Study of TelmisartanFor the Prevention of Acute GVHD Post Allogeneic Hematopoietic Stem Cell Transplantation

Summary

This is single-center, open-label, prospective study of telmisartan for the prevention of acute GVHD in approximately 60 subjects undergoing allogeneic HCT for treatment of a hematologic malignancy.

Timeline

Start

2015-07-07

Primary completion

2023-01-05

Completion

2023-01-05

Publications

• Background Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood. 2000 May 1;95(9):2754-9.
• Background Chen X, Dodge J, Komorowski R, Drobyski WR. A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease. Blood. 2013 May 9;121(19):3970-80. doi: 10.1182/blood-2012-08-445130. Epub 2013 Mar 25.
• Background Eriguchi Y, Takashima S, Oka H, Shimoji S, Nakamura K, Uryu H, Shimoda S, Iwasaki H, Shimono N, Ayabe T, Akashi K, Teshima T. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of alpha-defensins. Blood. 2012 Jul 5;120(1):223-31. doi: 10.1182/blood-2011-12-401166. Epub 2012 Apr 24.
• Background Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012 May 11;12(6):443-58. doi: 10.1038/nri3212.
• Background Wolf D, von Lilienfeld-Toal M, Wolf AM, Schleuning M, von Bergwelt-Baildon M, Held SA, Brossart P. Novel treatment concepts for graft-versus-host disease. Blood. 2012 Jan 5;119(1):16-25. doi: 10.1182/blood-2011-08-339465. Epub 2011 Sep 26.
• Background Choi S, Reddy P. Graft-versus-host disease. Panminerva Med. 2010 Jun;52(2):111-24.
• Background Ringden O, Shrestha S, da Silva GT, Zhang MJ, Dispenzieri A, Remberger M, Kamble R, Freytes CO, Gale RP, Gibson J, Gupta V, Holmberg L, Lazarus H, McCarthy P, Meehan K, Schouten H, Milone GA, Lonial S, Hari PN. Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma. Bone Marrow Transplant. 2012 Jun;47(6):831-7. doi: 10.1038/bmt.2011.192. Epub 2011 Sep 26.
• Background Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY, Carabasi MH, Gale RP, Giralt S, Hale GA, Ilhan O, McCarthy PL, Socie G, Verdonck LF, Weisdorf DJ, Horowitz MM. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 2002 Jul 15;100(2):406-14. doi: 10.1182/blood.v100.2.406.
• Background Signori A, Crocchiolo R, Oneto R, Sacchi N, Sormani MP, Fagioli F, Rambaldi A, Ciceri F, Bacigalupo A. Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors. Bone Marrow Transplant. 2012 Nov;47(11):1474-8. doi: 10.1038/bmt.2012.58. Epub 2012 Apr 2.
• Background Patterson AE, Korngold R. Infusion of select leukemia-reactive TCR Vbeta+ T cells provides graft-versus-leukemia responses with minimization of graft-versus-host disease following murine hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2001;7(4):187-96. doi: 10.1053/bbmt.2001.v7.pm11349805.
• Background Fanning SL, Zilberberg J, Stein J, Vazzana K, Berger SA, Korngold R, Friedman TM. Unraveling graft-versus-host disease and graft-versus-leukemia responses using TCR Vbeta spectratype analysis in a murine bone marrow transplantation model. J Immunol. 2013 Jan 1;190(1):447-57. doi: 10.4049/jimmunol.1201641. Epub 2012 Nov 30.
• Background Komanduri KV. Targeting neovascularization in GVHD. Blood. 2013 Apr 25;121(17):3303-4. doi: 10.1182/blood-2013-01-480483.
• Background Leonhardt F, Grundmann S, Behe M, Bluhm F, Dumont RA, Braun F, Fani M, Riesner K, Prinz G, Hechinger AK, Gerlach UV, Dierbach H, Penack O, Schmitt-Graff A, Finke J, Weber WA, Zeiser R. Inflammatory neovascularization during graft-versus-host disease is regulated by alphav integrin and miR-100. Blood. 2013 Apr 25;121(17):3307-18. doi: 10.1182/blood-2012-07-442665. Epub 2013 Jan 17.
• Background Penack O, Socie G, van den Brink MR. The importance of neovascularization and its inhibition for allogeneic hematopoietic stem cell transplantation. Blood. 2011 Apr 21;117(16):4181-9. doi: 10.1182/blood-2010-10-312934. Epub 2011 Jan 21.
