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Methods of sustaining dietary ketosis and its effects on lipid profile

a ketogenic and lipid profile technology, applied in the field of ketogenic supplements, can solve the problems of difficult for most humans, physiological decrease of glucose and insulin, etc., and achieve the effects of suppressing hunger, rapid and sustained elevation of blood ketones, and improving metabolic health and performan

Inactive Publication Date: 2016-11-03
UNIV OF SOUTH FLORIDA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]As such, a composition is described which causes a rapid and sustained elevation of blood ketones with a single oral administration. Exploiting the metabolic and physiological advantages of sustained ketosis (e.g. keto-adaptation), which utilize ketones as an alternative fuel to potentially improve metabolic health and performance, and suppress hunger. Individuals on the SAD can expect to get peak fat oxidation from exercise between 60-65% of maximum (VO2 max); higher exertion levels will then deplete glycogen stores. Keto-adapted individuals draw proportionally more substrate from fats and ketones and can shift the peak to much higher VO2 levels and thus, sustain effort for an extended duration. A sustained physiological decrease in glucose and insulin are required for sustained hepatic ketogenesis, which is very difficult for most humans.
[0016]Accordingly, a composition comprising at least one ketone is disclosed, where the ketone is R,S-1,3-Butandiol, R,S-1,3-butanediol acetoacetate diester, or a combination of the two ketones. The composition has been found to suppress hunger. In light of improved effects ketosis has shown on ATP generation and utilization, as discussed above, the present composition can be used in reducing weight in individuals. The ketones are optionally administered between 2 grams and 50 grams, between 5 grams and 30 grams, or between 10 grams and 20 grams. For example, the ketone compounds are optionally administered at 2 grams, 4 grams, 5 grams, 6 grams, 7 grams, 8 grams, 9 grams, 10 grams, 11 grams, 12 grams, 13 grams, 14 grams, 15 grams, 17 grams, 19 grams, 20 grams, 22 grams, 24 grams, 26 grams, 28 grams, 30 grams, 32 grams, 34 grams, 36 grams, 38 grams, 40 grams, 42 grams, 44 grams, 46 grams, 48 grams, or 50 grams. Alternatively, the ketones are administered at between 5 g / kg to 10 g / kg. Nonlimiting examples include 5 g / kg, 5.5 g / kg, 6 g / kg, 6.5 g / kg, 7 g / kg, 7.5 g / kg, 8 g / kg, 8.5 g / kg, 9 g / kg, 9.5 g / kg, or 10 g / kg.

Problems solved by technology

A sustained physiological decrease in glucose and insulin are required for sustained hepatic ketogenesis, which is very difficult for most humans.

Method used

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  • Methods of sustaining dietary ketosis and its effects on lipid profile
  • Methods of sustaining dietary ketosis and its effects on lipid profile
  • Methods of sustaining dietary ketosis and its effects on lipid profile

Examples

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example 1

[0052]BD was purchased from Sigma (Milwaukee, Wis.). R,S-1,3-butanediol acetoacetate diester (KE) synthesized as previously described (D'Agostino, et al., Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. Am J Physiol Regul Integr Comp Physiol. 2013 May 15; 304(10):R829-36). Briefly, R,S-1,3-butanediol and t-butylacetoacetate were purchased from Sigma (Milwaukee, Wis., USA). All commercial solvents and reagents used were high-purity reagent-grade materials. KEs were synthesized by transesterification of t-butylacetoacetate with R,S-1,3-butanediol (Savind Inc., Seymour, Ill.). The resultant product consisted of a mixture of monoesters and diester, the ratio of which could be adjusted by varying the stoichiometry of reactants. Following synthesis the crude product was distilled under reduced pressure to remove all solvents and starting materials, and the resultant BD-AcAc or BD-AcAc2 was obtained and assessed for purity using gas chr...

example 2

[0061]Animals treated from Example 1 were sacrificed by CO2 between 4-8 hours after gavage-treatment at the end of 4 weeks (28 days at the dose of 5-10 g / kg), which were determined to be peak ketone elevation. Brain, Lungs, Liver, Kidneys, Spleen and Heart were harvest and weighed using AWS-1000 1 kg portable digital scale (AWS, Charleston, S.C.). Organs were then either flash frozen in liquid nitrogen or preserved in paraformaldehyde for future analysis.

