Research Advances on the Treatment of Ulcerative Colitis with Tacrolimus
ZHANGChun-ling1, XUShuo2, WANGYing1
1. Pharmacy Department, Beijing Health Vocational College, Beijing 102433, China; 2. Department of Pharmaceutical Science, Beijing Hospital, National Center of Gerontology, Beijing Key Laboratory of Drug Clinical Risk and Personalized Medication Evaluation, Beijing 100730, China
Abstract��Tacrolimus, a regularly used immunosuppressant, was reported to apply on the treatment of a chronic nonspecific inflammatory bowel disease ulcerative colitis in recent years. However, no study was conducted in China, and even no review was published in domestic journals. This paper reviewed the related research progress in this area, and summarized the possible mechanism and clinical researches. Inflammatory cytokines and transmitters play important role in the occurrence and development of ulcerative colitis, and the possible mechanism for the treatment of ulcerative colitis was the inhibition of T cell proliferation, the secretion of intestinal epithelial cells, and the activation of cytokines. The clinical researches started from 1998 and included prospective studies, retrospective studies, and comparative studies with anti-TNF-�� agents. The studies indicated that tacrolimus was not only effective in the short-term induction therapy as well as anti-TNF-�� agents, such as infliximab, but also valuable in the long-term maintenance therapy of ulcerative colitis. This review can provide references for the new use of tacrolimus as well as the new treatment of ulcerative colitis.
�Ŵ���, ��˶, ��ӱ. ����Ī˾���������Խ᳦���о���չ[J]. �й�ҩѧ��־, 2019, 54(7): 521-525.
ZHANGChun-ling, XUShuo, WANGYing. Research Advances on the Treatment of Ulcerative Colitis with Tacrolimus. Chinese Pharmaceutical Journal, 2019, 54(7): 521-525.
LI J. Clinical Pharmacology (�ٴ�ҩ��ѧ) [M]. 5th ed. Beijing:People��s Medical Publishing House, 2014:390-391.
[2]
BAUMGART D C, SANDBORN W J. Inflammatory bowel disease:clinical aspects and established and evolving therapies[J]. Lancet, 2007, 369(9573):1641-1657.
[3]
ELLINGHUS D, BETHUNE J, PETERSEN B S, et al. The genetics of Crohn��s disease and ulcerative colitis-status quo and beyond[J]. Scand J Gastroenterol, 2014, 50(1):13-23.
[4]
CONRAD K, ROGGENBUCK D, LAASS M W. Diagnosis and classification of ulcerative colitis [J]. Autoimmu Rev, 2014, 13(4-5):463-466.
[5]
HANAI H, IIDA T, IKEYA K, et al. A new paradigm in ulcerative colitis:regulatory T cells are key factor which induces/exacerbates UC through an immune imbalance[J]. Mol Immuno, 2013, 54(2):173-180.
[6]
DE T L, DI N A, MAGAGNA S, et al. Altered chemokine signalling in endothelial progenitor cells from acute ulcerative colitis patients[J]. Gastroenterol Res Pract, 2015, 2015(45):843980.
[7]
PARK S C, JEEN Y T. Current and emerging biologics for ulcerative colitis[J]. Gut & Liver, 2015, 9(1):18-27.
[8]
RENNA S, COTTONE M, ORLANDO A. Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease[J]. World J Gastroenterol, 2014, 20(29):9675-9690.
[9]
MEIER J, STURM A. Current treatment of ulcerative colitis[J]. World J Gastroenterol, 2011, 17(27):3204-3212.
[10]
MILLER J L, ERICSON S G. Cyclosporin A and tacrolimus (FK506) differentially alter T-cell receptor expression in vivo[J]. Immunopharmacol Immunotoxicol, 2007, 29(1):105-118.
[11]
NAKANOT K, ANDOH T, TAYAMA M, et al. Effects of topical application of tacrolimus on acute itch-associated responses in mice[J]. Biol Pharm Bull, 2008, 31(4):752-754.
[12]
YU J, HE S, LIU P, et al. Interleukin21 promotes the development of ulcerative colitis and regulates the proliferation and secretion of follicular T helper cells in the colitides microenvironment[J]. Mol Med Rep, 2015, 11(2):1049-1056.
[13]
VAN DIEREN J M, VAN DER WOUDE C J, LAMBERS M E H, et al. Possible mechanism of action of tacrolimus in IBD:inhibition of NKT cell-and intestinal epithelial cell-activation[J]. Eur J Gastroen Hepat, 2006, 18(1):A28.
[14]
VAN DIEREN J M, KUIPERS E J, SAMSOM J N, et al. Revisiting the immunomodulators tacrolimus, methotrexate, and mycophenolate mofetil:their mechanisms of action and role in the treatment of IBD [J]. Inflammy Bowel Dis, 2006, 12(4):311-327.
[15]
MIZOSHITA T, TANIDA S, TSUKAMOTO H, et al. Colon mucosa exhibits loss of ectopic MUC5AC expression in patients with ulcerative colitis treated with oral tacrolimus[J]. ISRN Gastroenterol, 2013, 2013:1-7.
[16]
FELLERMANN K, LUDWIG D, STAHL M, et al. Steroid-unresponsive acute attacks of inflammatory bowel disease:immunomodulation by tacrolimus (FK506)[J]. Am J Gastroenterol, 1998, 93(10):1860-1866.
