Title: Atherosclerosis Drug Discovery
Description: Although atherosclerosis is the leading cause of death in the called affluent societies, there is presently no drug in our pharmacologic armamentarium against disease to either prevent or reverse this insidious killer and debilitant of human lives. Because of this void the First Brook Lodge Symposium on Antirosclerosis Drug Discovery was convened at Brook Lodge in Augusta, Michigan, August 13-15, 1975. The symposium was sponsored The Upjohn Company and was international in scope, with investitors attending from such countries as England, Japan, Belgium, Italy. The symposium focused on the problems associated with the discovery and evaluation of new drugs effective in preventing reversing atherosclerosis. The thrust of material is centered around animal models useful as tools in the search and evaluation new drugs. Broadly categorized, the models are nonhuman primates, rabbits, rodents, quail, and tissue culture.

The material is a mix of studies on serum lipids and, more importantly, of studies on the artery, irrespective of serum lipid levels. The revention of arterial lesions, not reduction of serum lipids, is emphasized. A review of all anti-atherosclerotic agents, with the exception of hypolipidemic agents, is included in this volume of the proceedings of the symposium. Data are reported on the utility of selectively bred SEA Japanese quail for random screening for anti-atherosclerosis drugs, at the arterial level, in the pharmaceutical industry. The small size and cost of the animal coupled with its susceptibility to atherosclerosis induction make it a good model to detect, initially, agents that prevent lesion development in the artery itself. After screening large numbers of compounds in quail, active leads can be further evaluated in a nonhuman primate animal model such as Macaca fascicularis, which is well described in this volume.

The quail and nonhuman primate system also has the potential for detection and evaluation of agents active in reversing the atherosclerotic process. Although finding agents active against atherosclerosis directly at the arterial level is emphasized, a consideration of serum lipids and, especially, lipoproteins is not excluded. A new class of lipoprotein modifying agents is reported on for the first time. These compounds, such as 1-[p-(l'-adamantyloxy)phenyl]-piperidine, have the unique ability to markedly reduce atherogenic lipoproteins while concomitantly increasing nonatherogenic ones in hypercholesterolemic animals such as the rat. A detailed system for large scale screening for such agents is presented. The approach of attacking atherogenesis through modification of specific atherogenic lipoproteins appears more promising than the nonselective reduction of serum total cholesterol.

The goal is to reduce atherogenic low density lipoproteins and increase nonatherogenic high density lipoproteins. The potential utilization of tissue culture techniques for the detection and evaluation of anti-atherosclerotic agents is presently a popular area of research. Some potential uses are explored in this volume. It should be recognized, however, that any agent possessing a desired activity in tissue culture must ultimately be tested in a whole animal system in vivo. As illustrated by one report in the tissue culture section, agents active in tissue culture may not be active in whole animals because of problems in absorption, distribution, metabolism, or excretion of drug. Because of the relative lack of drugs effective against atherosclerosis, even in experimental animals, the first Brook Lodge symposium was necessarily concerned with means to discover and evaluate such agents.

I hope that the tools reported here for drug discovery and evaluation will be applied so that the second Brook Lodge symposium will deal specifically with promising anti-atherosclerosis drugs.
Subjects: Arteriosclerosis, Cardiovascular agents, Methods, Drug evaluation, Research, Animal models, Congresses, Drug therapy, Animal Disease Models, Preclinical Drug Evaluation