医師を対象としたアンケート調査では、呼吸器内科担当の外来看護師中87%が吸入指導を業務負担と感じていた。吸入指導外来開設後は、全ての看護師が業務負担の軽減を実感していた。

Effects of low-dose remifentanil infusion on analgesic or antiemetic requirement during brain function mapping: A retrospective cohort study

Shiraki A., Goto W., Fukagawa H., Arakawa Y., Kikuchi T., Mineharu Y., Yamao Y., Yasuda T., Hattori E., Fukui A., Matsui Y., Yonezawa A., Furukawa K., Mizota T.

Acta Anaesthesiologica Scandinavica （Acta Anaesthesiologica Scandinavica） 64 （ 6 ） 735 - 741 2020年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00015172

Background: Pain and discomfort during the awake phase in awake craniotomy should be relieved to facilitate brain mapping. Although some anaesthesiologists use low-dose (0.01-0.05 µg/kg/min) remifentanil infusion to provide analgesia during this phase, its efficacy and side effects have never been evaluated. Therefore, this study primarily aimed to investigate the effects of low-dose remifentanil infusion on the need for antiemetic treatment during brain mapping and secondarily aimed to determine its effects on the need for additional analgesic treatment. Methods: This retrospective study included 218 patients who underwent awake craniotomy at our centre from 2008 to 2018. The relationship between low-dose remifentanil infusion during the awake phase and the requirement for analgesic or antiemetic treatment was examined. A multivariable competing risk regression analysis was performed to adjust for patient and operative variables. Results: Sixty-six patients (30.3%) received low-dose (median rate: 0.01 µg/kg/min) remifentanil infusion during the awake phase. Forty-nine patients (22.5%) received an antiemetic and 99 (45.4%) received additional analgesic treatment. The difference in additional analgesic treatment was not significant between patients who received low-dose remifentanil infusion and those who did not (adjusted hazard ratio: 1.13; 95% confidence interval: 0.75-1.70; P =.570); however, the use of antiemetics significantly increased in patients who received remifentanil (adjusted hazard ratio: 1.78; 95% confidence interval: 1.01-3.15; P =.047). Conclusion: Low-dose remifentanil infusion during the awake phase in awake craniotomy significantly increased the need for antiemetics but did not decrease the need for additional analgesic treatment.

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Prevalence of and risk factors for adverse events in Alzheimer's patients receiving anti-dementia drugs in at-home care

Imai H., Hirai T., Kumazawa R., Nakagawa S., Yonezawa A., Matsubara K., Nakao H.

PLoS ONE （PLoS ONE） 15 （ 4 ） e0231226 2020年04月

研究論文（学術雑誌）, 共著, 査読有り

Objective The objective of this study was to clarify the types and prevalence of, and the risk factors for, the adverse events that occur in patients receiving anti-dementia drugs. Methods A questionnaire survey was conducted. The respondents were pharmacists who were dispensing anti-dementia drugs. The pharmacists responded to questions about patients who were receiving anti-dementia drugs delivered to them at home by the pharmacists. The survey questions included questions about whether or not the patients experienced adverse reactions to the drugs, about the patients' background characteristics, about the numbers of drugs the patients were taking when the pharmacists first visited the patients at home, and about the pharmacists' assessments of the appropriateness of the use of the anti-dementia drugs. Results Data were collected on 3712 patients from 1673 pharmacies in a nationwide survey. Antidementia drugs had been prescribed to 863 of these patients; and 801 (92.8%) of these 863 patients were 75 years of age or older, and. confirmed adverse events occurred in 170 (21%) of these 863 patients. The most common adverse event was excitation/anxiety, at 45.1%. A multivariate analysis found that polypharmacy (10 or more types of drugs per day) (P = 0.030), inappropriate use (P = 0.002), and irregular medication use (P = 0.034) were risk factors. Interpretation In order to avoid adverse events when using anti-dementia drugs, doctors and pharmacists should carefully examine the prescribing of multiple medications, assess the applicability of the use of anti-dementia drugs, and investigate how to best manage patients' drug use.

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Cisplatin, rather than oxaliplatin, increases paracellular permeability of LLC-PK1 cells via activating protein kinase C

Zhang Y., Yonezawa A., Nakagawa S., Imai S., Denda M., Omura T., Nakagawa T., Matsubara K.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics） 35 （ 1 ） 111 - 116 2020年02月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 13474367

The clinical use of cisplatin is limited by its adverse events, particularly serious nephrotoxicity. It was clarified that cisplatin is transported by a kidney-specific organic cation transporter (OCT2). OCT2 also mediates the uptake of oxaliplatin into renal proximal tubular cells; however, this agent does not lead nephrotoxicity. In the present study, we carried out comparative experiments with cisplatin and oxaliplatin using porcine kidney LLC-PK1 cell monolayers. In the fluorescein-labeled isothiocyanate-dextran flux assay, the basolateral application of cisplatin, but not oxaliplatin, resulted in an increase in the paracellular permeability of cell monolayers. Even though the cellular accumulation of platinum at 50 μM oxaliplatin could reach the same level at 30 μM cisplatin, oxaliplatin did not induce hyper-permeability in cell monolayers. Cisplatin, but not oxaliplatin, significantly activated PKC. In addition, the combination of PKC inhibitors recovered the increase in paracellular permeability. In conclusion, pharmacodynamic mechanisms via PKC could explain the difference in nephrotoxicity between cisplatin and oxaliplatin.

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Add-on effects of tadalafil in tamsulosin-treated patients with small benign prostatic enlargement: A randomized, placebo-controlled, double-blind, crossover study

Negoro H., Goto T., Akamatsu S., Terada N., Kobayashi T., Matsui Y., Yamamoto T., Omura T., Yonezawa A., Matsubara K., Ogawa O.

Neurourology and Urodynamics （Neurourology and Urodynamics） 39 （ 1 ） 237 - 242 2020年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07332467

Aim: To assess the add-on effects of tadalafil in patients with a relatively small benign prostatic enlargement (BPE) treated with tamsulosin. Methods: From September 2014 to July 2018, we prospectively studied patients (aged 50 years or more) attending our hospital who had received tamsulosin for small BPE (20–40 mL) for 4 weeks at least and still had residual lower urinary tract symptoms (LUTS) with total International Prostate Symptom Scores (IPSS) of at least 8 and IPSS-quality of life scores at least 3. We randomized eligible patients into two groups: one of which received tadalafil 5 mg once daily for 6 weeks, followed by placebo for 6 weeks, and the other of which received placebo followed by tadalafil in the same manner. The patients were reviewed at our outpatient clinic after 2, 6, 8, and 12 weeks. Results: There were 13 patients in the tadalafil-placebo and 13 in the placebo-tadalafil group. Their median ages (range) were 70 (65-85) and 73 (50-80) years, prostatic volumes (median) 30.0 (22.0-39.7) and 32.0 (20.1-39.5) mL, and total IPSS (median) 17 (10-27) and 16 (10-24), respectively. The primary endpoints, namely mean changes of total IPSS from baseline, were 1.85 on placebo and −3.42 on tadalafil; this difference is statistically significant (difference: −1.57; 95% confidence interval: −3.00, −0.69; P =.032). We encountered no adverse effects. Conclusions: Add-on of tadalafil for symptomatic patients with small BPE treated with tamsulosin appears to be effective and safe.

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京都大学医学部附属病院における2012-2018年の病棟薬剤師業務の質的変化〜リファンピシン処方に対する介入を指標として

吉田優子, 佐藤夕紀, 傳田将也, 池見泰明, 杉本充弘, 山際岳朗, 中川俊作, 今井哲司, 大村友博, 尾崎淳子, 深津祥央, 矢野育子, 北田徳昭, 米澤淳, 中川貴之, 松原和夫

日本病院薬剤師会雑誌（(一社)日本病院薬剤師会） 56 （ 6 ） 643 - 650 2020年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1341-8815

2012年は薬剤師の臨床業務にとって極めて大きな転機であった。すなわち、六年制薬学教育を受けた薬剤師の誕生と、薬剤師の病棟専任に対する診療報酬加算の実施の2つである。しかし、これら2つの転機が薬剤師の臨床業務の質に影響を及ぼしたかの評価はされていない。そこで、併用薬剤との相互作用が多いリファンピシンに焦点を絞り、病棟薬剤師がその処方に適切に介入できていたかを調査し、薬剤師の病棟業務の質を評価した。2012年(加算前)、2013年(加算直後)、2018年(加算5年後)において、該当薬剤の処方を病棟薬剤師が認識した割合は、調査年を追うごとに増加した。薬学的介入のなかで適切な提案ができている割合は、それぞれ75.0、87.5および86.6%であった。これらの結果から、病棟薬剤師業務加算の実施は、薬剤師の病棟業務の質的向上に寄与していると考えられる。一方で、薬学教育年数の延長が及ぼす効果を評価するために、卒後4年以内の病棟薬剤師の四年および六年制教育課程修了者について精査したところ、六年制修了者のほうが有意に処方介入度合いが高かった。このことから卒業直後は教育年数の延長効果が認められることが示唆された。しかし、今回の調査のみで、六年制薬学教育を修了した薬剤師の質を測ることは困難であり、今後様々な角度からの調査が必要である。(著者抄録)

Improvement of peripheral vascular impairment by a phosphodiesterase type 5 inhibitor tadalafil prevents oxaliplatin-induced peripheral neuropathy in mice

Ogihara T., Nakagawa T., Hayashi M., Koyanagi M., Yonezawa A., Omura T., Nakagawa S., Kitada N., Imai S., Matsubara K.

Journal of Pharmacological Sciences （Journal of Pharmacological Sciences） 141 （ 4 ） 131 - 138 2019年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13478613

Oxaliplatin, a platinum-based chemotherapeutic drug, frequently induces peripheral neuropathy. Accumulating evidences suggest a possible relationship between peripheral vascular impairment and peripheral neuropathy. In this study, we investigated the effects of vasodilators on cumulative peripheral neuropathy induced by repeated injections of oxaliplatin (10 mg/kg) once a week for 8 weeks in mice. Single injections of vasodilators, including a phosphodiesterase type 5 inhibitor tadalafil acutely alleviated oxaliplatin-induced cold hypersensitivity, while tadalafil had no effect on the mechanical hypersensitivity. By contrast, long-term administration of tadalafil (0.1% in chow diets) during the oxaliplatin injection period reduced the oxaliplatin-induced decreases in skin temperature and blood flow without affecting platinum concentrations in blood, sciatic nerves, and dorsal root ganglion. The long-term administration significantly suppressed cold, mechanical, and electrical current hypersensitivities as well as thermal hypoesthesia. Furthermore, it prevented the decreases in sensory nerve conductance velocity and the number of endoneurial microvessels, and axon degeneration in the sciatic nerves. In vitro studies confirmed that tadalafil does not interfere with the cytotoxicity of oxaliplatin against human cancer cell lines. Altogether, these results suggest that improvement of peripheral vascular impairment by tadalafil could alleviate and prevent oxaliplatin-induced peripheral neuropathy.

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Multiplexed monitoring of therapeutic antibodies for inflammatory diseases using Fab-selective proteolysis nSMOL coupled with LC-MS

Iwamoto N., Takanashi M., Yokoyama K., Yonezawa A., Denda M., Hashimoto M., Tanaka M., Ito H., Matsuura M., Yamamoto S., Honzawa Y., Matsubara K., Shimada T.

Journal of Immunological Methods （Journal of Immunological Methods） 472 44 - 54 2019年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00221759

Monoclonal antibodies have accelerated the availability of treatment options for many diseases in which the molecular mechanism has been elucidated in detail. Therefore, an assay that can universally analyze antibodies for clinical pharmacokinetics and cross-sectional studies would be indispensable. We have developed a universal antibody bioanalysis with a Fab-selective tryptic reaction, named nano-surface and molecular-orientation limited (nSMOL) proteolysis, that collects the specific antibody signature peptides in biological samples. Using the nSMOL method, we have fully validated the bioanalysis of many antibodies, Fc-fusion proteins, and their biosimilars. Inflammatory immune diseases often require long-term clinical management because of the remission and relapse observed. Accurate antibody monitoring in systemic circulation could contribute to the improvement of clinical outcomes. Because several biopharmaceuticals can be selected as practical treatment options, the assay development that quantitates many antibodies simultaneously would be applicable in many theraprutic monitoring. In this study, we have validated the LC-MS bioanalysis method for seven-mixed antibodies (Infliximab, Adalimumab, Ustekinumab, Golimumab, Eculizumab, Etanercept, and Abatacept) using the nSMOL normal reaction condition and two-mixed antibodies (Tocilizumab and Mepolizumab) using the acidified reduction acceleration condition, as reported in our previous papers. Moreover, this multiplexed assay has been verified using clinical patient samples. The nSMOL approach enables the quantitation of several immunosuppressive antibodies simultaneously in human serum, and nSMOL can potentially be applicable to the drug-drug interaction assays or therapeutic antibody monitoring of several inflammatory immune diseases to optimize administration.

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Concentration and Glycoform of Rituximab in Plasma of Patients with B Cell Non-Hodgkin’s Lymphoma

Yonezawa A., Otani Y., Kitano T., Mori M., Masui S., Isomoto Y., Tsuda M., Imai S., Ikemi Y., Denda M., Sato Y., Nakagawa S., Omura T., Nakagawa T., Yano I., Hayakari M., Takaori-Kondo A., Matsubara K.

