EP0568545A1 - Procede permettant de reduire des taux eleves de glycemie chez l'homme - Google Patents

Procede permettant de reduire des taux eleves de glycemie chez l'homme

Info

Publication number
EP0568545A1
EP0568545A1 EP92901248A EP92901248A EP0568545A1 EP 0568545 A1 EP0568545 A1 EP 0568545A1 EP 92901248 A EP92901248 A EP 92901248A EP 92901248 A EP92901248 A EP 92901248A EP 0568545 A1 EP0568545 A1 EP 0568545A1
Authority
EP
European Patent Office
Prior art keywords
inositol
chiro
blood sugar
levels
phosphatase
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.)
Withdrawn
Application number
EP92901248A
Other languages
German (de)
English (en)
Other versions
EP0568545A4 (en
Inventor
Joseph Larner
Alison Kennington
Laura C. Huang
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.)
UVA Licensing and Ventures Group
University of Virginia UVA
Original Assignee
University of Virginia UVA
University of Virginia Patent Foundation
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 University of Virginia UVA, University of Virginia Patent Foundation filed Critical University of Virginia UVA
Publication of EP0568545A1 publication Critical patent/EP0568545A1/fr
Publication of EP0568545A4 publication Critical patent/EP0568545A4/en
Withdrawn legal-status Critical Current

