HISTORY OF THE COMPANY

Since its clinical introduction some 20 years ago, angioplasty (PCTA) has increased in popularity as a clinically effective method for improving blood flow though stenosis or occluded arteries. However, over the next 3 to 6 months, restenosis occurs in approximiately 30-40% of patients, thereby constituting a significant limitation to the long-term success of this procedure. A number of trials using drugs effective in animals for reducing restinosis have produced negative clinical results. The complexity of the restenosis process, species particularities, and sub-optimal drug dosing may partially explain these differences. Restenosis is predominantly due to neointimal hyperplasia and constrictive remodeling. Inadequate compensatory enlargment of a vessel after angioplasty (inadequate vascular remodeling) is considered an important mechanism of post-PTCA restenosis.

Constrictive remodeling can be effectively countered by the use of stents, which may account for the decreased incidence of restenosis observed with their use. Despite the use of stents, restenosis continued to limit the long-term success of PTCA. Stenting may provoke an exuberant proliferative response compared to balloon angioplasty. The favorable effect of stents in countering constrictive remodeling is therefore in some cases offset by the increased neointimal hyperplasis associated with stenting, causing difficult to treat in-stent restenosis.

Few effective therapies existed at this time of neointimal proliferation. Vascular smooth muscle cell (SMC) migration and proliferation occur as early as 36 hours following arterial injury. The number of SMC in the neointima peaks around 2 weeks and cell replication rate after these first few weeks is countered by cell death. Accumulation of extracellular matrix and connective tissue which may constitute the bulk of neointima further increases the intimal thickness.

The doctors at the Montreal Heart Institute found that the endothelium had important inhibitory effects on platelet aggression, monocyte adhesion and vascular smooth-muscle cell proliferation. Endothelial injury, with consequent endothelial dysfunction, is caused by PTCA and may play an important role in subsequent restenosis. What was found further was that prolonged systemically administered 17B estradiol accelerates endothelial recovery in vivo after arterial injury.

The important conclusion was: since endothelial injury due to PCI is a local event, the institute investigated the efficacy of a local delivery of a single dose of 17B-E, following PCI to reduce restenosis and potentially to enhance endothelial recovery. The hope was that reendothelialization and recovery of nitric oxide synthase activity might influence restenosis. Administration of L-arginine and eNOS gene therapy have been shown to reduce intimal thickening and restenosis after balloon injury.

The preliminary studies were meant to show:

1. the effects of local delivery of 17 B_E on late luminal loss and restenosis after PCI (Percutaneous Coronary Intervention)
2. to investigate the improvement in endothelial function after local delivery of 17B-E and stent implantation.
3. to understand the mechanism for the clinical benefit of local 17 B-E delivery in vascular healing

Conclusion: The studies at the Institute found a reduction in restenosis after stenting with 17 B-E administration in a porcine coronary artery model. Further, there was a significant reduction in the extracellular matrix and collagen expression after local administration of 17B-E and stenting.