Article

Azathioprine And 6-Mercaptopurine For Maintenance Of Remission In Ulcerative Colitis

German Cochrane Center, Stefan Meier Str. 26, Freiburg, Germany, 79104.
Cochrane database of systematic reviews (Online) (Impact Factor: 5.94). 02/2007; 9(1):CD000478. DOI: 10.1002/14651858.CD000478.pub2
Source: PubMed

ABSTRACT Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.
To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.
The MEDLINE database was used to search literature from 1966 to 2006. A manual search was also performed using references from these articles as well as review articles, proceedings from major gastrointestinal meetings and data available from the Cochrane Collaboration database. Authors of maintenance trials were asked about unpublished studies.
Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (mesalamine) were included.
Data were extracted by two raters using standard forms. Disagreements were solved by informal consent, including a third rater. Jadad scores were applied to assess study quality. Analyses were performed separately by type of control (placebo, or active comparator). Pooled odds ratios were calculated based on the fixed effects model unless heterogeneity was shown.
Six studies were identified including 286 patients with ulcerative colitis. The study quality was mostly poor. Azathioprine was shown to be superior for the maintenance of remission as compared to placebo based on four trials (failure to maintain remission: OR 0.41; 95% CI 0.24 to 0.70). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity. Both studies using active comparators were open label. Adverse effects occurred in 11 of 127 patients receiving azathioprine, including acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases).
Azathioprine may be an effective maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine.

