CA2404864A1 - Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes - Google Patents
Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes Download PDFInfo
- Publication number
- CA2404864A1 CA2404864A1 CA002404864A CA2404864A CA2404864A1 CA 2404864 A1 CA2404864 A1 CA 2404864A1 CA 002404864 A CA002404864 A CA 002404864A CA 2404864 A CA2404864 A CA 2404864A CA 2404864 A1 CA2404864 A1 CA 2404864A1
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- succinic acid
- mammal
- choline
- 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
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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic 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
- A61K31/13—Amines
- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Emergency Medicine (AREA)
- Endocrinology (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
This invention relates to compositions and methods for achieving a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal. More specifically, this invention relates to synergistic composition comprising amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, which are presented in amounts sufficient to cause synergistic effects in treating insulin resistance and diabetes mellitus in a mammal. Further, this invention relates to methods for achieving a synergistic effects in treating insulin resistance and diabetes mellitus in a mammal, which methods comprise administering to said mammal, either stepwise or simultaneously, effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof. Further, this invention relates to a novel derivative of choline. More specifically, this invention relates to bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the novel salt of choline formed by choline base and succinic acid in the molar ratio 2:1, a process for producing the salt, and use of the salt in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, or diabetes mellitus.
Description
SYNERGISTIC COMPOSITIONS CONTAINING CHOLINE BASE AND SUCCINIC ACID FOR INSULIN
RESISTANCE AND DIABETES
TECHNICAL FIELD OF THE INVENTION
s This invention relates to compositions and methods for achieving a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal. More specifically, this invention relates to synergistic composition comprising amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, which to are presented in amounts sufficient to cause synergistic effects in treating insulin resistance and diabetes mellitus in a mammal. Further, this invention relates to methods for achieving a synergistic effects in treating insulin resistance and diabetes mellitus in a mammal, which methods comprise administering to said mammal, either stepwise or simultaneously, effective Is amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof. Further, this invention relates to a novel derivative of choline. More specifically, this invention relates to bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the novel salt of choline formed by choline base and succinic acid in the molar 2o ratio 2:1, a process for producing the salt, and use of the salt in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, or diabetes mellitus.
BACKGROUND OF THE INVENTION
2s Insulin is the major anabolic hormone in the body and has multiple effects on a variety of tissues. Insulin stimulates the glucose uptake in muscle and fat and inhibits the glucose release from the liver. In addition, insulin regulates both plasma and tissue lipid metabolism, protein synthesis, cell growth and electrolyte balance.
3o Insulin resistance is defined as an impaired biological response to either exogenous or endogenous insulin. The measured biological responses could reflect metabolic processes such as changes in carbohydrate, lipid or protein metabolism as well as mitogenic processes such as alterations in growth, differentiation, DNA synthesis, and regulation of gene transcription.
Insulin resistance has clearly emerged as an important cause of glucose intolerance leading to type 2 diabetes and a cluster of abnormalities, s including hyperlipidemia and dyslipidemia, high blood pressure, hyperuricemia, and a decrease in plasma fibrinolytic activity. Reaven, G. M.
Physiol-Rev. 75(3): 473-86 (1995); "Consensus development conference on insulin resistance", Diabetes Care, 21 (2) 1998. Insulin resistance can be associated with a variety of disease states such as gestational diabetes ~o mellitus, obesity, ageing, atherosclerosis, cardiovascular syndrome X, AIDS, cancer, wasting/cachexia, sepsis, trauma associated with burns, malnutrition, lupus and other autoimmune diseases, endocrine diseases, polycystic ovary syndrome, or complications arising from athletic activity.
Clinically, insulin resistance manifesting itself in pathologically elevated is fasting plasma insulin levels and can be assessed by measurement of insulin concentration in plasma.
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
2o Clinically, diabetes mellitus manifesting itself in pathologically elevated plasma glucose levels and can be assessed by measurement of glucose concentration in blood.
Treating insulin resistance by succinic acid or salts thereof was described in the international application PCT/RU 99/00055.
2s Succinic acid or salts thereof were described in JP patent 61171417 as antidiabetics useful for stimulating insulin secretion. Contrary to JP
61171417, MacDonald et al. found that succinic acid and salts thereof did not stimulate insulin secretion from pancreas, and only esters of succinic acid are potent insulin secretagogues. MacDonald, M.J. and Fahien, L.A. Diabetes 37(7):
~0 997-999 (1988). Also, succinic acid was described in JP patent 6062798 as a component of food for person with poor glucose-tolerance in combination with acetic, lactic, and gluconic acid. Disodium succinate was described as a component of the composition for decreasing blood glucose in rabbits with alloxan diabetes in combination with citric and acetic acid. Dzvonkevich, N.D.
et al., Ukr. Biokhim. Zh., 46(5):547-552(1974).
Until the invention described herein, there was no report of use of choline base or a pharmaceutically acceptable salt thereof together with s succinic acid or a pharmaceutically acceptable salt thereof to achieve synergistic effects in treating insulin resistance or diabetes mellitus.
Monocholine succinate, the acid salt formed by choline base and succinic acid in the molar ratio 1:1, was described in US patent 5,124,061 as a component of plant cryoprotectant composition. However, this salt has not ~o been obtained as the product with reproducible properties and was defined only by reference to process in which choline base and succinic acid were entered in molar ratio 1:1. Acidity of monocholine succinate and absence of reproducible properties restricts the use of the described monocholine succinate in medicine.
Is Until the invention described herein, there was no report of bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the neutral salt formed by choline base and succinic acid in the molar ratio 2:1, a process for producing the salt, and use of the salt in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, 2o dyslipidemia, or diabetes mellitus. Herein and after, the chemical name "bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate" is used in the invention instead of trivial name "dicholine succinate", since the name "dicholine succinate" was frequently used in literature for description of a widely known ester of succinic acid and choline.
SUMMARY OF THE INVENTION
This invention relates to compositions and methods for achieving a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal. More specifically, this invention relates to synergistic composition ~o comprising amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, which are presented in amounts sufficient to cause synergistic effects in treating insulin resistance and diabetes mellitus in a mammal. Further, this invention relates to methods for achieving a synergistic effects in treating insulin resistance and diabetes mellitus in a mammal, which methods comprise administering to said mammal, either stepwise or simultaneously, effective amounts of choline base or a pharmaceutically acceptable salt thereof and s succinic acid or a pharmaceutically acceptable salt thereof. Further, this invention relates to a novel derivative of choline. More specifically, this invention relates to bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the novel salt of choline formed by choline base and succinic acid in the molar ratio 2:1, a process for producing the salt, and use of the salt in medicine, to preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, or diabetes mellitus.
