Therapeutic inhibitor of vascular smooth muscle cells

• US 8,097,642 B2
• Filed: 02/27/2007
• Issued: 01/17/2012
• Est. Priority Date: 02/15/1995
• Status: Expired due to Fees

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Inventors: Kunz, Lawrence L., Anderson, Peter G.
• Primary Examiner(s): VIVLEMORE, TRACY ANN
• Application Number:
  US11/679,650
• Publication Number:
  US 20070148207A1
• Time in Patent Office: 1,785 Days
• Field of Search: None
• US Class Current: 514/411
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/04 Nitro compounds
• CPC Class Codes: A61K 31/131 acyclic
• 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 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/365 Lactones
• 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 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 47/50 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
• CPC Class Codes: A61K 47/51 the non-active ingredient being a modifying agent
• 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 47/6923 : the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 47/6927 : the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 47/6957 : the form being a device or a kit, e.g. stents or microdevices
• 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: A61L 2300/416 : Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/602 : Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/604 : Biodegradation
• CPC Class Codes: A61L 2300/606 : Coatings
• CPC Class Codes: A61L 31/148 : Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: G01N 2800/323 : Arteriosclerosis, Stenosis
• CPC Class Codes: Y10S 977/775 : Nanosized powder or flake, e.g. nanosized catalyst
• CPC Class Codes: Y10S 977/808 : Exterior attachment for targeting, e.g. drug targeting
• CPC Class Codes: Y10S 977/905 : Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/906 : Drug delivery
• CPC Class Codes: Y10S 977/916 : Gene therapy

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.

Claims

1. A method of maintaining vessel luminal area, comprising inserting into the mammalian vessel an intravascular stent comprising a cytostatic amount of a cytoskeletal inhibitor effective to inhibit or reduce stenosis or restenosis upon placement of the stent, wherein the cytoskeletal inhibitor is not staurosporin or colchicine, wherein the cytostatic amount of the cytoskeletal inhibitor is an amount of the cytoskeletal inhibitor that exerts minimal protein synthesis inhibition and cytotoxicity on vascular smooth muscle cells, and exerts significant DNA synthesis inhibition on the vascular smooth muscle cells.

2. The method of claim 1 wherein the intravascular stent comprises metal or plastic.

3. The method of claim 1 wherein the intravascular stent comprises a biodegradable material.

4. The method of claim 3 wherein the intravascular stent consists essentially of a biodegradable material.

5. The method of claim 1 wherein the cytoskeletal inhibitor is in sustained release form.

6. The method of claim 5 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

7. The method of claim 5 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to vascular smooth muscle cells, stromal cells or interstitial matrix surrounding vascular smooth muscle cells.

8. The method of claim 1 wherein the intravascular stent comprises a biodegradable coating or a porous non-biodegradable coating comprising the cytoskeletal inhibitor.

9. The method of claim 1 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

10. The method of claim 1 wherein the vessel is subjected to further vascular trauma.

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

12. The method of claim 9 wherein the cytochalasin is cytochalasin B or an analog thereof.

13. A method for maintaining vessel luminal area, comprising inserting into a mammalian vessel an intravascular stent comprising a matrix and a cytostatic amount of a cytochalasin or an analog thereof effective to inhibit or reduce stenosis or restenosis upon placement of the stent, wherein the cytostatic amount of the cytochalasin or an analog thereof is an amount of the cytochalasin or an analog thereof that exerts minimal protein synthesis inhibition and cytotoxicity on vascular smooth muscle cells, and exerts significant DNA synthesis inhibition on the vascular smooth muscle cells.

14. The method of claim 13 wherein the cytochalasin or analog thereof is in sustained release form.

15. The method of claim 13 wherein the matrix of the stent is impregnated with the cytochalasin or analog thereof.

16. The method of claim 15 wherein the intravascular stent further comprises a coating comprising an amount of an inhibitor of vascular smooth muscle cell proliferation.

17. The method of claim 13 wherein the intravascular stent comprises a coating comprising the cytochalasin or analog thereof.

18. The method of claim 17 wherein the matrix is impregnated with an amount of an inhibitor of vascular smooth muscle cell proliferation.

19. The method of claim 13, 14, 15 or 17 wherein the cytochalasin comprises cytochalasin B.

24. The method of claim 14 or 21 wherein the sustained release form comprises a binding peptide or protein capable of specifically binding to vascular smooth muscle cells, stromal cells or interstitial matrix surrounding vascular smooth muscle cells.

25. The method of claim 16, 17, or 19, wherein the coating is formed form a biodegradable material.

26. The method of claim 13 or 20 wherein the vessel is subjected to angioplasty prior to stent placement.

20. A method for maintaining vessel luminal area, comprising inserting into a mammalian vessel an intravascular stent which comprises a matrix and a coating on said matrix, wherein the coating and the matrix together comprise a cytostatic amount of a cytoskeletal inhibitor effective to inhibit or reduce stenosis or restenosis upon placement of the intravascular stent, wherein the cytoskeletal inhibitor is not staurosporin or colchicine, wherein the cytoskeletal inhibitor is an amount of the cytoskeletal inhibitor that exerts minimal protein synthesis inhibition and toxicity on vascular smooth muscle cells, and exerts significant DNA synthesis inhibition on the vascular smooth muscle cells.

21. The method of claim 20 wherein the cytoskeletal inhibitor is in sustained release form.

22. The method of claim 20 wherein the cytoskeletal inhibitor comprises a cytochalasin or an analog thereof.

23. The method of claim 22 wherein the cytochalasin comprises cytochalasin B.

27. A method for maintaining vessel luminal area, comprising administering to a mammal a cytostatic amount of a cytoskeletal inhibitor effective to biologically stent said vessel, wherein the cytoskeletal inhibitor is administered in conjunction with intravascular stent placement, wherein the cytoskeletal inhibitor is not staurosporin or colchicine, wherein the cytostatic amount of the cytoskeletal inhibitor is an amount of the cytoskeletal inhibitor that exerts minimal protein synthesis inhibition and cytotoxicity on vascular smooth muscle cells, and exerts significant DNA synthesis inhibition on the vascular smooth muscle cells.

28. The method of claim 27, wherein the cytostatic amount of the cytoskeletal inhibitor is effective to inhibit or reduce stenosis or restenosis following stent placement.

29. The method of claim 27 wherein the cytostatic amount of the cytoskeletal inhibitor is effective to inhibit vascular smooth muscle cell proliferation.