Drugs

, Volume 70, Issue 9, pp 1131–1148 | Cite as

Pharmacotherapy for Hepatic Encephalopathy

  • Paula V. Phongsamran
  • Jiwon W. Kim
  • Jennifer Cupo Abbott
  • Angela Rosenblatt
Review Article

Abstract

Hepatic encephalopathy (HE) is a challenging clinical complication of liver dysfunction with a wide spectrum of neuropsychiatric abnormalities that range from mild disturbances in cognitive function and consciousness to coma and death. The pathogenesis of HE in cirrhosis is complex and multifactorial, but a key role is thought to be played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia. Therapeutic treatment options for HE are currently limited and have appreciable risks and benefits associated with their use. Management of HE primarily involves avoidance of precipitating factors, limitation of dietary protein intake, and administration of various ammonia-lowering therapies such as non-absorbable disaccharides and select antimicrobial agents.

Non-absorbable disaccharides, such as lactulose, have traditionally been regarded as first-line pharmacotherapy for patients with HE. However, multiple adverse events have been associated with their use. In addition, recent literature has questioned the true efficacy of the disaccharides for this indication.

Neomycin, metronidazole and vancomycin may be used as alternative treatments for patients intolerant or unresponsive to non-absorbable disaccharides. Antimicrobials reduce bacterial production of ammonia and other bacteria-derived toxins through suppression of intestinal flora. Neomycin has been reported to be as effective as lactulose, and similar efficacy has been reported with vancomycin and metronidazole for the management of HE. However, the adverse effects frequently associated with these antimicrobials limit their use as first-line pharmacological agents. Neomycin is the most commonly used antimicrobial for HE and, although poorly absorbed, systemic exposure to the drug in sufficient amounts causes hearing loss and renal toxicity. Long-term neomycin therapy requires annual auditory testing and continuous monitoring of renal function. Long-term use of metronidazole has been associated with neurotoxicity in patients with cirrhosis, including dose-dependent peripheral neuropathy. Vancomycin may be a safer option for HE in patients with chronic liver disease; however, limited experience, possible bacterial overgrowth and risk for enteric bacteria resistance preclude the routine use of vancomycin for HE.

Rifaximin is a novel antimicrobial agent with a wide spectrum of activity that has shown promise as an alternative antimicrobial treatment option for HE. Several clinical trials have compared rifaximin to the disaccharides, lactulose and lactitol, and the antimicrobial neomycin. Rifaximin appears to be at least as effective as conventional drug therapy and has been associated with fewer adverse effects due to its limited systemic absorption. The available clinical data appear to support a favourable benefit-risk ratio for rifaximin, which has shown efficacy with an improved tolerability profile. Future studies are needed in order to truly characterize its cost effectiveness in today’s healthcare environment.

Other less frequently utilized alternative treatment options include administration of benzodiazepine receptor antagonists, branched-chain amino acids, ornithine aspartate, zinc supplementation, sodium benzoate, dopamine receptor agonists, acarbose and probiotics. Presently, there is relatively limited clinical data supporting their routine use in HE.

