Validation of sensitivity to praziquantel using Schistosoma mansoni worm muscle tension and Ca 2+-uptake as possible in vitro correlates to in vivo ED 50 determination

Abstract

Schistosome worm muscle tension and [ 45Ca 2+]-uptake were tested as possible correlates of susceptibility to praziquantel (PZQ) assessed by estimating the drug ED 50. Schistosoma mansoni cercariae of PZQ sensitive (S-CD, S-MOC and S-GP) and insensitive S. mansoni isolates (I-EE2, I-BANL and I-Senegal 47) were used to infect batches of CD-1 Swiss albino mice. Seven weeks after infection, animals of each batch were divided into six groups. Five of them received PZQ in doses of 12.5, 25, 50, 100 or 200 mg/kg PZQ, respectively, for five consecutive days, while the sixth was left as untreated controls. Two weeks after treatment mice were sacrificed, perfused and PZQ ED 50's were estimated. Male worms recovered from infected untreated controls were examined for their muscle tension increase in response to PZQ using a physiological recorder coupled to a photooptic transducer. [ 45Ca 2+]-uptake of male worms in the presence and absence of PZQ was determined using a liquid scintillation beta counter. Data revealed that PZQ insensitive isolates had significantly higher drug ED 50 (>130 mg/kg) than PZQ sensitive isolates with ED 50's <100 mg/kg. Moreover, in response to PZQ they were found to possess significant reductions in their worm muscle tension and their [ 45Ca 2+]-uptake were <100%. Both parameters showed a significant negative correlation to PZQ ED 50 in vivo and a significant positive correlation to each other.