Restenosis inhibition

Due to the pivotal role of platelets in thrombus formation, especially in the arterial system, inhibition of platelet function has become a central pharmacological approach. Antiplatelet drugs are given in order to prevent and treat thromboembolic diseases such as coronary heart disease, peripheral and cerebrovascular disease. They have also revolutionized the procedures of invasive coronary interventions as they reduce the risk of restenosis and thrombosis. 

Horvath C, Welt FG, Nedelman M, Rao P, Rogers C. Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates inhibitory potential depends on type of injury and leukocytes targeted. Circ Res 2002 90(4) 488 494. 

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. 

Arterial restenosis occurs in 30-40% of patients after angioplasty. The dilated vessel subsequently narrows again because of neointimal hyperplasia. We introduced HVJ liposome containing ec-NOS expression vector into injured rat carotid artery [20], At 2 weeks after the transfer, histological analysis revealed a 70% reduction in neointimal area. In contrast, no inhibition of neointima formation was observed in the control vector transfection group. 

NO plays multiple roles in the arterial wall, which are dilatation of the artery, inhibition of platelet aggregation, prevention of adhesion of leukocyte with endothelium, and suppression of growth of VSMC. Multiple factors are involved in the induction of restenosis, so that the strategy to augment NO production may be the most practical approach for its treatment. 

The ERASER Investigators, Acute platelet inhibition with abcix-imab does not reduce in-stent restenosis (ERASER study). Circulation 1999 100 799,... 

Other drugs that have an impact on serum lipids have also been examined. Probucol pretreatment has been shown to lower the rate of restenosis after balloon angioplasty in clinical trials (88,89). Although its lipid-lowering effect is due to an increase in the fractional catabolic rate of LDL cholesterol (90), its antirestenotic effect is believed to be related to other properties, including inhibition of LDL oxidation, promotion of endothelial regeneration, and anti-inflammatory effects (91). However, probucol is not widely available due to its ability to lower HDL-cholesterol and concerns relating to proarrhythmia. 

Petronio AS, Amoroso G, Limbruno U, et al. Simvastatin does not inhibit intimal hyperplasia and restenosis but promotes plaque regression in normocholesterolemic patients undergoing coronary stenting a randomized study with intravascular ultrasound. Am Heart J 2005 149 520-526. 

Tranilast Inhibits SMC migration and proliferation, decreases collagen synthesis TREAT (25) TREAT-2 (26) PRESTO (27) Lower restenosis Lower restenosis No difference... 

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

Cilastozole Inhibitory effect on SMC migration by inhibiting P-selectin release ESPIRIT (45) Kimishirado (46) CREST (47) Low restenosis Low restenosis and TLR Low restenosis... 

Pemirolast Inhibition of smooth muscle cell proliferation and migration Ohsawa (55) Low restenosis and neointimal hyperplasia... 

Sarprogrelate Inhibits serotonin induced SMC proliferation Fujita et al. (56) Low restenosis... 

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. ... 

As previously mentioned, for SMC proliferation after coronary angioplasty, cell activation and cell-to-cell interaction of platelets and leukocytes mediated by adhesion molecules are considered to be important. Coronary stenting produces the release of an adhesion molecule, P-selectin, from d-granule of activated platelets. P-selectin-mediated platelet-leukocyte interaction has a crucial role in the development of stent restenosis. Cilostazol is an antiplatelet, antithrombotic, phosphodiesterase III inhibitor that by inhibiting P-selectin release has inhibitory effects on SMC migration. In addition, cilostazol may directly act to inhibit intimal hyperplasia. 

The drug dosages needed to achieve sufficient levels to inhibit restenosis are higher than therapeutic doses or tolerable doses. 

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