Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20307-5100, USA.
Molecules. 2009 Dec 25;15(1):40-57. doi: 10.3390/molecules15010040.
Preclinical studies in rodents have demonstrated that artemisinins, especially injectable artesunate, can induce fetal death and congenital malformations at a low dose range. The embryotoxicity can be induced in those animals only within a narrow window in early embryogenesis. Evidence was presented that the mechanism by which embryotoxicity of artemisinins occurs seems to be limited to fetal erythropoiesis and vasculogenesis/ angiogenesis on the very earliest developing red blood cells, causing severe anemia in the embryos with higher drug peak concentrations. However, this embryotoxicity has not been convincingly observed in clinical trials from 1,837 pregnant women, including 176 patients in the first trimester exposed to an artemisinin agent or artemisinin-based combination therapy (ACT) from 1989 to 2009. In the rodent, the sensitive early red cells are produced synchronously over one day with single or multiple exposures to the drug can result in a high proportion of cell deaths. In contrast, primates required a longer period of treatment of 12 days to induce such embryonic loss. In humans only limited information is available about this stage of red cell development; however, it is known to take place over a longer time period, and it may well be that a limited period of treatment of 2 to 3 days for malaria would not produce serious toxic effects. In addition, current oral intake, the most commonly used route of administration in pregnant women with an ACT, results in lower peak concentration and shorter exposure time of artemisinins that demonstrated that such a concentration-course profile is unlikely to induce the embryotoxicity. When relating the animal and human toxicity of artemisinins, the different drug sensitive period and pharmacokinetic profiles as reviewed in the present report may provide a great margin of safety in the pregnant women.
临床前研究在啮齿动物中已经证明，青蒿素类药物，尤其是注射用青蒿琥酯，在低剂量范围内可导致胎儿死亡和先天畸形。这种胚胎毒性仅在胚胎早期发育的一个狭窄窗口内才能在动物中诱导产生。有证据表明，青蒿素类药物的胚胎毒性发生的机制似乎仅限于胎儿红细胞生成和血管发生/血管生成，对最早发育的红细胞产生严重影响，导致胚胎中药物峰浓度较高的严重贫血。然而，在从 1989 年到 2009 年的 176 例接受青蒿素类药物或青蒿素类复方疗法（ACT）治疗的 1 期孕妇的 1837 例孕妇的临床试验中，并未令人信服地观察到这种胚胎毒性。在啮齿动物中，敏感的早期红细胞在一天内同步产生，单次或多次暴露于药物会导致大量细胞死亡。相比之下，灵长类动物需要更长的治疗时间（12 天）才能诱导这种胚胎丢失。在人类中，关于这个红细胞发育阶段的信息有限；然而，已知这个阶段需要更长的时间，而且很可能是在疟疾的 2 到 3 天的有限治疗期内不会产生严重的毒性作用。此外，目前口服摄入是孕妇中最常用的 ACT 给药途径，导致青蒿素类药物的峰值浓度较低，暴露时间较短，这表明这种浓度-时间曲线不太可能引起胚胎毒性。在将青蒿素类药物的动物毒性与人类毒性联系起来时，本报告中综述的不同药物敏感期和药代动力学特征可能为孕妇提供了很大的安全性保障。
