WO1993012793A1 - Procede therapeutique de traitement de pathologies du diabete de type ii - Google Patents

Procede therapeutique de traitement de pathologies du diabete de type ii Download PDF

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Publication number
WO1993012793A1
WO1993012793A1 PCT/US1992/011166 US9211166W WO9312793A1 WO 1993012793 A1 WO1993012793 A1 WO 1993012793A1 US 9211166 W US9211166 W US 9211166W WO 9312793 A1 WO9312793 A1 WO 9312793A1
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Prior art keywords
insulin
subject
dopamine agonist
prolactin
daily
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PCT/US1992/011166
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English (en)
Inventor
Anthony H. Cincotta
Albert H. Meier
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The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College
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Publication date
Application filed by The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College filed Critical The Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College
Priority to CZ941554A priority Critical patent/CZ282909B6/cs
Priority to RU94037557A priority patent/RU2104698C1/ru
Publication of WO1993012793A1 publication Critical patent/WO1993012793A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Diabetics as group, are far more often afflicted with blindness, heart disease, stroke, kidney diseas hearing loss, gangrene and impotence.
  • One third of all visits to physicians are occasione by this disease and its complications are a leading cause of death in this country.
  • Diabetes adversely affects the way the body uses sugars and starches which during digestion, are converted into glucose.
  • Insulin a hormone produced by the pancreas makes the glucose available to the body's cells for energy.
  • adipose (fat) an connective tissues, insulin facilitates the entry of glucose into the cells by an action on th cell membranes.
  • the injected glucose is normally metabolized in the liver to CO 2 and H 2 (50%); to glycogen (5 %), and to fate (30-40%), which is stored in fat depots.
  • Fatty acid are circulated, returned to the liver and metabolized to ketone bodies for utilization by th tissues.
  • the fatty acids are also metabolized by other organs, fat formation being a majo pathway for carbohydrate utilization.
  • the net effect of insulin is to promote the storage an use of carbohydrates, protein and fat. Insulin deficiency is a common and serious pathologi condition in man. In Type I diabetes the pancreas produces little or no insulin, and insuli must be injected daily for the survival of the diabetic. In Type II diabetes the pancrea produces insulin, but the amount of insulin is insufficient, or less than fully effective due t cellular resistance, or both. In either form there are widespread abnormalities, but th fundamental defects to which the abnormalities can be traced are (1) a reduced entry o glucose into various "peripheral" tissues and (2) an increased liberation of glucose into th circulation from the liver (increased hepatic glucogenesis).
  • Insulin resistance ca be defined as a state in which a normal amount of insulin produces a subnormal biologi response. In insulin-treated patients with diabetes, insulin resistance is considered to b present whenever the therapeutic dose of insulin exceeds the secretory rate of insulin in normal persons. Insulin resistance is also found in the setting defined by higher-than-normal levels of insulin — i.e., hyperinsulinemia — when there is present normal or elevated levels of blood glucose. Despite decades of research on these serious health problems, the etiology of obesity and insulin resistance is unknown.
  • Daily rhythms have been reported for many hormones inclusive of the adrenal steroids, e.g., the glucocorticosteroids, notably cortisol, and prolactin, a hormone secreted by the pituitary.
  • the glucocorticosteroids notably cortisol
  • prolactin a hormone secreted by the pituitary.
  • the early article, discussing the state- of-the-art at that time it is reported that "Although correlations have been made between hormone rhythms and other rhythms, there is little direct evidence that the time of the daily presence or peak level of hormones has important physiological relevance.” See Temporal Synergism of Prolactin and Adrenal Steroids by Albert H. Meier, General and Comparative
  • the circadian variations of cortisol were similar irrespective of sex, seasonal condition and daylight.
  • the circadian variation of insulin in contrast, differed markedly. Neither the daily feeding pattern or glucose concentration varied appreciably with seasonal condition, or daylight. The time of day, or the season, it is reported do not appear to affect the concentrations in glucose or cortisol levels. It is postulated that the daily rhythms of cortisol and insulin are regulated by different neural pacemaker systems, and that changes in the phase relations of circadian systems account in part for seasonal changes in body fat stores.
