thioguanine-anhydrous and Nausea

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

Topics: Abnormalities, Drug-Induced; Adult; Aged; Azathioprine; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Child; Cost-Benefit Analysis; Drug Administration Schedule; Drug Approval; Drug Costs; Drug Hypersensitivity; Drug Interactions; Female; Genetic Testing; Humans; Immunosuppressive Agents; Infections; Kidney Diseases; Lactation; Male; Methyltransferases; Nausea; Neoplasms; Off-Label Use; Patient Education as Topic; Pregnancy; Risk Factors; Skin Diseases; Thioguanine; Virus Diseases

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

6-thioguanine, an antimetabolite not potentiated by allopurinol, has been used in the treatment of 29 patients with polycythemia vera. All but two of the patients had been treated previously by venesection and/or radioactive phosphorus (32p) and/or alkylating agents. The usual dose was 40-160 mg daily alternate weeks according to individual response. The treatment period varied from 6-66 months (mean, 31 months). Of 27 evaluable patients 24 (89%) responded to treatment and at one year there was a significant fall in all blood count parameters. Seven patients relapsed while on treatment and four were withdrawn because of side effects. 6-thioguanine merits further evaluation in the management of polycythemia vera, particularly in those patients who have received large cumulative doses of 32p and/or alkylating agents and in whom an alternative mode of therapy is desirable.

Topics: Aged; Blood Cell Count; Drug Administration Schedule; Drug Evaluation; Hematocrit; Humans; Male; Middle Aged; Nausea; Patient Compliance; Polycythemia Vera; Recurrence; Skin Diseases; Thioguanine

Topics: Blood Cell Count; Breast Neoplasms; Drug Evaluation; Female; Humans; Middle Aged; Nausea; Neoplasm Metastasis; Neoplasm Recurrence, Local; Thioguanine; Time Factors

Topics: Administration, Oral; Adolescent; Adult; Age Factors; Aged; Anemia; Child; Cytarabine; DNA, Neoplasm; Female; Humans; Injections, Intravenous; Leukemia, Myeloid, Acute; Leukocytes; Male; Middle Aged; Muramidase; Nausea; Remission, Spontaneous; Sex Factors; Thioguanine; Thrombocytopenia; Time Factors; Vomiting

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow; Cytarabine; Drug Synergism; Female; Humans; Hydroxyurea; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Middle Aged; Nausea; Remission, Spontaneous; Thioguanine; Vomiting

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