Prevention of Restenosis: Gene and Other Biologic Strategies

Saturday, March 2, 1996 than those used in animals to avoid side effects. One approach to avoiding this problem is to deliver the drugs directly to the angioplasty site. Methods developed to perform such local drug delivery include the use of occlusive double-balloon catheters, perforated angioplasty balloons, electrophoretic devices, hydrogelcoated angioplasty balloons, angioplasty balloons with external delivery channels, luminal paving with polymer gels, and stents coated with controlled drug-release systems. These systems have been used to deliver tracer materials; antithrombotic, antimigratory, and antiproliferative drugs; and genetic material. Many questions remain to be answered regarding local drug delivery. What is the appropriate drug to deliver? For how long should the drug be delivered? Can a sufficient amount of drug be delivered to have a biologic effect? Can the drug be retained in the arterial wall long enough to have a biologic effect? Summary Animal studies have given us considerable information regarding the physiologic processes involved in arterial repair after injury. Furthermore, these studies have aided us in identifying pharmacologic agents that can interfere with the repair process. These studies have not provided us with a complete picture of all the physiologic processes involved; consequently, we cannot be sure a particular drug can prevent restenosis. Given the complexity of the arterial repair process, prevention of restenosis will require a mix of drugs given in a specific sequence designed to block the specific stages of repair. Sell~cted Bibliography Berk BC, Han-is K. Restenosis after percutaneous transluminal coronary angioplasty: new therapeutic insights from pathogenic mechanisms. Adv Intern Med 1995; 40:445-501.

Currier ]W, Faxon DP. Restenosis after percutaneous transluminal coronary angioplasty: have we been aiming at the wrong target? J Am ColI Cardiol 1995; 25: 516-520. Di Mario C, Gil R, Camenzind E, et al. Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional atherectomy. Am J Cardiol 1995; 75:772-777.

Franklin SM, Faxon DP. Pharmacologic prevention of restenosis after coronary angioplasty: review of the randomized clinical trials. Coron Artery Dis 1993; 4: 232-242.

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Jackson CL. Animal models of restenosis. Trends Cardiovasc Med 1994; 4:122-130. Jackson CL, Schwartz SM. Pharmacology of smooth muscle cell replication. Hypertension 1992; 20:713-736. Kakuta T, Currier ]W, Haudenschild CC, Ryan TJ, Faxon DP. Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model. Circulation 1994; 89:2809-2815. Libby P, Schwartz D, Brogi E, Tanaka H, Clinton SK. Cascade model for restenosis: special case of atherosclerosis progression. Circulation 1992; 86(suppl 3HII-47-52. Lincoff AM, Topol EJ, Ellis SG. Local drug delivery for the prevention of restenosis. Fact, fancy and future. Circulation 1994; 90:2070-2084. Liu, MW, Roubin GS, King SB. Restenosis after coronary angioplasty: potential biologic determinants and role of intimal hyperplasia. Circulation 79:1374-1387. Nobuyoshi M, Kimura T, Nosaka H, et al. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol 1988; 12:616-623. Popma JJ, Califf RM, Topol E]. Clinical trials of restenosis after coronary angioplasty. Circulation 1991; 84:1426-1436. Senuys PW, Luijten HE, Beatt K], et a!. Incidence of restenosis after successful coronary angioplasty: time-related phenomenon. Circulation 1988; 77:361371. Schwartz RS, Holmes DR, Topol E]. Restenosis paradigm reviSited: alternative proposal for cellular mechanisms. J Am Coll Cardiol 1992; 20:1284-1293.

4:50 pm Prevention of Restenosis: Gene and Other Biologic Strategies Gary H. Gibbons, MD (See earlier article "Restenosis: Remodeling versus Intimal Hyperplasia")

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