Use Of 6-thioguanine Research Articles

Further experience with the use of 6-thioguanine in patients with Crohnʼs disease

6-Thioguanine (6-TG) is efficacious in patients with Crohn's Disease (CD) failing conventional immunosuppression but there are reports of hepatotoxicity. We report our experience of the safety and efficacy of 6-TG in a series of patients with CD. A retrospective study of patients with CD who failed thiopurines +/- methotrexate between 2001 and 2006 was performed. Indications for 6-TG were; active disease, to allow infliximab withdrawal, steroid sparing, or fistula closure. Patients underwent regular review and those treated longer than 1 year were advised to have liver magnetic resonance imaging (MRI) and liver biopsy. All 30 patients treated with 6-TG during the period were included. The median dose and duration of 6-TG was 40 mg daily and 21.5 months, respectively. Initial clinical response was achieved in 18/30 (60%). Eleven of 29 (38%) (1 unrelated death) remained in remission at a median 44 months follow-up. Seven of 30 (23%) discontinued 6-TG due to adverse effects; 7/30 (23%) patients developed abnormal liver function tests (LFTs) during treatment, mostly transient and mild. One patient developed a portal hypertensive syndrome resolving on cessation of 6-TG. Of 11 liver biopsies, none showed nodular regenerative hyperplasia (NRH). The median red blood cell 6-thioguanine nucleotide (6-TGN) level was 807 pmol/10(8). 6-TG has good clinical efficacy for third-line immunosuppression in CD but hepatotoxicity remains a concern. However, previous reports of NRH in 6-TG-treated inflammatory bowel disease patients have not been substantiated by this cohort.

Absence of nodular regenerative hyperplasia after low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients

Background The use of 6-thioguanine has been proposed as a rescue drug for inflammatory bowel disease patients. Initial data on short-term efficacy and toxicity of 6-thioguanine were promising; however, these have been challenged by reports concerning its potential hepatotoxic effect (nodular regenerative hyperplasia). We proposed that these histological liver abnormalities may well be dose- or level-dependent. Aims We performed a prospective multi-centre study on the hepatotoxic potential of long-term and (as compared with prior studies) low-dose 6-thioguanine use. Patients Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled. Methods Liver biopsy specimens were scored by two pathologists, unaware of clinical data. Laboratory parameters, determined prior to initiation of 6-thioguanine therapy and prior to biopsy, were reviewed. Results Twenty-eight biopsies were analysed. The majority of patients (89%) were azathioprine and/or 6-mercaptopurine intolerant inflammatory bowel disease patients. In 26 patients (93%) no signs of nodular regenerative hyperplasia were detected; in two additional patients nodular regenerative hyperplasia could not be excluded due to inconclusive pathological findings. The mean 6-thioguanine dosage, 6-thioguaninenucleotides level, duration of use and cumulative dosage were 19.5 mg, 564 pmol/8 × 10 8 RBC, 38 months and 22491 mg, respectively. Conclusions We have demonstrated that low-dose 6-thioguanine maintenance therapy in inflammatory bowel disease patients is not likely to be associated with induction of nodular regenerative hyperplasia. The induction of nodular regenerative hyperplasia appears to be 6-thioguanine dose or 6-thioguaninenucleotides level dependent.

Thiopurines in Inflammatory Bowel Disease - The Role of Pharmacogenetics and Therapeutic Drug Monitoring