• Background Penack O, Henke E, Suh D, King CG, Smith OM, Na IK, Holland AM, Ghosh A, Lu SX, Jenq RR, Liu C, Murphy GF, Lu TT, May C, Scheinberg DA, Gao DC, Mittal V, Heller G, Benezra R, van den Brink MR. Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. J Natl Cancer Inst. 2010 Jun 16;102(12):894-908. doi: 10.1093/jnci/djq172. Epub 2010 May 12.
• Background Petrovic A, Alpdogan O, Willis LM, Eng JM, Greenberg AS, Kappel BJ, Liu C, Murphy GJ, Heller G, van den Brink MR. LPAM (alpha 4 beta 7 integrin) is an important homing integrin on alloreactive T cells in the development of intestinal graft-versus-host disease. Blood. 2004 Feb 15;103(4):1542-7. doi: 10.1182/blood-2003-03-0957. Epub 2003 Oct 16.
• Background Reshef R, Luger SM, Hexner EO, Loren AW, Frey NV, Nasta SD, Goldstein SC, Stadtmauer EA, Smith J, Bailey S, Mick R, Heitjan DF, Emerson SG, Hoxie JA, Vonderheide RH, Porter DL. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med. 2012 Jul 12;367(2):135-45. doi: 10.1056/NEJMoa1201248.
• Background Engelhardt BG, Jagasia M, Savani BN, Bratcher NL, Greer JP, Jiang A, Kassim AA, Lu P, Schuening F, Yoder SM, Rock MT, Crowe JE Jr. Regulatory T cell expression of CLA or alpha(4)beta(7) and skin or gut acute GVHD outcomes. Bone Marrow Transplant. 2011 Mar;46(3):436-42. doi: 10.1038/bmt.2010.127. Epub 2010 May 31.
• Background Engelhardt BG, Sengsayadeth SM, Jagasia M, Savani BN, Kassim AA, Lu P, Shyr Y, Yoder SM, Rock MT, Crowe JE Jr. Tissue-specific regulatory T cells: biomarker for acute graft-vs-host disease and survival. Exp Hematol. 2012 Dec;40(12):974-982.e1. doi: 10.1016/j.exphem.2012.08.002. Epub 2012 Aug 10.
• Background Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011 Jan 20;117(3):1061-70. doi: 10.1182/blood-2010-07-293795. Epub 2010 Oct 15.
• Background Liu Z, Zhao Y, Wei F, Ye L, Lu F, Zhang H, Diao Y, Song H, Qi Z. Treatment with telmisartan/rosuvastatin combination has a beneficial synergistic effect on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. Atherosclerosis. 2014 Mar;233(1):291-9. doi: 10.1016/j.atherosclerosis.2013.12.004. Epub 2014 Jan 10.
• Background Mihaescu A, Santen S, Jeppsson B, Thorlacius H. Rho kinase signalling mediates radiation-induced inflammation and intestinal barrier dysfunction. Br J Surg. 2011 Jan;98(1):124-31. doi: 10.1002/bjs.7279. Epub 2010 Sep 29.
• Background Arab HH, Al-Shorbagy MY, Abdallah DM, Nassar NN. Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease. PLoS One. 2014 May 15;9(5):e97193. doi: 10.1371/journal.pone.0097193. eCollection 2014.
• Background Kobayashi N, Ohno T, Yoshida K, Fukushima H, Mamada Y, Nomura M, Hirata H, Machida Y, Shinoda M, Suzuki N, Matsuoka H. Cardioprotective mechanism of telmisartan via PPAR-gamma-eNOS pathway in dahl salt-sensitive hypertensive rats. Am J Hypertens. 2008 May;21(5):576-81. doi: 10.1038/ajh.2008.27. Epub 2008 Mar 20.
• Background Iyengar S, Zhan C, Lu J, Korngold R, Schwartz DH. Treatment with a rho kinase inhibitor improves survival from graft-versus-host disease in mice after MHC-haploidentical hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014 Aug;20(8):1104-11. doi: 10.1016/j.bbmt.2014.04.029. Epub 2014 May 2.
