The Blood Concentration and Therapeutic Efficacy of Azathioprine in Patients Receiving Infliximab Combination Therapy for Refractory Crohn's Disease:A Clinical Study

摘要

Crohn's disease is a chronic inflammatory bowel disease of unknown cause that can damage any area of the gastrointestinal tract. Refractory Crohn's disease can be treated with immunosuppressive drugs such as azathioprine (AZA) and 6-mercaptopurine, and also with the anti-tumour necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody, infliximab (IFX). In the present study, the blood concentrations of AZA metabolites were measured in patients with refractory Crohn's disease receiving a combination of AZA and IFX, in order to clarify the interaction of the two drugs, and also their efficacy and safety. The patients were enrolled at the Gastroenterology Division, Department of Internal Medicine, Toho University Medical Center Sakura Hospital, where they were receiving AZA (Imuran, GlaxoSmithKline, Dartford, UK) alone, or in combination with IFX (Remicade, Mitsubishi Tanabe Pharma, Osaka, Japan). In order to judge the effect of AZA objectively, the blood concentrations of its active metabolites, 6-thioguanme nucleotides (6-TGNs) were monitored. 6-TGNs in blood were measured as their 6-thioguanine (6-TG) denucleotidized forms using high-performance liquid chromatography (HPLC) with UV detection. The combined use of AZA and IFX was shown to increase the blood 6-TGNs concentrations of AZA metabolites. At a 6-TG concentration of more than 250 pmol/8x10~8 RBC, the treatment was observed to be effective, and a negative correlation between the number of IFX treatments and the blood 6-TGNs concentration was observed. The present findings suggest that AZA and IFX combination therapy suppresses Crohn's disease activity more effectively than AZA monotherapy. We think that as an increase in the AZA concentration can be considered one of the synergistic effects of IFX, monitoring of the blood concentration of AZA metabolites would be a useful approach for evaluating the efficacy and safety of combined AZA and IFX therapy.