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No entry for malaria parasite

By Dr Matt Wilkinson , 19-Jan-2007

Researchers have discovered a new antimalarial therapy that acts by targeting the method of entry of the parasite into red blood cells.

The new beta-blocker / antimalarial combination therapy, currently in preclinical trials, could provide hope for millions of malaria sufferers who do not respond to conventional treatments. Due to the prevalence of generic beta-blockers many lives may be saved while researchers look for new and more refined therapies.

The study, published in PLoS Medicine, showed that both parasite invasion and intracellular parasite proliferation could be stopped by blocking the erythrocyte (red blood cell) guanine nucleotide regulatory protein G

s

.

Malaria is the most widespread parasitic disease and claims more than a million lives a year. In Africa, it is estimated that a child dies every 30 seconds due to the disease.

"This opens the possibility for important new drugs for malaria that [parasites] won't become resistant [to]," said Kasturi Haldar, principal investigator for the study and the Charles E. and Emma H. Morrison Professor in the department of pathology at The Feinberg School of Medicine at Northwestern University.

"New drugs are urgently needed because the parasite has evolved resistance against virtually all types of commonly used drugs."

Malaria is caused by a range of protozoan parasites, the most lethal being Plasmodium falciparum, spread by female Anopheles mosquitoes.

The parasites hijack red blood cells and then multiply wildly to cause the life-threatening symptoms of malaria. These include anaemia, fever, chills, flu-like illness and in severe cases, coma and death.

Traditionally, antimalarials attack the parasite itself. However, due to rapid multiplication and mutation, parasites can become resistant to antimalarial drugs very quickly. A drug that acts directly on the red blood cells, allowing them to reject parasite entry in the first place, would be much more difficult for a parasite to develop resistance to.

As malaria poses such a global health threat, existing drugs must continue to be used while the discovery and development of more effective drugs and vaccines goes on.

The study found that the off-patent drug propanolol, a beta-blocker that targets the G

s

protein, reduced the dose of antimalarial drugs needed to kill the parasites tenfold in studies on human cell cultures and mice. This is a crucial finding, as high doses of antimalarials (often necessary to combat increased resistance) can be toxic. Propanolol is safe even for pregnant women, who are particularly vulnerable to malaria.

Propanolol was originally launched as Inderal in 1965 by ICI Pharmaceuticals (now part of AstraZeneca) and was one of the inventions that led to Sir James Black being awarded the Nobel Prize for Medicine in 1988.

One problem associated with the use of propanolol is that it is counterindicated for use with quinidine and may have adverse effects with other quinoline drugs commonly used to treat malaria. However, only minor problems are associated with chloroquine, sulfadoxine-pyrimethamine and artemisinin.

"We're working on developing a unique drug that would combine anti-malarial drugs with blood pressure medication. We think it has a high likelihood of success," said Haldar, who believes it is now an appropriate time to evaluate combinations containing beta-blockers and antimalarials for infections that fail to respond to current optimised therapies.

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