Ketone bodies and ketone body esters as blood lipid lowering agents
Inventors
Clarke, Kieran • Veech, Richard Lewis
Assignees
Oxford University Innovation Ltd • US Department of Health and Human Services
Publication Number
US-9211275-B2
Publication Date
2015-12-15
Expiration Date
2029-01-05
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Abstract
The subject disclosure provides compositions for reducing serum cholesterol and/or triglyceride levels in subjects. These compositions can comprise racemic β-hydroxybutyrate or D-β-hydroxybutyrate, optionally in the acid form, physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate, esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 or more monomeric units in either linear or cyclic form, racemic 1,3 butandiol or R-1,3 butandiol alone and can be, optionally, administered in conjunction with a low fat diet to a subject. Alternatively, compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate, optionally in the acid form, physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate, esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 or more monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol or combinations thereof can be formulated as nutritional supplements (also referred to as nutritional compositions) or incorporated into therapeutic compositions containing a) anti-hypertensive agents; b) anti-inflammatory agents; c) glucose lowering agents; or d) anti-lipemic agents) which are administered to a subject, optionally in combination with a low fat diet, in order to cause a reduction or lowering of: serum cholesterol levels; triglyceride levels; serum glucose levels, serum homocysteine levels, inflammatory proteins (e.g., C reactive protein) and/or hypertension in treated subjects. Alternatively, compositions disclosed herein can be administered alone, or in combination with other therapeutic agents to prevent or reverse vascular disease.
Core Innovation
The invention provides compositions for reducing serum cholesterol and/or triglyceride levels in subjects. These compositions can comprise racemic β-hydroxybutyrate or D-β-hydroxybutyrate, optionally in the acid form, physiologically compatible salts thereof, esters of D-β-hydroxybutyrate, oligomers containing from 2 to 20 or more monomeric units in linear or cyclic form, racemic 1,3 butandiol or R-1,3 butandiol, either alone or in combination. These compositions can be administered with or without a low fat diet and can also be formulated as nutritional supplements or combined with other therapeutic agents to treat various conditions.
The problem addressed by the invention is the vascular insufficiency resulting from occlusive processes in the vasculature, common in diseases such as coronary insufficiency, cerebrovascular insufficiency, peripheral vascular insufficiency, and impaired kidney perfusion. Predisposing factors include elevated serum cholesterol, triglycerides, glucose, homocysteine, inflammatory proteins, and hypertension. Traditional pathways for triglyceride and cholesterol synthesis involve substrates that ketone bodies cannot provide since ketone bodies cannot be utilized by liver for their synthesis. The inventors found that feeding subjects diets including ketone body esters or oligomers of D-β-hydroxybutyrate along with a lowered fat diet can reverse several predisposing factors to vascular diseases.
The compositions can be used alone or combined with a) anti-hypertensive agents; b) anti-inflammatory agents; c) glucose lowering agents; or d) anti-lipemic agents. The administration of these compositions leads to reduction or lowering of serum cholesterol levels, triglyceride levels, serum glucose levels, serum homocysteine levels, inflammatory proteins such as C reactive protein, and hypertension. They may also be employed to prevent or reverse vascular disease.
Claims Coverage
The patent includes one independent claim that focuses on a method for lowering serum levels in a healthy non-diabetic subject.
Method for lowering serum cholesterol, triglycerides, and glucose using R-1,3 butandiol ester of D-β-hydroxybutyrate
A method comprising administering to a healthy non-diabetic subject a composition comprising a R-1,3 butandiol ester of D-β-hydroxybutyrate alone or with other therapeutic agents to raise blood levels of D-β-hydroxybutyrate plus acetoacetate between 0.1 to 20 mM.
Administration in subject's diet
The composition comprising a R-1,3 butandiol ester of D-β-hydroxybutyrate can be administered as part of the subject’s diet.
Combination administration with a therapeutic agent
Administering a first composition containing the ester in combination with a second composition comprising a therapeutic agent; the compositions can be administered separately, sequentially or together, each in unit dosage form.
Therapeutic agent selection
The therapeutic agent can be selected from an extensive list of anti-hypertensive agents, glucose lowering agents, anti-lipemic agents, cholesterol absorption inhibitors, fibric acid derivatives, HMG-CoA reductase inhibitors, anti-inflammatory agents, among others, as enumerated in the claim.
Reduced dietary fat intake
The method can include reducing dietary fat intake or consuming a low fat diet during administration.
Dosage range for ester administration
Administering the R-1,3 butanediol ester of D-β-hydroxybutyrate in amounts to achieve blood levels of D-β-hydroxybutyrate plus acetoacetate ranging from 0.1 to 25 mM or corresponding to 2-100% of total caloric intake of the subject.
The claims collectively cover a method of lowering serum cholesterol, triglycerides, and glucose in healthy non-diabetic subjects by administering compositions containing a R-1,3 butandiol ester of D-β-hydroxybutyrate, alone or in combination with various therapeutic agents, optionally with a low fat diet, and specify dosage ranges and administration forms.
Stated Advantages
Lowering of serum cholesterol and triglyceride levels in subjects.
Reduction of serum glucose levels, serum homocysteine levels, inflammatory proteins, and hypertension.
Ability to prevent or reverse vascular disease.
Versatile administration routes, including dietary incorporation, oral, parenteral, injection, or rectal routes.
Potential for combination therapy with anti-hypertensive, anti-inflammatory, glucose lowering, or anti-lipemic agents to enhance therapeutic effects.
Documented Applications
Use for reducing serum cholesterol levels in subjects.
Use for lowering triglyceride levels in subjects.
Lowering serum glucose levels in subjects.
Reducing serum homocysteine and inflammatory proteins such as C reactive protein.
Prevention or reversal of vascular diseases related to occlusive vascular processes.
Combination therapies with anti-hypertensive agents, anti-inflammatory agents, glucose lowering agents, or anti-lipemic agents to treat hypertension, inflammation, hyperlipidemia, and hyperglycemia.
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