HK1228242B - Methods for inhibiting stenosis, obstruction, or calcification of a stented heart valve or bioprosthesis - Google Patents

Description

Method for inhibiting stenosis, obstruction, or calcification of stent-type heart valves or bioprostheses

Incorporated by reference

All documents cited or referenced herein ("herein-cited documents"), and all documents cited or referenced by the herein-cited documents, together with any manufacturer's instructions, descriptions, product inserts, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated by reference and may be used in the practice of the present invention. More specifically, all referenced documents are incorporated by reference herein to the same extent as if each document was specifically and individually indicated to be incorporated by reference.

Field of the Invention

The present invention relates to methods for inhibiting stenosis, obstruction or calcification of heart valves and heart valve prostheses.

Background of the Invention

The heart is a hollow, muscular organ that circulates blood throughout the body through rhythmic contractions. In mammals, the heart has four chambers, positioned so that the right atrium and ventricle are completely separated from the left atrium and ventricle. Normally, blood flows from the systemic veins into the right atrium, then into the right ventricle, from which it is driven to the lungs via the pulmonary artery. When blood returns from the lungs, it enters the left atrium and then into the left ventricle, from which it is driven to the systemic arteries.

Four major heart valves—the tricuspid, pulmonary, mitral, and aortic valves—prevent the backflow of blood during rhythmic contractions. The tricuspid valve separates the right atrium from the right ventricle, the pulmonary valve separates the right atrium from the pulmonary artery, the mitral valve separates the left atrium from the left ventricle, and the aortic valve separates the left ventricle from the aorta. Generally speaking, patients with heart valve abnormalities are characterized as having valvular heart disease.

Heart valves can malfunction by failing to open properly (stenosis) or by leaking (regurgitation). For example, a patient with a malfunctioning aortic valve may be diagnosed with aortic stenosis or aortic regurgitation. In either case, valve replacement, performed surgically, may be a viable treatment option. The replacement valve may be an autologous graft, an allograft, or a xenograft, as well as a mechanical valve, or a valve made in part from another animal, such as a pig or cow. Unfortunately, over time, the replacement valve itself is susceptible to problems such as degeneration, thrombosis, calcification, and/or obstruction. In addition, the process of valve replacement can cause perforation of surrounding tissue, and may also lead to stenosis, degeneration, thrombosis, calcification, and/or obstruction.

Therefore, new methods for inhibiting stenosis, obstruction, or calcification of heart valves and heart valve prostheses are needed.

Citation or disclosure of any document in this patent application is not an admission that such document is available as prior art to the present invention.

SUMMARY OF THE INVENTION

The present invention relates to a method for inhibiting stenosis, obstruction or calcification of a valve after implantation of a valve prosthesis in a patient in need thereof. The method may include: arranging a coating composition on an elastic stent, a Gortex graft material or a valve leaflet, wherein the coating composition may contain one or more therapeutic agents; and fixing the valve prosthesis, which may include a collapsible elastic valve, which is mounted on the elastic stent at a desired position in the patient's body so that the elastic stent contacts the valve, or the Gortex graft material contacts the prosthesis, thereby inhibiting stenosis, obstruction or calcification of a surgical replacement of a valve or stent or a bioprosthesis after implantation of the valve prosthesis in a patient in need thereof.

It is therefore an object of the present invention to exclude from the scope of the present invention any heretofore known product, process for making a product, or method of using a product, such that applicants reserve the right and hereby disclose a specific disclaimer of any heretofore known product, process, or method. It is further noted that the present invention is not intended to exclude from the scope of the present invention any product, process, or method of making a product or using a product that does not satisfy the written description and enabling requirements of the USPTO (35 U.S.C. §112, first paragraph) or the EPO (Article 83 of the EPC), such that applicants reserve the right and hereby disclose a specific disclaimer of any heretofore described product, process for making a product, or method of using a product.

It is noted that in this disclosure, particularly in the claims and/or paragraphs, terms such as "comprising," "including," "having," and the like may have the meanings they have in U.S. patent law; for example, they may mean "including," "comprising," "having," and the like; and terms such as "consisting essentially of..." have the meanings they have in U.S. patent law, for example, they allow for elements not expressly recited but exclude elements that are present in the prior art or that affect the basic or novel characteristics of the invention.

These and other embodiments are disclosed by, are obvious from, and are encompassed by, the following detailed description.

In other aspects, the present invention may be illustrated in the following numbered clauses:

1. A method for inhibiting stenosis, obstruction, or calcification of a bioprosthetic valve after implantation of the bioprosthetic valve into a blood vessel having a wall, the method comprising:

Providing a bioprosthetic valve for surgical replacement of a native diseased valve, the bioprosthetic valve comprising an elastic stent;

providing a coating composition on the elastomeric stent, the bioprosthetic valve, or both, wherein the coating composition comprises one or more therapeutic agents that inhibit cell proliferation and calcification in combination with an effective amount of atorvastatin that inhibits cell attachment by reducing inflammation;

implanting the bioprosthetic valve into the blood vessel by surgically removing a native valve and replacing the native valve with the bioprosthesis, or placing the bioprosthesis over the native valve having valve leaflets such that the native valve leaflets are pressed against the blood vessel wall;

eluting the combination of therapeutic agents from the elastomeric stent, the bioprosthetic valve, or both; and

Inhibition of stenosis, obstruction, or calcification of the bioprosthetic or native valve, or both, following implantation of the bioprosthetic valve.

2. The method of clause 1, wherein any of the anti-restenotic agents used with stents, Goltex grafts, and bioprostheses include antiproliferative and anticalcific agents including sirolimus (and analogs), Paclitaxel, Taxane, Dexamethasone, M-prednisolone, Interferon gamma-1b, Leflunomide, Tacrolimus, Mycophenolic acid, Mizoribine, Cyclosporine, Tranilast, Biorest, antiproliferative agents, Rapamycin (Sirolmus) (and analogs), Paclitaxel, Taxane, Actinomycin D, Methotrexate, Angiopeptide, Vincristine, Mitomycin, C Myc antisense, RestenASE, 2-chloro-deoxyadenylic acid, PCNA ribozyme: smooth muscle cell migration inhibitors, extracellular matrix regulators, batimastat, prolyl hydroxylase inhibitors, halofuginone, C-proteinase inhibitors, probucol and MAP kinase inhibitor MEK (5.0-10 μg/ml) (drug dosages for existing drugs on stents in the US market: sirolimus 140mcg/cm2, paclitaxel dose 1mcg/mm2, everolimus dose 100mcg/cm2, tazolimus 10mcg/1mm stent length, biocysteine 15.6mcg/mm2) combined with an effective amount of 80mg of atorvastatin.

