mercaptopurine and Drug-Hypersensitivity

The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response.

Topics: Azathioprine; Drug Hypersensitivity; Erythrocytes; Female; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine-Pyrimidine Metabolism, Inborn Errors; Purines

Thiopurine S-methyltransferase (TPMT) enzyme metabolizes thiopurine drugs which are widely used in various disciplines as well as in leukemias. Individual enzyme activity varies depending on the genetic polymorphisms of TPMT gene located at chromosome 6. Up to 14% of population is known to have a decreased enzyme activity, and if treated with standard doses of thiopurines, these individuals are at a high risk of severe Adverse Drug Reactions (ADR) as myelosuppression, gastrointestinal intolerance, pancreatitis and hypersensitivity. However, TPMT-deficient patients can successfully be treated with decreased thiopurine doses if enzyme status is identified by a prior testing. TPMT status identification is a pioneering experience in application of pharmacogenetic testing in clinical settings. 4 TPMT (*2, *3A, *3B, *3C) alleles are known to account for 80-95% of a decreased enzyme activity, and therefore, identifying the presence of these alleles supported by phenotypic measurement of the enzyme activity can reveal patient's TPMT status. Evaluation of the levels of thiopurine metabolites further supports the practice of appropriate dose adjustment by providing the efficient monitoring of drug cytotoxicity.. We hereby review the thiopurine pharmacogenetics and the methods applied in common practice to evaluate patient's TPMT status.

Topics: Animals; Drug Hypersensitivity; Gene Frequency; Genotyping Techniques; Humans; Mercaptopurine; Methyltransferases; Pharmaceutical Preparations; Pharmacogenetics; Polymorphism, Single Nucleotide; Purine-Pyrimidine Metabolism, Inborn Errors

Azathioprine and 6-mercaptopurine remain pivotal therapies for the maintenance of disease remission in patients with Crohn's disease and ulcerative colitis. While thiopurine S-methyltransferase deficiency was the first pharmacogenetic phenomenon to be recognized to influence thiopurine toxicity and reliably predict leukopenia, it does not predict other adverse effects, nor does it explain most cases of thiopurine resistance. In recent years, a number of other genetic polymorphisms have received increasing attention in the literature. In particular, SNPs in NUDT15 and in the class II HLA locus have been shown to predict thiopurine-related leukopenia and pancreatitis. The aim of this review is to provide a concise update of genetic variability which may influence patient response to azathioprine and 6-mercaptopurine.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genotype; Histocompatibility Antigens Class II; Humans; Inflammatory Bowel Diseases; Mercaptopurine; Pharmacogenetics; Polymorphism, Single Nucleotide; Purine-Pyrimidine Metabolism, Inborn Errors; Pyrophosphatases

No drug therapy is completely risk free, and the costs associated with non-response and adverse effects can exceed the cost of the therapy. The ultimate goal of pharmacogenetic research is to find robust genetic predictors of drug response that enable the development of prospective genetic tests to reliably identify patients at risk of non-response or of developing an adverse effect prior to the drug being prescribed. Currently, thiopurine S-methyltransferase (TPMT) deficiency is the only pharmacogenetic factor that is prospectively assessed before azathioprine or 6-mercaptopurine immunomodulation is commenced in patients with Crohn's disease (CD). As yet no other inherited determinant of drug response has made the transition from bench to bedside for the management of this disease. In this review we summarize what is known about TPMT deficiency and explore whether there is evidence to support a role of other genetic polymorphisms in predicting the response of CD patients to thiopurine drugs, methotrexate, and anti-tumor necrosis factor α (TNFα) therapy.