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    • "For patients with steroid-dependent or steroid-refractory ulcerative colitis (UC), immunomodulatory agents, such as azathioprine (AZA), 6-mercaptopurine (6-MP), cyclosporine , or methotrexate, have been used for the induction and maintenance of clinical remission of the disease [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]. While thiopurines (AZA/6-MP) are the most commonly used agents to maintain clinical remission in patients with UC [1] [2], the use of AZA/6-MP for inducing remission of active UC is still controversial [3] [4] [5] [6] [7] [8]. "
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    ABSTRACT: Background: The role of azathioprine (AZA) and 6-mercaptopurine (6-MP) in the induction of remission in patients with ulcerative colitis (UC) remains unclear. Aims: To compare the efficacy and safety of low-dose thiopurine (AZA/6-MP) and cytapheresis (CAP) for the induction of remission in patients with steroid-dependent UC. Patients and Methods: We reviewed the clinical course of 65 patients with steroid-dependent UC with moderate activity, who were treated with either low-dose AZA/6-MP (T-group, n = 38) or with CAP (C-group, n = 27). The efficacy and safety for the first 10 weeks after the start of the therapies were compared between the two groups. The cumulative probability curves of treatment failure were estimated by the Kaplan-Meier method. Clinical remission was defined as an ulcerative colitis activity index value of less than 150 without any other treatments. Results: Neither clinical characteristics, concomitant therapies, nor laboratory data (except for serum albumin levels) were different between the two groups. The remission rate at 10 weeks was not different between the two groups (55.3% in the T-group and 70.4% in the C-group, p = 0.22 in the intention-to-treat analysis). The frequencies of adverse events did not differ be-tween the two groups (p = 0.12). The cumulative pro-bability of treatment failure at 10 weeks was 44.7% for the T-group and 29.6% for the C-group (p = 0.23). Conclusions: Low-dose thiopurine therapy is an alter-native candidate for the induction of remission in pa-tients with steroid-dependent, moderate UC.
    Open Journal of Gastroenterology 01/2012; 02(01). DOI:10.4236/ojgas.2012.21002
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    • "A recent meta‐analysis of four trials confirmed that patients with UC who continued with azathioprine are less likely to experience a relapse than those who received placebo (OR 0.41; 95% CI: 0.24–0.70) [32]. In coincidence with trials in CD the most effective doses appear to be for azathioprine 2–3 mg/kg and for 6‐mercaptopurine 1–1.5 mg/kg daily, although there has not been a direct comparison of different dose levels or a comparative study evaluating azathioprine versus 6‐ mercaptopurine. "
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    ABSTRACT: The perception that Crohn's disease is a more severe process than ulcerative colitis, led to the initial development of a majority drugs, and testing of treatment strategies, in the former. In the absence of similar studies in ulcerative colitis, information of Crohn's disease studies may help the clinician in decision making in UC. Studies on aminosalicylates show that drugs with a topical effect which are not effective in Crohn's disease may still have efficacy in ulcerative colitis, and this should be considered in future drug development. The best efficacy of corticorteroids is achieved with high doses of 1 mg/kg/day, and reaching remission may be delayed by several weeks, although non-response in the initial days should lead to treatment escalation, in particular in severe patients. Thiopurines have a steroid-sparing effect, and the duration of treatment should be at least 4 years; caution should be exerted in using these drugs in EBV negative young patients and in the older population for the risk of lymphoma. Anti-TNF monoclonal antibody therapy is optimized by use of induction followed by scheduled maintenance as opposed to episodic treatment, resulting in higher sustained response rates and lower immunogenicity. Associations of non-biological immunosuppressants with anti-TNF antibodies can further increase therapeutic efficacy maintaining a safe profile. Patients under combined therapy with sustained clinical and biological remission and mucosal healing may be candidates to stop anti-TNF treatment. The majority of these recommendations need to be specifically studied in patients with ulcerative colitis before generalization in clinical practice.
    Current drug targets 04/2011; 12(10):1467-77. DOI:10.2174/138945011796818162 · 3.60 Impact Factor
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    • "The immune modulating thiopurines 6-mercaptopurine (6-MP) and its pro-drug azathioprine (AZA) have proven efficacy , especially in maintenance of remission of inflammatory bowel disease (IBD). (Present et al., 1980; Candy et al., 1995; George et al., 1996; Sandborn et al., 2000; Timmer et al., 2007) However, in a recent study up to 40% of IBD patients discontinued AZA or 6-MP prematurely due to adverse events. (Jharap et al., 2010) Administration of another thiopurine, 6-thioguanine (6-TG), has been proposed as a rescue therapy for patients with IBD who are intolerant of AZA and/or 6-MP (de Boer et al., 2007b; 2008). "
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    ABSTRACT: Although 6-mercaptopurine and azathioprine are effective treatments in inflammatory bowel disease (IBD), many patients discontinue treatment because of side effects. 6-Thioguanine (6-TG) may be an alternative rescue therapy in these intolerant patients but the pharmacokinetics of 6-TG are not fully described. Here we have measured the pharmacokinetics of the biotransformation of 6-TG into the pharmacologically active metabolites, 6-thioguanine nucleotides (6-TGN), in IBD patients. In 12 patients with IBD, levels of 6-TGN and activities of thiopurine S-methyltransferase, xanthine oxidase and hypoxanthine guanine-phosphoribosyl-transferase were measured in a two-stage (i.v. and p.o. administration of 0.3 mg·kg(-1) 6-TG), prospective study. Median exposure of 6-TGN in red blood cells (RBC) was expressed as the ratio of the area under the curve (AUC) per mg 6-TG after i.v. dosing and that after p.o. dosing. The median AUC per mg 6-TG was 1068 (p.o.) and 7184 (i.v.) pmol·h (8 × 10(8) RBC)(-1) . Median exposure of 6-TGN in RBC was 15% (9-28). Hypoxanthine guanine-phosphoribosyl-transferase activity correlated with peak 6-TGN and with AUC per mg (r= 0.7, P= 0.02 and r= 0.6, P= 0.03 respectively). Thiopurine S-methyltransferase activity was inversely related to AUC per mg (r=-0.8, P= 0.001), whereas that of xanthine oxidase was correlated with a lower peak 6-TGN (r=-0.7, P= 0.02). The great variability of the AUC per mg for 6-TG observed after p.o. and i.v. administration of 6-TG, was partly explained by variability in activities of metabolizing enzymes. Exposure of 6-TGN was low in all patients.
    British Journal of Pharmacology 02/2011; 163(4):722-31. DOI:10.1111/j.1476-5381.2011.01265.x · 4.99 Impact Factor
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