  • Insulin is a hormone with a multitude of biological activities, many of whic are tissue specific. For example, insulin can augment milk production in the mammar gland, stimulate fat synthesis in the liver, promote the transport of glucose into muscle tissue stimulate growth of connective tissues, and the like. The effects of the insulin molecule i one tissue are not necessarily dependent upon its effect in other tissues. That is, these insuli activities can be and are molecularly separate from each other. In contradistinction from th previous art of Meier and Cincotta which teaches that dopamine agonists (e.g.
  • bromocriptin inhibit liver cell lipogenic ( or fat synthesizing) responsiveness to insulin
  • the new technolog described and demonstrated herein teaches that appropriately timed daily administration o a dopamine agonist (e.g., bromocriptine) has another new and distinctly unique beneficial medicinal capability which is to stimulate whole body (primarily muscle) tissue hypoglycemic (or glucose disposal) responsiveness to insulin.
  • dopamine agonists e.g., bromocriptine
  • This new discovery of this new medical utility of dopamine agonists represents an entirely opposite effect, upon an entirely different biological activity of the insulin molecule, and upon an entirely different tissue of the body from the previous dopamine agonist work of Meier and Cincotta.
  • a more specific object is to provide a process for resetting the circadian neural centers of animals, including humans, to decrease obesity and maintain the more normal body fat stores of a lean animal, or lean human, on a long term basis.
  • a further, and equally specific object is to provide a process for resetting on a long term basis the circadian neural centers, particularly in humans, to increase and
  • SUBSTITUTE SHEET improve the sensitivity and responsiveness of the cells to insulin, and suppres hyperinsulinemia and hyperglycemia, or both.
  • phase relationship of the prolactin oscillation, and preferably both neural oscillations are modified and reset such that, on cessation of the daily dosages of the dopamine agonist, or prolactin inhibitor, the lipi metabolism of the animal, or human, continues over a long term period (at least one month), if not permanently, at the altered metabolic setpoint, or setpoints.
  • a dopamine agonist, or prolactin inhibiting compound is administered to the vertebrate, animal or human, preferably orally, sublingually or by subcutaneous or intramuscular injection into the bloodstream.
  • a prolactin-inhibiting compound preferably an ergot-related prolactin-inhibiting compound, is administered to a subject exhibiting any one or more of the symptoms desirable of change, e.g., obesity, insulin resistance, hyperinsulinemia or hyperglycemia.
  • prolactin-inhibiting, ergot related compounds are 2-bromo-alpha-ergocryptine; 6-methyl-8beta-carbobenzyloxy- aminomethyl-lOalpha-ergoline; 1 ,6-dimethyl-8beta carbobenzyloxy-aminomethyl-lOalpha- ergoline; 8-acylaminoergolenes, such as 6-methyl-8alpha-(N-acyl)amino-9-ergolene and 6- methyl-8alpha-(N-phenylacetyl)amino-9-ergolene; ergocomine; 9, 10-dihydroergocomine; and D-2-halo-6-alkyl-8-substituted ergolines, e.g., D-2-bromo-6-methyl-8-cyanomethylergoline.
  • the non-toxic salts of the prolactin-inhibiting ergot-related compounds formed from pharmaceutically acceptable acids are also useful in the practice of this invention
  • the stores of body fat can b depleted or increased, the treatments continued until the stores of body fat are stabilized an optimum or near-optimum level dependent on the level of body fat stores desired in th subject, for time sufficient that on termination of the treatment the prolactin rhythm, an preferably both the prolactin and glucocorticosteroid rhythms, is reset to maintain on a lon term basis the reduced, or increased, body weight stores.
  • the objective is almos invariably to reduce body fat stores, and obesity. It has been established that a relationshi exists between obesity and insulin resistance, and that obesity can lead to increased insuli resistance.
  • the glucocorticosteroids e.g., cortisol
  • cortisol will peak during a 24 hour period at a given hour (generally at a time different from that of prolactin); in a human generally several hours after waking.
  • the phase relations of the cortisol and prolactin rhythms differ in lean and fat animals.
  • the peak period of prolactin and glucocorticosteroid production, respectively, may differ to some extent between male and females of any given species.
  • dosages of the dopamine agonist, orprolact are given once a day on a daily basis, generally over a period ranging from about 10 da to about 150 days, at levels ranging from about 3 micrograms to about 100 micrograms, p pound of body weight, to reset the circadian plasma prolactin rhythm.
