EFFICACY OF ORAL AND INTRAVENOUS ARTESUNATE IN MALE TANZANIAN ADULTS WITH PLASMODIUM-FALCIPARUM MALARIA AND IN-VITRO SUSCEPTIBILITY TO ARTEMISININ, CHLOROQUINE, AND MEFLOQUINE

The clinical efficacy of oral and intravenous (iv) artesunate was comp ared in an open randomized trial in 50 male adult patients with uncomp licated Plasmodium falciparum malaria in Kibaha, Tanzania. Oral artesu nate treatment was started with 2 X 50 mg initially followed by 50 mg 12 hr later and then 50 mg twice a day for four days (total dose = 550 mg or 9.6 mg/kg). Intravenous artesunate administration began with 2 X 0.8 mg/kg initially followed by 0.8 mg/kg 12 hr later and then 0.8 m g/kg twice a day for four days (total dose = 8.8 mg/kg). The mean +/- SD parasite clearance times (PCTs) were nearly identical at 23.4 +/- 5 .9 hr and 24.2 +/- 7.2 hr after oral and iv administration, respective ly. Mean +/- SD fever subsidence times (FSTs) were also similar at 18. 7 +/- 8.3 hr and 21.0 +/- 4.8 hr,respectively. All patients remained n egative for P. falciparum for at least 14 days. Recrudescence/reinfect ion occurred between days 21 and 28 in five of 25 patients (20%) after oral treatment and in four of 25 patients (16%) after iv treatment. T he mean erythrocyte count and hemoglobin concentration were slightly r educed after iv treatment but remained in the normal range. Otherwise, there was no change in blood biochemistry, hematology, and electrocar diograms monitored prior to and during the last dose. It is concluded that treatment with oral and iv artesunate was equally efficacious and well tolerated. A 24-hr in vitro susceptibility test of P. falciparum to artemisinin, chloroquine, and mefloquine was performed in samples from all patients. The three compounds exhibited 100% inhibition with the exception of three isolates, which showed chloroquine resistance. Parameter estimates of a sigmoid E(max) model (drug concentration at w hich 50% of the growth inhibition occurs [EC(50)]), the sigmoidicity f actor s and EC(95) fitted to the growth inhibition data differed betwe en compounds and isolates, indicating different sensitivity of P. falc iparum isolates. There was no correlation between artemisinin and mefl oquine EC(50) values, while artemisinin and chloroquine EC(50) values showed weak correlation (r(2) = 0.223, P = 0.006). There was no correl ation between parameters describing clinical outcome (the PCT, the tim e needed for reduction of the parasite density to 50% and 95% of the i nitial parasitemia, and the FST) and those describing in vitro suscept ibility.