Links

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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • This invention pertains to the administration of chiro-inositol for the treatment of a variety of disease conditions associated with a failure of pyruvate dehydrogenase-mediated metabolic pathways, or disease conditions otherwise linked to a failure of metabolic activation of PDH pathways, glycogen synthase pathways or other blood sugar maintenance pathways including glucose 6-phosphatase and mechanisms of insulin resistance in mammals.
  • chiro-inositol dietary supplements are provided for the biosynthesis of a chiro-inositol containing insulin mediator capable of stimulating PDH and glycogen synthase and inhibiting glucose 6-phosphatase and thus overcoming insulin resistance, lowering blood sugar and lowering elevated tactic acid.
  • chiro-inositol as a dietary supplement, is demonstrated and claimed in that parent application as an effective treatment for insulin-resistant diabetics and lowering blood sugar.
  • Other copending applications are directed to the mediator itself, as well as a method of screening individuals for diabetic conditions, involving assaying body fluids, including urine and serum, for the presence of chiro-inositol.
  • insulin resistance which is characterized by the manifestation of non-insulin-dependent diabetes mellitus (NIDDM) is frequently associated with hypertension, coronary artery disease (arter-iosclerosis) lactic acidosis and obesity, as well as related disease states.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the insulin mediator incorporating chiro-inositol is apparently responsible for the activation of at least one or both of the glycogen synthase metabolic pathway and the pyruvate dehydrogenase complex, specifically, activation of pyruvate dehydrogenase-phosphatase or PDH-P as well as a glycogen synthase phosphatase or GS-P. It also inhibits glucose 6-phosphatase.
  • the chiro-inositol containing insulin mediator activates PDH-P, thus initiating the conversion of phosphorylated inactive PDH to dephobphorylated or active PDH, which is responsible, among other things, for oxidative glucose metabolism.
  • This mediator also activates GS-P thus initiating the conversion of phosphorylated inactive GS to dephosphorylated active GS responsible among other things for non-oxidative glucose metabolism. It also inhibits glucose 6-phosphatase, the enzyme responsible for increasing blood sugar.
  • This failure may be partial or complete.
  • a failure of the body's glucose metabolism is directly implicated in a wide variety of the disease states associated, on a statistical basis, with insulin- resistance, including obesity, and a predisposition to coronary artery disease.
  • lactic acidosis implicates at least a partial failure of the PDH complex.
  • An active PDH complex would lower lactic acid levels. Hypertension and its associated insulin resistance may be directly related to a failure of the PDH complex, although the specific pathway remains unclear.
  • a failure of the PDH complex or of the GS complex, or of the glucose 6-phosphatase due to a low level or absence of chiro-inositol mediator (referred to as insulin mediator in the parent application) , caused by a failure of chiro-inositol synthesis, may be treated by administration of a dietary Bupplement of chiro-inositol.
  • High levels of chiro-inositol may lead to synthesis of the insulin mediator, allowing a restoration of "normal, insulin direction of PDH complex and GS complex activity and glucose 6-phosphatase activity pathways, through the role of this critical mediator.
  • the invention comprises the administration of chiro-inositol to individuals suffering from disease conditions related to a partial or complete failure of the PDH complex, glycogen synthase pathway or related blood sugar level maintenance mechanisms including glucose 6-phosphatase, owing to a low level or absence of chiro-inositol necessary for the synthesis of the insulin mediator responsible for the activation of PDH-P and GS-P and inhibition of glucose 6-phosphatase or additional unknown mechanisms involving chiro-inositol.
  • administration of chiro-inositol through a variety of pathways, makes possible the synthesis of this essential mediator, alleviating the disease condition by treating its source, rather than symptomatic treatment as is generally prescribed in the art.
  • the net result is a substantial reduction of hallmark elevated blood sugar levels.
  • treatment by the administration of chiro-inositol, according to the claimed invention may be accompanied by symptomatic treatment, to the extent such remains appropriate.
  • the essential, non-dietary carbohydrate that is the focus of this invention, chiro-inositol, is related to myo-inositol, the structures of the various optically active compounds being set forth herein below.
  • D iro-tnosit L-C iro-lnositol Myo-inositol chiro-inositol is available from non-dietary sources, in forms that may not be readily assimilated by the body.
  • the methylester of chiro-inositol is found in sugar pine hardwood (PINUS LAMBERTIANA DOUGL) (Anderson, AB 1953 Ind. Ency. Chem. 45, 593-596) .
  • Various esterified forms can also be isolated from legumes (Schweizer, T. F., Horman, I., Wuersch, P, 1978, J. Sci. Food A ric. r 29, pages 148-154.
  • the assi ilatable sugar itself is not believed to appear, in sufficient quantities, in normal dietary foods, to make up for a lack of the ability to synthesize the sugar.
  • This inability may prevent the formation of the chiro-inositol containing insulin mediator responsible for the activation of PDH-P, GS-P or other suitable pathways for lowering blood sugar including glucose 6-phosphatase.
  • Administration of chiro-inositol to those identified, through an appropriate screening test, as exhibiting low levels of chiro-inositol, may be employed to achieve the goals of this invention.
  • chiro-inositol can be isolated from natural sources through purification and deesterification reactions. It can also be synthesized directly from myo- inositol, commonly available, by direct inversion of the hydroxyl on the three position.
  • chiro-inositol is not present in substantial concentrations. Accordingly, the dietary supplement need be present only in vitamin-like concentrations to provide an adequate means of intervening in clinical conditions, as well as preventing the onset of clinical symptoms in those predisposed to their development.
  • dosage values will range from 250 to 5000 milligrains, and may be achieved through a variety of pathways.
  • An alternative dosage formulation would be administered in the range of 3.5-300 mg/kg, preferably 3.5-70 mg/kg of body weight, more preferably 5-20 mg/kg.
  • Adequacy of dosage levels may be determined by assaying patient urine or serum levels for chiro-inositol.
  • Urinary levels below about 1.0 ⁇ g/ml, or serum levels below about 0.1 ⁇ g/ml, are indicative of chiro-inositol insufficiency.
  • the carbohydrate is directly absorbed, and thus may be most conveniently administered orally. Other forms of administration are also suitable.
  • the active agent may be administered alone, or together with other actives.
  • the actives may be combined, by oral administration, with additives chosen from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid,; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid,
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulobe, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g.
  • lecithin a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate) , a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., haptadecaethyleneoxycetanol) , a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate) , or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e. g. , polyoxyethylene sorbitan mono-oleate) .
  • a condensation product of an alkylene oxide with a fatty acid e.g., polyoxyethylene stearate
  • a condensation product of ethylene oxide with a long chain aliphatic alcohol e.g., haptadecaethyleneoxycetanol
  • the aqueous suspension may also contain one or more preservative such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agent, one or more flavoring agent, and one or more sweetening agent, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oil suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservative. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water.
  • Derivatives of chiro-inositol designed to increase absorption and cellular transfer may include fatty acid short or long chain esters or ethers, succinates, diacylglycerol derivatives, esters of lactic or pyruvic acid or a ino acid or peptide ester derivatives or other derivatives to be defined on the basis of biological activity in vivo to lower blood sugar levels. There are no known toxic or deleterious side effects from the administration of chiro-inositol.
  • the chiro-inositol can be administered to virtually all those diagnosed either exhibiting clinical symptoms of elevated blood sugar-related hypertension, obesity, coronary artery disease, lactic acidosis, and obesity in combination with insulin-resistant diabetes, or genetically predisposed to the development, through the screening test discussed above.
  • the dietary additive addressed herein may be administered to infants over the age of one year, and all others at risk or exhibiting clinical symptoms. Under the age of one year, it is believed that the digestive system may be insufficiently developed to achieve positive results through the addition of the dietary supplement.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

