mercaptopurine and Nausea

The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.

Topics: Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Mercaptopurine; Nausea; Neoplasms; Neutropenia; Opportunistic Infections; Pancreatitis

Thiopurines have been shown to effectively maintain remission of both Crohn's disease (CD) and ulcerative colitis (UC), and to behave as disease modifiers if used for >12 months in UC. Gastric intolerance manifesting as nausea constitutes a demanding drawback of thiopurines, at times forcing treatment discontinuance. A few studies have now indicated that some patients might tolerate mercaptopurine (6-MP) for azathioprine. In this paper, we review the literature, and reappraise our own data against the published figures. The data which form the basis for this study span over all visit reports that were released between January 2008 and December 2011 in a primary care Hospital, in Turin, Italy. For the aim of this study we searched our own database and the MedLine using the key-words "azathioprine", "mercaptopurine", "thiopurine", "inflammatory bowel disease", "Crohn's disease", "ulcerative colitis". We retrieved 85 azathioprine prescriptions for 42 UC, 37 CD, and 6 miscellaneous patients. There were 10 episodes of gastric intolerance to azathioprine, which were switched to 6-MP: 6 out of 10 (60%) responded and tolerated the switch drug in a median follow-up of 66 months. Female gender prevailed (p=0.038) in the azathioprine intolerant subset. A trial with 6-MP is worth being offered to azathioprine intolerant inflammatory bowel disease subjects at any center matching the standard figures of specific performance.

Topics: Adult; Aged; Anti-Inflammatory Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Substitution; Female; Gastrointestinal Agents; Humans; Italy; Male; Mercaptopurine; Middle Aged; Nausea; Remission Induction; Sex Factors; Time Factors; Treatment Outcome; Young Adult

Metabolism of thiopurine drugs--azathioprine, 6-mercaptopurine, and 6-thioguanine--has provided a powerful pharmacogenetic model incorporating polymorphism of the enzyme thiopurine methyltransferase (TPMT) and the primary active metabolite, thioguanine nucleotide (TGN). However, a sense of uncertainty about the usefulness of TGNs and other thiopurine metabolites has appeared. This review critically appraises the basis of thiopurine metabolism and reveals the problems and complexities in TGN research. Erythrocyte TGN is used in transplantation medicine and in chronic inflammatory conditions such as Crohn's disease, as a "surrogate" pharmacokinetic parameter for TGN in the target cells: leukocytes or bone marrow. It is not generally appreciated that erythrocytes do not express the enzyme IMP dehydrogenase and cannot convert mercaptopurine to TGN, which explains some of the confusion in interpretation of erythrocyte TGN measurements. TGN routinely measured in erythrocytes derives from hepatic metabolism. Another concern is that TGN are not generally assayed directly: most methods assay the thiopurine bases. Ion-exchange HPLC and enzymatic conversion of TGNs to nucleosides have been used to overcome this, and may reveal undisclosed roles for an unusual cytotoxic nucleotide, thio-inosine triphosphate, and methylated thiopurines. There appear to be additional interactions between xanthine oxidase and TPMT, and folate and TPMT, that could predict leukopenia. Difficult questions remain to be answered, which may be assisted by technological advances. Prospective TGN studies, long overdue, are at last revealing clearer results.

Topics: Azathioprine; Drug Monitoring; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Leukopenia; Mercaptopurine; Methylation; Methyltransferases; Nausea; Thioguanine; Thionucleotides; Xanthine Oxidase

