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Ornithine phenylacetate revisited

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Abstract

In patients with liver failure hyperammonemia is associated with the development of hepatic encephalopathy (HE) and immune impairment. Treatment of hyperammonemia is an unmet clinical need. Ornithine phenylacetate (OP) is a novel drug that is targeted at reducing ammonia concentration in patients with liver disease and therefore a potential treatment for HE. This review describes the mechanism of action of OP and its effect on plasma ammonia levels, brain function and inflammation of OP in both acute and chronic liver failure. Ammonia levels could shown to be reduced for up to 24 h in animal models until 120 h in patients with repeated dosing of the drug. Reduction of plasma ammonia levels is due to the stimulation of ammonia removal in the form of glutamine (through glutamine synthetase), the direct excretion of ammonia in the form phenylacetylglutamine and to a normalisation of glutaminase activity in the gut. Administration of OP is associated with a reduction of brain oedema in rats with chronic bile duct ligation and diminution of intracranial hypertension in a pig model of ALF. Studies to date have indicated that it is safe in humans and trials in overt HE are underway to establish OP as a treatment for this major complication of liver disease.

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Abbreviations

HE:

Hepatic encephalopathy

ALF:

Acute liver failure

CLF:

Chronic liver failure

Gln:

Glutamine

Glu:

Glutamate

GS:

Glutamine synthetase

OP:

Ornithinephenylacetate

GA:

Phosphate-activated glutaminase

PAGN:

Phenyl-acetyl-glutamine

BDL:

Bile duct ligation

PAGN:

Phenylacetylglutamine

AES:

Adverse events

FDA:

Food and drug administration

ISHEN:

International society for hepatic encephalopathy and nitrogen metabolism

iNOS:

Inducible nitrite oxide synthase

NF-kB:

Nuclear factor kappa B

LPS:

Lipopolysaccharide

ADMA:

Asymmetric dimethylarginine

cGMP:

Cyclic guanosine monophosphate

References

  • Acharya SK BV, Sreenivas V, Khanal S, Panda SK (2009) Efficacy of L-Ornithine L-Aspartate in acute liver failure: a doubleblind, randomized, placebo—controlled study. Gastroenterology In Press

  • Balasubramaniyan V, Davies NA, Wright G, Dalton RN, Turner C, Williams R, Jalan R, Mookerjee RP (2009) Treatment with infliximab increases E-Nos activity in cirrhosis through modulation of the Ddah-Adma pathway. J Hepatol 50:S270–S270

    Article  Google Scholar 

  • Balasubramaniyan V, Wright G, Sharma V, Davies NA, Sharifi Y, Habtesion A, Mookerjee RP, Jalan R (2012) Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 302:G145–G152

    Article  PubMed  CAS  Google Scholar 

  • Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP (2010) Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362:1071–1081

    Article  PubMed  CAS  Google Scholar 

  • Bosoi CR, Rose CF (2009) Identifying the direct effects of ammonia on the brain. Metab Brain Dis 24:95–102

    Article  PubMed  CAS  Google Scholar 

  • Cordoba R, Baturina TI, Sese J, Yu Mironov A, De Teresa JM, Ibarra MR, Nasimov DA, Gutakovskii AK, Latyshev AV, Guillamon I, Suderow H, Vieira S, Baklanov MR, Palacios JJ, Vinokur VM (2013) Magnetic field-induced dissipation-free state in superconducting nanostructures. Nature Commun 4:1437

    Article  CAS  Google Scholar 

  • Dadsetan S, Sorensen M, Bak LK, Vilstrup H, Ott P, Schousboe A, Jalan R, Keiding S, Waagepetersen HS (2012) Interorgan metabolism of ornithine phenylacetate (OP)-A novel strategy for treatment of hyperammonemia. Biochemical pharmacology

  • Davies NA, Wright G, Ytrebo LM, Stadlbauer V, Fuskevag OM, Zwingmann C, Davies DC, Habtesion A, Hodges SJ, Jalan R (2009) L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology 50:155–164

    Article  PubMed  CAS  Google Scholar 

  • Feillet F, Leonard JV (1998) Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis 21(Suppl 1):101–111

    Article  PubMed  CAS  Google Scholar 

  • Jalan R, Wright G, Davies NA, Hodges SJ (2007) L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses 69:1064–1069

