Rune Gangsøy Kristiansen

Glycine and hyperammonemia: potential target for the treatment of hepatic encephalopathy.

Rune Gangsøy Kristiansen, Christopher F. Rose, Lars Marius Ytrebø.

L-Ornithine Phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway.

Rune Gangsøy Kristiansen, Christopher Rose, Ole Martin Fuskevåg, Hanne Mæhre, Arthur Revhaug, Rajiv Jalan, Lars Marius Ytrebø.

L-Ornithine Phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway.

Rune Gangsøy Kristiansen, Christopher F. Rose, Ole-Martin Fuskevåg, Hanne Mæhre, Arthur Revhaug, Rajiv Jalan, Lars Marius Ytrebø.

OpenAccess

L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway.

Rune Gangsøy Kristiansen, Christopher F. Rose, Ole-Martin Fuskevåg, Hanne Mæhre, Arthur Revhaug, Rajiv Jalan, Lars Marius Ytrebø.

OpenAccess

Neuropathological changes in the brain of pigs with acute liver failure.

Rune Gangsøy Kristiansen, Sigurd Lindal, Kate Myreng, Arthur Revhaug, Lars Marius Ytrebø, Christopher F. Rose.

OpenAccess

L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure.

Lars Marius Ytrebø, Rune Gangsøy Kristiansen, Hanne Maehre, Ole Martin Fuskevåg, Trine Kalstad, Arthur Revhaug, María Jover Cobos, Rajiv Jalan, Christopher F. Rose.

Ultrastructural changes of the brain in pigs with acute liver failure.

Lars M. Ytrebø, L. Sigurd, K. Myreng, Rune G. Kristiansen, Arthur Revhaug, Christopher F. Rose.

L-ornithine phenylacetate attenuates increase in arterial ammonia and intracranial pressure in a devascularised pig model of acute liver failure: A novel ammonia-lowering strategy for hepatic encephalopathy.

Lars M. Ytrebø, Rune Gangsøy Kristiansen, Ole Martin Fuskevåg, Hanne Maehre, Arthur Revhaug, Rajiv Jalan, Christopher Rose.

Ammonia is central in the pathogenesis of HE and its arterial levels predict brainstem herniation which accounts for mortality in about 30% of patients with ALF. Treatment options for hyper- ammonemia and raised intracranial pressure (ICP) in ALF remain unmet clinical needs. Ammonia levels in liver failure are regulated by the critical interplay of ammonia, glutamate and glutamine metabolism involving the muscle, gut and kidneys. Based on this knowledge, we have formulated L-Ornithine Phenylacetate (OP), a novel concept to reduce plasma ammo- nia. L-Ornithine stimulates ammonia removal through glutamine synthetase (glutamine production) in skeletal muscle and pheny- lacetate excretes the ornithine-related glutamine as pheny- lacetylglutamine in the urine. To evaluate the therapeutic efficacy of OP, pigs with ALF (induced by liver devasculariza- tion) were treated with L-ornithine 0.05g/kg/hr (i.v) and phenylbutyrate (pro-drug) 0.07g/kg/hr (i.g) and compared to pigs with ALF (vehicle treated) and shams. ICP and ca^rdiovas- cular hemodynamics were continuously monitored for the dura- tion of the experiment (8 hours) following liver devascularization. Arterial blood and urine was sampled every 2 hours to measure ammonia and phenylacetylglutamine respectively. A lumbar puncture cerebrospinal fluid (CSF) sam- ple was taken at the end of the experiment to measure ammo- nia. Over 8 hours, arterial concentrations of ammonia did not change significantly in the sham group (50.7±8.7 µmol/L), but in the ALF group it increased to 589.6±56.7µmol/L (p<0.001 compared to sham). This increase was attenuated in the OP- treated group (365.2±60.4µmol/L, p<0.01 compared to ALF). Furthermore, ICP (expressed as percent baseline) did not change in the sham group (18.2±14.9%), but increased signi- ficantly in the ALF group (98.5±9.1%, p<0.01 compared to sham). In the ALF+OP-treated group, ICP was normalized (25.5±17.3%, p<0.05 compared to ALF). This was accompa- nied with a reduction in CSF ammonia in the ALF-OP treated pigs compared to ALF pigs (158.50±29.01µmol/L vs 233.50±39.51µmol/L respectively). In acco^rdance with the hypothesis, treatment with OP resulted in increased urine phenylacetylglutamine levels in ALF-OP treated pigs compared to ALF pigs (9.0±4.5µmol/L vs 0.05±0.04µmol/L). In conclu- sion, OP is a novel approach to treat hyperammonemia and HE, which successfully attenuated an increase in arterial and CSF concentrations of ammonia and, normalized ICP in this large-animal model of ALF. These positive results demonstrating its efficacy in pigs with ALF provides the rationale for further development of this drug and a clinical trial of OP in ALF.

