Cholesterol lowering drugs for the treatment of hepatic encephalopathy
Inventors
DeMorrow, Sharon • MacMillin, Matthew
Assignees
US Department of Veterans Affairs
Publication Number
US-11160826-B1
Publication Date
2021-11-02
Expiration Date
2038-03-05
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Abstract
The present disclosure is concerned with cholesterol lowering agents including, but not limited to, statins and cyclodextrins, for the treatment of hepatic encephalopathy. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to methods and compositions for the treatment of hepatic encephalopathy through the administration of cholesterol reducing agents. It discloses that cholesterol lowering agents, including statins and cyclodextrins, may be used to treat hepatic encephalopathy by reducing brain cholesterol levels and modifying liver X receptor beta (LXRβ) signaling. The methods cover administering these agents to a subject diagnosed with or in need of treatment for hepatic encephalopathy, as well as modifying LXRβ signaling in cells or subjects via cholesterol reducing agents.
Hepatic encephalopathy is a range of neurological complications arising from liver failure or cirrhosis, with symptoms ranging from mild cognitive impairment to severe neuromuscular dysfunction and coma. The molecular pathogenesis was poorly understood, and current treatments are limited, particularly for severe cases. The background notes that aberrant bile acid signaling in the brain may contribute to the development of hepatic encephalopathy, inducing neurological dysfunction through activation of bile acid receptors such as FXR, leading to altered cholesterol homeostasis and neurosteroid synthesis.
The summary and detailed description reveal that increased bile acid content in the brain during liver failure activates FXR, which downregulates cholesterol clearance pathways in the brain by suppressing expression of the enzyme Cyp46A1 responsible for converting cholesterol to 24-(S)-hydroxycholesterol. This results in brain cholesterol accumulation, contributes to neurosteroid synthesis dysregulation, and exacerbates neurological impairments of hepatic encephalopathy. The invention proposes that reducing brain cholesterol using cholesterol reducing agents may attenuate neurological decline, addressing a key mechanism in hepatic encephalopathy's pathogenesis.
Claims Coverage
The patent includes one independent claim focusing on a method of treating hepatic encephalopathy using a specific cyclodextrin compound.
Use of specific cyclodextrins to treat hepatic encephalopathy
A method of treating hepatic encephalopathy in a subject by administering a therapeutically effective amount of a single active cyclodextrin agent selected from β-cyclodextrin and γ-cyclodextrin. The cyclodextrin can be further selected from 2-hydroxypropyl-β-cyclodextrin, methylated β-cyclodextrin, hydroxyethyl-β-cyclodextrin, sulfobutylether β-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin, with emphasis on 2-hydroxypropyl-β-cyclodextrin.
The claims focus on the therapeutic use of specific cyclodextrins as cholesterol reducing agents for treating hepatic encephalopathy, highlighting the selection of cyclodextrin derivatives effective in this method.
Stated Advantages
Cholesterol reducing agents may delay the neurological decline and increase time to hepatic coma in subjects with hepatic encephalopathy.
Targeting cholesterol accumulation in the brain offers a novel therapeutic approach to managing hepatic encephalopathy symptoms.
The method can alleviate cognitive and neuromuscular impairment without directly influencing underlying liver damage.
Documented Applications
Treatment of hepatic encephalopathy in subjects diagnosed with the condition or in need of treatment.
Modification of liver X receptor beta (LXRβ) signaling in subjects or cells needing such modification.
Use of cholesterol reducing agents including statins and cyclodextrins to prevent or reduce neurological complications associated with acute and chronic liver failure conditions leading to hepatic encephalopathy.
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