ARTICLE
Inhibition of neointima formation by tranilast in pig coronary arteries after balloon angioplasty and stent implantation
Sugao Ishiwata, MD, FACC*,
Stefan Verheye, MD*,
Keith A. Robinson, PhD, FACC ,
Mahomed Y. Salame, MRCP*,
Hector de Leon, MD, PhD*,
Spencer B. King, III, MD, FACC* and
Nicolas A. F. Chronos, MD, FACC
* Andreas Gruentzig Cardiovascular Center, Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, Georgia, USA
Atlanta Cardiovascular Research Institute, Atlanta, Georgia, USA
Manuscript received June 29, 1999;
revised manuscript received October 27, 1999,
accepted December 15, 1999.
Reprint requests and correspondence: Dr. Nicolas Chronos, Atlanta Cardiovascular Research Institute, Suite 225, 5665 Peachtree Dunwoody Road, Atlanta, GA 30342
nchronos{at}acri.com
 |
Abstract
|
|---|
OBJECTIVES
We evaluated the effect of orally administered tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, on histologic and histomorphometric changes after angioplasty or stent implantation in pig coronary arteries.
BACKGROUND
Tranilast, which has antikeloid and antiallergic properties and therefore may modulate the fibrotic and inflammatory tissue responses to angioplasty and stenting, has been shown to inhibit angiographic restenosis in small clinical trials. However, its effect on histomorphometric changes in coronary arteries after angioplasty and stenting is unknown.
METHODS
Following initial pharmacokinetic studies in two pigs to determine desirable plasma levels of orally administered tranilast, 36 crossbred juvenile pigs were randomized to placebo or tranilast before undergoing balloon angioplasty in both the left anterior descending and left circumflex plus stent implantation in the right coronary artery. Oral tranilast was administered at 3 g/day starting 3 days before coronary injury and continued for 28 days until euthanasia. Injured vessels were harvested and sections analyzed by computer-assisted microscopic planimetry.
RESULTS
In balloon-injured vessels, tranilast was associated with a 37% reduction in neointimal area normalized to fracture length (0.47 ± 0.01 vs. 0.74 ± 0.03 mm; p < 0.001) and a 23% reduction in adventitial area normalized to vessel size (0.43 ± 0.02 vs. 0.56 ± 0.03; p = 0.003). In stented arteries, neointimal area normalized to injury score was 32% lower in the tranilast-treated group compared to control (1.94 ± 0.17 vs. 2.86 ± 0.29; p = 0.01).
CONCLUSIONS
In pig coronary arteries, tranilast was associated with a reduction in neointima formation and adventitial reaction after balloon injury. In stented vessels, tranilast was associated with a reduction in neointima formation normalized to injury score.
|
Abbreviations and Acronyms
| | AA | = adventitial area | | FL | = fracture length | | IA | = neointimal area | | IS | = injury score | | MIT | = maximal intimal thickness | | PDGF | = platelet-derived growth factor | | PTCA | = percutaneous transluminal coronary angioplasty | | SMC | = smooth muscle cell | | TGF | = transforming growth factor | | VA | = vessel area |
|
Restenosis remains the most problematic complication of percutaneous transluminal coronary angioplasty (PTCA) with significant costs to the health care system (1). Stent implantation initially appeared promising, with rates of 20% to 30% in so-called ideal lesions (2,3), but with improvement of stent technology, the indications of stenting have broadened, with a consequent restenosis rate ranging from 15% to 60% (4,5) at six months depending on lesion morphology and other factors. Pharmacological approaches in humans have been largely disappointing (6). However, recent clinical studies using oral tranilast have demonstrated promise through a decrease in the rates of angiographic restenosis (7).
Tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid (molecular weight 327 Da), has been used for the prevention and treatment of keloids and hypertrophic scarring and for the treatment of a range of allergic conditions (8,9). In in vitro studies using vascular smooth muscle cells (SMC), tranilast has been shown to inhibit cellular proliferation (10,11), cellular migration (10,11), collagen synthesis (10,11), angiotensin-II–mediated SMC contraction (12) and to restore cytokine-induced nitric oxide production against platelet-derived growth factor (PDGF) (13). Tranilast has also been shown to inhibit collagen synthesis in fibroblasts derived from hypertrophic tissues and keloids (14), to suppress mast cell degranulation and histamine release (15,16) and to suppress oxygen free radical production by neutrophils (17,18). In in vivo studies using either carotid or peripheral arteries of small animals (19–23), tranilast was effective in reducing neointimal area on histomorphometry.
Clinical efficacy studies evaluating tranilast for restenosis prevention have now been completed in over 700 Japanese male patients who underwent PTCA. In the TREAT study (Tranilast REstenosis following Angioplasty Trial), a double-blind, randomized, multicenter trial, tranilast (600 mg/day for three months) reduced the angiographic restenosis rate at three months’ post-PTCA from 46.5% to 14.7%, a relative reduction of 68%, p < 0.001 (personal communication, Dr. H. Tamai). This result was confirmed by the TREAT-2 study, with similar relative reduction in the restenosis rate (personal communication, Dr. H. Tamai). Tranilast was also found to decrease the angiographic restenosis in stented lesions (personal communication, Dr. H. Tamai) and in patients undergoing directional coronary atherectomy (7). A large multicenter trial to investigate the effects of tranilast on restenosis (PRESTO) in over 11,000 patients undergoing PTCA and/or stent implantation has recently started.
Despite the clinical promise being shown by this oral agent for restenosis prevention, few data are available about the influence of tranilast on arterial wound healing in the setting of coronary interventions. We therefore investigated the effects of tranilast on histologic and histomorphometric changes in pig coronary arteries after balloon angioplasty and stent implantation.
|
Methods
|
|---|
All experiments and animal care conformed to the National Institutes of Health and American Heart Association guidelines for the care and use of animals and were approved by the Emory University Institutional Animal Care and Use Committee.
Pharmacokinetic study.
Because tranilast had not been previously used in pigs we examined the pharmacokinetic profile (Emax and t1/2) of oral tranilast in juvenile pigs before initiating the efficacy study. A right atrial cannula was placed in two pigs via the jugular vein on the day prior to dosing. A first dose of either 50 to 100 mg/kg was given by mixing with corn syrup and pig chow; the alternate dose was given the following day. Blood samples (0, 30 min, 2, 8, and 24 h) were obtained following these single-dose oral administrations of tranilast. Plasma was separated by centrifugation, frozen, protected from light exposure and analyzed for tranilast content (Kissei Pharmaceutical, Japan). A dose of 100 mg/kg/day resulted in a peak plasma concentration of 38.6 ± 1.27 µg/ml (118 ± 3.9 µmol/liter) at 2 h and a t1/2 of 8.9 h. Based on these findings and considering previous in vitro and in vivo animal studies (10–23), tranilast was given in the efficacy study at a dose of 1500 mg/pig twice daily. As pigs initially weighed between 22.8 and 31.3 kg, this corresponded to a dosing range of 95.8 to 131.6 mg/kg. Oral treatment was started three days before coronary injury and continued until tissue harvest. Blood samples for drug levels and liver function tests were collected at the time of the procedure as well as at day 28 for analysis.
Efficacy study design.
Thirty-six female or castrated male juvenile pigs (25 to 30 kg) were randomized to receive placebo (n = 18) or oral tranilast (n = 18). All pigs underwent balloon overstretch injury of the left anterior descending (LAD) and circumflex (CX) coronary arteries, and oversize stent implantation in the right coronary artery (RCA) according to established methods (24,25). Briefly, pigs were sedated with telazol (5 mg/kg IM), intubated and ventilated with isoflurane in a mixture of 50% O2 and 50% N2O at a rate of  30 ml/kg/min. An 8F sheath and guiding catheter were introduced via the right femoral artery. Acetylsalicylate (2 mg/kg), heparin (200 IU/kg), and lidocaine (2 mg/kg) were administered intra-arterially. Angioplasty was performed using a 3.5-mm balloon, and a 4.0-mm balloon expandable stainless steel stent (slotted tube stainless steel PS153; Cordis, Miami Lakes, Florida) was implanted in the RCA after previous overstretch injury to achieve a 1:1.2–1.3 balloon-to-artery ratio; the operator was unaware of the treatment group assignment. Intracoronary nitroglycerin (200 µg) was administered in each artery before injury. Immediately postprocedure, angiograms were performed to assess vessel patency; the femoral sheath was removed, the femoral artery ligated, the skin closed and the animal allowed to recover. Pigs were returned to routine care including daily monitoring and drug feeding until 28 days.
