Emerging Therapies for the Management of Hepatic Encephalopathy

ABSTRACT

Effective treatment options for hepatic encephalopathy (HE) are limited. Conventional therapeutic approaches are directed at reducing bacterial production of ammonia and enhancing its elimination. Nonabsorbable disaccharides are first-line therapy for HE, but published clinical studies evaluating their safety and efficacy are limited, and patient tolerance of these agents is poor. Recent data from several clinical studies support the use of rifaximin, an oral, minimally absorbed antibiotic. Rifaximin appears to be well tolerated and to confer therapeutic benefits at least comparable with, and possibly exceeding, those of nonabsorbable disaccharides and systemic antibiotics. Other potentially useful pharmacotherapies under study include acarbose, levocarnitine, and probiotics. In hospitalized patients with severe HE, the use of liver support devices (e.g., molecular adsorbent recirculating system) in the treatment of HE has shown promise in early-stage clinical investigation.

KEYWORDS

Hepatic encephalopathy - rifaximin - lactulose - levocarnitine

REFERENCES

• 1 Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei A T. Hepatic encephalopathy-definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.  Hepatology. 2002;  35 716-721
• 2 Abou-Assi S, Vlahcevic Z R. Hepatic encephalopathy: metabolic consequence of cirrhosis often is reversible.  Postgrad Med. 2001;  109 52-60, 63
• 3 Riordan S M, Williams R. Treatment of hepatic encephalopathy.  N Engl J Med. 1997;  337 473-479
• 4 Blei A T, Cordoba J. Hepatic encephalopathy.  Am J Gastroenterol. 2001;  96 1968-1976
• 5 Jiang Z D, Ke S, Palazzini E, Riopel L, Dupont H. In vitro activity and fecal concentration of rifaximin after oral administration.  Antimicrob Agents Chemother. 2000;  44 2205-2206
• 6 Huang D B, DuPont H L. Rifaximin: a novel antimicrobial for enteric infections.  J Infect. 2005;  50 97-106
• 7 Pakyz A L. Rifaximin: a new treatment for travelers' diarrhea.  Ann Pharmacother. 2005;  39 284-289
• 8 Paik Y H, Lee K S, Han K H et al.. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study.  Yonsei Med J. 2005;  46 399-407
• 9 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 51-58
• 10 Loguercio C, Federico A, De Girolamo V, Ferrieri A, Del Vecchio Blanco C. Cyclic treatment of chronic hepatic encephalopathy with rifaximin: results of a double-blind clinical study.  Minerva Gastroenterol Dietol. 2003;  49 53-62
• 11 Miglio F, Valpiani D, Rossellini S R, Ferrieri A. Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy: a double-blind, randomised trial.  Curr Med Res Opin. 1997;  13 593-601
• 12 Williams R, James O F, Warnes T W, Morgan M Y. Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study.  Eur J Gastroenterol Hepatol. 2000;  12 203-208
• 13 Bucci L, Palmieri G C. 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;  13 109-118
• 14 Bass N M. Review article: the current pharmacological therapies for hepatic encephalopathy.  Aliment Pharmacol Ther. 2007;  25(suppl 1) 23-31
• 15 Pedretti G, Calzetti C, Missale G, Fiaccadori F. Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics: a double-blind, randomized trial.  Ital J Gastroenterol. 1991;  23 175-178
• 16 Di Piazza S, Gabriella F M, Valenza L M et al.. Rifaximin versus neomycin in the treatment of portosystemic encephalopathy.  Ital J Gastroenterol. 1991;  23 403-407
• 17 Puxeddu A, Quartini M, Massimetti A, Ferrieri A. Rifaximin in the treatment of chronic hepatic encephalopathy.  Curr Med Res Opin. 1995;  13 274-281
• 18 Testa R, Eftimiadi C, Sukkar G S et al.. A non-absorbable rifamycin for treatment of hepatic encephalopathy.  Drugs Exp Clin Res. 1985;  11 387-392
• 19 Bass N M, Ahmed A, Johnson L et al.. Rifaximin treatment is beneficial for mild hepatic encephalopathy.  Hepatology. 2004;  40(suppl 4) 646A Abstract 1116
• 20 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;  54 598-609
