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Feb 26, 2010

Scientists Use shRNA to Remove Key HIV Co-Receptor

  • A type of blood pressure medication shows promise at overcoming some drug-resistant tuberculosis (TB), according to laboratory tests conducted by researchers at UT Southwestern Medical Center. However, in another study, they also found that the Mycobacterium tuberculosis bacterium, which causes the disease, might be resistant to treatment in more people than previously thought.

    Tawanda Gumbo, M.D., associate professor of internal medicine at UT Southwestern and senior author of the studies, said the research challenges current thinking about how the TB bacterium works in the body, as well as how best to kill it.

    The first study, available online and in the April 15 edition of The Journal of Infectious Diseases, is titled “Efflux-Pump–Derived Multiple Drug Resistance to Ethambutol Monotherapy in Mycobacterium tuberculosis and the Pharmacokinetics and Pharmacodynamics of Ethambutol”. Dr. Gumbo and his colleagues used an experimental apparatus to simulate the way TB bacteria grow in the human lung. When they exposed the bacteria to drugs commonly used to treat the disease—ethambutol and isoniazid—the bacterial cells activated a cellular mechanism that pumps each drug out of the cells.

    The pumping action enables the rapid emergence of high-level resistance to the drugs whether administered together or individually, Dr. Gumbo said. "We treat TB with multiple drugs, essentially to protect each other from resistance, but yet we’ve been puzzled with why you find resistance to both drugs together," Dr. Gumbo explains. "Our findings make sense—it is more efficient from the bacteria’s viewpoint to employ the same mechanism to get rid of multiple attackers, whether they strike alone or at the same time."

    Resistance was drastically reduced, however, when the researchers administered the blood-pressure drug reserpine, which is known to block this pumping action to the TB cells, before administering ethambutol and isoniazid. "There is already a known solution to this problem," Dr. Gumbo says. "Hopefully now we can reduce resistance to TB treatment drugs." The next step in his research, Dr. Gumbo continues, is to test all the first-line drug treatments together with the pump blocker in humans.

    Dr. Gumbo’s second study, available online and in the April edition of Antimicrobial Agents and Chemotherapy, is titled “New Susceptibility Breakpoints for First-Line Antituberculosis Drugs Based on Antimicrobial Pharmacokinetic/Pharmacodynamic Science and Population Pharmacokinetic Variability”. The researchers found that more people might harbor drug-resistant TB than currently believed.

    Guidelines for testing whether a person is infected with a drug-resistant TB strain were developed more than 40 years ago. They involve determining the lowest concentration of a drug that will kill at least 95% of the TB bacteria in a patient. The TB is said to be resistant to the drug if more than 1% of TB still grows at that concentration.

    Dr. Gumbo said those guidelines are useful for showing trends, but are not effective for predicting how an individual will respond to therapy. Recommended drug concentrations and dosages, for example, do not account for factors such as body weight, height, race, and how much food a person ate before being tested. "Science has evolved," Dr. Gumbo said. "We have better tools now so we can do more and predict better treatment."

    In the second study, he again simulated TB in the human lung and virtually simulated eight clinical trials involving 10,000 patients. The computer simulation factored in pharmacokinetics to determine how likely a dose of a given drug is to kill TB.

    Dr. Gumbo’s research team found that the concentrations typically used in practice are too low, leading people to think they have treatable TB, when in fact their disease might be resistant to common drugs.

    "There is likely more multidrug-resistant TB than previously thought—possibly up to four times as much," Dr. Gumbo notes. "That means some people may be getting underdosed with medicine weaker than the disease, and they die." The next step, Dr. Gumbo said, is to confirm these computer-driven results in patients.



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