WO2018009208A1 - Nutritional mitiggation of the cns effects of traumatic brain injury - Google Patents
Nutritional mitiggation of the cns effects of traumatic brain injury Download PDFInfo
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- WO2018009208A1 WO2018009208A1 PCT/US2016/041467 US2016041467W WO2018009208A1 WO 2018009208 A1 WO2018009208 A1 WO 2018009208A1 US 2016041467 W US2016041467 W US 2016041467W WO 2018009208 A1 WO2018009208 A1 WO 2018009208A1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- the invention relates to traumatic brain injury. More particularly, the invention relates to mitigation of further brain damage in the aftermath of traumatic brain injury that is caused by trauma-induced physiological and biochemical changes in the brain
- Traumatic brain injury occurs when a traumatic event causes the brain to move rapidly within the skull, leading to damage.
- the skull can make direct contact with an object (impact), or encounter a non-impact force such as blast waves or rapid acceleration or deceleration.
- a TBI happens every 15 seconds in the US, generating 1.7 million new head injury victims each year. These events are responsible for 50,000 annual deaths, leave 80,000 individuals with permanent disabilities, and cost more than US $77 billion on average each year.
- the frequency of brain injury is currently higher than that of any other affliction disease, including complex diseases such as breast cancer, AIDS, Alzheimer's disease, Parkinson's disease and multiple sclerosis.
- moderate to severe TBI and even repeated mild TBI, might be associated with increased risk of neurodegenerative diseases such as Alzheimer-like dementia disease, chronic traumatic encephalopathy (CTE) and Parkinson's disease.
- CTE chronic traumatic encephalopathy
- open head injury damage occurs because the person receives a blow to the head or other force that whips the head forward and back or from side to side (as in a car crash), causing the brain to collide at high velocity with the bony skull in which it is housed.
- the specific areas of the brain involved most often the frontal and temporal lobes, suffer brain tissue bruising and tearing of brain blood vessels.
- the rapid movement of the brain can stretch and injure neuronal axons that link brain cells together and the brain to the rest of the body, causing widespread impairment of function.
- Open head injury the second type of TBI, occurs when the skull is penetrated and has more focal damage.
- Impairment of cerebral glucose utilization can occur so that key parts of the brain may become energy-deprived.
- central nervous system (CNS) lactate content increases, reflecting a likely block in glycolysis or in pyruvate oxidative decarboxylation to acetyl-CoA in mitochondria.
- PPP pentose phosphate pathway
- NADPH nicotinamide adenine diphosphate
- PARP -mediated DNA repair can deplete cytosolic NAD+ pools and inhibit glyceraldehyde 3 -phosphate dehydrogenase
- ketogenic diet has been tested as a means for mitigating this further damage.
- the classical ketogenic diet has been in clinical use for more than 80 years, primarily for the symptomatic treatment of epilepsy. It is a high fat content diet in which carbohydrates are nearly eliminated (on a caloric basis, 90% fat, 2% carbohydrate and 8% protein) so that the body has minimal dietary sources of glucose. During high rates of fatty acid oxidation, large amounts of acetyl-CoA are generated. These exceed the capacity of the TCA cycle and lead to the synthesis of three ketone bodies within liver mitochondria.
- Intravenous infusion of ⁇ -hydroxybutyrate resulted in improved brain ATP concentration, but long-term intravenous ketone infusions are associated with unsafe plasma osmolality changes, and in the only study to measure brain ketone levels, only about one percent of the blood levels achieved actually got into cerebral spinal fluid.
- Oral ketone esters have been tried for this purpose, but in the one human clinical trial conducted, 12 of 12 healthy volunteers reported significant side effects such as nausea, abdominal distension, headache, diarrhea, dizziness, chest pain and upper abdominal pain. There is a need, therefore, for new methods for keeping cerebral ketone body concentrations elevated on a sustained basis in TBI victims, during (i) the recovery period, and (ii) during a stabilization and maintenance period.
- the invention relates to mitigation of further injury in the aftermath of a traumatic brain injury that gives rise to diffuse and focal histopathological, physiological and biochemical brain lesions.