References

  1. 1.
    Gitlin N. Hepatic encephalopathy. In: Zakim D, Boyer TD, editors. Hepatology: a textbook of liver disease. Philadelphia (PA): WB Saunders, 1996: 605–17Google Scholar
  2. 2.
    Butterworth RF, Giguere JF, Michaud J, et al. Ammonia: key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 1987; 6: 1–23PubMedCrossRefGoogle Scholar
  3. 3.
    Haussinger D, Kircheis G, Fischer R, et al. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol 2000; 32: 1035–8PubMedCrossRefGoogle Scholar
  4. 4.
    Capocaccia L, Ferenci P, Fischer JE, et al. Mechanisms of hepatic encephalopathy. Gastroenterol Int 1989; 2: 131–40Google Scholar
  5. 5.
    Bass NM. Review article: the current pharmacological therapies for hepatic encephalopathy. Aliment Pharmacol Ther 2006; 25 Suppl. 1: 23–31Google Scholar
  6. 6.
    Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med 1997; 337(7): 473–79PubMedCrossRefGoogle Scholar
  7. 7.
    Mas A, Salmeron JM, Rodes J. Diagnosis and therapy of hepatic encephalopathy. Adv Exp Med Biol 1994; (368): 119–23Google Scholar
  8. 8.
    Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol 2001; 96: 1968–76PubMedCrossRefGoogle Scholar
  9. 9.
    Riggio O, Balducci G, Ariosto F, et al. Lactitol in prevention of recurrent episodes of hepatic encephalopathy in cirrhotic patients with portal-systemic shunt. Dig Dis Sci 1989; 34(6): 823–9PubMedCrossRefGoogle Scholar
  10. 10.
    Morgan MY, Hawley KE. Lactitol vs. lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized trial. Hepatology 1987; 7(6): 1278–84Google Scholar
  11. 11.
    Morgan MY, Blei A, Grüngreiff K, et al. The treatment of hepatic encephalopathy. Metab Brain Dis 2007; 22: 389–405PubMedCrossRefGoogle Scholar
  12. 12.
    Cordóba J, Blei AT. Treatment of hepatic encephalopathy. Am J Gastroenterol 1997; 92(9): 1429–39PubMedGoogle Scholar
  13. 13.
    Clausen MR, Mortensen PB. Lactulose, disaccharides and colonic flora: clinical consequences. Drugs 1997; 53(6): 930–42PubMedCrossRefGoogle Scholar
  14. 14.
    Eroglu Y, Byrne W. Hepatic encephalopathy. Emerg Med Clin N Am 2009; 27: 401–14CrossRefGoogle Scholar
  15. 15.
    Lactulose. Thompson Micromedex [online]. Available from URL: http://www.micromedex.com/ [Accessed 2009 Oct 20]
  16. 16.
    Uribe M, Campollo O, Vargas F, et al. Acidifying enemas (lactitol and lactulose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial. Hepatology 1987; 7(4): 639–43Google Scholar
  17. 17.
    Saito T, Shinzawa H, Watanabe H, et al. Home lactulose enema: prevention of hepatic encephalopathy at home. J Gastroenterol 2002; 27: 68–9CrossRefGoogle Scholar
  18. 18.
    Heredia D, Terés J, Orteu N, et al. Lactitol vs. lactulose in the treatment of chronic recurrent portal-systemic encephalopathy. J Hepatol 1988; 7: 106–10Google Scholar
  19. 19.
    Horsmans Y, Solbreux PM, Daenens C, et al. Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Aliment Pharmacol Ther 1997; 11(1): 165–70PubMedCrossRefGoogle Scholar
  20. 20.
    Watanabe A, Sakai T, Sato S, et al. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997; 26(6): 1410–4PubMedCrossRefGoogle Scholar
  21. 21.
    Dhiman RK, Sawhney MS, Chawla YK, et al. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2000; 45(8): 1549–52PubMedCrossRefGoogle Scholar
  22. 22.
    Prasad S, Dhiman RK, Duseja A, et al. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 2007; 45(3): 549–59PubMedCrossRefGoogle Scholar
  23. 23.
    Morgan MY, Alonso M, Stanger LC. Lactitol and lactulose for the treatment of subclinical hepatic encephalopathy in cirrhotic patients: a randomized, cross-over study. J Hepatol 1989; 8: 208–17PubMedCrossRefGoogle Scholar
  24. 24.
    Lanthier PL, Morgan MY. Lactitol in the treatment of chronic hepatic encephalopathy: an open comparison with lactulose. Gut 1985; 26: 415–20PubMedCrossRefGoogle Scholar
  25. 25.
    Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systemic review of randomized clinical trials. BMJ 2004; 328: 1046–51PubMedCrossRefGoogle Scholar