Topics: Antibodies, Monoclonal; Azathioprine; Biotransformation; Crohn Disease; Drug Hypersensitivity; Drug Interactions; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Humans; Immunologic Factors; Infliximab; Mercaptopurine; Methotrexate; Patient Selection; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Precision Medicine; Purine-Pyrimidine Metabolism, Inborn Errors; Risk Assessment; Risk Factors; Tumor Necrosis Factor-alpha

No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy.. Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1-24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (<10 years vs ≥10 years), and white blood cell count at diagnosis (<50 × 10(9)/L vs ≥50 × 10(9)/L) by minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcomes were event-free survival and overall survival. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07355119.. 533 MRD high-risk patients were randomly assigned to receive standard (n=266) or augmented (n=267) post-remission therapy. After a median follow-up of 70 months (IQR 52-91), 5-year event-free survival was better in the augmented treatment group (89·6% [95% CI 85·9-93·3]) than in the standard group (82·8% [78·1-87·5]; odds ratio [OR] 0·61 [95% CI 0·39-0·98], p=0·04). Overall survival at 5 years was numerically, but not significantly, higher in the augmented treatment group (92·9% [95% CI 89·8-96·0]) than in the standard therapy group (88·9% [85·0-92·8]; OR 0·67 [95% CI 0·38-1·17], p=0·16). More adverse events occurred in the augmented treatment group than in the standard group (asparaginase-related hypersensitivity in 18 [6·7%] in the augmented group vs two [0·8%] in the standard group and asparaginase-related pancreatitis in eight [3·0%] vs one [0·4%]; intravenous methotrexate-related mucositis in 11 [4·1%] vs three [1·1%] and methotrexate-related stomatitis in 48 [18·0%] vs 12 [4·5%]).. Our findings suggest that children and young people with acute lymphoblastic leukaemia and 0·01% or more MRD at the end of remission induction therapy could benefit from augmented post-remission therapy. However, the asparaginase and intravenous methotrexate used in the augmented treatment regimen is associated with more adverse events than is the standard post-remission treatment regimen.. Medical Research Council and Leukaemia and Lymphoma Research.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child; Child, Preschool; Consolidation Chemotherapy; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Infant; Male; Mercaptopurine; Methotrexate; Mucositis; Neoplasm, Residual; Pancreatitis; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Risk Assessment; Stomatitis; Survival Rate; Vincristine

L-Asparaginase, in the dose of greater than or equal to 6000 IU/sq m three times weekly, was demonstrated to be an effective agent in reinduction of remissions in childhood leukemia. Four hundred thirteen children with acute lymphocytic leukemia were treated with L-asparaginase. Doses i.m. ranged from 300 to 12,000 IU/sq m. None of the patients had received prior asparaginase therapy. 6-Mercaptopurine was given p.o. concurrently. All of the patients had experienced several previous relapses, and their disease was not responsive to 6-mercaptopurine. L-Asparaginase was found to be effective in reinducing remissions at the following rates: 9.5% for 300 IU/sq m; 35.1% for 3,000 IU/sq m; 53.5% for 6,000 IU/sq m; and 62.5% for 12,000 IU/sq m. The drug was given three times weekly for four weeks. Hypersensitivity reactions occurred in 6.5% of patients.

Topics: Asparaginase; Child; Child, Preschool; Clinical Trials as Topic; Drug Administration Schedule; Drug Hypersensitivity; Drug Therapy, Combination; Humans; Leukemia, Lymphoid; Mercaptopurine; Neutropenia; Remission, Spontaneous

Topics: Alopecia; Antibody Formation; Bone Marrow; Bone Marrow Cells; Child; Child, Preschool; Chromosome Aberrations; Daunorubicin; Drug Hypersensitivity; Heart; Humans; Immunosuppressive Agents; Inflammation; Intestinal Mucosa; Leukemia; Leukocytes; Leukopenia; Lymphocyte Activation; Mercaptopurine

Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.

Topics: Antimetabolites, Antineoplastic; Brain Infarction; Child, Preschool; Drug Hypersensitivity; Homozygote; Humans; Infections; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Mucositis; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Pyrophosphatases; Sepsis

Topics: Antidepressive Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Mercaptopurine; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primaquine; Purine-Pyrimidine Metabolism, Inborn Errors; Succinylcholine; Warfarin

