thioguanine-anhydrous and Crohn-Disease

Thiopurines (azathioprine, mercaptopurine, thioguanine) and methotrexate are widely used in a variety of clinical management scenarios for ulcerative colitis and Crohn's disease. With the introduction of biologic therapies over the last 2 decades, controversies have emerged as to how these immunomodulators should be used in clinical practice, either alone as monotherapies or in combination with biologic therapies. Here, we provide a summary of evidence and our interpretations regarding how physicians can or should incorporate these agents into clinical practice. We have organized the review into sections regarding their utility as monotherapy or as combination therapy with biologics and safety considerations. Clinical pharmacologic considerations are important regarding both efficacy and safety.

Topics: Anti-Inflammatory Agents; Azathioprine; Biological Products; Clinical Decision-Making; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Mercaptopurine; Methotrexate; Purines; Risk Factors; Thioguanine; Treatment Outcome

Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug-Related Side Effects and Adverse Reactions; Humans; Mercaptopurine; Metabolic Networks and Pathways; Methyltransferases; Pharmacogenomic Testing; Pyrophosphatases; Thioguanine

Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: 'azathioprine', 'thiopurine', 'Crohn's disease', 'inflammatory bowel disease', 'nodular regenerative hyperplasia', 'mercaptopurine', 'thioguanine', 'ulcerative colitis'. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.

Topics: Animals; Antimetabolites; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Focal Nodular Hyperplasia; Gastrointestinal Agents; Humans; Pancreatitis; Risk Factors; Thioguanine; Treatment Outcome

Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far, a definite cure of the disease is still out of scope. An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy. Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine, are widely used in the therapy of chronic active inflammatory bowel disease (IBD). Their steroid sparing potential and efficacy in remission maintenance are out of doubt. Unfortunately, untoward adverse events are frequently observed and may preclude further administration or be life threatening. This review will focus on new aspects of thiopurine therapy in IBD, its efficacy and safety.

Topics: Animals; Anti-Infective Agents; Azathioprine; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Mercaptopurine; Patient Selection; Purines; Remission Induction; Risk Factors; Thioguanine; Treatment Outcome; Wound Healing

Nodular regenerative hyperplasia (NRH) is increasingly being recognised in patients with inflammatory bowel disease (IBD). However, the pathogenesis and incidence of NRH in IBD, and the putative roles played by azathioprine (AZA), mercaptopurine (MP), or tioguanine (TG) remain unclear.. To summarise the data on the association between NRH and thiopurine therapy in patients with IBD.. A literature search was performed in PubMed and MEDLINE databases using the keywords 'nodular regenerative hyperplasia AND (inflammatory bowel disease OR Crohn's disease OR ulcerative colitis) AND (azathioprine OR mercaptopurine OR tioguanine OR thioguanine).' No time limit was placed on studies included.. Inflammatory bowel disease patients treated with AZA have a cumulative incidence of NRH of approximately 0.6% and 1.28% at 5 and 10 years, respectively, whereas those treated with high-dose TG (>40 mg/day) have a frequency of NRH of up to 62%, which is higher in patients with elevated liver enzymes and/or thrombocytopaenia than those without these abnormalities (frequency 76% vs. 33%). Conversely, low-dose TG therapy (<20 mg/day) is relatively safe, with no cases of NRH observed. NRH has also been found in 6% of operated thiopurine-naïve IBD patients. Male gender, older age, and stricturing disease/small bowel resection have been consistently identified as high-risk factors for NRH.. The pathogenesis of nodular regenerative hyperplasia in patients with IBD is complex and multifactorial involving disease-specific, genetic and iatrogenic risk factors. Clinicians should maintain a high index of suspicion for diagnosing nodular regenerative hyperplasia, especially in IBD patients with high-risk factors on thiopurine therapy, regardless of the presence of laboratory abnormalities.

Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Female; Focal Nodular Hyperplasia; Humans; Immunosuppressive Agents; Incidence; Male; Mercaptopurine; Risk Factors; Thioguanine; Time Factors

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis, Rheumatoid; Azathioprine; Chlorambucil; Colitis, Ulcerative; Crohn Disease; Cyclophosphamide; Granulomatosis with Polyangiitis; Hepatitis; Humans; Immune Complex Diseases; Immunosuppressive Agents; Infections; Liver Cirrhosis, Biliary; Lupus Erythematosus, Systemic; Mercaptopurine; Methotrexate; Nephrotic Syndrome; Ophthalmia, Sympathetic; Psoriasis; Thioguanine; Uveitis

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

Adverse events (AE) leading to discontinuation or dose-reduction of thiopurine therapy (TP) occur in 9-28% of patients with inflammatory bowel disease. 6-Thioguanine (6-TG) has been proposed as an alternative treatment in patients intolerant for azathioprine (AZA), but some concerns have been raised about drug safety.. We evaluated in a prospective manner the tolerance and efficacy of 6-TG in 23 Crohn's disease (CD) patients (13 men, median age 41 (19-65) years) with prior intolerance (n=18) or resistance (n=5) to AZA and/or 6-mercaptopurine (6-MP). In addition, eight patients had tried mycophenolate mofetil. Seventeen patients (74%) had undergone intestinal resection, often several times.. Patients were treated with a median daily dose of 40 mg 6-TG (range 20-60) for 259 (15-2272) days. Seven of 13 patients (54%) with active disease went into remission after 8 (4-26) weeks. Sixteen patients (70%) experienced AE that lead to discontinuation (n=10) after 85 (15-451) days or dose reduction (n=6) after 78 (10-853) days. Ten of 18 patients (56%) with prior TP-intolerance discontinued 6-TG treatment due to AE compared to none of five patients with TP-resistance (p=0.046). Of 13 patients that tolerated 6-TG, eight discontinued the drug due to therapeutic failure (n=5) or safety concerns (n=3). Eight patients (35%) continued treatment beyond 12 months. There was no significant difference in maximum thioguanine nucleotide levels between patients with AE leading to discontinuation/dose reduction and patients without AE, 652 (99-2488) vs. 551 (392-1574) pmol/8 x 10(8) RBC; p=0.80.. In this cohort of CD patients with severe disease failing traditional thiopurine treatment, a small fraction (22%) had long-term benefit of 6-TG-treatment. 6-TG therapy seems to offer a limited therapeutic gain for patients intolerant to both AZA and 6-MP and other treatment options should be considered.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Azathioprine; Crohn Disease; Drug Resistance; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Prospective Studies; Remission Induction; Severity of Illness Index; Sweden; Thioguanine; Young Adult

There have been no reports on 6-thioguanine nucleotide (6-TGN) concentrations in Japanese patients with inflammatory bowel disease (IBD) undergoing azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy. The aim of this study was to assess 6-TGN concentrations in Japanese IBD patients.. Eighty-three patients with Crohn's disease (n = 42) and ulcerative colitis (n = 41) were enrolled. In 69 patients, AZA was prescribed at 50 mg/day, and seven patients were given 75 (n = 5) or 100 mg/day (n = 2). 6-MP was administered at 30 mg/day (n = 7). The 6-TGN concentrations were then assayed by high-performance liquid chromatography.. The mean 6-TGN concentrations of the entire study population (n = 83) were 277.9 +/- 179.8 pmol/8 x 10(8) red blood cells (RBC). The mean 6-TGN concentrations in those patients with active disease (n = 38) and those in remission (n = 45) were 232.9 +/- 159.7(mean +/- SD) and 342.8 +/- 184.6 pmol/8 x 10(8) RBC, respectively (P < 0.05). The odds ratio of being in remission and having a 6-TGN value >235 pmol/8 x 10(8) RBC was 2.6 (95% CI 1.05-6.2). A significant inverse correlation was found between the white blood cell (WBC) counts and 6-TGN concentrations (r = -0.301, P < 0.05, n = 83); the mean WBC counts of the active patients (6780 +/- 2412) were significantly higher than the patients in clinical remission (5468 +/- 1920, P < 0.05). Three patients with severe leukopenia and 10 patients with high 6-TGN concentrations had no thiopurine S-methyl transferase mutations.. The 6-TGN concentrations in Japanese patients with IBD on low-dose AZA and 6-MP therapy were comparable to those reported from Western countries. The monitoring of 6-TGN concentrations may be helpful for developing a therapeutic strategy for Japanese IBD patients.

