pharmacological attempts to prevent restenosis by pharmacologic means have thus far been unsuccessful and all involve systemic administration of the trial agents . neither aspirin - dipyridamole , ticlopidine , acute heparin administration , chronic warfarin ( 6 months ) nor methylprednisolone have been effective in preventing restenosis although platelet inhibitors have been effective in preventing acute reocclusion after angioplasty . the calcium antagonists have also been unsuccessful in preventing restenosis , although they are still under study . other agents currently under study include thromboxane inhibitors , prostacyclin mimetics , platelet membrane receptor blockers , thrombin inhibitors and angiotensin converting enzyme inhibitors . these agents must be given systemically , however , and attainment of a therapeutically effective dose may not be possible ; antiproliferative ( or anti - restenosis ) concentrations may exceed the known toxic concentrations of these agents so that levels sufficient to produce smooth muscle inhibition may not be reached ( lang et al ., 42 ann . rev . med ., 127 - 132 ( 1991 ); popma et al ., 84 circulation , 1426 - 1436 ( 1991 )). additional clinical trials in which the effectiveness for preventing restenosis of dietary fish oil supplements , thromboxane receptor antagonists , cholesterol lowering agents , and serotonin antagonists has been examined have shown either conflicting or negative results so that no pharmacological agents are as yet clinically available to prevent post - angioplasty restenosis ( franklin , s . m . and faxon , d . p ., 4 coronary artery disease , 232 - 242 ( 1993 ); serruys , p . w . et al ., 88 circulation , ( part 1 ) 1588 - 1601 , ( 1993 ). conversely , stents have proven useful in preventing reducing the proliferation of restenosis . stents , such as the stent 10 seen in layout in fig4 balloon - expandable slotted metal tubes ( usually but not limited to stainless steel ), which when expanded within the lumen of an angioplastied coronary artery , provide structural support to the arterial wall . this support is helpful in maintaining an open path for blood flow . in two randomized clinical trials , stents were shown to increase angiographic success after ptca , increase the stenosed blood vessel lumen and to reduce the lesion recurrence at 6 months ( serruys et al ., 331 new eng jour . med , 495 , ( 1994 ); fischman et al ., 331 new eng jour . med , 496 - 501 ( 1994 ). additionally , in a preliminary trial , heparin coated stents appear to possess the same benefit of reduction in stenosis diameter at follow - up as was observed with non - heparin coated stents . additionally , heparin coating appears to have the added benefit of producing a reduction in sub - acute thrombosis after stent implantation ( serruys et al ., 93 circulation , 412 - 422 , ( 1996 ). thus , 1 ) sustained mechanical expansion of a stenosed coronary artery has been shown to provide some measure of restenosis prevention , and 2 ) coating of stents with heparin has demonstrated both the feasibility and the clinical usefulness of delivering drugs to local , injured tissue off the surface of the stent . numerous agents are being actively studied as antiproliferative agents for use in restenosis and have shown some activity in experimental animal models . these include : heparin and heparin fragments ( clowes and karnovsky , 265 nature , 25 - 626 , ( 1977 ); guyton , j . r . et al . 46 circ . res ., 625 - 634 , ( 1980 ); clowes , a . w . and clowes , m . m ., 52 lab . invest ., 611 - 616 , ( 1985 ); clowes , a . w . and clowes , m . m ., 58 circ . res ., 839 - 845 ( 1986 ); majesky et al ., 61 circ res ., 296 - 300 , ( 1987 ); snow et al ., 137 am . j . pathol ., 313 - 330 ( 1990 ); okada , t . et al ., 25 neurosurgery , 92 - 898 , ( 1989 ) colchicine ( currier , j . w . et al ., 80 circulation , 11 - 66 , ( 1989 ), taxol ( ref ), agiotensin converting enzyme ( ace ) inhibitors ( powell , j . s . et al ., 245 science , 186 - 188 ( 1989 ), angiopeptin ( lundergan , c . f . et al ., 17 am . j . cardiol . ( suppl . b ); 132b - 136b ( 1991 ), cyclosporin a ( jonasson , l . et . al ., 85 proc . nati , acad . sci ., 2303 ( 1988 ), goat - anti - rabbit pdgf antibody ( ferns , g . a . a ., et al ., 253 science , 1129 - 1132 ( 1991 ), terbinafine ( nemecek , g . m . et al ., 248 j . pharmacol . exp . thera ., 1167 - 11747 ( 1989 ), trapidil ( liu , m . w . et al ., 81 circulation , 1089 - 1093 ( 1990 ), interferon - gamma ( hansson , g . k . and holm , 84 j . circulation , 1266 - 1272 ( 1991 ), steroids ( colburn , m . d . et al ., 15 j . vasc . surg ., 510 - 518 ( 1992 ), see also berk , b . c . et al ., 17 j . am . coll . cardiol ., 111b - 1 17b ( 1991 ), ionizing radiation ( ref ), fusion toxins ( ref ) antisense oligonucleotides ( ref ), gene vectors ( ref ), and rapamycin ( see below ). of particular interest in rapamycin . rapamycin is a macrolide antibiotic which blocks il - 2 - mediated t - cell proliferation and possesses antiinflammatory activity . while the precise mechanism of rapamycin is still under active investigation , rapamycin has been shown to prevent the g 1 to s phase progression of t - cells through the cell cycle by inhibiting specific cell cyclins and cyclin - dependent protein kinases ( siekierka , immunol . res . 13 : 110 - 116 , 1994 ). the antiproliferative action of rapamycin is not limited to t - cells ; marx et al . ( circ res 76 : 412 - 417 , 1995 ) have demonstrated that rapamycin prevents proliferation of both rat and human smc in vitro while poon et al . have shown the rat , porcine , and human smc migratin can also be inhibited by rapamycin ( j clin invest 98 : 2277 - 2283 , 1996 ). thus , rapamycin is capable of inhibiting both the inflammatory response known to occur after arterial injury and stent implantation , as well as the smc hyperproliferative response . in fact , the combined effects of rapamycin have been demonstrated to result in a diminished smc hyperproliferative response in a rat femoral artery graft model and in both rat and porcine arterial balloon injury models ( gregory et al ., transplantation 55 : 1409 - 1418 , 1993 ; gallo et al ., in press , ( 1997 )). these observations clearly support the potential use of rapamycin in the clinical setting of post - angioplasty restenosis . although the ideal agent for restenosis has not yet been identified , some desired properties are clear : inhibition of local thrombosis without the risk systemic bleeding complications and continuous and prevention of the dequale of arterial injury , including local inflammation and sustained prevention smooth muscle proliferation at the site of angioplasty without serious systemic complications . inasmuch as stents prevent at least a portion of the restenosis process , an agent which prevents inflammation and the proliferation of smc combined with a stent may provide the most efficacious treatment for post - angioplasty restenosis . agents : rapamycin ( sirolimus ) structural analogs ( macrocyclic lactones ) and inhibitors of cell - cycle progression . local delivery of such agents ( rapamycin ) from the struts of a stent , from a stent graft , grafts , stent cover or sheath . involving comixture with polymers ( both degradable and nondegrading ) to hold the drug to the stent or graft . or entrapping the drug into the metal of the stent or graft body which has been modified to contain micropores or channels , as will be explained further herein . or including covalent binding of the drug to the stent via solution chemistry techniques ( such as via the carmeda process ) or dry chemistry techniques ( e . g . vapour deposition methods such as rf - plasma polymerization ) and combinations thereof . catheter delivery intravascularly from a tandem balloon or a porous balloon for intramural uptake uses : for inhibition of cell proliferation to prevent neointimal proliferation and restenosis . prevent ingrowth of tissue into catheters and shunts inducing their failure . solution of rapamycin , prepared in a solvent miscible with polymer carrier solution , is mixed with solution of polymer at final concentration range 0 . 