TY - JOUR
T1 - Comparative embryotoxicity of different antimalarial peroxides
T2 - In vitro study using the rat whole embryo culture model (WEC)
AU - Longo, Monica
AU - Zanoncelli, Sara
AU - Brughera, Marco
AU - Colombo, Paolo
AU - Wittlin, Sergio
AU - Vennerstrom, Jonathan L.
AU - Moehrle, Joerg
AU - Craft, J. Carl
PY - 2010/12
Y1 - 2010/12
N2 - Three groups of compounds: (i) active peroxides (artemisinin and arterolene), (ii) inactive non-peroxidic derivatives (deoxyartemisinin and carbaOZ277) and (iii) inactive peroxide (OZ381) were tested by 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 anemia and subsequent tissue damage in rat embryos, with NOELs for RBC damage at 0.1 and 0.175μg/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, IC50s for activity in Plasmodium falciparum strains and the NOELs for RBCs were compared. From this comparison, arterolane showed a better safety margin than artemisinin.
AB - Three groups of compounds: (i) active peroxides (artemisinin and arterolene), (ii) inactive non-peroxidic derivatives (deoxyartemisinin and carbaOZ277) and (iii) inactive peroxide (OZ381) were tested by 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 anemia and subsequent tissue damage in rat embryos, with NOELs for RBC damage at 0.1 and 0.175μg/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, IC50s for activity in Plasmodium falciparum strains and the NOELs for RBCs were compared. From this comparison, arterolane showed a better safety margin than artemisinin.
KW - Artemisinins
KW - Embryotoxicity
KW - Malaria
KW - Plasmodium falciparum
KW - Primitive red blood cells
KW - Synthetic peroxides
KW - Whole embryo culture
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U2 - 10.1016/j.reprotox.2010.07.011
DO - 10.1016/j.reprotox.2010.07.011
M3 - Article
C2 - 20708075
AN - SCOPUS:78649458344
VL - 30
SP - 583
EP - 590
JO - Reproductigve Toxicoloy
JF - Reproductigve Toxicoloy
SN - 0890-6238
IS - 4
ER -