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Title: A search for novel biomarkers predicting toxicity and response to thiopurine treatment in patients with inflammatory bowel disease
Author: Blaker, Paul Andrew
ISNI:       0000 0004 5368 0337
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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The thiopurines, mercaptopurine (MP) and its pro-drug azathioprine (AZA), are the first line immunomodulators used in the management of inflammatory bowel disease (IBD). Unfortunately, 30 - 40% of patients are unable to derive benefit from these medicines as a result of drug toxicity or treatment non-response. The main active metabolites of these drugs are the phosphorylated thioguanine nucleotides (TGNs) and methylated derivatives of mercaptopurine (MeMP). Recent experience suggests that measurement of these metabolites can be used to explain inter-individual variation in response to treatment and identify opportunities to optimize therapy. In particular, some patients with IBD display sub-optimal TGN levels and unexpectedly high MeMP concentrations, a phenotype which is known as thiopurine hypermethylation. Importantly this skewed drug metabolism can be circumvented using a low dose of AZA/MP in combination with allopurinol. This thesis provides an original contribution to knowledge by firstly exploring and characterizing thiopurine hypermethylation in patients with IBD to determine its impact on clinical response. Secondly, it investigates the mechanism of thiopurine hypermethylation and other thiopurine-induced drug toxicities using both candidate gene and genome-wide approaches, with the goal of identifying biomarkers that can be used to predict outcomes prior to the start of treatment. Finally, it resolves the biochemical interaction between thiopurines and allopurinol, which has remained unexplained for over half a century.
Supervisor: Sanderson, Jeremy Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available