Details of a Researcher - Yonezawa, Atsushi

Papers - Yonezawa, Atsushi

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Association of Initial Trough Concentrations of Vancomycin with Outcomes in Pediatric Patients with Gram-Positive Bacterial Infection.

Miko Kondo, Shunsaku Nakagawa, Satoru Orii, Kotaro Itohara, Mitsuhiro Sugimoto, Tomohiro Omura, Yuki Sato, Satoshi Imai, Atsushi Yonezawa, Takayuki Nakagawa, Kazuo Matsubara

Biological & pharmaceutical bulletin (Biological and Pharmaceutical Bulletin) 43 ( 10 ) 1463 - 1468 2020.10

Research paper (scientific journal), Joint Work, Accepted, 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 (≥ 5 µg/mL) was significantly lower than that of the patients with lower trough level (< 5 µg/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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Outcomes of Hospital Formulary System in Antiviral Drugs for Influenza

Yoshiki Katada, Atsushi Yonezawa, Mitsuhiro Sugimoto, Masanori Kimata, Yuko Yoshida, Kotaro Itohara, Syunsaku Nakagawa, Noriaki Kitada, Satoshi Imai, Yasuaki Ikemi, Sachio Fukatsu, Takayuki Nakagawa, Yasufumi Matsumura, Miki Nagao, Kazuo Matsubara

Journal of Japanese Society of Hospital Pharmacists ((一社)日本病院薬剤師会) 56 ( 10 ) 1155 - 1160 2020.10

Research paper (scientific journal), Joint Work, Accepted, 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.

Mpumelelo Ntogwa, Satoshi Imai, Ren Hiraiwa, Madoka Koyanagi, Mayuna Matsumoto, Takashi Ogihara, Shunsaku Nakagawa, Tomohiro Omura, Atsushi Yonezawa, Takayuki Nakagawa, Kazuo Matsubara

Brain, behavior, and immunity (Brain, Behavior, and Immunity) 88 325 - 339 2020.08

Research paper (scientific journal), Joint Work, Accepted, 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 2020.08

Research paper (scientific journal), Joint Work, Accepted, 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.

Atsuko Shiraki, Wataru Goto, Hiroshi Fukagawa, Yoshiki Arakawa, Takayuki Kikuchi, Yohei Mineharu, Yukihiro Yamao, Takayuki Yasuda, Etsuko Hattori, Ayaka Fukui, Yoshihiro Matsui, Atsushi Yonezawa, Keiko Furukawa, Toshiyuki Mizota

Acta anaesthesiologica Scandinavica (Acta Anaesthesiologica Scandinavica) 64 ( 6 ) 735 - 741 2020.07

Research paper (scientific journal), Joint Work, Accepted, 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.

Hirohisa Imai, Takuya Hirai, Ryosuke Kumazawa, Shunsaku Nakagawa, Atsushi Yonezawa, Kazuo Matsubara, Hiroyuki Nakao

PloS one (PLoS ONE) 15 ( 4 ) e0231226 2020.04

Research paper (scientific journal), Joint Work, Accepted

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. Anti-dementia 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.

Yunpeng Zhang, Atsushi Yonezawa, Shunsaku Nakagawa, Satoshi Imai, Masaya Denda, Tomohiro Omura, Takayuki Nakagawa, Kazuo Matsubara

Drug metabolism and pharmacokinetics (Drug Metabolism and Pharmacokinetics) 35 ( 1 ) 111 - 116 2020.02

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, 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.

Hiromitsu Negoro, Takayuki Goto, Shusuke Akamatsu, Naoki Terada, Takashi Kobayashi, Yoshiyuki Matsui, Takashi Yamamoto, Tomohiro Omura, Atsushi Yonezawa, Kazuo Matsubara, Osamu Ogawa

Neurourology and urodynamics (Neurourology and Urodynamics) 39 ( 1 ) 237 - 242 2020.01

Research paper (scientific journal), Joint Work, Accepted, 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

Research paper (scientific journal), Joint Work, Accepted, 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.

