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( Toshiyuki Sato ),( Tetsuya Takagawa ),( Yoichi Kakuta ),( Akihiro Nishio ),( Mikio Kawai ),( Koji Kamikozuru ),( Yoko Yokoyama ),( Yuko Kita ),( Takako Miyazaki ),( Masaki Iimuro ),( Nobuyuki Hida ) 대한장연구학회 2017 Intestinal Research Vol.15 No.3
Background/Aims: Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). Methods: One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. Results: None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. Conclusions: Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurineinduced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD. (Intest Res 2017;15:328-337)
( Takato Maeda ),( Hirotake Sakuraba ),( Hiroto Hiraga ),( Shukuko Yoshida ),( Yoichi Kakuta ),( Hidezumi Kikuchi ),( Shogo Kawaguchi ),( Keisuke Hasui ),( Tetsuya Tatsuta ),( Daisuke Chinda ),( Tatsu 대한장연구학회 2022 Intestinal Research Vol.20 No.1
Background/Aims: Thiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C>T) has been shown to be associated with thiopurine-induced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype. Methods: A total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records. Results: Of 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19-0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104-298) pmol/8×10<sup>8</sup> red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P=0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P=0.339 and P=0.422, respectively). Conclusions: Low-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype. (Intest Res 2022;20:90-100)
( Rintaro Moroi ),( Katsuya Endo ),( Katsutoshi Yamamoto ),( Takeo Naito ),( Motoyuki Onodera ),( Masatake Kuroha ),( Yoshitake Kanazawa ),( Tomoya Kimura ),( Yoichi Kakuta ),( Atsushi Masamune ),( Yo 대한장연구학회 2019 Intestinal Research Vol.17 No.1
Background/Aims: Few reports have described the long-term treatment outcomes of the anti-tumor necrosis factor-α antibody for Japanese Crohn’s disease (CD) patients. The aim of this study was to evaluate them and clarify the clinical factors that affect the long-term prognosis of the anti-tumor necrosis factor-α treatments. Methods: This was a retrospective, observational, single-center cohort study. Japanese CD patients treated with either infliximab or adalimumab as a first-line therapy were analyzed. The cumulative retention rates of the biologics, relapse-free survival, and surgery-free survival were analyzed using Kaplan-Meier methods. The clinical factors associated with the long-term outcomes were estimated by both the log-rank test and Cox proportional hazard model. Results: The cumulative retention rate was significantly higher in the group with a concomitant elemental diet of ≥900 kcal/day, baseline C-reactive protein (CRP) levels <2.6 mg/dL, and baseline serum albumin levels ≥3.5 g/dL, respectively. The baseline serum albumin levels were also associated with both relapse-free and surgery-free survival. The lack of concomitant use of an elemental diet ≥900 kcal/day was identified as the only independent risk factor for the withdrawal of the biologics. Conclusions: Baseline CRP levels and serum albumin levels could affect the long-term outcomes in CD patients. Concomitant elemental diet of ≥900 kcal/day could have a positive influence on clinical treatment course. (Intest Res 2019;17:94-106)
Kim, Han Sang,Cheon, Jae Hee,Jung, Eun Suk,Park, Joonhee,Aum, Sowon,Park, Soo Jung,Eun, Sungho,Lee, Jinu,Ruther, Ulrich,Yeo, Giles S H,Ma, Marcella,Park, Kyong Soo,Naito, Takeo,Kakuta, Yoichi,Lee, Ji BMJ Publishing Group Ltd 2017 Gut: journal of the British Society of Gastroenter Vol.66 No.11
<P>Conclusions The results suggest that the hypomorphic FTO p.A134T variant is associated with thiopurine-induced leukopenia. These results shed light on the novel physiological role of FTO and provide a potential pharmacogenetic biomarker for thiopurine therapy.</P>