thioguanine-anhydrous and Hyperplasia

Thiopurines are an important therapy for the maintenance of remission in inflammatory bowel disease (IBD). However, the use of thioguanine has been limited by concerns regarding its toxicity. We performed a systematic review to evaluate its effectiveness and safety in IBD.. Electronic databases were searched to identify studies reporting clinical responses and/or adverse events of thioguanine therapy in IBD. We calculated the pooled clinical response and clinical remission rates of thioguanine in IBD. Subgroup analyses were done for the dosage of thioguanine and the type of studies (prospective or retrospective). Meta-Regression was used to analyze the impact of dose on clinical efficacy and occurrence of nodular regenerative hyperplasia.. A total of 32 studies were included. The pooled clinical response rate of thioguanine therapy in IBD was 0.66 (95% C.I. 0.62 - 0.70; I. TG is an efficacious and well-tolerated drug in most patients with IBD. Nodular regenerative hyperplasia, cytopenias, and liver function abnormalities occur in a small subset. Future studies should look into TG as primary therapy in IBD.

Topics: Humans; Hyperplasia; Inflammatory Bowel Diseases; Prospective Studies; Retrospective Studies; Thioguanine

The potential therapeutic effect of thioguanine in the management of inflammatory bowel disease (IBD) is hindered due to association with vascular hepatotoxicity. The study aimed to assess the evidence for efficacy of thioguanine in IBD management and the association with nodular regenerative hyperplasia (NRH) and other thioguanine-related hepatotoxicities.. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for literature search. Due to the lack of randomized controlled trials (RCTs), the search was extended to observational studies. Quality of the included studies were graded A to C based on evaluation tools used to determine efficacy (subjective and objective grading tools) and nodular regenerative hyperplasia safety (liver biopsy and imaging tools).. Two hundred and ninety studies were identified, but following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines only 13 studies were evaluated for efficacy and safety of thioguanine. Outcome measures were consistent across the included studies. Thioguanine appeared efficacious and well-tolerated in patients who were intolerant/non-responsive to existing immunomodulators. There was a trend toward a positive association between dose of thioguanine and NRH but not with other adverse events such as liver biochemical abnormalities or with portal hypertension.. The evidence to support thioguanine treatment is limited to observational studies. While encouraging, there is a need for prospective RCTs to determine the role of thioguanine in the management of IBD.

Topics: Gastrointestinal Agents; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver; Observational Studies as Topic; Thioguanine

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.. 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.. Inflammatory bowel disease patients using 6-thioguanine for at least 30 consecutive months and consenting to undergo a liver biopsy were enrolled.. 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.. 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 19.5mg, 564 pmol/8 x 10(8) RBC, 38 months and 22491 mg, respectively.. 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.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Female; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver; Male; Middle Aged; Prospective Studies; Thioguanine; Treatment Outcome

Topics: Adolescent; Adult; Aged; Azathioprine; Female; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver Diseases; Male; Mercaptopurine; Middle Aged; Thioguanine; Young Adult

Thioguanine (TG) is a treatment for inflammatory bowel disease, but association with nodular regenerative hyperplasia has restricted its use. We conjectured that splitting a therapeutic daily dose of TG would be efficacious and should avoid liver toxicity.. We report on 62 patients with severe inflammatory bowel disease not responding to prednisolone, conventional thiopurines, biologics, or calcineurin inhibitors. Patients were prescribed oral split-daily TG to avoid individual doses >0.3 mg/kg. Data on concomitant medication, clinical efficacy measured by Harvey-Bradshaw Index for Crohn's, or Simple Clinical Colitis Score for ulcerative/indeterminate colitis (UC), and some paired endoscopies were available. Safety was followed clinically and with bloods at 2 centers. All patients at the U.K. center had a liver biopsy or magnetic resonance imaging after 6 months. Twenty-one patients had serial ultrasounds at the Australian center.. At 6 months, 19/21 of patients with Crohn's disease and 27/38 with ulcerative colitis had improved clinical activity. At study end, 53% of patients maintained improved clinical activity of steroids. Median duration of TG was 8 (0.3-45) months, median dose was 0.6 (0.3-1) mg/kg per day. Previous thiopurine-related adverse reactions were not encountered. Twenty-nine patients withdrew because of loss to follow-up, medical adverse events, or surgery. Possible early nodular regenerative hyperplasia was found on liver biopsy in 1 patient who was heterozygote deficient for thiopurine methyltransferase; the TG dose was lowered. TG was discontinued in a patient with nodular regenerative hyperplasia and concomitant antiphospholipid syndrome. There was 1 successful term pregnancy; cord blood and breast milk TG were low.. Split-dose TG seemed well tolerated and efficacious in this retrospective study of patients with difficult inflammatory bowel disease.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Chemical and Drug Induced Liver Injury; Cohort Studies; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver; Male; Middle Aged; Prognosis; Severity of Illness Index; Thioguanine; Young Adult

