thioguanine-anhydrous and Leukopenia

We herein conducted a systematic review and meta-analysis of published studies to estimate diagnostic accuracy of NUDT15 gene polymorphisms for detection of thiopurine-induced leukopenia. Eligible studies were identified through a comprehensive search on PubMed, Web of Knowledge, Cochrane and OpenGrey datasets up to April 2018. The methodological quality of eligible studies was assessed using the QUADAS-2 criteria. The diagnostic odds ratio (DOR) was used as a single measure of diagnostic performance. Sixteen studies including a total of 3538 thiopurine-treated patients fulfilled inclusion criteria for the systematic review. Among these, 16 studies were available for the meta-analysis of rs116855232, 6 studies for rs186364861 and 5 studies for rs554405994 of NUDT15. A higher DOR was found for rs116855232 (8.44, 95% CI: 5.46-13.03), as compared to rs554405994 (4.336, 95% CI 2.924-6.429) or rs186364861 (2.742, 95% CI 1.453-5.175). Results of meta-regression analysis showed that incidence of leukopenia (relative DOR: 0.96; 95%CI: 0.93-1.00, p = 0.037) and leukopenia onset (late vs early leukopenia, relative DOR: 0.41, 95% CI 0.20-0.85, p = 0.0189) significantly influenced diagnostic accuracy of rs116855232. Subgroup analysis for rs186364861 and rs554405994 revealed a significant DOR for early-onset leukopenia (rs186364861: 4.04, 95% CI 1.78-9.20; rs554405994: 2.94, 95% CI 1.74-4.95), but not for late-onset leukopenia (rs186364861: 1.52, 95% CI 0.52-4.43; rs554405994: 2.02, 95% CI 0.93-4.40). The present meta-analysis points to rs116855232, rs554405994 and rs186364861 of NUDT15 as clinically relevant predictors of thiopurine-induced leukopenia. Nevertheless, prospective studies of genotype-guided dosing of thiopurines are warranted to prove clinical benefit and cost-effectiveness of pretreatment NUDT15 gene testing across different populations.

Topics: Antineoplastic Agents; Azathioprine; Humans; Leukopenia; Mercaptopurine; Polymorphism, Genetic; Pyrophosphatases; Thioguanine

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

The effects of 6-mercaptopurine (6-MP) are mediated via its intracellular conversion to 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) nucleotide metabolites, the latter genetically controlled by thiopurine methyltransferase (TPMT). We sought to determine optimal therapeutic 6-MP metabolite levels and their correlation with medication-induced toxicity and TPMT genotype.. Therapeutic response was determined in 92 pediatric patients with inflammatory bowel disease coincidentally with hematologic, pancreatic, and hepatic laboratory parameters, and compared with erythrocyte metabolite levels and TPMT genotype.. Clinical response was highly correlated with 6-TG levels (P < 0.0001) but not with any other variable, including 6-MMP levels, drug dose, gender, and concurrent medications. The frequency of therapeutic response increased at 6-TG levels > 235 pmol/8 x 10(8) erythrocytes (P < 0.001). Hepatotoxicity correlated with elevated 6-MMP levels (>5700 pmol/8 x 10(8) erythrocytes; P < 0.05). Although leukopenia was associated with higher 6-TG levels (P < 0.03), it was observed in only 8% of responders. Patients heterozygous for TPMT (8/92) had higher 6-TG levels (P < 0.0001), and all responded to therapy.. 6-MP metabolite levels and TPMT genotyping may assist clinicians in optimizing therapeutic response to 6-MP and identifying individuals at increased risk for drug-induced toxicity.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Inflammatory Bowel Diseases; Leukopenia; Liver; Male; Mercaptopurine; Mesalamine; Methyltransferases; Prospective Studies; Thioguanine; Treatment Outcome