This prospective study describes the procedure-related anxiety, treatment-related anxiety, pain, and nausea experienced by children with standard-risk acute lymphoblastic leukemia (ALL) during the first year of treatment.. This study was undertaken at 31 Children's Oncology Group (COG) sites. Eligible children who were 2 to 9.99 years old were enrolled in a COG trial for patients with newly diagnosed standard-risk ALL from 2005 to 2009. Parents completed a demographic survey at the baseline and the Pediatric Quality of Life Inventory 3.0 Cancer Module (proxy version) and the General Functioning Scale of the Family Assessment Device 1, 6, and 12 months after the diagnosis. The association between patient-related (age, sex, ethnicity, and treatment), parent-related (marital status and education), and family-related factors (functioning, income, and size) and symptom scores was evaluated.. The mean scores for procedure-related anxiety, treatment-related anxiety, and pain improved during the first year of treatment (P < .0389). The mean nausea score was poorer 6 months after the diagnosis in comparison with the other assessments (P = .0085). A younger age at diagnosis was associated with significantly worse procedure-related anxiety (P = .004). An older age (P = .0002) and assignment to the intensified consolidation study arm (P = .02) were associated with significantly worse nausea.. Children with ALL experienced decreasing treatment-related anxiety, procedure-related anxiety, and pain during the first year of treatment. In comparison with scores at 1 and 12 months, nausea was worse 6 months after the diagnosis. Minimization of procedure-related anxiety in younger children and improved nausea control in older children and those receiving more intensified treatment should be prioritized.

Topics: Antineoplastic Combined Chemotherapy Protocols; Anxiety; Asparaginase; Child; Child, Preschool; Consolidation Chemotherapy; Cyclophosphamide; Cytarabine; Dexamethasone; Female; Humans; Induction Chemotherapy; Longitudinal Studies; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Nausea; Pain; Parents; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Surveys and Questionnaires; Vincristine

The purpose of this study was to determine the effectiveness of intravenous ondansetron in preventing vomiting after the administration of intrathecal chemotherapy in children.. Twenty-six children (ages 18 mo to 15 y) receiving intrathecal chemotherapy with either methotrexate or the combination of methotrexate, hydrocortisone, and Ara-C for the prophylactic treatment of central nervous system leukemia were randomly assigned to receive an infusion of normal saline or ondansetron at one of two doses (0.15 or 0.45 mg/kg) 30 minutes before undergoing the procedure. One hundred forty-six infusions were administered (51 placebo, 47 at the lower ondansetron dose, and 48 at the higher dose). Each patient acted as his or her own control, and each patient was studied at least three times.. Twenty-three of 26 patients (88.5%) had postprocedural vomiting on at least one occasion. At least one episode of vomiting occurred during the 24 hours after the procedure in fifty-two of the procedures (35.6%). The incidence of vomiting was significantly greater after infusion of placebo than after either low-dose or high-dose ondansetron. The likelihood of severe vomiting was even more significantly reduced by the preadministration of ondansetron. Almost all of the intrathecal treatments associated with severe vomiting occurred after the infusion of placebo.. Vomiting induced by intrathecal chemotherapy can be greatly reduced by the intravenous administration of ondansetron before the procedure, and severe vomiting can be virtually eliminated.

Topics: Adolescent; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cross-Over Studies; Cytarabine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Headache; Humans; Hydrocortisone; Injections, Intravenous; Leukemia; Male; Mercaptopurine; Methotrexate; Nausea; Ondansetron; Risk; Serotonin Antagonists; Treatment Outcome; Vincristine; Vomiting

Topics: Adenocarcinoma; Anemia; Bone Marrow Diseases; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Colonic Neoplasms; Humans; Leukopenia; Lung Neoplasms; Mercaptopurine; Nausea; Neoplasms; Rectal Neoplasms; Stomach Neoplasms; Thrombocytopenia; Vomiting

The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting.. All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported.. Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2-75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn's disease (p = .04).. Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.

