Tag: #statins #medicine

Statins

 

The birth of statin medications goes back to the 1985 Nobel Prize for Medicine which was shared by Michael Brown and Joseph Goldstein for their research. This would be the beginning of an overwhelming war on cholesterol. At this point in time the link between cholesterol and heart disease was growing stronger by the day. Today we know that reality is a little more complicated, but the “bad” cholesterol misinformation was spread so far and wide that it would set off a pharmaceutical arms race. Prior to statins the only cholesterol lowering medications available were nicotinic acid (niacin), clofibrate an early precursor to fenofibrate which is still used today and cholestyramine a resin which binds cholesterol in the gut preventing its reabsorption. Cholestyramine was the most effective but also had GI side effects that many patients could not tolerate. So, it is easy to see how the medical establishment would look at something that reduces cholesterol as a panacea for heart disease.

Although Mevacor (Lovastatin) developed by Merck gets the title of the first approved statin the story begins in Japan at a drug company called Sankyo. The first experimental statin known as compactin was developed to inhibit cholesterol synthesis and it did a fantastic job in vitro. Unfortunately, in animal testing the therapeutic effect would disappear in a few hours as rats were able to increase the enzyme it blocked tenfold quickly overwhelming the cholesterol reduction. Normally a failure of this magnitude would result in the drug being scrapped completely but to Sankyo’s credit they would spend two years identifying why it did not work in rats and conducting further studies in hens, dogs, and monkeys where it would prove effective. Compactin would go as far as phase 2 trials in humans where it was effective in lowering cholesterol. Development would be stopped due to two issues; the first were crystalline microstructures discovered in the liver of rats who received high doses, toxicologists were concerned that these were toxic metabolites. After nine months of study researchers were able to identify these microstructures as cholesterol which was not toxic. The second would come when dogs that were given extremely high doses would develop lymphomas. The doses that caused it were nowhere near what was being used in human patients, but two strikes were enough to stop the development in its tracks and even halted a competitors drug lovastatin for fear of lymphomas. Merck would later decide that the positive human trials of compactin warranted further research and development was restarted and they would submit their new drug application in 1986 with approval coming the following year.