3. The method of clause 1 , further comprising implanting the bioprosthetic valve by catheterization.

4. The method of clause 1 , wherein the bioprosthetic valve is an aortic bioprosthetic valve.

5. The method of clause 1 , wherein the bioprosthetic valve is a bioprosthetic mitral valve.

6. The method of clause 1 , wherein the bioprosthetic valve is a bioprosthetic pulmonary valve.

7. The method of clause 1 , wherein the bioprosthetic valve is a bioprosthetic tricuspid valve.

8. The method of clause 1 , wherein the bioprosthetic valve comprises one or more cusps of biological origin.

9. The method of clause 8, wherein the one or more cusps are porcine, bovine, or human.

10. The method of clause 8, further comprising introducing a nucleic acid encoding nitric oxide synthase into one or more cusps.

11. The method of clause 8, further comprising introducing a drug eluting treatment encoating on both sides of one or more cusps with an anti-proliferative and anticalcific treatment.

12. The method of clause 1 , wherein the resilient support is substantially cylindrical.

13. The method of clause 12, wherein the resilient support has a diameter of about 15 mm to about 42 mm.

14. A valve prosthesis comprising:

Elastic bracket;

Goltex grafts;

a bioprosthetic valve having leaflets operably coupled to the elastic stent;

Combinations with an effective amount of atorvastatin, including antiproliferative and anticalcifying agents including sirolimus (and analogs), paclitaxel, taxanes, dexamethasone, M-prednisolone, interferon gamma-1b, leflunomide, tacrolimus, mycophenolic acid, mizoribine, cyclosporine, tranilast, biolast, antiproliferative agents, rapamycin (and analogs), paclitaxel, taxanes, actinomycin D, methotrexate, angiopeptide, vincristine, mitomycin, C any one of the anti-restenotic agents used with stents, Goltex grafts and bioprostheses, including Myc antisense, RestenASE, 2-chloro-deoxyadenylic acid, PCNA ribozyme, smooth muscle cell migration inhibitors, extracellular matrix modulators, batimastat, prolyl hydroxylase inhibitors, halofuginone, C-proteinase inhibitors, probucol and the MAP kinase inhibitor MEK, in combination with atorvastatin, deposited on the sides of the elastomeric stent, Goltex graft, bioprosthetic valve leaflets, or both, the effective amount being configured to elute from the elastomeric stent, Goltex graft, bioprosthetic valve leaflets, or both;

wherein the bioprosthetic valve is configured to be implanted into a blood vessel having a vascular wall to replace a naturally diseased valve;

The bioprosthetic valve is configured to inhibit stenosis, obstruction, or calcification of the bioprosthetic valve and the native valve after implantation of the bioprosthetic valve prosthesis.

15. The bioprosthetic valve of clause 14, wherein the bioprosthetic valve is coupled to a surgical sewing ring.

16. The bioprosthetic valve of clause 14, wherein the therapeutic agent is selected from the group consisting of paclitaxel, sirolimus, biocysteine, everolimus, tadalafil, and combinations thereof, including antiproliferative and anticalcific agents including sirolimus (and analogs), paclitaxel, taxanes, dexamethasone, M-prednisolone, interferon gamma-1b, leflunomide, tacrolimus, mycophenolic acid, mizoribine, cyclosporine, tranilast, biolast, antiproliferative agents, rapamycin (and analogs), taxol, taxanes, actinomycin D, methotrexate, angiopeptides, vincristine, mitomycin, C Any of the anti-restenotic agents used with stents, Goltex grafts, and bioprostheses, including Myc antisense, RestenASE, 2-chloro-deoxyadenylic acid, PCNA ribozymes, smooth muscle cell migration inhibitors, extracellular matrix modulators, batimastat, prolyl hydroxylase inhibitors, halofuginone, C-proteinase inhibitors, probucol, and the MAP kinase inhibitor MEK, are used in combination with an effective dose of atorvastatin.

17. The bioprosthetic valve of clause 14, sized and configured to be implanted into a coronary valve of a patient via catheterization.

18. The bioprosthetic valve of clause 14, wherein the valve is an aortic valve.

19. The bioprosthetic valve of clause 14, wherein the bioprosthetic valve comprises one or more cusps of biological origin.

20. The bioprosthetic valve of clause 19, wherein the one or more cusps are porcine, bovine, or human.

21. The bioprosthetic valve of clause 19, further comprising a nucleic acid encoding nitric oxide synthase in one or more cusps.

22. The resilient mount of clause 14 is sized, constructed and arranged to have a substantially cylindrical configuration.

23. The valve prosthesis of clause 14, wherein the diameter of the elastic support is about 15 mm to about 42 mm.

24. The method of clause 1, wherein the elastomeric scaffold has a surface configuration and arrangement configured to reduce neointimal proliferation.

25. The valve prosthesis of clause 14, wherein the resilient stent has a surface configuration and arrangement configured to reduce neointimal proliferation.

26. The method of clause 1, wherein the bioprosthetic valve has a surface texture and wherein the antiproliferative and anticalcific agents include sirolimus (and analogs), paclitaxel, taxanes, dexamethasone, M-prednisolone, interferon gamma-1b, leflunomide, tacrolimus, mycophenolic acid, mizoribine, cyclosporine, tranilast, biolast, antiproliferative agents, rapamycin (and analogs), paclitaxel, taxanes, actinomycin D, methotrexate, angiopeptides, vincristine, mitomycin, C Any anti-restenotic agent used with stents, Goltex grafts and bioprostheses, including Myc antisense, RestenASE, 2-chloro-deoxyadenylic acid, PCNA ribozyme: smooth muscle cell migration inhibitors, extracellular matrix modulators, batimastat, prolyl hydroxylase inhibitors, halofuginone, C-proteinase inhibitors, probucol and MAP kinase inhibitor MEK (5.0-10 μg/ml) (doses of current drugs on stents for the US market: sirolimus 140mcg/cm2, paclitaxel dose 1mcg/mm2, everolimus dose 100mcg/cm2, tazolimus 10mcg/1mm stent length, biocysteine 15.6mcg/mm2) in combination with an effective amount of 80mg of atorvastatin to improve the efficacy of calcification inhibition and extend the life of prosthetic materials including stents, valves and Goltex covers.

28. The bioprosthetic valve of clause 14, sized, constructed, and arranged to be implanted into a coronary valve of a patient by catheterization.

29. The bioprosthetic valve of clause 14, wherein the valve is an aortic valve.

30. The bioprosthetic valve of clause 14, wherein the bioprosthetic valve comprises one or more cusps of biological origin.

31. The bioprosthetic valve of clause 30, wherein the one or more cusps are porcine, bovine, or human.

32. The bioprosthetic valve of clause 14, further comprising a nucleic acid encoding nitric oxide synthase in one or more cusps.

33. The method of clause 1, further comprising providing a sewing ring operably coupled to the bioprosthetic valve, the sewing ring having a surface configuration and arrangement configured to reduce neointimal proliferation.

34. The valve prosthesis of clause 14, further comprising a sewing ring operably coupled to the bioprosthetic valve, the sewing ring having a surface configuration and arrangement configured to reduce neointimal proliferation and pannus formation.

