US20010014696A1 - Therapeutic compositions (II) - Google Patents

Therapeutic compositions (II) Download PDF

Info

Publication number
US20010014696A1
US20010014696A1 US09/799,124 US79912401A US2001014696A1 US 20010014696 A1 US20010014696 A1 US 20010014696A1 US 79912401 A US79912401 A US 79912401A US 2001014696 A1 US2001014696 A1 US 2001014696A1
Authority
US
United States
Prior art keywords
hydroxybutyrate
formula
human
blood
cyclic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US09/799,124
Other languages
English (en)
Inventor
Richard Veech
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BTG International Ltd
Original Assignee
BTG International Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BTG International Ltd filed Critical BTG International Ltd
Priority to US09/799,124 priority Critical patent/US20010014696A1/en
Assigned to BTG INTERNATIONAL LIMITED reassignment BTG INTERNATIONAL LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VEECH, RICHARD L.
Publication of US20010014696A1 publication Critical patent/US20010014696A1/en
Priority to US10/734,586 priority patent/US7351736B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to compositions suitable for administration to humans and animals which have the properties of increasing levels of (R)-3-hydroxybutyrate ((R)-3-hydroxybutyric acid or D- ⁇ -hydroxybutyrate) when so administered; particularly when administered orally, topically, subcutaneously or parenterally, but most advantageously orally.
  • Administration of (R)-3-hydroxybutyric acid has a number of beneficial actions on the human and animal body. These include inter alia, increasing cardiac efficiency, e.g. in heart failure, provision of an alternative energy source to glucose, e.g. in diabetes and insulin resistant states, and treating disorders caused by damage to neuronal cells, e.g. CNS cells, particularly by retarding or preventing brain damage such as found in Alzheimer's and Parkinsonism and similar diseases and conditions.
  • EP 0780123 A1 further teaches use of acetoacetate, ⁇ -hydroxybutyrate, monohydric, dihydric or trihydric alcohol esters of these or linear oligomers of 2 to 10 repeats of ⁇ -hydroxybutyrate for suppressing cerebral edema, protecting cerebral function, rectifying cerebral energy metabolism and reducing the extent of cerebral infarction.
  • Intravenous infusion of sodium salts of (R)-3-hydroxybutyrate has been performed on normal human subjects and patients for a number of conditions, e.g. those undergoing treatment for severe sepsis in an intensive care unit and is found to be non-toxic and capable of decreasing glucose free fatty acids and glycerol concentration, but ineffective in decreasing leucine oxidation.
  • the present inventor has further determined that compounds and compositions that raise blood levels of (R)-3-hydroxybutyric acid and/or acetoacetate also have utility in reducing free radicals in vivo, and thus have a place in treatment of free radical associated diseases.
  • (R)-3-hydroxybutyrate and acetoacetate provide a normal physiological alternative to the usual energy producing substrates, glucose and fatty acids.
  • fatty acids are converted by liver to (R)-3-hydroxybutyric acid and acetoacetate which can be utilized by most major tissues of the body except liver.
  • total blood ketone bodies are elevated to about 7 mM.
  • extrahepatic tissues such as brain, heart and skeletal muscle utilize these ketone bodies within the mitochondria to provide reducing power in the form of NADH which is the primary substrate of the electron transport system and generator of the energy required for the synthesis of ATP.
  • the inventor has thus determined that free radical damage resulting from excess reduced Q or inhibition of NADH dehydrogenase, such as occurs in MPP induced toxicity, can be reduced by administration of agents which elevate ketone body levels in vivo.
  • a number of disease processes involve damage by free radicals among which are the neurological diseases: Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and cerebral ischemia.
  • excessive free radical damage has been implicated as playing a role in coronary reperfusion, diabetic angiopathy, inflammatory bowel disease and pancreatitis.
  • the inventor's copending WO 98/41201 discloses the administration of linear esters of (R)-3-hydroxybutyric acid and/or acetoacetate in producing elevated levels of the free compounds in vivo.
  • Oral administration of 4 mM solutions of the oligomer tetra-(R)-3-hydroxybutyrate or its acetoacetyl ester was shown to raise blood levels of ketone bodies such that (R)-3-hydroxybutyrate levels could be measured to have increased by 1 to 2 mM for periods in excess of 2 hours.
  • the inventor has now determined that unexpected advantages are provided when the (R)-3-hydroxybutyric acid component of such composition is administered as a cyclic oligomer.
  • These advantages may include, inter alia, (a) increased efficiency in raising blood (R)-3-hydroxybutyric acid levels such that levels may be increased by more than 2 mM, including attainment of near fasting levels and beyond, (b) maintenance of elevated levels for periods of several hours, (c) ability to be administered without counterion, such as sodium or methylglucamine, where it is desirable not to increase a patient's salt load or where significant dosing is envisaged and (d) relative ease of manufacture of pure compound from polymeric starting materials available through bioculture.
  • the present application particularly addresses the problem of neurodegenerative diseases, particularly disease where neurons are subject to neurotoxic effects of pathogenic agents such as protein plaques and oxidative damage and further provides compositions for use in treating these and the aforesaid disorders.
  • the present invention provides elevation of blood ketones necessary to correct the defects described above and can be accomplished by parenteral or enteral administration. Particularly it does not require the administration of potentially toxic pharmacological agents.
  • the present invention's improved efficacy in raising levels, particularly blood levels, of ketone bodies provides therapeutic effects of the classical ketogenic diet, which is not itself found to be toxic in children, with none of the side effects that render that unused adults.
  • the inventor has determined that with the correction of the aforesaid metabolic and toxic defects, cytokine responses and the increase in apoptotic peptides in degenerating cells will decrease due to the increase in neuronal cell energy status and the increased trophic stimulation resulting from increased neurotransmitter, e.g. acetyl choline, synthesis.
  • the treatment that the present inventor provides goes beyond ketone body effects on circulation, as it provides treatment for cells that are unable to function due to neuro-degeneration and/or metabolic defects, particularly in metabolism of glucose, e.g. caused by neurotoxic agents such as peptides, proteins, free radical damage and effect of genetic abnormality.
  • the treatment involves action of ketone bodies on the cells themselves and not the flow of blood to them.
  • n is an integer of 1 or more
  • free cyclic oligomer may be preferred. Where cations are present in a complex preferred cations are sodium, potassium, magnesium and calcium, and are balanced by physiologically acceptable counter-anion providing a salt complex.
  • physiologically acceptable salts will be selected from sodium, potassium, magnesium, L-Lysine and L-arginine or e.g. more complex salts such as those of methyl glucamine salts.
  • n is an integer from 1 to 200, more preferably from 1 to 20, most preferably from 1 to 10 and particularly conveniently is 1, i.e. (R, R, R)-4,8,12-trimethyl-1,5,9-trioxadodeca-2,6,10-trione, 2,3,4 or 5.
  • the cyclic esters of the invention are preferably used in the treatment of disease states mediated by free radicals, toxic agents such as peptides and proteins, genetic defects detrimental to nerve cell metabolism, insulin resistance or other glucose metabolism defects or defect inducing states, ishemia, head trauma and/or for increasing cell efficiency, e.g. cardiac cell efficiency e.g. in heart failure.
