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Two different regimens of praziquantel, 40 mg/kg in a single dose and 60 mg/kg in two divided doses administered 6 hr apart, for the treatment of Schistosoma mansoni infection were compared in Abu Homos, Egypt. Participants in this study included 1,588 subjects of both sexes between five and 50 years old from two rural communities; 730 from Farshout and 858 from Om El-Laban. The prevalence of S. mansoni infection was 57.9% in Farshout and 69.0% in Om El-Laban. Infected subjects received 60 mg/kg of praziquantel in two divided doses 6 hr apart at Farshout and 40 mg/kg in a single dose at Om El-Laban. Eight to ten weeks after treatment, three stool samples were collected from each treated subject on three consecutive days and evaluated quantitatively by the modified Kato technique. The failure rate was significantly higher at Om El-Laban than at Farshout (14.5% versus 4.1% (odds ratio [OR] = 3.95, P < 0.0001). A significantly higher failure rate was consistent after adjustment for age and number of excreted S. mansoni eggs per gram of feces before treatment (OR = 3.75, P < 0.0001). In spite of differences among cure rates between the two regimens, we recommend 60 mg/kg on an individual basis but not for population treatment, since administration of a single dose of a drug is more practical than two doses given 6 hr apart.