Tissue processing and histomorphometry.
Animals were euthanized with a lethal dose of pentobarbital, the heart was quickly removed and the coronary vasculature was perfusion-fixed with 10% buffered formalin at 100 mm Hg pressure for 15 min. The heart was then immersed in 10% buffered formalin overnight. The balloon-injured arterial segments were cut into 3–4-mm segments, embedded in paraffin, sectioned to 4 µm thickness, and stained with hematoxylin–eosin (H&E), Verhoeff–van Gieson’s (VVG) elastic tissue stain and Masson’s trichrome. Injured arteries were defined as those in which there was a complete rupture of the tunica media. Stented arteries were embedded in methyl-butyl methacrylate and sectioned using a low-speed saw. Serial sections spanning the injury site were glued to acrylic slides, ground to 100 µm thickness, polished to optical smoothness, and stained with H&E or VVG.
Computer-assisted planimetry using Image Pro Plus (Media Cybernetics, 3.0.01.00
[EC]
) with external instrument calibration at 20x magnification was used to measure luminal area (LA), internal elastic lamina area (IELA; area within the perimeter of the internal elastic lamina), vessel area (VA; area within the perimeter of the external elastic lamina), adventitial area (AA), maximal neointimal thickness (MIT, determined by drawing a radial line from the lumen border to the internal elastic lamina at the point of maximal neointima), arc length of the medial fracture or fracture length (FL) in ballooned arteries and injury score (IS) in stented arteries. The IS used was an adaptation of the scoring system described by Schwartz et al. (26), which consisted of five grades according to the extent of stent strut penetration into the vessel wall: Grade 0: stent strut in the neointima but not in contact with the internal elastic lamina (IEL); Grade 1: stent strut in the neointima and contacting but not penetrating the IEL; Grade 2: stent strut penetrating the IEL, but not contacting the external elastic lamina (EEL); Grade 3: stent strut penetrating the media to contact the EEL; and Grade 4: the stent strut breaching the EEL and contacting the adventitia. The ratios of neointimal area/fracture length (IA/FL) and IA/IS provide normalized values of intimal area related to the extent of vessel injury (27). The ratio of (AA–VA)/VA refers to the extent of adventitial reaction normalized for vessel size. The neointimal area (IA) and the medial area (MA) were calculated and their ratio was expressed by IA/MA. The histomorphometric parameters measured on 6 to 10 sections per vessel were averaged and expressed as mean value ± SEM. Vessel sections were measured by an experienced investigator who was unaware of the treatment group assignment.
Statistical analysis.
Data were expressed as mean value ± SEM. Between-group differences were assessed using the unpaired Student t test or Mann-Whitney rank-sum test. Data analysis was performed using a statistical software program (Sigma-Stat, Jandel Scientific). An alpha level of p  0.05 was considered to indicate a significant difference. The interobserver variability of histomorphometric measurements was found to be 10%.
|
Results
|
|---|
Tranilast dosing.
The initial pharmacokinetic studies revealed that peak plasma concentrations were obtained at 2 h and the t1/2 was found to be 8.9 h. Based on these findings, tranilast was given in the efficacy study at a dose of 1500 mg/pig twice daily, resulting in a dose range of 95.8 to 131.6 mg/kg in the study. Plasma levels of tranilast in treated pigs were 1.01 ± 0.49 mmol/liter at the time of angioplasty and 0.99 ± 0.53 mmol/liter at tissue harvest (p = NS); these values are about 10-fold higher than those obtained with a single-dose administration, indicating an accumulation in serum and/or tissue compartments with repeated administration. Serum levels of total protein, albumin, creatinine, transaminase, total bilirubin and lactate dehydrogenase were within normal limits and did not differ between the control and tranilast-treated groups.
