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

Abstract

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 Ϯ 0.10 g/ml [mean Ϯ SE]) was higher than the Cmax of artesunate (0.09 Ϯ 0.04 g/ml) and the tmax of dihydroartemisinin (1.13 Ϯ 0.58 hr) was higher than the tmax of artesunate (0.58 Ϯ 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.

In Vitro Activity and Interaction of Clindamycin Combined with Dihydroartemisinin against Plasmodium falciparum

“…Peak levels of dihydroartemisinin found in Gabonese children after rectal artesunate treatment were 468 nM and therefore far beyond EC values found in the course of this study (9). Peak plasma concentrations for clindamycin are reported to be 17 M in adults after single administration of a 600-mg clindamycin hydrochloride capsule (8).…”

“…Although resistance to artemisinin derivatives was induced in vitro and despite reports of in vivo treatment failure of artesunate, these findings seem to be of limited clinical relevance due to high recrudescence rates when artesunate is used in monotherapy for too short a treatment duration (2,10,11). The development of drug resistance is further curbed by particularly short plasma half lives of both drugs (8,9,17,28). Moreover the sesquiterpene lactones rapidly reduce the parasite load by a factor of approximately 10 Ϫ4 per asexual life cycle (i.e., 48 h) in vivo and are known to inhibit gametocytogenesis to a certain degree, a potential asset for the prevention of propagation of resistance (25,28).…”

Bioavailability and Preliminary Clinical Efficacy of Intrarectal Artesunate in Ghanaian Children with Moderate Malaria

“…Two study drugs were used: ARS suppositories (Rectocaps; capsules with 200 or 50 mg of ARS; Mepha Pharmaceuticals Ltd.), formulated as described previously (8), and parenteral ARS (Guilin No. 2 Factory, Guangxi, People's Republic of China).…”

“…ARS is currently formulated for administration by the oral and parenteral routes (3,11). ARS suppositories (Rectocaps; 50 mg of artesunate; Mepha Pharmaceuticals Ltd.) Aesch-Basle, Switzerland) have recently undergone preliminary assessment in Gabonese children (8). However, formal bioavailability studies with this formulation are lacking.…”

Induction of cell cycle arrest and apoptosis in JAR trophoblast by antimalarial drugs

“…Though the IC50 value of these antimalarial drugs on JAR cells (from 6.49-6.96 μg/mL) are higher than the effective antimalarial concentration [plasma level ranging from 0.2-5.0 μg/mL (1,8,21,24)] for treatment, a detrimental effect on the trophoblasts was observed at the lowest dose of the drugs used (3.13 μg/mL). Interestingly, it had been reported that the quinine treatment regimen for patients in Thailand, could lead to a plasma level of quinine as high gression was accompanied by the induction of apoptosis.…”