Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis

Hibi, Toshifumi; Naganuma, Makoto; Kitahora, Tetsuji; Kinjyo, Fukunori; Shimoyama, Takashi

doi:10.1007/s00535-003-1139-2

Cited by 116 publications

(127 citation statements)

References 26 publications

(41 reference statements)

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“…TPMT activity is reported to depend on the genetic polymorphism of high-versus lowmetabolizing alleles (5,6) (13). In this study, we found TPMT*3C mutation in 0.9% of the Japanese population, and this is similar to the observations by Kubota et al (11,14).…”

Section: Discussionsupporting

confidence: 90%

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

et al. 2008

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Section: Discussionsupporting

confidence: 90%

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

et al. 2008

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“…In particular, Japanese populations are sensitive to thiopurines, and relatively lower doses of AZA (0.6-1.2 mg/kg/day) are recommended for the treatment of Japanese IBD patients (11). Similar to TPMT A719G and ITPase C94A, we recently showed that MRP4 G2269A is a new factor accounting for heightened thiopurine sensitivity in Japanese patients with IBD (24).…”

Section: Discussionmentioning

confidence: 96%

“…However, in 15-30% of patients, these drugs have to be discontinued due to adverse effects including bone marrow suppression, hepatotoxicity, pancreatitis, fever, rash and gastrointestinal intolerance (4)(5)(6)(7)(8)(9). Furthermore, an AZA dosage of 2-3 mg/kg is recommended for the treatment of IBD patients in Western countries (10), but lower doses of AZA (0.6-1.2 mg/kg/day) are used in Japanese patients due to their relatively heightened sensitivity (11).…”

Section: Introductionmentioning

confidence: 99%

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Osaki¹,

Imaeda²,

Ban³

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Thiopurine drugs are the most common drugs used to maintain clinical remission in inflammatory bowel disease (IBD). Three single-nucleotide polymorphisms (SNPs), TPMT A719G (rs1142345), inosine triphosphate pyrophosphatase (ITPase) C94A (rs1127354) and multidrug resistance protein 4 MRP4 G2269A (rs3765534), have been reported to account for heightened sensitivity to thiopurine drugs in the Japanese population. We investigated the usefulness of the TaqMan ® PCR assay (Applied Biosystems) for the rapid detection of these SNPs to improve the safety of thiopurine therapy. We enrolled 44 healthy volunteers and 235 IBD patients. Genotyping of the SNPs was performed using Custom TaqMan SNP genotyping assays, direct sequencing and PCR-RFLP. Genotyping for MRP4 G2269A by the TaqMan PCR assay was successfully achieved in all samples. Comparison with our previous data using direct sequencing indicated one discordant result, and re-sequencing showed that the TaqMan PCR assay was correct. The overall accuracy of the TaqMan assay for MRP4 G2269A was 100%. The TaqMan PCR genotyping for TPMT A719G and ITPase C94A was successfully performed in all samples. The results of TPMT A719G by the TaqMan assay were identical with those of PCR-RFLP. In ITPase C94A, a comparison of the TaqMan assay and PCR-RFLP yielded 12 discordant results, and direct sequencing showed that the TaqMan PCR assay was correct. The allelic frequency determined by the TaqMan assay was 0.145 for MRP4 G2269A, 0.009 for TPMT A719G and 0.121 for ITPase C94A, respectively. In conclusion, the TaqMan ® PCR assay is useful for genotyping of SNPs responsible for thiopurine sensitivity in Japanese IBD patients.

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“…The high expression of P-gp in the peripheral blood lymphocytes of patients with systemic lupus erythematosus resulted indecreased lymphocyte glucocorticoid levels, steroid-resistance, and reduced efficacy (Hibi et al, 2003). A study by Wasilewska et al (2007) also showed that steroid-resistance or -dependence in children with nephrotic syndrome was related to P-gp expression in peripheral lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Multidrug resistance gene and its relationship to ulcerative colitis and immune status of ulcerative colitis

Zhang

Wang

et al. 2014

Genet. Mol. Res.

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ABSTRACT. We examined the relationship among the multidrug resistance (MDR1) gene product P-glycoprotein (P-gp), ulcerative colitis, and immune status under ulcerative colitis. MDR1 P-gp expression and interleukin-8 levels in ulcerative colitis were determined using immunohistochemistry and a double-antibody sandwich avidinbiotin complex-enzyme-linked immunosorbent assay, respectively. Nitric oxide content and nitric oxide synthase activity in the colonic mucosa were determined using a colorimetric method; CD4 + and CD25 + T cell subset percentages in the peripheral blood were determined by flow cytometry. The positive expression rate of P-gp in patients with ulcerative colitis (17.4%) was significantly lower than that in the control group (31.4%). The expression rate decreased to 10.1, 9.2, and 8.3% after 12, 18, and 24 months of treatment, respectively, which were significantly lower than the expression rate before treatment (17.4%). P-gp expression levels during the remission phase and active phase of ulcerative colitis were 15.2 and 17.1%, respectively, which were significantly lower than that in normal controls (31.4%). Compared with P-gp-negative patients, nitric oxide content, nitric oxide synthase activity, and interleukin-8 levels were significantly higher in P-gppositive patients with moderately active, severely active, early onset, chronic relapsing, chronic persistent, and acute fulminant ulcerative colitis. CD4 + and CD25 + T cell subsets were significantly lower in the peripheral blood of patients with severely active and acute fulminant ulcerative colitis than in control subjects. Expression of the multidrug resistance gene and its product P-gp was observed in normal colon tissues and may be closely related to ulcerative colitis.

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Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis

Abstract: A dose of 50 mg/day of AZA is effective and safe for maintenance of remission in the Japanese population. Investigation of the TPMT allele may be useful for predicting the appearance of bone marrow suppression, when low-dose 6-MP or AZA is given.

Cited by 116 publications

References 26 publications

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Multidrug resistance gene and its relationship to ulcerative colitis and immune status of ulcerative colitis

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