- the invention provides new methods for elevating the cerebral concentration of ketone bodies in individuals who have experienced acute traumatic brain injury (TBI).
- TBI acute traumatic brain injury
- the invention comprises administering to an individual having TBI an amount of one or more precursors of ketone bodies or carrier vehicles of ketone bodies, other than simple ketone esters or 1,3-butanediol, capable of raising the blood concentration of ketone bodies to at least about 2 to 4 mM.
- the precursor is a medium chain triglyceride.
- the precursor or carrier vehicle may itself be esterified to ketone bodies or fatty acids of various chain lengths and degrees of unsaturation.
- the precursor may be used in combination with a ketogenic diet.
- FIG. 1 A shows examples of structured oils according to the invention.
- FIG. IB shows examples of random copolymer oils according to the invention.
- the invention relates to mitigation of further injury in the aftermath of the traumatic brain injury that gives rise to biochemical and physiological CNS lesions (diffuse and/or focal) .
- the invention provides new methods for elevating the blood concentration of ketone bodies in victims of traumatic brain injury (TBI).
- the invention comprises administering to an individual having TBI an amount of one or more precursor of ketone bodies or carrier vehicle of ketone bodies (KB), other than simple ketone esters or 1,3-butanediol, sufficient to raise the blood concentration of ketone bodies to at least 2 to 4 mM.
- KB ketone bodies
- the precursor is a medium chain triglyceride (MCT) or mixture of MCT, such as glycerol esters of caproic acid, caprylic acid and capric acid.
- the precursor may be medium chain fatty acids esterified to ketone bodies.
- the precursor may be used in combination with a ketogenic diet.
- the precursor is provided in a formulation comprising MCT.
- a formulation comprising MCT.
- Fuel for Thought ® (“F4T”, Cognate Nutritionals) and its related proprietary ketogenic foods.
- the ketone body is preformed and is provided in a vehicle that carries the KB to the part of the GI tract where the KB is split off from its carrier by digestive hydrolysis and then transported directly into the blood circulation for utilization by the brain and other tissues and organs.
- the formulation comprises medium chain fatty acids esterified to glycerol esters of ketone bodies to form a structured oil.
- the structured oil has a ketone body to medium chain fatty acid ratio of about 2: 1. In some embodiments, the structured oil has a ketone body to medium chain fatty acid ratio of about 1 :2. (See Fig. 1A). These may be formed from glycerol, ⁇ -hydroxybutyric acid, t-butyl acetoacetate and one or more MCT-containing oil, such as coconut oil or palm kernel oil.
- the precursor is provided in a formulation comprising medium chain fatty acids esterified directly to ketone bodies to form a random copolymer oil.
- the random copolymer oil has a ketone body to medium chain fatty acid ratio of from about 2: 1 to about 10: 1.
- the random copolymer oil has a ketone body
- 6 to medium chain fatty acid ratio of about 5: 1. See Fig. IB).
- These may be formed from ⁇ - hydroxybutyric acid, t-butyl acetoacetate and one or more MCT-containing oil, such as coconut oil or palm kernel oil.
- the precursor is provided in a formulation comprising one or more of an MCT-containing oil, a structured oil and a random copolymer oil, each of which is orally bioavailable and can be enterally administered, e,g., orally or via GI tube .
- the elevation of ketones by the method according to the invention in an individual following TBI provides an alternative energy source to mitigate neuronal cell damage and death, mitigates free radical production, deactivates PARP and depletion of cytosolic NAD+, mitigates inflammation and oxidative stress caused by reactive oxygen species (ROS), and provides long- term stabilization and maintenance of neuronal cell performance through ongoing nutritional support for neurons that is more efficient on a molecular weight basis than glucose. (Prins, 2013).
- a "simple ketone ester” is an ester of one or more ketones.
- simple ketone esters are D-P-hydroxybutyrate, R-l,3-butanediol monoester, 1,3- butanediol acetoacetate esters, glycerol-tris-3-hydroxybutyrate, butanediol diester acetoacetate, and other oligoketone esters.