35. The valve prosthesis of clause 14, wherein the bioprosthetic valve comprises a GolTex graft, wherein said portion of said valve prosthesis comprises an antiproliferative and anticalcifying agent comprising sirolimus (and analogs), paclitaxel, taxanes, dexamethasone, M-prednisolone, interferon gamma-1b, leflunomide, tacrolimus, mycophenolic acid, mizoribine, cyclosporine, tranilast, biolast, antiproliferative agents, rapamycin (and analogs), paclitaxel, taxanes, actinomycin D, methotrexate, angiopeptide, vincristine, mitomycin, C Any of the anti-restenotic agents used with stents, Goltex grafts and bioprostheses, including Myc antisense, RestenASE, 2-chloro-deoxyadenylic acid, PCNA ribozymes, smooth muscle cell migration inhibitors, extracellular matrix modulators, batimastat, prolyl hydroxylase inhibitors, halofuginone, C-proteinase inhibitors, probucol and MAP kinase inhibitor MEK, are deposited in combination with an effective amount of atorvastatin to enhance the efficacy of calcification inhibition and extend the life of prosthetic materials including stents, valves and Goltex coverings.

36. The valve prosthesis of clause 35, wherein the effective amount of atorvastatin reduces pannus formation along a surface of the graft.

37. The method of clause 1, further comprising administering an oral dose of 80 mg atorvastatin 80 mg/day and reducing stem cell attachment to stents, GolTex grafts, and valves.

38. Antiproliferative Agents (MAP Kinase Inhibitors) MEK inhibitors at doses ranging from 5 to 10 μg/ml inhibited the proliferation of mesenchymal valve cells induced by PDGF at a concentration of 10 μg/ml, as shown in FIG16 .

39. The method of clause 37, further comprising administering aspirin 80 mg/day and an oral P2Y12 inhibitor selected from clopidogrel 75 mg/day with a loading dose of 300 mg/day during intervention, prasugrel 60 mg/day with a maintenance dose of 10 mg/day, and ticagrelor with a loading dose of 180 mg/day and a maintenance dose of 90 mg twice daily.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description is given by way of examples, but is not intended to limit the present invention to the specific embodiments described. Instead, it can be better understood in conjunction with the accompanying drawings.

FIG. 1 is a front perspective view of a bioprosthetic aortic valve showing leaflets 16 and stent 10 .

FIG. 2 is a front perspective view of another type of aortic valve showing leaflets 26 and stent 28 .

3 is a schematic front view of the aorta showing the aorta in which the aortic valve of FIG. 1 is interposed at the time of initial implantation before any disease may have occurred in the aorta due to the stent.

4 is a front cross-sectional view of the aorta 32 in which the aortic valve of FIG. 2 is inserted at the time of initial implantation before any disease may develop in the aorta 32 caused by the stent 28 .

Figure 5 is a schematic diagram of the aorta having the aortic valve of Figure 1, wherein the aorta surrounding the stent has been partially blocked by a stenosis caused by the proliferation and differentiation of vascular smooth muscle cells into osteoblasts following stent injury adjacent to the aorta, the proliferation and differentiation of c-kit stem cells into osteoblasts secondary to inflammation, and the homing of c-kit stem cells into osteoblasts.

Figure 6 is a front cross-sectional view of the aorta, which shows that the aorta surrounding the stent of Figure 2 is partially blocked by a stenosis caused by the proliferation and differentiation of vascular smooth muscle cells into osteoblasts after stent injury adjacent to the aorta, the proliferation and differentiation of c-kit stem cells into osteoblasts secondary to inflammation, and the homing of c-kit stem cells into osteoblasts.

7 is a top view of a mesh for the stented aortic valve of FIG. 2 .

8 is a top view showing the mesh of FIG. 7 coated with an anti-proliferative coating that inhibits stenosis of the stent surrounding the aorta, inhibiting smooth muscle cell proliferation and calcification of the aorta, which is a treatment and invention for this type of stent.

FIG. 9 is a photograph of a Portico™ valve prosthesis being inserted into a patient's aorta using a catheter.

10 is a photograph showing a Portico™ transcatheter heart valve and an 18-F delivery catheter used to insert the heart valve into the aorta.

FIG. 11 is a photograph showing the valve leaflets of FIG. 1 treated with an anti-proliferative coating along stent 10 and valve leaflets 16 .

12 is a photograph showing the valve leaflets of FIG. 2 treated with an anti-proliferative agent coating along the stent and valve leaflets.

FIG13 depicts pannus formation and calcification in a valve explanted from a human patient during surgical valve replacement of a failed bioprosthetic heart valve, secondary to proliferating mesenchymal stem cells attached to the valve and stent, which calcify and lead to valve leaflet and stent destruction.

FIG. 14 is a graph showing RNA expression of ckit-positive stem cells attached to calcified heart valves.

FIG. 15 depicts the results of testing the anti-inflammatory agent atorvastatin at 80 mg/day.

FIG. 16 depicts the results of an assay in which the growth factor PDGF triggers cell proliferation and a MEK inhibitor blocks cell proliferation.

Figure 17 depicts two mechanisms of two different agents that combine to enhance the efficacy of inhibition of mesenchymal cell attachment, inhibiting mesenchymal cell proliferation and calcification to improve stents, GolTex grafts and valves, extending the life of these prostheses by targeting activated inflammation when exogenous prostheses are introduced into the human body.

Detailed Description of the Invention

The present invention provides a method for inhibiting stenosis, obstruction or calcification of a stented aorta and valve leaflets or a bioprosthesis with or without a sewing ring after implantation of a valve prosthesis in a patient in need thereof, the method may include: disposing a coating composition on an elastic stent, a Goltex covering and a bioprosthesis, wherein the coating composition may include one or more therapeutic agents to enhance the efficacy of inhibiting calcification and extend the life of the prosthetic materials including the stent, valve and Goltex covering.

; fixing a collapsible elastic bioprosthetic valve, which is mounted on an elastic stent at a desired position in a patient's body so that the elastic stent contacts a natural valve that may or may not be surgically removed, and optionally arranging a coating composition on both sides of a valve leaflet, stent or sewing ring through which the bioprosthetic valve is fixed, thereby inhibiting stenosis, obstruction or calcification of the stented aorta after implantation of a stented valve prosthesis or surgical replacement of a bioprosthesis that replaces the natural valve in a patient in need thereof.

As used herein, the term "stenosis" can refer to a narrowing of a heart valve, which can block or impede blood flow from the heart and cause a regression of blood flow and pressure in the heart. Valvular stenosis can be caused by a variety of reasons, including but not limited to scarring due to diseases such as rheumatic fever; progressive calcification; progressive wear and tear, etc. This is not important for stent-type treatments, but it is important for valves, which is very consistent with the rest of this patent.

As used herein, the term "valve" may refer to any of the four major heart valves that prevent the backflow of blood during rhythmic contraction. The four major heart valves are the tricuspid valve, the pulmonary valve, the mitral valve, and the aortic valve. The tricuspid valve separates the right atrium from the right ventricle, the pulmonary valve separates the right atrium from the pulmonary artery, the mitral valve separates the left atrium from the left ventricle, and the aortic valve separates the left ventricle from the aorta.

