Review article: thiopurines in inflammatory bowel disease

Derijks, Luc J. J.; Gilissen, Lennard P L; Hooymans, P. M.; Hommes, Daniël W.

doi:10.1111/j.1365-2036.2006.02980.x

Cited by 144 publications

(153 citation statements)

References 138 publications

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“…There was no clinical evidence of toxicity in these patients. It is possible that this group had a greater baseline MCV due to, as yet, unidentified genetic factors or disease-related factors such as vitamin B 12 or folate deficiency. Our study did not include assessments of B 12 levels or folate as potential causes of macrocytosis.…”

Section: Discussionmentioning

confidence: 99%

“…Although MCV levels reached a plateau, they never returned to baseline, indicating a likely sustained effect of azathioprine rather than a confounding factor. If vitamin B 12 or folate deficiency were presumed to be the confounding factor, one would expect MCV to return to baseline as the clinical status of the disease improved. This did not occur.…”

Section: Discussionmentioning

confidence: 99%

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Change in Hematologic Indices over Time in Pediatric Inflammatory Bowel Disease Treated with Azathioprine

et al. 2010

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Azathioprine leads to changes in mean corpuscular volume (MCV) and white blood cell (WBC) indices reflecting efficacy or toxicity. Understanding the interactions between bone marrow stem cells and azathioprine could highlight abnormal response patterns as forerunners for hematologic malignancies. This study gives a statistical description of factors influencing the relationship between MCV and WBC in children with inflammatory bowel disease treated with azathioprine. We found that leukopenia preceded macrocytosis. Macrocytosis is therefore not a good predictor of leukopenia. Further studies will be necessary to determine the subgroup of patients at increased risk of malignancies based on bone marrow response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Change in Hematologic Indices over Time in Pediatric Inflammatory Bowel Disease Treated with Azathioprine

et al. 2010

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“…ioguanine, as an alternative to azathioprine or 6-mercaptopurine, has been used in some series with successful management in patients with allergic reactions or intolerance to azathioprine / 6-mercaptopurine (135,136) . However, there is a risk of nodular regenerative hyperplasia or venoocclusive disease of the liver (137) that may be related to increased levels of thioguanine nucleotides (135) .…”

Section: Moderate To Severe Diseasementioning

confidence: 99%

Management of Crohn's Disease in Adults

2009

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Guidelines for clinical practice are intended to suggest preferable approaches to particular medical problems as established by interpretation and collation of scientifi cally valid research, derived from extensive review of published literature. When data that will withstand objective scrutiny are not available, a recommendation may be made based on a consensus of experts. Guidelines are intended to apply to the clinical situation for all physicians without regard to specialty. Guidelines are intended to be fl exible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are infl exible and rarely violated. Given the wide range of choices in any health-care problem, the physician should select the course best suited to the individual patient and the clinical situation presented. These guidelines are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee. Expert opinion is solicited from the outset for the document. The quality of evidence upon which a specifi c recommendation is based is as follows: Grade A: Homogeneous evidence from multiple well-designed randomized (therapeutic) or cohort (descriptive) controlled trials, each involving a number of participants to be of suffi cient statistical power. Grade B: Evidence from at least one large well-designed clinical trial with or without randomization, from cohort or case -control analytic studies, or well-designed meta-analysis. Grade C: Evidence based on clinical experience, descriptive studies, or reports of expert committees. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fi elds. The fi nal recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientifi c developments at a later time.

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“…For instance, ITPA deficiency may be responsible for adverse drug reactions in patients treated with the purine analog azathioprine (12), an immunosuppressive drug used in the treatment of inflammatory bowel diseases, leukemia, and autoimmune complications in connection with organ transplants.…”

mentioning

confidence: 99%

Crystal Structure of Human Inosine Triphosphatase

Stenmark

Kursula

Flodin

et al. 2007

Journal of Biological Chemistry

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Inosine triphosphatase (ITPA) is a ubiquitous key regulator of cellular non-canonical nucleotide levels. It breaks down inosine and xanthine nucleotides generated by deamination of purine bases. Its enzymatic action prevents accumulation of ITP and reduces the risk of incorporation of potentially mutagenic inosine nucleotides into nucleic acids. Here we describe the crystal structure of human ITPA in complex with its prime substrate ITP, as well as the apoenzyme at 2.8 and 1.1 Å , respectively. These structures show for the first time the site of substrate and Mg 2؉ coordination as well as the conformational changes accompanying substrate binding in this class of enzymes. Enzyme substrate interactions induce an extensive closure of the nucleotide binding grove, resulting in tight interactions with the base that explain the high substrate specificity of ITPA for inosine and xanthine over the canonical nucleotides. One of the dimer contact sites is made up by a loop that is involved in coordinating the metal ion in the active site. We predict that the ITPA deficiency mutation P32T leads to a shift of this loop that results in a disturbed affinity for nucleotides and/or a reduced catalytic activity in both monomers of the physiological dimer.

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Review article: thiopurines in inflammatory bowel disease

Abstract: SUMMARY BackgroundIn the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity.

Cited by 144 publications

References 138 publications

Change in Hematologic Indices over Time in Pediatric Inflammatory Bowel Disease Treated with Azathioprine

Change in Hematologic Indices over Time in Pediatric Inflammatory Bowel Disease Treated with Azathioprine

Management of Crohn's Disease in Adults

Crystal Structure of Human Inosine Triphosphatase

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