(Circulation. 2001;103:2289.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Paclitaxel Stent Coating Inhibits Neointimal Hyperplasia at 4 Weeks in a Porcine Model of Coronary Restenosis
Presented in part at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 10–13, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-288).
From the Division of Cardiology (A.W.H., G.M.J., B.S.A., K.E.B., J.A.B.) and Department of Pathology (R.H.H., B.R.), Johns Hopkins School of Medicine, and the National Institute on Aging, National Institutes of Health (L.C., P.F.H., D.-W.K., M.W., C.N., J.L.K., S.J.S., E.G.L., J.P.F.), Baltimore, Md; and Angiotech Pharmaceuticals, Inc, Vancouver, BC, Canada (W.L.H.).
Correspondence to Alan W. Heldman, MD, Division of Cardiology, Carnegie 565, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail aheldman{at}jhmi.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Despite limiting elastic recoil and late vascular remodeling after angioplasty, coronary stents remain vulnerable to restenosis, caused primarily by neointimal hyperplasia. Paclitaxel, a microtubule-stabilizing drug, has been shown to inhibit vascular smooth muscle cell migration and proliferation contributing to neointimal hyperplasia. We tested whether paclitaxel-coated coronary stents are effective at preventing neointimal proliferation in a porcine model of restenosis.
Methods and Results—Palmaz-Schatz stents were dip-coated with paclitaxel (0, 0.2, 15, or 187 µg/stent) by immersion in ethanolic paclitaxel and evaporation of the solvent. Stents were deployed with mild oversizing in the left anterior descending coronary artery (LAD) of 41 minipigs. The treatment effect was assessed 4 weeks after stent implantation. The angiographic late loss index (mean luminal diameter) decreased with increasing paclitaxel dose (P<0.0028 by ANOVA), declining by 84.3% (from 0.352 to 0.055, P<0.05) at the highest level tested (187 µg/stent versus control). Accompanying this change, the neointimal area decreased (by 39.5%, high-dose versus control; P<0.05) with increasing dose (P<0.040 by ANOVA), whereas the luminal area increased (by 90.4%, high-dose versus control; P<0.05) with escalating dose (P<0.0004 by ANOVA). Inflammatory cells were seen infrequently, and there were no cases of aneurysm or thrombosis.
Conclusions—Paclitaxel-coated coronary stents produced a significant dose-dependent inhibition of neointimal hyperplasia and luminal encroachment in the pig LAD 28 days after implantation; later effects require further study. These results demonstrate the potential therapeutic benefit of paclitaxel-coated coronary stents in the prevention and treatment of human coronary restenosis.
Key Words: paclitaxel • stents • angioplasty • restenosis
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Restenosis remains a frequent cause of late failure after initially successful coronary angioplasty.1 Coronary stents reduce restenosis by limiting the extent of elastic recoil and late vascular remodeling.2 Despite these improvements, the incidence of restenosis remains high because of neointimal hyperplasia, which is induced by all forms of dilating mechanical injury and is aggravated by the presence of the stent ("in-stent restenosis").3 Combining the mechanical support of a stent with a treatment to limit neointimal ingrowth should further improve therapeutic outcomes. This combined approach has been used successfully in intracoronary brachytherapy.4 5 Late thrombosis and edge stenosis (the "candy wrapper effect") are potential complications that may limit the effectiveness of this approach.5 6
Pharmacological inhibitors of
neointimal hyperplasia, like paclitaxel, represent
an alternative to radiation
therapy.7 8
Paclitaxel (Taxol) is a derivatized diterpenoid that exerts an
antineoplastic effect by interfering with cell microtubule
function.9 10
Paclitaxel alters the dynamic equilibrium between microtubules and 
-
and ß-tubulin by favoring the formation of abnormally stable
microtubules.11 This leads
to the inhibition of cell division and migration, intracellular
signaling, and protein secretion, which all rely on the rapid and
efficient depolymerization of microtubules.
Systemic application of paclitaxel in the rat showed that a significant
(70%) reduction in neointimal proliferation could be
achieved at blood concentrations 100 times lower than antineoplastic
levels.7 In
rat7 and
human8 cultured cell models,
paclitaxel prevented growth factor–stimulated vascular smooth muscle
cell migration and proliferation, consistent with its effects
on neointimal formation in vivo. As an alternative to
systemic therapy, local drug delivery offers the advantages of allowing
high local concentrations of drug at the treatment site while
minimizing systemic toxic effects. For paclitaxel, local delivery might
be achieved by a drug-delivery
catheter8 or by a coated
stent.12
The sustained delivery of paclitaxel to the arterial wall can be achieved with polymeric stent coatings, but these coatings may induce inflammation and thrombosis.12 After an initial failed attempt with polymer-coated stents, we resorted to dip-coating metallic stents with paclitaxel dissolved in a volatile solvent (ethanol). Evaporation of the solvent leaves a fine residue of paclitaxel that adheres to the surface of the stent. By limitation of the coating to paclitaxel, the undesirable complications associated with certain polymers were avoided. The dip-coating technique also allows paclitaxel to have immediate contact with the vessel wall, favoring its rapid accumulation by arterial tissue. This strategy for local drug delivery resembles short-term irradiation4 by optimizing the conditions for blocking the earliest cellular events triggered by injury.13 14
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Stent Preparation
Palmaz-Schatz stents (Johnson & Johnson) were coated by dipping the stent into ethanolic paclitaxel and evaporating the solvent. This procedure left a fine residue of paclitaxel covering the surface of the stent. Results of local extravascular paclitaxel delivery studies in the rat (10 µg paclitaxel effectively inhibited neointimal growth; unpublished results) were used to establish 4 treatment groups: control (0 µg/stent), low-dose (0.2 µg/stent), intermediate-dose (15 µg/stent), and high-dose (187 µg/stent). Coated stents were checked for the uniformity of drug application by selecting several stents at random from each batch, extracting them in ethanol, and measuring paclitaxel by high-performance liquid chromatography (HPLC; Gilson). Paclitaxel was eluted from a 25-cmx4.6-mm pentafluorophenyl column (ES Industries) in a mobile phase consisting of 45% acetonitrile and 55% water flowing at 1.5 mL/min and monitored at 227 nm with a UV detector (Gilson model 116). Paclitaxel-coated stents were mounted on 3.0-mm balloons (PS1530 balloon delivery catheter; Johnson & Johnson) with a manufacturer-supplied crimping tool. Sterilization was carried out with ethylene oxide gas. Drug losses associated with the mounting and crimping procedure were evaluated by extracting the demounted stents in ethanol and subjecting the extract to HPLC. Loss of paclitaxel to the blood was determined by incubating paclitaxel-coated stents at 37°C in pig whole blood treated with 1 mmol/L EDTA to prevent clotting. The incubation time was varied to establish a paclitaxel washout curve.
