Comparative embryotoxicity of different antimalarial peroxides: in vitro study using the rat whole embryo culture model (WEC).
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, IC(50)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.
Longo
Monica
M
Accelera S.r.l., Viale Pasteur 10, Nerviano, Milan, Italy. monica.longo@accelera.org
Zanoncelli
Sara
S
Brughera
Marco
M
Colombo
Paolo
P
Wittlin
Sergio
S
Vennerstrom
Jonathan L
JL
Moehrle
Joerg
J
Craft
J Carl
JC
D000218:Adamantane / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000633:toxicity*; D037621:Artemisinins / Q000633:toxicity; D001934:Branchial Region / Q000187:drug effects / Q000473:pathology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D047108:Embryonic Development / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000633:toxicity; D020128:Inhibitory Concentration 50; D019055:No-Observed-Adverse-Effect Level; D010545:Peroxides / Q000737:chemistry / Q000633:toxicity*; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship; D013723:Teratogens / Q000737:chemistry / Q000633:toxicity*; D015017:Yolk Sac / Q000098:blood supply / Q000187:drug effects / Q000473:pathology
D000962:Antimalarials; D037621:Artemisinins; D006573:Heterocyclic Compounds, 1-Ring; C528887:OZ381; D010545:Peroxides; D013141:Spiro Compounds; D013723:Teratogens; C489136:arterolane; D000218:Adamantane