DETAILED DESCRIPTION OF THE INVENTION
The term "synergistic" as used herein means that the effect achieved Is with the methods and compositions of this invention is greater than the sum of the effects that result from methods and compositions comprising choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof separately and in the amounts employed in the methods and compositions hereof.
2o Accordingly to this invention, it is now possible to achieve a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal with amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof which, if administered in said amounts singly, are not capable of achieving said effect 2s and which effect is greater than the sum of the effects achieved for choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof separately.
The term "treating" as used herein means the management and care of a mammal for the purpose of combating the disease, condition, or disorder ~o and includes the administration of choline base or a pharmaceutically acceptable salt thereof and 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 insulin resistance includes increasing insulin sensitivity in a mammal and other effects, which are resulted from increasing insulin sensitivity in a mammal. Such effects include, but are not limited to, improving in carbohydrate, lipid, or protein metabolism, alterations in growth, s differentiation, DNA synthesis, and regulation of gene transcription.
The present invention provides a method for achieving a synergistic effect in treating insulin resistance in a mammal in need thereof, which comprises administering to said mammal an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a to pharmaceutically acceptable salt thereof. Preferred effect achieved according to this invention in treating insulin resistance is lowering pathologically elevated plasma insulin levels. Insulin resistance in the mammal can be associated with disorders such as diabetes mellitus and its chronic complications; gestational diabetes mellitus; impaired glucose tolerance;
is obesity; ageing; atherosclerosis; syndrome X; cardiovascular disease; AIDS;
cancer; wasting/cachexia; 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. Preferably, insulin resistance is associated with 2o diabetes mellitus in the mammal.
Further, the present invention provides a method for achieving a synergistic effect in treating diabetes mellitus in a mammal in need thereof, which comprises administering to said mammal an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid 2s or a pharmaceutically acceptable salt thereof. Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels.
Preferably, choline base or a pharmaceutically acceptable salt thereof of the invention is choline chloride. Preferably, succinic acid or a ~o pharmaceutically acceptable salt thereof of the invention is disodium succinate.
The administration of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof can be stepwise in time or simultaneous with the simultaneous method being preferred.
Choline base or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, topically, or rectally. Preferably, choline base s or a pharmaceutically acceptable salt thereof is administered parenterally.
Succinic acid or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, topically, or rectally. Preferably, succinic acid or a pharmaceutically acceptable salt thereof is administered parenterally.
Preferably, the choline base or a pharmaceutically acceptable salt to thereof is administered for a period of 1 day or longer, more preferably for a period of 3 to 7 days. Preferably, 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 present invention provides a composition for achieving a ~s synergistic effect in treating insulin resistance in a mammal in need thereof, which comprises an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Preferred effect achieved according to this invention in treating insulin resistance is 20 lowering pathologically elevated plasma insulin levels.
Further, the present invention provides a composition for achieving a synergistic effect in treating diabetes mellitus in a mammal in need thereof, which comprises an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable 2s salt thereof, and a pharmaceutically acceptable diluent or carrier.
Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels.
The pharmaceutically acceptable salt of the choline base is prepared by known methods from nontoxic organic and inorganic acids. Such acids ~o include, but are not limited to, hydrogen chloride, hydrogen bromide, citric acid, tartaric acid, and succinic acid. Preferably, choline base or a pharmaceutically acceptable salt thereof of the invention is choline chloride.
WO 01/76583 ~ PCT/RU00/00122 The pharmaceutically acceptable salt of the succinic acid is prepared by known methods from organic and inorganic bases. Such bases include, but are not limited to, nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium s hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, triethanolamine, and choline base. Preferably, succinic acid or a pharmaceutically acceptable salt thereof of the invention is disodium succinate.
Some examples of suitable carriers and diluents include lactose, to dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl- and propylhydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil. The compositions of the invention can additionally include lubricating agents, wetting agents, emulsifying and Is suspending agents, preserving agents, sweetening agents, or flavoring agents.
Compositions of the invention can be administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, 20 lozenges, troches, hard candies, powders, sprays, aqueous solutions, elixirs, syrups and the like.
The effective amount of choline base or a pharmaceutically acceptable salt thereof for use in the methods and compositions of this invention is preferably from 3 to 300 mg per day per kg of body weight of the mammal.
2s The effective amount of succinic acid or a pharmaceutically acceptable salt thereof for use in the methods and compositions of this invention is preferably from 1 to 250 mg per day per kg of body weight of the mammal.
The present invention provides bis(2-hydroxy-N,N,N
trimethylethanaminium) succinate, which has the chemical formula given 3o below:
[(CH3)3N+CH2CH20H]2 -OOCCH2CHzC00-The present invention provides a process for producing bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, which comprises reacting choline base with succinic acid in the presence of water, alcohol, or mixture thereof.
Preferably, bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate is s prepared by reacting the choline base and succinic acid, wherein the mole ratio of choline base to succinic acid entered in reaction is about 2:1, but no lower than 1.9:1 and no higher than 2.1:1. The reaction take place at ambient temperatures and the reaction is quantitative. The desired product is obtained as a white crystalline powder with reproducible properties.
to Also provided according to the present invention is the use of bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, and diabetes mellitus in a mammal in need thereof. Preferred effect achieved according to this invention in treating insulin Is resistance is lowering pathologically elevated plasma insulin levels.
Preferred effects achieved according to this invention in treating hyperlipidemia are lowering pathologically elevated plasma triglycerides and cholesterol levels.
Preferred effects achieved according to this invention in treating dyslipidemia are lowering low-density lipoprotein cholesterol levels and increasing high-2o density lipoprotein cholesterol levels. Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels.
The following examples are presented to demonstrate the invention.
The examples are illustrative only and are not intended to limit the scope of 2s the invention in any way.
This example shows the synergistic effects in treating insulin resistance and diabetes mellitus achieved by co-administration of effective amounts of ~o choline chloride and disodium succinate to diabetic rats.
Assay. Plasma insulin concentrations were determined using a kit ("Dako", Dutch) with a rat insulin standard (Novo Research Institute, Bagsvard, WO 01/76583 y PCT/RU00/00122 Denmark). Plasma glucose concentrations were determined using a kit ("Agat", Russia). Plasma triglycerides and cholesterol concentrations were determined with reagents FS, "DiaSys", Germany; HDL cholesterol with reagents "Cormay", Poland; and LDL cholesterol with reagents "Boehringer s Mannheim", Germany.
