Track topics on Twitter Track topics that are important to you
The purpose of the study is to determine whether L-Ornithine L-Aspartate infusion improves the survival of patients with acute liver failure.
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.
Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
Acute Liver Failure
All India Institute of Medical Sciences
Active, not recruiting
All India Institute of Medical Sciences, New Delhi
Published on BioPortfolio: 2014-08-27T03:38:42-0400
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...
The study aimed to assess the effectiveness and safety of L-ornithine-L-aspartate in the management of hepatic encephalopathy.
The purpose of this study is to determine whether L-Ornithine L-Aspartate is effective for the improvement of Overt 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...
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...
Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting...
Acute liver failure is accompanied by a pathologic syndrome common to numerous different etiologies of liver injury. This acute liver failure syndrome leads to potentially widespread devastating end-o...
The current gold standard for the management of acute liver failure is liver transplantation. However, because of organ shortages, other modalities of therapy are necessary as a possible bridge. This ...
Varied injuries may manifest clinically as acute liver failure. The pathologic features include variable amounts of necrosis and regeneration. This article reviews pathologic classification of pattern...
The definition of acute liver failure (ALF) usually implies no previous liver injury. Though, some patients admitted to liver transplantation centers with the diagnosis of ALF are obese or have diabet...
Sudden liver failure in the presence of underlying compensated chronic LIVER DISEASE (e.g., LIVER CIRRHOSIS; HEPATITIS; and liver injury and failure) due to a precipitating acute hepatic insult.
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.
A spectrum of clinical liver diseases ranging from mild biochemical abnormalities to ACUTE LIVER FAILURE, caused by drugs, drug metabolites, herbal and dietary supplements 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)
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase 'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...