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The Cochrane Database of Systematic... Oct 2016The 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
We searched MEDLINE, EMBASE and the Cochrane Library from inception to 30 October 2015. 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: Adult; Antimetabolites; Azathioprine; Crohn Disease; Glucocorticoids; Humans; Immunosuppressive Agents; Induction Chemotherapy; Infliximab; Mercaptopurine; Mesalamine; Prednisone; Randomized Controlled Trials as Topic; Sulfasalazine; Withholding Treatment
PubMed: 27783843
DOI: 10.1002/14651858.CD000545.pub5 -
Zhongguo Dang Dai Er Ke Za Zhi =... Sep 2017Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and... (Review)
Review
Mercaptopurine is a common chemotherapeutic drug and immunosuppressive agent and plays an important role in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. It may cause severe adverse effects such as myelosuppression, which may result in the interruption of treatment or complications including infection or even threaten patients' lives. However, the adverse effects of mercaptopurine show significant racial and individual differences, which reveal the important role of genetic diversity. Recent research advances in pharmacogenomics have gradually revealed the genetic nature of such differences. This article reviews the recent research advances in the pharmacogenomics and individualized application of mercaptopurine.
Topics: Antimetabolites, Antineoplastic; Humans; Mercaptopurine; Methyltransferases; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrophosphatases
PubMed: 28899477
DOI: 10.7499/j.issn.1008-8830.2017.09.019 -
Journal of Clinical Gastroenterology Jan 2017The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines.
OBJECTIVE
The objective of the study was to define the clinical, biochemical, and histologic features of liver injury from thiopurines.
BACKGROUND
Azathioprine (Aza) and 6-mercaptopurine (6-MP) can cause liver injury, but no large series exist.
METHODS
Clinical and laboratory data and 6-month outcomes of patients with thiopurine hepatotoxicity from the Drug-Induced Liver Injury Network Prospective Study were analyzed.
RESULTS
Twenty-two patients were identified, 12 due to Aza and 10 due to 6-MP, with a median age of 55 years; the majority were female (68%). Inflammatory bowel disease was the indication in 55%, and the median thiopurine dose was 150 (range, 25 to 300) mg daily. The median latency to onset was 75 (range, 3 to 2584) days. Injury first arose after a dose escalation in 59% of patients, the median latency after dose increase being 44 (range, 3 to 254) days. At onset, the median alanine aminotransferase level was 210 U/L, alkaline phosphatase was 151 U/L, and bilirubin was 7.4 mg/dL (peak, 13.4 mg/dL). There were no major differences between Aza and 6-MP cases, but anicteric cases typically had nonspecific symptoms and a hepatocellular pattern of enzyme elevations, whereas icteric cases experienced cholestatic hepatitis with modest enzyme elevations in a mixed pattern. One patient with preexisting cirrhosis required liver transplantation; all others resolved clinically. One patient still had moderate alkaline phosphatase elevations 2 years after onset.
CONCLUSIONS
Nearly three-quarters of patients with thiopurine-induced liver injury present with self-limited, cholestatic hepatitis, typically within 3 months of starting or a dose increase. The prognosis is favorable except in patients with preexisting cirrhosis.
Topics: Adolescent; Adult; Aged; Alanine Transaminase; Alkaline Phosphatase; Azathioprine; Bilirubin; Chemical and Drug Induced Liver Injury; Child; Cholestasis; Databases, Factual; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Prospective Studies; Time Factors; Young Adult
PubMed: 27648552
DOI: 10.1097/MCG.0000000000000568 -
Revista Espanola de Enfermedades... Jan 2017Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited. (Observational Study)
Observational Study
BACKGROUND
Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited.
AIMS
To assess the possible therapeutic indications, efficacy and safety of mercaptopurine as an alternative to azathioprine in inflammatory bowel disease.
METHODS
Retrospective observational study in patients treated with mercaptopurine in a total cohort of 1,574 patients with inflammatory bowel disease.
RESULTS
One hundred and fifty-two patients received mercaptopurine, 15.7% of these patients as an initial thiopurine, 5.3% after azathioprine failure, and 79% after azathioprine intolerance. In 52.6% of patients (n = 80), adverse effects of mercaptopurine occurred, resulting in withdrawal in 49 of them. Mercaptopurine was effective in 39% of cases (95% CI 31-48%). In the remaining patients, failure was due mainly to withdrawal due to side effects (55.1%) and therapeutic step-up (33.7%). The average total time of mercaptopurine exposure was 36 months (IQR: 2-60). Myelotoxicity with mercaptopurine was more common in patients with intermediate TPMT activity than in those with normal activity (p = 0.046).
CONCLUSIONS
In our setting, mercaptopurine is primarily used as a rescue therapy in patients with azathioprine adverse effects. This could explain its modest efficacy and the high rate of adverse effects. However, this drug is still an alternative in this group of patients, before a therapeutic step-up to biologics is considered.
