Developmental toxicity of artesunate and an artesunate combination in the rat and rabbit.
The artemisinins are playing an increasingly important role in treating multidrug-resistant malaria. The artemisinin, artesunate, is currently in use in Southeast Asia and is advocated for use in Africa. In these areas, more than one million people die of malaria each year, with the highest mortality occurring in children and pregnant women. To test the developmental toxicity in ICH-compliant animal studies, embryofetal development studies were conducted in rats and rabbits treated with artesunate alone or a three-drug combination (CDA) consisting of chlorproguanil hydrochloride, Dapsone, and artesunate in the ratio 1.00:1.25:2.00. Developmental toxicity seen with CDA could be attributed to the administered dose of artesunate. The hallmark effect of artesunate exposure was a dramatic induction of embryo loss, apparent as abortions in rabbits and resorptions in both rats and rabbits. In addition, low incidences of cardiovascular malformations and a syndrome of skeletal defects were induced at or close to embryolethal doses of artesunate in both rats and rabbits. The cardiovascular malformations consisted of ventricular septal and vessel defects. The skeletal syndrome consisted of shortened and/or bent long bones and scapulae, misshapen ribs, cleft sternebrae, and incompletely ossified pelvic bones. These developmental effects were observed largely in the absence of any apparent maternal toxicity. The no or low adverse effect levels were in the range of 5 to 7 mg/kg/day artesunate. Encouragingly, no adverse drug-related developmental effects have been observed in a limited number of pregnant women (more than 100 first trimester and 600 second and third trimester) treated with artemisinins, primarily artesunate. Investigations of the mechanism of developmental toxicity are ongoing to attempt to determine whether rats and rabbits are more sensitive to artemisinins than humans.
Clark
Robert L
RL
Safety Assessment, GlaxoSmithKline, King of Prussia, PA 19406-0939, USA. robert.L.clark@gsk.com
White
Tacey E K
TE
A Clode
Sally
S
Gaunt
Ian
I
Winstanley
Peter
P
Ward
Stephen Andrew
SA
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D000962:Antimalarials / Q000633:toxicity*; D037621:Artemisinins / Q000633:toxicity*; D000077332:Artesunate; D003622:Dapsone / Q000633:toxicity*; D004338:Drug Combinations; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D011247:Pregnancy; D002727:Proguanil / Q000031:analogs & derivatives* / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000633:toxicity*
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D012717:Sesquiterpenes; D000077332:Artesunate; C007030:chlorproguanil; D003622:Dapsone; D002727:Proguanil