• Background Song EK, Yim JM, Yim JY, Song MY, Rho HW, Yim SK, Jeon SY, Kim HS, Yhim HY, Lee NR, Kwak JY, Sohn MH, Park HS, Jang KY, Yim CY. Rosiglitazone prevents graft-versus-host disease (GVHD). Transpl Immunol. 2012 Oct;27(2-3):128-37. doi: 10.1016/j.trim.2012.09.001. Epub 2012 Sep 13.
• Background Walcher D, Hess K, Heinz P, Petscher K, Vasic D, Kintscher U, Clemenz M, Hartge M, Raps K, Hombach V, Marx N. Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-gamma. Hypertension. 2008 Feb;51(2):259-66. doi: 10.1161/HYPERTENSIONAHA.107.099028. Epub 2007 Dec 24.
• Background Cianchetti S, Del Fiorentino A, Colognato R, Di Stefano R, Franzoni F, Pedrinelli R. Anti-inflammatory and anti-oxidant properties of telmisartan in cultured human umbilical vein endothelial cells. Atherosclerosis. 2008 May;198(1):22-8. doi: 10.1016/j.atherosclerosis.2007.09.013. Epub 2007 Oct 22.
• Background Siragusa M, Sessa WC. Telmisartan exerts pleiotropic effects in endothelial cells and promotes endothelial cell quiescence and survival. Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1852-60. doi: 10.1161/ATVBAHA.112.300985. Epub 2013 May 23.
• Background Usui T, Sugisaki K, Iriyama A, Yokoo S, Yamagami S, Nagai N, Ishida S, Amano S. Inhibition of corneal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4370-6. doi: 10.1167/iovs.07-0964.
• Background Nagai N, Noda K, Urano T, Kubota Y, Shinoda H, Koto T, Shinoda K, Inoue M, Shiomi T, Ikeda E, Tsubota K, Suda T, Oike Y, Ishida S. Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 2005 Mar;46(3):1078-84. doi: 10.1167/iovs.04-1101.
• Background Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003 Jun;4(6):446-56. doi: 10.1038/nrm1128.
• Background Yoneda A, Multhaupt HA, Couchman JR. The Rho kinases I and II regulate different aspects of myosin II activity. J Cell Biol. 2005 Aug 1;170(3):443-53. doi: 10.1083/jcb.200412043. Epub 2005 Jul 25.
• Background Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X, Surks HK. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res. 2009 Feb 27;104(4):531-40. doi: 10.1161/CIRCRESAHA.108.188524. Epub 2009 Jan 8.
• Background Vicari RM, Chaitman B, Keefe D, Smith WB, Chrysant SG, Tonkon MJ, Bittar N, Weiss RJ, Morales-Ballejo H, Thadani U; Fasudil Study Group. Efficacy and safety of fasudil in patients with stable angina: a double-blind, placebo-controlled, phase 2 trial. J Am Coll Cardiol. 2005 Nov 15;46(10):1803-11. doi: 10.1016/j.jacc.2005.07.047. Epub 2005 Oct 19.
• Background Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H, Katagiri T, Yamauchi K, Yui Y, Minamino T, Nakashima M, Kato K. Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J Cardiovasc Pharmacol. 2002 Nov;40(5):751-61. doi: 10.1097/00005344-200211000-00013.
• Background Fukumoto Y, Mohri M, Inokuchi K, Ito A, Hirakawa Y, Masumoto A, Hirooka Y, Takeshita A, Shimokawa H. Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina. J Cardiovasc Pharmacol. 2007 Mar;49(3):117-21. doi: 10.1097/FJC.0b013e31802ef532.
• Background Otsuka T, Ibuki C, Suzuki T, Ishii K, Kodani E, Atarashi H, Kishida H, Takano T. Vasodilatory effect of subsequent administration of fasudil, a rho-kinase inhibitor, surpasses that of nitroglycerin at the concentric coronary stenosis in patients with stable angina pectoris. Circ J. 2006 Apr;70(4):402-8. doi: 10.1253/circj.70.402.
• Background Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation. 2002 Apr 2;105(13):1545-7. doi: 10.1161/hc1002.105938.
• Background Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J Am Coll Cardiol. 2003 Jan 1;41(1):15-9. doi: 10.1016/s0735-1097(02)02632-3.
• Background Inokuchi K, Ito A, Fukumoto Y, Matoba T, Shiose A, Nishida T, Masuda M, Morita S, Shimokawa H. Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery. J Cardiovasc Pharmacol. 2004 Sep;44(3):275-7. doi: 10.1097/01.fjc.0000134775.76636.3f.
