Patent Publication Number: US-2006004437-A1

Title: Structurally variable stents

Description:
CROSS-REFERENCE TO RELATED APPLICATION  
      This application is a continuation-in-part of U.S. application Ser. No. 09/941,327 filed on Aug. 29, 2001, the contents of which are herein incorporated by reference. 
    
    
     BACKGROUND OF THE INVENTION  
      This invention relates to stents used to support arterial and venous conduits in the human body. More particularly, it refers to a tubular stent having a non-uniform structure along its longitudinal length to provide good flexibility and radial strength.  
      There are four major classes of stents employed in the prior art. These four major classes of stents are described as follows:  
      1. Coil Stents are made from a single wire. The wire is bent in various ways and formed into a stent. Examples of this type of stent are those shown in U.S. Pat. Nos. 4,969,458; 4,681,110 and 5,824,056.  
      2. Slotted Tube Stents are laser cut using a tube of either stainless steel, nickel/titanium alloy (NITINOL), titanium or any other suitable materials. These designs are preprogrammed into a machine language and a laser is used to cut the programs. These stents have a uniform design and a uniform thickness from the beginning to the end of the stent. In other words, the same segment is repeated from one end of the stent to the other. Examples of this type of stent are described in U.S. Pat. Nos. 4,733,665; 4,739,762; 4,776,337 and 4,793,348.  
      3. Self Expanding Stents are usually braided or knitted with multiple wire filaments such that they have a lower profile when stretched and they expand from a lower profile to a higher profile when unconstrained in the body. These stents are called self-expanding stents and are described in U.S. Pat. No. 4,655,771.  
      4. Hybrid Stents are similar to slotted tube stents except that they do not have a closed cell structure but have an open cellular structure with flexible interconnections between each segment of the design. These interconnections provide the flexibility while the segments provide the radial strength and other important properties of the stent. Examples of this stent are described in U.S. Pat. Nos. 5,514,154; 5,562,728; 5,649,952 and 5,725,572.  
      In use, each of the four classes of stents described above are coated as described in various patents as follows:  
      1. U.S. Pat. No. 5,759,174 describes a balloon that has a radiopaque segment attached to one of the longitudinal ends of the balloon. When the balloon is inflated, the stent is pressed against the ends of the artery and this indicates the center portion of the dilated stenosis. The external radiopaque marker band is typically made from a dense radiopaque metal such as tantalum, gold, platinum or an alloy of those dense metals.  
      2. U.S. Pat. No. 5,725,572 describes gold plating on the ends of a stent such that the gold plating marks two bands at the ends of a stent. The patentee mentions that the limitation of gold coating is the stiffening of the stent surface. Hence, the gold plating is done only at the ends where the stiffening does not significantly alter the properties of the stent. Also described is another embodiment where only the exterior of the stent is coated with a radiopaque material.  
      3. U.S. Pat. No. 5,919,126 describes a patent where the body of the stent is formed from a non-radioactive structural material, a radiopaque material coats the body and a beta emitting radioisotope ion is implanted into the radiopaque material.  
      4. U.S. Pat. No. 5,824,056 describes an implantable medical device formed from a drawn refractory metal having an improved biocompatible surface. The method by which the device is made includes coating a refractory metal article with platinum by a physical vapor deposition process and subjecting the coated article to drawing in a diamond die. The drawn article can be incorporated into an implanted medical device without removing the deposited material.  
      5. U.S. Pat. No. 5,824,077 describes a stent which is formed of multiple filaments arranged in two sets of oppositely directed helical windings interwoven with each other in a braided configuration. Each of the filaments is a composite including a central core and a case surrounding the core. The core is formed of a radiopaque material while the outer casing is made of a relatively resilient material, e.g., a cobalt chromium based alloy. Alternative composite filaments described in the patent employ an intermediate barrier layer between the case and the core, a biocompatible cover layer surrounding the case, and a radiopaque case surrounding the central core.  
      6. U.S. Pat. No. 5,871,437 describes a non-radioactive metallic stent which is coated with a biodegradable or non-biodegradable thin coating of less than about 100 microns in thickness which is selected to avoid provoking any foreign body reaction. This coating contains a radioactive source emitting Beta particles with an activity level of approximately one micro curie and on top of this layer is an anticoagulant substance to inhibit early thrombus formation.  
      7. U.S. Pat. No. 6,099,561 describes a stent having a biocompatible metal hollow tube constituting a base layer having a multiplicity of openings through an open ended tubular wall thereof, the tube constituting a single member from which the entire stent is fabricated. A thin tightly adherent intermediate layer of noble metal overlies the entire exposed surface area of the tube including edges of the openings as well as exterior and interior surfaces and ends of the wall. A third outermost ceramic like layer composed of an oxide, hydroxide or nitrate of a noble metal is formed atop and in adherent relation to an intermediate layer.  
      8. U.S. Pat. No. 5,722,984 describes a stent which has an antithrombogenic property and contains an embedded radioisotope that makes the coating material radioactive.  
      9. Other relevant patents that describe the coating technology or coating properties include U.S. Pat. Nos. 5,818,893; 5,980,974; 5,700,286; 5,858,468; 5,650,202 and 5,696,714.  
      Although some of the above mentioned stents have good flexibility and others have good radial strength, there is no optimum stent in the prior art that has both good flexibility and radial strength together with the ability to retain a useful coating.  
     SUMMARY OF THE INVENTION  
      The present invention describes a fifth class of stents having multiple designs of structurally variable configuration along the longitudinal length of the stent. The stent has one pattern at both ends of the stent to provide optimal flexibility and a different pattern at the mid-portion of the stent to provide optimal radial strength. Alternatively, the stent has one pattern at each end, a different pattern at its mid-portion and a third pattern in-between the mid-portion and each end. The stent has both closed cell and open cell configuration along its longitudinal length and the closed cells and open cells are interlinked with either straight or wavy configurations in a single stent.  
      A preferred pattern contains at least three different configurations selected from an open cell design, a closed cell design, a straight interlink or articulation and one wavy interlink or articulation along a variable thickness of connecting stents. Because of the variable thickness of the stents, the amount of drug loaded on the stent is varied along with the release characteristics.  
      The structurally variable stents of this invention usually have a stainless steel or nickel/titanium alloy (NITINOL) base material with two layers of coating together not exceeding ten microns in depth. One layer is an undercoat in direct contact with the base metal both on the inside and outside surface of the base metal. The topmost layer is in contact with the blood. Both the undercoat and top coat are of the same material such as metallic, biological, synthetic material, or polymeric material. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      The invention can be best understood by those having ordinary skill in the art by reference to the following detailed description when considered in conjunction with the accompanying drawings in which:  
       FIG. 1  shows a closed cell design of a stent.  
       FIG. 2  shows a closed cell design of a stent interconnected by a straight bridge.  
       FIG. 3  shows an exterior design of a closed cell stent.  
       FIG. 4  shows a design of an open cell stent with a radiopaque coating on one section of the stent.  
       FIG. 5  shows a design of a coil stent.  
       FIG. 6  shows a design of a structurally variable stent having an open cell design on the ends and a closed cell design at the center of the stent.  
       FIG. 7  shows a design of a structurally variable stent with variable thickness of the open and closed cell design.  
       FIG. 8  shows a design of a structurally variable stent with open cell at the ends and closed cell at the mid-portion and alternating articulations between both the open and closed cell.  
       FIG. 9  shows a design of a structurally variable stent with both open and closed cell design and the articulations at the end of the closed cell design is an S-shape rather than a W-shape.  
       FIG. 10  shows a design of a structurally variable stent with both open and closed cell design and alternating articulations at various sections of the stent.  
       FIG. 11  shows a design of a structurally variable stent with an open cell design at the ends with multiple S-shapes and a straight articulating member and closed cell design and the mid-portion with a complex plus sign articulation.  
       FIG. 12  shows a design of a structurally variable stent with a circle at a mid-portion of the open cell design.  
       FIG. 13  shows a design of a structurally variable stent with different wall thickness along the length of the stent.  
       FIG. 14  shows a cross sectional view of a portion of the structurally variable stent including two coating layers.  
       FIG. 15  shows a partial view of a section of stent including a plurality of reservoirs therein.  
       FIG. 16  shows a section view of the partial section of  FIG. 15 .  
       FIGS. 17A-17F  show reservoir configurations of the stent of  FIG. 15 .  
