Application research of L-Ornithine-L-aspartate salt

Introduction

L-ornithine-L-aspartate salt (LOLA;Figure 1) is a compound used in the management of hepatic encephalopathy where it has shown significant efficacy. It is ingested as a crystalline salt with the L-ornithine and L-aspartate hydrogen bond separating on dissolution or exposure to gastric acidity. Both of these amino acids enter the urea cycle and, among other reactions, help to produce glutamine and urea, reducing the levels of ambient ammonia. Much of this activity takes place in liver, kidney and muscle. This makes it difficult to dissect the direct effects of L-ornithine-L-aspartate salt itself on brain metabolism from peripherally induced effects associated with plasma ammonia reduction. In healthy brain, the impact of L-ornithine-L-aspartate salt administration on brain metabolism remains largely unknown.[1]  LOLA maybe administered orally or parenterally. The benefits of LOLA for the lowering of blood ammonia and consequently for the treatment of hepatic encephalopathy (HE) have been known for 50 years. Within that time, numerous randomized clinical trials and an associated meta-analysis have been performed to establish the efficacy of L-ornithine-L-aspartate salt  for the treatment of HE in cirrhosis.[2] It is formulated and marketed in low and high doses. Low doses are used as a food supplement and high doses (above 5 g) as a medicinal product to lower blood ammonia concentration and to eliminate symptoms of hepatic encephalopathy associated with liver cirrhosis.

Impact on Brain Energy Metabolism

L-Ornithine-L-aspartate salt (LOLA) is used primarily in the management of hepatic encephalopathy. The degree to which it might penetrate the brain, and the effects it might have on metabolism in brain are poorly understood. Here, to investigate the effects of L-Ornithine-L-aspartate salt on brain energy metabolism we incubated brain cortical tissue slices from guinea pig (Cavea porcellus) with the constituent amino acids of L-Ornithine-L-aspartate salt, L-ornithine or L-aspartate, as well as L-Ornithine-L-aspartate salt, in the presence of [1-13C]D-glucose and [1,2-13C]acetate; these labelled substrates are useful indicators of brain metabolic activity. L-Ornithine produced significant "sedative" effects on brain slice metabolism, most likely via conversion of ornithine to GABA via the ornithine aminotransferase pathway, while L-aspartate showed concentration-dependent excitatory effects. The metabolic effects of L-Ornithine-L-aspartate salt reflected a mix of these two different processes and were concentration-dependent. Researchers also investigated the effect of an intraperitoneal bolus injection of L-ornithine, L-aspartate or LOLA on levels of metabolites in kidney, liver and brain cortex and brain stem in mice (C57Bl6J) 1 h later. No significant changes in metabolite levels were seen following the bolus injection of L-aspartate, most likely due to rapid metabolism of aspartate before reaching the target tissue. Brain cortex glutamate was decreased by L-ornithine but no other brain effects were observed with any other compound. Kidney levels of aspartate were increased after injection of L-ornithine and L-Ornithine-L-aspartate salt which may be due to interference by ornithine with the kidney urea cycle. It is likely that without optimising chronic intravenous infusion, L-Ornithine-L-aspartate salt has minimal impact on healthy brain energy metabolism due to systemic clearance and the blood - brain barrier.[1]

Pharmacokinetic and Pharmacodynamic Properties

L-Ornithine-L-aspartate salt is a colorless crystalline powder with the molecular formula C₉H₁₉N₃O₆ that is freely soluble in water and sparingly soluble in ethanol. LOLA, the stable salt of the naturally occurring amino acids l-ornithine and l-aspartate, is available in granular form in 5-g sachets, containing L-ornithine and L-Ornithine-L-aspartate salt 3.0 g and small amounts of additional ingredients including anhydrous citric acid, lemon favor, orange favor,sodium saccharine, sodium cyclamate, yellow orange dye S(E 110), poly [1-vinyl-2-pyrolidone] and laevulose. L-ornithine and L-Ornithine-L-aspartate salt is also available for injection as a 50% solution in 10.0 mL ampoules containing LOLA 5.0 g in water.

