Effects of the antimalarial drug dihydroartemisinin (DHA) on rat embryos in vitro.
Artemisinin derivatives are not currently recommended for use during the first trimester of pregnancy because they cause embryo death and some abnormalities in early pregnancy in animals. We studied the effects of dihydroartemisinin (DHA) in rat whole embryo cultures (WEC). DHA was added to the culture medium for the entire 48-h culture, 1.5 h at the beginning or at the end of the culture at 0.01-2 microg/mL. DHA affected primarily red blood cells during yolk sac hematopoiesis. Higher concentrations and longer exposure inhibited angiogenesis. Tissue damage (cell deaths) and effects on embryo morphology (neural tube, branchial arches, somites and caudal region defects) were attributed to these events. The viability of severely affected embryos beyond the 48-h assay is uncertain. These results help explain findings from animal data and provide evidence that the yolk sac is highly susceptible to artemisinin compounds. Extrapolating results to pregnant women exposed in the first trimester remains difficult. Pharmacovigilance and further studies of the mechanism of damage are needed.
Longo
Monica
M
Department of Preclinical Development, Nerviano Medical Sciences S.r.l., Viale Pasteur 10, 20014 Nerviano, Milan, Italy. monica.longo@nervianoms.com
Zanoncelli
Sara
S
Manera
Debora
D
Brughera
Marco
M
Colombo
Paolo
P
Lansen
Jacqueline
J
Mazué
Guy
G
Gomes
Melba
M
Taylor
Walter R J
WR
Olliaro
Piero
P
D000818:Animals; D000962:Antimalarials / Q000633:toxicity*; D037621:Artemisinins / Q000633:toxicity*; D047108:Embryonic Development / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects / Q000473:pathology; D066298:In Vitro Techniques; D051381:Rats; D012717:Sesquiterpenes / Q000633:toxicity*
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C039060:artenimol