       FIG. 18  shows a design of a structurally variable stent with both open and closed cell designs including reservoirs at various sections of the stent. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      The present invention provides a hollow-tubular self support structure composed of a biocompatible material which can be used as a stent to support arterial and venous conduits in the human body. The stent can include one or more patterns of interconnected lattice works which can be connected by strut members. The patterns can be in the form of a “closed” cell or “open” cell design, wherein “closed cell” and “open cell” are terms of art that a person of ordinary skill in the art would readily understand and appreciate what is covered by the recitation of “closed cell” and “open cell.” Specifically, an open cell stent is defined as a stent that has circumferential sets of strut members with most of the curved sections that are not connected by a longitudinal connecting link to an adjacent circumferential set of struts. A closed cell stent has every curved section of every circumferential set of strut members, except at the distal and proximal end of the stent, attached to a longitudinal connecting link. The definitions of “open cell” and “closed cell” are provided, for example, in U.S. Pat. No. 6,540,774, to Fischell et al, entitled Ultraflexible Open Cell Stent.  
      Referring now to the drawing figures in which like reference designators refer to like elements, there is shown in  FIG. 1 , a longitudinal sectional view of a stent  10  of the present invention. The stent  10  includes a series of cells  12  which are longitudinal connected in series, where the cells  12  are interconnected by bridge or strut member  14 . The longitudinal serial connections of the cells  12  define the stent as a “closed” cell stent.  
      The cells  12  are depicted as having a substantially elliptical shape. However, as shown in  FIG. 2 , the cells  12  can have a more complex shape. The exterior look of such a stent  10  is provided in  FIG. 3 .  
      Referring to  FIG. 4 , a stent  16  includes a series of cells  18 . The cells  18  are shown as circumferential sets of strut members forming an “open” cell stent  16 . The circumferential sets of strut members are interconnected with connecting struts  28 . Furthermore, at least on one section  20  of the open cell stent  16  can include a radiopaque coating  22  on at a portion of the cell  18 . The radiopaque coating  22  can provide an increased visibility of the stent  16  by means of an x-ray, ultrasound, MRI, or other known viewing device.  
      Referring to  FIG. 5 , a coil stent  24  is provided. A coil stent  24  includes at least one curved segment which is arced about the longitudinal axis of the stent  24 .  
      Referring to  FIG. 6 , a stent  26  is provided includes a plurality of interconnected cells of differentiating patterns. For example, first and second end portions of the stent  26  have a first pattern  16  and an intermediate portion of the stent  26  has a second pattern  10 . The first pattern  16  can be in the form of an open cell configuration and the second pattern  10  be in the form of a closed cell configuration. Connecting struts  28  can join the patterns  10 ,  16  of the stent  26 .  
      Referring to  FIG. 7 , a stent  26 A is provided. The stent  26 A includes a similar structure to stent  26 , where the end portions of the stent  26  have an open cell configuration (first pattern)  16  and the intermediate portion of the stent  26  has a closed cell configuration (second pattern)  10 . In the stent  26  of  FIG. 6 , the first and second patterns are depicted as having a uniform material thickness along the length of the stent  26 . However, as shown in  FIG. 7 , the stent  26 A can have a varying material thickness along the length of the stent  26 A. For example, the first pattern  16  can have a greater material thickness than a material thickness of the second pattern  10 . Similarly, the second pattern  10  can have a greater material thickness than the material thickness of the first pattern  16 . Alternatively, the material thickness can vary within each of the patterns  10  and  16 .  
      The closed cell configurations  10  further includes articulations  30 , where the articulations  30  allow for expansion of the stent  26 A. The articulation  30  can be provided in a variety of patterns. For example, the articulations  30  can be provided in a W-pattern. Additional articulation  30  patterns are disclosed in U.S. Pat. No. 6,375,677 to Penn at al, the contents of which are herein incorporated by reference in its entirety.  
      Referring to  FIG. 8 , the closed cells  10  can include a plurality of differing shaped articulation. For example, a number of the closed cells  10  can include articulations  30  having a first pattern, the W-pattern, and articulations  32  having a second pattern, an S-pattern.  
