Artesunate-induced depletion of embryonic erythroblasts precedes embryolethality and teratogenicity in vivo.
BACKGROUND
Artesunate (ART), an artemisinin antimalarial, is embryolethal and teratogenic in rats, with the most sensitive days being 10 and 11 postcoitum (pc), respectively (Clark et al.: Birth Defects Res B 71:380-394, 2004; White et al.: Birth Defects Res A 70:265, 2004).


METHODS
In this study, pregnant rats were administered a single oral dose of 17 mg/kg ART on Days 10-11 pc and conceptuses were evaluated through Day 14 pc.


RESULTS
Paling of visceral yolk sacs was observed within 3-6 hr after treatment. Within 24 hr, marked paling and embryonic erythroblast depletion were observed macroscopically, which preceded malformations and embryo death, and persisted through Day 14 pc. Histologically, embryonic erythroblasts were reduced and cells showed signs of necrosis within 24 hr, were maximally depleted by 48 hr, and had partially rebounded within 3-4 days after treatment (Days 13 and 14 pc). Iron accumulation was evident in treated erythroblasts as early as 6 hr after treatment, suggesting impairment of heme synthesis. Heart abnormalities (swollen or collapsed chambers) were observed within 24 hr in approximately 25-60% of embryos and within 48 hr in 100% of embryos, correlating with histologic signs of cardiac myopathy (thinned and underdeveloped heart walls and enlarged chambers). Delays in limb and tail development occurred by Day 13 pc. Embryos were viable through Day 13 pc, but approximately 77% of embryos had died by Day 14 pc, presumably due to hypoxia and/or cardiac abnormalities.


CONCLUSIONS
In summary, embryonic erythroblasts are the primary target of ART toxicity in the rat embryo after in vivo treatment, preceding embryolethality and malformations.
White
Tacey E K
TE
Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. tacey.e.white@gsk.com
Bushdid
Paul B
PB
Ritter
Sandra
S
Laffan
Susan B
SB
Clark
Robert L
RL
D000014:Abnormalities, Drug-Induced; D000818:Animals; D037621:Artemisinins / Q000633:toxicity*; D000077332:Artesunate; D001773:Blood Cells / Q000187:drug effects; D004900:Erythroblasts / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D005260:Female; D005328:Fetal Viability / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000633:toxicity*; D013997:Time Factors; D015017:Yolk Sac / Q000002:abnormalities* / Q000166:cytology / Q000187:drug effects* / Q000473:pathology
D037621:Artemisinins; D012717:Sesquiterpenes; D000077332:Artesunate