Therapeutic Efficacy of L-Ornithine L-Aspartate Infusion in Patients With Acute Liver Failure

12:51 EDT 2nd September 2014 | BioPortfolio

Summary

The purpose of the study is to determine whether L-Ornithine L-Aspartate infusion improves the survival of patients with acute liver failure.

Description

Acute liver failure (ALF) has a high mortality. However, those who survive recover completely without any sequel. Liver transplantation is logistically and financially difficult in most countries with the highest disease burden. It also entails a lifelong commitment to immunosuppression. We therefore need new treatment options to improve the survival of medically managed patients with ALF.

Ammonia is believed to be the major neurotoxin in ALF. There is experimental evidence of direct and indirect ammonia neurotoxicity in ALF. The brain does not have a urea cycle, and relies on glutamine synthesis in the astrocytes for removal of excess ammonia. Increased intracellular glutamine in the astrocytes leads to cellular swelling. Increased brain ammonia concentrations also result in altered expression of key astrocyte proteins including glial fibrillary acidic protein, glutamate and glycine transporters and "peripheral-type" (mitochondrial) BZD receptors. Accumulation of ammonia in brain results in a redistribution of cerebral blood flow from cortical to sub-cortical structures, and also has direct effects on neurotransmission. Increased ammonia concentration upregulates the peripheral-type benzodiazepine (PTBR) receptors in the outer membrane of astroglial mitochondria, and enhance the synthesis and release of neurosteroids, some of which are known GABA (A) receptor agonists.

There is now evidence of high blood ammonia levels in ALF , with a substantial blood-to-brain ammonia transfer.Brain-blood ammonia concentration ratios (normally of the order of 2) are increased up to 4 fold in liver failure. Higher ammonia levels have been co-related with higher mortality and complications in human clinical trials. Clemmesen et al found that ALF patients who died of cerebral herniation had higher ammonia levels as compared to the survivors. We have also previously shown that higher ammonia levels at admission predicts a poorer survival rate, and arterial ammonia levels are an independent predictor of mortality by logistic regression analysis. An arterial ammonia level of > 124 μmol/l was found to predict mortality with 78.6% sensitivity and 76.3% specificity.There is thus a strong rationale for using ammonia lowering therapies in ALF.

LOLA is a compound salt of Ornithine and Aspartate. The mechanism of its ammonia lowering action has been defined. LOLA provides critical substrates for both urea and glutamine synthesis- the key pathways of ammonia detoxification in the liver. Urea synthesis is carried out in a low affinity, high capacity system that exists largely in the periportal hepatocytes. In these cells, Ornithine serves as an activator of ornithine-carbamoyltransferase and carbamylphosphate-synthetase. In addition, Ornithine itself acts as a substrate for urea genesis. Hence LOLA can activate the periportal urea cycle. Glutamine synthesis is a high affinity, relatively low capacity system located in the perivenous hepatocytes. Ornithine is converted to α -ketoglutarate, and taken up by these perivenous hepatocytes and serves as a carbon source for glutamine synthesis. LOLA also upregulates glutamine synthesis in the skeletal muscle via glutamine synthetase (GS). Recently, in animal models an increased transport of ornithine across the blood brain barrier and an increase in the brain glutamine synthesis after LOLA treatment has been described, and suggests that LOLA may have both centrally (CNS) and peripherally mediated effects. , LOLA has been shown to reduce raised ammonia levels in experimental models of hyper-ammonemia, and in human cirrhotic patients. In patients with cirrhosis,LOLA improves psychometric performance and improves the mental status.

LOLA is therefore a promising agent for use in ALF patients. It has scientific rationale and has been found to be effective in cirrhosis. There is however only a single experimental study of LOLA in a rat model of acute liver injury. LOLA infusion could normalize the plasma ammonia and lead to a significant reduction in brain water content. We would like to study whether LOLA infusion in patients with ALF can reduce ammonia levels and improve survival.