      Further, non-limiting, exemplary cell and articulation patterns are provided in the following FIGS. In  FIG. 9 , the stent  26 B has a closed cell design  10  at its mid-portion and an open cell design  16  at each end. The articulations  32  are all in the shape of an S-pattern. In  FIG. 10 , the stent  26 C has a closed cell design  10  at its mid-portion and an open cell design  16  at each end, but with alternating S-pattern  32  and W-pattern  30  articulations. In  FIG. 11 , the stent  26 D has an open cell design  16  at its ends in an S-pattern, a straight articulating member  34 , a closed cell  10  mid-portion with a complex plus sign pattern articulation  36 . In  FIG. 12 , the stent  26 E has an open cell design  16  at its ends with a circle  38  in the open cell design. The center portion is a closed cell design  10 .  
      Referring to  FIG. 13 , the stent  26 F includes first and second patterns  16  and  10  having varying material thickness. The end portion of the stent  26 F includes an open cell configuration. The open cell configuration  16  includes a portion having a thick  40  material thickness and another portion having a thin  42  material thickness. Similarly, the mid portion includes a closed cell configuration  10 , which can include portions having a thick  40  material thickness and a thin  42  material thickness. For example, the articulations  32  of the closed cell configuration  10  can have a thick  42  material thickness.  
      The thickness of the open cell design  16  versus the closed cell design  10  may vary as seen in the drawings. For example, the open cell design  16  can be twenty-five percent thicker than the mid-portion or closed cell design  10 .  
      The combination of an open cell  16  and closed cell  10  stent design creates a stent having both flexibility and radial strength along the length of the stent. The variable stent thickness  40  and  42  provides greater functional properties for coating the stent. If the coating is to enhance the radio opacity, then the ends can be made more radiopaque than the mid-portion. Furthermore, when the stent is coated with a pharmaceutical agent, the thick material can allow for an increased dosage of the pharmaceutical agent to be coated onto the stent. For example, as restenosis occurs in a stent invariably at its ends, a higher pharmaceutical concentration at the ends can more thoroughly inhibit such restenosis.  
      Referring to  FIG. 14 , the stent  26  can include a plurality of coatings. For example, the stent  26  can include two layers of coatings, a base coat  44  of metal and a top coat  46  of metal enhances radio opacity of the stent  26 . Alternatively, the base coat  44  can be a polymeric coating having a top coat  46  which can include a pharmaceutical agent. The pharmaceutical agent can slowly diffuse through the top coat  46  of the stent  26  over a period of time. The variable thickness design of the stents  26 - 26 F can allow for a greater quantity of the pharmaceutical agent to be loaded onto the thick  42  sections of the stent  26 , which can facilitate a graded release profile. For example, as noted above, the open cell  16  end portion of the stents  26 - 26 F can have a thick  42  material thickness allowing for a greater quantity of the pharmaceutical agent to be coated onto the end portions of the stents  26 - 26 F.  
      A coating of at least two layers over the base metal has a depth not to exceed ten microns. Typical coatings are set forth in U.S. Pat. Nos. 5,759,174; 5,725,572; 5,824,056; and 5,871,437 and are herein incorporated by reference.  
      Referring to  FIGS. 15 and 16 , the stents  26 - 26 F may include a plurality of reservoirs  48 . The reservoirs  48  are dimensioned to receive a pharmaceutical agent  50  therein. The reservoirs  48  are sized to have a volume of at least 1 μg. A coating  52  can be provided to cover the reservoirs  48 . The coating  52  can be absorbable or non-absorbable material with the pharmaceutical agent  50  released by diffusing through the coating  52 . The coating  52  can be sufficiently permeable to selectively, controllably, release the pharmaceutical agent  50 . Alternatively, for an absorbable coating  52 , the pharmaceutical agent  50  is released as the coating  52  is absorbed. Alternatively, the coating  52  is coatings  44  and/or  46 . The drug  50  is released by slowly diffusing through the coatings  44  and/or  46 .  
      The reservoirs  48  have an opening with a diameter “w” and a depth “d.” The opening of each of the reservoirs  48  may have a uniform diameter “w,” or in the alternative, the opening of each of the reservoirs  48  may have non-uniform diameters “w.” 
      Similarly, each of the reservoirs  48  may have a uniform depth “d,” or in the alternative, the depth of the each of the reservoirs  48  may be non-uniform. The depth “d” of the reservoir is less than the thickness of the stent material, such that an individual reservoir  48  does not pass completely through the stent material. The reservoir  48  can be formed on the stent by laser cutting, chemical etching, or other related techniques.  