Pharmaceutical Research （Pharmaceutical Research） 36 （ 6 ） 82 - 82 2019年06月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り, ISSN 07248741

Purpose: Therapeutic antibodies have heterogeneities in their structures, although its structural alteration in the body is unclear. Here, we analyzed the change of amino acid modifications and carbohydrate chains of rituximab after administration to patients. Methods: Twenty B cell non-Hodgkin’s lymphoma patients who were treated with rituximab for the first time or after more than one year’s abstinence were recruited. Structural analysis of rituximab was carried out at 1 h after administration and at the trough by using liquid chromatography/time-of-flight-mass spectrometry. Plasma rituximab concentration and pharmacodynamic markers were also determined. Results: Of recruited twenty, 3 patients exhibited rapid rituximab clearance. Nine types of carbohydrate chains were detected in rituximab isolated from the blood. The composition ratios in some glycoforms were significantly different between at 1 h after administration and at the trough, although consisted amino acids remained unchanged. The patients with high clearance showed extensive alterations of glycoform composition ratios. However, pharmacodynamics makers were not different. Conclusion: Inter-individual variations in plasma concentrations of rituximab were found in some B-NHL patients. We could analyze a change in glycoforms of rituximab in the patients, and this finding may affect the pharmacokinetics of rituximab.

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Effects of fasting on warfarin sensitivity index in patients undergoing cardiovascular surgery

Katada Y., Nakagawa S., Nishimura A., Sato Y.k., Taue H., Matsumura K., Yamazaki K., Minakata K., Yano I., Omura T., Imai S., Yonezawa A., Sato Y., Nakagawa T., Minatoya K., Matsubara K.

European Journal of Clinical Pharmacology （European Journal of Clinical Pharmacology） 75 （ 4 ） 561 - 568 2019年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00316970

Purpose: Warfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and pharmacodynamics. Sufficient understanding of factors affecting the response to warfarin is necessary to achieve improved outcomes for warfarin therapy. In this study, we evaluated effects of fasting on the anticoagulant properties of warfarin. Methods: We conducted a retrospective observational study involving a total of 58 patients, who received cardiovascular surgeries and subsequent warfarin therapy. The effect of dietary intake on the anticoagulant properties with warfarin was assessed by measurement of the international normalized ratio of prothrombin time (PT-INR): the anticoagulant activities of warfarin were expressed as the warfarin sensitivity index (WSI). Additionally, fluctuations in WSI during the study period were obtained as differences between the maximum and minimum WSI. Results: The maximum PT-INR and WSI values were significantly higher for patients who were fasting for different reasons during the postoperative period than those in the group without reduced dietary intake. The differences between maximum and minimum WSI in the fasting group significantly increased compared with those in the groups with moderate or no reduced dietary intake. Meanwhile, effects of other markers of clinical conditions including the baseline Child-Pugh score and Charlson Comorbidity Index on WSI were not significant. Conclusions: Our results indicate that postoperative fasting was significantly associated with the anticoagulation activity of warfarin. In patients fasting for different reasons during the postoperative period, closer control of PT-INR values and warfarin adjustments may be required to avoid adverse effects such as bleeding in warfarin treatment.

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Acceleration of nano-surface and molecular-orientation limited (nSMOL) proteolysis with acidified reduction pretreatment for quantification of Tocilizumab

Iwamoto N., Yonezawa A., Matsubara K., Shimada T.

Journal of Pharmaceutical and Biomedical Analysis （Journal of Pharmaceutical and Biomedical Analysis） 164 467 - 474 2019年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07317085

Antibody drugs are effective therapeutic agents and provide treatment for many types of diseases such as cancer and rheumatoid arthritis. Because many antibody drugs are developed and approved, quantification technologies of antibodies are required for drug development and individualized therapy. We recently reported a high reproducible and robust therapeutic drug monitoring method for antibody drugs. This method was developed to be applicable to all type of antibody drugs and to provide accurate quantification values. The method is named nano-surface and molecular-orientation limited (nSMOL) proteolysis. nSMOL limits the access of protease to immunoglobulin G molecules and aims to selectively proteolyze on Fab region of substrate. However, the bioanalysis of Tocilizumab using nSMOL has not been validated. We newly discovered that acidified reduction pretreatment of Tocilizumab promotes digestive efficiency by nSMOL proteolysis. Exposure of Tocilizumab to Tris(2-carboxyethyl)phosphine hydrochloride before nSMOL proteolysis significantly improved the recovery of peptides. Under this condition, the quantification range of Tocilizumab in human serum was from 0.781 to 200 μg/mL. The quantification values of quality control samples fulfilled all guideline criteria for bioanalytical validation. The signature peptide with the highest quantitative sensitivity was on H-chain VTMLR. From these results, it is expected that the pretreatment with TCEP will broaden the application of antibody drugs quantification by nSMOL proteolysis.

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Safety and Plasma Concentrations of a Cyclin-dependent Kinase 9 (CDK9) Inhibitor, FIT039, Administered by a Single Adhesive Skin Patch Applied on Normal Skin and Cutaneous Warts

Sumi E., Nomura T., Asada R., Uozumi R., Tada H., Amino Y., Sawada T., Yonezawa A., Hagiwara M., Kabashima K.

Clinical Drug Investigation （Clinical Drug Investigation） 39 （ 1 ） 55 - 61 2019年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 11732563

Background: Cutaneous warts are caused by human papilloma virus (HPV) infection. FIT039, a specific inhibitor of CDK9, suppresses the proliferation of DNA viruses in vitro. Purpose: We evaluated the safety, plasma concentrations, and efficacy of FIT039 delivered by single application of an adhesive skin patch on normal back skin and cutaneous warts. Patients and Methods: In this placebo-controlled, dose-escalation, open-label, two-cohort phase I/II clinical trial, after a single administration of a 1% FIT039 patch, 3% FIT039 patch, or placebo on back skin, patients with cutaneous warts were treated with cryotherapy followed by a 1% FIT039 patch for 24 h in the first cohort. In the second cohort, cutaneous warts were treated with cryotherapy followed by a 3% FIT039 patch for 24 h. Adverse events and adverse drug reactions, the concentrations of FIT039, and surface area of cutaneous warts were evaluated. Results: Neither irritant reactions nor symptoms related to FIT039 occurred when the FIT039 patches were applied to patients’ backs or on warts in ten patients. The concentrations of FIT039 were under 0.1 ng/ml at every time point. The median wart surface area at 1 week after application of the 1% FIT039 patch was similar to baseline, while that of the 3% FIT039 patch was smaller than baseline. Conclusion: The FIT039 patch showed no topical or systemic adverse reactions when applied on normal skin or cutaneous warts. The safety and good adherence of the FIT039 patch are encouraging and support further studies to evaluate the efficacy of FIT039 in patients with cutaneous warts.

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A Minimal Physiologically-Based Pharmacokinetic Model for Tacrolimus in Living-Donor Liver Transplantation: Perspectives Related to Liver Regeneration and the cytochrome P450 3A5 (CYP3A5) Genotype

Itohara K., Yano I., Tsuzuki T., Uesugi M., Nakagawa S., Yonezawa A., Okajima H., Kaido T., Uemoto S., Matsubara K.

CPT: Pharmacometrics and Systems Pharmacology （CPT: Pharmacometrics and Systems Pharmacology） 8 （ 8 ） 587 - 595 2019年

研究論文（学術雑誌）, 共著, 査読有り

In adult patients after living-donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically-based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living-donor liver transplantation. The clearance was about 1.35-fold higher in the recipients who had a liver with the CYP3A5*1 allele than in those with the CYP3A5*3/*3 genotype, whereas bioavailability was ~0.7-fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP3A5*3/*3. In conclusion, the constructed physiologically-based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent.

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Plasma infliximab monitoring contributes to optimize Takayasu arteritis treatment: a case report.

Masui S, Yonezawa A, Izawa K, Hayakari M, Asakura K, Taniguchi R, Isa M, Shibata H, Yasumi T, Nishikomori R, Takita J, Matsubara K

Journal of pharmaceutical health care and sciences 5 9 - 9 2019年

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 2055-0294

Background: Infliximab (IFX), a mouse-human chimeric monoclonal antibody against human tumor necrosis factor alpha, is used in refractory cases of Takayasu arteritis. Several factors influence the pharmacokinetics of therapeutic antibodies including IFX. Monitoring plasma levels of IFX could be a useful approach in optimizing treatment via individual dose adjustment. Case presentation: Here, we report the case of a 4-year-old Takayasu arteritis girl who was resistant to standard therapy. IFX was started at 5 mg/kg (day 0). C-reactive protein (CRP) levels decreased from 8.7 (day 0) to 1.6 mg/dL (day 10). CRP levels were thereafter elevated again on day 23 (9.0 mg/dL), and body fluid leakage at the inflammation site in the legs was observed. Trough IFX levels decreased from 23.6 (day 10) to 2.5 μg/mL (day 23). Based on the trough levels, IFX was given biweekly at 8 mg/kg. Plasma IFX levels gradually increased, and CRP levels decreased to around 2 mg/dL. A similar pattern -initial decreases followed by increases- was observed between clinical course of IFX and IgG levels. It was speculated that IgG and IFX losses were due to fluid leakage from the patient's necrotizing legs. Conclusions: Monitoring of plasma IFX levels can be a potential tool to optimize the treatment in Takayasu arteritis patients.

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Pharmacokinetics and pharmacodynamics of once-daily tacrolimus compared with twice-daily tacrolimus in the early stage after living donor liver transplantation

Iwasaki M., Yano I., Fukatsu S., Hashi S., Yamamoto Y., Sugimoto M., Fukudo M., Masuda S., Nakagawa S., Yonezawa A., Kaido T., Uemoto S., Matsubara K.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 40 （ 6 ） 675 - 681 2018年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01634356

Background: This study investigates the pharmacokinetics and pharmacodynamics of tacrolimus using the once-daily (OD) formulation in the early stage after living donor liver transplantation (LDLT) in comparison with those using the twice-daily (TD) formulation. Methods: Nine patients undergoing primary LDLT and treated with the OD tacrolimus formulation were included. The trough blood concentration (C0) of tacrolimus was monitored every day for 3 weeks after LDLT. A time course study of the blood tacrolimus concentrations and calcineurin (CN) phosphatase activity in peripheral blood mononuclear cells was performed 3 weeks after LDLT. Pharmacokinetic and pharmacodynamic parameters were compared with previously reported data using the TD formulation. Results: The interindividual variability in the daily dose of tacrolimus was significantly larger in the OD formulation than in the TD formulation (P < 0.001). In the time course study, the tacrolimus blood concentrations at 4, 8, and 12 hours after administration and the area under the concentration-time curve from 0 to 24 hours (AUC0 24) in the OD group were significantly higher than in the TD group, although the C0 was equivalent. In addition, the C0 was not significantly correlated with the AUC0 24 in the OD formulation. The apparent clearance and the pharmacodynamic parameters examined were not significantly different between the OD and TD groups. Conclusions: The C0 monitoring of the OD formulation may not be optimal in patients at the early stage after LDLT because the C0 was not correlated with the AUC0-24. If clinicians target the same C0 using the OD and TD formulations, the exposure of tacrolimus can be higher in the OD formulation, and excessive immunosuppression should be noted. Particular attention should be paid to the patients in the early stage after LDLT in the use of the OD oral formulation of tacrolimus.

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Ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) prevents cell death in a cellular model of Parkinson's disease

Omura T., Matsuda H., Nomura L., Imai S., Denda M., Nakagawa S., Yonezawa A., Nakagawa T., Yano I., Matsubara K.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications） 506 （ 3 ） 516 - 521 2018年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006291X

Endoplasmic reticulum (ER) stress may play a role in the etiology of Parkinson's disease (PD). We have previously reported that ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase degradation 1 (HRD1) involved in ER stress degrades unfolded protein that accumulates in the ER due to loss of function of Parkin, which is a causative factor in familial PD. We have also demonstrated that cell death is suppressed by the degradation of unfolded proteins. These findings indicate that HRD1 may serve as a compensatory mechanism for the loss of function of Parkin in familial PD patients. However, the role of HRD1 in sporadic PD has not yet been identified. This study aimed to reveal the roles of HRD1 and associated molecules in a cellular model of PD. We demonstrated that expressions of HRD1 and Suppressor/Enhancer Lin12 1-like (SEL1L: a HRD1 stabilizer) increased in SH-SY5Y human neuroblastoma cells upon exposure to 6-hydroxydopamine (6-OHDA). The 6-OHDA-induced cell death was suppressed in cells overexpressing wt-HRD1, whereas cell death was enhanced in cells with knockdown of HRD1 expression. These results suggest that HRD1 is a key molecule involved in 6-OHDA-induced cell death. By contrast, suppression of SEL1L expression decreased the amount of HRD1 protein. As a result, 6-OHDA-induced cell death was enhanced in cells suppressing SEL1L expression, and this cell death was much more evident than that in cells with suppression of HRD1 expression. These findings strongly indicate that SEL1L is necessary for maintaining and stabilizing the amount of HRD1 protein, and stabilizing the amount of HRD1 protein through SEL1L may serve to protect against 6-OHDA-induced cell death. Furthermore, the expression of Parkin was reinforced when HRD1 mRNA had been suppressed in cells, but was not observed when SEL1L mRNA had been restrained. It is possible that Parkin expression is induced as a compensatory mechanism when HRD1 mRNA decreases. This intracellular transduction may suppress the enhancement of 6-OHDA-induced cell death caused by the loss of HRD1. Taken together with these results, it is suggested that HRD1 and its stabilizer (SEL1L) are key molecules for elucidating the pathogenesis and treatment of PD.

