WO2001003700A1 - Combinaison de chrome et de vanadium pour traiter ou prevenir les troubles du metabolisme du glucose - Google Patents

Combinaison de chrome et de vanadium pour traiter ou prevenir les troubles du metabolisme du glucose Download PDF

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Publication number
WO2001003700A1
WO2001003700A1 PCT/US1999/015585 US9915585W WO0103700A1 WO 2001003700 A1 WO2001003700 A1 WO 2001003700A1 US 9915585 W US9915585 W US 9915585W WO 0103700 A1 WO0103700 A1 WO 0103700A1
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Prior art keywords
chromium
vanadium
body weight
program
hbalc level
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Stuart A. Fine
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Akesis Pharmaceuticals Inc
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Akesis Pharmaceuticals Inc
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Priority to PCT/US1999/015585 priority Critical patent/WO2001003700A1/fr
Priority to AU50944/99A priority patent/AU5094499A/en
Publication of WO2001003700A1 publication Critical patent/WO2001003700A1/fr
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    • 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
    • A61K31/28—Compounds containing heavy metals

Definitions

  • Diabetes mellitus is generally caused by diminished rates of secretion of insulin by the beta cells of the islets of Langerhans in the pancreas, or by reduced insulin sensitivity.
  • Insulin a hormone produced by the pancreas, makes the glucose available to the body's cells for energy.
  • muscle, adipose (fat), and connective tissues insulin facilitates the entry of glucose into the cells by an action on the cell membranes.
  • the ingested glucose is normally converted in the liver to CO 2 and H 2 O (50%); to glycogen (5%); and to fat (30-40%), the latter being stored in fat depots.
  • Type 1 diabetes juvenile-onset, insulin-dependent diabetes mellitus [IDDM]
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non-insulin dependent diabetes mellitus
  • Type 1 diabetes the pancreas produces little or no insulin, and insulin must be injected daily.
  • Type 2 diabetes the pancreas retains the ability to produce insulin and in fact may produce higher than normal amounts of insulin, but the amount of insulin is relatively insufficient, or less than fully effective, because of cellular resistance to insulin.
  • Type 2 diabetes may present as non-obese NIDDM, obese NIDDM, or maturity-onset diabetes of the young (MODY).
  • Type 1 is likely to occur in those with a family history of diabetes and is characterized by blurred vision, itching, unusual thirst, drowsiness, obesity, fatigue, skin infections, slow healing, and tingling or numbness in the feet.
  • Type 1 Diabetes is likely to occur in those with a family history of diabetes and is characterized by blurred vision, itching, unusual thirst, drowsiness, obesity, fatigue, skin infections, slow healing, and tingling or numbness in the feet.
  • Type 1 diabetes accounts for around ten percent of all cases of diabetes mellitus.
  • the action of Type 1 diabetes is to cause hyperglycemia (elevated blood glucose concentration) and a tendency towards diabetic ketoacidosis (DKA).
  • DKA diabetic ketoacidosis
  • Treatment requires chronic administration of insulin. No single standard exists for patterns of administration of insulin and treatment plans vary and may be selected from one of three treatment regimens: conventional, multiple subcutaneous injections, or continuous subcutaneous insulin infusion.
  • Conventional insulin therapy involves the administration of one or two injections a day of intermediate-activity insulin such as zinc insulin or isophane insulin with or without the addition of small amounts of regular insulin.
  • Regular insulin has a duration of action lasting from three to eight hours, whereas other forms of insulin are absorbed slowly from the injection site and therefore have effects that may last as long as ten to forty-eight hours.
  • the multiple subcutaneous insulin injection technique involves administration of intermediate- or long-acting insulin in the evening as a single dose together with regular insulin prior to each meal.
  • Continuous subcutaneous insulin infusion involves the use of a small battery-driven pump that delivers insulin subcutaneously into the abdominal wall, usually through butterfly needle. Insulin is delivered at a basal rate continuously throughout the day, with increased rates programmed prior to meals. Insulin may also be delivered by way of an implant that is administered parenterally, or by way of slow-release formulations.
  • Type 2 diabetes is marked by hyperglycemia that is not linked with DKA. Sporadic or persistent incidence of hyperglycemia may be controlled by administering insulin. Uncontrolled hyperglycemia may transiently adversely affect the insulin-producing cells of the pancreas (the beta-islet cells), which may eventually result in greater insulin deficiencies.
  • the fundamental defects to which such abnormalities may be traced include (1) a reduced entry of glucose into various "peripheral" tissues, and (2) an increased liberation of glucose into the circulation from the liver. Consequently, there is an extracellular glucose excess and an intracellular glucose deficiency. There is also a decrease in the entry of amino acids into muscle and an increase in lipolysis.
  • Type 2 diabetic subjects may be treated with insulin, if necessary.
  • Type 2 often develops in subjects of certain at risk populations. Obesity predisposes an individual to Type 2 diabetes due to long-term effects on insulin resistance.
  • Other populations thought to be at risk for developing Type 2 diabetes are the elderly; certain minorities; persons with Syndrome X; persons with concomitant hyperinsulinemia; persons with insulin resistance characterized by hyperinsulinemia and by failure to respond to exogenous insulin; and persons with abnormal insulin and/or evidence of glucose disorders associated with excess circulating glucocorticoids, growth hormone, catecholamines, glucagon, parathyroid hormone, and other insulin-resistant conditions.
  • Diabetes has become a leading health care issue in the United States and other countries, accounting for one seventh of the entire U.S. health care budget.
  • the incidence of diagnosed diabetes has increased five-fold in America over the past 35 years, with currently 8 million diagnosed diabetic patients, another estimated 8 to 12 million undiagnosed diabetic individuals, and still an additional 23 million Americans with pre-diabetes, or impaired glucose tolerance (IGT).
  • ITT impaired glucose tolerance
  • the American populace continues its trend towards aging, obesity, and greater minority representation, the numbers of individuals who are diabetic or suffer from other glucose metabolism disorders is likely to increase.
  • diabetes e.g. ketoacidosis, dehydration, and non-ketotic hyperosmolar coma
  • less progress has been made in preventing or minimizing the chronic complications of the disease e.g. premature atherosclerosis, retinopathy, nephropathy, and neuropathy.
  • a diabetic patient's life is shortened by 10 to 15 years, and those years of life are distinguished by significantly increased medical care costs as compared to a non-diabetic patient.
  • Some complications of diabetes include blindness and end-stage renal disease.
  • diabetes mellitus Another complication of diabetes mellitus is diabetic neuropathy (also called neuritis), which has been an unusually refractive complication of diabetes. Endoneural hypoxia is the overt cause of diabetic neuropathy. Early symptoms include numbness, irritation, and pain, usually in the extremities, and more advanced ones include gastroparesis and impotence.
  • EFA essential fatty acid
  • GLA gamma-linolenic acid
  • Prostacyclin is a vasoprotective molecule with multiple physiological functions, and the enzyme cyclooxygenase (cox) is involved in its synthesis.
  • cox-1 which produces both prostacyclin and anti-inflammatory prostaglandins
  • cox-2 which produces both thromboxane A 2 (TxA 2 ) and some of the prostaglandins responsible for inflammation.
  • neurotrophic factors such as the superfamiliy of neurotrophins including nerve growth factor, may present an alternative pathogenic mechanism that results in neuropathy.
  • Another complication of diabetes is increased cardiovascular risk factor, especially among women.
  • a man's risk of dying by heart disease doubles upon developing diabetes, whereas a woman's risk increases three to five-fold.
  • Type 2 diabetes presents a number of co-existent cardiovascular metabolic risk factors, e.g., insulin resistance, hyperinsulinemia, central obesity, hypertriglyceridemia, low HDL level, quantitatively abnormal LDL (diabetic dyslipidemia), hypertension, glucose intolerance, and elevated blood pressure.
  • cardiovascular metabolic risk factors e.g., insulin resistance, hyperinsulinemia, central obesity, hypertriglyceridemia, low HDL level, quantitatively abnormal LDL (diabetic dyslipidemia), hypertension, glucose intolerance, and elevated blood pressure.
  • This state has been identified as "Syndrome X.”
  • These cardiovascular risk factors may precede the onset of diabetes by as much as a decade, and they may explain the presence of overt clinical cardiovascular disease in as many as 60% of newly diagnosed diabetic patients.
  • elevated glycated hemoglobin (HbAlc) is believed to be a risk marker for short-term mortality following acute myocardial infarction in non-diabetic subjects.
  • Diabetic dyslipidemia is another complication of diabetes and is of import to cardiovascular health.
  • Plasma cholesterol and triglycerides are transported in lipoproteins (HDL, VLDL, and LDL).