      Referring to  FIGS. 17A-17F  the reservoirs  48  can have circular, elliptical, rectangular, triangular, polygon, or other geometric cross sectional area. Alternatively, the reservoirs  48  can have a free-formed cross-sectional area.  
      Referring to  FIG. 18 , the reservoirs  48  can be selectively positioned along the length of the stent  26 G. For example, the reservoirs  48  can be positioned in the open cell  16  end portions, the closed cell  10  mid-portion, the articulations  30 , the connecting struts, or any combinations thereof. Exemplary configurations include, positioning the reservoirs  48  only on the end portions  16 , or only on the mid-portion  10 . However, it is contemplated that other reservoir  48  configurations can be utilized.  
      Additionally, the selectively positioning of the reservoirs  48  further includes controlling the size and density of the reservoirs on each of the stent  26 G sections. For example, as restenosis occurs in a stent invariably at its ends, a higher pharmaceutical agent  50  concentration at the ends can more thoroughly inhibit such restenosis. The open cell  16  end portions can have greater reservoir  48  sizes than the closed cell  10  mid-portion of the stent  26 G, allowing for a greater pharmaceutical agent  50  concentration to be provide at the end-portions  16  than at the mid-portion  10  of the stent  26 G. Alternatively, the open cell  16  end portions can have greater reservoir  48  densities than the closed cell  10  mid-portion of the stent  26 G, allowing for a greater pharmaceutical agent  50  concentration to be provided at the end-portions  16  than at the mid-portion  10  of the stent  26 G.  
      It is further contemplated that the reservoirs  48  can be used in combination with the thick  42  and thin  40  materials sections of stent  26 - 26 F. The thick  42  material sections of the stent can allow for increased reservoir  48  sizes and densities to be provided thereon, such that the thick  42  sections of the stent can have a greater pharmaceutical agent  50  concentration than on the thin  40  sections of the stent.  
      Similarly, the reservoirs  48  can be used in combination with the coating  44  and  46  of  FIG. 14 . As discussed above, the coatings  44  and  46  can be used to cover the reservoirs  48 , wherein the pharmaceutical agent  50  is released by diffusing through the coating  44  and  46 . The combination of the coating  44  and  46  and the selective positioning of the reservoirs  48  can be utilized to control the concentration of and release rate of the pharmaceutical agent  50 .  
      As noted above, the coating  46  can similarly include a pharmaceutical agent  50 . Where it is desired to have an increased pharmaceutical agent  50  concentration, reservoirs  48  can be provided to be used in combination with the coating  46 .  
      The reservoirs  48  and the coating  46  can include the same pharmaceutical agent  50 . Alternatively, the reservoirs  48  and the coating  46  can include different pharmaceutical agents, where the different pharmaceutical agent can be selectively positioned on the stents.  
      It is additionally contemplated that the reservoirs  48 , coatings  44  and  46 , and the thick  42  and thin  40  material thickness can be used individually or in combination to control the pharmaceutical agent  50  concentration along the stent.  
      The stents  26 - 26 G of this invention are longitudinal, cylindrical, metal structures having at least an open cell and closed cell design joined together by struts. The metal can be nickel-titanium alloy (NITINOL) titanium, stainless steel or a noble base metal.  
      The pharmaceutical agent  50  can include an agent which acts on a calcium independent cellular pathway and may be a macrolide immunosuppressant, or more specifically, rapamycin. Alternatively, the pharmaceutical agent  50  can include an agent to treat or prevent the disease process of the vascular disease. The agent can include an anti-inflammatory agent, non-proliferative agent, anti-coagulant, anti-platelet agent, Tyrosine Kinase inhibitor, anti-infective agent, anti-tumor agent, anti-leukemic agent, or any combination thereof.  
      Examples of anti-inflammatory agents include, but are not limited to, Zinc compounds, dexarnethasone and its derivatives, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen and naproxin), TNF-α inhibitors (such as tenidap and rapamycin or derivatives thereof), or TNF-α antagonists (e.g., infliximab, OR1384), prednisone, dexamethasone, Enbrel®, cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such as Naproxen®, Celebrex®, or Vioxx®), CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, other IMPDH inhibitors, such as mycophenolate (CellCept®), integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, therapies for the treatment of irritable bowel syndrome (e.g., Zelmac® and Maxi-K® openers), or other NF-κB inhibitors, such as corticosteroids, calphostin, CSAIDs, 4-substituted imidazo[1,2-A]quinoxalines, glucocorticoids, aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, and tenidap.  
