Therapeutic inhibitor of vascular smooth muscle cells

• US 5,811,447 A
• Filed: 05/25/1995
• Issued: 09/22/1998
• Est. Priority Date: 01/28/1993
• Status: Expired due to Term

• Current Assignee: Boston Scientific Scimed, Inc. (Boston Scientific Corporation)
• Original Assignee: NeoRx Corporation
• Inventors: Grainger, David J., Kunz, Lawrence L., Anderson, Peter G., Reno, John M., Metcalfe, James C., Klein, Richard A., Weissberg, Peter L.
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US08/450,793
• Time in Patent Office: 1,216 Days
• Field of Search: 514/411
• US Class Current: 514/411
• 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 method for biologically stenting a mammalian blood vessel, which method comprises:

administering to the blood vessel of a mammal cytochalasin B or a cytochalasin that is a functional analog of cytochalasin B in an amount and for a period of time effective to inhibit the contraction of vascular smooth muscle cells while not eliminating their ability to secrete extracellular matrix.

2. The method of claim 1 wherein the vessel is subjected to angioplasty.

3. The method of claim 1 wherein the cytochalasin is infused to achieve a concentration of about 10^-3 to 10^-12 M.

4. The method of claim 1 wherein the cytochalasin is locally administered in one or more doses.

5. The method of claim 4 wherein the cytochalasin is administered by catheter.

6. The method of claim 1 wherein the cytochalasin is administered in solution.

7. The method of claim 1 further comprising the administration of a cytostatic agent in a sustained release dosage form.

8. The method of claim 7 wherein the cytostatic agent is effective to inhibit cellular proliferation subsequent to stenting.

15. The method of claim 1 wherein the administration of cytochalasin B or a functional analog thereof is before, during or after the trauma.

9. A therapeutic method comprising maintaining or expanding blood vessel luminal area by systemically administering to a mammal an effective amount of cytochalasin B or a cytochalasin that is a functional analog of cytochalasin B.

10. The method of claim 9 wherein the cytostatic agent comprises cytochalasin B or a cytochalasin that is a functional analog thereof.

11. The method of claim 10 wherein the sustained release formulation comprises microparticles or nanoparticles comprising said cytochalasin B or said functional analog thereof.

13. The method of claim 10 wherein the cytostatic agent comprises taxol or a structural analog thereof.

14. The method of claim 10 wherein the sustained release formulation comprises microparticles or nanoparticles comprising said cytochalasin B or said functional analog thereof.

16. The method of claim 10 wherein the administration of cytochalasin B or a functional analog thereof is before, during or after the trauma.

17. The method of claim 16 wherein the administration of cytochalasin B or a functional analog thereof and the administration of the cytostatic agent is simultaneous.

18. The method of claim 10 wherein the administration of the cytostatic agent is before or after the trauma.

12. A method for biologically stenting a mammalian blood vessel, which method comprises administering to the blood vessel of a mammal a cytoskeletal inhibitor in an amount and for a period of time effective to inhibit the contraction or migration of the vascular smooth muscle cells.