  • a second aspect of the invention provides methods of treating cells that are subject to malfunction due to action of free radicals, toxic agents such as peptides and proteins, genetic defects detrimental to cell metabolism, insulin resistance or other glucose metabolism defects or defect inducing states, ischemia, head trauma and/or for increasing cell efficiency characterised in that it comprises administration of a cyclic oligomer of formula (I). This may include treatment of such disease states in humans and/or animals.
  • This aspect includes such use as a neuronal stimulant e.g. capable of stimulating axonal and/or dendritic growth in nerve cells, e.g. in hippocampal or substantia nigral cells, in vivo or in vitro, particularly in conditions where neurodegeneration has serious clinical consequences, through its elevating effect on blood and plasma (R)-3-hydroxybutyrate and acetoacetate levels.
  • a neuronal stimulant e.g. capable of stimulating axonal and/or dendritic growth in nerve cells, e.g. in hippocampal or substantia nigral cells, in vivo or in vitro, particularly in conditions where neurodegeneration has serious clinical consequences, through its elevating effect on blood and plasma (R)-3-hydroxybutyrate and acetoacetate levels.
  • a third aspect of the invention provides a method of enteral or parenteral nutrition, preferably oral route nutrition, comprising administration of a cyclic oligomer of formula (I).
  • a fourth aspect of the invention provides the use of a cyclic ester formula I for the manufacture of a medicament for the treatment of disease states mediated by free radicals, toxic agents such as peptides and proteins, genetic defects detrimental to cell metabolism, insulin resistance or other glucose metabolism defects or defect inducing states, ischemia, head trauma and/or for increasing cell efficiency.
  • a fifth aspect of the invention provides composition characterised in that it comprises a cyclic oligomer of formula (I) in physiologically acceptable form e.g. with a physiologically acceptable carrier.
  • composition is suitable for parenteral or enteral administration, particularly for oral administration.
  • composition is for parenteral use it is sterile and pyrogen free.
  • the composition may include a foodstuff base and may be in the form of an emulsion or mere admixture with solid food.
  • the cyclic oligomer(s) comprise an effective amount of the total composition, e.g. at least 2% or more, e.g. at least 5%, of the composition by weight, more preferably 20% or more and most preferably 50% to 100%.
  • the composition may be adapted for oral, parenteral or any other conventional form of administration.
  • the compound of formula (I) is administered together with a physiological ratio of acetoacetate or a metabolic precursor of acetoacetate.
  • metabolic precursor thereof particularly relates to compounds that incorporate acetoacetyl moieties such as acetoacetyl-1,3-butandiol, preferably acetoacetyl-(R)-1,3-butandiol, acetoacetyl-(R)-3-hydroxybutyrate, and acetoacetylglycerol.
  • Esters of any such compounds with monohydric, dihydric or trihydric or higher, e.g. glucosyl, alcohols are also envisaged.
  • the present inventor has determined that supplementing type II diabetics with cyclic oligomers of the invention will allow better control of blood sugar, thus preventing the vascular changes in eye and kidney which occur now after 20 years of diabetes and which are the major cause of morbidity and mortality in diabetics.
  • therapy is improved by use of cyclic oligomers, due to the reduction or elimination of both high lipid and carbohydrate content.
  • Such patients include those with genetic defects in the brain glucose transporter system, in glycolysis or in PDH itself such as in Leigh's syndrome, endotoxic shock or high stress states.
  • Particular disorders treatable with these medicaments are applicable to all conditions involving PDH blockage, including those conditions occuring after head trauma, or involving reduction or elimination of acetyl CoA supply to the mitochondrion such as insulin coma and hypoglycaemia, defects in the glucose transporter in the brain, or elsewhere (80), or in glycolytic enzyme steps.
  • the medicament or nutraceutical comprises acetoacetate it is preferably not stored for a prolonged period or exposed to temperatures in excess of 40° C. Acetoacetate is unstable on heating and decomposes violently at 100° C. into acetone and CO 2 . In such circumstances it is preferred that acetoacetate is generated by the composition on contact with the bodies metabolic processes.
  • the composition comprises an ester precursor of actetoacetate.
  • a sixth aspect of the invention provides a method of treating a human or animal neuronal cell, e.g. brain cells, subject to cell damage related disorder, particularly those which lead to cell death, as referred to for the second to fourth aspects, particularly a neurodegenerative disorder e.g. such as those related to neurotoxic conditions such as presence of amyloid protein, e.g. a memory or movement associated disorder such as Alzheimer's or Parkinson's diseases, or epileptic seizures, comprising administering to that person at least one of the materials for use in the first to fifth aspects of the invention.
  • a human or animal neuronal cell e.g. brain cells
  • cell damage related disorder particularly those which lead to cell death
  • a neurodegenerative disorder e.g. such as those related to neurotoxic conditions such as presence of amyloid protein, e.g. a memory or movement associated disorder such as Alzheimer's or Parkinson's diseases, or epileptic seizures
  • ketone bodies provided by administration of the cyclic oligomers of (R)-3-hydroxybutyric acid in amounts sufficient to raise total blood ketone body concentration to elevated levels result in more than simple maintenance of cell viability but actually improve cell function and growth beyond that of normal, i.e. control levels in a manner unrelated to blood flow or nutrition.
  • the invention further provides use of the cyclic oligomers as agents capable of producing neuronal stimulation, i.e. nerve growth factor like activity, increase of metabolic rate and increase of extent of functional features such as axons and dendrites.
  • This aspect of the present invention offers a mechanism for improvement of neuronal function as well as mere retardation of degredation.
  • the recent work of Hoshi and collaborators (77, 78) strongly suggests that a part of the amyloid protein whose accumulation is the hallmark of Alzheimer's disease, A ⁇ 1-42 , acts to stimulate mitochondrial histidine protein kinase which phosphorylates and inactivates the pyruvate dehydrogenase multienzyme complex.
  • the PDH complex is a mitochondrial enzyme responsible for the generation of acetyl CoA and NADH from the pyruvate produced by glycolysis within the cytoplasm.
  • the mitochondrial acetyl CoA formed condenses with oxaloacetate to start the Krebs TCA cycle completely combusting pyruvate to CO 2 while providing the mitochondria with the reducing power which becomes the substrate for the electron transport system through which the energy required for mitochondrial ATP synthesis is generated
  • Ketone body utilization in brain is limited by the transport, with lesser utilization occurring in the basal ganglion at blood levels below 1 mM (76). However, at levels of 7.5 mM achieved in normal man by prolonged fasting, the rate of ketone body entry into brain is sufficient to take over the majority of cerebral energy needs and to prevent hypoglycemic symptoms, even in the face of blood sugar levels which would normally cause convulsions or coma (63) .
  • the released free fatty acids can then be taken up and used as a source of energy by muscle, heart, kidney and liver in the process of ⁇ -oxidation.