Topics: Adult; Azathioprine; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Italy; Kaplan-Meier Estimate; Male; Mercaptopurine; Middle Aged; Nausea; Prospective Studies

Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes.. A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy.. Of fifteen IBD patients, XO activity decreased from 0.18 (IQR 0.08-0.3) during thiopurine monotherapy to 0.14 (IQR 0.06-0.2) and 0.11 (IQR 0.06-0.2; p=0.008) mU/hour/ml at 4 and 12 weeks, respectively. HGPRT activity increased from 150 (IQR 114-176) to 180 (IQR 135-213) and 204 nmol/(h×mg protein) (IQR 173-213; p=0.013). TPMT activity seemed not to be affected. 6-Thioguanine nucleotide concentrations increased from 138 (IQR 119-188) to 235 (223-304) and to 265 pmol/8×10^8 (IQR 188-344), whereas 6-methyl mercaptopurine ribonucleotides concentrations decreased from 13230 (IQR 7130-17420) to 690 (IQR 378-1325) and 540 (IQR 240-790) pmol/8×10^8 at 4 and 12 weeks of combination therapy (both p<0.001).. Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.

Topics: Adult; Allopurinol; Azathioprine; Drug Therapy, Combination; Enzyme Activation; Enzyme Inhibitors; Fatigue; Female; Guanine Nucleotides; Humans; Hypoxanthine Phosphoribosyltransferase; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Methyltransferases; Middle Aged; Nausea; Prospective Studies; Thioinosine; Thionucleotides; Xanthine Oxidase

Thiopurines are a common, effective means of maintaining remission in pediatric Crohn disease (CD). Methotrexate (MTX) may be considered for those intolerant of or unresponsive to thiopurines. The purpose of this study was to examine the effectiveness of MTX as maintenance therapy in patients previously treated with thiopurines.. All of the patients at Nationwide Children's Hospital from 1998 to 2007 with an International Classification of Diseases code indicative of CD were identified. Patients with a diagnosis of CD, a history of prior thiopurine use, no current infliximab therapy, and at least 6 months of follow-up after MTX initiation were included. The primary outcome was defined as steroid-/infliximab-free remission determined by the physician global assessment at 6 and 12 months. Secondary outcomes included subsequent treatment with infliximab and/or corticosteroids, rate of discontinuation of MTX, and adverse events (AEs).. Twenty-seven patients (17 boys, 63%) with a mean age at diagnosis of 12.3 ± 0.7 years and mean disease duration of 1.49 ± 0.3 years were identified. Indications for MTX included nonresponse to thiopurines, AE, and poor adherence to thiopurines. At 6 and 12 months, 13 of 27 patients (48.1%) and 9 of 27 patients (33.3%), respectively, were in steroid-/infliximab-free remission. A total of 10 patients (37.0%) required infliximab therapy during the 12-month period and 5 patients discontinued MTX. Nausea was the most commonly reported AE. Transient transaminase elevation occurred in 4 patients and transient leukopenia in 2 patients.. MTX can be effective as maintenance therapy for patients with pediatric CD previously intolerant of or unresponsive to thiopurines; however, greater than one third of this cohort required escalation to antitumor necrosis factor therapy within 12 months following MTX initiation. MTX was well tolerated.

Topics: Antibodies, Monoclonal; Child; Crohn Disease; Drug Tolerance; Female; Humans; Infliximab; Leukopenia; Male; Mercaptopurine; Methotrexate; Methyltransferases; Nausea; Outcome Assessment, Health Care; Patient Compliance; Remission Induction; Retrospective Studies; Transaminases

Ondansetron is a commonly used medication in the treatment of nausea and vomiting arising from many etiologies, including chemotherapy. Although it is a highly safe drug, ondansetron use has been associated, rarely, with hypokalemia. However, it is unknown whether hypokalemia is due to the medication itself or to an underlying potassium disturbance caused by prior metabolic derangements, including vomiting. We relate a patient who presents with hypokalemia of unknown etiology, with evidence suggesting a possible relationship to ondansetron. We also present a proposed mechanism for this phenomenon.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Child, Preschool; Cytarabine; Dexamethasone; Female; Humans; Hypokalemia; Mercaptopurine; Methotrexate; Nausea; Ondansetron; Polyethylene Glycols; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Vincristine

