CN1452482A - Synergistic composition containing choline and succinic acid for treating insulin resistance and diabetes - Google Patents
Synergistic composition containing choline and succinic acid for treating insulin resistance and diabetes Download PDFInfo
- Publication number
- CN1452482A CN1452482A CN00819413A CN00819413A CN1452482A CN 1452482 A CN1452482 A CN 1452482A CN 00819413 A CN00819413 A CN 00819413A CN 00819413 A CN00819413 A CN 00819413A CN 1452482 A CN1452482 A CN 1452482A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical salts
- succinic acid
- choline
- effective dose
- curative effect
- 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.)
- Pending
Links
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 title claims abstract description 118
- 229960001231 choline Drugs 0.000 title claims abstract description 71
- 239000001384 succinic acid Substances 0.000 title claims abstract description 58
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 48
- 230000002195 synergetic effect Effects 0.000 title claims abstract description 20
- 206010022489 Insulin Resistance Diseases 0.000 title abstract description 9
- 239000000203 mixture Substances 0.000 title abstract description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 59
- 239000003814 drug Substances 0.000 claims abstract description 29
- 241000124008 Mammalia Species 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 22
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims abstract description 11
- 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 9
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 122
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- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 14
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 13
- 235000019743 Choline chloride Nutrition 0.000 claims description 13
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 13
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- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 abstract 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 24
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 8
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- 239000003513 alkali Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
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- 231100000252 nontoxic Toxicity 0.000 description 3
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- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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- ZKMDOYRDBAGOAD-UHFFFAOYSA-L butanedioate;2-hydroxyethyl(trimethyl)azanium Chemical compound C[N+](C)(C)CCO.C[N+](C)(C)CCO.[O-]C(=O)CCC([O-])=O ZKMDOYRDBAGOAD-UHFFFAOYSA-L 0.000 description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The present invention relates to compositions and methods for synergistic effects in the treatment of insulin resistance and diabetes in mammals. More specifically, the present invention relates to synergistic compositions comprising choline base (or a pharmaceutically acceptable salt thereof) and succinic acid (or a pharmaceutically acceptable salt thereof) in amounts sufficient to provide a synergistic effect in treating insulin resistance and diabetes in a mammal. The present invention also relates to a synergistic method for treating insulin resistance and diabetes in a mammal comprising administering gradually or simultaneously doses of a choline base (or a pharmaceutically acceptable salt thereof) and succinic acid (or a pharmaceutically acceptable salt thereof). In addition, the invention also provides a new choline derivative, specifically bis (2-hydroxy-N, N, N-trimethyl acetylcholine) succinate, which is prepared from choline base and succinic acid according to the molar ratio of 2: 1, can be used in medicine, and is particularly suitable for preparing medicines for treating diseases such as insulin resistance, hyperlipidemia, dyslipidemia, diabetes and the like.
Description
Technical field
The present invention relates in mammiferous insulin resistant of treatment and diabetes process, play synergistic constituent and method.Or rather, in the collaborative constituent involved in the present invention, contain the choline base (or its pharmaceutical salts) and the succinic acid (or its pharmaceutical salts) of some, these two kinds of compositions play synergism to treating mammiferous insulin resistant and diabetes when liberal quantity.In addition, the invention still further relates to and play synergistic method to treating mammiferous insulin resistant and diabetes, these methods comprise choline base (or its pharmaceutical salts) from effective dose to described mammal and the succinic acid (or its pharmaceutical salts) of progressively or simultaneously supplying with.In addition, the invention still further relates to a kind of new choline derivative, or rather, relate to a kind of two (2-hydroxy-n, N, N-pivaloyl choline) succinate.This new choline salt is formulated according to 2: 1 mol ratio by choline base and succinic acid, and this salt can be used for medicine, is specially adapted to prepare sick medicines such as treatment insulin resistant, hyperlipemia, dyslipidemia and diabetes.
Background technology
As anabolic hormone main in the human body, insulin produces multiple-effect to the various tissues of human body.It promotes the picked-up of glucose in muscle and the fat, suppresses liver simultaneously and discharges glucose.And it can also regulate the metabolism of lipid in blood plasma and the tissue, the growth and the electrolytical balance of proteinic synthetic, cell.
