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Ugeskrift For Laeger May 2014Thiopurines are effective in maintaining remission in chronic inflammatory bowel diseases, but incomplete response or side effects are common during standard-dose... (Review)
Review
Thiopurines are effective in maintaining remission in chronic inflammatory bowel diseases, but incomplete response or side effects are common during standard-dose treatment. In this article thiopurine metabolism and pharmacogenetic aspects are summarized showing their benefits in improving therapy in chronic inflammatory bowel disease. An increasing body of evidence suggests that a large part of the observed non-pancreatic side effects and poor responses can be solved by tailoring thiopurine therapy using measurement of thiopurine methyltransferase and metabolites and by using a combination therapy with low-dose thiopurines and allopurinol.
Topics: Algorithms; Allopurinol; Antimetabolites; Azathioprine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases
PubMed: 25352005
DOI: No ID Found -
Alimentary Pharmacology & Therapeutics Aug 2007Inflammatory bowel disease (IBD) affects mainly the young population. The effect of IBD and its treatment on fertility and pregnancy is therefore an important clinical... (Review)
Review
BACKGROUND
Inflammatory bowel disease (IBD) affects mainly the young population. The effect of IBD and its treatment on fertility and pregnancy is therefore an important clinical consideration.
AIM
To review the best management of IBD in the reproductive and pregnant population.
METHODS
A MEDLINE and an EMBASE search were performed using mainly the search phrases 'pregnancy AND IBD,''sulphasalazine AND male fertility,''abdominal surgery AND female fertility,''AZA AND placenta' and 'infliximab AND pregnancy.' No language or date restrictions were placed. References of review articles were examined.
RESULTS
Overall male and female fertility are not affected by IBD. Sulphasalzine reduces male fertility. No other drugs used in IBD affect significantly fertility in humans. The risk of pregnancy-related complications and the disease behaviour during pregnancy depends mainly on disease activity at time of conception. Proactive treatment for maintenance of disease remission during gestation is recommended. Except for methotrexate, drugs used in IBD appear safe in pregnancy. Breast feeding should be encouraged.
CONCLUSION
The management of IBD in the young and pregnant population remains controversial because the literature comes mostly from retrospective studies. Further studies particularly large prospective trials are needed to guide clinicians in decision making.
Topics: Adult; Azathioprine; Breast Feeding; Female; Fertility; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Reproduction; Sulfasalazine
PubMed: 17661756
DOI: 10.1111/j.1365-2036.2007.03397.x -
Therapeutic Drug Monitoring Dec 2017The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure,... (Review)
Review
The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) metabolites are monitored and related to therapeutic response and adverse events, respectively. Therapeutic drug monitoring of thiopurines, however, is hampered by several analytical limitations resulting in an impaired translation of metabolite levels to clinical outcome in IBD. Thiopurine metabolism is cell specific and requires nucleated cells and particular enzymes for 6-TGN formation. In the current therapeutic drug monitoring, metabolite levels are assessed in erythrocytes, whereas leukocytes are considered the main target cells of these drugs. Furthermore, currently used methods do not distinguish between active nucleotides and their unwanted residual products. Last, there is a lack of a standardized laboratorial procedure for metabolite assessment regarding the substantial instability of erythrocyte 6-TGN. To improve thiopurine therapy in patients with IBD, it is necessary to understand these limitations and recognize the general misconceptions in this procedure.
Topics: Antimetabolites; Azathioprine; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine
PubMed: 29040228
DOI: 10.1097/FTD.0000000000000455 -
World Journal of Gastroenterology Jul 2010To evaluate the relationship between thiopurine S-methyltransferase (TPMT) polymorphisms and thiopurine-induced adverse drug reactions (ADRs) in inflammatory bowel... (Meta-Analysis)
Meta-Analysis Review
AIM
To evaluate the relationship between thiopurine S-methyltransferase (TPMT) polymorphisms and thiopurine-induced adverse drug reactions (ADRs) in inflammatory bowel disease (IBD).