Study Design

Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Conditions

Acute Liver Failure

Intervention

L-Ornithine L-Aspartate

Location

All India Institute of Medical Sciences
Delhi
India

Status

Active, not recruiting

Source

All India Institute of Medical Sciences, New Delhi

Results (where available)

View Results

Links

Clinical Trials [1212 Associated Clinical Trials listed on BioPortfolio]

Efficacy of L-Ornithine-L-Aspartate in Acute Hepatic Encephalopathy

Hepatic encephalopathy is caused by the effects on the brain of substances that under normal circumstances are efficiently metabolized in the liver. The hyperammonemia is the main factor r...

Therapeutic Efficacy of Oral L-Ornithine-L-Aspartate on Minimal Encephalopathy

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Efficacy of L-Ornithine-L-Aspartate in Cirrhotics With Hepatic Encephalopathy

The purpose of this study is to determine whether L-Ornithine L-Aspartate is effective for the improvement of Overt Hepatic Encephalopathy.

Efficacy of Combined Oral L-Ornithine-L-Aspartate and Lactulose in Patients With Hepatic Encephalopathy

Hypothesis: Is the combination of oral L-ornithine-L-aspartate and lactulose more efficacious than oral lactulose alone in treatment of hepatic encephalopathy? Study design; Randomized, do...

A Multi-Center Trial to Study Acute Liver Failure in Adults

The purpose of this study is to collect clinical and epidemiological data as well as serum, plasma, urine, tissue and DNA samples on individuals who have acute liver failure and on individ...

PubMed Articles [14170 Associated PubMed Articles listed on BioPortfolio]

Ornithine Transcarbamylase Deficiency Presenting With Acute Reversible Cortical Blindness.

Acute focal neurologic deficits are a rare but known presentation of ornithine transcarbamylase deficiency, particularly in females. We describe here a 6-year-old girl with newly diagnosed ornithine t...

Liver Transplantatation- an Overview.

Liver transplantation is a therapeutic option of choice for acute and chronic end-stage liver disease. Indications, contraindications, and surgical procedures for the liver transplantation have become...

Liver Transplantation during Pregnancy for Acute Liver Failure due to HBV Infection: A Case Report.

Acute hepatic failure during pregnancy is a life-threatening situation for the mother and fetus and might need a super-urgent liver transplantation. Many pregnancies with positive outcomes are reporte...

Development and Validation of a Prognostic Score to Predict Mortality in Patients with Acute on Chronic Liver Failure.

Acute-on Chronic Liver Failure (ACLF) is a frequent syndrome (30% prevalence) characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops an...

Proliferation of mouse liver stem/progenitor cells induced by plasma from patients with acute liver failure is modulated by P2Y2 receptor-mediated JNK activation.

We recently reported that acute liver failure plasma (ALF-P) promotes the proliferation of mouse liver oval cells (OCs) through c-jun N-terminal kinase (JNK) activation. The aim of this study was to i...

Medical and Biotech [MESH] Definitions

A form of rapid-onset LIVER FAILURE, also known as fulminant hepatic failure, caused by severe liver injury or massive loss of HEPATOCYTES. It is characterized by sudden development of liver dysfunction and JAUNDICE. Acute liver failure may progress to exhibit cerebral dysfunction even HEPATIC COMA depending on the etiology that includes hepatic ISCHEMIA, drug toxicity, malignant infiltration, and viral hepatitis such as post-transfusion HEPATITIS B and HEPATITIS C.

A spectrum of clinical liver diseases ranging from mild biochemical abnormalities to ACUTE LIVER FAILURE, caused by drugs, drug metabolites, and chemicals from the environment.

Severe inability of the LIVER to perform its normal metabolic functions, as evidenced by severe JAUNDICE and abnormal serum levels of AMMONIA; BILIRUBIN; ALKALINE PHOSPHATASE; ASPARTATE AMINOTRANSFERASE; LACTATE DEHYDROGENASES; and albumin/globulin ratio. (Blakiston's Gould Medical Dictionary, 4th ed)

A severe irreversible decline in the ability of kidneys to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism. Renal failure, either acute (KIDNEY FAILURE, ACUTE) or chronic (KIDNEY FAILURE, CHRONIC), requires HEMODIALYSIS.

A urea cycle enzyme that catalyzes the formation of orthophosphate and L-citrulline (CITRULLINE) from CARBAMOYL PHOSPHATE and L-ornithine (ORNITHINE). Deficiency of this enzyme may be transmitted as an X-linked trait. EC 2.1.3.3.

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