Prevention and treatment of cardiovascular pathologies with tamoxifen analogues
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.