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Hepatitis Drug May Fight Anthrax

Lab study promising, but researchers have long way to go

MONDAY, Feb. 16, 2004 (HealthDayNews) -- Not only has Wei-Jen Tang shown that a drug for hepatitis blocks the action of the anthrax bacteria in the lab, but he thanks the media for making the discovery possible.

In January 2002, Tang, an associate professor at the University of Chicago's Ben May Institute for Cancer Research, published a paper that described the structure of edema factor, one of three major toxins secreted by the anthrax bacteria. His report also showed how it worked.

Soon after, a pharmaceutical company researcher who had read of Tang's exploits in the newspaper contacted him about testing adefovir dipivoxil (brand name Hepsera) for anthrax. Adefovir had been approved in 2002 to treat chronic hepatitis B virus infection and the scientist thought it might work on the pathway Tang had described in his research.

"That's how things started," says Tang, whose findings appear in this week's issue of the Proceedings of the National Academy of Sciences. "It was a major quantum leap to advance our studies because it usually takes two to three years to get a [drug] lead and then it has to be approved."

Even so, this research is in its infancy. "This is a demonstration in principle that this drug may work in anthrax. I think there's a long way to go to show that it's useful clinically," says Dr. Adrian Di Bisceglie, a professor of internal medicine at St. Louis University and an expert in the treatment of hepatitis B.

Anthrax started appearing in mail rooms and post offices in the fall of 2001, killing nearly half of those who breathed in the deadly spores. Many survivors have lingering health problems such as fatigue, shortness of breath and memory loss, report the authors.

About the only defense doctors have against anthrax are antibiotics, but these work only in the early stages of infection. Scientists have been eager to find more effective treatments.

In addition to edema factor, the anthrax bacteria actually secretes two other major toxins, lethal factor and protective antigen (this latter toxin actually acts as an escort, helping the other toxins enter the cells).

Edema factor interferes with the host's immune response in the first stages of infection. This gives the bacteria a chance to multiply, spread and produce yet more deadly toxins. Later on in the infection, this same edema factor causes massive tissue damage.

In test tubes, adefovir blocked the action of edema factor.

Further examination revealed exactly how the drug worked: Adefovir binds onto the surface of edema factor and stops it from mimicking an enzyme called adenylyl cyclase, which helps regulate signaling between cells.

"In tissue culture cells, adefovir also prevented edema factor from interfering with normal communications between blood cells that are vital for us to defend bacterial pathogens," Tang explains. "Consequently, adefovir will likely allow our body to mount more effective and direct defenses against anthrax bacteria. Adefovir could also block the damages of vital organs caused by edema factor or the combination of edema factor and lethal factor."

The drug actually binds 10,000 times better than the natural enzyme does. Not only does that make it effective, it also indicates it may be able to be given in such small amounts that there will be few, if any, side effects.

"We were surprised at how well it works," Tang says. "We were pleasantly surprised to find it has about a 10,000-fold higher affinity. That's a shocker to me."

Because the drug is already approved, it can immediately go into animal testing. It will never be tested in humans for ethical reasons.

"The problem with anthrax is that you can't do any clinical trials in advance because there are so few people and when you have them, it's an emergency," Di Bisceglie says. Animal studies will answer some questions, but not all.

Will it work in humans? "It's hard to tell," Tang says. "There's an outside chance it will work based on our understanding, but that doesn't mean it will work. Having said that, I will wait until we have other data."

Adefovir may also have applications beyond anthrax, specifically on Bordetella pertussis, which causes whooping cough, Yersinia pestis, which causes plague, and Pseudomonas aeruginosa, which causes many hospital-acquired infections.

"Potentially this can be used in those settings," Tang says. "We understand much less and therefore the applications may be significantly further away.

Although all three of these pathogens are considered potential bioterror agents, according to the study, Tang makes the point that whooping cough has been largely eradicated and plague is rarely seen. "The only thing that may have a clinical implication is hospital-acquired infections, and we've yet to find out how effective this is even in a tissue-culture setting," he says.

More information

For more on anthrax, visit the U.S. Centers for Disease Control and Prevention or the University of Wisconsin.

SOURCES: Wei-Jen Tang, Ph.D., associate professor, Ben May Institute for Cancer Research, University of Chicago; Adrian Di Bisceglie, M.D., professor, internal medicine, St. Louis University; Feb. 16-20, 2004, Proceedings of the National Academy of Sciences
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