Methods for inhibiting stenosis, obstruction, or calcification of a stented heart valve or bioprosthesis

• US 10,058,630 B2
• Filed: 05/22/2017
• Issued: 08/28/2018
• Est. Priority Date: 10/22/2012
• Status: Active Grant

• Current Assignee: ConcieValve, LLC
• Original Assignee: ConcieValve, LLC
• Inventors: Rajamannan, Nalini M.
• Primary Examiner(s): Mathew, Seema
• Application Number:
  US15/601,236
• Publication Number:
  US 20170304497A1
• Time in Patent Office: 463 Days
• CPC Class Codes: A61F 2/2412 with soft flexible valve members, e.g. tissue valves shaped like natural valves check valves with flexible valve members in general F16K15/14
• CPC Class Codes: A61F 2/2418 Scaffolds therefor, e.g. support stents
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• 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 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 2300/204 with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
• CPC Class Codes: A61L 2300/21 Acids
• CPC Class Codes: A61L 2300/258 Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
• 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 2300/606 Coatings
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• CPC Class Codes: A61L 2430/20 for reconstruction of the heart, e.g. heart valves
• CPC Class Codes: A61L 27/3625 Vascular tissue, e.g. heart valves
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

Methods for inhibiting stenosis, obstruction and/or calcification of a heart valve following implantation in a vessel having a wall are disclosed. In one aspect the method includes providing a bioprosthetic heart valve mounted on an elastical stent; treating the bioprosthetic heart valve with a tissue fixative; coating the stent and the bioprosthetic valve with a coating composition including one or more therapeutic agents; implanting the bioprosthetic valve into the vessel in a diseased natural valve site; eluting the coating composition from the bioprosthetic valve; and inhibiting stenosis, obstruction and/or calcification of the bioprosthetic heart valve by preventing the attachment of stem cells to the bioprosthetic heart valve, the stem cells circulating external and proximate to the bioprosthetic heart valve by activating nitric oxide production (i) in the circulating stem cells, (ii) in an endothelial cell lining covering the bioprosthetic heart valve tissue, (iii) or both.

Claims

1. A method for inhibiting stenosis, obstruction and/or calcification of a heart valve following implantation in a vessel having a wall, said method comprising:

providing a bioprosthetic heart valve comprising tissue having one or more cusps, said bioprosthetic heart valve mounted on an elastical stent for replacement of a natural diseased valve;

treating said bioprosthetic heart valve with a tissue fixative prior to applying a coating composition comprising one or more therapeutic agents;

coating said stent, one or more cusps, or both with the coating composition after treating the bioprosthetic heart valve with the tissue fixative, said coating composition including (i) a nitric oxide activator;

(ii) an anti-proliferative agent; and

(ii) an inhibitor of extracellular protein matrix production;

implanting said bioprosthetic valve into said vessel in a diseased natural valve site;

eluting said coating composition from said elastical stent, one or more cusps, or both;

inhibiting stenosis, obstruction and/or calcification of the bioprosthetic heart valve by preventing the attachment of stem cells to the bioprosthetic heart valve, said stem cells circulating external and proximate to the bioprosthetic heart valve, elastical stent or both by (a) activating nitric oxide production, (b) inhibiting cell proliferation, and (c) inhibiting extracellular protein matrix production, (i) in the circulating stem cells, (ii) in an endothelial cell lining covering the bioprosthetic heart valve tissue, (iii) or both.

2. The method of claim 1 wherein said stem cells are selected from cKit positive stem cells SCA1 cells, COP cells, mesenchymal stem cells and combinations of the foregoing.

3. The method of claim 1 wherein the nitric oxide activator is selected from Atorvastatin, Rosuvastatin, Pravastatin, Mevastatin, Fluvastatin, Simvastatin, Lovastatin, L-Arginine, citrulline, NADPH, acetylcholine, histamine, arginine vasopressin, norepinephrine, epinephrine, bradykinin, adenosine di,triphosphate, 5-Hydroxytrptamine, thrombin, insulin, glucocorticoids, salicylates, L-NMMA, L-NAME, nitroglycerine, isosorbide dinitrate, isosorbide 5-mononitrate, amyl nitrite, nicorandil, tetrahydrobiopterin, Zetia, a PCSK9 inhibitor and combinations of the foregoing.

4. The method of claim 3 further comprising administering an oral dosage of said eNOS nitric oxide activators.

5. The method of claim 4 wherein said oral dosages comprises 10 mg to 80 mg per day of Atorvastatin;

10 mg to 40 mg Simvastatin per day;

5 mg to 40 mg Rosuvastatin per day;

10 mg to 40 mg Pravastatin per day;

1 mg to 4 mg Pitavastatin per day;

10 mg Ezetimibe per day and combinations of the foregoing.

6. The method of claim 1 wherein inhibiting extracellular protein matrix production is for inhibiting bone formation in an osteoblast cell originating from said stem cells.

7. The method of claim 1 wherein said anti-proliferative agent is selected from paclitaxel, sirolimus, biolimus, everolimus and combinations of the foregoing.

8. The method of claim 1 wherein said inhibitor of extracellular protein matrix production is selected from an anti-farnysitransferase inhibitor, an anti-palmitoylation inhibitor or both.

9. The method of claim 8 wherein said anti-farnysltransferase inhibitor, an anti-palmitoylation inhibitor are selected from Lonafarnib, Tipifarnib R115777, FTI SCH66336, STI571, FLT-3 Inhibitor, Proteasome Inhibitor, MAPK Inhibitor, BMS-214662, Type I non-lipid inhibitors of protein palmitoylation, farnesyl-peptide palmitoylation or Type 2 inhibitors myristoyl-peptide palmitoylation, palmitoylation acyltransferase inhibitors, lipid based palmitoylation inhibitors including 2-bromopalmitoyl (2BP), tunicamycin, cerulnin and combinations of the foregoing.

10. The method of claim 9 further comprising administering an oral dosage of said anti-farnysltransferase inhibitor, said anti-palmitoylation inhibitor or both.

11. The method of claim 10 wherein said dosage comprises Lonafarnib in a dosage of 115 mg/m2 dose with a range from 115 mg/m2 to 150 mg/m2, in combination with an effective amount of Zetia of 10 mg.

12. The method of claim 1 wherein said inhibitor of extracellular protein matrix production is selected from anti-osteoporotic agents such as bisphosphonate drugs including Alendronate, Risedronate, Zoledronic acid, Etidronate, Ibandronate, Pamidronate, Tiludronate, Denosumab antibody, Calcitonin-Calcimare, Miacalcin, Forteo teriparatide, raloxfine and combinations of the foregoing.

13. The method of claim 1 further comprising administering an effective amount of a PCSK9 inhibitor by intramuscular or subcutaneous injection.

14. The method of claim 13 wherein an initial dose of the PCSK9 inhibitor is from 0.25 mg/kg to 1.5 mg/kg.

15. The method of claim 14 wherein said initial dose of the PCSK9 inhibitor is from 0.5 mg/kg to 1 mg/kg.

16. The method of claim 13 wherein said effective amount of said PCSK9 inhibitor is Alirocumab 75-150 mg every 2 to 4 weeks, Evolocumab 140 mg every 2 weeks or monthly and combinations of the foregoing.