Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design

Staedt, U.; Leweling, H.; Gladisch, R; Kortsik, C; Hagmüller, E.; Holm, Eggert

doi:10.1016/s0168-8278(05)80553-7

Cited by 97 publications

(75 citation statements)

References 19 publications

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“…Consistent with the latter, alanine concentrations were found to be significantly increased both in plasma and CSF of OA-treated animals. In a study of the effects of OA on plasma amino acids in patients with cirrhosis, increases in plasma glutamate and alanine were also reported (Staedt et al, 1993) suggesting that amino acid changes similar to those observed in the present study occur in humans with chronic liver disease following OA treatment. Finally, increased glutamate availability would be expected to stimulate branched-chain amino acid (BCAA) aminotransferases resulting in increased synthesis (or decreased catabolism) of BCAAs.…”

Section: Discussionsupporting

confidence: 83%

“…However, few treatments of hyperammonemic syndromes have so far been designed to counteract the molecular actions of ammonia. Clinical studies have shown that L-ornithine-L-aspartate (OA) reduces blood ammonia concentrations and improves the clinical symptoms of HE in chronic liver disease (Staedt et al, 1993;Kircheis et al, 1997). However, the mechanism responsible for OA's ammonia-lowering action has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Rose

Michalak

Pannunzio

et al. 1998

Metabolic Brain Disease

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Strategies aimed at the lowering of blood ammonia remain the treament of choice in portal-systemic encephalopathy (PSE). L-ornithine-L-aspartate (OA) has recently been shown to be effective in the prevention of ammonia-precipitated coma in humans with PSE. These findings prompted the study of mechanisms of the protective effect of OA in portacaval-shunted rats in which reversible coma was precipitated by ammonium acetate administration (3.85 mmol/kg i.p.). OA infusions (300 mg/kg/h, i.v) offered complete protection in 12/12 animals compared to 0/12 saline-infused controls. This protective effect was accompanied by significant reductions of blood ammonia, concomitant increases of urea production and significant increases in blood and cerebrospinal fluid (CSF) glutamate and glutamine. Increased CSF concentrations of leucine and alanine also accompanied the protective effect of OA. These findings demonstrate the therapeutic efficacy of OA in the prevention of ammonia-precipitated coma in portacaval-shuntedrats and suggest that this protective effect is both peripherally-mediated (increased urea and glutamine synthesis) and centrally-mediated (increased glutamine synthesis).

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Untitled

Rose

Michalak

Pannunzio

et al. 1998

Metabolic Brain Disease

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“…The placebo solution contained riboflavin and polyethylene glythat OA can reduce blood ammonia and improve the sympcol to make the control solution identical to the OA infusate in aptoms and laboratory features of HE. [24][25][26][27] pearance, behavior, and viscosity. All patients were given a nutriExperimental and clinical findings in liver, muscle, and tious diet containing 1 g meat-vegetable dietary protein per kg body brain have provided new insights into the mechanisms of weight per day.…”

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confidence: 99%

“…The quantity of protein was divided at the test days action of these ''ammonia-lowering'' amino acids, especially among three main meals of the day in such a way that, as in a in the therapy of HE. These tissues are important target previous study, 27 the quantity of protein consumed with breakfast organs in the removal of ammonia in hyperammonemia. 14-was 0.25 g/kg body weight and that consumed with lunch was 0.5 g/ kg body weight.…”

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confidence: 99%

Therapeutic efficacy ofL-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: Results of a placebo-controlled, double-blind study