  • the dopamine agonist, or prolactin inhibitor is given daily, preferably at dosage leve ranging from about 3 micrograms to about 40 micrograms, more preferably from micrograms to about 20 micrograms, per pound of body weight.
  • Such treatments over period of about 10 days to about 150 days, preferably about 30 days to about 120 days, mo preferably from about 30 days to about 90 days, most preferably about 30 days to about 6 days, given an obese person daily just a short period after — generally about 1 hour to abo 8 hours thereafter, preferably from about 4 hours to about 8 hours thereafter ⁇ the prolacti concentration peaks in a lean person will modify and reset the lipid metabolism of the obes person to that of a lean person.
  • Body fat deposits inclusive of adipose, arterial wall and plasma fat, within the obese person will be reduced levelled out and maintained after the treatments are discontinued at that of a lean person, ove an extended period of time.
  • hyperinsulinemia and/or hyperglycemia or both insulin resistance and hyperinsulinemia and/or hyperglycemia, treated with the dopamine agonist, or prolactin inhibitor, will become more sensitive to Insulin (i.e., will have a lower insulin resistance), and the effects of hyperinsulinemia and/or hyperglycemia will be reduced on a long term basis.
  • the injections of the dopamine agonist, or prolactin inhibitor will thus reset the phase relations of the two neural oscillations and their multiple circadian expressions to alter metabolism on a long term basis, if not permanently.
  • prolactin and glucocorticosteroid levels can be defined as that body weight over 20 percent above the ideal body weight for a given population.
  • the time of day when the prolactin and glucocorticosteroid levels, respectively, will peak in the blood of humans during a day differs between obese subjects and lean subjects, and the peak in each type of subject can be readily determined by measurement of the fat and lean specimens, as defined.
  • body weight patterns correlated with the prolactin and glucocorticosteroids levels, respectively, in the plasma of the lean and obese members, respectively.
  • the levels differ between members of the different species, but among members of the same species there is close correlation between the prolactin and glucocorticosterone levels, respectively, at certain time of the day dependent on the obesity or leanness of a given specimen.
  • LD refers to the light/dark cycle
  • the first number following the expression LD refers to the hours of light
  • LD 14:10 refers to a cycle having 14 hours of light and 10 hours of darkness
  • SUE3STITUTE SHEET and the period of a day is expressed in terms of 2400 hours.
  • the letter n refers to th number of animals in a group, "BW” designates body weight, g represents grams and " ⁇ g is an expression of micrograms.
  • Backfat thickness was used as an index in deterrnining fat stores.
  • Plasma was sampled at 1600, 2000 and 2400 after two weeks of treatment. Each pig of the treatment group and control group was sampled.
  • Iipogenesis is normally greatest in pigs, bromocriptine reduced plasma triglyceride concentration by 48%. Since lipid is produced in the liver and transported in the blood to
  • bromocriptine has an inhibitory effect on fat synthesis and deposition.
  • the reduction i plasma insulin concentration was not statistically significant, bromocriptine reduced plasm glucose levels by 13 % during the early period of darkness (2000-2400).
  • the reduction i blood glucose, without an increase in blood insulin concentration, can be explained as decrease in insulin resistance (greater hypoglycemic responsiveness to insulin).
  • blood glucose concentration was shown by routine testing to be near 250 mg/dl.
  • the patient's glucose levels fell to 180 mg/dl, to 155 mg/dl, to 135 mg/dl, to 97 mg/dl and to 101 mg/dl. Fasting levels below 120 mg/dl are considered normal. Body weight and indices of body fat were also reduced about 12% by the treatment.
  • hypoglycemic agent diabenase
  • hypoglycemic agent sodium bicarbonate
  • hypoglycemic agent sodium bicarbonate
  • the blood glucose level fell dramatically to 80 mg/dl in 2 weeks.
  • Removal of the hypoglycemic agent allowed glucose levels to rise and remain near 100 mg/dl (a normal level) in the succeeding two months. Body weight and fat were reduced about 10% by the bromocriptine treatment.
  • Example 5 Fifteen persons, diagnosed with noninsulin dependent (Type D) diabetes, were treated with bromocriptine to determine the effects of the treatments on body fat and hyperglycemia. Seven diabetics (2 males and 5 females) were being treated orally with stimulants for endogenous insulin secretion (hypoglycemic drugs: diabenase and micronase) and seven diabetics (2 males and 5 females) were receiving daily injections (morning and evening administrations) of insulin. Only those who were found to be very hyperglycemic (i.e., fasting plasma glucose > 160 mg/dl) in the morning after a night of fasting and before insulin injection or taking other medications were accepted for the study. One obese man with severe hyperglycemia who refused conventional treatment for diabetes was permitted to participate in this bromocriptine study and is included with the group receiving hypoglycemic drugs.