    Article  PubMed  CAS  Google Scholar 

  • Jover-Cobos M, Noiret L, Habtesion A, Balasubramaniyan V, Sharifi Y, Romero-Gomez M, Davies N, Jalan R (2010) The mechanism behind synergistic action of l-ornithine and phenylacetate to reduce ammonia in Cirrhoticrats. Hepatology 52(Suppl):893A

    Google Scholar 

  • Kircheis G, Nilius R, Held C, Berndt H, Buchner M, Gortelmeyer R, Hendricks R, Kruger B, Kuklinski B, Meister H, Otto HJ, Rink C, Rosch W, Stauch S (1997) Therapeutic efficacy of L-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 25:1351–1360

    Article  PubMed  CAS  Google Scholar 

  • Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O’Hara B, Rossiter S, Anthony S, Madhani M, Selwood D, Smith C, Wojciak-Stothard B, Rudiger A, Stidwill R, McDonald NQ, Vallance P (2007) Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med 13:198–203

    Article  PubMed  CAS  Google Scholar 

  • Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2:725–734

    Article  PubMed  CAS  Google Scholar 

  • Moldave K, Meister A (1957) Synthesis of phenylacetylglutamine by human tissue. J Biol Chem 229:463–476

    PubMed  CAS  Google Scholar 

  • Montoliu C, Piedrafita B, Serra MA, del Olmo JA, Urios A, Rodrigo JM, Felipo V (2009) IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy. J Clin Gastroenterol 43:272–279

    Article  PubMed  CAS  Google Scholar 

  • Montoliu C, Rodrigo R, Monfort P, Llansola M, Cauli O, Boix J, Elmlili N, Agusti A, Felipo V (2010) Cyclic GMP pathways in hepatic encephalopathy. Neurological and therapeutic implications. Metab Brain Dis 25:39–48

    Article  PubMed  CAS  Google Scholar 

  • Mookerjee RP, Malaki M, Davies NA, Hodges SJ, Dalton RN, Turner C, Sen S, Williams R, Leiper J, Vallance P, Jalan R (2007) Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology 45:62–71

    Article  PubMed  CAS  Google Scholar 

  • Olde Damink SW, Deutz NE, Dejong CH, Soeters PB, Jalan R (2002a) Interorgan ammonia metabolism in liver failure. Neurochem Int 41:177–188

    Article  PubMed  CAS  Google Scholar 

  • Olde Damink SW, Jalan R, Redhead DN, Hayes PC, Deutz NE, Soeters PB (2002b) Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology 36:1163–1171

    Article  PubMed  CAS  Google Scholar 

  • Oria M, Chatauret N, Chavarria L, Romero-Gimenez J, Palenzuela L, Pardo-Yules B, Arranz JA, Bodega G, Raguer N, Cordoba J (2010) Motor-evoked potentials in awake rats are a valid method of assessing hepatic encephalopathy and of studying its pathogenesis. Hepatology 52:2077–2085

    Article  PubMed  Google Scholar 

  • Oria M, Romero-Gimenez J, Arranz JA, Riudor E, Raguer N, Cordoba J (2012) Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by intestinal blood in rats with portacaval anastomosis. J Hepatol 56:109–114

    Article  PubMed  CAS  Google Scholar 

  • Rama Rao KV, Jayakumar AR, Tong X, Alvarez VM, Norenberg MD (2010) Marked potentiation of cell swelling by cytokines in ammonia-sensitized cultured astrocytes. J Neuroinflammation 7:66

    Article  PubMed  Google Scholar 

  • Rees CJ, Oppong K, Al Mardini H, Hudson M, Record CO (2000) Effect of L-ornithine-L-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial. Gut 47:571–574

    Article  PubMed  CAS  Google Scholar 

  • Rodrigo R, Cauli O, Gomez-Pinedo U, Agusti A, Hernandez-Rabaza V, Garcia-Verdugo JM, Felipo V (2010) Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy. Gastroenterology 139:675–684

    Article  PubMed  CAS  Google Scholar 

  • Romero-Gomez M (2010) Pharmacotherapy of hepatic encephalopathy in cirrhosis. Expert Opin Pharmacother 11:1317–1327

    Article  PubMed  CAS  Google Scholar 

  • Romero-Gomez M, Ramos-Guerrero R, Grande L, de Teran LC, Corpas R, Camacho I, Bautista JD (2004) Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol 41:49–54