Topics: Antimetabolites; Colitis, Ulcerative; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Hyperplasia; Liver; Middle Aged; Thioguanine

Topics: Antimetabolites, Antineoplastic; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Humans; Hyperplasia; Liver; Thioguanine

6-Thioguanine is used in inflammatory bowel disease since 2001, with promising short-term results. In 2003, liver histology of some 6-thioguanine treated patients showed nodular regenerative hyperplasia. Recently, magnetic resonance imaging revealed nodular regenerative hyperplasia in patients with normal histology.. Investigating the presence of nodular regenerative hyperplasia in long-term 6-thioguanine treated patients.. Inflammatory bowel disease patients, using 6-thioguanine minimally 24 months, were asked to undergo liver biopsy and magnetic resonance imaging.. Fourteen patients used 6-thioguanine minimally 24 months, 13 participated. Mean 6-thioguanine therapy duration, daily dose and 6-thioguanine nucleotide levels were: 36 months, 18.8 mg (0.28 mg/kg) and 705 pmol/8x10(8) erythrocytes, respectively. Liver histology and magnetic resonance imaging showed no nodular regenerative hyperplasia.. Liver biopsy and magnetic resonance imaging showed no nodular regenerative hyperplasia in these long-term 6-thioguanine treated inflammatory bowel disease patients. 6-thioguanine dose and metabolite levels were lower compared with previous nodular regenerative hyperplasia reports, suggesting dose or metabolite level-dependent effects. Otherwise, nodular regenerative hyperplasia is related with inflammatory bowel disease itself and immunosuppressives, including azathioprine and 6-mercaptopurine.. 6-Thioguanine is debated due to nodular regenerative hyperplasia. We found no nodular regenerative hyperplasia in inflammatory bowel disease patients with long-term, low dosed 6-thioguanine, suggesting metabolite level-dependent effects. Therefore, 6-thioguanine still seems useful, but in selected patients, intolerant for other immunosuppressives, low dosed and under close surveillance of metabolite levels and hepatotoxity.

Topics: Adult; Biopsy; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Thioguanine

Although 6-thioguanine (6-TG) has been suggested as an effective treatment option for patients with inflammatory bowel disease (IBD), the recent description of its hepatotoxicity has led to the recommendation not to consider this drug. We initiated a multicenter safety study in IBD-patients treated with 6-TG to investigate hepatic changes by liver biopsy and magnetic resonance imaging (MRI).. Forty-five patients from three European centers treated with 6-TG (40-80 mg/d) at least for 8 weeks were enrolled. In all patients liver biopsy and MRI were performed. Slides and MR images were independently read by two pathologists and radiologists, respectively, and interpreted according to predefined criteria by consent.. In 8 patients nodular regenerative hyperplasia (NRH) was diagnosed by liver biopsy, in 8 additional patients NRH could not be excluded due to equivocal pathological findings. MRI demonstrated a sensitivity of 77% and a specificity of 72% in the detection of pathohistological findings consistent with and/or possibly related to NRH.. Our study suggests that 6-TG therapy in IBD patients is associated with NRH of the liver. Based on a special MRI protocol, non-invasive diagnosis of NRH with promising sensitivity and specificity was demonstrated.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Biopsy; Chemical and Drug Induced Liver Injury, Chronic; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Reproducibility of Results; Safety; Thioguanine; Time Factors; Treatment Outcome

Successful drug discovery requires accurate decision making in order to advance the best candidates from initial lead identification to final approval. Chemogenomics, the use of genomic tools in pharmacology and toxicology, offers a promising enhancement to traditional methods of target identification/validation, lead identification, efficacy evaluation, and toxicity assessment. To realize the value of chemogenomics information, a contextual database is needed to relate the physiological outcomes induced by diverse compounds to the gene expression patterns measured in the same animals. Massively parallel gene expression characterization coupled with traditional assessments of drug candidates provides additional, important mechanistic information, and therefore a means to increase the accuracy of critical decisions. A large-scale chemogenomics database developed from in vivo treated rats provides the context and supporting data to enhance and accelerate accurate interpretation of mechanisms of toxicity and pharmacology of chemicals and drugs. To date, approximately 600 different compounds, including more than 400 FDA approved drugs, 60 drugs approved in Europe and Japan, 25 withdrawn drugs, and 100 toxicants, have been profiled in up to 7 different tissues of rats (representing over 3200 different drug-dose-time-tissue combinations). Accomplishing this task required evaluating and improving a number of in vivo and microarray protocols, including over 80 rigorous quality control steps. The utility of pairing clinical pathology assessments with gene expression data is illustrated using three anti-neoplastic drugs: carmustine, methotrexate, and thioguanine, which had similar effects on the blood compartment, but diverse effects on hepatotoxicity. We will demonstrate that gene expression events monitored in the liver can be used to predict pathological events occurring in that tissue as well as in hematopoietic tissues.