The activity of the enzyme thiopurine methyltransferase (TPMT) is regulated by a common genetic polymorphism. One in 300 individuals lack enzyme activity and 11% are heterozygous for a variant low activity allele and have an intermediate activity. The thiopurine drugs azathioprine, mercaptopurine and thioguanine are substrates for TPMT; these drugs exhibit well documented myelosuppressive effects on haematopoietic cells and have a track record of idiosyncratic drug reactions. The development of severe bone marrow toxicity, in patients taking standard doses of thiopurine drugs, is associated with TPMT deficiency whilst the TPMT heterozygote is at an increased risk of developing myelosuppression. Factors influencing TPMT enzyme activity, as measured in the surrogate red blood cell, are discussed in this review to enable an appreciation of why concordance between TPMT genotype and phenotype is not 100%. This is particularly important for lower/intermediate TPMT activities to avoid misclassification of TPMT status. TPMT testing is now widely available in routine service laboratories. The British National Formulary suggests TPMT testing before starting thiopurine drugs. Dermatologists were quick to adopt routine TPMT testing whilst gastroenterologists do not specifically recommend TPMT screening. TPMT testing is mandatory prior to the use of mercaptopurine in childhood leukaemia. Thiopurine drug dose and other treatment related influences on cell counts explain some of the differing recommendations between clinical specialities. TPMT testing is cost-effective and the major role is in the identification of the TPMT deficient individual prior to the start of thiopurine drugs.

Topics: Antimetabolites, Antineoplastic; Azathioprine; Cost-Benefit Analysis; Drug Hypersensitivity; Drug Labeling; Genetic Testing; Genotype; Humans; Mercaptopurine; Methyltransferases; Phenotype; Purine-Pyrimidine Metabolism, Inborn Errors; Thioguanine

Thiopurine S-methyltransferase (TPMT) is an excellent example of an enzyme whose pharmacogenetic polymorphisms affect efficacy and toxicity of a drug. The association between TPMT activity and thiopurine-related myelosuppression is well recognized. To study the significance of TPMT deficiency in thiopurine metabolism and immunosuppressive activity in vitro, we established RNA interference-based TPMT knockdown (kd) in a Jurkat cell line.. In Jurkat TPMT kd cells, TPMT expression was reduced to 73% at the RNA level and 83% at the protein level. TPMT kd cells were more sensitive to 6-mercaptopurine (6-MP) (10 μmol/L) and 6-thioguanine (6-TG) (8 μmol/L) than wild-type (wt) cells, (32% versus 20%) and (18% versus 9%), respectively. Both Jurkat wt and kd cells were more sensitive to 6-TG-induced apoptosis than to 6-MP. 6-TG activity was also more affected by TPMT levels than was 6-MP as reflected by IC60, concentrations that is, 6-MP [4.6 μmol/L (wt) and 4.7 μmol/L (kd)], 6-TG [2.7 μmol/L (wt) and 0.8 μmol/L (kd)]. IC60 concentrations induced significant apoptosis in both Jurkat wt and kd cells (257%, versus 314%) with 6-MP and (323% versus 306%) with 6-TG, respectively. At IC60 (6-MP) 6-thioguanine nucleotides (6-TGN) accumulation in cells was 518 versus 447 pmol/million cells in wt and kd cells, respectively. On the other hand 6-TGN accumulation at IC60 (6-TG) was 477 versus 570 pmol/million cells in wt and kd cells, respectively. 6-Methylated mercaptopurine (6-MeMP) concentrations were more affected than 6-TGN by TPMT kd (194 versus 10 pmol/million cells) in wt and kd cells, respectively.. We conclude that TPMT kd cells are an appropriate in vitro model to investigate the significance of TPMT deficiency with thiopurine therapy and could be helpful in understanding possible clinical consequences of TPMT polymorphism.

Topics: Apoptosis; Cell Line, Tumor; Drug Hypersensitivity; Gene Knockdown Techniques; Guanine Nucleotides; Humans; Immune Tolerance; Jurkat Cells; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Purine-Pyrimidine Metabolism, Inborn Errors; T-Lymphocytes; Thioguanine; Thionucleotides

Topics: Anti-Inflammatory Agents; Colitis, Ulcerative; Drug Hypersensitivity; Humans; Male; Mercaptopurine; Middle Aged; Muscle Weakness