In one embodiment of the method, the bioprosthetic valve and the diseased valve can be an aortic valve, a pulmonary valve, a tricuspid valve, or a mitral valve.

As used herein, the term "valvular prosthesis" may refer to a device used to replace or supplement a defective, malfunctioning, or missing heart valve. Examples of valve prostheses include, but are not limited to, bioprostheses; mechanical prostheses, and the like, including the ATS Aortic Bioprosthesis, Carpentier-Edwards PERIMOUNT Magna Ease Aortic Valve, Carpentier-Edwards PERIMOUNT Magna Aortic Valve, Carpentier-Edwards PERIMOUNT Magna Mitral Valve, Carpentier-Edwards PERIMOUNT Aortic Valve, Carpentier-Edwards PERIMOUNT Plus Mitral Valve, Carpentier-Edwards PERIMOUNT Theon Aortic Valve, Carpentier-Edwards PERIMOUNT Theon Mitral Valve Replacement System, Carpentier-Edwards Porcine Aortic Bioprosthesis, Carpentier-Edwards Duraflex Low Pressure Porcine Mitral Bioprosthesis, Carpentier-Edwards Duraflex Mitral Bioprosthesis (Porcine), Carpentier-Edwards Porcine Mitral Bioprosthesis, and the like. SAV porcine aortic bioprosthesis, Edwards Prima Plus stentless bioprosthesis, Edwards Sapien transcatheter heart valve, Medtronic aortic root bioprosthesis, II stent-type bioprosthesis, Hancock II bioprosthesis, bioprosthesis, Mosaic bioprosthesis, St. Jude Medical Biocor ^™ Supar, pericardial, Biocor ^™ stentless, Epic ^™ , Epic Supra ^™ , Toronto porcine stentless valve Toronto SPVTrifecta, Sorin Group Mitroflow aortic pericardial valve, Cryolife, Cryolife aortic valve, Cryolife pulmonary valve, Cryolife-O'Brien stentless aortic xenograft valve.

Generally speaking, a bioprosthesis comprises a valve having one or more cusps, and the valve is mounted on a frame or stent, both of which are usually elastic. As used herein, the term "elastic" means that the device is able to flex, contract, expand, or a combination thereof. The cusps of the valve are usually made from mammalian tissue, such as, but not limited to, pig (porcine), cow (bovine), horse, sheep, goat, monkey, and human.

According to the method of the present invention, the valve may be a collapsible elastic valve having one or more cusps, and the collapsible elastic valve may be mounted on an elastic support.

In one embodiment, the collapsible elastic valve may include one or more cusps of biological origin.

In another embodiment, one or more cusps are porcine, bovine, or human.

Examples of bioprostheses may include a collapsible elastic valve having one or more cusps and mounted on an elastic support, including but not limited to the SAPIEN transcatheter heart valve manufactured by Edwards Lifesciences and the transcatheter heart valve manufactured by Medtronic and the Portico-Melody by Medtronic.

The elastic stent portion of the valve prosthesis used in the present invention can be self-expanding or expandable via a balloon catheter. The elastic stent can be comprised of any biocompatible material known to those skilled in the art. Examples of biocompatible materials include, but are not limited to, ceramics; polymers; stainless steel; titanium; nickel-titanium alloys such as nitinol; tantalum; and cobalt-containing alloys such as tantalum and tantalum.

According to the method of the present invention, the coating composition may include one or more therapeutic agent combinations, and the coating composition is arranged on the elastic support portion of the valve prosthesis. The process of arranging the coating composition that may include one or more therapeutic agent combinations can be any process known in the art. The coating composition with the drug combination can be prepared by dissolving or suspending the polymer and the therapeutic agent in a solvent. Suitable solvents that can be used to prepare the coating composition include those solvents that can dissolve or suspend the polymer and the therapeutic agent in the solution. Examples of suitable solvents include but are not limited to tetrahydrofuran, methyl ethyl ketone (MEK), chloroform, toluene, acetone, isooctane, 1,1,1-trichloroethane, dichloromethane, isopropyl alcohol and mixtures thereof. However, in many cases, a solvent is not required.

The coating composition can be applied to the surface of the elastomeric support portion of the valvular prosthesis or bioprosthesis and the sewing ring by any method known to those skilled in the art. Suitable methods for applying the coating composition to the surface of the elastomeric support portion of the valvular prosthesis include, but are not limited to, spraying, brushing, rolling, electrostatic deposition, inkjet coating, and batch processes such as air suspension, pan coating, or ultrasonic spraying, or combinations thereof.

After the coating composition is applied, it can be cured. As used herein, "curing" can refer to a process in which any polymeric material is converted into a finished or usable state by applying heat, vacuum, and/or chemical reagents, which causes physical-chemical changes. As known to those skilled in the art, the time and temperature suitable for curing are determined by the specific polymer involved and the specific therapeutic agent used. In addition, after the elastic stent is coated, it can be sterilized by sterilization methods known in the art (see, for example, Guidance for Industry and FDA Staff-Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems (Guidance for Industry and FDA Staff-Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems) http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm071863.htm and U.S. Patent No. 7,998,404 entitled "Reduced temperature sterilization of stents (low temperature sterilization of stents)").

As used herein, the term "therapeutic agent" may refer to a bioactive material, and the therapeutic agents described herein include their analogs and derivatives. Suitable therapeutic agents include, but are not limited to, microtubule stabilizers, such as paclitaxel, its analogs and derivatives thereof; macrolide antibiotics, such as sirolimus (rapamycin), its analogs and derivatives thereof; or combinations thereof, such as Bioliums or Everolimus (see "Transcatheter Aortic Valve Replacement with St. Jude Medical Portico Valve", Journal of American College of Cardiology, Vol. 60., No. 7, 2012: 581-6, 6 pages, dated August 14, 2012, which is hereby incorporated by reference). The elastic stent portion of the valve prosthesis can be prepared to provide a desired therapeutic agent release profile.

There are several other antiproliferative drugs being studied in human clinical trials. Generally, these are analogs of sirolimus. Like sirolimus, these antiproliferative drugs block the effects of mTOR. Medtronic developed tadalafil; unlike sirolimus and paclitaxel, this sirolimus analog is designed for use in stents that use a choline phosphate carrier. Their ZoMaxx stent is a tadalafil-eluting, stainless steel and tantalum-based stent that is modified to slowly release choline phosphate. The Medtronic Endeavor stent, a cobalt alloy that also uses choline phosphate to carry tadalafil, was approved in Europe in 2005 and is currently pending approval by the US FDA.

http://en.wikipedia.org/wiki/Drug-eluting_stent provides a list of currently FDA-approved and investigational drugs undergoing therapeutic testing with stents.

