Emerging therapies for portal hypertension in cirrhosis

Expert Opinion on Emerging Drugs

Volumn 21, Issue 2, 2016, Pages 167-181

  Nair, Harikumar ^a   Berzigotti, Annalisa ^a   Bosch, Jaime ^a,b  

^a UNIVERSITY OF BERN   (Switzerland)

^b UNIVERSITY OF BARCELONA   (Spain)

Author keywords

endothelial dysfunction; hepatic stellate cells; Hepatic vascular resistance; hepatic vein pressure gradient; liver fibrosis; liver sinusoidal endothelial cells; portal pressure; splanchnic circulation

Indexed keywords

ANTIHYPERTENSIVE AGENT; ANTIOXIDANT; ASCORBIC ACID; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; CARVEDILOL; EMRICASAN; FENOFIBRATE; FLAVONOID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; ISOSORBIDE MONONITRATE; MANGANESE SUPEROXIDE DISMUTASE; NADOLOL; NITRIC OXIDE; OBETICHOLIC ACID; OCTREOTIDE; PHOSPHODIESTERASE V INHIBITOR; PRAZOSIN; PROPRANOLOL; RESVERATROL; RIFAXIMIN; SERELAXIN; SIMVASTATIN; SOMATOSTATIN; SORAFENIB; TAURINE; TERLIPRESSIN; TETRAHYDROBIOPTERIN; UDENAFIL; UNINDEXED DRUG; VAPREOTIDE; ANGIOGENESIS INHIBITOR;

ADRENERGIC ACTIVITY; ANGIOGENESIS; ANTIHYPERTENSIVE THERAPY; ARTERIAL PRESSURE; ARTERY BLOOD FLOW; BACTERIAL TRANSLOCATION; BLOOD VESSEL TONE; BOLUS INJECTION; COLLATERAL CIRCULATION; CONTINUOUS INFUSION; DRUG BIOAVAILABILITY; DRUG HALF LIFE; FIBROGENESIS; HEART OUTPUT; HUMAN; KIDNEY BLOOD FLOW; KUPFFER CELL; LIVER CIRCULATION; LIVER CIRRHOSIS; LIVER FUNCTION; LIVER PERFUSION; LIVER TRANSPLANTATION; MULTICENTER STUDY (TOPIC); MYOFIBROBLAST; NONHUMAN; OXIDATIVE STRESS; PH; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PORTAL HYPERTENSION; PORTAL VEIN BLOOD FLOW; PORTAL VEIN BLOOD PRESSURE; PROGNOSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; RESTING HEART RATE; REVIEW; SPLANCHNIC BLOOD FLOW; STELLATE CELL; SYSTOLIC BLOOD PRESSURE; VASCULAR RESISTANCE; VASCULAR SMOOTH MUSCLE CELL; VASODILATATION; VENOUS PRESSURE; ANIMAL; CLINICAL TRIAL (TOPIC); COMPLICATION; DISEASE COURSE; DRUG DESIGN; HYPERTENSION, PORTAL; METHODOLOGY; PATHOPHYSIOLOGY; PROCEDURES;

ANGIOGENESIS INHIBITORS; ANIMALS; CLINICAL TRIALS AS TOPIC; DISEASE PROGRESSION; DRUG DESIGN; HUMANS; HYPERTENSION, PORTAL; LIVER CIRRHOSIS; RESEARCH DESIGN; VASODILATION;

EID: 84975292511     PISSN: 14728214     EISSN: 17447623     Source Type: Journal    
DOI: 10.1080/14728214.2016.1184647     Document Type: Review

References (104)