Topics: Adolescent; Alopecia; Anti-Inflammatory Agents, Non-Steroidal; Bone Marrow; Crohn Disease; Drug Hypersensitivity; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mercaptopurine; Mesalamine; Methyltransferases; Pancytopenia; Phenotype; Purine-Pyrimidine Metabolism, Inborn Errors

The antimetabolite mercaptopurine is commonly used as part of treatment regimens for acute lymphoblastic leukemia and as treatment for inflammatory bowel diseases. Adverse effects associated with mercaptopurine include myelosuppression, hepatotoxicity, and hyperpigmentation. We describe a 36-year-old man with Philadelphia chromosome-negative pre-B-cell acute lymphoblastic leukemia who experienced a serious mercaptopurine-induced hypersensitivity reaction requiring prolonged hospitalization and extensive laboratory testing and imaging. He was treated with a multiagent chemotherapy regimen. Mercaptopurine 60 mg/m(2)/day orally was started as part of his third course of chemotherapy. On day 9 of mercaptopurine therapy, the patient developed persistent fevers, skaking chills, and rigors that persisted in the absence of documented infection, consistent with drug fever. All symptoms and signs resolved after discontinuation of mercaptopurine. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship between the patient's development of fever and mercaptopurine therapy. Mercaptopurine-induced fever has been reported in patients with inflammatory bowel diseases, but this case report is the first, to our knowledge, in a patient with acute lymphoblastic leukemia. Health care professionals should be aware of the possible development of fever as a hypersensitivity reaction in patients with acute lymphoblastic leukemia treated with mercaptopurine.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Drug Hypersensitivity; Fever; Humans; Male; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Topics: Acute Disease; Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Prednisolone; Treatment Outcome

Crohn's disease and ulcerative colitis are chronic, immune-mediated inflammatory bowel diseases (IBDs) of unknown etiology with high morbidity in patients who are not receiving adequate medical treatment. A variety of medical therapies are currently available, and much progress has been made to alleviate symptoms and restore quality of life. The mainstay of treatment in those with moderate to severe disease consists of medications that alter or suppress the body's immunologic attack on its own gastrointestinal tract. The medications currently in use are highly effective when given in the appropriate clinical context, but side effects are not uncommon and must be treated expeditiously when they occur. One class of immunosuppressive medication, 6-mercaptopurine and its prodrug azathioprine, is effective at inducing remission and improving the lives of patients with IBD. The most common side effects of these drugs are allergic reactions and rarely can they be severe and life threatening. These reactions can sometimes be overcome by desensitizing the immune system to the drug. This review emphasizes allergy to 6-mercaptopurine and azathioprine and the process of desensitization when these allergic reactions occur in order to continue use of this important class of medication in the total treatment of IBD.

Topics: Azathioprine; Desensitization, Immunologic; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine

Adverse drug reactions are a significant reason for therapeutic failure during thiopurine treatment of inflammatory bowel disease. Some smaller series in this patient population have shown that a switch to mercaptopurine may be successful in many cases of azathioprine intolerance.. To assess the long-term outcome of mercaptopurine treatment in a large patient population with azathioprine intolerance.. We identified 135 patients (74 women; median age 40 years) with Crohn's disease (n = 88) or ulcerative colitis (n = 47) and reviewed their medical records.. A total of 70 patients (52%) tolerated mercaptopurine and were followed up for 736 (362-1080) days; 65 patients discontinued mercaptopurine due to adverse events after 25 (8-92) days. Mercaptopurine was tolerated in 71% (12/17) with hepatotoxicity and in 68% (13/19) with arthralgia/myalgia during azathioprine treatment. Previous abdominal surgery was more common in mercaptopurine intolerant patients [39/65 (60%) vs. 27/70 (39%); P = 0.02] and thiopurine methyltransferase activity was higher in mercaptopurine tolerant patients than in mercaptopurine intolerant patients [13.2 (11.4-15.3) vs. 11.8 (9.6-14.2) U/mL red blood cells; P = 0.04; n = 81].. A trial of mercaptopurine should be considered in azathioprine intolerance, as half of the patients tolerate a switch to mercaptopurine. Patients with hepatotoxicity or arthralgia/myalgia during azathioprine treatment might benefit more often than those with other types of adverse events.

