Use of a xanthine oxidase inhibitor in autoimmune hepatitis

Al-Shamma, S; Erőss, Bálint; McLaughlin, Simon D.

doi:10.1002/hep.26198

Cited by 21 publications

(18 citation statements)

References 5 publications

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“…Xanthine oxidase inhibition by allopurinol was also found to be protective in primary rat hepatocytes [10]. A recent case study reported that the addition of allopurinol with appropriate AZA dose reduction may correct AZA-induced hepatotoxicity and can induce remission [50]. In AZA or 6-MP nonresponders, addition of allopurinol also demonstrated safety and efficacy for long-term maintenance in IBD patients [51, 52].…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Azathioprine-Induced Cytotoxicity in anIn VitroRat Hepatocyte System

Maruf

Wan

O’Brien

2014

BioMed Research International

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Azathioprine (AZA) is widely used in clinical practice for preventing graft rejection in organ transplantations and various autoimmune and dermatological diseases with documented unpredictable hepatotoxicity. The potential molecular cytotoxic mechanisms of AZA towards isolated rat hepatocytes were investigated in this study using “Accelerated Cytotoxicity Mechanism Screening” techniques. The concentration of AZA required to cause 50% cytotoxicity in 2 hrs at 37°C was found to be 400 μM. A significant increase in AZA-induced cytotoxicity and reactive oxygen species (ROS) formation was observed when glutathione- (GSH-) depleted hepatocytes were used. The addition of N-acetylcysteine decreased cytotoxicity and ROS formation. Xanthine oxidase inhibition by allopurinol decreased AZA-induced cytotoxicity, ROS, and hydrogen peroxide (H2O2) formation and increased % mitochondrial membrane potential (MMP). Addition of N-acetylcysteine and allopurinol together caused nearly complete cytoprotection against AZA-induced hepatocyte death. TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl), a known ROS scavenger and a superoxide dismutase mimic, and antioxidants, like DPPD (N,N′-diphenyl-p-phenylenediamine), Trolox (a water soluble vitamin E analogue), and mesna (2-mercaptoethanesulfonate), also decreased hepatocyte death and ROS formation. Results from this study suggest that AZA-induced cytotoxicity in isolated rat hepatocytes may be partly due to ROS formation and GSH depletion that resulted in oxidative stress and mitochondrial injury.

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Section: Resultsmentioning

confidence: 99%

Evaluation of Azathioprine-Induced Cytotoxicity in anIn VitroRat Hepatocyte System

Maruf

Wan

O’Brien

2014

BioMed Research International

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“…[26][27][28][29][30] A total of 14 patients (13 with AIH and one with autoimmune pancreatitis) on thiopurine/allopurinol treatment were included in the detailed analysis. Thirteen AIH patients were started electively on combination therapy due to refractory disease or toxicity.…”

Section: Allopurinol Combination Therapy and Autoimmune Hepatitis: Rementioning

confidence: 99%

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

Deswal

Srivastava

2017

Journal of Clinical and Experimental Hepatology

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Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes. After absorption and getting converted to 6MP, it is converted to 6-thiouric acid, 6-methyl mercaptopurine (6MMP) and 6-thioguanine (6TG) by different enzymes. Elevated 6MMP levels are associated with hepatotoxicity and also poor efficacy due to simultaneous lower levels of 6TG, which is the active drug metabolite related to both efficacy and myelosuppression. Allopurinol, a xanthine oxidase inhibitor shifts the metabolism of AZA away from 6MMP toward 6TG. This combination of allopurinol with reduced dose of AZA is an alternative to more expensive and toxic second line therapy to induce remission in patients with AIH. This article discusses the mechanism of action of allopurinol in inducing response to AZA, reviews the published literature on this combination therapy and gives guidelines on the use of allopurinol in patients with AIH. ( J CLIN EXP HEPATOL 2017;7:55-62)

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“…Some synthetic xanthine oxidase inhibitors such as allopurinol [3] and febuxostat [4] have shown remarkable effectiveness against chronic gout. However, they may also cause side effects such as skin rashes, systemic vasculitis, and renal failure [5].…”

Section: Introductionmentioning

confidence: 99%

Development of a method to screen and isolate potential xanthine oxidase inhibitors from Panax japlcus var via ultrafiltration liquid chromatography combined with counter-current chromatography

Tang

Liu

et al. 2015

Talanta

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Use of a xanthine oxidase inhibitor in autoimmune hepatitis

Cited by 21 publications

References 5 publications

Evaluation of Azathioprine-Induced Cytotoxicity in anIn VitroRat Hepatocyte System

Evaluation of Azathioprine-Induced Cytotoxicity in anIn VitroRat Hepatocyte System

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

Development of a method to screen and isolate potential xanthine oxidase inhibitors from Panax japlcus var via ultrafiltration liquid chromatography combined with counter-current chromatography

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