1. M.Blachier, H.Leleu, M.Peck-Radosavljevic, et al. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608.• A total of 260 studies on liver epidemiology in last 5 years included and comes handy for market size evaluations and feasibility assessment.
2. W.Brouwer, F.Rutten, M.A.Koopmanschap Costing in economic evaluations. In: M.F.Drummond, A.McGuire, editors. Economic evaluation in health care: merging theory with practice. Oxford: Oxford University Press; 2001. p. 68–93.
3. E.A.Tsochatzis, J.Bosch, A.K.Burroughs. Liver cirrhosis. Lancet. 2014;383(9930):1749–1761.• A comprehensive yet “quick read” review on natural history ad prognostication of cirrhosis.
4. J.Bosch, J.G.Abraldes, A.Berzigotti, et al. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol. 2009;6:573–582.•• A guide on the use of hvpg and its utility in the evaluation of drugs for portal hypertension.
5. G.D’Amico, J.C.Garcia-Pagan, A.Luca, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology. 2006;131:1611–1624.
6. A.Berzigotti, J.Bosch. Pharmacologic management of portal hypertension. Clin Liver Dis. 2014 May;18(2):303–317.• A well written review; clearly explains how pathophysiologcal aspects of PH translates into targets of pharmacotherapy.
7. D.V.Garbuzenko. Contemporary concepts of the medical therapy of portal hypertension under liver cirrhosis. World J Gastroenterol. 2015 May 28;21(20):6117–6126.
8. R.De Franchis. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015 Sep;63(3):743–752.•• Update on portal hypertension by a faculty coalition setting guidelines intreatment and research on portal hypertension every 5 years.
9. C.Ding, X.Wu, X.Fan, et al. Hemodynamic effects of continuous versus bolus infusion of terlipressin for portal hypertension: a randomized comparison. J Gastroenterol Hepatol. 2013;28:1242–1246.
10. A.Escorsell, J.C.Bandi, E.Moitinho, et al. Time profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol. 1997 Mar;26(3):621–627.
11. J.Lata. Hepatorenal syndrome. World J Gastroenterol. 2012;18:4978–4984.
12. R.Moreau, D.Lebrec. The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond. Hepatology. 2006;43:385–394.
13. H.Reynaert, A.Geerts. Pharmacological rationale for the use of somatostatin and analogues in portal hypertension. Aliment Pharmacol Ther. 2003;18:375–386.
14. J.Wang, L.Wang, G.Song, et al. The mechanism through which octreotide inhibits hepatic stellate cell activity. Mol Med Rep. 2013;7(5):1559–1564.
15. M.Mejias, E.Garcia-Pras, C.Tiani, et al. The somatostatin analogue octreotide inhibits angiogenesis in the earliest, but not in advanced, stages of portal hypertension in rats. J Cell Mol Med. 2008;12:1690–1699.
16. A.Escorsell, J.C.Bandi, V.Andreu, et al. Desensitization to the effects of intravenous octreotide in cirrhotic patients with portal hypertension. Gastroenterology. 2001;120:161–169.
17. G.Garcia-Tsao, J.Bosch. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med. 2010;362:823–832.
18. P.Calès, C.Masliah, B.Bernard, et al. Early administration of vapreotide for variceal bleeding in patients with cirrhosis. N Engl J Med. 2001 Jan 4;344(1):23–28.
19. D.Tripathi, P.C.Hayes. Beta-blockers in portal hypertension: new developments and controversies. Liver Int. 2014;34:655–667.
20. J.Bosch, A.Berzigotti, J.C.Garcia-Pagan, et al. The management of portal hypertension: rational basis, available treatments and future options. J Hepatol. 2008;48(Suppl 1):SS68-S92.
21. A.Ferrarese, E.Tsochatzis, A.K.Burroughs, et al. Beta blockers in cirrhosis: therapeutic window or an aspirin for all? J Hepatol. 2014;61:449–450.
22. P.S.Ge, B.A.Runyon. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol. 2014;60:643–653.
23. A.Krag, F.Bendtsen, J.H.Henriksen, et al. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut. 2010;59:105–110.