- an "individual” and like terms means a human or other mammal.
- a mixture of ⁇ -hydroxybutyric acid (52.0 g, 0.5 mole), and coconut oil (45 g, 0.1 mole) is heated to about 110°C for approximately 18 hours. Reaction is performed under nitrogen. Ethyl alcohol produced and remaining ⁇ -hydroxybutyric acid is removed through distillation (1 mmHg, 80°C). The composition is confirmed by NMR.
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Abstract
The invention provides methods for elevating the cerebral concentration of ketone bodies in individuals having traumatic brain injury. The methods comprise administering to an individual having traumatic brain injury an amount of a precursor of ketone bodies.
Description
IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
APPLICATION FOR UNITED STATES LETTERS PATENT
FOR
NUTRITIONAL MITIGATION OF THE CNS EFFECTS OF TRAUMATIC
BRAIN INJURY
BY
Theodore B. Vanltallie, M.D. Robert A. Firger
Assignee: Cognate Nutritionals, Inc.
NUTRITIONAL MITIGATION OF THE CNS EFFECTS OF TRAUMATIC
BRAIN INJURY
BACKGROUND OF THE INVENTION
Field of the invention
The invention relates to traumatic brain injury. More particularly, the invention relates to mitigation of further brain damage in the aftermath of traumatic brain injury that is caused by trauma-induced physiological and biochemical changes in the brain
Summary of the related art
Traumatic brain injury (TBI) occurs when a traumatic event causes the brain to move rapidly within the skull, leading to damage. The skull can make direct contact with an object (impact), or encounter a non-impact force such as blast waves or rapid acceleration or deceleration. A TBI happens every 15 seconds in the US, generating 1.7 million new head injury victims each year. These events are responsible for 50,000 annual deaths, leave 80,000 individuals with permanent disabilities, and cost more than US $77 billion on average each year. The frequency of brain injury is currently higher than that of any other affliction disease, including complex diseases such as breast cancer, AIDS, Alzheimer's disease, Parkinson's disease and multiple sclerosis. In addition, there is evidence to suggest that moderate to severe TBI, and even repeated mild TBI, might be associated with increased risk of neurodegenerative diseases such as Alzheimer-like dementia disease, chronic traumatic encephalopathy (CTE) and Parkinson's disease.
In closed head injury, damage occurs because the person receives a blow to the head or other force that whips the head forward and back or from side to side (as in a car crash), causing the brain to collide at high velocity with the bony skull in which it is housed. The specific areas of the brain involved, most often the frontal and temporal lobes, suffer brain tissue bruising and tearing of brain blood vessels. In addition, the rapid movement of the brain can stretch and injure neuronal axons that link brain cells together and the brain to the rest of the body, causing widespread impairment of function.
Open head injury, the second type of TBI, occurs when the skull is penetrated and has more focal damage.
Because little can be done to reverse the initial brain damage caused by trauma, medical personnel currently try to stabilize an individual with TBI and focus on containing the injury and preventing secondary complications. Primary concerns include ensuring proper oxygen and nutrient supply to the brain and the rest of the body, maintaining adequate blood flow and controlling blood pressure. Additional trauma can be triggered by the percussion injury.
Impairment of cerebral glucose utilization can occur so that key parts of the brain may become energy-deprived. At the same time central nervous system (CNS) lactate content increases, reflecting a likely block in glycolysis or in pyruvate oxidative decarboxylation to acetyl-CoA in mitochondria. During the period of depressed glucose metabolism, there is an increased flux of glucose through the pentose phosphate pathway (PPP) resulting in increased production of the nicotinamide adenine diphosphate (NADPH) which is important in preventing oxidative damage During the period of depressed glucose metabolism, there is an increased flux of glucose through the pentose phosphate pathway (PPP), free radical production and activation of poly-adenosine diphosphate ribose polymerase (PARP) via DNA damage. PARP -mediated DNA repair can deplete cytosolic NAD+ pools and inhibit glyceraldehyde 3 -phosphate dehydrogenase
(GADPH). These and other biochemical changes can lead to extensive further brain cell death. (Prins, 2013).