METHODS
Eligible articles that compared the frequency of TPMT polymorphisms among thiopurine-tolerant and -intolerant adult IBD patients were included. Statistical analysis was performed with Review Manager 5.0. Sub-analysis/sensitivity analysis was also performed.
RESULTS
Nine studies that investigated a total of 1309 participants met our inclusion criteria. The incidence of TPMT gene mutation was increased 2.93-fold (95% CI: 1.68-5.09, P = 0.0001) and 5.93-fold (95% CI: 2.96-11.88, P < 0.00001), respectively, in IBD patients with thiopurine-induced overall ADRs and bone marrow toxicity (BMT), compared with controls. The OR for TPMT gene mutation in IBD patients with thiopurine-induced hepatotoxicity and pancreatitis was 1.51 (95% CI: 0.54-4.19, P = 0.43) and 1.02 (95% CI: 0.26-3.99, P = 0.98) vs controls, respectively.
CONCLUSION
This meta-analysis suggests that the TPMT polymorphisms are associated with thiopurine-induced overall ADRs and BMT, but not with hepatotoxicity and pancreatitis.
Topics: Adult; Azathioprine; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methyltransferases; Polymorphism, Genetic
PubMed: 20593505
DOI: 10.3748/wjg.v16.i25.3187 -
American Journal of Veterinary Research Jul 2015To investigate the cytotoxic effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine hepatocytes.
OBJECTIVE
To investigate the cytotoxic effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine hepatocytes.
SAMPLE
Commercially available cryopreserved canine primary hepatocytes.
PROCEDURES
The study consisted of 2 trials. In trial 1, hepatocytes were incubated with azathioprine, 6-mercaptopurine, or 6-thioguanine at 1 of 6 concentrations (0.468, 0.937, 1.875, 3.750, 7.500, or 15.000 μmol/L) for 24, 48, or 72 hours. At each time, cell viability and lactate dehydrogenase (LDH) activity were determined for each thiopurine-concentration combination, and alanine aminotransferase (ALT) activity was determined for cells incubated with each thiopurine at a concentration of 15 μmol/L. In trial 2, hepatocytes were incubated with azathioprine, 6-mercaptopurine, or 6-thioguanine at 1 of 3 concentrations (18.75, 37.50, or 75.00 μmol/L) for 24 hours, after which the free glutathione concentration was determined for each thiopurine-concentration combination and compared with that for hepatocytes incubated without a thiopurine (control).
RESULTS
Incubation of hepatocytes with each of the 3 thiopurines adversely affected cell viability in a time- and concentration-dependent manner; however, this decrease in cell viability was not accompanied by a concurrent increase in LDH or ALT activity. Likewise, free glutathione concentration for hepatocytes incubated for 24 hours with supratherapeutic thiopurine concentrations (> 18.75 μmol/L) did not differ significantly from that of control cells.
CONCLUSIONS AND CLINICAL RELEVANCE
Results indicated that thiopurines adversely affected the viability of canine hepatocytes in a time- and concentration-dependent manner but had a nonsignificant effect on the LDH and ALT activities and free glutathione depletion of those hepatocytes.
Topics: Animals; Azathioprine; Cell Line; Cell Survival; Dogs; Dose-Response Relationship, Drug; Hepatocytes; Immunosuppressive Agents; Mercaptopurine; Thioguanine
PubMed: 26111096
DOI: 10.2460/ajvr.76.7.649 -
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 -
Inflammatory Bowel Diseases Jun 2017Use of azathioprine (AZA) for inflammatory bowel disease is limited by side effects or poor efficacy. Combining low-dose azathioprine with allopurinol (LDAA) bypasses...
BACKGROUND
Use of azathioprine (AZA) for inflammatory bowel disease is limited by side effects or poor efficacy. Combining low-dose azathioprine with allopurinol (LDAA) bypasses side effects, improves efficacy, and may be appropriate as first-line therapy. We test the hypothesis that standard-dose azathioprine (AZA) and LDAA treatments work by similar mechanisms, using incorporation of the metabolite deoxythioguanosine into patient DNA, white-blood cell counts, and transcriptome analysis as biological markers of drug effect.
