Artesunate: developmental toxicity and toxicokinetics in monkeys

Abstract

Artesunate was embryolethal at > or =12 mg/kg/day when dosed for at least 12 days at the beginning of organogenesis, but not when dosed for 3 or 7 days, indicating that developmental toxicity of artesunate is dependent upon duration of dosing in cynomologus monkeys.

Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish

“…Among the side effects arising from the use of artemisinin-related compounds, the danger of embryotoxicity appears to be more serious. The typical embryotoxic effects of artemisinin that have been observed in mice, rats, rabbits and monkeys include embryonic death, developmental retardation, skeletal defects and cardiovascular malfunction [12][13][14][15][16] . In view of these side effects, artemisinin and its derivatives are not recommended for use in the first trimester of pregnancy by the World Health Organization (WHO).…”

Therapeutic and Toxicological Inhibition of Vasculogenesis and Angiogenesis Mediated by Artesunate, a Compound with Both Antimalarial and Anticancer Efficacy

“…Although no data exist at this time to prove the timing of the switchover from primitive to definitive erythroblasts in monkeys, the erythroblasts visible in the sections of embryos from GD 26, 32, and 36 were > 90% nucleated, suggesting that they were probably primitive erythroblasts during GD 18 to 36. On GD 50, only 9% of blood cells were nucleated, indicating that the transition from primitive to definitive erythroblasts was nearly complete on GD 50 (Clark et al, 2008a). The time window of AS/DHA sensitivity observed in animal studies would hypothetically correspond to humans during organogenesis.…”

“…The time window of AS/DHA sensitivity observed in animal studies would hypothetically correspond to humans during organogenesis. The earliest primitive erythrocytes are formed in the yolk sac starting at GD 18.5 (Clark et al, 2008a;Lensch & Daley, 2004). The onset of blood circulation coincides with the onset of the embryonic heartbeat, which probably occurs between GD 19 and GD 21 in humans, evidenced by the appearance of primitive erythrocytes in the cardiac cavity.…”

“…All three live embryos in the 30 mg/kg/day AS group dosed from GD 20 were removed by caesarean section on GD 26, 32 and 36 respectively, and these embryos showed marked reduction in erythroblasts. Since embryo death was observed only after more than 12 days of daily treatment at 12 mg/kg, the lack of developmental toxicity at a dose of 30 mg/kg/day indicates that a shorter treatment period decreases the potential for AS induced embryotoxicity in monkeys (Clark et al, 2008a). Primitive erythroblasts develop in the visceral yolk sac and are released into the embryonic circulation on GD 10 in rats, at about the same time that the heart begins to beat.…”

“…Based on this information, if human embryos were sensitive to AS or DHA in the same way as rat and monkey embryos, then the most sensitive period for human development toxicity induced by ARTs would be predicted to begin with the onset of circulation in week 4 of gestation and end at approximately week 9 to 10 of gestation. At this time in gestation, the nucleated primitive erythroblasts have been largely replaced by non-nucleated definitive erythroblasts (Clark et al, 2008a). If primitive erythrocytes are formed over a longer period than that in rodents, then AS/DHA dosing for longer than 12 days may be required to produce a severe effect on the early blood cell population in primates or humans (Clark et al, 2008;WHO2006b).…”