The Success Story of LDL Cholesterol Lowering.

We can look back at >100 years of cholesterol research that has brought medicine to a stage where people at risk of severe or fatal coronary heart disease have a much better prognosis than before. This progress has not come about without resistance. Perhaps one of the most debated topics in medicine, the cholesterol controversy, could only be brought to rest through the development of new clinical research methods that were capable of taking advantage of the amazing achievements in basic and pharmacological science after the second World War. It was only after understanding the biochemistry and physiology of cholesterol synthesis, transport and clearance from the blood that medicine could take advantage of drugs and diets to reduce the risk of atherosclerotic diseases. This review points to the highlights of the history of low-density lipoprotein-cholesterol lowering, with the discovery of the low-density lipoprotein receptor and its physiology and not only the development of statins as the stellar moments but also the development of clinical trial methodology as an effective tool to provide scientifically convincing evidence.

Where are we with probucol: a new life for an old drug?

Probucol has a long history of clinical application with established efficacy and safety profiles. Probucol is a potent anti-oxidant drug that has been in clinical use during the past few decades for the treatment and prevention of cardiovascular diseases. Here we review the current status of knowledge on the pharmacology, clinical benefits, and the mechanism of actions of this unique drug. Probucol has diverse pharmacological properties with therapeutic effects on the cardiovascular systems. Its mechanism of pharmacologic actions at the molecular level has recently been elucidated with the new concept of HDL metabolism associated with cholesteryl ester transfer protein (CETP) or scavenger receptor class B type I (SR-BI). HDL-C reduction may not be a "side effect" but it most likely might reflect a mechanism of action of probucol. Probucol could be reconsidered as an option at least in case statins, which are known to be effective in lowering low-density lipoproteins (LDL) and coronary artery disease (CAD) risk, are not effective. In particular, a marked CAD risk reduction has been recently reported in long-term probucol treatment of patients with heterozygous familial hypercholesterolemia (FH) in Japan. Therefore, probucol could be a more common therapeutic drug for the treatment of patients with FH as well. There is more than enough reason to believe that this old drug has much more to offer than hitherto known.

Statins: in the beginning.

Since the first human trial of a hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitor in 1978, the growth in importance of this drug class, both financially and medically, has been staggering. The aim of this paper is to summarise how this drug class was developed, highlighting the role ofAkira Endo.

Foundations for blockbuster drugs in federally sponsored research.

'Blockbuster' drugs, which are widely prescribed and improve the health of millions, often originate in fundamental laboratory research. An important example of such drugs are the cholesterol-lowering drugs called 'statins', including Zocor, Pravachol, and Lipitor, which millions of people take in the U.S. every year. This short paper outlines the direct and indirect contributions of federally sponsored research to the development of these important drugs.

Preventing coronary artery disease by lowering cholesterol levels: fifty years from bench to bedside.

In the more than 50 years since the founding of the National Heart, Lung, and Blood Institute and the American Heart Association, medical science has moved from an era in which hypercholesterolemia, as it is now defined, was not believed to be abnormal to one in which controlling hypercholesterolemia is known to reduce not only coronary artery disease morbidity and mortality but also total mortality. While the efforts and successes of many researchers involved in this evolution are impressive, atherosclerosis is still a major cause of death and disability in many developed nations, mostly in the form of myocardial infarction and stroke, and is an increasing cause of morbidity and mortality in developing nations. Many questions about the detailed pathogenesis of the disease remain. Elucidating the roles of high-density lipoprotein, other lipoproteins, and homocysteine, as well as the roles of cytokines and growth factors, will permit better understanding and treatment of atherosclerosis. With continuing support for research and encouragement of physicians and patients to follow recommended preventive regimens, further progress can be made against this major cause of death.