Advertisement

Treating atherosclerosis: local drug delivery from laboratory studies to clinical trials

      Abstract

      Treating only the specific section of the vascular bed that is diseased appears to make sense. Giving drugs systematically to treat perhaps only a few centimetres of affected artery carries with it the risk of systemic side effects and reduced efficacy consequent on low concentrations of agent at the site of the problem. There has thus been great interest since the early 1990s in local drug delivery. Initial targets were the thrombotic response to plaque disruption but the problems arising from the incidental damage inflicted by devices used in interventional cardiology and the pathological consequences of this, namely smooth muscle cell initiated intimal hyperplasia, soon became the focus of pre-clinical studies. Problems to be overcome were the low efficiency of delivery of drugs and the low retention rates. Solutions to these problems included the development of strategies to target drugs, through the use of antibodies directed at antigens newly released at the site of damage. As it became clear that stents were becoming central to the attainment of a better clinical response to intervention by their inherent physical properties, it also became obvious that stents could be used to deliver agents. Issues such as which stent, how to load the drug onto the stent and what drug to use to inhibit the unwanted pathobiological response are ongoing issues.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Stevenson R.
        • Ranjadayalan K.
        • Wilkinson P.
        • et al.
        Short and long term prognosis of acute myocardial infarction since the introduction of thrombolysis.
        Br. Med. J. 1993; 307: 349-353
        • Davies M.J.
        • Thomas A.C.
        Plaque fissuring—the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina.
        Br. Heart J. 1985; 53: 363-373
        • Conti C.R.
        Vascular events responsible for thrombotic occlusion of a blood vessel.
        Clin. Cardiol. 1993; 16: 761-762
        • Gershlick A.H.
        • Syndercombe Court D.
        • Mills P.
        Young infarct patients with single-vessel occlusion do not have an underlying prothrombotic state to explain their coronary occlusion.
        Int. J. Cardiol. 1992; 36: 49-56
        • Chesebro J.
        • Rauch U.
        • Fuster V.
        • Badimon J.J.
        Pathogenesis of thrombosis in coronary artery disease.
        Haemostasis. 1997; 27: 12-18
      1. Anonymous. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. New Engl J Med. 1998; 339: 436–43.

        • Kereikes D.J.
        • Kleiman N.S.
        • Ambrose J.
        • et al.
        Randomised double blind placebo- controlled dose ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty.
        J. Am. Coll. Cardiol. 1996; 27: 536-542
        • Moore R.S.
        • Rutty G.
        • Underwood M.J.
        • et al.
        Time sequence of vessel wall changes in an experimental model of angioplasty.
        J. Pathol. 1994; 172: 287-292
        • Carter A.J.
        • Laird J.R.
        • Farb A.
        • et al.
        Morphological characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model.
        J. Am. Coll. Cardiol. 1994; 24: 1398-1405
        • Waller B.F.
        • Johnson D.E.
        • Schnitt S.J.
        • et al.
        Histologic analysis of directional coronary atherectomy samples. A review of findings and their clinical relevance.
        Am. J. Cardiol. 1993; 72: 80E-87E
        • O'Brien E.R.
        • Bennett K.L.
        • Garvin M.R.
        • et al.
        Betaig-h3, a transforming growth factor beta inducible gene is overexpressed in atherosclerotic and restenotic human vascular lesions.
        Arterioscl. Thromb. Vasc. Biol. 1996; 16: 576-584
        • Grant M.B.
        • Wargovich T.J.
        • Ellis E.A.
        • et al.
        Expression of IGF-I, IGF-I receptor and IGF binding proteins -1,-2,-3,-4 and -5 in human atherectomy specimens.
        Regul. Pept. 1996; 67: 137-144
        • Marmur J.D.
        • Poon M.
        • Rossikhina M.
        • Taubman M.B.
        Induction of PDGF-responsive genes in vascular smooth muscle. Implications for the early response to vessel injury.
        Circulation. 1992; 86: III53-60
        • Strauss B.H.
        • Robinson R.
        • Batchelor W.B.
        • et al.
        In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases.
        Circ. Res. 1996; 79: 541-550
        • Javed Q.
        • Spring L.S.
        • de Bono D.P.
        Plasminogen activator and plasminogen activator inhibitor expression in vascular culture.
        Eur. Heart J. (Abstract). 1999; 20: 42
        • Moisseva E.P.
        • Spring E.L.
        • Baron J.H.
        • et al.
        Galectin 1 modulates attachment, spreading and migration of cultured vascular smooth muscle cells via interactions with cellular receptors and components of extracellular matrix.
        J. Vasc. Res. 1999; 36: 47-58
        • Topol E.J.
        • Califf R.M.
        • Weisman H.F.
        • et al.
        Randomised trail of coronary intervention with antibody against IIb/IIIa integrin for reduction of clinical restenosis: results at six months.
        Lancet. 1994; 343: 881-886
        • Carter A.J.
        • Laird J.R.
        • Kufs W.M.
        • et al.
        Coronary stenting with a novel stainless steel balloon-expandable stent: determinants of neointimal formation and changes in arterial geometry after placement in an atherosclerotic model.
        J. Am. Coll. Cardiol. 1996; 27: 1270-1277
        • Mintz G.S.
        • Popma J.J.
        • Hong M.K.
        • et al.
        Intravascular ultrasound to discern device-specific effects and mechanisms of restenosis.
        Am. J. Cardiol. 1996; 78: 18-22
      2. Serruys PW, de Jaegere P, Kiemeneij F, et al. For the Benestent group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease, New Engl J Med 1994; 331: 489–95.