Stent Deployment
All animal protocols were approved by the animal care
and use committees of the National Institute on Aging, NIH, and Johns
Hopkins University and were conducted according to established
guidelines for the humane use and treatment of laboratory animals. Male
and female NIH minipigs (n=43) weighing 35 to 45 kg were pretreated
with aspirin (325 mg) and diltiazem (Cardizem CD; 180 mg) the day
before stent implantation. Aspirin (325 mg) was given daily throughout
the evaluation period. The animals were sedated with ketamine
(20 mg/kg IM) and acetylpromazine (0.22 mg/kg IM) and given sodium
pentobarbital (4 mg/kg IV) to facilitate supine positioning and
endotracheal intubation. Anesthesia was maintained with 1%
to 2% isoflurane in oxygen flowing at 2 L/min. An 8F
arterial sheath was inserted into the right carotid artery
under sterile surgical technique, and heparin (5000 U) was administered
as an intra-arterial bolus. The stent was delivered to the
left anterior descending coronary artery (LAD) through an 8F
Judkins right guiding catheter and deployed by two 30-second balloon
inflations at 8 atm. The segment of artery to be stented was selected
to allow 
1.2 times oversizing by visual estimation. Angulated and
branching segments were stented if necessary to permit this degree of
oversizing. Stent implantation was done by a single pair of operators
(A.W.H. and M.W.) who were blinded to the treatment groups.
Coronary angiography was performed in 2 views (generally
anteroposterior and 30° left anterior oblique) immediately before and
after stent implantation.
Angiographic Analysis
Angiograms were performed during the initial
catheterization and at 4-week follow-up. The
angiographic mean luminal diameter (MLD) within the stented
segment was measured by computerized coronary angiography
(ImageComm) by 2 blinded investigators (A.W.H. and B.S.A.). Two views
were measured and averaged for each arterial segment.
Neointimal encroachment of the lumen was evaluated from the
late loss index (LLI), defined as
LLI=(MLD0-MLD4wks)/MLD0,
where MLD0 and MLD4wks
are the MLDs immediately after stenting and at follow-up,
respectively.
Histological Preparation
and Histomorphometric Analysis
After the terminal angiogram, the heart was excised
and perfusion-fixed with 10% formalin at 100 mm Hg for 15
minutes. After overnight immersion-fixation, a segment of the LAD
containing the stent was dissected from the myocardium. The
LAD segment was embedded in acrylic plastic and cut into 3 blocks
containing the proximal, middle, and distal portions of the stent.
Three cross sections were cut from each of these blocks with a tungsten
carbide knife and stained with elastic van Gieson or Movat
pentachrome. Arterial tissue from adjacent
(proximal and distal), nonstented segments of the LAD were
paraffin-embedded and stained with the above dyes or hematoxylin and
eosin. Histomorphometric analysis of the tissue sections was
performed by computerized video imaging with an Axioplan microscope
(Zeiss) and a black-and-white MTI video camera (Dage-MTI Inc). Video
images were analyzed with IBAS 2.0 software (IBAS, Kontron
Electronik). The vessel injury score was determined by the method of
Schwartz et al.15 The
luminal and neointimal areas were evaluated for each of the
tissue cross sections, averaged, and expressed as the absolute area in
square millimeters. The neointimal and medial wall
thicknesses (in millimeters) were measured halfway between each pair of
strut openings (in-between distance) and averaged over all tissue cross
sections. Neointimal thickness was also measured at each
strut site (strut-lumen distance). All morphometric analyses
were made by investigators (L.C. and C.N.) blinded to the treatment
groups.
Determination of Postdeployment Paclitaxel
Levels
Palmaz-Schatz stents dip-coated at the intermediate
(16 µg/stent) and high (177 µg/stent) paclitaxel doses were
deployed in the LAD and left in place for 10 to 15 minutes. The heart
was removed and perfused with 10% formalin before dissection of the
stented arterial segment to preserve the tissue
architecture and minimize drug losses. The excised stent and
surrounding segment of LAD were each extracted with 1 mL of absolute
ethanol for 72 hours at room temperature. Paclitaxel in the ethanol
extracts was determined quantitatively by HPLC.