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Effect of medication adherence on disease activity among Japanese patients with rheumatoid arthritis

Nakagawa S., Nakaishi M., Hashimoto M., Ito H., Yamamoto W., Nakashima R., Tanaka M., Fujii T., Omura T., Imai S., Nakagawa T., Yonezawa A., Imai H., Mimori T., Matsubara K.

PLoS ONE （PLoS ONE） 13 （ 11 ） e0206943 2018年11月

研究論文（学術雑誌）, 共著, 査読有り

For the optimum efficacy of disease-modifying anti-rheumatic drugs (DMARDs), patients need to be adherent to their medication regimen. To clarify the effects of medication adherence on disease activity in Japanese patients with rheumatoid arthritis (RA), we conducted a cohort study in patients with various stages of RA. Patients were enrolled from the Kyoto University RA Management Alliance cohort, and followed up prospectively for 12 months. In this study, a total of 475 patients were analyzed and divided into 9 groups according to their medication adherence and the RA disease duration. The primary outcomes were based on the rate of a disease flare. The secondary outcomes were the changes in disease activity score using 28 joints (DAS28-ESR), simplified disease activity index (SDAI) and physical disability by health assessment questionnaire-disability index (HAQ). The changes in DAS28-ESR, HAQ, and the risk of disease flare in the highly adherent patients were significantly lower than those of the less adherent patients among the groups with RA 4.6 years but not those among the other groups. Taken together, this study identified a significant association between medication adherence and the disease flare during early-stage RA or short disease duration. These results emphasize the need to pay more attention to medication adherence in preventing the disease progression of RA.

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医療現場における薬物相互作用へのかかわり方実験研究および調査研究事例

百賢二, 米澤淳, 岩本卓也, 大野能之, 木村丈司, 樋坂章博, 伊藤清美, 日本医療薬学会学術第一小委員会

医療薬学（(一社)日本医療薬学会） 44 （ 11 ） 559 - 567 2018年11月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 1346-342X

薬物相互作用に関する実験研究として、以下について概説した。1)非臨床試験データ等に基づくペランパネルの薬物相互作用、2)エゼチミブによるビタミンKの吸収阻害を介したワルファリンの相互作用、3)医薬品と飲料・健康食品の薬物動態学的相互作用。次いで、医療現場における薬物相互作用に関する調査研究に関して、事例を示しつつ、調査研究を行う際の注意点やポイントについて述べた。

医療現場における薬物相互作用へのかかわり方新しいガイドラインと医療現場でのマネジメント

大野能之, 樋坂章博, 岩本卓也, 木村丈司, 百賢二, 米澤淳, 伊藤清美, 日本医療薬学会学術第一小委員会

医療薬学（(一社)日本医療薬学会） 44 （ 11 ） 537 - 545 2018年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

日本医療薬学会学術第一小委員会では、医療現場において薬物相互作用をどのように評価しマネジメントに取り組むか、薬物相互作用に関連する問題点をどのように抽出し研究を進めるか、などに関して手引きの作成を検討している。会員に対し実施した手引き作成に関するアンケート調査の結果を紹介するとともに、医療現場における薬物相互作用の評価とマネジメント、薬物相互作用のガイドライン改定について解説した。

医療現場における薬物相互作用へのかかわり方対応事例・問題点に関するこれまでの報告と特別な背景をもつ患者における薬物相互作用の考え方

木村丈司, 岩本卓也, 大野能之, 樋坂章博, 百賢二, 米澤淳, 伊藤清美, 日本医療薬学会学術第一小委員会

医療薬学（(一社)日本医療薬学会） 44 （ 11 ） 546 - 558 2018年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

医療現場における薬物相互作用への対応事例とその問題点について、以下の項目に分けて述べた。1)薬剤師による薬物相互作用のマネジメント・介入の報告、2)システムの問題、3)薬剤師による介入に影響を与える要因や介入時の注意点。また、薬物動態が変動する特別な背景をもつ患者における相互作用の考え方について、ゲノム変異、腎機能低下、肝機能低下、心機能低下、高齢者、新生児・幼児・小児、妊娠に分けて解説した。

A therapeutic angiogenesis of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel sheets in a canine chronic myocardial infarction model

Kumagai M., Minakata K., Masumoto H., Yamamoto M., Yonezawa A., Ikeda T., Uehara K., Yamazaki K., Ikeda T., Matsubara K., Yokode M., Shimizu A., Tabata Y., Sakata R., Minatoya K.

Heart and Vessels （Heart and Vessels） 33 （ 10 ） 1251 - 1257 2018年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09108327

This study investigated the safety and efficacy of a sustained release of basic fibroblast growth factor (bFGF) with biodegradable gelatin hydrogel sheets as therapeutic angiogenesis in canine chronic myocardial infarction (MI) models. Canine chronic MI model was induced by ligating the left anterior descending coronary artery and its diagonal branches. At 4 week post-induction, we applied either saline (Control group, n = 5) or 200 μg of bFGF (Treatment group, n = 6) soaked gelatin hydrogel sheets on the ischemic area of the left ventricular (LV) wall. At 6 weeks after the procedure, we evaluated the efficacy by echocardiography and immunohistochemical study. There were no procedure-related adverse events or deaths. The serum bFGF level was under detectable levels in all animals at any sampling points. In terms of efficacy, echocardiographic evaluation demonstrated that fractional shortening was significantly improved in the treatment group. In addition, immunohistochemical study showed that the capillary density in the border zone of the MI area, as well as the MI area, significantly increased in the treatment group. Therapeutic angiogenesis by bFGF using biodegradable gelatin hydrogel sheets was safe, increased the capillary density, and improved LV function in canine chronic MI models.

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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

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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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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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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プロトコルに基づいた薬物治療管理の臨床アウトカム評価~TDMオーダを含めたバンコマイシン処方設計支援~

片田佳希, 中川俊作, 田上裕美, 津田真弘, 都築徹教, 端幸代, 小高瑞穂, 米澤淳, 萱野勇一郎, 矢野育子, 南方謙二, 坂田隆造, 松原和夫

医療薬学（(一社)日本医療薬学会） 42 （ 1 ） 14 - 22 2016年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-342X

心臓血管外科病棟におけるバンコマイシン(VCM)治療に焦点を当てて、プロトコルの基づく薬物治療管理(PBPM)の臨床的アウトカムを定量化し、VCM治療における薬剤師介入の効果について検討した。VCMが開始され治療薬物モニタリング(TDM)を行った54例を対象とし、プロトコル導入以前にVCM治療を行った29例(男性21名、女性8名、70±18歳)(I群)、プロトコル導入後にVCM治療を行った25例(男性17名、女性8名、67±15歳)(II群)に分けた。急性腎障害発現はI群9例(31.0%)、II群2例(8.0%)であった。治療域維持率の中央値は、I群50%、II群80%、中毒域到達率の中央値は、I群17%、II群0%であった。治療域維持率及び中毒域到達率に関する2群間の差は、敗血症、肺炎、感染性心内膜炎の背景を有する場合において大きい値であった。VCM血中濃度の日内変動はI群で大きい傾向があった。

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Harnessing the innate immune system to treat cancer: Enhancement of antibody-dependent cellular cytotoxicity with anti-CD137 Ab

Yonezawa A., Chester C., Rajasekaran N., Kohrt H.E.

Chinese Clinical Oncology （Chinese Clinical Oncology） 5 （ 1 ） 5 2016年

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 23043865

Background: Monoclonal antibodies are an invaluable therapeutic class when it comes to cancer therapy. One of the primary mechanisms of anti-tumor activity of monoclonal antibodies is antibody dependent cell-mediated cytotoxicity (ADCC) mediated by natural killer (NK) cells. Innate immune effector cells play important roles in generating and maintaining antitumor immunity to enhance ADCC. Methods: Efficacy of anti-CD137 mAb was examined by in vitro and in vivo experiments. Clinical trials of anti-CD137 mAb are also on-going. Results: CD137 is a costimulatory receptor that belongs to the tumor necrosis factor receptor (TNFR) superfamily. CD137 is expressed on T cell, activated NK cells and other immune cells. We recently showed that an agonistic anti-CD137 mAb activates NK cells, resulting in increased ADCC against cancer cells. Anti-CD137 agonistic mAb therapy may both increase ADCC due to mAb-activated NK cells and promote the proliferation and cytotoxicity of antigen-specific T cells induced by mAb treatment. Conclusions: We discuss some of the promising strategies that could potentially enhance ADCC with anti-CD137 mAbs.

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Population pharmacokinetic modeling of levetiracetam in pediatric and adult patients with epilepsy by using routinely monitored data

Ito S., Yano I., Hashi S., Tsuda M., Sugimoto M., Yonezawa A., Ikeda A., Matsubara K.

Therapeutic Drug Monitoring （Therapeutic Drug Monitoring） 38 （ 3 ） 371 - 378 2016年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01634356

Background: Levetiracetam, a second-generation antiepileptic drug, is frequently used for managing partial-onset seizures. About 70% of the administered dose is excreted in urine unchanged, and dosage adjustment is recommended based on the individual's renal function. In this study, a population pharmacokinetic model of levetiracetam was developed using routinely monitored serum concentration data for individualized levetiracetam therapy. Methods: Patients whose serum concentrations of levetiracetam at steady-state were routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were enrolled. The influence of patient characteristics on levetiracetam pharmacokinetics was evaluated using the nonlinear mixed-effects modeling (NONMEM) program. Results: A total of 583 steady-state concentrations from 225 patients were used for the analysis. The median patient age and estimated glomerular filtration rate (eGFR) were 38 (range: 1-89) years and 98 (15-189) mLmin211.73 m22, respectively. Serum concentration-time data of levetiracetam were well described by a 1-compartment model with first-order absorption. Oral clearance was allometrically related to the individual body weight and eGFR. An increase in the dose significantly increased oral clearance. No improvement in model fit was observed by including the covariate of any concomitant antiepileptic drugs. The population mean clearance for an adult weighing 70 kg and with a normal renal function was 4.8 and 5.9 L/h for 500 mg bis in die (bid) and 1500 mg bid, respectively. Conclusions: Oral clearance allometrically related with body weight and eGFR can well predict the routine therapeutic drug monitoring data from pediatric to aged patients with varying renal function. Dosage adjustments based on renal function are effective in controlling the trough and peak concentrations in similar ranges.

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Pharmacokinetics and pharmacodynamics of mycophenolic acid in Nagase analbuminemic rats: Evaluation of protein binding effects using the modeling and simulation approach

Yoshimura K., Yano I., Kawanishi M., Nakagawa S., Yonezawa A., Matsubara K.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics） 30 （ 6 ） 441 - 448 2015年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

This study aimed to examine the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in Nagase analbuminemic rats (NARs) to evaluate the effect of protein binding on the associated inosine-5-monophosphate dehydrogenase (IMPDH) activity. Free fractions of MPA in the control rats and NARs were 2.09 and 24.8%, respectively. Pharmacokinetic and pharmacodynamic parameters simultaneously obtained by the nonlinear mixed effects modeling program NONMEM explained reasonably well the concentrations of MPA and MPA glucuronide as well as IMPDH activity in both rats. NARs showed a higher clearance and a smaller volume of distribution based on the free MPA concentration than the controls did, besides the increase in free fraction. The half-maximal inhibitory concentration based on free MPA was estimated as 163 ng/mL for both rats. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters showed that the area under the IMPDH activity-time curve decreased non-linearly according to the increase in free fraction of MPA. In conclusion, the experimental data obtained from NARs followed by the modeling and simulation approach quantitatively clarified that the free MPA concentration was suitable for the biomarker of immunosuppressive effect of MPA. Dose adjustments based on the total MPA may cause unnecessary overexposure to MPA in patients with hypoalbuminemia.

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Gefitinib and erlotinib lead to phosphorylation of eukaryotic initiation factor 2 alpha independent of epidermal growth factor receptor in A549 cells

Koyama S., Omura T., Yonezawa A., Imai S., Nakagawa S., Nakagawa T., Yano I., Matsubara K.

PLoS ONE （PLoS ONE） 10 （ 8 ） e0136176 2015年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1932-6203

Gefitinib and erlotinib are anticancer agents, which inhibit epidermal growth factor receptor (EGFR) tyrosine kinase. Interstitial lung disease (ILD) occurs in patients with non-small cell lung cancer receiving EGFR inhibitors. In the present study, we examined whether gefitinib- and erlotinib-induced lung injury related to ILD through endoplasmic reticulum (ER) stress, which is a causative intracellular mechanism in cytotoxicity caused by various chemicals in adenocarcinomic human alveolar basal epithelial cells. These two EGFR inhibitors increased Parkinson juvenile disease protein 2 and C/EBP homologous protein mRNA expressions, and activated the eukaryotic initiation factor (eIF) 2α/activating transcription factor 4 pathway without protein kinase R-like ER kinase activation in A549 cells. Gefitinib and erlotinib caused neither ER stress nor cell death; however, these agents inhibited cell growth via the reduction of cyclin-D1 expression. Tauroursodeoxycholic acid, which is known to suppress eIF2α phosphorylation, cancelled the effects of EGFR inhibitors on cyclin-D1 expression and cell proliferation in a concentration-dependent manner. The results of an EGFR-silencing study using siRNA showed that gefitinib and erlotinib affected eIF2α phosphorylation and cyclin-D1 expression independent of EGFR inhibition. Therefore, the inhibition of cell growth by these EGFR inhibitors might equate to impairment of the alveolar epithelial cell repair system via eIF2α phosphorylation and reduced cyclin-D1 expression.

