巯嘌呤甲基转移酶检测在炎症性肠病治疗中的作用

巯嘌呤甲基转移酶（TPMT）是硫唑嘌呤（AZA）／6-巯基嘌呤（6-MP）代谢的关键酶之一,而AZA／6-MP广泛用于难治性炎症性肠病（IBD）的治疗。TPMT的活性／基因型与AZA／6-MP的疗效和不良反应相关,进行TPMT活性／基因型检测有可能预测骨髓抑制等不良反应的发生,并能指导个体化治疗。     

嘌呤类似物治疗炎症性肠病的药理作用和临床应用

1990年以前,仅有少数医疗中心将免疫调节剂用于炎症性肠病(IBD)患者,其适应证和疗效也颇具争议性,近10年来则积累了很多临床经验。目前已有硫唑嘌呤(AZA)、6-巯基嘌呤(6-MP)、甲氨蝶呤(MTX)、霉酚酸酯(商品名:骁悉)、他克莫司(商品名:普乐可复)和环孢素A等几大类化学性免疫抑制剂以及生物制剂(抗肿瘤坏死因子单克隆抗体等)应用于临床,其中尤以AZA和6-MP应用得较早、较广。本文就此两种药物治疗克罗恩病(CD)和溃疡性结肠炎(UC)的药理作用以及临床应用现状和进展作一综述。     

硫唑嘌呤治疗疑诊炎症性肠病所致严重感染1例报告

正硫唑嘌呤(AZA)是6-巯基嘌呤(6-MP)的咪唑衍生物,该药用于多种自身免疫性疾病的诊治。国内外研究显示,大部分炎症性肠病患者可以耐受AZA治疗,总不良反应发生率为43.5%,包括胃肠道反应、肝功能异常、血液系统损害、继发感染等。另外,还有少数患者有胰腺炎、淋巴瘤、肌痛和(或)关节痛等。本院收治的1例疑诊炎症性肠病患者,给予硫唑嘌呤治疗1个月,病程中出现粒细胞缺乏,     

合理使用免疫抑制剂以提高炎症性肠病的疗效

在炎症性肠病(IBD)药物治疗中,免疫抑制剂[常用的如硫唑嘌呤(AZA)和6-巯基嘌呤(6-MP)]主要用于糖皮质激素(简称为激素)治疗无效或激素依赖的患者,合理使用可提高疗效并最大限度地减少药物不良反应的发生.免疫抑制剂用于IBD的治疗,近20年来在国外已广泛推广并不断有深入的研究,但在我国应用的经验和临床研究尚少.     

炎症性肠病免疫调节剂治疗的再评价

1990年前,炎症性肠病(IBD)的免疫调节剂治疗仅限于少数治疗中心且有很大争议,然而近5年来此方面的基础理论研究已获迅速发展。本文将重点介绍硫唑嘌呤(AZA)、6-巯基嘌呤(6 MP)、环胞素(CYA)及甲氨喋呤(MTX)的药理学、治疗反应、安全性以及剂量、毒性监测、治疗适应证和选用原则。     

英夫利西单抗联合巯嘌呤类药物与单药治疗炎症性肠病疗效比较的meta分析

背景:生物制剂英夫利西单抗(IFX)对炎症性肠病(IBD)的治疗已取得显著疗效,然而仍有部分患者在治疗过程中出现病情加重、复发、并发症等。目的:系统评价IFX与巯嘌呤类药物(AZA或6-MP)联合治疗IBD的效果和安全性。方法:计算机检索MEDLINE、Embase、Pub Med、Science Direct数据库,纳入IFX联合AZA/6-MP与单药治疗IBD的随机对照试验。采用Rev Man 5.3软件对纳入文献行meta分析。结果:共纳入5篇文献。Meta分析显示,与IFX单药组相比,联合用药组临床缓解率(RR=1.26,95%CI:1.08～1.48;Z=2.90,P=0.004)、内镜缓解率(RR=1.28,95%CI:1.02～1.60;Z=2.17,P=0.03)均显著增高,而严重不良反应(RR=0.85,95%CI:0.58～1.27;Z=0.78,P=0.44)和一般不良反应(RR=1.09,95%CI:1.00～1.19;Z=1.90,P=0.06)均无明显差异。与AZA/6-MP单药组相比,联合用药组临床缓解率(RR=1.87,95%CI:1.52～2.31;Z=5.83,P0.000 01)、内镜缓解率(RR=1.99,95%CI:1.51～2.62;Z=4.93,P0.000 01)均显著增高。结论:对于IBD患者,IFX与AZA/6-MP联合用药的临床缓解率、内镜缓解率均显著优于IFX或AZA/6-MP单药治疗,且不良反应无明显差异。     

耐受6-MP治疗的炎症性肠病患者6-MP代谢的生物化学特点

目前应用6-巯基嘌呤/硫唑嘌呤(6-MP/AZA)治疗炎症性肠病患者已经取得较好的疗效,但是仍然有约40％的患者治疗无效,研究发现药物治疗的临床疗效与实际6-MP/AZA用药剂量无关,而与药物代谢的活性成分水平相关,其中6-硫代鸟嘌呤核苷酸(6-TGN)水平与临床疗效最为密切,而在硫嘌呤甲基转移酶(TPMT)作用下产生的6-甲基巯嘌呤核苷酸(6-MMPR)水平与药物所致血液系统及肝脏毒     

