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WO2000059499A1 - Utilisation d'acide succinique ou de ses sels dans le traitement du diabete et la cicatrisation de blessures - Google Patents

Utilisation d'acide succinique ou de ses sels dans le traitement du diabete et la cicatrisation de blessures Download PDF

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Publication number
WO2000059499A1
WO2000059499A1 PCT/RU1999/000100 RU9900100W WO0059499A1 WO 2000059499 A1 WO2000059499 A1 WO 2000059499A1 RU 9900100 W RU9900100 W RU 9900100W WO 0059499 A1 WO0059499 A1 WO 0059499A1
Authority
WO
WIPO (PCT)
Prior art keywords
succinic acid
pharmaceutically acceptable
acceptable salt
insulin
signal transduction
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.)
Ceased
Application number
PCT/RU1999/000100
Other languages
English (en)
Inventor
Igor Anatolievich Pomytkin
Olga Evgenievna Kolesova
Tatiyana Jurievna Ukhanova
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Individual
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Individual
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 Individual filed Critical Individual
Priority to PCT/RU1999/000100 priority Critical patent/WO2000059499A1/fr
Priority to EP99933303A priority patent/EP1165063A1/fr
Priority to CA002362116A priority patent/CA2362116A1/fr
Priority to AU49376/99A priority patent/AU4937699A/en
Priority to IL14570100A priority patent/IL145701A0/xx
Publication of WO2000059499A1 publication Critical patent/WO2000059499A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom

Definitions

  • Diabetes and systemic glucocorticoid treatment caused a severe defect in wound healing accompanied by reduced expression of PDGF receptors. Beer, H.D. et al., I Invest. Dermatol. 109:132-8(1997).
  • the levels of IGF-1 was reported to be reduced in the wound enviroment of diabetics, whereas treatment of these wounds with IGF-1 reverses diabetes-induced wound healing impairment.
  • Wound healing is impaired under ageing due to delay in appearance of growth factors such as PDGF, EGF and their receptors in the wound enviroment. Ashcroft, G.S. et al., J. Anat.
  • PTPases of the invention play a role in cellular signal transduction.
  • the inhibiting PTPase activity by succinic acid or a pharmaceutically acceptable salt thereof is useful for modulating signal transduction and regulation cellular processes which are governed by signal transduction.
  • signal transduction includes the multiple pathways that are regulated by reversible phosphorylation of specific tyrosine residues on proteins involved in signaling.
  • modulating means upregulation or downregulation of a signaling pathway.
  • Cellular processes under the control of signal transduction may include, but are not limited to, normal processes such as proliferation, differentiation, transcription of specific genes, adhesion, apoptosis, and survival; and abnormal processes such as transformation, and blocking differentiation.
  • Dysfunctional signal transduction can result from imbalance between activity of PTPases and proteine tyrosine kinases which play roles in a signaling pathway.
  • the disease states may be caused by dysfunctional signal transduction of insulin receptor, members of insulin-like growth factor receptor family, epidermal growth factor receptor family, transforming growth factor receptor family, fibroblast growth factor receptor family, hepatocyte growth factor receptor family, vascular endothelial growth factor receptor family, transforming growth factor, platelet-derived growth factor receptor, the T-cell receptor, the B-cell receptor, members of the type 2 to 4 cytokine receptor families, and erythropoietin receptor.
  • the present invention provides a method of treating wounds, which comprises administering to a mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof.
  • wounds may include, but are not limited to, incised wounds, burn wounds, gastrointenstinal mucosal erosions and ulcers, periodontal wounds, and bone fractures.
  • the invention provides a method of treating disease state caused by dysfunctional signal transduction in a mammal, which comprises administering to a mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof stepwise or in physical combination with an effective amount of a protein tyrosine kinase activator.
  • receptor include but are not limited to, insulin receptor, members of insulin-like growth factor receptor family, epidermal growth factor receptor family, fibroblast growth factor receptor family, hepatocyte growth factor receptor family, vascular endothelial growth factor receptor family, nerve growth factor, platelet-derived growth factor, the T-cell receptor, the B-cell receptor, members of the type 2 to 4 cytokine receptor families, and erythropoietin receptor.
  • the invention provides for the use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament or a nutritional supplement effective for treating disease state caused by dysfunctional signal transduction in a mammal, preferably in a human.
  • Succinic acid or a pharmaceutically acceptable salt thereof is useful in nutritional and medicinal formulations according to the present invention for treating disease state caused by dysfunctional signal transduction in a mammal, preferably in a human.
  • the medicament or nutritional supplement of the invention is prepared by known procedures using well-known ingredients. In making the medicament or nutritional supplement, the active ingredients will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, tablet, paper or other container.
  • the carrier When the carrier serves as a diluent, it may be a solid, semisolid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • the nutritional supplements can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules.
  • the medicament can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, aerosoles, suppositories, sterile injectable solutions, and sterile packaged powders.
  • suitable carriers include lactose, dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil.
  • the medicaments or nutritional supplements can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • the orally ingestible nutritional supplement of the invention can comprise deionized water, succinic acid or salt thereof, maltodextrin, sodium caseinate, corn syrup solids, medium chain triglycerides, canola oil, calcium caseinate, soy protein, potassium citrate, magnesium chloride, sodium citrate, tricalcium phosphate, soy lecithine, sodium invention is synergistically effective in downregulating signal transduction that normally downregulated by dephosphorylation of phosphotyrosine residues in proteins involved in signaling pathways.
  • the protein tyrosine kinase activator of the composition is insulin.
  • Insulin of the invention is any standard insulin prepared by methods well-known in the art.
  • the new combination of succinic acid or a pharmaceutically acceptable salt thereof with insulin is synergistically effective in triggering or enhancing insulin receptor signal transduction that is accordingly effective for treating disease states caused by dysfunctional signal transduction of insulin receptor.
  • the disease states caused by dysfunctional insulin receptor signal transduction is diabetes mellitus.
  • Insulin is administered parenterally in the method of the invention.
  • the effective amount of insulin is selected from 2 units to 100 units per day per mammalian subject.
  • the mammal of the invention is a human.
  • the succinic acid has the chemical structure given below:
  • mice Male albino Wistar rats 8-10 weeks of age 200-250 grams of body weight were used. The rats were housed at the temperature of 18 ⁇ 21°C on a 12 hour light-dark cycle. Rats were fed on a stock laboratory diet (59 % carbohydrates; 17 % protein; 3 % fat; 21 % minerals, water, cellulose) and allowed water ad libitum.
  • Adipocytes preparation Isolated rat adipocytes were prepared by the method of
  • Rat livers were washed with cold phosphate- buffered saline and homogenized in buffer containing 100 mM Tris-HCl, 1.15% KCl, and pH 7.4. The homogenate was centrifuged at 200 g for 10 min to remove debris, and a postnuclear supernatant (35.6 mg of protein per ml) was used in the experiments.
  • Disodium succinate hexahydrate was assayed for its activity in inhibiting PTPase activity in the cellular fractions (rat adipocytes and liver supernatant).
  • the PTPase assay 60 ⁇ l of the cell fraction was incubated in 40 ⁇ l of a reaction buffer containing 50 mM Tris/HCl, pH 7.5 and 10 mM phosphotyrosine as the substrate, and with or without (control) 2 mM disodium succinate hexahydrate. After a 5, 10, or 20 min incubation period at 37°C, the reaction was terminated by the addition of 40 ⁇ l 10% BSA and 120 ⁇ l 25% tricloroacetic acid.
  • EXAMPLE 2 This example shows that administering disodium succinate mimics insulin in totally pancreatectomized rats.
  • Plasma triglycerides and cholesterol concentrations in High Density Lipoprotein (HDL) and Low Density Lipoprotein (LDL) were determined by enzymatic methods with kits (Boeringher Mannheim, Mannheim, Germany) with Multistat 3 F LS apparatus (Instrumentation Laboratories, Lexington, USA).
  • NIDDM humans were metabolically stable and had fasting glucose levels more than
  • This example shows that administering an effective amount of disodium salt of succinic acid is effective for treating wounds.
  • a suppurative wounds were prepared by the method of Eliseev. Eliseev, N.G. "Connective tissue", Moscow (1961).
  • the 30 male Wistar rats maintained as described in example 1 of the invention were used in this experiment.
  • the rats were anaesthetized with 1% solution of nembutal (0.2 ml/100 g of body weight, intramuscularly). Incisions of 15 to 20 mm length in inguinal region of rats were made.
  • a four celluloid balls of 2 mm diameter were entered into the each wound.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne l'utilisation d'acide succinique, ou de sels d'acide succinique pharmaceutiquement acceptables, dans la fabrication de médicaments ou d'additifs nutritionnels efficaces qui permettent de traiter des états maladifs induits par un dysfonctionnement de la transduction de signaux, de préférence le diabète, et qui permettent de cicatriser des blessures. Cette invention concerne plus précisément des procédés qui permettent d'inhiber l'activité de la protéine tyrosine phosphatase, et de traiter des états maladifs induits par un dysfonctionnement de la transduction de signaux. Ces procédés consistent à administrer de l'acide succinique, ou des sels pharmaceutiquement acceptable de celui-ci, soit seul, soit en combinaison avec des activateurs de protéine tyrosine kinases, de préférence avec de l'insuline.
PCT/RU1999/000100 1999-04-02 1999-04-05 Utilisation d'acide succinique ou de ses sels dans le traitement du diabete et la cicatrisation de blessures Ceased WO2000059499A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/RU1999/000100 WO2000059499A1 (fr) 1999-04-05 1999-04-05 Utilisation d'acide succinique ou de ses sels dans le traitement du diabete et la cicatrisation de blessures
EP99933303A EP1165063A1 (fr) 1999-04-05 1999-04-05 Utilisation d'acide succinique ou de ses sels dans le traitement du diabete et la cicatrisation de blessures
CA002362116A CA2362116A1 (fr) 1999-04-05 1999-04-05 Utilisation d'acide succinique ou de ses sels dans le traitement du diabete et la cicatrisation de blessures
AU49376/99A AU4937699A (en) 1999-04-05 1999-04-05 Use of succinic acid or salts thereof for the treatment of diabetes mellitus andwound healing
IL14570100A IL145701A0 (en) 1999-04-02 2000-03-31 Purine derivatives having phosphodiesterase iv inhibition activity

