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  • Tacrolimus is a proven cytostatic drug which selectively inhibits smooth muscle cells proliferation and migration while permitting enhanced re-endothelialization. Tacrolimus is structurally related to Sirolimus; both drugs exert their effect in the same stage of the cell cycle. Sirolimus and Tacrolimus arrest the cell before it enters the dividing cycle, therefore they are regarded as cytostatic drugs. Cytostatic (vs. cytotoxic) drugs have the advantage of stopping cell proliferation without killing cells, thereby minimizing the risks of tissue pathology. Tacrolimus has also anti-inflammatory properties. Inflammation at the site of stent implantation may contribute to the complex development of restenosis.
  • Largest size of Angioplasty Market – 1995 Largest size of Metallic Stent Market – 2000 Largest projected size of DES Market – 2008: includes $400MM VP market and 25% price premium on Bifurcation stents
  • The benefits of bioresorbable
  • Slide 1 - Cardiology news, educational programming ...

    1. 1. Next Generations Drug Eluting Stents will safety be addressed? Ron Waksman MD FACC FSCAI Professor of Medicine, Georgetown University, Associate Chief of Cardiology, Washington Hospital Center, Washington DC Any use of trade names is for reference only; no promotion of particular devices or products should be inferred.
    2. 2. Drug-Eluting Stents Next Generation Stent design and delivery system Pharmacologic agent Drug carrier vehicle Drug-Eluting Stent New Designs to address small vessels bifurcations Bioresorbable polymers no polymers Pro healing, New Drugs, combination of drugs, change in release kinetics Complete Resorbable Stents
    3. 3. New Solutions for the Next Generation of Drug-eluting Stents <ul><li>New coating (absorbable coating, no coating) </li></ul><ul><li>New Biological target: (Endothelium, thrombosis, inflammation) </li></ul><ul><li>New drug (less cytostatic or cytotoxic) </li></ul><ul><li>New technique of elution (reservoir, dual elution) </li></ul><ul><li>Pro Healing approach (EPC capture) </li></ul><ul><li>Pro Healing approach + Sirolimus or Paclitaxel </li></ul><ul><li>Complete Absorbable metallic or polymeric platform </li></ul><ul><li>New Stent Design for challenging targets bifurcations </li></ul>
    4. 4. New DES Programs <ul><li>NO Donors Blue Medical </li></ul><ul><li>Biolimus A9 Biosensors, Terumo, Devax </li></ul><ul><li>Zotarolimus Zomax, Endeavor CR </li></ul><ul><li>Pimecrolimus Biotronik, Conor, Avantac </li></ul><ul><li>Melatonin Blue Medical </li></ul><ul><li>Gleevec Novartis </li></ul><ul><li>Everolimus Guidant </li></ul><ul><li>Tacrolimus Sorin </li></ul><ul><li>EPC Progenitors Orbus </li></ul><ul><li>Restin-NG AVI Biopharma </li></ul><ul><li>Genistein Sahajanand </li></ul><ul><li>Paclitaxel Balloon B- Braun </li></ul><ul><li>Bioabsorbable Guidant, Biotronik, Reva </li></ul>More More More !!!!!
    5. 5. Current Problems with Polymers <ul><li>Durable Coatings-Potential for: </li></ul><ul><ul><li>Continuing source of inflammation </li></ul></ul><ul><ul><li>Poor healing/thrombosis risk </li></ul></ul>Shortcomings often associated with polymers during stent delivery Non uniform polymer coating “ Webbed” polymer surface leading to stent expansion issues” Polymer delamination
    6. 6. New Polymers and Coating <ul><li>Bioabsrobable Polymers </li></ul><ul><li>PLLA </li></ul><ul><li>PLA </li></ul><ul><li>PLG </li></ul><ul><li>PLGA </li></ul><ul><li>No Polymers </li></ul><ul><li>Textured Surface </li></ul><ul><li>Depot Technology </li></ul><ul><li>Setagon Nano Technology </li></ul><ul><li>Surface Modifications </li></ul><ul><li>Nano membranous Filters </li></ul><ul><li>Photolithographic Etching </li></ul><ul><li>Hydroxyappetite HA </li></ul>
    7. 7. Advanced Approaches to Drug Release <ul><li>Bioabsorbable polymers </li></ul><ul><li>Controlled polymer application </li></ul><ul><li>Non polymer release (porous surface) </li></ul><ul><li>Bioabsorbable stents </li></ul>BioFlex I Biosensors
    8. 8. A Completely Polymer-Free Strategy Translumina YUKON ® Choice DES <ul><li>Polymer-free coating </li></ul><ul><li>Unique roughened surface </li></ul><ul><li>Adjustable dosage for individualized treatment </li></ul><ul><li>Free choice of drugs </li></ul>
    9. 9. Directional Drug Delivery (ablumenal preference) <ul><li>Selective coating on the outside surface of the stent </li></ul><ul><ul><li>Reduced drug/polymer </li></ul></ul><ul><ul><li>Lumenal surface BMS </li></ul></ul><ul><ul><li>Drug only where needed </li></ul></ul>Labcoat JA™Coating Technology
