The allergy medication astemizole could have another
life as a potential treatment for malaria, according to a
study conducted by researchers from the Johns Hopkins
Bloomberg School of Public Health and the Johns Hopkins
School of Medicine. The study, largely funded by the
Johns
Hopkins Malaria Research Institute, determined that in
a test tube the antihistamine killed the parasite
Plasmodium falciparum, which causes malaria in humans,
including strains that were resistant to traditional
malaria therapies. The drug also was shown to be effective
in mouse models. The findings are published in the July 2
advanced online edition of Nature Chemical
Biology.
"Time and money are major roadblocks when it comes to
developing new drugs for the treatment of neglected
diseases like malaria," said senior study author David
Sullivan, an associate professor with the Malaria Research
Institute and the Bloomberg School's
W.
Harry Feinstone Department of Molecular Microbiology and
Immunology. "Astemizole is promising as an antimalarial
but still needs to be evaluated for effectiveness as an
antimalarial in humans."
For the study, Sullivan and colleagues Curtis Chong
and Jun Liu, both of the School of Medicine's Department of
Pharmacology, first assembled the Johns Hopkins Clinical
Compound Library, a collection of 2,687 drugs. Seventy
percent of the compounds are approved by the U.S. Food and
Drug Administration and the other 30 percent by regulatory
agencies in other countries. Screening the drugs for their
effectiveness in killing the malaria-causing parasite, the
researchers found that astemizole was one of the more
promising.
The researchers then gave astemizole, along with the
drug's major human metabolite, desmethylastemizol, to mice
infected with Plasmodium. They measured 80 percent
reduction in parasite counts with moderate doses of the
drug in chloroquine-sensitive mice and 40 percent
reductions in chloroquine-resistant mice. Higher doses
completely eliminated Plasmodium infection.
Astemizole was voluntarily withdrawn from the U.S. and
European markets in 1999, after 15 years of use, when sales
became sluggish following warnings about the drug's safety
and the introduction of newer antihistamines. The drug was
reported to cause rare but life-threatening heart
arrhythmias when patients took an overdose or took it with
drugs that affected its metabolism. However, arrhythmias
are also reported with existing malaria drugs and with
other antihistamines now sold over the counter. Astemizole
is currently used in 30 countries, including Cambodia,
Thailand and Vietnam, where malaria is endemic.
Human studies are planned to evaluate the
effectiveness of astemizole directly in asymptomatic
malaria patients, a process that will be accelerated by the
fact that the medication has been through an approval
process. The researchers hope next to validate this drug
class for use in combination with existing malaria drugs,
such as artemisinin or the quinolines.
The Johns Hopkins Clinical Compound Library will now
be available to screen existing drugs for new uses for
diseases affecting the developing world. "This line of
research can be applied to many neglected diseases," said
Chong, the lead author of the study.
The study was written by Chong, Xiaochun Chen, Lirong
Shi, Liu and Sullivan.
In addition to the Johns Hopkins Malaria Research
Institute, the research was supported by the Johns Hopkins
University Fund for Medical Discovery and Department of
Pharmacology, and the Keck Foundation.
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