Statistical Analysis
Angiographic and histological data
were analyzed by comparing control and paclitaxel-coated stents
by use of a 1-way ANOVA. Pairwise comparisons involving the control and
different treatment groups were performed according to the post hoc
Dunnett test, which corrects for multiple comparisons. The level of
significance was taken as
P<0.05. Results are reported
as mean±SEM.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Forty-three pigs underwent stent placement in the LAD with paclitaxel-coated Palmaz-Schatz stents. All pigs survived to completion of the 4-week study without evidence of myocardial infarction on gross inspection. Forty-one pigs in 4 treatment groups were analyzed: 11 in the control (0 µg/stent), 8 at the low dose (0.2 µg/stent), 15 at the intermediate dose (15 µg/stent), and 7 at the high dose (187 µg/stent). Because efficacy was judged by the ability to inhibit neointimal hyperplasia induced by injury, animals with low injury scores and incomplete engagement of the stent struts were eliminated from further analysis. This occurred in 2 pigs in the control group with injury scores of 0.17 and 0.21; the mean injury score for the remaining 41 animals was 1.19±0.08 (mean±SEM). Uniformity of the applied injury was evident from the similarity in oversize ratios (1.26±0.02; P<0.231 by ANOVA) and injury scores (P<0.755 by ANOVA), which were not significantly different in the 4 treatment groups (Table 1
).
|
Angiographic Analysis
The 4-week follow-up angiograms
(Figure 1) showed a graded effect of paclitaxel dose, with
the largest reduction in neointimal encroachment at the
high dose. In the control angiogram, a distinctive narrowing of the
stented LAD segment was evident that was less severe at the
intermediate dose. At the high dose, a step-down in the luminal
diameter occurred between the stented and nonstented segments,
indicating effective inhibition of neointimal growth and/or
mild arterial dilatation in the drug-applied region. No
hyperplastic edge effects or aneurysmal dilatations were found
in any of the treatment groups. Angiograms were evaluated for the MLD
and LLI during the 4-week period
(Figure 2). Application of ANOVA to the LLI data revealed
that the difference between the treatment groups was significant
(P<0.0028). The LLI was
dose-dependent; between the control and high paclitaxel doses, the LLI
fell from 0.352 to 0.055, declining by 84%
(P<0.05 by Dunnett’s test).
The change in MLD with increasing drug dose was inversely related to
the decline in LLI. The gain in MLD rose to 146% of the control group
at the high paclitaxel dose
(P<0.05 by Dunnett’s test)
and was highly significant across all group comparisons
(P<0.0012 by
ANOVA).
|
|
Histomorphometric Analysis
Representative
arterial cross sections from the different treatment groups
are shown in
Figure 3. In the control
(Figure 3A) and low-dose
(Figure 3B) groups, the stent strut sites were clearly
visible between the neointima and internal elastic lamina,
causing mild compression of the medial wall. A progressive decline in
the extent of neointimal formation was observed with
increasing drug dose. This inhibition was particularly evident at the
high dose
(Figure 3D), where the strut sites protruded into the lumen
attached to the vessel wall by a narrow pedestal of acellular material.
Expansion of the stent would have initially forced the struts into the
medial wall like the control group, suggesting that these changes
involved expansion of the vessel wall (ectasia or dilatation).
Incomplete deployment of the stent as the cause of this effect was
ruled out by the similarity in oversize ratios, injury scores, and
stent circumferences
(Table 1
). Illumination of the acellular material with
polarized light revealed that it was noncrystalline, which excluded
paclitaxel or a metabolite as its probable source. Similar, less
intensely stained deposits were seen surrounding the strut sites at the
lower doses
(Figure 3C) but were completely absent from the control
group. Other histological changes
(Table 2) included medial wall cell necrosis with associated
calcified deposits and focal neointimal and medial wall
hemorrhage. The frequency of these changes increased with the
applied drug dose, implicating paclitaxel in their origin. Infiltration
of cells with inflammatory morphology was seen infrequently in the
cross sections and was not correlated with the paclitaxel dose. A small
number of sections showed a perivascular inflammation that was probably
injury-related. The identification of endothelial cells
was limited by the tissue processing technique; however,
endothelium-like cells were occasionally seen
surrounding the lumen, forming an incomplete barrier, in all of the
treatment groups.
|
|
Figure 4A shows the dose-dependence of the
neointimal area calibrated to the drug dose applied to the
stent. Consistent with the relationship found in the LLI, the
high-dose treatment group showed a significant reduction of
neointimal formation compared with controls (39%;
P<0.05 by Dunnett’s test);
the significance with all group comparisons included was
P<0.0402 by ANOVA. A similar
dose-dependence was observed in the neointimal thickness
index
(Figure 4C). Neointimal thickness declined
significantly between the control and high-dose groups (55% in-between
and 75% strut-lumen; P<0.05
by Dunnett’s test) and was significant over all groups
(P<0.0058 in-between and
P<0.0001 strut-lumen by
ANOVA). As shown in
Figure 4D, medial wall thickness was also reduced by 26% at
the high drug dose compared with the control group
(P<0.05 by Dunnett’s test).
The decrease in medial wall thickness was not significant by ANOVA
(P<0.09), however, suggesting
that the medial wall cells may be less sensitive to paclitaxel than
those found in the neointima.
|
The change in luminal area with increasing drug dose was
inversely related to the decline in the LLI and neointimal
area
(Figure 4B). The luminal area at the high dose was 190% of
that for the control group
(P<0.05 by Dunnett’s test),
and the difference in luminal area was highly significant across all
group comparisons (P<0.0004 by
ANOVA). An unintentional bias in oversizing the stent was ruled out on
the grounds that the mean stent circumference, determined by summation
of the strut-to-strut distances, was not significantly different in the
4 treatment groups
(Table 1).