METHODS
DNA was extracted from peripheral whole-blood from patients with IBD treated with AZA or LDAA, and analyzed for DNA-incorporated deoxythioguanosine. Measurement of red-blood cell thiopurine metabolites was part of usual clinical practice, and pre- and on-treatment (12 wk) blood samples were used for transcriptome analysis.
RESULTS
There were no differences in reduction of white-cell counts between the 2 treatment groups, but patients on LDAA had lower DNA-incorporated deoxythioguanosine than those on AZA; for both groups, incorporated deoxythioguanosine was lower in patients on thiopurines for 24 weeks or more (maintenance of remission) compared to patients treated for less than 24 weeks (achievement of remission). Patients on LDAA had higher levels of red-blood cell thioguanine nucleotides than those on AZA, but there was no correlation between these or their methylated metabolites, and incorporated deoxythioguanosine. Transcriptome analysis suggested down-regulation of immune responses consistent with effective immunosuppression in patients receiving LDAA, with evidence for different mechanisms of action between the 2 therapies.
CONCLUSIONS
LDAA is biologically effective despite lower deoxythioguanosine incorporation into DNA, and has different mechanisms of action compared to standard-dose azathioprine.
Topics: Allopurinol; Azathioprine; Biomarkers; DNA; Deoxyguanosine; Drug Therapy, Combination; Gene Expression; Gene Expression Profiling; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Leukocyte Count; Methyltransferases; Pilot Projects; United Kingdom
PubMed: 28452864
DOI: 10.1097/MIB.0000000000001131 -
Blood Aug 1988We conducted a randomized, double-blind comparison of prednisone and placebo (group I) v prednisone and azathioprine (1.5 mg/kg/day) (group II) as early treatment of... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.
We conducted a randomized, double-blind comparison of prednisone and placebo (group I) v prednisone and azathioprine (1.5 mg/kg/day) (group II) as early treatment of extensive chronic graft-v-host disease (GVHD). Patients with platelet counts less than 100,000/microL were placed into therapy with prednisone alone (group III). All three groups received identical doses of prednisone (1 mg/kg every other day) and one double-strength trimethoprim-sulfamethoxazole (TMP-SMX) tablet twice daily. Between January 1980 and December 1983, 179 previously untreated patients were enrolled and 164 were evaluable. Patients randomized to group I (n = 63) and group II (n = 63) were well matched for prognostic factors; those placed into group III (n = 38) had more frequent acute GVHD and progressive onset of chronic GVHD. Median duration of therapy was 2 years. Complications included diabetes (5%), aseptic necrosis (5%) and infection. For groups I, II, and III, the respective incidence of infection was disseminated varicella, 11%, 24%, 34%; bacteremia, 6%, 11%, 34%; and interstitial pneumonia, 5%, 14%, 18%. Recurrent malignancy was the most frequent cause of death and did not differ significantly across the groups. Nonrelapse mortality, however, did differ: 21% in group I, 40% in group II, and 58% in group III (I v II, P = .003; I v III, P = .001). Forty patients in group I, 30 in group II, and 10 in group III survive with a minimum follow-up of 3.8 years. Karnofsky performance scores for 68 survivors are 90% to 100%, scores for seven survivors are 70% to 89% and scores for five survivors are less than 70%. Actuarial survival at 5 years after transplant is 61% in group I, 47% in group II, and 26% in group III (I v II, P = .03; I v III, P = .0001). Treatment with prednisone alone results in fewer infections and better survival than prednisone and azathioprine in standard-risk chronic GVHD. Treatment with prednisone alone is less effective in high-risk patients with thrombocytopenia, and other strategies are required.
Topics: Adolescent; Adult; Azathioprine; Bone Marrow Transplantation; Child; Child, Preschool; Chronic Disease; Clinical Trials as Topic; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Infant; Infections; Male; Middle Aged; Prednisone; Prognosis; Thrombocytopenia; Transplantation, Homologous
PubMed: 3042041
DOI: No ID Found -
Rheumatology (Oxford, England) May 2023Cognitive dysfunction (CD) is a common manifestation of SLE that can have detrimental consequences for those affected. To date, no treatments have been approved for...