Histology and histomorphometry.
Thirty-six animals underwent interventions on 108 coronary arteries; 72 arteries were ballooned and 36 stented. There were no significant differences in body weight between the tranilast-treated and control groups either at angioplasty (26.9 ± 0.7 vs. 26.7 ± 0.7 kg) or 28 days (35.2 ± 1.0 vs. 33.6 ± 0.9 kg).
Balloon-injred vessels
Balloon injury was associated with complete medial rupture in 71 out of the 72 balloon-injured arteries, obvious neointima formation and an increase in AA, especially adjacent to the area of medial rupture (Fig. 1). Masson’s trichrome staining revealed abundant collagen in the neointima as well as adjacent adventitia. The histomorphometric changes due to balloon injury in the placebo and tranilast-treated groups are shown in Table 1. No significant differences existed between the treatment and control groups in either the extent of injury (as seen by the magnitudes of the FL) or the vessel size (as seen by the magnitudes of the VA). Compared with placebo, tranilast was associated with a significantly smaller IA (0.79 ± 0.06 vs. 1.32 ± 0.12 mm2, p < 0.001), IA normalized to FL (0.47 ± 0.01 vs. 0.74 ± 0.03 mm, p < 0.001), MIT (0.51 ± 0.02 vs. 0.63 ± 0.03 mm, p = 0.009), AA (5.61 ± 0.21 vs. 6.68 ± 0.26 mm2, p = 0.004), AA normalized to VA (0.43 ± 0.02 vs. 0.56 ± 0.03, p = 0.003) and IA/MA (0.88 ± 0.09 vs. 1.77 ± 0.24, p < 0.001).
View larger version (148K):
[in this window]
[in a new window]
|
Figure 1 Light microscopy of VVG-stained sections of pig coronary arteries harvested four weeks after overstretch balloon angioplasty. Top panels are from control; bottom panels from tranilast-treated animal. Left panels are 40x instrument magnification; right panels 200x. Note decreased neointima formation in artery of tranilast-treated pig despite balloon injury similar to control. L = lumen; M = tunica media; A = tunica adventitia; N = neointima.
|
|
Stented vessels
All stents were seen to be well developed within the vessel, resulting in thinning of the media adjacent to the stent struts (Fig. 2). In the rare vessels with stent protrusion into the adventitia, there was evidence of perivascular hemorrhage. Inflammatory infiltrates adjacent to the stent struts were observed but with no discernible differences between tranilast-treated and control groups. The histomorphometry of the stented vessels is shown in Table 2. No significant difference was seen in vessel size (EELA) between tranilast-treated group and placebo. The IS ranged between 1 and 2.4 overall and was 1.60 ± 0.07 for the treated group compared to 1.43 ± 0.08 for the controls (p = 0.14). The neointimal area (IA) normalized to injury score (IA/IS) was significantly lower in the tranilast-treated group compared to controls (1.94 ± 0.17 vs. 2.86 ± 0.29; p = 0.01). There was a strong trend toward reduction in absolute IA in the tranilast-treated group compared to controls (3.13 ± 0.30 vs. 4.11 ± 0.45, p = 0.07). There was also a significant difference in the medial area between the tranilast-treated group and placebo (p = 0.05) and a significant difference in IA/MA between the two groups (1.16 ± 0.14 vs. 1.73 ± 0.13, p = 0.002).
View larger version (101K):
[in this window]
[in a new window]
|
Figure 2 Light microscopy of H&E-stained sections of pig coronary arteries harvested four weeks after stenting. Top panels are from control; bottom panels from tranilast-treated animal. Left panels are 20x instrument magnification; right panels 200x. Note similar neointima formation in artery of tranilast-treated pig despite stent injury greater than control (arrows in panel 2c). L = lumen; M = tunica media; A = tunica adventitia; N = neointima.
|
|
|
Discussion
|
|---|
The major findings of this study are that tranilast significantly reduced neointima formation as well as adventitial reaction after balloon injury at four weeks in pig coronary arteries; in stented vessels, tranilast significantly reduced neointima formation normalized to IS. To our knowledge, this is the first study to demonstrate these effects. These data as well as preliminary clinical trials (7) suggest the potential for using tranilast as a clinical therapeutic strategy in coronary restenosis prevention.
