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-10154982-B2
Publication Date
2018-12-18
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 comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate (optionally in the acid form), physiologically compatible salts thereof, esters, oligomers containing 2 to 20 or more monomeric units in linear or cyclic form, racemic or R-1,3 butandiol, or combinations thereof. These compositions are for reducing serum cholesterol and/or triglyceride levels in subjects, optionally administered in conjunction with a low fat diet.
The compositions can be formulated as nutritional supplements or incorporated into therapeutic compositions with anti-hypertensive, anti-inflammatory, glucose lowering, or anti-lipemic agents. Administration of these compositions causes reductions in serum cholesterol, triglycerides, glucose, homocysteine, inflammatory proteins (e.g., C reactive protein), and/or hypertension. Alternatively, the compositions may be administered alone or with other therapeutic agents to prevent or reverse vascular disease.
The problem solved by the invention addresses vascular insufficiency due to occlusive vascular processes associated with elevated serum cholesterol, triglycerides, glucose, homocysteine, inflammatory processes, and hypertension. Since ketone bodies cannot be used by the liver to synthesize triglycerides or cholesterol, the compositions based on D-β-hydroxybutyrate esters or oligomers, combined with reduced dietary fat, can reverse these predisposing factors leading to vascular disease.
Claims Coverage
The patent contains two independent claims focusing on methods for lowering serum cholesterol levels in diabetic subjects using compositions comprising esters of D-β-hydroxybutyrate, optionally in combination with other therapeutic agents. The main inventive features relate to compositions, dosage ranges, administration forms, and combination therapies.
Method for lowering serum cholesterol levels in diabetic subjects by administering esters of D-β-hydroxybutyrate
The method involves oral administration of compositions comprising esters of D-β-hydroxybutyrate, optionally with an additional therapeutic agent, to raise blood D-β-hydroxybutyrate plus acetoacetate levels between 0.1 to 20 mM, with alternative preferred ranges including 0.5 to 10 mM or 1 to 3 mM.
Administration of esters of D-β-hydroxybutyrate in combination with therapeutic agents
The method covers administering esters of D-β-hydroxybutyrate together with therapeutic agents selected from anti-lipemic, anti-hypertensive, glucose lowering, or anti-inflammatory agents, optionally while the diabetic subject consumes a low fat diet.
The independent claims cover methods of lowering serum cholesterol and related metabolic factors in diabetic subjects by orally administering esters of D-β-hydroxybutyrate, alone or combined with therapeutic agents, with specific blood level targets and dosage proportions relative to caloric intake, and optionally in combination with a low fat diet.
Stated Advantages
Reduces serum cholesterol and triglyceride levels in subjects.
Lowers serum glucose and blood sugar levels without inducing insulin shock.
Reduces serum homocysteine and inflammatory proteins such as C reactive protein.
Lowers hypertension and associated blood pressure levels.
Prevents or reverses vascular disease in subjects.
Documented Applications
Treatment of vascular insufficiency and related diseases including coronary, cerebrovascular, peripheral vascular insufficiency, and impaired kidney perfusion.
Use in diabetic subjects to lower serum cholesterol, triglycerides, glucose, homocysteine, inflammatory markers, and hypertension.
Formulation as nutritional supplements or inclusion in therapeutic compositions combined with anti-hypertensive, anti-inflammatory, glucose lowering, or anti-lipemic agents.
Administration alone or with other therapeutic agents to prevent or reverse vascular disease.
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