24. J.Llach, P.Gines, V.Arroyo, et al. Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites. Gastroenterology. 1988;94:482–487.
25. A.Krag, R.Wiest, A.Albillos, et al. The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease. Gut. 2012;61:967–969.• Betablockers which had been standard treatment for three decades recently have been suggested to be useful only in a window period.
26. L.Bossen, A.Krag, H.Vilstrup, et al. Non-selective β-blockers do not affect mortality in cirrhosis patients with ascites: post hoc analysis of three RCTs with 1198 patients. Hepatology. 2015 Nov 24. doi:10.1002/hep.28352. [Epub ahead of print]• Evidence against the “window hypothesis” on betablockers.
27. L.Bellis, A.Berzigotti, J.G.Abraldes, et al. Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis. Hepatology. 2003 Feb;37(2):378–384.
28. D.Kravetz. Prevention of recurrent esophageal variceal hemorrhage: review and current recommendations. J Clin Gastroenterol. 2007;41(Suppl 3):S318–S322.
29. A.Albillos, J.L.Lledó, I.Rossi, et al. Continuous prazosin administration in cirrhotic patients: effects on portal hemodynamics and on liver and renal function. Gastroenterology. 1995;109:1257–1265.
30. R.Bañares, E.Moitinho, B.Piqueras, et al. Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology. 1999;30:79–83.
31. N.Aguilar-Olivos, M.Motola-Kuba, R.Candia, et al. Hemodynamic effect of carvedilol vs. propranolol in cirrhotic patients: systematic review and meta-analysis. Ann Hepatol. 2014;13:420–428.
32. E.Sinagra, G.Perricone, M.D’Amico, et al. Systematic review with meta-analysis: the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis. Aliment Pharmacol Ther. 2014;39:557–568.• Metaanalysis showing that carvedilol reduces HVPG significantly more than propranolol.
33. L.D.De Leve. Hepatic microvasculature in liver injury. Semin Liver Dis. 2007;27:390–400.
34. M.Pinzani, P.Gentilini. Biology of hepatic stellate cells and their possible relevance in the pathogenesis of portal hypertension in cirrhosis. Semin Liver Dis. 1999;19:397–410.
35. J.Gracia-Sancho, R.Maeso-Díaz, J.Bosch. Pathophysiology and a Rational Basis of Therapy. Dig Dis. 2015;33(4):508–514.• The novel therapeutic area in PH, namely, microvascular dysfunction explained with illustrations. potential therapeutic targets mentioned.
36. J.G.Abraldes, A.Rodríguez-Vilarrupla, M.Graupera, et al. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. J Hepatol. 2007;46:1040–1046.
37. J.Trebicka, M.Hennenberg, W.Laleman, et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology. 2007;46:242–253.
38. C.Zafra, J.G.Abraldes, J.Turnes, et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004 Mar;126(3):749–755.
39. J.G.Abraldes, A.Albillos, R.Banares, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009;136:1651–1658.• Placebo controlled phase-2 study showing benefficial effects of statins on HVPG and liver function in patients with cirrhosis.
40. P.Pollo-Flores, M.Soldan, U.C.Santos, et al. Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: a randomized controlled trial. Dig Liver Dis. 2015 Nov;47(11):957–963.
41. J.G.Abraldes, C.Villanueva, C.Aracil, et al. Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology. 2016;150(5):1160–1170.• First prospective randomised clinical trial showing that simvastatin may improve survival in advanced cirrhosis.
42. A.Mohanty, J.P.Tate, G.Garcia-Tsao Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C-related compensated cirrhosis. Gastroenterology. 2016 Feb;150(2):430–440.e1. Epub 2015 Oct 17.• Further evidence on the potential of statins in providing survival advantage in patients with cirrhosis.
43. J.Gracia-Sancho, B.Lavina, A.Rodriguez-Vilarupla, et al. Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology. 2008;47:1248–1256.