Recently, a ketogenic diet has been tested as a means for mitigating this further damage. The classical ketogenic diet has been in clinical use for more than 80 years, primarily for the symptomatic treatment of epilepsy. It is a high fat content diet in which carbohydrates are nearly eliminated (on a caloric basis, 90% fat, 2% carbohydrate and 8% protein) so that the body has minimal dietary sources of glucose. During high rates of fatty acid oxidation, large amounts of acetyl-CoA are generated. These exceed the capacity of the TCA cycle and lead to the synthesis of three ketone bodies within liver mitochondria. Plasma levels of ketone bodies rise, with acetoacetate and β-hydroxybutyrate increasing three to four- fold from basal levels of 100 and 200 μΜ (0.1-0.2mM) respectively. At these modestly increased concentrations, these ketone bodies are readily used for energy by neurons.
Efforts to utilize the ketogenic diet to produce a neuroprotective effect in TBI have been promising, but there remains a need to get higher levels of ketone bodies to the affected area of the brain. Intravenous infusion of β-hydroxybutyrate resulted in improved brain ATP concentration, but long-term intravenous ketone infusions are associated with unsafe plasma osmolality changes, and in the only study to measure brain ketone levels, only about one percent of the blood levels achieved actually got into cerebral spinal fluid. Oral ketone esters have been tried for this purpose, but in the one human clinical trial conducted, 12 of 12 healthy volunteers reported significant side effects such as nausea, abdominal distension, headache, diarrhea, dizziness, chest pain and upper abdominal pain. There is a need, therefore, for new methods for keeping cerebral ketone body concentrations elevated on a sustained basis in TBI victims, during (i) the recovery period, and (ii) during a stabilization and maintenance period.
BRIEF SUMMARY OF THE INVENTION
The invention relates to mitigation of further injury in the aftermath of a traumatic brain injury that gives rise to diffuse and focal histopathological, physiological and biochemical brain lesions. The invention provides new methods for elevating the cerebral concentration of ketone bodies in individuals who have experienced acute traumatic brain injury (TBI).
The invention comprises administering to an individual having TBI an amount of one or more precursors of ketone bodies or carrier vehicles of ketone bodies, other than simple ketone esters or 1,3-butanediol, capable of raising the blood concentration of ketone bodies to at least about 2 to 4 mM. In some embodiments, the precursor is a medium chain triglyceride. In some embodiments, the precursor or carrier vehicle may itself be esterified to ketone bodies or fatty acids of various chain lengths and degrees of unsaturation. In some embodiments, the precursor may be used in combination with a ketogenic diet.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 A shows examples of structured oils according to the invention. FIG. IB shows examples of random copolymer oils according to the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention relates to mitigation of further injury in the aftermath of the traumatic brain injury that gives rise to biochemical and physiological CNS lesions (diffuse and/or focal) . The invention provides new methods for elevating the blood concentration of ketone bodies in victims of traumatic brain injury (TBI).
The invention comprises administering to an individual having TBI an amount of one or more precursor of ketone bodies or carrier vehicle of ketone bodies (KB), other than simple ketone esters or 1,3-butanediol, sufficient to raise the blood concentration of ketone bodies to at least 2 to 4 mM. This can typically be achieved with a serving size having the ketogenic potential equivalent to from about a 20 g to 50 g serving size of pure ketone ester. In some embodiments, the precursor is a medium chain triglyceride (MCT) or mixture of MCT, such as glycerol esters of caproic acid, caprylic acid and capric acid. In some embodiments, the precursor may be medium chain fatty acids esterified to ketone bodies. In some embodiments, the precursor may be used in combination with a ketogenic diet. In some embodiments, the precursor is provided in a formulation comprising MCT. One example of such a formulation is Fuel for Thought® ("F4T", Cognate Nutritionals) and its related proprietary ketogenic foods.
