A Randomized, Double-Blind, Placebo-Controlled Trial on Restenosis Prevention by the Receptor Tyrosine Kinase Inhibitor Imatinib

Zohlnhöfer, Dietlind; Hausleiter, Jörg; Kastrati, Adnan; Mehilli, Julinda; Goos, Christoph; Schühlen, Helmut; Pache, Jürgen; Pogátsa-Murray, Gisela; Heemann, Uwe; Dirschinger, Josef; Schömig, Albert

doi:10.1016/j.jacc.2005.07.060

Cited by 24 publications

(20 citation statements)

References 25 publications

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“…In this regard, we recently reported that this bioabsorbable polymeric NP-eluting stent system has unique aspects in vascular compatibility and an efficient drug delivery system (stable delivery of NP into the neointima and medial layers until day 28 after deployment of a NP-eluting stent), compared to a dip-coated polymer-eluting stent 19) . In contrast to our present findings, prior studies failed to demonstrate the inhibitory effect of imatinib on in-stent neointima formation in rabbits (oral administration at 10 mg/kg per day for 6 weeks) 16) , pigs (600 g/stent) 15) , and patients (oral administration at 600 mg/body per day for 10 days) 17) . The estimated dose of imatinib loaded on our NP-eluting stent was 21 8 g/stent, which is markedly lower than the doses used in these prior studies; therefore, it is likely that the inhibition of in-stent neointima formation is mediated by slower release and longer retention of imatinib at the imatinib-NP-eluting stent site in this porcine coronary artery model.…”

Section: Discussioncontrasting

confidence: 99%

“…In contrast, imatinib had no effect on in-stent neointima formation in rabbits when administered at a clinically relevant dosage (10 mg/kg per day) 16) . Recent clinical studies in humans have detected no beneficial effects of the oral administration of imatinib (600 mg/day for 10 days) 17) on in-stent restenosis. These data suggest that systemic administration of imatinib at clinical dosages may not be sufficient to antagonize PDGF-induced vascular responses.…”

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confidence: 99%

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Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

Masuda

Nakano

Funakoshi

et al. 2011

JAT

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Aim:The use of currently marketed drug-eluting stents (DES) presents safety concerns, including an increased risk for late thrombosis in the range of 0.6% per year in patients, including acute coronary syndrome, which is thought to result from delayed endothelial healing effects. A new DES system targeting vascular smooth muscle cells without adverse effects on endothelial cells is therefore needed. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of restenosis; therefore, we hypothesized that imatinib mesylate (PDGF receptor tyrosine kinase inhibitor) encapsulated bioabsorbable polymeric nanoparticle (NP)-eluting stent attenuates in-stent neointima formation. Methods: Effects of imatinib-incorporated NP-eluting stent on neointima formation and endothelial healing were examined in a pig coronary artery stent model. Effects of imatinib-NP were also examined in cultured cells. Results: In a cultured cell study, imatinib-NP attenuated the proliferation of vascular smooth muscle cells associated with inhibition of the target molecule (phosphorylation of PDGF receptor-), but showed no effect on endothelial proliferation. In a pig coronary artery stent model, imatinib-NPeluting stent markedly attenuated in-stent neointima formation and stenosis by approximately 50% as assessed by angiographic, histopathological, and intravascular ultrasound imaging analyses. Imatinib-NP-eluting stent also attenuated MAP kinase activity, but did not affect inflammation and re-endothelialization. Conclusion: These data suggest that suppression of neointima formation by a imatinib-NP-eluting stent holds promise as a molecular-targeting NP delivery system for preventing in-stent restenosis.

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Section: Discussioncontrasting

confidence: 99%

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confidence: 99%

Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

Masuda

Nakano

Funakoshi

et al. 2011

JAT

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“…588,589 Table 41 summarizes four randomized trials examining the use of imatinib for nonpulmonary indications. [588][589][590][591] All these studies provided important information regarding toxicity.…”

Section: Imatinib Mesylate Oralmentioning

confidence: 99%

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

Baughman

Meyer

Nathanson

et al. 2012

Chest

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Objectives: Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and infl ammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. Methods: Committee members developed and refi ned a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. Conclusions: It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease. CHEST 2012; 142(5):e1S-e111SAbbreviations: ACCP 5 American College of Chest Physicians; ALT 5 alanine aminotransferase; ATG 5 antithymocyte globulin; CHF 5 congestive heart failure; CMV 5 cytomegalovirus; CNI 5 calcineurin inhibitor; COI 5 confl ict of interest; CsA 5 cyclosporin A; FDA 5 US Food and Drug Administration; HBV 5 hepatitis B virus; HMG-CoA 5 b -hydroxy-bmethylglutaryl-coenzyme A; HSP 5 Health and Science Policy Committee; IL2RA 5 IL-2 receptor a ; ILD 5 interstitial lung disease; IPF 5 idiopathic pulmonary fi brosis; ITP 5 idiopathic thrombocytopenia purpura; LAM 5 lymphangioleiomyomatosis; MESNA 5 sodium 2-sulfonylethanesufonate; MPA 5 mycophenolic acid; mTOR 5 mammalian target of rapamycin; PTLD 5 posttransplant lymphoproliferative disease; RCT 5 randomized controlled trial; SIRS 5 systemic infl ammatory response syndrome; TNF 5 tumor necrosis factor; TPMT 5 thiopurine methyltransferase

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“…In contrast, STI571 had no effect on neointima formation in rabbits when administered in a clinically relevant dosage (10 mg/kg per day). 8 Recent clinical studies in humans have detected no beneficial effects of oral administration of STI571 (600 mg/d for 10 days) 9 on in-stent restenosis. These data suggest that systemic administration of STI571 at clinical dosages may not be sufficient to antagonize PDGF-induced vascular responses at the site of vascular injury.…”

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confidence: 99%

Local Delivery of Imatinib Mesylate (STI571)-Incorporated Nanoparticle Ex Vivo Suppresses Vein Graft Neointima Formation

et al. 2008

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Background-Clinical outcome of surgical revascularization using autologous vein graft is limited by vein graft failure attributable to neointima formation. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of vein graft failure. Therefore, we hypothesized that nanoparticle (NP)-mediated drug delivery system of PDGF-receptor (PDGF-R) tyrosine kinase inhibitor (imatinib mesylate: STI571) could be an innovative therapeutic strategy. Methods and Results-Uptake of STI571-NP normalized PDGF-induced cell proliferation and migration. Excised rabbit jugular vein was treated ex vivo with PBS, STI571 only, FITC-NP, or STI571-NP, then interposed back into the carotid artery position. NP was detected in many cells in the neointima and media at 7 and 28 days after grafting. Significant neointima was formed 28 days after grafting in the PBS group; this neointima formation was suppressed in the STI571-NP group. STI571-NP treatment inhibited cell proliferation and phosphorylation of the PDGF-R-␤ but did not affect inflammation and endothelial regeneration. Conclusions-STI571-NP-induced

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A Randomized, Double-Blind, Placebo-Controlled Trial on Restenosis Prevention by the Receptor Tyrosine Kinase Inhibitor Imatinib

Abstract: Systemic imatinib therapy does not affect the risk of recurrence in patients with ISR.

Cited by 24 publications

References 25 publications

Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

Imatinib Mesylate-Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

Local Delivery of Imatinib Mesylate (STI571)-Incorporated Nanoparticle Ex Vivo Suppresses Vein Graft Neointima Formation

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