Topics: Administration, Oral; Azathioprine; Biomarkers, Pharmacological; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Erythrocyte Count; Humans; Immunosuppressive Agents; Japan; Leukocyte Count; Mercaptopurine; Methyltransferases; Mutation; Odds Ratio; Remission Induction; Thioguanine; Treatment Outcome

The proposed metabolic advantage of 6-thioguanine (6-TG) is the direct conversion into the pharmacologically active 6-thioguaninenucleotides (6-TGN). The authors assessed metabolic characteristics of 6-TG treatment in patients with Crohn's disease (N = 7) on therapy with 20 mg 6-TG. 6-thioguanine-monophosphate (6-TGMP), 6-thioguanine-diphosphate (6-TGDP), and 6-thioguanine-triphosphate (6-TGTP) were measured by high-performance liquid chromatography analysis in erythrocytes. Thiopurine S-methyltransferase activity and total 6-TGN levels were determined by standard methods. High interindividual variance in metabolite measurements was observed. Main metabolites were 6-TGTP (median = 531 pmol/8 x 10(8) red blood cells) and 6-TGDP (median = 199 pmol/8 x 10(8) red blood cells). Traces of 6-TGMP (median = 39 pmol/8 x 10(8) red blood cells) and 6-TG (2 patients) could be detected. 6-TGN levels correlated with 6-TGTP levels (r = 0.929, P = .003) and with the sum of separate nucleotides (r = 0.929, P = .003). No correlations were established between TPMT activity (median = 13 pmol/h/10(7)) and 6-TG metabolites. The 1-step metabolism of 6-TG still leads to high interindividual variance in metabolite concentrations. Total 6-TGN level monitoring may suffice for clinical practice.

Topics: Adult; Crohn Disease; Erythrocytes; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Male; Middle Aged; Thioguanine; Thionucleotides

Thiopurine methyltransferase (TPMT) activity determines biotransformation of azathioprine and, thereby, drug efficacy and safety. Evaluation of a possible long-term effect of mesalazine or azathioprine on TPMT activity is of particular clinical importance because both drugs can to be given for several years in inflammatory bowel disease. Monitoring of TPMT activity and three thiopurine metabolites was performed prospectively during a 1 year postoperative period in 21 patients with Crohn's disease randomly assigned to azathioprine (2.0-2.5 mg/kg per day) or mesalazine (4 g/day). TPMT activity did not change significantly within each treatment group during 52 weeks. At any study visit, TPMT activity was not different between 13 patients on azathioprine and eight patients on mesalazine. Concentrations of 6-thioguanine nucleotides (6-TGN, active moiety of azathioprine) and 6-methyl-mercaptopurine ribonucleotides (6-MMPR) did not alter significantly during the observation period, except for a slight decrease in 6-TGN levels when comparing the first with the last visit. In this first report of serial monitoring of 6-methyl-thioguanine nucleotides (6-MTGN) in patients with inflammatory bowel disease taking azathioprine, high levels of 6-TGN were correlated with high levels of 6-MTGN, with the mean 6-TGN:6-MTGN ratio being 2.4. In a well-standardized clinical setting of inflammatory bowel disease, neither mesalazine nor azathioprine significantly affected TPMT activity during a whole year of treatment.

Topics: Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Crohn Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Female; Gene Frequency; Genotype; Guanine Nucleotides; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Mesalamine; Methyltransferases; Middle Aged; Phenotype; Postoperative Period; Prospective Studies; Thioguanine; Thionucleotides; Time Factors

Tioguanine (thioguanine) has been suggested as a therapeutic alternative for patients with Crohn's disease resistant or intolerant to azathioprine or mercaptopurine. However, pharmacokinetic data on tioguanine in inflammatory bowel disease are missing.. To determine the disposition of three different 40 mg tablet preparations of tioguanine in patients with Crohn's disease.. Six patients with chronic active Crohn's disease were included in a randomized, cross-over, single-dose study. Pharmacokinetic analysis was based on plasma concentrations of tioguanine during 6 h after dosing. Tioguanine was measured by a validated high-pressure liquid chromatographic method.. The areas under the curve (AUC) varied 4-7-fold between patients. In two patients, tioguanine was not detected in plasma following the intake of one of the three tablets; another patient did not absorb tioguanine in two of the three different preparations. No significant differences were found in the AUC and Cmax values between the three tablets. In all patients, there was a second peak in plasma concentration following a meal 3 h after drug administration.. The absorption of tioguanine is highly variable in patients with Crohn's disease, which may be responsible for treatment failure. Therapy with tioguanine may be improved by monitoring tioguanine nucleotides as a surrogate parameter of efficacy.

Topics: Adult; Anti-Inflammatory Agents; Crohn Disease; Cross-Over Studies; Female; Humans; Intestinal Absorption; Male; Middle Aged; Thioguanine; Treatment Outcome

A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy.. Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities.. Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity.. 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.

Topics: Adult; Antimetabolites; Azathioprine; Child; Crohn Disease; Drug Resistance; Female; Humans; Male; Maximum Tolerated Dose; Mercaptopurine; Middle Aged; Pilot Projects; Thioguanine; Treatment Outcome

Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response.. A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of

Topics: Administration, Oral; Adult; Azathioprine; Crohn Disease; Dose-Response Relationship, Drug; Double-Blind Method; Erythrocytes; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infusions, Intravenous; Leukocyte Count; Male; Methyltransferases; Middle Aged; Prednisone; Remission Induction; Thioguanine

6-Mercaptopurine (6-MP) has confirmed short and longterm efficacy in the treatment of IBD. However, the relation between its metabolism, efficacy, and side effects is not well understood.. To assay 6-MP metabolites and to correlate levels with drug compliance, disease activity, and adverse effects of treatment.. Heparinised blood was obtained prior to daily administration of 6-MP in 25 adolescent Crohn's disease patients (14 ileocolitis, 11 colitis) receiving 1.2 (range 0.4-1.6) mg/kg/day for a mean of 17 (range 4-65) months.. Erythrocyte free bases 6-thioguanine (6-TG) and 6-methyl-mercaptopurine (6-MMP) were measured (pmol/8 x 10(8) red blood cells) using reverse phase high performance liquid chromatography.. Disease activity (modified Harvey-Bradshaw index) improved significantly with 6-MP (p = 0.001). Clinical remission was achieved in 72% of patients, who stopped taking prednisone, or were successfully weaned to a low alternate day dose (< 0.4 mg/kg/OD). Remission correlated well with erythrocyte 6-TG (p < 0.05), but not 6-MMP levels. Neutropenia was associated with 6-MP use (p < 0.005), but did not correlate with erythrocyte 6-MP metabolite levels. One patient refractory to 6-MP had 6-TG, but no measureable 6-MMP production, suggesting deficient thiopurine methyl-transferase activity or poor compliance. 6-MP induced complications (hepatitis, pancreatitis, and marrow suppression) were generally associated with increased 6-MMP levels.. These results suggest that high performance liquid chromatography measurement of erythrocyte 6-MP metabolites may provide a quantitative assessment of patient responsiveness and compliance to treatment. The data support an immunosuppressive role for 6-TG, and potential cytotoxicity of raised 6-MMP levels.

Topics: Adolescent; Adult; Child; Chromatography, High Pressure Liquid; Crohn Disease; Erythrocytes; Humans; Immunosuppressive Agents; Mercaptopurine; Patient Compliance; Thioguanine; Treatment Outcome

Thioguanine is an alternative thiopurine for inflammatory bowel disease (IBD) patients.. To evaluate the short-term efficacy and safety of low-dose therapeutic drug-monitored (TDM) thioguanine.. A retrospective evaluation of IBD patients intolerant to conventional thiopurines started on thioguanine from 2017 to 2019 with dosing guided by TDM was conducted. Clinical response was defined for ulcerative colitis (UC) as a reduction of partial Mayo score ≥3 with reduction in rectal bleeding score of at least 1 and a final rectal bleeding subscore of 0-1 at Week 12 of therapy. Crohn disease (CD) response was defined as a reduction of Harvey-Bradshaw index ≥3 (HBI) at Week 12 of therapy. Remission was defined in UC as partial Mayo score of <2 and in CD as HBI score of <5.. Forty-six patients were included in the study. The median thioguanine dose was 20 mg/day (standard deviation 7.3; range: 10-40 mg/day) with a median 6-thioguanine nucleotide level of 577 pmol/8 × 108 (interquartile range (IQR) IQR 378.5-878.75) for CD and 677.5 pmol/8 × 108 (IQR 523.25-842.25) for UC. The overall clinical response rate was 62% (13/21), intention to treat (ITT). Maintenance of remission was 76% (19/25, ITT). Thirty-seven percent (17/46) of patients experienced an adverse effect. No early cases of nodular regenerative hyperplasia (NRH) were seen.. Thioguanine was tolerated well in 63% of patients. A clinical response was seen in 62% of patients, and maintenance of remission was high at 76%. No cases of early NRH were seen. Longer-term follow up is required to ensure safety and to assess durability of response.