In balloon-injured vessels, the significant reduction observed in neointima formation, coupled with the lack of increase in the vessel area, suggests that tranilast may reduce restenosis by an inhibitory effect on neointima formation rather than by promoting chronic positive vessel remodeling. This lack of effect on vessel remodeling (i.e., alteration of EELA) occurred despite significant reduction in the adventitial reaction as determined by cross-sectional area, observed in the tranilast-treated group at four weeks.
In theory, the reduction in neointima formation due to tranilast could have resulted from an inhibition in cellular proliferation or a reduction in net extracellular matrix content. Several mechanisms of tranilast’s action that might influence neointima formation have been elucidated. Tranilast inhibits spontaneous collagen synthesis and transforming growth factor-ß1 (TGF-ß1)-induced collagen and glycosaminoglycan synthesis, as well as PDGF-induced migration and proliferation of vascular SMC (10). The mechanism of the inhibitory action on PDGF-BB–induced proliferation is due to S-phase blockade; furthermore, tranilast suppresses the expression of the proto-oncogene c-myc (28). The role of c-myc in abnormal proliferation of vascular SMC after PTCA has recently received attention because its mRNA levels are enhanced after injury (29). Additionally, the antisense suppression of c-myc mRNA has an inhibitory effect on vascular SMC proliferation following balloon angioplasty (30). Thus, tranilast could suppress early stages of neointima formation by inhibiting c-myc expression in arterial cells.
Additionally, prior studies have suggested that adventitial fibroblasts may contribute to neointima formation as well as remodeling (31,32). Phenotypic transformation of adventitial cells into myofibroblasts may chronically constrict the injured vessel and contribute to the process of arterial remodeling and late lumen loss after angioplasty (31). The proliferation of adventitial fibroblasts and modulation of their phenotype to myofibroblasts are all associated with the development of a thickened adventitia that eventually results in vascular remodeling and shrinkage of the vessel in a process analogous to scar contraction (31–33). Upregulation of TGF-ß1 expression may provide a signal to transform adventitial fibroblasts into myofibroblasts (34). Tranilast is known to inhibit TGF-ß1–induced collagen and glycosaminoglycan synthesis (10) and to inhibit the TGF-ß–independent phenotypic alterations of fibroblasts to myofibroblast-like cells and their proliferation (35). Our results demonstrate that tranilast suppressed neointima formation and adventitial reaction; this may be due in part to reduction in cellular proliferation as well as extracellular matrix deposition.
In-stent restenosis is a vexing problem in interventional cardiology. Stents have decreased the restenosis rate by preventing early elastic recoil and late negative arterial remodeling, but profound neointima formation is the main cause of restenosis. Although statistically significant, the effects of tranilast in the stented group compared to the balloon group were less pronounced. In the tranilast-treated group, IA/IS was reduced by 32%. It has been suggested that pharmacological approaches may not be as effective in reducing stent versus balloon-induced neointima formation (36). Part of the reasoning behind this is that the stent prosthesis induces a foreign-body response in which both inflammation and continued low-level cell proliferation play important roles. Additionally, the thrombus burden in stented arteries may be more substantial than in balloon angioplasty (37). Despite these concerns oral administration of tranilast was associated with substantial reduction of neointima in stented arteries.