The efficiency and toxicity of treatment regimens for nonintensive cytoreduction in 57 outpatients with refractory acute leukemia (mean age 56 years, 51 AML, six ALL/AUL) were retrospectively studied. Seventeen patients received one treatment regimen, 19 patients two treatment regimens, and 21 patients three or more treatment regimens. The treatment regimens analyzed were 6-thioguanine p.o. (daily) (T), 6-thioguanine p.o. (4-7 days/week) + cytarabine s.c./i.v. (once a week) (T+C), 6-mercaptopurine p.o. (daily) (MP), 6-mercaptopurine p.o. (daily) + methotrexate p.o./i.v. (once a week) (MP+MTX), etoposide p.o. (daily) (E), and mitoxantrone i.v. (M). The median leukocyte count was higher for M (73 x 10(9)/l) than for the other treatment regimens (T: 27 x 10(9)/l, T+ C: 37 x 10(9)/l, MP: 24 x 10(9)/l, MP + MTX: 30 x 10(9)/l, E: 31 x 10(9)/l). A cytoreduction >50% in the peripheral blood was achieved by T in 11/19, by T+C in 7/11, by MP in 5/8, by MP+MTX in 3/6, by E in 3/4, and by M in 16/22 patients. The period of cytoreduction was regarded as the duration of response - T: median 53 days, range 5-98; T+C: median 61 days, range 14-226; MP: median 37 days, range 4-192; MP + MTX: median 58 days, range 36-59; E: median 121 days, range 26-159; M: median 39 days, range 8-78. T and T + C were well tolerated by all but three patients (stomatitis, diarrhea, WHO grade 2). MP was accompanied by a rise of transaminases (WHO 1-3) in 5/6 patients. E led to stomatitis (WHO 1,2) in 4/5 and M to nausea/vomiting (WHO 1,2) in 5/22 and to stomatitis (WHO 2) in 4/22 cases. The mean survival time after start of palliative cytoreduction was 16 weeks (2-65). In summary, 6-thioguanine +/- cytarabine was best tolerated with effective but in oral monotherapy - often protracted cytoreduction in 60% of patients. Mitoxantrone showed tolerable side effects and potent cytoreduction in 73% of patients even after ineffective palliative pretreatment. Palliative cytoreductive therapy does not reduce the quality of life and can prevent complications of significant leukocytosis in refractory acute leukemia.

Topics: Acute Disease; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Diarrhea; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Leukemia; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Middle Aged; Nausea; Palliative Care; Retrospective Studies; Stomatitis; Thioguanine

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Child; Child, Preschool; Colitis, Ulcerative; Female; Follow-Up Studies; Humans; Leukopenia; Male; Mercaptopurine; Nausea; Prednisone; Radiography; Recurrence; Sulfasalazine; Time Factors; Vomiting

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Aged; Child; Child, Preschool; Colitis, Ulcerative; Female; Humans; Leukopenia; Male; Mercaptopurine; Middle Aged; Nausea; Recurrence; Sigmoidoscopy; Sulfasalazine; Time Factors

Topics: Adolescent; Anemia, Aplastic; Antineoplastic Agents; Central Nervous System; Child; Child, Preschool; Cyclophosphamide; Daunorubicin; Diarrhea; Drug Combinations; Female; Follow-Up Studies; Humans; Leukemia, Lymphoid; Male; Mercaptopurine; Methotrexate; Nausea; Pneumonia, Pneumocystis; Prednisone; Radiotherapy; Recurrence; Remission, Spontaneous; Stomatitis, Aphthous; Vincristine; Vomiting

Topics: Adolescent; Adult; Aged; Agranulocytosis; Allopurinol; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Blood Transfusion; Cytarabine; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mercaptopurine; Methotrexate; Middle Aged; Muramidase; Nausea; Prednisolone; Thrombocytopenia; Vincristine

Topics: Antimetabolites; Arthritis, Rheumatoid; Azathioprine; Chronic Disease; Feeding and Eating Disorders; Humans; Mercaptopurine; Methotrexate; Nausea; Time Factors