• Background Kishi T, Hirooka Y, Masumoto A, Ito K, Kimura Y, Inokuchi K, Tagawa T, Shimokawa H, Takeshita A, Sunagawa K. Rho-kinase inhibitor improves increased vascular resistance and impaired vasodilation of the forearm in patients with heart failure. Circulation. 2005 May 31;111(21):2741-7. doi: 10.1161/CIRCULATIONAHA.104.510248.
• Background Witzenrath M, Ahrens B, Schmeck B, Kube SM, Hippenstiel S, Rosseau S, Hamelmann E, Suttorp N, Schutte H. Rho-kinase and contractile apparatus proteins in murine airway hyperresponsiveness. Exp Toxicol Pathol. 2008 Jun;60(1):9-15. doi: 10.1016/j.etp.2008.03.002. Epub 2008 Apr 22.
• Background Noma K, Rikitake Y, Oyama N, Yan G, Alcaide P, Liu PY, Wang H, Ahl D, Sawada N, Okamoto R, Hiroi Y, Shimizu K, Luscinskas FW, Sun J, Liao JK. ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. J Clin Invest. 2008 May;118(5):1632-44. doi: 10.1172/JCI29226.
• Background Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, Keller M, Forster R, Critchley DR, Fassler R, Sixt M. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature. 2008 May 1;453(7191):51-5. doi: 10.1038/nature06887.
• Background Smith A, Bracke M, Leitinger B, Porter JC, Hogg N. LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment. J Cell Sci. 2003 Aug 1;116(Pt 15):3123-33. doi: 10.1242/jcs.00606. Epub 2003 Jun 10.
• Background van Buul JD, Hordijk PL. Signaling in leukocyte transendothelial migration. Arterioscler Thromb Vasc Biol. 2004 May;24(5):824-33. doi: 10.1161/01.ATV.0000122854.76267.5c. Epub 2004 Feb 19.
• Background Benais-Pont G, Punn A, Flores-Maldonado C, Eckert J, Raposo G, Fleming TP, Cereijido M, Balda MS, Matter K. Identification of a tight junction-associated guanine nucleotide exchange factor that activates Rho and regulates paracellular permeability. J Cell Biol. 2003 Mar 3;160(5):729-40. doi: 10.1083/jcb.200211047. Epub 2003 Feb 25.
• Background Li B, Zhao WD, Tan ZM, Fang WG, Zhu L, Chen YH. Involvement of Rho/ROCK signalling in small cell lung cancer migration through human brain microvascular endothelial cells. FEBS Lett. 2006 Jul 24;580(17):4252-60. doi: 10.1016/j.febslet.2006.06.056. Epub 2006 Jun 30.
• Background Nohria A, Grunert ME, Rikitake Y, Noma K, Prsic A, Ganz P, Liao JK, Creager MA. Rho kinase inhibition improves endothelial function in human subjects with coronary artery disease. Circ Res. 2006 Dec 8;99(12):1426-32. doi: 10.1161/01.RES.0000251668.39526.c7. Epub 2006 Nov 9.
• Background Bardi G, Niggli V, Loetscher P. Rho kinase is required for CCR7-mediated polarization and chemotaxis of T lymphocytes. FEBS Lett. 2003 May 8;542(1-3):79-83. doi: 10.1016/s0014-5793(03)00351-x.
• Background Lee JH, Katakai T, Hara T, Gonda H, Sugai M, Shimizu A. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J Cell Biol. 2004 Oct 25;167(2):327-37. doi: 10.1083/jcb.200403091.
• Background Xue F, Takahara T, Yata Y, Xia Q, Nonome K, Shinno E, Kanayama M, Takahara S, Sugiyama T. Blockade of Rho/Rho-associated coiled coil-forming kinase signaling can prevent progression of hepatocellular carcinoma in matrix metalloproteinase-dependent manner. Hepatol Res. 2008 Aug;38(8):810-7. doi: 10.1111/j.1872-034X.2008.00333.x. Epub 2008 May 27.
• Background Wong CC, Wong CM, Ko FC, Chan LK, Ching YP, Yam JW, Ng IO. Deleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma. PLoS One. 2008 Jul 23;3(7):e2779. doi: 10.1371/journal.pone.0002779.
