US20030060428A1 - Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome - Google Patents

Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome Download PDF

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US20030060428A1
US20030060428A1 US10/210,787 US21078702A US2003060428A1 US 20030060428 A1 US20030060428 A1 US 20030060428A1 US 21078702 A US21078702 A US 21078702A US 2003060428 A1 US2003060428 A1 US 2003060428A1
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mammal
medicament
stevioside
composition
substance
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Kjeld Hermansen
Soren Gregersen
Per Jeppesen
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STEVIA Ltd
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Stevia ApS
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Publication of US20030060428A1 publication Critical patent/US20030060428A1/en
Priority to US10/933,297 priority Critical patent/US20050038126A1/en
Priority to US11/819,659 priority patent/US20080051341A1/en
Priority to US12/187,487 priority patent/US20080318866A1/en
Priority to US13/917,032 priority patent/US9636314B2/en
Assigned to STEVIA APS reassignment STEVIA APS ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GREGERSEN, SOREN, HERMANSEN, KJELD, JEPPESEN, PER BENDIX
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
    • C07C13/62—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with more than three condensed rings
    • C07C13/66—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with more than three condensed rings the condensed ring system contains only four rings
    • C07C13/68—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with more than three condensed rings the condensed ring system contains only four rings with a bridged ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C61/16—Unsaturated compounds
    • C07C61/35—Unsaturated compounds having unsaturation outside the rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/256—Polyterpene radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/86—Ring systems containing bridged rings containing four rings

