Sensitive periods for developmental toxicity of orally administered artesunate in the rat.
BACKGROUND
Artesunate has been reported to cause embryolethality and malformations when administered orally to rats during organogenesis. The purpose of this study was to determine the most sensitive period(s) for the induction of these effects in order to provide clues about possible mechanisms and to identify a short treatment regimen for further studies.


METHODS
Pregnant rats were orally administered artesunate (10, 17 or 30 mg/kg/day) on single or multiple days of gestation. Cesarean sections and fetal evaluations were conducted on Day 21 postcoitum (pc).


RESULTS
Embryolethality, cardiovascular malformations and a syndrome of skeletal defects were observed after single doses on days 10 to 14 pc, while no developmental effects were observed before (day 9 pc) or after (days 16 or 17 pc) that period. The most sensitive day for embryo lethality was day 11 pc, where lethality occurred with a very steep dose response (postimplantation loss was approximately 15% at 10 mg/kg and 100% at 17 mg/kg/day). The most sensitive day for the induction of malformations was day 10 pc. Malformations tended to occur in partially resorbed litters and included cardiovascular defects and bent and misshapen long bones and scapulae.


CONCLUSIONS
The sensitive window for developmental toxicity of artesunate in the rat was identified as days 10 to 14 pc. Single oral doses produced embryolethality and similar cardiovascular and skeletal malformations as previously reported in longer term dosing experiments. These single dose treatment regimens could be useful to further investigate the mechanistic basis for artesunate-induced developmental toxicity.
White
Tacey E K
TE
Safety Assessment, Glaxo SmithKline, King of Prussia, Pennsylvania 19406-0939, USA. tacey.e.white@gsk.com
Clark
Robert L
RL
D000284:Administration, Oral; D000818:Animals; D037621:Artemisinins / Q000008:administration & dosage* / Q000633:toxicity*; D000077332:Artesunate; D002585:Cesarean Section; D020964:Embryo Loss / Q000139:chemically induced; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects*; D009139:Musculoskeletal Abnormalities / Q000139:chemically induced / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000473:pathology*; D051381:Rats; D013997:Time Factors
D037621:Artemisinins; D000077332:Artesunate