    Article  PubMed  CAS  Google Scholar 

  • Rose C, Michalak A, Rao KV, Quack G, Kircheis G, Butterworth RF (1999) L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure. Hepatology 30:636–640

    Article  PubMed  CAS  Google Scholar 

  • Rose C, Ytrebo LM, Davies NA, Sen S, Nedredal GI, Belanger M, Revhaug A, Jalan R (2007) Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure. Hepatology 46:1883–1892

    Article  PubMed  CAS  Google Scholar 

  • Rose CF (2012) Ammonia-lowering strategies for the treatment of hepatic encephalopathy. Clin Pharmacol Ther 92:321–331

    Article  PubMed  CAS  Google Scholar 

  • Shawcross D, Jalan R (2005) The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell Mol Life Sci 62:2295–2304

    Article  PubMed  CAS  Google Scholar 

  • Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40:247–254

    Article  PubMed  CAS  Google Scholar 

  • Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, Auzinger G, Bernal W, Wendon JA (2011) Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol 54:640–649

    Article  PubMed  CAS  Google Scholar 

  • Smith I (1981) The treatment of inborn errors of the urea cycle. Nature 291:378–380

    Article  PubMed  CAS  Google Scholar 

  • Ventura-Cots MS-TM, Torrens M, Arranz JA, Riudor E, Blanco A, Cordoba Cardona J (2012) Effects of ornithine penylacetate in patients with cirrhosis and upper gastrointestinal bleeding: an open-label, dose-escalating, single cohort study. Hepatology 56

  • Wong D, Dorovini-Zis K, Vincent SR (2004) Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood–brain barrier. Exp Neurol 190:446–455

    Article  PubMed  CAS  Google Scholar 

  • Wright G, Noiret L, Olde Damink SW, Jalan R (2011) Interorgan ammonia metabolism in liver failure: the basis of current and future therapies. Liver Int 31:163–175

    Article  PubMed  CAS  Google Scholar 

  • Wright G, Shawcross D, Olde Damink SW, Jalan R (2007) Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 22:375–388

    Article  PubMed  CAS  Google Scholar 

  • Wright G, Vairappan B, Stadlbauer V, Mookerjee RP, Davies NA, Jalan R (2012) Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic rats. Liver Int 32:410–419

    PubMed  CAS  Google Scholar 

  • Ytrebo LM, Kristiansen RG, Maehre H, Fuskevag OM, Kalstad T, Revhaug A, Cobos MJ, Jalan R, Rose CF (2009) L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure. Hepatology 50:165–174

    Article  PubMed  Google Scholar 

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Acknowledgments

Intra-European Fellowship Marie Curie in Seventh Framework Programme (FP7-PEOPLE- 2010-IEF number PIEF-GA-2010-272485). Ornithinephenlacetate has been provided by Ocera Therapeutics, San Diego, CA. The authors are grateful to Dr Nathan Davies and Dr Raj Mookerjee for helpful advice.

Conflict of interest

UCL have licensed ornithine phenylacetate to Ocera Therapeutics, USA.

Author information

Authors and Affiliations

  1. Liver Failure Group, UCL Institute for Liver and Digestive Health, The Royal Free Hospital, University College London, Pond Street, London, NW3 2PF, UK

    Maria Jover-Cobos, Lorette Noiret, Yalda Sharifi & Rajiv Jalan

  2. CoMPLEX, UCL, Gower Street, London, WC1E 6BT, United Kingdom

    Lorette Noiret

  3. Institute for Liver and Digestive Health, Liver Failure Group, UCL Institute of Hepatology, The Royal Free Hospital, Upper Third UCL Medical School, Pond Street, London, NW3 2PF, UK

    Rajiv Jalan

Authors
  1. Maria Jover-Cobos
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  2. Lorette Noiret
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  3. Yalda Sharifi
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  4. Rajiv Jalan
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Corresponding author

Correspondence to Rajiv Jalan.

Additional information

In this publication the term ammonia is referred to ammonium (NH4 +) and ammonia (NH3) indistinctly.

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Jover-Cobos, M., Noiret, L., Sharifi, Y. et al. Ornithine phenylacetate revisited. Metab Brain Dis 28, 327–331 (2013). https://doi.org/10.1007/s11011-013-9391-5

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  • DOI: https://doi.org/10.1007/s11011-013-9391-5

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