Postdeployment Paclitaxel Levels
Short-term studies to determine the postdeployment
paclitaxel levels
(Table 3) showed that at the high paclitaxel dose, 68%
of the drug originally deposited on the stent was recovered. Of this,
slightly less than 50% of the dose was associated with the tissue. At
the intermediate dose, only 34% of the drug was recovered, and the
variation in recovery was larger than observed at the high dose. These
results suggest that a significant loss of the applied paclitaxel
occurred before it reached the tissue.
|
In a separate set of in vitro experiments, drug retention on
the stent after balloon mounting averaged only 52% of the applied dose
(19.7 µg/stent), and additional losses (up to 17%) occurred during
ex vivo manipulation subsequent to mounting. These losses may have
resulted from cracking and flaking of the paclitaxel film caused by
distortion of the stent during crimping. Simple handling of the stent
before mounting resulted in <5% drug loss. Additional losses to the
blood lipids may occur during the brief (30-second) exposure to the
coronary circulation before deployment. This was demonstrated
in washout experiments in which a 30-second exposure to pig blood at
37°C resulted in loss of <5% of the applied paclitaxel
dose.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In this study, a pig model of coronary stent restenosis was used to test whether local paclitaxel delivery would prevent neointimal hyperplasia induced by vascular stretch injury. Palmaz-Schatz stents were coated with a range of paclitaxel doses and were deployed with mild oversizing in the LAD. Preliminary experiments that applied paclitaxel by use of a nonbiodegradable (ethylene vinyl acetate) polymeric stent coating were marked by an intense inflammatory response, severe luminal narrowing, thrombosis, and death. To reduce these risks, we chose to eliminate the polymer and apply paclitaxel to the bare stent with a dip-coating technique (see Methods). We assumed that this approach would be optimal for rapid drug elution and high drug tissue concentrations because there is no barrier to prevent paclitaxel from gaining immediate access to the injured arterial tissue.
Locally applied paclitaxel produced a dose-dependent
inhibition of neointimal formation, as revealed by the
pattern of change in the angiographic and histomorphometric indices
during the 4-week evaluation period. Analysis of the data by
ANOVA showed that inhibition of the tissue hyperplastic response was
significant (neointimal area,
P<0.040; LLI,
P<0.0028) or highly
significant (luminal area,
P<0.0004) over all treatment
groups. In pairwise comparisons involving Dunnett’s test, statistical
significance was routinely observed when the high-dose treatment group
was compared with the controls. Specifically, the LLI
(Figure 2A) and luminal area
(Figure 4B) showed the largest differences (84% for LLI;
90% for luminal area), whereas the percentage change in the MLD (46%)
and neointimal area (39%) were less pronounced. Although
the effects of paclitaxel on each of the indices were qualitatively
consistent (eg, the changes in neointimal and
luminal area were inversely related), inhibition of
neointimal growth at the high dose (0.78
mm2 versus control) alone could not account
for the increase in luminal area (1.35
mm2 versus control). Exposure to the high
dose of paclitaxel eliminated direct contact between the strut sites
and medial wall
(Figure 3D), implying that the vessel wall had undergone
dilatation relative to the stent. This was consistent with
angiographic records, which showed a step-down in luminal diameter
between the drug-applied (stented) and nonstented regions
(Figure 1C). From the discrepancy between the
neointimal and luminal area changes, wall dilatation
accounted for as much as 42% of the luminal increase at the high
paclitaxel dose and 36% at the intermediate dose. Part of the gain in
luminal diameter can be traced to a reduction in medial wall thickness
(Figure 4D), which was significant only at the high
paclitaxel dose. This suggests that in addition to
neointimal growth inhibition and arterial wall
dilatation,16 a third
component of the mechanism of action of paclitaxel involves the loss of
vascular smooth muscle cells from a quiescent, nondividing population
in the medial wall. This effect probably represents true
necrosis of the medial wall, with perhaps a smaller contribution from
apoptosis.
The cytostatic effects of paclitaxel on
neointimal formation were complicated by local cytotoxic
effects that manifested as a decrease in medial wall thickness, focal
neointimal and medial wall hemorrhage, and cell
necrosis. Inflammatory cells were an infrequent finding at all
paclitaxel doses
(Table 2), arguing against the drug-eluting coating as a
stimulus to inflammation. At the high dose of paclitaxel, a reduction
in cell number8 and/or
extracellular protein mass may have been responsible for the decline in
medial wall thickness. Various cellular repair mechanisms, responding
to arterial dilatation and changing wall tension, may
compensate for these changes. The acellular material (eg, fibrin)
bridging the gap between the medial wall and strut sites
(Figure 3D) may be a manifestation of cellular repair
mechanisms acting to stabilize the arterial wall against
further dilatation. Although none of the pigs died from vascular
complications during the 4-week period, concern about possible evolving
complications (aneurysm, wall rupture) will require subsequent
long-term experiments to evaluate the safety of this treatment
strategy. Long-term studies should reveal whether cellular repair
mechanisms respond to injury and cytotoxicity by overcompensation; this
might reduce the long-term therapeutic benefit of paclitaxel,
particularly at the high dose, at which medial wall necrosis and
neointimal inhibition were significant. The requirement for
long-term follow-up is underscored by the disparity between 1-month
data17 18 and
long-term
results6 19
obtained with intracoronary brachytherapy, which is complicated
by a late dose-dependent increase in neointimal formation
and delayed healing of the endothelium. Further study
will determine whether local paclitaxel delivery produces a sustained
benefit or whether complications similar to those associated with
brachytherapy diminish its therapeutic potential.