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A novel protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery under cardiopulmonary bypass

Odaka M., Minakata K., Toyokuni H., Yamazaki K., Yonezawa A., Sakata R., Matsubara K.

General Thoracic and Cardiovascular Surgery （General Thoracic and Cardiovascular Surgery） 63 （ 8 ） 446 - 452 2015年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 18636705

Objective: This study aimed to develop and assess the effectiveness of a protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery. Methods: We established a protocol for antibiotic prophylaxis based on preoperative kidney function in patients undergoing open heart surgery. This novel protocol was assessed by comparing patients undergoing open heart surgery before (control group; n = 30) and after its implementation (protocol group; n = 31) at Kyoto University Hospital between July 2012 and January 2013. Results: Surgical site infections (SSIs) were observed in 4 control group patients (13.3 %), whereas no SSIs were observed in the protocol group patients (P < 0.05). The total duration of antibiotic use decreased significantly from 80.7 ± 17.6 h (mean ± SD) in the control group to 55.5 ± 14.9 h in the protocol group (P < 0.05). Similarly, introduction of the protocol significantly decreased the total antibiotic dose used in the perioperative period (P < 0.05). Furthermore, antibiotic regimens were changed under suspicion of infection in 5 of 30 control group patients, whereas none of the protocol group patients required this additional change in the antibiotic regimen (P < 0.05). Conclusion: Our novel antibiotic prophylaxis protocol based on preoperative kidney function effectively prevents SSIs in patients undergoing open heart surgery.

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Boosting cancer immunotherapy with anti-CD137 antibody therapy

Yonezawa A., Dutt S., Chester C., Kim J., Kohrt H.E.

Clinical Cancer Research （Clinical Cancer Research） 21 （ 14 ） 3113 - 3120 2015年07月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 10780432

In the past 5 years, immunomodulatory antibodies have revolutionized cancer immunotherapy. CD137, a member of the tumor necrosis factor receptor superfamily, represents a promising target for enhancing antitumor immune responses. CD137 helps regulate the activation of many immune cells, including CD4+ T cells, CD8+ T cells, dendritic cells, and natural killer cells. Recent studies indicate that the antitumor efficacy of therapeutic tumor-targeting antibodies can be augmented by the addition of agonistic antibodies targeting CD137. As ligation of CD137 provides a costimulatory signal in multiple immune cell subsets, combination therapy of CD137 antibody with therapeutic antibodies and/or vaccination has the potential to improve cancer treatment. Recently, clinical trials of combination therapies with agonistic anti-CD137 mAbs have been launched. In this review, we discuss the recent advances and clinical promise of agonistic anti-CD137 monoclonal antibody therapy.

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Association of decreased mRNA expression of multidrug and toxin extrusion protein 1 in peripheral blood cells with the development of flutamide-induced liver injury

Nakano K., Ando H., Kurokawa S., Hosohata K., Ushijima K., Takada M., Tateishi M., Yonezawa A., Masuda S., Matsubara K., Inui K.I., Morita T., Fujimura A.

Cancer Chemotherapy and Pharmacology （Cancer Chemotherapy and Pharmacology） 75 （ 6 ） 1191 - 1197 2015年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 03445704

Purpose: The anti-prostate cancer drug flutamide occasionally causes hepatotoxicity, and predictive biomarkers of flutamide-induced liver injury (FILI) are needed to improve safety of this drug. The aim of this prospective study was to identify such a biomarker by analyzing peripheral blood samples from patients before flutamide therapy. Methods: Blood samples were obtained from 52 patients with prostate cancer before flutamide therapy. FILI was defined as treatment-related elevation of the serum concentration of aspartate or alanine aminotransferase to more than twice the upper limit of the reference range. The patients were monitored for at least 6 months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. Results: Seventeen patients developed FILI. Microarray analysis of the training set in 15 patients detected 11 annotated genes showing >twofold expression changes between the groups (p < 0.005). Quantitative PCR analysis of both the training set and validation set confirmed that mRNA levels of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1, encoded by 1 of the 11 genes) were significantly lower in patients with FILI. A small experiment on mice (three per group) showed that Mate1 knockout mice had an elevated serum concentration of 4-nitro-3-(trifluoromethyl)phenylamine, a major metabolite of flutamide, 2 h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. Conclusions: The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.

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Enhancement of antibody-dependent cell mediated cytotoxicity: a new era in cancer treatment.

Rajasekaran N, Chester C, Yonezawa A, Zhao X, Kohrt HE

ImmunoTargets and therapy 4 91 - 100 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2253-1556

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Extracellular nucleotides from dying cells act as molecular signals to promote wound repair in renal tubular injury

Shunsaku Nakagawa, Tomohiro Omura, Atsushi Yonezawa, Ikuko Yano, Takayuki Nakagawa, Kazuo Matsubara

American Journal of Physiology - Renal Physiology （American Physiological Society） 307 （ 12 ） F1404 - F1411 2014年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1522-1466

Acute kidney injury (AKI) often correlates with poor prognosis and is followed by various severe unfavorable systemic outcomes. It is important to understand the pathophysiology of AKI for the development of novel therapeutic approaches toward promoting renal regeneration after injury. Recent studies have indicated that AKI-induced tubular cell death plays an active role in the onset of tissue regeneration
however, the mechanisms underlying renal tubular repair after injury have yet to be understood. In the present study, we explored molecules that might serve as “danger” signals in mediating tubular regeneration. Kidneys of rats systemically administered the nephrotoxicant cisplatin (to induce AKI) exhibited massive cell proliferation. The proportion of proliferating cells in the total cell distribution was highest in the outer stripe of the outer medulla coincided with where the tubular damage was the most severe in this study. This finding suggests that soluble factors may have been released from damaged cells to stimulate the proliferation of neighboring tubular epithelial cells. In elucidating the mechanism of dying cell-to-surviving cell communication using normal rat kidney NRK-52E epithelial cells, we found a significant increase in ATP levels in supernatants of these cells after the induction of cell death using ultraviolet irradiation. Furthermore, treatment of conditioned supernatants with apyrase or suramin, which inhibits purinergic signaling, resulted in significant decreases in cell proliferation and migration activities. These results demonstrate a novel role for extracellular nucleotides, probably as danger signals in aggravating tubular regeneration after AKI.

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A randomized controlled clinical trial of topical insulin-like growth factor-1 therapy for sudden deafness refractory to systemic corticosteroid treatment

Nakagawa T., Kumakawa K., Usami S.i., Hato N., Tabuchi K., Takahashi M., Fujiwara K., Sasaki A., Komune S., Sakamoto T., Hiraumi H., Yamamoto N., Tanaka S., Tada H., Yamamoto M., Yonezawa A., Ito-Ihara T., Ikeda T., Shimizu A., Tabata Y., Ito J.

BMC Medicine （BMC Medicine） 12 （ 1 ） 219 2014年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1741-7015

Background: To date, no therapeutic option has been established for sudden deafness refractory to systemic corticosteroids. This study aimed to examine the efficacy and safety of topical insulin-like growth factor-1 (IGF-1) therapy in comparison to intratympanic corticosteroid therapy. Methods: We randomly assigned patients with sudden deafness refractory to systemic corticosteroids to receive either gelatin hydrogels impregnated with IGF-1 in the middle ear (62 patients) or four intratympanic injections with dexamethasone (Dex; 58 patients). The primary outcome was the proportion of patients showing hearing improvement (10 decibels or greater in pure-tone average hearing thresholds) 8 weeks after treatment. The secondary outcomes included the change in pure-tone average hearing thresholds over time and the incidence of adverse events. Results: In the IGF-1 group, 66.7% (95% confidence interval [CI], 52.9-78.6%) of the patients showed hearing improvement compared to 53.6% (95% CI, 39.7-67.0%) of the patients in the Dex group (P=0.109). The difference in changes in pure-tone average hearing thresholds over time between the two treatments was statistically significant (P=0.003). No serious adverse events were observed in either treatment group. Tympanic membrane perforation did not persist in any patient in the IGF-1 group, but did persist in 15.5% (95% CI, 7.3-27.4%) of the patients in the Dex group (P=0.001). Conclusions: The positive effect of topical IGF-1 application on hearing levels and its favorable safety profile suggest utility for topical IGF-1 therapy in patients with sudden deafness.

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Impact of cytochrome P450 3A5 polymorphism in graft livers on the frequency of acute cellular rejection in living-donor liver transplantation

Uesugi M., Kikuchi M., Shinke H., Omura T., Yonezawa A., Matsubara K., Fujimoto Y., Okamoto S., Kaido T., Uemoto S., Masuda S.

Pharmacogenetics and Genomics （Pharmacogenetics and Genomics） 24 （ 7 ） 356 - 366 2014年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17446872

OBJECTIVE: We investigated whether the cytochrome P450 3A5*3 (CYP3A5*3) genotype affects tacrolimus pharmacokinetics and the risk of acute cellular rejection in living-donor liver transplant patients in Japan. MATERIALS AND METHODS: Between July 2004 and June 2011, we enrolled 410 living-donor liver transplant patients receiving tacrolimus. Biopsy specimens of intestinal mucosa and graft liver at surgery were obtained to examine the mRNA expression of CYP3A subfamilies as well as the genotyping of CYP3A5*3 polymorphism. RESULTS: The CYP3A5 genotype in the native intestine had no significant effect on the occurrence of acute cellular rejection between postoperative days 14 and 23 in cases with identical or compatible ABO blood types (11.5% for the CYP3A5*1 allele vs. 7.4% for CYP3A5*3/*3; P=0.2643), although the concentration/dose ratio of tacrolimus was significantly higher in patients with the intestinal CYP3A5*3/*3 genotype than in those with the CYP3A5*1 allele for 5 post-transplant weeks. However, patients who received a graft liver with the CYP3A5*1 allele showed a higher rate of acute cellular rejection than those who received a graft liver with the CYP3A5*3/*3 genotype (14.5 vs. 5.7%; P=0.0134). The relative risk for acute cellular rejection associated with the CYP3A5*1 liver allele was 2.629 (P=0.018, Cox regression model). Consequently, graft liver CYP3A5*1 genotype might increase the risk for acute cellular rejection after living-donor liver transplantation, possibly by associating with the local hepatic tacrolimus concentration. CONCLUSIONS: The target level of tacrolimus may be affected by the CYP3A5*3 genotype of the liver, rather than by that of the small intestine, after postoperative day 14. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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Assessment of four methodologies (microparticle enzyme immunoassay, chemiluminescent enzyme immunoassay, affinity column-mediated immunoassay, and flow injection assay-tandem mass spectrometry) for measuring tacrolimus blood concentration in Japanese liver transplant recipients

Hashi S., Masuda S., Kikuchi M., Uesugi M., Yano I., Omura T., Yonezawa A., Fujimoto Y., Ogawa K., Kaido T., Uemoto S., Matsubara K.

Transplantation Proceedings （Transplantation Proceedings） 46 （ 3 ） 758 - 760 2014年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00411345

Therapeutic drug monitoring (TDM) and subsequent dosage adjustment for individual patients in the treatment with tacrolimus are required after liver transplantation to prevent rejection and over-immunosuppression, which leads to severe infection and adverse reactions including nephrotoxicity. The purpose of this study was to evaluate the analytical performance among commercially available immunoassay methods, which were microparticle enzyme immunoassay (MEIA), chemiluminescent enzyme immunoassay (CLIA), and affinity column-mediated immunoassay (ACMIA), compared with an assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, the flow injection assay (FIA-MS/MS) was also evaluated to determine whether it could be available as a new method of analysis in tacrolimus therapy. The blood tacrolimus concentrations in samples from liver transplant recipients (n = 102) were measured using MEIA, CLIA, ACMIA, and LC-MS/MS. Additional blood samples from liver transplant recipients (n = 54) were analyzed using both FIA-MS/MS and LC-MS/MS. Because the assay performance and characteristics of MEIA, CLIA, ACMIA, and FIA-MS/MS are relatively different, the measured data should be carefully considered depending on the methodology. © 2014 by Elsevier Inc. All rights reserved.

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Successful telaprevir treatment in combination of cyclosporine against recurrence of hepatitis C in the Japanese liver transplant patients

Kikuchi M., Okuda Y., Ueda Y., Nishioka Y., Uesugi M., Hashimoto E., Takahashi T., Kawai T., Hashi S., Shinke H., Omura T., Yonezawa A., Ito T., Fujimoto Y., Kaido T., Chiba T., Uemoto S., Matsubara K., Masuda S.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 37 （ 3 ） 417 - 423 2014年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 09186158

Telaprevir (TVR) is a protease inhibitor used in combination with pegylated interferon alfa-2b and ribavirin for hepatitis C, and TVR strongly inhibits CYP3A4 and CYP3A5. We reported successful TVR treatment of liver transplant patients with recurrence of hepatitis C during receiving immunosuppressive therapy. Before initiation of triple therapy, all patients switched from tacrolimus to cyclosporine, which has a lower inhibitory effect on CYP3A4 and CYP3A5 than tacrolimus. To avoid graft failure, we measured the cyclosporine blood concentrations at 0, 2, and 6 h after administration to maintain the target level (150-200 ng/mL) within 1 week after initiation of TVR and adjusted the dose of cyclosporine. The dose of cyclosporine was decreased 0.24-0.40 fold in all patients after initiation of TVR treatment. In 3 patients, the dose of TVR was decreased two-thirds of starting dose because of adverse effects, including anorexia and skin rash. However, the HCV RNA level rapidly decreased to undetectable levels within 1 month. Furthermore, all patients completed the TVR therapy in 12 weeks and did not experience liver graft rejection. In addition, we found the rapid elimination of inhibitory effect of TVR on the disposition of cyclospirne in the all four cases and therefore, rapid increase in the dosage of cyclosporine would be required immediately after the end of TVR administration. These results suggest that frequent measurement of cyclosporine levels was important for successful TVR triple therapy and prevention of rejection. © 2014 The Pharmaceutical Society of Japan.