  26. 26.
    Strauss E, Tramote R, Silva EPS, et al. Double-blind, randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 1992; 39: 542–5PubMedGoogle Scholar
  27. 27.
    Orlandi F, Freddara U, Candelaresi MT, et al. Comparison between neomycin and lactulose in 173 patients with hepatic encephalopathy: a randomized clinical study. Dig Dis Sci 1981; 26: 498–506PubMedCrossRefGoogle Scholar
  28. 28.
    Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy: a controlled, double-blind clinical trial. Am J Dig Dis 1978; 23: 398–406PubMedCrossRefGoogle Scholar
  29. 29.
    Conn HO, Leavy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy: a double-blind controlled trial. Gastroenterology 1977; 72: 573–83PubMedGoogle Scholar
  30. 30.
    Festi D, Mazzella G, Orsini M, et al. Rifaximin in the treatment of chronic hepatic encephalopathy: results of a multicenter study of efficacy and safety. Curr Ther Res 1993; 54(5): 598–609CrossRefGoogle Scholar
  31. 31.
    Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin 1993; 13: 109–18PubMedCrossRefGoogle Scholar
  32. 32.
    Massa P, Vallerino E, Dodero M. Treatment of hepatic encephalopathy with rifaximin: double-blind, double-dummy study versus lactulose. J Clin Res 1993; 4: 7–18Google Scholar
  33. 33.
    Fera G, Agostinacchio F, Nigro M, et al. Rifaximin in the treatment of hepatic encephalopathy. Eur J Clin Res 1993; 4: 57–66Google Scholar
  34. 34.
    Mas A, Rodes J, Sunyer L, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 2003; 38: 51–8PubMedCrossRefGoogle Scholar
  35. 35.
    Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 2007; 52: 737–41PubMedCrossRefGoogle Scholar
  36. 36.
    Paik YH, Lee KS, Han KH, et al. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Med J 2005; 46(3): 399–407PubMedCrossRefGoogle Scholar
  37. 37.
    Greenberg LH, Momary H. Audiotoxicity and nephrotoxicity due to orally administered neomycin. JAMA 1965; 194: 237–8CrossRefGoogle Scholar
  38. 38.
    Berk DP, Chalmers T. Deafness complicating antibiotic therapy of hepatic encephalopathy. Ann Intern Med 1970; 73: 393–6PubMedGoogle Scholar
  39. 39.
    Dawson AM, McLaren J, Sherlock S. Neomycin in the treatment of hepatic coma. Lancet 1957; 273(7008): 1262–8PubMedGoogle Scholar
  40. 40.
    Tarao K, Ikeda T, Hayashi K, et al. Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy. Gut 1990; 31: 702–6PubMedCrossRefGoogle Scholar
  41. 41.
    Morgan MH, Read AE, Speller DC. Treatment of hepatic encephalopathy with metronidazole. Gut 1982; 23: 1–7PubMedCrossRefGoogle Scholar
  42. 42.
    Scarpignato C, Pelosini I. Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy 2005; 51 Suppl. 1: 36–66PubMedCrossRefGoogle Scholar
  43. 43.
    Adachi JA, DuPont HL. Rifaximin: a novel nonabsorbed rifamycin for gastrointestinal disorders. Clin Infect Dis 2006; 42(4): 541–7PubMedCrossRefGoogle Scholar
  44. 44.
    Huang DB, DuPont HL. Rifaximin: a novel antimicrobial for enteric infections. J Infect 2005; 50: 97–106PubMedCrossRefGoogle Scholar
  45. 45.
    Jiang ZD, DuPont HL. Rifaximin: in vitro and in vivo antibacterial activity: a review. Chemotherapy 2005; 51 Suppl. 1: 67–72PubMedCrossRefGoogle Scholar
  46. 46.
    Brigidi P, Swennen E, Rizzello F, et al. Effects of rifaximin administration on the intestinal microbiota in patients with ulcerative colitis. J Chemother 2002; 14: 290–5PubMedGoogle Scholar
  47. 47.
    Xifaxan (rifaximin) tablets [prescribing information]. Palo Alto (CA): Salix Pharmaceuticals, 2004Google Scholar
  48. 48.
    Scarpignato C, Pelosini I. Experimental and clinical pharmacology of rifaximin, a gastrointestinal selective antibiotic. Digestion 2006; 73 Suppl. 1: 13–27PubMedCrossRefGoogle Scholar
  49. 49.
    Pedretti G, Calzetti C, Missale G, et al. Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics: a double-blind, randomized trial. Ital J Gastroenterol 1991; 23: 175–8PubMedGoogle Scholar
  50. 50.
