Three groups of compounds, namely (i) active peroxides (artemisinin and arterolene), (ii) inactive non-peroxidic derivatives (deoxyartemisinin and carbaOZ277) and (iii) an inactive peroxide (OZ381) were tested using the WEC system to provide insights into the relationship between chemical structure and embryotoxic potential, and to assess the relationship between embryotoxicity and antimalarial activity. Deoxyartemisinin, OZ381 and carbaOZ277 did not affect rat embryonic development. Artemisinin and arterolane affected primarily nucleated red blood cells (RBCs), inducing anaemia and subsequent tissue damage in rat embryos, with NOELs for RBC damage at 0.1 and 0.175 µg/ml, respectively. These data support the idea that only active antimalarial peroxides are able to interfere with normal embryonic development. In an attempt to establish whether and to what extent activity as antimalarials and embryotoxicity can be divorced, IC<sub>50</sub>s for activity in Plasmodium falciparum strains and the NOELs for RBCs were compared. From this comparison, arterolane showed a better safety margin than artemisinin.
Brughera, M.; Colombo, C.; Craft, J.C.; Longo, M.; Moehrle, J.; Vennerstrom, J.L.; Wittlin, S.; Zanoncelli, S. Comparative embryotoxicity of different antimalarial peroxides: In vitro study using the rat whole embryo culture model (WEC)&#9734;. Reproductive Toxicology (2010) 30 (4) 583-590. [DOI: 10.1016/j.reprotox.2010.07.011]
Comparative embryotoxicity of different antimalarial peroxides: In vitro study using the rat whole embryo culture model (WEC).