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Methods of treating liver disease

A liver disease, steatohepatitis technology, applied in the field of prevention and / or treatment of liver disease, can solve the problem of NAFLD drug treatment and other problems

Inactive Publication Date: 2019-06-25
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] No effective pharmacological treatment for NAFLD, despite initial reports suggesting an active lifestyle can prevent or reverse liver damage

Method used

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  • Methods of treating liver disease
  • Methods of treating liver disease
  • Methods of treating liver disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Example 1. Efficacy of the Rat NASH Model

[0080] The following study was performed to evaluate the efficacy of a combination of an ASK1 inhibitor and a FXR agonist in a rodent model of nonalcoholic steatohepatitis (NASH), relative to the efficacy of the agents alone in the model. By giving a choline-deficient high-fat diet (CDHFD) and chronically administering sodium nitrite (CDHFD / NaNO 2 ), to induce NASH in male Wistar rats. This model utilizes the "double-click theory" of NASH by inducing metabolic dysfunction (CDHFD) and oxidative stress (NaNO 2 ) lead to liver fibrosis with features and severity similar to those observed in patients with advanced NASH.

[0081] Rats were fed CDHFD for a total of 14 weeks and NaNO was administered from week 4 to week 14 2 . Compound of formula (III) (supplied as admixture in the diet adjusted to deliver 30 mg / kg / day), compound of formula (I) (administered as admixture in 0.2% of the diet) or vehicle at weeks 4 to 14 . The fo...

Embodiment 2

[0105] Example 2. Efficacy of NASH mouse model

[0106] The following study was performed to evaluate the efficacy of a combination of an ASK1 inhibitor and a FXR agonist in a mouse model of nonalcoholic steatohepatitis (NASH), relative to the efficacy of the individual agents alone in the model. NASH was induced in male C57BL / 6 mice by chronic administration of a "fast food" diet (FFD) rich in saturated fat, cholesterol and sugar for a total of 10 months, while lean control animals were maintained on normal chow. Establishment of a NASH phenotype for 7 months in FFD mice compared to control mice, characterized by obesity, hypercholesterolemia, and elevated AST / ALT; and histological features of NASH, such as macrovesicular fat in hepatocytes Degeneration and ballooning degeneration. See Charlton M et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. American journal of phys...

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Abstract

The present disclosure relates to a method of preventing and / or treating liver disease comprising administering an ASK1 inhibitor in combination with a FXR agonist to a patient in need thereof.

Description

technical field [0001] The present invention relates to methods of preventing and / or treating liver diseases. Background technique [0002] Liver disease is usually classified as acute or chronic based on the duration of the disease. Liver disease can be caused by infection, injury, exposure to drugs or toxic compounds, alcohol, food impurities, and abnormal accumulation of normal substances in the blood, autoimmune processes, genetic defects (such as hemochromatosis), or unknown causes. [0003] Liver disease is the leading cause of death worldwide. In particular, a high-fat diet has been seen to damage the liver in a manner strikingly similar to hepatitis. The American Liver Foundation estimates that more than 20 percent of the population has nonalcoholic fatty liver disease (NAFLD). Obesity, unhealthy diet and sedentary lifestyle have been shown to contribute to the high incidence of NAFLD. When left untreated, NAFLD can progress to nonalcoholic steatohepatitis (NASH)...

Claims

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Application Information

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IPC IPC(8): A61K31/4439A61P1/16
CPCA61P1/16A61K31/4439A61K2300/00
Inventor D.G.C.布雷肯里奇G.R.布达斯J.T.利莱斯W.J.沃特金斯
Owner GILEAD SCI INC
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