Topics: Adult; Aged; Azathioprine; Cyclosporine; Erythrocytes; Female; Heart Transplantation; Humans; Leukocyte Count; Leukopenia; Male; Methyltransferases; Middle Aged; Reference Values; Thioguanine

Thiopurine drugs, such as thioguanine, mercaptopurine and azathioprine, are used for treating inflammatory bowel disease, such as ulcerative colitis. One must be aware of the serious side effects these drugs can have (e.g. bone marrow depression). A 56-year-old man with ulcerative colitis was treated with mercaptopurine. He developed leukopenia as a result. Thioguanine was started ten months later, resulting in life-threatening pancytopenia. Thiopurine methyltransferase (TPMT) genotyping proved that the patient was a poor metaboliser of thioguanine (TPMT3A*/3A*). Dose reduction is recommended for patients with reduced or absent TPMT activity. This life-threatening side effect could have been prevented by taking a number of relatively simple precautions.

Topics: Colitis, Ulcerative; Humans; Leukopenia; Male; Mercaptopurine; Middle Aged; Pancytopenia; Thioguanine

Few data on azathioprine (AZA) therapy for inflammatory bowel disease (IBD) exist for children. We evaluated whether the 6-thioguanine nucleotides (6-TGN) level predicts AZA refractoriness in children with IBD and whether children benefit an AZA dose escalation. Seventy-eight children with IBD initially treated with an AZA dose of 1.5-2.5 mg/kg/day were retrospectively included. The dose was adjusted based on the clinical status. The receiver operating characteristic curve and logistic regression were used to determine predictors for AZA resistance. Initially, 18 of 40 (45%) patients receiving a dose of <2 mg/kg/day and 11 of 38 (28.9%) patients receiving a dose of 2-2.5 mg/kg/day achieved remission. The 6-TGN level above 250 pmol/8.10(8) RBCs was associated with a higher remission rate, though non-significant. Among 35 patients with a dose escalation due to treatment failure, 12 (34.3%) achieved remission (the median 6-TGN level increased from 260 to 394 pmol/8.10(8) RBCs [P = .002]), 23 (67.6%) were AZA refractory. A 6-TGN level above 405 pmol/8.10(8) RBCs was the only predictor for AZA resistance (sensitivity 78.3%, specificity 75%, OR 10.8 [95% CI: 2.1-55.7, P = .004]). Serial metabolite monitoring is useful to identify children with IBD resistant to AZA. Children who cannot achieve remission despite a 6-TGN level above 405 pmol/8.10(8) RBCs should receive alternative therapies than dose increase.

Topics: Adolescent; Antimetabolites; Azathioprine; Child; Child, Preschool; Drug Resistance; Female; Humans; Inflammatory Bowel Diseases; Leukopenia; Male; Mercaptopurine; Thioguanine

Thiopurine drugs are widely used in the treatment of inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and adverse events occurrence. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the effects of TPMT and hypoxanthine guanine phosphoribosyltransferase (HPRT) activities on 6-thioguanine nucleotides (6-TGNs) concentrations and thiopurine-induced leukopenia in patients with IBD.. Clinical data and blood samples were collected from 120 IBD patients who were receiving azathioprine (AZA)/6-mercaptopurine (6-MP) therapy. Erythrocyte TPMT, HPRT activities and 6-TGNs concentrations were determined. HPRT activity and its correlation with TPMT activity, 6-TGNs level, and leukopenia were evaluated.. The HPRT activity of all patients ranged from 1.63-3.33 (2.31 ± 0.36) μmol/min per g Hb. HPRT activity was significantly higher in patients with leukopenia (27, 22.5%) than without (P < 0.001). A positive correlation between HPRT activity and 6-TGNs concentration was found in patients with leukopenia (r = 0.526, P = 0.005). Patients with HPRT activity > 2.70 μmol/min per g Hb could have an increased risk of developing leukopenia (odds ratio = 7.47, P < 0.001). No correlation was observed between TPMT activity and HPRT activity, 6-TGNs concentration, or leukopenia.. High levels of HPRT activity could be a predictor of leukopenia and unsafe 6-TGN concentrations in patients undergoing AZA/6-MP therapy. This could partly explain the therapeutic response or toxicity that could not be adequately explained by the polymorphisms of TPMT.

