MXPA97006953A - Pinitol and derivatives from the same for the treatment of metaboli diseases - Google Patents
Pinitol and derivatives from the same for the treatment of metaboli diseasesInfo
- Publication number
- MXPA97006953A MXPA97006953A MXPA/A/1997/006953A MX9706953A MXPA97006953A MX PA97006953 A MXPA97006953 A MX PA97006953A MX 9706953 A MX9706953 A MX 9706953A MX PA97006953 A MXPA97006953 A MX PA97006953A
- Authority
- MX
- Mexico
- Prior art keywords
- pinitol
- composition
- plasma
- insulin
- metabolite
- Prior art date
Links
- DSCFFEYYQKSRSV-CEDNOLFGSA-N D-1-O-Methyl-muco-inositol Natural products COC1[C@@H](O)[C@H](O)C(O)[C@@H](O)[C@H]1O DSCFFEYYQKSRSV-CEDNOLFGSA-N 0.000 title claims abstract description 131
- DSCFFEYYQKSRSV-KLJZZCKASA-N D-pinitol Chemical compound CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@H]1O DSCFFEYYQKSRSV-KLJZZCKASA-N 0.000 title claims abstract description 121
- 201000010099 disease Diseases 0.000 title description 6
- 210000002381 Plasma Anatomy 0.000 claims abstract description 75
- 239000000203 mixture Substances 0.000 claims abstract description 49
- 239000002207 metabolite Substances 0.000 claims abstract description 29
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 28
- 239000000194 fatty acid Substances 0.000 claims abstract description 28
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 27
- 206010012601 Diabetes mellitus Diseases 0.000 claims abstract description 22
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- 206010058108 Dyslipidaemia Diseases 0.000 claims abstract description 6
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- 201000001320 atherosclerosis Diseases 0.000 claims abstract description 6
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- 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 106
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Abstract
The pinitol and the derivatives and metabolites thereof are useful in medical and nutritional compositions to decrease levels of fatty acid in the plasma and to treat conditions associated with insulin resistance, such as those resulting from diabetes mellitus and its chronic complications; obesity, hyperlipidemia and dyslipidemia, atherosclerosis, hypertension, cardiovascular disease, AIDS, cancer, emanation / cachexia, sepsis, trauma associated with burns, malnutrition and stress, aging, lupus and other autoimmune diseases, endocrine diseases, hyperuricemia, polycystic ovary syndrome and complications that arise from athletic activity
Description
PINITOL AND DERIVATIVES OF THE SAME FOR THE TREATMENT OF METABOLIC DISEASES
COMPENDIUM OF THE INVENTION
The invention relates to pinitol and derivatives and metabolites thereof, and compositions containing them to decrease the levels of free fatty acids in plasma and for the treatment of conditions associated with insulin resistance. Conditions associated with insulin resistance can result from diseases such as diabetes mellitus and its chronic complications; obesity; hyperlipidemias and dyslipidemias; atherosclerosis; hypertension; cardiovascular diseases; AIDS; Cancer; wasting / cachexia; sepsis; trauma associated with burns; malnutrition and tension; aging; lupus and other autoimmune diseases; endocrine diseases; hyperuricemia, polycystic ovary syndrome and complications arising from athletic activity or inactivity. The compositions of the invention are preferably provided in the form of doses of 0.1 milligram to 1.0 gram per day of pinitol, derivative or metabolite thereof per kilogram of body weight of a mammal. The compositions can be administered orally, enterally or intravenously and are effective in decreasing the levels of free fatty acids in plasma, glucose, insulin and lipids in plasma. A method to obtain pinitol from soy fractions is also provided. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the average levels of pinitol, D-chiro-inositol, and L-chiro-inositol in the plasma of non-insulin-dependent Type II diabetics fed a pinitol fraction derived from soy. Figure 2 shows average insulin levels in the plasma of diabetics fed with pinitol compared to myo-inositol. BACKGROUND OF THE INVENTION Insulin is the main anabolic hormone in the body and has multiple effects on a variety of tissues. The actions that are most familiar are their ability to stimulate glucose adsorption in insulin-sensitive tissues such as muscle and fat and to inhibit the release of glucose from the liver. In addition, insulin regulates the metabolism of lipids in both plasma and tissues, turns them into proteins, develops cells and balances electrolytes. Insulin acts to bind a specific receptor to the cell membrane, which is a glycoprotein that includes two alpha subunits and two beta subunits. The binding of insulin to the alpha subunit activates the autophosphorylation of the beta subunit, which then becomes an active tyrosine kinase. Through the phosphorylation of tyrosine residues of other proteins the activated insulin receptor gives rise to a cascade of biochemical effects. The full understanding of the actions of insulin and the identification of mediators have yet to be elucidated. However, even when insulin is essential for life, excessive levels of insulin in plasma are frequently observed in insulin-resistant diseases and are associated with harmful effects. These include increased cardiovascular disease, atherosclerosis, low-density lipoprotein cholesterol (HDL), elevated triglycerides in plasma and