In September 2003, the US 26th Marine Expeditionary Unit entered Liberia for a brief peacekeeping operation. While ashore, more than 100 marines contracted Plasmodium falciparum malaria. Five of the cases were so severe, they had to be rushed back to the United States for emergency treatment with intravenous quinidine, a derivative of quinine. In the most severe malaria cases, intense fever and nausea demands immediate intravenous treatment for its fast action and because patients can't keep anything in their stomachs.

"At first we didn't identify them as malaria cases, so it advanced to severe malaria," says Lieutenant Colonel Bryan L. Smith, director of the Armed Forces Research Institute of Medical Sciences (AFRIMS) clinical trials center in Bangkok. "That kicked us in the rear about better diagnostics. Then we realized we didn't have the best drug in the world - artesunate."

In the 1980s, the military had taken steps to add a derivative of artemisinin to the list after learning about it from the Chinese military. The move followed decades of malaria breakthroughs from the Walter Reed Army Institute of Research (WRAIR): chloroquine in 1949, sulfadoxine-pyrimethamine in 1983, mefloquine in 1989, doxycycline in 1992, and atovaquone-proguanil in 2000, to name several.

But then, Thomas Brewer, then at AFRIMS, discovered that the preferred derivative, arteether, caused brainstem lesions in animals. He suspected it would affect all the drugs in the class. As a result, artemisinin research took a backseat while the unit focused on other drugs. "Early on, we didn't appreciate its real importance," recalls a rueful Brewer, who's now with the Bill and Melinda Gates Foundation.

A year after the 2003 Liberia fiasco rejuvenated the program, WRAIR filed a 1,400-page investigative new drug application with the Food and Drug Administration and quickly completed a first round of safety trials for an intravenous version of artesunate. Col. Peter Weina, who directs the artemisinin project from WRAIR's Silver Spring, Md., headquarters, still hopes to have a final efficacy trial underway this winter, even though they were recently dealt a setback when their industrial partner, Sanofi-Aventis, pulled out of the collaboration. "They feared they would be asked to provide it at a loss to the developing world," Weina said.

While a US FDA-approved intravenous antimalarial drug will be warmly welcomed by malariologists, they're upset by the military's glacial pace. White at Mahidol University in Thailand led a team that published a seminal study in the Lancet last year, showing that intravenous artesunate was 33% better and less toxic than quinine for treatment of severe malaria.¹ However, their study used a Chinese version of the drug, which doesn't meet western manufacturing standards, and thus can't be used by the US military or purchased by aid agencies for the developing world.