An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy
Corresponding Author
Dr. Marla C. Dubinsky
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Marla C. Dubinsky, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Ernest G. Seidman, Royalty agreement for the use of the 6-mercaptopurine metabolite levels for the management of IBD with Prometheus Laboratories
Stephan R. Targan, Prometheus Laboratories
Eric A. Vasiliauskas, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Search for more papers by this authorPhilip V. Hassard
Division of Gastroenterology, Department of Medicine, Ottawa General Hospital, University of Ottawa, Ottawa, Ontario
Search for more papers by this authorCorresponding Author
Dr. Ernest G. Seidman
Division of Gastroenterology & Nutrition, Department of Pediatrics, Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada
Marla C. Dubinsky, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Ernest G. Seidman, Royalty agreement for the use of the 6-mercaptopurine metabolite levels for the management of IBD with Prometheus Laboratories
Stephan R. Targan, Prometheus Laboratories
Eric A. Vasiliauskas, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Search for more papers by this authorLori Y. Kam
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Search for more papers by this authorMaria T. Abreu
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Search for more papers by this authorCorresponding Author
Dr. Stephan R. Targan
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Marla C. Dubinsky, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Ernest G. Seidman, Royalty agreement for the use of the 6-mercaptopurine metabolite levels for the management of IBD with Prometheus Laboratories
Stephan R. Targan, Prometheus Laboratories
Eric A. Vasiliauskas, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Search for more papers by this authorCorresponding Author
Eric A. Vasiliauskas
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Marla C. Dubinsky, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Ernest G. Seidman, Royalty agreement for the use of the 6-mercaptopurine metabolite levels for the management of IBD with Prometheus Laboratories
Stephan R. Targan, Prometheus Laboratories
Eric A. Vasiliauskas, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Search for more papers by this authorCorresponding Author
Dr. Marla C. Dubinsky
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Marla C. Dubinsky, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Ernest G. Seidman, Royalty agreement for the use of the 6-mercaptopurine metabolite levels for the management of IBD with Prometheus Laboratories
Stephan R. Targan, Prometheus Laboratories
Eric A. Vasiliauskas, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Search for more papers by this authorPhilip V. Hassard
Division of Gastroenterology, Department of Medicine, Ottawa General Hospital, University of Ottawa, Ottawa, Ontario
Search for more papers by this authorCorresponding Author
Dr. Ernest G. Seidman
Division of Gastroenterology & Nutrition, Department of Pediatrics, Sainte-Justine Hospital, University of Montréal, Montréal, Québec, Canada
Marla C. Dubinsky, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Ernest G. Seidman, Royalty agreement for the use of the 6-mercaptopurine metabolite levels for the management of IBD with Prometheus Laboratories
Stephan R. Targan, Prometheus Laboratories
Eric A. Vasiliauskas, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Search for more papers by this authorLori Y. Kam
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Search for more papers by this authorMaria T. Abreu
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Search for more papers by this authorCorresponding Author
Dr. Stephan R. Targan
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Marla C. Dubinsky, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Ernest G. Seidman, Royalty agreement for the use of the 6-mercaptopurine metabolite levels for the management of IBD with Prometheus Laboratories
Stephan R. Targan, Prometheus Laboratories
Eric A. Vasiliauskas, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Search for more papers by this authorCorresponding Author
Eric A. Vasiliauskas
Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, UCLA, Los Angeles, California
Marla C. Dubinsky, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Ernest G. Seidman, Royalty agreement for the use of the 6-mercaptopurine metabolite levels for the management of IBD with Prometheus Laboratories
Stephan R. Targan, Prometheus Laboratories
Eric A. Vasiliauskas, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, CA 90048, U.S.A.
Search for more papers by this authorAbstract
Background and Aims
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.
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