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU1999/000100 WO2000059499A1 (fr) 1999-04-05 1999-04-05 Utilisation d'acide succinique ou de ses sels dans le traitement du diabete et la cicatrisation de blessures

Publications (1)

Publication Number Publication Date
WO2000059499A1 true WO2000059499A1 (fr) 2000-10-12

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Family Applications (1)

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PCT/RU1999/000100 Ceased WO2000059499A1 (fr) 1999-04-02 1999-04-05 Utilisation d'acide succinique ou de ses sels dans le traitement du diabete et la cicatrisation de blessures

Country Status (4)

Country Link
EP (1) EP1165063A1 (fr)
AU (1) AU4937699A (fr)
CA (1) CA2362116A1 (fr)
WO (1) WO2000059499A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001076583A1 (fr) * 2000-04-10 2001-10-18 Verteletsky, Pavel Vasilievich Compositions synergiques contenant une base de choline et de l'acide succinique pour traiter l'insulinoresistance et le diabete
WO2002098414A1 (fr) * 2001-06-07 2002-12-12 Wyeth Procedes d'utilisation d'inhibiteurs de ptpase et d'insuline
WO2003006072A1 (fr) * 2001-07-10 2003-01-23 Penam Investments Pty Ltd Procede de traitement et/ou de prophylaxie des ulceres
WO2003055476A1 (fr) * 2001-12-25 2003-07-10 Pomytkin Igor A Utilisation d'acide succinique et de ses sels dans l'inhibition de l'agregation plaquetaire
WO2004112773A1 (fr) * 2003-04-24 2004-12-29 Shin-Jen Shiao Compositions pharmaceutiques utilisees pour le traitement de maladie immune et amelioration
AU2002344698B2 (en) * 2001-07-10 2006-07-27 Penam Investments Pty Ltd A method of treatment and/or prophylaxis of ulcers
EP1682570A4 (fr) * 2003-10-27 2006-12-06 Medvet Science Pty Ltd Motif de liaison et methodes de regulation d'une fonction cellulaire
WO2008099742A3 (fr) * 2007-02-16 2008-12-31 Canon Kk Liquide d'éjection et procédé d'éjection
WO2019244133A1 (fr) 2018-06-22 2019-12-26 Enzene Biosciences Limited Acide succinique et dérivés destinés au traitement de troubles hématologiques

Citations (6)

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Publication number Priority date Publication date Assignee Title
JPS56125312A (en) * 1980-03-09 1981-10-01 Lion Corp Remedy for damage
JPS61171417A (ja) * 1985-01-23 1986-08-02 Wakunaga Seiyaku Kk 抗糖尿病剤
JPH03236320A (ja) * 1990-02-09 1991-10-22 Kobayashi Kose Co Ltd 皮膚外用剤
JPH0662798A (ja) * 1992-08-19 1994-03-08 Nakano Vinegar Co Ltd 低耐糖能者用食品
JPH09124472A (ja) * 1995-10-27 1997-05-13 Noevir Co Ltd コラゲナーゼ阻害剤
WO1997048414A1 (fr) * 1996-06-20 1997-12-24 Novo Nordisk A/S Preparations d'insuline contenant du nacl

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56125312A (en) * 1980-03-09 1981-10-01 Lion Corp Remedy for damage
JPS61171417A (ja) * 1985-01-23 1986-08-02 Wakunaga Seiyaku Kk 抗糖尿病剤
JPH03236320A (ja) * 1990-02-09 1991-10-22 Kobayashi Kose Co Ltd 皮膚外用剤
JPH0662798A (ja) * 1992-08-19 1994-03-08 Nakano Vinegar Co Ltd 低耐糖能者用食品
JPH09124472A (ja) * 1995-10-27 1997-05-13 Noevir Co Ltd コラゲナーゼ阻害剤
WO1997048414A1 (fr) * 1996-06-20 1997-12-24 Novo Nordisk A/S Preparations d'insuline contenant du nacl