  • Dyslipoproteinemias are conditions in which the concentration and composition of these cholesterol- or triglyceride-carrying lipoproteins are abnormal. Elevated concentration of lipoproteins LDL and VLDL may accelerate the development of atherosclerosis, with the secondary possibilities of thrombosis and infarction. Evidence suggests that reduction of the concentration of lipoproteins LDL and VLDL in plasma may diminish the increased risk of atherosclerosis that accompanies hyperlipoproteinemia.
  • Dyslipoproteinemias have been designated as either primary or secondary.
  • dyslipoproteinemias involve complications of a more generalized metabolic disturbance, such as diabetes mellitus or excessive intake of ethanol.
  • primary dyslipoproteinemias are typically caused either by an inherited single-gene defect (monogenic dyslipoproteinemias) or a combination of multiple subtle genetic factors that act together with environmental ones (multifactorial or polygenic dyslipoproteinemias).
  • This increase risk of cardiac mortality is secondary to both the atherogenicity of insulin resistance, which may precede the onset of diabetes by at least 8 years, and the atherogenicity of undiagnosed and uncontrolled hyperglycemia, which may be present for 9-12 years before diabetes is first diagnosed.
  • the present invention provides compositions, methods for using them, and programs thereof, that have been observed to alleviate or prevent glucose metabolism disorders, such as diabetes, and associated sequelae. Summary of the Invention
  • the present invention represents new and important treatments or nutritional regimes for maintaining or promoting health, including the treatment of diabetes, pre-diabetics and the reduction or avoidance of the onset of diabetes.
  • the present invention provides compositions and supplements, and methods of using the same, for preventing, reducing or treating in animal subjects (including humans and other mammals) one or more of the following physiological conditions: insulin resistance (the sensitivity of the cellular response of a species to insulin), beta cell attrition, hyperinsulinemia, hyperglycemia, hepatic glucose neogenesis, onset of diabetes or diabetic symptoms, elevated HbAlc levels, and elevated or inappropriately controlled blood glucose levels.
  • the present invention abates, or otherwise reduces the severity of, diabetes and other glucose metabolism disorders, including Type 1, Type 2, MODY, and IGT, and any related sequelae, including, for example, obesity, obesity-related hypertension, retinopathy, nephropathy, neuropathy, cataracts, coronary artery disease and arteriosclerosis.
  • the present invention provides supplements or compositions, and methods of using the same, for regulating, modulating or altering glucose metabolism in a manner beneficial to the patient.
  • various embodiments of the invention may be applied or tailored to specifically treat or address each condition described herein and others like them, including any condition or disorder related to glucose metabolism disorders.
  • supplements and compositions, and methods of using the same are provided to modulate at least one of body fat stores, blood pressure, hyperlipoproteinemia, hypertriglyceridemia, serum cholesterol level, HDL level, and LDL level.
  • the present invention abates or otherwise reduces the severity of dyslipidemia, atherosclerosis and CHD.
  • the present invention provides supplements or compositions, and methods of using the same, for regulating, modulating or altering lipid metabolism in a manner beneficial to the patient.
  • the present invention provides compositions and supplements, and methods for using the same, to reduce appetite for cosmetic purposes or treatment of illness, dysfunction or obesity.
  • the invention compositions include at least a therapeutically effective amount of a bioavailable source of chromium and a bioavailable source of vanadium.
  • embodiments of the present invention may include any of the other components set forth herein and others known to those of skill in the art, including any agents, components or ingredients that are beneficial in the treatment or prevention of glucose metabolism disorders or any sequelae related to such disorders.
  • the present invention is designed to regulate any of the physiological processes described herein so as to achieve a desired level of a physiological parameter (e.g., a HbAlc level of about 5%), which may result in an appreciable improvement in the level.
  • a desired level of a physiological parameter e.g., a HbAlc level of about 5%
  • such a result is accomplished without subjecting a patient to elevated levels of such a parameter.
  • Still other embodiments of the invention are particularly preferred in preserving health or reducing, preventing or delaying the onset of diabetes or diabetic symptoms without the patient experiencing the full thrust of such medical conditions. Some of these aspects of the invention may be particularly helpful in preventive care regimes.
  • HbAlc is one means of assessing the state of an individual's glucose metabolism over a several month period.
  • a desirable HbAlc level is less than 7%, and less than 6% is generally considered non-diabetic.
  • medical intervention is called for if a subject's HbAlc level exceeds 8%.
  • the average HbAlc levels of the ten individuals before the program was 9.40%), and the range was 12.7 to 8.1%.
  • the average HbAlc level for the ten individuals was 7.29%, and the range was 8.9 to 5.7%. This program therefore resulted in an average drop of 2.11% in HbAlc levels, and the HbAlc levels for eight of the ten subjects was reduced below 8%.
  • the present invention contemplates monitoring such disorders or conditions as part of any therapeutic regimen.
  • the subject compositions or supplements may be used in the manufacture of a medicament to treat any of the foregoing conditions or diseases.
  • the present invention is directed to a method for formulating compositions or supplements of the present invention in a pharmaceutically acceptable excipient.
  • the present invention contemplates compositions or supplements of the present invention for the treatment any of the foregoing conditions or diseases.
  • the present invention is directed to a dietary supplement that may be formulated for people individuals in an increased risk category as identified by any number of risk factors, including familial history.
  • the present invention contemplates programs for prevention or treatment of any of the foregoing disorders or conditions.
  • one or more physiological parameters will be measured, and dosing and/or composition of supplement will be varied to reflect the health of the individual.
  • Certain programs require that the patient ingest the supplement for a minimum time period, whereupon the same physiological parameters will be measured again to determine what affect the supplement may have caused.
  • the programs call for changes in dosing, components, or formulation of the supplement depending on the results reported after an initial trial period on a program.
  • programs of the present invention may require monitoring by the patients or additional treatment or prevention activities, such as dietary recommendations or exercise suggestions.
  • the programs may include instructions for the patients concerning the scope and purpose of the program.
  • anti-diabetic shall mean any composition or supplement, or method of using the same, that is useful in one or more of the following: treating, preventing, or otherwise reducing the severity of any glucose metabolism disorder, or any complications thereof, including any of the conditions, disease, or complications described herein.
  • bioavailable means that a compound, composition, supplement, component, or material is in a form that allows for it, or a portion of the amount administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject to whom it is administered.
  • bioavailable sources of components of supplements or compositions of the present invention containing a transition metal, including chromium, vanadium and others are contemplated, as discussed in more detail herein.
  • An embodiment of the invention is said to have an "insulinotropic activity" if it is able (i) to stimulate, or cause the stimulation of, the synthesis or expression of the hormone insulin, or (ii) to increase the half-life or the apparent potency of insulin in vivo.
  • Insulin may be any naturally occurring form of the polypeptide, or any form of insulin, including any polypeptide that achieves the same effect of insulin, administered to a patient.
  • parenteral administration and “administered parenterally” means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • modulation refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart.
  • phrases "pharmaceutically acceptable” refers to those supplements, components, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any supplement or composition, or component thereof, from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any supplement or composition, or component thereof, from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the supplement and not injurious to the patient.
  • materials which may serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • compositions of the present invention refers to the relatively non-toxic, inorganic and organic acid addition salts of components of compositions of the present invention.
  • systemic administration means the administration of a subject supplement, composition, therapeutic or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • compositions of the present invention may be administered in a sufficient amount to modulate glucose metabolism at a reasonable benefit/risk ratio applicable to such treatment.
  • the present invention provides methods and compositions for modification and regulation of glucose and lipid metabolism, generally to reduce insulin resistance, hyperglycemia, hyperinsulinemia, obesity, dyslipidemia, hyperlipoproteinemia (such as VLDL), and to regulate body fat and more generally lipid stores, and, more generally, to improve of metabolism disorders, especially those associated with diabetes, obesity, atherosclerosis, or
  • administering improves one or more aberrant indices associated with glucose metabolism disorders (e.g., glucose intolerance, insulin resistance, hyperglycemia, hyperinsulinemia, diabetic dyslipidemia, and Type 2 diabetes).
  • administration of a subject supplement, or methods thereof, in an effective amount improves aberrant indices associated with CHD or obesity.
  • the supplements and compositions have anti-diabetic activities, and may be used in the treatment of disorders marked by aberrant glucose metabolism (including storage).
  • supplements or compositions, or components thereof, of the present invention are useful as insulin enhancing or insulinotropic agents.
  • the subject compositions or methods may be useful for the treatment and/or prophylaxis of a variety of disorders, including one or more of dyslipidemia, hyperglycemia, obesity, glucose tolerance insufficiency or impairment, insulin resistance, and diabetic complications.
  • the invention compositions include at least a therapeutically effective amount of a bioavailable source of chromium and a bioavailable source of vanadium.