low-density lipoprotein (LDL) cholesterol, hypertension, abdominal obesity, and decreased fibrinolytic activity in plasma. In this way, it is sometimes desirable to control or reduce insulin levels in the plasma. Since elevated plasma insulin levels reflect insulin resistance, insulin reduction in the plasma can be achieved if insulin sensitivity is improved. Studies in the past suggest that some of the actions of insulin can be mediated through inositol phosphoglycan molecules released from cell membranes in response to insulin. Increasing the release of these molecules is a way to improve insulin sensitivity. The inositol phosphoglycans are very small molecules of approximately 1500 daltons which are dissociated from phospholipases and inositol phospholipids. Inositol is a key component of the phosphoglycans related to insulin and almost all mammalian inositol in myo-inositol. Nevertheless, D-chiro-inositol was found after the hydrolysis of 6N HCl because the inositol was unique or predominant in some of the analyzed inositol phosphoglycans. This finding led to the measurement of D-chiro-inositol in diabetic tissues and fluids. The results showed reduced urinary and tissue levels of D-chiro-inositol (Kennington, AS, Hill, CR, Craig, J., Bogardus, C, Raz, I., Ortmeyer, HK, Hansen, BC, Romero, G. , Lick, J. 1990. Low urinary chiro-inositol in non-insulin-dependent diabetes mellitus, N. Engl. J. Med. 323: 373-378). These results suggest a rationalization for the treatment of diabetics and insulin resistant patients with D-chiro-inositol as proposed in US Pat. No. 5,124,360. In the latter work with the improved analytical technique, increased excretion of urinary D-chiro-inositol was demonstrated (Ostlund, RE, Jr., McGill, JB, Herskowitz, I., Kipnis, DM, Santiago, JV, Sherman, WU 1993. D-chiro-inositol Metabolism in Diabetes Mellitus, Proc. Nati. Acad. Sci. USA 90: 1988-1992). In this way, the previous work left open records regarding tissue levels or the excretion of the possible insulin mediator, and focused only on the hydrolysis of the D-chiro-inositol product. The prior technique is also subnormal due to lack of knowledge regarding the exact structure of the insulin mediating molecules with inositol phosphoglycan and the lack of knowledge of the distribution of substances similar to chiro-inositol in foods and body fluids. Pinitol is a methyl ether of D-chiro-inositol and is easily hydrolyzed to D-chiro-inositol. It is known that pinitol is found in pine wood and pulses. A substance similar to pinitol of undisclosed structure extracted from Bougainvillea spectabilis was found to lower the blood glucose of both normal and insulin-deficient mice treated with alloxan at a minimum dose level of 0.01 g / kg (Narayanan, CR, Joshi , DD, Mujumdar, AM, Dhekne, VV 1987. Pinitol
A new anti-diabetic compound from the leaves of
Bougainvillea spectabilis. Current Science 56: 139-141). The effectiveness of pinitol for the treatment of insulin resistant conditions, especially of humans, is unknown until the present invention. The prior art exemplified by U.S. Pat. 5,124,360 has pinitol focused as a source for the manufacture of D-chiro-inositol wherein D-chiro-inositol from pine-derived pinitol can be released using the severe conditions of hydrolysis with concentrated hydroiodic acid at elevated temperature rather than over the direct use of pinitol in medical applications. The same reference identifies pinitol incorrectly as an ester instead of a D-chiro-inositol ether. Phillips, and collaborators, J. Agrie. Food Chem.,
Vol. 30, pages 456-466 (1982) describes various cyclitoles present in soybean plants. Philip Nordin, Plant Physiol., Vol. 76, pages 313-315 (1984) describes the preferential leaching of bean pinitol during inhibition. A.E. Smith et al., Crop Science, Vol. 20, pages 75-77 (1980) describes the presentation of pinitol in the foliage of several species of forage-digesting legumes. The U.S. Patent No. 5,124,360 describes the administration of a supplement for the therapeutic treatment of insulin-resistant type II diabetes comprising D-chiro-inositol. The U.S. Patent No. 5,091,596 describes a method for producing D-chiro-inositol from Kasugamycin or pinitol which were considered as precursors of D-chiro-inositol and are not used for treatment purposes. The preparation of D-chiro-inositol from Kasugamycin is a much more difficult process than that of soy as is carried out by the present invention. Y. Pak and collaborators. The Journal of Biological Chemistry, Vol. 267, No. 24, pages 16904-16910 (August 1992) describes the in vivo conversion of myoinositol to chiroinositol in rat tissues. The present invention shows for the first time that insulin resistance in humans is directly treatable with pinitol. This result is unexpected based on the prior art in the type I insulin deficient diabetic rat (treated with alloxan) model. The present invention demonstrates that human type II diabetics respond effectively to pinitol and that insulin and glucose levels and the levels of free fats in the plasma are decreased with pinitol. It is an object of the present invention to provide compositions comprising an effective amount of pinitol or a derivative or metabolite thereof to treat conditions associated with insulin resistance. Conditions associated with insulin resistance can result from diseases such as diabetes mellitus and its chronic complications; obesity; hyperlipidemia and dyslipidemia; atherosclerosis; hypertension; cardiovascular diseases; AIDS; Cancer; wasting / cachexia; sepsis;