    Miglio F, Valpiani D, Rossellini SR, et al. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy: a double-blind, randomized trial. Curr Med Res Opin 1997; 13(10): 593–601PubMedCrossRefGoogle Scholar
  51. 51.
    Riggio O, Masini A, Efrati C, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J Hepatol 2005; 42: 674–9PubMedCrossRefGoogle Scholar
  52. 52.
    Sharma BC, Sharma P, Agrawal A, et al. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009; 137: 885–91PubMedCrossRefGoogle Scholar
  53. 53.
    Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362(12): 1071–81PubMedCrossRefGoogle Scholar
  54. 54.
    Poordad F, Bass N, Sanyal A, et al. The protective effect of rifaximin (1100 mg daily) from hepatic encephalopathy observed in a double-blind placebo controlled study is substantiated and durable over the long term [abstract]. The Liver Meeting, American Association for the Study of Liver Diseases; 2009 Oct 31; Boston (MA)Google Scholar
  55. 55.
    Huang E, Esrailian E, Spiegel BMR. The cost-effectiveness and budget impact of competing therapies in hepatic encephalopathy: a decision analysis. Aliment Pharmacol Ther 2007; 26: 1147–61PubMedCrossRefGoogle Scholar
  56. 56.
    Sama Ca, Morselli-Labate AM, Pianta P, et al. Clinical effects of rifaximin in patients with hepatic encephalopathy intolerant or nonresponsive to previous lactulose treatment: an open-label, pilot study. Clin Ther Res 2004; 65(5): 413–20CrossRefGoogle Scholar
  57. 57.
    Neff GW, Kemmer N, Zacharias T, et al. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplant Proc 2006; 38: 3552–55PubMedCrossRefGoogle Scholar
  58. 58.
    Morgan MY. Branched chain amino acids in the management of chronic liver disease: facts and fantasies. J Hepatol 1990; 11: 133–41PubMedCrossRefGoogle Scholar
  59. 59.
    James JH, Ziparo V, Jeppsson B, et al. Hyperammonaemia, plasma amino-acid balance, and blood-brain amino-acid transport: a unified theory of portal-systemic encephalopathy. Lancet 1979; 2: 772–5PubMedCrossRefGoogle Scholar
  60. 60.
    Horst d, Grace ND, Conn Ho, et al. Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology 1984; 4: 279–87PubMedCrossRefGoogle Scholar
  61. 61.
    Marchesini G, Dioguardi FS, Bianchi GP, et al. Long-term branched chain amino acid treatment in chronic hepatic encephalopathy. J Hepatol 1991; 11: 92–101CrossRefGoogle Scholar
  62. 62.
    Naylor CD, O’Rouke K, Detsky As, et al. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy: a meta-analysis. Gastroenterology 1989; 97: 1033–42PubMedGoogle Scholar
  63. 63.
    Als-Nielsen B, Koretz RL, Kjaergard LL, et al. Branchedchain amino acids for hepatic encephalopathy. Cochrane Database Syst Rev 2003; (2): CD001939Google Scholar
  64. 64.
    Abou-Assi S, Vlahcevic ZR. Hepatic encephalopathy: metabolic consequence of cirrhosis often is reversible. Postgrad Med 2001; 109: 52–90PubMedCrossRefGoogle Scholar
  65. 65.
    Staedt U, Leweling H, Gladisch R, et al. Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis: a double-blind, randomized study using a four-fold crossover design. J Hepatol 1993; 19: 424–30PubMedCrossRefGoogle Scholar
  66. 66.
    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 1998; 25: 1351–60CrossRefGoogle Scholar
  67. 67.
    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: 856–64PubMedCrossRefGoogle Scholar
  68. 68.
    Acharya SK, Bhatia V, Sreenivas V, et al. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology 2009; 136: 2159–68PubMedCrossRefGoogle Scholar
  69. 69.
    Loomba V, Pawar G, Khar KL, et al. Serum zinc levels in hepatic encephalopathy. Indian J Gastroenterol 1995; 14: 51–3PubMedGoogle Scholar
  70. 70.
    Riggio O, Ariosto F, Merli M, et al. Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy: results of a double-blind crossover trial. Dig Dis Sci 1991; 36: 1204–8PubMedCrossRefGoogle Scholar
  71. 71.
    Marchesini G, Fabbri A, Bianchi G, et al. Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis. Hepatology 1996; 23: 1084–92PubMedCrossRefGoogle Scholar
  72. 72.