  • Liver has the capacity to convert the free fatty acids to a metabolic fuel, ketones, for use by extra-hepatic organs, including the brain, as an alternative to glucose during periods of fasting.
  • the hepatic synthesis of ketone bodies occurs from mitochondrial acetyl CoA generated during the ⁇ -oxidation of fatty acids by liver.
  • ketone bodies enter extra-hepatic tissues on the same carrier, where other monocarboxylates can act as competitive inhibitors.
  • Unphysiological isomers such as D-lactate or (S)-3-hydroxybutyrate can also act as competitive inhibitors to ketone body transport. Since ketone body transport across the blood brain barrier is a limiting factor to ketone body utilization in brain (76) every effort should be made to keep the blood concentration of these unphysiological enantiomers at low levels during ketogenic therapy.
  • blood ketone body concentrations are elevated to levels found in starvation, heart, muscle, kidney and brain utilize ketone bodies as the preferred energy substrate.
  • the present inventor has thus determined that the mitochondrial acetyl CoA derived from ketone bodies as produced using the cyclic oligomers taught by the present invention can thus replace the acetyl CoA deficiency which occurs during inhibition of PDH multienzyme complex in tissues dependent upon the metabolism of glucose for their supply of metabolic energy.
  • the mitochondrial citrate supplied can also be transported to cytoplasm by the tri or dicarboxcylic acid transporter where it can be converted to cytoplasmic acetyl CoA required for the synthesis of acetyl choline.
  • the reactions of the Krebs cycle are shown in Scheme 1 to help illustrate these concepts further.
  • Ketone bodies in contrast to free fatty acids, cannot produce acetyl CoA in liver. Since acetyl CoA is the essential precursor of fatty acid, they cannot result in either increased fatty acid or cholesterol synthesis in liver, which usually accounts for over half of the body's synthesis of these two potentially pathogenic materials. Liver is sensitive to the ratio of acetoacetate/(R)-3-hydroxybutyrate presented to it and will alter its mitochondrial free [NAD + ]/[NADH], because of the near equilibrium established by ⁇ -hydroxybutyrate dehydrogenase (EC 1.1.1.30) (31).
  • the aforementioned also indicates that one can provide a method of increasing the efficiency of mitochondrial energy production in a human or animal not suffering from a chronic or acute metabolic disease comprising administering to the human or animal an amount of a cyclic oligomer of formula (I) sufficient to raise blood levels of (R)-3-hydroxybutyrate to from 0.5 to 20 mM.
  • the ketogenic diet comprised mainly of lipid, has been used since 1921 for the treatment of epilepsy in children, particularly myoclonic and akinetic seizures (109) and has proven effective in cases refractory to usual pharmacological means (71). Either oral or parenteral administration of free fatty acids or triglycerides can increase blood ketones, provided carbohydrate and insulin are low to prevent re-esterification in adipose tissue.
  • Rats fed diets comprised of 70% corn oil, 20% casein hydrolysate, 5% cellulose, 5% McCollum's salt mixture, develop blood ketones of about 2 mM. Substitution of lard for corn oil raises blood ketones to almost 5 mM (Veech, unpublished).
  • the levels of ketone bodies achieved on such diets are about 2 mM (R)-3-hydroxybutyrate and 1 mM acetoacetate while the levels of free fatty acids are about 1 mM.
  • Other variations of composition have been tried including medium chain length triglycerides.
  • compliance with such restricted diets has been poor because of their unpalatability (56).
  • High lipid, low carbohydrate diets also have been tried as therapeutic agents in cancer patients to reduce glucose availability to tumors (88), as weight reducing diets in patients with and without diabetes (74, 112) and to improve exercise tolerance (83).
  • racemic 1,3 butandiol has been extensively studied as a cheap caloric source in animal food and has even been used experimentally in human diets (81, 101) the production of the unnatural L-isomer is likely in the long run to produce significant toxicity as has been shown for the human use of the unnatural D-lactate (64).
  • One disadvantage of administering the unnatural L isomer is that it competes for transport with the natural (R)-3-hydroxybutyrate.
  • provision of the (R) 1,3 butandiol as a precursor of ketone bodies is one possibility that avoids unnecessary administration or production of the unnatural isomer.
  • esters of (R) 1,3 butandiol can be used, either alone or as the acetoacetate ester.
  • Studies in rats have shown that feeding racemic 1,3 butandiol caused liver cytosolic [NAD + ]/[NADH] to decrease from 1500 to about 1000 (87).
  • administration of ethanol reduces hepatic [NAD ⁇ ]/[NADH] to around 200 (106).
  • Acetoacetate when freshly prepared, can be used in infusion solutions where it can be given in physiologically normal ratios with (R)-3-hydroxybutyrate to optimum effect (95). Because of manufacturing requirements which currently require long shelf life and heat sterilized fluids, acetoacetate has frequently been given in the form of an ester. This has been done to increase its shelf life and increase its stability to heat during sterilization. In the blood stream, esterase activity has been estimated to be about 0.1 mmol/min/ml and in liver about 15 mmol/min/g (68).
  • a physiological ratio of ketones should be produced through administration of cyclic oligomers and acetoacetate. If it is not, in the whole animal, the liver will adjust the ratio of ketones in accordance with its own mitochondrial free [NAD + ]/[NADH]. If an abnormal ratio of ketones is given the liver will adjust the ratio, with coincident changes in liver [NAD + ]/[NADH].
  • the cyclic oligomers for use in the present invention are conveniently synthesized from the microorganism produced polyesters.
  • Natural polyesters of (R)-3-hydroxybutyrate are sold as articles of commerce e.g. as polymers of 530,000 MW from Alcaligenes eutrophus (Sigma Chemical Co. St. Louis) or as 250,000 MW polymers for sugar beets (Fluka, Switzerland).
  • the bacteria produce the polymer as a source of stored nutrient. The fermentation of these polymers by bacteria was developed in the 1970s by ICI in the UK and Solvay et Cie in Belgium, as a potentially biodegradable plastic for tampon covers and other uses.
  • the system responsible for the synthesis of the poly (R)-3-hydroxybutyrate has now been cloned and variations in the composition of the polymer produced, based on the substrates given to the bacteria.
  • the genes responsible for the synthesis of polyalkanoates have been cloned and expressed in a number of micro-organisms (93, 102, 113) allowing for production of this material in a variety of organisms under extremely variable conditions.
  • Preferred forms of cyclic oligomeric (R)-3-hydroxybutyrate are, at least in part, readily digestable and/or metabolised by humans or animals. These preferably are of 2 to 200 repeats, typically 2 to 20 and most conveniently from 3 to 10 repeats long, particularly of 3 repeats, i.e. the triolide. It will be realised that mixtures of such oligomers may be employed with advantage that a range of uptake characteristics might be obtained. Similarly mixtures with the monomer or linear oligomers or polymers may be provided in order to modify the blood level profile produced.
  • Cyclic oligomers for use in the invention may be provided, inter alia, by methods described by Seebach et al. Helvetia Chimica Acta Vol 71 (1988) pages 155-167, and Seebach et al. Helvetia Chimica Acta, Vol 77 (1994) pages 2007 to 2033. For some circumstances such cyclic oligomers of 5 to 7 or more (R)-3-hydroxybutyrate units may be preferred as they may be more easily broken down in vivo. The methods of synthesis of the compounds described therein are incorporated herein by reference.
  • the ketone bodies are transported to extrahepatic tissues where they can be utilized.
