Site-specific dexamethasone delivery for the prevention of neointimal thickening after vascular stent implantation.
BACKGROUND
Site-directed pharmacologic therapy using drug-impregnated polymers may achieve high local tissue levels at sites of arterial injury without systemic side effects. The aim of this study was to determine whether sustained, local administration of the synthetic glucocorticoid dexamethasone reduces the severity of intimal hyperplasia induced by arterial stenting in a porcine model of restenosis.


METHODS
Dexamethasone-impregnated silicone polymers (20% loading by weight) were formulated and tested in vitro to determine the time course of drug release. Oversized metallic stents were implanted in both carotid arteries of 14 juvenile Yorkshire farm pigs. A dexamethasone-impregnated polymer matrix was then placed around the external surface of the stented artery on one side, and a control polymer was placed contralaterally in an identical manner. Two animals were killed 5 days after stent implantation and the remainder after 35 +/- 1 days.


RESULTS
Ex-vivo dexamethasone release from the silicone polymers was estimated to be 5 mg/day for the first 3 days and 0.3 mg/day thereafter. The arterial tissue dexamethasone levels after 5 days were 1307 +/- 498 ng/g of tissue on the treated side and 7.5 +/- 1.0 ng/g of tissue on the control side. The plasma dexamethasone level was 1.6 +/- 0.3 ng/ml, with no step-up in concentration across the segment surrounded by the drug-impregnated polymer. After 35 days, macroscopic examination and computerized morphometric analysis showed a substantial difference in the extent of polymer-induced adventitial and perivascular scarring but no difference in the extent of neointimal thickening. The adventitia:media ratio was 2.99 +/- 0.33 on the dexamethasone-treated side but 4.29 +/- 0.36 on the control side (P < 0.02). The intima:media ratios were 0.48 +/- 0.09 and 0.52 +/- 0.07, respectively.


CONCLUSIONS
Sustained, local dexamethasone therapy has potent anti-inflammatory and anti-fibrotic effects but, with the dose and route of administration used in this study, does not reduce the intimal hyperplastic response to injury in this model.
Muller
D W
DW
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0022.
Golomb
G
G
Gordon
D
D
Levy
R J
RJ
D000818:Animals; D016893:Carotid Stenosis / Q000517:prevention & control* / Q000628:therapy; D003907:Dexamethasone / Q000008:administration & dosage* / Q000627:therapeutic use; D006965:Hyperplasia / Q000517:prevention & control; D066298:In Vitro Techniques; D012008:Recurrence; D012826:Silicone Elastomers; D015607:Stents; D013552:Swine; D017539:Tunica Intima / Q000473:pathology*
D012826:Silicone Elastomers; D003907:Dexamethasone