Claims
- 1. A method of normalizing blood glucose levels which comprises maintaining chronic steady state plasma levels between about 60 picomoles/liter and about 200 picomoles/liter of a GLP-1 analog or derivative in biologically active form having an in vitro potency within two-fold the in vitro potency of Val8-GLP-1(7-37)OH wherein the GLP-1 analog or derivative is administered by subcutaneous injection to a human subject no more than once or twice every 24 hours.
- 2. A method of treating a condition selected from the group consisting of: hyperglycemia, type 2 diabetes, obesity, stroke, myocardial infarction, catabolic changes that occur after surgery, and irritable bowel syndrome which comprises maintaining chronic steady state plasma levels between about 60 picomoles/liter and about 200 picomoles/liter of a GLP-1 analog or derivative in biologically active form having an in vitro potency within two-fold the in vitro potency of Val8-GLP-1(7-37)OH wherein the GLP-1 analog or derivative is administered by subcutaneous injection to a human subject no more than once or twice every 24 hours.
- 3. A method of preventing β-cell deterioration which comprises maintaining steady state chronic plasma levels between about 60 picomoles/liter and about 200 picomoles/liter of a GLP-1 analog or derivative in biologically active form having an in vitro potency within two-fold the in vitro potency of Val8-GLP-1(7-37)OH wherein the GLP-1 compound is administered by subcutaneous injection to a human subject no more than once or twice every 24 hours.
- 4. A method of inducing weight loss which comprises maintaining chronic steady state plasma levels between about 60 picomoles/liter and about 200 picomoles/liter of a GLP-1 analog or derivative in biologically active form having an in vitro potency within two-fold the in vitro potency of Val8-GLP-1(7-37)OH wherein the GLP-1 compound is administered by subcutaneous injection to a human subject no more than once or twice every 24 hours.
- 5. The method of any one of claims 1 through 4 wherein the plasma levels are maintained between about 100 picomolar and about 200 picomolar.
- 6. The method of claim 5 wherein the plasma levels are maintained between about 100 picomolar and about 180 picomolar.
- 7. A method of normalizing blood glucose levels which comprises maintaining chronic steady state plasma levels between about 60/X picomolar and about 200/X picomolar of a GLP-1 analog or derivative in biologically active form wherein X is the in vitro potency of the GLP-1 analog or derivative relative to Val8-GLP-1(7-37)OH which is given a reference value of 1 and wherein the GLP-1 analog or derivative is administered by subcutaneous injection to a human subject no more than once or twice every 24 hours.
- 8. A method of treating a condition selected from the group consisting of: hyperglycemia, type 2 diabetes, obesity, stroke, myocardial infarction, catabolic changes that occur after surgery, and irritable bowel syndrome which comprises maintaining chronic steady state plasma levels between about 60/X picomolar and about 200/X picomolar of a GLP-1 analog or derivative in biologically active form wherein X is the in vitro potency of the GLP-1 analog or derivative relative to Val8-GLP-1(7-37)OH which is given a reference value of 1 and wherein the GLP-1 analog or derivative is administered by subcutaneous injection to a human subject no more than once or twice every 24 hours.
- 9. A method of preventing β cell deterioration which comprises maintaining chronic steady state plasma levels between about 60/X picomolar and about 200/X picomolar of a GLP-1 analog or derivative in biologically active form wherein X is the in vitro potency of the GLP-1 analog or derivative relative to Val8-GLP-1 (7-37)OH which is given a reference value of 1 and wherein the GLP-1 analog or derivative is administered by subcutaneous injection to a human subject no more than once or twice every 24 hours.
- 10. A method of inducing weight loss which comprises maintaining chronic steady state plasma levels between about 60/X picomolar and about 200/X picomolar of a GLP-1 analog or derivative in biologically active form wherein X is the in vitro potency of the GLP-1 analog or derivative relative to Val8-GLP-1(7-37)OH which is given a reference value of 1 and wherein the GLP-1 analog or derivative is administered by subcutaneous injection to a human subject no more than once or twice every 24 hours.
- 11. The method of any one of claims 7 through 10 wherein the plasma levels are maintained between about 100/X picomolar and about 200/X picomolar.
- 12. The method of claim 11 wherein the plasma levels are maintained between about 100/X picomolar and about 180/X picomolar.
- 13. The method of any one of claims 1 through 12 wherein the GLP-1 analog or derivative is administered not more than once every 24 hours.
- 14. The method of any one of claims 1 through 6 wherein the GLP-1 analog or derivative is selected from the group consisting of: Val8-GLP-1(7-37)OH, Val8-GLP-1(7-36)NH2, Gly8-GLP-1(7-37)OH, Gly8-GLP-1(7-36)NH2, Val8-Lys22-GLP-1(7-37)OH Val8-Lys22-GLP-1(7-36)NH2, Val8-Glu30-GLP-1(7-37)OH, Val8-Glu30-GLP-1(7-36)NH2, Gly8-Glu30-GLP-1(7-37)OH, Gly8-Glu30-GLP-1(7-36)NH2, Val8-His37-GLP-1(7-37)OH, and Val8-His37-GLP-1(7-36)NH2, Arg34-GLP-1(7-36)NH2, Arg34-GLP-1(7-37)OH.
