L-Ornithine-L-Aspartate 5g/10ml solution for infusion ampoules

This manuscript represents an appraisal of the evidence in support of L-ornithine-L-aspartate (LOLA) for the management and treatment of hepatic encephalopathy (HE) in cirrhosis. Meta-analyses of randomized controlled trials (RCTs) conducted over the last two decades generally reveal evidence of benefit of LOLA in a range of clinical presentations. This included improvement of mental state grade in overt HE (OHE) assessed by West Haven criteria as well as in minimal HE (MHE) assessed by psychometric testing where the oral formulation of LOLA was determined to be particularly effective. However, concerns over study quality were noted in one meta-analysis. Nevertheless, the concomitant lowering of fasting blood ammonia was reported in all RCTs using this endpoint. Network meta-analyses showed that LOLA appears to be comparable (or superior) in efficacy to non-absorbable disaccharides or probiotics. Emerging evidence from single RCTs show efficacy of LOLA for the treatment of post-transjugular intrahepatic portosystemic shunt (TIPSS) HE as well as for secondary HE prophylaxis. These findings provide support for the use of LOLA in the treatment of HE and future trials should focus on the use of LOLA for prophylaxis.

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BACKGROUND: Hepatic encephalopathy is a common complication of cirrhosis and has high associated morbidity and mortality. The condition is classified as overt if it is clinically apparent or minimal if only evident though psychometric testing. The exact pathogenesis of this syndrome is unknown although ammonia is thought to play a key role. L-ornithine L-aspartate has ammonia-lowering properties and may, therefore, benefit people with cirrhosis and hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of L-ornithine L-aspartate versus placebo, no intervention, or other active interventions in people with cirrhosis and hepatic encephalopathy. SEARCH METHODS: We undertook electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS and Science Citation Index Expanded to December 2017 and manual searches of meetings and conference proceedings; checks of bibliographies; and corresponded with investigators and pharmaceutical companies. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, or blinding. We included participants with cirrhosis who had minimal or overt hepatic encephalopathy or who were at risk for developing hepatic encephalopathy. We compared: L-ornithine L-aspartate versus placebo or no intervention; and L-ornithine L-aspartate versus other active agents such as non-absorbable disaccharides, antibiotics, probiotics, or branched-chain amino acids. DATA COLLECTION AND ANALYSIS: Two review authors, working independently, retrieved data from published reports and correspondence with investigators and pharmaceutical companies. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented the results as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed bias control using the Cochrane Hepato-Biliary Group domains; we evaluated the risk of publication bias and other small trial effects in regression analyses; conducted subgroup and sensitivity analyses; and performed Trial Sequential Analyses. We determined the quality of the evidence using GRADE. MAIN RESULTS: = 0%); hepatic encephalopathy (RR 1.13, 95% CI 0.81 to 1.57); serious adverse events (RR 0.69, 95% CI 0.22 to 2.11); or non-serious adverse events (RR 0.05, 95% CI 0.01 to 0.18). In comparison with probiotics, L-ornithine L-aspartate had no effect on mortality (RR 1.01, 95% CI 0.11 to 9.51); serious adverse events (RR 1.07, 95% CI 0.23 to 4.88); or changes in blood ammonia concentrations from baseline (RR -2.30 95% CI -6.08 to 1.48), but it had a possible beneficial effect on hepatic encephalopathy (RR 0.71, 95% CI 0.56 to 0.90). Finally, in comparison with rifaximin, L-ornithine L-aspartate had no effect on mortality (RR 0.33, 95% CI 0.04 to 3.03; 2 trials; 105 participants); hepatic encephalopathy (RR 1.06, 95% CI 0.57 to 1.96); serious adverse events (RR 0.32, 95% CI 0.01 to 7.42), or non-serious adverse events (RR 0.32, 95% CI 0.01 to 7.42). AUTHORS' CONCLUSIONS: The results of this review suggest a possible beneficial effect of L-ornithine L-aspartate on mortality, hepatic encephalopathy, and serious adverse events in comparisons with placebo or no-intervention, but, because the quality of the evidence is very low, we are very uncertain about these findings. There was very low quality evidence of a possible beneficial effect of L-ornithine L-aspartate on hepatic encephalopathy, when compared with probiotics, but no other benefits were demonstrated in comparison with other active agents. Additional access to data from completed, but unpublished trials, and new randomised placebo-controlled, double-blind clinical trials are needed.

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INTRODUCTION: While hyperammonemia is traditionally associated with decompensated cirrhosis, emerging evidence suggests that disturbances in nitrogen homeostasis contribute to disease progression in earlier stages of steatohepatitis and fibrosis. L-ornithine L-aspartate (LOLA), an established ammonia scavenger, targets key pathophysiological mechanisms shared by metabolic dysfunction-associated steatotic liver disease (MASLD), including oxidative stress, mitochondrial dysfunction and hepatic stellate cell activation. This systematic review synthesizes current experimental and clinical research to evaluate the potential therapeutic role of LOLA in MASLD. METHODS: A systematic search of PubMed, Embase and SCOPUS was conducted up to December 1, 2025, following PRISMA 2020 guidelines. Eligible studies included experimental (in vivo/in vitro) and clinical trials evaluating the effects of LOLA or L-aspartate on hepatic steatosis, inflammation, or fibrosis in the context of MASLD. Data extraction and quality assessment were performed independently by two reviewers using appropriate tools for animal and human studies. RESULTS: Nineteen studies were included, comprising 10 experimental pre-clinical models (9 in vivo animal studies and 1 in vitro study) and 9 clinical studies involving approximately 1671 participants. Experimental studies consistently demonstrated that LOLA intervention ameliorates hepatic steatosis, inflammation and collagen deposition. Identified molecular mechanisms included the activation of the LKB1-AMPK axis, restoration of mitochondrial bioenergetics and modulation of the gut-liver-muscle axis. In clinical studies, results from three randomized controlled trials (RCTs) indicated significant improvements in liver enzymes (ALT, AST) and lipid profiles, with reductions in hepatic steatosis. Evidence from six observational and open-label studies corroborated these biochemical improvements and further demonstrated significant reductions in blood ammonia levels, improved intrahepatic microcirculation and reduced liver stiffness and patient-reported fatigue. However, clinical evidence remains limited by study heterogeneity and a lack of large-scale randomized trials using specific MASLD criteria. CONCLUSIONS: Preclinical evidence suggests that LOLA exerts pleiotropic hepatoprotective effects in MASLD by targeting hyperammonemia-induced fibrosis and metabolic dysregulation. While growing clinical data indicate benefits in biochemical normalization, structural improvement and symptom relief, further robust clinical research is required to validate these findings and establish LOLA as a standard therapeutic option for MASLD patients.

