L-Ornithine and phenylacetate: A novel and effective therapy for hepatic encephalopathy

Background: The major therapeutic target for the treatment of hepatic encephalopathy is ammonia. Our extensive investigations in animal models and also in humans with cirrhosis support the view that the major organ removing ammonia in patients with cirrho sis is the muscle, converting ammonia to glutamine, a reaction in which glutamate is utilised. In liver failure, the enzyme responsible for this reaction, glutamine synthetase is induced and the provision of glutamate would increase ammonia detoxification . Ornithine, a precursor of glutamate, detoxifies ammonia through amidation to glutamine. However, our preliminary studies have shown that this glutamine recirculates and regenerates ammonia. Preliminary studies using our novel compound L-Ornithine Phenyl acetate (OP) suggests that Ornithine is transaminated to glutamate in the muscle which provides the substrate for the formation of glutamine. This glutamine formed, carrying a molecule of ammonia, is excreted by Phenylacetate in the urine as the compound Phenylacetylglutamine. Aims: This proposal will test the hypothesis that in pigs with acute liver failure this compound produces sustained reduction in ammonia and define the operative mechanisms and will determine whether this reduction in ammonia with OP is associated with attenuation in the rise in intracranial pressure and brain water. Methods: Randomised sham and acute liver failure pigs will be studied following administration of L-Ornithine, Phenylacetate, OP or placebo. We will monitor these pig s invasively and sample the brain, muscle, gut and the kidneys following infusion of stable isotopes to determine the mechanism through which OP reduces ammonia concentrations. In order to study the brain effects of OP and determine the pathophysiologic b asis of therapy, we will measure changes in the intracranial pressure and brain water. Impact on Clinical Practice: It is likely that this OP compound has the potential to treat hepatic encephalopathy.