OBJECTIVES
Cognitive dysfunction (CD) is a common manifestation of SLE that can have detrimental consequences for those affected. To date, no treatments have been approved for SLE-CD. This study aims to assess the association of azathioprine (AZA) and mycophenolate (MMF) use with SLE-CD, given that these medications have demonstrated neuroprotective qualities in prior studies.
METHODS
Consecutive adult SLE patients presenting to a single healthcare center were considered for participation. The ACR neuropsychological battery for SLE was administered to consenting patients at 0, 6 and 12 months. Scores were compared with age- and sex-matched controls. Primary outcome was CD, defined as a z-score ≤-1.5 in two or more cognitive domains. Mixed-effects logistic regression models were constructed to estimate the odds of CD with respect to AZA and MMF use.
RESULTS
A total of 300 participants representing 676 patient visits completed the study; 114 (38%) met criteria for CD at baseline. The cumulative AZA dose (g/kg) was associated with reduced odds of CD [odds ratio (OR) 0.76 (95% CI 0.58, 0.98), P = 0.04]. Years of AZA treatment was also associated with reduced odds of CD [OR 0.72 (95% CI 0.54, 0.97), P = 0.03]. MMF use was not associated with CD.
CONCLUSION
AZA use was associated with significantly lower odds of SLE-CD, while MMF use was not. Additional studies are warranted to further investigate the relationship of AZA and SLE-CD.
Topics: Adult; Humans; Azathioprine; Mycophenolic Acid; Immunosuppressive Agents; Enzyme Inhibitors; Cognition; Lupus Erythematosus, Systemic
PubMed: 36135792
DOI: 10.1093/rheumatology/keac540 -
Iranian Journal of Kidney Diseases Jan 2008Achievements in short-term graft survival since the introduction of cyclosporine has not been matched by improvement in long-term graft function, and chronic allograft... (Clinical Trial)
Clinical Trial
INTRODUCTION
Achievements in short-term graft survival since the introduction of cyclosporine has not been matched by improvement in long-term graft function, and chronic allograft nephropathy remains the second commonest cause of graft attrition over time. We aimed to evaluate the long-term results of conventional immunosuppression by steroid and azathioprine in comparison with cyclosporine-based triple therapy in living donor kidney transplants.
MATERIALS AND METHODS
We evaluated the long-term follow-up data of 369 living related kidney transplant recipients that were on prednisolone-azathioprine immunosuppressive therapy (group 1) or triple therapy by prednisolone, cyclosporine, and azathioprine (group 2). All recipients were followed-up for more than 10 years (mean, 240 +/- 12 months). Comparative analyses included patient and graft survival rates, condition at last follow-up, graft rejection, and graft function.
RESULTS
There were 130 patients in group 1 and 239 in group 2. The overall frequency of acute rejection episodes was not significantly different between the two groups. However, the proportion of patients with chronic allograft nephropathy was significantly higher in group 2 (21% versus 35%, P = .001). Graft survival rates were 85.3% versus 92.4% at 1 year, 69.9% versus 71.9% at 5 years, and 52.5% versus 50.8% at 10 years in groups 1 and 2, respectively (P = .03). The two groups were comparable regarding posttransplant malignancies, diabetes mellitus, serious bacterial infections, and hepatic diseases. However, hypertensive patients were significantly more frequent in group 2.
CONCLUSIONS
Chronic allograft nephropathy was significantly higher in patients receiving cyclosporine, possibly due to the risk of drug-induced nephrotoxicity, glomerular disease recurrence, and hypertension. Nowadays, it is possible to achieve excellent calcineurin inhibitors-free regimen using newer maintenance immunosuppressive agents.
Topics: Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Prednisolone; Transplantation, Homologous; Young Adult
PubMed: 19367007
DOI: No ID Found