Clinical trials are currently testing two stents carrying everolimus, a sirolimus analog. Guidant, which holds an exclusive license to use everolimus in drug-eluting stents, is the manufacturer of both stents. Guidant's vascular business was subsequently sold to Abbott. The Champion stent uses a bioresorbable polylactic acid carrier on a stainless steel stent. In contrast, its Xience stent uses a durable (non-bioresorbable) polymer on a cobalt alloy stent.

An alternative to drug eluting stents is a stent with a surface configuration and arrangement configured to reduce neointimal proliferation. One such form is the Genous bioengineered stent.

To replace the stainless steel (now cobalt-chromium) currently used in stents, a variety of biodegradable frameworks are in early stages of research. Because metals, as foreign substances, trigger inflammation, scarring, and thrombosis (clotting), it is hoped that biodegradable or bioabsorbable stents may prevent some of these effects. Stents based on magnesium alloys have been tested in animals, although no drug-eluting vehicles currently exist. One promising biodegradable framework is made of poly-L-lactide, a polymer that is a derivative of L-lactic acid. One of these stents, the Igaki-Tamai stent, was studied in pigs; tranilast and paclitaxel were used as the eluting drugs. Additionally, none of these have been used, suggested, or implicated for use in the aorta.

According to the method of the present invention, the valve prosthesis can be fixed in a desired position in the patient's heart so that the elastic support contacts the valve or valve wall. The desired position of the valve prosthesis can be easily determined using methods known to those of ordinary skill in the art of heart valve replacement using echo imaging, CT imaging, and catheterization. In one embodiment, the valve prosthesis can be configured to be implanted by means of cardiac catheterization echo imaging, CT imaging, and catheterization. Catheter delivery of the valve prosthesis can be achieved using methods well known to those skilled in the art, such as mounting the elastic support portion on an inflatable sac provided at the distal end of a delivery catheter, and expanding the valve prosthesis in the desired position.

The elastic stent portion of the valve prosthesis can be cylindrical in any shape, with the final shape being cylindrical, or can initially be funnel-shaped, all of which are required to contact the valve or valve wall, wherein, without being bound by theory, the therapeutic agent is released and absorbed by the valve or valve wall or the aorta including the aortic valve, mitral valve, tricuspid valve, and vena cava valve.

In one embodiment, the resilient support portion may be substantially cylindrical so as to contact the valve or valve wall when secured.

In another embodiment, the diameter of the resilient support portion may be about 15 mm to about 42 mm.

According to one embodiment of the present invention, the method may further comprise introducing a nucleic acid encoding nitric oxide synthase into one or more cusps of the valve prosthesis. Methods for introducing a nucleic acid encoding nitric oxide synthase into one or more cusps are described in U.S. Patent No. 6,660,260, issued on December 9, 2003, which is hereby incorporated by reference in its entirety.

While the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions, and modifications may be made thereto without departing from the spirit and scope of the invention as defined by the appended claims. In current forms of stents, there is no treatment for preventing stenosis caused by stent injury to the aorta. As described herein, this is an invention for preventing stenosis that can occur in the aorta of a vessel or in the valve leaflets attached to a stented valve that is induced by these stented valve treatments.

The present invention will be further illustrated in the following examples, which are given for illustrative purposes only and are not intended to limit the present invention in any way.

For coronary stents, see "Effect of Biolimus-Eluting Stents with Biodegradable Polymer vs. Bare-Metal Stents on Cardiovascular Events Among Patients with Acute Myocardial Infarction, The COMFORTABLE AMI Randomized Trial", JAMA: The Journal of the American Medical Association, Vol. 308, No. 8, August 22/29, 2012, which is hereby incorporated by reference.

Detailed description

As best shown in FIG1 , a coating 12 is disposed on a flexible stent 10. The coating composition comprises one or more therapeutic agents. The method includes the steps of disposing the coating composition 12 on the flexible stent 10. A valve prosthesis 14 is mounted on the flexible stent 10. The valve prosthesis 14 is a collapsible elastic valve 16 that is mounted on the flexible stent 10 at a desired location 18 within the patient's body. The stent and valve are positioned within the coronary valve of the aorta. The flexible stent 10 contacts the valve 16. The coating composition 12 inhibits stenosis, obstruction, or calcification of the valve prosthesis 16 implanted with the valve prosthesis 14 within the patient's body.

The therapeutic agents referred to above can be selected from the group comprising paclitaxel, sirolimus, biocysteine and everolimus. The implantation of the valve is preferably performed using a catheter as shown in the attached document: Journal of the of the American College of Cardiology, Vol. 60, No. 7, 2012, August 14, 2012; 581-6 Figure 9, Transcatheter Aortic Valve Replacement with the St Jude Medical Portico Valve, which is hereby incorporated by reference. The aorta 20 is shown in Figure 3, and the valve prosthesis 14 is inserted therein. In one or more optional embodiments of the present invention, the retractable elastic valve 16 may have one or more cusps 22 of biological origin. As is generally known in the art, the cusps 22 may be porcine, bovine or human. In an alternative embodiment of the present invention, a nucleic acid 24 encoding nitric oxide synthase may be introduced into one or more cusps 22 to inhibit stenosis, obstruction or calcification of the valve. In a preferred embodiment, the elastic stent 10 is substantially cylindrical and has a length of about 18 mm to about 29 mm. Although it is known to prevent stenosis, calcification and obstruction of other valves except the aorta, it is not expected that antiproliferative agents will be needed because the size of the aorta is larger than the coronary valve. The diameter of the aorta is 2 cm, while the diameter of the coronary artery is 4 mm. Most stents, such as the stent shown in Figures 1-8, are constructed of titanium to avoid thrombosis. It is known that statins are used for coronary valves to prevent stenosis, obstruction or calcification, but not for aortic valves. The statin used is 80 mg of Lipitor/day.

In a preferred embodiment, the coating 12 on the elastomeric stent 10 is paclitaxel, a mitotic inhibitor previously used in cancer chemotherapy. Previously, it was sold dissolved in a cremafor EL and ethanol delivery agent. Newer formulations of paclitaxel are bound to albumin and sold under the brand name Abraxane. The use of paclitaxel to inhibit restenosis is known. Paclitaxel is used as an antiproliferative agent to prevent restenosis (recurrence of stenosis) in coronary stents delivered locally to the coronary artery wall. Paclitaxel coatings limit the growth of neointimal (scar tissue) within the stent. Reference: Paclitaxel, footnote 39. Paclitaxel stent coatings inhibited neointimal hyperplasia and a weak symptomatic model of coronary restenosis after four weeks (PMID 11342479). "Paclitaxel," Wikipedia, the free encyclopedia, http://en.wikipedia.org/wiki/Paclitaxel , 10/4/2012, incorporated herein by reference. In an alternative embodiment, in a large clinical trial with four years of follow-up, biocysteine and equivalent sirolimus analogs derived from biodegradable polylactic acid were comparable to and more effective than sirolimus-eluting stents with respect to major adverse clinical events.

