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Chronicles Booklet.Indd Page 1 UCSD Emeriti Association 214 University Center, UCSD La Jolla, California 92093-0002 Chronicles Newsletter of the UCSD Emeriti Association Volume V, No. 1 September 2005 RETURN SERVICE REQUESTED Frontiers of Medicine “The Cholesterol Wars:” How the Statins Won anyway, why bother your head? So the met with great skepticism. What the discovery of the statin drugs, drugs that skeptics failed to consider is that no SEPTEMBER 2005 lower cholesterol levels dramatically one was proposing to block cholesterol and safely (by inhibiting the body’s own synthesis completely; that very well synthesis of cholesterol), played a major might be bad. But if you could titrate the role in ending “The Great Cholesterol dose of the inhibitor so as to achieve a Controversy.” lowering of blood cholesterol without First, it was necessary to overcome reducing the amount of intracellular concerns about the feasibility and safety cholesterol needed for optimal health, —by Daniel Steinberg, of inhibiting the natural synthesis of you might have a novel way to correct M.D., Ph.D. cholesterol. The human body can hypercholesterolemia. Emeritus Professor of Medicine Chronicles make all the cholesterol it needs by That was the gist of the proposal breaking down other foodstuffs (fats put forward in the early 1950s by Jean Mark Your Calendar! n an earlier issue of this newsletter, Newsletter of the UCSD Emeriti Association and carbohydrates) and converting Cottet and his collaborators in France I briefl y chronicled the uphill battle I the fragments into cholesterol. In fact, and by Steinberg and Fredrickson here. waged through the 20th century to Wednesday, October 19 most people make as much cholesterol However, neither group came up with a convince the medical profession that every day as they consume in their diet. clinically effective compound. It turned a high blood cholesterol level was a Price Center (Room TBA) Because of this ability to manufacture out that the drug introduced by Cottet major cause of heart attacks. Many Briefi ng (3:30 - 4:00) followed (4:00 - 5:30) by Editorial Board cholesterol, the body does not rely on and coworkers (alpha-phenylbutyric in the fi eld were convinced of this as cholesterol in the diet; cholesterol is not acid) was inhibiting the incorporation Sanford Lakoff Editor early as the 1960s but only in 1984 did an essential foodstuff. of a radioactively labeled precursor into the National Institutes of Health fi nally Offi cers However, while cholesterol in the cholesterol but not actually blocking net make it an offi cial public health goal to diet is not essential, the presence of production of cholesterol molecules. Mary Corrigan President lower cholesterol levels to prevent heart cholesterol in all the cells of the body Steinberg and Fredrickson, following Jack Fisher Vice President/President Elect disease. My book in preparation, The Colin Bloor Secretary-Treasurer is. What if you had a low dietary up on observations made by Tomkins, Cholesterol Wars, explores the several cholesterol intake and in addition took Sheppard and Chaikoff at Berkeley, Executive Council reasons for the initial reluctance of the a drug that prevented the cells from confi rmed that a close chemical relative medical profession to accept the causal Mel Green, Robert Hamburger, Donald Hellinski, making their own cholesterol? That of cholesterol (delta-4-cholestenone) relationship despite a considerable Faustina Solis, Avrum Stroll might cause trouble. Indeed, when could inhibit cholesterol synthesis and body of evidence. One important inhibition of cholesterol synthesis was went on to show that it reduced blood Ex-Offi cio: Past President Marvin Goldberger reason was the unavailability of safe, fi rst proposed as a way of treating cholesterol levels. However, the toxic potent drugs for lowering cholesterol Arthur Wagner Please report all address changes to our administrative offi cer in the high blood cholesterol, the notion was side effects of the compound precluded Academic Senate: levels. If you can’t do anything about it [Continued on p.2] On the Teaching of Acting Gaye Hill [email protected], (858) 534-3641, mail code 0002 UCSD Emeriti Association Page 2 Page 7 [Steinberg from p. 1] dishes sat around too long and got at this point. They went on to try [Lakoff from p. 6] [Steinberg from p. 3] contaminated by a fungus. The bacteria compactin in dogs and there the results clinical use. These early efforts did originally seeded onto his culture dish were quite different. In dogs they saw a the new breed of administrators Clark disease mortality. All-cause mortality dl. These drugs are so remarkably safe not solve the problem but they at least had grown thickly all over the dish very signifi cant and consistent lowering Kerr had identifi ed as managers of