Insulin resistant refers to, to the biological respinse of the infringement that exogenous insulin and endogenous insulin presented.By the test organisms reaction, can understand metabolic process, as the variation that in saccharide, lipid and protein metabolism process, occurs, can also know mitogenetic process, as the variation in growth, differentiation, the DNA building-up process, and the adjusting of genetic transcription.
Glucose tolerance is bad, makes the people suffer from type 2 diabetes mellitus, occurs hyperlipoidemia and dyslipidemia in the body, hypertension, hyperuricemia, and a series of disorder such as blood plasma fibrinolytic reduction, and insulin resistant is exactly the major reason that causes glucose tolerance bad.[Reaven, GM.Physiol-Rev.75 (3): 473-86 (1995); " insulin resistant consistent develop meeting ", treating diabetes, 21 (2) 1998.] insulin resistant is relevant with many condition of illness, as gestational diabetes, obesity, aging, atherosclerosis, cardiovascular syndrome X, acquired immune deficiency syndrome (AIDS), cancer, ablation disease/cachexia, sepsis, the wound that burn or scald cause, malnutrition, lupus and other autoimmune disease, endocrinopathy, polycystic ovary syndrome, and the complication that occurs in the motion, or the like.
Clinically, insulin resistant shows as, and the fasting plasma insulin level is in morbid state and raises, and can diagnose according to the size of insulin concentration in the blood plasma.
Diabetes refer to the metabolism disorder that multiple cause of disease causes, the feature of this disease is a chronic hyperglycemia, and by hypoinsulinism in the human body or insulin response defective, perhaps both have concurrently and cause.
Clinically, diabetes show as, and blood sugar level is in morbid state and raises, and can diagnose according to the size of concentration of glucose in the blood.
In the international application of PCT/RU 99/00055, proposed about using the method for succinic acid or its esters treatment insulin resistant.
Propose in the Japan Patent 61171417, succinic acid or its esters are the diabetes active drugs, are used to promote secretion of insulin.The viewpoint that the viewpoint of MacDonald and Japan Patent 61171417 proposes is on the contrary, and he finds, succinic acid or its salt can not the stimulating pancreas excreting insulins, and he points out that the succinic acid esters is only effective insulin secretagogue simultaneously.[select from MacDonald, the paper diabetes 37 (7) that M.J. and Fahien delivered in 1988: 997-999.]。Point out also in the Japan Patent 6062798 that succinic acid is during as the composition of food of a kind of people picked-up, and is extremely low with the bonded glucose tolerance of acetic acid, lactic acid and gluconic acid.Disodium succinate can be used as ingredient, combines with citric acid and acetic acid, is used in the rabbit on one's body time that suffers from alloxan diabetes, effectively blood sugar lowering concentration.[select from the paper Ukr.Biokhim.Zh. that Dzvonkevich delivered in 1974,46 (5): 547-552.]
Before the present invention, nobody proposes to use choline base (or its pharmaceutical salts) and succinic acid (or its pharmaceutical salts), in treatment insulin resistant and diabetes process, obtains synergism.
United States Patent (USP) 5,124 is mentioned in 061, single choline succinate, be a kind of by choline base and succinic acid according to the formulated plant antifreeze ingredient of 1: 1 mol ratio.Yet this salt does not have reproducibility, and its characteristic can only define according to choline and the succinic acid process by 1: 1 mol ratio preparation.The acidity of single choline succinate and not reproducible can not be widely used in pharmaceutically it.
Before the present invention, nobody proposes pharmaceutically using two succinate (2-hydroxy-ns, N, N-pivaloyl choline), it is a kind of neutral salt, formulated by choline base and succinic acid according to 2: 1 mol ratio, be particularly useful for preparing sick medicines such as treatment insulin resistant, hyperlipidemia and diabetes.Herein and in the follow-up narration, use two succinate (2-hydroxy-ns, N, N-pivaloyl choline succinate) this chemical name, replaced popular name " two choline succinates " (dicholine succinate), popular name " two choline succinates " (dicholine succinate) past occurs on the document of being everlasting, and represents a kind of esters that is widely known by the people that contains succinic acid and choline.