        • Fischman D.
        • Leon M.
        • Baim D.
        • et al.
        A randomised comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease.
        New Engl. J. Med. 1994; 331: 496-501
        • Klugherz B.D.
        • de Angelo D.L.
        • Kim B.K.
        • et al.
        Three year follow up after Palmaz–Schatz stenting.
        J. Am. Coll. Cardiol. 1996; 27: 1185-1191
        • Eeckout E.
        • van Melle G.
        • Stauffer J.C.
        • et al.
        Can early closure and restenosis after endoluminal stenting be predicted from clinical, procedural, and angiographic variablesat the time of intervention.
        Br. Heart J. 1995; 74: 592-597
        • Wong S.C.
        • Baim D.S.
        • Schatz R.A.
        • et al.
        Immediate results and late outcomes after stent implantation in saphenous vein graft lesions: the multicenter US Palmaz–Schatz experience.
        J. Am. Coll. Cardiol. 1995; 26: 704-712
        • Foley J.B.
        • Brown R.I.
        • Penn I.M.
        Thrombosis and restenosis after stenting in failed angioplasty: comparison with elective stenting.
        Am. Heart J. 1994; 128: 12-20
        • Nunes G.
        • Pinto I.
        • Matters L.
        • et al.
        Coronary stenting in vessels smaller than 3 mm is associated with higher restenosis rates.
        Eur. Heart J. (Abstract). 1996; 17: 173
        • Moscucci M.
        • Piana R.N.
        • Kuntz R.E.
        Effect of prior coronary restenosis on the risk of subsequent restenosis after stent placement or directional atherectomy.
        Am. J. Cardiol. 1994; 73: 1147-1153
        • Van Belle E.
        • Bauters C.
        • Hubert E.
        • et al.
        Restenosis rates in diabetic patients: a comparison of stenting and balloon angioplasty in native coronary vessels.
        Circulation. 1997; 96: 1454-1460
        • Baim D.S.
        • Lavine M.J.
        • Leon M.B.
        • et al.
        Management of restenosis within the Palmaz–Schatz coronary artery stent (the US multicenter experience).
        Am. J. Cardiol. 1993; 71: 364-366
        • Schwartz L.
        • Lesperance J.
        • Bourassa M.G.
        • et al.
        The role of antiplatelet agents in modifying the extent of restenosis following percutaneous transluminal coronary angioplasty.
        Am. Heart J. 1990; 119: 232-236
        • Serruys P.W.
        • Rutsch W.
        • Heyndrickx G.R.
        • et al.
        Prevention of retsenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade.
        Circulation. 1991; 84: 1568-1580
        • Serruys P.W.
        • Klein W.
        • Tijssen J.P.
        • et al.
        Evaluation of ketanserin in the prevention of restenosis after percutaneous transluminal coronary angioplasty.
        Circulation. 1993; 88: 1588-1601
        • Karsch K.R.
        • Presack M.B.
        • Baildon R.
        • et al.
        Low molecular weight heparin (reviparin) in transluminal coronary angioplasty. Results of a randomised, double blind, unfractionated heparin and placebo-controlled, multicentre trial (REDUCE Trial).
        J. Am. Coll. Cardiol. 1996; 28: 1437-1443
        • Cairns J.A.
        • Gill J.
        • Morton B.
        • et al.
        • The EMPAR study
        Fish oils and low molecular weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty.
        Circulation. 1996; 94: 1553-1560
        • Foley D.P.
        • Serruys P.W.
        Fluvastatin for the prevention of restenosis after coronary balloon angioplasty; angiographic and methodological background of the fluvastatin angioplasty restenosis trial.
        Br. J. Clin. Pract. (Suppl). 1996; 77A: 40-53
        • Maresta A.
        • Balducelli M.
        • Cantini L.
        • et al.
        Trapidil (triazolpyrimidine), a platelet -derived growth factor antagonist, reduces restenosis after percutaneous transluminal coronary angioplasty. Results of the randomised double-blind STARC study.
        Circulation. 1994; 90: 2710-2715
        • Emanuelson H.
        • Beatt K.J.
        • Bagger J.P.
        • et al.
        Long term effects of angiopeptin treatment in coronary angioplasty. Reduction of clinical events but not angiographic restenosis.
        Circulation. 1995; 91: 1689-1696
        • Hoberg E.
        • Kubler W.
        Prevention of restenosis after PTCA: role of calcium antagonists.
        J. Cardiovasc. Pharmacol. (Suppl). 1991; 18: S15-S19
      3. Anonymous. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial. Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group. Circulation 1992;86:100–10