Topics: Adult; Azathioprine; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Treatment Outcome

Despite the wide use of azathioprine/mercaptopurine (AZA/MP) therapy in the management of both Crohn's disease (CD) and ulcerative colitis (UC), approximately 20% of patients cannot tolerate the drugs and 30% do not respond.. To examine the efficacy and safety profile of methotrexate (MTX) in patients with CD or UC who are either intolerant or non-responsive to AZA/MP.. A total of 131 patients with IBD treated with MTX were identified. Retrospective data were obtained by case note review. Clinical response (defined as steroid withdrawal, normalization of previously raised CRP or physician's clinical assessment of improvement) was assessed at 6 months.. Clinical response in Crohn's disease occurred in 18 of 29 patients (62%) refractory to AZA/MP and 42 of 70 patients (60%) intolerant to AZA/MP, with no difference between the groups (P = 1.0). In UC, clinical response was seen in 7 of 9 (78%) patients refractory to AZA/MP and 15 of 23 (65%) intolerant to thiopurines. MTX was well tolerated in a majority of individuals.. Methotrexate appears effective in both CD and UC patients who fail to respond to or are intolerant to AZA/MP therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Azathioprine; Drug Hypersensitivity; Drug Resistance; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methotrexate; Middle Aged; Treatment Outcome; Young Adult

To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease.. Twenty nine previously confirmed Crohn's disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies (CDAI/CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment.. In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses.. About one-third of the previously AZA-intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Steroids

Azathioprine intolerance is a common clinical problem, requiring drug withdrawal in up to 30% of patients. The successful use of mercaptopurine is described, but data to support this strategy are needed.. To assess the tolerability of mercaptopurine in inflammatory bowel disease patients previously intolerant of azathioprine, and identify predictive factors.. Sixty-one azathioprine-intolerant patients (31 males, median age at diagnosis 32 years, 31 with Crohn's disease, 30 with ulcerative colitis) who had been treated with mercaptopurine were identified. Intolerances included nausea and vomiting, flu-like illness, neutropenia, hepatotoxicity and pancreatitis.. Mercaptopurine was tolerated by 59% (36 of 61) of azathioprine-intolerant patients (median dose 1.0 mg/kg), 61% (17 of 28) in patients with azathioprine-related nausea and vomiting, 61% (11 of 18) with flu-like illness, 33% (three of nine) with hepatotoxicity, 100% (one of one) with neutropenia, 100% (three of three) with rash and 0% (zero of one) with pancreatitis. Mercaptopurine intolerance was frequently for a different adverse event. Those intolerant of mercaptopurine were younger (28.4 years vs. 37.0 years; P = 0.014) and more frequently female (14/30 vs. 2/29, P = 0.027). Mercaptopurine tolerability was not affected by diagnosis, location, behaviour, surgery, smoking, family history or extra-intestinal manifestations.. Mercaptopurine may be tolerated in up to 60% of azathioprine-intolerant patients, and treatment should be considered, particularly if intolerance was due to nausea, vomiting, flu-like illness or rash.

Topics: Adult; Age Distribution; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Administration Schedule; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Sex Distribution; Statistics, Nonparametric

Measurement of thiopurine metabolite levels may be useful as a clinical tool to optimize thiopurine treatment of paediatric inflammatory bowel disease (IBD).. The authors evaluated correlations between 6-thioguanine nucleotide (6-TGN) and therapeutic response, metabolite levels and drug toxicity.. Fifty-six paediatric IBD patients treated with thiopurines had 326 metabolite level measurements and were retrospectively reviewed. Clinical status and laboratory parameters were compared with metabolite levels.. There was significant correlation between 6-TGN levels and therapeutic response, with higher median 6-TGN levels among patients with therapeutic response than those with non-therapeutic response (194 vs. 146 pmol/8 x 10(8) RBC; P = 0.0004). Patients with 6-TGN levels >235 pmol/8 x 10(8) RBC were more likely to achieve therapeutic response than those below the cut-off (odds ratio, 2.5; 95% CI, 1.5-4.1). Patients who developed leukopenia tended to have higher median 6-TGN levels than those without leukopenia (261 vs. 160 pmol/8 x 10(8) RBC) but the difference was not statistically significant. There was no correlation between 6-methylmercaptopurine levels and hepatotoxicity. Two patients developed acute pancreatitis. Metabolite level measurements were helpful in identifying non-compliance in nine patients.. Monitoring of thiopurine metabolite levels is useful to guide and optimize dosing, as an adjunct to clinical judgement, blood count and liver biochemistry measurements to minimize the risk of drug toxicity and to confirm non-compliance.

