LOCALIZED DELIVERY OF HEPARIN TO ANGIOPLASTY SITES WITH IONTOPHORESIS

Drug delivery by iontophoresis involves the application of an electric field to move selectively charged drug molecules across biological me mbranes. The purpose of this study was to assess the efficacy of intra vascular iontophoresis in the local delivery of heparin to balloon ang ioplasty sites by using a recently designed iontophoretic catheter. In vivo heparin iontophoresis was assessed in 33 rats and 21 pigs in fou r protocols designed to measure the technical determinants of intramur al drug deposition, the pharmacokinetics and localization of coronary delivery, and the effect of this technique on platelet deposition foll owing balloon injury. First, iontophoresis of H-3-heparin into the aor ta of 33 rats was performed to determine the effects of iontophoretic current, iontophoretic membrane balloon inflation pressure, iontophore sis time, and heparin concentration on intramural drug deposition, Sec ond, iontophoresis of H-3-heparin was performed in 16 porcine coronary arteries to quantitate immediate drug delivery and subsequent wash-ou t over 24 h, Third, iontophoresis of fluorescent heparin was performed in 8 porcine coronary arteries to define intramural localization of l ocally delivered drug, Fourth, In-111-labeled platelet deposition was measured 1 h following balloon angioplasty and local iontophoretic hep arin delivery in 16 porcine carotid and iliac vessels, Contralateral c ontrol vessels that were dilated with the same size balloon and treate d with iontophoresis of saline served as controls, Rat aortic studies demonstrated that iontophoresis resulted in 13 times more intramural h eparin deposition than passive delivery (passive: 0.3 +/- 0.4 mu g, io ntophoresis: 4.6 +/- 1.6 mu g, P < 0.0004), Iontophoretic membrane bal loon inflation pressure had no significant effect on intramural drug d eposition, but longer iontophoresis times and higher heparin concentra tions resulted in higher levels of intramural heparin (P < 0.05). Porc ine coronary studies demonstrated successful intramural deposition of heparin in all arteries without adverse electrical or hemodynamic sequ elae, with persistence of the drug for at least 24 h, Localization stu dies demonstrated immediate deposition of fluorescent heparin in the i ntima and internal elastic lamina, with subsequent rapid diffusion of the drug into the media. Porcine platelet studies demonstrated that he parin iontophoresis decreased platelet deposition following balloon in jury by approximately 66% compared with saline-treated control vessels (heparin-treated: 1.46 +/- 2.51 x 10(8), control: 4.27 +/- 7.02 x 10( 8), P = 0.001), This study has demonstrated that local intramural hepa rin delivery is feasible with an intravascular iontophoretic catheter. Following intracoronary heparin iontophoresis in the porcine model, i ntramural drug is detected for at least 24 h. Local delivery of hepari n with this technique significantly decreases early platelet depositio n following balloon injury in peripheral porcine arteries. (C) 1997 Wi ley-Liss, Inc.