In some embodiments, the ketone body is preformed and is provided in a vehicle that carries the KB to the part of the GI tract where the KB is split off from its carrier by digestive hydrolysis and then transported directly into the blood circulation for utilization by the brain and other tissues and organs. In some embodiments, the formulation comprises medium chain fatty acids esterified to glycerol esters of ketone bodies to form a structured oil. In some
embodiments, the structured oil has a ketone body to medium chain fatty acid ratio of about 2: 1. In some embodiments, the structured oil has a ketone body to medium chain fatty acid ratio of about 1 :2. (See Fig. 1A). These may be formed from glycerol, β-hydroxybutyric acid, t-butyl acetoacetate and one or more MCT-containing oil, such as coconut oil or palm kernel oil.
In some embodiments, the precursor is provided in a formulation comprising medium chain fatty acids esterified directly to ketone bodies to form a random copolymer oil. In some embodiments the random copolymer oil has a ketone body to medium chain fatty acid ratio of from about 2: 1 to about 10: 1. In some embodiments the random copolymer oil has a ketone body
6
to medium chain fatty acid ratio of about 5: 1. (See Fig. IB). These may be formed from β- hydroxybutyric acid, t-butyl acetoacetate and one or more MCT-containing oil, such as coconut oil or palm kernel oil.
In each of these embodiments, it is possible to improve the absorption and digestibility of the formulated oil by mixing in one or more polyunsaturated and/or monounsaturated long chain fatty acid into the ester, as described in co-pending applications nos. 61/981,418 and 61/981,423.
In some embodiments, the precursor is provided in a formulation comprising one or more of an MCT-containing oil, a structured oil and a random copolymer oil, each of which is orally bioavailable and can be enterally administered, e,g., orally or via GI tube .
The elevation of ketones by the method according to the invention in an individual following TBI provides an alternative energy source to mitigate neuronal cell damage and death, mitigates free radical production, deactivates PARP and depletion of cytosolic NAD+, mitigates inflammation and oxidative stress caused by reactive oxygen species (ROS), and provides long- term stabilization and maintenance of neuronal cell performance through ongoing nutritional support for neurons that is more efficient on a molecular weight basis than glucose. (Prins, 2013).
For puposes of the invention a "simple ketone ester" is an ester of one or more ketones. Examples of simple ketone esters are D-P-hydroxybutyrate, R-l,3-butanediol monoester, 1,3- butanediol acetoacetate esters, glycerol-tris-3-hydroxybutyrate, butanediol diester acetoacetate, and other oligoketone esters. For purposes of the invention, an "individual" and like terms means a human or other mammal.
The following examples are intended to further illustrate certain embodiments of the invention and are not to be construed as limiting its scope.
Example 1
Interesterification of a glycerol ester of MCT and a ketone ester, β-hvdroxybutyrate, at an average ratio of 1 :2
A mixture of glycerol (9.2 g, 0.1 mole), β-hydroxybutyric acid (20.1 g, 0.2 mole), and coconut oil 45 g, 0.1 mole) is heated to about 110°C for approximately 18 hours. Reaction is
7
performed under nitrogen. Ethyl alcohol produced and remaining β-hydroxybutyric acid is removed through distillation (1 mmHg, 80°C). The composition is confirmed by NMR.
Example 2
Interesterificationof a glycerol ester of MCT and β-hydroxybutyrate at an average ratio of 2: 1 A mixture of glycerol (9.2 g, 0.1 mole), (R)P-hydroxybutyric acid (10. Og, 0.1 mole), and coconut oil (90 g, 0.2 mole) is heated to about 110°C for approximately 18 hours. Reaction is performed under nitrogen. Ethyl alcohol produced and remaining β-hydroxybutyric acid is removed through distillation (1 mmHg, 80°C). The composition is confirmed by NMR.
Example 3
Interesterification of a random copolymer of MCT and β-hydroxybutyrate at an average ratio of
5
A mixture of β-hydroxybutyric acid (52.0 g, 0.5 mole), and coconut oil (45 g, 0.1 mole) is heated to about 110°C for approximately 18 hours. Reaction is performed under nitrogen. Ethyl alcohol produced and remaining β-hydroxybutyric acid is removed through distillation (1 mmHg, 80°C). The composition is confirmed by NMR.
