Tranilast Kissei Pharmaceutical

Kissei, in collaboration with SmithKline Beecham, is developing tranilast (Rizaben) as a prophylactic agent for restenosis, following percutaneous transluminal coronary angioplasty (PTCA). As of May 1997, tranilast was awaiting approval in Japan as an oral formulation given for three months following PTCA [246273], [248281]. The agent has been launched for use in allergic rhinitis, asthma and atopic dermatitis. Analysts had expected the early approval of Rizaben for PTCA-associated restenosis. However, due to delays by the Ministry of Health and Welfare, it is unlikely that Rizaben will be approved until the end of 1998. Sales of Rizaben for the treatment of its launched indications did not reach company expectations. The companies are also developing tranilast, in a nasal spray formulation, as a potential treatment for allergic rhinitis. The drug is in phase II trials for this indication [262810]. EP-00588518 from Kissei discloses the use of tranilast for the treatment of restenosis. Kissei has also filed patents disclosing the use of tranilast for arteriosclerosis (JP-09227371) and diabetic retinopathy (WO-09729744).     

Probucol inhibits neointimal thickening and macrophage accumulation after balloon injury in the cholesterol-fed rabbit.

Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis.