PMID- 25846055 OWN - NLM STAT- MEDLINE DCOM- 20150930 LR - 20181113 IS - 1365-2249 (Electronic) IS - 0009-9104 (Print) IS - 0009-9104 (Linking) VI - 181 IP - 2 DP - 2015 Aug TI - 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. PG - 362-72 LID - 10.1111/cei.12640 [doi] AB - 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. CI - (c) 2015 British Society for Immunology. FAU - Israeli, E AU - Israeli E AD - Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem. FAU - Goldin, E AU - Goldin E AD - Department of Gastroenterology, Shaarei Zedek Medical Center, Jerusalem. FAU - Fishman, S AU - Fishman S AD - Department of Gastroenterology, Tel Aviv-Sourasky Medical Center, Tel Aviv. FAU - Konikoff, F AU - Konikoff F AD - Department of Gastroenterology, Meir Medical Center, Kfar Saba. FAU - Lavy, A AU - Lavy A AD - Department of Gastroenterology, Bnai Zion Hospital, Haifa. FAU - Chowers, Y AU - Chowers Y AD - Department of Gastroenterology, Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa. FAU - Melzer, E AU - Melzer E AD - Department of Gastroenterology, Kaplan Medical Center, Rehovot. FAU - Lahat, A AU - Lahat A AD - Department of Gastroenterology, Sheba Medical Center, Tel Hashomer. FAU - Mahamid, M AU - Mahamid M AD - Department of Gastroenterology, Holy Family Hospital, Nazareth. FAU - Shirin, H AU - Shirin H AD - Department of Gastroenterology, Assaf Harofeh Medical Center, Zerifin. FAU - Nussinson, E AU - Nussinson E AD - Department of Gastroenterology, Ha'emek Medical Center, Afula. FAU - Segol, O AU - Segol O AD - Department of Gastroenterology, Carmel Medical Center, Haifa, Israel. FAU - Ya'acov, A Ben AU - Ya'acov AB AD - Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem. FAU - Shabbat, Y AU - Shabbat Y AD - Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem. FAU - Ilan, Y AU - Ilan Y AD - Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem. LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Clin Exp Immunol JT - Clinical and experimental immunology JID - 0057202 RN - 0 (Antimetabolites) RN - 0 (Delayed-Action Preparations) RN - 0 (E-Selectin) RN - 0 (Gastrointestinal Agents) RN - E7WED276I5 (Mercaptopurine) SB - IM MH - Administration, Oral MH - Adolescent MH - Adult MH - Aged MH - Antimetabolites/*administration & dosage/adverse effects/pharmacokinetics MH - Biological Availability MH - Cell Adhesion/drug effects MH - Crohn Disease/*drug therapy/immunology/metabolism/pathology MH - Delayed-Action Preparations/*administration & dosage/adverse effects/pharmacokinetics MH - Double-Blind Method MH - E-Selectin/immunology MH - Female MH - Gastrointestinal Agents/*administration & dosage/adverse effects/pharmacokinetics MH - Gastrointestinal Tract/drug effects/immunology/metabolism/pathology MH - Humans MH - Intestinal Absorption MH - Male MH - Mercaptopurine/*administration & dosage/adverse effects/pharmacokinetics MH - Middle Aged MH - Surveys and Questionnaires MH - T-Lymphocytes/drug effects/immunology/pathology MH - Treatment Outcome PMC - PMC4516452 OTO - NOTNLM OT - 6-mercaptopurine OT - Crohn's disease OT - gut immune system OT - oral therapy EDAT- 2015/04/08 06:00 MHDA- 2015/10/01 06:00 PMCR- 2016/08/01 CRDT- 2015/04/08 06:00 PHST- 2015/02/22 00:00 [received] PHST- 2015/03/17 00:00 [revised] PHST- 2015/03/17 00:00 [accepted] PHST- 2015/04/08 06:00 [entrez] PHST- 2015/04/08 06:00 [pubmed] PHST- 2015/10/01 06:00 [medline] PHST- 2016/08/01 00:00 [pmc-release] AID - 10.1111/cei.12640 [doi] PST - ppublish SO - Clin Exp Immunol. 2015 Aug;181(2):362-72. doi: 10.1111/cei.12640.