title: An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy.
abstract: OBJECTIVE
  A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy.
  
  
  METHODS
  Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities.
  
  
  RESULTS
  Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity.
  
  
  CONCLUSIONS
  6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California 90048, USA. dubinskym@csmc.edu
authors.forename: M C
authors.initials: MC
authors.lastname: Dubinsky
authors.forename: P V
authors.initials: PV
authors.lastname: Hassard
authors.forename: E G
authors.initials: EG
authors.lastname: Seidman
authors.forename: L Y
authors.initials: LY
authors.lastname: Kam
authors.forename: M T
authors.initials: MT
authors.lastname: Abreu
authors.forename: S R
authors.initials: SR
authors.lastname: Targan
authors.forename: E A
authors.initials: EA
authors.lastname: Vasiliauskas
mesh_terms: D000328:Adult; D000963:Antimetabolites / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001379:Azathioprine / Q000627:therapeutic use; D002648:Child; D003424:Crohn Disease / Q000188:drug therapy*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D015122:Mercaptopurine / Q000627:therapeutic use; D008875:Middle Aged; D010865:Pilot Projects; D013866:Thioguanine / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000963:Antimetabolites; D015122:Mercaptopurine; D013866:Thioguanine; D001379:Azathioprine