White Tacey E K, Bushdid Paul B, Ritter Sandra, Laffan Susan B, Clark Robert L
Safety Assessment, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
Birth Defects Res B Dev Reprod Toxicol. 2006 Oct;77(5):413-29. doi: 10.1002/bdrb.20092.
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).
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.
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.
In summary, embryonic erythroblasts are the primary target of ART toxicity in the rat embryo after in vivo treatment, preceding embryolethality and malformations.
青蒿琥酯（ART）是一种青蒿素类抗疟药，对大鼠具有胚胎致死性和致畸性，最敏感的时期分别是交配后（pc）第10天和第11天（Clark等人：《出生缺陷研究B》71:380 - 394，2004年；White等人：《出生缺陷研究A》70:265，2004年）。
在本研究中，于妊娠大鼠交配后第10 - 11天给予单次口服剂量17 mg/kg的ART，并在交配后第14天之前对胚胎进行评估。
治疗后3 - 6小时内观察到内脏卵黄囊变淡。24小时内，宏观上观察到明显变淡和胚胎成红细胞减少，这先于畸形和胚胎死亡，并持续到交配后第14天。组织学上，胚胎成红细胞减少，细胞在24小时内出现坏死迹象，48小时时减少到最大程度，治疗后3 - 4天（交配后第13天和第14天）部分恢复。早在治疗后6小时，处理过的成红细胞中就明显出现铁蓄积，提示血红素合成受损。在24小时内，约25 - 60%的胚胎出现心脏异常（心室肿胀或塌陷），48小时内100%的胚胎出现心脏异常，这与心肌病的组织学征象（心肌壁变薄、发育不全和心室扩大）相关。到交配后第13天，肢体和尾巴发育出现延迟。胚胎在交配后第13天之前仍存活，但到交配后第14天约77%的胚胎死亡，可能是由于缺氧和/或心脏异常。
总之，在体内治疗后，胚胎成红细胞是ART对大鼠胚胎毒性的主要靶点，先于胚胎致死性和畸形。
