title: Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial.
abstract: Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12-week, double-blind controlled trial. The primary end-point was the percentage of subjects with clinical remission [Crohn's Disease Activity Index (CDAI) < 150] or clinical response (100-point CDAI reduction). Twenty-six (56·5%) and 13 (54·2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR-6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62(+) expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug-induced leucopenia in the DR-6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.
authors.affiliation: Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem.
authors.forename: E
authors.initials: E
authors.lastname: Israeli
authors.affiliation: Department of Gastroenterology, Shaarei Zedek Medical Center, Jerusalem.
authors.forename: E
authors.initials: E
authors.lastname: Goldin
authors.affiliation: Department of Gastroenterology, Tel Aviv-Sourasky Medical Center, Tel Aviv.
authors.forename: S
authors.initials: S
authors.lastname: Fishman
authors.affiliation: Department of Gastroenterology, Meir Medical Center, Kfar Saba.
authors.forename: F
authors.initials: F
authors.lastname: Konikoff
authors.affiliation: Department of Gastroenterology, Bnai Zion Hospital, Haifa.
authors.forename: A
authors.initials: A
authors.lastname: Lavy
authors.affiliation: Department of Gastroenterology, Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa.
authors.forename: Y
authors.initials: Y
authors.lastname: Chowers
authors.affiliation: Department of Gastroenterology, Kaplan Medical Center, Rehovot.
authors.forename: E
authors.initials: E
authors.lastname: Melzer
authors.affiliation: Department of Gastroenterology, Sheba Medical Center, Tel Hashomer.
authors.forename: A
authors.initials: A
authors.lastname: Lahat
authors.affiliation: Department of Gastroenterology, Holy Family Hospital, Nazareth.
authors.forename: M
authors.initials: M
authors.lastname: Mahamid
authors.affiliation: Department of Gastroenterology, Assaf Harofeh Medical Center, Zerifin.
authors.forename: H
authors.initials: H
authors.lastname: Shirin
authors.affiliation: Department of Gastroenterology, Ha'emek Medical Center, Afula.
authors.forename: E
authors.initials: E
authors.lastname: Nussinson
authors.affiliation: Department of Gastroenterology, Carmel Medical Center, Haifa, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Segol
authors.affiliation: Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem.
authors.forename: A Ben
authors.initials: AB
authors.lastname: Ya'acov
authors.affiliation: Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem.
authors.forename: Y
authors.initials: Y
authors.lastname: Shabbat
authors.affiliation: Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem.
authors.forename: Y
authors.initials: Y
authors.lastname: Ilan
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000963:Antimetabolites / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001682:Biological Availability; D002448:Cell Adhesion / Q000187:drug effects; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004311:Double-Blind Method; D019040:E-Selectin / Q000276:immunology; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D011795:Surveys and Questionnaires; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000963:Antimetabolites; D003692:Delayed-Action Preparations; D019040:E-Selectin; D005765:Gastrointestinal Agents; D015122:Mercaptopurine
keywords: 6-mercaptopurine; Crohn's disease; gut immune system; oral therapy
references.citation: Gastroenterology. 2004 Sep;127(3):723-9
references.pmid: 15362027
references.citation: Biochem Pharmacol. 1993 Apr 6;45(7):1455-63
references.pmid: 7682415
references.citation: Eur J Gastroenterol Hepatol. 2000 Nov;12(11):1227-33
references.pmid: 11111780
references.citation: J Clin Pharmacol. 2013 Jun;53(6):670-4
references.pmid: 23585236
references.citation: J Crohns Colitis. 2012 Jul;6(6):698-707
references.pmid: 22398098
references.citation: Curr Pharm Des. 2009;15(11):1191-202
references.pmid: 19355960
references.citation: BMC Gastroenterol. 2010;10:26
references.pmid: 20196836
references.citation: J Neuroimmunol. 2010 Oct 8;227(1-2):10-7
references.pmid: 20580440
references.citation: Am J Gastroenterol. 2006 Mar;101(3):561-8
references.pmid: 16542292
references.citation: Cochrane Database Syst Rev. 2013;(4):CD000545
references.pmid: 23633304
references.citation: Immunol Rev. 2011 May;241(1):241-59
references.pmid: 21488901
references.citation: Therap Adv Gastroenterol. 2010 Jan;3(1):23-30
references.pmid: 21180587
references.citation: Curr Drug Targets. 2011 Aug;12(9):1364-71
references.pmid: 21291384
references.citation: Gut. 1995 Mar;36(3):411-8
references.pmid: 7535284
references.citation: Gastroenterology. 2013 Oct;145(4):758-65.e2; quiz e14-5
references.pmid: 23644079
references.citation: J Clin Invest. 2003 Apr;111(8):1133-45
references.pmid: 12697733
references.citation: Eur J Gastroenterol Hepatol. 2009 Feb;21(2):167-75
references.pmid: 19212205
references.citation: Gut. 2009 Mar;58(3):396-403
references.pmid: 18832521
references.citation: J Neurol Sci. 2008 Nov 15;274(1-2):9-12
references.pmid: 18804221
references.citation: Aliment Pharmacol Ther. 2007 Oct 1;26(7):987-1003
references.pmid: 17877506
references.citation: J Immunol. 2010 Sep 15;185(6):3401-7
references.pmid: 20720210
references.citation: Gastroenterology. 2000 Oct;119(4):895-902
references.pmid: 11040176
references.citation: Br J Nutr. 2013 Jan;109 Suppl 2:S3-11
references.pmid: 23360879
references.citation: Aliment Pharmacol Ther. 2013 Nov;38(10):1255-66
references.pmid: 24117596
references.citation: Hum Immunol. 2009 Oct;70(10):768-76
references.pmid: 19559742
references.citation: Gastroenterology. 2011 Dec;141(6):2109-18
references.pmid: 21925467
references.citation: Diabetes. 2007 Aug;56(8):2103-9
references.pmid: 17456848
references.citation: Dig Dis Sci. 2014 Jun;59(6):1207-12
references.pmid: 24390675
references.citation: Clin Dev Immunol. 2012;2012:425021
references.pmid: 22162715
references.citation: J Exp Med. 2007 Jan 22;204(1):33-9
references.pmid: 17200409