Prospects for drug therapy for hyperlipoproteinaemia.

Prospects for therapy for hyperlipoproteinaemia are likely to rely more heavily on improvement of known molecules than on development of new ones aimed at various components of the plasma lipid transport system. Promising advances are revealed in both directions. A new synthetic inhibitor of HMG CoA reductase, atorvastatin, lowers plasma low-density lipoprotein (LDL)-cholesterol and triglycerides and increases high-density lipoprotein (HDL)-cholesterol with greater potency than currently available drugs of this class. A highly selective thyromimetic, CGS 26214, virtually devoid of cardiovascular effects, has potent cholesterol-lowering activity in several models, reduces post-prandial response to a fat load in rats and markedly lowers Lp(a) concentrations in monkeys. There is a trend to develop inhibitors of acyl CoA: cholesterol acyltransferase (ACAT) with more than one desirable activity. Thus, ACA-147, which inhibits cholesterol absorption, reduces LDL, prevents their oxidation and increases HDL-cholesterol, was antiatherogenic in cholesterol-fed rabbits. Sch48461 has emerged as an inhibitor of cholesterol absorption by an as yet unknown mechanism unrelated to ACAT inhibition, while a synthetic saponin, CP- 148,623, which prevents the entry of cholesterol into intestinal mucosa, has a potential for combination therapy. Approaches which may find applications in a more distant future include molecular cages to trap cholesterol selectively, "cholesterol vaccination", overexpression of the apolipoprotein E gene in the skin, and gene therapy. With improvements in understanding of the pathophysiology of dyslipoproteinaemias, drug discovery and development may focus more in future on the specific causes of disease.