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Background Hepatic encephalopathy (HE) represents a collection of metabolic disturbances and regulatory imbalances within the central nervous system that result from advanced liver conditions. Purpose This article explores the efficacy and safety evaluation of L-ornithine L-aspartate (LOLA) combined with lactulose in the treatment of hepatic encephalopathy based on meta-analysis, providing a rational reference for clinical medication use. Methods Following the PICOS principle, we searched for literature on the treatment of hepatic encephalopathy with Ornithine aspartate combined with lactulose. The literature search was conducted up to and including September 21, 2024. For studies that met the criteria, the Review Manager 5.4 software was used to perform a meta-analysis. Results A total of 12 articles were ultimately included, involving 858 patients, with 433 in the treatment group and 425 in the control group. Meta-analysis results: In terms of the total effective rate (RR: 1.31, 95%CI: 1.22, 1.42), the result is statistically significant ( Z = 7.15, P = 0.00001 < 0.05), and for AST, ALT, NH3, TBIL, P = 0.00001 < 0.05. The pooled (RR: 1.31 [95% CI = 1.22, 1.42]), which is statistically significant, LOLA and Lactulose is 31% more effective than Lactulose alone in the control group in treating HE. Conclusion This study indicates that the combination of LOLA and lactulose in the treatment of hepatic encephalopathy has a higher total effective rate in clinical practice and can significantly reduce the levels of AST, ALT, TBIL, and NH3. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD42024592957.

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Minimal hepatic encephalopathy (MHE) is an early stage of hepatic encephalopathy (HE) and is highly prevalent. The efficacy of L-ornithine L-aspartate (LOLA) for the treatment of HE is well known but its role in MHE remains uncertain. The objectives of the current study were to evaluate the efficacy of LOLA for the treatment of MHE in patients with cirrhosis. The Cochrane Library, PubMed, EMBASE, Web of Science and Ovid databases were searched. Only randomized controlled trials (RCTs) that compared the efficacy of LOLA with placebo or no intervention for the treatment of MHE in patients with cirrhosis were included from inception to January 2023. The primary outcomes were reversal of MHE and development of overt hepatic encephalopathy (OHE). Overall, six RCTs comprising 292 patients were included. Compared with placebo or no intervention, LOLA was more effective in reversing MHE (RR = 2.264, 95 % CI = 1.528, 3.352, P = 0.000, I 2 = 0.0 %) and preventing progression of OHE (RR = 0.220, 95 % CI = 0.076, 0.637, P = 0.005, I 2 = 0.0 %). Based on subgroup analyses, oral LOLA treatment appeared more likely to reverse MHE (RR = 2.648, 95 % CI = 1.593, 4.402, P = 0.000, I 2 = 0.0 %), intravenous LOLA treatment yielded a similar probability of reversing MHE (RR = 1.669, 95 % CI = 0.904, 3.084, P = 0.102, I 2 = 0.0 %). LOLA did not show a superior possibility in reducing mortality (RR = 0.422, 95 % CI = 0.064, 2.768, P = 0.368, I 2 = 0.0 %) and ammonia levels (SMD = 0.044, 95 % CI = -0.290, 0.379, P = 0.795, I 2 = 0.0 %) compared with placebo or no intervention. LOLA has significant beneficial effects on reversal of MHE and prevention of OHE in patients with cirrhosis compared with placebo or no intervention.

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The present systematic review with meta-analysis was undertaken to review the evidence base in support of a beneficial effect of L-ornithine L-aspartate (LOLA) for the prevention/prophylaxis of overt hepatic encephalopathy (OHE) in patients with cirrhosis. Using appropriate keywords and electronic and manual searches together with established inclusion/exclusion criteria, six randomized controlled trials (RCTs) for a total of 384 patients were identified five of which were of high quality and low risk of bias according to Jadad-Cochrane criteria. Treatment with LOLA resulted in significant reductions in the risk of progression to OHE in MHE patients (3 studies) with RR: 0.23 [95% CI: 0.07, 0.73], p < 0.01. LOLA was also effective for secondary OHE prophylaxis with RR: 0.389 [95% CI: 0.174-0.870] p < 0.002 as well as for primary prophylaxis for OHE following acute variceal bleeding [RR: 0.42 [95% CI: 0.16-0.98] p < 0.03 and for OHE prophylaxis post-TIPSS [RR: 0.30 [95% CI: 0.03-2.66] compared to placebo/no intervention in all cases. OHE prevention/prophylaxis was accompanied by significant reductions of blood ammonia. Both oral and intravenous formulations of LOLA appeared to be effective for the prevention of progression to OHE in patients with MHE. These findings provide the first direct evidence of potential benefit of LOLA for the prevention of OHE in cirrhosis across a range of clinical presentations.

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