L-ornithine phenylacetate attenuates increase in arterial ammonia and intracranial pressure in a devascularised pig model of acute liver failure: A novel ammonia-lowering strategy for hepatic encephalopathy.

Lars M. Ytrebø, Rune Gangsøy Kristiansen, Ole Martin Fuskevåg, Hanne Maehre, Arthur Revhaug, Rajiv Jalan, Christopher Rose.

Oral

L-ornithine phenylacetate attenuates increase in arterial ammonia and intracranial pressure in a devascularised pig model of acute liver failure: A novel ammonia-lowering strategy for hepatic encephalopathy.

Christopher *Rose, Lars M. Ytrebø, Rune Gangsøy Kristiansen, Ole Martin Fuskevåg, Hanne Maehre, Arthur Revhaug, Rajiv Jalan, Christopher Rose.

In patients with acute liver failure, the occurrence of hepatic encephalopathy (HE) defines poor prognosis. Ammonia is central in the pathogenesis of HE and its arterial levels predict brainstem herniation which accounts for mortality in about 30% of patients with acute liver failure. A Cochrane-metanalysis concluded the lack of proof for any available therapy for HE and placebo controlled clinical trials in HE are justified. Studies on interorgan metabolism suggest that ammonia levels in liver failure are regulated by the critical interplay of ammonia, glutamate and glutamine metabolism involving the muscle, gut and kidneys. Based on this knowledge, we have formulated a novel concept to reduce plasma ammonia, L-Ornithine Phenylacetate (OP). L-Ornithine stimulates ammonia removal through glutamine synthetase (glutamine production) in skeletal muscle and phenylacetate excretes the ornithine-related glutamine as phenylacetylglutamine in the urine. To evaluate the therapeutic efficacy of OP, groups of pigs with ALF (induced by liver devascularization) were treated with L-ornithine 0.05 g/kg/hr (i.v) and phenylacetate 0.07 g/kg/hr (i.g). Over 8 hours, ICP (expressed as percent baseline) did not rise significantly in the sham group (23.2±14.6%), but increased significantly in the ALF group (102.8±18.4%, p<0.01 compared to sham). In the ALF+OP-treated group, increased ICP was attenuated (46.3±35.7%, p<0.05 compared to ALF). Arterial concentrations of ammonia did not change significantly in the sham group over 8 hours (34.6±3.8 µmol/L), but in the ALF group it increased to 676.3±46.1 µmol/L (p<0.001 compared to sham). This increase was attenuated in the OP-treated group (230.9±67.8 µmol/L, p<0.01 compared to ALF). In conclusion, OP, a novel approach to treating hyperammonemia and HE, successfully attenuated an increase in arterial concentrations of ammonia and ICP in this large-animal model of ALF. As both L-ornithine and phenylacetate are already available for human use, this data showing its usefulness in pigs with ALF could translate quickly into providing the much needed therapy for HE patients.

Rune Gangsøy Kristiansen, MD, Ph.D.

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