Method for the long term reduction of body fat stores, insulin resistance, hyperinsulinemia and hyperglycemia in vertebrates

• US 5,344,832 A
• Filed: 06/24/1991
• Issued: 09/06/1994
• Est. Priority Date: 01/10/1990
• Status: Expired due to Term

• Current Assignee: Board of Supervisors of Louisiana State University Agricultural & Mechanical College (Louisiana State University System), VeroScience, LLC
• Original Assignee: Ergo Science Incorporated, Board of Supervisors of Louisiana State University Agricultural & Mechanical College (Louisiana State University System)
• Inventors: Cincotta, Anthony H., Meier, Albert H.
• Primary Examiner(s): Cintins, Marianne M.
• Assistant Examiner(s): WEDDINGTON, KEVIN E
• Application Number:
  US07/719,745
• Time in Patent Office: 1,170 Days
• Field of Search: 514/250, 514/288, 514/866
• US Class Current: 514/288
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/221 with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4515 having a butyrophenone group in position 1, e.g. haloperidol pipamperone A61K31/4545
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/48 : Ergoline derivatives, e.g. lysergic acid, ergotamine
• CPC Class Codes: A61K 31/496 : Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4985 : Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/54 : having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61K 31/5415 : ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/55 : having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 : having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5513 : 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/695 : Silicon compounds
• CPC Class Codes: A61K 38/2257 : Prolactin
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: G01N 33/74 : involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

A process for the long term modification and regulation of lipid and glucose metabolism--generally to reduce obesity, insulin resistance, and hyperinsulinemia or hyperglycemia, or both (these being the hallmarks of noninsulin dependent, or Type II diabetes)--by administration to a vertebrate, animal or human, of a dopamine agonist and a prolactin stimulator. The dopamine agonist and prolactin stimulator are administered in daily dosages, respectively, at a time of day dependent on the normal circadian rhythm of fat and lean members of a similar species. Decreases in body fat deposits result by treatment of an obese species on a daily timed sequence based on circadian rhythms of the peak prolactin, or peak prolactin and peak glucocorticosteroid, blood level established for lean insulin sensitive members of a similar species. The dopamine agonist is administered at the time of, or just after the time of peak plasma prolactin concentration found in lean animals of the same species and the prolactin stimulator is administered at a time just before the plasma prolactin rhythm reaches its peak in lean animals. Insulin resistance, and hyperinsulinemia or hyperglycemia, or both, can also be controlled in humans on a long term basis by treatment corresponding to that of the treatment for obesity. The short term daily injections reset hormonal timing in the neural centers of the brain to produce long term effects.

Claims

1. A method for modifying and regulating at least one of the lipid and glucose metabolism in a vertebrate animal or human subject in need of such treatment comprising:

administering a dopamine agonist to said subject on a times daily basis at a first predetermined time of day in a first dosage amount sufficient to reduce the hormonal prolactin level in the blood of said subject; and

additionally

administering a prolactin stimulator to said subject on a time daily basis at a second predetermined time of day in a second dosage amount sufficient to increase hormonal prolactin level in the blood of said subject;

continuing said administrations for periods of time sufficient to modify and reset on a long-term basis the subject'"'"'s daily prolactin cycle to cause it to mimic the low level and peak of the daily prolactin cycle of a lean healthy member of the same species, thereby achieving in said subject at least one of the following modifications in lipid and glucose metabolism;

decrease in insulin resistance, reduction in fat stores, suppression of hyperinsulinemia and reduction of hyperglycemia.

2. The method of claim 1 wherein said subject is a human and wherein said administration are continued for periods of time sufficient to modify and reset on a long-term basis the subject'"'"'s daily prolactin cycle to cause it to mimic the low day level and the nightly time peak of the daily prolactin cycle of a lean healthy human.

3. The method of claim 1 further comprising discontinuing said administrations after lapse of said periods of time, said modifications persisting over the long-term after cessation of said administrations.

4. The method of claim 1 wherein the dopamine agonist and prolactin stimulator are administered respectively on timed daily bases to said subject in amounts and for periods of time sufficient to modify and reset on a long-term basis the daily cycles of both prolactin and glucocorticosteroid in said subject.

5. The method of claim 1 wherein the timed daily dosages of the dopamine agonist and prolactin stimulator are given daily, once a day, over a period ranging from about 10 days to about 150 days, the dopamine agonist being administered in an amount within the range from about 3 micrograms to about 100 micrograms, per pound of body weight, and the prolactin stimulator being administered in an amount within the range from about 10 micrograms to about 100 micrograms per pound of body weight.

6. The method of claim 1 wherein said subject is a human and the timed dosages of the dopamine agonist are given daily, once a day, in an amount within the range from about 3 micrograms to about 20 micrograms, per pound of body weight, and the timed dosages of the prolactin stimulator are given daily, once a day, in an amount ranging from about 10 micrograms to about 100 micrograms, per pound of body weight.

7. The method of claim 6 wherein the subject is an obese human and the dopamine agonist is given daily at a time ranging from about 2 hours to about 8 hours after the time at which the prolactin concentration peaks in a lean human to modify and reset the lipid metabolism of the obese human to that of a lean human.

8. The method of claim 1 wherein the dopamine agonist is selected from the group consisting of 6-methyl-8-beta-carbobenzyloxy-aminoethyl-10 alpha-ergoline;

1,6-dimethyl-8-beta-carbobenzyloxy-aminoethyl-10 alpha-ergoline;

8-acylaminoergolenes;

ergocornine;

9,10-dihydroergocornine;

bromocriptine, and D-2-halo-6-alkyl-8-substituted ergolines.