Animals. Male Wistar rats 8-10 weeks of age 210-230g 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, and cellulose) to and allowed water ad libitum. Diabetes mellitus was induced in Wistar male rats by twice i.v. injection (tail vein) of alloxan (40 mg/kg body wt) with break of 48 hours. The rats were used in experiments at 6t" day from the first alloxan injection. Fasting plasma glucose, insulin, total cholesterol (Ch), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol is (LDL), and triglycerides (TG) levels of these animals are presented in Table 1 as Mean~SD in comparison with healthy control. Insulin resistance, hyperinsulinemia, hyperglycemia, hyperlipidemia, and dyslipidemia characterize the rats prepared by this means.
2o Table 1. Fasting plasma parameters in rats at 6t" day since the first alloxan injection.
Rats Glucos Insulin,HDL, LDL, TG, Ch, e,mmol ~U/I mmol/I mmol/I mmol/I mmol/I
/I
Healthy rats 4.3 2.0 2.0 0.8 0.5 1.7 (n=10) 0.7 0.5 0.3 0.2 0.1 0.3 Diabetic rats 13.9 4.8 1.0 1.0 1.3 2.5 (n=10) 2.3* 0.8* 0.3* 0.3 0.3* 0.5*
*Differs significantly from healthy control (P< 0.01 ) Treatment. The diabetic animals were divided into four groups: a diabetic 2s control group (n=10) and three diabetic groups treated with daily i.v.
injections WO O1 /76583 ~ 0 PCT/RU00/00122 of choline chloride (240 mg/kg body weight, n=10), disodium succinate (70 mg/kg body weight, n=10), or the combination of choline chloride (240 mg/kg body weight) with disodium succinate (70 mg/kg body weight, n=10) for the 5 days.
s Fasting plasma glucose was measured at the 6t" day since treating beginning. Data are shown in Table 2. In diabetic control, the mean of glucose level was found to be 12.5 mmol/I. OGlucose is difference between means of fasting plasma glucose in control and treated rats calculated by equation: D Glucose = 12.5 - Mean (mmol/I).
~o Effect of the combination is 7.8 mmol/I decreasing in fasting plasma glucose level from the control. The sum of effects of choline chloride and disodium succinate administered individually is 2.8 mmol/I (-1.1 +3.9 =2.8) decreasing in fasting plasma glucose level of control. Since glucose-lowering effect of the combination is greater than the sum of glucose-lowering effects is of choline and succinate administered individually, the combination is synergistically effective in lowering pathologically elevated plasma glucose levels.
Table 2. Fasting plasma glucose at 6t" day since treating beginning.
Treatment Glucose, mmol/I o Glucose, mmol/I
(Mean SD) Control 12.5 2.4* 0 Choline chloride 13.6 2.2* -1.1 Disodium succinate 8.6 1.8*t +3.9 Combination 4.7 0.8t +7,g 20 * Differs significantly from the combination (P< 0.01 ) t Differs significantly from control (P< 0.01) Fasting plasma insulin levels were measured at the 6t" day since treating beginning. Data are shown in Table 3. In diabetic control, the mean of 2s insulin level was found to be 5.7 pU/I. Olnsulin is difference between means of WO 01/76583 1 ~ PCT/RU00/00122 fasting plasma insulin in control and treated rats calculated by equation: D
Insulin = 5.7 - Mean (~U/I).
Effect of the combination is 4.1 p.U/I decreasing in fasting plasma insulin level from the control. The sum of effects of choline chloride and s disodium succinate administered individually is 2.1 ~U/I (0.9 + 1.2 =2.1 ) decreasing in fasting plasma insulin level of control. Since insulin-lowering effect of the combination is greater than the sum of insulin-lowering effects of choline and succinate administered individually, the combination is synergistically effective in lowering pathologically elevated plasma insulin to levels.
Table 3. Fasting plasma insulin at 6t" day since treating beginning.
Treatment Insulin, ~,U/I (Mean~ Insulin, ~,U/I
SD) Control 5.7 1.1 * 0 Choline chloride 4.8 0.7* 0.9 Disodium succinate 4.5 0.6*t 1.2 Combination 1.6 0.3t 4.1 * Differs significantly from the combination (P<0.01) t Differs significantly from control (P<0.01) Bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate is effective in treating insulin resistance, hyperlipidemia, dyslipidemia, and diabetes mellitus in diabetic rats.
Animals. Diabetic rats were prepared as described in Example 1 of the invention.
Treatment. The animals were divided into two groups: a diabetic control group (n=10) and diabetic group treated with daily i.v. (tail vein) injections of bis(2-2s hydroxy-N,N,N-trimethylethanaminium) succinate (120 mg/kg body weight, n=10) for the 3 days. Fasting plasma glucose, insulin, total cholesterol (Ch), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels were measured at the 7t" day since treating beginning and shown in Table 4 as Mean~SD.
s Table 4. Fasting plasma parameters at 7t" day since treating beginning.
Blood parameters, Treatment (MeanSD) Control rats Treated rats Fasting plasma glucose,12.5 2.4 4.2 0.6**
mmol/I
Fasting plasma insulin,6.0 1.0 1.3 0.5**
~,U/I
Total cholesterol, 3.0 0.4 1.5 0.3**
mmol/I
LDL cholesterol, 1.1 0.3 0.8 0.2*
mmol/I
HDL cholesterol, 0.8 0.2 2.0 0.2**
mmol/I
Triglycerides, mmol/I1.4 0.3 0.7 0.1 **
* Differs from control (P<0.05) ** Differs significantly from control (P<0.01 ) ~o The process for producing bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate.
To a solution of 121 g (1 mole) of choline base in methanol was added 59 g (0.5 mole) of succinic acid. The reaction mixture was stirred at ambient Is temperature for 20 minutes and concentrated under vacuum to dryness at a temperature of 40-50°C. The desired bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate is obtained at a yield approximating 100%
as a solid white crystalline material: mp 135-137°C (from tert-butanol);
NMR'H (D20):8 2.24 (s, 4H), 3.07 (s, 18H), 3.38 (m, 4H), 3.93 (m, 4H); NMR
20 '3C (D20):8 34.5, 54.2, 56.0, 67.8, 182.6; Anal. Calculated for C~4H32NZOg:
C, 51.83; H, 9.94. Found: C, 51.66; H 9.86.