  • a supplement includes an effective amount of chromium polynicotinate and/or chromium picolinate as the chromium source, an effective amount of vanadyl sulfate as the vanadium source, an effective amount of magnesium as either a complex of chloride or Krebs (citrate, fumarate, malate, glutarate and succinate complex), an effective amount of vitamin E as free 2R, 4'R, 8'R-alpha-tocopherol, an effective amount of aspirin as standardized willow bark, an effective amount of folic acid and alpha-lipoic acid, as well as sufficient amounts of other vitamin and mineral sources.
  • the present invention is directed to supplements or compositions capable of preventing, treating, or otherwise reducing the severity of disorders of glucose metabolism.
  • Insulin resistance is the pathophysiologic indicator of patients with IGT and Type 2 diabetes, which often occurs many years before clinically evident disease is present.
  • subjects may remain euglycemic, but hyperinsulinemic, as long as beta cells maintain sufficient insulin concentrations.
  • the disease or condition progresses from insulin resistance with hyperinsulinemia to impaired glucose tolerance, resulting in modest increases in post-prandial glucose concentrations, followed by clinical diabetes and hyperglycemia.
  • the supplements and compositions of the present invention, and methods of using the same are intended to delay the onset of Type 2 diabetes and its associated sequelae by addressing disorders of glucose metabolism at an early stage.
  • the present invention also provides methods for enhancing the natural control of blood glucose levels in a person by daily administration of the subject composition and nutritional supplement.
  • the present invention contemplates administration of a supplement of the present invention to control the blood sugar by reducing insulin resistance in diabetic and IGT patients, thereby preventing the chronic complications from developing in these high risk patients.
  • the present invention also provides for kits containing at least one dose of a subject supplement or composition, and often many doses, and other materials for a treatment regimen.
  • kits of the present invention contains sufficient supplement for thirty days and equipment and supplies necessary to measure one or more indices relevant to glucose metabolism, such as blood glucose levels.
  • kits of the present invention contain all the materials and supplies, including supplements and compositions, for carrying out any methods of the present invention.
  • the present invention provides for programs whereby the supplements or compositions of the present invention are ingested by a subject having a condition described herein, including subjects that are pre-diabetic.
  • the program format of the present invention allows for a variety of variables to be addressed in providing composition and supplements of the present invention. Some of these variables include: one or more conditions to be addressed by any one program, compositions and supplements to be used in any such program, and dosing regimen of any such program.
  • a program may include a kit of the present invention. Many of the features of any program, including for example the dosing regimen, may be provided for in instructions to the subject participating in any program.
  • Such instructions may, in certain embodiments, require the subject to decide whether to continue any program depending on the results obtained while on the program.
  • the length of such trial period may vary with the particular program. Typically, trial periods may be between about one to about six or more months, and alternatively, the trial periods may be between one and three months.
  • the subject may be required to assess their progress on the program by monitoring a parameter relevant to their particular condition.
  • a program directed to prevention or treatment of a glucose metabolism disorders may require subjects to monitor their HbAlc levels. After a certain period on such a program, during which the subject would have used the composition or supplement prescribed by the program in the manner dictated thereby, the program may require the subject to determine their HbAlc level. Depending on whether the HbAlc level changed by a particular amount, the subject may continue with the particular program, discontinue the program altogether, or alter the program. The foregoing decision may depend on the initial condition of the subject.
  • the dose of chromium administered to a patient in a composition varies with the initial HbAlc level.
  • the chromium dosages would be as follows: for a patient having an HbAlc level in the range of about 7 up to about 8, a dose of chromium is in the range of about 0.003 mg Cr or less/kg of body weight up to about 0.009 mg Cr or less/kg, for a patient having an HbAlc level in the range of about 8 up to about 9, a dose of chromium is in the range of about 0.005 mg Cr/kg of body weight up to about 0.01 mg Cr/kg of body weight, for a patient having an HbAlc level in the range of about 10 up to about 11, a dose of chromium is in the range of about 0.006 mg Cr/kg of body weight up to about 0.015 mg Cr/kg of body weight, and for a patient having an HbAlc
  • the particular dose of chromium would be maintained for a trial period, whereupon the HbAlc level would be measured again. If the patient's HbAlc level had dropped during the trial period, then the dose of chromium ingested could be reduced; if the HbAlc level had not decreased, the patient would have a number of options: the dose of chromium could be increased, the same dose could be ingested for a longer time period, or a different chromium complex with potentially differing bioavailability and potency for the particular individual could be used.
  • This program could be applied to any other component or ingredient of the present invention, including, for example, any vanadium containing complex.
  • a number of parameters of blood serum may be measured to assess the efficacy of any supplement or method of the present invention in attending to the conditions described herein. Any of these parameters may serve as the basis of a program of the present invention.
  • Useful parameters include: LDL-cholesterol, HDL-cholesterol, apolipoprotein Al, apolipoprotein B, HbAlc, and blood sugar level (fasting, post-prandial and urine). It has been observed that the subject compositions are especially effective in improving blood glucose control after eating, so the post-prandial measurement is preferred in certain programs of the present invention.
  • measurements of import for any subject invention include heart rate, blood pressure, weight, and temperature.
  • the amounts of the individual components of preparations of this invention may vary, although in certain preparations the components are present in amounts lying within certain ranges presented herein.
  • the present invention typically contemplates administering the dosages of any supplement or composition on a daily basis, or at other frequencies appropriate to the supplement or composition and its mode of delivery.
  • a dose of a composition of the present invention may be ingested or administered daily in a single serving, e.g., a tablet or a liquid, or in multiple servings.
  • the dosages of the present invention may be ingested over a several day period or over any other time period so as to achieve the desired therapeutic effects.
  • Certain supplements and compositions of the present invention contemplate components that are transition metal chelates.
  • Certain of the metal chelates contemplated by the present invention may have, in addition to any chelating ligand or ligands that are bound covalently or through ionic interactions to said metal ion, a counter-ion that is generally not bound to the metal ion (or if associated, only weakly so), and counters any charge of the metal-ligand complex.
  • a counter-ion that is generally not bound to the metal ion (or if associated, only weakly so)
  • the sulfate would generally be considered a counter-ion to the vanadyl ion metal-ligand complex.
  • the metal chelates may have a number of waters of hydration associated with them.
  • one form of magnesium di chloride is magnesium di chloride hexahydrate, in which six waters of hydration are part of the metal complex.
  • a metal chelate that is identified as an hydrate may have one or more waters of hydration.
  • the number of molecules of waters of hydration may be a non- integer number when expressed as a ratio of one molecule of metal complex to the molecular number of the waters of hydration.
  • One means of determining the numbers of water of hydration is by elemental analysis.
  • the number of waters of hydration may affect the bioavailability, water solubility and other properties of a metal complex.
  • the most appropriate dose may depend, in part, on the nature of the metal chelate. Certain transition metal or mono- or multi- valent ion complexes may be more readily assimilated than others, and may therefore be more effective in achieving the desired therapeutic response than other complexes.
  • Another important factor may be the water solubility of any metal complex.
  • Another relevant factor may be the mode of administration. Consequently, dosages of the complexes typically contemplated by the present invention usually depend on the identity of the complex, the means of administration, and the formulation in which the complex is administered.
  • chromium picolinate appears to be absorbed at a rate about four times greater than chromium trichloride upon oral administration to rats.
  • chromium picolinate is preferred over chromium trichloride as the administered complex.
  • chromium polynicotinate will be preferred over chromium picolinate as it contemplated that chromium polynicotinate will generally have better absorption and metabolic properties than chromium picolinate.
  • transition metal chelates or other metal chelates
  • the metal chelate or other inorganic complex administered to a subject may differ from the form that is responsible for any biological activity.
  • a transition metal complex may undergo any number of reactions in vivo. including: hydrolysis, which depends greatly on pH conditions; redox reactions, whereby the transition metal, or even a chelating ligand, may change electronic state, which depends greatly on the local redox environment; and other ligation reactions, whereby a molecule may, because of, for example, superior binding characteristics and/or affinity or greater concentration, displace a ligand chelating the metal. It is not uncommon for a transition metal complex, especially those containing first row transition metals, to undergo complete hydrolysis upon ingestion or administration to a subject and possibly chelation by a molecule present in vivo.
  • complexed forms of such metals will be selected to direct or maintain the desired form of the metal in the body.
  • Other potentially desirable characteristics in metal complexes include: a neutral charge to the complex, sufficient water solubility (e.g., capable of forming an at least a 0.1 mM solution); and capable of being absorbed orally and gastro-intestinally.
  • compositions that serve as components in the subject supplements, particular complexes are discussed in more detail herein.
  • pharmaceutically acceptable salts of such transition metals that may serve as components in the subject preparations generally include the conventional non-toxic salts of the compounds, e.g., salts derived from non-toxic organic or inorganic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, valeric, oleaic, lauric, lactic, lactobionic, laurylsulphic, and the like.
  • inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric,
  • Contemplated equivalents of the components of the subject compositions of the present invention include compounds or materials that otherwise correspond thereto, and which have the same general properties thereof, wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in the composition or in use in the contemplated method.
  • the present invention readily enables the design and implementation of trials in warm-blooded animals, including humans and mammals, necessary for easily determining or tailoring the form and dose for any supplement, and the components thereof, of the present invention.
  • the nutritional supplements of the present invention may supplant other forms of diabetes and IGT treatment, such as appropriate diet and exercise or insulin.
  • programs of the present invention require that the subject compliment such treatment methods with the compositions of the present invention.
  • a dietary supplement containing effective amounts of metabolically available forms of vanadium, chromium, magnesium, and vitamin E in combination with naturally available sources of aspirin, alpha-lipoic acid, and folic acid improves the metabolism of glucose.
  • Such compositions may be also used to arrest, treat or otherwise reduce the severity of many of the cardiovascular complications or risk factors associated with diabetes or pre-diabetes.
  • the present invention contemplates combinations of components or ingredients in different supplements or compositions to produce a therapeutic effect in a patient with a glucose metabolism disorder, such as Type 2 diabetes, IGT, Syndrome X, insulin resistance, or hyperinsulinemia.
  • a glucose metabolism disorder such as Type 2 diabetes, IGT, Syndrome X, insulin resistance, or hyperinsulinemia.
  • the therapeutic effect may be measured by reference to any number of indices that are directly related to glucose metabolism, such as blood glucose level or HbAlc level, or other parameters that may otherwise be affected by such a disorder or a related condition or disease.
  • the present invention teaches how to test supplements or compositions containing any one or more of the components set forth herein to determine whether any particular combination of components in a supplement or composition results in a desirable therapeutic effect upon administration to a patient.
  • the subject compositions contain at least a therapeutically effective amount of a bioavailable source of chromium and a bioavailable source of vanadium.
  • the subject supplements consist essentially of the components indicated for that particular supplement.
  • Chromium is a trace mineral found in human tissues. Claims surrounding the use of chromium as a supplement, such as weight loss and building muscle mass, have been made for non-diabetic individuals. Notwithstanding such claims, the status of chromium supplementation, even for diabetic patients, appears to be unsettled. Although chromium supplementation may be prescribed for individuals who are chromium deficient, the prevalence of chromium deficiency in diabetic patients appears to be difficult to establish.
  • chromium at the appropriate dosage and form may cause improved glucose or lipid metabolism by overcoming insulin resistance.
  • Chromium may increase insulin binding to cells by increasing the number of insulin receptors.
  • chromium may increase insulin sensitivity by increasing insulin receptor phosphorylation.
  • the present invention contemplates metal complex of chromium in which the chromium is bioavailable.
  • sources of chromium include chromium trichloride, chromium acetate, chromium nicotinate (or polynicotinate), chromium picolinate, chromium glycinate, chromium oxalate, chromium perchlorate, chromium salicylate, chromium nicotinate glycinate, chromium 4-oxo-pyridine-2,6-dicarboxylate, chromium chelidamate or arginate; and chromium tris-acetylacetonate.
  • chromium complexes contemplated by the present invention may differ in bioavailability and potency.
  • the chromium complexes may contain chromium in the (III) (i.e., trivalent), (VI) (i.e., hexavalent), or other valent states, although it is believed that the trivalent state is responsible for biological effects of interest in the present invention and is therefore preferred.
  • Chromium in many of the chromium containing complexes contemplated by the present invention typically have chromium in the (III) valency.
  • Certain embodiments of the present invention contemplate doses of chromium from aboutlOO meg to about 5000 meg or higher.
  • the dose amounts referred to herein refer to the amount of chromium in any particular form, such as complex or in any particular valency.
  • a patient would need to ingest about 610 meg of chromium trichloride.
  • Particular dosages of chromium contemplated by the present invention include about 200 meg, 300 meg, 333 meg, 500 meg, 650 meg, 750 meg, 1000 meg, 1250 meg, 1500 meg, 2000 meg, 2500 meg, 3000 meg, 3500 meg, 4500 meg, and 5000 meg, as well as other possible dosages determined by one of skill in the art.
  • Higher dosages, while they may be daily dosages, may be used as short term regimes (e.g. less than about one month) and may taper into dosages in the lower end of the taught ranges. In certain instances, it may be advantageous not to fall below about 250 to 600 meg of chromium per day when tapering the dose.
  • the dose of chromium may be modified if the supplement or composition contains a bioavailable source of vanadium.
  • the dose of chromium may be reduced by from about 10% to about 75%, or alternatively 25%, 33%, 55%, or 66%.
  • the amount of reduction in the chromium dose may depend, in part, on the dose of vanadium provided for in any supplement of the present invention, as well as the source of the vanadium and the means of administration.
  • the dose may be varied as necessary, for example, to treat one or more specific conditions set forth herein, or for example, to reflect any differences in administration or the nature of the components employed in any particular composition, method or program of the present invention.
  • the dose of chromium may be reduced as ingestion of the supplement results in improved blood glucose control.
  • the patient may need to monitor a number of indices, such as blood glucose levels or HbAlc levels, to determine the appropriate dosing.
  • the dose of chromium is based on the weight of the intended recipient. Accordingly, in one embodiment of the present invention, the dose of chromium is in the range of about 0.001 mg or less/kg of body weight up to about 0.06 mg or more/kg of body weight. In another embodiment of the present invention, the dose is at least about 0.01 mg/kg body weight. In still another embodiment of the present invention, the dose is in the range of about 0.002 mg/kg of body weight up to about 0.02 mg/kg of body weight. In further embodiments of the present invention, the dose of chromium may be determined based on the intended recipient's condition. For example, in one embodiment, the dose of chromium may depend on the subject's HbAlc level.
  • a dose of chromium is in the range of about 0.003 mg or less/kg of body weight up to about 0.009 mg or less/kg
  • a dose of chromium is in the range of about 0.005 mg/kg of body weight up to about 0.01 mg/kg of body weight
  • a dose of chromium is in the range of about 0.006 mg/kg of body weight up to about 0.015 mg/kg of body weight
  • a dose of chromium in the range of about 0.007 mg/kg of body weight up to about 0.04 mg or more/kg of body weight.
  • Dosing for a particular's subject condition may be based on any of the parameters known in the art or described herein useful for assessing the condition of any subject. For example, a number of parameters of blood serum, in addition to HbAlc levels, may be used to determine appropriate dosing. Other measurements of import of potential use for dosing purposes are described herein.
  • Chromium in the trivalent state is one of the least toxic nutrients: the reference dose established by the US EPA is 350 times the upper limit of the Estimated Safe and Adequate
  • ESADDI Daily Dietary Intake
  • vanadium compounds of the present invention are believed to have an insulin mimetic effect.
  • Vanadium often in the form of vanadate appears in certain tissues to stimulate glucose transport, activate glycogen synthase, increase glycogen syntheses in fat cells, and stimulate carbohydrate uptake in the liver like insulin.
  • vanadyl sulfate A commonly used source of vanadate is vanadyl sulfate. Upon ingestion, vanadyl sulfate is typically reduced to vanadate, which is a salt, of vanadic acid.
  • Glycogen synthase is an enzyme that causes the conversion of glucose into glycogen. Vanadate appears to activate glycogen synthase in the same manner as insulin. For example, vanadate appears to have no effect if insulin concentration is at a maximum, whereas if insulin is at less than maximum, vanadate increases both glycogen synthase activation state and 2-deoxyglucose transport to the level obtained if insulin were at maximized. Vanadate and insulin activate glycogen synthase within similar time frames, and adrenaline partially reverses both vanadate and insulin activated glycogen synthase. Also, insulin and vanadate counteract the activating effect of adrenaline on glycogen phosphorylase.
  • Dosages of vanadium in compositions of the present invention range from less than 5 mg to more than 100 mg. Unless expressly provided otherwise, the dose amounts referred to herein refer to the amount of vanadium in any particular form, such as any particular complex or in any particular valency. Particular dosages of vanadium contemplated by the present invention include about 0.1 mg, 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, and 125 mg. In certain embodiments, the amount of vanadium administered is about 5 mg to 50 mg. Typically, these are daily dosages. Higher dosages, while they may be daily dosages, may be used as short term regimes (e.g. less than about one month) and may taper into dosages in the lower end of the taught ranges.
  • VO 2+ vanadyl
  • Such dosages would be: 0.1 mg V, 0.13 mg VO 2+ ; 1 mg V, 1.3 mg VO 2+ ; 5 mg V, 6.55 mg VO 2+ ; 10 mg V, 13.1 mg VO 2+ ; 20 mg V, 26.2 mg VO 2+ ; 25 mg V, 32.8 mg VO 2+ ; 50 mg V; 65.5 mg VO 2+ ; 75 mg V, 98.3 mg VO 2+ ; 100 mg V, 131 mg VO 2+ ; and 125 mg V, 164 mg VO 2+ .