Procédé de traitement destiné à un ensemble de maladies associées à des taux élevés de glycémie comprenant l'administration d'un supplément alimentaire de chiro-inositol. Le chiro-inositol est un élément essentiel pour la synthèse d'un médiateur d'insuline qui est apparemment responsable de l'activation de la pyruvate déhydrogènase-phosphatase. En administrant une dose suffisante de chiro-inositol pour obtenir des taux métaboliques normaux, on traite des états pathologiques associés communément à l'insulinorésistance, tels que l'hypertension, l'acidose lactique, l'obésité, la coronaropathie et analogue.
EP19920901248 1991-01-23 1991-09-04 Method of reducing elevated blood sugar levels in humans Withdrawn EP0568545A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US64463991A 1991-01-23 1991-01-23
US644639 1991-01-23

Publications (2)

Publication Number Publication Date
EP0568545A1 true EP0568545A1 (fr) 1993-11-10
EP0568545A4 EP0568545A4 (en) 1993-11-24

Family

ID=24585768

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19920901248 Withdrawn EP0568545A4 (en) 1991-01-23 1991-09-04 Method of reducing elevated blood sugar levels in humans

Country Status (5)

Country Link
EP (1) EP0568545A4 (fr)
JP (1) JPH06504278A (fr)
AU (1) AU662720B2 (fr)
CA (1) CA2101775C (fr)
WO (1) WO1992012706A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5550166A (en) * 1995-03-17 1996-08-27 Ostlund; Richard E. Pinitol and derivatives thereof for the treatment of metabolic disorders
US20010039297A1 (en) * 1998-05-19 2001-11-08 Insmed Pharmaceuticals, Inc. Compositions and method for improving insulin sensivity and glucose metabolism in individuals with impaired fasting glucose or impaired glucose tolerance
CA2374269C (fr) 1999-05-20 2007-04-24 Humanetics Corporation Stimulation du transport de glucose dans un tissu animal par administration du pinitol
CA2405181A1 (fr) 2000-04-07 2001-10-18 Merck Patent Gesellschaft Mit Beschraenkter Haftung Phosphatase deshydrogenese pyruvate humaine
JP4623996B2 (ja) * 2004-04-21 2011-02-02 株式会社スリービー たもぎ茸抽出物を有効成分とする血圧降下剤
WO2013016741A1 (fr) * 2011-07-22 2013-01-31 Smith Conrad Anton Complément alimentaire utilisable dans le cadre d'un programme d'amaigrissement

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0465508B1 (fr) * 1989-03-08 2000-05-31 The University Of Virginia Patent Foundation Preparation pharmaceutique pour diabetiques resistant a l'insuline
JPH04138126A (ja) * 1990-09-29 1992-05-12 Tookai:Kk 靴拭いマット

Also Published As

Publication number Publication date
AU662720B2 (en) 1995-09-14
CA2101775A1 (fr) 1992-07-24
WO1992012706A1 (fr) 1992-08-06
JPH06504278A (ja) 1994-05-19
EP0568545A4 (en) 1993-11-24
CA2101775C (fr) 1998-09-29
AU9056691A (en) 1992-08-27

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