Summary of the invention
The invention provides a kind ofly in treatment mammiferous insulin resistant and diabetes process, play synergistic constituent and method.Or rather, what the present invention relates to rises in the synergistic constituent, contain the choline base (or its pharmaceutical salts) and the succinic acid (or its pharmaceutical salts) of some, these two kinds of chemical constituents play synergism to treating mammiferous insulin resistant and diabetes when liberal quantity.In addition, the present invention also provides a kind of and has played synergistic method to treating mammiferous insulin resistant and diabetes, comprises progressively or supply with to mammal simultaneously the choline base (or its pharmaceutical salts) and the succinic acid (or its pharmaceutical salts) of effective dose.In addition, the invention allows for a kind of new choline derivative, two more precisely (2-hydroxy-ns, N, N-pivaloyl choline) succinate, this new choline salt is formulated according to 2: 1 mol ratio by choline and succinic acid, and this salt can pharmaceutically use, and is specially adapted to prepare sick medicines such as treatment insulin resistant, hyperlipemia, dyslipidemia and diabetes.
The specific embodiment
" synergism " here refers to, and method that proposes among the present invention and constituent are compared with composition with using the method that only contains choline (or its pharmaceutical salts) or succinic acid (or its pharmaceutical salts), and the former has more notable therapeutic effect than the latter.
According to the present invention, in mammiferous insulin resistant of treatment and diabetes process, use the choline base (or its pharmaceutical salts) and the succinic acid (or its pharmaceutical salts) of doses, can obtain synergism.If but these two kinds of compositions use respectively, even the same among the dosage that uses and the present invention, can not obtain synergism yet, in other words, use choline base and succinic acid synthetic drug, with choline base (or its pharmaceutical salts) or single, better therapeutic effect is arranged than single with succinic acid (or its pharmaceutical salts).
" treatment " here refers to, mammal is carried out certain processing and nursing, treatment disease, uncomfortable and matrix is disorderly, comprise and use choline base (or its pharmaceutical salts) and succinic acid (or its pharmaceutical salts), prevent disease and complication, palliate a disease and the symptom of complication, or eliminate a disease, disorderly in the uncomfortable and body.The treatment of insulin resistant comprises the intravital insulin sensitivity of raising mammal, and obtain other some therapeutic effect by improving insulin sensitivity, these effects include, but is not limited to increase saccharide, lipid and protein metabolism, the variation that produces in growth, differentiation, the DNA building-up process, and the adjustment of genetic transcription.
The invention provides and a kind ofly play synergistic method in treatment mammal process of insulin resistance, this method comprises choline base (or its pharmaceutical salts) from effective dose to mammal and the succinic acid (or its pharmaceutical salts) of supplying with.According to the present invention, reaching ideal effect in the treatment process of insulin resistance is to make to be in the insulin level reduction that morbid state raises in the blood plasma originally.Mammiferous insulin resistant is relevant with intravital various disorders, as diabetes and chronic complication thereof; Gestational diabetes; Glucose tolerance is lowered; Obesity; Old and feeble; Atherosclerosis; The cardiovascular syndrome X; Cardiovascular disease; Acquired immune deficiency syndrome (AIDS); Cancer; Ablation disease/cachexia; Sepsis; The wound that burn or scald cause; Malnutrition; Lupus and other autoimmune disease; Endocrinopathy; Hyperuricemia; Hyperlipidemia; Polycystic ovary syndrome; And the complication that occurs in the motion, or the like.To a great extent, insulin resistant and mammiferous diabetes are closely related.
The present invention further provides and a kind ofly played synergistic method in the process of treatment mammal diabetes, this method comprises choline base (or its pharmaceutical salts) from effective dose to mammal and the succinic acid (or its pharmaceutical salts) of supplying with.According to the present invention, reaching ideal effect in treatment diabetes process is to make to be in the blood sugar level reduction that morbid state raises originally.
Employed choline base (or its pharmaceutical salts) can be a choline chloride among the present invention; Succinic acid (or its pharmaceutical salts) can be a disodium succinate.
On the time of supplying with, can be progressively to supply with choline base (or its pharmaceutical salts) and succinic acid (or its pharmaceutical salts), also can be both supply with simultaneously.By comparison, both methods of supplying with simultaneously are better.
Choline base (or its pharmaceutical salts) can be oral, parenteral dispensing, local application or rectal administration, and is better with the parenteral dispensing.Succinic acid (or its pharmaceutical salts) can be oral, parenteral dispensing, local application or rectal administration, and is better with the parenteral dispensing.
Choline base (or its pharmaceutical salts) the medication phase is one day or longer time, preferably three to seven days.Succinic acid (or its pharmaceutical salts) the medication phase is one day or longer time, preferably three to seven days.