As described above, the elastic support 10 shown in Figures 1-6 can include any biocompatible material known to those of ordinary skill in the art. Examples of biocompatible materials include, but are not limited to, ceramics; polymers; stainless steel; titanium; nickel-titanium alloys such as nitinol; tantalum; cobalt-containing alloys such as elgioloy and the like.

As best shown in FIG8 , according to the methods of the present invention, a coating composition 12 that may include one or more therapeutic agents is disposed on the elastomeric support 10 portion of a valve prosthesis 14. The process for disposing the coating composition 12 that may include one or more therapeutic agents can be any process known in the art. The coating composition 12 can be prepared by dissolving or suspending the polymer and the therapeutic agent in a solvent. Suitable solvents that can be used to prepare the coating composition 12 include those that can dissolve or suspend the polymer and the therapeutic agent in solution. Examples of suitable solvents include, but are not limited to, tetrahydrofuran, methyl ethyl ketone (MEK), chloroform, toluene, acetone, isooctane, 1,1,1-trichloroethane, dichloromethane, isopropyl alcohol, and mixtures thereof.

The coating composition 12 can be applied to the surface of the elastomeric support 10 portion of the valve prosthesis 14 by any method known to those skilled in the art. Suitable methods for applying the coating composition 12 to the surface of the elastomeric support 10 portion of the valve prosthesis 14 include, but are not limited to, spraying, brushing, rolling, electrostatic deposition, inkjet coating, and batch processes such as air suspension, pan coating, or ultrasonic spraying, or combinations thereof.

After the coating composition 12 is applied, it can be cured. As used herein, "curing" can refer to the process of converting any polymeric material into a finished or usable state by applying heat, vacuum, and/or chemical agents, which causes physical-chemical changes. As known to those skilled in the art, the time and temperature suitable for curing are determined by the specific polymer involved and the specific therapeutic agent used. In addition, after the elastic stent is coated, it can be sterilized by sterilization methods known in the art (see, for example, Guidance for Industry and FDA Staff-Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm071863.htm and U.S. Patent No. 7,998,404 entitled "Reduced temperature sterilization of stents").

As used herein, the term "therapeutic agent" may refer to a bioactive material. The therapeutic agents described herein include their analogs and derivatives. Suitable therapeutic agents include, but are not limited to, microtubule stabilizers such as paclitaxel, its analogs and derivatives thereof; macrolide antibiotics such as sirolimus (rapamycin), its analogs and derivatives thereof; or combinations thereof Bioliums or everolimus (see "Transcatheter Aortic Valve Replacement with St. Jude Medical Portico Valve", Journal of American College of Cardiology, Vol. 60., No. 7, 2012: 581-6, 6 pages, dated August 14, 2012, which is hereby incorporated by reference). The elastic stent portion of the valve prosthesis can be prepared to provide a desired therapeutic agent release profile.

The implantation of the Portico transcatheter heart valve can be seen in the accompanying Figure 10. In a preferred embodiment, the heart valve 16 spans the aortic arch 24. The transcatheter heart valve expands in the left ventricular outflow tract 26. The transcatheter heart valve functions during positioning. The open valve can be seen in Figure 1. Transcatheter aortic valve replacement with the St. Jude Medical Portico valve: first-in-human experience . Willson AB, Rodes- Cabau J, Wood DA, Leipsic J, Cheung A, Toggweiler S, Binder RK, Freeman M, DeLarochelliere R, Moss R, Nombela-Franco L, Dumont E, Szummer K, Fontana GP, Makkar R, Webb JG.J.Am Coll Cardiol. 2012 Aug 14; 60(7):581-6. Published online on May 30, 2012. Willson AB, Rodes-Cabau J, Wood DA, Leipsic J, Cheung A, Toggweiler S, Binder RK, Freeman M, DeLarochelliere R, Moss R, Nombela-Franco L, Dumont E, Szummer K, Fontana GP,Makkar R, Webb JG. J. Am Coll Cardiol. 2012, August 14, Vol. 60, No. 7, pp. 581–586. Epub 2012 May 30.

As shown in FIG2 , a Medtronic core valve 26 is shown in a coated stent 28. Edwards LifeSciences Sapien Valve, A New Treatment for Valvular Aortic Stenosis—Transcatheter Aortic Valve Implantation with the SAPIEN Heart Valve. Thielmann M, Eggebrecht H, Wendt D, Kahlert P, Ideler B, Kottenberg-Assenmacher E, Erbel R, Jakob H. Minim Invasive Ther AlliedTechnol. 2009;18(3):131-4. The geometry and degree of adhesion of the CoreValve ReValving System were examined using multiple slices after implantation in patients with aortic stenosis. Schultz CJ, Weustink A, Piazza N, Otten A, Mollet N, Krestin G, van Geuns RJ, de Feyter P, Serruys PW, de Jaegere PJ Am Coll Cardiol. 2009 Sep 1;54(10):911-8.

As shown in FIG3 , an Edwards Sapien valve 30 is disclosed as being contained within an aorta 32, which is non-diseased. Similarly, in FIG4 , a Medtronic CoreValve 26 is positioned within a stent 28 through aorta 32. In both FIG3 and FIG4 , the aorta is shown as being non-diseased. As best shown in FIG5 , aorta 32 is shown with an Edwards Sapien valve 30, also numbered 16, fixedly positioned within a stent 10. However, in this case, the stent and valve are not coated with the antiproliferative agent of the present invention. Consequently, stenosis, obstruction, and calcification occur. Similarly, in FIG6 , a Medtronic CoreValve 26 is positioned within a stent 28 and contained within aorta 32. Again, in the absence of the antiproliferative agent of the present invention, stenosis, obstruction, and calcification occur. The leaflets or cusps 22 shown in FIG1-6 can be constructed from mammalian tissue. The stent can also be constructed from a biodegradable polymer to provide controlled drug release, or the bioleaflets can be composed of porcine or human cells. Alternatively, any non-murine species having heart valve tissue, including but not limited to mammals such as pigs, cows, horses, sheep, goats, monkeys, and humans can be used for leaflets. US Patent No. 6,660,260, which describes such heart valve cells, is hereby incorporated by reference.

As shown in Figures 7 and 8, a stent 10 is disclosed without any coating 12 thereon. In Figure 8, the same stent 10 is shown with a coating 12 thereon, which is an anti-proliferative agent such as paclitaxel, sirolimis, everolimus, or Biolimius.

Figures 11 and 12 show a treated valve and stent having a coating 12 thereon which is an anti-proliferative agent such as paclitaxel, sirolimus, everolimus or Biolimius.

The present inventors have discovered that as part of an antiproliferative treatment to reduce pannus formation around GoreTex, a specific dosing regimen is effective for any prosthetic heart valve and vessel containing a GoreTex graft covering by applying the antiproliferative drug to any device covered with GoreTex. These include Gore Medical's Gore-Tex Vascular Grafts, Gore-Tex Stretch Vascular Grafts, Gore Propaten Vascular Grafts, St. Jude, Medtronic, and Edwards Lifesciences' Annuloplasty Rings (which contain a GoreTex covering and any type of GoreTex including GoreTex with expanded polytetrafluoroethylene surgical material).

