Sirolimus restenosis

Percutaneous coronary intervention A minimally invasive procedure whereby access to the coronary arteries is obtained through the femoral artery up the aorta to the coronary os. Contrast media is used to visualize the coronary artery stenosis using a coronary angiogram. A guidewire is used to cross the stenosis and a small balloon is inflated and/or stent is deployed to break up atherosclerotic plaque and restore coronary artery blood flow. The stent is left in place to prevent acute closure and restenosis of the coronary artery. Newer stents are coated with antiproliferative drugs, such as paclitaxel and sirolimus, which further reduce the risk of restenosis of the coronary artery. 

Zotarolimus (53 Endeavor stent) Sirolimus (33) Macrolide antibiotic Semi-synthetic NP Microbial Cardiovascular surgery Inhibits cell proliferation, preventing scar tissue formation and minimizes restenosis in angioplasty patients 467 74... 

Rapamycin (sirolimus), a macrolide antibiotic, has been used recently in organ transplantation for its potent immunosuppressive actions by inhibiting both cytokine mediated and growth factor mediated proliferation of smooth muscle cells and lymphocytes [55, 56]. In the RAVEL trial of non-acute single vessel lesions, the Sirolimus-eluting stent was compared to bare metal stent (BMS) in a 1 1 fashion [57]. One-year major adverse cardiovascular events and 6 month neointimal proliferation as assessed by late luminal loss (-0.01 0.33 mm in Sirolimus stent versus 0.80 0.53 mm in BMS) were improved. The Sirolimus-eluting stent thus virtually eliminated in-stent restenosis with no evidence of edge effect, dissection, or in-stent thrombosis. 

Holmes DR Jr, Leon MB, Moses JW, Popma JJ, Cutlip D, Fitzgerald PI, Brown C, Fischell T, Wong SC, Midei M, Snead D, Kuntz RE. Analysis of 1-year clinical outcomes in the SIRIUS trial a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation. 2004 Feb 10 109(5) 634-40. 

In a pilot study after coronary angioplasty in 22 patients, sirolimus was given orally in a loading dose of 6 mg followed by 2 mg/day over 4 weeks. Sirolimus was withdrawn after an average of 15 days in 11 patients because of adverse effects, including hypertriglyceridemia (n — 3), leukopenia (n = 3), raised liver function tests, stomatitis, acne, flu-like symptoms, and physician preference (n — 1 each). The rate of coronary restenosis was 87%. Sirolimus did not benefit patients with recalcitrant stenosis and adverse effects were frequent (1069). 

Sirolimus Inhibition of CDK complexes, antiproliferative ORBIT (32) ORAR (35) ORAR II (36) Lower restenosis Lower restenosis Lower restenosis... 

Systemic immunosuppressive therapies in the treatment of restenosis sirolimus and sirolimus analogs in experimental and clinical data... 

Multivariate analysis, (Table 9) showed that randomization to control group was the only independent predictor of restenosis (odds ratio OR 6,01 95% Confidence Interval 2.19-16.46) P < 0,0001, As we see in Table 8, compared with the control group, patients who received oral rapamycin had a significantly smaller amount of late loss [0,66 mm in the sirolimus group vs. 

Relative reduction of late loss and binary restenosis in oral sirolimus and control group of oral rapamycin to prevent restenosis II randomized. 

This prospective, randomized and controlled trial in patients with de novo lesions demonstrated a significant reduction of angiographic binary restenosis and late loss when patients were allocated to the oral sirolimus arm, and both the endpoints were determined by blind operators. Clinical safety and efficacy parameters of restenosis such as target vessel, target lesion revascularization, and Major Adverse Cardiovascular Events at follow-up were also significantly improved with oral sirolimus therapy As we can see in Table 10, compared with control... 

Hausleiter J, Kastrati A, Mehilli J, et al. Randomized, double blind, placebo controlled trial of oral sirolimus for restenosis prevention in patients with in-stent restenosis. The oral sirolimus to inhibit recurrent in-stent stenosis trial (OSIRIS). Circulation 2004 I 10 790. 

Chaves AJ, Sousa AG, Mattos L, etal, Pilot study with an intensified oral sirolimus regimen for the prevention of in-stent restenosis in de novo lesions, Catheter Cardiovasc Interv 2005 66 535-540. 

Commeau (155) (ISR II study) 2005 BX Velocity Polyethyl methacrylate Human coronary art (In-stent restenosis) Sirolimus 1,4 xg/mm2 ... 

Carter AJ, Bailey LR, Llanos G, et al. Stent based sirolimus delivery reduces neointimal proliferation in a porcine coronary model of restenosis [abstr], J Am Coll Cardiol 2000 35(suppl A) 13. 

Rensing BJ, Vos J, Smits PC, et al. Coronary restenosis elimination with a sirolimus eluting stent first European human experience with 6-month angiographic and intravascular ultrasonic follow-up. Eur Heart J 2001 22(22) 2125-2130. 

Ardissino D, Cavallini C, Bramucci E, etal. Sirolimus-eluting vs uncoated stents for prevention of restenosis in small coronary arteries a randomized trial. JAMA 2004 292(22) 2727-2734. 

Hoye A, Tanabe K, Lemos PA, et al. Significant reduction in restenosis after the use of sirolimus-eluting stents in the treatment of chronic total occlusions. J Am Coll Cardiol 2004 43(1 I) 1954-1958. 

Kwok OH, Chow WH, Law TC, et al. First human experience with angiopeptin-eluting stent a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Catheter Cardiovasc Interv2005 66(4) 54l-546. Nakamura M, Wada M, Hara H, et al. Angiographic and clinical outcomes of a pharmacokinetic study of sirolimus-eluting stents lesson from restenosis cases. Circ J 2005 69(10) ... 

Holmes DR, Teirstein R Satlet L, et al, Sirolimus-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents the SISR randomized trial. JAMA 2006 295 1264-1273. 

Saia p Lemos PA, Hoye A, et al. Clinical outcomes for sirolimus-eluting stent implantation and vascular brachytherapy for the treatment of in-stent restenosis. Catheter Cardiovasc Interv 2004 62(3) 283-288. 

This chapter focuses on percutaneous transluminal coronary angioplasty (PTCA), provides a summary of the underlying immune activities of the diseased vasculature, and focuses in part on the role of immune and inflammatory mediators in the restenotic process. In addition, the mechanism of action of sirolimus, the drug used in the first successful DES for reduction of restenosis will be highlighted. Finally, the potential role for immune mediators on the overall processes of atherosclerosis will be explored. 

Sirolimus has pleotropic effects on a wide variety of cell types with relevance to restenosis. The underlying mechanism of action of the compound is as an inhibitor of the cell cycle, with its principal effect on the G I to S transition (40), Importantly, sirolimus affects the numerous cell types thought to be involved in the restenotic process including cells typically resident to the vascular wall, such as SMCs, as well as those recruited from the circulation at times of injury such as immune constituents, As the complete delineation of the steps and mechanisms of restenosis remain to be determined, the benefit of sirolimus may be due to its ability to affect the multiple cell types involved. 

Tanabe K, Degertekin M, Regar E, Ligthart JM, van der Giessen WJ, Serruys PW. No delayed restenosis at I 8 months after implantation of sirolimus-eluting stent. Catheter Cardiovasc Interv2002 57 65-68. 

Indications Ischemic heart disease, restenosis Category Angiogenesis inhibitor Macrolide immunosuppressant (Derivative of sirolimus) mTOR inhibitor Half-life 33 to 36 hours... 

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