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New test shows source of disease side-effects
2008-02-25
A new panel of tests aimed at finding out how drugs may damage cells has turned up a series of interactions that may explain some of the serious side-effects of statin drugs, researchers said on Sunday. Statins, the wildly popular cholesterol-lowering drugs, may interact with at least one blood pressure drug to damage the mitochondria, the powerhouses of cells, the researchers reported in the journal Nature Biotechnology. Their study also may lead to the development of drugs to treat diabetes and diseases of aging and better ways to screen for drug side-effects, the researchers said. Vamsi Mootha of the Broad Institute at Harvard University and the Massachusetts Institute of Technology said they had made their new database freely available to other scientists to use for screening drugs. The mitochondria are structures in cells that make adenosine triphosphate, or ATP, which helps power cells. Mootha's team tested more than 2,000 drugs on cells to see how they might interfere with this process. Their test looks at gene function, ATP levels and other measures of how well the mitochondria are working. Many patients who take statins have reported side-effects that include muscle pain and weakness. The cause is not well understood but Mootha has long suspected the mitochondria are involved. The effects have been hard to pin down because studies of different groups have produced conflicting results. Mootha's team said their findings showed some statins lower ATP levels and interfere with the mitochondria. "Of the six statins present in our screening collection, three (fluvastatin, lovastatin and simvastatin) produced strong decreases in cellular ATP levels and (mitochondrial) activity," they wrote. Fluvastatin is sold by Novartis under the brand name Lescol, lovastatin is sold under the brand name Mevacor and simvaststin is sold as Zocor. PATTERN OF DYSFUNCTION Three others -- atorvastatin, made by Pfizer under the brand name Lipitor, pravastatin or Pravachol, made by Bristol Myers Squibb and rosuvastatin, sold under the Crestor brand name by AstraZeneca -- had little effect, they said. "We asked what pattern of dysfunction they cause in the mitochondria," Mootha said in a telephone interview. "Once we figured out what the pattern was we asked what other FDA-approved drugs give rise to that same pattern of mitochondrial dysfunction." They found a few. "We were struck by the fact that one of these nearest-neighbor drugs is propranolol, a widely used antihypertensive agent," they wrote. Propranolol is a so-called beta blocker drug sold by Wyeth under the brand name Inderal and also available generically. "That was a bit of a surprise," Mootha said. "And it is important because so many patients are on a statin as well as blood pressure medication." Other drugs that resembled statins in their activity in mitochondria included amoxapine, cyclobenzaprine, griseofulvin, pentamidine, paclitaxel, propafenone, ethaverine, trimeprazine and amitriptyline. A similar process may be going on in diabetes, nerve degeneration and aging, Mootha's team said. They found a number of drugs, including the cancer drug vinblastine may counter this process. Mootha cautioned that his group has worked only in batches of muscle cells grown in the lab so far and that far more tests are needed. (Editing by Bill Trott)
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