the was 30% lower in the treated group that some, half in jest, have proposed sparked an interest in the possibility that except for neat circles surrounding the of blood cholesterol levels. They also multiversity rather than educational and there was no increase in mortality putting it “in the drinking water” or at cholesterol synthesis might after all be a intrusive fungus. Having a prepared showed that it worked in rabbits, hens, innovators in the style of Hutchins, from any single category of disease. It least selling it over-the-counter. We may legitimate pharmacologic target. mind, Fleming realized that the fungus and monkeys. Finally, in 1980 Endo and Eliot, or Meiklejohn. But the truth is is now clear that the marginal “toxic” not be quite ready to go that far but it To the pharmaceutical industry, was making something that killed the colleagues reported that compactin that Atkinson was so successful here effects seen in the early trials was only is noteworthy that such proposals are inhibition of cholesterol synthesis bacteria in its immediate vicinity and given by mouth at a dose of 50 mg per because he respected the faculty and apparent, attributable in part to the no longer “unthinkable.” looked like a sitting duck. All the 25 that that just might be important! His day decreased cholesterol levels in students enough to let them make their small sizes of the populations studied or so steps by which the body makes discovery was serendipitous but soon patients with hypercholesterolemia by own decisions. He saw his job as one of and in part to the modest lowering of [The author is indebted to Drs. Akira cholesterol had been fully characterized the search for fungal antibiotics became an average of 27%! In some, the drop helping them and listening carefully to cholesterol levels and the accompanying Endo and P. Roy Vagelos for in depth and the properties of the enzymes that deliberate and was being pursued on a was as much as 30 to 35%. A second them, not dictating to them or imposing modest decreases in coronary heart interviews.] catalyze them were well understood. large scale. clinical study in seven patients with his own narrow vision. disease events. Over the next decade a large number Akira Endo, working at the Sankyo familial hypercholesterolemia, which is It is perfectly consistent of him to Third, the large statin studies made uuu of drug companies and university Co. in Tokyo, decided that the broths in much harder to treat, was published in have withdrawn his name for consid- it clear that treatment benefi ts women laboratories set out to synthesize which fungi were grown in the hunt for the prestigious New England Journal of eration because students had not been as well as men; the old as well as the compounds analogous in their chemical new and better penicillins might also Medicine. It showed a highly signifi cant consulted. That deference to faculty and young; those with low initial LDL structure to one of the compounds on contain natural inhibitors of cholesterol student judgment is what made him so levels as well as those with high initial drop in total cholesterol levels from 390 [Mills from p. 5] the pathway leading to cholesterol. The synthesis. He and his associates began to down to 303. There was no doubt now effective and also what has made UCSD levels; diabetics as well as nondiabetics. favorite target was the step known to be test each of the fungal broths for ability that, barring the possibility of some a great educational institution. It is the None of the earlier studies had been the rate-limiting or “bottleneck” step. to inhibit cholesterol synthesis. Endo unsuspected toxicity showing up in reason above all others that we ought large enough to make this evident and Andy Wright (witty and acerbic as That is the step in which HMG coenzyme and his colleagues began testing in 1971. larger and longer clinical trials, this to have Atkinson College. consequently women, the elderly, those ever), Bob Eliot, Sig Burkhardt, and A is converted to mevalonic acid by the Week after week they patiently applied drug and others like it were going to with “low” LDL levels, and diabetics the inimitable and unfathomable Roy key enzyme, HMG coenzyme reductase. their assay to these broths but the results be wonder drugs. Reprinted from the UCSD student news- were undertreated for many years. Harvey Pearce. And now we could get Dozens and dozens of compounds were uniformly and depressingly Endo’s dramatic clinical fi ndings paper, The Guardian, May 31, 2005. The advent of the statins made on with it. were found to work beautifully on the negative. Finally, two years and over with compactin caught the eye of the it possible to settle the “cholesterol David Mahlon Bonner was born purifi ed HMGCoA reductase enzyme 6,000 tests later, they fi nally made a hit.
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