RESISTANCE AND DIABETES
TECHNICAL FIELD OF THE INVENTION
s This invention relates to compositions and methods for achieving a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal. More specifically, this invention relates to synergistic composition comprising amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, which to are presented in amounts sufficient to cause synergistic effects in treating insulin resistance and diabetes mellitus in a mammal. Further, this invention relates to methods for achieving a synergistic effects in treating insulin resistance and diabetes mellitus in a mammal, which methods comprise administering to said mammal, either stepwise or simultaneously, effective Is amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof. Further, this invention relates to a novel derivative of choline. More specifically, this invention relates to bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the novel salt of choline formed by choline base and succinic acid in the molar 2o ratio 2:1, a process for producing the salt, and use of the salt in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, or diabetes mellitus.
BACKGROUND OF THE INVENTION
2s Insulin is the major anabolic hormone in the body and has multiple effects on a variety of tissues. Insulin stimulates the glucose uptake in muscle and fat and inhibits the glucose release from the liver. In addition, insulin regulates both plasma and tissue lipid metabolism, protein synthesis, cell growth and electrolyte balance.
3o Insulin resistance is defined as an impaired biological response to either exogenous or endogenous insulin. The measured biological responses could reflect metabolic processes such as changes in carbohydrate, lipid or protein metabolism as well as mitogenic processes such as alterations in growth, differentiation, DNA synthesis, and regulation of gene transcription.
Insulin resistance has clearly emerged as an important cause of glucose intolerance leading to type 2 diabetes and a cluster of abnormalities, s including hyperlipidemia and dyslipidemia, high blood pressure, hyperuricemia, and a decrease in plasma fibrinolytic activity. Reaven, G. M.
Physiol-Rev. 75(3): 473-86 (1995); "Consensus development conference on insulin resistance", Diabetes Care, 21 (2) 1998. Insulin resistance can be associated with a variety of disease states such as gestational diabetes ~o mellitus, obesity, ageing, atherosclerosis, cardiovascular syndrome X, AIDS, cancer, wasting/cachexia, sepsis, trauma associated with burns, malnutrition, lupus and other autoimmune diseases, endocrine diseases, polycystic ovary syndrome, or complications arising from athletic activity.
Clinically, insulin resistance manifesting itself in pathologically elevated is fasting plasma insulin levels and can be assessed by measurement of insulin concentration in plasma.
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
2o Clinically, diabetes mellitus manifesting itself in pathologically elevated plasma glucose levels and can be assessed by measurement of glucose concentration in blood.
Treating insulin resistance by succinic acid or salts thereof was described in the international application PCT/RU 99/00055.
2s Succinic acid or salts thereof were described in JP patent 61171417 as antidiabetics useful for stimulating insulin secretion. Contrary to JP
61171417, MacDonald et al. found that succinic acid and salts thereof did not stimulate insulin secretion from pancreas, and only esters of succinic acid are potent insulin secretagogues. MacDonald, M.J. and Fahien, L.A. Diabetes 37(7):
~0 997-999 (1988). Also, succinic acid was described in JP patent 6062798 as a component of food for person with poor glucose-tolerance in combination with acetic, lactic, and gluconic acid. Disodium succinate was described as a component of the composition for decreasing blood glucose in rabbits with alloxan diabetes in combination with citric and acetic acid. Dzvonkevich, N.D.
et al., Ukr. Biokhim. Zh., 46(5):547-552(1974).
Until the invention described herein, there was no report of use of choline base or a pharmaceutically acceptable salt thereof together with s succinic acid or a pharmaceutically acceptable salt thereof to achieve synergistic effects in treating insulin resistance or diabetes mellitus.
Monocholine succinate, the acid salt formed by choline base and succinic acid in the molar ratio 1:1, was described in US patent 5,124,061 as a component of plant cryoprotectant composition. However, this salt has not ~o been obtained as the product with reproducible properties and was defined only by reference to process in which choline base and succinic acid were entered in molar ratio 1:1. Acidity of monocholine succinate and absence of reproducible properties restricts the use of the described monocholine succinate in medicine.
Is Until the invention described herein, there was no report of bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the neutral salt formed by choline base and succinic acid in the molar ratio 2:1, a process for producing the salt, and use of the salt in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, 2o dyslipidemia, or diabetes mellitus. Herein and after, the chemical name "bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate" is used in the invention instead of trivial name "dicholine succinate", since the name "dicholine succinate" was frequently used in literature for description of a widely known ester of succinic acid and choline.
SUMMARY OF THE INVENTION
This invention relates to compositions and methods for achieving a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal. More specifically, this invention relates to synergistic composition ~o comprising amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, which are presented in amounts sufficient to cause synergistic effects in treating insulin resistance and diabetes mellitus in a mammal. Further, this invention relates to methods for achieving a synergistic effects in treating insulin resistance and diabetes mellitus in a mammal, which methods comprise administering to said mammal, either stepwise or simultaneously, effective amounts of choline base or a pharmaceutically acceptable salt thereof and s succinic acid or a pharmaceutically acceptable salt thereof. Further, this invention relates to a novel derivative of choline. More specifically, this invention relates to bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, the novel salt of choline formed by choline base and succinic acid in the molar ratio 2:1, a process for producing the salt, and use of the salt in medicine, to preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, or diabetes mellitus.
DETAILED DESCRIPTION OF THE INVENTION
The term "synergistic" as used herein means that the effect achieved Is with the methods and compositions of this invention is greater than the sum of the effects that result from methods and compositions comprising choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof separately and in the amounts employed in the methods and compositions hereof.
2o Accordingly to this invention, it is now possible to achieve a synergistic effect in treating insulin resistance and diabetes mellitus in a mammal with amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof which, if administered in said amounts singly, are not capable of achieving said effect 2s and which effect is greater than the sum of the effects achieved for choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof separately.
The term "treating" as used herein means the management and care of a mammal for the purpose of combating the disease, condition, or disorder ~o and includes the administration of choline base or a pharmaceutically acceptable salt thereof and 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 insulin resistance includes increasing insulin sensitivity in a mammal and other effects, which are resulted from increasing insulin sensitivity in a mammal. Such effects include, but are not limited to, improving in carbohydrate, lipid, or protein metabolism, alterations in growth, s differentiation, DNA synthesis, and regulation of gene transcription.