An important property of paclitaxel is its insolubility in water, which minimizes loss to the blood during catheterization (<5% during a 30-second exposure) and facilitates tissue uptake after contact with the arterial wall. The lipophilic nature of paclitaxel may enhance cellular uptake by enabling it to pass through the hydrophobic barrier of cell membranes.20 21 A significant fraction may also be retained by membrane lipids and remain there as a depot for continuous release. In diseased human vessels, variations in the lipid content of plaque may alter the drug distribution pattern and reduce its efficacy. Another concern from the standpoint of therapeutics is whether adequate tissue levels of paclitaxel can be maintained to prevent a resurgence of neointimal growth over longer periods of time. The compound coating material used in some sustained-release devices can extend the period of paclitaxel availability (weeks, months) and maintain inhibitory control in the presence of paclitaxel washout and/or metabolism. It can also protect against drug losses from the stent during the procedures leading up to and including implantation (mounting, crimping, handling). Tests with our dip-coated stents showed that most of the drug loss occurred before stent expansion and deployment, arguing for modification of the coating procedure. This might be achieved by encapsulating paclitaxel in a fast-release polymer or by applying paclitaxel to the stent after mounting. Although the dip-coated stent used in this study may have advantages for efficacy (barrier-free drug elution) and safety (biocompatibility), it should not be regarded as a final preclinical design.
|
Acknowledgments |
|---|
Research funding was provided by Angiotech Pharmaceuticals, Inc, Vancouver, Canada, through a Cooperative Research and Development Award (CRADA) with the National Institutes of Health and Johns Hopkins University. The authors express their appreciation to Frances O’Connor for help in performing the statistical analysis.
Received September 28, 2000; revision received December 15, 2000; accepted December 19, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Popma JJ, Califf RM, Topol EJ. Clinical trials of restenosis after coronary angioplasty. Circulation. 1991;84:1426–1436.
2.
Serruys PW, de
Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable stent
implantation with balloon angioplasty in patients with coronary
artery disease. N Engl J
Med. 1994;331:489–495.
3.
Edelman ER, Rogers
C. Hoop dreams: stents without restenosis.
Circulation. 1996;94:1199–1202.
4.
Teirstein PS,
Massullo V, Jani S, et al. Three-year clinical and angiographic
follow-up after intracoronary radiation: results of a
randomized clinical trial.
Circulation. 2000;101:360–365.
5.
Albiero R, Adamian
M, Kobayashi N, et al. Short- and intermediate-term results of
32P radioactive ß-emitting stent
implantation in patients with coronary artery disease: the
Milan dose-response study.
Circulation. 2000;101:18–26.
6.
Costa MA, Sabaté
M, van der Giessen WJ, et al. Late coronary occlusion after
intracoronary brachytherapy.
Circulation. 1999;100:789–792.
7. Sollott SJ, Cheng L, Pauly RR, et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J Clin Invest. 1995;95:1869–1876.
8.
Axel DI, Kunert W,
Goggelmann C, et al. Paclitaxel inhibits arterial smooth
muscle cell proliferation and migration in vitro and in vivo using
local drug delivery.
Circulation. 1997;96:636–645.
9. Wani MC, Taylor HL, Wall ME, et al. Plant antitumor agents, VI: the isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971;93:2325–2327.[Medline] [Order article via Infotrieve]
10.
Rowinsky EK,
Donehower RC. Paclitaxel (Taxol). N
Engl J Med. 1995;332:1004–1014.
11.
Schiff PB,
Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells.
Proc Natl Acad Sci
U S A. 1980;77:1561–1565.
12.
van der Giessen
WJ, Lincoff AM, Schwartz RS, et al. Marked inflammatory sequelae to
implantation of biodegradable and nonbiodegradable polymers in porcine
coronary arteries.
Circulation. 1996;94:1690–1697.
13. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury, I: smooth muscle growth in the absence of endothelium. Lab Invest. 1983;49:327–333.[Medline] [Order article via Infotrieve]
14.
Brieger D, Topol
E. Local drug delivery systems and prevention of restenosis.
Cardiovasc Res. 1997;35:405–413.
15. Schwartz RS, Huber KC, Murphy JG, et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol. 1992;19:267–274.[Abstract]
16.
Herdeg C,
Oberhoff M, Baumbach A, et al. Local paclitaxel delivery for the
prevention of restenosis: biological effects and efficacy in
vivo. J Am Coll Cardiol. 2000;35:1969–1976.
17.
Hehrlein C,
Gollan C, Donges K, et al. Low-dose radioactive endovascular stents
prevent smooth muscle cell proliferation and neointimal
hyperplasia in rabbits.
Circulation. 1995;92:1570–1575.
18.
Laird JR, Carter
AJ, Kufs WM, et al. Inhibition of neointimal proliferation
with low-dose radiation from a ß-particle–emitting stent.
Circulation. 1996;93:529–536.
19.
Taylor AJ, Gorman
PD, Farb A, et al. Long-term coronary vascular response to
32P ß-particle emitting stents in a canine
model. Circulation. 1999;100:2366–2372.
20. Baumbach A, Herdeg C, Kluge M, et al. Local drug delivery: impact of pressure, substance characteristics, and stenting on drug transfer into the arterial wall. Cathet Cardiovasc Intervent. 1999;47:102–106.[Medline] [Order article via Infotrieve]
21.
