IN-VITRO AND IN-VIVO EVALUATION OF THE SITE-SPECIFIC ADMINISTRATION OF D-PHENYLALANYL-L-PROLYL-L-ARGINYL CHLOROMETHYL KETONE (PPACK) - A POWERFUL THROMBIN INHIBITOR

D-Phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (PPACK) was inco rporated into thin films of ethylene vinyl acetate copolymer (EVA, 33% vinyl acetate content). The release devices sustained the release of PPACK for approximately 120 min and delivered approximately 47 mug of PPACK/cm2/h in vitro at 4-degrees-C. The chemical degradation of PPACK was evaluated by HPLC and by H-1-NMR spectroscopy. In spite of its lo w chemical stability, PPACK could be released from the polymeric matri x without apparent degradation. As a functional test of the release of PPACK from a polymer, the ability to inhibit platelet deposition on a metallic coronary stent was tested in vivo in a clinically relevant b aboon model. In control experiments, the stent itself as well as stent s in contact with plain films of EVA were found to be highly thromboge nic. However, when the coronary stent was placed in contact with a pol ymer film loaded with PPACK, there was a marked diminution in the numb er of platelets deposited on the stent for the duration of the 2-h exp eriment. Those studies provide the first experimental confirmation of the concept that the intraarterial, site-specific release of a thrombi n inhibitor can reduce platelet deposition on an artificial polymeric surface in vivo.