Pharmacogenetics represents the study of variability in drug response due to genetic variations. Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterized by a chronic or relapsing inflammation of the digestive tract. The thiopurines 6-mercaptopurine (6-MP) and azathioprine (AZA), an imidazol derivative and pro-drug of 6-MP, are widely used in IBD, particularly in Crohn's disease. The metabolism of thiopurines is complex and individually variable. Thiopurine methyltransferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for a defective enzyme. The formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably due to the TPMT activity. Patients with decreased TPMT activity are at increased risk of developing severe side effects if treated with conventional thiopurine doses, due to the accumulation of toxic metabolites. Determination of the TPMT phenotype or genotype is often used to identify individuals with increased risk for adverse events. Twenty-one variant TPMT alleles have been described, of which three are more common than the others. An association between inosine triphosphate pyrophosphatase polymorphisms and adverse events during thiopurine treatment has also been proposed. In this review, the clinical value of TPMT status determination and pharmacological monitoring of thiopurine metabolites are discussed as well as the increased interest in the use of 6-thioguanine, a thiopurine with a less complex metabolism, as an alternative for patients who do not tolerate AZA or 6-MP. It can be concluded that TPMT determination before start of thiopurine therapy is of value to identify individuals with increased risk for adverse reactions due to genetic enzyme deficiency. However, large prospective studies are still needed to evaluate the true benefit of monitoring thiopurine metabolites during thiopurine treatment. © 2006 Bentham Science Publishers Ltd.

Promising treatment of autoimmune hepatitis with 6-thioguanine after adverse events on azathioprine

The use of corticosteroids in autoimmune hepatitis is an established therapy. To avoid the possible serious side effects of corticosteroids, immunosuppression with azathioprine is often warranted. Azathioprine, a purine analogue, is frequently used to taper or replace corticosteroids. However, approximately 10% of the patients are intolerant to azathioprine. Alternative therapies using mycophenolate, tacrolimus, budesonide, cyclosporine and 6-mercaptopurine have been studied, with variable results. The use of 6-thioguanine, an agent more directly leading to the down-stream active metabolites of azathioprine (6-thioguanine nucleotides) in inflammatory bowel disease patients intolerant to azathioprine or 6-mercaptopurine showed conflicting results. We report three patients with autoimmune hepatitis who could not tolerate azathioprine but tolerated 6-thioguanine 0.3 milligram per kilogram daily well. All three patients improved clinically. Therapeutic drug monitoring was performed. The prospective evaluation of 6-thioguanine as a possible immunosuppressive drug in autoimmune hepatitis patients is warranted.

Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations

There is a growing interest in the use of thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) for the management of inflammatory bowel disease. The genetically controlled thiopurine ( S)-methyltransferase enzyme is involved in the metabolism of these agents and is hypothesised to determine the clinical response to thiopurines. Diminished activity of this enzyme decreases the methylation of thiopurines, theoretically resulting in potential overdosing, while high thiopurine ( S)-methyltransferase status leads to overproduction of toxic metabolites and ineffectiveness of azathioprine and 6-mercaptopurine. In practice, controversies exist regarding the utility of standard thiopurine ( S)-methyltransferase pheno- and genotyping. Current pharmacogenetic insights suggest that another enzyme system may participate in the efficacy and toxicity of thiopurines; inosine triphosphate pyrophosphatase. Other topics discussed in this review are the utilisation of therapeutic drug monitoring and the experimental use of 6-thioguanine in the treatment of inflammatory bowel disease. 6-Thioguanine has a less genetically controlled metabolism and skips genetically determined metabolic steps. On theoretical basis, 6-thioguanine might therefore have a more predictable profile than azathioprine and 6-mercaptopurine. However, the use of 6-thioguanine has been associated with an increased risk of nodular regenerative hyperplasia of the liver and veno-occlusive disease. Further research is warranted before 6-thioguanine can be considered as a treatment option for inflammatory bowel disease.

6-Thioguanine in the Treatment of Psoriasis: A Case Report and Literature Review

Background: 6-Thioguanine is a purine analog primarily indicated for acute myelogenous leukemia. Its use in psoriasis was first investigated in the 1950s and current interest in serious treatments for psoriasis, such as cyclosporine, has renewed interest in this medication. Newer therapies, such as PUVA and retinoids, have side effects as do some older treatments, such as methotrexate, which fell into favor at the same time 6-thioguanine was being investigated. Reexamining older treatments can open up new therapeutic options in difficult cases. Objective: The goal of this article is to provide a comprehensive review of the literature regarding the use of 6-thioguanine in the treatment of psoriasis as well as an illustrative case report demonstrating the use and side effects of 6-thioguanine in a patient with pustular psoriasis. Topics reviewed include efficacy, side effects, laboratory monitoring, different dosing regimens, and proposed mechanisms of action. Conclusions: 6-Thioguanine has been highly effective in treating and maintaining improvement in patients with psoriasis. A study comparing efficacies with methotrexate would be extremely useful. Because of the possibility of severe bone marrow depression, 6-thioguanine is not a first-line treatment. However, with new dosing regimens, proper laboratory monitoring, and further studies, use of 6-Thioguanine could expand in the future.