    Van der Rijt CC, Schalm SW, Schat H, et al. Overt hepatic encephalopathy precipitated by zinc deficiency. Gastroenterology 1991; 100: 1114–8PubMedGoogle Scholar
  73. 73.
    Sushma S, Dasarathy S, Tandon RK, et al. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology 1992; 16: 138–44PubMedCrossRefGoogle Scholar
  74. 74.
    Pomier-Layrargues G, Rose C, Spahr L, et al. Role of manganese in the pathogenesis of portal-systemic encephalopathy. Metab Brain Dis 1998; 13: 311–7CrossRefGoogle Scholar
  75. 75.
    Uribe M, Farca A, Marquez MA, et al. Treatment of chronic portal systemic encephalopathy with bromocriptine: a double-blind controlled trial. Gastroenterology 1979; 76: 1347–51PubMedGoogle Scholar
  76. 76.
    Gyr K, Meier R, Haussler J, et al. Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double blind, randomised, placebo controlled multicentre study. Gut 1996; 39: 319–24PubMedCrossRefGoogle Scholar
  77. 77.
    Cadranel JF, el Younsi M, Pidoux B, et al. Flumazenil therapy for hepatic encephalopathy in cirrhotic patients: a double-blind pragmatic randomized, placebo study. Eur J Gastroenterol Hepatol 1995; 7: 325–9PubMedGoogle Scholar
  78. 78.
    Pomier-Layrargues JF, Giguere JF, Javoie J, et al. Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Hepatology 1994; 19: 32–7PubMedGoogle Scholar
  79. 79.
    Van der Rijt CC, Schalm SW, Meulstee J, et al. Flumazenil therapy for hepatic encephalopathy: a double-blind cross over study. Gastroenterol Clin Biol 1995; 19: 572–80PubMedGoogle Scholar
  80. 80.
    Barbaro G, Dilorenzo 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: 374–8PubMedCrossRefGoogle Scholar
  81. 81.
    Als-Nielsen B, Kjaergard Ll, Gluud C. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy. Cochrane Database Syst Rev 2004; (2): CD002798Google Scholar
  82. 82.
    Gentile S, Guarino G, Romano M, et al. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005; 3: 184–91PubMedCrossRefGoogle Scholar
  83. 83.
    Liu Q, Duan ZP, Ha da K, et al. Symbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 1994; 39: 1441–9CrossRefGoogle Scholar
  84. 84.
    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: 39–46PubMedCrossRefGoogle Scholar
  85. 85.
    Bajaj JS, Saejan K, Christensen KM, et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 2008; 103: 1707–15PubMedCrossRefGoogle Scholar
  86. 86.
    Sharma P, Sharma BC, Puri V, et al. An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2008; 20: 506–11PubMedCrossRefGoogle Scholar
  87. 87.
    Malaguarnera M, Greco F, Barone G, et al. Bifidobacterium longum with fructo-oligosaccharide (FOS) treatment in minimal hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Dig Dis Sci 2007; 52: 3259–65PubMedCrossRefGoogle Scholar
  88. 88.
    Malaguarnera M, Pistone G, Elvira R, et al. Effects of L-carnitine in patients with hepatic encephalopathy. World J Gastroenterol 2005; 11: 7197–202PubMedGoogle Scholar
  89. 89.
    del Olmo JA, Castillo M, Rodrigo JM, et al. Effects of L-carnitine upon ammonia tolerance test in cirrhotic patients. Adv Exp Med Biol 1990; 272: 197–208PubMedCrossRefGoogle Scholar
  90. 90.
    A study of the safety and efficacy of HPN-100 for maintaining remission in subjects with cirrhosis and episodic hepatic encephalopathy (HALT-HE) [ClinicalTrials.gov identifier NCT00999167]. US National Institute of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 May 3]
  91. 91.
    Vogels BA, Maas MA, Daalhuisen J, et al. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology 1997; 25: 820–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Paula V. Phongsamran
    • 1
  • Jiwon W. Kim
    • 1
  • Jennifer Cupo Abbott
    • 1
  • Angela Rosenblatt
    • 2
  1. 1.Department of Clinical Pharmacy, USC University Hospital Department of PharmacyUniversity of Southern California School of PharmacyLos AngelesUSA
  2. 2.Department of Pharmacy ServicesRiverside County Regional Medical CenterMoreno ValleyUSA

Personalised recommendations