Definitions

  • the present invention relates to a new medicament for the treatment of non-insulin dependent diabetes mellitus, hypertension, metabolic syndromes and other conditions in mammals.
  • Non-insulin dependent diabetes mellitus comprises about 85% of diabetes most commonly occurring at the age above 40 years. The incidence of non-insulin dependent diabetes mellitus is increasing and is at a global level expected to surpass 200 million subjects at year 2010.
  • Diabetes is associated with increased morbidity and a 2-4-fold increase in mortality primarily due to cardiovascular diseases and strokes.
  • Non-insulin dependent diabetes mellitus develops especially in subjects with insulin resistance and a cluster of cardiovascular risk factors such as obesity, hypertension and dyslipidemia, a syndrome which first recently has been recognized and is named “The metabolic syndrome” (Alberti K. G., Zimmet P. Z.; Definition, diagnosis and classification of diabetes mellitus and its complications”. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. Jul. 15, 1998 (7), p. 539-53).
  • micro albuminuria urine albumin excretion: ⁇ 20 ⁇ g min ⁇ 1 or albumin/creatinine ratio ⁇ 2.0 mg/mmol.
  • control group demonstrated a significant increase in insulin output of about 16 times above the basal release value in the presence of 20 mmol/l D-glucose increase. It is therefore uncertain whether the insulin releasing effect is due to the increased glucose level or the presence of stevioside.
  • No diabetic islet cells were studied and the skilled person within the art will know that the mechanism for stimulating normal pancreatic islet cells either not functions at its optimum or not functions at all in the diabetic pancreatic cells, and that the study provided no certain indication of the possible use of stevioside in the treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome.
  • the produced stevioside tablets were for no apparent reason and medical indication applied to patients in the Wuhan Second Hospital. No data on the influence of stevioside on blood glucose, insulin and/or blood pressure is revealed. It is stated that the tablets were effective to diabetes and hypertension during preliminary clinical observations. However, total lack of data on blood glucose, insulin and/or blood pressure i.e., lack of support by test results and the missing information of which types of diabetes that were treated, makes this an unsupported and unconfirmed assertion.
  • Glucagon a pancreatic islet hormone, acts as a diabetogenic hormone by increasing the hepatic glucose output thereby elevating blood glucose.
  • the present invention relates to a selectively responsive composition
  • a selectively responsive composition comprising at least one substance including a bicyclo [3.2.1] octan in a double ring system having a basic chemical skeletal of a kaurene structure having the structural formula II:
  • the substance responds only at an elevated plasma glucose concentrations.
  • the response of the substance is initiated by a plasma glucose concentration of 6 mmol/l or larger.
  • the substance is selected from the group consisting of steviol, isosteviol, glucosilsteviol, gymnemic acid, steviolbioside, stevioside Rebaudioside A, Rebaudioside B, Rebaudioside C, Rebaudioside D, Rebaudioside E and Dulcoside A, their pharmaceutically acceptable analogues or their pharmaceutically acceptable derivates.
  • the substance can be isolated from a plant source and can be used alone or in combination with at least one soy protein alone or in combination with at least one isoflavone.
  • the substance and composition can be used as a dietary supplement or as a medicament for a mammal.
  • the substance or composition is responsive in the mammal only when the mammal's plasma glucose concentrations are elevated.
  • the medicament can be used for treating the mammal for non-insulin dependent diabetes mellitus, metabolic syndrome, to stimulate insulin production, to reduce glucagon concentrations, to suppress fasting plasma triglycerides or total cholesterol levels in the mammal, or for treating hypertension in the mammal.
  • the medicament is an oral medicament and is self-regulating.
  • the invention also relates to a method of making a selectively responsive composition which comprises associating with a carrier a bicyclo [3.2.1] octan in a double ring system having a basic chemical skeletal of a kaurene structure having the structural formula II, wherein the substance responds only at an elevated plasma glucose concentrations.
  • the composition that is made can be used as a dietary supplement or as one of the medicaments mentioned above.
  • the invention also relates to various treatment methods for mammals, including treating non-insulin dependent diabetes mellitus, treating metabolic syndrome, treating hypertension, suppressing fasting plasma triglycerides, suppressing total cholesterol level, or suppressing appetite.
  • FIG. 1 shows the chemical structure of steviol, isosteviol and stevioside
  • FIG. 2 a shows the effect of stevioside on blood glucose during i.v. glucose tolerance test in normal Wistar rats
  • FIG. 2 b shows the effect of stevioside on blood glucose during i.v. glucose tolerance test in GK rats
  • FIG. 3 a shows the effect of stevioside on glucose-induced release during i.v. glucose tolerance test in normal Wistar rats
