Method of restoring the incretin effect
View Patent ↗The present invention relates to methods of treating metabolic syndrome, Type 2 diabetes mellitus, atherogenic dyslipidemia and/or obesity. The present invention also relates to methods of restoring the incretin effect, to restoring physiologic control of glucagon levels, to restoring first-phase insulin secretion, and to restoring the physiologic glucose-dependent insulin secretion. The methods of the present invention comprise administration of a selective κ-receptor antagonist, such as guanidinylated naltrindole (GNTI), or pharmaceutically acceptable derivatives thereof to a subject in need thereof.
1. A method of restoring the incretin effect in a subject, comprising administering to subject an effective amount of a selective κ-receptor antagonist, or a pharmaceutically acceptable derivative thereof, wherein a μ-agonist is not co-administered and wherein the selective κ-receptor antagonist is characterized by its μ/κ antagonism K e selectivity ratio, the ratio being greater than 35.
2. A method of restoring the incretin effect in a subject, comprising administering to subject an effective amount of a selective κ-receptor antagonist, or a pharmaceutically acceptable derivative thereof, wherein a μ-agonist is not co-administered, and wherein the selective κ-receptor antagonist is guanidinylated naltrindole (GNTI).
3. The method of claim 1 , wherein the selective κ-receptor antagonist acts peripherally, and is substantially free of CNS activity.
4. The method of claim 1 , wherein the selective κ-receptor antagonist is administered weekly or daily.
5. A method of restoring the incretin effect in a subject, comprising administering to subject an effective amount of a selective κ-receptor antagonist, or a pharmaceutically acceptable derivative thereof, wherein a μ-agonist is not co-administered, wherein the selective κ-receptor antagonist is characterized by its μ/κ antagonism K e selectivity ratio, the ratio being greater than 35, and wherein the selective κ-receptor antagonist is administered in an amount from about 30 ng to about 300 ng per kg of body weight weekly.
6. The method of claim 4 , wherein the selective κ-receptor antagonist is administered in an amount from about 8 ng to about 80 ng per kg of body weight daily.
7. The method of claim 1 , wherein the selective κ-receptor antagonist is administered sublingually, orally, enterally, parenterally, topically, systemically or injected intravascularly, subcutaneously, peritoneally.
8. The method of claim 1 , further comprising co-administration of an effective amount of an insulinogenic agent.
9. The method of claim 8 , wherein the insulinogenic agent is an extended release composition.
10. A method of treating metabolic syndrome, comprising administering to a subject a therapeutically effective amount of a selective κ-receptor antagonist, or a pharmaceutically acceptable derivative thereof, wherein a μ-agonist is not co-administered and wherein the selective κ-receptor antagonist is characterized by its μ/κ antagonism K e selectivity ratio, the ratio being greater than 35.
11. A method of treating metabolic syndrome, comprising administering to a subject a therapeutically effective amount of a selective κ-receptor antagonist, or a pharmaceutically acceptable derivative thereof, wherein a μ-agonist is not co-administered, and wherein the selective κ-receptor antagonist is guanidinylated naltrindole (GNTI).
12. The method of claim 10 , wherein the selective κ-receptor antagonist is administered weekly or daily.
13. A method of treating metabolic syndrome, comprising administering to a subject a therapeutically effective amount of a selective κ-receptor antagonist, or a pharmaceutically acceptable derivative thereof, wherein a μ-agonist is not co-administered and wherein the selective κ-receptor antagonist is characterized by its μ/κ antagonism K e selectivity ratio, the ratio being greater than 35, and wherein the selective κ-receptor antagonist is administered weekly in an amount from about 30 ng to about 300 ng per kg of body weight weekly.
14. The method of claim 12 , wherein the selective κ-receptor antagonist is administered daily in an amount from about 8 ng to about 80 ng per kg of body weight daily.
15. The method of claim 10 , wherein the selective κ-receptor antagonist is administered sublingually, orally, enterally, parenterally, topically, systemically or injected intravascularly, subcutaneously, peritoneally.
16. The method of claim 10 , further comprising co-administration of an effective amount of an insulinogenic agent.
17. The method of claim 16 , wherein the insulinogenic agent is an extended release composition.
18. The method of claim 10 , wherein the effective amount of selective κ-receptor antagonist restores the incretin effect in a subject in need thereof.