Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women

Abstract

<p>Background: Malaria during pregnancy implies a high risk for the mother and the developing child. However, the</p><p>therapeutic options for pregnant women have historically been very limited, especially during the first trimester</p><p>of pregnancy due to potential adverse effects on embryo-fetal development. Recently, there has been great</p><p>controversy regarding these potential embryo-fetal adverse effects because the results of rodent studies were not</p><p>in accordance with the clinical data available, and finally the WHO has changed the recommendations for</p><p>pregnant women with uncomplicated <em>P. falciparum</em> malaria to treatment with artemether-lumefantrine during</p><p>the first trimester. The discrepancy between pre-clinical and clinical studies has been attributed to speciesdifferences</p><p>in the duration of the window of susceptibility of circulating primitive erythroblasts.</p><p>Methods: Here we provide a tool based on an alternative method to animal experimentation that accelerates the</p><p>research of novel drugs for pregnant women. We have adapted the zebrafish embryo developmental toxicity</p><p>assay to include hemoglobin staining in the embryos and two time-points of lethality and dysmorphogenesis</p><p>evaluation. These two time-points were selected to include one when the development is independent of and one</p><p>when the development is dependent of erythrocytes function. The method was used to test four marketed</p><p>antimalarial drugs and three new antimalarial drug candidates.</p><p>Results: Our combination of tests can correctly predict the teratogenic and non-teratogenic effects of several</p><p>antimalarial marketed drugs (artemisinin, quinine, chloroquine, and dihydroartemisinin + desbutyl-lumefantrine).</p><p>Furthermore, we have tested three new drug candidates (GS-GUAN, DONE3TCl, and YAT2150) with novel</p><p>mechanisms of action, and different from those of the marketed antimalarial drugs.</p><p>Conclusions: We propose a decision tree combining the results of the two time-points of evaluation together with</p><p>the information on significant erythrocyte depletion. The aim of this decision tree is to identify compounds with</p><p>no or lower hazard on teratogenicity or erythrocyte depletion at an early phase of the drug development process.</p>