Method and composition for inhibiting cardiovascular cell proliferation

• US 6,605,115 B1
• Filed: 06/05/2000
• Issued: 08/12/2003
• Est. Priority Date: 06/05/1999
• Status: Expired due to Term

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Rothbard, Jonathan B., Cooke, John P., Kown, Murray H., Fathman, Garrison C., Robbins, Robert C., Uemura, Shiro
• Primary Examiner(s): McDermott, Corrine
• Assistant Examiner(s): BARRETT, THOMAS C
• Application Number:
  US09/587,647
• Time in Patent Office: 1,163 Days
• Field of Search: 623/1.48, 623/1.42, 128/898, 427/2.24, 427/2.25
• US Class Current: 623/1.48
• CPC Class Codes: A61K 38/03 Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 33/12 Polypeptides, proteins or derivatives thereof , e.g. degradation products thereof
• CPC Class Codes: A61L 33/128 Other specific proteins or polypeptides not covered by A61L33/122 - A61L33/126
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C08L 77/04 Polyamides derived from alpha-amino carboxylic acids C08L77/10 takes precedence

Abstract

Cardiovascular cell proliferation in a blood vessel subjected to trauma, such as angioplasty, vascular graft, anastomosis, or organ transplant, can be inhibited by contacting the vessel with a polymer consisting of from 6 to about 30 amino acid subunits, where at least 50% of the subunits are arginine, and the polymer contains at least six contiguous arginine subunits. Exemplary polymers for this purpose include arginine homopolymers 7 to 15 subunits in length.

Claims

1. A method for inhibiting trauma-induced intimal hyperplasia in a graft or vascular vessel receiving a graft, comprising:

contacting a graft, prior to grafting, with a polymer consisting of from 6 to about 30 amino acid subunits in a pharmaceutically acceptable vehicle, wherein at least 50% of said subunits are arginine residues, and said polymer contains at least six contiguous arginine residues.

2. The method of claim 1, wherein at least 70% of the subunits in the polymer are arginine residues.

3. The method of claim 1, wherein at least 90% of the subunits in the polymer are arginine residues.

4. The method of claim 1, wherein no two arginine residues are separated by more than one non-arginine subunit.

5. The method of claim 1, wherein the arginine residues are all L-arginine residues.

6. The method of claim 1, wherein the amino acid subunits other than the arginine residues are natural or unnatural amino acid subunits that do not significantly reduce the rate of membrane transport of the polymer.

7. The method of claim 6, wherein the amino acid subunits other than the arginine residues are selected from the group consisting of glycine, alanine, cysteine, valine, leucine, isoleucine, methionine, serine, threonine, α

-amino-β

-guanidinopropionic acid, α

-amino-γ

-guanidinobutyric acid, and α

-amino-ε

-guanidinocaproic acid.

8. The method of claim 1, wherein said polymer is an arginine homopolymer.

9. The method of claim 8, wherein said polymer is an L-arginine homopolymer.

10. The method of claim 8, wherein said polymer contains 7 to 15 arginine residues.

11. The method of claim 1, wherein the trauma comprises an incision to the graft or vascular vessel receiving a graft, transplant of an organ containing the graft, or a combination thereof.

12. The method of claim 11, wherein the graft is grafted into the vascular vessel.

13. The method of claim 2, wherein the vascular vessel is undergoing a bypass procedure.

14. The method of claim 11, wherein the graft is grafted onto the vascular vessel.

15. The method of claim 14, wherein the vascular vessel is a vein undergoing an arterial venous anastomosis procedure for the purpose of dialysis.

16. The method of claim 11, wherein the graft is contained within a transplanted organ.

17. The method of claim 16, wherein said contacting comprises immersion of the organ in a solution of the polymer.

18. The method of claim 1, wherein the graft is a vascular conduit for a vascular graft procedure, and said contacting is carried out for a time sufficient for the polymer to be transported into the wall of the vascular conduit, such that the level of the polymer in the conduit wall is effective to reduce the level of post-graft intimal hyperplasia in and/or adjacent to the conduit, relative to the level of post-graft intimal hyperplasia that would occur in the absence of such contacting with the polymer.

19. The method of claim 18, wherein said contacting is limited to contacting the polymer-containing liquid with the interior of the vascular conduit.

20. The method of claim 18, wherein the polymer is an arginine homopolymer.

21. The method of claim 20, wherein the polymer is an L-arginine homopolymer.

22. The method of claim 20, wherein the polymer contains 7 to 15 arginine residues.

23. A graft treated according to the method recited in claim 1.

24. The graft of claim 23, wherein the contacting polymer is an arginine homopolymer.

25. The graft of claim 24, wherein the contacting polymer is an L-arginine homopolymer.

26. The graft of claim 24, wherein the contacting polymer contains from 7 to 15 arginine residues.

27. A method of increasing NO production in a graft or vascular vessel receiving a graft, comprising contacting the graft, prior to grafting, with a polymer consisting of from 6 to about 30 amino acid subunits, wherein at least 50% of said subunits are arginine residues, and said polymer contains at least six contiguous arginine residues, in a pharmaceutically acceptable vehicle.

28. The method of claim 27, wherein said polymer is an L-arginine homopolymer containing 7 to 15 L-arginine residues.