  • the blood levels of ketones achieved are not subject to variation caused by noncompliant ingestion of carbohydrate, as is the case with the present ketogenic diet. Rather, they would simply be an additive to the normal diet, given in sufficient amounts to produce a sustained blood level, typically of between 0.3 to 20 mM, more preferably 2 to 7.5 mM, over a 24 hour period, depending upon the condition being treated. In the case of resistant childhood epilepsy, blood levels of 2 mM are currently thought to be sufficient.
  • Alzheimer's disease attempts could even be made to keep levels at 7.5 mM or more, as achieved in the fasting man studies, in an effort to provide alternative energy and acetyl CoA supplies to brain tissue in Alzheimer's patients where PDH capacity is impaired because of excess amounts of A ⁇ 1-42 amyloid peptide (77, 78).
  • compositions of the invention are preferably sterile and pyrogen free, particularly endotoxin free. Secondly, they are preferably formulated in such a way that they can be palatable when given as an additive to a normal diet to improve compliance of the patients in taking the supplements.
  • the cyclic oligomers are generally smell free. Formulations of the cyclic oligomers of (R)-3-hydroxybutyrate and its mixtures with acetoacetate may be coated with masking agents or may be targeted at the intestine by enterically coating them or otherwise encapsulating them as is well understood in the pharmaceuticals or nutraceuticals art.
  • ketone bodies contain from about 4 to 6 calories/g, there is preferably a compensatory decrease in the amounts of the other nutrients taken to avoid obesity.
  • the cyclic oligomers of the invention can be used in oral and parenteral use in emulsions, whereas acetoacetate, in the unesterified state, is less preferred as it is subject to spontaneous decarboxylation to acetone with a half time at room temperature of about 30 days.
  • acetoacetate in the unesterified state, is less preferred as it is subject to spontaneous decarboxylation to acetone with a half time at room temperature of about 30 days.
  • the compositions of the invention do include acetoacetate this may be in the form of a precursor.
  • Acetoacetate may conveniently be provided as (R)-3-hydroxybutyrate esters as provided by the copending ‘therapeutic compositions’ application.
  • Preferred cyclic oligomers e.g. the triolide
  • the latter can be provided as an aqueous solution, e.g. as a salt, e.g. sodium, potassium, magnesium or calcium salt
  • the human adult patient could consume 198 g of cyclic esters of the present invention per day.
  • a 2000 calorie diet of the same proportions one could consume 264 g of ketones per day.
  • blood ketones are elevated to about 2 mM, which proves to be effective to some degree at least in over 60% of children treated.
  • ketone levels should be higher because ketones have been substituted at the caloric equivalent of fat, that is 1.5 g of ketone/ g of fat. Accordingly, blood ketones should be approximately 3 mM, an effective level in children, but still below the level achieved in fasting man of 7.5 mM.
  • the present inventor has determined that, while any elevation of ketone bodies may be desirable, a preferred amount of cyclic ester to be administered will be sufficient, with any acetoacetyl component, to elevate blood ketone body levels to the 0.5 to 20 mM level, preferably to the 2 mM to 7.5 mM level and above, particularly when attempting to arrest the death of brain cells in diseases such as Alzheimer's and Parkinsonism. While dead cells cannot be restored, arrest of further deterioration and at least some restoration of function is to be anticipated.
  • the total amount of ketone bodies used in treatment of neurodegeneration such as Alzheimer's and Parkinsonism will preferably elevate blood levels of ketone bodies by from 0.5 mM to 20 mM.
  • the treatment is through maintenance of cells against the effects of neurotoxin this may be at a level sufficient to act as a significant caloric source, e.g. 2 to 7.5 mM in blood.
  • the amount administered may be lower, e.g. to provide 0.2 to 4 mM increase, but can of course be more for this or other disease.
  • treatment for neurodegenerative diseases such as Alzheimer's or Parkinsonism will most effectively be given soon after identifying patient's with a predisposition to develop the disease.
  • treatment for Alzheimers' most effectively follows a positive test result for one or more conditions selected from the group (i) mutations in the amyloid precursor protein gene on chromosome 21, (ii) mutations in the presenilin gene on chromosome 14, (iii) presence of isoforms of apolipoprotein E.
  • Other tests shown to be indicative of Alzheimer's will of course be applicable.
  • triolide was mixed with 5 g Co-op brand Black Cherry yoghurt in separate feeding bowls for 9 of the rats. The remaining 3 rats were given 5 g of the yoghurt without the triolide as controls. The yoghurt containing bowls were placed in the cages and the rats timed while they ate. Two of the three control rats ate all the yoghurt and four of the six triolide yoghurt rats ate approximately half the provided amount. The remaining six rats slept.
  • the two control rats ate 5.2 ⁇ 0.1 g yoghurt and their plasma (R)-3-hydroxybutyrate concentrations were about 0.45 mM at 60 minutes and 180 minutes.
  • the four triolide fed rats ate 0.39 ⁇ 0.03 g of the triolide and 2.6 ⁇ 0.2 g of yoghurt.
  • Their plasma (R)-3-hydroxybutyrate concentrations were 0.8 mM after 80 minutes and 1.1 mM for the group sacrificed at about 150 minutes. All rats displayed no ill effects from ingestion of triolide.
  • serum (R)-3-hydroxybutyrate was found to be elevated by 0.65 mM by feeding of only 0.4 g triolide. Note, as the rats had been fasted, the initial levels of (R)-3-hydroxybutyrate were elevated from the 0.1 mM fed state to about 0.45 mM.
  • test rats thus showed increase in plasma (R)-3-hydroxybutyrate over at least 3 hours with no ill effects. It should be noted that two other rats fed approximately 1.5 g triolide each in ‘Hob-Nob’ biscuit showed no ill effects after two weeks.
  • the primary hippocampal cultures were removed from Wistar embryos on day 18 and dispersed by gentle agitation in a pipette. The suspension was centrifuged at 1,500 ⁇ g for 10 min and the supernatant discarded. The pellet was resuspended in new media to a final cell count of 0.4-0.5 ⁇ 10 6 cells/ml. Ten ⁇ l of this suspension was pipetted into the center of poly D-lysine coated culture wells and the plates incubated at 38° C. for 4 hrs and then 400 ⁇ l of fresh Neurobasal media was added. After 2 days of incubation, half of the media was exchanged for fresh media and the incubation continued for 2 more days.
  • the medium was changed with DMEM/F12 medium containing 5 ⁇ M insulin, 30 nM 1-thyroxine, 20 nM progesterone, 30 nM Na selenite 100 U/ml penicillin and 100 ⁇ g/ml streptomycin.
  • the wells were divided into 4 groups: half the wells received (R)-3-hydroxybutyrate to a final concentration of 8 mM while and half of the wells received 5 nM amyloid ⁇ 1-42 (Sigma).
  • These media were exchanged 2 days later (day 8) and the cells were fixed on day 10 and stained with anti MAP2 (Boehringer Manheim, Indianapolis, Ind.) to visualize neurons and vimentin and GFAP (Boehringer) to visualize glial cells.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polyesters Or Polycarbonates (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
US09/799,124 1998-09-15 2001-03-06 Therapeutic compositions (II) Abandoned US20010014696A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09/799,124 US20010014696A1 (en) 1998-09-15 2001-03-06 Therapeutic compositions (II)
US10/734,586 US7351736B2 (en) 1998-09-15 2003-12-15 Therapeutic compositions (II)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10037198P 1998-09-15 1998-09-15
PCT/US1999/021015 WO2000015216A1 (en) 1998-09-15 1999-09-15 Therapeutic compositions (ii)
US09/799,124 US20010014696A1 (en) 1998-09-15 2001-03-06 Therapeutic compositions (II)