Topics: Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Humans; Inflammatory Bowel Diseases; Retrospective Studies; Thioguanine

Both methotrexate and tioguanine can be considered as treatment options in patients with Crohn's disease after failure of conventional thiopurines. This study aimed to compare tolerability and drug survival of methotrexate and tioguanine therapy after failure of conventional thiopurines in patients with Crohn's disease.. We conducted a retrospective, multicentre study, including patients with Crohn's disease initiating monotherapy methotrexate or tioguanine after failure [all causes] of conventional thiopurines. Follow-up duration was 104 weeks or until treatment discontinuation. The primary outcome was cumulative therapy discontinuation incidence due to adverse events. Secondary outcomes included total number of [serious] adverse events, and ongoing monotherapy.. In total, 219 patients starting either methotrexate [n = 105] or tioguanine [n = 114] were included. In all 65 [29.7%] patients (methotrexate 43.8% [46/105 people], tioguanine 16.7% [19/114 people], p <0.001) discontinued their treatment due to adverse events during follow-up. Median time until discontinuation due to adverse events was 16 weeks (interquartile range [IQR] 7-38, p = 0.812). Serious adverse events were not significantly different. Patients treated with methotrexate experienced adverse events more often [methotrexate 83%, tioguanine 46%, p <0.001]. Total monotherapy drug survival after 104 weeks was 22% for methotrexate and 46% for tioguanine [p <0.001].. We observed a higher cumulative discontinuation incidence due to adverse events for methotrexate [44%] compared with tioguanine [17%] in Crohn's disease patients after failure of conventional thiopurines. The total adverse events incidence during methotrexate use was higher, whereas serious adverse events incidence was similar. These favourable results for tioguanine treatment may guide the selection of immunosuppressive therapy after failure of conventional thiopurines.

Topics: Crohn Disease; Humans; Immunosuppressive Agents; Methotrexate; Retrospective Studies; Thioguanine; Treatment Outcome

Thiopurines are drugs widely used in patients for the maintenance of remission in inflammatory bowel disease. The optimal plasma levels are known, but there is controversy about whether the need for other drugs is reduced or is cost-effective. The aim of this study is to describe the use of the optimised treatment with thiopurines in paediatric patients with inflammatory bowel disease followed up in this Unit since the introduction of determining the drug levels.. A descriptive retrospective study was conducted in which the plasma values of 6-thioguanine (6-TGN), 6-methyl-mercapto-purine (6-MMP), and their ratios were analysed using liquid chromatography. Other variables were collected, such as clinical status, analytical and demographic variables of patients with inflammatory bowel disease followed up in this Unit.. A total of 72 patients were included, and 149 determinations of metabolites were performed. The 6-TGN levels were found to below the therapeutic range in 61.5% of patients (in 7 cases due to lack of adherence to therapy), and 6-MMP was in the toxicity range in 7.4%. After the determination of 77 specimens, some action was taken, such as modifying the dose, change of formula, or withdrawing the drug. Only 9 patients were scaled to a biological drug (13.4% of the total on single therapy). No association was found between the activity of the disease and the thiopurine levels.. In our experience, the monitoring of thiopurine levels helped to modify the drug dose that the patient received, adjusting their therapeutic levels, and potentially avoiding the addition of new drugs.

Topics: Adolescent; Child; Child, Preschool; Chromatography, Liquid; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Mercaptopurine; Retrospective Studies; Thioguanine; Treatment Outcome

Thiopurine and allopurinol in combination are associated with clinical remission in inflammatory bowel diseases but their influence on subsequent outcomes is unclear. We compared outcomes during exposure to both thiopurines and allopurinol versus thiopurines alone.. We established a nationwide cohort of patients with inflammatory bowel diseases exposed to thiopurines ± allopurinol during 1999-2014, using registry data. Patients were followed until hospitalization, surgery, anti-TNFα, or death (as a primary composite outcome). We used Poisson regression analyses to calculate incidence rate ratios overall and stratified by calendar period (assuming the combined exposure was unintended before 2009).. A total of 10,367 patients with inflammatory bowel diseases (Crohn's disease,. Our nationwide inflammatory bowel disease cohort study shows that concomitant thiopurine-allopurinol is as safe to use as thiopurines alone, with a tendency towards a positive effect on clinical outcomes in recent calendar periods when combined use was intended.

Topics: Adult; Allopurinol; Azathioprine; Colitis, Ulcerative; Crohn Disease; Denmark; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Middle Aged; Remission Induction; Severity of Illness Index; Signal Transduction; Thioguanine; Treatment Outcome

Off-label prescribing is encountered across various fields of medicine and creates alternative treatment options, but is associated with unknown safety risks. The use of off-label drugs for the treatment of patients with inflammatory bowel diseases (IBD) has not been characterised before.. To assess the proportion and characteristics of off-label prescribing for IBD in tertiary care centres in the Netherlands.. A prospective database of IBD patients from all Dutch university hospitals was used to collect data on drug prescriptions for IBD and demographics. Drugs were classified as off-label if they were unlicensed for Crohn's disease and/or ulcerative colitis by the Medicines Evaluation Board. Uni- and multivariable analyses were used to identify patient-specific characteristics predictive of increased off-label use.. For the induction and/or maintenance treatment of 4583 IBD patients, 12 651 historical and current drug records were available in the database. Of these, 2374 (19%) were considered off-label prescriptions. Out of 4583 IBD patients, 1477 (32%) were exposed to off-label drugs. Commonly prescribed off-label IBD drugs were mercaptopurine (18%), beclomethasone (12%), thioguanine (4%) and allopurinol (3%). Non-thiopurine/methotrexate off-label drugs were prescribed in 243 patients (6%), including biological agents or tofacitinib in 47 IBD patients (1%). Off-label prescriptions were more common in ulcerative colitis than Crohn's disease (37% vs 29%, P < 0.001). Smokers and patients that received ≥5 drug types during their disease course were more likely to be exposed to off-label drugs (smoking 33% vs 27% and multiple drug use 66% vs 22%, both P < 0.001).. About one-fifth of prescriptions for IBD were off-label and one-third of IBD patients, especially ulcerative colitis patients, were exposed to off-label drugs.

Topics: Adolescent; Adult; Allopurinol; Beclomethasone; Colitis, Ulcerative; Crohn Disease; Databases, Factual; Female; Humans; Male; Mercaptopurine; Methotrexate; Netherlands; Off-Label Use; Thioguanine; Young Adult

Topics: Apoptosis; Azathioprine; Case-Control Studies; Crohn Disease; Humans; Inflammation; Intestinal Mucosa; Leukocytes, Mononuclear; Macrophages; Monocytes; Peptidoglycan; rac1 GTP-Binding Protein; Signal Transduction; Thioguanine

Level of 6-thioguanine nucleotides (6-TGN) has been reported to be associated with clinical remission in patients with Crohn's disease (CD) receiving maintenance treatment with thiopurines. Whether 6-TGN levels are associated with mucosal healing (MH) has seldom been investigated. We aimed to assess the correlation between 6-TGN levels and MH in patients with CD.. This was a retrospective, cross-sectional, observational, multicenter study of 119 patients with CD treated with thiopurines in 3 inflammatory bowel disease referral centers (France, Australia, and China) between June 2012 and April 2016. Established CD patients who underwent ileocolonoscopy during thiopurine treatment were included. MH was defined as simple endoscopic score-CD <3. Univariate and multivariable regression analyses were used to evaluate variables associated with MH.. The mean concentration of 6-TGN in the MH group was higher compared with that in the non-MH group (359.0 ± 226.7 pmol/8 × 108 red blood cell count [RBC] vs 277.1 ± 170.5 pmol/8 × 108 RBC; P = 0.017). The cutoff 6-TGN concentration of 397.3 pmol/8 × 108 RBC was 86.7% specific to MH, with a sensitivity of 35.3% and area under curve (AUC) of 0.631 (P = 0.010). On multivariable analysis, 6-TGN levels were associated with MH (odds ratio [OR], 3.287; 95% confidence interval [CI], 1.348-8.017; P = 0.009) whereas late initiation of AZA (longer duration from disease onset) was inversely associated with MH (OR, 0.972; 95% CI, 0.954-0.991; P = 0.004).. Higher 6-TGN levels are independently associated with a reduced rate of endoscopically active disease and a higher rate of mucosal healing in CD patients. Prospective studies of adequate sample size are required to confirm these findings.

Topics: Adolescent; Adult; Australia; Azathioprine; Biomarkers; China; Crohn Disease; Cross-Sectional Studies; Drug Monitoring; Endoscopy, Gastrointestinal; Female; France; Guanine Nucleotides; Humans; Immunosuppressive Agents; Linear Models; Male; Mucous Membrane; Multivariate Analysis; Retrospective Studies; ROC Curve; Thioguanine; Thionucleotides; Young Adult

Two meta-analyses have found that the risk of relapse in Crohn's disease (CD) was ~40 and 50% 1 and 2 years, respectively, after withdrawal of anti-tumour necrosis factor-α (anti-TNFα). The aim of this study was to evaluate relapse rates in CD when thiopurine therapy was optimized before anti-TNFα withdrawal.. An observational study was conducted including patients with CD in remission with optimized thiopurine therapy before anti-TNFα withdrawal. We defined optimized thiopurine therapy as 6-thioguanine levels of at least 150 nmol/mmol haemoglobin (∼300 pmol×10 red blood cells) and clinical/biochemical remission as Harvey-Bradshaw Index of 5 or less and faecal calprotectin of 200 µg/g or less.. We included 33 patients (median age: 31 years, 55% males, and median disease duration: 7 years) followed for a median of 36 months. A total of three (9%) patients relapsed during the first year and six patients (in total 27%) relapsed after 2 years. After 2 years, none of the additional patients relapsed. The disease duration and duration of anti-TNFα treatment and faecal calprotectin levels before inclusion did not predict relapse. Calprotectin levels of at least 180 after 1 year predicted relapse at year 2.. This study found that 73% of patients with CD maintained remission (>2 years) when thiopurine therapy was optimized before withdrawal of anti-TNFα. Additional prospective evidence is needed to confirm the findings.

