Clinical application of synthetic heparin - mimicking polyanionic compounds in in-stent restenosis
Chaim Lotan MD and Shmuel Ben-Sasson PhD
EuroCor GMBH, Germany
The pathogenesis of restenosis and accelerated atherosclerosis involves abnormal migration and proliferation of smooth muscle cells (SMC) infiltrated with macrophages and embedded in extracellular matrix (ECM) of adhesive glycoproteins, proteoglycans and collagens. Vascular SMCs are ordinarily protected by the smooth luminal lining of the arteries composed of vascular endothelial cells. Following angioplasty SMCs are often left exposed and in a futile effort to repair the wound, the cells proliferate and clog the artery. It has already been shown that heparin and heparin sulfate (HS) participate in the regulation of many cellular processes, e.g., cell growth, differentiation, angiogenesis, restenosis, lipoprotein metabolism and atherosclerosis.
Compounds that modulate functional properties of heparin/HS are therefore of increasing importance for the development of therapeutic agents. By acid-catalyzed polymerization of phenols and formaldehyde we have synthesized negatively charged, non-sulfated polyanionic compounds. Using this approach a series of non-toxic linear polyanionic polymers with repeating phenol-based monomers were identified, one of which RG-13577, mimics some of the effects of heparin.
Heparin-coated stents have significantly lower rates of thrombosis in animals. Coating stents with anti-proliferative polyanionic heparin mimetics may additionally minimize the risk of abrupt stent closure.
Pharmacokinetic studies of drug release.
Pre-clinical trials with large animals (pigs).