  • hypoglycemic drugs i.e., fasting plasma glucose > 160 mg/dl
  • Bromocriptine was taken orally daily at times calculated to reset circadian hormone rhythms to phase relationships that cause loss of body fat. Generally, bromocriptine was administered in the morning within 5 hours after awakening. Nausea was usually avoided by starting with the lower dosage (1.25 mg) for 2-3 days and then raising the dosage levels to 2.5 mg daily. Only mild nausea was observed by less that 10% of the participants
  • SUBSTITUTE SHEET was transient, lasting only for the first few days. The participants were carefully instructed not to alter their daily activity or eating habits during the course of treatment. Patient compliance was excellent as indicated by weekly interviews of subjects who monitored their food intake, and the transient anorexic effects sometimes produced by higher doses of bromocriptine did not occur in this study.
  • Skinfold thickness was measured on the left side of the body by a trained anthropometrist in four regions: biceps, triceps, subscapular, and suprailiac, following the recommendations of the International Biological Program. Because of its frequent use, percent body fat was estimated from the common logarithm of the sum of the four skinfolds, using the equations of Durnin and Rahman and of Siri. A recent study indicates very similar estimations of body fat by hydrodensitometry and skinfold thickness measurement methods. Skinfold measurements were taken initially and at weekly intervals by the same individual. Blood pressure was also determined at these times. Morning fasting plasma glucose in the diabetic group was determined initially and after 4-8 weeks. Reference is made to the Table below.
  • SUBSTITUTE SHEET 1 Every individual in the groups taking hypoglycemic drugs (8 subjects) or insulin (7 subjects) lost plasma glucose, skinfold thickness and total body fat. The losses are signigicant (p ⁇ 0.05).
  • hypoglycemic medication was completely discontinued during bromocriptine treatment in three individuals and blood glucose levels remained near normal ( ⁇ 1 20 mg/dl) for at least two months after bromocriptine treatment was terminated.
  • Doses of hypoglycemic drugs and insulin were reduced in three other subjects during bromocriptine treatment.
  • Body fat stores were substantially reduced by timed bromocriptine treatment in NIDDM subjects taking hyperglycemic drugs as evidenced by a mean reduction of 21 % in the skinfold measurements at the four regions examined. This reduction amounts to a mean loss of 10 pounds for each individual and a decline in total body fat of 10.7% within 4 to 8 weeks.
  • the reductions in skinfold (16%), body fat (3.1 pounds) and % body fat (5.1) were less in those subjects taking insulin.
  • Body weights were perhaps shghtly reduced (2.4 pounds per subject, not statistically significant) in subjects taking hypoglycemic drugs and not at all reduced in those taking insulin.
  • bromocriptine treatment can dramatically reduce body fat stores in human subjects.
  • Bromocriptine treatment also substantially reduced hyperglycemia within two months in noninsulin dependent (Type H) diabetics. These results were achieved without changing individual existing diets and exercise regimens.
  • the reduction of body fat produced by bromocriptine treatment differs in a significant way from reduction of fat achieved by caloric restriction. With very low calorie diets only about 45 % of the weight loss is lipid: the remainder includes protein, carbohydrate and water.
  • the data show that metabolic states are regulated at least in part by an interaction of circadian neuroendocrine rhythms. This hypothesis proposes that the daily rhythms of cortisol and prolactin are individual expressions of two separate circadian systems and that the daily injections of these hormones can reset the phase relations of these two systems.
  • the 0-hour relation resets the circadian oscillations into a pattern that maintains the lean, insulin sensitive state and the 12- hour relation permits retention of a pattern that maintains the obese, insulin resistant state.
  • Another important addition of the present study is that the effects of timed injections of a dopamine agonist, or prolactin inhibiting compound, are long lasting.
  • the phase relation of the two circadian oscillations tends to maintain its altered pattern. Changes in the phase relations of two circadian neuroendocrine oscillations are evidenced by changes in the phase relations of their circadian expressions. This expectation is fulfilled respecting plasma glucocorticosteroid and prolactin rhythms. In several species examined, the phase relations of the two hormone rhythms differ in lean and fat animals.