Topics: Adalimumab; Adult; Crohn Disease; Feces; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Leukocyte L1 Antigen Complex; Male; Mercaptopurine; Recurrence; Thioguanine; Tumor Necrosis Factor-alpha; Withholding Treatment; Young Adult

Patient-reported outcomes and experiences are indicative of the impact and the quality of care. Thioguanine, a generic drug initially developed for leukemia, has been explored and relicensed as a certified treatment for patients with inflammatory bowel diseases (IBD). The patients' perception of this treatment has not been evaluated before. In this study, we aimed to assess self-reported experiences with thioguanine for IBD.. Questionnaires were sent out to members of the Dutch National Crohn's and Colitis patient organization. The Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) was used to address questions regarding the satisfaction and impact of thioguanine therapy on the disease and their daily life. Furthermore, data on demographics, disease and (historical) treatment characteristics were collected. Open-ended questions were used for additional comments to the questionnaire.. A total of 173 organization members (73% female) reported to be previous or current users of thioguanine. A total of 74% were satisfied with the effectiveness of thioguanine, whereas 5% were not. Eighty percent of the respondents were satisfied with the quality of care. A good or excellent impact on daily life was reported by 54%. A neutral or bad impact on daily life was reported by 40% and 6%, respectively. Improvement of disease activity was reported by 58%. This remained stable or worsened in 39% and 3%, respectively.. In this self-report survey, among thioguanine treated patients with IBD who had failed with traditional therapies, 80% reported satisfaction with medical care and 74% with the effectiveness of the therapy. In the evaluation of new or rediscovered therapies, patient-reported outcomes and experiences should be considered as a key instrument.

Topics: Activities of Daily Living; Adult; Anti-Inflammatory Agents; Colitis, Ulcerative; Cost of Illness; Crohn Disease; Drug Approval; Drugs, Generic; Female; Gastrointestinal Agents; Health Care Surveys; Humans; Male; Middle Aged; Netherlands; Patient Reported Outcome Measures; Patient Safety; Patient Satisfaction; Remission Induction; Risk Assessment; Risk Factors; Thioguanine; Treatment Outcome

The benefit of concomitant immunomodulation with adalimumab (ADA) in Crohn's disease is poorly understood. We aimed to compare ADA monotherapy with combination therapy with thiopurines, stratified by thioguanine nucleotides (TGNs).. Retrospective observational study of ADA induction and maintenance. Thiopurines were classified according to TGNs (>235 pmol/8 × 10 red blood cell therapeutic).. At induction, response was more frequent in combination than ADA monotherapy (83% versus 61%, P = 0.02) and with therapeutic compared with subtherapeutic TGNs (87% versus 70% P = 0.011). Among 280 maintenance semesters in 91 patients, remission was higher with combination than monotherapy (81% versus 60%, P < 0.0001) and therapeutic versus subtherapeutic TGNs (85% versus 58%, P = 0.004). Therapeutic TGN (odds ratio [OR] 4.32, 95% CI, 1.41-13.29, P = 0.01) and albumin (OR 1.09, 95% CI, 1.01-1.18, P = 0.03) were predictors of response to induction. Therapeutic TGN (OR 3.71, 95% CI, 1.87-7.34, P < 0.0001) and ileal disease (OR 0.21, 95% CI, 0.08-0.57, P = 0.002) were predictors of remission semesters. Concomitant immunomodulation at induction was associated with longer time to failure (69 versus 36 months, P = 0.009). Therapeutic TGN at induction (P = 0.03) and male sex (P = 0.026) were associated with time to failure.. Combination therapy was superior to ADA monotherapy for induction and during maintenance. This benefit was increased further when thiopurines resulted in therapeutic TGNs. Early use of adequately dosed thiopurines (≥3 months before starting ADA) was associated with improved clinical outcomes.

Topics: Adalimumab; Adolescent; Adult; Crohn Disease; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Maintenance Chemotherapy; Male; Mercaptopurine; Retrospective Studies; Thioguanine; Treatment Outcome; Young Adult

Postoperative recurrence of Crohn's disease is common. This study sought to assess whether the postoperative management should be based on biological therapy alone or combined with thiopurines and whether the therapy should be started immediately after surgery or guided by either endoscopic or clinical recurrence.. A Markov model was developed to estimate expected health outcomes in quality-adjusted life years (QALYs) and costs in Canadian dollars (CAD$) accrued by hypothetical patients with high recurrence risk after ileocolic resection. Eight strategies of postoperative management were evaluated. A lifetime time horizon, an annual discount rate of 5%, a societal perspective, and a cost-effectiveness threshold of 50,000 CAD$/QALY were assumed. Deterministic and probabilistic sensitivity analyses were conducted. The model was validated against randomized trials and historical cohorts.. Three strategies dominated the others: endoscopy-guided full step-up therapy (14.80 QALYs, CAD$ 462,180), thiopurines immediately post-surgery plus endoscopy-guided biological step-up therapy (14.89 QALYs, CAD$ 464,099) and combination therapy immediately post-surgery (14.94 QALYs, CAD$ 483,685). The second strategy was the most cost-effective, assuming a cost-effectiveness threshold of 50,000 CAD$/QALY. Probabilistic sensitivity analysis showed that the second strategy has the highest probability of being the optimal alternative in all comparisons at cost-effectiveness thresholds from 30,000 to 100,000 CAD$/QALY. The strategies guided only by clinical recurrence and those using biologics alone were dominated.. According to this decision analysis, thiopurines immediately after surgery and addition of biologics guided by endoscopic recurrence is the optimal strategy of postoperative management in patients with Crohn's disease with high risk of recurrence (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B654).

Topics: Adult; Biological Therapy; Canada; Cost-Benefit Analysis; Crohn Disease; Decision Support Techniques; Endoscopy; Female; Humans; Male; Markov Chains; Mercaptopurine; Postoperative Period; Quality-Adjusted Life Years; Recurrence; Thioguanine

Impact of first-line induction therapy on medium-term outcomes in the setting of early thiopurine (TP) use in children with Crohn's disease has not been evaluated, in particular whether choice of exclusive enteral nutrition (EEN) over corticosteroids (CS) for induction impacts clinical outcomes at 12 and 24 months.. In this retrospective study, 89 children from our database with new diagnosis CD and follow-up of at least 2 years following induction with exclusive course of CS or EEN and early, dose-optimized TP (within 6 months from diagnosis) were evaluated. We compared steroid dependency (relapse <3 months of tapering first course CS or inability to wean <10 mg prednisolone), need for IFX, linear growth, and surgical resections over the first 2 years.. Choice of EEN over CS induction was associated with reduced linear growth failure (7 vs. 26%, p = 0.02), CS dependency (7 vs. 43%, p = 0.002), and improved primary sustained response to IFX (86 vs. 68%, p = 0.02). Combined CS/IFX-free remission and surgical resection rates were similar.. In the setting of early TP commencement, EEN induction is superior to CS induction for reducing growth failure, CS dependency, and loss of response to IFX over the first 2 years.

Topics: Adolescent; Child; Cohort Studies; Crohn Disease; Databases, Factual; Drug Administration Schedule; Enteral Nutrition; Female; Follow-Up Studies; Glucocorticoids; Hospitals, Pediatric; Humans; Infliximab; Male; Prednisolone; Queensland; Recurrence; Remission Induction; Retrospective Studies; Risk Assessment; Severity of Illness Index; Thioguanine; Time Factors; Treatment Outcome

In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD.

