Uses of oxygenated cholesterol sulfates (OCS)
Inventors
Ren, Shunlin • Theeuwes, Felix • Brown, James E. • Lin, WeiQi
Assignees
Virginia Commonwealth University • Durect Corp • US Department of Veterans Affairs
Publication Number
US-10786517-B2
Publication Date
2020-09-29
Expiration Date
2034-12-23
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Abstract
Methods of preventing and/or treating ischemia, organ dysfunction and/or organ failure, including multiple organ dysfunction syndrome (MODS), and necrosis and apoptosis associated with organ dysfunction/failure, are provided. For instance, the methods involve contacting organ(s) with an oxygenated cholesterol sulfate (OCS), e.g. 5-cholesten-3,25-diol, 3-sulfate (25H-C3S). The organ(s) may be in vivo (e.g. in a patient that is treated with the OCS) or ex vivo (e.g. an organ that has been harvested from a donor and is to be transplanted).
Core Innovation
The invention provides methods of preventing and/or treating ischemia, organ dysfunction and/or organ failure, including multiple organ dysfunction syndrome (MODS), and necrosis and apoptosis associated with organ dysfunction/failure, by contacting organ(s) with an oxygenated cholesterol sulfate (OCS), such as 5-cholesten-3,25-diol, 3-sulfate (25HC3S). The organ(s) can be in vivo in a patient or ex vivo as harvested organs intended for transplantation.
The problem addressed is the lack of agents available that can reverse established organ failure and the limitations of current therapies that only treat the root cause and provide supportive care. Organ dysfunction and failure have high clinical and economic impact with high mortality rates. Additionally, organs harvested for transplant can suffer damage during transport and storage, and there is a need for agents that are biologically compatible and improve preservation of harvested organs.
Claims Coverage
The patent presents one independent claim focused on a method of treating acute liver dysfunction or failure using a specific oxygenated cholesterol sulfate compound.
Method of treating acute liver dysfunction or acute liver failure
Administering 5-cholesten-3,25-diol, 3-sulfate (25HC3S) or its pharmaceutically acceptable salt in an amount sufficient to treat acute liver dysfunction or failure, particularly alcoholic hepatitis where the subject has a serum bilirubin level greater than 1.9 mg/dL prior to treatment.
Administration routes and dosage of 25HC3S
The 25HC3S compound is administered by oral, subcutaneous, intramuscular, intravenous, or injection routes with dosages ranging about 0.001 mg/kg to about 100 mg/kg, with specific ranges down to about 0.1 mg/kg to about 10 mg/kg, and administered from once to three times per day.
The claims cover methods of treating acute liver dysfunction/failure with oxygenated cholesterol sulfate compounds, focusing on specific dosing and administration protocols, and encompass treatment of subjects with alcoholic hepatitis at defined bilirubin levels.
Stated Advantages
Highly bioavailable oxygenated cholesterol sulfates, including when administered orally.
Effective prevention and treatment of ischemia, necrosis, apoptosis, organ dysfunction and failure in vivo and ex vivo.
Significant reduction of mortality in animal models of acetaminophen-induced acute liver failure.
Ability to decrease markers of organ injury in treated animals.
Enhanced preservation and viability of harvested organs for transplantation.
Prolonged survival in animal models of sepsis induced by endotoxins.
Potential to treat multiple organs including liver, kidney, heart, brain, pancreas, lungs, intestines, and others.
Documented Applications
Preventing and/or treating ischemia including cardiac, brain, bowel, limb, and cutaneous ischemia.
Treatment of necrosis and apoptosis associated with organ dysfunction/failure.
Prevention and treatment of organ dysfunction and failure including liver, kidney, heart, brain, pancreas and multiple organ dysfunction syndrome (MODS).
Treatment and prevention of acetaminophen (ATMP)-induced acute liver failure and kidney failure.
Use in preservation and transplantation of organs, tissues and cells ex vivo.
Prevention and treatment of sepsis and sepsis-associated organ damage.
Protection of organs and tissues from injury during surgery and ischemia/reperfusion injury.
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