trauma associated with burns; malnutrition and tension, aging; lupus and other autoimmune diseases; endocrine diseases; hyperuricemia, polycystic ovary syndrome and complications that arise from inactivity or athletic activity. It is also an object of the present invention to provide compositions comprising an effective amount of pinitol or a derivative or metabolite thereof to decrease the levels of free fatty acids in the plasma. It is a further object of this invention to provide methods for decreasing free fatty acids in plasma and for treating conditions of insulin resistance in mammals which comprises administering an effective amount of pinitol or a derivative or metabolite thereof, in oral or intravenous form , as a nutritional supplement or medication. It is still a further object of this invention to provide a method for obtaining and purifying pinitol from This invention relates to a composition useful for decreasing levels of free fatty acids in plasma and for treating insulin resistance conditions in mammals (preferably homo sapiens) comprising an effective amount of pinitol or a derivative or etabolite thereof. The pinitol and derivatives and metabolites thereof are useful in medicinal and nutritional compositions in accordance with the present invention for decreasing the levels of free fatty acids in plasma and in the treatment of conditions associated with insulin resistance. The con icions associated with insulin resistance can result from diseases such as diabetes mellitus and its complications.; obesity; hyperlipideinias and dyslipidemia; atherosclerosis; hypertension; cardiovascular diseases; SID ?; Cancer; wasting / cachexia; sepsis; Lruuma associated with burns; malnutrition and tension, aging; lupus and other diseases that are immune, endocrine ages; hyperuricemia, polycystic ovarian syndrome and complications that SUJ yen from inactivity or athletic activity. The p n i t i ng the chemical t r uc tur given to contua tion:
OH OH Suitable derivatives and metabolites of pinitol include pinitol glycosides, pinitol phospholipids, esterified pinitol, lipid bound pinitol, pinitol phosphates and pinitol phytates and mixtures thereof. Pinitol and its derivatives or metabolites are available from a number of natural sources (such as, for example, pine needles, chickpeas, bougainvillea leaves, alfalfa, soybeans and other legumes) and in synthetic processes but are preferably obtained from soy fractions. The present invention also provides a method for obtaining pinitol of relatively high purity and yield of soybean fractions comprising the steps of: a) removing the protein from said soybean fraction, b) treating said deproteinized soybean fraction from a ) with activated charcoal, c) treat the soy material resulting from b) with ion exchange resins to deionize said material, d) remove sugars without inositol, unwanted material c) by contacting said material with a resin of exchange of anions in the form of hydroxide, and e) recover said pinitol. Still further the present invention provides a method for decreasing levels of free fatty acids in plasma in a mammal, which comprises administering an effective amount of pinitol or a derivative or metabolite thereof and a method for treating insulin resistance conditions in a mammal comprising the administration of an effective amount of pinitol or a derivative or metabolite thereof. Also provided in accordance with the present invention is the use of pinitol or a derivative or metabolite thereof in the preparation of a medicated or nutritional formulation for decreasing the levels of free fatty acids in plasma in a mammal and the use of pinitol or a derivative or metabolite thereof in the preparation of a medicament or nutritional formulation for treating conditions of insulin resistance in a mammal. The compositions of this invention provide an effective amount of pinitol or its derivatives or metabolites in a dosage form for administration to mammals to decrease the levels of free fatty acids in the plasma and to treat conditions of insulin resistance. The compositions can be administered enterally, e.g. orally or parenterally, v.gr. intravenously The compositions are also effective in improving insulin sensitivity associated with hyperinsulinemia and impaired glucose tolerance. The reduction of free fatty acid levels in the plasma induces the decrease of plasma glucose levels, decreasing plasma insulin levels and improving plasma lipid levels. Therefore, the composition of the present invention is also effective in improving plasma lipoprotein and lipid levels by reducing triglycerides or low density lipoprotein cholesterol or by increasing high density lipoprotein cholesterol. Fatty acids are found in all classes of lipids in plasma such as low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, phospholipids and triglycerides where they are linked by an ester bond to glycerol and other molecules. However, there is a fraction of fatty acids in plasma that are also not esterified and this fraction exists as free fatty acid anions (referred to herein as free fatty acids in plasma) and bind primarily to albumin in the plasma . Free fatty acids are important in the generation of insulin resistance. The reduction of free fatty acids in plasma by pinitol or its derivatives or metabolites is consequently effective in the treatment of diabetes mellitus or insulin resistance.
