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Timing of antimalarials affects resistance

Malaria fight Resistance to the last line of defence against malaria could be avoided by changing the timing of medication, suggests new research.

Professor Leann Tilley, of the Bio21 Institute at the University of Melbourne, and colleagues, report their findings today in the Proceedings of the National Academy of Sciences.

Artemesinin drugs were originally developed by Chinese researchers, based on wormwood, an ancient herbal treatment for fevers.

The World Health Organization has recommended artemesinins be used to treat malaria for nearly a decade. The drugs are now considered the last line of defence against the disease, given the development of resistance to other antimalarials.

"It's been an incredibly successful drug," says Tilley.

But now, she says, there are signs of resistance developing to artemesinins too, with parasites taking a lot longer to clear from the blood.

"The worry is that this is the start of a slow decline where eventually the drug will no longer be effective," says Tilley.

What has been frustrating for researchers, she says, is that apparently resistant parasites don't appear to be resistant when tested in the lab.

Now Tilley and colleagues have a obtained a better understanding of how resistance develops and can explain this puzzle.

Activating artemesinin

Scientists believe that artemesinin is activated to a toxic form by interacting with haem, which is produced when haemoglobin is digested by malaria parasites.

This theory was supported by her previous research that found haemoglobin digestion was necessary for artemesinin activation.

Electron microscope studies by Tilley and colleagues has also found that the parasite's digestive system is not developed when it is immature.

This suggests immature parasites would not be digesting haemoglobin and therefore would be protected from the toxic effects of artemesinins.

But, this had not been picked up by the resistance tests to date, which had exposed the parasites to the drug over their entire period of development, long enough for it to have an effect on them.

A matter of timing

In their most recent study, Tilley and colleagues developed a new invitro test to better mimic what happens when malaria is exposed to the drug in the body.

In practice, the parasites are only exposed to the artemesinins for two hours, after which the drug is cleared from the body.

"Rather than exposing the parasite to the drug for two or three days, which is the standard assay, we just did it for two to three hours," says Tilley.

"Under those conditions we see dramatic differences between the sensitivity of the immature parasites and the mature parasites."

The researchers found the immature parasites were 100 times less sensitive to artemesinins than the mature ones, and they found different strains of parasite also showed different sensitivity to the drug.

"If the parasite in the immature stage is exposed to the drug, a number of parasites will likely survive that treatment and there will be selection for strains that are resistant," says Tilley.

Tilley says the new test will help scientists detect resistant parasites more quickly in the field, and help in the search for genetic markers for resistance.

She says the findings also suggest the current approach of administering the drug once a day for three days would not maximise the chance of hitting the parasite when it is most sensitive.

"You would be better trying to hit it more often," says Tilley.

She also says the findings suggest a newer class of longer-lived artemesinin-type drugs will be more likely to hit the parasite when it's most sensitive.

"We predict those antimalarials will be more effective," says Tilley.

The research was funded by the National Health and Medical Research Council.