Topics: Adolescent; Azathioprine; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Pancreatitis; Retrospective Studies; Thioguanine; Thrombocytopenia; Treatment Refusal

5-Aminosalicylic acid (5-ASA)-containing drugs are the mainstay of therapy in inflammatory bowel disease, but adverse reactions to these medications are relatively common. Because there may be a lack of cross-reactivity among the various 5-ASA formulations, treatment with alternative preparations is sometimes possible even after an apparent allergic reaction to a 5-ASA product.. To describe a patient with a possible allergy to 2 different 5-ASA drugs who tolerated a third.. A 27-year-old man with Crohn disease developed a rash while taking mesalamine (Pentasa and Asacol). Treatment with 5-ASA products was discontinued, and 6-mercaptopurine and prednisone were prescribed. He then experienced multiorgan failure secondary to herpes simplex infection, which required discontinuation of the immunosuppressive therapy. After recovery from the acute infection, he underwent successful graded challenge with balsalazide.. The patient continued treatment with balsalazide for 9 months, with good control of his inflammatory bowel disease and no adverse effects.. Adverse reactions to 1 or more 5-ASA medications do not necessarily preclude the use of others in the same class. A treatment algorithm for patients with adverse reactions to 5-ASA is outlined based on the case report and review of the literature.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Crohn Disease; Cross Reactions; Drug Hypersensitivity; Exanthema; Herpes Simplex; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Phenylhydrazines; Prednisone

Approximately 10% of inflammatory bowel disease (IBD) patients receiving 6-mercaptopurine (6-MP) or azathioprine (AZA) develop drug hypersensitivity reactions necessitating early discontinuation of these traditional thiopurines. These allergic reactions typically reoccur upon rechallenge. Our recently published pilot study suggested that thioguanine (6-TG), a closely related thiopurine, was efficacious and well tolerated in IBD patients resistant to 6-MP/AZA. The aim of this study was to determine if hypersensitivity reactions to 6-MP/AZA reoccur with 6-TG therapy.. IBD patients allergic to 6-MP and/or AZA were treated with 6-TG as an alternate thiopurine. Hypersensitivity reactions to 6-MP/AZA must have been documented within 6 wk of 6-MP/AZA initiation.. 6-TG was initiated in 21 IBD patients at a median (range) dose of 20 (10-40) mg/day. 6-TG hypersensitivity reaction occurred in only four of 21 (19%) patients after a median time interval of 9 days. Pancreatitis did not reoccur with 6-TG. Eighty-two percent of 6-TG tolerant patients were assessed as improved at last follow-up.. These results suggest that 6-TG may be considered as a possible alternate thiopurine in patients allergic to traditional 6-MP/AZA. Despite these favorable results, candidates for 6-TG should be selected with caution, and its use should be reserved for IBD patients well informed about potential toxicities.

Topics: Adult; Azathioprine; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mercaptopurine; Middle Aged; Pilot Projects; Prospective Studies; Safety; Thioguanine; Treatment Outcome

Topics: Azathioprine; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mercaptopurine; Thioguanine

Topics: Crohn Disease; Desensitization, Immunologic; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Mercaptopurine; Middle Aged

Topics: Adolescent; Adult; Azathioprine; Bone Marrow; Child; Colorectal Neoplasms; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Pancreatitis; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Randomized Controlled Trials as Topic