• Background Ogawa T, Tashiro H, Miyata Y, Ushitora Y, Fudaba Y, Kobayashi T, Arihiro K, Okajima M, Asahara T. Rho-associated kinase inhibitor reduces tumor recurrence after liver transplantation in a rat hepatoma model. Am J Transplant. 2007 Feb;7(2):347-55. doi: 10.1111/j.1600-6143.2006.01647.x. Epub 2007 Jan 4.
• Background Wang DS, Dou KF, Li KZ, Song ZS. Enhancement of migration and invasion of hepatoma cells via a Rho GTPase signaling pathway. World J Gastroenterol. 2004 Jan 15;10(2):299-302. doi: 10.3748/wjg.v10.i2.299.
• Background Vishnubhotla R, Sun S, Huq J, Bulic M, Ramesh A, Guzman G, Cho M, Glover SC. ROCK-II mediates colon cancer invasion via regulation of MMP-2 and MMP-13 at the site of invadopodia as revealed by multiphoton imaging. Lab Invest. 2007 Nov;87(11):1149-58. doi: 10.1038/labinvest.3700674. Epub 2007 Sep 17.
• Background Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H. Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res. 2003 Jul;9(7):2632-41.
• Background Sahai E, Marshall CJ. ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol. 2002 Jun;4(6):408-15. doi: 10.1038/ncb796.
• Background Croft DR, Sahai E, Mavria G, Li S, Tsai J, Lee WM, Marshall CJ, Olson MF. Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis. Cancer Res. 2004 Dec 15;64(24):8994-9001. doi: 10.1158/0008-5472.CAN-04-2052.
• Background Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X, Chung DC. Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. J Biol Chem. 2006 May 19;281(20):13957-63. doi: 10.1074/jbc.M511763200. Epub 2006 Mar 16.
• Background Somlyo AV, Phelps C, Dipierro C, Eto M, Read P, Barrett M, Gibson JJ, Burnitz MC, Myers C, Somlyo AP. Rho kinase and matrix metalloproteinase inhibitors cooperate to inhibit angiogenesis and growth of human prostate cancer xenotransplants. FASEB J. 2003 Feb;17(2):223-34. doi: 10.1096/fj.02-0655com.
• Background Somlyo AV, Bradshaw D, Ramos S, Murphy C, Myers CE, Somlyo AP. Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells. Biochem Biophys Res Commun. 2000 Mar 24;269(3):652-9. doi: 10.1006/bbrc.2000.2343.
• Background Ying H, Biroc SL, Li WW, Alicke B, Xuan JA, Pagila R, Ohashi Y, Okada T, Kamata Y, Dinter H. The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models. Mol Cancer Ther. 2006 Sep;5(9):2158-64. doi: 10.1158/1535-7163.MCT-05-0440.
• Background Bourguignon LY, Zhu H, Shao L, Zhu D, Chen YW. Rho-kinase (ROK) promotes CD44v(3,8-10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells. Cell Motil Cytoskeleton. 1999;43(4):269-87. doi: 10.1002/(SICI)1097-0169(1999)43:43.0.CO;2-5.
• Background Barreiro O, Yanez-Mo M, Serrador JM, Montoya MC, Vicente-Manzanares M, Tejedor R, Furthmayr H, Sanchez-Madrid F. Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol. 2002 Jun 24;157(7):1233-45. doi: 10.1083/jcb.200112126. Epub 2002 Jun 24.
• Background Bivalacqua TJ, Champion HC, Usta MF, Cellek S, Chitaley K, Webb RC, Lewis RL, Mills TM, Hellstrom WJ, Kadowitz PJ. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9121-6. doi: 10.1073/pnas.0400520101. Epub 2004 Jun 7.
• Background Ming XF, Viswambharan H, Barandier C, Ruffieux J, Kaibuchi K, Rusconi S, Yang Z. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol. 2002 Dec;22(24):8467-77. doi: 10.1128/MCB.22.24.8467-8477.2002.
• Background Tominaga T, Sugie K, Hirata M, Morii N, Fukata J, Uchida A, Imura H, Narumiya S. Inhibition of PMA-induced, LFA-1-dependent lymphocyte aggregation by ADP ribosylation of the small molecular weight GTP binding protein, rho. J Cell Biol. 1993 Mar;120(6):1529-37. doi: 10.1083/jcb.120.6.1529.
• Background Sanchez-Madrid F, del Pozo MA. Leukocyte polarization in cell migration and immune interactions. EMBO J. 1999 Feb 1;18(3):501-11. doi: 10.1093/emboj/18.3.501.