Topics: Adult; Aged; Erythrocytes; Female; Humans; Hypoxanthine Phosphoribosyltransferase; Inflammatory Bowel Diseases; Leukopenia; Male; Methyltransferases; Middle Aged; Polymorphism, Genetic; Prognosis; Thioguanine

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

We evaluated the effect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine.. Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sulphasalazine 4 g/day, or balsalazide 6.75 g/day. The primary outcome measure was the occurrence of clinically important leucopenia during the study, defined separately as total leucocyte counts < 3.0 x 10(9)/l and < or = 3.5 x 10(9)/l. Whole blood 6-thioguanine nucleotide concentrations were determined.. Three patients could not be evaluated for the primary outcome measure. In the remaining 31 patients, the frequency of total leucocyte counts < 3.0 and < or = 3.5 were: 1/10 and 5/10 in the mesalamine group; 1/11 and 6/11 in the sulphasalazine group; and 0/10 and 2/10 in the balsalazide group. There were significant increases in mean whole blood 6-thioguanine nucleotide concentrations from baseline at most time points in the mesalamine and sulphasalazine groups but not in the balsalazide group.. In patients with Crohn's disease receiving azathioprine or 6-mercaptopurine, coadministration of mesalamine, sulphasalazine, and possibly balsalazide results in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leucopenia.

Topics: Adult; Aminosalicylic Acids; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Binomial Distribution; Chromatography, High Pressure Liquid; Confidence Intervals; Drug Interactions; Female; Humans; Immunosuppressive Agents; Leukopenia; Male; Mercaptopurine; Mesalamine; Methyltransferases; Phenylhydrazines; Sulfasalazine; Thioguanine

Some authors suggest that efficacy of 6-mercaptopurine (6-MP) in patients with inflammatory bowel disease correlates with circulating 6-thioguanine (6-TG) levels more than 235 pmol/8 x 10(8) red blood cells. The authors evaluated the relation between 6-MP metabolite levels and disease activity in children and adolescents with inflammatory bowel disease.. Clinical status and hematologic and hepatic parameters were determined in 101 children with inflammatory bowel disease from a single center and compared with 6-MP metabolite levels.. There was a trend for higher 6-TG levels among patients in remission than among those with active disease (217 vs. 173); however the difference was not statistically significant ( P = 0.09). The likelihood of therapeutic response did not increase significantly at 6-TG levels greater than 235 pmol/8 x 10(8) red blood cells (odds ratio 1.7; P = 0.1). In the current study, 58% of patients in remission had 6-TG levels less than 235. However, serial measurements of 6-MP metabolite levels in 50 patients with active disease showed that increasing 6-TG levels correlated significantly with disease remission in patients followed up longitudinally ( P = 0.04). Leukopenia was significantly associated with high 6-TG levels ( P = 0.03) but not with clinical response ( P = 0.2).. These data suggest that the target range of 6-TG levels previously described by others did not apply to 58% of the pediatric patients with IBD in remission. However, serial monitoring of 6-MP metabolite levels in individual patients with active disease should allow dose escalation and induction of remission while minimizing the risk of toxicity.

