Viability of Plasmodium falciparum ex vivo: comparison of the effects of artemether and sulfadoxine-pyrimethamine.
OBJECTIVE
Severe malaria is increasingly treated with artemether and sulfadoxine-pyrimethamine, but their effects on the viability of Plasmodium falciparum ex vivo following therapeutic doses, and the relationship between conventional indices of therapeutic response and parasite viability, have not been evaluated. We assessed these parameters in children with severe non-cerebral falciparum malaria.


METHODS
Between May and August 1995, 17 children with severe non-cerebral malaria were randomized to receive therapeutic doses of artemether or sulfadoxine-pyrimethamine. Parasitemia quantification and withdrawal of blood culture of P. falciparum in vitro were done before and at specific intervals after drug administration. Therapeutic indices of response were determined by the conventional method. The corresponding viability estimates ex vivo were derived for each drug and compared with conventional therapeutic indices.


RESULTS
Artemether produced a significantly more rapid reduction of parasitemia and fever than sulfadoxine-pyrimethamine. Resistance to sulfadoxine-pyrimethamine was present in three out of seven patients (RI, RII and RIII) and was readily detectable by the functional viability estimate ex vivo. Ex vivo, functional reduction of parasite viability was significant 8 or 12 h after administration of artemether, with no functionally viable parasites 30 h after administration. In contrast, functional viability in isolates sensitive to sulfadoxine-pyrimethamine became significant by 16-20 h after drug administration and viable parasites were still evident after 36 h in some isolates. Indices of therapeutic response estimated by the conventional methods, i.e., time to 50% or 90% reduction of parasitemia and parasite clearance time, were significantly higher than those derived from the corresponding functional viability estimates ex vivo for each drug. There was correlation between some of the two sets of parameters.


CONCLUSIONS
These data suggest the rapid and relatively broad stage effects of artemether when compared with sulfadoxine-pyrimethamine on P. falciparum asexual forms. Estimation of parasite viability indices ex vivo permits comparison of the relative speed of antimalarial drug action.
Department of Pharmacology and Therapeutics and Postgraduate Institute for Medical Research and Training, University of Ibadan, Nigeria.
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Sowunmi
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Oduola
D000293:Adolescent; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D000077549:Artemether; D037621:Artemisinins; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D011739:Pyrimethamine / Q000627:therapeutic use; D012044:Regression Analysis; D012717:Sesquiterpenes / Q000627:therapeutic use; D013413:Sulfadoxine / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D012717:Sesquiterpenes; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D000077549:Artemether; D011739:Pyrimethamine