Preferably the compositions of this invention are in a dosage form, either individual or multiple, which is provided from 0.1 milligram to 1 gram, more preferably 1 to 10 milligrams, per day of pinitol or derivative or metabolite per kilogram of body weight of the mammalian subject to which it is to be administered the composition. The composition may be in the form of an orally ingestible nutritional supplement. This nutritional supplement can be in a variety of forms such as free fluidizing powders, bars, tablets, capsules or other solid dosage forms; or liquid forms, such as an oral or intravenous solution, dispersion or emulsion, e.g. enteral with water base. For example, an enteral composition of the present invention preferably comprises deionized water, pinitol, maltodextrin, sodium caseinate, corn syrup solids, medium chain triglycerides, canola oil, calcium caseinate, soy protein, potassium citrate, magnesium chloride, sodium citrate, tricalcium phosphate, soy lecithin, sodium ascorbate, choline chloride, potassium chloride, vitamin E, molybdenum yeast, selenium yeast, carrageenan, chromium yeast, biotin, niacinamide, sulfate zinc, ferrous sulfate, calcium pantothenate, vitamin A, cyanocobala ina, manganese sulfate, copper gluconate, vitamin K, thia ina, pyridoxine hydrochloride, vitamin D, riboflavin, folic acid, potassium iodide, antifoaming agents, and sweeteners and natural or artificial flavors. Ingredients that may also be added to the inert compositions of this invention include fructose, soybean oil, sunflower oil, cannula oil, carnitine, taurine, and other natural components such as beef, peach puree, peas, green beans, and orange juice. The orally ingestible compositions of this invention preferably contain pinitol, water, maltodextrin, sugar, corn oil, sodium caseinate, soy protein isolate, calcium casein, potassium citrate, tricalcium phosphate, magnesium chloride, sodium citrate, lecithin, potassium chloride, choline chloride, arborobic acid, potassium hydroxide, carrageenan, vitamin E, carrageenan, zinc sulfate, ferrous sulfate, niacinamide, biotin, vitamin A, calcium pantothenate, copper gluconate, cyanocobalamin, sulphate manganese, vitamin K, potassium iodide and natural and artificial flavors. Orally ingestible compositions in dry powder form preferably contain pinitol, fat-free dry milk, sugar, cocoa, carrageenan, polysorbate 80, magnesium oxide, salt, vanilla, vitamin E, arborobic acid, ferric orthophosphate, zinc sulfate, vitamin A , niacinamide, altol, copper gluconate, calcium pantothenate, pyridoxine hydrochloride, thiamine, cyanocobalamin, vitamin D3, folic acid, riboflavin, biotin, and natural and artificial flavors. This dry powder can be mixed with milk or water before consumption. Another preferred powder composition for oral consumption includes maltodextrin, pinitol, citric acid, calcium hydroxide, salt, aspartate, arborobic acid, potassium citrate, orange juice solids, vitamin E, polysorbate 60, zinc sulfate, ferrous sulfate , biotin, niacinamide, copper gluconate, calcium pantothenate, cyanocobalamin, vitamin D3, folic acid, pyridoxine hydrochloride, riboflavin, and natural and artificial colors and flavors. The ingredients may also include magnesium gluconate, dipotassium phosphate, magnesium sulfate trihydrate, manganese sulfate monohydrate and thiamine. This powder composition can be mixed with water or with fruit juices before consumption. Another preferred powder composition comprises pinitol with a dextrose or maltodextrin carrier that can be added to juices and foods. A preferred composition of this invention in the form of a nutrition bar comprises pinitol, raisins, chopped nuts, pineapple, guar gum, protein blend, fructose, caramel, honey, high maltose corn syrup, lecithin, soy bean oil, salt, magnesium oxide, vitamins and minerals, and natural and artificial colors and flavors. Intravenous solutions suitable for use in accordance with the present invention comprise pinitol, or its derivative or metabolite, in a sterile liquid carrier such as water or 1,3-butanediol. The various compositions of the invention may also contain other conventional ingredients such as suspending or wetting agents, preservatives, antioxidants, thickeners and the like. The compositions of the present invention are useful in methods for decreasing levels of free fatty acids in plasma and in the treatment of mammals with insulin resistance, or particularly homo sapiens, which comprises administering an effective amount of pinitol or a derivative or metabolite thereof. The pinitol or derivative or metabolite thereof is preferably administered as multiple doses or continuous doses over a period of 1 day or more; more preferably 3 days or more. The effective amount of said pinitol or derivative or metabolite thereof for use in the method of this invention is preferably 0.1 mg to 1.0 gram per day per kilogram of body weight, and is preferably administered orally.
The present invention also relates to a method for obtaining pinitol from a soybean fraction as described above. The soy fractions used in this method preferably comprise soy solubles, soy whey and mixtures thereof. The method produces a recovered product which is about 20% or more, preferably 50% or more, of pinitol on a dry weight basis. Soluble fractions derived from the production of soy protein contain D-chiro-inositol at approximately 4% dry weight, and most of it is in the form of pinitol (3-O-methyl-D-chiro-inositol ). It is desirable to purify this material at least 50% dry weight for medicinal food use. Preferably, the soy solubles or other fractions are first deproteinized and treated with activated charcoal to prepare them for column chromatography. The material is then preferably deionized by passing over a cation exchange column, then by an anion exchange column. The sugars without undesired inositol are removed on a strong base anion exchange resin in the form of hydroxide. The final fraction does not bind to the column containing pinitol in about 20% (preferably 50%) by weight or more based on the total weight of the final fraction. It is important to separate the processes of sugar removal and ion exchange. The removal of ions and unwanted sugars by anion exchange chromatography in the form of hydroxide occurs by different mechanisms. The removal of the anion results from the binding of sample anions to the column and its replacement in the solution by hydroxide ions. In contrast, the binding of sugar to the strong ion exchange columns is an adsorption process where no hydroxide is released from the ion exchange resin. Under many conditions, ions and sugars compete with one another and mutually reduce the efficiency of purification. For example, the separation of anions results from the release of hydroxide ions and results in the operation of pH levels of 12-13. However, this pH inhibits sugar binding because the sugars can be partially or completely removed from the anion