        • Serruys P.W.
        • Foley D.P.
        • Kirkeeide R.L.
        • King III, S.B.
        Restenosis revisited: insights provided by quantitative coronary angiography.
        Am. Heart J. 1993; 126: 1243-1267
        • Clowes A.W.
        • Karnowski M.J.
        Supression by heparin of smooth muscle cell proliferation in injured arteries.
        Nature. 1977; 265: 625-626
        • Brack M.J.
        • Ray S.
        • Chauhan A.
        • Fox J.
        • et al.
        The Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial. Results of a multicenter randomized trial investigating the effects of high dose unfractionated heparin on angiographic restenosis and clinical outcome.
        J. Am. Coll. Cardiol. 1995; 26: 947-954
        • Powell J.S.
        • Clozel J.P.
        • Muller R.K.M.
        • et al.
        Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury.
        Science. 1989; 245: 186-188
        • Gellman J.
        • Ezekowitz M.D.
        • Sarembock I.J.
        • et al.
        Effect of lovastatin on intimal hyperplasia after balloon angioplasty: a study in an atherosclerotic hypercholesterolaemic rabbit.
        J. Am. Coll. Cardiol. 1991; 17: 251-259
        • Sarembock I.J.
        • Gertz S.
        • Gimple L.W.
        • et al.
        Effectiveness of recombinant desulphatohirudin in reducing retsenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.
        Circulation. 1991; 84: 232-243
        • Serruys P.W.
        • Herrman J.P.R.
        • Simon R.
        • et al.
        A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. The HELVETICA trial.
        New Engl. J. Med. 1995; 333: 757-763
        • Michel J.F.
        • Fram D.B.
        • Palme D.F.
        • et al.
        Enhanced intracoronary thrombolysis with urokinase using a novel local drug delivery system. In vitro, in vivo and clinical studies.
        Circulation. 1995; 91: 785-793
        • Camenzid E.
        • Kint P.P.
        • Di Mario C.
        • et al.
        Intracoronary heparin delivery in humans. Acute feasibility and long term results.
        Circulation. 1995; 92: 2463-2472
        • Tahlil O.
        • Brami M.
        • Feldman L.
        • et al.
        The dispatch catheter as a delivery tool for arterial gene transfer.
        Cardiovasc. Res. 1997; 33: 181-187
        • Gunn J.
        • Holt L.
        • Shepard H.
        • et al.
        Local delivery of antisense oligonucleotide via a double skinned porous balloon; where does the drug go.
        Eur. Heart. J. (Abstract). 1995; 16: 484
      4. Meneveau N, Schiele F, Grollier G, et al. Local delivery of Nadrparin for the prevention of neointimal hyperplasia following stent implantation: Results of the IMPRESS Trial. Eur Heart J 2000;21:1767–75.