The present invention provides a method for achieving a synergistic effect in treating insulin resistance in a mammal in need thereof, which comprises administering to said mammal an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a to pharmaceutically acceptable salt thereof. Preferred effect achieved according to this invention in treating insulin resistance is lowering pathologically elevated plasma insulin levels. Insulin resistance in the mammal can be associated with disorders such as diabetes mellitus and its chronic complications; gestational diabetes mellitus; impaired glucose tolerance;
is obesity; ageing; atherosclerosis; syndrome X; cardiovascular disease; AIDS;
cancer; wasting/cachexia; 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. Preferably, insulin resistance is associated with 2o diabetes mellitus in the mammal.
Further, the present invention provides a method for achieving a synergistic effect in treating diabetes mellitus in a mammal in need thereof, which comprises administering to said mammal an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid 2s or a pharmaceutically acceptable salt thereof. Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels.
Preferably, choline base or a pharmaceutically acceptable salt thereof of the invention is choline chloride. Preferably, succinic acid or a ~o pharmaceutically acceptable salt thereof of the invention is disodium succinate.
The administration of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof can be stepwise in time or simultaneous with the simultaneous method being preferred.
Choline base or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, topically, or rectally. Preferably, choline base s or a pharmaceutically acceptable salt thereof is administered parenterally.
Succinic acid or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, topically, or rectally. Preferably, succinic acid or a pharmaceutically acceptable salt thereof is administered parenterally.
Preferably, the choline base or a pharmaceutically acceptable salt to thereof is administered for a period of 1 day or longer, more preferably for a period of 3 to 7 days. Preferably, 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 present invention provides a composition for achieving a ~s synergistic effect in treating insulin resistance in a mammal in need thereof, which comprises an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Preferred effect achieved according to this invention in treating insulin resistance is 20 lowering pathologically elevated plasma insulin levels.
Further, the present invention provides a composition for achieving a synergistic effect in treating diabetes mellitus in a mammal in need thereof, which comprises an effective amounts of choline base or a pharmaceutically acceptable salt thereof and succinic acid or a pharmaceutically acceptable 2s salt thereof, and a pharmaceutically acceptable diluent or carrier.
Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels.
The pharmaceutically acceptable salt of the choline base is prepared by known methods from nontoxic organic and inorganic acids. Such acids ~o include, but are not limited to, hydrogen chloride, hydrogen bromide, citric acid, tartaric acid, and succinic acid. Preferably, choline base or a pharmaceutically acceptable salt thereof of the invention is choline chloride.
WO 01/76583 ~ PCT/RU00/00122 The pharmaceutically acceptable salt of the succinic acid is prepared by known methods from organic and inorganic bases. Such bases include, but are not limited to, nontoxic alkali metal and alkaline earth bases, for example, calcium, lithium, sodium, and potassium hydroxide; ammonium s hydroxide and nontoxic organic bases, such as triethylamine, butylamine, diethanolamine, triethanolamine, and choline base. Preferably, succinic acid or a pharmaceutically acceptable salt thereof of the invention is disodium succinate.
Some examples of suitable carriers and diluents include lactose, to dextrose, sorbitol, mannitol, calcium phosphate, alginates, gelatin, calcium silicate, microcrystalline cellulose, methylcellulose, polyvinylpyrrolidone, water, methyl- and propylhydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil. The compositions of the invention can additionally include lubricating agents, wetting agents, emulsifying and Is suspending agents, preserving agents, sweetening agents, or flavoring agents.
Compositions of the invention can be administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, 20 lozenges, troches, hard candies, powders, sprays, aqueous solutions, elixirs, syrups and the like.
The effective amount of choline base or a pharmaceutically acceptable salt thereof for use in the methods and compositions of this invention is preferably from 3 to 300 mg per day per kg of body weight of the mammal.
2s The effective amount of succinic acid or a pharmaceutically acceptable salt thereof for use in the methods and compositions of this invention is preferably from 1 to 250 mg per day per kg of body weight of the mammal.
The present invention provides bis(2-hydroxy-N,N,N
trimethylethanaminium) succinate, which has the chemical formula given 3o below:
[(CH3)3N+CH2CH20H]2 -OOCCH2CHzC00-The present invention provides a process for producing bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, which comprises reacting choline base with succinic acid in the presence of water, alcohol, or mixture thereof.
Preferably, bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate is s prepared by reacting the choline base and succinic acid, wherein the mole ratio of choline base to succinic acid entered in reaction is about 2:1, but no lower than 1.9:1 and no higher than 2.1:1. The reaction take place at ambient temperatures and the reaction is quantitative. The desired product is obtained as a white crystalline powder with reproducible properties.
to Also provided according to the present invention is the use of bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate in medicine, preferably for the manufacture of a medicament for treating insulin resistance, hyperlipidemia, dyslipidemia, and diabetes mellitus in a mammal in need thereof. Preferred effect achieved according to this invention in treating insulin Is resistance is lowering pathologically elevated plasma insulin levels.
Preferred effects achieved according to this invention in treating hyperlipidemia are lowering pathologically elevated plasma triglycerides and cholesterol levels.
Preferred effects achieved according to this invention in treating dyslipidemia are lowering low-density lipoprotein cholesterol levels and increasing high-2o density lipoprotein cholesterol levels. Preferred effect achieved according to this invention in treating diabetes mellitus is lowering pathologically elevated blood glucose levels.
The following examples are presented to demonstrate the invention.
The examples are illustrative only and are not intended to limit the scope of 2s the invention in any way.
This example shows the synergistic effects in treating insulin resistance and diabetes mellitus achieved by co-administration of effective amounts of ~o choline chloride and disodium succinate to diabetic rats.
Assay. Plasma insulin concentrations were determined using a kit ("Dako", Dutch) with a rat insulin standard (Novo Research Institute, Bagsvard, WO 01/76583 y PCT/RU00/00122 Denmark). Plasma glucose concentrations were determined using a kit ("Agat", Russia). Plasma triglycerides and cholesterol concentrations were determined with reagents FS, "DiaSys", Germany; HDL cholesterol with reagents "Cormay", Poland; and LDL cholesterol with reagents "Boehringer s Mannheim", Germany.
