Effect of Nadroparin, a Low-Molecular-Weight Heparin, on Clinical and Angiographic Restenosis After Coronary Balloon Angioplasty

Lablanche, Jean‐Marc; McFadden, Eugène; Meneveau, Nicolas; Lusson, Jean-René; Bertrand, Bernard; Metzger, J; Legrand, Victor; Grollier, Gilles; Macaya, Carlos; Bruyne, Bernard De; Vahanian, Alec; Grentzinger, A.; Masquet, C; Wolf, Jean-Éric; Tobelem, Gérard; Fontecave, Sylvie; Vacheron, A; d'Azemar, P.; Bertrand, M

doi:10.1161/01.cir.96.10.3396

Cited by 40 publications

(13 citation statements)

References 19 publications

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“…The data presented indicated that LMW fucoidan reduced neointimal hyperplasia by Ϸ60% and increased the luminal area by Ϸ25%, making this compound one of the most efficient ever tested in experimental restenosis by using a noncontinuous administration regimen. 16 In contrast to heparin tested in animal models of balloon angioplasty 17,18 and clinical trials, 19 HMW fucoidan was already used at high dose (25 mg/kg in mice, 20 100 mg/kg in rats, 21 and 10 mg/kg per hour in rabbits 22 ) without bleeding. In the present study, the fraction of LMW fucoidan (8 kDa), used in rabbits at low dose (5 mg/kg), exhibited no anticoagulant activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia in Rabbit Iliac Artery In-Stent Restenosis Model

Deux

Meddahi‐Pellé

Blanche

et al. 2002

ATVB

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Objective-Smooth muscle cell (SMC) proliferation within the intima is regulated by heparan sulfates. We studied a low molecular weight (LMW) fucoidan (sulfated polysaccharide from brown seaweed) on SMC proliferation in vitro and intimal hyperplasia in vivo. Methods and Results-In vitro study revealed that LMW fucoidan reduces rabbit SMC proliferation and is internalized in SMC perinuclear vesicles. On rabbit iliac arteries perfused in vivo with fluorolabeled LMW fucoidan after angioplasty, the labeling was mainly located on sites of injury. Pharmacokinetic studies showed that LMW fucoidan exhibited in rats an elimination half-life of 56Ϯ25 minutes (nϭ8) after intravenous administration and a constant plasma rate for Ն6 hours after intramuscular administration. After stent implantation in their iliac arteries, rabbits were also treated with LMW fucoidan (5 mg/kg IM twice a day Key Words: fucoidan Ⅲ hyperplasia Ⅲ restenosis Ⅲ stent Ⅲ vascular smooth muscle cell proliferation I ntimal hyperplasia due to migration and proliferation of smooth muscle cells (SMCs) from the media to the intima is a major component of restenosis after stent implantation. 1,2 Polysaccharides constitute a large family of molecules capable of developing molecular interactions with cellular targets within the arterial wall. 3 For instance, heparin, a natural sulfated polysaccharide, displays pleiotropic effects independent of the anticoagulant activity, including SMC growth inhibition, 4 anti-inflammatory activity, 5 and growth factor protection. 6 Fucoidan is a sulfated polysaccharide extracted from brown seaweed that reduces rat SMC proliferation in vitro in a more intensive manner than heparin. 7 We recently succeeded in producing and characterizing new homogeneous fractions of low molecular weight (LMW) fucoidan with low anticoagulant activity.The aims of the present study were to investigate the ability of LMW fucoidan to regulate vascular SMCs. For this purpose, we first tested the ability of LMW fucoidan to inhibit rabbit SMC proliferation in vitro. We explored the pharmacokinetics of LMW fucoidan injected in rats and the effect of LMW fucoidan on intimal hyperplasia. The results described below indicate that LMW fucoidan is a strong inhibitor of intimal hyperplasia and may be potentially relevant for the treatment of in-stent restenosis. Methods PolysaccharidesLMW fucoidan was isolated and hydrolyzed by a radical depolymerization process 8 from high molecular weight (HMW) extracts of brown marine algae. The characteristics of LMW fucoidan according to previously reported analytical methods 9 are as follows: weightaverage molecular mass 8Ϯ1 kDa; fucose content 35% (wt/wt); uronic acid content 3% (wt/wt); and sulfate content 34% (wt/wt). The anticoagulant activity in vitro of the LMW fucoidan was measured by an activated partial thromboplastin time (APTT), and the amount of LMW fucoidan required to obtain an APTT of 80 seconds (control 40 seconds) was 25 g/mL. 10 The anticoagulant activity in vivo of LMW fucoidan was measured in rabbit...

