Long‐term outcome of using allopurinol co‐therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease

Ansari, Azhar; Elliott, T.; Baburajan, Bijay; Mayhead, Phillip; O’Donohue, John; Chocair, Pedro Renato; Sanderson, Jeremy; Duley, John A.

doi:10.1111/j.1365-2036.2008.03782.x

Cited by 106 publications

(103 citation statements)

References 20 publications

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“…Another potential alternative explanation for the decrease in 6-MMPR is that the reduced thiopurine dosage results in suboptimal concentrations for TPMT to function. 36,37 Although we observed a marked effect of allopurinol in 6-TGN formation, it is not clear whether the combination is optimal and if a similar effect would be observed at lower doses of allopurinol. Study of other XO-inhibitors might therefore be of great interest.…”

Section: 29mentioning

confidence: 67%

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

Seinen

Asseldonk

Boer

et al. 2013

Journal of Crohn's and Colitis

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Introduction: Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. Methods: A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy. Conclusion: Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.

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Section: 29mentioning

confidence: 67%

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

Seinen

Asseldonk

Boer

et al. 2013

Journal of Crohn's and Colitis

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“…It has been reported that XO has the potential to generate ROS in human hepatocytes [32] and that the oxidation of 6-MP by XO is involved in the AZA-induced liver injury in patients with inflammatory bowel disease. [33] Another metabolic pathway converts 6-MP into 6-thioinosine monophosphate via hypoxanthine-guanine phosphoribosyl transferase, and this intermediate is then metabolized into active 6-thioguanine nucleotides (6-TGNs). [34] 6-TGNs are also responsible for the cytotoxic side effects.…”

Section: Discussionmentioning

confidence: 99%

Preventive role of chamomile flowers and fennel seeds extracts against liver injury and oxidative stress induced by an immunosuppressant drug in rats

Mannaa¹,

Ibrahim²,

Ibrahim³

et al. 2015

Hepatoma Res

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Aim: The present study was conducted to investigate the protective effect of chamomile fl owers methanolic extract (CFME) and fennel seeds methanolic extract (FSME) on azathioprine (AZA), an immunosuppressant drug, which induced a liver injury and oxidative stress in rats. Methods: Rats were divided into 6 groups (8 rats each) and treated orally for 28 consecutive days as follows. Group 1: rats were given normal saline and used as controls; group 2: rats treated with CFME (200 mg/kg); group 3: rats treated with FSME (200 mg/kg); group 4: rats treated with AZA (25 mg/kg); and groups 5 and 6: rats treated with CFME (200 mg/kg) or FSME (200 mg/kg) 15 min prior to AZA (25 mg/kg) treatment. At the end of experimental period, blood and liver samples were collected from all groups for biochemical analysis and histological examination. Results: The obtained data revealed that AZA-induced hepatic injury in the rats as evidenced by the signifi cant increase in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, cholesterol, and direct bilirubin as well as hepatic malondialdehyde level accompanied with signifi cant decrease in reduced glutathione content and total antioxidant capacity in the liver. Moreover, body weight gain showed the signifi cant decrease and relative liver weight showed the signifi cant increase on AZA treatment. The sequential signifi cant changes in biochemical parameters were accompanied by severe histological changes in the liver tissue, including hepatocytes disorganization with pyknotic nuclei, fatty degeneration, congestion, fi brosis, and bile duct necrosis around the portal tract. The areas of hemorrhages in blood vessels and in between hepatocytes were also seen. However, the results showed the potential hepatoprotective effects of CFME and FSME against AZA-induced liver injury and oxidative stress. They succeeded in restoring the biochemical parameters and improving the histological picture of the liver. This improvement was more pronounced in the rats pretreated with FSME. Conclusion: It could be concluded that CFME and FSME have hepatoprotective potentials against AZA probably due to their antioxidant properties and radical scavenging activity.Key words: Azathioprine; chamomile fl owers; fennel seeds; liver; oxidative stress Preventive role of chamomile fl owers and fennel seeds Preventive role of chamomile fl owers and fennel seeds extracts against liver injury and oxidative stress induced by an extracts against liver injury and oxidative stress induced by an immunosuppressant drug in rats immunosuppressant drug in rats This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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“…8 Three further small, retrospective, single-centre studies, including one in a pediatric cohort, have replicated these results, although one viral infectious complication was reported in a total 28 patients. [9][10][11] A summation of the current published retrospective studies shows that combination azathioprine-allopurinol therapy safely and effectively optimizes thiopurine metabolism and achieves the resultant clinical benefits. Prospective studies are underway to further validate the role of combination therapy in otherwise thiopurine-resistant IBD patients.…”

Section: Allopurinol and Azathioprine Combination Therapymentioning

confidence: 99%

Azathioprine and allopurinol: A two‐edged interaction

Gearry

Day

Barclay

et al. 2010

J of Gastro and Hepatol

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Long‐term outcome of using allopurinol co‐therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease

Cited by 106 publications

References 20 publications

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

Preventive role of chamomile flowers and fennel seeds extracts against liver injury and oxidative stress induced by an immunosuppressant drug in rats

Azathioprine and allopurinol: A two‐edged interaction

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