Steroid compound for use in the treatment of hepatic encephalopathy
Inventors
Doverskog, Magnus • Möhler, Hanns • Felipo, Vicente • Bäckström, Torbjörn
Assignees
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Publication Number
US-9801894-B2
Publication Date
2017-10-31
Expiration Date
Abstract
The present invention provides the steroidal compound 3□-ethynyl-3□-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, for use in treatment of hepatic encephalopathy.
Core Innovation
The disclosure provides 3α-ethynyl-3β-hydroxyandrostan-17-one oxime, or a pharmaceutically acceptable salt thereof, for treating hepatic encephalopathy in a patient in need thereof. The treatment is positioned for hepatic encephalopathy subtypes including minimal hepatic encephalopathy and overt hepatic encephalopathy, including types A, B, and C. The disclosure also frames patient contexts including acute liver failure; chronic liver disease with or without acute-on-chronic liver failure; and treatment before, during, or after liver transplantation.
The disclosure characterizes the compound as a modulating steroid antagonist selective for inhibiting positive modulation of GABA_A receptor activation by endogenous steroids, including allopregnanolone and tetrahydrodeoxycorticosterone (THDOC). It further states that the compound does not antagonize GABA and is associated with activity at specific GABA_A receptor subunits, namely α11 and α115. The safety rationale presented is related to avoiding convulsions.
The disclosure reports non-ammonia-lowering effects in rat hepatic encephalopathy models, stating that there is no significant change in blood ammonia levels. It further reports restoration of spatial learning/memory and motor coordination, and improvements in circadian and motor activity. Electrophysiology is described as showing antagonism of THDOC-enhanced GABA_A activation while not affecting GABA activation.
Claims Coverage
The independent claims cover two treatment intents: administering the compound to treat hepatic encephalopathy and administering the compound to prevent hepatic encephalopathy. Across the dependent refinements, the inventive features are centered on the compound, the specified hepatic encephalopathy indication(s), optional timing around liver transplantation, and optional co-administration with ammonia-lowering compounds.
Administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime
A method of treating hepatic encephalopathy comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof to a patient in need thereof.
Administering a pharmaceutically effective amount to prevent hepatic encephalopathy
A method of preventing hepatic encephalopathy comprising administering a pharmaceutically effective amount of 3α-ethynyl-3β-hydroxyandrostan-17-one oxime or a pharmaceutically acceptable salt thereof to a patient in need thereof.
Selecting hepatic encephalopathy subtype, including minimal and overt forms
The methods are further specified by treating or preventing minimal hepatic encephalopathy and overt hepatic encephalopathy, and by further specifying hepatic encephalopathy as type A (and, in the disclosure, types B and C are described as relevant subtypes).
Timing the administration relative to liver transplantation
The methods are further specified as administering the compound before, during, or after a liver transplantation.
Co-administering with an ammonia-lowering compound
The methods are further specified by co-administering the 3α-ethynyl-3β-hydroxyandrostan-17-one oxime with an ammonia-lowering compound, with ammonia-lowering compounds including rifaximin, lactulose, ornithine phenylacetate, and glycerol phenyl butyrate.
Overall, the claim coverage centers on administering 3α-ethynyl-3β-hydroxyandrostan-17-one oxime (or a pharmaceutically acceptable salt) to treat or prevent hepatic encephalopathy, with dependent refinements covering minimal/overt and type A/B/C subtypes, optional administration timing around liver transplantation, and optional co-administration with specific ammonia-lowering compounds.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating hepatic encephalopathy, including minimal hepatic encephalopathy and overt hepatic encephalopathy, including type A/B/C.
Preventing hepatic encephalopathy in a patient in need thereof.
Treatment contexts including acute liver failure; chronic liver disease with or without acute-on-chronic liver failure; and administration before, during, or after liver transplantation.
Combination therapy in which the compound is co-administered with ammonia-lowering compounds including rifaximin, lactulose, ornithine phenylacetate, and glycerol phenyl butyrate.
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