et al. 1997

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prandial venous ammonia concentrations in the OAOne hundred twenty-six patients with cirrhosis, hytreated group showed improvements in comparison perammonemia (ú50 mmol/L), and chronic (persistent) with placebo. In addition, venous fasting blood ammonia hepatic encephalopathy (HE), which developed spontaconcentration (P õ .01), mental state gradation (P õ neously without the existence of known precipitating .001), and PSEI (P õ .01), which includes the mental state factors, were enrolled in a randomized, double-blind, gradation, NCT-A time, and postprandial venous ammoplacebo-controlled clinical trial of intravenously adminnia in this trial, improved to a much higher degree in Hepatic encephalopathy (HE) is one of the major complicapresented are based on the total study sample (intent-to-tions of cirrhosis. Five years after the diagnosis of cirrhosis, treat analysis), which included 63 patients in the placebo the probability of developing at least one episode of this spegroup and 63 patients in the OA group. Of the 126 pa-cific form of decompensated cirrhosis is in the range of 26%. 1 tients, 114 met all the criteria for inclusion and com-Once clinical decompensation has occurred, however, the pleted the trial and treatment as outlined in the protocol prognosis (16% 1 to 22% 2 probability of survival at 5 years) (treated-per-protocol analysis). During baseline, the pla-compared with a survival probability of 55% 2 to 70% 1 in circebo and treatment groups were homogeneous with re-rhotic patients without HE is very poor. 1,2 Therefore, prevengard to mental states, NCT-A performance time, fasting tion and effective treatment of HE may have important progvenous blood ammonia levels, and Child-Pugh criteria. nostic implications in cirrhotic patients. Although a slight improvement occurred in the placeboHyperammonemia 3,4 by a variety of postulated mechagroup, NCT-A performance times (P õ .001) and post-nisms 3-8 is felt to be one of the primary pathogenetic factors in the development of HE. 8 The majority of therapeutic measures currently in use are therefore directed at reducing blood Abbreviations: HE, hepatic encephalopathy; SHE, subclinical hepatic encephalopathy; ammonia levels, 9-13 mainly by diminishing enteric ammonia OA, L-ornithine-L-aspartate; GS, glutamine synthetase; NCT-A, number connection test A; PSEI, portal systemic encephalopathy index.production. Otherwise, it is known that liver and muscle play From the 1 Martin-Luther-University Halle-Wittenberg, Department of Internal Median important part within the ammonia detoxification system, cine, Halle;

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“…Orn is also synthesized endogenously from amino acids including L-arginine, especially in the liver. In pharmacological therapy, Orn is used to decrease blood ammonia levels and reduce the symptoms of hepatic encephalopathy associated with liver cirrhosis (6). In addition, many human studies have indicated several beneficial effects of Orn, including attenuation of fatigue evoked by exercise or alcohol consumption (7,8), stimulation of growth hormone release (9), and improvements in sleep disturbance (10,11).…”

Section: Introductionmentioning

confidence: 99%

The Effect of L-Ornithine on the Phosphorylation of mTORC1 Downstream Targets in Rat Liver

Kokubo

Maeda

Tazumi

et al. 2015

JFN

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A non-protein amino acid, L-ornithine (Orn), has been shown to stimulate the urea cycle and tissue protein synthesis in the liver. The purpose of the current study was to assess whether Orn affects the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway, which is involved in protein synthesis. Primary cultured cells isolated from Wistar rat liver were incubated in an amino acid-free medium, followed by addition of Orn for 3 h. The cell lysate was subjected to immunoblotting to evaluate the phosphorylation of downstream targets of mTORC1, including p70S6K, S6, and 4EBP1. To assess the involvement of mTORC1 for the effect of Orn, the cells were pretreated with the mTOR inhibitor rapamycin before the addition of Orn and the cell lysate was subjected to immunoblotting. We next examined whether the effects of Orn were exerted in vivo. Orn was orally administered to 18 h food-deprived rats, the blood and the livers were collected at 1 and 3 h after administration for immunoblotting. Orn treatment for primary cultured cells for 3 h enhanced the phosphorylation of p70S6K, S6, and 4EBP1. In addition, rapamycin blocked the effects of Orn completely (p70S6K and S6) or partially (4EBP1). The oral administration of Orn to the rat also augmented the phosphorylation of mTORC1 downstream targets notably in S6 at 1 h. Our findings demonstrate that Orn has the potential to induce the phosphorylation of downstream targets of mTORC1 in the rat liver. This may be mediated by the augmentation of mTORC1 activity.

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Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a four-fold crossover design

Cited by 97 publications

References 19 publications

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Therapeutic efficacy ofL-ornithine-L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: Results of a placebo-controlled, double-blind study

The Effect of L-Ornithine on the Phosphorylation of mTORC1 Downstream Targets in Rat Liver

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