[0062]KE ketone supplements significantly decreased the weight of the liver in the rats. BD supplemented animals showed no significant change in non-liver organ weight, as seen in FIG. 14(A). However, KE treatment did result in a statistically significant reduction in liver weight, as seen in FIG. 14(B).

[0063]Livers from rats administered maximum tolerable dose of ketone supplementation were assessed via histology. The livers from rats treated 4-weeks with ketone supplementation appeared normal in color, size and texture in all grou...

example 3

[0065]Ketones, beta-hydroxybutyrate (βHB) and acetoacetate (AcAc), are derived from acetyl-CoA generated from the oxidation of fatty acids in the liver. In extrahepatic tissues, they are converted back to acetyl-CoA where they serve as important fuel sources—especially in the heart and skeletal muscle. Most tissues in mature animals, under nutrient replete conditions, do not use ketones but can adapt to their use during starvation or prolonged exercise when glycogen stores become depleted. The underlying hypothesis behind the use of ketogenic agents for induction of nutritional ketosis is that ketones are a metabolic substrate that can be exploited through the oral administration of specific forms of supplementation. This global metabolic profiling study was conducted to examine the systemic and brain metabolic responses of healthy rats subjected to two different diets capable of inducing nutritional ketosis.

[0066]Rats were treated as described in Example 1, and brain and serum samp...

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Abstract

The ketogenic diet (KD) has therapeutic implications in many disease states. It was hypothesized ketone precursor supplementation would elevate blood ketone levels to therapeutic ranges (2-7 mM) without need for dietary restriction. The effects of ketogenic agents were tested on blood glucose, ketones, and lipids with a 28-day dose escalation study in male Sprague-Dawley rats: R,S-1,3-Butandiol (BD), acetoacetate ketone ester (KE), and control (H2O) (n≧8). Days 1-28, rats received a daily 5 g / kg intragastric gavage, based on previous toxicology studies. Once weekly, whole blood samples (10 μl) were acquired for analysis of glucose and βHB at 0, 0.5, 1, 4, 8, and 12 hours after test substance administration, or until βHB returned to baseline. At day 1 and 28, 10 μL of whole blood were collected to measure triglycerides, total cholesterol, and HDL concentration. Significant elevation of blood ketone was observed with a significant inverse relationship with blood glucose for the duration of the experiment. There were no significant changes in the lipid panel for any of the substances. There were significant reductions in body weight when animals were treated with either BD or KE as compared to control.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of and claims priority to International Patent Application No. PCT / US2015 / 011165, with the same title, filed Jan. 13, 2015, which claims priority to U.S. Provisional Patent Application 61 / 926,635, with the same title, filed on Jan. 13, 2014, and claims priority to the application, the contents of which are hereby incorporated by reference.STATEMENT OF GOVERNMENT SUPPORT[0002]This invention was made with government support under Grant # N00014-13-1-0062 awarded by the Department of Defense, Office of Naval Research. The government has certain rights in the invention.FIELD OF INVENTION[0003]This invention relates to ketogenic supplements to produce elevated and sustained levels of ketone bodies in the blood. More specifically, the invention provides a ketogenic treatment to suppress hunger.BACKGROUND OF THE INVENTION[0004]Ketogenic diets (KDs), calorie restriction (CR), therapeutic fasting and ketogenic pr...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/225
CPCA61K31/225A61K31/22C07C31/207C07C69/16C07C69/34C07B2200/07A61P3/04
Inventor D'AGOSTINO, DOMINIC PAULKESL, SHANNON
Owner UNIV OF SOUTH FLORIDA
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