Systematic pharmacokinetic and pharmacodynamic studies in experimental models of liver failure and in patients have resulted in a clear understanding of the mechanisms that underpin the effective ammonia-lowering actions of LOLA. Transformations of the constituent amino acids of LOLA either via the hepatic urea cycle into urea per se or into glutamine via glutamine synthetase expressed by perivenous hepatocytes, brain, and skeletal muscle afford multiple pathways whereby ammonia is readily removed. The efficacy of LOLA for ammonia reduction and concomitant improvements in HE has been substantiated in randomized clinical trials and a meta-analysis. Moreover, recent studies provide evidence to suggest that LOLA may also have protectiveness properties and may assist in the prevention of sarcopenia in patients with cirrhosis.

Treatment of cirrhotic rats with L-ornithine and L-Ornithine-L-aspartate salt

CCl4-induced cirrhosis of rats was used for studying the influence of L-ornithine and L-Ornithine-L-aspartate salt on hyperammonemia. LOLA given to cirrhotic rats (2 g/kg daily) for 2 wk slightly increased net body weight and led to a significant increase in plasma urea levels and a decrease in plasma ammonia levels. Serum concentrations of glutamate, glutamine and arginine decreased significantly. In the livers of the LOLA-treated rats the activities of carbamoylphosphate synthetase I and arginase increased by 30 and 40%, respectively, approaching normal levels. No change in the activities of the other urea cycle enzymes as well as of glutamate dehydrogenase, glutaminase and glutamine synthetase was found. The negative correlation between glutamine synthetase activity and plasma ammonia levels reported previously for cirrhotic rats was corroborated for cirrhotic animals not treated with L-ornithine and L-Ornithine-L-aspartate salt, but was no longer apparent in LOLA-treated cirrhotic rats. Despite this improvement, plasma ammonia levels still varied considerably reflecting the variable accessibility and activities of glutamine synthetase in cirrhotics. Cultured hepatocytes from the two groups of rats showed a similar stimulation of urea production by addition of ammoniumacetate and/or LOLA to Hanks' buffered salt solution. In Williams medium E, however, the hepatocytes from the L-ornithine and L-Ornithine-L-aspartate salt group produced significantly more urea than those from controls. These results suggest that treatment of cirrhotic rats with LOLA considerably improves urea production favoring the detoxification of ammonia that, however, is still limited by the severe alterations in liver architecture that are not influenced by L-ornithine and L-Ornithine-L-aspartate salt in a 2-wk period.[3]

Efficacy of administration of L-ornithine-L-aspartate salt in conditions of relative deficiency

Administration of L-Ornithine-L-aspartate salt in high doses reduced high blood ammonia induced either by ammonium chloride or protein ingestion or existing as a clinical complication of cirrhosis. In health and with proper diet, L-ornithine and L-aspartate are synthesized de novo in sufficient quantities, but in the states of disease, tissue damage, organ insufficiency, excessive metabolic demand, growth, pregnancy, or urea cycle enzyme deficiencies, these amino acids need to be supplemented with the food. The review of available data indicate that there is direct and indirect (resulting from physiology) scientific rationale for dietary use of L-Ornithine-L-aspartate salt, depending on an individual's physiological, metabolic or pathological conditions. In conditional ornithine deficiency, daily supplementation with L-Ornithine-L-aspartate salt at doses about 1 g/day is safe and, as demonstrated in vitro, should be sufficient to saturate tissue ornithine concentration to prevent postprandial hyperammonemia and to stimulate tissue regeneration.[4]

References

[1] Das A, Fröhlich D, Achanta LB, et al. L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism. Neurochem Res. 2020;45(6):1438-1450. doi:10.1007/s11064-020-03044-9

[2] Kircheis G, Lüth S. Pharmacokinetic and Pharmacodynamic Properties of L-Ornithine L-Aspartate (LOLA) in Hepatic Encephalopathy. Drugs. 2019;79(Suppl 1):23-29. doi:10.1007/s40265-018-1023-2

[3] Gebhardt R, Beckers G, Gaunitz F, et al. Treatment of cirrhotic rats with L-ornithine-L-aspartate enhances urea synthesis and lowers serum ammonia levels. J Pharmacol Exp Ther. 1997;283(1):1-6.

[4] Sikorska H, Cianciara J, Wiercińska-Drapało A. Fizjologiczne funkcje L-ornityny i L-asparaginianu oraz celowość podawania asparaginianu ornityny w stanach wzglednego niedoboru [Physiological functions of L-ornithine and L-aspartate in the body and the efficacy of administration of L-ornithine-L-aspartate in conditions of relative deficiency]. Pol Merkur Lekarski. 2010;28(168):490-495. 

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