  • FIG. 3 b shows the effect of stevioside on glucose-induced release during i.v. glucose tolerance test in GK rats
  • FIG. 4 a shows the effect of stevioside on glucose-stimulated insulin secretion from isolated mouse islets
  • FIG. 4 b shows the effect of steviol on glucose-stimulated insulin secretion from isolated mouse islets
  • FIG. 5 a shows the effect of an i.v. bolus injection of glucose on plasma glucagon levels during an intravenous glucose tolerance test in GK rats
  • FIG. 5 b shows the effect of an i.v. bolus injection of glucose and stevioside on plasma glucagon levels during a glucose tolerance test in GK rats
  • FIG. 6 a shows the systolic blood pressure during 6 weeks treatment of GK rats with stevioside
  • FIG. 6 b shows the diastolic blood pressure in GK rats treated with stevioside.
  • FIG. 7 a shows the effect of 10 ⁇ 3 mmol/l stevioside on the insulin secretion from isolated mouse islets in the presence of glucose ranging between 0 and 16,7 mmol/l,
  • FIG. 7 b shows the effect of 10 ⁇ 6 mmol/l steviol on the insulin secretion from isolated mouse islets in the presence of glucose ranging between 0 and 16,7 mmol/l
  • FIGS. 8 a - d shows the acute effects of stevioside in type II diabetic patients
  • FIGS. 9 a - g shows the effects of the action of the combination of stevioside and soy based dietary supplementation in diabetic GK-rats.
  • This bicyclo [3.2.1] octan can be found in e.g. steviol, isosteviol and in stevioside.
  • the formula I structure has also been recognised in glucosilsteviol, gymnemic acid, steviolbioside, Rebaudioside A, Rebaudioside B, Rebaudioside C, Rebaudioside D, Rebaudioside E and Dulcoside A.
  • the substances comprising the chemical structures, which includes the formula I or II, did not cause an insulin release as long as the plasma glucose concentration was below approximately 6 mmol/l.
  • the stimulating effect of the compounds provided an elevated plasma insulin concentration resulting in an immediate suppression of plasma glucose concentration thereby keeping this at a normal level.
  • the present inventors have surprisingly found that the substances comprising the chemical structures including the formula I or II also have the capabilities of reducing the glucagon concentration in the blood.
  • NIDDM non-insulin dependent diabetes mellitus
  • stevioside infusion at normal blood glucose did not cause any hypoglycemia irrespective of it being given as a bolus or at a constant intravenous infusion.
  • the substances provide a self-regulatory system responding only at elevated plasma glucose concentration.
  • the substances are preferably used in medicaments for oral medication.
  • the glycosylated substances can be partially metabolised but the basic skeletal structure of the formula I or II will not be changed and the different characteristic effects mentioned above will be preserved.
  • the treatment with a medicament including these substances provides an attractive alternative to different types of drugs available and presently used today for the treatment of NIDDM, such drugs being drugs for stimulating the insulin secretion (sulphonylureas or repaglinide), drugs for improving the insulin sensivity (biguanides and thiazolidinediones) or drugs for retarding gastrointestinal carbohydrate absorption ( ⁇ -glucosidase inhibitors).
  • drugs for stimulating the insulin secretion sulphonylureas or repaglinide
  • drugs for improving the insulin sensivity biguanides and thiazolidinediones
  • drugs for retarding gastrointestinal carbohydrate absorption ⁇ -glucosidase inhibitors
  • the substances further bring along the blood pressure reducing effect.
  • stevioside acutely suppresses blood pressure in diabetic rat. This important discovery is of the benefit to the diabetic patients that have developed hypertension in relation to or besides their disease.
  • a medicament also comprising at least one soy protein alone or in combination with at least one isoflavone
  • a combined preparation of a drug for the treatment of patients with the metabolic syndrome in accordance with the previously definition.
  • Such a medicament may advantageously be used in prophylactic treatment of patient in a risk group.
  • a slow-release drug on the basis composition mentioned above provides a convenient treatment for the patient with the metabolic syndrome.
  • the inventors of the present invention have demonstrated that the combination of the substances according to the invention and at least one soy protein have a new unexpected and surprisingly synergistic effect surpassing the additive effect of the single components of the medicament thereby providing a completely new and very important medicament for therapeutic or prophylactic treatment of the metabolic syndrome.
  • the present inventors have used the combination of the substances according to the invention and at least one soy protein as a dietary supplementation in human studies.
  • the test results significantly proved, as will be seen in the following examples, that such combination has a beneficial impact on cardiovascular risk markers in type II diabetic subjects.