• 21 Parini P, Cipolla A, Ronchi M et al.. Effect of rifaximin and paromomycin in the treatment of portal-systemic encephalopathy.  Curr Ther Res. 1992;  52 34-39
• 22 Sama C, Morselli-Labate A M, 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.  Curr Ther Res. 2004;  65 413-422
• 23 Lata J, Hulek P, Spicak J et al.. Safety and efficacy of rifaximin in the treatment of hepatic encephalopathy in liver cirrhosis.  Hepatology. 2002;  36(suppl 2) 519A Abstract 1425
• 24 Massa P, Vallerino E, Dodero M. Treatment of hepatic encephalopathy with rifaximin: double blind, double dummy study versus lactulose.  Eur J Clin Res. 4 1993;  7-18
• 25 Giacomo F, Francesco A, Michele N et al.. Rifaximin in the treatment of hepatic encephalopathy.  Eur J Clin Res. 1993;  4 57-66
• 26 De Marco F, Amato P S, D'Arienzo A. Rifaximin in collateral treatment of portal-systemic encephalopathy: a preliminary report.  Curr Ther Res. 1984;  36 668-674
• 27 Venturini I, Ferrieri A, Farina F et al.. Evaluation of rifaximin, placebo and lactulose in reducing the levels of benzodiazepine-like compounds in patients with liver cirrhosis: a pilot study.  Drugs Exp Clin Res. 2005;  31 161-168
• 28 Als-Nielsen B, Gluud L L, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials.  BMJ. 2004;  328 1046
• 29 Sigal S H, Stanca C M, Kontorinis N, Bodian C, Ryan E. Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis.  Am J Gastroenterol. 2006;  101 1490-1496
• 30 Gentile S, Guarino G, Romano M et al.. A randomized controlled trial of acarbose in hepatic encephalopathy.  Clin Gastroenterol Hepatol. 2005;  3 184-191
• 31 Levocarnitine Injection USP [prescribing information]. Available at: http://www.bedfordlabs.com/products/inserts/levocarnitine_pi.pdf Accessed March 29, 2007
• 32 Raskind J Y, El Chaar G M. The role of carnitine supplementation during valproic acid therapy.  Ann Pharmacother. 2000;  34 630-638
• 33 Siciliano M, Annicchiarico B E, Lucchese F, Bombardieri G. Effects of a single, short intravenous dose of acetyl-L-carnitine on pattern-reversal visual-evoked potentials in cirrhotic patients with hepatic encephalopathy.  Clin Exp Pharmacol Physiol. 2006;  33 76-80
• 34 Malaguarnera M, Pistone G, Elvira R, Leotta C, Scarpello L, Liborio R. Effects of L-carnitine in patients with hepatic encephalopathy.  World J Gastroenterol. 2005;  11 7197-7202
• 35 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. 2006;  51 2242-2247
• 36 del Olmo J A, Castillo M, Rodrigo J M et al.. Effect of L-carnitine upon ammonia tolerance test in cirrhotic patients.  Adv Exp Med Biol. 1990;  272 197-208
• 37 Sushma S, Dasarathy S, Tandon R K, Jain S, Gupta S, Bhist M S. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial.  Hepatology. 1992;  16 138-144
• 38 Efrati C, Masini A, Merli M, Valeriano V, Riggio O. 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
• 39 Mendenhall C L, Rouster S, Marshall L, Weesner R. A new therapy for portal systemic encephalopathy.  Am J Gastroenterol. 1986;  81 540-543
• 40 Liu Q, Duan Z P, Ha D K, Bengmark S, Kurtovic J, Riordan S M. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis.  Hepatology. 2004;  39 1441-1449
• 41 Lighthouse J, Naito Y, Helmy A et al.. Endotoxinemia and benzodiazepine-like substances in compensated cirrhotic patients: a randomized study comparing the effect of rifaximine alone and in association with a symbiotic preparation.  Hepatol Res. 2004;  28 155-160
• 42 Sen S, Mookerjee R P, Davies N A, Williams R, Jalan R. Review article: the molecular adsorbents recirculating system (MARS) in liver failure.  Aliment Pharmacol Ther. 2002;  16(suppl 5) 32-38
• 43 Heemann U, Treichel U, Loock J et al.. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study.  Hepatology. 2002;  36 949-958
• 44 Hassanein T, Tpfteng F, Brown Jr R et al.. Efficacy of albumin dialysis (MARS) in patients with cirrhosis and advanced grades of hepatic encephalopathy: a prospective, controlled, randomized multicenter trial [abstract].  Hepatology. 2004;  4(suppl 1) 726A