exchange columns by 0.01 normal or stronger NaOH. Conversely, the binding of sugar to the anion exchange columns competes with the removal of anions if both the sugars and the salts occur at the same time in neutral solutions. In the new process, the ions are first removed after the sugars are removed. In order to ensure complete deionization the material is passed over a cation exchanger in the hydrogen form to create a decationized stream with a pH of about 1-2. When it is passed subsequently on a hydroxide of an anion exchanger the acidic pH leads to the end of the deionization despite the presence of sugars. The deionized material is then further purified in the absence of ions. The affinity of the anion exchangers in the form of hydroxide for the undesired sugars is relatively low so that a longer contact time with the column is necessary for the efficient adsorption of sugars as for deionization. In addition, according to the conditions of the upper column the loading of unwanted sugars "bleeds" from the column and reduces the purification achieved. The deproteinization and the carbon treatment of the sample before the ion exchange treatment is important to avoid blockage of the column, precipitation in the column and alteration of the binding properties of the sugar in the resin. The pinitol recovered from this process can be used in accordance with the present invention in a variety of applications as described herein. The pinitol can also be converted to D-chiro-inositol, such as by hydrolysis. A preferred method for obtaining pinitol from soybean fractions is as follows: I Deproteinization and treatment with charcoal 1. Acid precipitation of soy solubles. To 100 ml of soybean solubles after the removal of ethanol from the soluble fractions of soy were added 0.4 ml of 12 normal HCl and 2.5 grams of activated carbon (Darco KB). The resulting pH is 3.95. After 1 hour the material is centrifuged at 1000 x g for 10 minutes and filtered. The clear colorless supernatant is applied to the ion exchange columns. This step removes both the proteins and the lipids that clog the chromatography columns. The heat treatment at 60-90 ° C or also in an autoclave at 121 ° C for 4 hours does not remove the proteins quantitatively and the precipitation in the columns is observed during the subsequent ion exchange chromatography. Charcoal treatment is not necessary for discoloration (the light yellow color present in the supernatant of acid precipitation will be completely removed from the columns), however it is essential to remove other materials that will adhere to the anion exchange resin, resist removal by the base or acid treatment, and significantly decrease the rate of removal of unwanted sugars. The residual carbon can be removed by filtration through a 0.22 micron particle filter, but this step is not routinely necessary. The yield is 82 ml. of supernatant. The acid pH acts as a preservative so that the sample can be kept refrigerated for months. 2. Ultrafiltration. Ultrafiltration completely removes proteins. However, it is still essential to treat the permeate with carbon to avoid clogging the column. If ultrafiltration is used, the permeate should be concentrated to approximately 5-10% solids before the next step. II. Deionization The resins used in this invention are commercially available ion exchange resins, such as, for example, IR-120 + (a strong acid cation exchanger) and IRA-400-OH (a strong base anion exchanger). . This complies with FDA standards for ion exchangers used in the food process and are prepared by Rohm & amp;; Haas. However, they can be replaced by any similar resins. Deionization is done before the removal of sugar. Since soy solubles have relatively few ions, only a relatively small amount of deionized resins are necessary. The exact equivalence of the resins with respect to the precipitate with acid, the soy soluble ones treated with carbon (from step 1 above) are determined by titration as follows: 1. Exchange of cations 13.1 ml of soy soluble / ml of wet resin 2 9.8 ml anion exchange As calculated in the following examples, it is assumed that the equivalent of the sample applies only to 80% of this capacity. The soy solubles are first applied to the cation exchange column and then to the anion exchange column. Although precipitation does not occur, our preference is for a net retention of 80 microns in the columns. This is a little greater than about 30 net micras normally used and this essentially eliminates any possibility of clogging the spine after prolonged use or in the presence of a precipitate. It is possible that deionization can be done by load. However, the charge processing is not as efficient as the column methods, the regeneration of the resin is stronger, and the deionization process takes a long time, for example, moderate turbulence of the sample. It is recommended to rotate the sample with each resin for at least 6 hours. The efficiency of ion removal can be monitored by conductivity measurements. The applied material has a conductivity of 8070 μohms and in the suitably deionized material it is reduced to less than 100 μohms. With the incomplete deionization of the charge, the removal of ions with a final conductivity of 1100 μohms was observed. The columns were regenerated in normal fashion with approximately 3 volumes of 1.5 normal HCl or 1.0 normal NaOH in the column then by washing with water. III. Sugar Removal on the Anion Exchange Column Sugars other than pinitol and other inositol are adsorbed with the anion exchange resin IRA-400-OH. If the applied sample is not suitably deionized, the hydroxide ions will be released and these will inhibit the binding of the sugar to the resin. 1. Amount of resin needed. The proper sugar removal requires 2.5 milliliters of resin per milliliter of soluble soy from step II above. In this way, this step will require more column capacity than deionization. 2. Chromatography technique. One milliliter of deionized material was applied to a 2.5 ml column. at 0.1 ml column volume / minute and recycled three times. It is often observed with the passage in the column that the adsorption process is slow and the adsorption is incomplete. The efficiency of sugar removal varies according to the aging of the column, however three passes in the column are sufficient even for older columns. The column is then washed with 1.2 ml of water to produce 85% applied pinitol. Additional washing is counterproductive so that a small amount of contaminating carbohydrate is desorbed from the column over time while very little pinitol is removed. In fact, this desorption becomes limited as more samples are applied to the column. The purification process can be monitored visually. A new column is orange / brown and translucent. With the union of the sugar it becomes dark brown and opaque, starting at the top of the column. The capacity of the effective column is reached when the dark area progresses about 2/3 of the lower path of the column. After regeneration (described below) the column assumes the original color. 