Pharmacoeconomic Analyses of Azathioprine, Methotrexate and Prospective Pharmacogenetic Testing for the Management of Inflammatory Bowel Disease

Priest, Virginia; Begg, Evan J.; Gardiner, Sharon J.; Frampton, Christopher; Gearry, Richard B.; Barclay, Murray L.; Clark, David W. J.; Hansen, Paul

doi:10.2165/00019053-200624080-00004

Cited by 87 publications

(65 citation statements)

References 40 publications

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“…This indicates that TPMT metabolizer status is a useful adjunct to (but not replacement for) regular blood count monitoring. The clinical usefulness of prospective determination of TPMT metabolizer status is supported by pharmacoeconomic studies (Marra et al, 2002;Oh et al, 2004;Winter et al, 2004;Dubinsky et al, 2005;Priest et al, 2005).…”

Section: Thiopurine Methyltransferasementioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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Section: Thiopurine Methyltransferasementioning

confidence: 99%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…However, as many patients are refractory to current classes of therapeutics there is a need to develop novel antiinflammatory drugs with relevance to enterocolitis (Priest et al, 2006). Zebrafish models have been successfully used to identify small molecules with therapeutic application, including oncogene suppression and hematopoietic stem cell expansion (North et al, 2007;Yeh et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

A chemical enterocolitis model in zebrafish larvae that is dependent on microbiota and responsive to pharmacological agents

Oehlers

Flores

Okuda

et al. 2010

Developmental Dynamics

120

168

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Inflammatory bowel disease (IBD) results from dysfunctional interactions between the intestinal immune system and microbiota, influenced by host genetic susceptibility. Because a key feature of the pathology is intestinal epithelial damage, potential disease factors have been traditionally analyzed within the background of chemical colitis models in mice. The zebrafish has greatly complemented the mouse for modeling aspects of disease processes, with an advantage for high content drug screens. Larval zebrafish exposed to the haptenizing agent trinitrobenzene sulfonic acid (TNBS) displayed impaired intestinal homeostasis and inflammation reminiscent of human IBD. There was a marked induction of pro-inflammatory cytokines, the degradative enzyme mmp9 and leukocytosis. Enterocolitis was dependent on microbiota and Toll-like receptor signaling, that can be ameliorated by antibiotic and anti-inflammatory drug treatments. This system will be useful to rapidly interrogate in vivo the biological significance of the IBD candidate genes so far identified and to carry out pharmacological modifier screens. Developmental Dynamics 240:288-298,

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“…Although .70% of myelosuppression related to azathioprine use is not associated with TPMT polymorphism [13,18,19], screening as few as 20 patients for TPMT deficiency can prevent one adverse event over 6 months of therapy [20]. Furthermore, pharmacoeconomic models and prospective studies have demonstrated that genotype or phenotype screening for TPMT polymorphisms is cost-effective in patients with rheumatological disorders [20], inflammatory bowel disease [21,22], paediatric leukaemia [23] and autoimmune skin disease [24]. Other small prospective screening studies of TPMT activity have not adequately predicted toxicity in patients with inflammatory bowel disease [25,26].…”

Section: Discussionmentioning

confidence: 99%

Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase

Perri

Cole²,

Friedman³

et al. 2007

European Respiratory Journal

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Current guidelines support the use of corticosteroids and azathioprine as one possible treatment strategy for idiopathic pulmonary fibrosis (IPF). However, some patients with genetic polymorphisms of thiopurine methyltransferase (TPMT) are at risk of severe azathioprine myelotoxicity.The current authors present the case of an 85-yr-old Caucasian male with IPF who developed diffuse alveolar haemorrhage as a complication of azathioprine-induced myelosuppression.Leukocyte genetic TPMT testing revealed that the patient had homozygous polymorphisms associated with the absence of TPMT activity and severe azathioprine-induced myelotoxicity.Thiopurine methyltransferase deficiency should be considered in patients who develop leukopenia early in treatment with azathiopurine, or who present with severe marrow suppression at usual doses. For centres with equipped laboratories, a dosing suggestion is provided based on thiopurine methyltransferase testing. Even with screening strategies, frequent monitoring of complete blood count and liver biochemistry should remain the mainstay of surveillance for azathioprine toxicity.

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Pharmacoeconomic Analyses of Azathioprine, Methotrexate and Prospective Pharmacogenetic Testing for the Management of Inflammatory Bowel Disease

Cited by 87 publications

References 40 publications

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

A chemical enterocolitis model in zebrafish larvae that is dependent on microbiota and responsive to pharmacological agents

Azathioprine and diffuse alveolar haemorrhage: the pharmacogenetics of thiopurine methyltransferase

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