Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in children.
BACKGROUND
Increasing drug resistance in Plasmodium falciparum has necessitated renewed search for cheap, effective alternatives to commonly available antimalarials, chloroquine and pyrimethamine-sulphadoxine, for the treatment of malaria in Africa. Probenecid, an inhibitor of organic anion transporters and multiresistance-associated proteins, can chemosensitize P. falciparum to pyrimethamine and sulphadoxine in vitro, but the clinical significance is unclear. We assessed the safety, treatment efficacy, and effects on gametocyte carriage of adding probenecid to pyrimethamine-sulphadoxine.


METHODS
We evaluated 151 children aged 12 years or younger who had uncomplicated P. falciparum malaria. Patients were randomly assigned pyrimethamine-sulphadoxine (25 mg/kg of the sulphadoxine component) or pyrimethamine-sulphadoxine as above plus probenecid 20-25 mg/kg of bodyweight in two divided doses daily for 3 days. The primary endpoints were parasitological cure rates on days 14 and 28.


RESULTS
Both regimens were well tolerated; no child was withdrawn because of drug intolerance. Fever (1.9 +/- 1.1 vs. 2.4 +/- 1.2 days, P = 0.02) and parasite clearance (2.3 +/- 0.9 vs. 2.7 +/- 1.1 days, P = 0.04) were significantly shorter, and the parasitological cure rate on day 14 (96.2%vs. 83.5%, P = 0.02) but not day 28 (79.4%vs. 72.6%, P = 0.4), was significantly higher in children treated with pyrimethamine-sulphadoxine-probenecid than in those treated with pyrimethamine-sulphadoxine. Gametocyte carriage was similar with both treatment regimens.


CONCLUSIONS
The combination of pyrimethamine-sulphadoxine, and probenecid, at a relatively moderate dose, improved treatment efficacy but had no effect on gametocyte carriage. The pyrimethamine-sulphadoxine-probenecid combination merits further evaluation as a potential treatment for use in Nigeria.
Sowunmi
A
A
Department of Pharmacology & Therapeutics and Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria. malaria.iba@alpha.linkserve.com
Fehintola
F A
FA
Adedeji
A A
AA
Gbotosho
G O
GO
Falade
C O
CO
Tambo
E
E
Fateye
B A
BA
Happi
T C
TC
Oduola
A M J
AM
D000208:Acute Disease; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors; D018512:Parasitemia / Q000188:drug therapy; D011339:Probenecid / Q000008:administration & dosage* / Q000009:adverse effects; D011739:Pyrimethamine / Q000008:administration & dosage* / Q000009:adverse effects; D013413:Sulfadoxine / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D000962:Antimalarials; D004338:Drug Combinations; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D011339:Probenecid; D011739:Pyrimethamine; D013413:Sulfadoxine; C001205:fanasil, pyrimethamine drug combination