Azathioprine (AZA) and 6-mercaptopurine (6-MP) are used in pediatric patients with ulcerative colitis and Crohn's disease to reduce disease activity, maintain remission, prevent relapse, and lower corticosteroid dosage, but their long-term side effects remain to be studied. The aim of this study was to analyze the safety of AZA and 6-MP and steroid reduction in this age group.. The investigators' database identified 118 patients who received either drug; 23 were excluded (single visit, noncompliance, or therapy < 1 week), leaving 95 patients, with a mean (+/-SD) age of 14.2 +/- 4.4 years. Medical files were reviewed for adverse side effects: fever, pancreatitis, infections, gastrointestinal intolerance, aminotransferase level increase, leukopenia, and thrombocytopenia. Prednisone doses before and after immunomodulatory therapy were compared.. AZA or 6-MP was tolerated in 51 of 95 patients (54%) without adverse reaction; 27 of 95 (28%) experienced side effects that responded to dose reduction (23 patients) or spontaneously (4 patients), most commonly increased aminotransferase level (13.7%). Cessation of therapy was needed in 17 of 95 patients (18%), including recurrent fever (4), pancreatitis (4), gastrointestinal intolerance (4), and recurrent infections (3). Mean prednisone dose decreased from 24.3 to 8.6 mg/day.. AZA and 6-MP were well tolerated in 82% of patients; of these, prednisone reduction occurred in 87%. However, 18% required discontinuation because of hypersensitivity or infectious side effects.

Topics: Adolescent; Adult; Azathioprine; Child; Child, Preschool; Databases as Topic; Drug Hypersensitivity; Humans; Immunosuppressive Agents; Infections; Inflammatory Bowel Diseases; Medical Records; Mercaptopurine; Prednisone

A patient with Crohn's disease developed acute pancreatitis 4 h after retaking one 50 mg dose of orally administered 6-mercaptopurine (6-MP). All seven previously reported patients who were rechallenged with 50 mg or more of 6-MP developed pancreatitis within 48 h. These findings suggest that 6-MP can produce pancreatitis due to an idiosyncratic immune-mediated response. Patients with this complication should not reuse 6-MP.

Topics: Adult; Crohn Disease; Drug Hypersensitivity; Humans; Male; Mercaptopurine; Pancreatitis; Time Factors

We assess toxicity related to 6-mercaptopurine in the treatment of inflammatory bowel disease by reporting our experience with 396 patients (120 patients with ulcerative colitis, 276 with Crohn disease) observed over 18 years. Follow-up data for a mean period of 60.3 months were obtained for 90% of the patients. Toxicity directly induced by 6-mercaptopurine included pancreatitis in 13 patients (3.3%), bone marrow depression in 8 (2%), allergic reactions in 8 (2%), and drug hepatitis in 1 (0.3%). These complications were reversible in all cases with no mortality. Most cases of marrow depression occurred earlier in our experience, when the initial drug doses used were higher. Infectious complications were seen in 29 patients (7.4%), of which 7 (1.8%) were severe, including one instance of herpes zoster encephalitis. All infections were reversible with no deaths. Twelve neoplasms (3.1%) were observed, but only 1 (0.3%), a diffuse histiocytic lymphoma of the brain, had a probable association with the use of 6-mercaptopurine. Our data, showing a low incidence of toxicity in 396 patients, coupled with the previously demonstrated efficacy of 6-mercaptopurine in the treatment of inflammatory bowel disease, indicate that the drug is a reasonable alternative in the management of patients with intractable inflammatory bowel disease.

Topics: Adolescent; Adult; Aged; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Colitis, Ulcerative; Crohn Disease; Double-Blind Method; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Infections; Male; Mercaptopurine; Middle Aged; Neoplasms; Pancreatitis; Pregnancy; Time Factors

A patient with myasthenia gravis is described who exhibited hypersensitivity including an apparent acute exacerbation of the underlying disorder when treated with azathioprine. 6-mercaptoprine (6-MP) also produced hypersensitivity which, in contrast, did not manifest as a myasthenic exacerbation.