  • phase relation between the circadian rhythm of plasma insulin concentration and the rhythm of lipogenic responsiveness to insulin is shown to differ in lean
  • phase relations of both prolactin and insulin rhythms as well as th rhythms of tissue responses to the hormones are important elements in the regulation o lipogenesis. All of these rhythms, then, would be phase adjusted to regulate lipogenesis. Phase adjustment of these and perhaps other rhythms may also account for insulin resistance. It is apparent that various modifications and changes can be made without departing the spirit and scope of this invention.

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  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

Procédé de modification et de régulation à long terme du métabolisme des lipides et des glucides - afin de réduire l'obésité, l'insulinorésistance ainsi que l'hyperinsulinémie et l'hyperglycémie, ou les deux (lesquelles constituent les marques du diabète non insulinodépendant ou de type II) - consistant à administrer (c'est-à-dire, par voie orale, sublinguale ou parentérale) à un vertébré, animal ou homme, un agoniste de dopamine, par exemple, la bromocriptine. L'administration de la bromocriptine a lieu pendant une durée limitée à un moment du jour dépendant du rythme circadien normal de membres insulinorésistants et insulinosensibles d'une espèce similaire. On peut maîtriser l'insulinorésistance, ainsi que l'hyperinsulinémie et l'hyperglycémie, ou les deux, chez l'homme, à long terme et au moyen dudit traitement puisque l'administration quotidienne à court terme réétablit le rythme hormonal dans les centres nerveux du cerveau afin de produire des effets à long terme.
PCT/US1992/011166 1991-12-23 1992-12-22 Procede therapeutique de traitement de pathologies du diabete de type ii WO1993012793A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CZ941554A CZ282909B6 (cs) 1991-12-23 1992-12-22 Použití agonisty dopaminu a stimulátoru prolaktinu pro přípravu farmaceutického přípravku a tento farmaceutický přípravek
RU94037557A RU2104698C1 (ru) 1991-12-23 1992-12-22 Способ лечения патологических отклонений при диабете типа ii

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US81313591A 1991-12-23 1991-12-23
US813,135 1991-12-23

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0735863A1 (fr) * 1993-12-22 1996-10-09 Ergo Science Incorporated Composition a liberation acceleree contenant de la bromocryptine
US5585347A (en) * 1988-05-10 1996-12-17 Ergo Science Incorporated Methods for the determination and adjustment of prolactin daily rhythms
EP0808164A1 (fr) * 1994-01-07 1997-11-26 Ergo Science Incorporated Procede de traitement de l'obesite comprenant l'administration de modulateurs de prolactine et l'application d'un regime
EP1776955A1 (fr) * 1996-05-07 2007-04-25 Pliva D.D. Therapie de troubles du metabolisme des lipides et du glucose et composition afferente
WO2008150480A1 (fr) 2007-05-29 2008-12-11 Veroscience, Llc Traitement thérapeutique du syndrome métabolique, du diabète de type 2, de l'obésité ou du prédiabète
JP2009046504A (ja) * 1994-07-07 2009-03-05 General Hospital Corp Dba Massachusetts General Hospital 免疫機能調整のためのプロラクチン減少剤及び／又は増強剤の使用
EP2217067A1 (fr) * 2007-11-07 2010-08-18 Burnham Institute for Medical Research Procédé et composés pour la régulation de la production d'insuline
AU2013263800B2 (en) * 2007-03-30 2016-05-05 Veroscience Llc Methods of treating metabolic syndrome using dopamine receptor agonists
US9352025B2 (en) 2009-06-05 2016-05-31 Veroscience Llc Combination of dopamine agonists plus first phase insulin secretagogues for the treatment of metabolic disorders
US9364515B2 (en) 2002-08-09 2016-06-14 Veroscience Llc Therapeutic process for the treatment of the metabolic syndrome and associated metabolic disorders
EP3311842A1 (fr) * 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659715A (en) * 1986-03-07 1987-04-21 Louisiana State University And Agricultural And Mechanical College Method of inhibiting body fat stores
