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Atherosclerosis drug discovery

Author: Charles E Day
Publisher: New York : Plenum Press, ©1976.
Series: Advances in experimental medicine and biology, v. 67.
Edition/Format:   Print book : Conference publication : EnglishView all editions and formats
Database:WorldCat
Summary:
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  Read more...
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Genre/Form: Congresses
Conference papers and proceedings
Congrès
Material Type: Conference publication
Document Type: Book
All Authors / Contributors: Charles E Day
ISBN: 0306390671 9780306390678
OCLC Number: 2074283
Notes: "Proceedings of the First Brook Lodge Symposium on Anti-atherosclerosis Drug Discovery held at Brook Lodge in Augusta, Michigan, August 13-15, 1975."
Description: x, 467 pages : illustrations ; 26 cm.
Contents: Section 1 Primate Models.- A Model for Therapeutic Interventions on Established Coronary Atherosclerosis in a Nonhuman Primate.- The Nonhuman Primates as Models for Studying Human Atherosclerosis: Studies on the Chimpanzee, the Baboon and the Rhesus Macacus.- Phylogenetic Variability of Serum Lipids and Lipoproteins in Nonhuman Primates Fed Diets with Different Contents of Dietary Cholesterol.- The Baboon in Atherosclerosis Research: Comparison with Other Species and Use in Testing Drugs Affecting Lipid Metabolism.- The Fine Structure of Nonatherosclerotic Intimal Thickening, of Developing, and of Regressing Atherosclerotic Lesions at the Bifurcation of the Left Coronary Artery.- Apo-Lipoprotein Localization in Human Atherosclerotic Arteries.- Section 2 Rabbit Models.- Rabbits as a Model for the Study of Hyperlipoproteinemia and Atherosclerosis.- Seasonal Variations in Severity of Experimental Atherosclerosis in Rabbits.- Study of Drugs Affecting Cholesterol-Induced Atherosclerosis in Rabbits.- Turnover and Aortic Uptake of Very Low Density Lipoproteins (VLDL) from Hypercholesteremic Rabbits as a Model for Testing Antiatherosclerotic Compounds.- Evaluation of Permeability Parameters (Influx, Efflux and Volume of Distribution) of Arterial Wall for LDL and Other Proteins.- Oxygen Diffusion and Atherosclerosis.- Section 3 Rodent Models.- High Volume Screening Procedures for Hypobetalipoproteinemic Activity in Rats.- Biological Activity of a Hypobetalipoproteinemic Agent.- Nonisotopic Method for Estimating Cholesterogenesis in the Rat.- Cholesterol Metabolism in Rats Sensitive to High Cholesterol Diet.- Importance of Sex and Estrogens in Amelioration of Lethal Circulatory Stress Reactions: Relationship to Microcirculatory and Reticuloendothelial System Function.- Inbred Mice and Their Hybrids as an Animal Model for Atherosclerosis Research.- Diet Induced Hypercholesterolemia in the Diabetic and Non-Diabetic Chinese Hamster.- Section 4 Avian Models.- Animal Model for Experimental Atherosclerosis Produced by Selective Breeding of Japanese Quail.- Morphologic Observations on Experimental Atherosclerosis in SEA Japanese Quail.- A Mechanism for Lipid Accumulation and Central Necrosis in Fibrous Plaques.- The Influence of Some Dietary Factors and/or Treadmill Exercise on Rat and Chicken Tissue Lipids and Serum Lipoproteins.- Section 5 Tissue Culture.- Effects of Cholesterol Derivatives on Sterol Biosynthesis.- Mechanism of Inhibition of Cholesterol Uptake by the Arterial Wall.- Lipoprotein Uptake and Degradation by Cultured Human Arterial Smooth Muscle Cells.- The Removal of Cellular Lipids from Landschutz Ascites Cells and Smooth Muscle Cells in Culture.
Series Title: Advances in experimental medicine and biology, v. 67.
Responsibility: edited by Charles E. Day.

Abstract:

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.

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