Rapamycin restenosis

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. 

Brara PS, Moussavian M, Grise MA, Peilly JP, Fernandez M, Schatz RA, Teirstein PS. Pilot trial of oral rapamycin for recalcitrant restenosis. Circulation 2003 107 1722-4. 

Abbreviations CDK, cyclin-dependent kinase CREST, cilostazol for restenosis trial MACE, major adverse cardiac events ORAR, oral rapamycin to prevent restenosis ORBIT, oral rapamune to inhibit restenosis REAR, peroxisome proliferator-activated receptor PRESTO, prevention of restenosis with tranilast and its outcomes SMC. smooth muscle cell ThR, target lesion revascularization tREAT, Tranilast restenosis following angioplasty trials TVR, target vessel failure. ... 

Marx SO, Marks AR, Bench to bedside the development of rapamycin and its application to stent restenosis. Circulation 2001 8 852-855. 

Waksman R, Ajani AE, Pichard AD, et al, Oral Rapamune to Inhibit Restenosis study, Oral rapamycin to inhibit restenosis after stenting of de novo coronary lesions the Oral Rapamune to Inhibit Restenosis (ORBIT) study, J Am Coll Cardiol 2004 44 1386-1392. 

Rodriguez AE, Alemparte MR, Vigo CF et al. Pilot study of Oral Rapamycin to prevent Restenosis in patients undergoing coronary stent therapy Argentina Single-Center Study (OFtAR trial) J Inv Cardiol 2003 15 581-584. 

Rodriguez AE, Granada Jp Rodriguez-Alemparte M, et al. OFfAR II Investigators, Oral rapamycin after coronary bare-metal stent implantation to prevent restenosis the Prospective, Randomized Oral Rapamycin in Argentina (ORAR II) Study. J Am Coll Cardiol 2006 47 1522-1529. 

A number of animal data supported the use of systemic immunosuppressive therapies in reducing smooth muscle cell growth, the mediator of neointimal proliferation (26,37,38). Preclinical studies have demonstrated a significant reduction of neointimal proliferation after balloon injury in the porcine or rabbits model of restenosis, with the systemic use of rapamycin (26). 

Abbreviations MACCE, major adverse cardiac and cerebrovascular events ORAR. oral rapamycin to prevent restenosis ORBIT, oral rapamune to inhibit restenosis TVR, target vessel revascularization. 

Oral rapamycin to prevent restenosis I pilot trial... 

Study design and patient population of oral rapamycin to prevent restenosis pilot study. 

Constructing a receiver operating characteristic (ROC) curve, which is a quantitative analysis, it showed that a rapamycin blood concentration of >8 ng/mL was the proper cutoff to define high blood concentration of the drug, and that it was in agreement with the mean rapamycin blood concentration in patients having no restenosis (7.9 ng/mL). 

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. 

Clinical implications of the oral rapamycin to prevent restenosis randomized study... 

Small observational and randomized studies with oral prednisone and oral rapamycin have been demonstrated as reduction of clinical and angiographic parameters of restenosis, Although the studies are relatively small sample sized, these studies were conducted without economic support of the industry, which represents the major strength of all studies, conceived and performed without any conflict of interest. 

The major advantages of the systemic approach to restenosis should be the relatively inexpensive and also powerful and safety method to reduce restenosis in selected group of patients. Oral rapamycin can also be used in determining high risk subsets of patients such as those with diabetes, bifurcations, and in-stent restenotic lesions, alone or in conjunction with DES. In insulin-dependant diabetic patients, oral rapamycin together with DES may help to reduce the still higher than acceptable risk of restenosis that is currently reported with DES. 

RodriguezA, Rodriguez Alemparte M, VigoC, etal. Pilot study of oral rapamycin to prevent restenosis in patients undergoing coronary stent therapy. Argentina single center study. J Invas Cardiol 2003 15 581-584. 

RodriguezA, Fernandez Pereira C, Rodriguez Alemparte M. Oral rapamycin in the treatment of diffuse proliferative in-stent restenosis in a patient with small reference vessel. J Invas Cardiol 2003 15 515-518. 

The last remaining question is if AVI-4126 will find a place in future therapeutic regimens for the prevention of restenosis this answer might be found in the results of phase II clinical studies currently being conducted, such as AVAIL. Our recent data on six-month follow-up on the patients enrolled in the AVAIL study (87) showed that AVI-4126 is effective in reducing neointimal formation, particularly when locally delivered in high dose. We also concluded that local delivery of antisense is safe and feasible, The results indicate that antisense (AVI-4126) can be as effective in prevention of the restenosis as most of the well-known antiproliferative agents do, but in contrast to other chemotherapeutics (paclitaxel, actinomycin D) c-myc antisense inhibits cell cycle in the G-1 phase, which make its effect less toxic and comparable with that of rapamycin. 

With the aim to overcome the excessive VSMC proliferation observed after BMS implantation, devices able to locally deliver antiproliferative drugs (drug-eluting stents [DESs]) have been developed (Figure 15.21). The most used antiproliferative drugs are sirolimus (Rapamycin ) and paclitaxel (Taxol ). The delivery of these antiproliferative drugs from DES reduces artery restenosis (down to 5%-10% of treated patients [211,212]) more efficiently than BMS. However, DESs did not completely solve the problem [213] as they can trigger unwanted side effects such as stent thrombosis (ST) and delayed restenosis compared to BMS [214,215]. 

DESs have been the most recent breakthrough in stent technology. DESs consist of a metal stent covered with a thin polymer coating designed to improve vascular compatibility and elute antiproliferative agents. Drugs such as sirolimus (rapamycin) and paclitaxel serve to reduce restenosis by reducing hyperplasia caused by smooth muscle cell proliferation [37, 38]. 

The introduction of drug-eluting stents, Sirolimus-Eluting, may solve the problem of in-stent restenosis in LEAD fi 7) a gratifying experience similar to that with drug (rapamycine or taxol) eluting stents for coronary lesions. 

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