44. V.Shah, M.Toruner, F.Haddad, et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology. 1999;117:1222–1228.
45. W.Laleman, A.Omasta, C.M.Van De, et al. A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis. Hepatology. 2005;42:1382–1390.
46. V.Matei, A.Rodriguez-Vilarrupla, R.Deulofeu, et al. The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis. Hepatology. 2006;44:44–52.
47. S.L.Liu, R.T.Premont, C.D.Kontos, et al. A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension. Nature Medicine. 2005;11:952–958.
48. J.Gracia-Sancho, B.Laviña, A.Rodriguez-Vilarupla, et al. Evidence against NADPH oxidase modulating hepatic vascular tone in cirrhosis. Gastroenterology. 2007;133:959–966.
49. J.-C.García-Pagán, J.Gracia-Sancho, J.Bosch. Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J Hepatol. 2012;57:458–461.
50. R.Bataller, P.Gines, J.M.Nicolas, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 2000;118:1149–1156.
51. G.Marrone, L.Russo, E.Rosado, et al. The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins. J Hepatol. 2013;58:98–103.• Study providing mechanistic explanation on how klf2 regulates hepatic endothelial phenotype and deactivates hepatic stellate cells which are relevant in the antifibrotic and antiportal hypertensive effects of statins in cirrhosis.
52. V.La Mura, M.Pasarín, C.Z.Meireles, et al. Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction. Hepatology. 2013 Mar;57(3):1172–1181.
53. J.Gracia-Sancho, H.García-Calderó, D.Hide, et al. Simvastatin maintains function and viability of steatotic rat livers procured for transplantation. J Hepatol. 2013 Jun;58(6):1140–1146.
54. R.P.Mookerjee, G.Mehta, V.Balasubramaniyan, et al. Hepatic dimethylarginine-dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal hypertension. J Hepatol. 2015;62(2):325–331. Epub 2014 Aug 23.
55. L.Verbeke, R.Farre, J.Trebicka, et al. Obeticholic acid, a farnesoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology. 2014 Jun;59(6):2286–2298. Epub 2014 Apr 14.• Mechanistic explanation of the beneficial effects of obeticholic acid on portal hypertension.
56. M.Ubeda, M.Lario, L.Muñoz, et al. Obeticholic acid reduces bacterial translocation, restores intestinal barrier and inhibits inflammation in cirrhotic rats. J Hepatol. 2016;64(5):1049–1057.
57. R.Mookerjee, M.Rosselli, G.Pieri, et al. Effect of the FXR agonist obeticholic acid on portal pressure in alcoholic cirrhosis: a proof of concept phase 2a study. Hepatology. 2012;56:1529–1530.• Only human study on the role of obeticholic acid in portal hypertension.
58. V.Matei, A.Rodriguez-Vilarrupla, R.Deulofeu, et al. Three-day tetrahydrobiopterin therapy increases in vivo hepatic NOS activity and reduces portal pressure in CCl4 cirrhotic rats. J Hepatol. 2008;49:192–197.
59. E.Reverter, F.Mesonero, S.Seijo, et al. Effects of sapropterin on portal and systemic hemodynamics in patients with cirrhosis and portal hypertension: a bicentric double-blind placebo-controlled study. Am J Gastroenterol. 2015 Jul;110(7):985–992. Epub 2015 Jun 16.
60. W.K.Hong, K.Y.Shim, S.K.Baik, et al. Relationship between tetrahydrobiopterin and portal hypertension in patients with chronic liver disease. J Korean Med Sci. 2014 Mar;29(3):392–399. Epub 2014 Feb 27.
61. M.R.Loureiro-Silva, Y.Iwakiri, J.G.Abraldes, et al. Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers. J Hepatol. 2006 May;44(5):886–893.
62. K.C.Lee, Y.Y.Yang, Y.T.Huang, et al. Administration of a low dose of sildenafil for 1 week decreases intrahepatic resistance in rats with biliary cirrhosis: the role of NO bioavailability. Clin Sci (Lond). 2010 Apr 7;119(1):45–55.
63. P.Tandon, I.Inayat, M.Tal, et al. Sildenafil has no effect on portal pressure but lowers arterial pressure in patients with compensated cirrhosis. Clin Gastroenterol Hepatol. 2010 Jun;8(6):546–549.