Figure 13 depicts pannus formation and calcification in an explanted valve of a human patient during surgical valve replacement of a failed bioprosthetic heart valve. A control bioprosthetic valve is compared to a human explanted bioprosthetic valve. Figure (a1) ventricular surface of a control valve, (a2) ventricular surface of a diseased valve with pannus and calcification by stem cell attachment to the heart valve. Figure 14 is a graph showing RNA expression of ckit-positive mesenchymal stem cells attached to a calcified heart valve, as expressed by the well-known bone transcription factors cbfa1 (core binding factor a1) and opn (osteopontin), as well as extracellular matrix proteins, which cause calcification to occur on the valve. Results are expressed as a percentage of the control, which is 0 for all these markers. GAPDH is a housekeeping gene used as an experimental control.

Antiproliferative and anticalcific agents include sirolimus (and analogs), paclitaxel, taxanes, dexamethasone, M-prednisolone, interferon gamma-1b, leflunomide, tacrolimus, mycophenolic acid, mizoribine, cyclosporine, tranilast, biolast, antiproliferative agents, rapamycin (and analogs), paclitaxel, taxanes, actinomycin D, methotrexate, angiopeptide, vincristine, mitomycin, C Doses of any of the anti-restenotic agents used with stents, Goltex grafts and bioprostheses, including Myc antisense, RestenASE, 2-chloro-deoxyadenylic acid, PCNA ribozymes: smooth muscle cell migration inhibitors, extracellular matrix modulators, batimastat, prolyl hydroxylase inhibitors, halofuginone, C-proteinase inhibitors, probucol and MAP kinase inhibitor MEK (5.0-10 μg/ml) (current drug dosages on stents for the US market: sirolimus 140 mcg/cm2, paclitaxel dose 1 mcg/mm2, everolimus dose 100 mcg/cm2, tazolimus 10 mcg/1 mm stent length, biocysteine 15.6 mcg/mm2) are combined with an effective amount of 80 mg of atorvastatin to enhance the efficacy of calcification inhibition and extend the life of prosthetic materials including stents, valves and Goltex coverings.

Experimental animals were developed to test the effect of atorvastatin on inflammation and pannus formation in valve leaflets. Male New Zealand White rabbits weighing 2.5-3.0 kg were assigned to either a control group (N=10), a 0.5% cholesterol-fed group (N=10), or a cholesterol-fed and atorvastatin group (N=10). All animals were fed ad libitum for 12 weeks. Control rabbits were maintained on a standard diet. Cholesterol-fed animals received a diet supplemented with 0.5% (w/w) cholesterol (Purina Mills, Woodmont, IN), while the cholesterol-fed and atorvastatin group received oral administration of atorvastatin 3.0 mg/kg daily for statin treatment arm ^1. Prior to the start of the diet, rabbits underwent surgery to implant a bovine pericardial bioprosthetic valve (Perimount, Edwards, Irvine, CA) using an intramuscular injection of ketamine/xylazine (40/5 mg/kg). After 12 weeks, rabbits were anesthetized with an intramuscular injection of ketamine/xylazine (40/5 mg/kg) and then sacrificed by intracardial administration of 1 ml of Beuthanasia. Immediately after removal from the subcutaneous implant site, the bioprosthetic valves were fixed in 4% buffered formalin for 24 hours and then embedded in paraffin. Paraffin-embedded sections (6 μm) were cut and stained with Masson's trichrome for histopathological examination.

15 depicts the results of testing the anti-inflammatory drug atorvastatin, equivalent to a human dose of 80 mg/day, showing the percent reduction in stem cell RNA expression and stem cell-mediated pannus formation on valves treated with atorvastatin.

Figure 15 shows RNA gene expression for control, cholesterol, and cholesterol plus atorvastatin experimental analysis. Compared to the control and atorvastatin groups, Sox9, osteoblast transcription factor, cyclin, and cKit were increased in the lobules of cholesterol-fed animals (p < 0.05). Table 1 is the RTPCR data for the experimental model. Compared to the control analysis, serum cholesterol levels in the cholesterol-fed group were significantly higher (1846.0 ± 525.3 mg/dL vs. 18.0 ± 7 mg/dL, p < 0.05). The atorvastatin-treated experimental arm showed lower cholesterol levels than the cholesterol diet alone group (824.0 ± 152.1 mg/dL, p < 0.05). Compared to the control analysis, hsCRP serum levels in the cholesterol-fed group increased (13.6 ± 19.7 vs. 0.24 ± 0.1, p < 0.05), which was reduced by atorvastatin (7.8 ± 8.7, p < 0.05). These analyses were tested in a rabbit model of experimental hypercholesterolemia with and without atorvastatin at a dose equivalent to 80 mg/day in humans.Previous experiments were conducted to test the low dose range of 20 mg/day and 40 mg/day atorvastatin, which had zero therapeutic benefit.

Figure 16 shows the effect of in vitro analysis of cell proliferation using known growth factors platelet-derived growth factor and inhibitor MEK (PD0325901) that stimulate interstitial cell valve proliferation. Mesenchymal valve cells were isolated from the aortic valve of the heart by collagenase digestion. Cells were cultured in a humidified atmosphere of 5% _CO2 at 37°C in medium 199 with 10% (v/v) heat-inactivated fetal bovine serum. Cells between the 3rd and 7th passages were used. Mesenchymal cells were grown to confluence in 24-well plates and then growth arrested by incubation in serum-free medium for 24 hours. Test materials were added to the wells and incubated for 18 hours. Test materials included a combination of PDGF concentration (10-40 μg/ml) PDGF Sigma and a MEK inhibitor (PD0325901Mek inhibitor) (2.5-10 μg/ml). The wells were pulsed with tritiated thymidine at 1 μCi/well for 4 hours. Newly synthesized DNA was then identified by radioactive incorporation of acid-precipitated cell material. All samples were analyzed in quadruplicate in the wells. Positive control wells were given PDGF (10 μg/ml) Sigma (St.Louis, MO), and negative control wells received serum-free culture medium. Figure 16 A is the mesenchymal stem cell proliferation results of the dose-response treatment of platelet-derived growth factor, Figure B is the effect of MEK inhibitors in the dose range of (2.5 μg/ml to 10 μg/ml) and the inhibitory effect of the dose range of (5 μg/ml to 10 μg/ml), Figure C is the western blot results of p42/44 protein expression, which shows that p42/44 protein expression increased in the presence of PDGF, indicating active cell proliferation, MEK inhibitors inhibited p42/44 expression, and higher doses of MEK had a dose-response effect.

Drug-eluting stents can also incorporate dual antiplatelet therapy to inhibit future thrombosis, including aspirin 80 mg/day and an oral P2Y12 inhibitor: 1) clopidogrel 75 mg/day with a loading dose of 300 mg/day at intervention or 2) prasugrel 60 mg/day followed by 10 mg/day for maintenance or 3) ticagrelor 180 mg/day for loading and 90 mg BID for maintenance.