Topics: Animals; Biopsy; Crohn Disease; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Enzyme Inhibitors; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Hydrolysis; Immunity, Innate; Inflammation; Intestinal Mucosa; Protein Kinases; rac1 GTP-Binding Protein; Remission Induction; Signal Transduction; Thioguanine

Metabolite monitoring and response predictors to azathioprine (AZA) in pediatric inflammatory bowel disease (IBD) are debatable. In an attempt to optimize thiopurine therapy and understand the mechanism of action of thiopurines, we correlated metabolites and other factors with AZA efficacy in children with IBD.. Data from 86 children with IBD with 440 metabolite measurements were retrospectively analyzed using multilevel logistic regression analyses. A therapeutic response was defined as a pediatric Crohn's disease activity index ≤10 for Crohn's disease or a pediatric ulcerative colitis activity index ≤10 for ulcerative colitis without any treatment with steroids, antitumor necrosis factor, other immunomodulators, or exclusive enteral nutrition.. The 6-thioguanine nucleotide levels >250 pmol per 8 × 10 red blood cells correlated with a higher response (odds ratio, 4.14; 95% confidence interval, 1.49-11.46, P = 0.007), whereas 6-methyl-mercaptopurine and 6-methyl-mercaptopurine:6-thioguanine nucleotide ratio showed no correlation. Other novel response predictors in children with IBD were relative leukopenia (odds ratio, 14.01; 95% confidence interval, 3.77-52.10; P < 0.001) and the absence of lymphopenia (odds ratio, 3.71; 95% confidence interval, 1.26-10.89; P = 0.017). Lower thiopurine methyltransferase activity (P = 0.015), lower platelet count (P = 0.020), and higher aspartate aminotransferase level (P = 0.009) also predicted therapeutic response. Age, gender, patient adherence, the duration of AZA therapy, IBD type, erythrocyte count, and erythrocyte sedimentation rate did not predict efficacy. The high interindividual variability accounting for 57.7% of variance in therapeutic response was observed.. The significant 6-thioguanine nucleotide level-response relationship may support metabolite monitoring to improve thiopurine efficacy in pediatric IBD. The reported response predictors may be helpful for treatment optimization in AZA-treated children with IBD, but should be proved in prospective studies.

Topics: Adolescent; Azathioprine; Biomarkers; Child; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; Humans; Male; Prognosis; Retrospective Studies; Thioguanine

Thiopurine immunosuppressants such as 6-mercaptopurine (6-MP) are widely used to maintain remission in children with both Crohn's disease and ulcerative colitis. Therapeutic efficacy is associated with higher red blood cell levels of the thiopurine metabolite 6-thioguanine (6-TGN). Studies in both children and adults have inexplicably failed to demonstrate a significant correlation between prescribed dose and level of 6-TGN. We aimed to quantify the relationship between 6-TGN levels and adherence.. We used electronic monitoring devices to assess adherence in children and adolescents with inflammatory bowel diseases who were prescribed 6-MP.. During 3230 days of monitoring in 19 subjects, adherence to 6-MP was 74.2%. Due to the generally low adherence to the prescribed dose of 6-MP, the 6-TGN level was not correlated with the prescribed dose. The 6-TGN level was significantly correlated with the adherence-adjusted dose (R(2) = 0.395). It was also significantly correlated to adherence alone (R(2) = 0.478). Adherence to 5-aminosalicylic acid and 6-MP were significantly positively correlated (r(s)(9) = 0.82, P = 0.00), and a significant relationship was found between 5-aminosalicylic acid adherence and 6-TGN levels independent of 6-MP adherence. Furthermore, low adherence to 6-MP was associated with increased likelihood of escalation of medical therapy.. Red blood cell 6-TGN levels are strongly correlated with the dose, when the dose is actually taken. Lack of efficacy of thiopurines may often be the result of poor adherence. Novel ways of assessing and improving adherence are necessary. Future trials should assess adherence in study participants. Intake of 5-aminosalicylic acid positively influences 6-TGN levels.

Topics: Adolescent; Adult; Child; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Monitoring; Erythrocytes; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Medication Adherence; Prognosis; Severity of Illness Index; Thioguanine; Young Adult

The value of azathioprine metabolites (6-thioguanine nucleotides [6-TGN]) in monitoring clinical treatment response is still controversially discussed. Data regarding thiopurine metabolite levels and endoscopic improvement are lacking.. Data were analyzed post hoc from a 1-year, multicenter, double-blind, double-dummy, randomized trial comparing azathioprine 2.0 to 2.5 mg/kg per day versus mesalamine 4 g/d in a subset of 23 postoperative patients with Crohn's disease (CD) treated with azathioprine and having moderate-to-severe endoscopic recurrence according to a modified 6-grade score. Red blood cell (RBC) concentrations of 6-TGN, 6-methyl-mercaptopurine ribonucleotides (6-MMPR), and 6-methyl-thioguanine nucleotides (6-MTGN) were indicated as follows: area under the concentration-time curve, average concentration (C av), and concentration at the final study visit.. Overall, 74% of patients showed an improvement in the modified endoscopic score (P = 0.022). Median endoscopic score reduced from 4 at the baseline to 2 at the final visit. Patients with a high C av for 6-TGN (≥ 193 pmol/8 × 10(8) RBC; P = 0.017) or 6-MTGN (≥ 79.2 pmol/8 × 10(8) RBC; P = 0.035) significantly improved in endoscopic score, and the improvement in endoscopic score correlated with C av for 6-TGN (r = -0.51; P = 0.013). For concentration at the final visit, higher values for 6-TGN (≥ 142 pmol/8 × 10(8) RBC; P = 0.017) were associated with a better postoperative score. Sensitivity analysis revealed a significant correlation between 6-TGN (area under the concentration-time curve) and postoperative endoscopic improvement.. Our post hoc analysis from a double-blind, randomized trial suggests that higher RBC 6-TGN levels are associated with endoscopic improvement in patients with severe postoperative endoscopic recurrence of CD. Thus, our study provides first evidence on the utility of monitoring of thiopurine metabolites to achieve mucosal response in CD.

Topics: Adolescent; Adult; Aged; Azathioprine; Biomarkers; Crohn Disease; Drug Administration Schedule; Drug Monitoring; Endoscopy, Gastrointestinal; Female; Guanine Nucleotides; Humans; Immunosuppressive Agents; Intestinal Mucosa; Male; Middle Aged; Recurrence; ROC Curve; Severity of Illness Index; Thioguanine; Thioinosine; Thionucleotides; Treatment Outcome; Young Adult

Azathioprine and mercaptopurine remain first line immunomodulatory treatments for inflammatory bowel disease. Toxicity and non-response are significant issues. Co-prescription of allopurinol with reduced-dose (25-33%) azathioprine or mercaptopurine may overcome these problems. We present the outcome of co-prescription in a large single-centre cohort.. Patients on thiopurine/allopurinol co-prescription were identified. Indication for and outcome on combination treatment were established. Blood parameters and metabolite results were compared on single agent and combination treatment. Toxicity associated with combination treatment was sought.. 110 patients on combination treatment were identified. Clinical remission was achieved in 60/79 (76%) of patients in whom the effect of thiopurine could be studied in isolation. 20/25 patients with hepatotoxicity tolerated combination treatment and normalised their liver function tests. 24/28 patients with atypical side effects tolerated co-therapy. 13/20 non-responders responded to combination treatment. In patients started on combination treatment as first line therapy, 15/23 achieved clinical remission. Thioguanine nucleotides were significantly higher and methylated metabolites significantly lower on combination therapy. Mean cell volume was higher and total white cell and neutrophil counts lower on combination treatment. 13 adverse events occurred, including 6 specific to co-therapy (3 rash, 2 abnormal liver function tests, 1 dosing error). All were minor and self-limiting.. This is the largest published experience of the use of allopurinol to optimise outcomes on thiopurine treatment. Combination therapy permitted successful treatment of a significant number of patients who would otherwise have been labelled as thiopurine failures. A few self-limiting side effects were encountered.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Azathioprine; Chemical and Drug Induced Liver Injury; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Methyltransferases; Middle Aged; Purine Nucleotides; Retrospective Studies; Statistics, Nonparametric; Thioguanine; Treatment Outcome; Young Adult

Circulating concentrations of 6-thioguanine nucleotide (6-TGN) and 6-methyl mercaptopurine (6-MMP) are associated with thiopurine efficacy and may predict toxicity. This study aimed to examine retrospectively the utility of measuring metabolite concentrations in patients with inflammatory bowel disease (IBD) who had continuing symptoms despite stable thiopurine treatment.. Concentrations of 6-TGN and 6-MMP were measured in lysates of washed red cells by high-performance liquid chromatography in peripheral blood drawn from 63 symptomatic patients with IBD (63% men, mean age 37, range 14-74 years, 67% Crohn's disease, 33% ulcerative colitis) treated with azathioprine or 6-mercaptopurine. Short-term clinical outcomes were examined.. 6-TGN concentrations weakly correlated with the thiopurine dose (r = 0.28, P = 0.08). On weight-based criteria, 50% of patients were underdosed. However, metabolite patterns suggested 7 (11%) patients were noncompliant, 18 (29%) were being underdosed, 33 (52%) were refractory to treatment with either appropriate (41%) or elevated (11%) metabolite concentrations, and 6 (10%) had a raised 6-MMP:6-TGN ratio consistent with aberrant thiopurine metabolism. The clinical outcome improved in 40 of 46 (87%) of patients in whom the course of action taken was as recommended by a metabolite-directed algorithm, while 3 of 17 patients (18%) improved where discordant actions were taken (P = 0.0001; Fisher's exact test). Fifteen patients (24%) avoided inappropriate escalation of therapy.. Dose-optimization or toxicity-avoidance strategies frequently result from metabolite testing in patients with inadequate efficacy from thiopurines, with evidence of better outcomes. Thiopurine metabolite testing is a potentially powerful tool for optimizing thiopurine usage in IBD.

Topics: Adolescent; Adult; Aged; Azathioprine; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Crohn Disease; Female; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Thioguanine; Treatment Failure; Young Adult

Topics: Colitis, Ulcerative; Crohn Disease; Evidence-Based Medicine; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Liver Cirrhosis; Thioguanine; Treatment Outcome

Portal hypertension (PH) is a complication that may occur in patients with inflammatory bowel disease (IBD). In these patients, the etiology of PH may not be alcoholic or viral cirrhosis (which cause 90% of cases in the general population). Consequently, etiologic study of PH in patients with IBD should always include a wide spectrum of possibilities. Moreover, the development of PH in IBD patients often requires a distinct therapeutic approach to IBD (both medical and surgical) as PH may be a contraindication for some drugs and is a risk factor for surgical morbidity and mortality. We present the cases of two patients with IBD who developed PH and review the most likely causes of PH in IBD, as well as preventive and therapeutic strategies.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Juvenile; Ascites; Crohn Disease; Female; Humans; Hypertension, Portal; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Pseudo-Obstruction; Liver Cirrhosis; Mesalamine; Mesenteric Veins; Methotrexate; Splenomegaly; Thioguanine; Thrombophilia; Varicose Veins

Topics: Chemical and Drug Induced Liver Injury; Crohn Disease; Humans; Hypertension, Portal; Immunologic Factors; Thioguanine

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.

Topics: Adolescent; Adult; Biopsy; Child; Crohn Disease; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Hypertension, Portal; Liver; Liver Function Tests; Magnetic Resonance Imaging; Male; Middle Aged; Remission Induction; Retrospective Studies; Safety; Thioguanine; Time Factors; Treatment Outcome; Young Adult

Few studies have described patients with foregut dysmotility in inflammatory bowel disease. The aim of this case series was to evaluate clinical characteristics of 5 patients with inflammatory bowel disease and symptoms and signs of upper gut dysmotility.. We describe a series of four patients with Crohn's disease and one with indeterminate colitis who presented with severe symptoms and signs of gastroparesis. We reviewed medical records of all cases. Gastric emptying of a solid meal was assessed by scintigraphy. Small bowel enteroclysis, gastroduodenoscopy and colonoscopy with biopsies were performed to estimate the activity of the disease and to exclude organic obstruction. None of the patients had any signs of active inflammation or stricture. All of the patients had markedly delayed gastric emptying with a mean t 1/2 of 234 minutes (range 110-380 minutes; normal values 54-94 minutes).. Clinicians should consider impaired gastric emptying when evaluating patients with Crohn's disease and severe symptoms of upper gut dysmotility, which cannot be attributed to active inflammation or organic obstruction of the digestive tract. Symptoms in these patients are refractory to various therapeutic interventions including tube feeding and gastric surgery.

Topics: Adrenal Cortex Hormones; Adult; Antimetabolites; Azathioprine; Crohn Disease; Drug Therapy, Combination; Female; Gastroenterostomy; Gastroparesis; Humans; Mercaptopurine; Middle Aged; Thioguanine; Treatment Outcome

An adolescent boy aged 17 years presented with sudden onset of visual impairment, which was rapidly diagnosed as bilateral anterior uveitis by an ophthalmologist. A systemic review noted episodes of nonbloody diarrhea, weight loss of 3 kg and a diminished appetite during the previous 10 months. The patient's family history revealed an older brother with Crohn's disease.. Visual acuity test, slit-lamp examination, ophthalmologic fundoscopy and endoscopic evaluation of the upper and lower gastrointestinal tract with biopsy.. Multifocal Crohn's disease, involving the terminal ileum and cecum, in addition to the stomach and duodenum.. Treatment with topical corticosteroids, in the form of ophthalmic drops and oral budesonide ileal-release capsules. Once remission was achieved, it was maintained with mercaptopurine.

Topics: Acute Disease; Adolescent; Blindness; Colonoscopy; Crohn Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Humans; Male; Ophthalmic Solutions; Thioguanine

Topics: Azathioprine; Child; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Humans; Immunosuppressive Agents; Mercaptopurine; Methyltransferases; Nucleotides; Remission Induction; Thioguanine

Tioguanine (thioguanine) has been proposed as a rescue thiopurine for azathioprine or mercaptopurine intolerant inflammatory bowel disease patients. The use of tioguanine leads to high 6-tioguaninenucleotide (6-thioguaninenucleotide) levels in red blood cells but, contra-intuitively, these have yet not been associated with an increased risk of myelotoxicity.. To assess the role of 6-tioguaninenucleotide concentrations in developing myelotoxicity during tioguanine treatment.. Database analysis of 25 patients treated with tioguanine. Clinical findings and laboratory parameters were related to 6-tioguaninenucleotide levels.. One patient developed a myelodepression (21 mg TG/day for 3 months and 6-tioguaninenucleotide 714 pmol/8 x 10(8) red blood cells). 6-Tioguaninenucleotide levels varied greatly between individuals (mean 6-tioguaninenucleotide level 621 pmol/8 x 10(8) red blood cells, s.d. 340 pmol/8 x 10(8) red blood cells and range 34-1653 pmol/8 x 10(8) red blood cells). The TG dosages (mean 20.6 mg/day and median 20 mg/day) did not correlate with 6-tioguaninenucleotide levels (r = 0.31, N.S.). High 6-tioguaninenucleotide levels (>450 pmol/8 x 10(8) red blood cells) did not effect haemoglobin concentrations (mean 8 mmol/L), peripheral leucocyte (mean 7.5 x 10(9)/L) or platelet counts (mean 298 x 10(9)/L). No correlations were established between laboratory parameters, type of disease and 6-tioguaninenucleotide level.. High 6-tioguaninenucleotide levels in erythrocytes (>450 pmol/8 x 10(8)) during TG treatment compared to azathioprine or mercaptopurine treatment are not indicative for (developing) myelotoxicity.

Topics: Adult; Antimetabolites, Antineoplastic; Bone Marrow Diseases; Celiac Disease; Colitis, Ulcerative; Crohn Disease; Female; Hepatitis, Autoimmune; Humans; Male; Thioguanine

6-Thioguanine is used as an escape thiopurine for treating inflammatory bowel disease patients intolerant or refractory to azathioprine, 6-mercaptopurine or methotrexate. Case reports show conflicting data on the use of 6-thioguanine throughout pregnancy. The administration of the standard thiopurines is believed to be relatively safe. We describe two patients with Crohn's disease treated with low-dose 6-thioguanine during all trimesters of their pregnancies. The pregnancies resulted in two healthy infants: without congenital abnormalities, laboratory signs of myelosuppression or hepatocellular injury. Thiopurine metabolites were measured in mother and infant. Significantly lower levels of 6-thioguaninenucleotides were found in the erythrocytes of the infant compared to the mother (ratio 1:12). Further studies are needed to determine the clinical importance of thiopurine metabolite measurements during pregnancy in mother and child.

Topics: Adult; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Gestational Age; Humans; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy, High-Risk; Risk Assessment; Severity of Illness Index; Thioguanine

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are well known for their lymphocytotoxic and bone marrow suppressive effects in the management of patients with leukemia. Although their immunosuppressive properties are mediated by the active AZA antimetabolite 6-thioguanine (6-TG), its mechanism of action is largely unknown. In IBD, a significant inverse correlation has been shown between erythrocyte 6-TG metabolite levels and disease activity, further supporting the proposed immunosuppressive role for 6-TG. Since leukocytes possess quantitatively different purine metabolic pathways compared to erythrocytes, this study aims to measure lymphocyte DNA 6-TG metabolites and correlate levels with the INF-gamma and IL-10 cytokine profile in patients with Crohn's disease (CD). Forty-six adult patients with CD, either naive (17) or on long-term (>4-month) AZA therapy (29), had erythrocyte and lymphocyte DNA 6-TG levels measured by reverse-phase HPLC under UV detection (6-TG, 340 nm). Lymphocyte DNA 6-TG was expressed as picomoles per milligram of DNA. Lymphocyte DNA 6-TG metabolite levels were correlated with INF-gamma and IL-10 cytokine profiles using the OptEIA kit (Pharmigen). Lymphocyte DNA 6-TG metabolite levels correlate with erythrocyte 6-TG levels (P < 0.03) but not total patient leukocyte levels. Erythrocyte 6-TG metabolite levels correlated (P < 0.01) inversely with INF-gamma but not IL-10 cytokine levels. This study suggests a preferential dampening of the TH1 response on exposure to 6-TG and a possible immunosuppressive mechanism of action for AZA. Future studies are needed to determine if cytokine profiles can be used to predict recalcitrant CD to AZA therapy.