• Background Alevriadou BR. CAMs and Rho small GTPases: gatekeepers for leukocyte transendothelial migration. Focus on "VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration". Am J Physiol Cell Physiol. 2003 Aug;285(2):C250-2. doi: 10.1152/ajpcell.00189.2003. No abstract available.
• Background Etienne S, Adamson P, Greenwood J, Strosberg AD, Cazaubon S, Couraud PO. ICAM-1 signaling pathways associated with Rho activation in microvascular brain endothelial cells. J Immunol. 1998 Nov 15;161(10):5755-61.
• Background Zhu F, Zhang Z, Wu G, Li Z, Zhang R, Ren J, Nong L. Rho kinase inhibitor fasudil suppresses migration and invasion though down-regulating the expression of VEGF in lung cancer cell line A549. Med Oncol. 2011 Jun;28(2):565-71. doi: 10.1007/s12032-010-9468-5. Epub 2010 Mar 19.
• Background Nakabayashi H, Shimizu K. HA1077, a Rho kinase inhibitor, suppresses glioma-induced angiogenesis by targeting the Rho-ROCK and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signal pathways. Cancer Sci. 2011 Feb;102(2):393-9. doi: 10.1111/j.1349-7006.2010.01794.x. Epub 2010 Dec 19.
• Background Washida N, Wakino S, Tonozuka Y, Homma K, Tokuyama H, Hara Y, Hasegawa K, Minakuchi H, Fujimura K, Hosoya K, Hayashi K, Itoh H. Rho-kinase inhibition ameliorates peritoneal fibrosis and angiogenesis in a rat model of peritoneal sclerosis. Nephrol Dial Transplant. 2011 Sep;26(9):2770-9. doi: 10.1093/ndt/gfr012. Epub 2011 Mar 4.
• Background Kuno M, Takai S, Matsushima-Nishiwaki R, Minamitani C, Mizutani J, Otsuka T, Harada A, Adachi S, Kozawa O, Tokuda H. Rho-kinase inhibitors decrease TGF-beta-stimulated VEGF synthesis through stress-activated protein kinase/c-Jun N-terminal kinase in osteoblasts. Biochem Pharmacol. 2009 Jan 15;77(2):196-203. doi: 10.1016/j.bcp.2008.10.014. Epub 2008 Oct 19.
• Background Takata K, Morishige K, Takahashi T, Hashimoto K, Tsutsumi S, Yin L, Ohta T, Kawagoe J, Takahashi K, Kurachi H. Fasudil-induced hypoxia-inducible factor-1alpha degradation disrupts a hypoxia-driven vascular endothelial growth factor autocrine mechanism in endothelial cells. Mol Cancer Ther. 2008 Jun;7(6):1551-61. doi: 10.1158/1535-7163.MCT-07-0428.
• Background Hata Y, Miura M, Nakao S, Kawahara S, Kita T, Ishibashi T. Antiangiogenic properties of fasudil, a potent Rho-Kinase inhibitor. Jpn J Ophthalmol. 2008 Jan-Feb;52(1):16-23. doi: 10.1007/s10384-007-0487-5. Epub 2008 Mar 28.
• Background Liu C, Li Y, Yu J, Feng L, Hou S, Liu Y, Guo M, Xie Y, Meng J, Zhang H, Xiao B, Ma C. Targeting the shift from M1 to M2 macrophages in experimental autoimmune encephalomyelitis mice treated with fasudil. PLoS One. 2013;8(2):e54841. doi: 10.1371/journal.pone.0054841. Epub 2013 Feb 13.
• Background Ozeki K, Tanida S, Morimoto C, Inoue Y, Mizoshita T, Tsukamoto H, Shimura T, Kataoka H, Kamiya T, Nishiwaki E, Ishiguro H, Higashiyama S, Joh T. Telmisartan inhibits cell proliferation by blocking nuclear translocation of ProHB-EGF C-terminal fragment in colon cancer cells. PLoS One. 2013;8(2):e56770. doi: 10.1371/journal.pone.0056770. Epub 2013 Feb 22.
• Background Sharpe M, Jarvis B, Goa KL. Telmisartan: a review of its use in hypertension. Drugs. 2001;61(10):1501-29. doi: 10.2165/00003495-200161100-00009.
• Background Smith DH, Matzek KM, Kempthorne-Rawson J. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol. 2000 Dec;40(12 Pt 1):1380-90.