64. J.-O.Clemmesen, A.Giraldi, P.Ott, et al. Sildenafil does not influence hepatic venous pressure gradient in patients with cirrhosis. World J Gastroenterol. 2008 Oct 28;14(40):6208–6212.
65. W.Kreisela, P.Deiberta, L.Kupcinskasb, et al. The phosphodiesterase-5-inhibitor udenafil lowers portal pressure in compensated preascitic liver cirrhosis. A dose-finding phase-II-study. Digestive and Liver Disease. 2015;47:144–150.
66. M.Metra, G.Cotter, B.A.Davison, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the relaxin in acute heart failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol. 2013 Jan 15;61(2):196–206.
67. N.J.Lachlan, N.Masson, H.Ireland, et al. Serelaxin reduced portal pressure gradient and portal vein pressure in patients with cirrhosis and portal hypertension [Abstract ID: 260]. Hepatology. 2015 Oct; 62s:345–46A. AASLD.
68. M.Hernandez-Guerra, J.C.Garcia-Pagan, J.Turnes, et al. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology. 2006;43:485–491.
69. A.De Gottardi, A.Berzigotti, S.Seijo, et al. Postprandial effects of dark chocolate on portal hypertension in patients with cirrhosis: results of a phase 2, double-blind, randomized controlled trial. Am J Clin Nutr. 2012;96:584–590.
70. M.Guillaume, A.Rodriguez-Vilarrupla, J.Gracia-Sancho, et al. Recombinant human manganese superoxide dismutase reduces liver fibrosis and portal pressure in CCl4-cirrhotic rats. J Hepatol. 2013;58:240–246.• First study demonstrating an antifibrotic effect of human rMnSOD in cirrhosis
71. H.Garcia-Caldero, A.Rodriguez-Vilarrupla, J.Gracia-Sancho, et al. Tempol administration, a superoxide dismutase mimetic, reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol. 2011;54:660–665.
72. B.Lavina, J.Gracia-Sancho, A.Rodriguez-Vilarrupla, et al. Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension. Gut. 2009;58:118–125.
73. M.Di Pascoli, M.Divi, A.Rodriguez-Vilarrupla, et al. Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats. J Hepatol. 2013;58:904–910.
74. N.M.Bass, K.D.Mullen, A.Sanyal, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071–1081.
75. J.Vlachogiannakos, A.S.Saveriadis, N.Viazis, et al. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment Pharmacol Ther. 2009;29:992–999.
76. J.Vlachogiannakos, N.Viazis, P.Vasianopoulou, et al. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol. 2013;28:450–455.• Study showing potential for the use of rifaximin in decreasing portal pressure.
77. M.Fernández, D.Semela, J.Bruix, et al. Angiogenesis in liver disease. J Hepatol. 2009;50:604–620.
78. J.Bosch, J.G.Abraldes, M.Fernandez, et al. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J Hepatol. 2010;53:558–567.
79. M.Mejias, E.Garcia-Pras, C.Tiani, et al. Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology. 2009;49:1245–1256.• First study suggesting arole of antiangiogenic agents in cirrhosis.
80. R.Coriat, H.Gouya, O.Mir, et al. Reversible decrease of portal venous flow in cirrhotic patients: a positive side effect of sorafenib. PLoS One. 2011;6:e16978.
81. M.Pinter, W.Sieghart, T.Reiberger, et al. The effects of sorafenib on the porta hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma a pilot study. Aliment Pharmacol Ther. 2012;35:83–91.
82. M.D’Amico, M.Mejias, E.Garcia-Pras, et al. Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1191–G1198.
83. M.Cohen-Naftaly, S.L.Friedman. Current status of novel antifibrotic therapies in patients with chronic liver disease. Therap Adv Gastroenterol. 2011;4:391–417.
84. D.C.Rockey. Current and future anti-fibrotic therapies for chronic liver disease. Clin Liver Dis. 2008 Nov;12(4):939–62, xi.
