Method and composition for inhibiting cardiovascular cell proliferation

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.

It is claimed:  
     
         1 . A method for inhibiting trauma-induced intimal hyperplasia in a blood vessel, comprising: 
 contacting with said vessel, in a pharmaceutically acceptable vehicle, a polymer consisting of from 6 to about 30 amino acid subunits, wherein at least 50% of said subunits are arginine, and said polymer contains at least six contiguous arginine subunits.    
     
     
         2 . The method of  claim 1 , wherein at least 70% of the subunits in the polymer are arginine.  
     
     
         3 . The method of  claim 1 , wherein at least 90% of the subunits in the polymer are arginine.  
     
     
         4 . The method of  claim 1 , wherein no arginine subunit is separated from another such subunit by more than one non-arginine subunit.  
     
     
         5 . The method of  claim 1 , wherein the arginine subunits are L-arginine.  
     
     
         6 . The method of  claim 1 , wherein non-arginine subunits are natural or unnatural amino acid subunits which do not significantly reduce the rate of membrane transport of the polymer.  
     
     
         7 . The method of  claim 6 , wherein said non-arginine subunits 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 vessel, excessive or prolonged pressure applied to the vessel, transplant of an organ containing the vessel, or a combination thereof.  
     
     
         12 . The method of  claim 1 , wherein the vessel is a vascular conduit or patch to be grafted into or onto an endogenous vessel.  
     
     
         13 . The method of  claim 11 , wherein the vessel is an endogenous vessel receiving a graft.  
     
     
         14 . The method of  claim 11 , wherein the vessel is a vein undergoing an arterial venous anastomosis procedure for the purpose of dialysis.  
     
     
         15 . The method of  claim 11 , wherein the vessel is subjected to angioplasty.  
     
     
         16 . The method of  claim 11 , wherein the vessel 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 . A method of preparing a vascular conduit for a vascular graft procedure, comprising: 
 contacting an isolated vessel conduit with an arginine polymer as recited in  claim 1 , in a pharmaceutically acceptable vehicle, for a time sufficient for the polymer to be transported into the wall of the vessel 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 vessel 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 . An isolated vessel conduit comprising, within the wall of the conduit, a polymer as recited in  claim 1 , present at a level 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 the polymer.  
     
     
         24 . The vessel conduit of  claim 23 , wherein the polymer is an arginine homopolymer.  
     
     
         25 . The vessel conduit of  claim 24 , wherein the polymer is an L-arginine homopolymer.  
     
     
         26 . The vessel conduit of  claim 24 , wherein the polymer contains from 7 to 15 arginine residues.  
     
     
         27 . A method of increasing NO production in a vascular cell or tissue, comprising contacting with said cell or tissue, a polymer as recited in  claim 1 , 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.