  • the compositions of the present invention include vanadyl sulfate hydrate as a vanadium source.
  • the amount of elemental vanadium in the source of vanadium sulfate hydrate was determined by elemental analysis to be approximately 20% by weight, which corresponds to about five to six waters of hydration per molecule of vanadyl sulfate.
  • some of the common doses of vanadium and the resulting amount of vanadyl sulfate hydrate necessary to provide that amount of vanadium would be: 0.1 mg of vanadium, 0.5 mg of vanadyl sulfate hydrate; 20 mg of vanadium, 100 mg of vanadyl sulfate hydrate; 100 mg of vanadium, 500 mg of vanadyl sulfate hydrate.
  • the dose of vanadium may be modified if the supplement or composition contains a bioavailable source of chromium.
  • the dose of vanadium may be reduced by from about 10% to about 75%, or alternatively 25%, 33%, 55%, or 66%.
  • the amount of reduction in the vanadium dose may depend, in part, on the dose of chromium provided for in any supplement of the present invention, as well as the source of the chromium and the means of administration.
  • the dose may be varied as necessary, for example, to treat one or more specific conditions set forth herein, or for example, to reflect any differences in administration or the nature of the components employed in any particular composition, method or program of the present invention.
  • the dose of vanadium may be reduced as ingestion of the supplement results in improved blood glucose control.
  • the patient may need to monitor a number of indices, such as blood glucose levels or HbAlc levels, to determine the appropriate dosing.
  • the dose of vanadium is based on the weight of the intended recipient. Accordingly, in one embodiment of the present invention, the dose of vanadium is in the range of about 0.1 mg or less/kg of body weight up to about 10 mg or more/kg of body weight. In another embodiment of the present invention, the dose is at least about 0.3 mg/kg body weight. In still another embodiment of the present invention, the dose is in the range of about 0.2 mg/kg of body weight up to about 0.8 mg kg of body weight.
  • dosages based on the subject's weight may be based on the amount of vanadyl required in any embodiment of the present invention.
  • the dose of vanadyl is in the range of about 0.13 mg or less/kg of body weight up to about 13 mg or more/kg of body weight.
  • the dose is at least about 0.42 mg/kg body weight.
  • the dose is in the range of about 0.26 mg/kg of body weight up to about 0.10 mg/kg of body weight.
  • the dose of vanadium may be determined based on the intended recipient's condition.
  • the dose of vanadium may depend on the subject's HbAlc level. Accordingly, in this particular example, for a patient having an HbAlc level in the range of about 7 up to about 8, a dose of vanadium is in the range of about 0.05 mg or less/kg of body weight up to about 0.45 mg/kg; for a patient having an HbAlc level in the range of about 8 up to about 9, a dose of vanadium is in the range of about 0.15 mg/kg of body weight up to about 0.6 mg/kg of body weight, for a patient having an HbAlc level in the range of about 10 up to about 11, a dose of vanadium is in the range of about 0.3 mg/kg of body weight up to about 1.0 mg/kg of body weight, and for a patient having an HbAlc level in the range of at least about 11, a dose of vanadium
  • Dosing for a particular's subject condition may be based on any of the parameters known in the art or described herein useful for assessing the condition of any subject. For example, a number of parameters of blood serum, in addition to HbAlc levels, may be used to determine appropriate dosing. Other measurements of import of potential use for dosing purposes are described herein.
  • a number of vanadium containing compounds may be used in the present invention. For instance, vanadyl sulfate does not appear not to be associated with any apparent toxicity during treatment periods of up to one year. In addition, it appears that vanadyl sulfate may be less toxic than vanadate forms of vanadium.
  • vanadium compounds contemplated by the present invention include any of the following: vanadium pentoxide; vanadium trisulfate; vanadyl chloride; vanadyl glycinate; vanadyl gluconate; vanadyl citrate; vanadyl lactate; vanadyl tartrate; vanadyl gluconate; vanadyl phosphate; sodium orthovanadate; vanadium chelidamate or arginate; and vanadyl complexes with monoprotic bidentate 2,4-diones.
  • vanadium complexes In addition to those vanadium complexes specifically set forth above, other organic, inorganic, salts and complexes of vanadium, including vanadyl complexes, known to those of skill in the art are contemplated by the present invention.
  • the different vanadium-containing metal complexes of the present invention may contain vanadium in any number of vanadium valencies. Vanadyl ion is VO 2+ , which has vanadium in plus four oxidation state, is one form of vanadium that is preferred in supplements of the present invention.
  • Magnesium in mammals typically resides in three compartments: (1) bone; (2) intracellular bound form or an intracellular unbound form; and (3) in circulating bound and unbound forms.
  • concentration of circulating magnesium in the bloodstream increases as a result of the dietary intake of magnesium, the magnesium is sequestered into one of the bound or intracellular forms.
  • Hypomagensium is generally defined as a serum magnesium level concentration of less than 1.5 mEq/1.
  • the incidence of magnesium deficiency in Type 1 and Type 2 diabetes appears to be unclear. The diabetic patient may be at risk for developing magnesium depletion via inadequate dietary intake and gastrointestinal and renal losses, especially with poorly controlled blood glucose and resultant glucosuria.
  • the diagnosing magnesium deficiency in the clinical setting remains extremely difficult because serum magnesium measures only 0.3% of the total body magnesium and is therefore difficult to determine.
  • Magnesium appears to improve glucose metabolism and to arrest or reduce any diabetes associated risk factors. Many preparations of magnesium are available but they may differ in potency, bioavailability (absorption), tolerability, and cost. Magnesium taken orally is absorbed primarily in the jejunum and ileum. Some magnesium salts, such as the oxide or the carbonate, although inexpensive, are not highly soluble in water, poorly absorbed and associated with gastrointestinal side effects, especially diarrhea. Other magnesium- containing complexes present better solubility, bioavailability, potency, tolerability, safety, and predictability in repleting intracellular and serum levels of magnesium.
  • Such molecules include: magnesium chloride; magnesium citrate; magnesium fumarate; magnesium succinate; magnesium orotate; magnesium aminodicarbonic acid fluoride, bromide and iodide; magnesium aspartate; magnesium stearate; magnesium glutamate; magnesium oxide; magnesium hydroxide; magnesium carbonate; magnesium hydrogen phosphate; magnesium glycerophosphate; magnesium trisilicate; magnesium hydroxide carbonate; magnesium acetate; magnesium citrate; magnesium gluconate; magnesium lactate; magnesium ascorbate; magnesium taurate; magnesium malate; and magnesium diglycinate.
  • magnesium orotate magnesium aspartate
  • magnesium citrate is soluble in gastric fluid and thus is readily available for passive abso ⁇ tion in the upper gastrointestinal tract.
  • Magnesium and taurine may act to improve insulin sensitivity and to reduce vasoconstriction and atherogenesis, and stabilize platelets.
  • Magnesium acetate, magnesium ascorbate and magnesium lactate are soluble in gastric fluid and share the upper gastrointestinal passive abso ⁇ tion potential of magnesium citrate.
  • the ascorbate radical serves as a source of vitamin C by conversion to ascorbic acid upon exposure to hydrochloric acid in the gastric fluid, whereas the magnesium ion is converted to soluble magnesium chloride.
  • the satisfactory water solubility of magnesium acetate, magnesium ascorbate, magnesium citrate and magnesium lactate provide for a diffusional gradient of magnesium in the upper small intestine where some passive abso ⁇ tion of magnesium occurs.
  • Magnesium oxide is converted to magnesium chloride in the stomach, and offers the advantage of a high ionic magnesium content, since 60% by weight of the magnesium oxide molecule is elemental magnesium.
  • Magnesium diglycinate represents a form of magnesium that is absorbed in part as an intact dipeptide in the proximal small intestine via a dipeptide transport pathway and therefore provides a third abso ⁇ tive mechanism for magnesium.
  • Magnesium stearate is useful as a lubricant when compressing the composition into tablets.
  • the observations for these magnesium complexes is illustrative of the type of processes and chemical reactions that may occur for any of the transitional metal complexes described herein, including the chromium- and vanadium-containing complexes.
  • a variety of dosages, in amount of magnesium, are contemplated by the present invention. Unless expressly provided otherwise, the dose amounts referred to herein refer to the amount of magnesium in any particular form, such as any particular complex.
  • the dose may range from about 5 mg or less to 1000 mg or more. Specific dosages include about 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, and 2000 mg.