Topics: 5-Aminolevulinate Synthetase; Animals; Antineoplastic Agents; Automation; Bile Ducts; Biotechnology; Carmustine; Computational Biology; Databases as Topic; Dose-Response Relationship, Drug; Down-Regulation; Drug Design; Drug Industry; Gene Expression; Humans; Hyperplasia; Liver; Male; Methotrexate; Nucleic Acid Hybridization; Oligonucleotide Array Sequence Analysis; Organ Size; Pharmacology; Rats; Rats, Sprague-Dawley; Reticulocytes; RNA; RNA, Complementary; Thioguanine; Time Factors; Tissue Distribution; Toxicology

Nodular hyperplasia (also referred to as nodular regenerative hyperplasia and nodular regenerative hyperplasia of the liver) is a sequel to therapy with thioguanine in patients with hematologic malignancies. Recently, 6-thioguanine has been used to treat patients with inflammatory bowel disease who have been resistant to other forms of therapy.. To study liver biopsies from 3 patients with inflammatory bowel disease who had received thioguanine for more than a year, and who had elevated serum liver enzyme values and underwent percutaneous liver biopsy.. Percutaneous liver biopsies and histologic examinations were performed, including staining with the reticulin silver impregnation method.. All 3 patients had foci of nodular regenerative hyperplasia, which was best seen with the reticulin silver impregnation method.. Thioguanine-treated inflammatory bowel disease patients are at risk for the development of nodular hyperplasia. Reticulin-stained histologic sections are necessary to recognize this change. Further studies are needed to determine the frequency and significance of this change.

Topics: Adult; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver; Male; Thioguanine

Topics: Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver; Thioguanine

Thioguanine (6-TG) has been studied as an alternative thiopurine in inflammatory bowel disease (IBD). Short-term safety and efficacy data were favorable. Experience with 6-TG in patients with acute lymphoblastic leukemia raised long-term safety concerns when implicated in nodular regenerative hyperplasia (NRH) of the liver and portal hypertension. The aim of this study was to describe the association between 6-TG and NRH in IBD.. Liver chemistries and complete blood counts were monitored, and patients were encouraged to undergo liver biopsy. Clinical data were collected by chart review, and associations were tested by univariate and multivariable analyses. Patients were classified based on the presence (group 1) or absence (group 2) of laboratory abnormalities.. Laboratory abnormalities occurred in 29 of 111 patients (26%). Elevations of liver enzymes and a decrease in platelet counts (<200,000) were most commonly observed. Male gender (odds ratio, 2.9; 95% CI, 1.1-7.3; P < 0.03) and preferential 6-methylmercaptopurine production on 6-mercaptopurine/azathioprine (odds ratio, 3.0; 95% CI, 1.2-7.4; P < 0.04) were independently associated with laboratory abnormalities. No association was seen with duration of 6-TG treatment, cumulative dose, or 6-TG nucleotide levels. The median increase in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels was 39, 30, and 75 U/L, respectively, in group 1, and the median decrease in platelet count was 115,000 in group 1 versus 7000 in group 2 (P < 0.001). NRH occurred in 76% of patients undergoing biopsy in group 1 and 33% in group 2.. NRH is a common finding in 6-TG-treated patients with IBD. The progression or reversibility of NRH remains unknown. Our findings suggest that 6-TG should not be considered as therapy for patients with IBD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biopsy; Female; Humans; Hyperplasia; Inflammatory Bowel Diseases; Liver; Male; Middle Aged; Thioguanine

5 patients receiving continuous busulphan and 6-thioguanine for chronic myeloid leukaemia (CML) were found to have oesophageal varices associated with abnormal liver function tests. 3 of these cases presented with gastrointestinal haemorrhage and 1 patient died. The 2 other cases had varices discovered at endoscopy. Nodular regenerative hyperplasia (NRH) of the liver was identified as the cause of portal hypertension in the 4 patients on whom liver biopsies were done. The administration of busulphan and thioguanine in combination is likely to be associated with the development of NRH, with portal hypertension and oesophageal varices occurring in a substantial proportion of cases.

Topics: Adult; Aged; Aged, 80 and over; Busulfan; Drug Therapy, Combination; Esophageal and Gastric Varices; Female; Gastrointestinal Hemorrhage; Humans; Hyperplasia; Leukemia, Myeloid; Liver; Male; Middle Aged; Thioguanine