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Treatment of hepatic encephalopathy and liver cirrhosis

a technology for liver cirrhosis and hepatic encephalopathy, which is applied in the field of treatment or prevention of hepatic encephalopathy and liver cirrhosis, can solve the problems of increased risk of infection, poor long-term outcome, and potentially life-threatening, and achieves the effects of improving the overall cognitive function of the treated subject, shortening the length of the hepatic encephalopathy episode, and reducing the severity

Inactive Publication Date: 2010-01-28
YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0020]The term “treatment” in the context of the present invention refers to at least one of the following: decrease in the severity of at least one undesired side effect associated with the disease; improvement in the overall cognitive function of the treated subject; delay in the progression from one disease stage to the other; shortening the length of an hepatic encephalopathy episode and lengthening the period between episodes.

Problems solved by technology

Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome.
Other potentially life-threatening complications are hepatic encephalopathy and bleeding from esophageal varices.
First, liver failure induces impaired glucose oxidative pathways and increased lactate synthesis in the brain which results in energy failure.
Second, hypoglycemia and hypoxia are also major contributors to the energy failure seen in hepatic encephalopathy.
When the liver fulls the body is incapable of efficiently converting ammonia to urea or glutamine, resulting in systemic hyperammonemia including the brain.
Unlike the liver, the brain lacks an effective urea cycle and therefore relies entirely on glutamine synthesis for the removal of blood-borne ammonia.
Since glutamine synthetase is dependent on an adequate level of ATP to amidate glutamate to glutamine, ammonia intoxication results in depletion of brain ATP resources and eventually cell death (Ott et al., 2005; Hardie, 2004).
Yet, attempts to balance energy failure at the expense of cerebral proteins may end in destructive brain proteolysis (Hardie and Carling, 1997).

Method used

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  • Treatment of hepatic encephalopathy and liver cirrhosis
  • Treatment of hepatic encephalopathy and liver cirrhosis
  • Treatment of hepatic encephalopathy and liver cirrhosis

Examples

Experimental program
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Effect test

example 1

Experimental Hepatic Encephalopathy is Accompanied by Activation of AMPK by Cannabinoids

[0078]To consider their role in AMPK stimulation, we studied the effects of giving exogenous cannabinoids to activate AMPK. In the first step, control mice were administrated with 0.01 to 10 mg / kg THC and hippocampal AMPK phosphorylation was analyzed. THC treatment showed a biphasic effect (Sulcova et al., 1998). While low levels of THC (less than 0.1 mg / kg) reduced the level of activated AMPK, higher concentrations exhibited a dose dependent elevation in activated enzyme, reaching a significant activation of AMPK (FIG. 1). In the next step, the effect of THC was tested in TAA treated mice. In this instance THC also demonstrated a biphasic effect. However, an inactivating effect was already observed in 0.01 mg / kg and AMPK activation was achieved by 0.1 mg / kg. Elevation of the cerebral responsiveness to THC suggested that low doses of THC, which do not activate the AMPK in the healthy animals, cou...

example 2

THC Activates AMPK and Improves Impaired Brain Function in Experimental Hepatic Encephalopathy

[0079]Since treatment of 0.1 mg / kg THC augmented AMPK activation in a similar manner to AICAR treatment, we chose this dose to test THC's physiological effects on the experimental hepatic encephalopathy. TAA treated mice were administrated daily with 0.1 mg / kg THC for 5 days. Amplification of AMPK activation in response to THC administration was confirmed in the brains of the experimental animals at the end of the behavioral studies (FIG. 2A).

[0080]Next, we investigated the outcome of AMPK activation increase on brain function. Following the treatment, TAA-induced impaired cognitive function was improved significantly (FIG. 2B), poor activity performances were restored (FIG. 2C) and the reduced neurological score was improved (FIG. 2D). To reveal the mechanism by which THC could improve brain function, we studied the catecholaminergic response to THC treatment. Brain tissue in animals with ...

example 3

AICAR and THC Treatment do not Improve Markers of Hepatic Function

[0081]To investigate the possibility that the neural benefits of AICAR and THC might also result from peripheral effects (i.e. improvement of liver function) rather than cerebral function, we studied their effects on liver function. Animals treated with TAA exhibited hyperammonemia as a result of the liver dysfunction; AICAR and THC treatment had no effect on the ammonia level (FIG. 3A). Bilirubin levels and liver enzymes activity are the most commonly used laboratory markers of liver function. TAA treated mice demonstrated increased levels of bilirubin (FIG. 3B), alanine transaminase (ALT) (FIG. 3C), aspartate aminotransferase (AST) (FIG. 3D) and gamma-glutamyltransferase (GGT) (FIG. 3E). Neither AICAR nor THC ameliorated these markers indicating lack of direct action on liver recovery. Glucose analysis revealed a systemic hypoglycemia following TAA treatment (FIG. 3F) providing additional evidence for the metabolic ...

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Abstract

The compounds D9-tetrahydrocannabinol (THC), cannabidiol (CBD) and capsaicin are useful for prevention, treatment, or both, of hepatic encephalopathy. The compounds capsaicin, 2-arachidonoylglycerol (2-AG), HU-308 and cannabidiol are useful for prevention, treatment, or both, of liver cirrhosis.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a composition and methods for the treatment or prevention of hepatic encephalopathy and liver cirrhosis.BACKGROUND OF THE INVENTION[0002]Cirrhosis is a consequence of acute and chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. Cirrhosis is most commonly caused by alcoholism, hepatitis C, toxins and fatty liver but has many other possible causes.[0003]Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome. Other potentially life-threatening complications are hepatic encephalopathy and bleeding from esophageal varices. Today, cirrhosis is generally irreversible once it occurs, and treatment generally focuses on preventing progression and complications. In advanced...

Claims

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Application Information

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IPC IPC(8): A61K31/352A61K31/05A61K31/165A61K31/22A61K31/09A61P1/16
CPCA61K31/05A61K31/09A61K31/352A61K31/232A61K31/165A61P1/16Y02A50/30
Inventor BERRY, ELLIOTAVRAHAM, YOSEFAMECHOULAM, RAPHAELILAN, YARONDAGON, YOSSIMAGEN, IDDOGRIGORIADIS, NICHOLASPOUTACHIDIS, THEOFILOS
Owner YISSUM RES DEV CO OF THE HEBREWUNIVERSITY OF JERUSALEM LTD
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