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Functional involvement of RFVT3/SLC52A3 in intestinal riboflavin absorption

Yoshimatsu H., Yonezawa A., Yao Y., Sugano K., Nakagawa S., Omura T., Matsubara K.

American Journal of Physiology - Gastrointestinal and Liver Physiology （American Journal of Physiology - Gastrointestinal and Liver Physiology） 306 （ 2 ） G102 - G110 2014年01月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 01931857

Riboflavin, also known as vitamin B2, is transported across the biological membrane into various organs by transport systems. Riboflavin transporter RFVT3 is expressed in the small intestine and has been suggested to localize in the apical membranes of the intestinal epithelial cells. In this study, we investigated the functional involvement of RFVT3 in riboflavin absorption using intestinal epithelial T84 cells and mouse small intestine. T84 cells expressed RFVT3 and conserved unidirectional riboflavin transport corresponding to intestinal absorption. Apical [3H]riboflavin uptake was pH-dependent in T84 cells. This uptake was not affected by Na+ depletion at apical pH 6.0, although it was significantly decreased at apical pH 7.4. The [3H]riboflavin uptake from the apical side of T84 cells was prominently inhibited by the RFVT3 selective inhibitor methylene blue and significantly decreased by transfection of RFVT3-small-interfering RNA. In the gastrointestinal tract, RFVT3 was expressed in the jejunum and ileum. Mouse jejunal and ileal permeabilities of [3H]riboflavin were measured by the in situ closed-loop method and were significantly reduced by methylene blue. These results strongly suggest that RFVT3 would functionally be involved in riboflavin absorption in the apical membranes of intestinal epithelial cells. © 2014 the American Physiological Society.

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Investigation of endogenous compounds for assessing the drug interactions in the urinary excretion involving multidrug and toxin extrusion proteins

Kato K., Mori H., Kito T., Yokochi M., Ito S., Inoue K., Yonezawa A., Katsura T., Kumagai Y., Yuasa H., Moriyama Y., Inui K.I., Kusuhara H., Sugiyama Y.

Pharmaceutical Research （Pharmaceutical Research） 31 （ 1 ） 136 - 147 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07248741

Purpose: Multidrug and toxin extrusion proteins (MATEs) are multispecific organic cation transporters mediating the efflux of various cationic drugs into the urine. The present study aimed at identifying endogenous compounds in human plasma and urine specimens as biomarkers to evaluate drug interactions involving MATEs in the kidney without administration of their exogenous probe drugs. Methods: An untargeted metabolomic analysis was performed using urine and plasma samples from healthy volunteers and mice treated with or without the potent MATE inhibitor, pyrimethamine. Plasma and urinary concentrations of candidate markers were measured using liquid chromatography-mass spectrometry. Transport activities were determined in MATE- or OCT2-expressing HEK293 cells. The deuterium-labeled compounds of candidates were administered to mice for pharmacokinetics study. Results: Urinary excretion of eleven compounds including thiamine and carnitine was significantly lower in the pyrimethamine-treatment group in humans and mice, whereas no endogenous compound was noticeably accumulated in the plasma. The renal clearance of thiamine and carnitine was decreased by 70%-84% and 90%-94% (p < 0.05), respectively, in human. The specific uptake of thiamine was observed in MATE1-, MATE2-K- or OCT2-expressing HEK293 cells with Km of 3.5 ± 1.0, 3.9 ± 0.8 and 59.9 ± 6.7 μM, respectively. The renal clearance of carnitine-d 3 was decreased by 62% in mice treated with pyrimethamine. Conclusions: Our findings indicate that MATEs account for the efflux of thiamine and perhaps carnitine as well as drugs into the urine. The urinary excretion of thiamine is useful to detect drug interaction involving MATEs in the kidney. © 2013 Springer Science+Business Media New York.

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Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

Foley A.R., Menezes M.P., Pandraud A., Gonzalez M.A., Al-Odaib A., Abrams A.J., Sugano K., Yonezawa A., Manzur A.Y., Burns J., Hughes I., McCullagh B.G., Jungbluth H., Lim M.J., Lin J.P., Megarbane A., Urtizberea J.A., Shah A.H., Antony J., Webster R., Broomfield A., Ng J., Mathew A.A., O'Byrne J.J., Forman E., Scoto M., Prasad M., O'Brien K., Olpin S., Oppenheim M., Hargreaves I., Land J.M., Wang M.X., Carpenter K., Horvath R., Straub V., Lek M., Gold W., Farrell M.O., Brandner S., Phadke R., Matsubara K., McGarvey M.L., Scherer S.S., Baxter P.S., King M.D., Clayton P., Rahman S., Reilly M.M., Ouvrier R.A., Christodoulou J., Züchner S., Muntoni F., Houlden H.

Brain （Brain） 137 （ 1 ） 44 - 56 2014年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00068950

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms. © 2013 The Author.

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Safety and Efficacy of Sustained Release of Basic Fibroblast growth Factor Using Biodegradable Gelatin Hydrogel in Patients With Critical Limb Ischemia

Motoyuki Kumagai, Akira Marui, Yasuhiko Tabata, Takahide Takeda, Masaya Yamamoto, Atsushi Yonezawa, Shiro Tanaka, Shigeki Yanagi, Toshiko Ito-Ihara, Takafumi Ikeda, Toshinori Murayama, Satoshi Teramukai, Toshiya Katsura, Kazuo Matsubara, Koji Kawakami, Masayuki Yokode, Akira Shimizu, Ryuzo Sakata

CIRCULATION （LIPPINCOTT WILLIAMS & WILKINS） 128 （ 22 ） 16154.0 2013年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-7322

Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models

Nakanishi H., Yonezawa A., Matsubara K., Yano I.

European Journal of Pharmacology （European Journal of Pharmacology） 710 （ 1-3 ） 20 - 28 2013年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00142999

Refractory epilepsy is reportedly associated with an overexpression of ATP-binding cassette transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (Bcrp). In this study, we examined the contribution of Pgp and Bcrp to the brain distribution of 12 antiepileptic drugs (AEDs) in Mdr1a/1b(-/-) and Mdr1a/1b(-/-)/Bcrp(-/-) mice within a therapeutic concentration range. The blood concentrations were sequentially determined, and the brain concentrations were measured at 60 min after intravenous administration. The plasma concentration profiles for each AED in the Mdr1a/1b(-/-) mice were equivalent to those in the wild-type mice. In contrast, the plasma concentration profiles of phenytoin, lamotrigine, topiramate, tiagabine, and levetiracetam in the Mdr1a/1b(-/-)/Bcrp(-/-) mice were significantly lower than the corresponding ones in the wild-type mice. The brain-to-plasma concentration ratio (Kpbrain) values of phenytoin, topiramate, and tiagabine in the Mdr1a/1b(-/-) mice were significantly higher than the corresponding ones in the wild-type mice. In contrast, the Kp brain values of phenobarbital, clobazam, zonisamide, gabapentin, tiagabine, and levetiracetam in the Mdr1a/1b(-/-)/Bcrp(-/-) mice were significantly higher than the corresponding ones in Mdr1a/1b(-/-) mice. The Kpbrain values of the 12 AEDs in the Mdr1a/1b(-/-)/Bcrp(-/-) mice, but not wild-type mice, significantly correlated with the corresponding molecular weight values. These findings suggest that both Pgp and Bcrp restrict brain access for several AEDs. Taken together, information on the contribution of each transporter may be useful in the development of strategic treatments of refractory epilepsy. © 2013 Elsevier B.V.

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Novel riboflavin transporter family RFVT/SLC52: Identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52

Yonezawa A., Inui K.

Molecular Aspects of Medicine （Molecular Aspects of Medicine） 34 （ 2-3 ） 693 - 701 2013年04月

研究論文（学術雑誌）, 共著, 筆頭著者, 責任著者, 査読有り, ISSN 00982997

Riboflavin, a water-soluble vitamin also known as vitamin B2, is essential for normal cellular functions. Riboflavin transporters play important roles in its homeostasis. Recently, three novel riboflavin transporters were identified, and designated as RFT1, RFT2 and RFT3. Because the RFTs did not show similarity to other SLC transporters, and RFT1 and RFT3 are similar in sequence and function, they were assigned into a new SLC family, SLC52. Subsequently, RFT1/GPR172B, RFT3/GPR172A and RFT2/C20orf54 were renamed as RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3, respectively. In this review, we summarize recent findings on the cloning, nomenclature, functional characterization and genetic diseases of RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3. © 2012 Elsevier Ltd. All rights reserved.

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Sodium tauroursodeoxycholate prevents paraquat-induced cell death by suppressing endoplasmic reticulum stress responses in human lung epithelial A549 cells

Omura T., Asari M., Yamamoto J., Oka K., Hoshina C., Maseda C., Awaya T., Tasaki Y., Shiono H., Yonezawa A., Masuda S., Matsubara K., Shimizu K.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications） 432 （ 4 ） 689 - 694 2013年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006291X

Paraquat is a commonly used herbicide; however, it is highly toxic to humans and animals. Exposure to paraquat causes severe lung damage, leading to pulmonary fibrosis. However, it has not been well clarified as how paraquat causes cellular damage, and there is no established standard therapy for paraquat poisoning. Meanwhile, endoplasmic reticulum stress (ERS) is reported to be one of the causative factors in many diseases, although mammalian cells have a defense mechanism against ERS-induced apoptosis (unfolded protein response). Here, we demonstrated that paraquat changed the expression levels of unfolded protein response-related molecules, resulting in ERS-related cell death in human lung epithelial A549 cells. Moreover, treatment with sodium tauroursodeoxycholate (TUDCA), a chemical chaperone, crucially rescued cells from death caused by exposure to paraquat. These results indicate that paraquat toxicity may be associated with ERS-related molecules/events. Through chemical chaperone activity, treatment with TUDCA reduced paraquat-induced ERS and mildly suppressed cell death. Our findings also suggest that TUDCA treatment represses the onset of pulmonary fibrosis caused by paraquat, and therefore chemical chaperones may have novel therapeutic potential for the treatment of paraquat poisoning. © 2013 Elsevier Inc.

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Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity

Nishihara K., Masuda S., Shinke H., Ozawa A., Ichimura T., Yonezawa A., Nakagawa S., Inui K.I., Bonventre J.V., Matsubara K.

Biochemical Pharmacology （Biochemical Pharmacology） 85 （ 4 ） 570 - 582 2013年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00062952

Because of the difficulty in detecting segment-specific response in the kidney, we investigated the molecular events underlying acute kidney injury in the proximal tubules of rats with cisplatin (cis-diamminedichloroplatinum II)-induced nephrotoxicity. Microarray analysis revealed that mRNA levels of several cytokines and chemokines, such as interleukin-1beta, chemokine (C-C motif) ligand (CCL) 2, CCL20, chemokine (C-X-C motif) ligand (CXCL) 1, and CXCL10 were significantly increased after cisplatin treatment in both isolated proximal tubules and whole kidney. Interestingly, tubular CCL2 mRNA levels increased soon after cisplatin administration, whereas CCL2 mRNA levels in whole kidney first decreased and then increased. Levels of both CCL2 and kidney injury molecule-1 (KIM-1) in the whole kidney increased after cisplatin administration. Immunofluorescence analysis revealed CCL2 changes in the proximal tubular cells initially and then in the medullary interstitium. Urinary CCL2 excretion significantly increased approximately 3-fold compared with controls the day after cisplatin administration (5 mg/kg), when no changes were observed plasma creatinine and blood urea nitrogen levels. Urinary levels of KIM-1 also increased 3-fold after cisplatin administration. In addition, urinary CCL2 rather than KIM-1 increased in chronic renal failure rats after administration of low-dose cisplatin (2 mg/kg), suggesting that urinary CCL2 was selective for cisplatin-induced nephrotoxicity in renal impairment. These results indicated that the increase in cytokine and chemokine expression in renal epithelial cells might be responsible for kidney deterioration in cisplatin-induced nephrotoxicity, and that urinary CCL2 is associated with tubular injury and serves as a sensitive and noninvasive marker for the early detection of cisplatin-induced tubular injury. © 2012 Elsevier Inc.

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Involvement of riboflavin transporter RFVT2/Slc52a2 in hepatic homeostasis of riboflavin in mice

Yao Y., Yonezawa A., Yoshimatsu H., Omura T., Masuda S., Matsubara K.

