Agents and devices for use in prevention of restenosis

Abstract

Agents that inhibit or prevent restenosis are identified by assaying test agents in a battery of assays to measure the effect of the test agent on cell proliferation, thrombosis, tissue modeling, and inflammation. Treatment for restenosis is provided using compositions of the invention.

What is claimed is: 
     
         1 . A device for use in a lumen of a vessel, comprising one or more drugs selected from the group consisting of 8-Azaguanine, Amodiaquin Dihydrochloride Dihydrate, Atovaquone, Betulin, Chlorambucil, Ciclopirox Ethanolamine, Cis-(Z)-Flupentixol Dihydrochloride, Clofilium Tosylate, Deferoxamine Mesylate, Doxazosin Mesylate, Esculetin, Monobenzone, Nifedipine, Primaquine Diphosphate, Securinine, Syrosingopine, Terconazole, a colchicine analog as defined in Structure I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently H, C 1-10 alkyl, C 1-6 cycloalkyl, C 1-10 alkenyl, C 1-6 cycloalkyl, C 1-6 cycloalkenyl or C 1-10  alkynyl, or together form a ring containing from 3 to 6 carbon atoms; provided that a carbon atom comprising an alkene or alkyne bond of R 1  and R 2  is not also simultaneously bound to N; 
         R 1  and R 2  optionally may be substituted with one or more of F, OR 9 , or NR 10 R 11  where R 9 , R 10  and R 11  are independently H or C 1-5  alkyl; 
         R 3  is H, C 1-10 alkyl, C 1-6 cycloalkyl, C 1-10 alkenyl, C 1-6 cycloalkyl, C 1-6 cycloalkenyl or C 1-10  alkynyl; 
         X is O or NOR 9 ; 
         R 4  is H; OR 9 , provided R 9  is not CH3; SR 9 ; NR 1 R 2  and 
         R 5  is H, OR 9 , SR 9 , NR 1 R 2 ; and 
         R 6 , R 7  and R 8  are independently H or C 1-5  alkyl, or R 6  and R 7  or R 7  and R 8  independently together form a cycle containing 1 or 2 carbon atoms, 
         and a colchicine analog as defined in Structure II 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently H, C 1-10  alkyl, C 1-6 cycloalkyl, C 1-10 alkenyl, C 1-6 cycloalkyl, C 1-6 cycloalkenyl or C 1-10  alkynyl, or together form a ring containing from 3 to 6 carbon atoms; provided that a carbon atom comprising an alkene or alkyne bond of R 1  and R 2  is not also simultaneously bound to N. R 1  and R 2  optionally may be substituted with one or more of F, OR 9 , or NR 10 R 11  where R 9 , R 10  and R 11  are independently H or C 1-5  alkyl; 
         R 3  is H, C 1-10 alkyl, C 1-6 cycloalkyl, C 1-10 alkenyl, C 1-6 cycloalkyl, C 1-6 cycloalkenyl or C 1-10  alkynyl; 
         X is O or NOR 9 ; 
         R 4  and R 5  are H, OR 9 , SR 9 , NR 1 R 2 ; and 
         R 6 , R 7  and R 8  are independently H or C 1-5  alkyl, or R 6  and R 7  or R 7  and R 8  independently form a cycle containing 1 or 2 carbon atoms. 
       
     
     
         2 . The device of  claim 1 , and further comprising therein an anti-inflammatory, anti-thrombotic or pro-healing agent. 
     
     
         3 . The device of  claim 1 , wherein said drug is selected as one defined in structure I, or a pharmaceutically acceptable salts thereof. 
     
     
         4 . The device of  claim 3 , wherein
 R 1  and R 2  are independently H, C 1-10  alkyl, or C 1-6 cycloalkyl   R 3  is H;   X is O;   R 4  is H; OR 9 , provided R 9  is not CH 3 ; SR 9 ; or NR 1 R 2      R 5  is H; and   R 6 , R 7  and R 8  are independently H or C 1-5  alkyl.   
     
     
         5 . The device of  claim 4 , wherein R 1  and R 2  are H, R 4  is OH and R 6 , R 7  and R 8  are H or CH 3 . 
     
     
         6 . The device of  claim 1 , wherein the drug is selected according to Formula I and has the structure 
       
         
           
           
               
               
           
         
       
     
     
         7 . The device of  claim 1 , wherein said device contains one or more active agents and a compound of structure II or pharmaceutically acceptable salts thereof of. 
     
     
         8 . The device of  claim 7 , wherein
 R 1  and R 2  are independently H, C 1-10  alkyl, or C 1-6 cycloalkyl   R 3  is H;   X is O;   R 4  is H, OR 9 , SR 9 , or NR 1 R 2 ;   R 5  is H; and   R 6 , R 7  and R 8  are independently H or C1-5 alkyl.   
     
     
         9 . The device of  claim 8 , wherein R 1  and R 2  are H, R 4  is OH or OCH3, and R 6 , R 7  and R 8  are H or CH3. 
     
     
         10 . The device of  claim 9 , wherein the compound has the structure 
       
         
           
           
               
               
           
         
       
     
     
         11 . A method of use of a device according to  claim 1 , wherein said device is a stent and comprising the step of inserting said stent inserted into a subject in need thereof. 
     
     
         12 . A method for reducing the incidence of restenosis, said method comprising the steps of:
 (a) providing a stent or other device as defined in  claim 1 , and   (b) implanting said stent or other device into the vasculature of a patient in need thereof.   
     
     
         13 . The device of  claim 1  which is a stent. 
     
     
         14 . The stent of  claim 13  combined with a biologically active agent selected from the group consisting of an anti-inflammatory agent, a pro-healing agent, a lipid metabolism modulating agent and an anti-thrombotic agent. 
     
     
         15 . The stent of  claim 13  wherein said drug has as defined in structure I or a pharmaceutically acceptable salts thereof. 
     
     
         16 . The stent of  claim 14 , wherein
 R 1  and R 2  are independently H, C 1-10  alkyl, or C 1-6  cycloalkyl;   R 3  is H;   X is O;   R 4  is H; OR 9 , provided R 9  is not CH3; SR 9 ; or NR 1 R 2      R 5  is H; and   R 6 , R 7  and R 8  are independently H or C1-5 alkyl.