Topics: Azathioprine; Drug Hypersensitivity; Humans; Male; Mercaptopurine; Middle Aged; Myasthenia Gravis

Topics: Adult; Aged; Anaphylaxis; Asparaginase; Asparagine; Aspartic Acid; Daunorubicin; Drug Hypersensitivity; Erwinia; Escherichia coli; Female; Half-Life; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Prednisone; Vincristine

Topics: Adolescent; Adult; Aged; Allopurinol; Anaphylaxis; Asparaginase; Blood Coagulation Disorders; Cytarabine; Daunorubicin; Drug Hypersensitivity; Female; Fever; Gastrointestinal Hemorrhage; Hallucinations; Humans; Hyperglycemia; Injections, Intravenous; Jaundice; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Liver; Male; Mercaptopurine; Methotrexate; Middle Aged; Oral Hemorrhage; Prednisone; Thioguanine; Uremia; Vincristine; Vomiting

Topics: Adjuvants, Immunologic; Animals; Antibody Formation; Azathioprine; Body Weight; Cattle; Chromatography; Cyclophosphamide; Drug Hypersensitivity; Guinea Pigs; Immunization; Immunoassay; Immunoglobulin G; Immunosuppressive Agents; Insulin; Insulin Antibodies; Insulin, Long-Acting; Male; Mercaptopurine; Methotrexate; Oils; Prednisolone; Protein Binding; Swine

Topics: Adolescent; Adult; Aged; Asparaginase; Azaserine; Burkitt Lymphoma; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Child; Drug Hypersensitivity; Escherichia coli; Female; Humans; Leukemia, Lymphoid; Leukopenia; Lymphoma, Non-Hodgkin; Lymphopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms; Pancreatitis; Thrombocytopenia

Topics: Adolescent; Angioedema; Daunorubicin; Drug Hypersensitivity; Female; Humans; Leukemia, Lymphoid; Mercaptopurine; Methotrexate; Prednisone; Remission, Spontaneous; Urticaria; Vincristine

Topics: Animals; Antigens; Aspirin; Cortisone; Corynebacterium; Cyclophosphamide; Dermatitis, Contact; Dexamethasone; Drug Hypersensitivity; Ear; Flumethasone; Glucocorticoids; Immunosuppressive Agents; Mercaptopurine; Mice; Oxazoles; Paramethasone; Phenylbutazone; Prednisone; Skin Tests

Topics: Adolescent; Adult; Aged; Azathioprine; Drug Hypersensitivity; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Mercaptopurine; Middle Aged; Nitrogen Mustard Compounds; Thrombocytopenia

Topics: Antigen-Antibody Reactions; Arthritis, Rheumatoid; Basement Membrane; Biopsy; Drug Hypersensitivity; Female; Glomerulonephritis; Gold; Humans; Kidney; Mercaptopurine; Microscopy, Electron; Middle Aged; Prednisolone

Topics: Animals; Antigen-Antibody Reactions; Chlorphenesin; Cyclophosphamide; Drug Hypersensitivity; Guinea Pigs; Mercaptopurine; Methotrexate; Muscles; Passive Cutaneous Anaphylaxis; Penicillin G; Serum Albumin, Bovine; Thioguanine

Topics: Diabetes Mellitus; Dimercaprol; Drug Hypersensitivity; Humans; Insulin; Insulin Resistance; Mechlorethamine; Mercaptopurine; Prednisone

Topics: Animals; Biological Transport, Active; Cell Division; Cytogenetics; Drug Hypersensitivity; Fluorouracil; Leukemia L1210; Mercaptopurine; Methotrexate; Mice; Molecular Biology; Neoplasm Transplantation; Tetrahydrofolate Dehydrogenase; Tritium

Topics: Animals; Drug Hypersensitivity; Fluorouracil; In Vitro Techniques; Leukemia L1210; Mercaptopurine; Methotrexate; Mice; Tetrahydrofolate Dehydrogenase

Topics: Adjuvants, Immunologic; Allergy and Immunology; Arthritis; Drug Hypersensitivity; Immunosuppressive Agents; Injections, Intramuscular; Injections, Intraperitoneal; Mechlorethamine; Mercaptopurine; Methotrexate; Pharmacology; Radiation Effects; Rats; Research; Tuberculin; Tuberculin Test

Topics: Child; Drug Hypersensitivity; Hypersensitivity; Mercaptopurine; Phenytoin; Prednisolone; Seizures; Toxicology