European Journal of Pharmacology （European Journal of Pharmacology） 714 （ 1-3 ） 281 - 287 2013年

研究論文（学術雑誌）, 共著, 責任著者, 査読有り, ISSN 00142999

Riboflavin (vitamin B2) acts as an intermediary during various biochemical oxidation-reduction reactions in the liver. Hepatic riboflavin homeostasis is suggested to be maintained through its transporter(s). Riboflavin transporters, RFVT2/Slc52a2 and RFVT3/Slc52a3, have been identified in rodents. However, the role of each RFVT in the hepatic homeostasis of riboflavin has not yet been fully clarified. In this study, we assessed the contribution of each RFVT to riboflavin uptake into the liver using in vitro and in vivo studies. The uptake of riboflavin by mouse primary hepatocytes increased in a time-dependent and a concentration-dependent manner. Riboflavin transport was independent of extracellular Na+. However, the uptake decreased slightly along with the extracellular pH increases. Real-time PCR analysis revealed that the mRNA level of Slc52α2, or coding for mouse (m)RFVT2, in the mouse liver was 10 times higher than that of Slc52α3 (coding for mRFVT3). The uptake of riboflavin at pH 7.4 by primary hepatocytes was significantly decreased by the transfection of Slc52α2-small interfering RNA (siRNA), but not Slc52α3-siRNA. Furthermore, we also confirmed the contribution of riboflavin transporters in vivo. The riboflavin concentrations in plasma, but not in the liver, were significantly decreased in mice fed on a riboflavin-deficient diet for 8 weeks. The expression of Slc52α2 mRNA was significantly upregulated by riboflavin deprivation. These results strongly suggest that mRFVT2 was involved in hepatic riboflavin homeostasis. © 2013 Elsevier B.V. All rights reserved.

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Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome

Haack T.B., Makowski C., Yao Y., Graf E., Hempel M., Wieland T., Tauer U., Ahting U., Mayr J.A., Freisinger P., Yoshimatsu H., Inui K., Strom T.M., Meitinger T., Yonezawa A., Prokisch H.

Journal of Inherited Metabolic Disease （Journal of Inherited Metabolic Disease） 35 （ 6 ） 943 - 948 2012年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01418955

Brown-Vialetto-Van Laere syndrome (BVVLS [MIM 211530]) is a rare neurological disorder characterized by infancy onset sensorineural deafness and ponto-bulbar palsy. Mutations in SLC52A3 (formerly C20orf54), coding for riboflavin transporter 2 (hRFT2), have been identified as the molecular genetic correlate in several individuals with BVVLS. Exome sequencing of just one single case revealed that compound heterozygosity for two pathogenic mutations in the SLC52A2 gene coding for riboflavin transporter 3 (hRFT3), another member of the riboflavin transporter family, is also associated with BVVLS. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities. While mutations in SLC52A3 cause decreased plasma riboflavin levels, concordant with a role of SLC52A3 in riboflavin uptake from food, the SLC52A2-mutant individual had normal plasma riboflavin concentrations, a finding in line with a postulated function of SLC52A2 in riboflavin uptake from blood into target cells. Our results contribute to the understanding of human riboflavin metabolism and underscore its role in the pathogenesis of BVVLS, thereby providing a rational basis for a high-dose riboflavin treatment. © 2012 SSIEM and Springer.

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Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis

Toyama K., Yonezawa A., Masuda S., Osawa R., Hosokawa M., Fujimoto S., Inagaki N., Inui K., Katsura T.

British Journal of Pharmacology （British Journal of Pharmacology） 166 （ 3 ） 1183 - 1191 2012年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00071188

BACKGROUNDS AND PURPOSE Lactic acidosis is a fatal adverse effect of metformin, but the risk factor remains unclear. Multidrug and toxin extrusion 1 (MATE1) is expressed in the luminal membrane of the kidney and liver. MATE1 was revealed to be responsible for the tubular and biliary secretion of metformin. Therefore, some MATE polymorphisms, that cause it to function abnormally, are hypothesized to induce lactic acidosis. The purpose of this study is to clarify the association between MATE dysfunction and metformin-induced lactic acidosis. EXPERIMENTAL APPROACH Blood lactate, pH and bicarbonate ion (HCO 3-) levels were evaluated during continuous administration of 3 mg·mL -1 metformin in drinking water using Mate1 knockout (-/-), heterozygous (+/-) and wild-type (+/+) mice. To determine the tissue accumulation of metformin, mice were given 400 mg·kg -1 metformin orally. Furthermore, blood lactate data were obtained from diabetic patients given metformin. KEY RESULTS Seven days after metformin administration in drinking water, significantly higher blood lactate, lower pH and HCO 3- levels were observed in Mate1 -/- mice, but not in Mate1 +/- mice. The blood lactate levels were not affected in patients with the heterozygous MATE variant (MATE1-L125F, MATE1-G64D, MATE2-K-G211V). Sixty minutes after metformin administration (400 mg·kg -1, p.o.) the hepatic concentration of metformin was markedly higher in Mate1 -/- mice than in Mate1 +/+ mice. CONCLUSION AND IMPLICATIONS MATE1 dysfunction caused a marked elevation in the metformin concentration in the liver and led to lactic acidosis, suggesting that the homozygous MATE1 variant could be one of the risk factors for metformin-induced lactic acidosis. © 2012 The British Pharmacological Society.

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Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics

Yonezawa A., Inui K.

British Journal of Pharmacology （British Journal of Pharmacology） 164 （ 7 ） 1817 - 1825 2011年12月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 00071188

The renal organic cation transport system mediates the tubular secretion of cationic compounds including drugs, toxins and endogenous metabolites into urine. It consists of a membrane potential-dependent organic cation transporter at the basolateral membrane and an H +/organic cation antiporter at the brush-border membrane. In 2005, human multidrug and toxin extrusion MATE1/SLC47A1 was identified as a mammalian homologue of bacterial NorM. Thereafter, human MATE2-K/SLC47A2 and rodent MATE were found. Functional characterization revealed that MATE1 and MATE2-K were H +/organic cation antiporter, mediating the renal tubular secretion of cationic drugs in cooperation with the basolateral organic cation transporter OCT2. Recently, substrate specificity, transcription mechanisms, structure, polymorphisms, in vivo contributions and clinical outcomes on MATE have been investigated intensively. In this review, we summarize recent findings on MATE1/SLC47A1 and MATE2-K/SLC47A2 and discuss the importance of these transporters to the pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics of cationic drugs. © 2011 The British Pharmacological Society.

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Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B

Ho G., Yonezawa A., Masuda S., Inui K.I., Sim K.G., Carpenter K., Olsen R.K.J., Mitchell J.J., Rhead W.J., Peters G., Christodoulou J.

Human Mutation （Human Mutation） 32 （ 1 ） E1976 - E1984 2011年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10597794

Riboflavin, or vitamin B2, is a precursor to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) molecules, required in biological oxidation-reduction reactions. We previously reported a case of a newborn female who had clinical and biochemical features of multiple acyl-CoA dehydrogenation deficiency (MADD), which was corrected by riboflavin supplementation. The mother was then found to be persistently riboflavin deficient, suggesting that a possible genetic defect in riboflavin transport in the mother was the cause of the transient MADD seen in the infant. Two recently-identified riboflavin transporters G protein-coupled receptor 172B (GPR172B or RFT1) and riboflavin transporter 2 (C20orf54 or RFT2) were screened for mutations. Two missense sequence variations, c.209A>G [p.Q70R] and c.886G>A [p.V296M] were found in GPR172B. In vitro functional studies of both missense variations showed that riboflavin transport was unaffected by these variations. Quantitative real-time PCR revealed a de novo deletion in GPR172B spanning exons 2 and 3 in one allele from the mother. We postulate that haploinsufficiency of this riboflavin transporter causes mild riboflavin deficiency, and when coupled with nutritional riboflavin deficiency in pregnancy, resulted in the transient riboflavin-responsive disease seen in her newborn infant. This is the first report of a genetic defect in riboflavin transport in humans. © 2010 Wiley-Liss, Inc.

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Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity

Nakamura T., Yonezawa A., Hashimoto S., Katsura T., Inui K.I.

Biochemical Pharmacology （Biochemical Pharmacology） 80 （ 11 ） 1762 - 1767 2010年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00062952

Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is expressed in the brush-border membrane of renal proximal tubules and mediates the efflux of cationic drugs. In the present study, the role of MATE1 in the nephrotoxicity of cisplatin was investigated in vivo and in vitro. Cisplatin (15. mg/kg) was administered intraperitoneally to wild-type (Mate1(+/+)) and Mate1 knockout (Mate1(-/-)) mice. Lifespan was significantly shorter in Mate1(-/-) mice than Mate1(+/+) mice. Three days after the administration of cisplatin, plasma creatinine and blood urea nitrogen (BUN) levels were increased in both Mate1(+/+) and Mate1(-/-) mice compared with vehicle-treated controls, and creatinine clearance was decreased. Moreover, a significant rise in creatinine and BUN levels was observed in cisplatin-treated Mate1(-/-) mice in comparison to Mate1(+/+) mice. A pharmacokinetic analysis revealed the plasma concentration and renal accumulation of cisplatin to be higher in Mate1(-/-) mice than Mate1(+/+) mice 1. h after a single intravenous administration of cisplatin (0.5. mg/kg). Furthermore, the combination of a selective MATE inhibitor, pyrimethamine, with cisplatin also elevated creatinine and BUN levels compared to cisplatin alone. In experiments in vitro, the cellular uptake of cisplatin was stimulated by the expression of mouse MATE1 as well as organic cation transporters OCT1 and OCT2. In conclusion, MATE1 mediates the efflux of cisplatin and is involved in cisplatin-induced nephrotoxicity. © 2010 Elsevier Inc.

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Topical insulin-like growth factor 1 treatment using gelatin hydrogels for glucocorticoid-resistant sudden sensorineural hearing loss: A prospective clinical trial

Nakagawa T., Sakamoto T., Hiraumi H., Kikkawa Y.S., Yamamoto N., Hamaguchi K., Ono K., Yamamoto M., Tabata Y., Teramukai S., Tanaka S., Tada H., Onodera R., Yonezawa A., Inui K.I., Ito J.

BMC Medicine （BMC Medicine） 8 76 2010年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1741-7015

Sudden sensorineural hearing loss (SSHL) is a common condition in which patients lose the hearing in one ear within 3 days. Systemic glucocorticoid treatments have been used as standard therapy for SSHL; however, about 20% of patients do not respond. We tested the safety and efficacy of topical insulin-like growth factor 1 (IGF1) application using gelatin hydrogels as a treatment for SSHL.Methods: Patients with SSHL that showed no recovery to systemic glucocorticoid administration were recruited. We applied gelatin hydrogels, impregnated with recombinant human IGF1, into the middle ear. The primary outcome measure was the proportion of patients showing hearing improvement 12 weeks after the test treatment. The secondary outcome measures were the proportion of patients showing improvement at 24 weeks and the incidence of adverse events. The null hypothesis was that 33% of patients would show hearing improvement, as was reported for a historical control after hyperbaric oxygen therapy.Results: In total, 25 patients received the test treatment at a median of 23 days (range 15-32) after the onset of SSHL, between 2007 and 2009. At 12 weeks after the test treatment, 48% (95% CI 28% to 69%; P = 0.086) of patients showed hearing improvement, and the proportion increased to 56% (95% CI 35% to 76%; P = 0.015) at 24 weeks. No serious adverse events were observed.Conclusions: Topical IGF1 application using gelatin hydrogels is well tolerated and may be efficacious for hearing recovery in patients with SSHL that is resistant to systemic glucocorticoids. © 2010 Nakagawa et al; licensee BioMed Central Ltd.

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Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain

Yao Y., Yonezawa A., Yoshimatsu H., Masuda S., Katsura T., Inui K.

Journal of Nutrition （Journal of Nutrition） 140 （ 7 ） 1220 - 1226 2010年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00223166

We isolated cDNA coding a new human riboflavin transporter (hRFT)3, which exhibits 86.7 and 44.1% amino acid identity with hRFT1 and hRFT2, respectively. It was predicted to have 10 putative membrane-spanning domains. The functional characteristics of hRFT3 were examined and compared with those of its isoforms, hRFT1 and hRFT2. Realtime PCR revealed that hRFT3 mRNA was strongly expressed in the brain and salivary gland. hRFT1 mRNA was strongly expressed in the placenta and small intestine, whereas hRFT2 mRNA was most abundantly expressed in the testis and strongly in the small intestine and prostate. hRFT-mediated uptake of [3H]riboflavin was evaluated using human embryonic kidney 293 cells transiently transfected with the cDNA coding each hRFT. The apparent Michaelis-Menten constants of hRFT1, hRFT2, and hRFT3 for riboflavin were 1.38, 0.98, and 0.33 μmol/L, respectively. The hRFT-mediated [3H] riboflavin uptake was independent of extracellular Na+ and Cl -. Specific uptake of [3H]riboflavin by hRFT2, but not hRFT1 and hRFT3, decreased as extracellular pH was changed from 5.4 to 8.4. The substrate specificities of the hRFT family were similar. hRFT-mediated uptake of [ 3H]riboflavin was inhibited by some riboflavin analogs, but not D-ribose, organic ions, or other vitamins. The newly isolated hRFT3 may play an important role in brain riboflavin homeostasis. Its amino acid sequence and functional characteristics are similar to those of hRFT1, but not hRFT2. © 2010 American Society for Nutrition.