        • More R.S.
        • Underwood M.J.
        • Brack M.J.
        • Pringle S.
        • de Bono D.P.
        • Gershlick A.H.
        In vitro studies of a bispecific monoclonal antibody antithrombotic conjugate {ATC(3)].
        Int. J. Angiol. 1995; 4: 83-87
        • More R.S.
        • Underwood M.J.
        • Brack M.J.
        • Pringle S.
        • de Bono D.P.
        • Gershlick A.H.
        A targeted antithrombotic conjugate with antiplatelet and fibrinolytic properties which reduces in vivo thrombus formation.
        Cardiovasc. Res. 1993; 27: 2200-2204
        • More R.S.
        • Underwood M.J.
        • de Bono D.P.
        Targeting fibrinolytic agents to the vessel wall; a new therapeutic niche?.
        Thromb. Haemost. 1994; 71: 158-159
        • Hogrefe K.
        • Foo R.S.
        • de Bono D.P.
        • Gershlick A.H.
        Targeting damaged vessel wall with a novel agent to improve local retention of GP IIb/IIIa receptor antagonist.
        Heart (Abstract). 1999; 81: P54
        • Hogrefe K.
        • Foo R.S.
        • Azrin M.
        • Ezekowitz M.
        • de Bono D.P.
        • Gershlick A.H.
        Targeted platelet inhibition with a novel bispecific antibody fragment that binds to platelet glycoprotein IIb/IIIa receptors and tissue factor.
        Circulation (Abstract). 1999; 100: 1-471
        • Anderson J.L.
        • Karagounis L.A.
        • Califf R.M.
        Metaanalysis of five reported studies on the relation of early coronary patency grades with mortality and outcomes after acute myocardial infarction.
        Am. J. Cardiol. 1996; 78: 1-8
        • Ross A.M.
        • Coyne K.S.
        • Moreyra E.
        • et al.
        Extended mortality benefit of early post infarction reperfusion. GUSTO -I angiographic investigators.
        Circulation. 1998; 97: 1549-1556
        • Noble S.
        • McTavish D.
        Reteplase. A review of its pharmacological properties and clinical efficacy in the management of acute myocardial infarction.
        Drugs. 1996; 52: 589-605
        • Brouwer M.A.
        • Bohncke J.R.
        • Veen G.
        • et al.
        Adverse long-term effects of reocclusion after coronary thrombolysis.
        J. Am. Coll. Cardiol. 1995; 26: 1440-1444
        • Kuntz R.E.
        • Gibson C.
        • Nobuyoshi M.
        • et al.
        Generalised model of restenosis after conventional balloon angioplasty stenting and directional atherectomy.
        J. Am. Coll. Cardiol. 1993; 21: 15-25
        • Carter A.J.
        • Laird J.R.
        • Farb A.
        • et al.
        Morphological characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model.
        J. Am. Coll. Cardiol. 1994; 24: 1398-1405
        • van Beusekom H.M.
        • van der Giessen J.W.
        • van Suylen R.
        • et al.
        Histology after stenting of human saphenous vein bypass grafts: observations from surgically excised grafts 3–320 days after stent implantation.
        J. Am. Coll. Cardiol. 1993; 21: 45-54
        • Kearney M.
        • Pieczek A.
        • Haley L.
        • et al.
        Histopathology of in stent restenosis in patients with peripheral vascular disease.
        Circulation. 1997; 95: 1998-2002
        • Teirsten P.S.
        • Massuillo V.
        • Jani S.
        • et al.
        Catheter-based radiotherapy to inhibit restenosis after coronary stenting.
        New Engl. J. Med. 1997; 336: 1697-1703
        • Teirstein P.S.
        • Massullo V.
        • Jani S.
        • et al.
        Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial.
        Circulation. 2000; 101: 360-365
        • Urban P.
        • Verin V.
        • Pipowski Y.
        • et al.
        Feasibility and safety of beta irradiation in human coronary arteries.
        Semin. Intervent. Cardiol. 1997; 2: 125-131
        • King III, S.B.
        • Williams D.O.
        • Chougule P.
        • et al.
        Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: results of the beta energy restenosis trial (BERT).
        Circulation. 1998; 97: 2025-2030
        • Costa M.A.
        • Sabat M.
        • van der Giessen J.W.
        • et al.
        Late coronary occlusion after intracoronary brachytherapy.
        Circulation. 1999; 100: 789-792
        • Aggarwal R.K.
        • Ireland D.C.
        • Azrin M.A.
        • et al.
        Antithrombotic potential of polymer-coated stents eluting platelet glycoprotein IIb/IIIa receptor antibody.
        Circulation. 1996; 94: 3311-3317
        • Matsuno H.
        • Stassen J.M.
        • Vermylen J.
        • et al.
        Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation.
        Circulation. 1994; 90: 2203-2206
      5. Baron JH, Aggrawal R, de Bono DP, Gershlick AH. Adsorption and elution of c7E3 Fab from polymer coated stents in-vitro. Abstr ESC 1997.

