Method for treating primary sclerosing cholangitis

A sclerosing, primary technology, used in the digestive system, pharmaceutical formulations, organic active ingredients, etc.

Inactive Publication Date: 2021-06-18
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the recurrence rate of primary sclerosing cholangitis after transplantation has been as high as 20%

Method used

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  • Method for treating primary sclerosing cholangitis
  • Method for treating primary sclerosing cholangitis
  • Method for treating primary sclerosing cholangitis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1. Repagliflozin orally administered reduces inflammatory cell infiltration, bile duct hyperplasia and interface hepatitis in TIA mice.

[0044] First, TNFα knockout (“KO”) C57BL / 6 mice (strain B6.129S-Tnf tmlGkl / J, deposit number 005540, Jackson Laboratories, Bar Flarbor, ME) and IL-10KO mice (strain B10.129P2(B6)-IL10 tmlCgn / J, Deposit 002251, Jackson Laboratories) were bred to produce a population of mice deficient in TNFα and IL-10. Since mice with TNFα- / - and IL10- / - genotypes spontaneously develop inflammatory bowel disease (“IBD”) (Hale 2012), a disease associated with poor breeding conditions (Nagy 2016), further research is needed. breeding to produce the AICDA population, which was generated by breeding offspring with TNFα- / - and IL10+ / - genotypes with AICDA- / - mice (obtained from Dr. TasukuHonjo (Muramatsu 2000)) to produce TNFα- / -, IL10- / - and AICDA+ / - ("TI-hetA") male and female mice. In turn, TI-hetA male and female mice were bred to generate...

Embodiment 2

[0053] Example 2. TIA mice show serological evidence of liver and / or bile injury.

[0054] Serum biochemical analysis of TIA mice was performed at week 11. Blood from euthanized animals was drawn into lithium heparin tubes and a Fleska Dry Chem 7000 analyzer was used to measure a panel of analytes including total protein, albumin, serum alkaline phosphatase (AP), alanine aminotransferase (ALT), and total bilirubin. Serum aspartate aminotransferase (AST) was measured in a separate assay. In 50% of the mice, elevated levels of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase at least 1.5 times the upper limit of normal were detected, which are considered indicators of cholestasis / hepatic injury.

[0055] As described in Example 1, histological analysis at week 11 showed substantial biliary and hepatic inflammation but relatively little fibrosis. These serum biochemical data also suggest autoimmune hepatitis.

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Abstract

The invention relates to the use of pharmaceutical compositions of the SGLT2 inhibitor, remogliflozin etabonate, to treat primary sclerosing cholangitis (PSC). Methods and compositions associated with the invention can improve or maintain clinical outcomes of PSC symptoms, such as ascites accumulation, hepatic encephalopathy, development of varices, jaundice, variceal bleeding, cholangiocarcinoma, hepatocellular carcinoma, evidence of cirrhosis, and colorectal cancer.

Description

technical field [0001] The present invention relates to compositions and methods related to the administration of remogliflozin etabonate for the treatment of primary sclerosing cholangitis (PSC). Background technique [0002] Primary sclerosing cholangitis (PSC) is a severe chronic cholestatic liver disease characterized by progressive autoimmune-mediated destruction of the bile ducts, Symptoms associated with sclerosing cholangitis, but eventually cirrhosis of the liver and its complications. Remissions and relapses characterize the course of the disease. Although the cause of primary sclerosing cholangitis is unknown, it is believed that damage to the bile ducts is caused by one or more of the following genetic abnormalities: immune regulation, viral infection, bacterial toxins in the gut, bacterial infection of the portal system , ischemic vascular injury, and toxic bile acids produced by gut bacteria. A specific immunoregulatory dysregulation, hyper-IgM syndrome, inc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/48A61K9/52A61K31/7056A61K47/30A61P1/00A61P3/04
CPCA61P1/00A61K31/7056A61P3/04A61K9/2054A61K9/2846A61K9/1676A61P1/16
Inventor W·O·威尔基森J·T·格林
Owner アヴォリント
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