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Impact of cyclin B2 and cell division cycle 2 on tubular hyperplasia in progressive chronic renal failure rats

Kumiko Nishihara, Satohiro Masuda, Shunsaku Nakagawa, Atsushi Yonezawa, Takaharu Ichimura, Joseph V. Bonventre, Ken-Ichi Inui

American Journal of Physiology - Renal Physiology （4） 298 （ 4 ） F923 - F934 2010年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0363-6127

To clarify the specific molecular events of progressive tubular damage in chronic renal failure (CRF), we conducted microarray analyses using isolated proximal tubules from subtotally nephrectomized (Nx) rats as a model of CRF. Our results clearly demonstrated time-dependent changes in gene expression profiles localized to proximal tubules. The expression of mitosis-specific genes Cyclin B2 and Cell division cycle 2 (Cdc2) was significantly and selectively increased in the proximal tubules during the compensated period but decreased to basal level in the end-stage period. Administration of everolimus, a potent inhibitor of mammalian target of rapamycin, markedly reduced compensatory hypertrophy and hyperplasia of epithelial cells, which was accompanied by complete abolishment of the expression of Cyclin B2 and Cdc2 enhancement
renal function was then severely decreased. Treatment with the Cdc2 inhibitor 2-cyanoethyl alsterpaullone clearly decreased epithelial cell hyperplasia, based on staining of phosphorylated histone H3 and Ki-67, while hypertrophy was not inhibited. In conclusion, we have demonstrated roles of Cyclin B2 and Cdc2 in the epithelial hyperplasia in response to Nx. These results advance the knowledge of the contribution of cell cycle regulators, especially M phase, in pathophysiology of tubular restoration and/or degeneration, and these two molecules are suggested to be a marker for the proliferation of proximal tubular cells in CRF. Copyright © 2010 the American Physiological Society.

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Heterozygous variants of multidrug and toxin extrusions (MATE1 and MATE2-K) have little influence on the disposition of metformin in diabetic patients

Toyama K., Yonezawa A., Tsuda M., Masuda S., Yano I., Terada T., Osawa R., Katsura T., Hosokawa M., Fujimoto S., Inagaki N., Inui K.

Pharmacogenetics and Genomics （Pharmacogenetics and Genomics） 20 （ 2 ） 135 - 138 2010年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 17446872

Multidrug and toxin extrusions (MATE1/SLC47A1 and MATE2-K/SLC47A2) play important roles in the renal excretion of metformin. We have previously identified the nonsynonymous MATE variants with functional defects at low allelic frequencies. The purpose of this study was to evaluate the effects of heterozygous MATE variants on the disposition of metformin in mice and humans. Pharmacokinetic parameters of metformin in Mate1(±) heterozygous mice were comparable with those in Mate1(+/+) wild-type mice. Among 48 Japanese diabetic patients, seven patients carried heterozygous MATE variant and no patient carried homozygous MATE variant. There was no significant difference in oral clearance of metformin with or without heterozygous MATE variants. In addition, creatinine clearance, but not heterozygous MATE variants, significantly improved the model fit of metformin clearance by statistical analysis using the nonlinear mixed-effects modeling program. In conclusion, heterozygous MATE variants could not influence the disposition of metformin in diabetic patients. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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MDR1 haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients

Hosohata K., Masuda S., Yonezawa A., Katsura T., Oike F., Ogura Y., Takada Y., Egawa H., Uemoto S., Inui K.

Pharmaceutical Research （Pharmaceutical Research） 26 （ 7 ） 1590 - 1595 2009年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 07248741

Purpose: This study investigated whether haplotypes in the multidrug resistance 1 (MDR1) gene had effects on mRNA expression levels of MDR1 and cytochrome P450 (CYP) 3A4, and on the pharmacokinetics of tacrolimus in living-donor liver transplant (LDLT) patients, considering the gender difference. Methods: Haplotype analysis of MDR1 with G2677T/A and C3435T was performed in 63 de novo Japanese LDLT patients (17 to 55 years; 44.4% women). The expression levels of MDR1 and CYP3A4 mRNAs in jejunal biopsy specimens were quantified by real-time PCR. Results: Intestinal CYP3A4 mRNA expression levels (amol/μg total RNA) showed significantly higher values in women carrying the 2677TT-3435TT haplotype (median, 10.7; range, 5.92-15.2) than those with 2677GG-3435CC (3.03; range 1.38-4.68) and 2677GT-3435CT (median, 4.31; range, 0.07-9.42) (P∈=∈0.022), but not in men (P∈=∈0.81). However, MDR1 haplotype did not influence mRNA expression levels of MDR1 nor the concentration/dose ratio [(ng/mL)/(mg/day)] of oral tacrolimus for the postoperative 7 days, irrespective of gender. Conclusion: MDR1 haplotype may have a minor association with the tacrolimus pharmacokinetics after LDLT, but could be a good predictor of the inter-individual variation of intestinal expression of CYP3A4 in women. © 2009 Springer Science+Business Media, LLC.

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Risk factors for recurrence of primary sclerosing cholangitis after living donor liver transplantation: A single center experience

Egawa H., Taira K., Teramukai S., Haga H., Ueda Y., Yonezawa A., Masuda S., Tsuji H., Ashihara E., Takada Y., Uemoto S.

Digestive Diseases and Sciences （Digestive Diseases and Sciences） 54 （ 6 ） 1347 - 1354 2009年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 01632116

We retrospectively reviewed our 10-year experience with living donor liver transplantation (LDLT) in 30 consecutive patients with end-stage primary sclerosing cholangitis (PSC) to determine long-term patient and graft survival and risk factors for recurrence of PSC. For strict diagnosis of recurrence, patients with hepatic artery thrombosis (n = 2), ABO blood type incompatible transplantation (n = 3), and postoperative survival shorter than 1 year (n = 5) were excluded from the study, leaving 20 patients for analysis. Recurrence was diagnosed in 11 patients 26-71 months after transplantation. Multivariate analysis showed that cytomegalovirus diseases within 3 months after transplantation and related donors were independent risk factors for recurrence. When the effects on recurrence were compared among donor-recipient relationships, there were significant differences, especially between nonrelated donors and parents. Multivariate analysis showed that age was an independent risk factor for time to graft loss. Cytomegalovirus prophylaxis and avoidance of related donors are important in reducing PSC recurrence, although this is a preliminary report with limitations due to the small number of patients. LDLT for young patients with PSC using grafts from their parents might have to be avoided where deceased donor liver transplantation is available. © 2009 Springer Science+Business Media, LLC.

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Absence of influence of concomitant administration of rabeprazole on the pharmacokinetics of tacrolimus in adult living-donor liver transplant patients: A case-control study

Hosohata K., Masuda S., Yonezawa A., Sugimoto M., Takada Y., Kaido T., Ogura Y., Oike F., Shinji U., Inui K.

Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics） 24 （ 5 ） 458 - 463 2009年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13474367

This study assesses the effects of rabeprazole on the pharmacokinetics of tacrolimus, considering the cytochrome P450 (CYP) 2C19 and CYP3A5 genotypes of living-donor liver transplant patients (native intestine) and their corresponding donors (graft liver). We examined the concentration/dose ratio of tacrolimus in transplant patients treated with (n=17) or without (n=38) rabeprazole at 10 mg/day on postoperative days 22-28. A stratified analysis revealed no significant differences between the control and rabeprazole groups in the median (range) concentration/dose ratio of tacrolimus [(ng/mL)/(mg/day)] for CYP2C19 extensive/intermediate metabolizers [2.71 (1.00-6.15) versus 2.55 (0.96-9.25); P=0.85] and for poor metabolizers [4.92 (2.44-7.00) versus 3.82 (2.00-7.31); P=0.68], respectively. Even based on the classification of CYP2C19 genotypes of donors, no significant difference in the concentration/dose ratio of tacrolimus was found for the two groups (CYP2C19 extensive/intermediate metabolizers, P=0.52; poor metabolizers, P=0.51). The same was observed for CYP3A5*1 carriers (P=0.97 for native intestine; P= 0.87 for graft liver) and CYP3A5*3/*3 carriers (P=0.89 for native intestine; P=0.56 for graft liver). These findings suggest a safer dosing and monitoring of tacrolimus coadministered with rabeprazole early on after liver transplantation regardless of the CYP2C19 and CYP3A5 genotypes of transplant patients and their donors.

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Significance of organic cation transporter 3 (SLC22A3) expression for the cytotoxic effect of oxaliplatin in colorectal cancer

Yokoo S., Masuda S., Yonezawa A., Terada T., Katsura T., Inui K.

Drug Metabolism and Disposition （Drug Metabolism and Disposition） 36 （ 11 ） 2299 - 2306 2008年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00909556

The effect of oxaliplatin against colorectal cancer is superior to that of cisplatin, but the molecular mechanism(s) involved is not clear. We found previously that oxaliplatin, but not cisplatin, was transported by human (h) and rat organic cation transporter 3 (OCT3)/SLC22A3. In the present study, we examined whether hOCT3 was significantly involved in the oxaliplatin-induced cytotoxicity and accumulation of platinum in colorectal cancer. The level of hOCT3 mRNA in the colon was 9.7-fold higher in cancerous than in normal tissues in six Japanese patients (P = 0.0247). In human colorectal cancer-derived cell lines, the mRNA of hOCT3 was highly expressed compared with that of other organic cation transporters. The release of lactate dehydrogenase (LDH) and accumulation of platinum with oxaliplatin treatment were increased in SW480 cells transfected with hOCT3 cDNA compared with empty vector-transfected cells. T84 and SW837 cells, with high levels of hOCT3, released more LDH and accumulated more platinum after oxaliplatin treatment than low hOCT3-expressing cells such as SW480, HCT116, HT29, and Lovo. However, the amount of platinum accumulated after cisplatin treatment did not differ among these six cell lines. The levels of hOCT3 expression in colon and rectum were also higher in cancerous than in normal tissues in Caucasian patients as determined by dot blotting. In conclusion, the hOCT3-mediated uptake of oxaliplatin into the cancers was suggested to be important for its cytotoxicity, and hOCT3 expression may be a marker for cancer chemotherapy including oxaliplatin. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

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Transcellular transport of organic cations in double-transfected MDCK cells expressing human organic cation transporters hOCT1/hMATE1 and hOCT2/hMATE1

Sato T., Masuda S., Yonezawa A., Tanihara Y., Katsura T., Inui K.

Biochemical Pharmacology （Biochemical Pharmacology） 76 （ 7 ） 894 - 903 2008年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00062952

To clarify the transcellular transport of organic cations via basolateral and apical transporters, we established double-transfected Madin-Darby canine kidney (MDCK) cells expressing both human organic cation transporter hOCT1 and hMATE1 (MDCK-hOCT1/hMATE1), and hOCT2 and hMATE1 (MDCK-hOCT2/hMATE1) as models of human hepatocytes and renal epithelial cells, respectively. Using the specific antibodies, hOCT1 and hMATE1 or hOCT2 and hMATE1 were found to be localized in the basolateral and apical membranes of MDCK-hOCT1/hMATE1 or MDCK-hOCT2/hMATE1 cells, respectively. A representative substrate, [14C]tetraethylammonium, was transported unidirectionally from the basolateral to apical side in these double transfectants. The optimal pH was showed to be 6.5 for the transcellular transport of [14C]tetraethylammonium, when the pH of the incubation medium on the apical side was varied from 5.5 to 8.5. The basolateral-to-apical transport also decreased in the presence of 10 mM 1-methyl-4-phenylpyridinium or 1 mM levofloxacin on the basolateral side of both double transfectants. In MDCK-hOCT2/hMATE1 cell monolayers, but not in MDCK-hOCT1/hMATE1 cell monolayers, the accumulation of [14C]tetraethylammonium was decreased in the presence of 10 mM 1-methyl-4-phenylpyridinium, but significantly increased in the presence of 1 mM levofloxacin. The uptake of [14C]tetraethylammonium, [3H]1-methyl-4-phenylpyridinium, [14C]metformin and [3H]cimetidine, but not of [14C]procainamide and [3H]quinidine, by HEK293 cells was stimulated by expression of the hOCT1, hOCT2 or hMATE1 compared to control cells. However, transcellular transport of [14C]procainamide and [3H]quinidine was clearly observed in both double-transfectants. These cells could be useful for examining the routes by which compounds are eliminated, or predicting transporter-mediated drug interaction. © 2008 Elsevier Inc. All rights reserved.

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Identification and functional characterization of a novel human and rat riboflavin transporter, RFT1

Yonezawa A., Masuda S., Katsura T., Inui K.I.

American Journal of Physiology - Cell Physiology （American Journal of Physiology - Cell Physiology） 295 （ 3 ） C632 - C641 2008年09月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 03636143

Absorption of riboflavin is mediated by transporter(s). However, a mammalian riboflavin transporter has yet to be identified. In the present study, the novel human and rat riboflavin transporters hRFT1 and rRFT1 were identified on the basis of our rat kidney mRNA expression database (Horiba N, Masuda S, Takeuchi A, Saito H, Okuda M, Inui K. Kidney Int 66: 29-45, 2004). hRFT1 and rRFT1 cDNAs have an open reading frame encoding 448- and 450-amino acid proteins, respectively, that exhibit 81.1% identity and 96.4% similarity to one another. In addition, an inactive splice variant of hRFT1, hRFT1sv, was also cloned. The hRFT1sv cDNA, which encodes a 167-amino acid protein, retains an intron between exons 2 and 3 of hRFT1. Real-time PCR revealed that the sum of hRFT1 and hRFT1sv mRNAs was expressed strongly in the placenta and small intestine and was detected in all tissues examined. In addition, hRFT1 and hRFT1sv were expressed in human embryonic kidney (HEK)-293 and Caco-2 cells. HEK-293 cells transfected with green fluorescent protein-tagged hRFT1 and rRFT1 exhibited a fluorescent signal in the plasma membrane. Overexpression of hRFT1 and rRFT1, but not hRFT1sv, increased the cellular accumulation of [ 3H]riboflavin. The transfection of small interfering RNA targeting both hRFT1 and hRFT1sv significantly decreased the uptake of [ 3H]riboflavin by HEK-293 and Caco-2 cells. Riboflavin transport is Na+, potential, and pH independent. Kinetic analyses demonstrated that the Michaelis-Menten constants for the uptake by HEK-293 and Caco-2 cells were 28.1 and 63.7 nM, respectively. We propose that hRFT1 and rRFT1 are novel mammalian riboflavin transporters, which belong to a new mammalian riboflavin transporter family. Copyright © 2008 the American Physiological Society.

