-
Current Pharmaceutical Design 20036-Mercaptopurine (6MP) and 6-thioguanine (6TG) are analogs of the natural purines: hypoxanthine and guanine. Both mercaptopurine and thioguanine are substrates for... (Review)
Review
6-Mercaptopurine (6MP) and 6-thioguanine (6TG) are analogs of the natural purines: hypoxanthine and guanine. Both mercaptopurine and thioguanine are substrates for hypoxanthine-guanine phosphoribosyltransferase and are converted into the ribonucleotides 6-thioguanosine monophosphate (6-thioGMP) and 6-thioinosine monophosphate (T-IMP) respectively. The accumulation of these monophosphates inhibits several vital metabolic reactions. Today, these thiopurine bases remain valuable agents for the induction and maintenance of remissions in patients with myelocytic and acute lymphocytic leukemia. Despite their proved clinical importance, 6MP and 6TG have certain therapeutic disadvantages, which have continued to stimulate the search for purine derivatives enhancing therapeutic efficacy. Considerable efforts have been made to prepare other novel mercaptopurine and thioguanine analogs and their nucleosides to improve the antitumor efficacy. The effectiveness of these thiopurines against certain tumor cell lines suggested that some of these mercaptopurine analogs and their nucleosides would be worthy of consideration in order to determine whether they exert a more selective effect against neoplastic cells than against normal cells or they might be useful in patients whose disease has become resistant to 6MP or 6TG. This review will focus on mercaptopurine analogs and their nucleosides as antimetabolite agents.
Topics: Antimetabolites, Antineoplastic; Drug Design; Humans; Mercaptopurine; Nucleosides; Pyrimidines; Structure-Activity Relationship; Thioguanine
PubMed: 14529546
DOI: 10.2174/1381612033453677 -
Clinical Pharmacology and Therapeutics Feb 2009Thiopurine methyltransferase (TPMT) activity shows significant interindividual variation, with approximately 90% of individuals having high (wild-type) activity, 10%... (Review)
Review
Thiopurine methyltransferase (TPMT) activity shows significant interindividual variation, with approximately 90% of individuals having high (wild-type) activity, 10% with intermediate activity, and 0.3% with low activity. Low and intermediate TPMT activity leads to toxicity from mercaptopurine and the need for dose reduction. Common variants in the TPMT gene have a strong association with mercaptopurine toxicity. However, recent research has shown that genetic contribution to mercaptopurine toxicity is more complex, possibly involving other genes, in particular ITPA, which encodes inosine triphosphate pyrophosphatase.
Topics: Animals; Gene Frequency; Humans; Mercaptopurine; Methyltransferases; Neoplasms; Pharmacogenetics
PubMed: 19151640
DOI: 10.1038/clpt.2008.219 -
The Cochrane Database of Systematic... Jun 2010The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease were conflicting... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease were conflicting and controversial. A meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.
OBJECTIVES
To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.
SEARCH STRATEGY
Studies were selected using the MEDLINE database (1966 to July 2009), abstracts from major gastrointestinal meetings and references from published articles and review. The Cochrane Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. This search strategy was updated using the MEDLINE, EMBASE and the International Pharmaceutical Abstracts databases as well as the Cochrane Register of Controlled Trials and the Cochrane IBD/FBD group Specialized Trials Register.
SELECTION CRITERIA
Randomized, double-blind, placebo-controlled trials of oral azathioprine or 6-mercaptopurine involving adult patients (> 18 years) with active Crohn's disease were selected for inclusion.
DATA COLLECTION AND ANALYSIS
Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel.
MAIN RESULTS
Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. The odds ratio (OR) of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.43 (95% CI 1.62 to 3.64). This corresponded to a number needed to treat (NNT) of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the OR was 2.06 (95% CI 1.25 to 3.39). Treatment of > 17 weeks resulted in an OR of 2.61 (95% CI 1.69 to 4.03). A steroid sparing effect was seen with an OR of 3.69 (95% CI 2.12 - 6.42), corresponding to a NNTof about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased with active therapy with an odds ratio of 3.44 (95% CI 1.52 to 7.77). The NNT to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.