  • a preferred dose is 46 mg of magnesium. Typically, these are daily dosages. Higher dosages, while the may be daily dosages, may be used as short term regimes (e.g. less than about one month) and may tamper into dosages in the lower end of the ranges. In many such instances it will be advantageous to not to fall below about 40 to 100 mg per day of magnesium when tampering the dose.
  • the appropriate dose of magnesium may be based on the weight of the intended recipient. Alternatively, as discussed for other components, the appropriate dose of magnesium may be based on the condition of any subject, as assessed by a number of variables of import. Alternatively, the dosages may depend on the mode of administration. Alternatively, magnesium does may vary with the identity and amounts of the other components in any supplement of the present invention. As for the other components of the subject compositions, appropriate dosages may depend on numerous factors, and may be readily determined by one of skill in the art.
  • Aspirin e.g. acetyl salicylic acid
  • Aspirin may be use to reduce the risk of either primary (high risk for cardiovascular disease) or secondary (cardiovascular disease).
  • the health promoting benefits of aspirin derive in part from its antiplatelet effect. It appears to work, in part, by inhibiting cyclooxygenase, an enzyme necessary for the synthesis of thromboxane, a potent stimulator of platelet aggregation, a condition known to be increased in diabetes and to be causative in the atherosclerotic process. In patients with diabetes and other glucose metabolism disorders, aspirin appears to correct this abnormal increase in platelet activity.
  • Platelet aggregation is implicated in thrombus formation, which involves interaction of aggregated platelets and activated coagulation factors with a damaged vascular wall. Platelets are normally non-adherent, but upon damage to the endothelial lining of a vessel, the platelets adhere to exposed subendothelial collagen. The von Willebrand factor (vWF) is involved in this adhesion. Collagen and thrombin initiate platelet activation and activate phospholipase C, which hydrolyzes membrane phospholipids. Protein kinase C is thereby activated, and the calcium concentration of platelet cytosol increases.
  • vWF von Willebrand factor
  • Arachidonic acid is liberated from membrane phospholipids and is oxidized in part to prostaglandin H 2 (PGH 2 ) and TxA,. After platelet aggregation, fibrinogen is converted to fibrin to secure the hemostatic platelet plug. Platelet aggregation is mediated by the PGH 2 derivative prostacyclin, which is also a vasodilator.
  • aspirin acts as a cyclooxygenase inhibitor, blocking the conversion of arachidonic acid to the PGH 2 precursor prostaglandin G 2 (PGG 2 ). Because PGG 2 is a precursor to both TxA 2 and prostacyclin, aspirin blocks both the aggregation inducing and aggregation inhibiting effects of these factors.
  • naproxen, indomethacin, piroxicam and acetaminophen inhibit production of the pain-producing prostaglandins by cox-2, but they all, other than aspirin, substantially inhibit cox-1, which produces prostacyclin.
  • Aspirin inhibits prostacyclin production the least (3- 4 hrs), and piroxicam the most (3-4 days). It is believed that that one aspirin taken every 3 days maximizes prostacyclin production and minimizes production of TxA 2 , which causes hypertension and has been implicated in development of vascular disease.
  • non- cylooxygenase inhibitors may be used for pain relief in addition to aspirin (e.g., Tramadol - Ultram), or inhibitors of cox-2 only (e.g., Meloxicam, and Sulindac (Clinorii)).
  • aspirin in doses above 80 mg per day may interfere with the synthesis of prostaglandins necessary to protect the gastric mucosa, gastrointestinal hemorrhage may result if aspirin is used above such a dose. Therefore, aspirin trials have used progressively smaller doses to avoid the risk of hemorrhage, and have found comparable suppression of thromboxane with doses as low as 10 mg per day and with equal or greater risk reduction for cardiovascular end point.
  • the present invention may use standardized willow bark as the source of aspirin.
  • Standardized willow bark is a Chinese herb and is highly standardized source of aspirin.
  • other, naturally occurring sources of acetyl salicylic acid may be used in the present invention.
  • Typical dosage ranges of acetyl salicylic acid include less than 10 mg to 100 mg or more.
  • Particular doses of aspirin include about 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg. Typically, these are daily dosages.
  • higher dosages are contemplated by the invention, they are less preferred because of potential gastric disturbances.
  • the appropriate dose of aspirin may depend on the mode of administration.
  • appropriate dosages may depend on numerous factors, and may be readily determined by one of skill in the art. Such factors include the weight of the intended recipient or the condition of the recipient.
  • homocysteine a sulfhydryl-containing amino acid
  • Homocysteine may injure arterial endothelial cells, may affect platelet-endothelial cell interaction, and may be thrombogenic. Such effects appear to accelerate the artherogenic process in diabetic patients.
  • High homocysteine levels may be normalized by folic acid treatment, which thereby may reduce arthersclerotic events.
  • the present invention may be practiced in the absence of folic acid, although in certain embodiments, the present invention will contain about 400 to about 600 meg folic acid, or alternatively, about 400 meg. Other possible doses include about 200 meg or less, 300 meg, 500 meg, 600 meg, and about 1000 meg or more. 3.1.6 Vitamin E and other anti-oxidants
  • Vitamin E Vitamin E (free 2R, 4'R, 8'R-alpha-tocopherol) is the most widely studied of the antioxidant vitamins.
  • the interest in vitamin E as an antioxidant is based on the many demonstrations in humans that giving vitamin E as a supplement decreases the oxidation of low density lipoprotein (LDL) ex vivo, an event critical in the atherogenic process.
  • LDL low density lipoprotein
  • Vitamin E supplementation reduces significantly atherosclerosis in primates, including humans. This observation assumes greater importance in those with diabetes, in view of the fact that as many as 60% of newly diagnosed diabetic patients already have clinically obvious cardiovascular disease. A number of studies confirm such observation/ A significantly lower risk of coronary artery disease was observed in a four year, prospective, observational study in healthy middle-aged men who had higher intakes of dietary vitamin E as compared to those consuming small amounts. In another prospective, epidemiological study, middle-aged women free of cardiovascular disease at baseline were found to have a highly significant reduced risk of coronary artery disease if they had been on vitamin E supplements for at least two years during the eight year study. In a more recent and similar seven year prospective study of postmenopausal women without cardiovascular disease, dietary vitamin E consumption, but not vitamin A or C, was inversely associated with the risk of death from coronary artery disease.
  • CHAOS Cambridge Heart Antioxidant Study
  • vitamin E supplementation Another benefit of vitamin E supplementation is believed to be the favorable effect it has on insulin sensitivity, glucose metabolism, and lipid levels in both healthy subjects and patients with Type 2 diabetes.
  • low concentration of plasma vitamin E at baseline was found to be an independent and powerful predictor for the development of Type 2 diabetes during the four year study.
  • a low level of vitamin E was associated with a greater than five- fold risk of developing diabetes in the ensuing four years.
  • vitamin E may restore reduced prostacyclin synthesis, thereby possibly treating neuropathy.
  • Vitamin E was well tolerated in the studies where it was given as a supplement, and in the CHAOS study, there was no difference between the alpha-tocopherol treatment (400 or 800 LU.) or placebo groups for side effects. Because of the unusually high incidence of clinical heart disease in newly diagnosed diabetic patients, and the favorable effect vitamin E has on the metabolic abnormalities of Type 2 diabetes, the present invention may contain vitamin E.
  • Dosages may range up to 1200 LU. or more, especially 400-800 I.U., and particularly 400 LU.
  • alpha-tocopherol and its analogs and esters thereof e.g., alpha- tocopherol acid succinate and alpha-tocopherol acetate
  • other equivalents of tocopherols may be used in the subject preparations, such as tocotrienols and their esters, and tocopheryl nicotinate.
  • Gamma tocopherol are believed to trap mutagenic electrophiles such as NOx.
  • Alpha-tocopherol acid succinate may be useful for preparing supplements in tablet form.
  • Alpha-lipoic acid is a antioxidant and is an essential a coenzyme in the utilization of sugar (glucose) for energy production. Alpha-lipoic acid also assists the body recycle and renew other antioxidants, e.g. vitamins C and E, Co-QlO and glutathione, and neutralizes both oxygen and nitrogen free radicals, which are believed to play major causal roles in cardiovascular diseases. It has been suggested that alpha-lipoic acid may increase intracellular glutathione levels. More recently, administration of alpha-lipoic acid to diabetic patients with neuropathy appeared to reduce significantly associated symptoms.
  • DL-lipoic acid has been recommended for treatment of a metabolic aberration of pyruvate dehydrogenase, which is symptomatic of diabetes.
  • alpha-lipoic acid has been used to treat circulatory problems resulting from diabetes.
  • the present invention will contain about 10 mg or less to about 600 mg or more alpha-lipoic acid, with the most preferred dose of 50 mg.
  • Other possible dosages include 10 mg or less, 25 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, and 750 mg or more. If a patient presents with neuropathy, an increased dose of alpha-lipoic acid may be appropriate.
