Prevention and treatment of cardiovascular pathologies with tamoxifen analogues

Abstract

A method for treating or preventing cardiovascular pathologies by administering a compound of the formula (I): wherein Z is C═O or a covalent bond; Y is H or O(C 1 -C 4 )alkyl, R 1 and R 2 are individually (C 1 -C 4 )alkyl or together with N are a saturated heterocyclic group, R 3 is ethyl or chloroethyl, R 4 is H, R 5 is I, O(C 1 -C 4 )alkyl or H and R 6 is I, O(C 1 -C 4 )alkyl or H with the proviso that when R 4 , R 5 , and R 6 are H, R 3 is not ethyl; or a pharmaceutically acceptable salt thereof, effective to elevate the level of TGF-beta to treat and/or prevent conditions such as atherosclerosis, thrombosis, myocardial infarction, and stroke is provided. Useful compounds include idoxifene, toremifene or salts thereof. Further provided is a method for identifying an agent that elevates the level of TGF-beta. Another embodiment of the invention is an assay or kit to determine TGF-beta in vitro. Also provided is a therapeutic method comprising inhibiting smooth muscle cell proliferation associated with procedural vascular trauma employing the administration of tamoxifin or structural analogs thereof, including compounds of formula (I).

1 - 152 . (canceled)  
   
   
       153 . A therapeutic method for preventing or treating a vascular indication in a mammal which indication is characterized by a decreased lumen diameter, comprising: 
 a) selecting an agent for TGF-beta elevation;    b) administering a cytostatic dose of the agent to the mammal so as to inhibit smooth muscle cell proliferation, inhibit lipid accumulation, increase plaque stability, or any combination thereof.    
   
   
       154 . A therapeutic method for preventing or treating a vascular indication in a mammal which indication is characterized by a decreased lumen diameter, comprising: 
 a) determining an agent for TGF-beta elevation;    b) selecting a cytostatic dose of the agent; and    c) administering the dose to the mammal so as to inhibit smooth muscle cell proliferation, inhibit lipid accumulation, increase plaque stability, or any combination thereof.    
   
   
       155 . The method of  claim 153  or  154  wherein the indication is a cardiovascular indication.  
   
   
       156 . The method of  claim 153  or  154  wherein the agent has reduced estrogenic activity or DNA adduct formation relative to tamoxifen.  
   
   
       157 . The method of  claim 153  or  154  wherein the administration is systemic.  
   
   
       158 . The method of  claim 153  or  154  wherein the administration is local.  
   
   
       159 . The method of  claim 153  or  154  wherein the agent is administered in a sustained release dosage form.  
   
   
       160 . The method of  claim 153  or  154  wherein the agent directly or indirectly increases the level of active TGF-beta.  
   
   
       161 . The method of  claim 153  or  154  wherein the agent is a TGF-beta production stimulator.  
   
   
       162 . The method of  claim 153  or  154  wherein the agent is a TGF-beta activator.  
   
   
       163 . The method of  claim 153  or  154  wherein the agent increases the production of TGF-beta mRNA.  
   
   
       164 . The method of  claim 153  or  154  wherein the agent is administered via a stent.  
   
   
       165 . The method of  claim 153  or  154  wherein the administration is oral.  
   
   
       166 . The method of  claim 153  or  154  wherein the smooth muscle cell proliferation is associated with procedural vascular trauma.  
   
   
       167 . The method of  claim 166  wherein the procedural vascular trauma is due to organ transplantation, vascular surgery, transcatheter vascular therapy, vascular grafting, placement of a shunt or placement of an intravascular stent.  
   
   
       168 . The method of  claim 166  wherein the administration is before or after, or both before and after said procedure.  
   
   
       169 . A method, comprising: 
 a) determining an agent for TGF-beta elevation; and    b) identifying a cytostatic dose of the agent effective to prevent or treat a vascular indication in a mammal which indication is characterized by a decreased lumen diameter.    
   
   
       170 . The method of  claim 169  wherein the agent directly or indirectly increases the level of active TGF-beta.  
   
   
       171 . The method of  claim 169  wherein the agent is a TGF-beta production stimulator.  
   
   
       172 . The method of  claim 169  wherein the agent is a TGF-beta activator.  
   
   
       173 . The method of  claim 169  wherein the agent increases the production of TGF-beta mRNA.