Response of Schistosoma mansoni Isolates Having Different Drug Sensitivity to Praziquantel Over Several Life Cycle Passages with and Without Therapeutic Pressure

Abstract

The stability of praziquantel (PZQ)-insusceptible S. mansoni isolates and the possible selection of PZQ-insusceptible parasites upon applying therapeutic pressure were examined over several life cycle passages (snails to mice). To test isolate stability, 3 PZQ-susceptible and 7 PZQ-insusceptible isolates were used to establish infection in mice, and they were passaged each for 2-5 life cycles. After each passage, 6 groups of mice were used to assess the PZQ dose at which the worm burden was decreased by 50% (ED50). Five of them were treated with doses of PZQ (12.5, 25, 50, 100, and 200 mg/kg for 5 days) 7 wk after infection; the last group represented infected, but untreated, controls. Possible selection of PZQ-insusceptible parasites under therapeutic pressure was examined by subjecting 1 PZQ-susceptible and 1 PZQ-insusceptible S. mansoni isolate to therapeutic pressure by PZQ for 8 passages. After the final passage, PZQ ED50 was estimated. All PZQ-susceptible S. mansoni isolates showed stable susceptibility to PZQ (mean PZQ ED50 = 85 mg/kg) over all passages. Two of the 7 PZQ-insusceptible S. mansoni isolates (847 and ER5) showed normal sensitivity to PZQ in 1-2 passages (although not the last passage, and without a declining ED50 profile), whereas the remaining passages kept a sustained insusceptibility to the drug (mean PZQ ED50 = 217 mg/kg). Worm maturity and sex were irrelevant to variability in drug ED50 within an individual isolate over different passages, revealing the heterogeneous nature of the parasite. Therapeutic pressure for limited life cycle passages did not result in a significant increase in drug ED50. The fact that reversion of some of the PZQ-insusceptible S. mansoni isolates to normal drug-sensitive state is not long lasting and that the therapeutic pressure by PZQ in the field is not comparable with that in the laboratory (unlimited), make monitoring the response of patients to the drug in the field an integral part of schistosomiasis control measures.

Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis

“…Collaborative experiments performed in independent laboratories in Italy, Egypt and the UK, using standard-operating procedures to estimate the ED 50 s of S. mansoni isolates that were putatively resistant and sensitive to PZQ, confirmed that different isolates of this species do seemingly have varied sensitivities to PZQ [85]. Further tests on the stability of PZQ-sensitivity of some of the isolates examined in the last study have been performed more recently [86 ].…”

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

“…8 Even though praziquantel is an effective drug for the treatment of the disease, it has been in use for more than 20 years and recent reports indicate that significant resistance to the drug may be present in different geographic locations. 9 The identification and study of novel molecular targets as well as the development of new drugs to treat this and other neglected tropical diseases are of utmost importance in drug discovery. [10][11][12] The parasite Schistosoma mansoni, one of the etiologic agents of human schistosomiasis, lacks the de novo pathway for purine biosynthesis and depends entirely on the salvage pathway for its purine requirements for synthesis of RNA and DNA.…”

Enzyme kinetics, structural analysis and molecular modeling studies on a series of Schistosoma mansoni PNP inhibitors

“…Additionally, praziquantel has been in use for more than 20 years and significant resistance to the chemotherapy has emerged. 2 Therefore, this scenario highlights the urgent need for the development of new drugs to treat the disease. 2,3 Enzymes are attractive biological targets for smallmolecule drug discovery.…”

“…2 Therefore, this scenario highlights the urgent need for the development of new drugs to treat the disease. 2,3 Enzymes are attractive biological targets for smallmolecule drug discovery. 4,5 Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is a key enzyme in the purine salvage pathway which has been primarily studied as a target for the treatment of T-cell proliferative diseases, such as T-cell leukemias or lymphomas, organ transplant rejection, rheumatoid arthritis, psoriasis, and some other autoimmune diseases.…”