AUTHORS' CONCLUSIONS
Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. Adverse events were more common among patients on active therapy.
Topics: Adult; Azathioprine; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Randomized Controlled Trials as Topic; Remission Induction
PubMed: 20556747
DOI: 10.1002/14651858.CD000545.pub3 -
Seminars in Hematology Jul 1991
Clinical Trial Review
Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prodrugs
PubMed: 1780746
DOI: No ID Found -
World Journal of Gastroenterology Oct 2011The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine, are efficacious in the arsenal of inflammatory bowel disease (IBD) therapy. Previous reports indicate... (Review)
Review
The thiopurine drugs, 6-mercaptopurine (6-MP) and azathioprine, are efficacious in the arsenal of inflammatory bowel disease (IBD) therapy. Previous reports indicate that 6-thioguanine nucleotide (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Due to their complex metabolism, there is wide individual variation in patient response therein, both in achieving therapeutic drug levels as well as in developing adverse reactions. Several strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to side-effects. In this report, we will review different approaches to administer the thiopurine medications, including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine; co-administration of thiopurine with allopurinol; co-administration of thiopurine with anti-tumor necrosis factor α; 6-TGN administration; desensitization trials; and split dosing of 6-MP.
Topics: Azathioprine; Disease Management; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Purines
PubMed: 22072847
DOI: 10.3748/wjg.v17.i37.4166 -
The Cochrane Database of Systematic... Apr 2013The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease have been conflicting and controversial. An updated meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.
OBJECTIVES
The primary objective was to determine the efficacy and safety of azathioprine and 6-mercaptopurine for induction of remission in active Crohn's disease.
SEARCH METHODS
A literature search for relevant studies (inception to June 13, 2012) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies.
SELECTION CRITERIA
Randomized controlled trials (RCTs) of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients with active Crohn's disease were selected for inclusion.
DATA COLLECTION AND ANALYSIS
Data were extracted by two independent observers based on the intention-to-treat principle. Outcomes of interest included: clinical remission, clinical improvement, fistula improvement or healing, steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. We calculated the pooled relative risk (RR) and 95% confidence intervals (95% CI) for each outcome. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria.
MAIN RESULTS
Thirteen RCTs (n = 1211 patients) of azathioprine and 6-mercaptopurine therapy in adult patients were identified: nine included placebo comparators and six included active comparators. The majority of included studies were rated as low risk of bias. There was no statistically significant difference in clinical remission rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (95/197) of patients receiving antimetabolites achieved remission compared to 37% (68/183) of placebo patients (5 studies, 380 patients; RR 1.23, 95% CI 0.97 to 1.55). There was no statistically significant difference in clinical improvement rates between azathioprine or 6-mercaptopurine and placebo. Forty-eight per cent (107/225) of patients receiving antimetabolites achieved clinical improvement or remission compared to 36% (75/209) of placebo patients (8 studies, 434 patients; RR 1.26, 95% CI 0.98 to 1.62). There was a statistically significant difference in steroid sparing (defined as prednisone dose < 10 mg/day while maintaining remission) between azathioprine and placebo. Sixty-four per cent (47/163) of azathioprine patients were able to reduce their prednisone dose to < 10 mg/day compared to 46% (32/70) of placebo patients (RR 1.34, 95% CI 1.02 to 1.77). GRADE analyses rated the overall quality of the evidence for the outcomes clinical remission, clinical improvement and steroid sparing as moderate due to sparse data. There was no statistically significant difference in withdrawals due to adverse events or serious adverse events between antimetabolites and placebo. Ten percent of patients in the antimetabolite group withdrew due to adverse events compared to 5% of placebo patients (8 studies, 510 patients; RR 1.70, 95% CI 0.94 to 3.08). Serious adverse events were reported in 14% of patients receiving azathioprine compared to 4% of placebo patients (2 studies, 216 patients; RR 2.57, 95% CI 0.92 to 7.13). Common adverse events reported in the placebo controlled studies included: allergic reactions. leukopenia, pancreatitis and nausea. Azathioprine was significantly inferior to infliximab for induction of steroid-free clinical remission. Thirty per cent (51/170) of azathioprine patients achieved steroid-free remission compared to 44% (75/169) of infliximab patients (1 study, 339 patients; RR 0.68, 95% CI 0.51 to 0.90). The combination of azathioprine and infliximab was significantly superior to infliximab alone for induction of steroid-free clinical remission. Sixty per cent (116/194) of patients in the combined azathioprine and infliximab group achieved steroid-free remission compared to 48% (91/189) of infliximab patients (2 studies, 383 patients; RR 1.23, 95% CI 1.02 to 1.47). Azathioprine or 6-mercaptopurine therapy was found to be no better at inducing steroid free clinical remission compared to methotrexate (RR 1.13, 95% CI 0.85 to 1.49) and 5-aminosalicylate or sulfasalazine (RR 1.24, 95% CI 0.80 to 1.91). There were no statistically significant differences in withdrawals due to adverse events between azathioprine or 6-mercaptopurine and methotrexate (RR 0.78, 95% CI 0.23 to 2.71); between azathioprine or 6-mercaptopurine and 5-aminosalicylate or sulfasalazine (RR 0.98, 95% CI 0.38 to 2.54); between azathioprine and infliximab (RR 1.47, 95% CI 0.96 to 2.23); or between the combination of azathioprine and infliximab and infliximab (RR 1.16, 95% CI 0.75 to 1.80). Common adverse events in the active comparator trials included nausea, abdominal pain, pyrexia and headache.
AUTHORS' CONCLUSIONS
Azathioprine and 6-mercaptopurine offer no advantage over placebo for induction of remission or clinical improvement in active Crohn's disease. Antimetaboilte therapy may allow patients to reduce steroid consumption. Adverse events were more common in patients receiving antimetabolites although differences with placebo were not statistically significant. Azathioprine therapy is inferior to infliximab for induction of steroid-free remission. However, the combination of azathioprine and infliximab was superior to infliximab alone for induction of steroid-free remission.
Topics: Azathioprine; Crohn Disease; Humans; Immunosuppressive Agents; Induction Chemotherapy; Mercaptopurine; Randomized Controlled Trials as Topic
PubMed: 23633304
DOI: 10.1002/14651858.CD000545.pub4 -
The Cochrane Database of Systematic... 2000To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease. (Review)
Review
OBJECTIVES
To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.
SEARCH STRATEGY
Studies were selected using the MEDLINE data base (1966 - December 1997), abstracts from major gastrointestinal meetings and references from published articles and reviews. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register was also searched.
SELECTION CRITERIA
Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms.
DATA COLLECTION AND ANALYSIS
Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel ('Odds Ratio' in MetaView).
MAIN RESULTS
The odds ratio of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.36 (95% CI 1.57-3.53). This corresponded to a number needed to treat of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the odds ratio of response was 2.04 (CI 1.24 - 3.35). Treatment >/= 17 weeks increased the odds ratio of a response to 2.51 (CI 1.63-3. 88). A steroid sparing effect was seen with an odds ratio of 3.86 (CI 2.14 - 6.96), corresponding to a number needed to treat of about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased on therapy with an odds ratio of 3.01 (CI 1.30 - 6.96). The number needed to treat to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.
REVIEWER'S CONCLUSIONS
Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The odds ratio of response increases after >/= 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on therapy.
Topics: Antimetabolites; Azathioprine; Crohn Disease; Drug Therapy, Combination; Humans; Mercaptopurine; Remission Induction
PubMed: 10796557
DOI: 10.1002/14651858.CD000545 -
European Journal of Clinical... 1992
Review
Topics: Azathioprine; Drug Interactions; Humans; Mercaptopurine; Pharmacogenetics
PubMed: 1451710
DOI: 10.1007/BF02220605 -
Alimentary Pharmacology & Therapeutics Nov 2013Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17%... (Meta-Analysis)
Meta-Analysis Observational Study Review
A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis.
BACKGROUND
Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17% of patients treated with azathioprine. Previous case series have addressed the success rates of re-treatment with mercaptopurine in these individuals.
AIMS
To determine the rate of tolerance when trialling mercaptopurine in azathioprine-intolerant patients and the factors predictive of success, and to perform a systematic review and meta-analysis of these data with other published data sets.