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Section: Discussionmentioning

confidence: 99%

Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia in Rabbit Iliac Artery In-Stent Restenosis Model

Deux

Meddahi‐Pellé

Blanche

et al. 2002

ATVB

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“…Although numerous agents, such as heparin, statins, and angiotensin-converting enzyme inhibitors, have shown a significant inhibitory effect on neointima formation in rats, none of them was successful in clinical trials. [15][16][17][18] SMC proliferation was suggested to contribute to neointima formation mainly in rats. However, other components, such as organized thrombi and extracellular matrix changes, were also observed in clinical restenotic lesions, pointing to the study limitation of a rat model of balloon injury.…”

Section: Discussionmentioning

confidence: 99%

Anti-Human von Willebrand Factor Monoclonal Antibody AJvW-2 Prevents Thrombus Deposition and Neointima Formation After Balloon Injury in Guinea Pigs

Kageyama

Yamamoto

Yoshimoto

2000

ATVB

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Abstract-Immediately after angioplasty, platelet adhesion to the injured arterial wall and subsequent release of various mitogens may contribute to neointima formation. The purpose of this study was to evaluate the inhibitory effect of AJvW-2, a monoclonal antibody against human von Willebrand factor (vWF), on neointima formation in a guinea pig model. The carotid artery was injured with a balloon catheter, and AJvW-2 was administered by a single bolus injection. AJvW-2 dose-dependently prevented neointima formation 14 days after injury. Significant inhibition was observed at 1.8 mg/kg, at which dose significant inhibition of platelet aggregation was achieved for 2 days. By elastic-Masson staining, organized thrombi were observed in the neointimal lesion on day 14. The thrombus area was significantly correlated with neointimal thickness. Furthermore, thrombus deposition, immunostained for vWF and fibrin(ogen), was observed on the media immediately after balloon injury. AJvW-2 significantly reduced the deposition of both adhesive proteins and reduced the incidence of organized thrombus formation, which might affect subsequent neointima formation. However, the proliferation of cultured smooth muscle cells was not affected by AJvW-2. These results suggest that AJvW-2 prevents neointima formation by inhibition of initial platelet-mediated thrombus formation rather than by direct inhibition of smooth muscle cell proliferation. (Arterioscler Thromb Vasc

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“…Restenosis has been characterised as a return to ≥70% stenosis and loss of ≥50% of initial gain; the loss of ≥0.7 mm of the vessel diameter; ≥50% stenosis; loss of 50% of initial gain; 50-75% stenosis; % loss of initial gain; change from <50% to ≥50% stenosis; ≥50% stenosis and >50% of initial gain or >20% luminal diameter; or the recurrence of clinical symptoms or adverse events. Binary stenosis divides the cohort of patients (or blockages) into those with <50% stenosis and those with ≥50% stenosis (regardless of initial gain) [5,8,14,21,22,46,53,[73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88]. Vein graft disease is usually measured as % stenosis.…”

Section: What Are Restenosis and Vein Graft Disease?mentioning

confidence: 99%

“…Local delivery of LMWH after vascular injury using a porous balloon catheter was associated with improved reendothelialization, and elevated early and reduced late SMC proliferation, resulting in reduced neointimal formation compared with control rabbits [162,163]. Clinically, systemic high dose LMWHs (with or without pretreatment) may improve patency in peripheral bypass grafts [39], but may not prevent restenosis [74,78,80,81]. Further clinical studies of locally delivered LMWH pinned in place with a stent after drug administration showed a decreased the degree of restenosis [82], but a study on "unsecured" LMWH delivered in a similar manner found that the drug was not effective [164].…”

Section: Antithrombotic and Antiplateletmentioning

confidence: 99%

Targeted Treatments for Restenosis and Vein Graft Disease

Thomas

2012

ISRN Vascular Medicine

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Surgery to restore blood flow in arteries blocked by atherosclerotic plaque is a common treatment in cardiovascular disease. Longterm complications of surgical treatment are vein graft disease and restenosis, a renarrowing of the blood vessel after bypass or removal of the culprit atherosclerotic plaque. Attempts to prevent or treat these complications by systemic pharmacological approaches have been largely unsuccessful in the clinic. This has led to an interest in developing targeted or locally delivered strategies. This paper discusses many of the various site-delivered therapies that are under examination as potential antirestenotic and antivein graft disease agents (including antithrombotic, antiproliferative, and anti-inflammatory agents) and why many therapies developed in animal models fail in clinical trials. Techniques of targeted delivery (including stents, "magic bullets," and adventitial delivery) and delivery systems (including nanoparticles and the use of gene therapy) are also discussed.

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Effect of Nadroparin, a Low-Molecular-Weight Heparin, on Clinical and Angiographic Restenosis After Coronary Balloon Angioplasty

Abstract: Pretreatment with the low-molecular-weight heparin nadroparin continued for 3 months after balloon angioplasty had no beneficial effect on angiographic restenosis or on adverse clinical outcomes.

Cited by 40 publications

References 19 publications

Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia in Rabbit Iliac Artery In-Stent Restenosis Model

Low Molecular Weight Fucoidan Prevents Neointimal Hyperplasia in Rabbit Iliac Artery In-Stent Restenosis Model

Anti-Human von Willebrand Factor Monoclonal Antibody AJvW-2 Prevents Thrombus Deposition and Neointima Formation After Balloon Injury in Guinea Pigs

Targeted Treatments for Restenosis and Vein Graft Disease

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