Therapeutic process for the treatment of the pathologies of Type II diabetes

• US 5,468,755 A
• Filed: 11/24/1993
• Issued: 11/21/1995
• Est. Priority Date: 05/10/1988
• Status: Expired due to Term

• Current Assignee: Board of Supervisors of Louisiana State University Agricultural & Mechanical College (Louisiana State University System)
• Original Assignee: 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:
  US08/158,153
• Time in Patent Office: 727 Days
• Field of Search: 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 31/15 Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• 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 31/4985 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: 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 carbohydrate metabolism--generally to reduce obesity, insulin resistance, and hyperinsulinemia or hyperglycemia, or both (these are the hallmarks of noninsulin dependent, or Type II diabetes)--by administration (i.e., by oral, sublingual or parenternal administration) to a vertebrate, animal or human, of a dopamine agonist, e.g., bromocriptine. Administration of the bromocriptine is made over a limited period at a time of day dependent on the normal circadian rhythm of insulin resistant and insulin sensitive members of a similar species. Insulin resistance, and hyperinsulinemia and hyperglycemia, or both, can be controlled in humans on a long term basis by such treatment inasmuch as the short term daily administration resets hormonal timing in the neural centers of the brain to produce long term effects.

Claims

1. A method for modifying or regulating glucose metabolism in an animal or human subject in need of such treatment comprising

administering to said subject a prolactin-inhibiting compound on a timed daily basis in a dosage amount and for a period sufficient to achieve in said subject at least one of the following modifications:

decrease in insulin resistance, reduction of hyperinsulinemia, increase in glucose tolerance, and reduction of hyperglycemia.

2. The method of claim 1 wherein the prolactin-inhibiting compound is a dopamine agonist.

3. The method of claim 2 wherein at least one of said modifications persists for at least one month after cessation of administration of said dopamine agonist.

4. The method of claim 2 wherein the dopamine agonist is administered once a day, and said dosage amount is within the range from about 3 micrograms to about 100 micrograms per pound of body weight of said subject.

5. The method of claim 4 wherein the dopamine agonist is administered for a period of time within the range of from about 10 to about 150 days.

6. The method of claim 2 wherein said subject is a human and the dopamine agonist is administered once a day, and said dosage amount is within the range from about 3 micrograms to about 100 micrograms per pound body weight of said subject.

7. The method of claim 6 wherein the dopamine agonist is administered for a period of time within the range from about 30 days to about 150 days.

8. The method of claim 6 wherein said human subject exhibits at least one of insulin resistance and Type II diabetes and the dopamine agonist is administered once a day, at a time from 1 hour to about 10 hours after the time at which the prolactin bloodstream level peaks in a lean, insulin sensitive human.

9. The method of claim 2 wherein the compound 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.

10. The method of any one of claims 1-9 wherein the compound is bromocriptine.

11. A method for modifying or resetting the prolactin rhythm of an insulin insensitive or diabetic animal or human subject which comprises

administering to said subject a prolactin-inhibiting compound once a day, at a predetermined time within a 24-hour period, in an amount sufficient, and for a period of time sufficient to accomplish at least one of the following:

decrease insulin resistance, decrease hyperglycemia, decrease hyperinsulinemia in said subject, and increase glucose tolerance.

18. The method of any one of claims 11-17 wherein said compound is bromocriptine.

12. A method for modifying or resetting the prolactin rhythm of an insulin insensitive or diabetic animal or human subject comprising

administering to said subject a prolactin-inhibiting compound on a timed daily basis at a time of day designed to cause the daytime prolactin bloodstream level of said subject to decrease at a time corresponding to the low daytime prolactin level of a lean, insulin sensitive subject, in a dosage amount sufficient and for a period of time sufficient to achieve in said subject at least one of the following modifications in glucose metabolism:

decrease in insulin resistance, reduction of hyperinsulinemia, improvement in glucose tolerance and reduction of hyperglycemia.