There has been concern about the potential side effects of tranilast, including organ and systemic toxicity involving the kidneys and liver. In our study we examined serum markers of kidney and liver function and did not observe an adverse effect of tranilast. Furthermore, the tranilast-treated pigs did not demonstrate any clinical symptoms suggestive of adverse cardiopulmonary or gastrointestinal sequelae. Shioda (8) and Okuda et al. (9) studied the antiallergic properties of tranilast in children and adults and found no serious side effects. In a study that demonstrated reduction of restenosis after coronary atherectomy, liver dysfunction or abdominal discomfort was present in 5 of 45 patients (7); the large multicenter investigation now underway (PRESTO) should help elucidate whether tranilast can be given safely and effectively for restenosis prevention. A final potential complication with the use of tranilast might be that, owing to its property to limit collagen synthesis and fibroblast proliferation, a severely limited fibrotic tissue reaction could compromise the adherence of the stent to the artery wall; however, our results indicate that, although neointima was reduced, a sufficient fibrotic response was present to support tissue incorporation of the stents, as documented by VVG-stained stent sections showing fibrous neointima enveloping the stent struts in all samples.
Study limitations.
Our results on the effect of tranilast after balloon injury and stenting should be interpreted cautiously and regarded as preliminary as they only reflect an interim response at four weeks. Studies evaluating the effect of tranilast on histomorphometric changes in the vessel wall at later time points have not been undertaken. The obvious possibility of interspecies variability in the biological response precludes direct extrapolation to humans. Furthermore, although our study demonstrated reduction of neointima and neoadventitia by tranilast, the putative mechanisms of these effects are as yet unknown.
Conclusions.
Oral administration of tranilast inhibited neointima formation and adventitial reaction in balloon-injured pig coronary arteries at four weeks. In stented coronary arteries tranilast was associated with a significant reduction in neointimal area normalized to the extent of injury, and it showed a strong trend in reducing absolute neointimal area. These results could explain the beneficial effects seen with the initial clinical studies evaluating tranilast in restenosis prevention.
|
Acknowledgments
|
|---|
We thank Mark Ungs, Boston Scientific Corporation, and Tetsuhiro Kubota, MD, in the Second Laboratories of Kissei Pharmaceutical Company, Hotaka, Nagano, Japan, for providing the drug. The technical assistance of George Lin, Pat Mulkey, Elizabeth Lakin, and Jill McCullers is greatly appreciated.
|
Footnotes
|
|---|
This study was supported in part by the Rich Foundation, Atlanta, Georgia.
|
References
|
|---|
1. King SB. Restenosis following angioplasty: scope of the problem. Waksman R. Vascular Brachytherapy. 2nd ed. Armonk, NY: Futura Publishing; 1999. p. 3–11
2. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med. 1994;331:496–501[Abstract/Free Full Text]
3. 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. Benestent Study Group. N Engl J Med. 1994;331:489–495[Abstract/Free Full Text]
4. Dussaillant GR, Mintz GS, Pichard AD, et al. Small stent size and intimal hyperplasia contribute to restenosis: a volumetric intravascular ultrasound analysis. J Am Coll Cardiol. 1995;26:720–724[Abstract]
5. Elezi S, Kastrati A, Neumann FJ, Hadamitzky M, Dirschinger J, Schomig A. Vessel size and long-term outcome after coronary stent placement. Circulation. 1998;98:1875–1880[Abstract/Free Full Text]
6. Franklin SM, Faxon DP. Pharmacologic prevention of restenosis after coronary angioplasty: review of the randomized clinical trials. Coron Artery Dis. 1993;4:232–242[Medline]
7. Kosuga K, Tamai H, Ueda K, et al. Effectiveness of tranilast on restenosis after directional coronary atherectomy. Am Heart J. 1997;134:712–718[CrossRef][Medline]