The invention provides a kind of mammiferous process of suffering from insulin resistant in treatment and play synergistic constituent, it comprises the choline base (or its pharmaceutical salts) and the succinic acid (or its pharmaceutical salts) of effective dose, and medical diluent or carrier.According to the present invention, the ideal effect that is reached when the treatment insulin resistant is to reduce the blood insulin level that morbid state raises.
In addition, the invention provides and a kind ofly play synergistic constituent in treatment suffers from the mammiferous process of diabetes, it comprises the choline base (or its pharmaceutical salts) and the succinic acid (or its pharmaceutical salts) of effective dose, and medical diluent or carrier.According to the present invention, the ideal effect that is reached when the treatment diabetes is to reduce the blood sugar level that morbid state raises.
The pharmaceutical salts of choline base is formulated by nontoxic organic acid and mineral acid by known method.These acid include, but is not limited to hydrochloric acid, bromic acid, citric acid, tartaric acid and succinic acid.Choline base among the present invention (or its pharmaceutical salts) preferably adopts choline chloride.
The pharmaceutical salts of succinic acid is by organic and inorganic base is formulated by known method.These alkali include, but is not limited to non-toxic alkali and alkaline-earth metal, as calcium, lithium, sodium, potassium hydroxide, aqua ammonia and non-toxic organic alkali, as triethylamine, butylamine. diethanolamine, triethanolamine and choline base.Succinic acid among the present invention (or its pharmaceutical salts) preferably adopts disodium succinate.
Suitable carriers and diluent comprise lactose, glucose, sorbitol, mannitol, calcium phosphate, alginate, gelatin, calcium silicates, microcrystalline Cellulose, methylcellulose, polyvinylpyrrolidone (PVP), water, methyl and propane hydrogen base benzoate, Muscovitum, magnesium stearate, stearic acid and mineral oil.Constituent of the present invention also can comprise lubricant, wetting agent, emulsifying agent and suspending agent, antiseptic, sweeting agent, or flavouring agent.
Constituent of the present invention can have multiple formulation forms, promptly they can with multiple medicinal inert carrier combination, be mixed with tablet, capsule, lozenge, tablet, hard sugar, powder, spray, solution, elixir, syrup, or the like.
The method according to this invention, the effective dose of choline base (or its pharmaceutical salts) are that medication every day 3 of average per kilogram of body weight is to 300mg.
The method according to this invention, the effective dose of succinic acid (or its pharmaceutical salts) are that medication every day 1 of average per kilogram of body weight is to 250mg.
Two (2-hydroxy-n, N, N-pivaloyl choline) succinate provided by the invention, its molecular formula is as follows:
[(CH
3)
3N
+CH
2CH
2OH]
2 -OOCCH
2CH
2COO
-
The invention provides a kind of technology that generates two (2-hydroxy-n, N, N-pivaloyl choline) succinates, it is included under the condition that water, ethanol or its mixture exist and allows choline base and succinic acid react.When the reaction by choline base and succinic acid generated two (2-hydroxy-n, N, N-pivaloyl choline) succinate, the mol ratio of the succinic acid of choline base and adding was approximately 2: 1, but is not less than 1.9: 1, also is not higher than 2.1: 1.Reaction is carried out at ambient temperature, and reaction is quantitative.The desired product of producing is the white crystal sprills, has reproducible characteristic.
The invention allows for two (2-hydroxy-n, N, N-pivaloyl choline) succinates in pharmaceutically application, it is particularly suitable for making a kind of medicament, can treat insulin resistant, hyperlipemia, dyslipidemias mass formed by blood stasis and diabetes that mammal suffers from.The desirable curative effect that obtains when the present invention treats insulin resistant is that it can reduce the plasma insulin level that pathologic raises.The desirable curative effect that obtains when the present invention treats hyperlipemia is that it can reduce triglyceride and cholesterol levels that pathologic raises.The desirable curative effect that the present invention obtains when treating the dyslipidemias mass formed by blood stasis is that it can reduce low-density lipoprotein cholesterol level and improve the HDL-C level.The desirable curative effect that obtains when the present invention treats diabetes is that it can reduce the blood sugar level that pathologic raises.
Below with instantiation explanation the present invention.But protection scope of the present invention is not limited to these examples.
Example 1
This example has shown by the administering drug combinations of the choline chloride of effective dose and disodium succinate treats insulin resistant of diabetes mouse and the synergism that diabetes are received.