Takashi Ogihara, Takayuki Nakagawa, Maho Hayashi, Madoka Koyanagi, Atsushi Yonezawa, Tomohiro Omura, Shunsaku Nakagawa, Noriaki Kitada, Satoshi Imai, Kazuo Matsubara

Journal of pharmacological sciences (Journal of Pharmacological Sciences) 141 ( 4 ) 131 - 138 2019.12

Research paper (scientific journal), Joint Work, Accepted, 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.

Noriko Iwamoto, Megumi Takanashi, Kotoko Yokoyama, Atsushi Yonezawa, Masaya Denda, Motomu Hashimoto, Masao Tanaka, Hiromu Ito, Minoru Matsuura, Shuji Yamamoto, Yusuke Honzawa, Kazuo Matsubara, Takashi Shimada

Journal of immunological methods (Journal of Immunological Methods) 472 44 - 54 2019.09

Research paper (scientific journal), Joint Work, Accepted, 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.

Atushi Yonezawa, Yuki Otani, Toshiyuki Kitano, Mayuko Mori, Sho Masui, Yui Isomoto, Masahiro Tsuda, Satoshi Imai, Yasuaki Ikemi, Masaya Denda, Yuki Sato, Shunsaku Nakagawa, Tomohiro Omura, Takayuki Nakagawa, Ikuko Yano, Makoto Hayakari, Akifumi Takaori-Kondo, Kazuo Matsubara

Pharmaceutical research (Pharmaceutical Research) 36 ( 6 ) 82 - 82 2019.06

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted, 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.

Yoshiki Katada, Shunsaku Nakagawa, Akiko Nishimura, Yu-Ki Sato, Hiromi Taue, Katsuyuki Matsumura, Kazuhiro Yamazaki, Kenji Minakata, Ikuko Yano, Tomohiro Omura, Satoshi Imai, Atsushi Yonezawa, Yuki Sato, Takayuki Nakagawa, Kenji Minatoya, Kazuo Matsubara

European journal of clinical pharmacology (European Journal of Clinical Pharmacology) 75 ( 4 ) 561 - 568 2019.04

Research paper (scientific journal), Joint Work, Accepted, 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 2019.02

Research paper (scientific journal), Joint Work, Accepted, 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 2019.01

Research paper (scientific journal), Joint Work, Accepted, 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.

Kotaro Itohara, Ikuko Yano, Tetsunori Tsuzuki, Miwa Uesugi, Shunsaku Nakagawa, Atsushi Yonezawa, Hideaki Okajima, Toshimi Kaido, Shinji Uemoto, Kazuo Matsubara

CPT: pharmacometrics & systems pharmacology (CPT: Pharmacometrics and Systems Pharmacology) 8 ( 8 ) 587 - 595 2019

Research paper (scientific journal), Joint Work, Accepted

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.

Sho Masui, Atsushi Yonezawa, Kazushi Izawa, Makoto Hayakari, Kayoko Asakura, Risa Taniguchi, Masahiko Isa, Hirofumi Shibata, Takahiro Yasumi, Ryuta Nishikomori, Junko Takita, Kazuo Matsubara

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

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, 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 2018.12

Research paper (scientific journal), Joint Work, Accepted, 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 2018.11

Research paper (scientific journal), Joint Work, Accepted, 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.

Shunsaku Nakagawa, Mayumi Nakaishi, Motomu Hashimoto, Hiromu Ito, Wataru Yamamoto, Ran Nakashima, Masao Tanaka, Takao Fujii, Tomohiro Omura, Satoshi Imai, Takayuki Nakagawa, Atsushi Yonezawa, Hirohisa Imai, Tsuneyo Mimori, Kazuo Matsubara

PloS one (PLoS ONE) 13 ( 11 ) e0206943 2018.11

Research paper (scientific journal), Joint Work, Accepted

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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