Emerging drugs for hepatic encephalopathy

Expert Opinion on Emerging Drugs

Volumn 14, Issue 3, 2009, Pages 537-549

  Riggio, Oliviero ^a   Ridola, Lorenzo ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Hepatic encephalopathy; Treatment

Indexed keywords

ACETYLCARNITINE; AMMONUL; ANTIBIOTIC AGENT; ANTIINFLAMMATORY AGENT; AST 120; BENZOIC ACID; BRANCHED CHAIN AMINO ACID; ENDOCANNABINOID; FLUMAZENIL; GLUTAMATE RECEPTOR ANTAGONIST; HPN 100; INDOMETACIN; LACTITOL; LACTULOSE; LAXATIVE; LEVACECARNINE; METRONIDAZOLE; NEOMYCIN; ORNITHINE ASPARTATE; PAROMOMYCIN; PHENYLACETIC ACID; PLACEBO; PREBIOTIC AGENT; PROBIOTIC AGENT; RIFAXIMIN; SILDENAFIL; SYNBIOTIC AGENT; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANCOMYCIN; VASOACTIVE AGENT; ZINC;

ALBUMIN DIALYSIS; ALZHEIMER DISEASE; BACTERIAL PERITONITIS; CLINICAL TRIAL; CONSTIPATION; CONTROLLED CLINICAL TRIAL; DRUG SAFETY; DRUG TOLERABILITY; GASTROINTESTINAL HEMORRHAGE; HEPATIC ENCEPHALOPATHY; HUMAN; HYPERAMMONEMIA; INTESTINE FLORA; INTESTINE LAVAGE; KIDNEY FAILURE; KINESIOTHERAPY; LIVER CIRRHOSIS; LUNG INFECTION; NEUROTOXICITY; NEUROTRANSMISSION; NITROGEN METABOLISM; NONHUMAN; PARENTERAL NUTRITION; PROTEIN RESTRICTION; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL; RECURRENT DISEASE; REVIEW; RISK FACTOR; SUPPLEMENTATION; TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT; URINARY TRACT INFECTION; ZINC DEFICIENCY;

ANTI-INFLAMMATORY AGENTS; BACTERIAL TOXINS; CLINICAL TRIALS AS TOPIC; DRUG DISCOVERY; DRUG INDUSTRY; HEPATIC ENCEPHALOPATHY; HUMANS; NITROGEN; RECURRENCE; SYNAPTIC TRANSMISSION;

EID: 69949135709     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728210903055067     Document Type: Review

References (93)

1. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy - definition, nomenclature, diagnosis and quantification. Hepatology 2002;35:716-721
2. Amodio P, Montagnese S, Gatta A, et al. Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 2004;19:253-267
3. Quero JC, Hartmann IJ, Meulstee J, et al. The diagnosis of subclinical hepatic encephalopathy in patients with cirrhosis using neuropsychological tests and automated electroencephalogram analysis. Hepatology 1996;24:556-560 (Pubitemid 26295997)
4. Amodio P, Del Piccolo F, Marchetti P, et al. Clinical features and survival of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology 1999;29:1662-1667 (Pubitemid 29247036)
5. Groeneweg M, Moerland W, Quero JC, et al. Screening of subclinical hepatic encephalopathy. J Hepatol 2000;32:748-753
6. Amodio P, Del Piccolo F, Petteno E, et al Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. J Hepatol 2001;35:37-45 (Pubitemid 32646222)
7. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Gastroenterology 2007;133:481-488
8. Sanyal AJ, Freedman AM, Shiffman ML, et al. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. Hepatology 1994;20:46-55 (Pubitemid 24196490)
9. Rossle M, Haag K, Ochs A, et al. The transjugular intrahepatic portosystemic stent-shunt procedure for variceal bleeding. N Engl J Med 1994;330:165-171 (Pubitemid 24026884)
10. Riggio O, Merli M, Pedretti G, et al. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Incidence and risk factors. Dig Dis Sci 1996;41:578-584
11. Salerno F, Borroni G, Moser P, et al. Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients. Am J Gastroenterol 1993;88:514-519 (Pubitemid 23106584)
12. Merkel C, Bolognesi M, Angeli P, et al. Prognostic indicators of survival in patients with cirrhosis and oesophageal varices, without previous bleeding. Am J Gastroenterol 1989;84:717-722 (Pubitemid 19184370)
13. Christensen E, Krintel JJ, Hansen SM, et al. Prognosis after the first episode of gastrointestinal bleeding or coma in cirrhosis. Survival and prognostic factors. Scand J Gastroenterol 1989;24:999-1006 (Pubitemid 19245611)
14. Del Olmo JA, Pena A., Serra MA, et al. Predictors of morbidity and mortality after the first episode of upper gastrointestinal bleeding in liver cirrhosis. J Hepatol 2000;32:19-24 (Pubitemid 30039442)
15. Bajaj JS. Minimal hepatic encephalopathy matters in daily life. World J Gastroenterol 2008;14:3609-3615
16. Bajaj JS, Saeian K, Hafeezullah M, et al. Patients with minimal hepatic encephalopathy have poor insight into their driving skills. Clin Gastroenterol Hepatol 2008;6:1135-1139
17. Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Navigation skill impairment: another dimension of the driving difficulties in minimal hepatic encephalopathy. Hepatology 2008;47:596-604 (Pubitemid 351280728)
18. Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations. Am J Gastroenterol 2007;102:1903-1909 (Pubitemid 47301540)
19. Available from: www.clinicaltrials.gov
20. Klempnaue J. Review: surgical shunts and encephalopathy. Metab Brain Dis 2001;16:21-28
21. Somberg KA, Riegler JL, LaBerge JM, et al. Hepatic encephalopathy after transjugular intrahepatic portosystemic shunts: incidence and risk factors. Am J Gastroenterol 1995;90:549-555
22. Riggio O, Efrati C, Catalano C, et al. High prevalence of spontaneous portal-systemic shunts in persistent hepatic encephalopathy: a case-control study. Hepatology 2005;42:1158-1165 (Pubitemid 43112683)
23. Riggio O, Angeloni S, Salvatori FM, et al. Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts. Am J Gastroenterol 2008;103:2738-2746
24. Uribe M, Campollo O, Vargas F, et al. Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial. Hepatology 1987;7:639-643 (Pubitemid 17130704)
25. Rolachon A, Zarski JP, Lutz JM, et al. Is the intestinal lavage with a solution of mannitol effective in the prevention of post-hemorrhagic hepatic encephalopathy in patients with liver cirrhosis? Results of a randomised prospective study. Gastroenterol Clin Biol 1994;18:1057-1062
26. Riggio O, Nicolao F, Angeloni S, et al. Intractable hepatic encephalopathy after tips with polytetrafluoroethylene-covered stent-graft. Scand J Gastroenterol 2003;38:570-572 (Pubitemid 36609868)
27. Uflacker R, d'Albuquerque LA, de Oliveira e Silva A, et al. Embolization to reverse severe recurrent hepatic encephalopathy. Arq Gastroenterol 1988;25:21-25
28. Schliess F, Görg B, Häussinger D. RNA oxidation and zinc in hepatic encephalopathy and hyperammonemia. Metab Brain Dis 2009;24:119-134
29. Norenberg MD, Jayakumar AR, Rama Rao KV, et al. Metab Brain Dis 2007;22:219-234
30. Häussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut 2008;57:1156-1165
31. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell Mol Life Sci 2005;62:2295-2304 (Pubitemid 41500545)
32. Hassanein TI, Tofteng F, Brown RS, et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 2007;46(6):1853-1862
