WO2000028944A2 - Utilisation d'acide succinique ou de sels de celui-ci, et procede de traitement de l'insulino-resistance - Google Patents

Utilisation d'acide succinique ou de sels de celui-ci, et procede de traitement de l'insulino-resistance Download PDF

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Publication number
WO2000028944A2
WO2000028944A2 PCT/RU1998/000374 RU9800374W WO0028944A2 WO 2000028944 A2 WO2000028944 A2 WO 2000028944A2 RU 9800374 W RU9800374 W RU 9800374W WO 0028944 A2 WO0028944 A2 WO 0028944A2
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WO
WIPO (PCT)
Prior art keywords
succinic acid
pharmaceutically acceptable
acceptable salt
insulin resistance
mammal
Prior art date
Application number
PCT/RU1998/000374
Other languages
English (en)
Inventor
Igor Anatolievich Pomytkin
Olga Evgenievna Kolesova
Tatiyana Jurievna Ukhanova
Original Assignee
Verteletsky, Pavel Vasilievich
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 Verteletsky, Pavel Vasilievich filed Critical Verteletsky, Pavel Vasilievich
Priority to PCT/RU1998/000374 priority Critical patent/WO2000028944A2/fr
Priority to AU26449/99A priority patent/AU2644999A/en
Publication of WO2000028944A2 publication Critical patent/WO2000028944A2/fr

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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

Definitions

  • the present invention is in the field of medicine, particularly in the treatment of states of insulin resistance such as those associated with Non- insulin dependent Diabetes Mellitus (NIDDM) and its chronic complications, gestational diabetes mellitus, impaired glucose tolerance, obesity, aging, atherosclerosis, syndrome X, cardiovascular disease, AIDS, cancer, wasting/cachecxia, sepsis, trauma associated with burns, malnutrition, lupus and other autoimmune diseases, endocrine diseases, hyperuricemia, hyperlipidemia, dyslipidemia, polycystic ovary syndrome or complications arising from athletic activity.
  • NIDDM Non- insulin dependent Diabetes Mellitus
  • Succinic acid is the physiologically occurring substrate of succinate dehydrogenase in mammals that play a role in cellular respiration and energy metabolism.
  • Insulin resistance is a condition in which the tissues of the body fail to respond normally to insulin.
  • DeFronzo R. A. J. Cardiomuscular Pharmacology 20 (Suppl. 11): SI -SI 6 (1992).
  • the insulin resistance manifesting itself in pathologically elevated endogenous insulin and glucose levels and predisposes to the development of a cluster of abnormalities, including some degree of impaired glucose tolerance, an increase in plasma triglycerides and low density lipoprotein cholesterol (LDL) levels, a decrease in high-density lipoprotein cholesterol (HDL) levels, high blood pressure, hyperuricemia, a decrease in plasma fibrinolytic activity, an increase in cardiovascular disease and atherosclerosis.
  • LDL low density lipoprotein cholesterol
  • HDL high-density lipoprotein cholesterol
  • Reaven G. M. Physiol-Rev. 75(3): 473-86 (1995).
  • the decompensated insulin resistance is widely believed to be an underlying cause of non-insulin dependent diabetes mellitus
  • a method of treating insulin resistance comprises administration of insulin.
  • a basic disorder in the case of insulin resistance lies in the glucose assimilation by peripheral tissues of a mammal body.
  • the present invention shows for the first time that succinic acid or salt thereof is useful for treating of insulin resistance in mammals, particularly in humans afflicted with Non-insulin Dependent Diabetes Mellitus.
  • the present invention provides a method of treating insulin resistance in a mammal, which comprises administering to a mammal in need thereof an effective amount of succinic acid or a pharmaceutically acceptable salt thereof.
  • Insulin resistance in the mammal can be associated with disorders such as non- insulin dependent diabetes mellitus and its chronic complications (NIDDM), or gestational diabetes mellitus, or impaired glucose tolerance, or obesity, or aging, or atherosclerosis, or syndrome X, or cardiovascular disease, or AIDS, or cancer, or wasting/cachecxia, or sepsis, or trauma associated with burns, or malnutrition, or lupus and other autoimmune diseases, or endocrine diseases, or hyperuricemia, or hyperlipidemia, or dyslipidemia, or polycystic ovary syndrome, or complications arising from athletic activity. More particularly, the present invention provides the method of treating insulin resistance in a human afflicted with Non-insulin Dependent Diabetes Mellitus.
  • Succinic acid has the chemical structure given below:
  • the pharmaceutically acceptable salt of the succinic acid is prepared by known methods from organic and inorganic bases.
  • bases include, but are not limited to, nontoxic alkali metal and akaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, triethanolamine and 2-ethyl-6-methyl-3-hydroxypyridine.
  • the succinic acid or a pharmaceutically acceptable salt thereof is preferably administered orally in the method of this invention.
  • the succinic acid or a pharmaceutically acceptable salt thereof may also be administered by a variety of other routes such as parenterally, e.g. intravenously, subcutaneously, intramuscularly,; topically or rectally.
  • the succinic acid or pharmaceutically acceptable salt thereof is administered for a period of 1 day or longer; more preferably for a period of 3 to 7 days.
  • the effective amount of succinic acid or a pharmaceutically acceptable salt thereof for use in the method of this invention is preferably from 0.1 milligram to 50 milligrams per day per kilogram of body weight of the mammalian subject, more preferably from 5 mg to 30 mg per day per kilogram of body weight of the mammalian subject.
  • Treating describes the managment and care of a mammal for the purpose of combating the disease, condition, or disorder and includes the administration of succinic acid or a pharmaceutically acceptable salt thereof to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • Treating of insulin resistance in a mammal includes increasing insulin sensitivity manifesting itself in a lowering of free fatty acid, insulin and glucose levels.
  • Also provided according to the present invention is the use of succinic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament or nutritional supplement useful for treating insulin resistance in a mammal.
  • mammal is a human.
  • the medicaments or nutritional supplements of the invention are prepared by known procedures using well-known ingredients.
  • 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 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 medicaments 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, diluents, and excipients 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 medicament or nutritional supplement of the invention is in a dosage form and can be administrated orally, or parenterally, or topically, or rectally.
  • the following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.
  • This example shows that administering an effective amount of succinic acid to non-insulin dependent diabetic rats is useful for treating insulin resistance.
  • Rats 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.
  • Non-insulin dependent diabetic rats herein and after «NIDDM rats» were prepared by the following method: the streptozotocin (Sigma, St. Louis, MO, USA) solved in citrate buffer (0.05M, pH 5.5) was injected into tail vein of male albino Wistar rats in a dose of 35 mg per kg of animal body weight to induce non-insulin dependent diabetes mellitus.
  • the rats with levels of glucose more than 14.0 mmol/1 were used in the experiment one week after the streptozotocin injection.
  • Assays. Plasma free fatty acids levels were determined by enzymatic method with a commercially available kit (Waho Chemicals Gmbh, Neuss, Germany) with Multistat 3 centrifugal analyzer (Instrumentation Laboratories, Lexington, USA).
  • Serum glucose concentrations were determined by the glucose oxidase method with a kit (Lachema, Slov.) with glucose analyzer (Beckman, Fullerton, Calif, USA).
  • Plasma insulin concentrations were determined by a double-antibody radioimmunoassay kit (Kabi Pharmacia Diagnostics, Uppsala, Sweden) using a rat insulin standard (Novo Research Institute, Bagsvard, Denmark).
  • 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,
  • NIDDM rats Non-insulin dependent diabetic rats
  • NIDDM rats (fifteen rats). Experimental NIDDM rats received daily injection
  • Plasma free fatty acid levels FFA
  • plasma Insulin levels and serum Glucose levels were measured in rats by tail clipping method in all NIDDM rats at zero day (before treatment), at third, fifth and seventh days (treatment period), and at tenth, fifteen, twentieth, twenty fifth and thirtieth days (after- treatment period).
  • Table 1 Mean Plasma Free Fatty Acid (FFA) levels in experimental NIDDM rats treated by succinic acid in comparison with control NIDDM rats non-treated by succinic acid.
  • FFA Plasma Free Fatty Acid
  • the data of the Table 1 through 3 demonstrate that treating NIDDM rats by the effective amount of succinic acid causes a significant improving in insulin sensitivity in experimental rats in comparison with control rats, especially in the after-treatment period, manifesting itself in lowering of pathologically elevated plasma free fatty acid levels, plasma insulin and serum glucose levels.
  • Administration of succinic acid to healthy rats causes no changes in plasma free fatty acid levels (0.08 ⁇ 0.03 ⁇ mol/1), in serum glucose (4.8 ⁇ 0.4 mmol/1) and plasma insulin levels (3.4 ⁇ 0.6 ng/ml) during thirty days of the experiment analogous to described above.
  • Example 2 This example shows that administering to non-insulin dependent diabetic humans an effective amount of succinic acid is an effective therapy for treating insulin resistance.
  • NIDDM Non-insulin Dependent Diabetes Mellitus
  • Assays were used as described in the example 1 of the invention. Plasma insulin concentrations were determined by a double-antibody radioimmunoassay kit (Kabi Pharmacia Diagnostics, Uppsala, Sweden).
  • Plasma free fatty acid levels, insulin levels and serum glucose levels, plasma high density lipoprotein cholesterol (HDL-cholesterol), low density lipoprotein cholesterol (LDL-cholesterol) and triglycerides were measured in humans at zero day (before treatment), at third and fifth days (treatment period), and at tenth, fifteen, twentieth, twenty fifth thirtieth and fortieth days (after- treatment period). The results are demonstrated in Tables 4 through 6. Table 4. Mean Plasma Free Fatty Acid levels in NIDDM humans treated by succinic acid.
  • succinic acid or salt thereof is an effective therapy for treating of insulin resistance.