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/021015 Continuation WO2000015216A1 (en) 1998-09-15 1999-09-15 Therapeutic compositions (ii)

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US39464403A Continuation 1998-09-15 2003-03-24

Publications (1)

Publication Number Publication Date
US20010014696A1 true US20010014696A1 (en) 2001-08-16

Family

ID=22279402

Family Applications (2)

Application Number Title Priority Date Filing Date
US09/799,124 Abandoned US20010014696A1 (en) 1998-09-15 2001-03-06 Therapeutic compositions (II)
US10/734,586 Expired - Fee Related US7351736B2 (en) 1998-09-15 2003-12-15 Therapeutic compositions (II)

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/734,586 Expired - Fee Related US7351736B2 (en) 1998-09-15 2003-12-15 Therapeutic compositions (II)

Country Status (18)

Country Link
US (2) US20010014696A1 (ko)
EP (1) EP1123094B1 (ko)
JP (1) JP2002524506A (ko)
KR (1) KR100805490B1 (ko)
CN (1) CN1273129C (ko)
AT (1) ATE359069T1 (ko)
AU (1) AU767238B2 (ko)
BR (1) BR9913680A (ko)
CA (1) CA2339941A1 (ko)
DE (1) DE69935799T2 (ko)
DK (1) DK1123094T3 (ko)
ES (1) ES2283133T3 (ko)
HK (1) HK1035665A1 (ko)
NZ (1) NZ509739A (ko)
PT (1) PT1123094E (ko)
RU (1) RU2242227C2 (ko)
WO (1) WO2000015216A1 (ko)
ZA (1) ZA200101260B (ko)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070299135A1 (en) * 2004-12-10 2007-12-27 Btg International Limited Compositions for Use in Surgery
US20080213691A1 (en) * 2003-09-12 2008-09-04 Headway Technologies, Inc. Method to print photoresist lines with negative sidewalls
US20100003730A1 (en) * 2008-07-03 2010-01-07 Accera, Inc. Enzymatic Synthesis of Acetoacetate Esters and Derivatives
US20100092422A1 (en) * 2003-09-01 2010-04-15 Kazunari Ushida Poly (ß-hydroxy short-medium chain fatty acid)
US20100197758A1 (en) * 2007-04-12 2010-08-05 Andrews Matthew T Ischemia/reperfusion protection compositions and methods of using
US8409585B2 (en) 2007-10-15 2013-04-02 Jbs United, Inc. Method for increasing performance of offspring
US9138420B2 (en) 2013-03-19 2015-09-22 University Of South Florida Compositions and methods for producing elevated and sustained ketosis
GB2490462B (en) * 2010-02-22 2018-02-28 Tdeltas Ltd Nutritional composition comprising ketone body precursors
US10051880B2 (en) 2008-08-21 2018-08-21 Oxford University Innovation Limited Hydroxybutyrate ester and medical use thereof
US10307398B2 (en) 2016-09-20 2019-06-04 Regents Of The University Of Minnesota Resuscitation composition and methods of making and using
GB2572185A (en) * 2018-03-21 2019-09-25 Chain Biotechnology Ltd Pharmaceutical compositions
US10478415B2 (en) 2012-11-05 2019-11-19 Tdeltas Limited Ketone bodies to protect tissues from damage by ionizing radiation
US10821062B2 (en) 2013-03-12 2020-11-03 Tdeltas Limited Compound for use in protecting skin
US10925843B2 (en) 2018-04-18 2021-02-23 Axcess Global Sciences, Llc Compositions and methods for keto stacking with beta-hydroxybutyrate and acetoacetate
US10973792B2 (en) 2019-02-13 2021-04-13 Axcess Global Sciences, Llc Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use
US10973786B2 (en) 2016-03-11 2021-04-13 Axcess Global Sciences, Llc R-beta-hydroxybutyrate, S-beta-hydroxybutyrate, and RS-beta-hydroxybutyrate mixed salt compositions
US10980772B2 (en) 2018-08-27 2021-04-20 Axcess Global Sciences, Llc Compositions and methods for delivering tetrahydrocannabinol and ketone bodies
US11020362B2 (en) 2016-03-11 2021-06-01 Axcess Global Sciences, Llc Beta-hydroxybutyrate mixed salt compositions and methods of use
US11033553B2 (en) 2019-06-21 2021-06-15 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
RU2753057C2 (ru) * 2016-12-21 2021-08-11 Универзитэтс-Киндершпиталь Байдер Базель Предотвращение и лечение мигрени
US11103470B2 (en) 2017-11-22 2021-08-31 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US11129802B2 (en) 2018-08-27 2021-09-28 Axcess Global Sciences, Llc Compositions and methods for delivering cannabidiol and ketone bodies
US11185518B2 (en) 2017-12-19 2021-11-30 Axcess Global Sciences, Llc S-beta-hydroxybutyrate compounds and compositions enriched with S-enantiomer
US11202769B2 (en) 2017-11-22 2021-12-21 Axcess Global Sciences, Llc Ketone body esters of s-beta-hydroxybutyrate and/or s-1,3-butanediol for modifying metabolic function
US11230722B2 (en) 2003-06-03 2022-01-25 Oxford University Innovation Limited Nutritional supplements and therapeutic compositions comprising (r)-3-hydroxybutyrate derivatives
US11241403B2 (en) 2016-03-11 2022-02-08 Axcess Global Sciences, Llc Beta-hydroxybutyrate mixed salt compositions and methods of use
US11241401B2 (en) 2020-02-06 2022-02-08 Axcess Global Sciences, Llc Enantiomerically pure r-beta-hydroxybutyrate mixed salt-acid compositions
US11419836B2 (en) 2019-02-13 2022-08-23 Axcess Global Sciences, Llc Racemic and near racemic beta-hydroxybutyrate mixed salt-acid compositions
WO2023001724A1 (en) 2021-07-17 2023-01-26 Ketoswiss Ag Combination of a ketone body or ketogenic compound with an analgesic or antioxidant