9. The method of claim 1 wherein the prolactin stimulator is selected from the group consisting of metoclopramide, haloperidol, pimozide, phenothiazine, sulpiride, chlorpromazine and serotonin agonists.

10. The method of claim 1 comprising further administering to said subject thyroid hormone, daily, in an amount within the range from about 0.1 milligrams to about 0.4 milligrams.

11. A method for modifying and resetting the neutral phase oscillations of the brain which control prolactin levels in the bloodstream of a vertebrate animal or human subject, the method comprising administering a dopamine agonist and a prolactin stimulator to said subject on a daily basis at different times predetermined to produce a change of the plasma prolactin rhythm of said subject to mimic that of a lean insulin-sensitive subject, said administrations continuing for periods of time sufficient to increase the cellular sensitivity of the subject to insulin and reduce hyperglycemia, said increase and reduction persisting after cessation of said administrations.

12. The method of claim 11 wherein the dopamine agonist and prolactin stimulator are administered to the subject to also reduce hyperinsulinemia.

13. A method for modifying and resetting the neutral phase oscillations of both the prolactin and glucocorticosteroid rhythms in an obese insulin resistant vertebrate animal or human subject, which comprises

administering a dopamine agonist to said obese insulin-resistant subject on a daily basis at a time of day just after the time that the prolactin level will reach its daily peak in the blood of a lean insulin-sensitive subject, in a dosage amount ranging from about 3 micrograms to about 20 micrograms, per pound of body weight, and additionally

administering a prolactin stimulator to said obese insulin-resistant subject on a daily basis at a time of day just before the prolactin level will peak in the blood of a lean insulin-sensitive member of the same species, in a dosage amount ranging from abut 10 micrograms to about 100 micrograms, per pound of body weight, and continuing the administrations over periods of time ranging from 10 days to 150 days sufficient to at least begin reducing the fat deposits in the body of the obese insulin-resistant subject to that of the lean insulin-sensitive member, such that on cessation of said administrations the fat deposits in the body of the treated subject, will continue to be reduced until they correspond substantially with that of the lean insulin-sensitive member, said substantial correspondence being thereafter maintained on a long-term basis.

15. The method of claim 13 wherein the dopamine agonist is administered daily to said obese subject to increase the cellular sensitivity of the obese subject to insulin.

16. The method of claim 13 wherein the dopamine agonist is administered daily to said obese subject to reduce hyperinsulinemia.

17. The method of claim 13 wherein the dopamine agonist is administered daily to the obese subject to reduce hyperglycemia.

18. The method of claim 13 wherein the dopamine agonist is selected from the group consisting of 6-methyl-8-beta-carbobenzyloxy-aminoethyl-10 alpha-ergoline;

8-acylaminoergolenes;

bromocriptine, and D-2-halo-6-alkyl-8-substituted ergolines.

14. A method for modifying lipid and glucose metabolism in a lean human in need of such treatment the method comprising:

administering a dopamine agonist and a prolactin stimulator to said lean human daily at different predetermined times of the day that will cause the prolactin level in the blood of said lean human to peak at substantially the same time of day as prolactin level peaks in a fat human, thereby causing the body fat content of said lean human to increase.

19. A method for modifying and regulating at least one of lipid and glucose metabolism in a human in need of such treatment, said method comprising administering bromocriptine to said human on a timed daily basis at a first predetermined time of day in a first dosage amount sufficient to reduce hyperglycemia and hyperinsulinemia and to reduce hormonal prolactin level in the blood of said human and additionally administering metoclopramide to said human on a timed daily basis at a second predetermined time of day in a second dosage amount sufficient to increase normal prolactin level in the blood of said human;

continuing said administrations for periods of time sufficient to modify and reset on a long-term basis the prolactin daily cycle of said human to mimic the low day levels and night time peak of the prolactin cycle of a lean healthy human, thereby achieving in said human at least one of the following long-term results;

a reduction in insulin resistance, a reduction in fat stores, suppression of hyperinsulinemia and a reduction in hyperglycemia.

20. A method for modifying and regulating lipid and glucose metabolism in a vertebrate animal or human subject in need of such treatment comprising administering daily to said subject at a predetermined time of day a prolactin stimulator wherein said predetermined time of day is shortly before the daily peak of the prolactin level of a lean healthy member of the same species as said subject, in an amount sufficient to increase the normal prolactin level in the blood of said subject to cause said subject'"'"'s daily prolactin level to peak at about the same time as the daily prolactin level of said lean healthy member of the same species.

21. The method of claim 20 wherein said subject is a human.

22. A method for treating Type II diabetes in a vertebrate animal or human subject in need of such treatment comprising

administering to said subject a dopamine agonist on a daily basis at a first predetermined time of day in a first dosage amount sufficient to reduce the hormonal prolactin level in the bloodstream of said subject;

and additionally

administering to said subject a prolactin stimulator on a daily basis at a second predetermined time of day in a second dosage amount sufficient to increase the hormonal prolactin level in the bloodstream of said subject; and

continuing said administration for periods of time sufficient to modify and reset on a long-term basis the daily prolactin cycle of said subject to mimic the low level and peak of the prolactin cycle of a lean healthy member of the same species, thereby achieving in said subject at least one of a decrease in insulin resistance, suppression of hyperinsulinemia and reduction of hyperglycemia, with or without concomitant reduction of body fat stores in said subject.

23. The method of claim 22 wherein after lapse of said periods of time, said administrations are discontinued but the modification and reset of the prolactin cycle of said subject persist thereafter on a long-term basis.

24. The method of claim 22 wherein said subject is a human and said low level is the low day level and said peak is the night time peak of the daily prolactin cycle of a lean healthy human.