Papers - Yonezawa, Atsushi

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

Tomohiro Omura, Luna Nomura, Ran Watanabe, Hiroki Nishiguchi, Kazuhiro Yamamoto, Satoshi Imai, Shunsaku Nakagawa, Kotaro Itohara, Atsushi Yonezawa, Takayuki Nakagawa, Junichi Kunimasa, Ikuko Yano, Kazuo Matsubara

Frontiers in Molecular Neuroscience (Frontiers Media SA)  14   748026 2021.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  16625099

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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.

Yoshiki Katada, Atsushi Yonezawa, Momoe Utsumi, Noriaki Kitada, Yu-Ki Sato, Katsuyuki Matsumura, Asami Sukeishi, Shunsaku Nakagawa, Satoshi Imai, Takayuki Nakagawa, Kenji Minakata, Hideo Kanemitsu, Kenji Minatoya, Shinichi Nomoto, Kazuo Matsubara

Journal of pharmaceutical health care and sciences (Journal of Pharmaceutical Health Care and Sciences)  7 ( 1 ) 5 - 5 2021.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2055-0294

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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 2021.11

Lead author, Last author, Corresponding author, Accepted,  ISSN  00214892

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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 2021.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-4892

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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.

Kazuto Nakae, Sho Masui, Atsushi Yonezawa, Motomu Hashimoto, Ryu Watanabe, Koichi Murata, Kosaku Murakami, Masao Tanaka, Hiromu Ito, Kotoko Yokoyama, Noriko Iwamoto, Takashi Shimada, Miyuki Nakamura, Masaya Denda, Kotaro Itohara, Shunsaku Nakagawa, Yasuaki Ikemi, Satoshi Imai, Takayuki Nakagawa, Makoto Hayakari, Kazuo Matsubara

PloS one (PLoS ONE)  16 ( 10 October ) e0258601 2021.10

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  1932-6203

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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.

Yuika Osada, Shunsaku Nakagawa, Kanako Ishibe, Shota Takao, Aimi Shimazaki, Kotaro Itohara, Satoshi Imai, Atsushi Yonezawa, Takayuki Nakagawa, Kazuo Matsubara

American journal of physiology. Renal physiology (American Journal of Physiology - Renal Physiology)  321 ( 4 ) F455 - F465 2021.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1931857X

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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 60 min, 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.NEW & NOTEWORTHY This study aimed to determine the impact of antibiotic-induced microbiome depletion (AIMD) on renal glucose metabolism in mice. This is the first report confirming that AIMD is associated with decreased levels of pyruvate, a key intermediate in glucose metabolism, which may have been caused by activation of renal gluconeogenesis. We hypothesized that AIMD can increase the susceptibility of the kidney to ischemia-reperfusion injury.

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Factors associated with somnolence during brain function mapping in awake craniotomy.

Toshiyuki Mizota, Miho Hamada, Atsuko Shiraki, Takayuki Kikuchi, Yohei Mineharu, Yukihiro Yamao, Etsuko Yamamoto Hattori, Atsushi Yonezawa, Keiko Furukawa, Yoshiki Arakawa

Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia (Journal of Clinical Neuroscience)  89   349 - 353 2021.07

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09675868

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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.

Madoka Koyanagi, Satoshi Imai, Yuki Iwamitsu, Mayuna Matsumoto, Mamiko Saigo, Akari Moriya, Takashi Ogihara, Yui Nakazato, Atsushi Yonezawa, Shunsaku Nakagawa, Takayuki Nakagawa, Kazuo Matsubara

Neuropharmacology (Neuropharmacology)  188   108514 - 108514 2021.05

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00283908

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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.

Madoka Koyanagi, Satoshi Imai, Mayuna Matsumoto, Yoko Iguma, Nobuko Kawaguchi-Sakita, Takeshi Kotake, Yuki Iwamitsu, Mpumelelo Ntogwa, Ren Hiraiwa, Kazuki Nagayasu, Mamiko Saigo, Takashi Ogihara, Atsushi Yonezawa, Tomohiro Omura, Shunsaku Nakagawa, Takayuki Nakagawa, Kazuo Matsubara

Cancer research (Cancer Research)  81 ( 8 ) 2207 - 2219 2021.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00085472

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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 line RAW 264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxel-induced 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. SIGNIFICANCE: These findings demonstrate that the elevation of plasma galectin-3 is a CIPN-related pathologic change common to humans and mice, and that targeting galectin-3 is a therapeutic option to delay CIPN progression.

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

Keiko Ikuta, Shunsaku Nakagawa, Kenji Momo, Atsushi Yonezawa, Kotaro Itohara, Yuki Sato, Satoshi Imai, Takayuki Nakagawa, Kazuo Matsubara

BMJ open (BMJ Open)  11 ( 2 ) e041543 2021.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2044-6055

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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.

Congyun Jin, Yoshihiro Matsui, Atsushi Yonezawa, Satoshi Imai, Takashi Ogihara, Kotaro Itohara, Shunsaku Nakagawa, Takayuki Nakagawa, Kazuo Matsubara

Biological & pharmaceutical bulletin (The Pharmaceutical Society of Japan)  44 ( 2 ) 283 - 286 2021.02

Research paper (scientific journal), Joint Work, Corresponding author, Accepted,  ISSN  09186158

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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.

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

Joe Yamamoto, Tomohiro Omura, Sachiko Kasamo, Shota Yamamoto, Masayoshi Kawata, Atsushi Yonezawa, Yosuke Taruno, Hisako Endo, Hitoshi Aizawa, Nobukatsu Sawamoto, Kazuo Matsubara, Ryosuke Takahashi, Yoshikazu Tasaki

Journal of neural transmission (Vienna, Austria : 1996) (Journal of Neural Transmission)  128 ( 1 ) 27 - 36 2021.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  03009564

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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.

Kazuhiro Yamamoto, Takeshi Ioroi, Kazuaki Shinomiya, Ayaka Yoshida, Kenichi Harada, Masato Fujisawa, Tomohiro Omura, Yasuaki Ikemi, Shunsaku Nakagawa, Atsushi Yonezawa, Osamu Ogawa, Kazuo Matsubara, Takuya Iwamoto, Kohei Nishikawa, Sayaka Hayashi, Daichi Tohara, Yoji Murakami, Takanobu Motoshima, Hirofumi Jono, Ikuko Yano

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

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09650407

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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% versus 23.1%, odds ratio = 11.67, 95% confidential interval = 3.06-44.46). Meanwhile, 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 -1697C/G 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

Congyun Jin, Atsushi Yonezawa, Hiroki Yoshimatsu, Satoshi Imai, Madoka Koyanagi, Kaori Yamanishi, Shunsaku Nakagawa, Kotaro Itohara, Tomohiro Omura, Takayuki Nakagawa, Junya Nagai, Kazuo Matsubara

Scientific Reports (Scientific Reports)  10 ( 1 ) 18443 2020.12

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

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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.

Yoshinao Ozaki, Hirotaka Imamaki, Aki Ikeda, Mitsuaki Oura, Shunsaku Nakagawa, Taro Funakoshi, Shigeki Kataoka, Yoshitaka Nishikawa, Takahiro Horimatsu, Atsushi Yonezawa, Takeshi Matsubara, Motoko Yanagita, Manabu Muto, Norihiko Watanabe

Cancer chemotherapy and pharmacology (Cancer Chemotherapy and Pharmacology)  86 ( 5 ) 693 - 699 2020.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  03445704

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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 2020.11

Lead author, Last author, Corresponding author, Accepted,  ISSN  13407007

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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.

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

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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

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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

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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

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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。