Animals. Male Wistar rats 8-10 weeks of age 210-230g 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, and cellulose) to and allowed water ad libitum. Diabetes mellitus was induced in Wistar male rats by twice i.v. injection (tail vein) of alloxan (40 mg/kg body wt) with break of 48 hours. The rats were used in experiments at 6t" day from the first alloxan injection. Fasting plasma glucose, insulin, total cholesterol (Ch), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol is (LDL), and triglycerides (TG) levels of these animals are presented in Table 1 as Mean~SD in comparison with healthy control. Insulin resistance, hyperinsulinemia, hyperglycemia, hyperlipidemia, and dyslipidemia characterize the rats prepared by this means.
2o Table 1. Fasting plasma parameters in rats at 6t" day since the first alloxan injection.
Rats Glucos Insulin,HDL, LDL, TG, Ch, e,mmol ~U/I mmol/I mmol/I mmol/I mmol/I
/I
Healthy rats 4.3 2.0 2.0 0.8 0.5 1.7 (n=10) 0.7 0.5 0.3 0.2 0.1 0.3 Diabetic rats 13.9 4.8 1.0 1.0 1.3 2.5 (n=10) 2.3* 0.8* 0.3* 0.3 0.3* 0.5*
*Differs significantly from healthy control (P< 0.01 ) Treatment. The diabetic animals were divided into four groups: a diabetic 2s control group (n=10) and three diabetic groups treated with daily i.v.
injections WO O1 /76583 ~ 0 PCT/RU00/00122 of choline chloride (240 mg/kg body weight, n=10), disodium succinate (70 mg/kg body weight, n=10), or the combination of choline chloride (240 mg/kg body weight) with disodium succinate (70 mg/kg body weight, n=10) for the 5 days.
s Fasting plasma glucose was measured at the 6t" day since treating beginning. Data are shown in Table 2. In diabetic control, the mean of glucose level was found to be 12.5 mmol/I. OGlucose is difference between means of fasting plasma glucose in control and treated rats calculated by equation: D Glucose = 12.5 - Mean (mmol/I).
~o Effect of the combination is 7.8 mmol/I decreasing in fasting plasma glucose level from the control. The sum of effects of choline chloride and disodium succinate administered individually is 2.8 mmol/I (-1.1 +3.9 =2.8) decreasing in fasting plasma glucose level of control. Since glucose-lowering effect of the combination is greater than the sum of glucose-lowering effects is of choline and succinate administered individually, the combination is synergistically effective in lowering pathologically elevated plasma glucose levels.
Table 2. Fasting plasma glucose at 6t" day since treating beginning.
Treatment Glucose, mmol/I o Glucose, mmol/I
(Mean SD) Control 12.5 2.4* 0 Choline chloride 13.6 2.2* -1.1 Disodium succinate 8.6 1.8*t +3.9 Combination 4.7 0.8t +7,g 20 * Differs significantly from the combination (P< 0.01 ) t Differs significantly from control (P< 0.01) Fasting plasma insulin levels were measured at the 6t" day since treating beginning. Data are shown in Table 3. In diabetic control, the mean of 2s insulin level was found to be 5.7 pU/I. Olnsulin is difference between means of WO 01/76583 1 ~ PCT/RU00/00122 fasting plasma insulin in control and treated rats calculated by equation: D
Insulin = 5.7 - Mean (~U/I).
Effect of the combination is 4.1 p.U/I decreasing in fasting plasma insulin level from the control. The sum of effects of choline chloride and s disodium succinate administered individually is 2.1 ~U/I (0.9 + 1.2 =2.1 ) decreasing in fasting plasma insulin level of control. Since insulin-lowering effect of the combination is greater than the sum of insulin-lowering effects of choline and succinate administered individually, the combination is synergistically effective in lowering pathologically elevated plasma insulin to levels.
Table 3. Fasting plasma insulin at 6t" day since treating beginning.
Treatment Insulin, ~,U/I (Mean~ Insulin, ~,U/I
SD) Control 5.7 1.1 * 0 Choline chloride 4.8 0.7* 0.9 Disodium succinate 4.5 0.6*t 1.2 Combination 1.6 0.3t 4.1 * Differs significantly from the combination (P<0.01) t Differs significantly from control (P<0.01) Bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate is effective in treating insulin resistance, hyperlipidemia, dyslipidemia, and diabetes mellitus in diabetic rats.
Animals. Diabetic rats were prepared as described in Example 1 of the invention.
Treatment. The animals were divided into two groups: a diabetic control group (n=10) and diabetic group treated with daily i.v. (tail vein) injections of bis(2-2s hydroxy-N,N,N-trimethylethanaminium) succinate (120 mg/kg body weight, n=10) for the 3 days. Fasting plasma glucose, insulin, total cholesterol (Ch), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels were measured at the 7t" day since treating beginning and shown in Table 4 as Mean~SD.
s Table 4. Fasting plasma parameters at 7t" day since treating beginning.
Blood parameters, Treatment (MeanSD) Control rats Treated rats Fasting plasma glucose,12.5 2.4 4.2 0.6**
mmol/I
Fasting plasma insulin,6.0 1.0 1.3 0.5**
~,U/I
Total cholesterol, 3.0 0.4 1.5 0.3**
mmol/I
LDL cholesterol, 1.1 0.3 0.8 0.2*
mmol/I
HDL cholesterol, 0.8 0.2 2.0 0.2**
mmol/I
Triglycerides, mmol/I1.4 0.3 0.7 0.1 **
* Differs from control (P<0.05) ** Differs significantly from control (P<0.01 ) ~o The process for producing bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate.
To a solution of 121 g (1 mole) of choline base in methanol was added 59 g (0.5 mole) of succinic acid. The reaction mixture was stirred at ambient Is temperature for 20 minutes and concentrated under vacuum to dryness at a temperature of 40-50°C. The desired bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate is obtained at a yield approximating 100%
as a solid white crystalline material: mp 135-137°C (from tert-butanol);
NMR'H (D20):8 2.24 (s, 4H), 3.07 (s, 18H), 3.38 (m, 4H), 3.93 (m, 4H); NMR
20 '3C (D20):8 34.5, 54.2, 56.0, 67.8, 182.6; Anal. Calculated for C~4H32NZOg:
C, 51.83; H, 9.94. Found: C, 51.66; H 9.86.
Claims (32)
1. A method for achieving a synergistic effect in treating insulin resistance in a mammal in need thereof, which comprises administering to said mammal an effective amounts of:
(a) choline base or a pharmaceutically acceptable salt thereof; and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect; and wherein the effect of the sum of the amounts of (a) and (b) is greater than the sum of the effects achievable with the amounts of (a) and (b) administered individually.
