Plasma levels of artesunate and dihydroartemisinin in children with Plasmodium falciparum malaria in Gabon after administration of 50-milligram artesunate suppositories.

A thermostable suppository of artesunate (artesunic acid) has been developed. In Gabon, 12 children with Plasmodium falciparum malaria received two administrations of this suppository in a 4-hr interval. Parasitemia and fever were then measured and the plasma levels of artesunate and its active metabolite, dihydroartemisinin, were determined by means of a reversed phase high-pressure liquid chromatography method using reductive electrochemical detection. Substantial parasite clearance (97-100%) was noted 24 hr after the beginning of the treatment and body temperature had returned to normal. Absorption, metabolism, and elimination of artesunate were rapid. Mean values of maximum plasma levels (Cmax) and maximum concentration peak times (tmax) were evaluated. The Cmax of dihydroartemisinin (0.18 +/- 0.10 microg/ml [mean +/- SE]) was higher than the Cmax of artesunate (0.09 +/- 0.04 microg/ml) and the tmax of dihydroartemisinin (1.13 +/- 0.58 hr) was higher than the tmax of artesunate (0.58 +/- 0.19 hr). Plasma levels 30 min after the second suppository administration were not consistently higher than those found 30 min after the first administration.

Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children.

BACKGROUND: The combination of atovaquone and proguanil is highly effective and safe for the treatment of Plasmodium falciparum malaria. We aimed in this randomised, double-blind, placebo-controlled study to assess the efficacy and safety of this combination for malaria prophylaxis. METHODS: 320 children who lived in a hyperendemic area for P falciparum malaria were stratified by weight and randomly assigned atovaquone plus proguanil or placebo once daily for 12 weeks. All children received initial curative treatment with atovaquone and proguanil before the start of chemosuppression. We recorded adverse events daily and collected thick blood smears once a week. The primary endpoint was a positive blood smear. FINDINGS: 25 of 140 children in the placebo group and none of the 125 children in the atovaquone plus proguanil group had positive smears during chemosuppression (p<0.001). Adverse events during the chemosuppression phase did not differ between the groups. INTERPRETATION: The combination of atovaquone plus proguanil is a highly effective and well-tolerated chemosuppressive antimalarial in children. This drug combination could replace current regimens.

PIP: The efficacy and safety of combined atovaquone and proquanil as a chemosuppressive antimalarial were investigated in a randomized placebo-control study of 315 schoolchildren 4-16 years of age from Lambarene, Gabon--an area where Plasmodium falciparum malaria is endemic and parasites are highly resistant to chloroquine. The children were categorized on the basis of weight (11-20, 21-30, 31-40, and 41 kg and over). At baseline, 115 children (37%) had a positive blood smear for malaria. In the initial phase of the study, all 315 children received the combined treatment. After 3 days of curative treatment, P. falciparum and P. malariae were still detected in 5 and 11 children, respectively. After 1 week of curative treatment, all children with these parasites had negative blood smears. Of the 265 children who completed the initial curative phase, 125 were assigned the combined treatment (dose adjusted for weight) and 140 received a placebo. During a total of 28 person-years of observation in the atovaquone and proquanil group, protective efficacy was 100%. In the 28 person-years of observation accumulated among untreated controls, positive blood smears were detected in 25 children; parasites began to emerge 4 weeks after the initial curative phase. During the 4-week follow-up period, during which time neither group received treatment, positive blood smears were found in 12 controls and 3 cases (emerging only in the last 4 observation days). Although gastrointestinal symptoms were reported, the rate did not differ significantly between cases and controls. These findings suggest that the combination of atovaquone and proquanil could replace current antimalarial regimens if donated supplies were available.

Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria.

BACKGROUND: Routine antipyretic therapy in children with infectious diseases has long been the source of controversy. Each year, in addition to antimalarial medication, millions of children with Plasmodium falciparum malaria receive paracetamol to reduce fever. However, the usefulness of this practice has not been proven. METHODS: In a randomised trial in Lambaréné, Gabon, 50 children with P falciparum malaria were treated with intravenous quinine, and received either mechanical antipyresis alone, or in combination with paracetamol. Rectal body temperature and parasitaemia were recorded every 6 h for 4 days. Plasma concentrations and inducible concentrations of tumour necrosis factor (TNF) and interleukin-6 were measured every 24 h. In addition, production of oxygen radicals was measured in both groups. FINDINGS: The mean fever clearance time was 32 h for children treated with paracetamol and 43 h for those who received mechanical antipyresis alone; however, this 11 h difference was not significant (95% CI -2 to 24 h; p = 0.176). Parasite clearance time was significantly prolonged in patients who received paracetamol with a difference of 16 h (8-24 h; p = 0.004). Plasma concentrations of TNF and interleukin-6 were similar in both groups during the study. However, the induced concentrations of TNF, and the production of oxygen radicals, were significantly lower in children treated with paracetamol than those who received mechanical antipyresis alone. INTERPRETATION: These data suggest that paracetamol has no antipyretic benefits over mechanical antipyresis alone in P falciparum malaria. Moreover, paracetamol prolongs parasite clearance time, possibly by decreased production of TNF and oxygen radicals.

PIP: Although paracetamol is routinely used to control fever in African children with Plasmodium falciparum, the usefulness of this treatment has not been established. In a randomized clinical trial, 50 children 2-7 years of age from Lambarene, Gabon, with P. falciparum malaria were treated with intravenous quinine and received either mechanical antipyresis alone (electric fanning, tepid sponging, and cool blankets) or in combination with paracetamol. The mean fever clearance time was 32 hours for children treated with paracetamol and 43 hours for those who received antipyresis alone--a nonsignificant difference. Parasite clearance time was significantly prolonged (by an average of 16 hours) in children who received paracetamol. Although plasma concentrations of tumor necrosis factor and interleukin-6 were similar in both groups, induced concentrations of tumor necrosis factor and the production of oxygen radicals were significantly lower in paracetamol-treated children. Overall, these findings indicate that paracetamol confers no benefits over mechanical antipyresis alone and actually prolongs parasite clearance time. Further studies are required, however, before recommendations for ancillary treatment can be changed.