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Saturday 19 January 2008

Tests home in on new hope against bird flu

By: Julia Hinde

A FLOOD of alarming reports detailing the horrors the world could expect in the event of another bird flu pandemic swept the globe in 2005 and 2006.

Prompted by cases in Asian countries, and the worldwide spread of the H5N1 virus by migrating birds, the coverage left no one in doubt that a new pandemic could be devastating. Further sobering details came with the publication by Australian and some other governments of necessarily draconian plans that would be available to deal with any serious outbreak - as well as the stockpiling of millions of doses of unproven antiviral drugs.

The reports about bird flu have slowed to a trickle. But the threat has not gone away.

Now a group of Australian researchers has published data that might point the way to an alternative - and potentially cheaper - way to fight the next major outbreak.

Led by Ian Clark of the Australian National University (ANU), the researchers used gemfibrozil, a drug already approved for human use as a cholesterol-lowering medication, to treat mice infected with a potent influenza virus.

The team reports a doubling in survival rates for infected mice when they were given a course of gemfibrozil, starting four days after they became infected.

According to ANU postdoctoral fellow Lisa Alleva, who is an author on the paper, gemfibrozil was chosen because as well as having cholesterol-lowering properties, it is known to have anti-inflammatory effects and reduces immune system particles called "proinflammatory cytokines".

Cytokines are important signalling molecules in the body which, during an immune response, signal immune cells to travel to the site of an infection.

But a number of recent studies have reported pronounced increases in proinflammatory cytokines after infection with potent influenza viruses. This has led many in the scientific community to suggest the high mortality associated with viruses such as avian flu might in fact be the result of a massive immune system overreaction - a so-called cytokine storm - which in turn triggers further inflammation, lung damage and even death.

Hence, the ANU team, rather than targeting the virus itself, set out to target the hypothesised immune system overreaction with an immune-modulating drug.

"We trawled through the literature believing that influenza mortality is primarily caused by an over-exuberant immune response," explains Alleva. "We looked for pre-existing drugs used in human populations that may have side effects which were anti-inflammatory.

"When we tried gemfibrozil, it worked so well, we ran with it."

In the paper - published in the journal Antimicrobial Agents and Chemotherapy (2007;51(8):2965-2968 - the researchers suggest that if this principle translates to patients, "a drug already approved for human use... might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain".

If this turns out to be true, governments across the world might have reason to breathe a sigh of relief. Current pandemic planning has largely involved stockpiling the expensive antiviral drugs Tamiflu and Relenza. These would almost certainly have to be rationed to workers in critical industries and other key figures, even in the nations that could afford them; they would probably not be available at all to the bulk of people in the world's poorest countries.

Existing planning also assumes that as soon as the precise nature of the infectious agent was known, work would start to develop a vaccine. However, this would take months before it was available, and mass vaccination programs would be a logistical challenge.

According to Alleva, the benefits of gemfibrozil - if it worked in humans - could be substantial.

"It's been used in the human population for 20 years, hence there is a very long safety record," she says.

"There are generic brands which are off-patent, so they are cheap. They are produced all around the world and are likely to be available where they will be most needed."

Additionally, the team's data suggests that enhanced survival does not depend on giving gemfibrozil before the onset of the illness, or even in the very early days, as is the case with antivirals.

Alleva says this is important "because we appreciate there are early immune responses which are protective". The time delay might be crucial in a pandemic where "it's going to be crazy".

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