• Background Stangier J, Su CA, Roth W. Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res. 2000 Jul-Aug;28(4):149-67. doi: 10.1177/147323000002800401.
• Background Forclaz A, Maillard M, Nussberger J, Brunner HR, Burnier M. Angiotensin II receptor blockade: is there truly a benefit of adding an ACE inhibitor? Hypertension. 2003 Jan;41(1):31-6. doi: 10.1161/01.hyp.0000047512.58862.a9.
• Background Levine JE, Paczesny S, Sarantopoulos S. Clinical applications for biomarkers of acute and chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2012 Jan;18(1 Suppl):S116-24. doi: 10.1016/j.bbmt.2011.10.019.
• Background Paczesny S. Discovery and validation of graft-versus-host disease biomarkers. Blood. 2013 Jan 24;121(4):585-94. doi: 10.1182/blood-2012-08-355990. Epub 2012 Nov 19.
• Background Levine JE, Logan BR, Wu J, Alousi AM, Bolanos-Meade J, Ferrara JL, Ho VT, Weisdorf DJ, Paczesny S. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood. 2012 Apr 19;119(16):3854-60. doi: 10.1182/blood-2012-01-403063. Epub 2012 Mar 1.
• Background Vander Lugt MT, Braun TM, Hanash S, Ritz J, Ho VT, Antin JH, Zhang Q, Wong CH, Wang H, Chin A, Gomez A, Harris AC, Levine JE, Choi SW, Couriel D, Reddy P, Ferrara JL, Paczesny S. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N Engl J Med. 2013 Aug 8;369(6):529-39. doi: 10.1056/NEJMoa1213299.
• Background Mueller T, Dieplinger B. The Presage((R)) ST2 Assay: analytical considerations and clinical applications for a high-sensitivity assay for measurement of soluble ST2. Expert Rev Mol Diagn. 2013 Jan;13(1):13-30. doi: 10.1586/erm.12.128.
• Background Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E, Teshima T, Levine JE, Choi SW, Huber E, Landfried K, Akashi K, Vander Lugt M, Reddy P, Chin A, Zhang Q, Hanash S, Paczesny S. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood. 2011 Dec 15;118(25):6702-8. doi: 10.1182/blood-2011-08-375006. Epub 2011 Oct 6.
• Background Holler E, Landfried K, Meier J, Hausmann M, Rogler G. The role of bacteria and pattern recognition receptors in GVHD. Int J Inflam. 2010 Oct 31;2010:814326. doi: 10.4061/2010/814326.
• Background Penack O, Holler E, van den Brink MR. Graft-versus-host disease: regulation by microbe-associated molecules and innate immune receptors. Blood. 2010 Mar 11;115(10):1865-72. doi: 10.1182/blood-2009-09-242784. Epub 2009 Dec 30.
• Background Cooke KR, Gerbitz A, Crawford JM, Teshima T, Hill GR, Tesolin A, Rossignol DP, Ferrara JL. LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest. 2001 Jun;107(12):1581-9. doi: 10.1172/JCI12156.
• Background Lv M, Ye HG, Zhao XS, Zhao XY, Chang YJ, Liu DH, Xu LP, Huang XJ. Ceruloplasmin is a potential biomarker for aGvHD following allogeneic hematopoietic stem cell transplantation. PLoS One. 2013;8(3):e58735. doi: 10.1371/journal.pone.0058735. Epub 2013 Mar 7.
• Background Romaschin AD, Klein DJ, Marshall JC. Bench-to-bedside review: Clinical experience with the endotoxin activity assay. Crit Care. 2012 Dec 3;16(6):248. doi: 10.1186/cc11495.
• Background Hilmi I, Kellum J, Planinsic R, Foster D, Abdullah A, Damian D, Gligor S, Klein D, Abu-elmagd K. Endotoxemia is common following abdominal organ transplantation and is associated with reperfusion and rejection.Journal of Organ Dysfunction. Dec 2009, Vol. 5 Issue 4, p254-260.
• Background Sanada Y, Mizuta K, Urahashi T, Ihara Y, Wakiya T, Okada N, Yamada N, Ushijima K, Otomo S, Sakamoto K, Yasuda Y, Kawarasaki H. Impact of endotoxin measured by an endotoxin activity assay during liver transplantation. J Surg Res. 2013 Apr;180(2):349-55. doi: 10.1016/j.jss.2012.05.004. Epub 2012 May 24.