Definition of conditions for the detection of genotoxic chemicals in the adult rat-liver epithelial cell/hypoxanthine—guanine phosphoribosyl transferase (ARL/HGRPT) mutagenesis assay

Conditions for the detection of genotoxic chemicals in the adult rat-liver epithelial cell/hypoxanthine—guanine phosphoribosyl transferase (ARL/HGPRT) mutagenesis assay have been defined. These included (1) a 3-day exposure to activation-dependent carcinogens; (2) a minimum of 14 days for induced mutant expression; (3) seeding density of 1 × 10 4 cells per cm 2 for selection of mutants; (4) use of 6-thioguanine and (5) acceptance of genotoxicity of test chemicals if induced mutant incidence is significantly above that of the parallel run control and beyond the 98% confidence limits of the mean of the population spontaneous mutant incidence. With this protocol, the ARL/HGPRT mutagenesis assay has the capacity to activate representative members of the mycotoxin, aminoazo dye, aromatic amine and nitrosamine-types of carcinogens. This assay, offering additional metabolic parameters through intrinsic metabolic capability and providing a reliable end-point of clear biologic significance serves as a useful supplement to the Salmonella/microsome bacterial mutagenesis assay in a battery for the detection of genotoxic chemicals.

Conditions necessary for quantifying ethyl methanesulfonate-induced mutations to purine-analogue resistance in Chinese hamster V79 cells

We have investigated conditions necessary to quantify the relationship between exposure to a mutagen, ethyl methanesulfonate (EMS), and the frequency of mutation induction at the hypoxanthine-guanine phosphoribosyl transferase locus in V79 cells. Maximal expression of potential mutants has been achieved by either subculturing at fewer than 5 X 10(5) cells/100-mm dish at 2-day intervals or by daily feeding of cultures. An expression period of 5 days (measure from 1 day after the initiation of treatment with the chemical mutagen) should be allowed, since at least 4 days of expression is required to reach to steady maximum of mutation frequency. It appears that there is no concentration dependence of expression time necessary to reach a plateau of mutation frequency with increasing concentrations of EMS up to 1.6 mg/ml. About 1.25 X 10(5) cells/100-mm dish or fewer should be plated for selection to avoid the loss of mutants which occurs at 1.5 X 10(5) cells/dish, presumably through cross-feeding (metabolic cooperation). The use of 6-thioguanine in hypoxanthine-free medium (supplemented with dialyzed fetal calf serum) appears to be a very stringent condition for selection. Mutation induction by EMS as a function of EMS exposure (EMS concentration X treatment time) increases linearly with concentration up to 12 h. For these treatment periods, the observed mutation frequencies for EMS are directly proportional to mutagen exposure regardless of the duration of the treatment.

Hypoxanthine-guanine phosphoribosyltransferase deficiency: chemical agents selective for mutant or normal cultured fibroblasts in mixed and heterozygote cultures.

Cultured fibroblasts established from skin biopsies from patients with the Lesch-Nyhan syndrome are deficient in hypoxanthine-guanine phosphoribosyl-transferase (EC 2.4.2.8) activity. This deficiency makes possible the use of chemicals that select either for or against deficient variants in cultured fibroblasts. Two-way selection has been achieved by the use of 6-thioguanine, which selects for the deficient mutant, and azaserine, which selects to some extent for the normal allele in mixed cultures, as well as in cultures from heterozygotes. Theoretical considerations predict that the phenomenon of metabolic cooperation would tend to reinforce the former and to weaken the latter type of selection, and this is in accordance with the experimental findings.