Local Drug Delivery for Restenosis and Thrombosis Ñ Progress?
Platelet activation, inflammation, recoil, tissue hyperplasia and remodeling are pivotal pathophysiologic factors in acute myocardial ischemia and restenosis development after angioplasty. Even after the rising use of stents, the tremendous amount of resulting tissue hyperplasia remains a therapeutic problem. It has been suggested that short duration of effective drug levels and poor efficiency of systemic drug administration account for the failure of therapy in clinical trials. A rational effective therapy for angina and restenosis should therefore be locally administered at the site of vascular obliteration. Special local drug delivery devices could be used to administer sufficient drug amounts at the site that needs to be treated. Local drug delivery systems using modified balloon systems, stent systems or newly designed catheters have been developed. In experimental studies, different effects can be demonstrated by using endoluminal and adventitial substance delivery. Endoluminal application usually resulted in < 1% effective drug delivery in the arterial wall and short lasting deposition. Adventitial deposition led to higher mural concentrations; the drug was detectable for up to 21 days. In media, the maximum is still comparable to the maximum obtained after systemic application. Experimental studies indicate positive therapeutic effects in restenosis models. Feasibility has been proven in clinical studies of unstable angina with anticoagulants or antithrombotics. Further preclinical and preliminary clinical studies are needed to clarify regional drug distribution, regional wash-out, adverse effects and evaluation of long-term therapeutic effects. Recent developments in catheter techniques might enable effective local drug application in angina and restenosis prophylaxis with a reduction in systemic adverse effects. (Supported by DFG Go 739/1-1).
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Deutsches Herzzentrum, Technical University Munich, Lazarettstrasse 36, 80636, Munich, Germany.