3. Concentration The final material is a concentration of approximately 1 mg / ml and preferably should be concentrated to approximately 100 mg / ml, which is suitable for the formulation. 4. Control temperature. The adsorption processes in general are more efficient in cold and are inhibited at high temperatures. The methods described herein work effectively at room temperature. However, at 4 ° C, compared to room temperature, the removal of the unwanted carbohydrate is increased to 8% and the amount of sugar that passes through the column without being adsorbed ("bleeding from the column") is reduced to 31%. This little advantage is probably not important. However, at 60 °, it is the highest temperature at which the ion exchange resins in the hydroxide form are stable, the "bleeding" of the column is increased by about 200%. From an operational point of view, cooler temperatures help marginally and temperatures above the ambient should be avoided. 5. Regeneration of the column. The column is washed in the reverse direction with 2.5 volumes of normal 1 NaOH and then with water. The following examples are presented to demonstrate the invention. The examples are intended to be illustrative and not limiting. Example 1 This example identifies the food source of D-chiro-inositol-like compounds and shows that alfalfa, and soybeans are rich in the material, which is present in the form of pinitol rather than D- free chiro-inositol. The highly normalized components of Purina Rodent Chow 5001 were analyzed by mass spectrometry-gas chromatography after hydrolysis in normal 6 HCl at 110 ° for 24 hours to convert the pinitol to D-chiro-inositol and the results are presented in Table 1 next: Table 1 Component D-chiro-inositol nMol / mg dry weight
Alfalfa 74.7 ± 5.2 Soybean meal 54.1 ± 4.1 Wheat germ 1,011 ± 0.008 Ground oats 0.758 ± 0.028 Fish meal 0.676 ± 0.012 Ground beet pulp 0.248 ± 0.003 Meat meal 0.058 ± 0.004 Yeast 0.049 ± 0.014 Intermediates 0.049 + 0.015 Corn ground 0.044 ± 0.003 Bleachable fat 0.018 ± 0.001 Melasas 0.010 ± 0.004 Serum 0.009 ± 0.001 These results show that legumes have a high pinitol content while other foods contain relatively little. Soy bean flour has approximately 1% D-chiro-inositol-like compounds by dry weight. However, the data shows that very few of the D-chiro-inositol-like compounds in the soy material are free of free D-chiro-inositol. After purification as described below 83% of the D-chiro-inositol-like compounds were pinitol as determined by the retention time of gas chromatography and mass spectrum when compared to the authentic pinitol prepared from sawdust Pine. Pinitol was present only in samples that had not undergone acid hydrolysis and was quantitatively converted to D-chiro-inositol after hydrolysis for 24 hours at 110 ° in normal 6 HCL. This shows that normal 6 HCl not only dissociates the phosphate linkages of the inositol phosphates but also the pinitol ether linkage. In contrast to other ether linkages, it is not necessary to use concentrated hydroiodic acid to convert pinitol to D-chiro-inositol as detailed in U.S. Pat. 5,091,596. EXAMPLE 2 This example illustrates the production of an enriched pinitol fraction of soybeans. Soy whey after precipitation of protein isolate at an acidic pH was found to contain 2.4% total D-chiro-inositol (bound and free measured after hydrolysis with acid) per dry weight. This material was spray dried and resuspended at a concentration of 25% solids. After centrifugation and filtration, it was autoclaved and then the supernatant was applied to an anion exchange column in the form of IRA 400 hydroxide in an amount equal to half the volume of the column bed followed by an exchange column. cations and hydrogen-shaped IR120 +. The final material was concentrated by evaporation, treated with charcoal and autoclaved. The total average D-chiro-inositol content after hydrolysis with acid was 22.5% by weight and 83% was originally in the form of pinitol. This material was used for the experiments of Example 3. EXAMPLE 3 This example shows that feeding a pinitol fraction derived from soy to non-insulin dependent Type II diabetic humans resulted in increased levels of pinitol and D-chiro- inositol in the plasma and the reduction of glucose and insulin levels in the plasma. Five diabetic subjects not dependent on insulin were studied on two separate occasions in a week. For three days the subjects received pinitol 4.15 mg / kg / day orally in a drink once a day for 3 days. The preparation also contained 0.85 mg / kg / day of D-chiro-inositol in other forms. The total inositol content by weight (including pmitol) was 22.5%. On the fourth day, the oral dose of oral hypoglycemic agents was not taken and reported to the Clinical Research Center. Blood samples were taken from the baseline at -90 and -60 minutes, and at -60 minutes a dose of pinitol identical to that taken during the previous three days was given orally. The material contained less than 5 calories. At time zero 75 grams of glucose were provided to start a glucose tolerance test, and blood samples were taken at one and a half hours for 3 hours. In random order subjects received either myo-inositol (5 mg / kg / day) or soy pinitol (total inositol content 5 mg / kg / day). Myo-inositol had no definitive effect on insulin or glucose in the plasma and was included as a control. Inositol levels in the plasma were measured by gas chromatography / mass spectrometry and insulin levels were measured by RIA. Inositol levels in the plasma changed shortly after feeding with myo-inositol during the glucose tolerance tests of control. Nevertheless, the pinitol in the plasma and the D-chiro-inositol levels were elevated more than 10 times during the feeding with pinitol as shown in Figure 1. The pinitol maxima in the plasma at 5.4 μM for three hours after the oral administration of pinitol while the levels of D-chiro-inositol in the plasma flowed down at all points of time and reached 1.7 μM four hours after dosing. The preponderant effect of feeding with soy pinitol, therefore, had an elevation of pinitol levels in the plasma. A significant reduction in insulin in the plasma during the glucose tolerance test was observed during the treatment with pinitol as shown in Table 2 and in Figure 2. Insulin and glucose levels in the baseline did not had change, but had a significant reduction in insulin during the glucose tolerance test, which started at time zero. The area of insulin (μU / ml insulin per minute) decreased to 25.2 ± 8.9%, p = 0.046: Table 2 Insulin Area (μU / ml x minutes) Percent Pinitol Substitute M_iQzinositol Change .. (Reduction)
1 8844 18066 51.1 2 4032 4599 12.3 3 1518 2253 32.6 4 1566 2256 30.6 5 1197 1191 0.5 He also had a reduction in the area of plasma glucose
(mg / dl x minute) during the glucose tolerance test of 18.8 ± 9.1%, p = 0.11.
