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Digestive Diseases (Basel, Switzerland) 2012For more than a decade, methotrexate has been known to be an effective therapeutic agent in the treatment of steroid-dependent active Crohn's disease. However,... (Review)
Review
For more than a decade, methotrexate has been known to be an effective therapeutic agent in the treatment of steroid-dependent active Crohn's disease. However, international data on medication utilization suggest that this drug is rarely used in clinical practice for an indication of Crohn's disease. This review investigates the potential reasons for the underuse of methotrexate in patients with inflammatory bowel diseases.
Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Humans; Methotrexate; Patient Preference; Treatment Outcome
PubMed: 23295701
DOI: 10.1159/000342735 -
Alimentary Pharmacology & Therapeutics Nov 2001The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and... (Review)
Review
The thioguanine derivative, azathioprine, is a prodrug of 6-mercaptopurine that is further metabolized by various enzymes present in the liver and gut. Azathioprine and 6-mercaptopurine have been used in the treatment of inflammatory bowel disease, i.e. ulcerative colitis and Crohn's disease, for more than 30 years. However, widespread use of azathioprine or 6-mercaptopurine in inflammatory bowel disease is of more recent origin, the primary reason being a long-standing debate on the efficacy of these agents in inflammatory bowel disease. Both drugs are slow acting, which is why clinical efficacy cannot be expected until several weeks or even months of treatment have elapsed. Consequently, azathioprine and 6-mercaptopurine have no place as monotherapy in the treatment of acute relapsing inflammatory bowel disease. Today, azathioprine and 6-mercaptopurine are the most commonly used immunomodulatory drugs in the treatment of inflammatory bowel disease. Their clinical effects are probably identical, although their exact mode of action is still unknown. The mode of action of azathioprine is thought to be multifactorial, including conversion to 6-mercaptopurine (which acts as a purine antimetabolite), possible blockade of thiol groups by alkylation, inhibition of several pathways in nucleic acid biosynthesis (preventing proliferation of cells involved in the determination and amplification of the immune response) and damage to DNA through the incorporation of thiopurine analogues. However, 6-thioguanine nucleotides may accumulate in toxic doses in myeloid precursor cells, resulting in life-threatening myelosuppression. Azathioprine and 6-mercaptopurine are further known to alter lymphocyte function, reduce the number of lamina propria plasma cells and affect natural killer cell function. The purpose of this comprehensive review is to suggest guidelines for the application of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease.
Topics: Azathioprine; Clinical Trials as Topic; DNA Damage; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Killer Cells, Natural; Lactation; Lymphocytes; Male; Mercaptopurine; Neoplasms; Practice Guidelines as Topic; Pregnancy; Pregnancy Complications; Risk Factors
PubMed: 11683683
DOI: 10.1046/j.1365-2036.2001.01102.x -
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 -
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 Jun 2015
Topics: Antibodies, Monoclonal; Azathioprine; Crohn Disease; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Male
PubMed: 25939461
DOI: 10.1111/apt.13179 -
BMJ Open Nov 2020The immune system is implicated in the aetiology and progression of Parkinson's disease (PD). Inflammation and immune activation occur both in the brain and in the... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
The immune system is implicated in the aetiology and progression of Parkinson's disease (PD). Inflammation and immune activation occur both in the brain and in the periphery, and a proinflammatory cytokine profile is associated with more rapid clinical progression. Furthermore, the risk of developing PD is related to genetic variation in immune-related genes and reduced by the use of immunosuppressant medication. We are therefore conducting a 'proof of concept' trial of azathioprine, an immunosuppressant medication, to investigate whether suppressing the peripheral immune system has a disease-modifying effect in PD.
METHODS AND ANALYSIS
AZA-PD is a phase II randomised placebo-controlled double-blind trial in early PD. Sixty participants, with clinical markers indicating an elevated risk of disease progression and no inflammatory or immune comorbidity, will be treated (azathioprine:placebo, 1:1) for 12 months, with a further 6-month follow-up. The primary outcome is the change in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale gait/axial score in the OFF state over the 12-month treatment period. Exploratory outcomes include additional measures of motor and cognitive function, non-motor symptoms and quality of life. In addition, peripheral and central immune markers will be investigated through analysis of blood, cerebrospinal fluid and PK-11195 positron emission tomography imaging.
ETHICS AND DISSEMINATION
The study was approved by the London-Westminster research ethics committee (reference 19/LO/1705) and has been accepted by the Medicines and Healthcare products Regulatory Agency (MHRA) for a clinical trials authorisation (reference CTA 12854/0248/001-0001). In addition, approval has been granted from the Administration of Radioactive Substances Advisory Committee. The results of this trial will be disseminated through publication in scientific journals and presentation at national and international conferences, and a lay summary will be available on our website.
TRIAL REGISTRATION NUMBERS
ISRCTN14616801 and EudraCT- 2018-003089-14.
Topics: Azathioprine; Double-Blind Method; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Parkinson Disease; Quality of Life; Treatment Outcome
PubMed: 33234645
DOI: 10.1136/bmjopen-2020-040527 -
Digestive and Liver Disease : Official... 2000The treatment of Crohn's disease and ulcerative colitis has evolved and has improved the quality of life of patients afflicted with these disorders. Immune modulators... (Review)
Review
The treatment of Crohn's disease and ulcerative colitis has evolved and has improved the quality of life of patients afflicted with these disorders. Immune modulators such as azathioprine and 6-mercaptopurine are an important class of medications used for the treatment of patients with inflammatory bowel disease. Controlled studies have demonstrated their efficacy in both induction and maintenance of remission in Crohn's disease, and similarly, for the induction and maintenance of remission in patients with ulcerative colitis. These agents have had an increasing importance in the management of steroid-resistant, steroid-dependent diseases, and fistulizing Crohn's disease. The primary limitations to these agents have been their slow onset of action and their side effect profile. Despite these limitations, these agents have demonstrated efficacy and have become paramount to the management of patients with these incurable potentially disabling disorders. The precise role of azathioprine/6-mercaptopurine, their limitations and their safety are reviewed in this paper.