US11566268B2 (en) 2013-03-14 2023-01-31 Government Of The Usa, As Represented By The Secretary, Department Of Health And Human Services Process for producing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
US11806324B2 (en) 2018-04-18 2023-11-07 Axcess Global Sciences, Llc Beta-hydroxybutyric acid compositions and methods for oral delivery of ketone bodies
US11944598B2 (en) 2017-12-19 2024-04-02 Axcess Global Sciences, Llc Compositions containing s-beta-hydroxybutyrate or non-racemic mixtures enriched with the s-enatiomer
US11950616B2 (en) 2019-06-21 2024-04-09 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
US11969430B1 (en) 2023-03-10 2024-04-30 Axcess Global Sciences, Llc Compositions containing paraxanthine and beta-hydroxybutyrate or precursor for increasing neurological and physiological performance
US12090129B2 (en) 2017-11-22 2024-09-17 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US12128020B2 (en) 2024-02-29 2024-10-29 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate and related compounds in humans

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6835750B1 (en) 2000-05-01 2004-12-28 Accera, Inc. Use of medium chain triglycerides for the treatment and prevention of alzheimer's disease and other diseases resulting from reduced neuronal metabolism II
WO2001082928A1 (en) 2000-05-01 2001-11-08 Accera, Inc. Use of medium chain triglycerides for the treatment and prevention of alzheimer's disease and other diseases resulting from reduced neuronal metabolism
GB0410266D0 (en) * 2004-05-07 2004-06-09 Ketocytonyx Inc Treatment of apoptosis
GB0420856D0 (en) * 2004-09-20 2004-10-20 Ketocytonyx Inc Cns modulators
EP1778615A4 (en) 2004-07-20 2010-01-06 Btg Int Ltd OLIGOMERE KETONE COMPOUNDS
US20070281892A1 (en) * 2004-09-21 2007-12-06 Martin Keith F Dopaminergic Mimetics
EP1915144A4 (en) 2005-06-20 2009-08-19 Accera Inc METHOD FOR REDUCING OXIDATIVE DAMAGE AND IMPROVING MITOCHONDRIA EFFICIENCY
ES2645816T3 (es) 2006-04-03 2017-12-07 Accera, Inc. Uso de compuestos cetogénicos para el tratamiento de la alteración de la memoria asociada a la edad
US7807718B2 (en) * 2006-06-30 2010-10-05 Sami A. Hashim Glyceride esters for the treatment of diseases associated with reduced neuronal metabolism of glucose
US8758740B2 (en) 2007-03-30 2014-06-24 Earthus, Inc Composition for promoting ketone body production
CN101293831B (zh) * 2007-04-27 2013-09-18 汕头大学 3-羟基脂肪酸及其衍生物在制备钙离子通道调节剂中的用途
PT2650382E (pt) 2007-07-31 2016-01-14 Accera Inc Utilização de testagem genómica e compostos cetogénicos para o tratamento de função cognitiva reduzida
CN106038532B (zh) * 2008-01-04 2019-05-14 牛津大学科技创新有限公司 用作降低血脂药剂的酮体和酮体酯
KR101734152B1 (ko) 2008-07-03 2017-05-11 액세라인크 신경계 장애의 치료를 위한 아세토아세테이트의 모노글리세리드 및 유도체
EP2389182A1 (en) 2009-01-24 2011-11-30 Phytopharm PLC Treatment of neurotrophic factor mediated disorders
AU2011203986C1 (en) * 2010-01-08 2015-03-05 Ionis Pharmaceuticals, Inc. Modulation of angiopoietin-like 3 expression
AU2011281336B2 (en) 2010-07-20 2015-03-05 Junaxo, Inc. Treatment of L-DOPA, dopamine agonist and/or dopamine enhancer induced disorders
US10292952B2 (en) 2016-03-11 2019-05-21 Axcess Global Sciences, Llc Mixed salt compositions for maintaining or restoring electrolyte balance while producing elevated and sustained ketosis
US10596130B2 (en) 2017-12-19 2020-03-24 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the S-enantiomer and methods of use
US10596129B2 (en) 2017-11-22 2020-03-24 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US10245243B1 (en) 2017-12-19 2019-04-02 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the S-enantiomer and methods of use
US10596131B2 (en) 2017-11-22 2020-03-24 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US10245242B1 (en) 2017-11-22 2019-04-02 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US11026929B2 (en) 2016-04-19 2021-06-08 Keto Patent Group, Inc. Administration of berberine metabolites
US12109182B2 (en) 2016-04-19 2024-10-08 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate and related compounds in humans
US20180057846A1 (en) 2016-08-30 2018-03-01 KetoneAid Inc. Partially buffered free acid and/or ketone blend for rapid onset ketosis and metabolic therapy
CA3047362A1 (en) * 2016-12-23 2018-06-28 Katholieke Universiteit Leuven 3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment
US10376528B2 (en) 2017-03-10 2019-08-13 Tecton Group, Llc Composition comprising ketone body and nicotinamide adenine dinucleotide modulator and methyl donor
US11760963B2 (en) 2017-08-23 2023-09-19 KetoneAid Inc. Ketogenic beer and alcoholic beverage mixture containing non-racemic ethyl 3-hydroxybutyrate and/or 1,3 butanediol
US10512615B1 (en) 2018-08-27 2019-12-24 Axcess Global Sciences, Llc Compositions and methods for delivering cannabidiol and ketone bodies
IT201900022854A1 (it) * 2019-12-03 2021-06-03 Dr Schaer S P A Formulazione alimentare e prodotto alimentare da forno per la gestione della dieta chetogenica