Measure: use an instrument Dako (Holland makes) to come plasma insulin concentration with mouse insulin standard (Denmark Bagsvard Novo institute).Use an instrument Agat (Russia's manufacturing) to measure blood sugar concentration.Measure blood plasma triglyceride and cholesterol concentration with Germany's system " DiaSys " FS reagent.Measure the HDL cholesterol with polish system " Cormay " reagent; Measure the LDL cholesterol with Germany's system " Boehringer Mannheim " reagent.
Animal: male Wei Sida (Wistar) mouse of using birth back 8-10 week, body weight 210-230 gram.Under 18 ± 21 ℃ of temperature, close the endowment Mus with 12 hours light-dark cycles.Feed with domestic animal laboratory diet (59% carbohydrate to mouse; 17% protein; 3% fat; 21% mineral, water and cellulose) and leave to drink water.Make the Wei Sida male wister rat suffer from diabetes by the 48 hours twice intravenous injection alloxan in interval (40 milligrams of every kg body weight).After injecting alloxan first the 6th day with mouse be used for the experiment.Listed the contrast of fasting glucose, insulin, T-CHOL (Ch), HDL-C (HDL), low-density lipoprotein cholesterol (LDL) and triglyceride (TG) value (means standard deviation) Yu the normal control group of these animals in the table 1.Have insulin resistant, hyperinsulinemia, hyperglycemia, hyperlipemia, these symptoms of dyslipidemias mass formed by blood stasis by the preliminary mouse of this method.
Table 1 is injected after the alloxan the 6th day mouse fasting plasma parameter first.
*With normal control group difference very big (P＜0.01)
| Mouse | The glucose mM/liter | The little U/ liter of insulin | The HDL-C mM/liter | The low-density lipoprotein cholesterol mM/liter | The triglyceride mM/liter | The cholesterol mM/liter |
| Healthy mouse (n=10) | 4.3±0.7 | 2.0±0.5 | ?2.0±0.3 | 0.8±0.2 | 0.5±0.1 | ?1.7±0.3 |
| Diabetes mouse (n=10) | 13.9±2.3 * | 4.8±0.8 * | 1.0±0.3 * | 1.0±0.3 * | 1.3±0.3 * | ?2.5±0.5 * |
Treatment: the diabetes mouse is divided into four groups: a diabetes matched group (n=10) and three diabetic groups, the mouse of diabetic groups is given intravenous injection choline chloride (240 mg/kg body weight every day, n=10), disodium succinate (70 mg/kg body weight, n=10) or joint injection choline chloride (240 mg/kg body weight) and disodium succinate (70 mg/kg body weight, n=10), inject 5 days altogether.
Treatment beginning back was measured fasting glucose on the 6th day.Data see table 2.At the diabetes matched group, the average level of glucose be 12.5 mMs/liter.The Δ glucose is the poor of fasting glucose meansigma methods between matched group and the treatment group mouse, calculates by this equation: Δ glucose=12.5-meansigma methods (mM/liter).
The effect of drug combination be fasting blood glucose level with respect to matched group reduced by 7.8 mMs/liter.To be fasting blood glucose level reduced by 2.8 mMs/liter (1.1+3.9=2.8) with respect to matched group to the individually dosed general effect of choline chloride and disodium succinate.Since drug combination reduces the general effect that the effect of glucose is better than choline chloride and the individually dosed reduction glucose of disodium succinate, then this medication combined use has synergism for the blood sugar level that reduces the pathologic rising.