硫唑嘌呤治疗炎症性肠病的不良反应分析

目的 了解硫唑嘌呤(AZA)治疗炎症性肠病不良反应的类型、发生率、发生时间及转归.方法 回顾性分析1995年3月～2009年9月北京协和医院接受硫唑嘌呤治疗的85例炎症性肠病患者的病历资料,其中溃疡性结肠炎37例,克罗恩病48例.结果 37例(43.5%)患者出现不良反应共43次,其中48%(20/43)的不良反应发生...     

5-氨基水杨酸对硫嘌呤类药物骨髓抑制的影响

目的 研究5-氨基水杨酸(5-ASA)对硫嘌呤类药物骨髓抑制的影响及其机制,探讨中国炎症性肠病(IBD)患者合用5-ASA时所需硫嘌呤类药物的剂量。方法 回顾性分析服用硫嘌呤类药物IBD患者的临床资料,检测硫嘌呤甲基转移酶(TPMT)活性和红细胞6-硫鸟嘌呤核苷酸(6-TGN)浓度。前瞻性研究中先予患者硫唑嘌呤(AZA) 50 mg/d治疗4周,继而加用5-ASA 3 g/d治疗4周,检测第4、8周末红细胞6-TGN浓度。结果 回顾性分析AZA/6-巯嘌呤(6-MP) +5-ASA组45例、AZA/6-MP组94例患者,两组骨髓抑制发生率分别为46.7％和16.0％,多因素回归分析显示合用5-ASA为增加骨髓抑制的惟一独立危险因素(OR= 3.45,95％CI：1.31～9.04)。TPMT活性在AZA/6-MP+ 5-ASA组和AZA/6-MP组之间差异无统计学意义(t=-0.351,P=0.734)。AZA/6-MP+5-ASA组6-TGN浓度显著高于AZA/6-MP组（中位浓度为384.9 pmol/8×108 RBC比286.4 pmol/8×108 RBC,F=29.15,P=0.00）。8例患者完成前瞻性研究,予AZA 50mg/d 4周后,7例患者6-TGN浓度＜230 pmol/8×108 RBC;加用5-ASA 4周后,7例患者6-TGN浓度≥230 pmol/8×108 RBC,其中3例6-TGN浓度≥420 pmol/8×108 RBC,2例发生骨髓抑制。结论 当中国IBD患者合用5-ASA治疗时,采用常规推荐剂量的AZA/6-MP时骨髓抑制的发生概率增加,其机制可能与红细胞内6-TGN浓度升高有关,降低AZA剂量有可能在保持疗效的同时降低骨髓抑制发生率。     

6-疏基嘌呤(6-MP)治疗炎症性肠病中所致胰腺炎的特性及病程

有报告硫唑嘌呤、6-MP等药物于治疗肾移植后、类风关、慢活肝、炎症性肠病(IBD)等疾病时可并发药物性胰腺炎.6-MP对IBD而言,是重要的治疗药物.本文分析1969～1986的15年间400例IBD应用6-MP治疗中13例(3.25%)并发急性胰腺炎的临床资料     

Gender-related issues in the female inflammatory bowel disease patient

Inflammatory bowel diseases (IBDs) commonly affect women in their childbearing years. Women identify unique psychologic issues compared with men related to body image and their ability to bear children. The menstrual cycle can be disrupted because of disease activity, medications and/or malnutrition. Oral contraceptives can be used; however, monitoring for thromboembolic events should be performed. Women with IBD are potentially at risk of higher rates of cervical dysplasia and should be screened as are other immunocompromised women. Fertility rates are comparable to those of women without IBD. The risk of disease activity during pregnancy depends on the disease activity at the time of conception. Pregnancy for the majority of women is uncomplicated, although women with Crohn’s disease do tend to deliver children of lower birthweights than do healthy women. The majority of medications used in the treatment of IBD are not harmful to the fetus and should be continued throughout pregnancy in order to maintain maternal health. Breastfeeding should not be discouraged and the majority of medications are safe for nursing. Menopause tends to occur earlier in women with IBD; the cause of this is unclear.     

Hepatobiliary associations with inflammatory bowel disease

Hepatobiliary disease is not uncommon in patients with inflammatory bowel disease (IBD). The most common autoimmune hepatic associations are primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). The immunosuppressant medications used in the treatment of IBD also have potential hepatotoxicity. PSC is most commonly associated with IBD, specifically ulcerative colitis. AIH, a more classic autoimmune disease diagnosed commonly in isolation of other conditions in the same individual, is less commonly associated with IBD. Additionally, a subgroup of patients have features of both PSC and AIH, termed overlap syndrome, that is also sometimes seen in IBD patients. This review will discuss the most common liver disease associations seen in patients with IBD: PSC, AIH and overlap syndrome. Additionally, the most common drug-related hepatotoxicities encountered when treating IBD will be reviewed.     