Kornowski R, Hong
MK, Tio FO, et al. In-stent restenosis: contributions of
inflammatory responses and arterial injury to
neointimal hyperplasia. J
Am Coll Cardiol. 1998;31:224–230.
This article has been cited by other articles:
 |
|
 |
|
  M. Vorpahl, A. V. Finn, M. Nakano, and R. Virmani Do We Really Understand Pimecrolimus? J. Am. Coll. Cardiol. Intv., October 1, 2009; 2(10): 1025 - 1027. [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Drachman Drug-Eluting Stents in Animals and Patients: Where Do We Stand Today? Circulation, July 14, 2009; 120(2): 101 - 103. [Full Text] [PDF]
|
|
|
|
|
|
Y. Suzuki, A. C. Yeung, and F. Ikeno The Pre-Clinical Animal Model in the Translational Research of Interventional Cardiology J. Am. Coll. Cardiol. Intv., May 1, 2009; 2(5): 373 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Byrne, R. Iijima, J. Mehilli, S. Pinieck, O. Bruskina, A. Schomig, and A. Kastrati Durability of Antirestenotic Efficacy in Drug-Eluting Stents With and Without Permanent Polymer J. Am. Coll. Cardiol. Intv., April 1, 2009; 2(4): 291 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Benndorf, M. Ionescu, M.V. y Alvarado, J. Hipp, and R. Metcalfe Wall Shear Stress in Intracranial Self-Expanding Stents Studied Using Ultra-High-Resolution 3D Reconstructions AJNR Am. J. Neuroradiol., March 1, 2009; 30(3): 479 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Chevalier, C. Di Mario, F.-J. Neumann, F. Ribichini, P. Urban, J. J. Popma, P. J. Fitzgerald, D. E. Cutlip, D. O. Williams, J. Ormiston, et al. A Randomized, Controlled, Multicenter Trial to Evaluate the Safety and Efficacy of Zotarolimus- Versus Paclitaxel-Eluting Stents in De Novo Occlusive Lesions in Coronary Arteries: The ZoMaxx I Trial J. Am. Coll. Cardiol. Intv., October 1, 2008; 1(5): 524 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Pinto Slottow and R. Waksman Overview of the 2007 Food and Drug Administration Circulatory System Devices Panel Meeting on the Endeavor Zotarolimus-Eluting Coronary Stent Circulation, March 25, 2008; 117(12): 1603 - 1608. [Full Text] [PDF]
|
|
|
|
|
|
R. Jabara, N. Chronos, D. Conway, W. Molema, and K. Robinson Evaluation of a novel slow-release Paclitaxel-eluting stent with a bioabsorbable polymeric surface coating. J. Am. Coll. Cardiol. Intv., February 1, 2008; 1(1): 81 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Wilson, J. E. Polovick, B. A. Huibregtse, and B. C. Poff Overlapping paclitaxel-eluting stents: Long-term effects in a porcine coronary artery model Cardiovasc Res, November 1, 2007; 76(2): 361 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. H. Lee, J. E. Lee, K. W. Lee, H. Y. Nam, H. J. Jeon, Y. J. Sung, J. S. Kim, H. J. Lim, J.-s. Park, J. Y. Ko, et al. Coating with paclitaxel improves graft survival in a porcine model of haemodialysis graft stenosis Nephrol. Dial. Transplant., October 1, 2007; 22(10): 2800 - 2804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S W Park, S H Lee, C H Kim, G S Jeon, S J Hong, J G Yi, and H J Jeon Inhibition of pseudointimal hyperplasia in swine TIPS models: the efficacy of local delivery of paclitaxel using a perforated balloon catheter Br. J. Radiol., September 1, 2007; 80(957): 702 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. M M Pires, D. Eefting, M. R de Vries, P. H A Quax, and J W. Jukema Sirolimus and paclitaxel provoke different vascular pathological responses after local delivery in a murine model for restenosis on underlying atherosclerotic arteries Heart, August 1, 2007; 93(8): 922 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Finn, G. Nakazawa, M. Joner, F. D. Kolodgie, E. K. Mont, H. K. Gold, and R. Virmani Vascular Responses to Drug Eluting Stents: Importance of Delayed Healing Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1500 - 1510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Scheller, U. Speck, and M. Bohm Prevention of restenosis: is angioplasty the answer? Heart, May 1, 2007; 93(5): 539 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Lim, T.-J. Kim, Y.-R. Jin, D.-W. Kim, J.-S. Kwon, J.-H. Son, J.-C. Jung, M. A. Avery, D. J. Son, J. T. Hong, et al. Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 648 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M.M. van Beusekom, F. Saia, J. D. Zindler, P. A. Lemos, S. L. S.-t. Hoor, M. A.H. van Leeuwen, P. J. de Feijter, P. W. Serruys, and W. J. van der Giessen Drug-eluting stents show delayed healing: paclitaxel more pronounced than sirolimus Eur. Heart J., April 12, 2007; (2007) ehm064v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Murphy, T. W. Johnson, M. H. Chamberlain, S. I. Rizvi, M. Wyatt, S. J. George, G. D. Angelini, K. R. Karsch, M. Oberhoff, and A. C. Newby Short- and long-term effects of cytochalasin D, paclitaxel and rapamycin on wall thickening in experimental porcine vein grafts Cardiovasc Res, February 1, 2007; 73(3): 607 - 617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Garcia-Touchard, S. E. Burke, J. L. Toner, K. Cromack, and R. S. Schwartz Zotarolimus-eluting stents reduce experimental coronary artery neointimal hyperplasia after 4 weeks Eur. Heart J., April 2, 2006; 27(8): 988 - 993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Roy-Chaudhury, V. P. Sukhatme, and A. K. Cheung Hemodialysis Vascular Access Dysfunction: A Cellular and Molecular Viewpoint J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1112 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Lee, H.