Severe Embryotoxicity of Artemisinin Derivatives in Experimental Animals, but Possibly Safe in Pregnant Women 英文参考文献.docVIP

Molecules 2010, 15, 40-57; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420–3049 /journal/molecules Review Severe Embryotoxicity of Artemisinin Derivatives in Experimental Animals, but Possibly Safe in Pregnant Women Qigui Li * and Peter J. Weina Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20307–5100, USA * Author to whom correspondence should be addressed; E–Mail: qigui.li@; Tel.: +1-301–319–9351; Fax: +1-301–319–7360. Received: 16 November 2009; in revised form: 22 December 2009 / Accepted: 24 December 2009 / Published: 25 December 2009 Abstract: 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