33. Ghanta RK, Mullen KD. Placebo controlled treatment trials in hepatic encephalopathy are feasible and ethical. Hepatology 2005;42:1206-1207
34. Merli M, Riggio O, Dally L, et al. Does malnutrition affect survival in cirrhosis? Hepatology 1996;23:1041-1046
35. Rodríguez D, Martín A, Martinez-Valle F, et al. Prognosis after surviving to the first episode of hepatic encephalopathy [Abstract]. Hepatology 1998;28:268
36. Hartmann IJ, Groeneweg M, Quero JC, et al. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 2000;95:2029-2034
37. Romero-Gomez M, Boza F, Garcia-Valdecasas MS, et al. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001;96:2718-2723 (Pubitemid 32889211)
38. Blei AT, Cordoba J. Hepatic Encephalopathy. Am J Gastroenterol 2001;96:1968-1976
39. Riggio O, Masini A, Efrati C, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomised controlled study. J Hepatol 2005;42:674-679 (Pubitemid 40501684)
40. Heyman JK, Whitfield CJ, Brock KE, et al Dietary protein intakes in patients with hepatic encephalopathy and cirrhosis: current practice in NSW and ACT. Med J Aust 2006;185:542-543
41. Bajaj JS, Saeian K, Christensen KM, et al. Probiotic yogurt for treatment of MHE. Am J Gastroenterol 2008;103:11707-11715
42. Kanematsu T, Koyanagi N, Matsumata T, et al. Lack of preventive effect of branched-chain amino acid solution on postoperative hepatic encephalopathy in patients with cirrhosis: a randomised, prospective trial. Surgery 1988;104:482-488 (Pubitemid 18218725)
43. Bajaj JS, Etemadian A, Hafeezullah M, et al. Testing for minimal hepatic encephalopathy in the United States: An AASLD Survey. Hepatology 2007;45:833-834 (Pubitemid 46450641)
44. Prasad S, Dhiman RK, Duseja A, et al. Lactulose improves cognitive function and health-related quality of life in cirrhotic patients with minimal hepatic encephalopathy. Hepatology 2007;45:549-559 (Pubitemid 46450607)
45. Bajaj JS, Hafeezullah M, Franco J, et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology 2008;135:1591-1600
46. Mardini AH, Saxby BK, Record CO. Computerized psychometric testing in minimal encephalopathy and modulation by nitrogen challenge and liver transplant. Gastroenterology 2008;135(5):1582-1590
47. Plauth M, Cabre E, Riggio O, et al. ESPEN Guidelines on Enteral Nutrition: Liver disease. Clin Nutr 2006;25:285-294 (Pubitemid 43811683)
48. Barbaro G, Di Lorenzo G, Soldini M et al. Flumazenil for hepatic encephalopathy grade III and IVa in patients with cirrhosis: an Italian multicenter double-blind, placebo-controlled, cross-over study. Hepatology 1998;28:374-378 (Pubitemid 28363661)
49. Sakurabajashi S, Sezai S, Yamamoto Y, et al. Embolization of portal- systemic shunts in cirrhotic patients with chronic-recurrent hepatic encephalopathy. Cardiovas Intervent Radiol 1997;20:120-124 (Pubitemid 27131346)
50. Kato T, Uematsu T, Nishigaki Y, et al. Therapeutic effect of balloon-occluded retrograde transvenous obliteration on portal-systemic encephalopathy in patients with liver cirrhosis. Inter Med 2001;40:677-678
51. Uflacker R, Silva Ade O, D'Albuquerque LA, et al. Chronic portosystemic encephalopathy: embolisation of portosystemic shunts. Radiology 1987;165:721-725 (Pubitemid 18003199)
52. Cordoba J, Olive G, Alonso J, et al. Improvement of magnetic resonance spectroscopic abnormalities but not pallidal hyperintensity followed amelioration of hepatic encephalopathy after occlusion of a large spleno-renal shunt. J Hepatol 2001;34:176-178 (Pubitemid 32102573)
53. Sanyal A. Bass NM, Teperman L, et al. Chronic rifaximine for maintenance of remission of hepatic encephalopathy: subgroup analysis of a phase 3 trial [Abstract]. J Hepatol 2009;50:222
54. Als-Nielsen B, Gluud LL, Gluud C, et al. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ 2004;328:1046-1052 (Pubitemid 38580827)
55. Morgan MY, Blei A, Grüngreiff K, et al. The treatment of hepatic encephalopathy. Metab Brain Dis 2007;22:389-405
56. Shawcross D, Jalan R. Dispelling myths in the treatment of hepatic encephalopathy. Lancet 2005;365:431-433 (Pubitemid 40179231)
57. Kircheis G, Nilius R, Held C, et al. Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 1997;25:1351-1360 (Pubitemid 27250753)
58. Stauch S, Kircheis G, Adler G, et al. Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study. J Hepatol 1998;28:856-864 (Pubitemid 28223491)
59. Ahmad I, Khan AA, Alam A, et al. L-ornithine-L-aspartate infusion efficacy in hepatic encephalopathy. J Coll Physicians Surg Pak 2008;18:684-687
60. Poo JL, Góngora J, Sánchez-Avila F, et al. Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study. Ann Hepatol 2006;5:281-288
61. Sushma S, Dasarathy S, Tandon RK, et al. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomised trial. Hepatology 1992;16:138-144
62. Efrati C, Masini A, Merli M, et al. Effect of sodium benzoate on blood ammonia response to oral glutamine challenge in cirrhotic patients: a note of caution. Am J Gastroenterol 2000;95:3574-3578