See also, "Oils and Fats Manual, A Comprehensive Treatise", Vol 2, Chapter 11, Transformation of Fat for Use in Food Products.
8
References
Prins, M ., Fujima, L.S. and Hovda, D.A. (2005) Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. J. Neurosci. Res. 82:413-420.
Prins, M., Greco, T., Alexander, D and Giza, C.C. (2013) The pathophysiology of traumatic brain injury at a glance. Disease Models and Mechanisms 6: 1307-1315.
Gaisor, M.,Rogawski, M.A. and Hartman, AX., (2006) Neuroprotective and disease-modifying effects of the ketogenic diet. Behav. Pharmacol. 17: 431-439.
Veech, R.L., Valeri, C.R. and Vanltallie, T.B. (2012) The mitochondrial permeability transition pore provides a key to the diagnosis and treatment of traumatic brain injury. IUBMB Life 64: 203-207.
Prins,. MX. and Hovda, D.A. (2009) The effects of age and ketogenic diet on Local Cerebral Metabolic rates of glucose after controlled Cortical Impact Injury in Rats. J. Neurotrauma 26: 1083-1093.
Prins, M. (2008) Diet, ketones and neurotrauma. Epilepsia 48(Suppl 8): 111-113.
Prins, MX. and Matsumoto, J. (2014) The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. J. Lipid Res. Doi.l0/194/jlr.R046706
Saatman et al, (2008) Classification of traumatic brain injury for Targeted therapies. J.
Neurotrauma 25:719-738.
9
Claims
1. A method for elevating the blood concentration of ketone bodies in individuals having traumatic brain injury (TBI), comprising administering to an individual having TBI an amount of a precursor of ketone bodies sufficient to raise the extracellular cerebral concentration of ketone bodies to at least about 2mM, wherein the precursor is not a simple ketone ester or 1,3 butanediol.
2. The method according to claim 1, wherein the precursor is provided in a formulation comprising one or more of medium chain triglycerides (MCT), a structured oil comprising a glycerol ester of a ketone body and a medium chain fatty acid, and a random copolymer oil comprising a ketone body esterified to a medium chain fatty acid.
3. The method of claim 2, wherein the formulation is (F4T).
4. The method according to claim 2, wherein the structured oil has a ketone body to medium chain fatty acid ratio of about 2: 1.
5. The method according to claim 2, wherein the structured oil has a ketone body to medium chain fatty acid ratio of about 1 :2.
6. The method according to claim 2, wherein the random copolymer oil has a ketone body to medium chain fatty acid ratio of from about 2: 1 to about 10: 1.
7. The method according to claim 2, wherein the random copolymer oil has a ketone body to medium chain fatty acid ratio of about 5: 1.
8. The method according to claim 1 or 2, wherein the formulation is administered in
combination with a ketogenic diet.
9. The method according to claim 1 or 2, wherein the extracellular cerebral concentration of ketone bodies is raised to from about 2 mM to about 8mM.
10
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US10736867B2 (en) | 2017-01-12 | 2020-08-11 | Neuroenergy Ventures, Inc. | Glyceryl 3-hydroxybutyrates for traumatic brain injury |
| US10792269B2 (en) | 2016-12-23 | 2020-10-06 | Neuroenergy Ventures, Inc. | Glyceryl 3-hydroxybutyrates for migraine symptom management |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10792269B2 (en) | 2016-12-23 | 2020-10-06 | Neuroenergy Ventures, Inc. | Glyceryl 3-hydroxybutyrates for migraine symptom management |
| US10736867B2 (en) | 2017-01-12 | 2020-08-11 | Neuroenergy Ventures, Inc. | Glyceryl 3-hydroxybutyrates for traumatic brain injury |
| US11638702B2 (en) | 2017-01-12 | 2023-05-02 | NeuroEnerygy Ventures, Inc. | Glyceryl 3-hydroxybutyrates for traumatic brain injury |
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