no fat for you, Mr. Corona!

With this pandemic you never know what the next piece of news will be, or what part of the world it will come from. Every once in a while it’s good news, and todays item is very much that. And we shouldn’t be surprised it originates from that little sliver of the Levant on the Mediterranean that houses a lot of the smartest people in the world. Thank God for Israel. The Israelis don’t claim all the credit for today’s feat. They had help from Mt. Sinai, the one in New York City.

Not that I can come close to getting into the head of a scientist at Hebrew U. or Mt. Sinai, let alone duplicate the workings there, but I think it went something like this:

  1. coronavirus infected lungs accumulate fat
  2. cells stoked with fat support more efficient replication of coronavirus
  3. drugs exist to reduce fat accumulation
  4. let’s do the experiment!

Despite what those emails you get say, there aren’t any drugs to keep you from putting on fat. But attempts to develop drugs that alter lipid (fat) metabolism have going on since cholesterol was declared a problem. Since 1976, when the Japanese biochemist Akira Endo of the Sankyo Company isolated a factor from the fungus Penicillium citrinum which he identified as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), we’ve had some pretty good drugs for this. Dr. Endo’s compound, which he named compactin or mevastatin, was the first statin to be administered to humans. It took 20 years to prove them safe and effective, and in 1996 Lipitor was released. The first cholesterol drug was clofibrate (Atromid-S), which increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis (fat breakdown!). Chylomicrons (the form fat takes to float around in your blood after you absorb it) are degraded, VLDLs (very low density lipoporotein, fat and protein complexes that can get into cells) are converted to LDLs (low density lipoprotein), and LDLs are converted to HDL (“good” cholesterol!). All the ‘DLs carry triglyceride (fat), but density goes up as triglycerides are pealed or eaten away. Where did it come from? Well, in 1954 J. Cottet of Paris reported that farm workers exposed to an insecticide which was sprayed from the air over fields in the region of Clermont-Ferrand in France became ill and were found to have remarkably low plasma cholesterol. This insecticide (phenyl ethyl acetic acid) had been developed by the agricultural division of Imperial Chemical Industries (ICI). A chemist in ICI, Jeff Thorp, recognized the potential of this substance and synthesized an analogue, chlorophenoxyisobutyrate (later called Atromid-S or clofibrate). Thorp contact Michael Oliver of the University of Edinburg to gauge his interest, which was substantial. A few years with rats, then with any normal folks hanging around he could cajole to get the dose right (no review boards in those days), then finally into clinical trials in 1964. The first big trial, conducted under the auspices of the World Health Organization, was a disappointment, with excess non-cardiac deaths and gallstones being problems. Although it never received FDA approval, clofibrate was the only cholesterol drug around in the 60s and early 70s. Other safer and more effective agents were developed and Atromid-S was taken off the market completely in 1978. Fenofibrate (TriCor) was developed by Groupe Fournier SA of France, patented in 1969, came into medical use in France in 1975, and was approved by the FDA in 2004. Its mechanism of action is basically the same as clofibrate’s. While its use to lower cholesterol has mainly been supplanted by the statins, there are some patients with high cholesterol whose main problem is with triglycerides. For them, TriCor is the drug of choice. It also lowers uric acid, and is used off-label in some difficult-to-control gout patients. I have prescribed it for that purpose myself. The problems with gallstones and excessive non-cardiac death have not emerged.

Funny how what goes around comes around. A chemical made to kill pests gives rise to a drug that lowers cholesterol mainly by breaking down fat which then shows it can break down the fat in lungs on which our biggest pest of the day is feeding, killing said pest! Take that Mr. Corona! We’re gonna get you one way or another!

Oliver M.  The clofibrate saga: a retrospective commentary.  Br J Clin Pharmacol. 2012 Dec; 74(6): 907–10.

Published by rike52

I retired from the Rheumatology division of Michigan Medicine end of June '19 after 36 years there. Upon hitting Ann Arbor for the second time (I went to school here) it took me almost 8 months to meet Kathy, 17 months to buy her a house (on Harbal, where we still live), and 37 months to marry her. Kids never came, but we've been blessed with a crowd of colleagues, friends, neighbors and family that continues to grow. Lots of them are going to show up in this log eventually. Stay tuned.

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