63. Riggio O, Merli M, Capocaccia L, et al. Zinc supplementation reduces blood ammonia and increase liver ornithine transcarbamylase activity in experimental cirrhosis. Hepatology 1992;16:785-789
64. Reding P, Duchateau J, Battaille C, et al. Oral zinc supplementation improves hepatic encephalopathy. Results of a randomised controlled trial. Lancet 1984;2:493-495
65. Riggio O, Ariosto F, Merli M, et al. Short term oral zinc supplementation does not improve chronic hepatic encephalopathy. Dig Dis Sci 1991;36:1204-1208
66. Goulenok C, Bernard B, Cadranel JF, et al. Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis. Aliment Pharmacol Ther 2002;16(3):361-372 (Pubitemid 34214514)
67. Als-Nielsen B, Kjaergard LL, Gluud C, et al. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy. Cochrane Database Syst Rev 2001;4:CD00279
68. Naylor CD, O'Rourke K, Detsky AS, et al. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. A meta analysis. Gastroenterology 1989;97:1033-1042 (Pubitemid 19239049)
69. Als-Nielsen B, Koretz RL, Kjaergard L, et al Branched-chain amino acids for hepatic encephalopathy. The Cochrane Library, John Wiley and Sons Chichester, UK, Issue 2;2004
70. Malaguarnera M, Pistone G, Astuto M, et al. Effects of L-Acetylcarnitine on cirrhotic patients with hepatic coma: randomized double blind, placebo controlled trial. Dig Dis Sci 200651:2242-2247
71. Loguercio C, Abbiati R, Rinaldi M, et al. Long-term effects of Enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1-2 hepatic encephalopathy. J Hepatol 1995;23:39-46
72. Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441-1449 (Pubitemid 38569067)
73. Gentile S, Guarino G, Romano M, et al. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005;3:184-191 (Pubitemid 40220314)
74. Hiraishi M, Takahama T, Yamazaki Z, et al. Int J Artif Organs 1989;12:114-120
75. Hiraishi M. The effect of oral adsorbent on surgically induced hepatic failure. Jpn J Surg 1987;17:517-527 (Pubitemid 18101837)
76. Nicaise C, Prozzi D, Viaene E, et al. Control of acute, chronic, and constitutive hyperammonemia by wild-type and genetically engineered Lactobacillus plantarum in rodents. Hepatology 2008;48:1184-1192
77. Carpenedo R, Mannaioni G, Moroni F, et al. Oxindole, a neurodepressant tryptophan metabolite, accumulates in blood or brain of rats with hepatic failure. J Neurochem 1998;70:1998-2003 (Pubitemid 28207823)
78. Carpenedo R, Carlà V, Moneti G, et al. Identification and measurement of oxindole (2-Indolinone) in the mammalian brain and other rat organs. Analyt Biochem 1997;244:74-79 (Pubitemid 27030529)
79. Ridola L, Angeloni S, Mannaioni G, et al. Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: relationship to hepatic encephalopathy [Abstract]. Hepatology 2008;48;S4
80. Olde Damink SWM, Jalan R, Dejong CHC, et al. Interorgan ammonia trafficking in liver disease. Met Brain Dis 2008;24:169-181
81. Jalan R, Kapoor D. Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver. Gut 2003;52:1041-1045 (Pubitemid 36765299)
82. Jalan R, Wright G, Davies NA, et al. L-ornithine phenylacetate: a novel treatment for hyperammoniemia and hepatic encephalopathy. Med Hypotheses 2007;69:1064-1069 (Pubitemid 47430227)
83. Wright G, Davies NA, Ytrebo LM, et al. L-Onithyne phenilacetate reduces arterial ammonia, improves brain osmolytes and reuces brain water in a bile duct ligated rat model of cirrhosis [Abstract]. Hepatology 2007
84. Enns GM, Berry SA, Berry GT, et al. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 2007;356:2282-2292
85. Dragon Y, Avraham Y. Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP activated kinase. FASEB J 2007;10:2431-2441 (Pubitemid 47230673)
86. Erceg S, Monfort P, et al. Oral administration of sildenafil restore learning ability in rats with hyperammoniemia and with portacaval shunts. Hepatology 200541:299-306
87. Canales JJ, Elayadi A, Errami A, et al. Chronic hyperammonemia alters motor and neurochemicals responses to activtion of group I metabotropic glutamate receptors in the nucleus accumbens in rats in vivo. Neurobiol Dis14:380-390
88. Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254 (Pubitemid 38115829)
89. Chung C, Gottstein J, Blei AT, et al. Indomethacin prevents the development of experimental ammonia-induced brain edema in rats after portacaval anastomosis. Hepatology 2001;34:249-254 (Pubitemid 32702336)
90. Ahboucha S, Jiang W, Chatauret N, et al. Indomethacin improves locomotor deficit and reduces brain concentrations of neuroinhibitory steroids in rats following portacaval anastomosis. Neurogastroenterol Motil 20082:949-957
91. Cauli O, Rodrigo R, Piedrafita B, et al. Hepatology 2007;46:514-519
92. Cordoba J, Gottstein J, Blai AT. Chronic hyponatremia exacerbated ammonia induced brain edema in rats after porta-caval anastomosis. J Hepatol 1998;29:589-594 (Pubitemid 28484948)
93. Gines P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance and management. Hepatology 2008;48:1002-1010