September 11, 2012
Anti-inflammatory Pain Drug Can Kill Resistant Tuberculosis
April Flowers for redOrbit.com - Your Universe Online
Researchers at Weill Cornell Medical College have found that an off-patent anti-inflammatory drug that costs about two cents for a daily dose can also kill both replicating and non-replicating drug-resistant tuberculosis in the laboratory. Few currently approved TB drugs can do this, and resistance to those is spreading.
Reported in the Proceedings of the National Academy of Sciences, the study points to a potential new therapy for the more than 500,000 people worldwide whose TB has become resistant to standard drug treatments. The research team worries, however, that the effective drug, oxyphenbutazone, may never be tested in TB clinical trials.
Dr. Carl Nathan and his research team found what they call the "completely surprising" ability of oxyphenbutazone to kill drug resistant TB after testing thousands of approved drugs against the bacteria. This repurposing of agents already on the market can lead to quicker testing for new uses.
"This agent might help save lives if there was a way to test it in TB patients," says Dr. Nathan. Oxyphenbutazone was originally marketed as a 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"It is difficult today to launch clinical studies on a medication that is so outdated in the United States, that it is mainly used here in veterinary medicine to ease pain," says Dr.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."
Nathan admits that oxyphenbutazone, known under the trademarked name of Tandearil, does have some toxicities, and should not be taken for pain if a safer alternative is available. The drug's major toxicities appear less frequently than the major side-effects of the drug regimens that are currently being used to treat TB, however.
Mycobacterium tuberculosis is unusual among disease-causing bacteria in that it naturally infects just humans. One-third of the world's population is infected with TB, but the bacteria typically remains dormant in a person with a healthy immune system.
However, it becomes active in enough people that TB is the leading cause of death in humans from a bacterial infection. TB is difficult to treat and the bacteria that causes it can become resistant to therapy.
Using first-line agents at full strength with non-counterfeit drugs, up to 95 percent of drug-sensitive patients can be cured in six months. However, if the TB becomes resistant to these drugs, second-line agents are administered every day for two years or more.
"These second-line drugs are often toxic and expensive, and are not readily available in developing countries, where most of the infections occur," Dr. Nathan says. Mortality in drug resistant TB patients can be as high as 80 percent.
Another major issue in treating TB is that the bacteria can reside hidden in the body in a non-replicating form, even when the patient is undergoing active TB treatment.
The team first identified four conditions that keep bacteria in that non-replicating 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. They then 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, researchers found oxyphenbutazone.
They found that oxyphenbutazone kills TB because the conditions in the body that allow the bacterium to remain dormant modify the drug to the point that it starts reacting against both forms of TB. The TB bacterium is unable to defend itself and it dies.
But the researchers were unable to test oxyphenbutazone in mice, because the animals metabolize the drug to an inactive form far faster than humans.
"This makes testing the drug for TB use in humans problematic since the FDA requires preclinical animal testing studies for safety and efficacy," Dr. Nathan says. "Yet there is a long track record of oxyphenbutazone's relatively safe use in hundreds of thousands of people over decades."
The team is continuing their search through hundreds of thousands of compounds, testing for their action against TB. Oxyphenbutazone is the second that they have found, nitazoxanide being the first.
Nitazoxanide, a drug with an excellent safety record, is still on patent for use against some infections caused by other microbes. Discussions have been held about testing it in TB, Dr. Nathan says, but have stalled because of the same problem as oxyphenbutazone. The drug is metabolized so quickly in mice that it cannot be tested against experimental TB in that species.
For both oxyphenbutazone and nitazoxanide, Dr. Nathan argues that the requirement for testing in animals with experimental TB should be waived, because these agents work against TB in the test tube, have already been used with relative safety in people and might address an urgent need for treatment of a contagious disease with high mortality and few other treatment options.