METHODS
A retrospective observational study of 149 patients with IBD (82 with Crohn's disease and 67 with ulcerative colitis) previously intolerant of azathioprine subsequently treated with mercaptopurine was performed. A meta-analysis was undertaken of all published studies of mercaptopurine use in azathioprine-intolerant patients (455 patients in 11 included studies).
RESULTS
Mercaptopurine was tolerated by 58% of azathioprine-intolerant patients in the Edinburgh cohort. In the meta-analysis, 68% tolerated mercaptopurine. A higher proportion of those in the meta-analysis with GI toxicity (62%) or hepatotoxicity (81%) were able to tolerate mercaptopurine than those with flu-like illness (36%). Among those patients who ceased mercaptopurine for further adverse effects, 59% experienced the same adverse effect as they had with azathioprine.
CONCLUSIONS
This meta-analysis shows that switching to mercaptopurine is a safe therapeutic strategy for over two-thirds of azathioprine-intolerant patients and may help optimise immunomodulatory therapy in inflammatory bowel disease. A trial of mercaptopurine should be attempted in IBD patients (except those with acute pancreatitis or bone marrow aplasia) before considering thiopurine intolerance.
Topics: Adult; Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies
PubMed: 24117596
DOI: 10.1111/apt.12511 -
The Cochrane Database of Systematic... Oct 2009The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease were conflicting... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The results from controlled clinical trials investigating the efficacy of azathioprine and 6-mercaptopurine for the treatment of active Crohn's disease were conflicting and controversial. A meta-analysis was performed to assess the effectiveness of these drugs for the induction of remission in active Crohn's disease.
OBJECTIVES
To determine the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn's disease.
SEARCH STRATEGY
Studies were selected using the MEDLINE database (1966 to July 2009), abstracts from major gastrointestinal meetings and references from published articles and review. The Cochrane Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. This search strategy was updated using the MEDLINE, EMBASE and the International Pharmaceutical Abstracts databases as well as the Cochrane Register of Controlled Trials and the Cochrane IBD/FBD group Specialized Trials Register.
SELECTION CRITERIA
Randomized, double-blind, placebo-controlled trials of oral azathioprine or 6-mercaptopurine involving adult patients (> 18 years) with active Crohn's disease were selected for inclusion.
DATA COLLECTION AND ANALYSIS
Data were extracted by three independent observers based on the intention to treat principle. Each study was given a quality score based on predetermined criteria. Extracted data were converted to 2X2 tables (response versus no response and antimetabolite versus placebo) and then synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel.
MAIN RESULTS
Eight randomized placebo controlled trials of azathioprine and 6-mercaptopurine therapy in adult patients were identified: five dealt with active disease and three had multiple therapeutic arms. The odds ratio (OR) of a response to azathioprine or 6-mercaptopurine therapy compared with placebo in active Crohn's disease was 2.43 (95% CI 1.62 to 3.64). This corresponded to a number needed to treat (NNT) of about 5 to observe an effect of therapy in one patient. When the two trials using 6-mercaptopurine in active disease were excluded from the analysis, the OR was 2.06 (95% CI 1.25 to 3.39). Treatment > 17 weeks increased the OR to 2.61 (95% CI 1.69 to 4.03). A steroid sparing effect was seen with an OR of 3.69 (95% CI 2.12 - 6.42), corresponding to a NNTof about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased with active therapy with an odds ratio of 3.44 (95% CI 1.52 to 7.77). The NNT to observe one adverse event in one patient treated with azathioprine or 6-mercaptopurine was 14.
AUTHORS' CONCLUSIONS
Azathioprine and 6-mercaptopurine are effective therapy for inducing remission in active Crohn's disease. The OR of response increases after > 17 weeks of therapy, suggesting that there is a minimum length of time for a trial of azathioprine or 6-mercaptopurine therapy. Adverse events were more common among patients on active therapy.
Topics: Azathioprine; Crohn Disease; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Mercaptopurine; Randomized Controlled Trials as Topic; Remission Induction
PubMed: 19821270
DOI: 10.1002/14651858.CD000545.pub2