Therapeutic inhibitor of vascular smooth muscle cells

• US 5,733,925 A
• Filed: 10/28/1996
• Issued: 03/31/1998
• Est. Priority Date: 01/28/1993
• Status: Expired due to Term

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: NeoRx Corporation
• Inventors: Anderson, Peter G., Grainger, David J., Kunz, Lawrence L., Reno, John M., Metcalfe, James C., Klein, Richard A., Weissberg, Peter L.
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US08/738,733
• Time in Patent Office: 519 Days
• Field of Search: 514/449, 514/411
• US Class Current: 514/449
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6817 Toxins
• CPC Class Codes: A61K 47/6831 Fungal toxins, e.g. alpha sarcine, mitogillin, zinniol or restrictocin
• CPC Class Codes: A61K 47/6843 the antibody targeting a material from animals or humans
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 47/6931 the material constituting the nanoparticle being a polymer
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: G01N 2800/323 Arteriosclerosis, Stenosis

Abstract

Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent. Also discussed are mechanisms for in vivo vascular smooth muscle cell proliferation modulation, agents that impact those mechanisms and protocols for the use of those agents.

Claims

1. A therapeutic method comprising inhibiting stenosis or restenosis of a blood vessel by administering to a mammal an effective amount of taxol or a structural analog thereof.

2. The method of claim 1 wherein an effective amount of taxol is administered.

3. The method of claim 1 or 2 wherein the administration is local.

4. The method of claim 3 wherein the administration is via a catheter.

5. The method of claim 1 or 2 wherein the administration is systemic.

6. The method of claim 5 wherein the administration is oral.

7. The method of claim 1 or 2 wherein vessel is subjected to procedural vascular trauma.

8. The method of claim 7 wherein the administration is before, during or after the trauma.

9. The method of claim 8 wherein the vascular trauma is associated with angioplasty, placement of a stent, or grafting.

10. The method of claim 1 wherein the amount is effective to inhibit proliferation of vascular smooth muscle cells.

11. The method of claim 1 wherein the administration is accomplished by a sustained release dosage form.

12. The method of claim 11 wherein the sustained release dosage form is biodegradable.

13. A method for biologically stenting a mammalian blood vessel which is subjected to procedural vascular trauma, which method comprises administering to the blood vessel an amount of taxol or a structural analog thereof effective to biologically stent the vessel.

14. The method of claim 13 wherein the amount does not eliminate the ability of vascular smooth muscle cells to secrete extracellular matrix.

15. The method of claim 13 wherein the administration is by a catheter.

16. The method of claim 13 wherein the administration is before, during or after the trauma.

17. The method of claim 13 wherein the vessel is subjected to angioplasty, placement of a stent, or grafting.

18. The method of claim 13 wherein the administration is local.

19. The method of claim 13 wherein taxol is administered.

20. The method of claim 13 wherein the administration further comprises the administration of a sustained release dosage form comprising a cytoskeletal inhibitor.

21. A therapeutic method comprising:

(a) administering to a blood vessel of a mammal traumatized by a surgical procedure an amount of taxol or a structural analog thereof effective to biologically stent the vessel; and

(b) administering an amount of a sustained release dosage form comprising an amount of a cytostatic agent effective to inhibit proliferation of the cells of the vessel caused by said procedure.

22. The method of claim 21 wherein the administration is local.

23. The method of claim 21 wherein the cytostatic agent comprises cytochalasin B or a cytochalasin that is a functional analog thereof.

24. The method of claim 21 wherein the cytostatic agent comprises taxol or a structural analog thereof.

25. The method of claim 21 wherein the sustained release dosage form comprises microparticles or nanoparticles.

26. The method of claim 21 wherein the administration of taxol or a structural analog thereof is before, during or after the trauma.

27. The method of claim 26 wherein the administration of taxol or a structural analog thereof and the administration of the cytostatic agent is simultaneous.

28. The method of claim 21 wherein the administration of the cytostatic agent is before or after the trauma.