Use of GLP-1 or analogs in treatment of myocardial infarction

• US 6,277,819 B1
• Filed: 08/21/1997
• Issued: 08/21/2001
• Est. Priority Date: 08/30/1996
• Status: Expired due to Term

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Efendic, Suad
• Primary Examiner(s): Saoud, Christine J.
• Application Number:
  US08/915,918
• Time in Patent Office: 1,461 Days
• Field of Search: 514/2, 514/12, 514/866, 530/300
• US Class Current: 514/6.8
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

This invention provides a method of reducing mortality and morbidity after myocardial infarction. GLP-1, a GLP-1 analog, or a GLP-1 derivative, is administered at a dose effective to normalize blood glucose.

Claims

1. A method of reducing mortality and morbidity after myocardial infraction, comprising administering to a patient in need thereof, a compound selected from the group consisting of GLP-1, GLP-1 analogs, GLP-1 derivatives and pharmaceutically-acceptable salts thereof, at a dose effective to normalize blood glucose.

2. The method of claim 1, wherein the compound is administered intravenously.

3. The method of claim 2, wherein the administration is continuous.

4. The method of claim 3 wherein the rate of administration of the compound is between 0.25 and 6 pmol/kg/min.

5. The method of claim 4 wherein the rate of administration of the compound is between 0.5 and 2.4 pmol/kg/min.

6. The method of claim 4 wherein said rate is between about 0.5 and about 1.2 pmol/kg/min.

7. The method of claim 2 wherein the intravenous administration is intermittent.

8. The method of claim 2 wherein the compound is administered intravenously and also administered by another parenteral route.

9. The method of claim 8 wherein the other parenteral route is the subcutaneous route.

10. The method of claim 1, wherein the compound is administered subcutaneously.

11. The method of claim 3, wherein the administration is continuous.

12. The method of claim 1 wherein the compound administered is GLP(7-36) amide, or a pharmaceutically-acceptable salt thereof.

13. A method of reducing mortality and morbidity after myocardial infraction, comprising administering a GLP-1 analog to a patient in need thereof at a dose effective to normalize blood glucose, said GLP-1 analog being represented by the following structural formula:

R₁—

X—

Glu—

Gly—

Thr—

Phe—

Thr—

Ser—

Asp—

Val—

Ser—

Ser—

Tyr—

Leu—

Y—

Gly—

Gln—

Ala—

Ala—

Lys—

Z—

Phe—

Ile—

Ala—

Trp—

Leu—

Val—

Lys—

Gly—

Arg—

R₂

and pharmaceutically-acceptable salts thereof,

wherein;

R₁ is selected from the group consisting of L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β

-hydroxy-histidine, homohistidine, alpha-fluoromethyl-histidine, and alpha-methyl-histidine;

X is selected from the group consisting of Ala, Gly, Val, Thr, Ile, and alpha-methyl-Ala;

Y is selected from the group consisting of Glu, Gin, Ala, Thr, Ser, and Gly;

Z is selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly;

R₂ is selected from the group consisting of NH₂, and Gly—

OH;

provided that the GLP-1 analog has an isoelectric point in the range from about 6.0 to about 9.0 and further providing that when R₁ is His, X is Ala, Y is Glu, and Z is Glu, R₂ must be NH₂.

14. A method of reducing mortality and morbidity after myocardial infraction in a patient with non-insulin dependent diabetes, said method comprising the step of administering to the patient, at a dose effective to normalize blood glucose, a compound selected from the group consisting of GLP-1, GLP-1 analogs, GLP-1 derivatives and pharmaceutically-acceptable salts thereof.