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Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity

Yokoo S., Yonezawa A., Masuda S., Fukatsu A., Katsura T., Inui K.

Biochemical Pharmacology （Biochemical Pharmacology） 74 （ 3 ） 477 - 487 2007年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00062952

The mechanism of severe nephrotoxicity caused by cisplatin, but not carboplatin, oxaliplatin, and nedaplatin, is not fully understood. The renal accumulation and subsequent nephrotoxicity of platinum agents were examined in rats. Among these four drugs, only cisplatin induced nephrotoxicity at 2 days after its intraperitoneal administration. The urinary activity of N-acetyl-β-d-glucosaminidase and expression of kidney injury molecule-1 mRNA and osteopontin were markedly enhanced in the cisplatin-treated rats. Although some markers were affected in the rats administered nedaplatin, only minor histological change was observed. The renal accumulation of cisplatin was much greater than that of the other drugs. In the in vitro study, the cellular accumulation of cisplatin and oxaliplatin was stimulated by the expression of rat (r) OCT2. Oxaliplatin was also transported by rOCT3. A luminal H+/organic cation antiporter, rMATE1 (multidrug and toxin extrusion) as well as human (h) MATE1 and hMATE2-K, stimulated the H+-gradient-dependent antiport of oxaliplatin, but not of cisplatin. Carboplatin and nedaplatin were not transported by these transporters. In conclusion, the nephrotoxicity of platinum agents was closely associated with their renal accumulation, which is determined by the substrate specificity of the OCT and MATE families. © 2007 Elsevier Inc. All rights reserved.

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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

日本病院薬剤師会雑誌 54: 307-312 (2018) 54 307 - 312 2007年

研究論文（学術雑誌）, 共著, 査読有り

Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family)

Yonezawa A., Masuda S., Yokoo S., Katsura T., Inui K.

Journal of Pharmacology and Experimental Therapeutics （Journal of Pharmacology and Experimental Therapeutics） 319 （ 2 ） 879 - 886 2006年11月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 00223565

We have examined the role of the human organic cation transporters [hOCTs and human novel organic cation transporter (hOCTN); SLC22A1-5] and apical multidrug and toxin extrusion (hMATE) in the cellular accumulation and cytotoxicity of platinum agents using the human embryonic kidney (HEK) 293 cells transiently transfected with the transporter cDNAs. Both the cytotoxicity and accumulation of cisplatin were enhanced by the expression of hOCT2 and weakly by hOCT1, and those of oxaliplatin were also enhanced by the expression of hOCT2 and weakly by hOCT3. The hOCT-mediated uptake of tetraethylammonium (TEA) was markedly decreased in the presence of cisplatin in a concentration-dependent manner. However, oxaliplatin showed almost no influence on the TEA uptakes in the HEK293 cells expressing hOCT1, hOCT2, and hOCT3. The hMATE1 and hMATE2-K, but not hOCTN1 and OCTN2, mediated the cellular accumulation of cisplatin and oxaliplatin without a marked release of lactate dehydrogenase. Oxaliplatin, but not cisplatin, markedly decreased the hMATE2-K-mediated TEA uptake. However, the inhibitory effect of cisplatin and oxaliplatin against the hMATE1-mediated TEA uptake was similar. The release of lactate dehydrogenase and the cellular accumulation of carboplatin and nedaplatin were not found in the HEK293 cells transiently expressing these seven organic cation transporters. These results indicate that cisplatin is a relatively good substrate of hOCT1, hOCT2, and hMATE1, and oxaliplatin is of hOCT2, hOCT3, hMATE1, and hMATE2-K. These transporters could play predominant roles in the tissue distribution and anticancer effects and/or adverse effects of platinum agent-based chemotherapy. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.

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Identification and functional characterization of a new human kidney-specific H<sup>+</sup>/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2

Masuda S., Terada T., Yonezawa A., Tanihara Y., Kishimoto K., Katsura T., Ogawa O., Inui K.

Journal of the American Society of Nephrology （Journal of the American Society of Nephrology） 17 （ 8 ） 2127 - 2135 2006年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10466673

A cDNA coding a new H+/organic cation antiporter, human kidney-specific multidrug and toxin extrusion 2 (HMATE2-K), has been isolated from the human kidney. The hMATE2-K cDNA had an open reading frame that encodes a 566-amino acid protein, which shows 94, 82, 52, and 52% identity with the hMATE2, hMATE2-B, hMATE1, and rat MATE1, respectively. Reverse transcriptase-PCR revealed that hMATE2-K mRNA but not hMATE2 was expressed predominantly in the kidney, and hMATE2-B was ubiquitously found in all tissues examined except the kidney. The immunohistochemical analyses revealed that the HMATE2-K as well as the hMATE1 was localized at the brush border membranes of the proximal tubules. HEK293 cells that were transiently transfected with the hMATE2-K cDNA but not hMATE2-B exhibited the H+ gradient-dependent antiport of tetraethylammonium (TEA). Transfection of hMATE2-B had no affect on the hMATE2-K-mediated transport of TEA. hMATE2-K also transported cimetidine, 1-methyl-4-phenylpyridinium (MPP), procainamide, metformin, and N 1-methylnicotinamide. Kinetic analyses demonstrated that the Michaelis-Menten constants for the hMATE2-K-mediated transport of TEA, MPP, cimetidine, metformin, and procainamide were 0.83 mM, 93.5 μM, 0.37 mM, 1.05 mM, and 4.10 mM, respectively. Ammonium chloride-induced intracellular acidification significantly stimulated the hMATE2-K-dependent transport of organic cations such as TEA, MPP, procainamide, metformin, N1- methylnicotinamide, creatinine, guanidine, quinidine, quinine, thiamine, and verapamil. These results indicate that hMATE2-K is a new human kidney-specific H+/organic cation antiporter that is responsible for the tubular secretion of cationic drugs across the brush border membranes. Copyright © 2006 by the American Society of Nephrology.

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Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons

Kume T., Sugimoto M., Takada Y., Yamaguchi T., Yonezawa A., Katsuki H., Sugimoto H., Akaike A.

European Journal of Pharmacology （European Journal of Pharmacology） 527 （ 1-3 ） 77 - 85 2005年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00142999

We previously reported that donepezil, a central-type acetylcholinesterase inhibitor, showed neuroprotective action via α4-and α7-nicotinic acetylcholine receptors against glutamate neurotoxicity in rat cortical culture. The present study was performed to investigate whether the neuroprotective action of acetylcholinesterase inhibitors is accompanied by the alteration of expression and function of nicotinic receptors. Four days treatment with acetylcholinesterase inhibitors (10 μM) enhanced the nicotine-induced increase of the intracellular calcium concentration. Immunoblot analysis revealed that donepezil increased both α4 and α7 subunit proteins. Donepezil and galanthamine increased the number of cells expressing α4- and α7-nicotinic receptors in immunocytochemical analysis. We examined whether up-regulation of nicotinic receptors affected the neuroprotective action of acetylcholinesterase inhibitors. Under up-regulating conditions, donepezil and galanthamine exerted neuroprotective action at lower concentrations. These results suggest that donepezil and galanthamine up-regulate nicotinic receptors in cortical neurons, and that the up-regulation of nicotinic receptors may make cortical neurons more sensitive to the neuroprotective action of donepezil and galanthamine. © 2005 Elsevier B.V. All rights reserved.

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Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat

Yonezawa A., Masuda S., Nishihara K., Yano I., Katsura T., Inui K.

Biochemical Pharmacology （Biochemical Pharmacology） 70 （ 12 ） 1823 - 1831 2005年12月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り, ISSN 00062952

Cisplatin is an effective anticancer drug, but has its severe adverse effects, especially nephrotoxicity. The molecular mechanism of cisplatin-induced nephrotoxicity is still not clear. In the present study, we examined the role of rat (r)OCT2, an organic cation transporter predominantly expressed in the kidney, in the tubular toxicity of cisplatin. Using HEK293 cells stably expressing rOCT2 (HEK-rOCT2), we evaluated the cisplatin-induced release of lactate dehydrogenase and the uptake of cisplatin. The release of lactate dehydrogenase and the accumulation of platinum were greater in HEK-rOCT2 cells treated with cisplatin than in mock-transfected cells. Moreover, cimetidine and corticosterone, OCT2 inhibitors, inhibited the cytotoxicity and the transport of cisplatin in HEK-rOCT2 cells. Pharmacokinetics of cisplatin was investigated in male and female rats because the renal expression level of rOCT2 was higher in male than female rats. The renal uptake clearance of cisplatin was greater in male than female rats, while the hepatic uptake clearance was similar between the sexes. In addition, glomerular filtration rate and liver function were unchanged, but N-acetyl-β-d-glucosaminidase activity in the bladder urine and the urine volume were markedly increased 2 days after the administration of 2 mg/kg of cisplatin in male rats. Moreover, cisplatin did not induce the elevation of urinary N-acetyl-β-d-glucosaminidase activity in the castrated male rats whose renal rOCT2 level was lower than that of the sham-operated rats. In conclusion, the present results indicated that renal rOCT2 expression was the major determinant of cisplatin-induced tubular toxicity. © 2005 Elsevier Inc. All rights reserved.

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Lansoprazole-Tacrolimus Interaction in Japanese Transplant Recipient with CYP2C19 Polymorphism

Takahashi K., Motohashi H., Yonezawa A., Okuda M., Ito N., Yamamoto S., Ogawa O., Inui K.I.

Annals of Pharmacotherapy （Annals of Pharmacotherapy） 38 （ 5 ） 791 - 794 2004年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 10600280

OBJECTIVE: To report a patient with a high tacrolimus blood concentration after lansoprazole administration and assess the potential interaction between tacrolimus and lansoprazole. CASE SUMMARY: A 34-year-old Japanese man underwent a living-donor kidney transplantation having received tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression. Lansoprazole was administered from postoperative day 4 as prophylaxis of ulcers. The trough concentration of tacrolimus increased markedly after the introduction of lansoprazole, while results of liver function tests were within normal limits. Lansoprazole was stopped on day 15 and was replaced with famotidine on day 17. The trough concentration of tacrolimus returned to the therapeutic range after administration of lansoprazole ceased. Genetic analysis revealed a heterozygous mutation at exon 5 of the CYP2C19 gene (CYP2C19*1/*2) in this patient. DISCUSSION: Lansoprazole is metabolized by 2 enzymes, CYP2C19 and CYP3A4. Since tacrolimus is also metabolized by CYP3A4, the blood concentration of tacrolimus in this patient who had a CYP2C19 gene mutation may have been elevated by decreased hepatic elimination of lansoprazole. An objective causality assessment revealed that this interaction was probable. CONCLUSIONS: Trough concentrations of tacrolimus should be monitored closely for optimizing the dosage regimen in patients receiving concomitant lansoprazole.

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Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons

Takada Y., Yonezawa A., Kume T., Katsuki H., Kaneko S., Sugimoto H., Akaike A.

Journal of Pharmacology and Experimental Therapeutics （Journal of Pharmacology and Experimental Therapeutics） 306 （ 2 ） 772 - 777 2003年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 00223565

Donepezil is a potent and selective acetylcholinesterase (AChE) inhibitor developed for the treatment of Alzheimer's disease. To elucidate whether donepezil shows neuroprotective action in addition to amelioration of cognitive deficits, we examined the effects of donepezil on glutamate-induced neurotoxicity using primary cultures of rat cortical neurons. A 10-min exposure of cultures to glutamate followed by a 1-h incubation with glutamate-free medium caused a marked loss of viability, as determined by Trypan blue exclusion. Glutamate neurotoxicity was prevented by 24-h pretreatment of donepezil in a concentration-dependent manner. Among AChE inhibitors examined, donepezil and certain AChE inhibitors such as tacrine and galanthamine showed potent neuroprotective action, although physostigmine did not affect glutamate neurotoxicity. Neuroprotective action of donepezil was antagonized by mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. Furthermore, both dihydro-β-erythroidine, an α4β2-neuronal nAChR antagonist, and methyllycaconitine, an α7-nAChR antagonist, each also significantly antagonized the effect of donepezil. Next, we examined the effects of donepezil on glutamate-induced apoptosis. Exposure of 100 μM glutamate to cortical neurons for 24 h induced apoptotic neuronal death and nuclear fragmentation. Donepezil for 24 h before and 24 h during glutamate exposure prevented nuclear fragmentation and glutamate-induced apoptosis. These results suggest that donepezil not only protects cortical neurons against glutamate neurotoxicity via α4β2- and α7-nAChRs but also prevents apoptotic neuronal death.

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