Therapeutic inhibitor of vascular smooth muscle cells

• US 6,358,989 B1
• Filed: 07/26/1999
• Issued: 03/19/2002
• Est. Priority Date: 05/13/1993
• Status: Expired due to Fees

• Current Assignee: Boston Scientific Scimed (Boston Scientific Corporation)
• Original Assignee: NeoRx Corporation
• Inventors: Kunz, Lawrence L., Reno, John M., Klein, Richard A.
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US09/361,194
• Time in Patent Office: 967 Days
• Field of Search: 514/411, 424/423, 424/402, 424/443, 424/445, 424/446, 424/447, 604/890.1, 604/891.1
• 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 47/6803 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 47/6849 : the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• 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 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 2300/432 : Inhibitors, antagonists A61L2300/402 - A61L2300/43 take precedence
• CPC Class Codes: A61L 2300/602 : Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/606 : Coatings
• CPC Class Codes: A61L 2300/622 : Microcapsules
• CPC Class Codes: A61L 31/08 : Materials for 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 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 9/00 : Drugs for disorders of the cardiovascular system
• 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: G01N 2800/323 : Arteriosclerosis, Stenosis
• CPC Class Codes: Y10S 977/906 : Drug delivery
• CPC Class Codes: Y10S 977/915 : Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10S 977/92 : Detection of biochemical

Abstract

Methods are provided for inhibiting stenosis or restenosis following vascular trauma in a mammalian host, comprising administering to the host a therapeutically effective dosage of a cytostatic agent and/or cytoskeletal inhibitor so as to biologically stent the traumatized vessel. Also provided is a method to inhibit or reduce vascular remodeling following vascular trauma, comprising administering an effective amount of a cytoskeletal inhibitor. Further provided are pharmaceutical compositions and kits comprising the therapeutic agents of the invention.

Claims

1. A pharmaceutical composition suitable for delivery via an implantable device, comprising:

(a) an amount of a cytochalasin or an analog thereof effective to inhibit or reduce stenosis or restenosis of a mammalian blood vessel traumatized by a surgical procedure; and

(b) a pharmaceutically acceptable non-liquid release matrix for said cytochalasin.

2. The composition of claim 1 wherein the composition is coated on the device.

3. The composition of claim 1 wherein the release matrix comprises a gel, permeable membrane or paste.

4. The composition of claim 1 wherein the release matrix comprises microparticles or nanoparticles comprising the cytochalasin or analog thereof.

5. The composition of claim 1 wherein the cytochalasin comprises cytochalasin B.

6. The composition of claim 1 wherein the cytochalasin comprises cytochalasin D.

7. The composition of claim 1 wherein the cytochalasin comprises cytochalasin A.

8. The composition of claim 1 wherein the cytochalasin is an analog of cytochalasin B.

9. The composition of claim 1 which is contained in a mesh.

10. The composition of claim 1 wherein the device is a shunt.

11. The composition of claim 1 wherein the device is a stent.

12. The composition of claim 1 wherein the device is an artificial graft.

13. The composition of claim 1 wherein the device is an adventitial wrap.

14. A therapeutic shunt comprising an amount of a cytoskeletal inhibitor effective to inhibit or reduce stenosis or restenosis following placement of the therapeutic shunt.

15. The therapeutic shunt of claim 14 wherein the cytoskeletal inhibitor comprises a cytochalasin, or an analog thereof.

16. A therapeutic adventitial wrap comprising an amount of a cytoskeletal inhibitor effective to inhibit or reduce stenosis or restenosis following placement of the therapeutic wrap.

17. The therapeutic adventitial wrap of claim 16 wherein the cytoskeletal inhibitor comprises a cytochalasin, or an analog thereof.

18. A therapeutic artificial graft comprising an amount of a cytochalasin or an analog thereof effective to inhibit or reduce stenosis or restenosis following placement of the therapeutic graft.

19. A therapeutic device comprising a stent overlayed with an artificial graft, wherein the graft comprises an amount of a cytoskeletal inhibitor effective to inhibit or reduce stenosis or restenosis following placement of the therapeutic device.

20. The therapeutic device of claim 19 wherein the cytoskeletal inhibitor comprises a cytochalasin, or an analog thereof.