Topics: Adult; Aged; Azathioprine; Cohort Studies; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Retrospective Studies; Treatment Failure
PubMed: 27809554
DOI: 10.17235/reed.2016.4546/2016 -
World Journal of Gastroenterology Oct 2021Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the...
Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the main causes of treatment discontinuation or interruption. Myelosuppression is the most frequent adverse effect; however, approximately 5%-20% of patients develop gastrointestinal toxicity. The identification of biomarkers able to prevent and/or monitor these adverse reactions would be useful for clinicians for the proactive management of long-term thiopurine therapy. In this editorial, we discuss evidence supporting the use of , , and genes, in addition to and as possible biomarkers for thiopurine-related gastrointestinal toxicity.
Topics: Azathioprine; Biomarkers; Humans; Immunologic Factors; Mercaptopurine; Methyltransferases; Pyrophosphatases
PubMed: 34720526
DOI: 10.3748/wjg.v27.i38.6348 -
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 -
Pharmacogenetics and Genomics Sep 2010
Topics: DNA; Guanine Nucleotides; Humans; Mercaptopurine; Prodrugs; Signal Transduction; Thionucleotides
PubMed: 19952870
DOI: 10.1097/FPC.0b013e328334338f -
Expert Opinion on Drug Metabolism &... Oct 2021Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment... (Review)
Review
INTRODUCTION
Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in gene encode diminished activity enzyme, enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response.
AREAS COVERED
This review gives an overview on gene and function, and discusses the pharmacogenomic implications of variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published since1990, and on PharmGKB.
EXPERT OPINION
To titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a preemptive genotyping to establish a safe initial dose with a close phenotypic monitoring of TPMT activity and/or of active metabolites during long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in heterozygotes and novel individualized TG regimens in maintenance for subjects could be investigated to improve outcomes while avoiding risk of severe hepatotoxicity.
Topics: Animals; Antimetabolites, Antineoplastic; Genotype; Humans; Mercaptopurine; Methyltransferases; Molecular Targeted Therapy; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioguanine
PubMed: 34452592
DOI: 10.1080/17425255.2021.1974398 -
International Journal of Molecular... May 2020Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent...
Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent inhibitors of the xanthine oxidase (XO)-catalyzed uric acid formation . However, the effects of conjugated flavonoid metabolites are poorly characterized. Furthermore, the inhibition of XO-catalyzed 6-mercaptopurine oxidation is an important reaction in the pharmacokinetics of this antitumor drug. The inhibitory effects of some compounds on xanthine vs. 6-mercaptopurine oxidation showed large differences. Nevertheless, we have only limited information regarding the impact of flavonoids on 6-mercaptopurine oxidation. In this study, we examined the interactions of flavonoid aglycones and some of their conjugates with XO-catalyzed xanthine and 6-mercaptopurine oxidation . Diosmetin was the strongest inhibitor of uric acid formation, while apigenin showed the highest effect on 6-thiouric acid production. Kaempferol, fisetin, geraldol, luteolin, diosmetin, and chrysoeriol proved to be similarly strong inhibitors of xanthine and 6-mercaptopurine oxidation. While apigenin, chrysin, and chrysin-7-sulfate were more potent inhibitors of 6-mercaptopurine than xanthine oxidation. Many flavonoids showed similar or stronger (even 5- to 40-fold) inhibition of XO than the positive control allopurinol. Based on these observations, the extremely high intake of flavonoids may interfere with the elimination of 6-mercaptopurine.
Topics: Allopurinol; Catalysis; Dose-Response Relationship, Drug; Flavonoids; Mercaptopurine; Oxidation-Reduction; Xanthine; Xanthine Oxidase
PubMed: 32380641
DOI: 10.3390/ijms21093256 -
Current Opinion in Pediatrics Feb 2017Outcomes for children with cancer have improved dramatically. Although the contribution of disease biology and therapy resistance to treatment failure continues to be a... (Review)
Review
PURPOSE OF REVIEW
Outcomes for children with cancer have improved dramatically. Although the contribution of disease biology and therapy resistance to treatment failure continues to be a focus of intense research efforts, the role of medication nonadherence on the part of caregivers or patients has been relatively neglected. Efforts to further improve childhood cancer cure rates must include a focus on improving medication adherence.
RECENT FINDINGS
Recent studies in children with acute lymphoblastic leukemia have conclusively demonstrated that nonadherence to oral antimetabolite therapy is associated with a significant increase in relapse risk. The impact of nonadherence to other oral medications in acute lymphoblastic leukemia and in other childhood cancers remains unknown. Tools by which clinicians can accurately identify nonadherent families are currently being developed but remain suboptimal. Similarly, while current efforts to develop interventions aimed at increasing adherence rates are underway, their feasibility and effectiveness is still unknown.
SUMMARY
Future studies must focus on the development and widespread implementation of methods by which to identify and minimize nonadherence. Doing so will allow for further improve childhood cancer cure outcomes.
Topics: Administration, Oral; Antineoplastic Agents; Child; Humans; Medication Adherence; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 27798425
DOI: 10.1097/MOP.0000000000000434