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DZVONKEVYCH, GULY: "Effects of Carboxylin, Acetate and Acids of the Tricarboxylic Cycle on the Content of Glucose in Blood and Citric acid in Urine of Rabbits with Alloxan Diabetes.", UKR. BIOKHIM. ZH., vol. 46, no. 5, 1974, pages 547 - 552, XP002123538 *
EBIHARA, KIYOSHI ET AL: "Comparative effects of various organic acids on glucose-flattening activity in rats fed a glucose solution", NUTR. REP. INT. (1989), 40(5), 1041-7, XP002123534 *
KOREC, R.: "Succinic acid alkyl esters-new genericoral anti-diabetic agents in alloxan and STZ diabetic rats", DIABETOLOGIA, vol. 40, no. suppl. 1, 1997, pages A375, XP002123539 *
LAMBERT, ANDRE E. ET AL: "Organ culture of fetal rat pancreas. II. Insulin release induced by amino and organic acids, by hormonal peptides, by cationic alterations of the medium, and by other agents", BIOCHIM. BIOPHYS. ACTA (1969), 184(3), 540-53, XP002123536 *
LANGTRY JA ET AL: "Topical lithium succinate ointment (Efalith) in the treatment of AIDS-related seborrhoeic dermatitis", CLINICAL AND EXPERIMENTAL DERMATOLOGY,GB,BLACKWELL SCIENTIFIC PUBLICATIONS, OXFORD, vol. 22, no. 5, pages 216-219, XP002105249, ISSN: 0307-6938 *
LECLERCQ-MEYER, V.; MALAISSE, W.J.: "Potentiation of GLP-1 Insulinotropic Action by a Nonglucidic Nutrient in the pancreas of Diabetic GK Rats.", BIOCHEMICAL AND MOLECULAR MEDICINE, vol. 59, no. 1, 1996, pages 87 - 90, XP002123540 *
MACDONALD, MICHAEL J. ET AL: "Glyceraldehyde phosphate and methyl esters of succinic acid. Two "new" potent insulin secretagogues", DIABETES (1988), 37(7), 997-9, XP002123535 *
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MIYAMOTO ET AL.: "Effects of cosmetics containing Bioactive substances on skin", JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS OF JAPAN, vol. 22, no. 4, 1989, pages 254 - 262, XP000856450 *
PATENT ABSTRACTS OF JAPAN vol. 1997, no. 09 30 September 1997 (1997-09-30) *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001076583A1 (fr) * 2000-04-10 2001-10-18 Verteletsky, Pavel Vasilievich Compositions synergiques contenant une base de choline et de l'acide succinique pour traiter l'insulinoresistance et le diabete
WO2002098414A1 (fr) * 2001-06-07 2002-12-12 Wyeth Procedes d'utilisation d'inhibiteurs de ptpase et d'insuline
US6797693B2 (en) 2001-06-07 2004-09-28 Wyeth Methods using PTPase inhibitors and insulin
WO2003006072A1 (fr) * 2001-07-10 2003-01-23 Penam Investments Pty Ltd Procede de traitement et/ou de prophylaxie des ulceres
AU2002344698B2 (en) * 2001-07-10 2006-07-27 Penam Investments Pty Ltd A method of treatment and/or prophylaxis of ulcers
WO2003055476A1 (fr) * 2001-12-25 2003-07-10 Pomytkin Igor A Utilisation d'acide succinique et de ses sels dans l'inhibition de l'agregation plaquetaire
WO2004112773A1 (fr) * 2003-04-24 2004-12-29 Shin-Jen Shiao Compositions pharmaceutiques utilisees pour le traitement de maladie immune et amelioration
EP1682570A4 (fr) * 2003-10-27 2006-12-06 Medvet Science Pty Ltd Motif de liaison et methodes de regulation d'une fonction cellulaire
WO2008099742A3 (fr) * 2007-02-16 2008-12-31 Canon Kk Liquide d'éjection et procédé d'éjection
US20100319696A1 (en) * 2007-02-16 2010-12-23 Canon Kabushiki Kaisha Ejection liquid and ejection method
WO2019244133A1 (fr) 2018-06-22 2019-12-26 Enzene Biosciences Limited Acide succinique et dérivés destinés au traitement de troubles hématologiques

Also Published As

Publication number Publication date
CA2362116A1 (fr) 2000-10-12
EP1165063A1 (fr) 2002-01-02
AU4937699A (en) 2000-10-23

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