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目的:研究服用硫唑嘌呤(AZA)中国肾移植患者红细胞(RBC)内活性代谢物6-硫鸟嘌呤核苷酸(6-TGNs)分布特征及影响因素,为临床合理应用嘌呤类药物提供依据。方法:以89例中国肾移植患者为研究对象,关联分析年龄、性别、体质量、AZA剂量和TPMT活性对RBC内6-TGNs浓度的影响,并应用SPSS v20.0软件进行多元线性回归分析。结果:89例中国肾移植患者RBC内6-TGNs浓度呈非正态分布(P<0.000 1),6-TGNs浓度中位数为167.60(四分位间距,108.10~300.80) pmol/8×108 RBC,个体间差异约24.3倍。关联分析显示患者年龄、性别、体质量、TPMT活性对6-TGNs浓度均无显著影响(P>0.05);而AZA剂量与6-TGNs浓度间呈显著正相关性(rs=0.307 1,P<0.01)。多元线性回归分析显示,RBC内6-TGNs浓度与AZA剂量间呈显著正相关(P<0.001),与TPMT活性呈显著负相关(P<0.05)。结论:AZA剂量和RBC内TPMT活性协同影响嘌呤类药物活性代谢物6-TGNs浓度,进而影响该类药物临床疗效和毒性反应。  相似文献   
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Relapse‐enriched somatic variants drive drug resistance in childhood acute lymphoblastic leukemia. We used digital droplet‐based polymerase chain reaction to establish whether relapse‐enriched mutations in emerging subclones could be detected in peripheral blood samples before frank relapse. Although limitations in sensitivity for some probes hindered detection of certain variants, we successfully detected variants in NT5C2 and PRPS1 at a fractional abundance of 0.005% to 0.3%, 41 to 116 days before relapse. As mutations in both these genes confer resistance to thiopurines, early detection protocols using peripheral blood could be implemented to preemptively alter maintenance therapy to extinguish resistant clones before overt relapse.  相似文献   
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Introduction: Conventional thiopurines are effective for the maintenance of remission of Crohn’s disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use.

Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: ‘azathioprine’, ‘thiopurine’, ‘Crohn’s disease’, ‘inflammatory bowel disease’, ‘nodular regenerative hyperplasia’, ‘mercaptopurine’, ‘thioguanine’, ‘ulcerative colitis’. Further relevant papers were identified from the reference lists of selected papers.

Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.  相似文献   
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硫嘌呤类药物作为一类常用的免疫抑制剂,广泛应用于临床.然而其治疗窗窄,药动学个体差异大一直是困扰该类药物临床应用的难题.尽管硫嘌呤甲基转移酶(thiopurine methyltransferase,TPMT)基因多态性被认为是影响硫嘌呤类药物药动学的主要遗传因素,但研究结论并不统一.而最近的一些研究将焦点集中到了次黄苷三磷酸焦磷酸酶(inosine triphosphate pyrophosphatase,ITPA)的遗传多态性上.因此,本文就ITPA遗传多态性对硫嘌呤类药物疗效和毒性影响的研究进展作一综述,以期为临床个体化应用硫嘌呤类药物提供理论指导.  相似文献   
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Introduction: As our medical armamentarium for IBD continues to expand, it is essential that clinicians understand both optimizing and sequencing of individual and combination therapeutic approaches with available medications.

Areas covered: This review summarizes dosing strategies and therapeutic drug monitoring for pharmacologic optimization in IBD. Aminosalicylates remain first-line therapies for mild-to-moderate UC but have limited evidence of efficacy in CD. Budesonide provides an alternative to aminosalicylates when targeted to appropriate sites in the distal small bowel and colon, as do conventional corticosteroids when applied rectally. Systemic steroids are highly efficacious but burdened by toxicity. Thiopurines or methotrexate can be utilized as steroid-sparing agents. Biologic agents targeting TNF remain important for steroid-sparing therapy in moderate-to-severe UC and CD. Newer biologics targeting lymphocyte trafficking and lymphocyte activation are also efficacious for moderate-to-severe IBD. Near future conventional drug options include oral agents such as tofacitinib and mongersen.

Expert commentary: Positioning therapies according to the location, phenotypes, and severity, as well as the use of therapeutic and clinical targets, will improve outcomes and minimize toxicities and therapeutic futilities. Future IBD treatment should focus on personalized therapy plans based on genetic determinants, targeted mechanisms of action, and pharmacologic optimization.  相似文献   
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Background: Recently, promulgated inflammatory bowel disease (IBD) guidelines seek to decrease the need for surgery by improving disease control. However, resection rates remain static. Aims: We therefore sought to determine the proportion of patients coming to surgery where preoperative management was not optimal according to guidelines. Methods: Case notes of all patients with resection surgery for IBD from January 2007 to March 2008 at a metropolitan teaching hospital were retrospectively reviewed. Judgement was made as to whether preoperative management was optimal or suboptimal depending on whether it met guidelines. Results: A total of 22 subjects with IBD‐related resections were identified (15 males and seven females). In total, 17 had Crohn's disease (CD) (11 males) and five ulcerative colitis (UC) (four males). There were 10 smokers (nine CD and one UC). The two most common indications for surgery were inflammatory mass/abscess (n= 8) and refractory to medical therapy (n= 7). While all patients with known IBD (20/22) had seen a gastroenterologist in the past, five known IBD patients had resections undertaken without preoperative gastroenterologist input. Overall preoperative management was judged as optimal in only (9/22) 41%. Of those whose therapy did not meet guidelines (n= 13), five had azathioprine at doses <2 mg/kg, one declined therapy and nine with CD were current smokers. Conclusions: Over 50% of IBD resection patients had suboptimal preoperative management, with sub‐therapeutic thiopurine dosing and smoking in CD the main problems. Thus, there are significant gains to be made with better use of standard therapies, as it appears that ~50% of resection surgery was ‘potentially avoidable’.  相似文献   
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