-C. Tan, and Y.-T. Lim Update on Drug-Eluting Stents for Prevention of Restenosis Asian Cardiovasc Thorac Ann, February 1, 2006; 14(1): 75 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Salu, J. M. Bosmans, Y. Huang, M. Hendriks, M. Verhoeven, A. Levels, S. Cooper, I. K. De Scheerder, C. J. Vrints, and H. Bult Effects of cytochalasin D-eluting stents on intimal hyperplasia in a porcine coronary artery model Cardiovasc Res, February 1, 2006; 69(2): 536 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Morton, N. D. Arnold, J. Gunn, R. Varcoe, S. E. Francis, S. K. Dower, and D. C. Crossman Interleukin-1 receptor antagonist alters the response to vessel wall injury in a porcine coronary artery model Cardiovasc Res, December 1, 2005; 68(3): 493 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Nawarskas and L. A. Osborn Paclitaxel-eluting stents in coronary artery disease Am. J. Health Syst. Pharm., November 1, 2005; 62(21): 2241 - 2251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wessely, A. Kastrati, and A. Schomig Late Restenosis in Patients Receiving a Polymer-Coated Sirolimus-Eluting Stent Ann Intern Med, September 6, 2005; 143(5): 392 - 394. [Full Text] [PDF]
|
|
|
|
|
|
A. V. Finn, F. D. Kolodgie, J. Harnek, L.J. Guerrero, E. Acampado, K. Tefera, K. Skorija, D. K. Weber, H. K. Gold, and R. Virmani Differential Response of Delayed Healing and Persistent Inflammation at Sites of Overlapping Sirolimus- or Paclitaxel-Eluting Stents Circulation, July 12, 2005; 112(2): 270 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Henry, M. M. Bonar, P. N. Kearns, H. Cui, M. M. Mutchler, M. V. Martin, A. R. Orsini, H. L. Elford, C. A. Bush, J. L. Zweier, et al. Inhibition of Ribonucleotide Reductase Reduces Neointimal Formation following Balloon Injury J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 70 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Balakrishnan, A. R. Tzafriri, P. Seifert, A. Groothuis, C. Rogers, and E. R. Edelman Strut Position, Blood Flow, and Drug Deposition: Implications for Single and Overlapping Drug-Eluting Stents Circulation, June 7, 2005; 111(22): 2958 - 2965. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Johnson, Y. X. Wu, C. Herdeg, A. Baumbach, A. C. Newby, K. R. Karsch, and M. Oberhoff Stent-Based Delivery of Tissue Inhibitor of Metalloproteinase-3 Adenovirus Inhibits Neointimal Formation in Porcine Coronary Arteries Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 754 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Schwartz, N. A. Chronos, and R. Virmani Preclinical restenosis models and drug-eluting stents: Still important, still much to learn J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1373 - 1385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Vogt, A. Stein, G. Rettemeier, N. Krott, R. Hoffmann, J. v. Dahl, A.-K. Bosserhoff, W. Michaeli, P. Hanrath, C. Weber, et al. Long-term assessment of a novel biodegradable paclitaxel-eluting coronary polylactide stent Eur. Heart J., August 1, 2004; 25(15): 1330 - 1340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R Sindermann, V. Verin, J. W Hopewell, H. P. Rodemann, and J. H Hendry Biological aspects of radiation and drug-eluting stents for the prevention of restenosis Cardiovasc Res, July 1, 2004; 63(1): 22 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sonoda, Y. Morino, J. Ako, M. Terashima, A. H. M. Hassan, H. N. Bonneau, M. B. Leon, J. W. Moses, P. G. Yock, Y. Honda, et al. Impact of final stent dimensions on long-term results following sirolimus-eluting stent implantation: Serial intravascular ultrasound analysis from the sirius trial J. Am. Coll. Cardiol., June 2, 2004; 43(11): 1959 - 1963. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-W. Kim, J.-S. Kwon, Y.-G. Kim, M. S. Kim, G.-S. Lee, T.-J. Youn, and M.-C. Cho Novel Oral Formulation of Paclitaxel Inhibits Neointimal Hyperplasia in a Rat Carotid Artery Injury Model Circulation, March 30, 2004; 109(12): 1558 - 1563. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gershlick, I. De Scheerder, B. Chevalier, A. Stephens-Lloyd, E. Camenzind, C. Vrints, N. Reifart, L. Missault, J.-J. Goy, J. A. Brinker, et al. Inhibition of Restenosis With a Paclitaxel-Eluting, Polymer-Free Coronary Stent: The European evaLUation of pacliTaxel Eluting Stent (ELUTES) Trial Circulation, February 3, 2004; 109(4): 487 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tanabe, P. W. Serruys, M. Degertekin, G. Guagliumi, E. Grube, C. Chan, T. Munzel, J. Belardi, W. Ruzyllo, L. Bilodeau, et al. Chronic Arterial Responses to Polymer-Controlled Paclitaxel-Eluting Stents: Comparison With Bare Metal Stents by Serial Intravascular Ultrasound Analyses: Data From the Randomized TAXUS-II Trial Circulation, January 20, 2004; 109(2): 196 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Scheller, U. Speck, A. Schmitt, M. Bohm, and G. Nickenig Addition of paclitaxel to contrast media prevents restenosis after coronary stent implantation J. Am. Coll. Cardiol., October 15, 2003; 42(8): 1415 - 1420. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Moses, M. B. Leon, J. J. Popma, P. J. Fitzgerald, D. R. Holmes, C. O'Shaughnessy, R. P. Caputo, D. J. Kereiakes, D. O. Williams, P. S. Teirstein, et al. Sirolimus-Eluting Stents versus Standard Stents in Patients with Stenosis in a Native Coronary Artery N. Engl. J. Med., October 2, 2003; 349(14): 1315 - 1323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. V. Dee and H. Samady Evolving Strategies for the Prevention and Treatment of Coronary Restenosis Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 281 - 293. [Abstract] [PDF]