    10. 10. BioMatrix ® II Stent Platform Design <ul><li>Biodegradable Drug/Carrier: </li></ul><ul><li>Biolimus A9 ® / Poly (Lactic Acid) 50:50 mix </li></ul><ul><li>abluminal surface only (contacts vessel wall) </li></ul><ul><li>15 µmeter coating thickness </li></ul><ul><li>degrades in 9 months releasing CO 2 + water </li></ul><ul><li>Stent Platform: </li></ul><ul><li>stainless steel (112  m) </li></ul><ul><li>corrugated ring, quadrature-link™ design </li></ul><ul><li>radius link enhances axial fatigue life </li></ul><ul><li>Parylene Durable Primer Coating: </li></ul><ul><li>5 µmeter thick, encapsulates stent </li></ul><ul><li>prevents surface metal ion migration </li></ul><ul><li>biostable + athrombogenic* </li></ul>BIOFLEX™ I * Data per NHLBI sponsored study, available from BSI BioFlex I stent
    11. 11. 2 Drugs with 2 Different Targets: Pimecrolimus-Paclitaxel Isoflavone-Sirolimus Dexamethazone-Zotarolimus Tacrolimus Pimecrolimus Sirolimus, Biolimus A9 Everolimus, Zotarolimus Isoflavone Inhibitor Paclitaxel
    12. 12. Conor Drug Release Technology Drug Reservoir Luminal Barrier Layer Simple Drug Reservoir Uniform Release Single Drug Structure Multiple Drug Structures Drug A released to arterial wall Barrier layer Drug B released into bloodstream Two Drugs, One Well Two Drugs, Two Wells Two Directions Luminal Barrier Mural Barrier Mural Side
    13. 13. Dual Elution Genistein and Sirolimus Five Layers of Genistein - Sirolimus <ul><li>Total Drug Dose: 2.51  g/mm 2 (112  g Genistein and 76  g Sirolimus content on 16 mm stent) </li></ul><ul><li>Unique Biodegradable Heparinized Polymers Blend includes-Poly L-Lactide, 50/50 Poly DL-Lactide-co-Glycolide and Polyvinyl Pyrrolidone </li></ul>No Drug- Top layer (Protective layer E) Genistein (Top layer D) Genistein + Sirolimus (Middle layer C) Genistein  + Sirolimus  (Middle layer B) Genistein (Base layer A)
    14. 14. Future Safe DES Platforms The Key is the Endothelium! active support of endothelial cell proliferation and migration after stent implantation accelerated endothelial cell strut coverage decreased smooth muscle activation & reduced collagen secretion optimal healing response = accelerated functional endothelium
    15. 15. Strut Coverage and Endothelization Cypher Taxus Endeavor % of Struts Endothelialized Virmani et. al; PCR 2006 Virmani et. al. PCR . 2006.
    16. 16. Endeavor DES System Key Components PC Technology Drug: Zotarolimus Stent Delivery System Driver Cobalt Alloy Stent
    17. 17. Endeavor DES System PC Technology 90% of phospholipids in the outer membrane of a red blood cell contain the PC (Phosphorylcholine) headgroup Inner Membrane Outer Membrane The Phosphoycholine (PC) Headgroup PC 1 mimics the chemical structure of the phospholipid headgroup O P O O O N
    18. 18. ENDEAVOR HCRI CEC Definition of Stent Thrombosis: EI n=100 1 2 3 12 13 14 Days Post Procedure 30 100 150 270 360 720 EII n=598 EII CA n=296 EIII n=323 = 1% = 0.5% = 0.0% = 0.0% Overall Thrombosis = 0.3% ENDEAVOR I-III Plavix Rx for ≥ 3 months 1080 No Late Stent Thrombosis in Over 1,300 Patients No Late Stent Thrombosis in 994 Patients > 2 yr f/u
    19. 19. Surfaces to Encourage Cell Growth <ul><li>Bioactive surfaces to accelerate functional endothelialization </li></ul>Orbus – EPC Capture cell drug peptide protein device surface Peptide linkers Cell specific peptide linkers (Affinergy) Nanotextured Surfaces Example of IrOx
    20. 20. Bioresorbable: The Future of Stenting? Past… Present… … Future Bare Metal Stent More efficacious than POBA Metal DES More efficacious than BMS BVS REVA Cordis Biotronik no drug drug
    21. 21. Conclusions New DES Solutions <ul><li>The new generations of DES will focus more on safety while preserving the efficacy. </li></ul><ul><li>New designed DES will emerge and become available. </li></ul><ul><li>These will address challenging anatomic subsets (bifurcation, small vessels etc). </li></ul><ul><li>Focus is on Prohealing and fast reendothelailization rather antiproliferation solving late thrombosis, hypersensitivity, abnormal vasomotion, etc). </li></ul><ul><li>Thinner biostable polymers, Bioabsorbable, no polymers and surface modification will be the future carrier </li></ul><ul><li>Gentle Drugs and Dual drug will lower cytotoxic doses. </li></ul><ul><li>Complete biodegradable stents with and without drugs are on the horizon </li></ul>