15. A method of reducing mortality and morbidity after myocardial infraction in a patient with non-insulin dependent diabetes, said method comprising the step of administering to the patient, at a dose effective to normalize blood glucose, a GLP-1 analog represented by the following structural formula:

R₁—

X—

Glu—

Gly—

Thr—

Phe—

Thr—

Ser—

Asp—

Val—

Ser—

Ser—

Tyr—

Leu—

Y—

Gly—

Gln—

Ala—

Ala—

Lys—

Z—

Phe—

Ile—

Ala—

Trp—

Leu—

Val—

Lys—

Gly—

Arg—

R₂

and pharmaceutically-acceptable salts thereof,

wherein;

R₁ is selected from the group consisting of L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β

-hydroxy-histidine, homohistidine, alpha-fluoromethyl-histidine, and alpha-methyl-histidine;

X is selected from the group consisting of Ala, Gly, Val, Thr, Ile, and alpha-methyl-Ala;

Y is selected from the group consisting of Glu, Gin, Ala, Thr, Ser, and Gly;

Z is selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly;

R₂ is selected from the group consisting of NH₂, and Gly—

OH;

provided that the GLP-1 analog has an isoelectric point in the range from about 6.0 to about 9.0 and further providing that when R₁ is His, X is Ala, Y is Glu, and Z is Glu, R₂ must be NH₂.

16. A method of reducing mortality and morbidity after myocardial infraction in a patient having a blood glucose level greater than 11 mmole/liter, said method comprising the step of administering to the patient, at a dose effective to normalize blood glucose, a compound selected from the group consisting of GLP-1, GLP-1 analogs, GLP-1 derivatives and pharmaceutically-acceptable salts thereof.

17. A method of reducing mortality and morbidity after myocardial infraction in a patient having a blood glucose level greater than 11 mmole/liter, said method comprising the step of administering to the patient, at a dose effective to normalize blood glucose, a GLP-1 analog represented by the following structural formula:

R₁—

X—

Glu—

Gly—

Thr—

Phe—

Thr—

Ser—

Asp—

Val—

Ser—

Ser—

Tyr—

Leu—

Y—

Gly—

Gln—

Ala—

Ala—

Lys—

Z—

Phe—

Ile—

Ala—

Trp—

Leu—

Val—

Lys—

Gly—

Arg—

R₂

and pharmaceutically-acceptable salts thereof,

wherein;

R₁ is selected from the group consisting of L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β

-hydroxy-histidine, homohistidine, alpha-fluoromethyl-histidine, and alpha-methyl-histidine;

X is selected from the group consisting of Ala, Gly, Val, Thr, Ile, and alpha-methyl-Ala;

Y is selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly;

Z is selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly;

R₂ is selected from the group consisting of NH₂, and Gly—

OH;

provided that the GLP-1 analog has an isoelectric point in the range from about 6.0 to about 9.0 and further providing that when R₁ is His, X is Ala, Y is Glu, and Z is Glu, R₂ must be NH₂.

18. A method of reducing mortality and morbidity after myocardial infraction in a patient with abnormal glucose tolerance, said method comprising the step of administering to the patient, at a dose effective to normalize blood glucose, a compound selected from the group consisting of GLP-1, GLP-1 analogs, GLP-1 derivatives and pharmaceutically-acceptable salts thereof.

19. A method of reducing mortality and morbidity after myocardial infraction in a patient having abnormal glucose tolerance, said method comprising the step of a GLP-1 analog to the patient, at a dose effective to normalize blood glucose, a GLP-1 analog represented by the following structural formula:

R₁—

X—

Glu—

Gly—

Thr—

Phe—

Thr—

Ser—

Asp—

Val—

Ser—

Ser—

Tyr—

Leu—

Y—

Gly—

Gln—

Ala—

Ala—

Lys—

Z—

Phe—

Ile—

Ala—

Trp—

Leu—

Val—

Lys—

Gly—

Arg—

R₂

and pharmaceutically-acceptable salts thereof,

wherein;

R₁ is selected from the group consisting of L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β

-hydroxy-histidine, homohistidine, alpha-fluoromethyl-histidine, and alpha-methyl-histidine;

X is selected from the group consisting of Ala, Gly, Val, Thr, Ile, and alpha-methyl-Ala;

Y is selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly;

Z is selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly;

R₂ is selected from the group consisting of NH₂, and Gly—

OH;

provided that the GLP-1 analog has an isoelectric point in the range from about 6.0 to about 9.0 and further providing that when R₁ is His, X is Ala, Y is Glu, and Z is Glu, R₂ must be NH₂.