      Examples of anti-proliferative agents include, but are not limited to, cytochalasins, Taxol®, somatostatin, somatostatin analogs, N-ethylmaleimide, antisense oligonucleotides and the like, cytochalasin B, staurosporin, nucleotide analogs like purines and pyrimidines, Taxol®, topoisomerase inhibitor like topoisomerase I inhibitor or a topoisomerase II inhibitor, alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide, melphalan (L-sarcolysin)), nitrosoureas (carnustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin), immunosuppressants (mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685)), paclitaxel, altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, octreotide, estramustine, and hydroxyurea.  
      Examples of anti-coagulant agents include, but are not limited to, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin, protaglandin inhibitors, platelet inhibitors, tick anti-platelet peptide, hirudin, hirulog, and warfarin.  
      Examples of anti-platelet agents include, but are not limited to, ReoPro®, ticlopidine, clopidrogel, and fibrinogen receptor antagonists.  
      Examples of Tyrosine Kinase inhibitors include, but are not limited to, c-Met, a receptor tyrosine kinase, and its ligand, scatter factor (SF), Epithelial Cell Kinase (ECK), inhibitors described in international patent applications WO 96/09294 and WO 98/13350 and U.S. Pat. No. 5,480,883 to Spada, et al., certain 2,3-dihydro-1H-[1,4]oxazino[3,2-g]quinolines, 3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinolines, 2,3-dihydro-1H-[1,4]thiazino[3,2-g]quinolines, and 3,4-dihydro-2H-[1,4]thiazino[2,3-g]quinolines, EGF, PDGF, FGF, src tyrosine kinases, PYK2 (a newly discovered protein tyrosine kinase) and PTK-X (an undefined protein tyrosine kinase).  
      Examples of anti-infective agents include, but are not limited to Leucovorin, Zinc compounds, cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the interaction between CD40 and CD154 (a.k.a. “gp39”), such as antibodies specific for CD40 and/or CD154, fusion proteins constructed from CD40 and/or CD154/gp39 (e.g., CD40Ig and CD8gp39), β-lactams (e.g., penicillins, cephalosporins and carbopenams), β-lactam and lactamase inhibitors (e.g., augamentin), aminoglycosides (e.g., tobramycin and streptomycin), macrolides (e.g., erythromycin and azithromycin), quinolones (e.g., cipro and tequin), peptides and deptopeptides (e.g. vancomycin, synercid and daptomycin), metabolite-based anti-biotics (e.g., sulfonamides and trimethoprim), polyring systems (e.g., tetracyclins and rifampins), protein synthesis inhibitors (e.g., zyvox, chlorophenicol, clindamycin, etc.), nitro-class antibiotics (e.g., nitrofurans and nitroimidazoles), fungal cell wall inhibitors (e.g., candidas), azoles (e.g., fluoconazole and vericonazole), membrane disruptors (e.g., amphotericin B), nucleoside-based inhibitors, protease-based inhibitors, viral-assembly inhibitors, and other antiviral agents such as abacavir.  
      Examples of anti-tumor agents include, but are not limited to, DR3 Ligand (TNF-Gamma) and MIBG.  
      Examples of anti-leukemic agents include, but are not limited to, mda-7, human fibroblast interferon, mezerein, and Narcissus alkaloid (pretazettine).  
      Examples of chemotherapeutic agents include, but are not limited to, antibiotic derivatives (e.g., doxorubicin, bleomycin, daunorubicin, and dactinomycin), antiestrogens (e.g., tamoxifen), antimetabolites (e.g., fluorouracil, 5-FU, methotrexate, floxuridine, interferon alpha-2b, glutamic acid, plicamycin, mercaptopurine, and 6-thioguanine), cytotoxic agents (e.g., carmustine, BCNU, lomustine, CCNU, cytosine arabinoside, cyclophosphamide, estramustine, hydroxyurea, procarbazine, mitomycin, busulfan, cis-platin, and vincristine sulfate), hormones (e.g., medroxyprogesterone, estramustine phosphate sodium, ethinyl estradiol, estradiol, megestrol acetate, methyltestosterone, diethylstilbestrol diphosphate, chlorotrianisene, and testolactone), nitrogen mustard derivatives (e.g., mephalen, chorambucil, mechlorethamine (nitrogen mustard) and thiotepa), steroids and combinations (e.g., bethamethasone sodium phosphate), and others (e.g., dicarbazine, asparaginase, mitotane, vincristine sulfate, vinblastine sulfate, and etoposide).  
      Examples of anti-angiogenic inhibitors include, but are not limited to, AG-3340 (Agouron, La Jolla, Calif.), BAY-12-9566 (Bayer, West Haven, Conn.), BMS-275291 (Bristol Myers Squibb, Princeton, N.J.), CGS-27032A (Novartis, East Hanover, N.J.), Marimastat (British Biotech, Oxford, UK), Metastat (Aetema, St-Foy, Quebec), EMD-121974 (Merck KcgaA Darmstadt, Germany), Vitaxin (Ixsys, La Jolla, Calif./Medimmune, Gaithersburg, Md.), Angiozyme (Ribozyme, Boulder, Colo.), Anti-VEGF antibody (Genentech, S. San Francisco, Calif.), PTK-787/ZK-225846 (Novartis, Basel, Switzerland), SU-101 (Sugen, S. San Francisco, Calif.), SU-5416 (Sugen/Pharmacia Upjohn, Bridgewater, N.J.), SU-6668 (Sugen), IM-862 (Cytran, Kirkland, Wash.), Interferon-alpha, IL-12 (Roche, Nutley, N.J.), and Pentosan polysulfate (Georgetown University, Washington, D.C.).  
      Other therapeutic agents include thrombolytic agents such as tissue plasminogen activator, streptokinase, and urokinase plasminogen activators; lipid lowering agents such as antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, HMG CoA synthatase inhibitors, etc.); and anti-diabetic drugs, or other cardiovascular agents (loop diuretics, thiazide type diuretics, nitrates, aldosterone antagonistics (i.e. spironolactone and epoxymexlerenone), angiotensin converting enzyme (e.g. ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, antiarrythmics, anti-hypertension agents, and calcium channel blockers).  
      In one example of combinatorial therapy, rapamycin may be combined with GLEEVEC®. GLEEVEC® is a compound which is highly selective for PDGFR alpha, Beta-associated v-Abl tyrosine kinase. These compounds are not only able to inhibit acute vascular lesion formation after denudation injury, but also the development of chronic lesions such as those seen in diffused diseases in the vessel wall. GLEEVEC® can be combined with rapamycin standardization and delivered to the vessel wall via an intravascular implant.  
      As another example, heparin is known to dissolve clots in the vessel wall. By combining heparin with rapamycin, the stent is much less susceptible to clot formation.  
      In still another example, curcumin (diferuloylmethane), an anti-inflammatory agent from  curcuma longa , affects the proliferation of blood mononuclear cells and vascular smooth muscle cells. Curcumin independently inhibited the proliferation of rabbit vascular smooth muscle cells stimulated by fetal calf serum. Curcumin had a greater inhibitory effect on platelet derived growth factor stimulated proliferation than on serum-stimulated proliferation. Curcumin is very useful in the prevention of pathologic changes of atherosclerosis and restenosis. The possible mechanisms of the antiproliferative and apoptic effects of curcumin on vascular smooth muscle cells were studied in rat aortic smooth muscle cell line. Curcumin inhibits cell proliferation, arrested the cell cycle progression and induced cell apoptosis in vascular smooth muscle cells.  
      Additional pharmaceutical agents as well as methods to apply these agents are set forth in U.S. Pat. No. 6,585,764 to Wright et al, as well as, commonly owned U.S. patent application Ser. No. 10/696,174 entitled Rationally Designed Therapeutic Intravascular Implant Coating and are herein incorporated by reference.  
      All references cited herein are expressly incorporated by reference in their entirety.  
      It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described herein above. In addition, unless mention was made above to the contrary, it should be noted that all of the accompanying drawings are not to scale. A variety of modifications and variations are possible in light of the above teachings without departing from the scope and spirit of the invention, which is limited only by the following claims.