Bile Acid Recycling Inhibitors for Treatment of Hypercholemia and Cholestatic Liver Disease

Abstract

Provided herein are methods of treating or ameliorating hypercholemia or a cholestatic liver disease by administering to an individual in need thereof a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising administering to an individual in need thereof a therapeutically effective amount of ASBTI or a pharmaceutically acceptable salt thereof.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 61 / 553,094, filed Oct. 28, 2011, U.S. Provisional Application No. 61 / 607,487, filed Mar. 6, 2012, which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION[0002]Hypercholemia and cholestatic liver diseases are liver diseases associated with impaired bile secretion (i.e., cholestasis), associated with and often secondary to the intracellular accumulation of bile acids / salts in the hepatocyte. Hypercholemia is characterized by increased serum concentration of bile acid or bile salt. Cholestasis can be categorized clinicopathologically into two principal categories of obstructive, often extrahepatic, cholestasis, and nonobstructive, or intrahepatic, cholestasis. Nonobstructive intrahepatic cholestasis can further be classified into two principal subgroups of primary intrahepatic cholestasis that result from constitut...

AI Technical Summary

Benefits of technology

[0023]In some cases, any of the methods or compositions described above reduce or ameliorate symptoms of hypercholemia and / or cholestatic liver disease and / or reduce severity of symptoms and / or reduce recurrence of hypercholemia and / or a cholestatic liver disease in a pediatric individual in need thereof. In some cases, any of the methods or compositions described above reduce or ameliorate pruritis in a pediatric individual in need thereof. In some cases, any of the methods or compositions described above lower serum bile acid concentrations or hepatic bile acid concentrations in a pediatric individual in need thereof. In some cases, for any of the methods and / or compositions described herein, the individual is an infant less than 2 years of age. In some cases, for any of the methods and / or compositions described herein, the individual is an infant between 0 to 18 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is an infant between 1 to 18 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is an infant between 2 to 18 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is an infant between 3 to 18 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is an infant between 4 to 18 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is an infant between 6 to 18 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is an infant between 18 to 24 months of age. In some cases, for any of the methods and / or compositions described herein, the individual is an infant between 6 to 12 months of age. In some instances, for any of the methods and / or compositions described herein, the individual is a child of between about 2 to about 10 years of age. In some instances, the individual is less than 10 years old. In some instances, the individual is more than 10 years old. In some cases, the individual is an adult.

[0024]Provided herein, in certain embodiments, are therapeutic methods and compositions using compounds that inhibit the Apical Sodium-dependent Bile Transporter (ASBT) or a pharmaceutically acceptable salt thereof, or any recuperative bile salt transporter for treatment of hypercholemia and / or cholestatic liver disease. In certain instances, use of the compounds provided herein reduces or inhibits recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided herein reduce intraenterocyte bile acids / salts and / or damage to ileal or hepatocellular architecture caused by hypercholemia and / or cholestatic liver disease and / or allow for regeneration of the intestinal lining or liver. In some embodiments, the bile transport inhibitors are non-systemic compounds. In other embodiments, the bile acid transporter inhibitors are systemic compounds delivered non-systemically. In other embodiments, the bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described herein enhance enteroendocrine peptide secretion by intestinal L-cells.

[0025]Provided herein, in certain embodiments, are therapeutic methods and compositions using compounds that inhibit the Apical Sodium-dependent Bile Transporter (ASBT) or a pharmaceutically acceptable salt thereof, or any recuperative bile salt transporter for treatment of pruritis. In certain instances, use of the compounds provided herein reduces or inhibits recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided herein reduce intraenterocyte bile acids / salts and / or damage to ileal or hepatocellular architecture caused by a cholestatic liver disease and / or allow for regeneration of the intestinal lining or liver. In some embodiments, the bile transport inhibitors are non-systemic compounds. In other embodiments, the bile acid transporter inhibitors are systemic compounds delivered non-systemically. In other embodiments, the bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described herein enhance enteroendocrine peptide secretion by intestinal L-cells.

[0026]Provided herein, in certain embodiments, are therapeutic methods and compositions using compounds that inhibit the Apical Sodium-dependent Bile Transporter (ASBT) or a pharmaceutically acceptable salt thereof, or any recuperative bile salt transporter for lowering serum bile acid concentrations. In certain instances, use of the compounds provided herein reduces or inhibits recycling of bile acid salts in the gastrointestinal tract. In some embodiments, the methods provided herein reduce intraenterocyte bile acids / salts and / or damage to ileal or hepatocellular architecture caused by a cholestatic liver disease and / or allow for regeneration of the intestinal lining or liver. In some embodiments, the bile transport inhibitors are non-systemic compounds. In other embodiments, the bile acid transporter inhibitors are systemic compounds delivered non-systemically. In other embodiments, the bile acid transporter inhibitors are systemic compounds. In certain embodiments, the bile transport inhibitors described herein enhance enteroendocrine peptide secretion by intestinal L-cells.

Problems solved by technology

Active treatment and prevention is limited.

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