8. Shioda H. A double-blind controlled trial of N-(3',4'-dimethoxycinnamoyl) anthranilic acid on children with bronchial asthma. N-5' Study Group in Children. Allergy. 1979;34:213–219[Medline]
9. Okuda M, Ishikawa T, Saito Y, Shimizu T, Baba S. A clinical evaluation of N-5' with perennial-type allergic rhinitis—a test by the multi-clinic, intergroup, double-blind comparative method. Ann Allergy. 1984;53:178–185[Medline]
10. Miyazawa K, Kikuchi S, Fukuyama J, Hamano S, Ujiie A. Inhibition of PDGF- and TGF-beta 1–induced collagen synthesis, migration and proliferation by tranilast in vascular smooth muscle cells from spontaneously hypertensive rats. Atherosclerosis. 1995;118:213–221[CrossRef][Medline]
11. Fukuyama J, Miyazawa K, Hamano S, Ujiie A. Inhibitory effects of tranilast on proliferation, migration, and collagen synthesis of human vascular smooth muscle cells. Can J Physiol Pharmacol. 1996;74:80–84[CrossRef][Medline]
12. Miyazawa K, Fukuyama J, Misawa K, Hamano S, Ujiie A. Tranilast antagonizes angiotensin II and inhibits its biological effects in vascular smooth muscle cells. Atherosclerosis. 1996;121:167–173[CrossRef][Medline]
13. Hishikawa K, Nakaki T, Hirahashi J, Marumo T, Saruta T. Tranilast restores cytokine-induced nitric oxide production against platelet-derived growth factor in vascular smooth muscle cells. J Cardiovasc Pharmacol. 1996;28:200–207[CrossRef][Medline]
14. Suzawa H, Kikuchi S, Arai N, Koda A. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol. 1992;60:91–96[Medline]
15. Azuma H, Banno K, Yoshimura T. Pharmacological properties of N-(3',4'-dimethoxycinnamoyl) anthranilic acid (N-5'), a new anti-atopic agent. Br J Pharmacol. 1976;58:483–488[Medline]
16. Komatsu H, Kojima M, Tsutsumi N, et al. Study of the mechanism of inhibitory action of tranilast on chemical mediator release. Jpn J Pharmacol. 1988;46:43–51[Medline]
17. Suzawa H, Kikuchi S, Ichikawa K, Koda A. Inhibitory action of tranilast, an anti-allergic drug, on the release of cytokines and PGE2 from human monocytes-macrophages. Jpn J Pharmacol. 1992;60:85–90[Medline]
18. Suzawa H, Ichikawa K, Kikuchi S, et al. Effect of tranilast, an anti-allergic drug, on carrageenin-induced granulation and capillary permeability in rats. Folia Pharmacol Jap. 1992;99:241–246[Medline]
19. Kikuchi S, Umemura K, Kondo K, Saniabadi AR, Nakashima M. Photochemically induced endothelial injury in the mouse as a screening model for inhibitors of vascular intimal thickening. Arterioscl Thromb Vasc Biol. 1998;18:1069–1078[Abstract/Free Full Text]
20. Fukuyama J, Ichikawa K, Hamano S, Shibata N. Tranilast suppresses the vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet. Eur J Pharmacol. 1996;318:327–332[CrossRef][Medline]
21. Muranaka Y, Yamasaki Y, Nozawa Y, et al. TAS-301, an inhibitor of smooth muscle cell migration and proliferation, inhibits intimal thickening after balloon injury to rat carotid arteries. J Pharmacol Exp Ther. 1998;285:1280–1286[Abstract/Free Full Text]
22. Miyazawa N, Umemura K, Kondo K, Nakashima M. Effects of pemirolast and tranilast on intimal thickening after arterial injury in the rat. J Cardiovasc Pharmacol. 1997;30:157–162[CrossRef][Medline]
23. Shiota N, Okunishi H, Takai S, et al. Tranilast suppresses vascular chymase expression and neointima formation in balloon-injured dog carotid artery. Circulation. 1999;99:1084–1090[Abstract/Free Full Text]
24. Robinson KA, Roubin G, King S, Siegel R, Rodgers G, Apkarian RP. Correlated microscopic observations of arterial responses to intravascular stenting. Scanning Microsc. 1989;3:665–678[Medline]
25. Karas SP, Gravanis MB, Santoian EC, Robinson KA, Anderberg KA, King SB. Coronary intimal proliferation after balloon injury and stenting in swine: an animal model of restenosis. J Am Coll Cardiol. 1992;20:467–474[Abstract]
26. 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]
27. Waksman R, Robinson KA, Crocker IR, Gravanis MB, Cipolla GD, King SB. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. A possible role for radiation therapy in restenosis prevention. Circulation. 1995;91:1533–1539[Abstract/Free Full Text]
