Cardiovascular drug reviews最新文献

Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration-dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B-containing lipoproteins into plasma. Avasimibe induced cholesterol 7alpha-hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol-fed as well as in non-cholesterol-fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol. Although total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol-lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol.

This special issue of the "Cardiovascular Drug Reviews" is dedicated in memory of Dr. Edward H. Ahrens, Jr., who died on Dec. 9th, 2000 at the Princeton Medical Center in New Jersey at the age of 85. Dr. Ahrens was the Director of the Lipid Metabolism Laboratory at the Rockefeller University. Dr. Alexander Scriabine conceived the idea for the issue at the special memorial symposium held at the Rockefeller University on Feb. 05, 2002 under the auspices of The New York Lipid and Vascular Biology Research Club. Dr. Ahrens was the first president of the club. He started this club with Drs. Howard Eder and DeWitt Goodman. Dr. Eder thought that it would be a fitting attribute to honor one of the founding fathers of the club by hosting a memorial symposium. I, as the President of the club for that academic year, had no hesitation in accepting the proposal. This year will be the 40th anniversary of the club and its continued success provides a glimpse of the fine legacy left behind by Dr. Ahrens. Dr. Ahrens also played a pivotal role in the establishment of the Journal of Lipid Research. This is the 43rd year of the journal and in this commemorative issue we are reproducing a review he wrote for the 25th anniversary of the journal. I was never personally acquainted with Dr. Ahrens. However, I am honored that I got this opportunity to pay tribute to a great scientist whose work has contributed immensely to the progress of lipid research. He was a person who touched many lives and still continues to do so. My involvement in the remembrance of Dr. Ahrens shows that science not only impacts your contemporaries but also generations that follow you. Scientific research is a journey where you can leave your trails behind and be remembered for your work long after your departure from this world. Dr. Ahrens contributed immensely to the understanding of cholesterol metabolism. In the early stages of his career he showed that phospholipids solubilize fat in the blood. Now we know that a monolayer of phospholipids surrounds the neutral lipid core of cholesterol esters and triglycerides in lipoproteins. This monolayer contains proteins, called apolipoproteins, which play a major role in lipoprotein catabolism. Lipoproteins are the major vehicles that transport triglycerides and cholesterol in the plasma. He also described a new form of primary biliary cirrhosis characterized by the presence of xanthomas and hyperlipidemia with normal translucent plasma. Subsequently, his group at the Rockefeller Institute developed methods for the separation of lipids using silicic acid columns, isolated highly unsaturated long chain fish oil fatty acids using gas-liquid chromatography, standardized techniques to study sterol metabolism, and introduced the concept of using beta-sitosterolemia as an internal marker for cholesterol balance studies. These studies revealed that individuals show a reproducible response to a given regimen when studied over time. In contrast, differen