EXAMPLE 4 This example shows that D-chiro-inositol in plasma is closely related to high density lipoprotein cholesterol and triglycerides in the plasma of diabetic subjects. Nineteen insulin-dependent diabetic subjects and 54 non-insulin-dependent diabetics were studied in a cross-sectional analysis of the determinants of high-density lipoprotein cholesterol and plasma triglyceride levels. Age, gender, body mass index, concomitant drug therapy, glycated hemoglobin, and insulin in plasma were measured as known covariates to influence lipoproteins and lipids in plasma. D-chiro-inositol was measured in plasma and all values were used in multiple regression equations to predict high density lipoprotein cholesterol and triglycerides in plasma. The following statistical associations were found:
Meaning Variant Dependent Predictive Variables Statistic R of Model
Insulin Dependent Diabetes Triglycerides in D-chiro-inositol plasma < 0.0001 0.683 Glycohemoglobin 0.003 Insulin dose 0.04 HDL cholesterol in D-chiro-inositol 0.005 0.632 Plasma Gender 0.021 Diabetes not dependent on insulin Triglycerides in plasma D-chiro-inositol 0.005 0.240 Glycohemoglobin 0.025 Diabetics not dependent on insulin with glycohemoglobin > 10 Triglycerides in plasma D-chiro-inositol 0.0001 0.623 Glycohemoglobin 0.0076 insulin 0.032 (R is multiple correlation coefficient) These data show that D-chiro-inositol in plasma was the strongest independent predictor of triglycerides in plasma in diabetics insulin-dependent as non-insulin-dependent and was the strongest predictor of high-density lipoprotein cholesterol in insulin-dependent diabetic subjects. It can be a component of insulin resistance in insulin-dependent diabetic subjects.
EXAMPLE 5 This example shows that free fatty acids in plasma are reduced in humans by the administration of pinitol. 10 non-insulin dependent diabetes patients maintained a diet of pinitol and D-chiro-inositol deficient (without legumes or citrus fruits) through the study. NIDDM subjects were recruited who were metabolically stable, did not take insulin, had glycated hemoglubin values between 6.5-15, did not take medications that interfered with glucose metabolism, had normal liver and kidney functions and had a BMI less than 37 kg / m2. The following table summarizes the characteristics of the patients. average ± SD Number 10 Age, years 62.1 ± 7.6 Sex, male / female 7/3 Race, white / black 9/1 Treatment with sulfonyl urea yes / no 8/2 Height, cm. 171.6 ± 9.4 Weight, kg 91.4 ± 17.7 BMI, kg / m2 31.0 ± 4.9 Glycated hemoglobin,% 10.3 ± 44 Glucose in the fasting plasma mg / di 173 ± 44 Each subject received both placebo and pinitol soy-derived in separate tests. After an initial 5-day washout period, subjects received 5 days of treatment with either pinitol 5 mg / kg BID (total dose 10 mg / kg / day) or with placebo without inositol. The material was given orally in 60 ml. of a calorie-free KOOL-AID drink. Twelve hours after the last dose, two fasting plasma samples were taken from each subject in fifteen minute parts. The levels of free fatty acid in the plasma were measured. A dose of pinitol was then supplied and the three-hour glucose tolerance test was performed. After a second washing period of 5 days and another 5 days of feeding with pinitol or placebo, the test was repeated. The order of treatment (pinitol or placebo) was randomized and the study of the investigators and those who carried out the analyzes were blinded in the order of the given treatment. The results of the studies are given below: Placebo Pinitol Value P
Free fatty acids in fasting plasma (μM) 645 ± 244 569 + 276 0.05
Pinitol in fasting plasma (μM) 9,014 + 0. .012 0.488 + 0. 290 < 0.0001 Chiro-inositol in the fasting plasma (μM) 0.115 ± 0. 123 0.633 ± 0. .855 < 0.0001 The pinitol and chiro-inositol in the plasma were substantially increased by feeding with pinitol as compared to the deficient diet in pinitol. The treatment with pinitol was associated with a statistically significant reduction of 12.2% in average of the fatty acids in the fasting plasma (p = 0.05 t test per pair). When measurements of free fatty acids in the fasting plasma were subjected to analysis of variation of reduction with the treatment of pinitol were greatly important (p = 0.004). There was also an important inverse relationship between the change in feeding with pinitol with respect to free fatty acids in fasting plasma and the level of pinitol in fasting plasma was achieved during feeding with pinitol (r = 0.660, p = 0.038). The data indicate that the decrease of free fatty acids in the plasma at baseline appeared to be an important indicator of physiological improvement as this was correlated with a reduction in the glucose area during a glucose tolerance test 3 hours (r = 0.748, p = 0.013). This invention was made with the support of the US government. under grant numbers DK 20579 and RR 00954 issued by the National Institutes of Health. The government of the U.S.A. has certain rights in the invention.
