The treatment of inflammatory bowel disease with 6‐mercaptopurine or azathioprine

Nielsen, Ole Haagen; Vainer, Ben; Rask-Madsen, J

doi:10.1046/j.1365-2036.2001.01102.x

Cited by 186 publications

(112 citation statements)

References 65 publications

(79 reference statements)

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“…Phase II, designed based on the results of phase I, used seven clinical strains of M. paratuberculosis of bovine or human origin and one M. avium strain, ATCC 35712, as a control. Some drugs to which M. paratuberculosis was not susceptible in phase I, specifically the SS drug family (SS, 5-ASA, and SP), were excluded, and AZA, a prodrug of 6-MP, was added to the trial (19,27).…”

Section: Drugs Testedmentioning

confidence: 99%

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

Shin

Collins

2008

Antimicrob Agents Chemother

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The in vitro susceptibility of human-and bovine-origin Mycobacterium paratuberculosis to the thioupurine drugs 6-mercaptopurine (6-MP) and azathioprine (AZA) was established using conventional plate counting methods and the MGIT 960 ParaTB culture system. Both 6-MP and AZA had antibacterial activity against M. paratuberculosis; isolates from Crohn's disease patients tended to be more susceptible than were bovine-origin isolates. Isolates of Mycobacterium avium, used as controls, were generally resistant to both AZA and 6-MP, even at high concentrations (>64.0 g/ml). Among rapidly growing mycobacteria, Mycobacterium phlei was susceptible to 6-MP and AZA whereas Mycobacterium smegmatis strains were not. AZA and 6-MP limited the growth of, but did not kill, M. paratuberculosis in a dose-dependent manner. Anti-inflammatory drugs in the sulfonamide family (sulfapyridine, sulfasalazine, and 5-aminosalycilic acid [mesalamine]) had little or no antibacterial activity against M. paratuberculosis. The conventional antibiotics azithromycin and ciprofloxacin, used as control drugs, were bactericidal for M. paratuberculosis, exerting their killing effects on the organism relatively quickly. Simultaneous exposure of M. paratuberculosis to 6-MP and ciprofloxacin resulted in significantly higher CFU than use of ciprofloxacin alone. These data may partially explain the paradoxical response of Crohn's disease patients infected with M. paratuberculosis to treatment with immunosuppressive thiopurine drugs, i.e., they do not worsen with anti-inflammatory treatment as would be expected with a microbiological etiologic pathogen. These findings also should influence the design of therapeutic trials to evaluate antibiotic treatments of Crohn's disease: AZA drugs may confound interpretation of data on therapeutic responses for both antibiotic-treated and control groups.

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Section: Drugs Testedmentioning

confidence: 99%

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

Shin

Collins

2008

Antimicrob Agents Chemother

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“…The preferential increase of 6-MMP but not 6-TGN concentrations was observed in 5 of 8 patients with multiple dose escalations without the desired rise of 6-TGN Ͼ250 pmol/8 ϫ 10 8 Ery. Because AZA dosage increases based on 6-TGN concentrations did not show the desired increase in the latter, irrespective of TPMT, other independent variables must influence metabolite steady-state concentrations; variable bioavailability in active inflammatory bowel disease (34,35 ) is one candidate. Our previous observations in active Crohn disease compared with other chronic inflammatory systemic diseases are also in agreement with these findings (36 ).…”

Section: Discussionmentioning

confidence: 99%

6-Thioguanine Nucleotide–Adapted Azathioprine Therapy Does Not Lead to Higher Remission Rates Than Standard Therapy in Chronic Active Crohn Disease: Results from a Randomized, Controlled, Open Trial

et al. 2007

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Background: A prospective randomized trial in patients with Crohn disease studied whether 6-thioguanine nucleotide (6-TGN) concentration-adapted azathioprine (AZA) therapy is clinically superior to a standard dose of 2.5 mg/kg/day AZA. Methods: After 2 weeks of standard therapy, patients (n ‫؍‬ 71) were randomized into standard (n ‫؍‬ 32) or adapted-dose (n ‫؍‬ 25) groups; 14 patients dropped out before randomization. In the adapted group, the AZA dose was adjusted to maintain 6-TGN concentrations between 250 and 400 pmol/8 ؋ 10 8 erythrocytes (Ery). Response criteria were the number of patients in remission after 16 weeks without steroids (primary) and remission after 24 weeks, frequency of side effects, and quality of life (secondary).Results: After 16 weeks, 14 of 32 (43.8%) patients in the standard group vs 11 of 25 (44%) in the adapted group were in remission without steroids (intent-to-treat analysis). After 24 weeks, 43.8% vs 40% were in remission. No significant differences were found concerning quality of life, disease activity, 6-TGN concentrations, AZA dose, or dropouts due to side effects. Sixty-six patients had a wild-type thiopurine S-methyltransferase (TPMT) genotype, with TPMT activities of 8 to 20 nmol/(mL Ery ؋ h). Five patients (dropouts after randomization) were heterozygous, with TPMT activities <8 nmol/(mL Ery ؋ h). 6-Methyl mercaptopurine (6-MMP) concentrations >5700 pmol/8 ؋ 10 8 Ery were not associated with hepatotoxicity. Conclusion: Standard and adapted dosing with the provided dosing scheme led to identical 6-TGN concentrations and remission rates. Adapted dosing had no apparent clinical benefit for patients with TPMT activity between 8 and 20 nmol/(mL Ery ؋ h). Additionally, 6-MMP monitoring had no predictive value for hepatotoxicity.

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“…7 m g / k g p e r d ay ) p r ove d t o b e e f f e c t ive i n maintaining remission in a French cohort of CD patients, which was lower than the dose used in clinical trials (2.5 mg/kg per day). Nielsen et al in their review in the year 2001, suggested a 0.25 ± 0.5 mg/kg daily initial (AZA equivalent) dose for the 6-MP, increasing to 1.0 ± 1.5 mg/kg daily [30] . Su and Lichtenstein, three years later, advocated "the optimal dose for the treatment of active CD is generally considered 2.5 mg/kg per day for azathioprine and 1.5 mg/kg per day for 6-MP" [17] .…”

mentioning

confidence: 99%

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

Nagy¹,

Molnár²,

Szepes³

et al. 2008

WJG

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AIM:To investigate the efficacy of 6-mercaptopurine (6-MP) in cases of azathioprine (AZA) hypersensitivity in patients with inflammatory bowel disease. METHODS: Twenty nine previously confirmed Crohn's disease (CD) (n = 14) and ulcerative colitis (UC) (n = 15) patients with a known previous (AZA) hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indices (CDAI/ CAI), laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS: In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 (8 UC, 4 CD) patients, and after the first year in 9 (6 UC, 3 CD) patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts (P = 0.01), CRP (P = 0.02), and serum iron (P = 0.05) values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION: About one-third of the previously AZAintolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.

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The treatment of inflammatory bowel disease with 6‐mercaptopurine or azathioprine

Cited by 186 publications

References 65 publications

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

6-Thioguanine Nucleotide–Adapted Azathioprine Therapy Does Not Lead to Higher Remission Rates Than Standard Therapy in Chronic Active Crohn Disease: Results from a Randomized, Controlled, Open Trial

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

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