The 6th day fasting glucose after the table 2 treatment beginning
| Treatment | Glucose, mM/liter (means standard deviation) | The Δ glucose, mM/liter |
| Matched group | 12.5±2.4 * | 0 |
| Choline chloride | 1?3.6±2.2 * | -1.1 |
| Disodium succinate | 8.6±1.8 *t | +3.9 |
| Associating | 4.7±0.8 t | +7.8 |
*With drug combination group difference very big (P＜0.01)
tWith matched group difference very big (P＜0.01)
The 6th day measurement fasting plasma insulin after the treatment beginning.Data see table 3.At the diabetes matched group, the average level of insulin be 5.7 μ U (atomerg quality)/liter.The Δ insulin is the poor of fasting plasma insulin meansigma methods between matched group and the treatment group mouse, calculates by this equation: Δ insulin=5.7-meansigma methods (μ U (atomerg quality)/liter).The effect of drug combination be the fasting plasma insulin level than matched group reduced by 4.1 μ U (atomerg quality)/liter.The individually dosed general effect of choline chloride and disodium succinate is that the fasting plasma insulin level has reduced by 2.1 μ U (atomerg quality)/liter (0.9+1.2=2.1) than matched group.Since drug combination reduces the general effect that the effect of insulin is better than choline chloride and the individually dosed reduction insulin of disodium succinate, then administering drug combinations has synergism for the plasma insulin level that reduces the pathologic rising.The 6th day fasting plasma insulin after the table 3 treatment beginning
*With drug combination group difference very big (P＜0.01)
tWith matched group difference very big (P＜0.01)
| Treatment | Insulin, μ U (atomerg quality)/liter (means standard deviation) | The Δ insulin, μ U (atomerg quality)/liter |
| Matched group | 5.7±1.1 * | 0 |
| Choline chloride | 4.8±0.7 * | 0.9 |
| Disodium succinate | 4.5±0.6 *t | 1.2 |
| Associating | 1.6±0.3 t | 4.1 |
Example 2
Two (2-hydroxy-n, N, N-pivaloyl choline) succinate is effective for insulin resistant, hyperlipemia, dyslipidemias mass formed by blood stasis and the diabetes that treatment diabetes mouse is suffered from.
Animal: get the diabetes mouse ready by example 1.
Treatment: this animal is divided into two groups: a diabetes matched group (n=10) and a treating diabetes group, the mouse of treatment group is given two (2-hydroxy-n, N, N-pivaloyl choline) succinate (the 120 mg/kg body weight of intravenous injection every day, n=10), inject 3 days altogether.The level (means standard deviation) of measuring fasting glucose, insulin, T-CHOL (Ch), HDL-C (HDL), low-density lipoprotein cholesterol (LDL) and triglyceride (TG) on the 7th day after the treatment beginning sees table 4.The 7th day fasting plasma parameter after the table 4 treatment beginning.
*With matched group variant (P＜0.05)
*With matched group difference very big (P＜0.01)
| Blood parameters (means standard deviation) | Treatment | |
| The matched group mouse | Treatment group mouse | |
| Fasting glucose, mM/liter | 12.5±2.4 | ?4.2±0.6 ** |
| The fasting plasma insulin, μ U (atomerg quality)/liter | 6.0±1.0 | ?1.3±0.5 ** |
| T-CHOL, mM/liter | 3.0±0.4 | ?1.5±0.3 ** |
| Low-density lipoprotein cholesterol, mM/liter | 1.1±0.3 | ?0.8±0.2 * |
| HDL-C, mM/liter | 0.8±0.2 | ?2.0±0.2 ** |
| Triglyceride, mM/liter | 1.4±0.3 | ?0.7±0.1 ** |
Example 3
The method of two (2-hydroxy-n, N, the N-pivaloyl choline) succinates of preparation.
Add 59 gram (0.5 mole) succinic acid to the methanol solution that contains 121 gram (1 mole) choline bases.Stirred reaction mixture is 20 minutes at ambient temperature, and is concentrate drying under 40-50 ℃ the vacuum state in temperature.Can obtain about 100% solid white lenticular material: its mp (fusing point) and be 135-137 ℃ (from the tert-butyl alcohol); NMR
1H (D
2O): δ 2.24 (s, 4H), 3.07 (s, 18H), 3.38 (m, 4H), 3.93 (m, 4H); NMR
13C (D
2O): δ 34.5,54.2, and 56.0,67.8,182.6; Analyze, calculate C
14H
32N
2O
6: C, 51.83; H, 9.94.Find: C, 51.66; H, 9.86.
Claims (32)
1, a kind ofly in suffering from the mammiferous therapeutic process of insulin resistant, obtain synergistic method, comprise the following material of granting effective dose to this mammal:
(a) choline base or choline base pharmaceutical salts; And
(b) succinic acid or succinic acid pharmaceutical salts),
(b) of wherein same dosage (a) and same dosage is under medication to obtain curative effect separately; And (a) of same dosage and (b) curative effect of drug combination be better than (a) and (b) the independent obtainable curative effect sum of medication.
2, method according to claim 1 is characterized in that described curative effect comprises the reduction plasma insulin level.