The mechanism of action of statins, which act as combined anti-inflammatory, anti-proliferative, and anti-calcifying agents, is thought to mediate inhibition of calcification and stem cell attachment. Atorvastatin reduces ckit stem cell attachment to the valve, thereby further reducing valve breakdown by activating endothelial nitric oxide synthase in the valve, in combination with anti-proliferative agents. In two models of calcification in these tissues, myofibroblast proliferation and extracellular matrix production were reduced by 95%.

Claims (26)

1. Use of the coating composition in the preparation of a bioprosthetic valve for inhibiting stenosis, occlusion, and/or calcification of the bioprosthetic valve after implantation into a vessel with a wall, wherein: Providing bioprosthetic valves for surgical replacement of naturally diseased valves, the bioprosthetic valves comprising multiple cusps coupled to an elastic stent; The elastic stent and/or cusp valve are coated with a coating composition comprising an effective amount of atorvastatin combined with an anti-restenosis agent to enhance the efficacy of inhibiting calcification and prolonging the lifespan of prosthetic materials, including the stent and/or cusp valve; and Inhibition of stenosis, obstruction, and/or calcification of the bioprosthetic valve, the naturally occurring diseased valve, or both, is achieved by reducing the number of ckit stem cells attached to the valve, thereby further reducing valve damage. 2. The use according to claim 1, wherein the effective amount of atorvastatin is 80 mg and the anti-restenosis agent is selected from: sirolimus, biolimus, everolimus, zotamoxetine, paclitaxel, taxane, dexamethasone, M-prednisolone, interferon γ-1b, leflunomide, tacrolimus, mycophenolic acid, imidazolidinone, cyclosporine, tranilast, thyroxine, actinomycin D, methotrexate, angiopeptidase, vincristine, mitomycin, C Myc antisense, Restenase, 2-chlorodeoxyadenosine monophosphate, palmastat, prolyl hydroxylase inhibitor, halofopontone, C-protease inhibitor, probucol, MAP kinase inhibitor, and combinations thereof. 3. The use according to claim 1, wherein the bioprosthetic valve is an aortic bioprosthetic valve. 4. The use according to claim 1, wherein the bioprosthetic valve is a bioprosthetic mitral valve. 5. The use according to claim 1, wherein the bioprosthetic valve is a bioprosthetic pulmonary valve. 6. The use according to claim 1, wherein the bioprosthetic valve is a bioprosthetic tricuspid valve. 7. The use according to claim 1, wherein the cusp valve has a biological origin. 8. The use according to claim 7, wherein one or more of the cusps are of pig, cattle or human origin. 9. The use according to claim 2, further comprising introducing a drug elution treatment on one or more of the cusp valves, the drug elution treatment comprising anti-proliferation and anti-calcification treatments. 10. The use according to claim 1, wherein the resilient support is substantially cylindrical. 11. The use according to claim 10, wherein the diameter of the resilient support is from about 15 mm to about 42 mm. 12. A valve prosthesis comprising: Flexible support; A bioprosthetic valve having one or more cusp valves operatively coupled to the elastic scaffold; A coating composition on the elastic stent and/or cusp valve, the coating composition comprising an effective amount of a combination of atorvastatin and an anti-restenosis agent, the coating composition being configured to elute from the elastic stent and/or cusp valve to enhance the efficacy of inhibiting calcification and prolong the lifespan of prosthetic materials including the stent and/or cusp valve; The bioprosthetic valve described therein is configured to be implanted into a blood vessel with a vascular wall to replace a naturally diseased valve. The bioprosthetic valve is configured to inhibit stenosis, obstruction, and/or calcification of the bioprosthetic valve, the naturally occurring diseased valve, or both, by reducing the number of ckit stem cells attached to the valve after implantation of the valve prosthesis, thereby further reducing valve damage. 13. The valve prosthesis of claim 12, wherein the bioprosthetic valve is coupled to a surgical suture ring. 14. The valve prosthesis according to claim 12, wherein the anti-restenosis agent is selected from: sirolimus, biolimus, everolimus, zotamoxetine, paclitaxel, taxane, dexamethasone, M-prednisolone, interferon γ-1b, leflunomide, tacrolimus, mycophenolic acid, imidazolidin, cyclosporine, tranilast, thyroxine, actinomycin D, methotrexate, angiopeptidase, vincristine, mitomycin, C Myc antisense, Restenase, 2-chloro-deoxyadenosine monophosphate, PCNA ribozyme, palmastat, prolyl hydroxylase inhibitor, halofopontone, C-protease inhibitor, probucol, MAP kinase inhibitor, and combinations thereof. 15. The valve prosthesis of claim 12, wherein the size and construction of the bioprosthetic valve are configured to be implanted into the aortic valve location of a patient via cardiac catheterization. 16. The valve prosthesis of claim 12, wherein the biological prosthetic valve is an aortic valve. 17. The valve prosthesis of claim 12, wherein one or more of the cusp valves have a biological origin. 18. The valve prosthesis of claim 17, wherein one or more of the cusp valves are of pig, bovine, or human origin. 19. The valve prosthesis of claim 12, wherein the size, construction, and arrangement of the resilient stent are configured as a substantially cylindrical shape. 20. The valve prosthesis of claim 12, wherein the diameter of the elastic stent is from about 15 mm to about 42 mm. 21. The valve prosthesis of claim 12, wherein the surface structure and arrangement of the elastic stent are configured to reduce neointimal proliferation. 22. The valve prosthesis of claim 12, further comprising a suture ring operatively coupled to the bioprosthetic valve, the suture ring having a surface configuration and arrangement configured to reduce neointimal proliferation and pannus formation. 23. The valve prosthesis of claim 12, wherein the bioprosthetic valve further comprises a Goltex graft, a portion of the effective amount of atorvastatin being deposited on the Goltex graft. 24. The valve prosthesis of claim 23, wherein the effective amount of atorvastatin reduces pannus formation along the graft surface. 25. The valve prosthesis according to claim 14, wherein the amount of the MAP kinase inhibitor is 5.0-10 ug/ml, the amount of sirolimus is 140 mcg/cm2, the amount of paclitaxel is 1 mcg/mm2, the amount of everolimus is 100 mcg/cm2, the amount of zotamolimus is 10 mcg/mm2, and the amount of baicalolimus is 15.6 mcg/mm2, all of the foregoing amounts being per unit length of the stent. 26. The use according to claim 2, wherein the amount of the MAP kinase inhibitor is 5.0-10 ug/ml, the amount of sirolimus is 140 mcg/cm2, the amount of paclitaxel is 1 mcg/mm2, the amount of everolimus is 100 mcg/cm2, the amount of zotamolimus is 10 mcg/mm2, and the amount of bicimox is 15.6 mcg/mm2, all of the foregoing amounts being per unit length of the stent.