Managing Risks of Neoplasia in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) has been linked with a variety of intestinal and extraintestinal cancers. This review summarizes the latest literature with regard to which cancers are truly linked with IBD and which are not, the absolute and relative risks of these cancers, how medications commonly prescribed for IBD affect this risk, and finally strategies for managing these risks. Physicians and health professionals may find this information useful for counseling and educating patients as well as for improving patient care.     

Hepatitis C Virus and Inflammatory Bowel Disease

Gastroenterologists frequently treat patients with complex illnesses such as chronic hepatitis C infections and inflammatory bowel disease (IBD). Occasionally, a patient will present with these two diseases which behave very differently and the treatment for one may potentially exacerbate the other. The purpose of this article is to review the current literature regarding hepatitis C virus therapy in the setting of IBD as well as the effects of common IBD therapies on the hepatitis C virus. Based on limited data, anti-viral therapy is probably safe in patients with well-controlled IBD, but there might be a risk of causing new onset of IBD. Also, it does not appear that the commonly used medications for IBD have much of an effect on the hepatitis C virus (HCV) or its course.     

Drug development in inflammatory bowel disease: the role of the FDA

All medicinal compounds sold in the United States for inflammatory bowel disease (IBD) are regulated by the Food and Drug Administration (FDA) via a number of regulations dating back to 1906. The primary contemporary role of the FDA is in the assessment of safety and efficacy, and subsequent marketing, of medications based on preclinical and clinical trial data provided by sponsors. This includes pharmacokinetic, toxicology and clinical studies, and postapproval safety monitoring. Mesalamine formulations, budesonide, and biologic therapies have all been assessed for efficacy and safety in IBD by the FDA via large randomized controlled trials (RCTs). There has been considerable evolution in the endpoints used by the FDA to approve medications for IBD, and the mechanisms through which newer agents have been approved. This review examines the methods of drug approval by the FDA, the bench-marks used to approve drugs for IBD, and recent controversies in the FDA's role in drug approval in general.     

Drug-induced acute pancreatitis due to medications used for inflammatory bowel disease: A VigiBase pharmacovigilance database study

BackgroundNearly all medications used for inflammatory bowel disease (IBD) have been reported as causes of acute pancreatitis (AP), with the thiopurines being among the most frequently described. However, with the development of newer medications, thiopurine monotherapy has largely been replaced by newer immunosuppressive drugs. There are few data on the association between AP and biologic/small molecule agents.MethodsVigiBase, the World Health Organization's Global Individual Case Safety Report database, was used to assess the association between AP and common IBD medications. A case/non-case disproportionality analysis was performed and disproportionality signals were reported as a reporting odds ratio (ROR) with 95% confidence intervals (CIs).ResultsA total of 4,223 AP episodes were identified for common IBD medications. Azathioprine (ROR 19.18, 95% CI 18.21–20.20), 6-mercaptopurine (ROR 13.30, 95% CI 11.73–15.07), and 5-aminosalicylic acid (ROR 17.44, 95% CI 16.24–18.72) all had strong associations with AP, while the biologic/small molecule agents showed weaker or no disproportionality. The association with AP was much higher for thiopurines when used for Crohn's disease (ROR 34.61, 95% CI 30.95–38.70) compared to ulcerative colitis (ROR 8.94, 95% CI 7.47–10.71) or rheumatologic conditions (ROR 18.87, 95% CI 14.72–24.19).ConclusionsWe report the largest real-world database study investigating the association between common IBD medications and AP. Among commonly used IBD medications including biologic/small molecule agents, only thiopurines and 5-aminosalicylic acid are strongly associated with AP. The association between thiopurines and AP is much stronger when the drug is used for Crohn's disease compared to ulcerative colitis and rheumatologic conditions.     

Perioperative complications in inflammatory bowel disease

Almost 50% of patients with inflammatory bowel disease (IBD) will undergo surgery for their disease at some stage of its clinical course. Complications seen following surgery may occur early or late in the postoperative period. Patient factors, including active inflammatory disease, malnutrition, and use of immunosuppressant medications, make these patients a challenging surgical group and at increased risk for surgical complications. The purpose of this review is to characterize the complications that are commonly seen following surgery in patients with IBD and to discuss the surgical and patient factors that may influence their development.     

Surgery for inflammatory bowel disease

Despite the new and ever expanding array of medications for the treatment of inflammatory bowel disease （IBD）, there are still clear indications for operative management of IBD and its complications. We present an overview of indications, procedures, considerations, and controversies in the surgical therapy of IBD.     

Pregnancy and nursing in inflammatory bowel disease

The peak age of onset for IBD coincides with the peak age for conception and pregnancy. Women with inactive IBD who become pregnant do not have increased complications compared with age-matched controls. Most medications for IBD are safe in pregnancy. The greatest danger to a normal conception and pregnancy is active disease, not the medicine used to treat it. This article outlines fertility in IBD, the effect of IBD on pregnancy, the effect of pregnancy on IBD, and the medical therapy available.