研究者詳細 - 米澤　淳

論文 - 米澤　淳

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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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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).

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