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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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation d'acide succinique ou de sels de celui-ci, acceptables sur le plan pharmacologique, dans la fabrication de médicaments ou de compléments nutritionnels efficaces dans le traitement de l'insulino-résistance chez les mammifères, de préférence chez des humains diabétiques non insulino-dépendants. L'insulino-résistance est associée à des troubles tels que le diabète sucré non insulino-dépendant et les complications chroniques de celui-ci, le diabète sucré de la grossesse, la tolérance insuffisante au glucose, l'obésité, la vieillesse, l'athérosclérose, le syndrome X, les maladies cardio-vasculaires, le SIDA, le cancer, l'atrophie/cachexie, la septicémie, les lésions associées aux brûlures, la malnutrition, le lupus et autres maladies auto-immunes, les maladies endocriniennes, l'hyperuricémie, l'hyperlipidémie, la dyslipidémie, la polykystose ovarienne, ou des complications provenant d'une activité sportive. L'invention concerne un procédé de traitement de l'insulino-résistance chez les mammifères, notamment chez l'homme, consistant à administrer à un mammifère nécessitant un tel traitement, de l'acide succinique ou des sels de celui-ci, acceptables sur le plan pharmacologique.
PCT/RU1998/000374 1998-11-12 1998-11-12 Utilisation d'acide succinique ou de sels de celui-ci, et procede de traitement de l'insulino-resistance WO2000028944A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/RU1998/000374 WO2000028944A2 (fr) 1998-11-12 1998-11-12 Utilisation d'acide succinique ou de sels de celui-ci, et procede de traitement de l'insulino-resistance
AU26449/99A AU2644999A (en) 1998-11-12 1998-11-12 Use of succinic acid or salts thereof and method of treating insulin resistance

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU1998/000374 WO2000028944A2 (fr) 1998-11-12 1998-11-12 Utilisation d'acide succinique ou de sels de celui-ci, et procede de traitement de l'insulino-resistance

Publications (1)

Publication Number Publication Date
WO2000028944A2 true WO2000028944A2 (fr) 2000-05-25

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AU (1) AU2644999A (fr)
WO (1) WO2000028944A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210267923A1 (en) * 2018-06-22 2021-09-02 Enzene Biosciences Limited Succinic acid and derivatives for the treatment of haemotological disorders

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210267923A1 (en) * 2018-06-22 2021-09-02 Enzene Biosciences Limited Succinic acid and derivatives for the treatment of haemotological disorders

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Publication number Publication date
AU2644999A (en) 2000-06-05

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