[17]
FELLERMANN K, TANKO Z, HERRLINGER K R, et al. Response of refractory colitis to intravenous or oral tacrolimus (FK506)[J]. Inflamm Bowel Dis, 2002, 8(5):317-324.
[18]
HOGENAUER C, WENZL H H, HINTERLEITNER T A, et al. Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis[J]. Aliment Pharmacol Ther, 2003, 18(4):415-423.
[19]
OGATA H, MATSUI T, NAKAMURA M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis[J]. Gut, 2006, 55(9):1255-1262.
[20]
OGATA H, KATO J, HIRAI F, et al. Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis[J]. Inflamm Bowel Dis, 2012, 18(5):803-808.
[21]
YAMAMOTO S, NAKASE H, MIKAMI S, et al. Long-term effect of tacrolimus therapy in patients with refractory ulcerative colitis[J]. Aliment Pharmacol Ther, 2008, 28(5):589-597.
[22]
INOUE T, MURANO M, NARABAYASHI K, et al. The efficacy of oral tacrolimus in patients with moderate/severe ulcerative colitis not receiving concomitant corticosteroide therapy[J]. Intern Med, 2013, 52(1):15-20.
[23]
KAWAMI K, INOUE T, MURANO M, et al. Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis[J]. World J Gastroenterol, 2015, 21(6):1880-1886.
[24]
BAUMGART D C, PINTOFFL J P, STURM A, et al. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease-a long-term follow up[J]. Am J Gastroenterol, 2006, 101(5):1048-1056.
[25]
BENSON A, BARRETT T, SPARBERG M, et al. Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn��s disease:a single center experience[J]. Inflamm Bowel Dis, 2008, 14(1):7-12.
[26]
SCHMIDT K J, HERRLINGER K R, EMMRICH J, et al. Short-term efficacy of tacrolimus in steroid-refractory ulcerative colitis-experience in 130 patients[J]. Aliment Pharmacol Ther, 2013, 37(1):129-136.
[27]
IKEYA K, SUGIMOTO K, KAWASAKI S, et al. Tacrolimus for remission induction in ulcerative colitis: mayo endoscopic subscore 0 and 1 predict long-term prognosis[J]. Dig Liver Dis, 2015, 47(5):365-371.
[28]
MIYOSHI J, MATSUOKA K, INOUE N, et al. Mucosal healing with oral tacrolimus is associated with favorable medium-and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients[J]. J Crohns Colitis, 2013, 7(12):e609-e614.
[29]
BOSCHETTI G, NANCEY S, MOUSSATA D, et al. Tacrolimus induction followed by maintenance monotherapy is useful in selected patients with moderate-to-severe ulcerative colitis refractory to prior treatment[J]. Dig Liv Dis, 2014, 46(10):875-880.
[30]
HIRAOKA S, INOKUCHI T, TAKEI D, et al. Tacrolimus therapy for outpatients with refractory ulcerative colitis[J]. Gastroenterology, 2015, 148 (4):870-871.
[31]
OLMEDO-MARTÍN R V, AMO-TRILLO V, GONZÁLEZ-GRANDE R, et al. Medium to long-term efficacy and safety of oral tacrolimus in moderate to severe steroid refractory ulcerative colitis[J]. Rev Esp Enferm Dig, 2017, 109(8):559-565.
[32]
KAWAMURA H, MATSUMOTO S, NAKAMURA N, et al. Rapid induction therapy with oral tacrolimus in elderly patients with refractory ulcerative colitis can easily lead to elevated tacrolimus concentrations in blood:a report of 5 cases[J]. Am J Case Rep, 2017, 18:405-409.
[33]
YAMAMOTO T, SHIMOYAMA T, UMEGAE S, et al. Tacrolimus vs anti-tumor necrosis factor agents formoderately to severely active ulcerative colitis:a retrospective observational study[J]. Aliment Pharmacol Ther, 2016, 43(6):705-716.
[34]
ENDO K, ONODERA M, SHIGA H, et al. A comparison of short-and long-term therapeutic outcomes of infliximab-versus tacrolimus-based strategies for steroid-refractory ulcerative colitis[J]. Gastroenterol Res Prac, 2016, 2016:1-11.
[35]
NUKI Y, ESAKI M, ASANO K, et al. Comparison of the therapeutic efficacy and safety between tacrolimus and infliximab for moderate-to-severe ulcerative colitis:a single center experience[J]. Scand J Gastroenterol, 2016, 51(6):700-705.
[36]
MATSUMOTO S, KAWAMURA H, NISHIKAWA T, et al. Tacrolimus versus anti-tumor necrosis factor agents for steroid-refractory active ulcerative colitis based on the severity of endoscopic findings:a single-center, open-label cohort study[J]. Clin Exp Gastroenterol, 2017, 10:249-258.
[37]
TAKEUCHI K, SHIMOYAMA T, YAMAMOTO T. Comparison of safety and efficacy of tacrolimus versus infliximab for active ulcerative colitis[J]. Dig Dis, 2018, 36(2):106-112.
[38]
LIU Y J, FAN H, ZHEN W W, et al. Pooled analysis of the comparative efficacy between tacrolimus and infliximab for ulcerative colitis[J]. Medicine, 2018, 97(32):1-7.
2019, Vol. 54 
