Study on the developmental toxicity of combined artesunate and mefloquine antimalarial drugs on rats.
Antimalarial drug combinations containing artemisinins (ACTs) have become first choice therapies for Plasmodium falciparum malaria. Data on safety of ACTs in pregnancy are limited and no previous study has been conducted on the developmental toxicity of artesunate-mefloquine combinations on the first trimester of gestation. To evaluate the developmental toxicity of an artesunate/mefloquine combination, pregnant rats were treated orally with artesunate (15 and 40 mg/kg bwt/day), mefloquine (30 and 80 mg/kg bwt/day) and artesunate/mefloquine (15/30 and 40/80 mg/kg bwt/day) on gestation days 9-11. Dams were C-sectioned on day 20, and their uteri and fetuses removed and examined for soft tissue and skeleton abnormalities. Artesunate increased embryolethality and the incidence of limb long bone malformations on the absence of overt maternal toxicity. Mefloquine (80 mg/kg bwt/day) was maternally toxic and enhanced fetal variations. Combination of artesunate and mefloquine did not enhance their toxicity compared to the toxicity observed after its separate administration. Embryotoxicity of artesunate was apparently attenuated when it is co-administered with mefloquine.
Department of Pharmacology, Federal University of Paraná, CEP 81531-990 Curitiba, PR, Brazil. boaretoana@gmail.com
Ana Cláudia
AC
Boareto
Juliane Centeno
JC
Müller
Samanta Luiza
SL
de Araujo
Ana Carolina
AC
Lourenço
Emerson Luiz Botelho
EL
Lourenço
Caroline
C
Gomes
Bruna
B
Minatovicz
Natália
N
Lombardi
Francisco Roma
FR
Paumgartten
Paulo Roberto
PR
Dalsenter
D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000209:etiology; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000633:toxicity*; D037621:Artemisinins / Q000008:administration & dosage / Q000633:toxicity*; D000077332:Artesunate; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D004338:Drug Combinations; D004347:Drug Interactions; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D015767:Mefloquine / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013723:Teratogens / Q000633:toxicity*; D014781:Viscera / Q000187:drug effects / Q000196:embryology
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D013723:Teratogens; D000077332:Artesunate; D015767:Mefloquine