Topics: Azathioprine; Crohn Disease; DNA; Erythrocytes; Female; Humans; Immunosuppressive Agents; Interferon-gamma; Interleukin-10; Leukocytes, Mononuclear; Male; Middle Aged; Thioguanine; Treatment Outcome

Topics: Adult; Crohn Disease; Female; Follow-Up Studies; Humans; Risk Assessment; Severity of Illness Index; Thioguanine; Thrombocytopenia

6-Thioguanine-nucleotides seem to be the active metabolites of thiopurine therapy, and their monitoring has been considered a useful tool for optimizing response in inflammatory bowel diseases. Tioguanine (thioguanine) therapy results in much higher levels of 6-thioguanine-nucleotide levels when compared with azathioprine or mercaptopurine.. To elucidate the influence of 6-thioguanine-nucleotide and methylated 6-thioguanine-nucleotide levels under tioguanine on efficacy and toxicity in Crohn's disease.. 6-Thioguanine-nucleotide and methylated 6-tioguanine-nucleotide levels were measured regularly in 26 Crohn's disease patients treated with tioguanine. Nucleotide levels were related to efficacy and toxicity.. 6-Thioguanine-nucleotide levels rose very high [median 1241 pmol/8 x 10(8) red blood cells (range 313-1853)]. Methylated 6-thioguanine-nucleotide levels were detected in all patients [491 pmol/8 x 10(8) red blood cells (154-1775)]. 6-Thioguanine-nucleotide and methylated 6-thioguanine-nucleotide concentrations correlated significantly (r = 0.7, P < 0.0001). Nucleotide levels from patients achieving remission (n = 14) did not differ significantly from non-remitters (n = 12) [6-thioguanine-nucleotide: 1077 (599-2160) vs. 1210 (534-4665); methylated 6-thioguanine-nucleotide: 510 (214-1222) vs. 421 (145-1284)]. One patient with intermediate thiopurine S-methyltransferase activity experienced bone marrow toxicity upon dose escalation parallel with excessively high thioguanine-nucleotide levels.. 6-Thioguanine-nucleotide as well as methylated 6-thioguanine-nucleotide levels under tioguanine therapy were not related to efficacy. This suggests that monitoring of 6-thioguanine-nucleotide levels is not a useful tool to predict response to thiopurines.

Topics: Adult; Biomarkers; Crohn Disease; Drug Monitoring; Erythrocytes; Female; Guanine Nucleotides; Humans; Male; Methylation; Middle Aged; Remission Induction; Thioguanine; Thionucleotides; Treatment Outcome

There are conflicting reports on the role of azathioprine (AZA) thioguanine nucleotide (TGN) metabolites in optimising therapy for inflammatory bowel disease (IBD). The aim of this study was to investigate TGN intrapatient variation, and the relationship between TGN concentrations and disease activity in IBD patients taking long term constant dose AZA.. TGN and methylmercaptopurine nucleotide (MeMPN) concentrations were measured at intervals over a two year period. Disease activity was assessed at each clinic visit using the Crohn's disease activity index or Walmsley simple index for ulcerative colitis.. Serial TGNs were measured in 159 patients (3-14 TGN assays, median 6). Intrapatient variation in TGN concentrations was 1-5-fold (median 1.6); the incidence of non-compliance was 13%. At the end of two years, 131 patients were evaluable at TGN steady state. Of this group, patients who remained in remission had significantly higher mean TGN concentrations than those patients who developed active disease (median TGNs 236 v 175, respectively; median difference 44 pmol (95% confidence interval 1-92); p = 0.04). MeMPN concentrations were not related to AZA efficacy or toxicity.. This study has shown that lower TGN concentrations were linked to the development of active disease, and that TGNs may act as useful markers of compliance. However, it is clear that repeat TGN measurements are required for an unambiguous index of active metabolite exposure. In view of the high intrapatient variability in TGN production over time, TGN measurements may not be currently advocated for routine clinical use.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antimetabolites, Antineoplastic; Azathioprine; Child; Child, Preschool; Colitis, Ulcerative; Crohn Disease; Erythrocytes; Female; Humans; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Patient Compliance; Thioguanine; Treatment Outcome

We aimed at determining the utility of measuring 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) in inflammatory bowel disease (IBD) patients on azathioprine (AZA) or 6-mercaptopurine (6-MP), whether the described therapeutic range for 6-TG (235-400 pmol/8 x 10(8) red blood cells, RBC) correlated with clinical remission or leukopenia, and if 6-MMP level was a marker for hepatotoxicity (>5,700 pmol/8 x 10(8) RBC).. Study eligibility included an IBD diagnosis of >6 months and either active disease or disease remission of <6 months and the use of AZA/6-MP for >10 wk consecutively. Metabolite levels were evaluated against clinical status, CBC, and hepatic parameters.. Seventy-four of 166 AZA/6-MP users were eligible. 6-TG levels >235 pmol/8 x 10(8) RBC were found in 22/59 (38%) with active disease and in 7/15 with remission (47%, p= 0.16). There was a trend of higher 6-TG levels among those in remission versus those with active disease (mean 325 +/- 284 vs 223 +/- 159 pmol/8 x 10(8) RBC, p= 0.2). No hepatotoxicity was observed, although 12.2% had 6-MMP levels > 5,700 pmol/8 x 10(8) RBC. The correlation between 6-MP dose and 6-TG levels was weak (r = 0.22, p= 0.08). The 6-TG level did not correlate with WBC. There were five instances, each of markedly low levels of both 6-TG and 6-MMP, suggesting noncompliance and of marked 6-MMP levels versus 6-TG.. There was a poor correlation between 6-TG levels and remission. Nonetheless, the measurements of these levels are helpful when patients are on high doses but not achieving remission since noncompliance or metabolism favoring 6-MMP can be established.

Topics: Adult; Azathioprine; Biomarkers; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Inflammatory Bowel Diseases; Male; Maximum Tolerated Dose; Mercaptopurine; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Assessment; Severity of Illness Index; Thioguanine; Treatment Outcome

6-Thioguanine (6-TG), the active metabolite of 6-mercaptopurine and its prodrug azathioprine, are thought to be responsible for clinical efficacy in the treatment of active Crohn's disease. Its use as a therapeutic agent for inflammatory bowel disease (IBD) has been limited to patients who are resistant to or intolerant of other antimetabolites. Short-term experience with this agent has not demonstrated an increased incidence of hematologic or hepatic toxicity; however long-term safety data are scarce. We herein report a patient who developed acute sinusoidal obstruction syndrome after 14 months of successful thioguanine treatment. This is the first report of such a complication in an adult treated with 6-TG for active Crohn's disease.

Topics: Acute Disease; Adult; Antimetabolites, Antineoplastic; Crohn Disease; Hepatic Veno-Occlusive Disease; Humans; Male; Syndrome; Thioguanine

Thiopurine drugs are commonly used immunosuppressants in the treatment of inflammatory bowel disease (IBD) as well as in autoimmune hepatitis (AIH), rheumatic diseases and in transplantation medicine. The relatively narrow therapeutic range requires useful therapy control. Therefore, the purpose of this study was to further investigate the rationale and usefulness of therapeutic drug monitoring in the surveillance of thiopurine drug therapy in Crohn's disease, ulcerative colitis and autoimmune hepatitis.. 6-Thioguanine nucleotide (TGN) and 6-methylmercaptopurine nucleotide (MMPN) levels were measured in 182 IBD patients and 18 AIH patients using HPLC-UV.. In our cohort of IBD patients, 18% had TGN levels < 235 pmol/8 x 10 red blood cells (RBC) (recommended range, 235-450 pmol/8 x 10 RBC), 41% of these patients were sent for drug failure. Twenty-four per cent of the IBD patients had TGN levels > 450 pmol/8 x 10 RBC, but only 27% of these experienced adverse effects. Fifty-nine per cent of the patients having drug failure had TGN levels in the recommended range and could therefore be classified as non-responders. In the AIH cohort 33% of the patients had TGN levels below the recommended range but showed clinical response to therapy. MMPN levels increased with the duration of treatment and could be useful for controlling compliance. There was 8.8% of IBD patients who were heterozygous for non-functional TPMT alleles.. TGN monitoring did not identify significant differences between patient groups but allowed the identification of non-responders from non-compliant patients and allowed the differentiation of mild side effects, such as malaise, from genuine toxicity caused by highly increased TGN levels.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chromatography, High Pressure Liquid; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Drug Monitoring; Female; Guanine Nucleotides; Hepatitis, Autoimmune; Heterozygote; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Male; Mercaptopurine; Middle Aged; Purines; Thioguanine; Thionucleotides

6-Thioguanine (6-TG) is a thiopurine analogue that is closely related to 6-mercaptopurine (6-MP) and azathioprine (AZA). These agents have potent cytotoxic and immunomodulatory effects and are useful in the treatment of a variety of conditions, including inflammatory bowel disease. Both 6-MP and AZA are widely used and are known to cause hepatotoxicity in a proportion of patients. 6-Thioguanine is being increasingly used in the treatment of inflammatory bowel disease but has not been reported to cause liver injury in this context. We describe a case of significant elevation of serum transaminases in a patient treated with 6-TG for a flare of Crohn's disease. We believe the temporal association of the abnormal liver enzymes in this patient, in the absence of other offending agents, argues strongly in favor of 6-TG as a cause of liver enzyme abnormalities. This case highlights the need to monitor liver enzymes in patients treated with 6-TG and identifies the need for additional research focused on the mechanism of thiopurine-induced hepatic injury.

