Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Davies, NA; Wright, G; Ytrebø, LM; Stadlbauer, V; Fuskevåg, OM; Zwingmann, C; Davies, DC; Habtesion, A; Hodges, SJ; Jalan, R.
L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats.
Hepatology. 2009; 50(1): 155-164.
Doi: 10.1002/hep.22897
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- Stadlbauer-Köllner Vanessa
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- Abstract:
- Treatment of hyperammonemia and hepatic encephalopathy in cirrhosis is an unmet clinical need. The aims of this study were to determine whether L-ornithine and phenylacetate/phenylbutyrate (administered as the pro-drug phenylbutyrate) (OP) combined are synergistic and produce sustained reduction in ammonia by L-ornithine acting as a substrate for glutamine synthesis, thereby detoxifying ammonia, and the phenylacetate excreting the ornithine-derived glutamine as phenylacetylglutamine in the urine. Sprague-Dawley rats were studied 4 weeks after bile duct ligation (BDL) or sham operation. Study 1: Three hours before termination, an internal carotid sampling catheter was inserted, and intraperitoneal saline (placebo), OP, phenylbutyrate, or L-ornithine were administered after randomization. BDL was associated with significantly higher arterial ammonia and brain water and lower brain myoinositol (P < 0.01, respectively), compared with sham-operated controls, which was significantly improved in the OP-treated animals; arterial ammonia (P < 0.001), brain water (P < 0.05), brain myoinositol (P < 0.001), and urinary phenylacetylglutamine (P < 0.01). Individually, L-ornithine or phenylbutyrate were similar to the BDL group. In study 2, BDL rats were randomized to saline or OP administered intraperitoneally for 6 hours or 3, 5, or 10 days and were sacrificed between 4.5 and 5 weeks. The results showed that the administration of OP was associated with sustained reduction in arterial ammonia (P < 0.01) and brain water (P < 0.01) and markedly increased arterial glutamine (P < 0.01) and urinary excretion of phenylacetylglutamine (P < 0.01) in each of the OP treated groups. Conclusion: The results of this study provide proof of the concept that L-ornithine and phenylbutyrate/phenylacetate act synergistically to produce sustained improvement in arterial ammonia, its brain metabolism, and brain water in cirrhotic rats.
- Find related publications in this database (using NLM MeSH Indexing)
- Ammonia - metabolism
- Animals -
- Body Water - drug effects Body Water - metabolism
- Brain - drug effects Brain - metabolism
- Drug Synergism -
- Liver Cirrhosis - metabolism
- Male -
- Ornithine - pharmacology
- Phenylacetates - pharmacology
- Phenylbutyrates - pharmacology
- Rats -
- Rats, Sprague-Dawley -