Malaria is a mosquito-borne infectious disease that has plagued humankind for more than 50,000 years. It is widespread in tropical and subtropical regions, and continues to be the leading cause of death in developing countries including Africa, Asia and South America. The parasite responsible for causing malaria is known as Plasmodium, and there are four species capable of infecting humans: P. falciparum, P. vivax, P. ovale and P. malariae.
Pyrimethamine is an antifolate drug that is commonly used for treating malaria. The drug interferes with tetrahydrofolic acid synthesis from folic acid, a process essential for the survival of Plasmodium. Unfortunately, the extensive use of pyrimethamine in Asia and South America has led to the emergence of drug-resistant P. vivax. Scientists must therefore look for new drugs to combat the disease.
Laurent Renia at the A*STAR Singapore Immunology Network and co-workers have now reviewed the potential of methotrexate, an antifolate drug that has long been used for treating leukemia and certain types of cancer, to treat drug-resistant P. vivax. The researchers collected 20 P. vivax isolates from malaria patients between May and June 2009. They tested pyrimethamine on the isolates and found ten that displayed a high level of drug resistance.
The researchers then tested methotrexate on these ten drug-resistant P. vivax isolates. They found that methotrexate was potent against all isolates, despite their resistance to pyrimethamine. The result is encouraging because it demonstrates the potential of methotrexate as an antimalarial drug at very low concentrations.
A study in 1970 in fact already reported the successful treatment of seven patients with P. vivax infection using methotrexate. However, the study was not followed up because at that time there was no apparent advantage of using methotrexate over pyrimethamine, which was still effective. Moreover, methotrexate has a range of serious side effects at the high doses given for cancer treatment.
Apart from the treatment of cancers, methotrexate is also used for the treatment of severe psoriasis and rheumatoid arthritis. This study clearly indicates that methotrexate has another use—a potent agent for combating malaria at doses much lower than are currently used in the long-term treatment of severe psoriasis and rheumatoid arthritis. “At these low doses, methotrexate side effects are minimal,” says Renia. “Our results suggest that methotrexate might be a potent alternative to some of the standard antimalarials that are now failing to treat malaria, especially in Asia and South America.”
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network.