- 15. The method of any one of claims 1 through 6 wherein the GLP-1 analog or derivative is a GLP-1 analog which is administered as a crystal suspension formulation.
- 16. The method of any one of claims 1 through 14 wherein the GLP-1 analog or derivative is an acylated GLP-1 derivative.
- 17. The method of claim 16 wherein the acylated GLP-1 derivative is a GLP-1 analog acylated at the epsilon-amino group of lysine present at position 26.
- 18. The method of claim 17 wherein the acylated GLP-1 derivative is Arg34Lys26-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37).
- 19. A method of normalizing blood glucose levels which comprises maintaining chronic steady state plasma levels between about 6 picomoles/liter and about 40 picomoles/liter of Exendin-4 wherein the Exendin-4 is administered by subcutaneous injection to a human subject.
- 20. A method of treating a condition selected from the group consisting of: hyperglycemia, type 2 diabetes, obesity, stroke, myocardial infarction, catabolic changes that occur after surgery, and irritable bowel syndrome which comprises maintaining chronic steady state plasma levels between about 6 picomoles/liter and about 40 picomoles/liter of Exendin-4 wherein the Exendin-4 is administered by subcutaneous injection to a human subject.
- 21. A method of preventing β-cell deterioration which comprises maintaining steady state chronic plasma levels between about 6 picomoles/liter and about 40 picomoles/liter of Exendin-4 wherein the Exendin-4 is administered by subcutaneous injection to a human subject.
- 22. A method of inducing weight loss which comprises maintaining chronic steady state plasma levels between about 6 picomoles/liter and about 40 picomoles/liter of Exendin-4 wherein the Exendin-4 is administered by subcutaneous injection to a human subject.
- 23. The method of any one of claims 1 through 38 wherein the GLP-1 reaches steady state plasma levels after six days of chronic once a day dosing.
- 24. The method of claim 23 wherein the GLP-1 compound accumulates approximately three-fold in the plasma after six days of chronic once a day dosing.
- 25. An article of manufacture for human pharmaceutical use comprising:
a) a container; b) a dosage form comprising an amount of a GLP-1 analog or derivative having an in vitro potency within two-fold that of Val8-GLP-1(7-37)OH; and c) a package insert that provides for
administration of the dosage form that results in maintaining GLP-1 compound plasma levels between 60 picomoles and 200 picomoles.
- 26. The article of claim 25 wherein the package insert directs use to treat a condition selected from the group consisting of: hyperglycemia, type 2 diabetes, stroke, myocardial infarction, catabolic changes that occur after surgery, obesity, and irritable bowel syndrome.
- 27. The article of claim 25 or 26 wherein the GLP-1 analog or derivative is selected from the group consisting of Val8-GLP-1(7-37)OH and Arg34Lys26-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-1(7-37).
- 28. An article of manufacture for human pharmaceutical use comprising:
a) a container; b) a dosage form comprising an amount of Exendin-4; and c) a package insert that provides for
administration of the dosage form that results in maintaining Exendin-4 plasma levels between 6 picomoles and 40 picomoles.
- 29. Use of a GLP-1 analog or derivative having an in vitro potency within 2-fold that of Val8-GLP-1(7-37)OH for the manufacture of a medicament for normalizing blood glucose, preserving β cells, inducing weight loss, or treating a condition selected from the group consisting of: hyperglycemia, type 2 diabetes, stroke, myocardial infarction, catabolic changes that occur after surgery, obesity, and irritable bowel syndrome which comprises maintaining chronic steady state plasma levels of the GLP-1 analog or derivative between about 60 picomolar and about 200 picomolar and wherein the GLP-1 analog or derivative is administered by subcutaneous injection to a human subject not more the once or trice every 24 hours.
- 30. The Use of claim 29 wherein the plasma levels are maintained between about 100 picomolar and about 200 picomolar.
- 31. Use of Exendin-4 for the manufacture of a medicament for normalizing blood glucose, preserving β cells, inducing weight loss, or treating a condition selected from the group consisting of: hyperglycemia, type 2 diabetes, stroke, myocardial infarction, catabolic changes that occur after surgery, obesity, and irritable bowel syndrome which comprises maintaining chronic steady state plasma levels of Exendin-4 between about 6 picomolar and about 40 picomolar and wherein the Exendin-4 is administered by subcutaneous injection to a human subject.
- 32. Use of a GLP-1 analog or derivative for the manufacture of a medicament for normalizing blood glucose, preserving β cells, inducing weight loss, or treating a condition selected from the group consisting of: hyperglycemia, type 2 diabetes, stroke, myocardial infarction, catabolic changes that occur after surgery, obesity, and irritable bowel syndrome which comprises maintaining chronic steady state plasma levels of the GLP-1 analog or derivative between about 60/X picomolar and about 200/X picomolar wherein X is the in vitro potency of the GLP-1 analog or derivative relative to Val8-GLP-1(7-37)OH which is given a reference value of 1 and wherein the GLP-1 analog or derivative is administered by subcutaneous injection no more than once or twice every 24 hours.
Parent Case Info
[0001] This application claims the benefit of U.S. Provisional Application No. 60/255,251, filed Dec. 13, 2000, No. 60/295,655, filed Jun. 4, 2001 and No. 60/298,652 filed Jun. 15, 2001.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/US01/44698 |
12/7/2001 |
WO |
|