Simvastatin

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Statin drugs are some of the most effective drugs in the battle against high cholesterol. They are the most efficacious in lowering LDL cholesterol. Furthermore, recent studies have shown that statins are capable of preventing heart attacks and reducing the risk of strokes. However, statins are only recently gaining public attention though they have been available for many years.
Various cholesterol-lowering agents had been discovered during the 1950s and 1960s. However, the majority had unwanted side effects. In 1971, Drs. Akira Endo and Masao Kuroda began searching for a cleaner drug to treat hypercholesterolemia. Various experiments on animals and humans had shown that cholesterol could either be absorbed from the diet or synthesized de novo, when the diet lacked sufficient cholesterol. Additionally, cholesterol synthesis halted almost completely when the diet was cholesterol rich. Previous work had shown that cholesterol production within the body was controlled by a feedback mechanism in which cholesterol inhibited the enzyme b-hydroxy-b-methylglutaryl-CoA reductase (HMG Co-A reductase). By inhibiting this enzyme, the conversion of HMG-CoA to mevalonic acid was effectively blocked, and cholesterol synthesis was prevented (Figure 1). Drs. Endo and Kuroda, therefore, set forth attempting to discover a substance that would inhibit the action of HMG-CoA reductase.
Turning to the microbial world, the researchers hoped to identify a microorganism that produced an HMG-CoA reductase inhibitor as a defense mechanism against attack by other microbes, which rely on sterols as part of their biochemical make up. Initially, researchers looked for organisms with the ability to inhibit the incorporation of carbon-14 acetate into lipids. Broths that acted as inhibitors between acetate and lipid were then tested to see whether they would inhibit the production of lipids from tritium-labeled mevalonate. Broths which inhibited carbon-14 assimilation, but not lipid



References: “Assessing the Statins” ed. Eve Hurley. Australian Prescriber. 1999. <http:// www.australianprescriber.com/magazines/vol22no5/statins.htm> Endo, A., “The Discovery and Development of HMG-CoA Reductase Inhibitors.” Journal of Lipid Research, 33, 1992, 1569-1582. “FDA Approves Zocor to Lower Both Cholesterol and Triglycerides”. Doctor’s Guide. < http://www.pslgroup.com/dg/44316.htm> RX-List:Simvastatin. < http://www.rxlist.com/cgi/generic/simva.htm> Zocor (Simvastatin). <http://www.merck.com/product/usa/zocor/cns/home.html>

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