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Thursday, Aug 26, 2004

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Fighting drug-resistant malaria

By N. Gopal Raj

Drug resistance and multidrug resistance are now common in many infectious diseases. Malaria is no exception.

WITH THE introduction of antibiotics and many other wonder drugs, it seemed at one time that humans had gained the upper hand in the age-long fight against disease-causing organisms. But the pathogens have fought back by modifying one or more of their genes and becoming drug-resistant, a scary example of evolution in action. Drug resistance and multidrug resistance are now common in many infectious diseases. Malaria is no exception.

Quinine, extracted from the bark of the Cinchona tree, has been used to treat malaria for over 350 years, long before the single-celled parasites of the genus Plasmodium were identified as its cause. Even though quinine was isolated from the bark in 1820 and the purified drug has since been used to treat malaria, it has not been possible to synthesise quinine on a commercially economic scale. During the Second World War, the Japanese seized Java, which had almost a complete monopoly over the world's supply of quinine. The Allies and the Germans therefore relied on synthetic drugs belonging to a class of chemicals called `aminoquinolines'. One of these drugs, chloroquine, turned out to be highly effective, safe and well-tolerated. Being synthetic, it could be mass-produced cheaply to meet global demand, and after the war became the mainstay of anti-malarial therapy worldwide. By the late 1950s, chloroquine-resistant forms of the malarial parasite were being reported from South-East Asia and South America. Resistance to chloroquine and other aminoquinolines has grown and spread rapidly.

In India too chloroquine resistance is growing. Plasmodium vivax, which causes chronic malaria but is rarely fatal, used to account for almost 85 per cent of the malaria cases. But in recent years about half the laboratory confirmed cases of malaria have been due to the more lethal Plasmodium falciparum, and P. falciparum resistant to chloroquine is said to be spreading. Chloroquine-resistant forms of P. vivax have also been reported.

Changes to the `P. falciparum chloroquine resistance transporter' (Pfcrt) gene, particularly a mutation labelled `K76T', have been associated with chloroquine resistance. Working with 73 blood samples with P. falciparum collected from various parts of the country in 1988 and between 1996 and 2002, a team of Indian researchers found that the P. falciparum in 70 samples had the K76T mutation. Although laboratory studies have shown a strong correlation between the Pfcrt K76T mutation and chloroquine resistance, the researchers pointed out in their paper published a few months ago in the American Journal of Tropical Medicine and Hygiene that actual response displayed by infected people to chloroquine therapy could depend on factors such as partial immunity to the disease in endemic areas.

"We need large-scale studies in this country to understand how far specific forms of the Pfcrt gene and other mutations correlate with actual chloroquine resistance in the field," G. Padmanabhan of the Indian Institute of Science, the corresponding author of the paper, told The Hindu . But since the K76T mutation was so widespread and given the trend towards increasing cases of chloroquine-resistant malaria in the country, the practice of large-scale chloroquine therapy for P. falciparum malaria needed to be re-evaluated.

In another recent journal publication, scientists at the All-India Institute of Medical Sciences in New Delhi similarly examined mutations that make P. falciparum resistant to sulfadoxine-pyrimethamine (SP), the combination that has become the second line of treatment. Mutations to the parasite's gene for the enzyme `dihydrofolate reductase' (DHFR) are associated with resistance to pyrimethamine and to the gene for the enzyme `dihydropteroate synthetase' (DHPS) with sulfadoxine resistance. Yagya Dutta Sharma and his fellow researchers studied the genetic makeup of P. falciparum from over 300 blood samples taken during 1995-1996 and again five years later during 2000-2001. "There has been a progressive rise in the number of mutations in the genes for both enzymes, resulting in a shift in the level of SP resistance over a 5-year period," they reported in a paper published in the journal Antimicrobial Agents and Chemotherapy. As resistance had not yet reached such alarming levels that SP treatment failures were occurring in India, the SP drug combination must be administered judiciously, warns Prof. Sharma. Indiscriminate use of these drugs would increase the mutation rate and hasten the development of highly resistant forms of the parasite.

In the face of chloroquine and multidrug-resistant malaria, the world is increasingly looking to another herbal compound for salvation. Sweet wormwood (Artemisia annua) has been prescribed for centuries by Chinese herbal medicine practitioners for fevers. Artemisinin extracted from the herb is now used to make derivatives such as artesunate and artemether, which are increasingly important in treating drug-resistant malaria. Recently, the journal Nature published the work of an international team of academic and drug company researchers that created a synthetic equivalent that promises to be even more effective than artemisinin derivatives and can be produced at low cost.

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