Topics: Adult; Alanine Transaminase; Antimetabolites, Antineoplastic; Aspartate Aminotransferases; Crohn Disease; Female; Humans; Liver; Liver Function Tests; Mercaptopurine; Thioguanine

Tioguanine may offer an alternative for immunosuppression in chronic active Crohn's disease. Recently, we have shown that tioguanine is effective in inducing rapid remission.. To evaluate the role of tioguanine in the maintenance of remission in chronic active Crohn's disease.. A follow-up study was performed to investigate the long-term efficacy and safety of and tolerance to tioguanine in chronic active Crohn's disease. Sixteen patients who had successfully received 6-tioguanine for remission induction were enrolled. The reasons for immunosuppressive therapy were steroid dependence (n = 10), steroid refractoriness (n = 6) and intolerance (n = 6) or refractoriness (n = 1) to azathioprine. After remission induction therapy for 6 months, patients were treated for another 6 months with a daily dose of 20-40 mg tioguanine. Primary outcomes were remission (Crohn's disease activity index < 150) and complete steroid reduction in steroid-dependent patients at 12 months. Laboratory controls of white blood count and liver enzymes, as well as erythrocyte tioguanine nucleotide levels, were performed regularly.. After 12 months of treatment, 14 of 16 (88%) patients were in remission, and 12 of these were completely free of systemic steroids. Adverse events during maintenance therapy included photosensitivity (one patient), minor viral infections (one), headache (four) and mild alopecia (one). One patient developed elevated liver enzymes, splenomegaly and thrombocytopenia, indicative of nodular regenerative hyperplasia of the liver.. In responders to tioguanine, the drug appears to be very effective in maintaining remission of chronic active Crohn's disease. Unfortunately, long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction. Therefore, to date, tioguanine cannot be recommended for general use outside clinical trials.

Topics: Adult; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Chronic Disease; Crohn Disease; Erythrocytes; Female; Follow-Up Studies; Humans; Male; Methyltransferases; Middle Aged; Phenotype; Steroids; Thioguanine; Treatment Outcome

Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases.. : To evaluate the tolerance and efficacy of TG in patients with Crohn's disease, intolerant or resistant to AZA/MP.. An open prospective study was made on Crohn's disease patients treated with TG. Intolerance to AZA/MP was defined as a reaction occurring within 1 month after introduction of AZA/MP, including pancreatitis, abdominal pain, fever, arthralgia, myalgia, cutaneous rash, fatigue, alopecia, hepatitis and digestive intolerance. Resistance to AZA/MP was defined as the persistence of activity after at least 3 months of AZA/MP therapy.. Forty-nine Crohn's disease patients (36 women, 13 men; intolerance: n = 39; resistance: n= 10) were treated with TG (20 mg/day). Clinical pancreatitis did not recur under TG. Five patients (10%) had to stop TG due to intolerant reactions observed 13-21 days after TG was started. No haematological side-effects were observed under TG. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79%, respectively, in the 40 patients with active disease at baseline. The probability of clinical relapse during maintenance TG therapy at 6 and 12 months was 29% and 53%, respectively, in the 28 patients in remission at baseline or who had achieved remission on TG.. TG is a possible alternative treatment in Crohn's disease patients, intolerant (especially for pancreatitis) or resistant to AZA/MP.

Topics: Adult; Antimetabolites; Azathioprine; Crohn Disease; Drug Resistance; Female; Humans; Male; Mercaptopurine; Middle Aged; Prospective Studies; Recurrence; Remission Induction; Thioguanine; Treatment Outcome

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have proven efficacy in the treatment of Crohn disease (CD). The immunosuppressive properties of AZA/6-MP are mediated by the intracellular metabolism of 6-MP into its active metabolites, 6-thioguanine nucleotides (6TGN) and 6methylmercaptopurine (6-MMP). Preliminary studies have suggested that the red blood cell concentration of 6TGN (RBC 6TGN) is a potential guide to therapy. The aims of the study were to evaluate the RBC 6TGN concentrations in adult patients with CD under long-term AZA/6-MP therapy and to correlate it with response to treatment and haematological parameters.. Twenty-eight CD patients treated for at least 3 months with AZA/6-MP were prospectively studied. Patients were separated into three main groups: group 1 (n = 19), corresponding to quiescent CD receiving AZA (dose: 2.05 +/- 0.4 mg/kg/day for a mean of 28.6 +/- 25 months) or 6-MP (dose: 1.4 +/- 01 mg/kg/day for a mean of 7.5 +/- 3.5 months) alone; group 2 (n = 6), corresponding to quiescent CD treated by AZA (dose: 2.14 +/- 0.5 mg/kg/day for a mean of 29.5 +/- 22 months) with oral steroids; and group 3 (n = 3), corresponding to active CD on AZA (dose: 1.94 +/- 0.6 mg/kg/day for a mean of 31.3 +/- 35 months) as the only treatment. An assessment was also made by merging groups 1 and 2 forming a larger group of patients (n = 25) defined by clinical remission and groups 2 and 3 forming a larger group of patients (n = 9), non-complete responders with AZA/6-MP alone. Crohn disease index activity (CDAI), blood samples for full blood count and differential white cell count and measurement of RBC 6TGN and 6-MMP concentrations were evaluated at inclusion and at 6 months (n = 17). RBC 6TGN were measured using high performance liquid chromatography (HPLC) on heparinized blood.. The baseline characteristics of the three groups of patients were similar. There was no significant difference among the three groups of patients regarding the dose and the duration of immunosuppressive treatment. There was no significant difference between groups according to various parameters tested. Particularly, the median RBC 6TGN concentration at inclusion was similar in the three groups of patients (166 (105-688), 183 (90-261) and 160 (52-194) pmol/8 x 10(8) RBC, respectively). The majority of patients had no detectable level of 6-MMP metabolite, except for 3 patients. There was also no difference between merging groups. Furthermore, there was no significant correlation between RBC 6TGN concentrations and the various biological parameters tested except for the mean erythrocyte volume. At 6 months, all patients of group 1 remained in remission and median RBC 6TGN concentration remained stable. No side effects were observed.. There is, contrary to preliminary studies, a broad overlap in RBC 6TGN levels as well as for haematological parameters in patients in remission or not and responders or not to AZA/6-MP therapy. This suggests, beside a variability in the metabolism of these drugs, the existence of complex mechanisms of action. Nevertheless, beside the use of RBC 6TGN determination to confirm compliance to therapy, this dosage could be useful in non-responding patients, allowing, in absence of leukopenia, to increase the dose of AZA/6-MP safely.

Topics: Adult; Azathioprine; Case-Control Studies; Crohn Disease; Drug Monitoring; Drug Therapy, Combination; Erythrocytes; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Mercaptopurine; Prospective Studies; Thioguanine; Time Factors

Topics: Antimetabolites; Crohn Disease; Humans; Mercaptopurine; Thioguanine

Topics: Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Bone Marrow Purging; Bone Marrow Transplantation; Crohn Disease; Cytarabine; Daunorubicin; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Thioguanine; Transplantation, Homologous

Topics: Antimetabolites; Antimetabolites, Antineoplastic; Azathioprine; Chromatography, High Pressure Liquid; Crohn Disease; Humans; Mercaptopurine; Methylthioinosine; Thioguanine

The effects of 6-mercaptopurine (6MP) in inflammatory bowel disease are believed to be primarily mediated by its metabolite 6-thioguanine (6TG). Our aim was to develop an assay for measuring leukocyte DNA 6TG levels in patients with Crohn's disease, and to correlate them with levels of 6TG in erythrocytes. Heparinized blood was obtained from 15 adolescent Crohn's disease patients receiving 6MP at an average dose of 1.3 mg.kg-1 day-1 (range 0.8-1.6 mg.kg-1 day-1) for a mean of 23.7 months (range 3-71 months). Leukocyte DNA and erythrocyte 6TG levels were measured by an HPLC assay. Leukocyte 6TG levels ranged from 100 to 2305 pmol/mg DNA, while erythrocyte 6TG levels ranged from 64 to 1038 pmol/8 x 10(8) red blood cells, demonstrating significant interpatient variability. Leukocyte DNA 6TG levels correlated directly with erythrocyte 6TG levels, as measured by the Spearman rank correlation coefficient (p < 0.05). The HPLC measurement of erythrocyte and leukocyte DNA 6TG levels can be useful clinically in monitoring compliance, as well as perhaps to tailor drug metabolite levels to achieve the desired clinical effect.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Child; Chromatography, High Pressure Liquid; Crohn Disease; DNA; Erythrocytes; Female; Humans; Immunosuppressive Agents; Leukocytes; Linear Models; Male; Mercaptopurine; Patient Compliance; Thioguanine