Thioguanine in inflammatory bowel disease: Long‐term efficacy and safety

Ward, Marc; Patel, Kamal; Kariyawasam, Viraj C.; Goel, Rishi; Warner, Ben; Elliott, T.; Blaker, Paul; Irving, Peter M; Sanderson, Jeremy

doi:10.1177/2050640616663438

Cited by 31 publications

(36 citation statements)

References 37 publications

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“…These risks increase in patients with combination therapy with corticosteroids and biologicals . Similar data on the long‐term safety profile of tioguanine are limited, presumably due to the short duration of the follow‐up which has been reported in literature until now . Moreover, utility of therapeutic drug monitoring during tioguanine treatment has not been verified yet.…”

Section: Introductionmentioning

confidence: 97%

“…One of these drugs was tioguanine, an alternative thiopurine‐derivative, which has shown promising therapeutic results in the treatment of both Crohn's disease and ulcerative colitis . Especially in IBD patients who failed prior therapy with conventional thiopurines , that is azathioprine or mercaptopurine, tioguanine has been reported to be both effective as well as tolerated in up to 80% . Potential benefits of tioguanine over conventional thiopurines have been ascribed to pharmacokinetic differences between the thiopurine‐derivatives (Figure ) .…”

Section: Introductionmentioning

confidence: 99%

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Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

Simsek

Deben

Horjus

et al. 2019

Aliment Pharmacol Ther

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Summary Background Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods In this nationwide, multicentre study, medical records of tioguanine‐ using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow‐up were listed and graded according to the common terminology criteria (CTC). Results Two hundred and seventy‐four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient‐years of follow‐up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty‐one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6‐thioguanine nucleotide threshold concentrations >682 pmol/8×108 RBC (P < 0.05). Conclusions Long‐term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6‐Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108 RBC is proposed as target level with higher odds for clinical effectiveness.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

Simsek

Deben

Horjus

et al. 2019

Aliment Pharmacol Ther

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“…Thioguanine (TG) was introduced in 1950 as treatment for leukaemia and about five decades later, clinicians started using it for treating IBD. Modern cases series suggest that TG offers better outcomes in terms of efficacy (51-60%) as rescue therapy, low incidence of adverse events and possibly a more rapid onset of action compared to conventional thiopurines [14][15][16]. However, its widespread use has been hampered due to concerns about hepatotoxicity (nodular regenerative hyperplasia [NRH]) but this is thought to be dose-dependent [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom

et al. 2020

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Background Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP. Methods A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected. Results A total of 193 patients (57% female and 64% Crohn’s disease) were included, with a median daily TG dose of 20 mg (range: 20–40 mg), a median treatment duration of 23 months (IQR 10–47) and a median follow-up of 36 months (IQR 22–53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145–1761) and 47 mu/L (IQR 34.5–96). Conclusions Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.

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“…Conventional thiopurines (6-mercaptopurine, 6-thioguanine, and azathioprine) are incorporated into the structure of natural biomolecules—they modify nucleic acid synthesis and are commonly used as effective anticancer and immunosuppressive drugs in the treatment of acute leukemia and autoimmune hepatitis (Prima et al 2013 ; Deswal and Srivastava 2017 ). Thiopurines remain the first line of therapy in inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and autoimmune hepatitis (Herreras and Iborra 2017 ; Ward et al 2017 ; Warner et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anticancer activity of multisubstituted purines and xanthines with one or two propynylthio and aminobutynylthio groups

2018

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A synthesis of new 2,6-disubstituted and 2,6,8-trisubstituted 7-methylpurines as well as 8-substituted 3,7-dimethylxanthines containing a triple bond chain have been worked out. Purinethiones and xanthinethiones were converted into propynylthio derivatives, which were then further transformed via a Mannich reaction into aminobutynylthio derivatives (amine = pyrrolidine, piperidine, morpholine, and diethylamine). The products thus obtained represent various types of the purine and xanthine structure: 8-mono-, 2,6- and 6,8-dipropynylthio, 6- and 8-monoaminobutynylthio, 2,6- and 6,8-diaminobutynylthio derivatives. All of these compounds were tested for their anticancer activity against human glioblastoma SNB-19, human adenocarcinoma MDA-MB-231, and melanoma C-32 cell lines. The anticancer activity depends on the nature of the substituent and its localization in the purine and xanthine framework. Generally, compounds possessing two alkynylthio groups (propynylthio or aminobutynylthio) were more active than those possessing only one group. Some compounds exhibited stronger or similar anticancer activity to cisplatin. All compounds were also tested for their cytotoxic activity against normal human fibroblasts (HFF-1). The most promising anticancer compounds were found to be 2,6-dipropynylthio-7-methylpurine 4, 2-chloro-6,8-dipropynylthio-7-methylpurine 14, and 2-chloro-6,8-di(N-morpholinylbutynylthio)-7-methylpurine 15c acting selectively on glioblastoma SNB-19, melanoma C-32, and adenocarcinoma MDA-MB-231 with the IC50 = 0.07–4.08 μg/mL.

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Thioguanine in inflammatory bowel disease: Long‐term efficacy and safety

Cited by 31 publications

References 37 publications

Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

Efficacy, safety and drug survival of thioguanine as maintenance treatment for inflammatory bowel disease: a retrospective multi-centre study in the United Kingdom

Synthesis and anticancer activity of multisubstituted purines and xanthines with one or two propynylthio and aminobutynylthio groups

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