  • Stevioside at a dose as high as 15 g/kg body weight was not lethal to either mice, rats or hamsters (Toskulkao C., Chaturat L., Temcharoen P., Glinsukon T. “Acute toxicity of stevioside, a natural sweetener, and its metabolite, steviol, in several animal species”. Drug Chem. Toxicol. Febuary 1997, May;20(1-2), p. 31-44). In rats and mice, LD 50 values of steviol were higher than 15 g/kg body weight while the LD 50 for hamsters were 5-6 g/kg body weight.
  • Stevioside is excreted by the urine (Melis M.S. “Renal excretion of stevioside in rats”. J. Nat. Prod. May 1992; 55(5), p. 688-90) and is not metabolised in the isolated perfused rat liver (Ishii-Iwamoto E. L., Bracht A. “Stevioside is not metabolised in the isolated perfused rat liver”. Res. Commun. Mol. Pathol. Pharmacol. Febuary 1995;87(2), p. 167-75).
  • Stevioside is not carcinogenic in F344 rats (Toyoda K., Matsui H., Shoda T., Uneyama C., Takada K., Takahashi M. “Assessment of the carcinogenicity of stevioside in F344 rats”. Food Chem. Toxicol. June 1997;35(6), p. 597-603). Doses as high as 2.5 g/kg body weight/day had no effect on growth or reproduction in hamsters (Yodyingyuad V., Bunyawong S. “Effect of stevioside on growth and reproduction”. Hum. Reprod. January 1991;6(l), p. 158-165).
  • GK type II diabetic Goto-Kakizaki
  • the rats had a weight of 300-350 g and the mice a weight of 22-25 g.
  • the animals were kept on a standard pellet diet and tap water ad libitum.
  • the stevioside is obtained from the Japanese company WAKO-TriCHEM.
  • the abbreviation IAUC means Incremental Area Under the Curve (above basal).
  • stevioside was tested on normal Wistar rats and on GK rats. 2.0 g glucose/kg body weight and 0.2 g stevioside/kg body weight were dissolved in 0.9% saline and infused intravenously. The plasma glucose and insulin levels were measured over a period of 2 hours.
  • Islet from 6-10 NMRI mice were isolated and incubated in the presence of 16.7 mmol/l and 10 ⁇ 9 -10 ⁇ 3 mol/l stevioside or 10 ⁇ 9 -10 ⁇ 3 mol/l steviol.
  • FIGS. 4 a and 4 b The results of these tests are illustrated in FIGS. 4 a and 4 b where each column represents mean ⁇ SEM from 24 incubations of single islets. Black bars in FIG. 4 a indicate that stevioside is present and hatched bars indicate that stevioside is absent.
  • Black bars in FIG. 4 b indicate that steviol is present and hatched bars indicate that steviol is absent.
  • GK rats were treated with stevioside 0.025 g/kg body weight/24 h for 6 weeks. Stevioside was administered in the drinking water. GK rats receiving drinking water with 0.111 g D-glucose/kg body weight/24 h served as controls.
  • the experiment was an acute, paired, cross-over study in which two test meals were served during the experiments (A: Standard meal supplemented with 1 g of stevioside given orally; B: Standard meal given together with 1 g of gelatine (placebo) given orally.
  • the total energy content of the test meals was 1725 kJ ( protein 16 E%, fat 30 E%, carbohydrate 54 E% ).
  • Stevioside reduced the postprandial blood glucose response by 18 ⁇ 5% (p ⁇ 0.004) compared to placebo (absolute IAUC 638 ⁇ 55 vs. 522 ⁇ 64 mmol/l ⁇ 240 min; p ⁇ 0.02) as seen in FIG. 8 a.
  • GLP-1 postprandial glucagon like peptide-1
  • the group receiving soy+stevioside has reduced incremental area under the insulin response curve compared to the Altromin+stevioside group (Alt+Ste) as seen in FIG. 9 and in Table I below. Considering the concomitant blood glucose responses this indicates that soy increases the insulin sensitivity. Stevioside did not alter the insulin responses in the Altromin and soy diets when studying the total response curve from 0 to 240 minutes. However, in both groups supplementation of the diets with stevioside significantly improved the first phase insulin responses—which is subdued as a characteristic feature of type II diabetes. The combination of soy+stevioside synergistically improved the first phase insulin response (p ⁇ 0.05) (FIG. 9 b ).
  • Stevioside causes a significant suppression of the fasting triglyceride levels in combination with either Altromin (p ⁇ 0.05) or soy (p ⁇ 0.02) (Table I). Soy significantly reduced the fasting triglyceride levels with or without supplementation of stevioside (p ⁇ 0.05 and p ⁇ 0.002, respectively) (Table I). Stevioside given in combination with soy synergistically reduced the fasting total cholesterol levels compared to diets containing Altromin alone (p ⁇ 0.0001). Soy alone also reduced the total cholesterol levels compared to Altromin alone (p ⁇ 0.002) (FIG. 9 f. and FIG. 9 g ) (Table I).
  • Stevioside exerts beneficial effects in type II diabetes i.e. reduces blood glucose, suppresses glucagon and improve first phase insulin secretion.
  • the results also indicates that soy improves insulin sensitivity, a characteristic feature of the metabolic syndrome.
  • Stevioside exerts a pronounced blood pressure reduction both with as well as without the presence of soy.
  • the combination of stevioside and soy has a synergistic suppressive effect on blood glucose levels, enhances first phase insulin secretion, suppresses fasting plasma triglycerides and total cholesterol and the combination of soy and stevioside seems to prevent weight gain.
  • Table I Areas under the p-glucose, -insulin and -glucagon response curves during the glucose tolerance test in the four experimental groups. Change in systolic blood pressure at start and at end of the study period. Fasting plasma- triglyceride and -total cholesterol concentrations by the end of the study.