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0522422A3 (en) 1991-07-01 1993-03-17 Mitsubishi Kasei Corporation Process for producing a biodegradable polymer
JP2885261B2 (ja) * 1993-05-17 1999-04-19 三菱瓦斯化学株式会社 ３−ヒドロキシ酪酸のオリゴマー及びその塩からなる輸液製剤
JP4598203B2 (ja) * 1995-12-01 2010-12-15 ビーティージー・インターナショナル・リミテッド 脳機能改善剤
DK1017379T3 (en) * 1997-03-17 2015-02-16 Btg Int Ltd Therapeutic compositions comprising ketone compounds and precursors thereof
US6323237B1 (en) * 1997-03-17 2001-11-27 Btg International Limited Therapeutic compositions
US6207217B1 (en) 1998-01-07 2001-03-27 Pioneer Hi-Bred International, Inc. Animal nutrition compositions
US6380244B2 (en) * 1998-07-22 2002-04-30 Metabolix, Inc. Nutritional and therapeutic uses of 3-hydroxyalkanoate oligomers

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11230722B2 (en) 2003-06-03 2022-01-25 Oxford University Innovation Limited Nutritional supplements and therapeutic compositions comprising (r)-3-hydroxybutyrate derivatives
US20100092422A1 (en) * 2003-09-01 2010-04-15 Kazunari Ushida Poly (ß-hydroxy short-medium chain fatty acid)
US9649332B2 (en) * 2003-09-01 2017-05-16 Earthus, Inc. Poly (β-hydroxy short-medium chain fatty acid)
US20080213691A1 (en) * 2003-09-12 2008-09-04 Headway Technologies, Inc. Method to print photoresist lines with negative sidewalls
US20070299135A1 (en) * 2004-12-10 2007-12-27 Btg International Limited Compositions for Use in Surgery
US9149450B2 (en) 2007-04-12 2015-10-06 Regents Of The University Of Minnesota Ischemia/reperfusion protection compositions and methods of using
US20100197758A1 (en) * 2007-04-12 2010-08-05 Andrews Matthew T Ischemia/reperfusion protection compositions and methods of using
US20110111049A1 (en) * 2007-04-12 2011-05-12 Matthew T Andrews Ischemia/reperfusion protection compositions and methods of using
US8728532B2 (en) 2007-04-12 2014-05-20 Regents Of The University Of Minnesota Ischemia/reperfusion protection compositions and methods of using
US9186340B2 (en) 2007-04-12 2015-11-17 Regents Of The University Of Minnesota Ischemia/reperfusion protection compositions and methods of using
US10583159B2 (en) 2007-04-20 2020-03-10 United Animal Health, Inc. Method for increasing performance of offspring
US9272009B2 (en) 2007-10-15 2016-03-01 Jbs United, Inc. Method for increasing performance of offspring
US8409585B2 (en) 2007-10-15 2013-04-02 Jbs United, Inc. Method for increasing performance of offspring
US9675651B2 (en) 2007-10-15 2017-06-13 Jbs United, Inc. Method for increasing performance of offspring
US8105809B2 (en) 2008-07-03 2012-01-31 Accera, Inc. Enzymatic synthesis of acetoacetate esters and derivatives
US20100003730A1 (en) * 2008-07-03 2010-01-07 Accera, Inc. Enzymatic Synthesis of Acetoacetate Esters and Derivatives
US10051880B2 (en) 2008-08-21 2018-08-21 Oxford University Innovation Limited Hydroxybutyrate ester and medical use thereof
GB2490462B (en) * 2010-02-22 2018-02-28 Tdeltas Ltd Nutritional composition comprising ketone body precursors
US10478415B2 (en) 2012-11-05 2019-11-19 Tdeltas Limited Ketone bodies to protect tissues from damage by ionizing radiation
US11234953B2 (en) 2012-11-05 2022-02-01 Tdeltas Limited Ketone bodies to protect tissues from damage by ionizing radiation
US10821062B2 (en) 2013-03-12 2020-11-03 Tdeltas Limited Compound for use in protecting skin
US11566268B2 (en) 2013-03-14 2023-01-31 Government Of The Usa, As Represented By The Secretary, Department Of Health And Human Services Process for producing (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
US9138420B2 (en) 2013-03-19 2015-09-22 University Of South Florida Compositions and methods for producing elevated and sustained ketosis
US11241403B2 (en) 2016-03-11 2022-02-08 Axcess Global Sciences, Llc Beta-hydroxybutyrate mixed salt compositions and methods of use
US11896565B2 (en) 2016-03-11 2024-02-13 Axcess Global Sciences, Llc Beta-hydroxybutyrate mixed salt compositions and methods of use
US11020362B2 (en) 2016-03-11 2021-06-01 Axcess Global Sciences, Llc Beta-hydroxybutyrate mixed salt compositions and methods of use
US10973786B2 (en) 2016-03-11 2021-04-13 Axcess Global Sciences, Llc R-beta-hydroxybutyrate, S-beta-hydroxybutyrate, and RS-beta-hydroxybutyrate mixed salt compositions
US10307398B2 (en) 2016-09-20 2019-06-04 Regents Of The University Of Minnesota Resuscitation composition and methods of making and using
US11166928B2 (en) 2016-12-21 2021-11-09 Universitats-Kinderspital Beider Basel Migraine prevention and treatment
US11890264B2 (en) 2016-12-21 2024-02-06 Universitats-Kinderspital Beider Basel Migraine prevention and treatment
