Effects of chloroquine and its enantiomers on the development of rat embryos in vitro.
The effects of the antimalarial drug chloroquine (CQ) and its enantiomers [(+)-CQ and (-)-CQ] on 9 1/2-day post-implantation rat conceptuses were studied by the whole-embryo culture technique over a 48 hr period. At a concentration of 500 ng/ml of culture medium (0.97 microM), which falls within serum levels attained during long-term CQ therapy, the drugs produced varying degrees of growth retardation and dysmorphogenesis in the conceptuses. These effects were most severe with exposure to racemic CQ (100%) and also to equimolar concentrations of the two enantiomers (90%). Dysmorphogenesis was least with (+)-CQ (30%) and intermediate in severity in those exposed to (-)-CQ (32%). In the CQ and combined enantiomer groups, there was significant reduction in yolk sac diameter to 81% and 73%, the crown-rump length to 77% and 71%, the number of somites to 76% and 74%, and the embryonic protein content to 64% and 49%, respectively, of control values. In the (-)-enantiomer group the only parameter significantly affected was the somite number which was reduced to 83% of control. The growth parameters of (+)-CQ-treated embryos did not differ significantly from controls. The commonest morphological abnormalities observed in all treatment groups were those of axial rotation. Unfused and underdeveloped cranial neural tube, microophthalmia and abnormal otic primordium also occurred frequently, especially in the CQ and enantiomeric combination groups. The results suggest that the commercially available form of chloroquine, CQ, is embryotoxic in doses comparable to serum levels reached during long-term therapy with the drug. It also appears that although the individual enantiomers show minimal embryotoxicity at the dosage used, they potentiate each other's effects in the racemic mixture.
Tagoe
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Department of Anatomy, University of Ghana Medical School, Accra, Ghana.
Ofori-Adjei
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D000014:Abnormalities, Drug-Induced; D000818:Animals; D000886:Anthropometry; D000962:Antimalarials / Q000737:chemistry / Q000633:toxicity*; D002738:Chloroquine / Q000737:chemistry / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000737:chemistry / Q000187:drug effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects; D006130:Growth Disorders / Q000139:chemically induced; D009436:Neural Tube Defects / Q000139:chemically induced; D009924:Organ Culture Techniques; D011506:Proteins / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000962:Antimalarials; D011506:Proteins; D002738:Chloroquine