13. The method of claim 12 wherein the prolactin-inhibiting compound is a dopamine agonist.

14. The method of claim 12 wherein said dosage amount is within the range of about 3 to about 100 micrograms per pound of body weight of said subject.

15. The method of claim 14 wherein on cessation of administration of the compound the prolactin rhythm of the treated subject will correspond substantially, on a long-term basis, with that of a lean, insulin-sensitive subject.

16. The method of claim 13 wherein said period of administration of the dopamine agonist is about 30 days to about 150 days.

17. 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;

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.

19. A method for modifying or regulating the glucose metabolism of a human subject exhibiting at least one of the pathologies characteristically associated with Type II diabetes comprising

administering a prolactin-inhibiting compound on a timed daily basis from about 1 hour to about 10 hours after the time at which the prolactin bloodstream level peaks in a member of the same species and sex as said subject, wherein said member is not exhibiting any of said pathologies associated with Type II diabetes, in a dosage amount within the range from about 3 micrograms to about 100 micrograms per pound body weight of said subject, and for a period of time sufficient to achieve in said subject at least one of the following modifications in glucose metabolism:

decrease in insulin resistance, reduction of hyperinsulinemia, reduction of hyperglycemia.

20. The method of claim 19 wherein the prolactin-inhibiting compound is a dopamine agonist.

21. The method of claim 20 wherein at least one modification persists over the long term after cessation of administration of the dopamine agonist.

22. The method of claim 20 wherein the period of administration of said dopamine agonist is sufficient to modify and reset the neural phase oscillations controlling at least one of the prolactin and glucocorticosteroid bloodstream levels of said subject.

23. The method of claim 20 wherein the compound 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.

24. The method of any one of claims 19-23 wherein said compound is bromocriptine.

25. A method for modifying and resetting the neural phase oscillations of the brain which control bloodstream prolactin levels of a human subject, said subject being diagnosed as being at least one of insulin insensitive and diabetic, said method comprising

administering to said subject a prolactin-inhibiting compound once a day, at an hour, in an amount, and for a period of time sufficient to decrease insulin insensitivity and decrease hyperglycemia in said subject.

26. The method of claim 25 wherein the prolactin-inhibiting compound is a dopamine agonist.

27. The method of claim 26 wherein the period of time of administration of said dopamine agonist is also sufficient to modify and reset the neural phase oscillations that control the glucocorticosteroid bloodstream levels of said subject.

28. The method of claim 26 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.

29. The method of any one of claims 25-28 wherein the compound is bromocriptine.

30. A method for modifying and regulating lipid metabolism in an animal or human subject in need of such treatment comprising

administering to said subject a prolactin-inhibiting compound on a timed basis in a dosage amount and for a period of time sufficient to achieve in said subject either a decrease in body fat stores or an increase in body fat stores.

31. The method of claim 30 wherein said subject is a human.

32. The method of claim 31 wherein the prolactin-inhibiting compound is a dopamine agonist.

33. The method of claim 32 wherein at least on of said decrease or increase continues for at least one month after cessation of administration of said dopamine agonist.

34. The method of claim 32 wherein the period of administration of said dopamine agonist is sufficient to modify and reset the neural phase oscillations controlling at least one of the prolactin and glucocorticosteroid bloodstream levels of said subject.

35. The method of claim 32 wherein the dopamine agonist is administered once a day, and said dosage amount is within the range from about 3 micrograms to about 100 micrograms per pound of body weight of said subject.

36. The method of claim 30 wherein the prolactin-inhibiting compound is administered once a day for a period of time within the range from about 30 days to about 150 days.

37. The method of claim 32 wherein said human subject suffers from obesity and the dopamine agonist is administered once a day, from 1 hour to about 10 hours after the time at which the prolactin bloodstream level peaks in a lean, insulin sensitive human of the same sex as said human subject, thereby decreasing body fat stores in said human subject.

38. The method of claim 32 wherein said compound 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.

39. The method of any one of claims 30-38 wherein said compound is bromocriptine.