Metabolic intervention with GLP-1 or its biologically active analogues to improve the function of the ischemic and reperfused brain

• US 6,429,197 B1
• Filed: 04/30/1999
• Issued: 08/06/2002
• Est. Priority Date: 10/08/1998
• Status: Expired

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Bionebraska, Inc.
• Inventors: Ehlers, Mario R. W., Coolidge, Thomas R.
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Mohamed, Abdel A.
• Application Number:
  US09/303,016
• Time in Patent Office: 1,194 Days
• Field of Search: 514/21, 514/2, 514/3, 514/12, 530/303, 530/308, 530/324, 530/350, 424/185.1
• US Class Current: 514/6.8
• 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 38/26 Glucagons
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• 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

It has now been discovered that GLP-1 treatment after acute stroke or hemorrhage, preferably intravenous administration, can be an ideal treatment because it provides a means for optimizing insulin secretion, increasing brain anabolism, enhancing insulin effectiveness by suppressing glucagon, and maintaining euglycemia or mild hypoglycemia with no risk of severe hypoglycemia.

Claims

1. A method of increasing insulinotropic response in ischemia injured brain cells comprising administering a composition containing glucagon-like peptide-1 (GLP-1) and a pharmaceutical carrier for a time sufficient and under conditions effective to increase insulinotropic response which produces insulin, with the produced insulin being neuroprotective by direct neurotropic effects and by controlling stroke-related hyperglycemia.

2. The method of claim 1 wherein the pharmaceutical carrier is selected from the group consisting of saline, buffered saline, dextrose, water, glycerol, ethanol, lactose, phosphate, mannitol, arginine, treholose, and combinations thereof.

3. The method of claim 1 wherein the administration commences within 4 hours of an ischemic event.

4. The method of claim 1 wherein the administration of the composition is continuous and intravenously at 0.1 pmol/kg/min to 10 pmol/kg/min.

5. The method of claim 1 wherein the administration of the composition is a bolus subcutaneous injection at 0.1 nmol/kg to 75 nmol/kg.

6. The method of claim 1 wherein the administration is by a method selected from the group consisting of subcutaneous or micropressure injection, deep lung insufflation, external or implant pump, depot injection, and other sustained release mechanisms, buccal and other cross skin and membrane mechanisms.

7. The method of claim 1 wherein the composition is administered intravenously at a dose of 0.1 pmol/kg/min up to 10 pmol/kg/min.

8. The method of claim 7 further comprising concurrent administration of glucose.

9. The method of claim 7 further comprising concurrent administration of an oxygen scavenger.

10. A method of increasing insulinotropic response in ischemia injured brain cells comprising administering to an individual in need of such treatment a dose of 0.1 pmol/kg/min to 10 pmol/kg/min of a composition containing glucagon-like peptide-1 (GLP-1) and a pharmaceutical carrier for a time sufficient and under conditions effective to increase insulinotropic response which produces insulin, with the produced insulin being neuroprotective by direct neurotropic effects and by controlling stroke-related hyperglycemia.