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Generic Pain Drug Kills Resistant Tuberculosis
Clinical trials unlikely for outdated medication (Sept. 10)
An off-patent anti-inflammatory drug that costs around two cents for a daily dose in developing countries has been found by researchers at Weill Cornell Medical College to kill both replicating and nonreplicating drug-resistant tuberculosis (TB) in the laboratory — a feat few currently approved TB drugs can do, and resistance to those drugs is spreading.
The findings, announced on September 10 and published online in PNAS, point to a potential new therapy for the more than 500,000 people worldwide whose TB has become resistant to standard drug treatments. But the researchers worry that the effective drug — oxyphenbutazone — may never be tested in TB clinical trials.
The research team, led by Dr. Carl Nathan, discovered the ability of oxyphenbutazone to kill drug-resistant TB after testing thousands of approved drugs against the bacteria.
"This agent might help save lives if there was a way to test it in TB patients," Dr. Nathan said. Oxyphenbutazone went on the market as a patented drug for arthritis-like pain in the early 1950s and lost its patent and market dominance by the 1970s.
"It is difficult today to launch clinical studies on a medication that is so outdated in the United States,” said Dr. Nathan. "No drug firm will pay for clinical trials if they don't expect to make a profit on the agent. And that would be the case for an off-patent drug that people can buy over the counter for pain in most of the world."
He added that oxyphenbutazone — best known as Tandearil — does have some established toxicities and that it is not a drug that should be taken for aches and pains if a safer alternative is available. But the drug's major toxicities appear to be less frequent than the major side effects of the drug regimens that are currently used to treat TB, he said.
To find agents that could attack nonreplicating TB, Dr. Nathan's research team first identified four conditions that keep bacteria in the nonreplicating state within the human body: low oxygen, mild acidity, a fat instead of sugar to eat, and a small amount of the natural defense molecule nitric oxide.
The researchers replicated those conditions in the test tube and then methodically tested the effectiveness of thousands of agents against the bacteria. After testing 5,600 drugs, the team found oxyphenbutazone.
The researchers then delved into the mechanism by which oxyphenbutazone kills TB and found that the conditions that allow the bacterium to remain dormant modify the drug to the point that it starts reacting against both nonreplicating and replicating TB.
For more information, visit the Weill Cornell Medical College Web site.