  • Vitamin A 3.1.7 Vitamin A
  • the present invention contemplates formulations containing vitamin A, including retinoids, ⁇ -carotene, ⁇ -carotene, cryptoxanthine, and other equivalents. Possible dosages of Vitamin A or its equivalents include up to 5000 LU. or more.
  • vitamins and minerals are important in the metabolism of glucose and the maintenance of good health and may be ingested from food or included in a supplement. Some of these other vitamins and minerals include calcium, copper, and zinc.
  • any supplement, or any component thereof, of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the supplement. Possible dosage ranges and particular dosages have been presented above in discussing different components that may be present in any supplement or composition of the present invention. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for supplements, or components thereof, may be readily determined by techniques known to those of skill in the art or as taught herein.
  • An effective dose or amount, and any possible affects on the timing of administration of the formulation may need to be identified for any particular supplement, or component thereof, of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate.
  • the effectiveness of any supplement and method of treatment or prevention may be assessed by administering the supplement and assessing the effect of the administration by measuring one or more indices associated with glucose metabolism, and comparing the post- treatment values of these indices to the values of the same indices prior to treatment.
  • the precise time of administration and/or amount of any particular supplement that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, etc.
  • the guidelines presented herein may be used to optimize the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing. While the subject is being treated, glucose metabolism may be monitored by measuring one or more of the relevant indices at predetermined times during a 24-hour period.
  • Treatment including supplement, amounts, times of administration and formulation, may be optimized according to the results of such monitoring.
  • the patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters, the first such reevaluation typically occurring at the end of four weeks from the onset of therapy, and subsequent reevaluations occurring every four to eight weeks during therapy and then every three months thereafter.
  • Therapy may continue for several months or even years, with a minimum of three months being a typical length of therapy for humans.
  • Adjustments to the amount(s) of agent(s) or supplement(s) administered and possibly to the time of administration may be made based on these reevaluations. For example, if after four weeks of treatment one of the metabolic indices has not improved but at least one other has, the dose of different components of the formulation might be increased by, for example, one-third. For example, if blood glucose levels have not decreased sufficiently after a period of treatment by a formulation of the present invention, then the dosages of chromium and vanadium- containing complexes may be increased, or alternatively other complexes may be used, whereas the dose of aspirin would not necessarily need to be adjusted. Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.
  • any supplement may reduce the required dosage for any individual component because the onset and duration of effect of the different components may be complimentary.
  • the different components may be delivered together or separately, and simultaneously or at different times within the day.
  • the different components may be administered substantially simultaneously, or alternatively as a composition or formulation containing both components.
  • vitamin C may regenerate and spare vitamin E, so any formulation having both of these compounds may provide complimentary protection against oxidative stress.
  • indices may need to be measured.
  • an oral glucose tolerance test a patient's physiological response to a glucose load or challenge is evaluated. After ingesting the glucose, the patient's physiological response to the glucose challenge is evaluated. Generally, this is accomplished by determining the patient's blood glucose levels (the concentration of glucose in the patient's plasma, serum, or whole blood) at several predetermined points in time.
  • Another related method is the hyperinsulinemic-euglycemic clamp.
  • Blood glucose measurements may be made by any number of methods.
  • the timing of any blood glucose test may be material, and the present invention contemplates determining the fasting blood glucose level and especially the post-prandial blood glucose level.
  • the desirable fasting glucose level or pre-prandial
  • a non-diabetic has a pre- prandial glucose level of less than 110 mg/dl.
  • the desirable post-prandial level or bedtime glucose level
  • a non-diabetic has a bedtime glucose level of less than 120 mg/dl.
  • glucose oxidase glucose oxidase
  • hexokinase glucose dehydrogenase
  • glucose dehydrogenase glucose oxidase
  • blood glucose is oxidized by glucose-oxidase to produce gluconic acid and hydrogen peroxide.
  • Glucose concentrations may be determined by measuring oxygen consumed or hydrogen peroxide produced (amperometric method), or by measuring gluconic acid produced (potentiometric method).
  • Non-invasive technologies that have been used or proposed for measuring glucose levels in tissue include: near-IR transmission and reflectance, Near-IR Kromoscopy, spatially resolved diffuse reflectance, polarimetry measurements, Raman measurements, and PA measurements.
  • blood glucose levels may be measured by irradiating blood vessels in the retina of the eye.
  • Other spectroscopic methods have been proposed and are known to those of skill in the art. Another clinical index for glucose metabolism is glycosylated hemoglobin A.
  • Hb Human adult hemoglobin
  • HbA Human adult hemoglobin
  • HbA2 Human adult hemoglobin
  • HbF also known as fetal hemoglobin
  • Chromatographic analysis of HbA has shown that it contains a number of minor hemoglobin species. These minor species have been designated HbAla, HbAlb, and HbAlc.
  • glycosylated hemoglobins are referred to as glycosylated hemoglobins or glycohemoglobins, and are formed by condensation of the amino group of the hemoglobin with a keto moiety of a sugar.
  • the sugar is glucose
  • the glycosylated hemoglobin is formed by the condensation of the N-terminal valine amino acid of each ⁇ -chain of hemoglobin with glucose to form an unstable Schiff base or aldimine (also known as pre-Alc), which then undergoes an Amadori rearrangement to form a stable ketoamine.
  • Methods have been developed to distinguish between the stable and labile forms of HbAlc so as to provide more accurate measurements of the stable HbAlc.
  • HbAlc glycosylated hemoglobins
  • the formation of glycosylated hemoglobins is non-enzymatic and occurs over the lifespan of the red cell, which is about 120 days under normal conditions.
  • the amount of HbAlc is proportional to the concentration of glucose in the blood, and is therefore related to time- averaged glucose concentration over the period prior to the measurement, which is approximately two to three months.
  • HbAlc values may be used to assess diabetic control, in which short-term fluctuations in plasma glucose levels do not affect the measurement.
  • the desirable HbAlc level is less than 7%, and less than 6% in a non-diabetic. Under the American Diabetes Clinical Practice Recommendations, additional action is recommended if a patient's HbAlc level exceeds 8%.
  • VHA guidelines recommend measuring HbAlc levels at least once annually.
  • Measurement of glycosylated hemoglobins may augment other traditional methods of assessing control of glucose metabolism. For example, measurement of glycosylated hemoglobins may be used when urine glucose records are inadequate, when blood glucose levels vary markedly throughout the day or from day to day, and for a new patient with known or suspected diabetes in whom there is no previous record of blood glucose concentration. Control of HbAlc levels by the present invention may reduce such AGE-related products.
  • Ion exchange chromatography may be conducted using resins containing weakly acidic cation exchanges or negatively charged carboxymethylcellulose resin.
  • High performance liquid chromatography provides a reliable reference method.
  • Affinity chromatography may be used to separate non-glycosylated hemoglobin from glycosylated hemoglobin.
  • a suitable affinity column is prepared having immobilized m- aminophenylboronic acid. The boronic acid reacts with the cis-diol groups of glucose bound to hemoglobin to form a reversible 5-membered ring complex, thus selectively binding the glycosylated hemoglobin to the affinity column. Sorbitol disassociates glycosylated hemoglobin from the column. For example, glycosylated hemoglobin may be measured by a modification of the method of Clegg and Schroeder.
  • a calorimetric method has been devised based on the observation that HbAlc, when subject to mild acid hydrolysis, releases 5-hydroxymethylfurfural (5-HMF).
  • Another spectrophotometric method involves the reaction of inositol hexaphosphate (phytic acid) with hemoglobin. Absorbance increases at 633 nm and decreases at 560 run. upon phytic acid binding to the N-terminal amino groups of the ⁇ -chains. This change only occurs for Hb A that is unglycosylated, so the change in absorbance induced by phytic acid is thus inversely proportional to the fraction of glycosylated hemoglobin.
  • Antibody directed against HbAlc may be prepared and used as the basis for a radioimmunoassay. Isoelectric focusing has also been used as a method of quantitating HbAlc. In another method, capillary electrophoresis may be used, usually in conjunction with an antibody directed against HbAlc. Kits for measuring glycosylated hemoglobin are known in the art, and contemplated by the present invention.
  • Fasting glucose levels may be measured by finger stick glucometer readings. Samples of apolipoproteins may be analyzed on a protein analyzer using proper standardization techniques. Other indices may be measured by techniques known to those of skill in the art. Animal-based studies may be conducted on different supplements, or components thereof, of the present invention as necessary to determine combinations of the different components that produce the greatest therapeutic effect. For example, in rats the diabetic state may be induced by injecting streptozoticin (STZ) at an appropriate dose, for example 60 mg/kg dissolved in 0.9% NaCl IC via the tail vein upon anaesthetization. The diabetic state may be confirmed at a later time, whereupon assaying of different supplements may begin thereafter.