3, a kind ofly in suffering from the mammiferous therapeutic process of diabetes, obtain synergistic method, comprise the following material of granting effective dose to this mammal:
(c) choline base or choline base pharmaceutical salts; And
(d) succinic acid or succinic acid pharmaceutical salts),
(b) of wherein same dosage (a) and same dosage is under medication to obtain curative effect separately; And (a) of same dosage and (b) curative effect of drug combination be better than (a) and (b) the independent obtainable curative effect sum of medication.
According to the described method of claim 3, it is characterized in that 4, described curative effect comprises the blood sugar lowering level.
According to any described method in the claim 1 to 4, it is characterized in that 5, the choline base of described doses or its pharmaceutical salts and succinic acid or its pharmaceutical salts are supplied with to described mammal simultaneously.
According to any described method in the claim 1 to 5, it is characterized in that 6, described choline base pharmaceutical salts is a choline chloride.
7, according to any described method in the claim 1 to 6, it is characterized in that described succinic acid pharmaceutical salts is a disodium succinate.
According to any described method in the claim 1 to 7, it is characterized in that 8, the effective dose of described choline base or its pharmaceutical salts is 3 to 300 milligrams of every kilogram of weight of mammal every days.
According to any described method in the claim 1 to 8, it is characterized in that 9, the effective dose of described succinic acid or its pharmaceutical salts is 1 to 250 milligram of every kilogram of weight of mammal every day.
According to any described method in the claim 1 to 9, it is characterized in that 10, that the choline base of described effective dose or the dosing mode of its pharmaceutical salts can be respectively is oral, parenteral dispensing, local application and rectal administration.
11, method according to claim 10 is characterized in that, the choline base of described effective dose or its pharmaceutical salts are the parenteral dispensings.
According to any described method in the claim 1 to 11, it is characterized in that 12, the succinic acid of described effective dose or its pharmaceutical salts can be respectively oral, parenteral, part and rectal administration.
13, method according to claim 12 is characterized in that, the succinic acid of described effective dose or its pharmaceutical salts are the parenteral dispensings.
14, according to any described method in the claim 1 to 13, it is characterized in that the medication cycle of the succinic acid of described effective dose or its pharmaceutical salts is no less than 1 day.
15, method according to claim 14 is characterized in that, the medication cycle of the succinic acid of described effective dose or its pharmaceutical salts is 3 to 7 days.
According to any described method in the claim 1 to 15, it is characterized in that 16, the choline base of described effective dose or the medication cycle of its pharmaceutical salts are no less than 1 day.
17, method according to claim 16 is characterized in that, the choline base of described effective dose or the medication cycle of its pharmaceutical salts are 3 to 7 days.
18, a kind ofly in suffering from the mammiferous therapeutic process of insulin resistant, obtain synergistic constituent, comprise the following material of effective dose:
(a) choline base or choline base pharmaceutical salts; And
(b) succinic acid or succinic acid pharmaceutical salts,
(b) of wherein same dosage (a) and same dosage is under medication to obtain curative effect separately; And (a) of same dosage and (b) curative effect of drug combination be better than (a) and (b) the independent obtainable curative effect sum of medication;
Describedly obtain synergistic constituent and also comprise medicinal diluent or carrier.
19, constituent according to claim 18 is characterized in that, described curative effect comprises the reduction plasma insulin level.
20, a kind ofly in suffering from the mammiferous therapeutic process of diabetes, obtain synergistic constituent, comprise the following material of effective dose:
(a) choline base or choline base pharmaceutical salts; And
(b) succinic acid or succinic acid pharmaceutical salts,
(b) of wherein same dosage (a) and same dosage is under medication to obtain curative effect separately; And (a) of same dosage and (b) curative effect of drug combination be better than (a) and (b) the independent obtainable curative effect sum of medication;
Describedly obtain synergistic constituent and also comprise medicinal diluent or carrier.
21, constituent according to claim 20 is characterized in that, described curative effect comprises the blood sugar lowering level.
22, according to any described constituent in the claim 18 to 21, it is characterized in that described choline pharmaceutical salts is a choline chloride.
23, according to any described constituent in the claim 18 to 22, it is characterized in that described succinic acid pharmaceutical salts is a disodium succinate.
According to any described constituent in the claim 18 to 23, it is characterized in that 24, the effective dose of described choline base or its pharmaceutical salts is 3 to 300 milligrams of every kilogram of weight of mammal every days.
