title: Activity of praziquantel enantiomers and main metabolites against Schistosoma mansoni.
abstract: A racemic mixture of R and S enantiomers of praziquantel (PZQ) is currently the treatment of choice for schistosomiasis. Though the S enantiomer and the metabolites are presumed to contribute only a little to the activity of the drug, in-depth side-by-side studies are lacking. The aim of this study was to investigate the in vitro activities of PZQ and its main metabolites, namely, R- and S-cis- and R- and S-trans-4'-hydroxypraziquantel, against adult worms and newly transformed schistosomula (NTS). Additionally, we explored the in vivo activity and hepatic shift (i.e., the migration of the worms to the liver) produced by each PZQ enantiomer in mice. Fifty percent inhibitory concentrations of R-PZQ, S-PZQ, and R-trans- and R-cis-4'-hydroxypraziquantel of 0.02, 5.85, 4.08, and 2.42 μg/ml, respectively, for adult S. mansoni were determined in vitro. S-trans- and S-cis-4'-hydroxypraziquantel were not active at 100 μg/ml. These results are consistent with microcalorimetry data and studies with NTS. In vivo, single 400-mg/kg oral doses of R-PZQ and S-PZQ achieved worm burden reductions of 100 and 19%, respectively. Moreover, worms treated in vivo with S-PZQ displayed an only transient hepatic shift and returned to the mesenteric veins within 24 h. Our data confirm that R-PZQ is the main effector molecule, while S-PZQ and the metabolites do not play a significant role in the antischistosomal properties of PZQ.
authors: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors: Isabel
authors: I
authors: Meister
authors: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors: Katrin
authors: K
authors: Ingram-Sieber
authors: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors: Noemi
authors: N
authors: Cowan
authors: School of Chemistry, Faculty of Science, University of Sydney, Sydney, Australia.
authors: Matthew
authors: M
authors: Todd
authors: School of Chemistry, Faculty of Science, University of Sydney, Sydney, Australia.
authors: Murray N
authors: MN
authors: Robertson
authors: Merck Serono, Global Early Development, Global Non Clinical Safety Merck-Living Innovation RBM S.p.A.-Istituto di Ricerche Biomediche A. Marxer, Colleretto Giacosa (TO), Italy.
authors: Claudia
authors: C
authors: Meli
authors: Department of Chemistry, University of Zurich, Zurich, Switzerland.
authors: Malay
authors: M
authors: Patra
authors: Department of Chemistry, University of Zurich, Zurich, Switzerland.
authors: Gilles
authors: G
authors: Gasser
authors: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland jennifer.keiser@unibas.ch.
authors: Jennifer
authors: J
authors: Keiser
mesh_terms: D000818:Animals; D008099:Liver / Q000469:parasitology; D051379:Mice; D011223:Praziquantel / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000188:drug therapy*; D012556:Schistosomicides / Q000494:pharmacology*
chemical_list: D012556:Schistosomicides; D011223:Praziquantel