It is possible that dose escalation can improve tolerance by reducing the rates of side effects such as gastrointestinal disturbance, fatigue, myalgias and arthralgias, but no studies have compared a dose escalation protocol to initial full Erastin dose thiopurine. Once target dose has been reached, performance of complete blood count and liver enzymes every 3 months is considered mandatory in view of the risk of late myelosuppression

and hepatotoxicity.[68] There are two ways of using thiopurine metabolites in clinical practice – reactively or proactively. The former is the standard approach where patients who exhibit an inadequate response to thiopurines after at least 3 months’ therapy on an adequate weight-based dose of thiopurines or have an

adverse event are tested. For patients who are in steroid-free remission and have no side effects, there would appear to be little LEE011 research buy advantage in measuring metabolites. As 6TGN levels take at least 2 weeks to achieve steady state after a dose change in adults[69] and up to 55 days in children,[70] metabolites should be monitored every month during optimization after a dose change until a therapeutic level is achieved. The second approach would include early measurement of thiopurine metabolites to hasten the optimization Grape seed extract of drug dosage. This would identify shunters, non-compliers, and fast and slow metabolizers early, and permit appropriate action taken rather to wait for inefficacy or adverse events to occur. This approach has been applied only to fast metabolizers to date,[61] but requires evaluation. The other major reason for failure of thiopurine therapy is the occurrence of adverse events leading to the drug’s cessation. Most episodes of myelosuppression and hepatotoxicity relate to elevated 6TGN and 6MMP levels,

respectively. In these situations, thiopurine metabolites should be measured and a reduced dose with or without the addition of allopurinol is indicated. However, a newer development is the management of idiosyncratic reactions to thiopurines, such as nausea, vomiting, myalgias, arthralgias, fatigue, fevers and a flu-like illness, which can affect up to 33% of patients.[69] In IBD in particular, where the therapeutic options are more limited, cessation of the drug and exclusion of thiopurines from that patient is undesirable. On the basis that the adverse events are due to the primary drug used and not its metabolites, up to 50% of patients who develop an idiosyncratic reaction on AZA (possibly the imidazole group[71]) can be safely switched to 6MP without recurrence of the adverse event.