28. Miyazawa K, Hamano S, Ujiie A. Antiproliferative and c-myc mRNA suppressive effect of tranilast on newborn human vascular smooth muscle cells in culture. Br J Pharmacol. 1996;118:915–922[Medline]
29. Miano JM, Vlasic N, Tota RR, Stemerman MB. Smooth muscle cell immediate-early gene and growth factor activation follows vascular injury. A putative in vivo mechanism for autocrine growth. Arterioscl Thromb. 1993;13:211–219[Abstract/Free Full Text]
30. Bennett MR, Anglin S, McEwan JR, Jagoe R, Newby AC, Evan GI. Inhibition of vascular smooth muscle cell proliferation in vitro and in vivo by c-myc antisense oligodeoxynucleotides. J Clin Invest. 1994;93:820–828[Medline]
31. Scott NA, Cipolla GD, Ross CE, et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation. 1996;93:2178–2187[Abstract/Free Full Text]
32. Shi Y, Pieniek M, Fard A, O’Brien J, Mannion JD, Zalewski A. Adventitial remodeling after coronary arterial injury. Circulation. 1996;93:340–348[Abstract/Free Full Text]
33. Andersen HR, Maeng M, Thorwest M, Falk E. Remodeling rather than neointimal formation explains luminal narrowing after deep vessel wall injury: insights from a porcine coronary (re)stenosis model. Circulation. 1996;93:1716–1724[Abstract/Free Full Text]
34. Shi Y, O’Brien JEJ, Fard A, Zalewski A. Transforming growth factor-beta-1 expression and myofibroblast formation during arterial repair. Arterioscler Thromb Vasc Biol. 1996;16:1298–1305[Abstract/Free Full Text]
35. Isaji M, Aruga N, Naito J, Miyata H. Inhibition by tranilast of collagen accumulation in hypersensitive granulomatous inflammation in vivo and of morphological changes and functions of fibroblasts in vitro. Life Sci. 1994;55:L287–L292
36. EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Evaluation of platelet IIb/IIIa inhibitor for stenting. Lancet. 1998;352:87–92[Medline]
37. Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans. Macroscopic, histological, and immunohistochemical analyses. Circulation. 1998;98:224–233[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
R. Khan, A. Agrotis, and A. Bobik
Understanding the role of transforming growth factor-{beta}1 in intimal thickening after vascular injury
Cardiovasc Res,
May 1, 2007;
74(2):
223 - 234.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A K Mitra and D K Agrawal
In stent restenosis: bane of the stent era.
J. Clin. Pathol.,
March 1, 2006;
59(3):
232 - 239.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Schomig, A. Kastrati, and R. Wessely
Prevention of Restenosis by Systemic Drug Therapy: Back to the Future?
Circulation,
November 1, 2005;
112(18):
2759 - 2761.
[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. G.P. Welt and C. Rogers
Inflammation and Restenosis in the Stent Era
Arterioscler Thromb Vasc Biol,
November 1, 2002;
22(11):
1769 - 1776.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. R. Holmes Jr, M. Savage, J.-M. LaBlanche, L. Grip, P.W. Serruys, P. Fitzgerald, D. Fischman, S. Goldberg, J. A. Brinker, A.M. Zeiher, et al.
Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial
Circulation,
September 3, 2002;
106(10):
1243 - 1250.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Ward, A. Agrotis, P. Kanellakis, J. Hall, G. Jennings, and A. Bobik
Tranilast Prevents Activation of Transforming Growth Factor-{beta} System, Leukocyte Accumulation, and Neointimal Growth in Porcine Coronary Arteries After Stenting
Arterioscler Thromb Vasc Biol,
June 1, 2002;
22(6):
940 - 948.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. C. Lowe, S. N. Oesterle, and L. M. Khachigian
Coronary in-stent restenosis: Current status and future strategies
J. Am. Coll. Cardiol.,
January 16, 2002;
39(2):
183 - 193.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Izawa, J.-i. Suzuki, W. Takahashi, J. Amano, and M. Isobe
Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model
Arterioscler Thromb Vasc Biol,
July 1, 2001;
21(7):
1172 - 1178.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods