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Inhibition of fibrosis in non-alcoholic fatty liver disease patients

A non-alcoholic, liver fibrosis technology, applied in the field of inhibition of fibrosis in patients with non-alcoholic fatty liver disease, can solve the problems of non-response to available treatments for fibrotic diseases, limitations of long-term treatment toxicity and side effects, etc.

Inactive Publication Date: 2019-07-26
GALMED RES & DEV LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Many patients do not respond to available treatments for fibrotic disease, and long-term treatment is limited by toxicity and side effects

Method used

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  • Inhibition of fibrosis in non-alcoholic fatty liver disease patients
  • Inhibition of fibrosis in non-alcoholic fatty liver disease patients
  • Inhibition of fibrosis in non-alcoholic fatty liver disease patients

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1 - Thioacetamide (TAA) induced liver fibrosis - a model for liver cirrhosis

[0135] Hepatic fibrosis was induced in Wistar rats by intraperitoneal injection of TAA (20 mg / 100 g body weight) twice weekly for 10 weeks. The application of intraperitoneal TAA resulted in central liver necrosis, elevated transaminase activity, and intense liver fibrosis. Treatment groups also included co-administration of Aramchol (1 or 5 mg / kg po) or obeticholic acid (OCA, 5 mg / kg). A control group of saline-treated rats (no TAA administered) was also included. The rats were then sacrificed and the livers were visually inspected for signs of cirrhosis and necrotic lesions after Masson Goldner staining and under a microscope. A fiber score calculated on a scale of 0-4, where 0 indicates no fibrosis and 4 indicates advanced fibrosis and cirrhosis, was determined for each sample.

[0136] As can be seen from Figures 1-2, treatment with Aramchol (5 mg / kg) significantly prevented ...

Embodiment 2

[0139] Example 2 - Inhibition of Collagen Synthesis in Stellate Cells

[0140] LX2 cells (150,000 cells per well) were seeded in DMEM medium containing antibiotics, glutamine and fetal bovine serum. After 24 hours of incubation, the medium was changed to 0% serum and incubated for an additional 16 hours. Then, Aramchol (10 mM) was added, and RNA was extracted with Trizol 24 hours later.

[0141] Surprisingly, as image 3 and 4 As seen in , Aramchol reduces COL1A1 expression in LX-2 human hepatic stellate cells through PPARγ upregulation.

[0142] Consistently, Aramchol significantly downregulated collagen production in LX-2 human hepatic stellate cells relative to DMSO control ( Figure 5 ). Also, it was surprisingly found that Aramchol was specifically effective in reducing collagen production in stellate cells.

Embodiment 3-A

[0143] Example 3 - Aramchol reduces established fibrosis in an MCD diet animal model

[0144] The study described below investigated the mechanism of action of Aramchol and its potential effect on fibrosis using a 0.1% methionine and choline deficient (0.1 MCD) dietary mouse model of NASH.

[0145]C57B1 / 6 were fed a methionine- and choline-deficient (MCD) diet and a control diet and sacrificed 4 weeks later. The MCD diet induced elevated transaminases and changes in liver histological features, characterized by steatosis, local inflammation, hepatocellular necrosis, and fibrosis. These changes occur rapidly and are morphologically similar to those observed in human NASH. In this study, the MCD diet contained 0.1% methionine to minimize and stabilize weight loss. At the end of the second week, after confirmation of established NASH, Aramchol (5 mg / Kg / day) or vehicle (n=10 per condition) was orally administered by gavage to 0.1 MCD-fed mice. Control diet fed mice were also tr...

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Abstract

The invention relates to inhibiting the development of hepatic fibrosis in a human subject afflicted with non-alcoholic fatty liver disease and having a fibrosis score of zero comprising administeringto the subject greater that 300 mg per day of 3beta-arachidylamido-7alpha,12alpha-dihydroxy-5beta-cholan-24-oic acid (Aramchol), or a pharmaceutically acceptable salt thereof, thereby inhibiting thedevelopment of hepatic fibrosis in said subject.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 475,132, filed March 22, 2017, and U.S. Provisional Application No. 62 / 420,009, filed November 10, 2016. Background technique [0002] fibrosis [0003] The formation of fibrous connective tissue is part of the normal healing process after tissue damage due to injury or inflammation. During this process, activated immune cells, including macrophages, stimulate the proliferation and activation of fibroblasts, which in turn deposit connective tissue. However, abnormal or overproduction of connective tissue can lead to a buildup of fibrous material that interferes with the normal function of the tissue. Even after the original injury has healed, the fibrotic growth can proliferate and invade healthy surrounding tissue. This abnormal formation of excess connective tissue that occurs during repair or reaction is called fibrosis. [0004] Liver fibrosis, also referred to herein as hepatic fibrosis,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61P1/16
CPCA61K31/575A61P1/16A61P3/10A61K9/0053
Inventor 利亚特·哈亚尔德尼-尼西莫伊夫塔利·高芬艾伦·巴哈拉夫约瑟·M·马托德拉巴斯
Owner GALMED RES & DEV LTD
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