Local pharmacologic therapy at the site of angioplasty injury is an attractive concept, but effective methods for realization of the concept have not previously been reported. The Principal Investigator and colleagues have recently demonstrated the experimental feasibility of the use of thermal energy to induce more than transient adherence of two insoluble, biocompatible drug carriers-albumin microspheres and erythrocytes-to the luminal surface. In addition to the use of heparin carriers, the discovery was made that heparin per se can be thermally bonded at a high concentration in vitro to erythrocytes (which comprise the bulk of thrombus), and that adequate in vitro persistence of heparin in erythrocytes and injured porcine aortas is found 2-6 days after thermal exposure. Since the concentration and quantity of intraluminally injectable aqueous heparin and other drugs is limited clinically, the hypothesis will be tested that a thermal method can be developed whereby a water soluble gelatin sleeve mounted on the surface of a laser balloon can be used to transfer either unbound drugs or drugs bound to insoluble drug carriers, impregnated within the sleeve at a high concentration (but a relatively small quantity), to the tissue luminal surface so that potentially clinically relevant in vivo persistence is achieved. In vitro studies will be performed to maximize the concentration of heparin, as the prototype drug to be investigated, to be encapsulated or bound to insoluble carriers, either erythrocytes and components (e.g., hemoglobin) or albumin microspheres. The effect of gelatin film composition, thickness, and concentration and type of entrapped heparin preparation (either free or bound), and thermal history, among other variables, on the in vitro release rate of 3H-heparin and radiolabelled carriers from the surface of the exposed (""""""""injured"""""""") inner layer of media of porcine aortic sections, human atherosclerotic aortic sections, and from thrombus will be determined at defined shear rates at 37 degrees C. In vivo studies of the release rate of 3H-heparin and radiolabelled carriers from the surface of thrombus in a dog model of thrombotic reocclusion after laser balloon angioplasty (LBA) and from the angioplastied surface of the rabbit normal iliac artery (a model of fibrosis which may have clinical relevance regarding LBA restenosis) will be performed iteratively with in vitro studies, in order to identify an optimal method which results in maximal loading and minimal loss. If successful, local heparin therapy after angioplasty could allow temporary cessation of systemic therapy for early femoral sheath removal, reduce the need for subacute anticoagulation therapy, and possibly improve chronic luminal dimensions. Alternative thermally stable drugs may be studied in a similar manner and may include beta-aminopropionitrile, an inhibitor of collagen cross-linking, which in a recent pilot study produced a marked reduction in the chronic loss in luminal diameter of the rabbit iliac when given systemically. As the most important goal, the methodology to be developed may provide a means for local application of a wide variety of other potentially useful agents to the arterial wall.
| Spears, J R; Yellayi, S S; Makkar, R et al. (1994) Effects of thermal exposure on binding of heparin in vitro to the arterial wall and to clot and on the chronic angiographic luminal response to local application of a heparin film during angioplasty in an in vivo rabbit model. Lasers Surg Med 14:329-46 |
| Spears, J R; Zhan, H; Khurana, S et al. (1994) Modulation by beta-aminopropionitrile of vessel luminal narrowing and structural abnormalities in arterial wall collagen in a rabbit model of conventional balloon angioplasty versus laser balloon angioplasty. J Clin Invest 93:1543-53 |