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US10/210,787 2000-02-01 2002-07-31 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome Abandoned US20030060428A1 (en)

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US10/933,297 US20050038126A1 (en) 2000-02-01 2004-09-03 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome
US11/819,659 US20080051341A1 (en) 2000-02-01 2007-06-28 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome
US12/187,487 US20080318866A1 (en) 2000-02-01 2008-08-07 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome
US13/917,032 US9636314B2 (en) 2000-02-01 2013-06-13 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome

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DKPA200000163 2000-02-01
DKPA200000163 2000-02-01
PCT/DK2001/000075 WO2001056959A1 (en) 2000-02-01 2001-02-01 A substance for the use in a dietary supplementation or for the preparation of a medicament for the treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome

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US10/933,297 Abandoned US20050038126A1 (en) 2000-02-01 2004-09-03 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or the metabolic syndrome
US11/819,659 Abandoned US20080051341A1 (en) 2000-02-01 2007-06-28 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome
US12/187,487 Abandoned US20080318866A1 (en) 2000-02-01 2008-08-07 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome
US13/917,032 Expired - Fee Related US9636314B2 (en) 2000-02-01 2013-06-13 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome

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US11/819,659 Abandoned US20080051341A1 (en) 2000-02-01 2007-06-28 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome
US12/187,487 Abandoned US20080318866A1 (en) 2000-02-01 2008-08-07 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome
US13/917,032 Expired - Fee Related US9636314B2 (en) 2000-02-01 2013-06-13 Medicament for treatment of non-insulin dependent diabetes mellitus, hypertension and/or metabolic syndrome

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EP (2) EP1255718A1 (ja)
JP (2) JP2003521528A (ja)
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AU (1) AU784422B2 (ja)
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US8017168B2 (en) 2006-11-02 2011-09-13 The Coca-Cola Company High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith
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US11219663B2 (en) 2015-07-27 2022-01-11 Suntory Holdings Limited Composition containing cyclic dipeptide and sweetening agent
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US20060148754A1 (en) * 2003-06-30 2006-07-06 Etienne Pouteau Composition for treating and/or preventing dysfunctions associated with type 2 diabetes mellitus and insulin resistance
WO2006086817A1 (de) * 2005-02-21 2006-08-24 Emakos - Naturnahe Nahrungsmitteltechnologien Gmbh Verfahren zum modifizieren eines organischen naturstoffes durch austauschreaktionen
US20080108710A1 (en) * 2005-11-23 2008-05-08 The Coca-Cola Company High-Potency Sweetener Composition With Preservative and Compositions Sweetened Therewith
US9101160B2 (en) 2005-11-23 2015-08-11 The Coca-Cola Company Condiments with high-potency sweetener
US20130216625A1 (en) * 2006-09-15 2013-08-22 Stevia Aps Treatment of insulin resistance or diseases associated with insulin resistance
US20100093861A1 (en) * 2006-09-15 2010-04-15 Stevia Aps Treatment of insulin resistance or diseases associated with insulin resistance
US8017168B2 (en) 2006-11-02 2011-09-13 The Coca-Cola Company High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith
US20120021088A1 (en) * 2009-07-21 2012-01-26 Regina Goralczyk Oral use
US9393190B2 (en) * 2009-07-21 2016-07-19 Dsm Ip Assets B.V. Methods for enhancing skin tan and reducing risks of UV skin damage
US20110189360A1 (en) * 2010-02-04 2011-08-04 Pepsico, Inc. Method to Increase Solubility Limit of Rebaudioside D in an Aqueous Solution
US11382911B2 (en) 2013-06-10 2022-07-12 Suntory Holdings Limited Plant extract containing diketopiperazine and method for producing same
US11219663B2 (en) 2015-07-27 2022-01-11 Suntory Holdings Limited Composition containing cyclic dipeptide and sweetening agent
WO2018075874A1 (en) * 2016-10-20 2018-04-26 The Coca-Cola Company Diterpene glycosides isolated from stevia, compositions and methods

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EP2330092A2 (en) 2011-06-08
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US20080318866A1 (en) 2008-12-25
US20080051341A1 (en) 2008-02-28
EP2330092A3 (en) 2012-07-25
US20140094408A1 (en) 2014-04-03
WO2001056959A1 (en) 2001-08-09
CN1416411A (zh) 2003-05-07
EP1255718A1 (en) 2002-11-13
CN100475757C (zh) 2009-04-08
AU784422B2 (en) 2006-03-30
US20050038126A1 (en) 2005-02-17
CA2762121A1 (en) 2001-08-09
AU3002801A (en) 2001-08-14
BR0108043A (pt) 2003-04-01
CA2398445A1 (en) 2001-08-09
JP2003521528A (ja) 2003-07-15
JP2012153721A (ja) 2012-08-16
WO2001056959B1 (en) 2002-02-07

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