|
|
|
|
|
|
B. Scheller, U. Speck, B. Romeike, A. Schmitt, M. Sovak, M. Bohm, and H.-P. Stoll Contrast media as carriers for local drug delivery: Successful inhibition of neointimal proliferation in the porcine coronary stent model Eur. Heart J., August 1, 2003; 24(15): 1462 - 1467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Park, W. H. Shim, D. S. Ho, A. E. Raizner, S.-W. Park, M.-K. Hong, C. W. Lee, D. Choi, Y. Jang, R. Lam, et al. A Paclitaxel-Eluting Stent for the Prevention of Coronary Restenosis N. Engl. J. Med., April 17, 2003; 348(16): 1537 - 1545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Karnik, B. S. Brooke, A. Bayes-Genis, L. Sorensen, J. D. Wythe, R. S. Schwartz, M. T. Keating, and D. Y. Li A critical role for elastin signaling in vascular morphogenesis and disease Development, March 2, 2003; 130(2): 411 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Finkelstein, D. McClean, S. Kar, K. Takizawa, K. Varghese, N. Baek, K. Park, M. C. Fishbein, R. Makkar, F. Litvack, et al. Local Drug Delivery via a Coronary Stent With Programmable Release Pharmacokinetics Circulation, February 11, 2003; 107(5): 777 - 784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-K. Hong, G. S. Mintz, C. W. Lee, J.-M. Song, K.-H. Han, D.-H. Kang, J.-K. Song, J.-J. Kim, N. J. Weissman, N. E. Fearnot, et al. Paclitaxel Coating Reduces In-Stent Intimal Hyperplasia in Human Coronary Arteries: A Serial Volumetric Intravascular Ultrasound Analysis From the ASian Paclitaxel-Eluting Stent Clinical Trial (ASPECT) Circulation, February 4, 2003; 107(4): 517 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R Bennett IN-STENT STENOSIS: PATHOLOGY AND IMPLICATIONS FOR THE DEVELOPMENT OF DRUG ELUTING STENTS Heart, February 1, 2003; 89(2): 218 - 224. [Full Text] [PDF]
|
|
|
|
|
|
M. N. Babapulle and M. J. Eisenberg Coated Stents for the Prevention of Restenosis: Part I Circulation, November 19, 2002; 106(21): 2734 - 2740. [Full Text] [PDF]
|
|
|
|
|
|
R. Virmani, F. Liistro, G. Stankovic, C. Di Mario, M. Montorfano, A. Farb, F. D. Kolodgie, and A. Colombo Mechanism of Late In-Stent Restenosis After Implantation of a Paclitaxel Derivate-Eluting Polymer Stent System in Humans Circulation, November 19, 2002; 106(21): 2649 - 2651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Deux, A. Meddahi-Pelle, A. F. Le Blanche, L. J. Feldman, S. Colliec-Jouault, F. Bree, F. Boudghene, J.-B. Michel, and D. Letourneur Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia in Rabbit Iliac Artery In-Stent Restenosis Model Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1604 - 1609. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kataoka, E. Grube, Y. Honda, Y. Morino, S.-H. Hur, H. N. Bonneau, A. Colombo, C. Di Mario, G. Guagliumi, K. E. Hauptmann, et al. 7-Hexanoyltaxol-Eluting Stent for Prevention of Neointimal Growth: An Intravascular Ultrasound Analysis From the Study to COmpare REstenosis rate between QueST and QuaDS-QP2 (SCORE) Circulation, October 1, 2002; 106(14): 1788 - 1793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. D. Kolodgie, M. John, C. Khurana, A. Farb, P. S. Wilson, E. Acampado, N. Desai, P. Soon-Shiong, and R. Virmani Sustained Reduction of In-Stent Neointimal Growth With the Use of a Novel Systemic Nanoparticle Paclitaxel Circulation, September 3, 2002; 106(10): 1195 - 1198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yasuda, T. Noguchi, M. Gohda, T. Arai, N. Tsutsui, Y. Nakayama, T. Matsuda, and H. Nonogi Local delivery of low-dose docetaxel, a novel microtubule polymerizing agent, reduces neointimal hyperplasia in a balloon-injured rabbit iliac artery model Cardiovasc Res, February 1, 2002; 53(2): 481 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.G. NABEL, M. BOEHM, L.M. AKYUREK, T. YOSHIMOTO, M.F. CROOK, M. OLIVE, H. SAN, and X. QU Cell Cycle Signaling and Cardiovascular Disease Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 163 - 170. [Abstract] [PDF]
|
|
|
|
|
|
F Liistro and A Colombo Late acute thrombosis after paclitaxel eluting stent implantation Heart, September 1, 2001; 86(3): 262 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Farb, P. F. Heller, S. Shroff, L. Cheng, F. D. Kolodgie, A. J. Carter, D. S. Scott, J. Froehlich, and R. Virmani Pathological Analysis of Local Delivery of Paclitaxel Via a Polymer-Coated Stent Circulation, July 24, 2001; 104(4): 473 - 479. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||