thioguanine-anhydrous and Body-Weight

Azathioprine (AZA), a pro-drug metabolised to the active metabolites 6-tioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn's disease (CD).. To investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations.. This multicentre, double-blind, randomised controlled trial compared the efficacy and safety of weight-based vs. individualised AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0 mg/kg/day (if intermediate TPMT) or 2.5 mg/kg/day (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250-400 pmol/8 × 10(8) red blood cells (RBC), or to a maximal dose of 4 mg/kg/day.. After randomising 50 subjects, the trial was stopped prematurely due to insufficient enrolment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualised arm vs. 16% in the weight-based arm (P = 0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualised arm and 25% in the weight-based arm (P = 0.12). At week 16, median 6TGN concentrations in PP remitters and nonremitters were 216 and 149 pmol/8 × 10(8) RBC respectively (P = 0.07).. Despite trends favouring individualised over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualised arm. [Clinicaltrials.Gov Identifier Nct00113503].

Topics: Adolescent; Adult; Azathioprine; Body Weight; Child; Crohn Disease; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Prodrugs; Thioguanine; Treatment Outcome; Young Adult

Antitumor activities of a combination chemotherapy with a water-soluble nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), and a single dose of 6-thioguanine were studied using three obstinate murine tumor systems, i.e., Lewis lung carcinoma, B16 melanoma, and an advanced stage of L1210 leukemia systems. Therapeutically synergistic effect was observed either definitely against 1- or 2-day-old Lewis lung carcinoma and 6-day-old L1210 leukemia or moderately against 1-day-old B16 melanoma. Single intravenous treatment on day 7 after subcutaneous implantation of Lewis lung carcinoma, when the tumors had already metastasized to the lungs, produced a significant regression of tumor and a significant increment in survival time of tumor-bearing mice. In comparative studies, the combination of ACNU and 6-thioguanine showed a greater and a wider spectrum of antitumor activities against these tumors than those obtained by the combination with ACNU and a single dose of 5-fluorouracil, methotrexate, or 6-mercaptopurine. Increment in lethal toxicity for normal and tumor-bearing mice was not observed by the combination of ACNU and 6-thioguanine in contrast to definite increases in this toxicity by the combination of ACNU and 5-fluorouracil. The present experimental results may suggest the clinical utility of the combination chemotherapy with ACNU and 6-thioguanine in the treatment of several solid tumors as well as acute leukemias.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Drug Synergism; Drug Therapy, Combination; Female; Injections, Intraperitoneal; Injections, Intravenous; Leukemia L1210; Lung Neoplasms; Male; Melanoma; Mercaptopurine; Mice; Neoplasms, Experimental; Nimustine; Nitrosourea Compounds; Thioguanine

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Body Weight; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Leukemia, Myeloid, Acute; Middle Aged; Remission, Spontaneous; Thioguanine; Vincristine

Topics: Allopurinol; Aminocaproates; Analgesics; Animals; Antineoplastic Agents; Azathioprine; Body Weight; Chloroquine; Colchicine; Cortisone; Cyclophosphamide; Cyproheptadine; Diazoxide; Dimethyl Sulfoxide; Encephalomyelitis, Autoimmune, Experimental; Hydrocortisone; Immunosuppressive Agents; Male; Mercaptopurine; Methotrexate; Methyldopa; Nialamide; Oils; Organ Size; Rats; Strychnine; Talc; Thalidomide; Thioguanine; Thiomalates

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Body Weight; Carcinoma, Ehrlich Tumor; Chemical Phenomena; Chemistry; Female; Formamides; Injections, Intraperitoneal; Leukemia, Experimental; Mice; Organ Size; Sarcoma 180; Thioguanine; Time Factors