• Background Marshall JC, Foster D, Vincent JL, Cook DJ, Cohen J, Dellinger RP, Opal S, Abraham E, Brett SJ, Smith T, Mehta S, Derzko A, Romaschin A; MEDIC study. Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study. J Infect Dis. 2004 Aug 1;190(3):527-34. doi: 10.1086/422254. Epub 2004 Jul 2.
• Background Ikeda T, Ikeda K, Suda S, Ueno T. Usefulness of the endotoxin activity assay as a biomarker to assess the severity of endotoxemia in critically ill patients. Innate Immun. 2014 Nov;20(8):881-7. doi: 10.1177/1753425913516885. Epub 2014 Jan 7.
• Background Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA, Liu C, West ML, Singer NV, Equinda MJ, Gobourne A, Lipuma L, Young LF, Smith OM, Ghosh A, Hanash AM, Goldberg JD, Aoyama K, Blazar BR, Pamer EG, van den Brink MR. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012 May 7;209(5):903-11. doi: 10.1084/jem.20112408. Epub 2012 Apr 30.
• Background Fricke WF, Maddox C, Song Y, Bromberg JS. Human microbiota characterization in the course of renal transplantation. Am J Transplant. 2014 Feb;14(2):416-27. doi: 10.1111/ajt.12588. Epub 2013 Dec 26.
• Background Arck P, Handjiski B, Hagen E, Pincus M, Bruenahl C, Bienenstock J, Paus R. Is there a 'gut-brain-skin axis'? Exp Dermatol. 2010 May;19(5):401-5. doi: 10.1111/j.1600-0625.2009.01060.x. Epub 2010 Jan 25.
• Background Gomez A, Hammer S, Braun T, Hanash S, Ferrara J, Greenson J, Wang H, Zhang Q, Vander Lugt M, Pongtornpipat P, Lamiman K, Colon M, Chang L, Choi S, Levine J, Harris A, Couriel D, Reddy P, Paczesny S. A novel CD4+CD146+CCR5+ T-cell population is a biomarker of intestinal graft-versus-host disease. 39th meeting of the European Group for Blood and Marrow Transplantation Wednesday, April 10, 2013, 09:30 - 09:42
• Background Cheng CI, Lin YC, Tsai TH, Lin HS, Liou CW, Chang WN, Lu CH, Yuen CM, Yip HK. The prognostic values of leukocyte Rho kinase activity in acute ischemic stroke. Biomed Res Int. 2014;2014:214587. doi: 10.1155/2014/214587. Epub 2014 Feb 27.
• Background Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.
• Background Patel PA, Patravale VB, Commercial Telmisartan Tablets: A Comparative Evaluation with Innovator Brand Micardis, International Journal of Pharma Sciences and Research (IJPSR) 2010, 1(8): 282-292.
• Background Michel MC, Bohner H, Koster J, Schafers R, Heemann U. Safety of telmisartan in patients with arterial hypertension : an open-label observational study. Drug Saf. 2004;27(5):335-44. doi: 10.2165/00002018-200427050-00005.
• Background Schumacher H, Mancia G. The safety profile of telmisartan as monotherapy or combined with hydrochlorothiazide: a retrospective analysis of 50 studies. Blood Press Suppl. 2008 Jun;1:32-40. doi: 10.1080/08038020802144383.
• Background Bahr IN, Tretter P, Kruger J, Stark RG, Schimkus J, Unger T, Kappert K, Scholze J, Parhofer KG, Kintscher U. High-dose treatment with telmisartan induces monocytic peroxisome proliferator-activated receptor-gamma target genes in patients with the metabolic syndrome. Hypertension. 2011 Oct;58(4):725-32. doi: 10.1161/HYPERTENSIONAHA.111.173542. Epub 2011 Aug 29.
• Background Chetty VT, Damjanovic S, Gerstein H, Singh N, Yusuf S, Anand SS, Sharma AM. Metabolic effects of telmisartan in subjects with abdominal obesity: a prospective randomized controlled trial. Blood Press. 2014 Feb;23(1):54-60. doi: 10.3109/08037051.2013.791411. Epub 2013 Jun 3.
• Background White WB. Comparative effects of telmisartan in the treatment of hypertension. J Clin Hypertens (Greenwich). 2002 Jul-Aug;4(4 Suppl 1):20-5. doi: 10.1111/j.1524-6175.2002.01585.x.

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