TY - JOUR
T1 - Sustained-release local hirulog therapy decreases early thrombosis but not neointimal thickening after arterial stenting
AU - Muller, David W.M.
AU - Gordon, David
AU - Topol, Eric J.
AU - Levy, Robert J.
AU - Golomb, Gershon
PY - 1996
Y1 - 1996
N2 - Adventitial heparin delivery has been shown to inhibit thrombosis and nonintimal thickening in a rat carotid injury model. To determine whether sustained, local delivery of hirulog, a potent antithrombin agent, inhibits thrombus formation and neointimal thickening after arterial stenting, silicone polymers containing hirulog were formulated at a concentration of 5.8% by weight and were tested in vitro to determine the rate of drug release. An oversized metallic stent WBS implanted in the carotid artery of 18 juvenile farm pigs. Hirulog-impregnated silicone polymers were placed around the adventitial surface of one stented segment of each animal and a control polymer was placed contralaterally. Intravenous hirulog (4 mg/kg/hr) was infused for the duration of the procedure to maintain the activated clotting time of >300 sec. Ex vivo testing estimated the release of hirulog to he 1.54 μg/mg matrix/day with no loss of anticoagulant activity of the released peptide. In four pigs killed on days 3 through 5, macroscopic thrombus was very faintly visible on the stent struts of one arterial segment treated with sustained-release hirulog but was readily evident in all control arteries. However, electron microscopy showed platelet adhesion and microscopic thrombus formation on each stent of both treated and untreated sides. Fourteen pigs were killed 32 ± 4 days after stenting. Histologic analysis showed no difference between hirulog-treated and control sides in the volume of neointima (540 ± 129 units vs 357 ± 95 units, p= 0.27) or in the average intima to media ratio (0.44 ± 0.12 vs 0.34 ± 0.24, p = 0.47) over the length of the stented segment. Late thrombotic occlusion occurred in two hirulog-treated and two control arteries. In this model, local adventitial hirulog delivery at the dose and delivery rate used may reduce, but does not prevent, thrombus formation and does not reduce the severity of neointimal thickening after carotid stent implantation.
AB - Adventitial heparin delivery has been shown to inhibit thrombosis and nonintimal thickening in a rat carotid injury model. To determine whether sustained, local delivery of hirulog, a potent antithrombin agent, inhibits thrombus formation and neointimal thickening after arterial stenting, silicone polymers containing hirulog were formulated at a concentration of 5.8% by weight and were tested in vitro to determine the rate of drug release. An oversized metallic stent WBS implanted in the carotid artery of 18 juvenile farm pigs. Hirulog-impregnated silicone polymers were placed around the adventitial surface of one stented segment of each animal and a control polymer was placed contralaterally. Intravenous hirulog (4 mg/kg/hr) was infused for the duration of the procedure to maintain the activated clotting time of >300 sec. Ex vivo testing estimated the release of hirulog to he 1.54 μg/mg matrix/day with no loss of anticoagulant activity of the released peptide. In four pigs killed on days 3 through 5, macroscopic thrombus was very faintly visible on the stent struts of one arterial segment treated with sustained-release hirulog but was readily evident in all control arteries. However, electron microscopy showed platelet adhesion and microscopic thrombus formation on each stent of both treated and untreated sides. Fourteen pigs were killed 32 ± 4 days after stenting. Histologic analysis showed no difference between hirulog-treated and control sides in the volume of neointima (540 ± 129 units vs 357 ± 95 units, p= 0.27) or in the average intima to media ratio (0.44 ± 0.12 vs 0.34 ± 0.24, p = 0.47) over the length of the stented segment. Late thrombotic occlusion occurred in two hirulog-treated and two control arteries. In this model, local adventitial hirulog delivery at the dose and delivery rate used may reduce, but does not prevent, thrombus formation and does not reduce the severity of neointimal thickening after carotid stent implantation.
UR - http://www.scopus.com/inward/record.url?scp=0030065126&partnerID=8YFLogxK
U2 - 10.1016/S0002-8703(96)90343-9
DO - 10.1016/S0002-8703(96)90343-9
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C2 - 8579010
AN - SCOPUS:0030065126
SN - 0002-8703
VL - 131
SP - 211
EP - 218
JO - American Heart Journal
JF - American Heart Journal
IS - 2
ER -