According to any described constituent in the claim 18 to 24, it is characterized in that 25, the effective dose of described succinic acid or its pharmaceutical salts is 1 to 250 milligram of every kilogram of weight of mammal every day.
26, two (2-hydroxy-n, N, N-pivaloyl choline) succinate.
27, two (2-hydroxy-n, N, N-pivaloyl choline) succinate is in pharmaceutically purposes.
28, purposes according to claim 27 is characterized in that, described purposes pharmaceutically is meant makes a kind of medicament for the treatment of the insulin resistant that mammal suffers from.
29, purposes according to claim 27 is characterized in that, described purposes pharmaceutically is meant makes a kind of medicament for the treatment of the diabetes that mammal suffers from.
30, purposes according to claim 27 is characterized in that, described purposes pharmaceutically is meant makes a kind of hyperlipemia that mammal suffers from or medicament of dyslipidemias mass formed by blood stasis for the treatment of.
31, the method for two (2-hydroxy-n, N, the N-pivaloyl choline) succinates of a kind of production comprises and allows choline base and succinic acid react.
32, method according to claim 31 is characterized in that, it is 2: 1 that the mol ratio of described choline base and succinic acid is approximately, but is not less than 1.9: 1, and is not 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 |
|---|---|
| CN1452482A true CN1452482A (en) | 2003-10-29 |
Family
ID=20129496
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00819413A Pending CN1452482A (en) | 2000-04-10 | 2000-04-10 | Synergistic composition containing choline and succinic acid for treating 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) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102223883B (en) * | 2008-11-26 | 2013-07-10 | 伊戈尔·安那托利维奇·波米特金 | choline salts of succinic acid for the treatment of depression, anxiety, schizophrenia, sleep disorders and epilepsy |
| CN107456449A (en) * | 2016-12-09 | 2017-12-12 | 杨远志 | A kind of composition and its application in muscular endurance is increased |
Families Citing this family (3)
| 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 |
| WO2009022933A1 (en) * | 2007-08-02 | 2009-02-19 | Buddha Biopharma Oy Ltd | Pharmaceutical compositions for intranasal administration comprising choline salts of succinic acid |
| US8314080B2 (en) | 2010-04-06 | 2012-11-20 | Kuwait University | Method of treating type I diabetes |
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 |
| ATE268170T1 (en) * | 1999-03-01 | 2004-06-15 | Verteletsky Pavel Vasilievich | USE OF SUMMERIC ACID OR SALTS THEREOF TO TREAT INSULIN RESISTANCE |
| EP1165063A1 (en) * | 1999-04-05 | 2002-01-02 | Verteletsky, Pavel Vasilievich | Use of succinic acid or salts thereof for the treatment of diabetes mellitus and wound healing |
-
2000
- 2000-04-10 KR KR1020027013553A patent/KR20020089444A/en not_active Application Discontinuation
- 2000-04-10 WO PCT/RU2000/000122 patent/WO2001076583A1/en not_active Application Discontinuation
- 2000-04-10 AU AU2000263274A patent/AU2000263274A1/en not_active Abandoned
- 2000-04-10 JP JP2001574101A patent/JP3944393B2/en not_active Expired - Fee Related
- 2000-04-10 CN CN00819413A patent/CN1452482A/en active Pending
- 2000-04-10 EP EP00950127A patent/EP1272171A1/en not_active Withdrawn
- 2000-04-10 BR BR0017206-5A patent/BR0017206A/en not_active IP Right Cessation
- 2000-04-10 CA CA002404864A patent/CA2404864A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102223883B (en) * | 2008-11-26 | 2013-07-10 | 伊戈尔·安那托利维奇·波米特金 | choline salts of succinic acid for the treatment of depression, anxiety, schizophrenia, sleep disorders and epilepsy |
| CN107456449A (en) * | 2016-12-09 | 2017-12-12 | 杨远志 | A kind of composition and its application in muscular endurance is increased |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001076583A1 (en) | 2001-10-18 |
| AU2000263274A1 (en) | 2001-10-23 |
| BR0017206A (en) | 2003-01-14 |
| KR20020089444A (en) | 2002-11-29 |
| JP3944393B2 (en) | 2007-07-11 |
| JP2004506605A (en) | 2004-03-04 |
| CA2404864A1 (en) | 2001-10-18 |
| EP1272171A1 (en) | 2003-01-08 |
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