      6. Baron JH, Aggrawal R, de Bono DP, Gershlick AH. c7E3 Fab inhibits adhesion of smooth muscle cells to vitronectin: a possible way of inhibiting in-stent restenosis Abstr ESC 1997.

        • Baron J.H.
        • de Bono D.P.
        • Gershlick A.H.
        Adsorption of c7E3 Fab onto polymer-coated Cook GR II stents: reopro eluting stents inhibit platelet deposition in vitro.
        Heart (Abstract). 1998; 55: 183
        • Azrin M.A.
        • Ling F.S.
        • Chen Q.
        • et al.
        Preparation, characterization, and evaluation of a monoclonal antibody against the rabbit platelet glycoprotein IIb/IIIa in an experimental angioplasty model.
        Circ. Res. 1994; 75: 268-277
        • Foo R.S.
        • Hogrefe K.
        • Baron J.H.
        • de Bono D.P.
        • Gershlick A.H.
        Activated protein C to prevent thrombosis in percutaneous coronary intervention.
        Clin. Sci. (Abstract). 1999; 96: 4P
      7. Swanson N, Hogrefe K, Baron J, et al. VEGF-eluting stents to reduce stent complications—pharmacokinetics of adsorption and elution. 6th International LDD&R Local Drug delivery meeting and cardiovascular course on Radiation & molecular strategies 28/1/2000- Abstract.

        • Jordan M.A.
        • Tosos R.J.
        • Wilson L.
        Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations.
        Proc. Natl. Acad. Sci. 1993; 90: 9552-9556
        • Sollott S.J.
        • Cheng L.
        • Pauly R.R.
        • et al.
        Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat.
        J. Clin. Invest. 1995; 95: 1869-1876