(a) choline base or a pharmaceutically acceptable salt thereof; and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect; and wherein the effect of the sum of the amounts of (a) and (b) is greater than the sum of the effects achievable with the amounts of (a) and (b) administered individually.
2. The method as claimed in Claim 1 wherein said effect comprises lowering plasma insulin levels.
3. A method for achieving a synergistic effect in treating diabetes mellitus in a mammal in need thereof, which comprises administering to said mammal an effective amounts of:
(a) choline base or a pharmaceutically acceptable salt thereof; and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect; and wherein the effect of the sum of the amounts of (a) and (b) is greater than the sum of the effects achievable with the amounts of (a) and (b) administered individually.
(a) choline base or a pharmaceutically acceptable salt thereof; and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect; and wherein the effect of the sum of the amounts of (a) and (b) is greater than the sum of the effects achievable with the amounts of (a) and (b) administered individually.
4. The method as claimed in Claim 3 wherein said effect comprises lowering plasma glucose levels.
5.The method as claimed in any one of Claims 1 to 4 wherein the amount of the choline base or a pharmaceutically acceptable salt thereof and the amount of the succinic acid or a pharmaceutically acceptable salt thereof is administered simultaneously.
6. The method as claimed in any one of Claims 1 to 5 wherein the pharmaceutically acceptable salt of choline is choline chloride.
7. The method as claimed in any one of Claims 1 to 6 wherein the pharmaceutically acceptable salt of succinic acid is disodium succinate.
8. The method as claimed in any one of Claims 1 to 7 wherein the effective amount of choline base or a pharmaceutically acceptable salt thereof is 3 to 300 mg per day per kg of body weight of the mammal.
9. The method as claimed in any one of Claims 1 to 8 wherein the effective amount of succinic acid or a pharmaceutically acceptable salt thereof is 1 to 250 mg per day per kg of body weight of the mammal.
10. The method as claimed in any one of Claims 1 to 9 wherein the effective amount of choline base or a pharmaceutically acceptable salt thereof is administered orally, parenterally, topically or rectally.
11. The method as claimed in Claim 10 wherein the effective amount of choline base or a pharmaceutically acceptable salt thereof is administered parenterally.
12. The method as claimed in any one of Claims 1 to 11 wherein the effective amount of succinic acid or a pharmaceutically acceptable salt thereof is administered orally, parenterally, topically or rectally.
13. The method as claimed in Claim 12 wherein the effective amount of succinic acid or a pharmaceutically acceptable salt thereof is administered parenterally.
14. The method as claimed in any one of Claims 1 to 13 wherein the effective amount of succinic acid or a pharmaceutically acceptable salt thereof is administered for a period of 1 day or longer.
15. The method as claimed in Claim 14 wherein the effective amount of succinic acid or a pharmaceutically acceptable salt thereof is administered for a period of 3 to 7 days.
16. The method as claimed in any one of Claims 1 to 15 wherein the effective amount of choline base or a pharmaceutically acceptable salt thereof is administered for a period of 1 day or longer.
17. The method as claimed in Claim 16 wherein the effective amount of choline base or a pharmaceutically acceptable salt thereof is administered for a period of 3 to 7 days.
18. A composition for achieving a synergistic effect in treating insulin resistance in a mammal in need thereof which comprises an effective amounts of:
(a) choline base or a pharmaceutically acceptable salt thereof; and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect; and wherein the effect of the sum of the amounts of (a) and (b) is greater than the sum of the effects achievable with the amounts of (a) and (b) administered individually, and a pharmaceutically acceptable diluent or carrier.
(a) choline base or a pharmaceutically acceptable salt thereof; and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect; and wherein the effect of the sum of the amounts of (a) and (b) is greater than the sum of the effects achievable with the amounts of (a) and (b) administered individually, and a pharmaceutically acceptable diluent or carrier.
19. The composition as claimed in Claim 18 wherein said effect comprises lowering plasma insulin levels.
20. A composition for achieving a synergistic effect in treating diabetes mellitus in a mammal in need thereof which comprises an effective amounts of:
(a) choline base or a pharmaceutically acceptable salt thereof; and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect; and wherein the effect of the sum of the amounts of (a) and (b) is greater than the sum of the effects achievable with the amounts of (a) and (b) administered individually, and a pharmaceutically acceptable diluent or carrier.
(a) choline base or a pharmaceutically acceptable salt thereof; and (b) succinic acid or a pharmaceutically acceptable salt thereof, wherein the amount of (a) alone and the amount of (b) alone is insufficient to achieve the effect; and wherein the effect of the sum of the amounts of (a) and (b) is greater than the sum of the effects achievable with the amounts of (a) and (b) administered individually, and a pharmaceutically acceptable diluent or carrier.
21. The composition as claimed in Claim 20 wherein said effect comprises lowering plasma glucose levels.
22. The composition as claimed in any one of Claims 18 to 21 wherein the pharmaceutically acceptable salt of choline is choline chloride.
23. The composition as claimed in any one of Claims 18 to 22 wherein the pharmaceutically acceptable salt of succinic acid is disodium succinate.
24. The composition as claimed in any one of Claims 18 to 23 wherein the effective amount of choline base or a pharmaceutically acceptable salt thereof is 3 to 300 mg per day per kilogram of body weight of the mammal.
25. The composition as claimed in any one of Claims 18 to 24 wherein the effective amount of succinic acid or a pharmaceutically acceptable salt thereof is 1 to 250 mg per day per kilogram of body weight of the mammal.
26. Bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate
27. Bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate for use in medicine.
28. The use as claimed in Claim 27 wherein said use in medicine is use for the manufacture of a medicament for treating insulin resistance in a mammal in need thereof.
29. The use as claimed in Claim 27 wherein said use in medicine is use for the manufacture of a medicament for treating diabetes mellitus in a mammal in need thereof.
30. The use as claimed in Claim 27 wherein said use in medicine is use for the manufacture of a medicament for treating hyperlipidemia or dyslipidemia in a mammal in need thereof.
31. A process for producing bis(2-hydroxy-N,N,N-trimethylethanaminium) succinate, which comprises reacting choline base with succinic acid.