Claims (23)
1. A composition comprising an effective amount of pinitol or a derivative or metabolite thereof in an effective dosage form for decreasing the levels of free fatty acids in the plasma or for the treatment of conditions of insulin resistance, hyperlipidemia or dyslipidemia in a mammal.
The composition of claim 1, wherein said dosage form is an orally ingestible nutritional supplement.
3. The composition of claim 1, wherein said dosage form is an orally ingestible medicament.
The composition of claim 1, wherein said dosage form is a liquid suitable for intravenous injection.
The composition of any of claims 1 to 4, wherein said dosage form provides from 0.1 milligram to 1.0 gram / day of said pinitol, derivative or metabolite thereof per kilogram of body weight of said mammal.
The composition of claim 5, wherein said dosage form provides from 1 to 10 milligrams / day of said pinitol, derivative or metabolite thereof per kilogram of body weight of said mammal.
7. The composition of any one of claims 1 to 6, wherein said dosage form is effective in decreasing the levels of free fatty acids in the plasma in said mammal.
The composition of any of claims 1 to 6, wherein said composition is effective for improving insulin sensitivity associated with hyperinsulinemia, insulin-stimulated glucose adsorption, and impaired glucose tolerance.
The composition of any of claims 1 to 6, wherein said composition is effective to reduce plasma glucose levels.
The composition of any of claims 1 to 6, wherein said composition is effective in reducing plasma insulin levels.
The composition of any one of claims 1 to 6, wherein said composition is effective in improving lipoprotein and lipid levels in plasma by reducing triglycerides or low density lipoprotein cholesterol or by increasing high lipoprotein cholesterol. density.
The composition of any of claims 1 to 11, wherein said pinitol, derivative or metabolite thereof is selected from the group consisting of pinitol, pinitol glycosides, pinitol phospholipids, esterified pinitol, lipid-bound pinitol, phosphates of pinitol and pinitol phytates and mixtures thereof.
13. A method for decreasing levels of free fatty acids in plasma in a mammal comprising administering an effective amount of pinitol or a derivative or metabolite thereof.
14. A method for treating conditions of insulin resistance in a mammal comprising administering an effective amount of pinitol or a derivative or metabolite thereof.
15. The method of claim 13 or 14, wherein said mammal is a homo sapiens.
16. The method of any of the claims 13 to 15, wherein said effective amount is from 0.1 milligram to 1.0 gram per kilogram of body weight per day.
The method of claim 16, wherein said effective amount is from 1 to 10 milligrams per kilogram of body weight per day.
18. The method of any of claims 13 to 17, wherein said pinitol or derivative or metabolite is administered orally.
19. The method of any of the claims 14 to 17, wherein said insulin resistance is associated with diabetes mellitus and its chronic complications; obesity; hyperlipidemias and dyslipidemias; atherosclerosis, hypertension, cardiovascular diseases; AIDS, cancer; wasting / cachexia; sepsis; trauma associated with burns; malnutrition and tension; aging; lupus and other autoimmune diseases; endocrine diseases, hyperuricemia, polycystic ovary syndrome and complications arising from athletic activities.
20. The method of any of the claims 13 to 19, wherein said pinitol, derivative or metabolite thereof is selected from the group consisting of pinitol, pinitol glycosides, pinitol phospholipids, esterified pinitol, lipid bound pinitol, pinitol phosphates and pinitol phytates and mixtures thereof.
The method of any of claims 13 to 20, wherein said pinitol, or derivative or metabolite thereof is administered as a multiple dose or continuous dose for a period of 1 day or longer.
22. The method of claim 13 or 14, wherein said pinitol, derivative or metabolite thereof is administered as a multiple dose or continuous dose over a period of 3 days or longer.
23. A method for obtaining pinitol from soybean fractions comprising: a) removing the protein from said soybean fraction, b) treating said deproteinized soybean fraction from a) with activated charcoal, c) treating the soybean material resulting from b. ) with cation exchange resins and anions to deionize said material, d) remove unwanted sugars from the material of c) by contacting said material with an anion exchange resin in the form of hydroxides, and e) recover said pinitol.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08407430 | 1995-03-17 | ||
US08/407,430 US5550166A (en) | 1995-03-17 | 1995-03-17 | Pinitol and derivatives thereof for the treatment of metabolic disorders |
Publications (2)
Publication Number | Publication Date |
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MX9706953A MX9706953A (en) | 1998-06-28 |
MXPA97006953A true MXPA97006953A (en) | 1998-10-30 |
Family
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