Topics: Azathioprine; Clinical Trials as Topic; Drug Interactions; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Neoplasms; Risk Factors
PubMed: 11057928
DOI: 10.1016/s1590-8658(00)80010-9 -
Alimentary Pharmacology & Therapeutics Feb 2005The armamentarium of medications for the treatment of inflammatory bowel disease is growing and becoming more complicated to use. Immunomodulators are a class of... (Review)
Review
The armamentarium of medications for the treatment of inflammatory bowel disease is growing and becoming more complicated to use. Immunomodulators are a class of medications that have found a niche for the treatment of Crohn's disease and ulcerative colitis. Because of the mounting supporting evidence for efficacy, the most commonly-used immunomodulators are azathioprine, mercaptopurine, methotrexate and ciclosporin. These medications are being used more often due to their steroid-sparing and potentially surgery-sparing effects. Immunomodulators are also known for a significant side-effect profile and require careful monitoring. This review provides the latest information for clinicians on efficacy, side-effects, dosing and monitoring of these medications for treatment of inflammatory bowel disease.
Topics: Azathioprine; Cyclosporine; Drug Monitoring; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Methotrexate
PubMed: 15709982
DOI: 10.1111/j.1365-2036.2005.02343.x -
The Cochrane Database of Systematic... Jul 2007Azathioprine is used for patients with primary biliary cirrhosis, but the therapeutic responses in randomised clinical trials have been conflicting. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Azathioprine is used for patients with primary biliary cirrhosis, but the therapeutic responses in randomised clinical trials have been conflicting.
OBJECTIVES
To assess the benefits and harms of azathioprine for patients with primary biliary cirrhosis.
SEARCH STRATEGY
Randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, The Chinese Biomedical Database, and LILACS, and manual searches of bibliographies to September 2005.
SELECTION CRITERIA
Randomised clinical trials comparing azathioprine versus placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status.
DATA COLLECTION AND ANALYSIS
Our primary outcomes were mortality, and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence interval (CI). Continuous outcomes were reported as weighted mean difference (WMD) or standardised mean difference (SMD). We examined the intervention effects by random-effects and fixed-effect models.
MAIN RESULTS
We identified two randomised clinical trials with 293 patients. Only one of the trials was regarded as having low bias risk. Azathioprine did not significantly decrease mortality (RR 0.80, 95% CI 0.49 to 1.31, 2 trials). Azathioprine did not improve pruritus at one-year intervention (RR 0.71, 95% CI 0.28 to 1.84, 1 trial), cirrhosis development, or quality of life. Patients given azathioprine experienced significantly more adverse events than patients given no intervention or placebo (RR 2.44, 95% CI 1.14 to 5.20, 2 trials). The common adverse events were rash, severe diarrhoea, and bone marrow depression.
AUTHORS' CONCLUSIONS
There is no evidence to support the use of azathioprine for patients with primary biliary cirrhosis. Researchers who are interested in performing further randomised clinical trials should be aware of the risks of adverse events.
Topics: Azathioprine; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 17636817
DOI: 10.1002/14651858.CD006000.pub2 -
Indian Journal of Dermatology,...Methotrexate is the most commonly used drug in the treatment of psoriasis with good efficacy and safety. Recently, weekly azathioprine pulse has been shown to be... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Methotrexate is the most commonly used drug in the treatment of psoriasis with good efficacy and safety. Recently, weekly azathioprine pulse has been shown to be effective in this disease.
AIM
The aim of this study is to compare the effectiveness and safety of weekly pulse doses of azathioprine and methotrexate for the treatment of chronic plaque psoriasis.
METHODS
In this randomized controlled trial, 80 patients with chronic plaque psoriasis were recruited. After detailed clinical and laboratory evaluation, patients were randomized to 2 groups to receive either weekly 300 mg azathioprine (n = 40) or 15 mg methotrexate every week (n = 40) for 20 weeks, following which the response to treatment and adverse effects were assessed. The patients were then followed up every 4 weeks for 3 months to determine any relapse.
RESULTS
Overall, 48 (60%) patients achieved PASI 75, while 36 (45%) and 59 (73.8%) patients achieved PASI 100 and 50, respectively. On intention to treat analysis, PASI ≥ 75 was achieved in 47.5% (19/40) patients in group 1 compared to 85% (34/40) patients in group 2 (p < 0.001). However, on per protocol analysis, PASI ≥ 75 was achieved in 86% (19/22) patients in group 1 and 92% (34/37) patients in group 2 (p = 0.497). Minor clinical and biochemical adverse effects were noted in both the groups, which were comparable. One (7.7%) patient in group 1 and 4 (17.4%) in group 2 relapsed during follow-up.
LIMITATIONS
Limitations of study include small sample size and short follow-up.
CONCLUSION
Weekly azathioprine pulse appears to be beneficial in the management of chronic plaque psoriasis. However, it is less effective than weekly methotrexate. It can thus be of use as a therapeutic option in patients with contraindication to methotrexate or other similar agents in this disease.
Topics: Adolescent; Adult; Azathioprine; Dermatologic Agents; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Psoriasis; Severity of Illness Index; Young Adult
PubMed: 33871211
DOI: 10.25259/IJDVL_718_18