Topics: Adolescent; Antimetabolites, Antineoplastic; Azathioprine; Child; Cross-Sectional Studies; Erythrocytes; Humans; Inflammatory Bowel Diseases; Leukocyte Count; Leukopenia; Liver; Male; Mercaptopurine; Odds Ratio; Retrospective Studies; Thioguanine; Treatment Outcome

Isoproterenol produces myocardial necrosis in rats. To investigate the possible role of oxygen free radicals generated by xanthine oxidase and neutrophils, we examined the effects of the xanthine oxidase inhibitors, 6-mercaptopurine (6MP) and 6-thioguanine (6TG) combined and allopurinol, or of irradiation (to induce leukopenia) on isoproterenol-induced myocardial necrosis (ISOMN). The incidence and severity of ISOMN was significantly reduced by 6MP + 6TG but not by the specific inhibitor of xanthine oxidase, allopurinol, indicating that the protective effects of 6MP + 6TG may be due to its free radical scavenging activity rather than its xanthine oxidase inhibitory activity. Irradiation provided complete protection against ISOMN in all rats. Marked leukopenia or other radiation-induced protective factors could play a role in the mechanism of the protection.

Topics: Allopurinol; Animals; Heart Diseases; Isoproterenol; Leukocytes; Leukopenia; Male; Mercaptopurine; Myocardium; Necrosis; Radiation Injuries, Experimental; Rats; Rats, Inbred Strains; Thioguanine

Eight patients with acute non-lymphocytic leukemia in adults refractory to Daunomycin (DM)-based conventional regimens were treated with AMSA-based regimens. Complete remission (CR) was obtained in 4 (50%) and partial remission (PR) in 2 (25%). The median time to CR was 26.5 days and 3 cases achieved CR in the first cycle. The median duration of CR was 8.3 months. Hematologic toxicity was severe and the nadir (median) of leukocytes and platelets was 0.15 x 10(3)/microliters and 15.5 x 10(3)/microliters, respectively. Other adverse effects were mucositis, nausea.vomiting and hepatotoxicity which occurred over 50%, while cardiac toxicity was not observed. This study indicates that AMSA is clinically non-cross-resistant to DM and considered to be an active drug for salvage therapy.

Topics: Adolescent; Adult; Aged; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Evaluation; Drug Resistance; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Leukopenia; Male; Middle Aged; Prednisolone; Remission Induction; Thioguanine; Thrombocytopenia

Treatment of chronic phase chronic myelogenous leukemia with hydroxyurea or busulfan rarely induces cytogenetic (true) remissions. Intensive chemotherapy induces brief true remissions in approximately 50% of patients. We added 13-cis-retinoic acid to daunorubicin, cytosine arabinoside, and thioguanine to determine if it could increase the incidence and duration of remission induced by cytotoxic chemotherapy. Of the 17 evaluable patients, one patient (6%) achieved complete remission, and seven patients (41%) achieved partial remissions. The median duration of remission was 1.6 months. We conclude that 13-cis-retinoic acid does not increase the incidence and duration of remission in chronic phase chronic myelogenous leukemia.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Chromosomes, Human, 21-22 and Y; Cytarabine; Daunorubicin; Humans; Isotretinoin; Leukemia, Myeloid; Leukopenia; Liver; Middle Aged; Stomatitis; Thioguanine; Thrombocytopenia; Time Factors; Tretinoin

In order to determine the mechanism of therapeutic synergism elicited by a combination of 6-thioguanine and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) against various murine tumors, side effects of host animals due to the combination of these two drugs were examined. The combination toxicity index of these drugs given simultaneously was determined to be 1.5, i.e., this indicates that the combination of ACNU and 6-thioguanine is less-than-additive with respect to the lethal toxicity. More-over, this combination treatment appeared to be at least no more than additive with respect to bone marrow toxicities as judged on the basis of bone marrow cellularity and peripheral white blood cell counts. In addition, the effects of treatment schedules, which were clearly observed in the therapeutic effect, on the side effects due to this combination treatment were also examined. However, no specific decrease or increase in side effects on host animals on this specific treatment schedule or the other treatment schedule was seen.