DE3722383A1 (de) * 1986-07-14 1988-01-28 Sandoz Ag Neue verwendung von bromocriptin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659715A (en) * 1986-03-07 1987-04-21 Louisiana State University And Agricultural And Mechanical College Method of inhibiting body fat stores
DE3722383A1 (de) * 1986-07-14 1988-01-28 Sandoz Ag Neue verwendung von bromocriptin

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 109, No. 9, issued 07 September 1988, LARSON et al., "Bromocriptine for the Treatment of Immune Disease", see page 65, column 1 and 2, abstract no. 66888W; & DE,A,3 722 383. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5585347A (en) * 1988-05-10 1996-12-17 Ergo Science Incorporated Methods for the determination and adjustment of prolactin daily rhythms
EP0735863A1 (fr) * 1993-12-22 1996-10-09 Ergo Science Incorporated Composition a liberation acceleree contenant de la bromocryptine
EP0735863A4 (fr) * 1993-12-22 1997-08-20 Ergo Science Inc Composition a liberation acceleree contenant de la bromocryptine
EP0808164A1 (fr) * 1994-01-07 1997-11-26 Ergo Science Incorporated Procede de traitement de l'obesite comprenant l'administration de modulateurs de prolactine et l'application d'un regime
EP0808164A4 (fr) * 1994-01-07 2001-02-07 Ergo Science Inc Procede de traitement de l'obesite comprenant l'administration de modulateurs de prolactine et l'application d'un regime
JP2009046504A (ja) * 1994-07-07 2009-03-05 General Hospital Corp Dba Massachusetts General Hospital 免疫機能調整のためのプロラクチン減少剤及び／又は増強剤の使用
EP1776955A1 (fr) * 1996-05-07 2007-04-25 Pliva D.D. Therapie de troubles du metabolisme des lipides et du glucose et composition afferente
US9655865B2 (en) 2002-07-29 2017-05-23 Veroscience, Llc Therapeutic treatment for metabolic syndrome, type 2 diabetes, obesity, or prediabetes
US9364515B2 (en) 2002-08-09 2016-06-14 Veroscience Llc Therapeutic process for the treatment of the metabolic syndrome and associated metabolic disorders
US9999653B2 (en) 2002-08-09 2018-06-19 Veroscience Llc Therapeutic process for the treatment of the metabolic syndrome and associated metabolic disorders
AU2013263800B2 (en) * 2007-03-30 2016-05-05 Veroscience Llc Methods of treating metabolic syndrome using dopamine receptor agonists
EP2162003A4 (fr) * 2007-05-29 2010-08-11 Veroscience Llc Traitement thérapeutique du syndrome métabolique, du diabète de type 2, de l'obésité ou du prédiabète
EP2162003A1 (fr) * 2007-05-29 2010-03-17 VeroScience LLC Traitement thérapeutique du syndrome métabolique, du diabète de type 2, de l'obésité ou du prédiabète
WO2008150480A1 (fr) 2007-05-29 2008-12-11 Veroscience, Llc Traitement thérapeutique du syndrome métabolique, du diabète de type 2, de l'obésité ou du prédiabète
EP2217067A1 (fr) * 2007-11-07 2010-08-18 Burnham Institute for Medical Research Procédé et composés pour la régulation de la production d'insuline
EP2217067A4 (fr) * 2007-11-07 2011-01-19 Burnham Inst Medical Research Procédé et composés pour la régulation de la production d'insuline
US8168391B2 (en) 2007-11-07 2012-05-01 Burnham Institute For Medical Research Method for modulating insulin production
US9352025B2 (en) 2009-06-05 2016-05-31 Veroscience Llc Combination of dopamine agonists plus first phase insulin secretagogues for the treatment of metabolic disorders
US9895422B2 (en) 2009-06-05 2018-02-20 Veroscience Llc Combination of dopamine agonists plus first phase insulin secretagogues for the treatment of metabolic disorders
US10688155B2 (en) 2009-06-05 2020-06-23 Veroscience Llc Combination of dopamine agonists plus first phase insulin secretagogues for the treatment of metabolic disorders
EP3311842A1 (fr) * 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques

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Publication number Publication date
HUT67688A (en) 1995-04-28
RU94037557A (ru) 1996-05-20
RU2104698C1 (ru) 1998-02-20
CZ282909B6 (cs) 1997-11-12
CZ155494A3 (en) 1995-08-16
AU3419293A (en) 1993-07-28
HU9401900D0 (en) 1994-09-28

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