32. The process as claimed in Claim 32 in which the mole ratio of choline base to succinic acid is about 2:1, but no lower than 1.9:1 and no higher than 2.1:1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/RU2000/000122 WO2001076583A1 (en) | 2000-04-10 | 2000-04-10 | Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2404864A1 true CA2404864A1 (en) | 2001-10-18 |
Family
ID=20129496
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002404864A Abandoned CA2404864A1 (en) | 2000-04-10 | 2000-04-10 | Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1272171A1 (en) |
| JP (1) | JP3944393B2 (en) |
| KR (1) | KR20020089444A (en) |
| CN (1) | CN1452482A (en) |
| AU (1) | AU2000263274A1 (en) |
| BR (1) | BR0017206A (en) |
| CA (1) | CA2404864A1 (en) |
| WO (1) | WO2001076583A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003236156A1 (en) * | 2003-04-24 | 2005-01-04 | Shin-Jen Shiao | Pharmaceutical compositions used for immune disease treatment and improvement |
| EA017094B1 (en) * | 2007-08-02 | 2012-09-28 | Игорь Анатольевич Помыткин | Pharmaceutical compositions for intranasal administration comprising choline salts of succinic acid |
| US8673977B2 (en) | 2008-11-26 | 2014-03-18 | Igor Anatolievich Pomytkin | Choline salts of succinic acid for the treatment of depression, anxiety, schizophrenia, sleep disorder, and epilepsy |
| US8314080B2 (en) | 2010-04-06 | 2012-11-20 | Kuwait University | Method of treating type I diabetes |
| CN106727476A (en) * | 2016-12-09 | 2017-05-31 | 杨远志 | A kind of composition and its application in animal muscle fiber types is improved |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR6346669D0 (en) * | 1962-02-12 | 1973-06-14 | Squibb & Sons Inc | PROCESS OF PREPARING A STABLE PHARMACEUTICAL COMPOSITION OF HILLS OF HILLS |
| JPS61171417A (en) * | 1985-01-23 | 1986-08-02 | Wakunaga Seiyaku Kk | Antidiabetic |
| US6294520B1 (en) * | 1989-03-27 | 2001-09-25 | Albert T. Naito | Material for passage through the blood-brain barrier |
| JPH03169498A (en) * | 1989-11-28 | 1991-07-23 | Yotsukaichi Gosei Kk | Water soluble flux for soldering |
| JPH0586319A (en) * | 1991-09-27 | 1993-04-06 | Pentel Kk | Water-base ink composition |
| US5895652A (en) * | 1996-07-29 | 1999-04-20 | Longevity Institute International | Method of metabolic adjuvanation and cellular repair |
| EP1156795B1 (en) * | 1999-03-01 | 2004-06-02 | Verteletsky, Pavel Vasilievich | Use of succinic acid or salts thereof and method of treating insulin resistance |
| CA2362116A1 (en) * | 1999-04-05 | 2000-10-12 | Igor Anatolievich Pomytkin | Use of succinic acid or salts thereof for the treatment of diabetes mellitus and wound healing |
-
2000
- 2000-04-10 BR BR0017206-5A patent/BR0017206A/en not_active IP Right Cessation
- 2000-04-10 JP JP2001574101A patent/JP3944393B2/en not_active Expired - Fee Related
- 2000-04-10 WO PCT/RU2000/000122 patent/WO2001076583A1/en not_active Application Discontinuation
- 2000-04-10 CA CA002404864A patent/CA2404864A1/en not_active Abandoned
- 2000-04-10 EP EP00950127A patent/EP1272171A1/en not_active Withdrawn
- 2000-04-10 AU AU2000263274A patent/AU2000263274A1/en not_active Abandoned
- 2000-04-10 KR KR1020027013553A patent/KR20020089444A/en not_active Application Discontinuation
- 2000-04-10 CN CN00819413A patent/CN1452482A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001076583A1 (en) | 2001-10-18 |
| JP3944393B2 (en) | 2007-07-11 |
| JP2004506605A (en) | 2004-03-04 |
| AU2000263274A1 (en) | 2001-10-23 |
| BR0017206A (en) | 2003-01-14 |
| CN1452482A (en) | 2003-10-29 |
| EP1272171A1 (en) | 2003-01-08 |
| KR20020089444A (en) | 2002-11-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5132324A (en) | Use of 3-guanidinopropionic acid in the treatment of non-insulin dependent diabetes mellitus (niddm) | |
| EP0474874B1 (en) | Maillard Reaction inhibitor compositions | |
| US8097635B2 (en) | Insulin resistance improving agent | |
| CA2502297C (en) | Compounds for the treatment of metabolic disorders | |
| CA2404864A1 (en) | Synergistic compositions containing choline base and succinic acid for insulin resistance and diabetes | |
| KR20050090443A (en) | Kynurenine-3-hydroxylase inhibitors for the treatment of diabetes by increasing the number of islets of langerhans cells | |
| JPH0816057B2 (en) | Glycation inhibitors | |
| WO2002012177A1 (en) | Composition of metformin with succinic acid or salts thereof and method for treating diabetes | |
| Rosen et al. | Corticosteroids and transaminase activity III. A relationship between changes in alanine transaminase activity and the growth of Walker carcinosarcoma 256 | |
| WO2018166494A1 (en) | Use of matrine derivative in treatment of diabetes mellitus | |
| US6509480B2 (en) | Glucose and lipid lowering compounds | |
| US6521665B1 (en) | Method of treating insulin resistance | |
| KR20010080428A (en) | Glucose and Lipid Lowering Compounds | |
| EP0443028A1 (en) | Non-injection carcinostatic agent for suppressing occurrence of inflammation due to 5-fluorouracil and method for curing cancer | |
| US6620424B1 (en) | Process for producing glycolytic metabolism regulators | |
| CA2478931A1 (en) | A method of treating diabetes mellitus including conditions associated with diabetes mellitus and complications of diabetes mellitus | |
| US20060105940A1 (en) | Compound useful in the treatment or prevention of cognitive disorders associated with diabetes and associated methods | |
| WO1992012706A1 (en) | Method of reducing elevated blood sugar levels in humans | |
| US20100305204A1 (en) | Composition useful for the prevention of adverse effect due to the use of ppar-gamma agonists | |
| US3910960A (en) | Gulonic acid salt | |
| WO2013057422A1 (en) | Anti-diabetic aminosteroid derivatives | |
| JPH072867A (en) | Production of biotin amide derivatives, and remedies against diabetes and diabetic complication containing them | |
| KR20060060376A (en) | A novel fungal species of micromucor ramannianus var. angulisporus crm000232 and protein tyrosin phosphatase 1b inhibitor comprising depside compounds isolated and purified from them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |