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nudt15 genotyping during azathioprine treatment in patients with inflammatory bowel disease:implications for a dose-optimization strategy

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Gastroenterology Report 2020年第6期8卷 437-444,I0002页

作者： Ye Xu Yu-Qi Qiao Han-Yang Li Mi Zhou Chen-Wen Cai Jun Shen Zhi-Hua Ran Division of Gastroenterology and Hepatology Key Laboratory of Gastroenterology and HepatologyMinistry of HealthInflammatory Bowel Disease Research CenterShanghai Institute of Digestive DiseaseRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina

Background:nudt15 R139C is an Asian-prevalent genetic variant related to azathioprine(AZA)intolerance in patients with inflammatory bowel disease(IBD).However,it remains unclear how to utilize the genotyping results to improve the step-up dosing strategy with an already low starting dose in Asian ***:Clinical data of eligible IBD patients who received AZA therapy and nudt15 R139C testing were retrospectively *** relationship between nudt15 genotype,AZA doses,and AZA-induced toxicity and efficacy were comprehensively ***:A total of 159 patients were included for toxicity *** with the wild genotype,patients heterozygous for R139C are more prone to developing myelotoxicity and alopecia(P=0.007;P=0.042).In particular,they had a 5.4-fold risk of developing myelotoxicity when AZA dosage was increased from 25 mg/d to 50mg/d(P15 patients who had received AZA for>4 months and maintained clinical remission on AZA monotherapy were included for further analysis.R139C heterozygotes were finally titrated to a significantly lower dose than the wild genotype[median(interquartile range):0.83(0.75–0.96)vs 1.04(0.89–1.33)mg/kg/d,P=0.001],whereas the clinical remission rates did not differ between groups(P=0.88).Conclusions:IBD patients with R139C heterozygote are highly susceptible to AZA-induced myelotoxicity at an escalated dose of 50 mg/***,they may require a smaller dose increase after a starting dose of 25 mg/*** final target dose of these patients could be set lower than that of the wild genotypes without compromising efficacy.

关键词： nudt15 azathioprine inflammatory bowel disease toxicity efficacy

Comparison of TPMT and nudt15 polymorphisms in Chinese patients with inflammatory bowel disease

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World Journal of Gastroenterology 2018年第8期24卷 941-948页

作者： Hong-Hui Wang Ying He Hong-Xian Wang Cheng-Ling Liao Yu Peng Li-Jian Tao Wei Zhang Hui-Xiang Yang Department of Gastroenterology Xiangya Hospital Central South University Department of Anesthesiology Kunming Angel Women’s & Children’s Hospital Department of Clinical Pharmacology Hunan Key Laboratory of Pharmacogenetics Xiangya Hospital Central South University Department of Nephrology Xiangya Hospital Central South University

AIM To observe gene polymorphisms of TPMT and nudt15, and compare their predictive value for azathioprine(AZA)-induced leukopenia in inflammatory bowel disease(IBD).METHODS This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and nudt15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced *** There were 219 patients with IBD(160 men and 59 women), including 39 who were confirmed with ulcerative colitis(UC), 176 with Crohn's disease(CD) and 4 with undetermined IBD(UIBD). There were 44 patients(20.1%) with mutant genotype of nudt15(C/T); among them, 16 received AZA, and 8(50%) developed leukopenia. There were 175 patients(79.7%) with wild genotype of nudt15(C/C); among them, 64 received AZA, and 11(17.2%) developed leukopenia. A significant difference was found between nudt15 C/T and its wild-type C/C(P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G(1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients(98.6%) were found to bear the wild genotype of TPMT(A/A); among them, 79 patients received AZA, and 18(22.8%) developed leukopenia, and there was no significant difference from those with A/G(P = 0.071). The frequency of TPMT mutation was 1.4%, and nudt15 mutation rate was significantly higher and reached 20.1%(P = 0.000). Therefore, NU

关键词： nudt15 TPMT Azathioprine Leukopenia Inflammatory bowel disease Individualized therapy

Influence of nudt15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines

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World Journal of Gastroenterology 2018年第4期24卷 511-518页

作者： Yuichiro Kojima Yosuke Hirotsu Wataru Omata Makoto Sugimori Shinya Takaoka Hiroshi Ashizawa Keiko Nakagomi Dai Yoshimura Kenji Hosoda Yoji Suzuki Hitoshi Mochizuki Masao Omata Department of Gastroenterology Yamanashi Prefectural Central Hospital Genome Analysis Center Yamanashi Prefectural Central Hospital Department of Dermatologic Oncology National Cancer Institute Division of Gastroenterology Department of Medicine Yokohama City University Graduate School of Medicine Department of Gastroenterology Genome Analysis Center Yamanashi Prefectural Central Hospital

AIM The single nucleotide polymorphism(SNP) c.415C>T in exon 3 of nudt15 affects thiopurine-induced leukopenia in Asian patients with Crohn's disease. Meanwhile, three additional genetic variants of nudt15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of nudt15 in patients with inflammatory bowel disease(IBD) treated with *** Ninety-six Japanese patients with IBD were enrolled. Genotyping for the nudt15 and TPMT genes was performed using Custom Taq Man SNP genotyping assays or Sanger sequencing. The changes in white blood cell(WBC) count, mean corpuscular volume(MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR were *** Genetic variants of exon 1 and exon 3 of nudt15 were identified in 24 of 96 patients(25.0%). C.52G > A and c.36_37 insG GAGTC in exon 1 were found in three patients each. All three patients with c.36_37 insG GAGTC in exon 1 were heterozygotes of ***139 Cys in exon 3. Eighteen patients had ***139 Cys in exon 3 alone. The WBC count gradually decreased after initiation of thiopurine treatment in the mutated cases(n = 24), and was significantly lower at 6, 8, 10, and 16 wk(P = 0.0271, 0.0037, 0.0051, and 0.0185, respectively). The WBC counts were also evaluated in patients with and without prednisolone treatment. In the patients with prednisolone treatment, the WBC count tended to show a greater decrease in the mutated cases, with significant differences at 8 and 10 wk(P = 0.012 and 0.029, respectively). In the patients without prednisolone treatment, the WBC count was significantly lower at 2, 4, 8, and 14 wk in mutated cases(P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine treatment in the mutated cases, and was significantly higher at 10 wk(P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR did not differ significantly between the wildtype and

关键词： Inflammatory bowel disease nudt15 Leukopenia Mean corpuscular volume Japanese

nudt15基因型对儿童急性淋巴细胞白血病6-MP个体化治疗的影响

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中国当代儿科杂志 2019年第1期21卷 100-104页

作者：贺晶刘伶大连市妇女儿童医疗中心血液肿瘤科辽宁大连116000

6-巯基嘌呤(6-MP)是急性淋巴细胞白血病(ALL)维持治疗阶段的重要药物,其副作用包括肝毒性和骨髓抑制,不同个体对6-MP的耐受差异较大,6-MP治疗需个体化。巯嘌呤甲基转移酶(TPMT)活性缺乏与6-MP不耐受具有相关性。但亚洲患者TPMT等位基因... 详细信息

6-巯基嘌呤(6-MP)是急性淋巴细胞白血病(ALL)维持治疗阶段的重要药物,其副作用包括肝毒性和骨髓抑制,不同个体对6-MP的耐受差异较大,6-MP治疗需个体化。巯嘌呤甲基转移酶(TPMT)活性缺乏与6-MP不耐受具有相关性。但亚洲患者TPMT等位基因的突变频率较低。近来发现存在nudt15基因突变的ALL患者6-MP耐受剂量低于常规剂量。该文就nudt15基因型对ALL患儿6-MP个体化治疗的影响进行综述。

关键词：急性淋巴细胞白血病 nudt15 6-巯基嘌呤

nudt15基因突变与硫唑嘌呤骨髓抑制相关性的Meta分析

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中华炎性肠病杂志（中英文） 2020年第4期4卷 322-327页

作者：谢宏钗陈金通郑玮玮俞星林艺娟刘艺娟范华王承党福建医科大学附属第一医院消化内科福建医科大学消化系疾病研究室福州350000

目的:分析炎症性肠病(IBD)人群中,nudt15基因多态性与硫唑嘌呤(AZA)导致骨髓抑制不良反应的相关性,为IBD临床治疗提供参考。方法:通过计算机检索中国知网、万方、维普数据库、PubMed、Cochrane图书馆和Web of Science,筛选nudt15基因突... 详细信息

目的:分析炎症性肠病(IBD)人群中,nudt15基因多态性与硫唑嘌呤(AZA)导致骨髓抑制不良反应的相关性,为IBD临床治疗提供参考。方法:通过计算机检索中国知网、万方、维普数据库、PubMed、Cochrane图书馆和Web of Science,筛选nudt15基因突变与AZA治疗IBD的随机对照试验文献,并对符合纳入标准的研究进行质量评价和资料提取,进行Meta分析。结果:纳入10篇文献,共3095例患者。Meta分析显示,亚洲IBD人群中nudt15基因突变率明显高于TPMT基因突变率(21.5%比2.8%,OR=0.10,95%CI:0.07~0.15,Pnudt15基因突变与AZA相关的白细胞减少具有显著相关性(OR=0.40,95%CI:0.34~0.47,Pnudt15突变的IBD患者更易在应用AZA的早期出现白细胞减少(OR=2.69,95%CI:1.67~4.33,Pnudt15基因纯合突变型(TT型)更易出现Ⅲ~Ⅳ级的骨髓抑制(OR=0.09,95%CI:0.04~0.18,Pnudt15基因突变具有显著相关性,较TPMT基因突变关系更为密切,并多发生于应用AZA的8周内。同时,nudt15基因TT纯合突变会增加重度骨髓抑制的风险。

关键词：炎症性肠病 nudt15 硫唑嘌呤骨髓抑制 Meta分析

nudt15基因多态性与巯嘌呤类药物所致白细胞减少的研究进展

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中国医院药学杂志 2017年第22期37卷 2307-2311页

作者：费祥束庆葛卫红方芸南京大学医学院附属鼓楼医院药学部江苏南京210008 中国药科大学基础医学与临床药学学院江苏南京210009

硫唑嘌呤(azathioprine,AZA)和6-巯基嘌呤(6-mercaptopurine,6-MP)被广泛用于炎症性肠病、急性淋巴细胞白血病的治疗,但以白细胞减少为主的不良反应一直是困扰临床安全用药的难题。研究发现个体间的基因差异与该不良反应密切相关,美国... 详细信息

硫唑嘌呤(azathioprine,AZA)和6-巯基嘌呤(6-mercaptopurine,6-MP)被广泛用于炎症性肠病、急性淋巴细胞白血病的治疗,但以白细胞减少为主的不良反应一直是困扰临床安全用药的难题。研究发现个体间的基因差异与该不良反应密切相关,美国食品药品监督管理局早在2005年就推荐服药前进行巯嘌呤类药物代谢相关的巯基嘌呤甲基转移酶(TPMT)的基因型检测以评估白细胞减少不良反应的发生,但该位点不能很好地预防亚洲人群中该不良反应的频发。新近研究提示nudt15基因位点与亚洲人群的白细胞减少更密切,本文将综述nudt15位点与亚洲人群服用AZA/6-MP后出现的白细胞减少之间的相关性研究。

关键词：硫唑嘌呤 nudt15 白细胞减少基因多态性亚洲人群

硫唑嘌呤致nudt15杂合突变天疱疮患者骨髓抑制一例

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中华皮肤科杂志 2017年第12期50卷 912-914页

作者：王莲周燕虹周兴丽吕小岩曾昕李薇四川大学华西医院皮肤科成都610041 四川大学华西医院实验医学科成都610041 四川大学华西口腔医院黏膜科

患者男，49岁，因口腔反复糜烂1年，加重伴皮肤红斑、水疱1个月就诊。结合组织病理和天疱疮抗体检查，确诊为寻常型天疱疮。予泼尼松联合硫唑嘌呤治疗1个月后，白细胞计数和中性分叶核粒细胞计数下降，停用硫唑嘌呤，予重组人粒细胞刺... 详细信息

患者男，49岁，因口腔反复糜烂1年，加重伴皮肤红斑、水疱1个月就诊。结合组织病理和天疱疮抗体检查，确诊为寻常型天疱疮。予泼尼松联合硫唑嘌呤治疗1个月后，白细胞计数和中性分叶核粒细胞计数下降，停用硫唑嘌呤，予重组人粒细胞刺激因子注射液150 μg皮下注射1次后，白细胞计数恢复正常。硫唑嘌呤用药相关基因分型检测示，nudt15（JZ274）杂合突变型，TPMT＊2、TPMT＊3C、ITPA均为野生纯合型。诊断：硫唑嘌呤致骨髓抑制。

关键词：硫唑嘌呤天疱疮杂合子骨髓 nudt15

nudt15基因多态性与儿童急性淋巴细胞白血病化疗中6-MP毒性相关性的Meta分析

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NUDT15基因多态性与儿童急性淋巴细胞白血病化疗中6-MP毒性相关性...

作者：梁麟龙南华大学

学位级别：硕士

目的系统评价儿童急性淋巴细胞白血病(ALL)患儿中nudt15基因c.415C>T位点多态性与化疗中6-巯基嘌呤(6-MP)毒性的相关性,为临床个体化治疗提供循证依据。方法系统检索国内外相关数据库:Pub Med、Em Base、Cochrane Library、中国知网、... 详细信息

目的系统评价儿童急性淋巴细胞白血病(ALL)患儿中nudt15基因c.415C>T位点多态性与化疗中6-巯基嘌呤(6-MP)毒性的相关性,为临床个体化治疗提供循证依据。方法系统检索国内外相关数据库:Pub Med、Em Base、Cochrane Library、中国知网、中国生物医学文献数据库、维普中文科技期刊数据库以及万方数据库,语种限定为中文或英文。纳入符合6-MP治疗儿童急性淋巴细胞白血病关于nudt15基因c.415C>T位点多态性相关毒性的病例对照研究或队列研究,检索时限均为从建库起至2020年10月1日。由2名研究者独立筛选文献,对符合纳入标准的文献进行资料数据提取,并评价纳入研究的文献质量后,应用Rev Man 5.3和Stata12.0软件对不同遗传模型下nudt15基因c.415C>T位点多态性与6-MP化疗过程中毒性的相关性进行Meta分析。结果最终纳入9项研究,8篇为队列研究,1篇为病例对照研究,共1 068例患儿。Meta分析结果表明,nudt15基因c.415C>T位点突变型与白细胞减少[TT+CT ***:OR=4.53,95%CI(2.74,7.49),P15.68,95%CI(4.21,58.48),P15.02),P=0.007;TT ***:OR=9.49,95%CI(2.38,37.86),P=0.001;T vs.C:OR=5.09,95%CI(2.40,10.79),P0.05)。结论nudt15基因c.415C>T位点突变型显著增加了6-MP化疗时白细胞减少及中性粒细胞减少的发生率,但对肝功能损害的发生无明显影响。

关键词：急性淋巴细胞白血病 nudt15 6-巯基嘌呤基因多态性 meta分析

急性淋巴细胞白血病患儿维持治疗期间6-巯基嘌呤使用剂量与TPMT和nudt15基因多态性的关系

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中国循证儿科杂志 2024年第1期19卷 52-56页

作者：吴新蕊刘玉峰李白刘莹刘姗姗郑州大学第一附属医院郑州450052

背景6-巯基嘌呤(6-MP)是急性淋巴细胞白血病(ALL)维持治疗最主要的药物之一,代谢酶基因多态性与药物的骨髓抑制程度有关。目的探讨ALL患儿维持治疗期间6-MP使用剂量与TPMT和nudt15基因多态性的关系。设计回顾性队列研究。方法纳入2020年... 详细信息

背景6-巯基嘌呤(6-MP)是急性淋巴细胞白血病(ALL)维持治疗最主要的药物之一,代谢酶基因多态性与药物的骨髓抑制程度有关。目的探讨ALL患儿维持治疗期间6-MP使用剂量与TPMT和nudt15基因多态性的关系。设计回顾性队列研究。方法纳入2020年1月至2021年12月于郑州大学第一附属医院明确诊断为ALL、经前期化疗骨髓达完全缓解、进入维持治疗阶段且口服6-MP治疗的患儿。口服6-MP前患儿行TPMT和nudt15基因型检测,分析TPMT、nudt15不同基因型患儿应用6-MP治疗的使用剂量和骨髓抑制情况。主要结局指标6-MP使用剂量。结果61例维持治疗的ALL患儿纳入本文分析。纳入TPMT基因多态性统计分析的ALL患儿48例(除外nudt15基因突变13例),野生型45例,突变型3例;纳入nudt15基因多态性统计分析的ALL患儿58例(除外TPMT基因突变3例),CC型45例,CT型9例,TT型4例。在6-MP维持治疗阶段,TPMT和nudt15不同基因型患儿的WBC、Hb、PLT计数差异均有统计学意义(均P15例,突变型3例;nudt15基因CC型15例,CT型5例,TT型4例;TPMT和nudt15不同基因型患儿骨髓抑制情况差异均有统计学意义(均Pnudt15不同基因型患儿6-MP使用剂量差异有统计学意义(均Pnudt15基因CC型、CT型和TT型6-MP使用剂量分别为(40.81±6.02)、(34.28±4.53)和(10.00±1.28)mg·m^(-2)·d^(-1)。结论TPMT和nudt15突变型患儿的骨髓抑制程度均较野生型严重。ALL患儿维持治疗期间6-MP使用剂量与TPMT和nudt15基因多态性相关。

关键词：急性淋巴细胞白血病 6-巯基嘌呤 TPMT nudt15 基因多态性药物使用剂量