RU2753057C9 (ru) * 2016-12-21 2021-09-10 Универзитэтс-Киндершпиталь Байдер Базель Предотвращение и лечение мигрени
RU2753057C2 (ru) * 2016-12-21 2021-08-11 Универзитэтс-Киндершпиталь Байдер Базель Предотвращение и лечение мигрени
US11103470B2 (en) 2017-11-22 2021-08-31 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US11690817B2 (en) 2017-11-22 2023-07-04 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US11202769B2 (en) 2017-11-22 2021-12-21 Axcess Global Sciences, Llc Ketone body esters of s-beta-hydroxybutyrate and/or s-1,3-butanediol for modifying metabolic function
US11786499B2 (en) 2017-11-22 2023-10-17 Axcess Global Sciences, Llc Ketone body esters of S-beta-hydroxybutyrate and/or S-1,3-butanediol for modifying metabolic function
US12090129B2 (en) 2017-11-22 2024-09-17 Axcess Global Sciences, Llc Non-racemic beta-hydroxybutyrate compounds and compositions enriched with the R-enantiomer and methods of use
US11944598B2 (en) 2017-12-19 2024-04-02 Axcess Global Sciences, Llc Compositions containing s-beta-hydroxybutyrate or non-racemic mixtures enriched with the s-enatiomer
US11185518B2 (en) 2017-12-19 2021-11-30 Axcess Global Sciences, Llc S-beta-hydroxybutyrate compounds and compositions enriched with S-enantiomer
GB2572185A (en) * 2018-03-21 2019-09-25 Chain Biotechnology Ltd Pharmaceutical compositions
US10925843B2 (en) 2018-04-18 2021-02-23 Axcess Global Sciences, Llc Compositions and methods for keto stacking with beta-hydroxybutyrate and acetoacetate
US11806324B2 (en) 2018-04-18 2023-11-07 Axcess Global Sciences, Llc Beta-hydroxybutyric acid compositions and methods for oral delivery of ketone bodies
US11793778B2 (en) 2018-04-18 2023-10-24 Axcess Global Sciences, Llc Compositions and methods for keto stacking with beta-hydroxybutyrate and acetoacetate
US10980772B2 (en) 2018-08-27 2021-04-20 Axcess Global Sciences, Llc Compositions and methods for delivering tetrahydrocannabinol and ketone bodies
US11129802B2 (en) 2018-08-27 2021-09-28 Axcess Global Sciences, Llc Compositions and methods for delivering cannabidiol and ketone bodies
US11419836B2 (en) 2019-02-13 2022-08-23 Axcess Global Sciences, Llc Racemic and near racemic beta-hydroxybutyrate mixed salt-acid compositions
US10973792B2 (en) 2019-02-13 2021-04-13 Axcess Global Sciences, Llc Racemic beta-hydroxybutyrate mixed salt-acid compositions and methods of use
US11033553B2 (en) 2019-06-21 2021-06-15 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
US11950616B2 (en) 2019-06-21 2024-04-09 Axcess Global Sciences, Llc Non-vasoconstricting energy-promoting compositions containing ketone bodies
US11241401B2 (en) 2020-02-06 2022-02-08 Axcess Global Sciences, Llc Enantiomerically pure r-beta-hydroxybutyrate mixed salt-acid compositions
WO2023001724A1 (en) 2021-07-17 2023-01-26 Ketoswiss Ag Combination of a ketone body or ketogenic compound with an analgesic or antioxidant
US11969430B1 (en) 2023-03-10 2024-04-30 Axcess Global Sciences, Llc Compositions containing paraxanthine and beta-hydroxybutyrate or precursor for increasing neurological and physiological performance
US12128020B2 (en) 2024-02-29 2024-10-29 Axcess Global Sciences, Llc Administration of R-beta-hydroxybutyrate and related compounds in humans

Also Published As

Publication number Publication date
WO2000015216A1 (en) 2000-03-23
EP1123094A1 (en) 2001-08-16
ATE359069T1 (de) 2007-05-15
CA2339941A1 (en) 2000-03-23
AU767238B2 (en) 2003-11-06
KR20010079830A (ko) 2001-08-22
DE69935799D1 (de) 2007-05-24
US20040171671A1 (en) 2004-09-02
AU5921299A (en) 2000-04-03
DE69935799T2 (de) 2007-12-27
KR100805490B1 (ko) 2008-02-20
PT1123094E (pt) 2007-06-28
RU2242227C2 (ru) 2004-12-20
EP1123094A4 (en) 2001-10-04
US7351736B2 (en) 2008-04-01
BR9913680A (pt) 2001-06-05
HK1035665A1 (en) 2001-12-07
EP1123094B1 (en) 2007-04-11
ZA200101260B (en) 2001-08-16
JP2002524506A (ja) 2002-08-06
DK1123094T3 (da) 2007-08-20
CN1316902A (zh) 2001-10-10
ES2283133T3 (es) 2007-10-16
NZ509739A (en) 2003-10-31
CN1273129C (zh) 2006-09-06

Similar Documents

Publication Publication Date Title
US7351736B2 (en) Therapeutic compositions (II)
US20180098956A1 (en) Therapeutic compositions
EP1017379B1 (en) Therapeutic compositions comprising ketone bodies and precursors thereof
US6207856B1 (en) Therapeutic compositions
US6316038B1 (en) Therapeutic compositions
WO1998041201A9 (en) Therapeutic compositions
MXPA01002672A (en) Therapeutic compositions (ii)

Legal Events

Date Code Title Description
AS Assignment

Owner name: BTG INTERNATIONAL LIMITED, ENGLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:VEECH, RICHARD L.;REEL/FRAME:011610/0611

Effective date: 20010110

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION