Canfiel CJ. Clinical studies of atovaquone, alone or in combinationwith other antimalarial drugs, for treatment of acute uncomplicated malaria

Abstract. The therapy of Plasmodium falciparum malaria continues to be a problem in many parts of Southeast Asia because of multidrug resistance to nearly all existing antimalarial drugs. Atovaquone is a novel hydroxynaphth oquinone with broad spectrum anti-protozoal activity. We recently evaluated the antimalarial activity of atovaquone in a series of dose-ranging studies in 3 17 patients with malaria at the Bangkok Hospital for Tropical Diseases. Originally, the drug was administered alone. Using atovaquone alone resulted in satisfactory, initial clinical responses in all patients; the mean parasite and fever clearance times were 62 and 53 hr. respectively. However, irrespective of the duration of therapy, overall cure rates were approximately 67%. In vitro sensitivity studies on parasites taken from patients prior to treatment and at the time of recrudescence showed a marked decrease in susceptibility to atovaquonc in the recrudescent parasites. To improve cure rates, atovaquone was administered in combination with other drugs with antimalarial activity. Proguanil and tetracycline were chosen due to laboratory evidence of poten tiation; doxycycline was selected because it has a longer half-life than tetracycline. Although pyrimethaminc did not show laboratory evidence of potcntiation with atovaquone, it was chosen as an alternative inhibitor of dihydrofolic acid reductase with a longer half-life than proguanil. The clinical studies with these drug combinations confirmed the laboratory results with marked improvement in cure rates for proguanil, tetracycline, and doxycyclinc; pyrimethamin