  • STZ streptozoticin
  • SHR insulin resistant spontaneously hypertensive rats
  • WKY Wistar Kyoto
  • ZDF Zucker diabetic fatty rat
  • ZLC ZLC
  • transgenic mouse models may be useful in the present invention.
  • the db/db mouse a genetically obese and diabetic strain of mouse, may be used in animal studies. The db/db mouse develops hyperglycemia and hyperinsulinemia concomitant with its development of obesity and thus serves as a model of obese Type 2 diabetes.
  • mice may purchased from, for example, the Jackson Laboratories (Bar Harbor, Me.).
  • sub-orbital sinus blood samples may be taken before and at some time after dosing of each animal.
  • Toxicity and therapeutic efficacy of supplements, or components thereof may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it may be expressed as the ratio LD 50 /ED 50 .
  • Compositions that exhibit large therapeutic indices are preferred.
  • supplements that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets the component(s) of any supplement responsible for any toxic effects to the desired site in order to reduce side effects.
  • the data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.
  • the dosage of any supplement, or alternatively of any components therein lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose may be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC 50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • compositions and supplements of the present invention may be administered in various forms, depending on the disorder or condition to be treated and the age, condition and body weight of the patient, as is well known in the art.
  • different components of any subject supplement may be administered by different methods as necessary for effective delivery of the component, or as otherwise necessary for convenience.
  • the formulation may be formulated as tablets, capsules, granules, powders or syrups.
  • formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations, or suppositories.
  • ophthalmic mucous membrane routes For application by the ophthalmic mucous membrane route, they may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the active ingredient may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • any conventional additive such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the supplements.
  • Formulations useful in the methods of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of supplement or components thereof which may be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration.
  • the amount of active ingredient which may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount may range from about 1 per cent to about ninety-nine percent of active ingredient, particularly from about 5 per cent to about 70 per cent, especially from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a supplement or components thereof with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a supplement or components thereof with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a supplement or components thereof as an active ingredient.
  • a supplement or components thereof may also be administered as a bolus, electuary, or paste.
  • solid dosage forms for oral administration capsules, tablets, pills, dragees, powders, granules and the like
  • the supplement or components thereof is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) abso ⁇ tion accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the supplement or components thereof moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • Tablets and other solid dosage forms may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by inco ⁇ orating sterilizing agents in the form of sterile solid compositions which may be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which may be used include polymeric substances and waxes. The active ingredient may also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the supplement or components thereof, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of this invention suitable for parenteral administration comprise one or more components of a supplement in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged abso ⁇ tion of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay abso ⁇ tion such as aluminum monostearate and gelatin.
  • Injectable depot forms are made by forming microencapsule matrices of components of a supplement in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of component release may be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the component in liposomes or microemulsions which are compatible with body tissue.
  • Example One The different supplements of the present invention are presently referred to as
  • GLUCOSTATTM One example of an embodiment of the present invention constitutes a packet containing 4 tablets:
  • Three tablets contain chromium picolinate, vanadyl sulfate hydrate, vitamin E natural, standardized willow bark (aspirin), folic acid, alpha-lipoic acid and a multivitamin/mineral formula; and,
  • each dose of this embodiment in this Example One contains the following (component, and amount): Chromium (as chromium picolinate) 333 meg, 1000 meg; Vanadyl sulfate hydrate, 100 mg; Vitamin E natural (free 2R, 4'R 8'R-alpha-tocopherol), 400 I.U.; Magnesium chloride hexahydrate 384 mg; Folic acid (folate), 400 meg; Vitamin A 5000 I.U.; Vitamin C, 60 mg; Vitamin K 34.00 meg; Thiamine, 3.00 mg; Riboflavin, 3.60 mg;
  • Niacinamide 20.10 mg; Vitamin B-6, 23.10 mg; Vitamin B-12, 48.00 meg; Biotin, 300 meg; Pantothenic acid, 10.00 mg; Calcium, 150 mg; Phosphorus, 115.00 mg; Iodine, 150.00 meg; Zinc, 15.00 mg; Selenium, 60.00 meg; Copper, 2.00 mg; Manganese, 11.00 Mg; Molybdenum, 75.00 meg.
  • This embodiment also contains 160 mg standardized willow bark (aspirin 20 mg), a Chinese herb and a source of aspirin.
  • chromium picolinate was obtained from Nutrition 21 or AMBI Inc.
  • chromium polynicotinate was obtained from InterHealth.
  • the vanadium sulfate hydrate in this Example One was determined to contain about 20%) elemental vanadium by weight, which corresponds to about five to six waters of hydration for every molecule of vanadyl sulfate.
  • Over twenty patients with both Type 1 and Type 2 diabetes using the present embodiment have reported a significant reduction in blood glucose levels, ranging from 30 mg/dl to as much as 115 mg/dl. These reductions have been noted within as little as two weeks from initiating the present system to as long as a seven to twelve week period. Patients have usually noted a 19 to 47% drop in their baseline blood sugars following treatment with this embodiment, with the average response being an approximate 30%> reduction.
  • HbAlc levels have dropped on average a point after 3 months of use with this embodiment, with one patient reporting an 8 point drop from the pre-system HbAlc. Generally, most patients report a 15%> reduction in baseline HbAlc after approximately three months of treatment.
  • the systolic drop in blood pressure has ranged from 20-30 mmHg, with a 10-22 mmHg drop in diastolic measurements. Overall, there has been an 8-12% drop in blood pressure.
  • a group of Type 2 diabetic individuals presenting with elevated HbAlc levels were placed on a program using another embodiment of the present invention.
  • the study was conducted as an open-label study at two different medical centers in the United States. The patients were on the program for three months, and were directed not to change their dietary habits or lifestyle, including exercise patterns. The patients were not taking any other medication for their diabetic condition.
  • Example Two one daily dose of this embodiment contained (component and amount):
  • Vitamin A 5000 IU; Vitamin C (Ascorbic Acid), 60 mg; Vitamin D-3, 400 IU; Vitamin E, 400 IU; Thiamine (as Thiamine Mononitrate), 3 mg; Riboflavin, 3.6 mg; Niacinamide, 20.1 mg; Vitamin B-6 (as Pyridoxine HO), 23.1 mg; Folic Acid, 400 meg; Vitamin B-12, 48 meg; Biotin, 300 meg; Pantothenic Acid (as Calcium Panto thenate), 10 mg; Calcium (from Calcium Carbonate/Phosphate), 150 mg; Phosphorous (from Calcium Phosphate), 115 mg; Iodine (from Sea Kelp), 150 mg; Magnesium (elemental Magnesium from 307 mg Magnesium Complex of citrate/fumuarte/malate/gluturate/succinate/chloride), 46 mg; Zinc, 15 mg; Selenium (from Selenium Krebs), 60 meg; Manganese (from Manganese Sulfate),

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Abstract

On décrit des compositions et des suppléments, des procédés et des programmes d'utilisation de ces derniers qui sont utiles pour traiter et prévenir le diabète, d'autres troubles du métabolisme du glucose ainsi que d'autres troubles ou états. Les compositions selon présente invention peuvent contenir par exemple, une source biodisponible de chrome et une source biodisponible de vanadium.
PCT/US1999/015585 1999-07-08 1999-07-08 Combinaison de chrome et de vanadium pour traiter ou prevenir les troubles du metabolisme du glucose Ceased WO2001003700A1 (fr)

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AU50944/99A AU5094499A (en) 1999-07-08 1999-07-08 Combination of chromium and vanadium for glucose metabolism disorders

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7010455B2 (en) * 2002-01-18 2006-03-07 Intelligence Devices S.R.L. Method and relevant device for revealing objects
WO2006064061A1 (fr) * 2004-12-16 2006-06-22 Genmedica Therapeutics Sl Amines, combinaison d'amines et sels de vanadium et d'amines et de vanadium pour le traitement prophylactique ou thérapeutique de la dyslipidémie
US12059446B1 (en) * 2005-05-20 2024-08-13 4Life Patents, Llc Compositions and methods for supporting metabolic and endocrine system function
CN107088202A (zh) * 2011-03-07 2017-08-25 Cfm医药控股有限公司 用于维持哺乳动物体内血糖量正常的钒化合物的用途
CN107088202B (zh) * 2011-03-07 2021-11-30 Cfm医药控股有限公司 用于维持哺乳动物体内血糖量正常的钒化合物的用途
US11426117B2 (en) 2020-12-29 2022-08-30 Kpn Innovations, Llc. Methods and systems for dietary communications using intelligent systems regarding endocrinal measurements
US12040072B2 (en) 2022-10-28 2024-07-16 Kpn Innovations, Llc. Apparatus and method for generating alimentary data within a geofence

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