Topics: Animals; Antineoplastic Agents; Bone Marrow; Drug Administration Schedule; Drug Therapy, Combination; Female; Leukopenia; Mice; Nimustine; Nitrosourea Compounds; Thioguanine

Cats frequently develop a variety of spontaneous hemolymphatic noeplasias. Long-term remissions in the nonlymphatic leukemic cat are difficult to obtain; therefore, more successful chemotherapeutic agents are sought for disease control. The purpose in the present study is to describe the clinical investigation of 3 antineoplastic drugs given to 23 normal cats. The cats tolerated doxorubican given at the dose level of 30 mg/m2 of body surface area once every 3 weeks; daunomycin, 15 to 30 mg/m2 once every 3 weeks; and 6-thioguanine, 25 mg/m2 for 5 days every 20 to 30 days.

Topics: Alopecia; Animals; Cat Diseases; Cats; Daunorubicin; Doxorubicin; Female; Leukocyte Count; Leukopenia; Male; Thioguanine; Thrombocytopenia

Beta-thioguanine deoxyriboside (betaTGdR) is a purine nucleoside derivative which was studied alone or in combination with arabinosyl cytosine (Ara-C) in patients with solid tumors and acute leukemia. No significant responses were observed in 22 patients with solid tumors. The response rate with betaTGdR alone in acute leukemia was 26% and in combination with Ara-C was 24%. Responses were generally of short duration. Toxicity included myelosuppression, nausea, stomatitis, hyperpigmentation, photosensitivity, and liver function abnormalities.

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Child, Preschool; Cytarabine; Deoxyguanosine; Deoxyribonucleosides; Drug Therapy, Combination; Female; Guanosine; Humans; Leukemia; Leukopenia; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Remission, Spontaneous; Thioguanine; Thionucleosides; Thrombocytopenia; Time Factors

16 courses of an 8-drug regimen including daunomycin, vincristine, cytosinearabinoside, thioguanine, methotrexate, cyclophosphamide, prednisolone and hydroxyurea, and 12 courses of a 7-drug regimen including the same drugs minus hydroxyurea were administered in 16 otherwise therapy-resistant cases of acute myeloid leukaemia. In spite of a significant and rapid reduction of the leukaemic cell-mass in all the cases treated, only two brief minimal remissions were obtained. The main toxic effect was myelosuppression. However, the treatment was associated with a high frequency of mucosal ulcerations of the oesophagus and stomach, and it cannot be excluded that the latter complication may be drug-related.

Topics: Adolescent; Adult; Aged; Candidiasis; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Resistance; Drug Therapy, Combination; Esophagitis, Peptic; Female; Humans; Hydroxyurea; Leukemia, Myeloid, Acute; Leukocyte Count; Leukopenia; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Stomach Ulcer; Thioguanine; Vincristine

Topics: Adolescent; Age Factors; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cytarabine; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Lymphoid; Leukopenia; Liver; Liver Function Tests; Male; Remission, Spontaneous; Thioguanine; Thrombocytopenia

Topics: Acute Disease; Amino Sugars; Anemia; Antibiotics, Antineoplastic; Antineoplastic Agents; Blood Cell Count; Cyclophosphamide; Cytarabine; Glycosides; Humans; Injections, Intravenous; Injections, Subcutaneous; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukopenia; Lymphoma; Prednisone; Remission, Spontaneous; Thioguanine; Thrombocytopenia; Vincristine

Topics: Adolescent; Adult; Age Factors; Azathioprine; Biopsy; Chlorambucil; Cortisone; Cyclophosphamide; Female; Glomerulonephritis; Humans; Kidney; Leukopenia; Lupus Erythematosus, Systemic; Male; Mechlorethamine; Mercaptopurine; Prednisolone; Proteinuria; Racial Groups; Serum Albumin; Sex Factors; Thioguanine

Topics: Adenocarcinoma; Alopecia; Antineoplastic Agents; Azaserine; Carcinoma, Squamous Cell; Diarrhea; Drug Eruptions; Drug Therapy; Geriatrics; Guanine; Leukopenia; Nausea; Neoplasms; Stomatitis; Thioguanine; Thrombocytopenia; Toxicology