85. M.Graupera, J.C.Garcia-Pagan, M.Pares, et al. Cyclooxygenase-1 inhibition correct endothelial dysfunction in cirrhotic rat livers. J Hepatol. 2003;39:515–521.
86. E.Rosado, A.Rodriguez-Vilarrupla, J.Gracia-Sancho, et al. Terutroban, a TP-receptor antagonist, reduces portal pressure in cirrhotic rats. Hepatology. 2013;58(4):1424–1435.
87. P.Tandon, J.G.Abraldes, A.Berzigotti, et al. Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol. 2010 Aug;53(2):273–282.
88. J.A.Grace, S.Klein, C.B.Herath, et al. Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology. 2013 Oct;145(4):874–884.
89. J.González-Abraldes, A.Albillos. Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis. Gastroenterology. 2001 Aug;121(2):382–388.
90. J.H.Kim, J.M.Kim, Y.Z.Cho. Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension. Clin Mol Hepatol. 2014 Dec;20(4):376–383. Epub 2014 Dec 24.
91. H.-Q.Feng, N.D.Weymouth, D.C.Rockey. Endothelin antagonism in portal hypertensive mice: implications for endothelin receptor-specific signaling in liver disease. Am J Physiol Gastrointest Liver Physiol. 2009 Jul;297(1):G27–33.
92. D.Lebrec, J.Bosch, R.Jalan, et al. Hemodynamics and pharmacokinetics of Tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis. Eur J Clin Pharmacol. 2012 May;68(5):533–541.
93. D.Tripathi, G.Therapondos, J.W.Ferguson, et al. Endothelin-1 contributes to maintenance of systemic but not portal haemodynamics in patients with early cirrhosis: a randomised controlled trial. Gut. 2006 Sep;55(9):1290–1295.
94. A.Albillos, J.L.Lledó, R.Bañares, et al. effects of alpha-adrenergic blockade with prazosin in cirrhotic patients with portal hypertension. Hepatology. 1994 Sep;20(3):611–617.
95. A.Albillos, J.C.García-Pagán, J.Iborra, et al. Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension. Gastroenterology. 1998 Jul;115(1):116–123.
96. A.Rodriguez-Vilarrupla, B.Lavina, H.Garcia-Caldero, et al. PPARa activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats. J Hepatol. 2012;56:1033–1039.
97. M.L.Shiffman, P.Pockros, J.G.McHutchison, et al. Clinical trial: the efficacy and safety of oral PF-03491390, a pancaspase inhibitor – a randomized placebo-controlled study in patients with chronic hepatitis C. Aliment Pharmacol Ther. 2007;31:969–978.
98. F.J.1.Barreyro, S.Holod, P.V.Finocchietto, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35(3):953–966. Epub 2014 Jun 6.
99. G.Garcia–Tsao, M.Fuchs, M.L.Shiffman et al. Emricassan(IDN-6556) administered orally for 28 days lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension [Abstract ID: LB6]. AASLD Annual Meeting 2015,CA. Available from: https://www.aasld.org/sites/default/files/documents/2015/…/LB06.pdf
100. J.Liang, X.Deng, Z.-X.Lin, et al. Attenuation of portal hypertension by natural taurine in rats with liver cirrhosis. World J Gastroenterol. 2009 Sep 28;15(36):4529–4537.
101. R.Schwarzer, R.Paternostro, M.Mandorfer, et al. Taurine lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized, placebo controlled, double blind pilot study [Abstract ID:149]. Hepatology. 2015 Oct;62s:284–5A. AASLD.
102. F.Cerini, M.Vilaseca, E.Lafoz, et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol. 2016;64(4):834–842.
103. E.Villa, C.Cammà, M.Marietta, et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology. 2012 Nov;143(5):1253–1254.• First study suggesting a survival benefit from anticoagulation in patients with cirrhosis.
104. E.Lawitz, Y.Tanaka, F.Poordad, et al. Safety, pharmacokinetics, and biologic activity of ND-L02-s0201, a novel targeted lipid-nanoparticle to deliver HSP47 siRNA for the treatment of patients with advanced liver fibrosis: interim results from clinical phase 1b/2 studies [AbstractID: 1433]. AASLD [Internet]. 2015. Available from: www.liverlearning.aasld.org/aasld/2015/thelivermeeting/110677