001 weight % to 30 weight % of drug . polymers are biocompatible ( i . e ., not elicit any negative tissue reaction or promote mural thrombus formation ) and degradable , such as lactone - based polyesters or copolyesters , e . g ., polylactide , polycaprolacton - glycolide , polyorthoesters , polyanhydrides ; poly - aminoacids ; polysaccharides ; polyphosphazenes ; poly ( ether - ester ) copolymers , e . g ., peo - plla , or blends thereof . nonabsorbable biocompatible polymers are also suitable candidates . polymers such as polydimethyl - siolxane ; poly ( ethylene - vingylacetate ); acrylate based polymers or copolymers , e . g ., poly ( hydroxyethyl methylmethacrylate , polyvinyl pyrrolidinone ; fluorinated polymers such as polytetrafluoroethylene ; cellulose esters . polymer / drug mixture is applied to the surfaces of the stent by either dip - coating , or spray coating , or brush coating or dip / spin coating or combinations thereof , and the solvent allowed to evaporate to leave a film with entrapped rapamycin . 2 . experimental stent delivery method — delivery from microporous depots in stent through a polymer membrane coating : stent , whose body has been modified to contain micropores or channels is dipped into a solution of rapamycin , range 0 . 001 wt % to saturated , in organic solvent such as acetone or methylene chloride , for sufficient time to allow solution to permeate into the pores . ( the dipping solution can also be compressed to improve the loading efficiency .) after solvent has been allowed to evaporate , the stent is dipped briefly in fresh solvent to remove excess surface bound drug . a solution of polymer , chosen from any identified in the first experimental method , is applied to the stent as detailed above . this outerlayer of polymer will act as diffusion - controller for release of drug . 3 . experimental stent delivery method — delivery via lysis of a covalent drug tether rapamycin is modified to contain a hydrolytically or enzymatically labile covalent bond for attaching to the surface of the stent which itself has been chemically derivatized to allow covalent immobilization . covalent bonds such as ester , amides or anhydrides may be suitable for this . a : polymeric sheet rapamycin is combined at concentration range previously highlighted , with a degradable polymer such as poly ( caprolactone - gylcolide ) or non - degradable polymer , e . g ., polydimethylsiloxane , and mixture cast as a thin sheet , thickness range 10μ to 1000μ . the resulting sheet can be wrapped perivascularly on the target vessel . preference would be for the absorbable polymer . b : conformal coating : rapamycin is combined with a polymer that has a melting temperature just above 37 ° c ., range 40 °- 45 ° c . mixture is applied in a molten state to the external side of the target vessel . upon cooling to body temperature the mixture solidifies conformally to the vessel wall . both non - degradable and absorbable biocompatible polymers are suitable . as seen in the figures it is also possible to modify currently manufactured stents in order to adequately provide the drug dosages such as rapamycin . as seen in fig1 a , 2 a and 3 a , any stent strut 10 , 20 , 30 can be modified to have a certain reservoir or channel 11 , 21 , 31 . each of these reservoirs can be open or closed as desired . these reservoirs can hold the drug to be delivered . fig4 shows a stent 40 with a reservoir 45 created at the apex of a flexible strut . of course , this reservoir 45 is intended to be useful to deliver rapamycin or any other drug at a specific point of flexibility of the stent . accordingly , this concept can be useful for “ second generation ” type stents . in any of the foregoing devices , however , it is useful to have the drug dosage applied with enough specificity and enough concentration to provide an effective dosage in the lesion area . in this regard , the reservoir size in the stent struts must be kept at a size of about 0 . 0005 ″ to about 0 . 003 ″. then , it should be possible to adequately apply the drug dosage at the desired location and in the desired amount . these and other concepts will are disclosed herein . it would be apparent to the reader that modifications are possible to the stent or the drug dosage applied . in any event , however , the any obvious modifications should be perceived to fall within the scope of the invention which is to be realized from the attached claims and their equivalents .
delivery of rapamycin locally , particularly from an intravascular stent , directly from micropores in the stent body or mixed or bound to a polymer coating applied on stent , to inhibit neointimal tissue proliferation and thereby prevent restenosis . this invention also facilitates the performance of the stent in inhibiting restenosis .